Misfolded protein therapeutics and diagnostics

Abstract

The invention relates to compounds useful for the treatment of diseases associated with misfolded proteins. Also disclosed are pharmaceutical formulations containing such compounds.

Description

MISFOLDED PROTEIN THERAPEUTICS AND DIAGNOSTICS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] Pursuant to 35 U.S.C. § 119(e), this application claims priority to the filing dates of United States Provisional Patent Application Serial Nos.63 / 564,731 filed March 13, 2024, 63 / 738,377 filed December 23, 2024, and 63 / 738,398 filed December 23, 2024, the disclosure of each of which is herein incorporated by reference in their entirety. GOVERNMENT SUPPORT

[0002] This invention was made with Government support under grant no.66721, 66323 and 66982 awarded by the Henry M. Jackson Foundation for the Uniformed Services University of the Health Services (USU). The Government has certain rights in the invention. FIELD OF THE INVENTION

[0003] The invention relates generally to the detection and treatment of diseases associated with misfolded proteins. BACKGROUND OF THE INVENTION

[0004] Prion diseases are characterized by the formation of proteins that adopt disease-specific conformations, propagate by converting additional molecules of the same protein to the pathologic conformation and accumulate as amyloid filaments. α-Synuclein prions contribute to the progression of Parkinson’s disease (PD) and multiple system atrophy (MSA).

[0005] Unexpectedly, the inventors have discovered certain compounds that inhibit the propagation of misfolded proteins. These compounds are thus useful in the treatment of prion diseases, such as α-synucleinopathies (Multiple System Atrophy [MSA], Parkinson’s Disease [PD], etc.). The invention further relates to the use of these compounds and isotopes thereof (labeled compounds) as diagnostic ligands for prion diseases.GENERAL INFORMATION

[0006] Before the present methods and uses are described, it is to be understood that this invention is not limited to particular steps, devices and compounds described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0007] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0008] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, some potential and preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. It is understood that the present disclosure supersedes any disclosure of an incorporated publication to the extent there is a contradiction.

[0009] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a scan" includes a plurality of such scans and reference to "the Biomarker of Response" includes reference to one or more such Biomarkers of Response and equivalents thereof known to those skilled in the art, and so forth.

[0010] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

[0011] All patents and publications, including all sequences disclosed within such patents and publications, referred to herein are expressly incorporated by reference. BRIEF SUMMARY OF THE INVENTION

[0012] In one aspect, the invention provides a compound, or a salt or a hydrate or a solvate thereof, having a structure according to formula (II):wherein X is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazolyl, or substituted or unsubstituted diazaindenyl; Z is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; Rais substituted or unsubstituted C1-C6alkyl or substituted or unsubstituted C3-C6cycloalkyl; and Rbis H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, or unsubstituted C3-C6 cycloalkyl.

[0013] In another aspect, the invention provides a method of inhibiting propagation of misfolded proteins by contacting the misfolded proteins with a compound described herein, or a pharmaceutically acceptable salt or a hydrate or a solvate thereof, thereby inhibiting propagation of the misfolded proteins.

[0014] In another aspect, the invention provides a method of treating a disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or a hydrate or a solvate thereof, thereby treating the disease in the subject.

[0015] In another aspect, the invention provides a method of detecting a disease in a mammalian tissue, comprising contacting the mammalian tissue with a labeled compound; and determining binding of the labeled compound to the mammalian tissue, wherein the labeled compound is a compound described herein, or a pharmaceutically acceptable salt or a hydrate or a solvate thereof, wherein one or more of its atoms is replaced with [2H], [3H], [11C], [18F], or [13N], thereby detecting the disease in the mammalian tissue. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The invention is best understood from the following detailed description when read in conjunction with the accompanying drawings. It is emphasized that, according to common practice, the various features of the drawings are not to scale. On the contrary, the dimensions of the various features are arbitrarily expanded or reduced for clarity. Included in the drawings are the following figures:

[0017] FIG.1 presents a list of chemical structures numbered 1-497 along with the IUPAC name for each of the structures shown.

[0018] FIG.2 presents activity results for compounds 1-515 regarding the propagation of synuclein fibrils from the MSA-A strain. +++ is < 100 nM; ++ is between 100 nM and 300 nM; + is between 300 nM and 1 µM; ND is Not Determined.

[0019] FIG.3 presents activity results for compounds 1-515 regarding the propagation of synuclein fibrils from the MSA-B strain. +++ is < 100 nM; ++ is between 100 nM and 300 nM; + is between 300 nM and 1 µM; ND is Not Determined. DETAILED DESCRIPTION OF THE INVENTION I. Definitions

[0020] The symbol , whether utilized as a bond or displayed perpendicular to a bond, indicates the point at which the displayed moiety is attached to the remainder of the compound.

[0021] As used herein, the term “alkyl” by itself or as part of another substituent refers to a saturated branched or straight-chain monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl; ethyl, propyls such as propan-1-yl or propan-2-yl; and butyls suchas butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl or 2-methyl-propan-2-yl. In some embodiments, an alkyl group comprises from 1 to 20 carbon atoms. In other embodiments, an alkyl group comprises from 1 to 10 carbon atoms. In still other embodiments, an alkyl group comprises from 1 to 6 carbon atoms, such as from 1 to 4 carbon atoms, such as from 1 to 3 carbon atoms.

[0022] "Alkanyl" by itself or as part of another substituent refers to a saturated branched, straight- chain or cyclic alkyl radical derived by the removal of one hydrogen atom from a single carbon atom of an alkane. Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl (t- butyl), cyclobutan-1-yl, etc.; and the like.

[0023] "Alkylene" refers to a branched or unbranched saturated hydrocarbon chain, usually having from 1 to 20 carbon atoms, more usually 1 to 10 carbon atoms and even more usually 1 to 6 carbon atoms, such as from 1 to 4 carbon atoms, such as from 1 to 3 carbon atoms. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), the propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-) and the like.

[0024] "Alkenyl" by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of an alkene. The group may be in either the cis or trans conformation about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop- 2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3- dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like.

[0025] "Alkynyl" by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of an alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

[0026] "Acyl" by itself or as part of another substituent refers to a radical -C(O)R30, where R30is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl as defined herein and substituted versions thereof. Representative examples include, but are not limited to formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, piperonyl, propionyl, succinyl, and malonyl, and the like.

[0027] The term "aminoacyl" refers to the group -C(O)NR21R22, wherein R21and R22independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R21and R22are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0028] "Alkoxy" by itself or as part of another substituent refers to a radical -OR31where R31represents an alkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.

[0029] "Cycloalkoxy" by itself or as part of another substituent refers to a radical -OR31where R31represents a cycloalkyl group as defined herein. Representative examples include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclohexyloxy and the like.

[0030] "Alkoxycarbonyl" by itself or as part of another substituent refers to a radical -C(O)OR31where R31represents an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, cyclohexyloxycarbonyl and the like.

[0031] "Aryl" by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of an aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like. In certain embodiments, an aryl groupcomprises from 6 to 20 carbon atoms. In certain embodiments, an aryl group comprises from 6 to 12 carbon atoms. Examples of an aryl group are phenyl and naphthyl.

[0032] "Arylalkyl" by itself or as part of another substituent refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, is replaced with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2- naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. Where specific alkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyl and / or arylalkynyl is used. In certain embodiments, an arylalkyl group is (C7-C30) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C1-C10) and the aryl moiety is (C6-C20). In certain embodiments, an arylalkyl group is (C7-C20) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C1-C8) and the aryl moiety is (C6-C12).

[0033] "Arylaryl" by itself or as part of another substituent, refers to a monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a ring system in which two or more identical or non-identical aromatic ring systems are joined directly together by a single bond, where the number of such direct ring junctions is one less than the number of aromatic ring systems involved. Typical arylaryl groups include, but are not limited to, biphenyl, triphenyl, phenyl-napthyl, binaphthyl, biphenyl-napthyl, and the like. When the number of carbon atoms in an arylaryl group are specified, the numbers refer to the carbon atoms comprising each aromatic ring. For example, (C5-C14) arylaryl is an arylaryl group in which each aromatic ring comprises from 5 to 14 carbons, e.g., biphenyl, triphenyl, binaphthyl, phenylnapthyl, etc. In certain embodiments, each aromatic ring system of an arylaryl group is independently a (C5-C14) aromatic. In certain embodiments, each aromatic ring system of an arylaryl group is independently a (C5-C10) aromatic. In certain embodiments, each aromatic ring system is identical, e.g., biphenyl, triphenyl, binaphthyl, trinaphthyl, etc.

[0034] "Cycloalkyl" by itself or as part of another substituent refers to a saturated or unsaturated cyclic alkyl radical derived by the removal of one hydrogen atom from a single carbon atom of the parent. Where a specific level of saturation is intended, the nomenclature "cycloalkanyl" or "cycloalkenyl" is used. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like. In certain embodiments,the cycloalkyl group is (C3–C10) cycloalkyl. In certain embodiments, the cycloalkyl group is (C3-C6) cycloalkyl.

[0035] "Heterocycloalkyl" or "heterocyclyl" by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom. Typical heteroatoms to replace the carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc. Where a specific level of saturation is intended, the nomenclature "heterocycloalkanyl" or "heterocycloalkenyl" is used. Typical heterocycloalkyl groups include, but are not limited to, groups derived from epoxides, azirines, thiiranes, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine and the like.

[0036] "Heteroalkyl, Heteroalkanyl, Heteroalkenyl and Heteroalkynyl" by themselves or as part of another substituent refer to alkyl, alkanyl, alkenyl and alkynyl groups, respectively, in which one or more of the carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatomic groups. Typical heteroatomic groups which can be included in these groups include, but are not limited to, -O-, -S-, -S-S-, -O-S-, -NR37R38-, =N-N=, -N=N-, - N=N-NR39R40, -PR41-, -P(O)2-, -POR42-, -O-P(O)2-, -S-O-, -S-(O)-, -SO2-, -SnR43R44- and the like, where R37, R38, R39, R40, R41, R42, R43and R44are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl.

[0037] "Heteroaryl" by itself or as part of another substituent, refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a heteroaromatic ring system. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, benzodioxole and the like. In certain embodiments, the heteroaryl group is from 5-20 membered heteroaryl. In certain embodiments, the heteroaryl group is from 5-10 membered heteroaryl. Incertain embodiments, heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.

[0038] "Heteroarylalkyl" by itself or as part of another substituent, refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, is replaced with a heteroaryl group. Where specific alkyl moieties are intended, the nomenclature heteroarylalkanyl, heteroarylalkenyl and / or heterorylalkynyl is used. In certain embodiments, the heteroarylalkyl group is a 6-30 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-10 membered and the heteroaryl moiety is a 5-20-membered heteroaryl. In certain embodiments, the heteroarylalkyl group is 6-20 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-8 membered and the heteroaryl moiety is a 5-12-membered heteroaryl.

[0039] "Aromatic Ring System" by itself or as part of another substituent, refers to an unsaturated cyclic or polycyclic ring system having a conjugated π electron system. Specifically included within the definition of "aromatic ring system" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc. Typical aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like.

[0040] "Heteroaromatic Ring System" by itself or as part of another substituent, refers to an aromatic ring system in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom. Typical heteroatoms to replace the carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Specifically included within the definition of "heteroaromatic ring systems" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, arsindole, benzodioxan, benzofuran, chromane, chromene, indole, indoline, xanthene, etc. Typical heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole,naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene and the like.

[0041] “Substituted” refers to a group in which one or more hydrogen atoms are independently replaced with the same or different substituent(s). Typical substituents include, but are not limited to, alkylenedioxy (such as methylenedioxy), -M, -R60, -O-, =O, -OR60, -SR60, -S-, =S, -NR60R61, =NR60, -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2O-, -S(O)2OH, -S(O)2R60, -OS(O)2O-, -OS(O)2R60, -P(O)(O-)2, -P(O)(OR60)(O-), -OP(O)(OR60)(OR61), -C(O)R60, -C(S)R60, -C(O)OR60, -C(O)NR60R61, -C(O)O-, -C(S)OR60, -NR62C(O)NR60R61, -NR62C(S)NR60R61, -NR62C(NR63)NR60R61and -C(NR62)NR60R61where M is halogen; R60, R61, R62and R63are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R60and R61together with the nitrogen atom to which they are bonded form a heterocycloalkyl or substituted heterocycloalkyl ring; and R64and R65are independently hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R64and R65together with the nitrogen atom to which they are bonded form a heterocycloalkyl or substituted heterocycloalkyl ring. In certain embodiments, substituents include -M, -R60, =O, -OR60, -SR60, -S-, =S, -NR60R61, =R60, -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2R60, -OS(O)2O-, -OS(O)2R60, -P(O)(O-)2, -P(O)(OR60)(O-), -OP(O)(OR60)(OR61), -C(O)R60, -C(S)R60, -C(O)OR60, -C(O)NR60R61, -C(O)O-, -NR62C(O)NR60R61. In certain embodiments, substituents include -M, -R60, =O, -OR60, -SR60, -NR60R61, -CF3, -CN, -NO2, -S(O)2R60, -P(O)(OR60)(O-), -OP(O)(OR60)(OR61), -C(O)R60, -C(O)OR60, -C(O)NR60R61, -C(O)O-. In certain embodiments, substituents include -M, -R60, =O, -OR60, -SR60, -NR60R61, -CF3, -CN, -NO2, -S(O)2R60, -OP(O)(OR60)(OR61), -C(O)R60, -C(O)OR60, -C(O)O-, where R60, R61and R62are as defined above. For example, a substituted group may bear a methylenedioxy substituent or one, two, or three substituents selected from a halogen atom, a (C1-4)alkyl group and a (C1- 4)alkoxy group.

[0042] “Amino" refers to the group -NRXRYwherein RXand RYare each independently H or a non-hydrogen substituent. Exemplary non-hydrogen substituents include alkyl groups (e.g. methyl, ethyl, and isopropyl).

[0043] “Ether” refers to a diradical group of formula -O-. For instance, if the ether group is connected to an alkyl group, then the overall group is an alkoxy group (e.g. -OCH3 or methoxy). If the ether is connected to a carbonyl group, then the overall group is an ester group of formula - OC(O)-.

[0044] “Halo” and “halogen” refer to the chloro, bromo, fluoro, and iodo groups.

[0045] “Nitro” refers to the group of formula -NO2.

[0046] As used herein, the terms "treat," "treatment," and "treating" refer to the reduction or amelioration or elimination of the progression, severity and / or effect associated with a misfolded protein disease and / or neurodegenerative disease described herein, or the improvement in the misfolded protein disease condition, or the improvement in the disease associated with the misfolded protein, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of a misfolded protein disease described herein resulting from the administration of one or more therapies described herein. In specific embodiments, the terms "treat," "treatment," and "treating" refer to the amelioration of at least one measurable physical parameter of a misfolded protein disease described herein, such as a biomarker or clinical symptom or clinical disability score. In other embodiments the terms "treat," "treatment," and "treating" refer to the inhibition of the propagation of misfolded proteins, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both. In an exemplary embodiment, treating provides an improvement, or a lack of progression, in the disease associated with the misfolded protein, and / or an improvement, or a lack of progression, in the symptoms associated with the misfolded protein disease or condition.

[0047] Treatment according to the present invention includes a "therapeutically effective amount" of the medicaments used. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the medicaments to elicit a desired response in the subject. Alternatively, this property of a compound may be evaluated by examining the ability ofthe compound to inhibit misfolded protein propagation by in vitro assays known to the skilled practitioner. A therapeutically effective amount of a compound may inhibit misfolded protein propagation, or otherwise ameliorate symptoms in a subject. One of ordinary skill in the art would be able to determine such amounts based on such factors as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected.

[0048] The terms "patient," "subject," and "human subject" are used interchangeably herein.

[0049] Unless otherwise specified, reference to an atom is meant to include all isotopes of that atom. For example, reference to H includes1H,2H (i.e. D or deuterium) and3H (i.e. tritium), and reference to C includes both12C and all other isotopes of carbon (e.g.13C). Unless specified otherwise, groups include all possible stereoisomers.

[0050] As to any of the groups disclosed herein which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and / or synthetically non-feasible. In addition, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.

[0051] In certain embodiments, a substituent may contribute to optical isomerism and / or stereo isomerism of a compound. Salts, solvates, hydrates, and prodrug forms of a compound are also of interest. All such forms are embraced by the present disclosure. Thus, the compounds described herein include salts, solvates, hydrates, prodrug and isomer forms thereof, including the pharmaceutically acceptable salts, solvates, hydrates, prodrugs and isomers thereof. In certain embodiments, a compound may be metabolized into a pharmaceutically active derivative. II. Introduction

[0052] The invention provides novel compounds. The novel compounds, as well as pharmaceutical formulations containing such compounds or combinations of these compounds with at least one additional therapeutic agent, can be used for, among other things, including diseases associated with misfolded proteins, including neurodegenerative diseases. III. Compounds

[0053] The present disclosure provides novel compounds. The novel compounds, as well as pharmaceutical formulations containing such compounds or combinations of these compounds with at least one additional therapeutic agent, can be used for, among other things, treating diseases described herein, such as multiple system atrophy (MSA).

[0054] In one aspect, the invention provides a compound of the invention. In an exemplary embodiment, the invention is a compound described herein. In some embodiments, the invention is a compound described herein, or a pharmaceutically acceptable salt or a hydrate or a solvate thereof. In some embodiments, the invention is a compound described herein, or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the invention is a compound according to a formula described herein. In some embodiments, the invention is a compound according to a formula described herein, or a pharmaceutically acceptable salt or a hydrate or a solvate thereof. In some embodiments, the invention is a compound according to a formula described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the invention is any of the compounds disclosed in FIG.1. In some embodiments, the invention is any of the compounds disclosed in FIG.1, or a pharmaceutically acceptable salt or a hydrate or a solvate thereof. In some embodiments, the invention is any of the compounds disclosed in FIG.1, or a pharmaceutically acceptable salt thereof.

[0055] In one aspect, the invention provides a compound, or a salt or a hydrate or a solvate thereof, having a structure according to formula (I): (I) wherein X is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazolyl, or substituted or unsubstituted diazaindenyl; Z is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; T isis substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted C3-C6 cycloalkyl; Rbis H, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, or unsubstituted C3-C6cycloalkyl.

[0056] In one aspect, the invention provides a compound, or a salt or a hydrate or a solvate thereof, having a structure according to formula (II): (II) wherein X is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazolyl, or substituted or unsubstituted diazaindenyl; Z is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; Rais substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted C3-C6cycloalkyl; Rbis H, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6 alkoxy, or unsubstituted C3-C6 cycloalkyl. Group T

[0057] In an exemplary embodiment, the compound is according to Formula (II) wherein X and Z are as described herein; Rais substituted or unsubstituted C1-C6alkyl or substituted or unsubstituted C3-C6 cycloalkyl; Rbis H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, or unsubstituted C3-C6 cycloalkyl. In an exemplary embodiment, the compound is according to Formula (II), wherein X and Z are as described herein; Rais unsubstituted C1-C6 alkyl, C1-C3 alkyl substituted with one or more halogen and / or C1-C3 alkoxy, unsubstituted cyclopropyl, cyclopropyl substituted with halogen or alkyl, unsubstituted cyclobutyl, or cyclobutyl substituted with halogen or alkyl; Rbis H, fluoro, chloro, unsubstituted C1-C6 alkyl, C1-C3 alkyl substituted with one or more halogen and / or C1-C3 alkoxy, unsubstituted cyclopropyl, cyclopropyl substituted with halogen or alkyl, unsubstituted cyclobutyl, or cyclobutyl substituted with halogen or alkyl. In an exemplary embodiment, the compound is according to Formula (II), wherein X and Z are as described herein; Rais methyl, ethyl, isopropyl, isobutyl, methoxymethyl, trifluoromethyl, cyclopropyl, fluorocyclopropyl, cyclobutyl, or difluorocyclobutyl, and Rbis H, fluoro, chloro, methyl, ethyl, isopropyl, isobutyl, methoxymethyl, trifluoromethyl, cyclopropyl, fluorocyclopropyl, cyclobutyl, or difluorocyclobutyl.

[0058] In an exemplary embodiment, the compound is according to Formula (I), wherein X and Z are as described herein, and T is ; Rais substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted C3-C6 cycloalkyl; Rbis halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6alkoxy, unsubstituted C3-C6cycloalkyl. In an exemplary embodiment, the compound is according to Formula (I), wherein X and Z are as described herein, T is as described in this paragraph, Rais unsubstituted C1-C6 alkyl, C1-C3 alkyl substituted with one or more halogen and / or C1-C3alkoxy, unsubstituted cyclopropyl, cyclopropyl substituted with halogen or alkyl, unsubstituted cyclobutyl, or cyclobutyl substituted with halogen or alkyl; Rbis fluoro, chloro, unsubstituted C1-C6 alkyl, C1-C3 alkyl substituted with one or more halogen and / or C1-C3alkoxy, unsubstituted cyclopropyl, cyclopropyl substituted with halogen or alkyl, unsubstituted cyclobutyl, or cyclobutyl substituted with halogen or alkyl. In an exemplary embodiment, the compound is according to Formula (I), wherein X and Z are as described herein, T is as described in this paragraph, Rais methyl, ethyl, isopropyl, isobutyl, methoxymethyl, trifluoromethyl, cyclopropyl, fluorocyclopropyl, cyclobutyl, or difluorocyclobutyl, and Rbis fluoro, chloro, methyl, ethyl, isopropyl, isobutyl, methoxymethyl, trifluoromethyl, cyclopropyl, fluorocyclopropyl, cyclobutyl, or difluorocyclobutyl.

[0059] In an exemplary embodiment, the compound is according to Formula (I), wherein X and Z are as described herein, and T is ; Rais as described herein. In an exemplary embodiment, the compound is according to Formula (I), wherein X and Z are as described herein,and T is . In an exemplary embodiment, the compound is according to Formula (I),wherein X and Z are as described herein, and T is ; Rais substituted or unsubstituted C1-C6alkyl or substituted or unsubstituted C3-C6cycloalkyl. In an exemplary embodiment, thecompound is according to Formula (I), wherein X and Z are as described herein, and T is ; Rais substituted or unsubstituted C3-C6cycloalkyl. In an exemplary embodiment, the compound is according to Formula (I), wherein X and Z are as described herein, and T is ; Rais substituted or unsubstituted cyclopropyl. In an exemplary embodiment, the compound is according to Formula (I), wherein X and Z are as described herein, and T is ; Rais substituted or unsubstituted cyclobutyl. In an exemplary embodiment, the compound is according to Formula (I), wherein X and Z are as described herein, T is as described in this paragraph, Rais unsubstituted C1-C6 alkyl, C1-C3 alkyl substituted with one or more halogen and / or C1-C3alkoxy, unsubstituted cyclopropyl, cyclopropyl substituted with halogen or alkyl, unsubstituted cyclobutyl, or cyclobutyl substituted with halogen or alkyl. In an exemplary embodiment, the compound is according to Formula (I), wherein X and Z are as described herein, and T is as described in this paragraph; Rais methyl, ethyl, isopropyl, isobutyl, methoxymethyl, trifluoromethyl, cyclopropyl, fluorocyclopropyl, cyclobutyl, or difluorocyclobutyl. In an exemplary embodiment, the compound is according to Formula (I), wherein X and Z are as described herein, and T is ; Rais fluoro, chloro, unsubstituted C1-C6 alkyl, C1-C3 alkyl is substituted with one or more halogen and / or C1-C3 alkoxy, unsubstituted cyclopropyl, cyclopropyl substituted with halogen or alkyl, unsubstituted cyclobutyl, or cyclobutyl substituted with halogen or alkyl. In an exemplary embodiment, the compound is according to Formula (I), wherein X and Z are as described herein, and T is ; Rais fluoro, chloro, methyl, ethyl,isopropyl, isobutyl, methoxymethyl, trifluoromethyl, cyclopropyl, fluorocyclopropyl, cyclobutyl, or difluorocyclobutyl.

[0060] In an exemplary embodiment, the compound is according to Formula (I), wherein X and Z are as described herein, anded or unsubstituted C1-C6 alkyl or substituted or unsubstituted C3-C6 cycloalkyl; Rbis halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6alkoxy, unsubstituted C3-C6cycloalkyl. In an exemplary embodiment, the compound is according to Formula (I), wherein X and Z are as described herein, T is as described in this paragraph, Rais unsubstituted C1-C6 alkyl, C1-C3 alkyl substituted with one or more halogen and / or C1-C3 alkoxy, unsubstituted cyclopropyl, cyclopropyl substituted with halogen or alkyl, unsubstituted cyclobutyl, or cyclobutyl substituted with halogen or alkyl; Rbis fluoro, chloro, unsubstituted C1-C6 alkyl, C1-C3 alkyl substituted with one or more halogen and / or C1-C3 alkoxy, unsubstituted cyclopropyl, cyclopropyl substituted with halogen or alkyl, unsubstituted cyclobutyl, or cyclobutyl substituted with halogen or alkyl. In an exemplary embodiment, the compound is according to Formula (I), wherein X and Z are as described herein, and T is as described in this paragraph; Rais methyl, ethyl, isopropyl, isobutyl, methoxymethyl, trifluoromethyl, cyclopropyl, fluorocyclopropyl, cyclobutyl, or difluorocyclobutyl, and Rbis fluoro, chloro, methyl, ethyl, isopropyl, isobutyl, methoxymethyl, trifluoromethyl, cyclopropyl, fluorocyclopropyl, cyclobutyl, or difluorocyclobutyl.

[0061] In an exemplary embodiment, the compound, or a salt, hydrate, or solvate thereof, is according to Formula (I), wherein X and Z are as described herein, and T is ,Group X

[0062] In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazolyl, or substituted or unsubstituted diazaindenyl. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl.

[0063] In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is substituted or unsubstituted phenyl. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is unsubstituted phenyl or phenyl substituted with 1, 2, 3, 4 or 5 members independently selected from the group consisting of halogen, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C1-3 alkyl, substituted or unsubstituted C3-6 cycloalkyl, and substituted or unsubstituted C1-3alkoxy. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is unsubstituted phenyl or phenyl substituted with 1, 2, 3, 4, or 5 members independently selected from the group consisting of halogen, unsubstituted C2-C4alkenyl, unsubstituted C3-C6cycloalkyl, unsubstituted C1-3alkyl, C1-3alkyl substituted with one or more halogen, unsubstituted C1-3alkoxy, and C1-3alkoxy substituted with one or more halogen. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is unsubstituted phenyl or phenyl substituted with 1, 2, 3, 4, or 5 members independently selected from the group consisting of F, Cl, Br,methyl, ethenyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, cyclopropyl, methoxy, trifluoromethoxy, difluoromethoxy, and 1,1-difluoroethoxy.

[0064] In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is unsubstituted phenyl. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X isaccording to: wherein Rf, Rg, and Rh are each independently selected from thegroup consisting of H, halogen, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C1-3 alkyl, substituted or unsubstituted C3-6 cycloalkyl, and substituted or unsubstituted C1-3alkoxy, wherein at least one of Rf, Rg, and Rhis not H. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein,and X is according to: wherein Rf, Rg, and Rh are each independently selected fromthe group consisting of H, halogen, C2-C4alkenyl, C3-C6cycloalkyl, unsubstituted C1-3alkyl, C1-3alkyl substituted with one or more halogen, unsubstituted C1-3 alkoxy, and C1-3 alkoxy substituted with one or more halogen, wherein at least one of Rf, Rg, and Rhis not H. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein,and X is according to: wherein Rf, Rg, and Rh are each independently selected fromthe group consisting of H, F, Cl, Br, methyl, ethenyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, cyclopropyl, methoxy, trifluoromethoxy, difluoromethoxy, and 1,1-difluoroethoxy, wherein at least one of Rf, Rg, and Rhis not H. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X isaccording to: wherein Rf, Rg, and Rhare each independently selected from the group consisting of H, F, Cl, methyl, isopropyl, trifluoromethyl, trifluoromethoxy, and difluoromethoxy, wherein at least one of Rf, Rg, and Rhis not H.

[0065] In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is substituted or unsubstituted pyridyl. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is unsubstituted pyridyl or pyridyl substituted with 1, 2, 3, or 4 members independently selected from the group consisting of halogen, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C1-3alkyl, substituted or unsubstituted C3-6cycloalkyl, and substituted or unsubstituted C1-3alkoxy. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is unsubstituted pyridyl or pyridyl substituted with 1, 2, 3, or 4 members independently selected from the group consisting of halogen, unsubstituted C2-C4alkenyl, unsubstituted C3-C6cycloalkyl, unsubstituted C1-3alkyl, C1-3alkyl substituted with one or more halogen, unsubstituted C1-3 alkoxy, and C1-3 alkoxy substituted with one or more halogen. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is unsubstituted pyridyl or pyridyl substituted with one or more members independently selected from the group consisting of F, Cl, Br, methyl, ethenyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, cyclopropyl, methoxy, trifluoromethoxy, difluoromethoxy, and 1,1-difluoroethoxy.

[0066] In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is unsubstituted pyridyl. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X isaccording to: wherein Rf and Rg are each independently selected from the groupconsisting of H, halogen, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C1-3alkyl, substituted or unsubstituted C3-6cycloalkyl, and substituted or unsubstituted C1-3alkoxy, wherein at least one of Rfand Rgis not H. In an exemplary embodiment, the compound isaccording to Formula (I), wherein T and Z are as described herein, and X is according to: wherein Rfand Rgare each independently selected from the group consisting of H, halogen, unsubstituted C2-C4alkenyl, unsubstituted C3-C6cycloalkyl, unsubstituted C1-3alkyl, C1-3alkyl substituted with one or more halogen, unsubstituted C1-3 alkoxy, and C1-3 alkoxy substituted with one or more halogen, wherein at least one of Rfand Rgis not H. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is according to:in Rfand Rgare each independently selected from the group consisting of H, F, Cl, Br, methyl, ethenyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, cyclopropyl, methoxy, trifluoromethoxy, difluoromethoxy, and 1,1-difluoroethoxy, wherein at least one of Rfand Rgis not H. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is according to: wherein Rfand Rgare each independently selected from the group consisting of H, F, methyl, ethenyl, isopropyl, trifluoromethyl, and 1,1-difluoroethyl, wherein at least one of Rfand Rgis not H.

[0067] In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is according to: wherein Rf, Rg, and Rhare each independently selected from the group consisting of H, halogen, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C1-3alkyl, substituted or unsubstituted C3-6cycloalkyl, and substituted or unsubstituted C1-3 alkoxy, wherein at least one of Rf, Rg, and Rhis not H. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are asdescribed herein, and X is according to: wherein Rf, Rg, and Rhare each independently selected from the group consisting of H, halogen, unsubstituted C2-C4alkenyl, unsubstituted C3-C6cycloalkyl, unsubstituted C1-3alkyl, C1-3alkyl substituted with one or more halogen, unsubstituted C1-3 alkoxy, and C1-3 alkoxy substituted with one or more halogen, wherein at least one of Rf, Rg, and Rhis not H. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is according to:wherein Rf, Rg, and Rhare each independently selected from the group consisting of H, F, Cl, Br, methyl, ethenyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, cyclopropyl, methoxy, trifluoromethoxy, difluoromethoxy, and 1,1-difluoroethoxy, wherein at least one of Rf, Rg, and Rhis not H. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is according to: wherein Rf, Rg, and Rhare each independently selected from the group consisting of H, Cl, and trifluoromethyl, wherein at least one of Rf, Rg, and Rhis not H.

[0068] In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is substituted or unsubstituted pyrazolyl. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is unsubstituted pyrazolyl or pyrazolyl substituted with 1, 2, or 3 members independently selected from the group consisting of halogen, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C1-3 alkyl, substituted or unsubstituted C3-6 cycloalkyl, and substituted or unsubstituted C1-3alkoxy. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is unsubstituted pyrazolyl or pyrazolyl substituted with 1, 2, or 3 members independently selected from the group consisting of halogen, unsubstituted C2-C4 alkenyl, unsubstituted C3-C6 cycloalkyl, unsubstituted C1-3 alkyl, C1-3alkyl substituted with one or more halogen, unsubstituted C1-3 alkoxy, and C1-3 alkoxy substituted with one or more halogen. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is unsubstituted pyrazolyl or pyrazolyl substituted with 1, 2, or 3 members independently selected from the group consisting of F, Cl, Br, methyl, ethenyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, cyclopropyl, methoxy, trifluoromethoxy, difluoromethoxy, and 1,1-difluoroethoxy.

[0069] In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is unsubstituted pyrazolyl. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X isaccording to:ein Rg and Rh are each independently selected from the groupconsisting of H, halogen, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C1-3alkyl, substituted or unsubstituted C3-6cycloalkyl, and substituted or unsubstituted C1-3alkoxy, and Rfis selected from the group consisting of H, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C1-3 alkyl, substituted or unsubstituted C3-6 cycloalkyl, and substituted or unsubstituted C1-3alkoxy, wherein at least one of Rf, Rg, and Rhis not H. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is according to:Rgand Rhare each independently selected from the group consisting of H, halogen, unsubstituted C2-C4 alkenyl, unsubstituted C3-C6 cycloalkyl, unsubstituted C1-3 alkyl, C1-3 alkyl substituted with one or more halogen, unsubstituted C1-3alkoxy, and C1-3alkoxy substituted with one or more halogen, and Rfis selected from the group consisting of H, unsubstituted C2-C4alkenyl, unsubstituted C3-C6cycloalkyl, unsubstituted C1-3 alkyl, C1-3 alkyl substituted with one or more halogen, unsubstituted C1-3 alkoxy, and C1-3 alkoxy substituted with one or more halogen, wherein at least one of Rf, Rg, and Rhis not H. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are asdescribed herein, and X is according to:Rgand Rhare each independently selected from the group consisting of H, F, Cl, Br, methyl, ethenyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, cyclopropyl, methoxy, trifluoromethoxy, difluoromethoxy, and 1,1-difluoroethoxy, and Rfis selected from the group consisting of H, methyl, ethenyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, cyclopropyl, methoxy, trifluoromethoxy, difluoromethoxy, and 1,1-difluoroethoxy, wherein at least one of Rf, Rg, and Rhis not H. In an exemplary embodiment, the compound is according to Formula (I), wherein T and Z are as described herein, and X is according to:wherein Rfis methyl, ethenyl, isopropyl, difluoromethyl, trifluoromethyl, and 1,1-difluoroethyl.

[0070] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and Z are as described herein, and X is substituted or unsubstituted diazaindenyl. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and Z are as described herein, and X is substituted or unsubstituted pyrazolo[1,5-a]pyridine. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and Z are as described herein, and X is diazaindenyl substituted with 1, 2, 3, or 4 members independently selected from the group consisting of halogen, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C1-3alkyl, substituted or unsubstituted C3-6cycloalkyl, and substituted or unsubstituted C1-3alkoxy. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and Z are as described herein, and X is diazaindenyl substituted with 1, 2, 3, or 4 members independently selected from the group consisting of halogen, unsubstituted C2-C4alkenyl, unsubstituted C3-C6 cycloalkyl, unsubstituted C1-3 alkyl, C1-3 alkyl substituted with one or more halogen, unsubstituted C1-3 alkoxy, and C1-3 alkoxy substituted with one or more halogen. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and Z are as described herein, and X is diazaindenyl substituted with 1, 2, 3, or 4 members independently selected from the group consisting of F, Cl,Br, methyl, ethenyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, cyclopropyl, methoxy, trifluoromethoxy, difluoromethoxy, and 1,1-difluoroethoxy.

[0071] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and Z are as described herein, and X is phenyl, 4- (trifluoromethyl)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-chloro-3-fluorophenyl, 4-chloro-3,5- difluorophenyl, 3,5-difluorophenyl, 4-methyl-3,5-difluorophenyl, 3-chloro-(4-cyclopropyl)phenyl, 3-fluoro-(4-fluoromethyl)phenyl, 3-fluoro-(4-difluoromethyl)phenyl, 4-(difluoromethyl)phenyl, 4- (methyl)phenyl, 3,4-difluorophenyl, 4-cyclopropyl-3-fluorophenyl, 3-fluoro-(4-methyl)phenyl, 3- fluoro-(4-methoxy)phenyl, 4-fluoro-5-methylpyridin-2-yl, 6-(trifluoromethyl)pyridin-3-yl, 5- trifluoromethylpyridin-2-yl, 1-(difluoromethyl)-1H-pyrazolyl, or pyrazolo[1,5-a]pyridyl. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and Z are as described herein, and X is phenyl. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and Z are as described herein, and X is 4- (trifluoromethyl)phenyl. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and Z are as described herein, and X is 4-fluorophenyl. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and Z are as described herein, and X is 4-chlorophenyl. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and Z are as described herein, and X is 4-chloro-3-fluorophenyl. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and Z are as described herein, and X is 4-chloro-3,5-difluorophenyl. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and Z are as described herein, and X is 4-methyl-3,5-difluorophenyl. Group Z:

[0072] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and X are as described herein, and Z is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.

[0073] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and X are as described herein, and Z is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted azaindenyl, substituted or unsubstituted diazaindenyl, substituted or unsubstituted triazaindenyl, substituted or unsubstituted tetraazaindenyl, substituted or unsubstituted isoquinolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted benzotriazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted quinolyl, substituted or unsubstituted naphthyl, substituted or unsubstituted diazanaphthyl, substituted or unsubstituted diazabicyclooctadienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted tolyl, substituted or unsubstituted isoindolinyl, substituted or unsubstituted isonicotinamide, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted oxaazanaphthyl, substituted or unsubstituted xyxyl, substituted or unsubstituted biphenylyl, substituted or unsubstituted furyl, or substituted or unsubstituted cinnolinyl.

[0074] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and X are as described herein, and Z is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted azaindenyl, substituted or unsubstituted diazaindenyl, substituted or unsubstituted triazaindenyl, substituted or unsubstituted tetraazaindenyl, substituted or unsubstituted isoquinolyl, substituted or unsubstituted quinolyl, substituted or unsubstituted indazolyl, and substituted or unsubstituted pyrazolyl.

[0075] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and X are as described herein, and Z is substituted or unsubstituted pyrazolo[1,5-a]pyrimidinyl, substituted or unsubstituted pyrazolo[1,5-a]pyrazinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted benzo[d]oxazolyl, substituted or unsubstituted 1H-pyrazolo[3,4-c]pyridinyl, substituted or unsubstituted isoindolinone, substituted or unsubstituted phenyl, substituted or unsubstituted 1H-indazolyl, substituted or unsubstituted 1H-pyrrolo[2,3-c]pyridinyl, substituted or unsubstituted 1H-pyrazolyl, substituted or unsubstituted 3,4-dihydroisoquinolin-1(2H)-one, substituted or unsubstituted pyridin-2-yl, or substituted or unsubstituted isoindolin-1-onelyl.

[0076] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and X are as described herein, and Z is substituted or unsubstituted pyrazolo[1,5-a]pyrimidin-2-yl, substituted or unsubstituted pyrazolo[1,5- a]pyrazin-2-yl, substituted or unsubstituted isoquinolin-3-yl, substituted or unsubstituted benzo[d]oxazol-6-yl, substituted or unsubstituted 1H-pyrazolo[3,4-c]pyridin-5-yl, substituted or unsubstituted isoindolin-1-one, substituted or unsubstituted 1H-indazol-5-yl, substituted or unsubstituted 1H-pyrrolo[2,3-c]pyridin-5-yl, substituted or unsubstituted 1H-pyrazol-3-yl, substituted or unsubstituted 1H-indazol-6-yl, substituted or unsubstituted 3,4-dihydroisoquinolin- 1(2H)-one, substituted or unsubstituted 1H-pyrazol-3-yl, pyridinyl substituted 1H-pyrazol-3-yl, substituted or unsubstituted isoindolin-1-onel-5-yl, or substituted or unsubstituted pyrazolo[1,5- a]pyrimidin-2-yl).

[0077] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and X are as described herein, and Z is methyl substituted pyrazolo[1,5-a]pyrimidin-2-yl, trifluoromethyl substituted pyrazolo[1,5-a]pyrimidin-2- yl, dimethyl substituted pyrazolo[1,5-a]pyrazin-2-yl, isoquinolin-3-yl, methyl substituted benzo[d]oxazol-6-yl, methyl substituted 1H-pyrazolo[3,4-c]pyridin-5-yl, methyl substituted isoindolin-1-one, difluoromethyl substituted phenyl, methyl substituted 1H-indazol-5-yl, methyl substituted 1H-pyrrolo[2,3-c]pyridin-5-yl, (pyridin-3-yl) substituted 1H-pyrazol-3-yl, methyl substituted 1H-indazol-6-yl, methyl substituted 3,4-dihydroisoquinolin-1(2H)-one, dihaloethyl substituted-1H-pyrazol-3-yl, dihalomethyl substituted-1H-pyrazol-3-yl, acetamidyl, halo substituted pyridin-2-yl, methyl substituted isoindolin-1-onel-5-yl, or halomethyl, methyl substituted pyrazolo[1,5-a]pyrimidin-2-yl).

[0078] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and X are as described herein, and Z is 7-methyl pyrazolo[1,5-a]pyrimidin-2-yl, 5,7-dimethyl pyrazolo[1,5-a]pyrimidin-2-yl, 7-trifluoromethyl pyrazolo[1,5-a]pyrimidin-2-yl, 4,6-dimethyl pyrazolo[1,5-a]pyrazin-2-yl, isoquinolin-3-yl, 2- methyl benzo[d]oxazol-6-yl, 1-methyl 1H-pyrazolo[3,4-c]pyridin-5-yl, 2-methyl isoindolin-1-one, 4-difluoromethyl phenyl, 1-methyl 1H-indazol-5-yl, 1-methyl 1H-pyrrolo[2,3-c]pyridin-5-yl, (pyridin-3-yl) 1H-pyrazol-3-yl, 1-methyl 1H-indazol-6-yl, 2-methyl 3,4-dihydroisoquinolin- 1(2H)-one, 1-(2,2-difluoroethyl)-1H-pyrazol-3-yl, 4-acetamidyl-5-fluoro-pyridin-2-yl, 2-methylisoindolin-1-onel-5-yl, 7-(fluoromethyl)-5-methylpyrazolo[1,5-a]pyrimidin-2-yl, or 5- (fluoromethyl)-7-methylpyrazolo[1,5-a]pyrimidin-2-yl.

[0079] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and X are as described herein, and Z is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted azaindenyl, substituted or unsubstituted diazaindenyl, substituted or unsubstituted triazaindenyl, substituted or unsubstituted isoquinolyl, or substituted or unsubstituted quinolyl. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and X are as described herein, and Z is unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl, or unsubstituted heterocycloalkyl. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and X are as described herein, and Z is unsubstituted phenyl, unsubstituted pyridyl, unsubstituted azaindenyl, unsubstituted diazaindenyl, unsubstituted triazaindenyl, unsubstituted tetraazaindenyl, unsubstituted isoquinolyl, unsubstituted indazolyl, unsubstituted pyrazolyl, unsubstituted benzotriazolyl, unsubstituted triazolyl, unsubstituted benzimidazolyl, unsubstituted quinolyl, unsubstituted naphthyl, unsubstituted diazanaphthyl, unsubstituted diazabicyclooctadienyl, unsubstituted thiazolyl, unsubstituted pyrimidinyl, unsubstituted tolyl, unsubstituted isoindolinyl, unsubstituted isonicotinamide, unsubstituted benzoxazolyl, unsubstituted quinoxalinyl, unsubstituted benzofuranyl, unsubstituted oxaazanaphthyl, unsubstituted xyxyl, unsubstituted biphenylyl, unsubstituted furyl, or unsubstituted cinnolinyl. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and X are as described herein, and Z is unsubstituted phenyl, unsubstituted pyridyl, unsubstituted azaindenyl, unsubstituted diazaindenyl, unsubstituted triazaindenyl, unsubstituted tetraazaindenyl, unsubstituted isoquinolyl, unsubstituted quinolyl, unsubstituted indazolyl, and unsubstituted pyrazolyl. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and X are as described herein, and Z is unsubstituted phenyl, unsubstituted pyridyl, unsubstituted azaindenyl, unsubstituted diazaindenyl, unsubstituted triazaindenyl, unsubstituted isoquinolyl, or unsubstituted quinolyl.

[0080] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and X are as described herein, and Z is asubstituted ring system as described in this section entitled “Group Z:”, and the substitution is one, two, or three members independently selected from the group consisting of nitro, cyano, halogen, C1-6alkyl, halogen substituted C1-6alkyl, hydroxy substituted C1-6alkyl, C1-6alkoxy substituted C1-6 alkyl, C3-6 cycloalkyl substituted C1-6 alkyl, azetidinyl substituted C1-6 alkyl, C2-6 alkenyl, halogen substituted C2-6 alkenyl, hydroxy substituted C2-6 alkenyl, C1-6 alkoxy substituted C2-6 alkenyl, C3-6cycloalkyl substituted C2-6alkenyl, azetidinyl substituted C2-6alkenyl, C2-6alkynyl, halogen substituted C2-6alkynyl, hydroxy substituted C2-6alkynyl, C1-6alkoxy substituted C2-6alkynyl, C3-6 cycloalkyl substituted C2-6 alkynyl, azetidinyl substituted C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkyl substituted C3-6 cycloalkyl, halogen substituted C3-6 cycloalkyl, hydroxy substituted C3-6cycloalkyl, C1-6alkoxy substituted C3-6cycloalkyl, azetidinyl substituted C3-6cycloalkyl, C1-6 alkoxy, halogen substituted C1-6 alkoxy, hydroxy substituted C1-6 alkoxy, C3-6 cycloalkyl substituted C1-6 alkoxy, azetidinyl substituted C1-6 alkoxy, C3-6 cycloalkoxy, C1-6 alkyl substituted C3-6cycloalkoxy, halogen substituted C3-6cycloalkoxy, hydroxy substituted C3-6cycloalkoxy, C1-6 alkoxy substituted C3-6 cycloalkoxy, azetidinyl substituted C3-6 cycloalkoxy, azetidinyl, C1-6 alkyl substituted azetidinyl, halogen substituted azetidinyl, hydroxy substituted azetidinyl, C1-6alkoxy substituted azetidinyl, and C3-6cycloalkyl substituted azetidinyl.

[0081] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and X are as described herein, and Z is a substituted ring system as described in this section entitled “Group Z:”, and the substitution is one, two, or three members independently selected from the group consisting of nitro, cyano, halogen, C1-6 alkyl, fluoro substituted C1-6 alkyl, chloro substituted C1-6 alkyl, hydroxy substituted C1-6 alkyl, methoxy substituted C1-6 alkyl, ethoxy substituted C1-6 alkyl, cyclopropyl substituted C1-6 alkyl, cyclobutyl substituted C1-6alkyl, azetidinyl substituted C1-6alkyl, C2-6alkenyl, fluoro substituted C2-6 alkenyl, chloro substituted C2-6 alkenyl, hydroxy substituted C2-6 alkenyl, methoxy substituted C2-6 alkenyl, ethoxy substituted C2-6 alkenyl, cyclopropyl substituted C2-6 alkenyl, cyclobutyl substituted C2-6alkenyl, azetidinyl substituted C2-6alkenyl, C2-6alkynyl, fluoro substituted C2-6alkynyl, chloro substituted C2-6alkynyl, hydroxy substituted C2-6alkynyl, methoxy substituted C2-6 alkynyl, ethoxy substituted C2-6 alkynyl, cyclopropyl substituted C2-6 alkynyl, cyclobutyl substituted C2-6 alkynyl, azetidinyl substituted C2-6 alkynyl, C3-6 cycloalkyl, methyl substituted C3-6cycloalkyl, ethyl substituted C3-6cycloalkyl, isopropyl substituted C3-6cycloalkyl, fluoro substituted C3-6 cycloalkyl, chloro substituted C3-6 cycloalkyl, hydroxy substituted C3-6 cycloalkyl, methoxy substituted C3-6 cycloalkyl, ethoxy substituted C3-6 cycloalkyl, azetidinylsubstituted C3-6 cycloalkyl, C1-6 alkoxy, fluoro substituted C1-6 alkoxy, chloro substituted C1-6 alkoxy, hydroxy substituted C1-6 alkoxy, cyclopropyl substituted C1-6 alkoxy, cyclobutyl substituted C1-6alkoxy, azetidinyl substituted C1-6alkoxy, C3-6cycloalkoxy, methyl substituted C3-6 cycloalkoxy, ethyl substituted C3-6 cycloalkoxy, isopropyl substituted C3-6 cycloalkoxy, fluoro substituted C3-6 cycloalkoxy, chloro substituted C3-6 cycloalkoxy, hydroxy substituted C3-6 cycloalkoxy, methoxy substituted C3-6cycloalkoxy, ethoxy substituted C3-6cycloalkoxy, azetidinyl substituted C3-6cycloalkoxy, azetidinyl, methyl substituted azetidinyl, ethyl substituted azetidinyl, isopropyl substituted azetidinyl, fluoro substituted azetidinyl, chloro substituted azetidinyl, hydroxy substituted azetidinyl, methoxy substituted azetidinyl, ethoxy substituted azetidinyl, cyclopropyl substituted azetidinyl, and cyclobutyl substituted azetidinyl.

[0082] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and X are as described herein, and Z is a substituted ring system as described in this section entitled “Group Z:”, and the substitution is one, two, or three members independently selected from the group consisting of nitro, cyano, fluoro, chloro, C1-3 alkyl, halogen substituted C1-3 alkyl, hydroxy substituted C1-3 alkyl, C1-6 alkoxy substituted C1-3alkyl, C3-6cycloalkyl substituted C1-3alkyl, azetidinyl substituted C1-3alkyl, C2-4alkenyl, halogen substituted C2-4alkenyl, hydroxy substituted C2-4alkenyl, C1-6alkoxy substituted C2-4 alkenyl, C3-6 cycloalkyl substituted C2-4 alkenyl, azetidinyl substituted C2-4 alkenyl, C2-4 alkynyl, halogen substituted C2-4 alkynyl, hydroxy substituted C2-4 alkynyl, C1-6 alkoxy substituted C2-4alkynyl, C3-6cycloalkyl substituted C2-4alkynyl, azetidinyl substituted C2-4alkynyl, C3-4cycloalkyl, C1-6 alkyl substituted C3-4 cycloalkyl, halogen substituted C3-4 cycloalkyl, hydroxy substituted C3-4 cycloalkyl, C1-6 alkoxy substituted C3-4 cycloalkyl, azetidinyl substituted C3-4 cycloalkyl, C1-3alkoxy, halogen substituted C1-3alkoxy, hydroxy substituted C1-3alkoxy, C3-6cycloalkyl substituted C1-3 alkoxy, azetidinyl substituted C1-3 alkoxy, C3-4 cycloalkoxy, C1-6 alkyl substituted C3-4 cycloalkoxy, halogen substituted C3-4 cycloalkoxy, hydroxy substituted C3-4 cycloalkoxy, C1-6alkoxy substituted C3-4cycloalkoxy, azetidinyl substituted C3-4cycloalkoxy, azetidinyl, C1-6alkyl substituted azetidinyl, halogen substituted azetidinyl, hydroxy substituted azetidinyl, C1-6 alkoxy substituted azetidinyl, and C3-6 cycloalkyl substituted azetidinyl.

[0083] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and X are as described herein, and Z is a substituted ring system as described in this section entitled “Group Z:”, and the substitution is one,two, or three members independently selected from the group consisting of nitro, cyano, fluoro, chloro, C1-3 alkyl, fluoro substituted C1-3 alkyl, chloro substituted C1-3 alkyl, hydroxy substituted C1-3alkyl, methoxy substituted C1-3alkyl, ethoxy substituted C1-3alkyl, cyclopropyl substituted C1-3 alkyl, cyclobutyl substituted C1-3 alkyl, azetidinyl substituted C1-3 alkyl, C2-4 alkenyl, fluoro substituted C2-4 alkenyl, chloro substituted C2-4 alkenyl, hydroxy substituted C2-4 alkenyl, methoxy substituted C2-4alkenyl, ethoxy substituted C2-4alkenyl, cyclopropyl substituted C2-4alkenyl, cyclobutyl substituted C2-4alkenyl, azetidinyl substituted C2-4alkenyl, C2-4alkynyl, fluoro substituted C2-4 alkynyl, chloro substituted C2-4 alkynyl, hydroxy substituted C2-4 alkynyl, methoxy substituted C2-4 alkynyl, ethoxy substituted C2-4 alkynyl, cyclopropyl substituted C2-4 alkynyl, cyclobutyl substituted C2-4alkynyl, azetidinyl substituted C2-4alkynyl, C3-4cycloalkyl, methyl substituted C3-4 cycloalkyl, ethyl substituted C3-4 cycloalkyl, isopropyl substituted C3-4 cycloalkyl, fluoro C3-4 cycloalkyl, chloro C3-4 cycloalkyl, hydroxy substituted C3-4 cycloalkyl, methoxy substituted C3-4cycloalkyl, ethoxy substituted C3-4cycloalkyl, azetidinyl substituted C3-4cycloalkyl, C1-3 alkoxy, fluoro substituted C1-3 alkoxy, chloro substituted C1-3 alkoxy, hydroxy substituted C1-3 alkoxy, cyclopropyl substituted C1-3 alkoxy, cyclobutyl substituted C1-3 alkoxy, azetidinyl substituted C1-3alkoxy, C3-4cycloalkoxy, methyl substituted C3-4cycloalkoxy, ethyl substituted C3-4cycloalkoxy, fluoro substituted C3-4cycloalkoxy, chloro substituted C3-4cycloalkoxy, hydroxy substituted C3-4 cycloalkoxy, methoxy substituted C3-4 cycloalkoxy, ethoxy substituted C3-4 cycloalkoxy, azetidinyl substituted C3-4 cycloalkoxy, azetidinyl, methyl substituted azetidinyl, ethyl substituted azetidinyl, fluoro substituted azetidinyl, chloro substituted azetidinyl, hydroxy substituted azetidinyl, methoxy substituted azetidinyl, ethoxy substituted azetidinyl, cyclopropyl substituted azetidinyl, and cyclobutyl substituted azetidinyl.

[0084] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and X are as described herein, and Z is a substituted ring system as described in this section entitled “Group Z:”, and the substitution is one, two, or three members independently selected from the group consisting of nitro, cyano, fluoro, chloro, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, 1-fluoroethyl, 2- fluoroethyl, 1,1-difluoroethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyethyl, hydroxymethyl, vinyl, ethynyl, 1-propynyl, 2-cyclopropylethynyl, cyclopropyl, cyclobutyl, azetidinyl, 1- methylcyclopropyl, methoxy, difluoromethoxy, 2-fluoroethoxy, cyclopropoxy, and (1- azetidinyl)carbonyl.

[0085] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (I), wherein T and X are as described herein, and Z is 1-(2- methoxyethyl)-1H-1,2,6-triazainden-5-yl, 1-(2-methoxyethyl)-6-isoquinolyl, 1-(trifluoromethyl)- 6-isoquinolyl, 1-cyclopropyl-1H-indazol-5-yl, 1-cyclopropyl-4-pyrazolyl, 1-fluoro-6-isoquinolyl, 1-isoquinolyl, 1-methoxy-6-isoquinolyl, 1-methyl-1,5-diaza-6-indanyl, 1-methyl-1,6-diaza-5- indanyl, 1-methyl-1H-1,2,3-benzotriazol-5-yl, 1-methyl-1H-1,2,4-triazainden-3-yl, 1-methyl-1H- 1,2,4-triazainden-5-yl, 1-methyl-1H-1,2,4-triazol-3-yl, 1-methyl-1H-1,2,4,6-tetraazainden-5-yl, 1- methyl-1H-1,2,5-triazainden-3-yl, 1-methyl-1H-1,2,5-triazainden-4-yl, 1-methyl-1H-1,2,5- triazainden-6-yl, 1-methyl-1H-1,2,6-triazainden-3-yl, 1-methyl-1H-1,2,6-triazainden-5-yl, 1- methyl-1H-1,2,6-triazainden-5-yl), 1-methyl-1H-1,2,7-triazainden-3-yl, 1-methyl-1H-1,2,7- triazainden-5-yl, 1-methyl-1H-1,3-benzimidazol-5-yl, 1-methyl-1H-1,3,5-triazainden-6-yl, 1- methyl-1H-1,4-diazainden-3-yl, 1-methyl-1H-1,4-diazainden-5-yl, 1-methyl-1H-1,4,6-triazainden- 5-yl, 1-methyl-1H-1,5-diazainden-6-yl, 1-methyl-1H-1,6-diazainden-3-yl, 1-methyl-1H-1,6- diazainden-5-yl, 1-methyl-1H-1,7-diazainden-5-yl, 1-methyl-1H-indazol-5-yl, 1-methyl-1H- indazol-6-yl, 1-methyl-2-oxo-6-quinolyl, 1-methyl-3-methyl-1H-indazol-5-yl, 1-methyl-4-methyl- 3-pyrazolyl, 1-methyl-4-pyrazolyl, 1-methyl-5-methyl-3-pyrazolyl, 1-methyl-6-isoquinolyl, 1- methyl-7-isoquinolyl, 1-naphthyl, 1-oxa-4-aza-2-indenyl, 1-oxa-4-aza-6-indenyl, 1-oxa-5-aza-6- indenyl, 1-oxa-6-aza-5-indanyl, 1-oxa-7-aza-5-indanyl, 1-oxa-7-aza-6-indanyl, 1,1-difluoro-4-aza- 5-indanyl, 1,2-diazabicyclo[3.3.0]octa-2,4-dien-3-yl, 1,2-diazabicyclo[3.3.0]octa-2,4-dien-4-yl, 1,3-benzoxazol-2-yl, 1,3,3a-triaza-2-indenyl, 1,3,3a-triaza-6-indenyl, 1,3a-diaza-2-indenyl, 1,3a- diaza-6-indenyl, 1,3a,4-triaza-2-indenyl, 1,3a,4-triaza-3-indenyl, 1,3a,6-triaza-5-indenyl, 1,4- diazabicyclo[3.3.0]octa-2,4-dien-3-yl, 1,4,7a-triaza-2-indenyl, 1,4,7a-triaza-3-indenyl, 1,4,7a- triaza-5-indenyl, 1,4,7a-triaza-6-indenyl, 1,5-diaza-3-naphthyl, 1,5,7a-triaza-4-indenyl, 1,6-diaza- 3-naphthyl, 1,7a-diaza-2-indenyl, 1,7a-diaza-6-indenyl, 2-(1-methylcyclopropyl)-4-pyridyl, 2-(1- propynyl)-4-pyridyl, 2-(2-cyclopropylethynyl)-4-pyridyl, 2-(difluoromethyl)-4-pyridyl, 2- (trifluoromethyl)-4-pyridyl, 2-(trifluoromethyl)-4-pyrimidinyl, 2-(trifluoromethyl)-6-quinolyl, 2- chloro-3-fluoro-4-pyridyl, 2-chloro-4-pyridyl, 2-chloro-6-methyl-4-pyridyl, 2-cyclobutyl-4- pyridyl, 2-cyclopropoxy-4-pyridyl, 2-cyclopropyl-1,3-thiazol-4-yl, 2-cyclopropyl-1,3-thiazol-5-yl, 2-cyclopropyl-4-pyridyl, 2-cyclopropyl-4-pyrimidinyl, 2-cyclopropyl-5-fluoro-4-pyrimidinyl, 2- difluoromethoxy-4-pyridyl, 2-ethyl-4-pyridyl, 2-ethyl-4-pyrimidinyl, 2-ethyl-5-fluoro-4- pyrimidinyl, 2-ethynyl-4-pyridyl, 2-ethynyl-5-fluoro-4-pyridyl, 2-ethynyl-6-fluoro-4-pyridyl, 2- fluoro-3-tolyl, 2-fluoro-5-tolyl, 2-fluoro-6-methyl-4-pyridyl, 2-fluoro-6-quinolyl, 2-fluoro-6-vinyl-4-pyridyl, 2-isoindolinyl, 2-isonicotinamide, 2-isopropyl-4-pyridyl, 2-methoxy-4-pyridyl, 2- methoxy-4-pyrimidinyl, 2-methoxy-6-quinolyl, 2-methyl-1-oxo-6-isoquinolyl, 2-methyl-1,3- benzoxazol-6-yl, 2-methyl-1,3-thiazol-4-yl, 2-methyl-1,3-thiazol-5-yl, 2-methyl-1,3a-diaza-5- indenyl, 2-methyl-1,3a,6-triaza-5-indenyl, 2-methyl-2H-1,2,4-triazainden-5-yl, 2-methyl-2H- 1,2,5-triazainden-4-yl, 2-methyl-2H-1,2,6-triazainden-5-yl, 2-methyl-2H-indazol-5-yl, 2-methyl- 2H-indazol-6-yl, 2-methyl-4-pyridyl, 2-methyl-4-pyrimidinyl, 2-methyl-6-quinolyl, 2-methyl-7- quinolyl, 2-naphthyl, 2-phenyl, 2-pyridyl, 2-quinolyl, 2-quinoxalinyl, 2,3-dihydro-1-benzofuran-4- yl, 2,3-dihydro-1-benzofuran-5-yl, 2,3-dihydro-1-benzofuran-6-yl, 2,4-diaza-2-indanyl, 2,6- dichloro-4-pyridyl, 2,6-dimethyl-4-pyridyl, 2,6-dimethyl-4-pyrimidinyl, 3-biphenylyl, 3-chloro-6- isoquinolyl, 3-chloro-6-methyl-2-pyridyl, 3-cyclopropyl-1,4,7a-triaza-6-indenyl, 3-fluoro-4- methyl-2-pyridyl, 3-fluoro-5-tolyl, 3-fluoro-6-methyl-2-pyridyl, 3-methyl-1,3a-diaza-5-indenyl, 3- methyl-1,3a-diaza-6-indenyl, 3-methyl-2,3a,6-triaza-7-indenyl, 3-methyl-6-isoquinolyl, 3-methyl- 6-quinolyl, 3-oxo-4-aza-5-indanyl, 3-quinolyl, 3,3-difluoro-4-aza-5-indanyl, 3,3-difluoro-5-aza-6- indanyl, 3,4-dihydro-2H-1-oxa-7-azanaphth-6-yl, 3,4-dimethyl-1-pyrazolyl, 3,5-xylyl, 3a,4,6- triaza-2-indenyl, 4-(1-azetidinyl)-2-pyridyl, 4-(1-fluoroethyl)-2-pyridyl, 4-(1-hydroxyethyl)-2- pyridyl, 4-(1,1-difluoroethyl)-2-pyridyl, 4-(2-fluoroethoxy)-2-pyridyl, 4-(2-fluoroethoxy)-2- pyrimidinyl, 4-(2-fluoroethoxy)-6-methyl-2-pyrimidinyl, 4-(2-fluoroethyl)-2-pyrimidinyl, 4-(2- fluoroethyl)-6-methyl-2-pyrimidinyl, 4-(2-hydroxyethyl)-6-methyl-2-pyrimidinyl, 4- (difluoromethyl)-2-pyridyl, 4-(trifluoromethyl)-2-pyridyl, 4-(trifluoromethyl)-2-pyrimidinyl, 4- [(1-azetidinyl)carbonyl]-2-pyridyl, 4-aza-5-indanyl, 4-biphenylyl, 4-chloro-3-fluorophenyl, 4- chloro-5-fluoro-2-pyridyl, 4-chloro-5-methoxy-2-pyridyl, 4-chloro-5-methyl-2-pyridyl, 4-chloro- 6-methyl-2-pyridyl, 4-cyclopropyl-2-pyridyl, 4-cyclopropyl-2-pyrimidinyl, 4-difluoromethoxy-2- pyridyl, 4-ethyl-2-pyridyl, 4-ethyl-6-(fluoromethyl)-2-pyridyl, 4-ethynyl-2-pyridyl, 4-fluoro-3- tolyl, 4-fluoro-5-methyl-2-pyridyl, 4-fluoro-6-methyl-2-pyridyl, 4-fluorophenyl, 4-isopropyl-2- pyridyl, 4-isoquinolyl, 4-methoxy-2-pyridyl, 4-methoxy-2-pyrimidinyl, 4-methoxy-5- (trifluoromethyl)-2-pyridyl, 4-methoxy-5-methyl-2-pyridyl, 4-methoxy-6-methyl-2-pyridyl, 4- methoxy-6-methyl-2-pyrimidinyl, 4-methyl-1,3-benzothiazol-2-yl, 4-methyl-1,3,3a-triaza-2- indenyl, 4-methyl-2-pyridyl, 4-methyl-2-pyrimidinyl, 4-methyl-6-(trifluoromethyl)-2-pyrimidinyl, 4-methyl-6-quinolyl, 4-methyl-7-quinolyl, 4-quinolyl, 4,5-dichloro-2-pyridyl, 4,5-dimethyl-1,3- thiazol-2-yl, 4,5-dimethyl-2-furyl, 4,5-dimethyl-2-pyridyl, 4,5,6,7-tetrahydro-2,3a-diaza-1- indenyl, 4,5,6,7-tetrahydro-2,3a-diaza-3-indenyl, 4,6-diaza-5-indanyl, 4,6-dimethyl-2-pyridyl, 4,6- dimethyl-2-pyrimidinyl, 5-(1-azetidinyl)-2-pyridyl, 5-(1,1-difluoroethyl)-2-pyridyl, 5-(difluoromethyl)-4-methyl-2-pyridyl, 5-chloro-2-pyridyl, 5-chloro-4-methoxy-2-pyridyl, 5-chloro- 4-methyl-2-pyridyl, 5-chloro-6-methoxy-2-pyridyl, 5-chloro-6-methyl-2-pyridyl, 5-cyclopropyl-2- pyridyl, 5-cyclopropyl-3-pyridyl, 5-cyclopropyl-4-methoxy-2-pyridyl, 5-difluoromethoxy-2- pyridyl, 5-fluoro-1,3a-diaza-2-indenyl, 5-fluoro-2-methyl-4-pyrimidinyl, 5-fluoro-4-methoxy-2- pyridyl, 5-fluoro-4-methyl-2-pyridyl, 5-fluoro-6-methyl-2-pyridyl, 5-isoquinolyl, 5-methoxy-2- pyrazinyl, 5-methoxy-2-pyridyl, 5-methoxy-2-pyrimidinyl, 5-methoxy-4-methyl-2-pyridyl, 5- methoxy-6-methyl-2-pyridyl, 5-methyl-1,3a-diaza-2-indenyl, 5-methyl-1,4,7a-triaza-3-indenyl, 5- methyl-2-pyrazinyl, 5-methyl-2-pyridyl, 5-methyl-2-pyrimidinyl, 5-methyl-2-quinolyl, 5-methyl- 3-pyridyl, 5-methyl-3-quinolyl, 5-quinolyl, 5,6-dimethyl-2-pyridyl, 5,6-dimethyl-3-pyridyl, 5,7- dihydro-4H-6-oxa-1,3a-diazainden-2-yl, 6-(1,1-difluoroethyl)-2-pyridyl, 6-(2-fluoroethoxy)-2- pyridyl, 6-(fluoromethyl)-2-pyridyl, 6-(fluoromethyl)-4-methyl-2-pyridyl, 6-(hydroxymethyl)-2- pyridyl, 6-(hydroxymethyl)-4-methyl-2-pyridyl, 6-(trifluoromethyl)-2-pyridyl, 6-chloro-1,3a- diaza-2-indenyl, 6-chloro-1,7a-diaza-2-indenyl, 6-chloro-3-quinolyl, 6-chloro-4-methyl-2-pyridyl, 6-chloro-5-methyl-2-pyridyl, 6-cinnolinyl, 6-cyano-2-pyridyl, 6-cyclopropyl-2-methyl-4- pyrimidinyl, 6-cyclopropyl-2-pyrazinyl, 6-cyclopropyl-2-pyridyl, 6-cyclopropyl-4-methyl-2- pyridyl, 6-cyclopropyl-4-pyrimidinyl, 6-ethyl-4-methyl-2-pyridyl, 6-ethyl-4-pyrimidinyl, 6- ethynyl-2-pyridyl, 6-ethynyl-4-pyrimidinyl, 6-fluoro-2-quinolyl, 6-fluoro-3-quinolyl, 6-fluoro-4- (fluoromethyl)-2-pyridyl, 6-fluoro-4-methyl-2-pyridyl, 6-fluoro-5-(hydroxymethyl)-2-pyridyl, 6- fluoro-5-methyl-2-pyridyl, 6-isoquinolyl, 6-methoxy-2-pyridyl, 6-methoxy-3-pyridyl, 6-methoxy- 4-methyl-2-pyridyl, 6-methoxy-5-methyl-2-pyridyl, 6-methoxy-5-methyl-3-pyridyl, 6-methyl- 1,3a-diaza-2-indenyl, 6-methyl-1,3a-diaza-3-indenyl, 6-methyl-1,4,7a-triaza-3-indenyl, 6-methyl- 2-pyrazinyl, 6-methyl-2-pyridyl, 6-methyl-2-quinolyl, 6-methyl-3-pyridyl, 6-methyl-3-quinolyl, 6- methyl-4-(trifluoromethyl)-2-pyridyl, 6-methyl-4-nitro-2-pyridyl, 6-methyl-4-pyrimidinyl, 6- quinolyl, 6,7-dihydro-4H-5-oxa-1,7a-diazainden-2-yl, 6,7-dihydro-5H-4-oxa-1,7a-diazainden-3-yl, 7-(trifluoromethyl)-3-quinolyl, 7-fluoro-2,3-dihydro-1-benzofuran-6-yl, 7-fluoro-3-quinolyl, 7- methoxy-3-quinolyl, 7-methyl-1,3,3a-triaza-2-indenyl, 7-methyl-1,3a-diaza-2-indenyl, 7-methyl- 1,3a-diaza-3-indenyl, 7-methyl-1,3a-diaza-5-indenyl, 7-methyl-1,4,7a-triaza-3-indenyl, 7-methyl- 1,7a-diaza-3-indenyl, 7-methyl-3-quinolyl, 7-quinolyl, 8-chloro-3-quinolyl, 8-fluoro-3-quinolyl, 8- fluoro-6-isoquinolyl, 8-isoquinolyl, 8-methoxy-3-quinolyl, 8-methyl-3-quinolyl, 8-methyl-6- isoquinolyl, 8-methyl-6-quinolyl, 8-quinolyl, m-chlorophenyl, m-fluorophenyl, or m-tolyl.Groups T & X:

[0086] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (V):wherein Z is as defined herein.

[0087] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (VI):wherein Z is as defined herein.

[0088] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (VII):wherein Z is as defined herein.

[0089] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (VIIa): (VIIa) wherein Z is as defined herein.

[0090] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (VIIb):wherein Z is as defined herein.

[0091] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (VIIc):wherein Z is as defined herein.

[0092] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (VIII): (VIII) wherein Z is as defined herein.

[0093] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (IX):wherein Z is as defined herein.

[0094] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (X):wherein Z is as defined herein.

[0095] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (Xa):wherein Z is as defined herein.

[0096] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (Xb):wherein Z is as defined herein.

[0097] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (Xc):wherein Z is as defined herein.

[0098] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (XI): (XI) wherein Z is as defined herein.

[0099] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (XII):wherein Z is as defined herein.

[0100] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (XIII): (XIII) wherein Z is as defined herein.

[0101] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (XIIIa):wherein Z is as defined herein.

[0102] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (XIIIb):wherein Z is as defined herein.

[0103] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (XIIIc):wherein Z is as defined herein.Groups X & Z:

[0104] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (XIV): (XIV) wherein T is as defined herein, and Z is 1-methylisoquinolin-6-yl, 2-(trifluoromethyl)pyrimidin-4- yl, 2-methylpyrimidin-4-yl, 1-methyl-6-isoquinolyl, 1-(2-hydroxyethyl)-6-isoquinolyl, 3- isoquinolyl, 6-quinolyl, 8-fluoro-3-quinolyl, 8-fluoro-7-quinolyl, 4-methyl-1,7a-diaza-2-indenyl, 1-thia-5-aza-2-indenyl, 1-(2-fluoroethyl)-1H-indazol-5-yl, 3-quinolyl, 2-cyclopropyl-2H-indazol- 5-yl, 6-fluoro-1,3-benzoxazol-2-yl, 5-fluoro-2-pyridyl, 1-benzofuran-2-yl, or phenyl.

[0105] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (XV): (XV) wherein T is as defined herein, and Z is 1-methylisoquinolin-6-yl, 2-(trifluoromethyl)pyrimidin-4- yl, 2-methylpyrimidin-4-yl, 1-methyl-6-isoquinolyl, 1-(2-hydroxyethyl)-6-isoquinolyl, 3- isoquinolyl, 6-quinolyl, 8-fluoro-3-quinolyl, 8-fluoro-7-quinolyl, 4-methyl-1,7a-diaza-2-indenyl, 1-thia-5-aza-2-indenyl, 1-(2-fluoroethyl)-1H-indazol-5-yl, 3-quinolyl, 2-cyclopropyl-2H-indazol- 5-yl, 6-fluoro-1,3-benzoxazol-2-yl, 5-fluoro-2-pyridyl, 1-benzofuran-2-yl, or phenyl.

[0106] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (XVI): (XVI) wherein T is as defined herein, and Z is 1-methylisoquinolin-6-yl, 2-(trifluoromethyl)pyrimidin-4- yl, 2-methylpyrimidin-4-yl, 1-methyl-6-isoquinolyl, 1-(2-hydroxyethyl)-6-isoquinolyl, 3- isoquinolyl, 6-quinolyl, 8-fluoro-3-quinolyl, 8-fluoro-7-quinolyl, 4-methyl-1,7a-diaza-2-indenyl, 1-thia-5-aza-2-indenyl, 1-(2-fluoroethyl)-1H-indazol-5-yl, 3-quinolyl, 2-cyclopropyl-2H-indazol- 5-yl, 6-fluoro-1,3-benzoxazol-2-yl, 5-fluoro-2-pyridyl, 1-benzofuran-2-yl, or phenyl. Groups T & Z:

[0107] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (XVII):wherein X is as defined herein, and Z is 1-methylisoquinolin-6-yl, 2-(trifluoromethyl)pyrimidin-4- yl, 2-methylpyrimidin-4-yl, 1-methyl-6-isoquinolyl, 1-(2-hydroxyethyl)-6-isoquinolyl, 3- isoquinolyl, 6-quinolyl, 8-fluoro-3-quinolyl, 8-fluoro-7-quinolyl, 4-methyl-1,7a-diaza-2-indenyl, 1-thia-5-aza-2-indenyl, 1-(2-fluoroethyl)-1H-indazol-5-yl, 3-quinolyl, 2-cyclopropyl-2H-indazol- 5-yl, 6-fluoro-1,3-benzoxazol-2-yl, 5-fluoro-2-pyridyl, 1-benzofuran-2-yl, or phenyl.

[0108] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (XVIII):wherein X is as defined herein, and Z is 1-methylisoquinolin-6-yl, 2-(trifluoromethyl) pyrimidin- 4-yl, 2-methylpyrimidin-4-yl, 1-methyl-6-isoquinolyl, 1-(2-hydroxyethyl)-6-isoquinolyl, 3- isoquinolyl, 6-quinolyl, 8-fluoro-3-quinolyl, 8-fluoro-7-quinolyl, 4-methyl-1,7a-diaza-2-indenyl, 1-thia-5-aza-2-indenyl, 1-(2-fluoroethyl)-1H-indazol-5-yl, 3-quinolyl, 2-cyclopropyl-2H-indazol- 5-yl, 6-fluoro-1,3-benzoxazol-2-yl, 5-fluoro-2-pyridyl, 1-benzofuran-2-yl, or phenyl.

[0109] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, has a structure according to formula (XIX):wherein X is as defined herein, and Z is 1-methylisoquinolin-6-yl, 2-(trifluoromethyl) pyrimidin- 4-yl, 2-methylpyrimidin-4-yl, 1-methyl-6-isoquinolyl, 1-(2-hydroxyethyl)-6-isoquinolyl, 3- isoquinolyl, 6-quinolyl, 8-fluoro-3-quinolyl, 8-fluoro-7-quinolyl, 4-methyl-1,7a-diaza-2-indenyl, 1-thia-5-aza-2-indenyl, 1-(2-fluoroethyl)-1H-indazol-5-yl, 3-quinolyl, 2-cyclopropyl-2H-indazol- 5-yl, 6-fluoro-1,3-benzoxazol-2-yl, 5-fluoro-2-pyridyl, 1-benzofuran-2-yl, or phenyl.

[0110] In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, is 4-cyclopropyl-1-[5-(p-fluorophenyl)-2-(1-methyl-6-isoquinolyl)-1,3-oxazol-4-yl]-2(1H)- pyrimidinone, or a salt or a hydrate or a solvate thereof. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, is 4-cyclopropyl-1-{2-(1-methyl-6-isoquinolyl)-5-[p-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-2(1H)-pyrimidinone, or a salt or a hydrate or a solvate thereof. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, is 4-cyclopropyl-1-{2-[6-(fluoromethyl)-5-methyl-2-pyridyl]-5-(3-fluoro-4- tolyl)-1,3-oxazol-4-yl}-2(1H)-pyrimidinone, or a salt or a hydrate or a solvate thereof. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, is 1-(5-(4- chloro-3-fluorophenyl)-2-(6-(fluoromethyl)-4-methylpyridin-2-yl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one, or a salt or a hydrate or a solvate thereof. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, is 4-cyclopropyl-1-[2-(6- fluoro-4-methyl-2-pyridyl)-5-(3-fluoro-4-tolyl)-1,3-oxazol-4-yl]-2(1H)-pyrimidinone, or a salt or a hydrate or a solvate thereof. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, is 1-[5-(4-chloro-3-fluorophenyl)-2-(6-fluoro-4-methyl-2-pyridyl)-1,3-oxazol- 4-yl]-4-cyclopropyl-2(1H)-pyrimidinone, or a salt or a hydrate or a solvate thereof. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, is 1-(5-(4- chloro-3-fluorophenyl)-2-(5,7-dimethylpyrazolo[1,5-a]pyrimidin-2-yl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one, or a salt or a hydrate or a solvate thereof. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, is 1-(5-(4-chloro-3- fluorophenyl)-2-(1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)oxazol-4-yl)-4-cyclopropylpyrimidin- 2(1H)-one, or a salt or a hydrate or a solvate thereof. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, is 4-cyclopropyl-1-(5-(4-fluorophenyl)-2-(1- methyl-1H-indazol-5-yl)oxazol-4-yl)pyrimidin-2(1H)-one, or a salt or a hydrate or a solvate thereof. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, is 1-[2-(m-chlorophenyl)-5-(p-fluorophenyl)-1,3-oxazol-4-yl]-4-cyclopropyl-2(1H)-pyrimidinone, or a salt or a hydrate or a solvate thereof.

[0111] In an exemplary embodiment, the salt of a compound in this section is a pharmaceutically acceptable salt. In an exemplary embodiment, the salt of a compound described herein is a pharmaceutically acceptable salt. In an exemplary embodiment, the salt of a compound of the invention is a pharmaceutically acceptable salt.

[0112] In an exemplary embodiment, the invention provides a compound described herein, or a salt, hydrate or solvate thereof, or a combination thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt, hydrate or solvate thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt thereof. Inan exemplary embodiment, the salt is a pharmaceutically acceptable salt. In an exemplary embodiment, the invention provides a compound described herein, or a hydrate thereof. In an exemplary embodiment, the invention provides a compound described herein, or a solvate thereof. In an exemplary embodiment, the invention provides a salt of a compound described herein. In an exemplary embodiment, the invention provides a pharmaceutically acceptable salt of a compound described herein. In an exemplary embodiment, the invention provides a hydrate of a compound described herein. In an exemplary embodiment, the invention provides a solvate of a compound described herein. In an exemplary embodiment, the invention provides any of the compounds described herein where none of its atoms are replaced with [2H], [3H], [11C], [18F], or [13N]. In an exemplary embodiment, the compounds disclosed in the Examples bind to 4-8 amino acid residues of amino acid residues 86-99 of SEQ ID NO: 9.

[0113] In an exemplary embodiment, the invention provides a labeled compound, which is a compound disclosed herein, or a salt, hydrate or solvate thereof, where one or more of its atoms is replaced with [2H], [3H], [11C], [18F], or [13N]. In an exemplary embodiment, the invention provides a labeled compound, which is a compound disclosed herein, or a salt, hydrate or solvate thereof, where one or more of its atoms is replaced with [2H], [3H], [11C], or [13N]. In an exemplary embodiment, the invention provides a labeled compound according to a formula described herein, or a salt, hydrate or solvate thereof, wherein one or more of its Z moiety atoms is replaced with [2H], [3H], [11C], or [13N]. In an exemplary embodiment, the invention provides a labeled compound according to a formula described herein, or a salt, hydrate or solvate thereof, wherein one of its Z moiety atoms is replaced with [2H], [3H], [11C], or [13N]. In an exemplary embodiment, the invention provides a labeled compound according to a formula described herein, or a salt, hydrate or solvate thereof, wherein one or more of its T moiety atoms is replaced with [2H], [3H], [11C], or [13N]. In an exemplary embodiment, the invention provides a labeled compound according to a formula described herein, or a salt, hydrate or solvate thereof, wherein one of its T moiety atoms is replaced with [2H], [3H], [11C], or [13N]. In an exemplary embodiment, the invention provides a labeled compound according to a formula described herein, or a salt, hydrate or solvate thereof, wherein one or more of its X moiety atoms is replaced with [2H], [3H], [11C], or [13N]. In an exemplary embodiment, the invention provides a labeled compound according to a formula described herein, or a salt, hydrate or solvate thereof, wherein one of its X moiety atoms is replaced with [2H], [3H], [11C], or [13N].

[0114] In an exemplary embodiment, the invention provides a labeled compound, which is a compound disclosed herein, or a salt, hydrate or solvate thereof, where one or more of its atoms is replaced with [18F]. In an exemplary embodiment, the invention provides a labeled compound, which is a compound disclosed herein, or a salt, hydrate or solvate thereof, where one of its atoms is replaced with [18F]. In an exemplary embodiment, the invention provides a labeled compound according to a formula described herein, or a salt, hydrate or solvate thereof, where one or more of its Z moiety atoms is replaced with [18F]. In an exemplary embodiment, the invention provides a labeled compound according to a formula described herein, or a salt, hydrate or solvate thereof, wherein one of its Z moiety atoms is replaced with [18F]. In an exemplary embodiment, the invention provides a labeled compound according to a formula described herein, or a salt, hydrate or solvate thereof, wherein one or more of its T moiety atoms is replaced with [18F]. In an exemplary embodiment, the invention provides a labeled compound according to a formula described herein, or a salt, hydrate or solvate thereof, wherein one of its T moiety atoms is replaced with [18F]. In an exemplary embodiment, the invention provides a labeled compound according to a formula described herein, or a salt, hydrate or solvate thereof, wherein one or more of its X moiety atoms is replaced with [18F]. In an exemplary embodiment, the invention provides a labeled compound according to a formula described herein, or a salt, hydrate or solvate thereof, wherein one of its X moiety atoms is replaced with [18F]. In an exemplary embodiment, the labeled compounds described herein bind to 4-8 amino acid residues of amino acid residues 86-99 of SEQ ID NO: 9. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, is 1-[5-(4-chloro-3-fluorophenyl)-2-(6-(fluoro-18F)-4-methyl-2-pyridyl)-1,3-oxazol-4-yl]- 4-cyclopropyl-2(1H)-pyrimidinone, or a salt or a hydrate or a solvate thereof. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, is 1-{5-(4-chloro-3- fluorophenyl)-2-[6-((fluoro-18F)methyl)-4-methyl-2-pyridyl]-1,3-oxazol-4-yl}-4-cyclopropyl- 2(1H)-pyrimidinone, or a salt or a hydrate or a solvate thereof. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, is 4-cyclopropyl-1-[2-(6-(fluoro-18F)-4- methyl-2-pyridyl)-5-(3-fluoro-4-tolyl)-1,3-oxazol-4-yl]-2(1H)-pyrimidinone, or a salt or a hydrate or a solvate thereof. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, is 4-cyclopropyl-1-{2-[6-((fluoro-18F)methyl)-5-methyl-2-pyridyl]-5-(3-fluoro-4- tolyl)-1,3-oxazol-4-yl}-2(1H)-pyrimidinone, or a salt or a hydrate or a solvate thereof. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, is 1-(5-(4- chloro-3-fluorophenyl)-2-(7-((fluoro-18F)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-2-yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one, or a salt or a hydrate or a solvate thereof. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, is 1-(5-(4- chloro-3-fluorophenyl)-2-(5-((fluoro-18F)methyl)-7-methylpyrazolo[1,5-a]pyrimidin-2-yl)oxazol- 4-yl)-4-cyclopropylpyrimidin-2(1H)-one, or a salt or a hydrate or a solvate thereof. In an exemplary embodiment, the compound, or a salt or a hydrate or a solvate thereof, is a radiolabeled version of 1-(5-(4-chloro-3-fluorophenyl)-2-(5,7-dimethylpyrazolo[1,5-a]pyrimidin-2-yl)oxazol-4- yl)-4-cyclopropylpyrimidin-2(1H)-one, or a salt or a hydrate or a solvate thereof.

[0115] In an exemplary embodiment, the invention provides a radiolabeled compound, which is a compound disclosed herein, or a salt, hydrate or solvate thereof, wherein one or more of its atoms is replaced with [2H], [3H], [11C], [13N], [15O], [18F], [52Mn], [55Co], [64Cu], [67Ga], [68Ga], [82Rb], [89Zr], [99mTc], [111In], [123I], or [201Tl]. In an exemplary embodiment, the invention provides a radiolabeled compound, which is a compound disclosed herein, or a salt, hydrate or solvate thereof, wherein one or more of its atoms is replaced with [15O], [52Mn], [55Co], [64Cu], [67Ga], [68Ga], [82Rb], [89Zr], [99mTc], [111In], [123I], or [201Tl]. In an exemplary embodiment, the invention provides a radiolabeled compound, which is a compound disclosed herein, or a salt, hydrate or solvate thereof, wherein one of its atoms is replaced with [15O], [52Mn], [55Co], [64Cu], [67Ga], [68Ga], [82Rb], [89Zr], [99mTc], [111In], [123I], or [201Tl]. In an exemplary embodiment, the invention provides a labeled compound according to a formula described herein, or a salt, hydrate or solvate thereof, where one or more of its Z moiety atoms is replaced with [15O], [52Mn], [55Co], [64Cu], [67Ga], [68Ga], [82Rb], [89Zr], [99mTc], [111In], [123I], or [201Tl]. In an exemplary embodiment, the invention provides a labeled compound according to a formula described herein, or a salt, hydrate or solvate thereof, wherein one of its Z moiety atoms is replaced with [15O], [52Mn], [55Co], [64Cu], [67Ga], [68Ga], [82Rb], [89Zr], [99mTc], [111In], [123I], or [201Tl]. In an exemplary embodiment, the invention provides a labeled compound according to a formula described herein, or a salt, hydrate or solvate thereof, wherein one or more of its T moiety atoms is replaced with [15O], [52Mn], [55Co], [64Cu], [67Ga], [68Ga], [82Rb], [89Zr], [99mTc], [111In], [123I], or [201Tl]. In an exemplary embodiment, the invention provides a labeled compound according to a formula described herein, or a salt, hydrate or solvate thereof, wherein one of its T moiety atoms is replaced with [15O], [52Mn], [55Co], [64Cu], [67Ga], [68Ga], [82Rb], [89Zr], [99mTc], [111In], [123I], or [201Tl]. In an exemplary embodiment, the invention provides a labeled compound according to a formula described herein, or a salt, hydrate or solvate thereof, wherein one or more of its X moiety atoms is replaced with [15O], [52Mn], [55Co], [64Cu], [67Ga], [68Ga], [82Rb], [89Zr], [99mTc], [111In], [123I],or [201Tl]. In an exemplary embodiment, the invention provides a labeled compound according to a formula described herein, or a salt, hydrate or solvate thereof, wherein one of its X moiety atoms is replaced with [15O], [52Mn], [55Co], [64Cu], [67Ga], [68Ga], [82Rb], [89Zr], [99mTc], [111In], [123I], or [201Tl]. In an exemplary embodiment, the radiolabeled compound disclosed herein can be used as an imaging agent for positron emission tomography (PET), single photon emission computed tomography (SPECT), or autoradiography. In an exemplary embodiment, the invention provides a radiolabeled compound, which is a compound disclosed herein where one or more of its atoms is replaced with [11C], [13N], [15O], [18F], [52Mn], [55Co], [64Cu], [68Ga], [82Rb], or [89Zr]. In an exemplary embodiment, the invention provides a radiolabeled compound, which is a compound disclosed herein where one or more of its atoms is replaced with [67Ga], [99mTc], [111In], [123I], or [201Tl]. In an exemplary embodiment, the invention provides a radiolabeled compound, which is a compound disclosed herein where one or more of its atoms is replaced with [11C], [13N], [15O], [18F], [52Mn], [55Co], [64Cu], [68Ga], [82Rb], or [89Zr]. IV. Pharmaceutical Formulations

[0116] The herein-discussed compounds can be formulated using any convenient excipients, reagents and methods. Compositions are provided in formulation with a pharmaceutically acceptable excipient(s). A wide variety of pharmaceutically acceptable excipients are known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A. Gennaro (2000) “Remington: The Science and Practice of Pharmacy,” 20th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., eds., 7thed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) A.H. Kibbe et al., eds., 3rded. Amer. Pharmaceutical Assoc.

[0117] In an exemplary embodiment, the invention provides a pharmaceutical formulation comprising: a) the compound, or a pharmaceutically acceptable salt or a hydrate or a solvate thereof, described herein; and b) a pharmaceutically acceptable excipient. The pharmaceutical formulation can be administered by any suitable means, such as for example oral and / or parenteral depot. Oral administration in the form of a pill, capsule, elixir, syrup, lozenge, troche, or the like is particularly preferred. Dosage levels of the order of from about 5 mg to about 250 mg per kilogram of body weight per day and more preferably from about 25 mg to about 150 mg per kilogram of body weight per day, are useful in the treatment of the diseases described herein.Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration and rate of excretion, drug combination and the severity of the particular disease undergoing therapy. Preferred compounds of the invention will have desirable pharmacological properties that include, but are not limited to, oral bioavailability, low toxicity, low serum protein binding and desirable in vitro and in vivo half-lives. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat peripheral disorders are often preferred. In an exemplary embodiment, the invention provides an oral pharmaceutical formulation comprising: a) the compound, or a pharmaceutically acceptable salt or a hydrate or a solvate thereof, described herein; and b) a pharmaceutically acceptable excipient suitable for oral administration. In an exemplary embodiment, the invention provides a parenteral pharmaceutical formulation comprising: a) the compound, or a pharmaceutically acceptable salt or a hydrate or a solvate thereof, described herein; and b) a pharmaceutically acceptable excipient suitable for parenteral administration. In an exemplary embodiment, the invention provides an intravenous pharmaceutical formulation comprising: a) the compound, or a pharmaceutically acceptable salt or a hydrate or a solvate thereof, described herein; and b) a pharmaceutically acceptable excipient suitable for intravenous administration. In some embodiments, the pharmaceutical formulation is an injectable formulation. In some embodiments, the pharmaceutical formulation is an oral formulation. In some embodiments, the pharmaceutical formulation is a parenteral formulation.

[0118] The subject compounds may be administered in a unit dosage form and may be prepared by any methods well known in the art. Such methods include combining the subject compound with a pharmaceutically acceptable carrier or diluent which constitutes one or more accessory ingredients. A pharmaceutically acceptable carrier is selected on the basis of the chosen route of administration and standard pharmaceutical practice. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. This carrier can be a solid or liquid and the type is generally chosen based on the type of administration being used.

[0119] The compounds of the invention may also be used in combination with additional therapeutic agents. In an exemplary embodiment, the invention provides a combination comprising: a) the compound, or a pharmaceutically acceptable salt or a hydrate or a solvate thereof, described herein; and b) at least one additional therapeutic agent. In an exemplary embodiment, the additional therapeutic agent is useful in treating a neurodegenerative disease.

[0120] Any drug delivery device or system that provides for the dosing regimen of the instant disclosure can be used. A wide variety of delivery devices and systems are known to those skilled in the art.

[0121] In some embodiments, a compound of the formulation is detectably labeled. In some embodiments, a compound of the formulation is detectably radiolabeled. Detectable labels include, without limitation: [2H], [3H], [11C], [13N], [15O], [18F], [52Mn], [55Co], [64Cu], [67Ga], [68Ga], [82Rb], [89Zr], [99mTc], [111In], [123I], or [201Tl]; or for example [11C], [13N], [15O], [18F], [52Mn], [55Co], [64Cu], [68Ga], [82Rb], or [89Zr]; or for example [67Ga], [99mTc], [111In], [123I], or [201Tl]; or for example [2H], [3H], [11C], [18F], [13N], etc. V. Methods of Inhibiting Propagation of Misfolded Proteins

[0122] In a certain aspect, the present disclosure provides methods of inhibiting propagation of misfolded proteins (such as those associated with a neurodegenerative disease), comprising contacting the misfolded proteins with a compound described herein; and thereby inhibiting the propagation of misfolded proteins. In some embodiments, the misfolded proteins are associated with a neurodegenerative disease, and the contacting with the compound described herein treats the neurodegenerative disease. In some embodiments, the inhibition is partial. In some embodiments, the inhibition is complete.

[0123] In a certain aspect, the present disclosure provides methods for halting propagation of misfolded proteins (such as those associated with a neurodegenerative disease), comprising contacting the misfolded proteins with a compound described herein; and thereby halting propagation of the misfolded proteins. In some embodiments, the method for halting propagation of misfolded proteins associated with a neurological disease treats the neurodegenerative disease.

[0124] The environment for the methods in this section may be any in which misfolded proteins occur including, without limitation, cell lysate, cell culture, mammalian brain tissue, etc. In some embodiments, the environment is mammalian brain tissue. In some embodiments, the mammalianbrain tissue is human brain tissue. In some embodiments, the environment is a cell lysate. In some embodiments, the environment is a cell culture. In some embodiments, the cell culture is mammalian cell culture. In some embodiments, the cell culture is human cell culture. In some embodiments, the cell culture comprises neurons. In some embodiments, the cell culture contains neurons. In some embodiments, the brain or brain tissue is within a subject having or is suspected to have a neurodegenerative disease.

[0125] In an exemplary embodiment, the neurodegenerative disease associated with misfolded proteins includes, without limitation, transmissible spongiform encephalopathies (such as Creutzfeldt–Jakob disease (CJD)), multiple system atrophy (MSA), Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis (ALS), Amyotrophic lateral sclerosis / Parkinsonism–dementia complex, anti-IgLON5-related tauopathy, Caribbean Parkinsonism, Chronic traumatic encephalopathy, Dementia with Lewy Bodies (DLB), Diffuse neurofibrillary tangles with calcification, Down syndrome, Familial British dementia, Familial Danish dementia, Niemann-Pick disease-type C, Non-Guamanian motor neuron disease with neurofibrillary tangles, Postencephalitic Parkinsonism, Primary age-related tauopathy, Progressive ataxia and palatal tremor, Tangle-only dementia, Familial frontotemporal dementia and Parkinsonism, Pick's disease, Argyrophilic grain disease, Corticobasal degeneration, Guadeloupean Parkinsonism, Globular glial tauopathy, Huntington's disease, Progressive supranuclear palsy, SLC9a-related Parkinsonism, or Tau astrogliopathy. In some embodiments, the neurodegenerative disease is multiple system atrophy (MSA). In some embodiments, the neurodegenerative disease is multiple system atrophy A strain (MSA-A). In some embodiments, the neurodegenerative disease is multiple system atrophy B strain (MSA-B). In some embodiments, the neurodegenerative disease is multiple system atrophy A strain (MSA-A) and multiple system atrophy B strain (MSA-B). In some embodiments, the neurodegenerative disease is Parkinson’s disease. In some embodiments, the neurodegenerative disease is Dementia with Lewy Bodies (DLB). In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0126] In an exemplary embodiment, the misfolded proteins of the present disclosure may be any that are associated with a disease. In an exemplary embodiment, the misfolded proteins of the present disclosure may be any that are associated with a neurodegenerative disease. Misfolded proteins that are associated with a neurodegenerative disease include, without limitation, prionsassociated with transmissible spongiform encephalopathies such as Creutzfeldt–Jakob disease (CJD), α-synuclein associated with multiple system atrophy (MSA) and Parkinson’s disease, amyloid β associated with Alzheimer’s and Parkinson’s disease, tau associated with Alzheimer’s and Parkinson’s disease, etc. In some embodiments, the misfolded proteins are α- synuclein. In some embodiments, the misfolded proteins are amyloid β. In some embodiments, the misfolded proteins are tau. In some embodiments, the misfolded proteins are a combination of the proteins described herein. VI. Methods of Treating a Disease

[0127] The present disclosure provides compounds for treating misfolded protein diseases. The present disclosure provides compounds for treating neurodegenerative diseases. The terms “neurodegenerative disease” and “neurological disease” may be used interchangeably. In certain embodiments, the neurodegenerative disease is a prion disease. In certain embodiments, the neurodegenerative disease is transmissible spongiform encephalopathies (such as Creutzfeldt– Jakob disease (CJD)), multiple system atrophy (MSA), Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis (ALS), Amyotrophic lateral sclerosis / Parkinsonism–dementia complex, anti-IgLON5-related tauopathy, Caribbean Parkinsonism, Chronic traumatic encephalopathy, Dementia with Lewy Bodies (DLB), Diffuse neurofibrillary tangles with calcification, Down syndrome, Familial British dementia, Familial Danish dementia, Niemann- Pick disease-type C, Non-Guamanian motor neuron disease with neurofibrillary tangles, Postencephalitic Parkinsonism, Primary age-related tauopathy, Progressive ataxia and palatal tremor, Tangle-only dementia, Familial frontotemporal dementia and Parkinsonism, Pick's disease, Argyrophilic grain disease, Corticobasal degeneration, Guadeloupean Parkinsonism, Globular glial tauopathy, Huntington's disease, Progressive supranuclear palsy, SLC9a-related Parkinsonism, or Tau astrogliopathy. In some embodiments, the neurodegenerative disease being treated is multiple system atrophy (MSA). In some embodiments, the neurodegenerative disease being treated is multiple system atrophy A strain (MSA-A). In some embodiments, the neurodegenerative disease being treated is multiple system atrophy B strain (MSA-B). In some embodiments, the neurodegenerative disease being treated is multiple system atrophy A strain (MSA-A) and multiple system atrophy B strain (MSA-B). In some embodiments, the neurodegenerative disease being treated is Parkinson’s disease. In some embodiments, theneurodegenerative disease being treated is Dementia with Lewy Bodies (DLB). In some embodiments, the neurodegenerative disease being treated is Alzheimer’s disease.

[0128] Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with memory loss, spatial disorientation, and gradual deterioration of intellectual capacity. Numerous pathological changes have been described in the postmortem brains of AD patients, including synaptic and neuronal loss, oxidative damage, activated inflammatory cells, amyloid plaques mainly composed of the ß‐amyloid peptide (Aß), and neurofibrillary tangles (NFTs) comprised of hyperphosphorylated and / or acetylated aggregates of the microtubule‐associated protein Tau, the latter two of which are considered the pathological hallmarks. For several reasons, research on the involvement of Aß in AD has progressed more quickly than that on Tau. The description of the “amyloid cascade hypothesis” based on the discovery of genetic mutations that cause autosomal familial AD centered the focus of research on Aß. Also, the biochemical studies of amyloid precursor protein (APP) and the presenilins have greatly enhanced the understanding of the molecular pathways leading to Aß generation. These studies favored the systematic development of disease‐modifying therapies based on Aß pathway.

[0129] Tau is a soluble protein that normally binds to microtubules and regulates their dynamic growing and shortening behaviors.^In Alzheimer’s disease (AD) and other neurodegenerative diseases, Tau dissociates from microtubules and self-associates to form abnormal fibrillar aggregates.^The distribution of these aberrant Tau structures is very well-correlated with neuronal cell death and the clinical progression of neurodegenerative diseases, suggesting an intimate link between aberrant Tau structure and neurodegeneration / dementia. Recent efforts to identify the neurotoxic species of Tau have shifted focus away from mature, fibrillar aggregates toward smaller oligomeric Tau species.^Studies with antibodies that selectively recognize Tau oligomers have demonstrated that these species are elevated in AD brains.^Cell to cell transmission of oligomeric Tau and other aberrant pre-fibrillar species may underlie the spread of Tau pathology,^and these species show promise as potential therapeutic targets.^A structural understanding of early Tau aggregates may lead to a deeper understanding of their neurotoxic mechanisms, as well as to the rational design of therapeutic drugs.

[0130] As a result of alternative RNA splicing there are 6 distinct isoforms of Tau that differ from one another depending upon the presence or absence of three inserts encoded by exons 2, 3 and 10 of the Tau gene. There are two important domains in each Tau isoform: the N-terminal projectiondomain determines the inter-microtubule spacing between bundled microtubules and also mediates interactions of microtubules with plasma membrane. Exons 2 and 3 each encode 29-residue acidic inserts located in the N-terminal projection domain. In contrast, the microtubule binding pseudo- repeat (MTBR) domain contains either three or four imperfect repeats (depending upon the presence or absence of exon 10 encoded sequences) and serves to bind microtubules directly and to regulate their dynamics. This same region of the protein makes up the core of fibrillar Tau aggregates, and Tau aggregation is accompanied by a regional transition from random coil to β- sheet structure. Fibrillar Tau aggregates have a cross-β-structure typical of amyloid fibrils. Finally, the 6 tau isoforms differ from one another not only structurally but also in terms of the relative expression levels and their rates and extents of fibril formation. Genetic evidence demonstrates unequivocally that functional differences must exist among the 6 different tau isoforms.

[0131] The amino acid sequence of the six human tau isoforms include the following: Isoform 1 (SEQ ID NO: 1):

[0132] MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKAEEAGIGDT PSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANAT RIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTP PKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIVYKPVDLSKVTSKCG SLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAK AKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL. Isoform 2 (SEQ ID NO: 2):

[0133] MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTE DGSEEPGSETSDAKSTPTAEAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKA KGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSP GTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTEN LKHQPGGGKVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIG SLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGS IDMVDSPQLATLADEVSASLAKQGL. Isoform 3 (SEQ ID NO: 3):

[0134] MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTE DGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSL EDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKS PSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIVYKPVDLSKVTSKCGSLG NIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKT DHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL. Isoform 4 (SEQ ID NO: 4):

[0135] MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKAEEAGIG DTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQAN ATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVR TPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKC GSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRV QSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSNV SSTGSIDMVDSPQLATLADEVSASLAKQGL. Isoform 5 (SEQ ID NO: 5):

[0136] MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTE DGSEEPGSETSDAKSTPTAEAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKA KGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSP GTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTEN LKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSL GNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAK TDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL. Isoform 6 (SEQ ID NO: 6):

[0137] MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTE DGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSL EDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIP AKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKS PSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKD NIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIG SLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGS IDMVDSPQLATLADEVSASLAKQGL. When specific amino acid numbers are referenced, the numbering refers to SEQ ID NO: 6 unless specifically indicated otherwise.

[0138] The classically described function of Tau is as a neuronal microtubule‐associated protein, mainly found in axons. Under physiological conditions, Tau exists as a highly soluble and natively unfolded protein that interacts with tubulin and promotes its assembly into microtubules, which helps to stabilize their structure. Recent evidence points to additional functions for Tau. For example, Tau phosphorylation enables neurons to escape from an acute apoptotic death through stabilizing ß‐catenin. Also, Tau exerts an essential role in the balance of microtubule‐dependent axonal transport of organelles and biomolecules by modulating the anterograde transport by kinesin and the dynein‐driven retrograde transport.

[0139] Soluble oligomeric species of amyloid-β (Aβ) are thought to be other key mediators of cognitive dysfunction in Alzheimer’s disease (AD) (M. Sheng, et al. (2012) Cold Spring Harb Perspect Biol 4; J. J. Palop et al. (2010) Nat Neurosci 13, 812). Neuritic plaques, a hallmark of Alzheimer’s Disease, are accumulations of aggregated, or oligomerized, amyloid beta (Aβ) peptides, including Aβ1-40 (Aβ40) and Aβ1-42 (Aβ42) that are derived from the processing of amyloid precursor protein (APP) by β- and γ-secretases. The vast majority of autosomal familial AD (FAD)-linked mutations are associated with increased levels of Aβ1-42. Transgenic mice expressing elevated levels of human Aβ experience memory loss and synaptic regression (M. Faizi et al., (2012) Brain Behav 2, 142; C. Perez-Cruz et al., (2011) J Neurosci 31, 3926; S. Knafo et al., (2009) Cereb Cortex 19, 586; M. Cisse et al., (2011) Nature 469, 47). Aβ production is thought to be activity-dependent (F. Kamenetz et al., (2003) Neuron 37, 925; J. Wu et al., (2011) Cell 147, 615), and even in wild type mice addition of soluble Aβ oligomers to hippocampal slices or cultures induces loss of long-term 2 potentiation (LTP), increases long-term depression (LTD) and decreases dendritic spine density (G. M. Shankar et al., (2007) J Neurosci 27, 2866; G. M. Shankar et al., (2008) Nat Med 14, 837; H. Hsieh et al., (2006) Neuron 52, 831). There are currently no effective therapies for arresting or reversing the impairment of cognitive function that characterizes AD.

[0140] Aβ oligomer levels are also elevated by about 200-300% in Down syndrome (DS) patients throughout life (reviewed in Head and Lott (2004) Curr Opin Neurol 17(2):95-100). The use of a γ-secretase inhibitor to lower β-amyloid levels in young mice that model DS corrected learning deficits characteristic of these mice, suggesting that therapies that interfere with Aβ oligomers will improve cognitive function in young DS patients as well (Netzer WJ, et al. (2010) PLoS One 5:e10943).

[0141] By Aβ, or “amyloid beta”, or “amyloid β”, it is meant a peptide of 36-43 amino acids that is derived from the processing of amyloid precursor protein (APP) by β- and γ-secretases. By “Aβ oligomers”, “amyloid β oligomers”, or “amyloid beta oligomers” it is meant aggregates of Aβ peptide. Aβ is the main component of deposits, called amyloid plaques, found in the brains of patients with Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA); it also associated with retinal ganglion cells in patients having glaucoma. Two major variants, Aβ1-40(“Aβ40”) (DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVV) (SEQ ID NO: 7) and Aβ1-42(“Aβ42”) (DAEFRHDSGYEVHHQKLVFAAEDVGSNKGAIIGLMVGGVVIA) (SEQ ID NO: 8), are produced by alternative carboxy-terminal truncation of APP (Selkoe et al. (1988) Proc. Natl. Acad. Sci. USA 85:7341-7345; Selkoe, (1993) Trends Neurosci 16:403-409). Aβ1-42is the more fibrillogenic and more abundant of the two peptides in amyloid deposits of both AD and CAA. Derivatives of the above peptides comprising a naturally occurring substitution, e.g. Aβ1-42 H13R, Aβ1-42V18A, Aβ1-42F19P, Aβ1-42E22D, Aβ1-42E22V, Aβ1-42E22A, Aβ1-42D23A, Aβ1-42G25A, Aβ1-42 N27A, Aβ1-42 K28A, Aβ1-42 G29A, Aβ1-42 I31A, Aβ1-42 G37A, the English Mutation, the Iowa Mutation, the Tottori-Japanese Mutation, the Flemish Mutation, the Arctic Mutation, the Italian Mutation, etc. In addition to the amyloid deposits that may occur in, for example, CNS tissue, amyloid deposition may occur in the vascular walls (Hardy (1997); Haan et al. (1990); Vinters (1987); Itoh et al. (1993); Yamada et al. (1993); Greenberg et al. (1993); Levy et al. (1990)). These vascular lesions are the hallmark of CAA, which can exist in the absence of AD.

[0142] Aβ oligomers are known in the art to have a number of effects on cells. These include, for example, reducing cell viability, and reducing synaptic plasticity, promoting synapse loss in neurons. By a “synapse” it is meant the structure on a neuron that permits the neuron to pass an electrical or chemical signal to another cell. By “synaptic plasticity” it is meant the ability of the synapse to change in strength, i.e. to become stronger or weaker, in response to either use or disuse, respectively, of transmission over that synaptic pathway. Such a change in strength is typically evident by one or more of the following structural changes: a change in the number of presynaptic vesicles, a change in the amount of neurotransmitter loaded per vesicle, a change in the number of dendritic spines, and / or a change in the number of neurotransmitter receptors positioned on the postsynaptic neuron. Reductions or enhancements in synaptic plasticity may be observed by assessing the ability of a postsynaptic neuron to evoke a long-term enhancement (“long term potentiation”, LTP) or long-term depression (LTD) in the activity of a presynaptic neuron, and / or by assaying for the subsequent changes in synaptic strength, e.g. by detecting oneor more of the above-mentioned structural changes. By “enhanced synaptic plasticity” it is meant greater synaptic strengthening (LTP), more stable synapses and a failure to remove synapses and the spines that carry synapses. By “reduced synaptic plasticity” it is meant enhanced synaptic weakening (LTD), less stable synapses, and fewer spines and synapses. By “synapse loss” it is meant a decrease in the number of synapses, for example, a loss in the connection between two neurons or, in instances in which multiple synapses exist between two neurons, in the loss of one or more of these synapses. As is well known in the art, synaptic activity and the change in the strength and number of synapses is central to almost all neurobiological processes, including learning, memory, and neuronal development. In further describing aspects of the invention, the following description focuses on the effects of Aβ oligomers on neurons. However, the subject methods and compositions also find use in inhibiting the effects of Aβ oligomers on other types of cells as well, for example, microglia.

[0143] Parkinson's disease (PD) is a major neurodegenerative disease that primarily affects motor systems but can also be accompanied by cognitive and behavioral problems. There is a widespread neuron degeneration in PD brains, affecting up to 70% of dopaminergic neurons in the substantia nigra (SN) by the time of death. The neuropathological hallmarks of PD include Lewy bodies (LBs) in the SN, brainstem, and rostral and forebrain regions and the selective deletion of dopaminergic neurons in the SN. Cell-death induced damage in SN may be the source of patient movement disorders. Although the causes of this cell death are generally unclear, researchers have observed an enrichment alpha-synuclein in neuronal Lewy bodies. Tau aggregates can also be observed in PD, for example in cases with LKKR2 mutations. Tau has also been associated with increased alpha synuclein deposits. Immunohistochemistry with anti-tau antibodies showed high level of NFTs in the substantia nigra from post-mortem human brain tissue. Researchers have also reported that tauopathies in PD and PD with dementia (PDD) were only observed in DA neurons of the nigrostriatal region, which contrasts with the wide-spread expression pattern of tau throughout the entire brain in AD.

[0144] In Parkinson disease, pigmented neurons of the substantia nigra, locus ceruleus, and other brain stem dopaminergic cell groups degenerate. Loss of substantia nigra neurons results in depletion of dopamine in the dorsal aspect of the putamen (part of the basal ganglia) and causes many of the motor manifestations of Parkinson disease.

[0145] A genetic predisposition is likely in at least in some cases of Parkinson disease. A genetic association with polymorphisms surrounding the tau gene is found in Parkinson disease and Alzheimer’s dementia. About 10% of PD patients have a family history of Parkinson disease. Several abnormal genes have been identified. Inheritance is autosomal dominant for some genes and autosomal recessive for others. Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most prevalent mutation in sporadic cases of Parkinson disease in patients, and it is the most prevalent autosomal dominant mutation of the inherited forms of the disease. Recent data shows that tau is particularly important in PD patient with LRRK2 mutation, thus the therapy proposed here could be particularly effective.

[0146] Diagnosis of Parkinson disease is clinical. Parkinson disease is suspected in patients with characteristic unilateral resting tremor, decreased movement, or rigidity. During finger-to-nose coordination testing, the tremor disappears (or attenuates) in the limb being tested. During the neurologic examination, patients cannot perform rapidly alternating or rapid successive movements well. Sensation and strength are usually normal. Reflexes are normal but may be difficult to elicit because of marked tremor or rigidity. Slowed and decreased movement due to Parkinson disease must be differentiated from decreased movement and spasticity due to lesions of the corticospinal tracts. To help distinguish Parkinson disease from secondary or atypical parkinsonism, clinicians often test responsiveness to levodopa. A large, sustained response strongly supports Parkinson disease.

[0147] Amyotrophic lateral sclerosis is a group of rare neurodegenerative diseases that mainly involve the nerve cells (neurons) responsible for controlling voluntary muscle movement. It is characterized by steady, relentless, progressive degeneration of corticospinal tracts, anterior horn cells, bulbar motor nuclei, or a combination. Symptoms vary in severity and may include muscle weakness and atrophy, fasciculations, emotional lability, and respiratory muscle weakness. Diagnosis involves nerve conduction studies, electromyography, and exclusion of other disorders via MRI and laboratory tests. Current treatment is supportive. The majority of ALS cases (90 percent or more) are considered sporadic.

[0148] Most patients with ALS present with random, asymmetric symptoms, consisting of cramps, weakness, and muscle atrophy of the hands (most commonly) or feet. Weakness progresses to the forearms, shoulders, and lower limbs. Fasciculations, spasticity, hyperactive deep tendon reflexes, extensor plantar reflexes, clumsiness, stiffness of movement, weight loss,fatigue, and difficulty controlling facial expression and tongue movements soon follow. Other symptoms include hoarseness, dysphagia, and slurred speech; because swallowing is difficult, salivation appears to increase, and patients tend to choke on liquids. Late in the disorder, a pseudobulbar affect occurs, with inappropriate, involuntary, and uncontrollable excesses of laughter or crying. Sensory systems, consciousness, cognition, voluntary eye movements, sexual function, and urinary and anal sphincters are usually spared. Death is usually caused by failure of the respiratory muscles; 50% of patients die within 3 yr of onset, 20% live 5 yr, and 10% live 10 yr. Survival for > 30 yr is rare.

[0149] MSA is a sporadic synucleinopathy of adult onset, with symptoms of parkinsonism, cerebellar ataxia and autonomic failure. Cases of MSA are classified as MSA-P, which show predominant parkinsonism caused by striatonigral degeneration, and MSA-C, which show cerebellar ataxia associated with olivopontocerebellar atrophy. Autonomic dysfunction is common to both subtypes. In neuropathological terms, MSA is defined by regional nerve cell loss and the presence of abundant filamentous α-synuclein inclusions in oligodendrocytes: glial cytoplasmic inclusions, known as Papp–Lantos bodies. Smaller numbers of α-synuclein inclusions are also present in nerve cells. The mean duration of the disease is 6–10 years, but survival times of 18–20 years have been reported. The late appearance of autonomic dysfunction correlates with prolonged survival.

[0150] Synucleinopathies are defined pathologically by the presence of α-Syn (α-synuclein or alpha synuclein) aggregates. Lewy body diseases consist of synucleinopathies with pathologic Lewy bodies and Lewy neurites which clinically manifest as PD, Parkinson disease dementia (PDD), or dementia with Lewy bodies (DLB). α-Syn aggregates in the form of glial cytoplasmic inclusions (GCIs) are characteristic of MSA. It has been shown previously that fibrils of α-Syn exist in PD and are expected to exist in other synucleinopathies. α-Syn fibrils formed in vitro also induce α-Syn inclusions when injected into model animals.

[0151] α-Syn is a 140 amino acid protein encoded by the gene synuclein alpha (SNCA) whose normal function is thought to be related to synaptic vesicle transmission. Residues 1–60 compose a lysine-rich N-terminal region with KTK lipid-binding repeats for vesicle binding. Familial SNCA gene mutations are found in this N-terminal region, including: A30P, A30G, E46K, G51D, A53E, A53V, A53T. Residues 61–95 comprise the non-amyloid b component (NAC) region that has been shown as essential for aggregation. Small peptides derived from this region were easilyable to aggregate. Furthermore, b-synuclein, which is similar to α-Syn but lacks amino acids 71– 82 in the NAC, has not been found to aggregate like α-Syn. Removing this region from α-Syn also prevents aggregation in vitro further supporting the importance of this region in aggregation. The amino acid sequence of α-Syn is MDVFMKGLSKAKEGVVAAAEKTKQGVAEAAGKTKEGVLYVGSKTKEGVVHGVATVA EKTKEQVTNVGGAVVTGVTAVAQKTVEGAGSIAAATGFVKKDQLGKNEEGAPQEGILE DMPVDPDNEAYEMPSEEGYQDYEPEA (SEQ ID NO: 9).

[0152] Clinically, PD is the second most common neurodegenerative disorder affecting 2%–3% individuals 65 and older, while DLB is thought to be the underlying cause of 10%–15% of all cases of dementia. PD is characterized by neuronal loss in the substantia nigra that causes striatal dopamine deficiency and leads to bradykinesia and other motor symptoms. PD can, however, progress to PDD, and DLB can progress to motor dysfunction similar to that seen in PD. PD, PDD, and DLB are generally considered to be on the same disease spectrum with similarities clinically and pathologically including α-Syn aggregates in the form of Lewy bodies and Lewy neurites. MSA is distinct clinically and pathologically from PD and DLB, with a lower prevalence in the general population. MSA is of sporadic onset and is characterized by parkinsonism, cerebellar ataxia, and / or autonomic failure. Similar to PD and DLB there are neuronal α-Syn inclusions and neuronal cell loss in MSA, however, α-Syn inclusions are more prevalent in oligodendrocytes as GCIs.

[0153] As is seen with tau fibrils, the structure of α-Syn fibrils varies among disease states. It was also shown that GCIs from MSA are 103-times more potent seeds of aggregation than fibrils derived from PD Lewy bodies. Recent characterization of amplified patient-derived fibrils suggests that PD and MSA fibrils share many characteristics, but MSA fibrils are more potent inducers of motor deficits, neurodegeneration, and α-Syn pathology. Although DLB and PD are thought to be on the same disease spectrum, DLB fibrils did not yield the significant neuropathology seen with PD fibrils. Though still recent, these results may suggest that PD fibrils and DLB fibrils contained in Lewy bodies may be less similar than previously thought.

[0154] Familial SNCA mutations disrupt the stabilizing interactions of the known wild-type α- Syn in vitro fold conformations. It has been shown that under the same conditions A53T, A53E, G51D, and E46K mutants of α-Syn form fibrils with distinct morphologies from wild-type fibrils.The E46K mutant α-Syn is toxic to neuronal cells. These fibrils were less stable and easily fragmented, but were also a better seed than wild-type fibrils, potentially indicating that toxicity is related to seeding rather than fibrils stability. These in vitro data suggest that mutations may affect fibril structure, stability, and effect on disease progression.

[0155] G51D and A53E mutations can cause mixed MSA and PD pathology in patients. G51 lies at the protofilament interface of the ex vivo MSA fibrils near K43, K45, and H50. Structurally, there may be room to accommodate the switch from glycine to aspartic acid; however, this switch would reduce the positive charge of the central cavity. It is difficult to speculate how a change in charge or amino acid side chain would affect the central cavity and the in vivo fibrils as a whole. However, it could change the nonproteinaceous compounds within the central cavity or potentially disrupt the fibril stability or even enhance fibril stability to make fibrils more stable and more pathogenic than wild-type α-Syn fibrils leading to mixed MSA and PD pathology.

[0156] Some of the in vitro fibrils imaged may be able to explain how some of the familial mutations pack in vivo and the ex vivo structures solved may be able to accommodate some of the familial SNCA mutations. However, additional ex vivo α-Syn structures of mutant fibrils will need to be solved in order to confirm the actual structure. The structure of fibrils from patients with familial mutations will be important to understanding why those mutations specifically cause disease and potentially lead to breakthroughs in understanding development and progression of sporadic disease as well.

[0157] In a certain aspect, the present disclosure provides methods of treating a disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or a hydrate or a solvate thereof, thereby treating the disease in the subject. In an exemplary embodiment, the disease being treated is a neurodegenerative disease. In an exemplary embodiment, the neurodegenerative disease being treated is a member selected from the group consisting of transmissible spongiform encephalopathies (such as Creutzfeldt–Jakob disease (CJD)), multiple system atrophy (MSA), Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis (ALS), Amyotrophic lateral sclerosis / Parkinsonism–dementia complex, anti-IgLON5-related tauopathy, Caribbean Parkinsonism, Chronic traumatic encephalopathy, Dementia with Lewy Bodies (DLB), Diffuse neurofibrillary tangles with calcification, Down syndrome, Familial British dementia, Familial Danish dementia, Niemann-Pick disease-type C, Non-Guamanian motor neuron disease withneurofibrillary tangles, Postencephalitic Parkinsonism, Primary age-related tauopathy, Progressive ataxia and palatal tremor, Tangle-only dementia, Familial frontotemporal dementia and Parkinsonism, Pick's disease, Argyrophilic grain disease, Corticobasal degeneration, Guadeloupean Parkinsonism, Globular glial tauopathy, Huntington's disease, Progressive supranuclear palsy, SLC9a-related Parkinsonism, or Tau astrogliopathy. In some embodiments, the neurodegenerative disease is multiple system atrophy (MSA). In some embodiments, the neurodegenerative disease is Parkinson’s disease. In some embodiments, the neurodegenerative disease is Dementia with Lewy Bodies (DLB). In some embodiments, the neurodegenerative disease is Alzheimer’s disease. In some embodiments, the administration is through oral administration. In some embodiments the administration is through parenteral depot. In some embodiments, the administration is intravenous. In some embodiments, the contacting involves administration of an effective dose of the compound to a subject having or is suspected to have a neurodegenerative disease. In some embodiment, a therapeutically effective dose is a dose sufficient to alleviate symptoms associated with the disease. The term therapeutically effective dose can also refer to the amount of an agent that is sufficient to effect beneficial or desired results. The therapeutically effective dose will vary depending upon the subject and disease being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The specific dose will vary depending on the particular compound chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, and the physical delivery system in which it is carried. The therapeutically effective dose is any that halts, reverses, or alleviates the disease.

[0158] The halting, reversal or alleviation of the disease may be determined by evaluating a subject having or suspected to have a disease before and after the contacting. The halting, reversal, or alleviation of the disease may be determined by determining if the propagation of misfolded proteins associated with a neurodegenerative disease is inhibited by, for example, using the detection methods disclosed herein.

[0159] In some embodiments, the compound is as described in Section III herein. In some embodiments, the compound is according to any one of the compounds in FIG.1. In some embodiments, the compound is as described in the Examples herein.VII. Methods of Detecting a Disease

[0160] The present disclosure provides methods for detecting a disease in a mammalian tissue, comprising contacting the mammalian tissue with a labeled compound (such as a radiolabeled compound), and determining the binding of the labeled compound (such as a radiolabeled compound) to the mammalian tissue; thereby detecting the disease in the mammalian tissue. In an exemplary embodiment, the disease is a neurodegenerative disease. In an exemplary embodiment, the disease is a neurodegenerative disease described herein. In an exemplary embodiment, the disease is associated with misfolded proteins. In an exemplary embodiment, the disease is a neurodegenerative disease. In an exemplary embodiment, the neurodegenerative disease is selected from the group consisting of Multiple System Atrophy, Parkinson’s Disease, and Alzheimer’s Disease. In an exemplary embodiment, the mammalian tissue has been separated from the mammal. In an exemplary embodiment, the mammalian tissue is brain tissue. In an exemplary embodiment, the mammalian tissue is human tissue. In an exemplary embodiment, the mammalian tissue is human brain tissue, and the disease is a neurodegenerative disease.

[0161] The present disclosure also provides methods for detecting a neurodegenerative disease in mammalian brain tissue comprising contacting the mammalian brain tissue with a labeled compound (such as a radiolabeled compound), determining the binding of the labeled compound (such as a radiolabeled compound) to the mammalian brain tissue; and thereby detecting the neurodegenerative disease.

[0162] The contacting may be any form of contacting that results in binding of the labeled compound (such as a radiolabeled compound) to the brain tissue. In some embodiments, the contacting is performed by administering the labeled compound (such as a radiolabeled compound) to a subject having or predicted to have the neurodegenerative disease. In some embodiments, the administering is performed by administering the labeled compound (such as a radiolabeled compound) to a subject having or predicted to have the neurodegenerative disease. In some embodiments, the administration is intravenous. In some embodiments, the contacting involves direct administration of the labeled compound (such as a radiolabeled compound) to the isolated brain tissue.

[0163] The natural environment may be any environment in which misfolded proteins associated with a neurodegenerative disease are found. In some embodiments, the natural environment isbrain tissue. In some embodiments, the brain tissue is mammalian brain tissue. In some embodiments, the brain tissue is human brain tissue.

[0164] Brain tissues of the present disclosure may be any brain tissue deemed useful. In some embodiments, the brain tissue has or is suspected to have a neurodegenerative disease. In some embodiments, the brain tissue is human brain tissue that has or is suspected to have a neurodegenerative disease. In an exemplary embodiment, the neurodegenerative disease being detected is a member selected from the group consisting of transmissible spongiform encephalopathies (such as Creutzfeldt–Jakob disease (CJD)), multiple system atrophy (MSA), Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis (ALS), Amyotrophic lateral sclerosis / Parkinsonism–dementia complex, anti-IgLON5-related tauopathy, Caribbean Parkinsonism, Chronic traumatic encephalopathy, Dementia with Lewy Bodies (DLB), Diffuse neurofibrillary tangles with calcification, Down syndrome, Familial British dementia, Familial Danish dementia, Niemann-Pick disease-type C, Non-Guamanian motor neuron disease with neurofibrillary tangles, Postencephalitic Parkinsonism, Primary age-related tauopathy, Progressive ataxia and palatal tremor, Tangle-only dementia, Familial frontotemporal dementia and Parkinsonism, Pick's disease, Argyrophilic grain disease, Corticobasal degeneration, Guadeloupean Parkinsonism, Globular glial tauopathy, Huntington's disease, Progressive supranuclear palsy, SLC9a-related Parkinsonism, or Tau astrogliopathy. In some embodiments, the neurodegenerative disease being detected is multiple system atrophy (MSA). In some embodiments, the neurodegenerative disease being detected is multiple system atrophy A strain (MSA-A). In some embodiments, the neurodegenerative disease being detected is multiple system atrophy B strain (MSA-B). In some embodiments, the neurodegenerative disease being detected is multiple system atrophy A strain (MSA-A) and multiple system atrophy B strain (MSA-B). In some embodiments, the neurodegenerative disease being detected is Parkinson’s disease. In some embodiments, the neurodegenerative disease being detected is Dementia with Lewy Bodies (DLB). In some embodiments, the neurodegenerative disease being detected is Alzheimer’s disease.

[0165] Detecting a neurodegenerative disease of the present disclosure involves contacting brain tissue with a labeled compound (such as a radiolabeled compound). The label may be one that is detectable using positron emission tomography (PET). Detectable labels include, without limitation, [2H], [3H], [11C], [18F], [13N], etc. Detectable labels that are detectable using PET areknown in the art and have been described by, for example, Sun et al (Acc Chem Res.2015 Feb 17;48(2):286-94) which is specifically incorporated by reference herein.

[0166] In some embodiments, the labeled compound is a molecule as described in Section III herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the radiolabeled compound is a molecule as described in Section III herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the labeled compound is a molecule according to any one of compounds in FIG.1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the radiolabeled compound is a molecule according to any one of compounds in FIG.1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the labeled compound is as described in the Examples herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the radiolabeled compound is as described in the Examples herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the labeled compound is any of the compounds discussed herein that is detectably labeled, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the radiolabeled compound is any of the compounds discussed herein that is detectably labeled, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0167] Determining the binding of the labeled compound (such as a radiolabeled compound) involves detecting the presence of the labeled compound (such as a radiolabeled compound) in the mammalian tissue. The determining may be any method that is able to visualize the presence of the labeled compound (such as a radiolabeled compound) in the mammalian tissue. The determining includes, without limitation, PET, autoradiography, imaging mass spectrometry, magnetic resonance imaging, etc. In some embodiments, the determining is performed using PET. In some embodiments, the determining is performed using imaging mass spectrometry. In some embodiments, the determining is performed using magnetic resonance imaging. In some embodiments, the determining is performed using autoradiography. When the brain tissue has misfolded proteins associated with a neurodegenerative disease, the labeled compound (such as a radiolabeled compound) will be bound to the misfolded proteins in the brain tissue thereby determining the neurodegenerative disease in the brain tissue. In some embodiment, when the brain tissue has misfolded proteins associated with a neurodegenerative disease, the labeledcompound (such as a radiolabeled compound) will co-localize with the misfolded proteins in the brain tissue thereby determining the neurodegenerative disease in the brain tissue. EXAMPLES

[0168] The following examples are put forth to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric. EXAMPLE 1 Synthesis of Compound 1.1-[5-(4-chloro-3-fluorophenyl)-2-(1-methyl-1H-indazol-5-yl)-1,3- oxazol-4-yl]-4-cyclopropyl-2(1H)-pyrimidinone: (E)-1-cyclopropyl-3-(dimethylamino)prop-2-en-1-one

[0169] 1-Cyclopropylethan-1-one (200 g, 236 mL, 1 Eq, 2.38 mol) was combined with DMF- DMA (425 g, 474 mL, 1.5 Eq, 3.57 mol) and the mixture was added to a 1 L autoclave. The resulting reaction mixture was stirred at 110 °C for 16 hours. The crude reaction was cooled to room temperature and concentrated under vacuum to afford (E)-1-cyclopropyl-3- (dimethylamino)prop-2-en-1-one (300 g, 2.16 mol, 90.6 %) as a brown liquid. This crude compound used for next step without purification. 4-cyclopropylpyrimidin-2(1H)-one

[0170] (E)-1-cyclopropyl-3-(dimethylamino)prop-2-en-1-one (300 g, 1 Eq, 2.16 mol) was combined with ethanol (500 mL), urea (168 g, 1.3 Eq, 2.80 mol), and sodium methoxide (233 g, 2.0 Eq, 4.31 mol) in a 1 L autoclave and the resulting reaction mixture was stirred at 90 °C for 16 hours. The reaction mixture was filtered, and the filtrate was neutralized with formic acid at 0 °C. The resulting solution was concentrated under reduced pressure to give crude product. The crude material was purified by normal phase chromatography (200 g silica gel, 5-15% MeOH in DCM).The fractions containing product were combined and evaporated. The resulting solid was triturated with IPA and collected by vacuum filtration. The material was then washed with IPA and dried under reduced pressure to afford 4-cyclopropylpyrimidin-2(1H)-one (120 g, 881 mmol, 40.9 %) as a solid.

[0171] (+esi)[M+H]=137.1+

[0172] 1H NMR (400 MHz, DMSO) δ 11.52 (s, 1H), 7.75 (d, J = 6.3 Hz, 1H), 6.29 (d, J = 6.3 Hz, 1H), 1.92 (tt, J = 7.7, 4.9 Hz, 1H), 1.07 – 0.92 (m, 4H).1-(4-chloro-3-fluorophenyl)-2,2-dihydroxyethan-1-one

[0173] To a stirred solution of 1-(4-chloro-3-fluorophenyl)ethan-1-one (100 g, 1 Eq, 579 mmol) in DMSO (1000 mL) was added hydrobromic acid (141 g, 94.4 mL, 3.0 Eq, 1.74 mol, 48% in water). The reaction mixture was stirred at 25 °C for 2 hours followed by stirring at 50 °C for 16 hours. The reaction mixture was cooled to 0 °C and ice-cold water was added. The solid precipitate was collected by vacuum filtration, washed with hexanes, and dried at 50 °C to afford 1-(4-chloro-3- fluorophenyl)-2,2-dihydroxyethan-1-one (75.0 g, 0.370 mol, 63 %) as a solid.

[0174] 1H NMR (400 MHz, DMSO) δ 8.00 (dd, J = 10.2, 1.9 Hz, 1H), 7.97 – 7.84 (m, 1H), 7.83 – 7.68 (m, 1H), 6.97 (d, J = 6.7 Hz, 2H), 5.62 (d, J = 5.5 Hz, 1H). N-(2-(4-chloro-3-fluorophenyl)-1-hydroxy-2-oxoethyl)formamide

[0175] To a stirred solution of 1-(4-chloro-3-fluorophenyl)-2,2-dihydroxyethan-1-one (75.0 g, 1 Eq, 367 mmol) in 1,4-Dioxane (750 mL) was added formamide (66.0 g, 58.4 mL, 4.0 Eq, 1.47 mol) and the resulting reaction mixture was heated at 90 °C for 2 h. The reaction was allowed to cool to room temperature and the dioxane was removed under reduced pressure. The resulting residue was poured into ice-cold water and the obtained precipitate was collected by vacuumfiltration. The solid was dissolved in ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The obtained solid was triturated with MTBE (100 mL), filtered, washed with MTBE, and dried under reduced pressure to afford N-(2-(4-chloro-3- fluorophenyl)-1-hydroxy-2-oxoethyl)formamide (65.0 g, 0.280 mol, 77%) as a solid.

[0176] 1H NMR (400 MHz, DMSO) δ 8.99 (d, J = 8.6 Hz, 1H), 8.12 – 8.05 (m, 1H), 7.92 (dd, J = 10.0, 1.8 Hz, 1H), 7.88 – 7.75 (m, 2H), 6.87 (dd, J = 7.0, 5.2 Hz, 1H), 6.32 (t, J = 7.9 Hz, 1H). N-(1-chloro-2-(4-chloro-3-fluorophenyl)-2-oxoethyl)formamide

[0177] To a stirred solution of N-(2-(4-chloro-3-fluorophenyl)-1-hydroxy-2-oxoethyl)formamide (10.0 g, 1 Eq, 43.2 mmol) in dichloromethane (100 mL) was added phosphorus pentachloride (10.8 g, 1.2 Eq, 51.8 mmol) under nitrogen at 0 °C and the reaction mixture was stirred at 0 °C. The reaction mixture was then allowed to warm to room temperature and stirred at temperature for 3 hours. The solvent was removed under reduced pressure to give crude solid compound, which was then triturated with hexanes, filtered, and dried under reduced pressure to afford N-(1-chloro- 2-(4-chloro-3-fluorophenyl)-2-oxoethyl)formamide (10.2 g, 40.8 mmol, 94.5 %) as a solid. This compound was directly used in the next step without characterization due to its instability. N-(2-(4-chloro-3-fluorophenyl)-1-(4-cyclopropyl-2-oxopyrimidin-1(2H)-yl)-2-oxoethyl)formamide

[0178] To a solution of 4-cyclopropylpyrimidin-2(1H)-one (5.00 g, 1 Eq, 36.7 mmol) in N,N- dimethylformamide (50 mL) and triethylamine (11.2 g, 15.4 mL, 3.0 Eq, 110 mmol) was added a solution of N-(1-chloro-2-(4-chloro-3-fluorophenyl)-2-oxoethyl)formamide (10.1 g, 1.1 Eq, 40.4 mmol) in DMF (30 mL) at room temperature under nitrogen. The resulting reaction mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture which was then extracted with ethyl acetate (3x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was triturated with diethyl ether, collected by vacuum filtration, washed with diethyl ether, and dried under reduced pressure to afford N-(2-(4-chloro-3-fluorophenyl)-1-(4- cyclopropyl-2-oxopyrimidin-1(2H)-yl)-2-oxoethyl)formamide (7.30 g, 21.0 mmol, 57%) as a solid.

[0179] 1H NMR (400 MHz, DMSO-d6) ppm 9.62 (d, J = 8.16 Hz, 1 H), 8.22 (s, 1 H), 8.17 (d, J = 6.97 Hz, 1H), 7.77 - 7.86 (m, 2 H), 7.68 (dd, J = 8.42, 1.84 Hz, 1 H), 7.21 (d, J = 8.16 Hz, 1 H), 6.57 (d, J = 6.97 Hz, 1 H), 1.93 - 2.01 (m, 1 H), 1.02 - 1.10 (m, 2 H), 0.95 - 1.01 (m, 2 H).1-(5-(4-chloro-3-fluorophenyl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one

[0180] N-(2-(4-chloro-3-fluorophenyl)-1-(4-cyclopropyl-2-oxopyrimidin-1(2H)-yl)-2- oxoethyl)formamide (3.50 g, 1 Eq, 10.0 mmol) was suspended in Eaton’s reagent (7.5% phosphorus(V) oxide in methanesulfonic acid, 36.0 g, 24.0 mL, 15 Eq, 0.150 mol) and the mixture was heated to 60 °C for 2 hours. The reaction mixture was poured into ice and basified with solid sodium bicarbonate. The mixture was then extracted with DCM (3 x 100 mL) and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give crude product. This material was then purified by normal phase chromatography (45 g silica gel, 1-2% MeOH in chloroform). The fractions containing product were evaporated to give a crude solid. This material was then triturated with MTBE, collected by vacuum filtration, and dried under reduced pressure to afford 1-(5-(4-chloro-3-fluorophenyl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one (650 mg, 1.96 mmol, 20%) as a solid.

[0181] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.69 - 8.73 (m, 1 H), 8.08 (d, J = 6.97 Hz, 1 H), 7.71 - 7.77 (m, 1 H), 7.43 - 7.49 (m, 1 H), 7.22 (dt, J = 8.42, 0.85 Hz, 1 H), 6.63 - 6.68 (m, 1 H) 2.06 - 2.16 (m, 1 H), 1.13 - 1.18 (m, 4 H).

[0182] (+esi)[M+H]=332.2 1-[5-(4-chloro-3-fluorophenyl)-2-(1-methyl-1H-indazol-5-yl)-1,3-oxazol-4-yl]-4-cyclopropyl- 2(1H)-pyrimidinone [Compound 1]

[0183] To a resealable vial were added 1-(5-(4-chloro-3-fluorophenyl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one (0.050 g, 1 Eq, 0.15 mmol), 5-bromo-1-methyl-1H-indazole (48 mg, 1.5 Eq, 0.23 mmol), pivalic acid (6.2 mg, 0.40 Eq, 60 μmol), Pd(OAc)2(3.4 mg, 0.10 Eq, 15 μmol), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphane (14 mg, 0.20 Eq, 30 μmol), and K2CO3 (62 mg, 3 Eq, 0.45 mmol). Toluene (1.5 mL) was added, and the vial was capped, purged with nitrogen for 5 minutes, and heated at 110 °C for 16 hours. The crude mixture was concentrated onto silica gel and directly purified by normal phase chromatography (12 g silica gel column, 0-5% MeOH / DCM) to afford 1-[5-(4-chloro-3-fluorophenyl)-2-(1-methyl-1H- indazol-5-yl)-1,3-oxazol-4-yl]-4-cyclopropyl-2(1H)-pyrimidinone (28.9 mg, 62.6 μmol, 42%) as a solid.

[0184] LCMS (M+H)+ = 462.0. LCAP % at 280 nm = 91.6%.

[0185] 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.16 – 8.09 (m, 2H), 7.66 (d, J = 6.9 Hz, 1H), 7.58 – 7.39 (m, 4H), 6.46 (dd, J = 12.3, 6.9 Hz, 1H), 4.16 (s, 3H), 2.00 (tt, J = 8.2, 4.5 Hz, 1H), 1.46 (p, J = 4.2 Hz, 2H), 1.29 – 1.19 (m, 2H).

[0186] The following compounds were prepared in an analogous manner from the appropriate starting materials using similar procedures. Compound (M+H)+Calc. Mass 2 422.0 421.859 3 422.0 421.859 4 422.9 422.847 5 422.9 422.847 6 423.0 422.847 7 423.9 423.835 8 424.2 423.835 9 436.0 435.886 10 436.9 436.874 11 436.9 436.874 12 437.3 436.874 13 437.3 436.874 14 438.1 437.862 15 438.1 437.862 16 438.8 438.846 17 439.1 438.846 18 439.8 439.849 19 439.9 439.849 20 439.9 439.849 21 440.0 439.849 22 440.1 439.834 23 441.0 440.837 24 441.0 440.837 25 441.1 440.837 26 441.1 440.837 27 441.1 440.837 28 442.0 442.277 29 444.0 443.265 30 448.0 447.857 31 448.0 447.857 32 448.0 447.857 33 449.0 448.885 34 449.0 448.845 35 449.0 448.84536 449.0 448.845 37 449.0 448.841 38 449.0 448.845 39 449.0 448.845 40 449.0 448.845 41 449.0 448.845 42 449.1 448.885 43 449.1 448.885 44 449.1 448.885 45 449.3 448.885 46 449.9 449.873 47 450.0 449.869 48 450.0 449.869 49 451.0 450.901 50 451.0 450.857 51 457.0 457.292 52 457.0 457.292 53 457.2 457.292 54 458.0 457.292 55 458.9 458.88 56 459.0 458.88 57 459.0 458.88 58 459.0 458.827 59 459.0 458.88 60 459.1 458.88 61 460.0 459.868 62 461.0 461.884 63 462.0 461.884 64 462.0 461.884 65 462.0 461.884 66 462.0 461.884 67 462.0 461.884 68 462.0 461.884 69 462.0 461.884 70 463.0 462.912 71 463.0 462.872 72 463.0 462.872 73 463.0 462.872 74 463.0 462.872 75 463.0 462.872 76 463.0 462.872 77 463.1 462.86878 463.0 462.872 79 463.0 462.872 80 466.0 465.847 81 468.0 467.844 82 473.0 472.907 83 473.0 472.907 84 473.0 472.907 85 473.0 472.907 86 473.0 472.907 87 473.0 472.907 88 473.1 472.854 89 473.1 472.907 90 475.0 474.826 91 476.0 475.911 92 476.8 476.817 93 476.8 476.817 94 477.0 476.87 95 477.0 477.71 96 477.0 476.87 97 477.8 477.805 98 488.0 487.922 99 489.0 488.91 100 489.3 488.906 101 491.0 490.844 102 527.0 526.877 Synthesis of compound 241-(5-(4-chloro-3-fluorophenyl)-2-(6-fluoro-4-methylpyridin-2-yl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one:

[0187] To a resealable vial were added 1-(5-(4-chloro-3-fluorophenyl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one (0.030 g, 1 Eq, 0.090 mmol), 2-bromo-6-fluoro-4- methylpyridine (21 mg, 1.2 Eq, 0.11 mmol), bromo(1,10-phenanthroline)(triphenylphosphine)copper(I) (8.0 mg, 0.15 Eq, 14 μmol), Pd(OAc)2 (3.1 mg, 0.15 Eq, 14 μmol), dicyclohexyl(2',6'- diisopropoxy-[1,1'-biphenyl]-2-yl)phosphane (8.4 mg, 0.20 Eq, 18 μmol), and K2CO3 (38 mg, 3 Eq, 0.27 mmol). Dioxane (1.0 mL) was added, and the vial was capped, purged with nitrogen for 5 minutes, and heated at 130 °C for 20 hours. The crude mixture was concentrated onto silica gel and directly purified by normal phase chromatography (12 g silica gel column, 0-5% MeOH / DCM) to afford 1-(5-(4-chloro-3-fluorophenyl)-2-(6-fluoro-4-methylpyridin-2-yl)oxazol- 4-yl)-4-cyclopropylpyrimidin-2(1H)-one (18.8 mg, 42.6 μmol, 47%) as a solid.

[0188] LCMS (M+H)+ = 441.0. LCAP % at 280 nm > 95%.

[0189] 1H NMR (400 MHz, Methanol-d4) δ 7.92 (s, 1H), 7.80 (d, J = 6.9 Hz, 1H), 7.51 – 7.46 (m, 2H), 7.31 (dd, J = 8.5, 2.0 Hz, 1H), 7.00 (s, 1H), 6.56 (d, J = 6.9 Hz, 1H), 2.53 (s, 3H), 2.05 (qd, 1H), 1.37 (p, J = 4.3 Hz, 2H), 1.27 (dq, J = 9.8, 7.9, 5.8 Hz, 2H). Compound (M+H)+Calc. Mass 24 441.0 440.837 Synthesis of compound 77 Cl1-(5-(4-chloro-3-fluorophenyl)-2-(2-methylbenzo[d]oxazol-6-yl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one:

[0190] To a resealable vial were added 1-(5-(4-chloro-3-fluorophenyl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one (0.050 g, 1 Eq, 0.15 mmol), 6-bromo-2-methyl-3a,7a- dihydrobenzo[d]oxazole (48 mg, 1.5 Eq, 0.225 mmol), pivalic acid (6.2 mg, 0.40 Eq, 60 μmol), Pd(OAc)2(3.4 mg, 0.10 Eq, 15 μmol), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2- yl)phosphane (14 mg, 0.20 Eq, 30 μmol), 4 angstrom molecular sieves (100 mg), K2CO3 (62 mg, 3 Eq, 0.45 mmol), and toluene (2.0 mL). The vial was capped, purged with nitrogen for 5 minutes, and heated at 110 °C for 16 hours. The crude reaction was directly purified by normal phase chromatography (24 g silica gel column, 0-5% MeOH in DCM) to afford 1-(5-(4-chloro-3-fluorophenyl)-2-(2-methylbenzo[d]oxazol-6-yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one (16.7 mg, 36.1 μmol, 24 %) as yellow solid.

[0191] LCMS (M+H)+ = 463.1. LCAP % at 280 nm 97%.

[0192] 1H NMR (400 MHz, MeOD) δ 8.38 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 6.9 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.53 (dd, J = 10.1, 2.0 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 6.9 Hz, 1H), 2.72 (s, 3H), 2.20 – 2.13 (m, 1H), 1.38 – 1.25 (m, 4H). Compound (M+H)+Calc. Mass 77 463.1 462.868 Synthesis of Compound 498, 1-(5-(4-chloro-3-fluorophenyl)-2-(7-methylpyrazolo[1,5- a]pyrimidin-2-yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one1-(5-(4-chloro-3-fluorophenyl)-2-(7-methylpyrazolo[1,5-a]pyrimidin-2-yl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one:

[0193] To a resealable vial were added 1-(5-(4-chloro-3-fluorophenyl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one (0.050 g, 1 Eq, 0.15 mmol), 2-bromo-7-methylpyrazolo[1,5- a]pyrimidine (48 mg, 1.5 Eq, 0.23 mmol), Cs2CO3 (0.15 g, 3.0 Eq, 0.45 mmol), CuI (4.3 mg, 0.15 Eq, 23 μmol), Pd(dppf)Cl2(17 mg, 0.15 Eq, 23 μmol), and DMF (2.0 mL). The vial was capped, purged with nitrogen for 5 minutes, and heated at 90 °C for 2.5 hours. The crude mixture was diluted with brine, extracted with EtOAc (2 x 10 mL), and the organic phase was concentrated onto Celite. This material was then purified with normal phase chromatography (24 g silica gel column, 0-5% MeOH / DCM) to afford 1-(5-(4-chloro-3-fluorophenyl)-2-(7-methylpyrazolo[1,5- a]pyrimidin-2-yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one (6.2 mg, 13 μmol, 8.9%) as a solid.

[0194] LCMS (M+H)+ = 463.1. LCAP % at 280 nm 98%.

[0195] 1H NMR (400 MHz, MeOD) δ 8.55 (d, J = 4.3 Hz, 1H), 8.13 (d, J = 6.9 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.56 (dd, J = 10.1, 1.9 Hz, 1H), 7.38 (d, J = 10.1 Hz, 2H), 7.10 (d, J = 4.3 Hz, 1H), 6.75 (d, J = 6.9 Hz, 1H), 2.92 (s, 3H), 2.17 (d, J = 8.4 Hz, 1H), 1.33 (dt, J = 19.6, 4.9 Hz, 4H). Compound (M+H)+Calc. Mass 498 463.1 462.87 Synthesis of Compound 499, 1-(5-(4-chloro-3-fluorophenyl)-2-(5,7-dimethylpyrazolo[1,5- a]pyrimidin-2-yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one 1-(5-(4-chloro-3-fluorophenyl)-2-(5,7-dimethylpyrazolo[1,5-a]pyrimidin-2-yl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one:

[0196] To a resealable vial were added 1-(5-(4-chloro-3-fluorophenyl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one (0.050 g, 1 Eq, 0.15 mmol), 2-bromo-5,7-dimethylpyrazolo[1,5- a]pyrimidine (51 mg, 1.5 Eq, 0.23 mmol), pivalic acid (6.2 mg, 0.40 Eq, 60 μmol), Pd(OAc)2(3.4 mg, 0.10 Eq, 15 μmol), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphane (14 mg, 0.20 Eq, 30 μmol), and K2CO3 (62 mg, 3 Eq, 0.45 mmol). Toluene (3.0 mL) was added, and the vial was capped, purged with nitrogen for 5 minutes, and heated at 110 °C for 16 hours. The crude mixture was concentrated onto silica gel and directly purified by normal phase chromatography (12 g silica gel column, 0-5% MeOH / DCM) to afford 1-(5-(4-chloro-3- fluorophenyl)-2-(5,7-dimethylpyrazolo[1,5-a]pyrimidin-2-yl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one (18.8 mg, 42.6 μmol, 47%) as a solid.

[0197] LCMS (M+H)+ = 477.0. LCAP % at 280 nm > 95%.

[0198] 1H NMR (400 MHz, Methanol-d4) δ 8.02 (d, J = 6.9 Hz, 1H), 7.62 – 7.54 (m, 1H), 7.52 (dd, J = 9.9, 2.0 Hz, 1H), 7.36 (ddd, J = 8.4, 2.1, 0.9 Hz, 1H), 7.19 (s, 1H), 6.96 (d, J = 1.1 Hz, 1H), 6.69 (d, J = 6.9 Hz, 1H), 2.86 (d, J = 0.9 Hz, 3H), 2.63 (s, 3H), 2.12 (tt, J = 8.3, 4.6 Hz, 1H), 1.33 (ddt, J = 27.6, 6.2, 3.9 Hz, 4H).Compound (M+H)+Calc. Mass 499 477.0 476.899 Synthesis of Compound 500, 1-(5-(4-chloro-3-fluorophenyl)-2-(7-(trifluoromethyl)pyrazolo[1,5- a]pyrimidin-2-yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one1-(5-(4-chloro-3-fluorophenyl)-2-(7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl)oxazol-4- yl)-4-cyclopropylpyrimidin-2(1H)-one:

[0199] To a resealable vial were added 1-(5-(4-chloro-3-fluorophenyl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one (0.050 g, 1 Eq, 0.15 mmol), 2-bromo-7- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine (60 mg, 1.5 Eq, 0.23 mmol), pivalic acid (6.2 mg, 0.40 Eq, 60 μmol), Pd(OAc)2(5.1 mg, 0.15 Eq, 23 μmol), dicyclohexyl(2',6'-diisopropoxy-[1,1'- biphenyl]-2-yl)phosphane (18 mg, 0.25 Eq, 38 μmol), 4 angstrom molecular sieves (100 mg), K2CO3 (62 mg, 3 Eq, 0.45 mmol), and toluene (3.0 mL). The vial was capped, purged with nitrogen for 5 minutes, and heated at 110 °C for 16 hours. The crude mixture was directly purified by normal phase chromatography (24 g silica gel column, 0-5% MeOH / DCM) to afford crude product. This material was then triturated in warm MeOH. The solid was collected by filtration and dried to afford 1-(5-(4-chloro-3-fluorophenyl)-2-(7-(trifluoromethyl)pyrazolo[1,5- a]pyrimidin-2-yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one (11.2 mg, 21.7 μmol, 14 %) as a solid.

[0200] LCMS (M+H)+= 517.1. LCAP % at 280 nm 96%.

[0201] 1H NMR (400 MHz, MeOD) δ 8.83 (d, J = 4.2 Hz, 1H), 8.13 (d, J = 6.9 Hz, 1H), 7.68 – 7.59 (m, 3H), 7.55 (dd, J = 10.0, 2.1 Hz, 1H), 7.44 – 7.37 (m, 1H), 6.76 (d, J = 6.9 Hz, 1H), 2.17 (ddd, J = 12.8, 7.8, 4.6 Hz, 1H), 1.42 – 1.26 (m, 4H). Compound (M+H)+Calc. Mass 500 517.1 516.84Synthesis of Compound 501, 1-(5-(4-chloro-3-fluorophenyl)-2-(4,6-dimethylpyrazolo[1,5- a]pyrazin-2-yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one1-(5-(4-chloro-3-fluorophenyl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one:

[0202] To a resealable vial were added 1-(5-(4-chloro-3-fluorophenyl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one (0.050 g, 1 Eq, 0.15 mmol), 2-bromo-4,6-dimethylpyrazolo[1,5- a]pyrazine (51 mg, 1.5 Eq, 0.23 mmol), Cs2CO3(0.15 g, 3.0 Eq, 0.45 mmol), CuI (4.3 mg, 0.15 Eq, 23 μmol), Pd(dppf)Cl2 (17 mg, 0.15 Eq, 23 μmol), and DMF (3.0 mL). The vial was capped, purged with nitrogen for 5 minutes, and heated at 90 °C for 2.5 hours. The crude mixture was diluted with brine, extracted with EtOAc (2 x 10 mL), and the organic layer was concentrated onto Celite. This material was purified with normal phase chromatography (24 g silica gel column, 0- 5% MeOH / DCM) to afford 1-(5-(4-chloro-3-fluorophenyl)-2-(4,6-dimethylpyrazolo[1,5- a]pyrazin-2-yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one (18.4 mg, 38.6 μmol, 26%) as a solid.

[0203] LCMS (M+H)+= 477.0. LCAP % at 280 nm > 95%.

[0204] 1H NMR (400 MHz, MeOD) δ 8.42 (s, 1H), 8.12 (d, J = 6.9 Hz, 1H), 7.68 – 7.59 (m, 2H), 7.54 (dd, J = 10.0, 2.0 Hz, 1H), 7.39 – 7.31 (m, 1H), 6.76 (d, J = 6.9 Hz, 1H), 2.83 (s, 3H), 2.55 (s, 3H), 2.17 (dt, J = 8.4, 3.6 Hz, 1H), 1.39 – 1.26 (m, 4H). Compound (M+H)+Calc. Mass 501 477.0 476.90Synthesis of Compound 502, 1-(5-(4-chloro-3-fluorophenyl)-2-(isoquinolin-3-yl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one 1-[5-(4-chloro-3-fluorophenyl)-2-(isoquinolin-3-yl)-1,3-oxazol-4-yl]-4-cyclopropyl-1,2- dihydropyrimidin-2-one:

[0205] Under inert atmosphere, 1-[5-(4-chloro-3-fluorophenyl)-1,3-oxazol-4-yl]-4-cyclopropyl- 1,2-dihydropyrimidin-2-one (0.080 g, 0.241 mmol, 1.0 eq), potassium carbonate (0.10 g, 0.723 mmol, 3.0 eq), bromo(1,10-phenanthroline)(triphenylphosphine)copper(I) (0.021 g, 0.036 mmol, 0.15 eq), RuPhos (0.023 g, 0.048 mmol, 0.2 eq), and 3-bromoisoquinoline (0.075 g, 0.362 mmol, 1.5 eq) were suspended in dioxane (1.6 mL). The resulting mixture was purged with Ar for 5 minutes prior to the addition of palladium(II) acetate (0.0080 g, 0.036 mmol, 0.15 eq). The reaction vial was sealed, and the reaction mixture was stirred at 120 °C for 2.5 hours. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and filtered through a pad of celite. The celite pad was washed with a mixture of dichloromethane and methanol (9 / 1, v / v). The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified via normal phase column chromatography (0-4% MeOH in DCM). Fractions containing the desired product were concentrated under reduced pressure. The residue was triturated with methanol, collected by filtration, washed with methanol, and dried under reduced pressure to give 1-[5-(4-chloro-3-fluorophenyl)-2-(isoquinolin-3-yl)-1,3-oxazol-4- yl]-4-cyclopropyl-1,2-dihydropyrimidin-2-one (0.056 g, 0.121 mmol, 50%).

[0206] LC-MS: 2.63 min, [M+H]+= 459.1, 99.0% @ 210 nm

[0207] 1H NMR (300 MHz, DMSO-d6) δ 9.51 (d, J = 1.1 Hz, 1H), 8.85 (s, 1H), 8.28 (d, J = 8.1 Hz, 1H), 8.25 – 8.17 (m, 2H), 8.01 – 7.88 (m, 1H), 7.88 – 7.84 (m, 1H), 7.84 – 7.74 (m, 1H), 7.63 (dd, J = 10.2, 2.0 Hz, 1H), 7.41 – 7.18 (m, 1H), 6.73 (d, J = 6.9 Hz, 1H), 2.20 – 2.05 (m, 1H), 1.24 – 1.09 (m, 4H).Compound (M+H)+Calc. Mass 502 459.1 458.88 Synthesis of 516, 1-(5-(4-chloro-3-fluorophenyl)-2-(7-(fluoromethyl)-5-methylpyrazolo[1,5- a]pyrimidin-2-yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one {2-bromo-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}methanol:

[0208] Ethyl 2-bromo-5-methylpyrazolo[1,5-a]pyrimidine-7-carboxylate (1.10 g, 3.87 mmol, 1.0 eq) was dissolved in a mixture of anhydrous tetrahydrofuran (11 mL) and anhydrous methanol (11 mL). The resulting mixture was cooled to -4 °C and then sodium borohydride (0.146 g, 3.87 mmol, 1.0 eq) was added. The reaction solution was stirred at -4 °C for 1 hour. The reaction was quenched with water and then extracted with EtOAc (3 x). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was triturated with diethyl ether, filtered and dried to yield {2-bromo-5- methylpyrazolo[1,5-a]pyrimidin-7-yl}methanol (0.370 g, 1.53 mmol, 39%).

[0209] 1H NMR (300 MHz, DMSO-d6) δ 7.02 (s, 1H), 6.78 (s, 1H), 5.95 (t, J = 5.8 Hz, 1H), 4.89 (d, J = 5.8 Hz, 2H), 2.56 (s, 3H). 2-bromo-7-{[(tert-butyldimethylsilyl)oxy]methyl}-5-methylpyrazolo[1,5-a]pyrimidine:

[0210] 2,6-Lutidine (0.328 g, 0.355 mL, 3.06 mmol, 2.0 eq) was added to a solution of {2-bromo- 5-methylpyrazolo[1,5-a]pyrimidin-7-yl}methanol (0.370 g, 1.53 mmol, 1.0 eq) in anhydrous dichloromethane (3.7 mL) at 0 °C. The resulting mixture was stirred for 5 minutes; then, tert- butyldimethylsilyl trifluoromethanesulfonate (0.848 g, 3.21 mmol, 2.1 eq) was added dropwise. The mixture was then stirred at room temperature for 16 hours. The reaction was quenched with water and diluted with dichloromethane. Then, aqueous solution of citric acid (10%, w / w) wasadded, and the mixture was extracted with dichloromethane (3x). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by normal phase column chromatography (0-20% EtOAc in cyclohexane) to give 2-bromo-7-{[(tert-butyldimethylsilyl)oxy]methyl}-5-methylpyrazolo[1,5-a]pyrimidine (0.314 g, 0.881 mmol, 58%).

[0211] 1H NMR (300 MHz, DMSO-d6) δ 6.92 (s, 1H), 6.80 (s, 1H), 5.09 (d, J = 1.3 Hz, 2H), 2.57 (s, 3H), 0.96 (s, 9H), 0.18 (s, 6H). 1-[2-(7-{[(tert-butyldimethylsilyl)oxy]methyl}-5-methylpyrazolo[1,5-a]pyrimidin-2-yl)-5-(4- chloro-3-fluorophenyl)-1,3-oxazol-4-yl]-4-cyclopropyl-1,2-dihydropyrimidin-2-one:

[0212] 1-(5-(4-Chloro-3-fluorophenyl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one (0.300 g, 0.904 mmol, 1.0 eq), 2-bromo-7-{[(tert-butyldimethylsilyl)oxy]methyl}-5-methylpyrazolo[1,5- a]pyrimidine (0.314 g, 0.882 mmol, 1.0 eq), potassium carbonate (0.375 g, 2.71 mmol, 3.0 eq), RuPhos (0.084 g, 0.181 mmol, 0.2 eq), and bromo(1,10- phenanthroline)(triphenylphosphine)copper(I) (0.079 g, 0.136 mmol, 0.15 eq) were suspended in anhydrous 1,4-dioxane (7.5 mL). The resulting mixture was purged with Ar for 5 minutes prior to the addition of palladium(II) acetate (0.030 g, 0.136 mmol, 0.15 eq). The reaction vial was sealed, and the reaction mixture was stirred at 100 °C for 4 hours. Brine was added, and the mixture was extracted with dichloromethane (3 x). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The crude material was purified by normal phase column chromatography (0-30% EtOAc in DCM). The purest fractions were concentrated separately from the impure fractions, which were triturated with methanol. The solid material was filtered, dried and combined with the purest fractions to give 1-[2-(7-{[(tert-butyldimethylsilyl)oxy]methyl}-5- methylpyrazolo[1,5-a]pyrimidin-2-yl)-5-(4-chloro-3-fluorophenyl)-1,3-oxazol-4-yl]-4- cyclopropyl-1,2-dihydropyrimidin-2-one (0.125 g, 0.202 mmol, 20%).

[0213] 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, J = 6.9 Hz, 1H), 7.82 – 7.74 (m, 1H), 7.61 (dd, J = 10.2, 2.0 Hz, 1H), 7.36 (s, 1H), 7.34 – 7.29 (m, 1H), 7.07 (s, 1H), 6.71 (d, J = 7.0 Hz, 1H), 5.21 (s, 2H), 2.63 (s, 3H), 2.17 – 2.08 (m, 1H), 1.22 – 1.12 (m, 4H), 0.98 (s, 9H), 0.22 (s, 6H). 1-[5-(4-chloro-3-fluorophenyl)-2-[7-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-2- yl]-1,3-oxazol-4-yl]-4-cyclopropyl-1,2-dihydropyrimidin-2-one:

[0214] A mixture of 1-[2-(7-{[(tert-butyldimethylsilyl)oxy]methyl}-5-methylpyrazolo[1,5- a]pyrimidin-2-yl)-5-(4-chloro-3-fluorophenyl)-1,3-oxazol-4-yl]-4-cyclopropyl-1,2-dihydropyrimidin-2-one (0.098 g, 0.161 mmol, 1.0 eq) in tetrahydrofuran (3.9 mL) was cooled to 0 °C. To this, a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.063 g, 0.242 mL, 0.242 mmol, 1.5 eq) was added. The resulting mixture was stirred at 0 °C for 30 minutes. The reaction was quenched by the addition of saturated ammonium chloride solution and extracted with diethyl ether (3 x). During the extraction, precipitation was observed. The solid was collected by filtration and combined with the concentrated organic layers. The crude material was then purified by normal phase column chromatography (0-4% MeOH in DCM) to give 1-[5-(4-chloro- 3-fluorophenyl)-2-[7-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-2-yl]-1,3-oxazol-4-yl]- 4-cyclopropyl-1,2-dihydropyrimidin-2-one (0.027 g, 0.055 mmol, 32.7%).

[0215] LC-MS: 3.55 min, [M+H]+= 493.11, 97.6% @ 220 nm

[0216] 1H NMR (300 MHz, DMSO-d6) δ 8.19 (d, J = 6.9 Hz, 1H), 7.83 – 7.73 (m, 1H), 7.61 (dd, J = 10.2, 2.0 Hz, 1H), 7.35 – 7.30 (m, 2H), 7.16 (s, 1H), 6.71 (d, J = 6.9 Hz, 1H), 6.00 (t, J = 5.7 Hz, 1H), 5.02 (d, J = 5.9 Hz, 2H), 2.62 (s, 3H), 2.20 – 2.07 (m, 1H), 1.21 – 1.12 (m, 4H). 1-(5-(4-chloro-3-fluorophenyl)-2-(7-(fluoromethyl)-5-methylpyrazolo[1,5-a]pyrimidin-2- yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one:

[0217] In a 4-mL vial charged with 1-(5-(4-chloro-3-fluorophenyl)-2-(7-(hydroxymethyl)-5- methylpyrazolo[1,5-a]pyrimidin-2-yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one (15 mg, 0.03 mmol, 1.0 equiv.) and THF (0.3 mL) was added DAST (10 mg, 0.06 mmol, 2.0 equiv.). The resulting mixture was allowed to stir at room temperature for 6 hours. At the conclusion of the reaction, all volatiles were removed, and the resulting solid was re-dissolved in DMF. This solution was submitted to reverse phase chromatography (C18 column, 10-100% MeCN in water with 0.1% TFA) to give 1-(5-(4-chloro-3-fluorophenyl)-2-(7-(fluoromethyl)-5- methylpyrazolo[1,5-a]pyrimidin-2-yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one (3 mg, 20%) as a white solid.

[0218] LCMS (M+H)+= 495.0.

[0219] 1H NMR (400 MHz, MeOD / CDCl3) δ 7.86 (d, J = 7.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.44 (dd, J = 9.7, 2.0 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.20 (s, 1H), 7.11 (s, 1H), 6.59 (d, J = 6.9 Hz, 1H), 5.96 (d, J = 45.9 Hz, 2H), 2.68 (s, 3H), 2.05 (tt, J = 8.2, 4.5 Hz, 1H), 1.35 (p, J = 4.2 Hz, 2H), 1.29 – 1.22 (m, 2H). Compound (M+H)+Calc. Mass 516 495.0 494.89Synthesis of 517, 1-(5-(4-chloro-3-fluorophenyl)-2-(5-(fluoromethyl)-7-methylpyrazolo[1,5- a]pyrimidin-2-yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one(2-bromo-7-methylpyrazolo[1,5-a]pyrimidin-5-yl)methanol:

[0220] In a 40-mL vial charged with sodium methoxide (10.0 mg, 0.1 Eq, 185 μmol) and methyl 2-bromo-7-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate (500 mg, 1 Eq, 1.85 mmol) was added MeOH (10 mL) at room temperature. Then, sodium borohydride (70.0 mg, 1 Eq, 1.85 mmol) was added to the previous mixture over 30 minutes, and the resulting mixture was allowed to stir for another 3 hours at room temperature. At the conclusion of reaction, all volatiles were removed, and the desired product was purified via ISCO silica gel column (0-25% of 3:1 EtOAc to EtOH in DCM) to give (2-bromo-7-methylpyrazolo[1,5-a]pyrimidin-5-yl)methanol (300 mg, 1.24 mmol, 67%) a white solid.

[0221] 1H NMR (400 MHz, CDCl3) δ 6.66 (s, 1H), 6.65 (d, J = 1.1 Hz, 1H), 4.77 (s, 2H), 2.76 (d, J = 0.9 Hz, 3H). 2-bromo-5-(fluoromethyl)-7-methylpyrazolo[1,5-a]pyrimidine:

[0222] In a 40-mL vial charged with (2-bromo-7-methylpyrazolo[1,5-a]pyrimidin-5-yl)methanol (120 mg, 1 Eq, 496 μmol) and THF (2 mL) was added N,N-diethyl-1,1,1-trifluoro-l4-sulfanamine (160 mg, 123 μL, 2 Eq, 991 μmol) in a dropwise fashion at 0 °C. The resulting mixture was gradually raised to room temperature over 10 minutes and was allowed to stir at the same temperature for 20 minutes. At the conclusion of reaction, all volatiles were removed, and thedesired product was purified by preparative HPLC (C18 column, 10-100% MeCN in water with 0.1% TFA) to give 2-bromo-5-(fluoromethyl)-7-methylpyrazolo[1,5-a]pyrimidine (26 mg, 0.11 mmol, 21%) as a white solid.

[0223] 1H NMR: (400 MHz, CDCl3) δ 6.91 (s, 1H), 6.68 (s, 1H), 5.46 (d, J = 46.7 Hz, 2H), 2.81 (d, J = 0.9 Hz, 3H). 1-(5-(4-chloro-3-fluorophenyl)-2-(5-(fluoromethyl)-7-methylpyrazolo[1,5-a]pyrimidin-2- yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one:

[0224] In a 4-mL vial charged with Pd(PPh3)4 (13 mg, 0.1 Eq, 11 μmol), cesium carbonate (0.11 g, 3 Eq, 0.33 mmol), bromo(1,10-phenanthroline)(triphenylphosphine)copper (6.5 mg, 0.1 Eq, 11 μmol), 1-(5-(4-chloro-3-fluorophenyl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one (37 mg, 1 Eq, 0.11 mmol), and 2-bromo-5-(fluoromethyl)-7-methylpyrazolo[1,5-a]pyrimidine (27 mg, 1 Eq, 0.11 mmol) was added toluene (1.1 mL) under nitrogen atmosphere. The resulting mixture was allowed to stir at 110 °C for 14 hours. At the conclusion of the reaction, all volatiles were removed. The crude material was purified by preparative HPLC (C18 column, 10-100% MeCN in water with 0.1% TFA) to give 1-(5-(4-chloro-3-fluorophenyl)-2-(5-(fluoromethyl)-7- methylpyrazolo[1,5-a]pyrimidin-2-yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one (7.6 mg, 15 µmol, 14%) as a white solid.

[0225] LCMS (M+H)+= 495.0.

[0226] 1H NMR: (400 MHz, MeOD / CDCl3) δ 7.90 (d, J = 6.8 Hz, 1H), 7.55 – 7.40 (m, 2H), 7.34 – 7.28 (m, 1H), 7.25 (s, 1H), 7.12 (s, 1H), 6.60 (d, J = 6.9 Hz, 1H), 5.49 (d, J = 46.6 Hz, 2H), 2.94 – 2.87 (m, 3H), 2.11 – 2.00 (m, 1H), 1.35 (p, J = 4.2 Hz, 2H), 1.31 – 1.18 (m, 2H). Compound (M+H)+Calc. Mass 517 495.0 494.89Synthesis of Compound 103.1-[5-(4-chloro-3-fluorophenyl)-2-(1-methyl-1,5-diaza-6-indanyl)- 1,3-oxazol-4-yl]-4-cyclopropyl-2(1H)-pyrimidinone: 1-(4-chloro-3-fluorophenyl)-2,2-dihydroxyethan-1-one

[0227] To a stirred solution of 1-(4-chloro-3-fluorophenyl)ethan-1-one (200 g, 1 Eq, 1.16 mol) in DMSO (2000 mL) was added hydrobromic acid (599 g, 402 mL, 47% Wt., 3.0 Eq, 3.48 mol) while maintaining an internal temperature between 10 °C and 20 °C during the addition. The resulting reaction mixture was stirred at 25 °C for 1 hour followed by stirring at 50 °C for 16 hours. The reaction mixture was allowed to cool to room temperature and poured into ice-cold water. The resulting solid precipitate was collected by vacuum filtration and washed with water. The crude compound was triturated with hexanes (1.0 L), triturated with 10% MTBE in hexane (1.0 L), collected by vacuum filtration, and dried under vacuum at 50 °C to afford 1-(4-chloro-3- fluorophenyl)-2,2-dihydroxyethan-1-one (150 g, 733 mmol, 63.3%) as an off white solid.

[0228] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.01 (dd, J = 10.26, 1.84 Hz, 1H), 7.93 (dd, J = 8.42, 1.32 Hz, 1H), 7.78 (dd, J = 8.29, 7.50 Hz, 1H), 6.99 (brd, J = 6.45 Hz, 2H), 5.61 (brs, 1H). N-(2-(4-chloro-3-fluorophenyl)-1-hydroxy-2-oxoethyl)formamide

[0229] To a stirred solution of 1-(4-chloro-3-fluorophenyl)-2,2-dihydroxyethan-1-one (150 g, 1 Eq, 733 mmol) and dioxane (1500 mL) was added formamide (132 g, 117 mL, 4.0 Eq, 2.93 mol), and the resulting reaction mixture was heated to 90 °C for 3 hours. The reaction mixture was allowed to cool to room temperature, and the excess solvent was evaporated under reduced pressure. The obtained residue was poured into ice water (3000 mL), and the resulting solid precipitate was collected by vacuum filtration, washed with hexanes (2000 mL), washed with 20% MTBE in hexanes (2000 mL), and dried under vacuum at 60 °C for 24 hours to afford N-(2-(4- chloro-3-fluorophenyl)-1-hydroxy-2-oxoethyl)formamide (120 g, 518 mmol, 70.7%) as a solid.

[0230] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.00 (brd, J = 8.42 Hz, 1H), 8.10 (s, 1H), 7.78 - 8.04 (m, 3H), 6.84 - 6.90 (m, 1H), 6.32 (t, J = 7.96 Hz, 1H). N-(1-chloro-2-(4-chloro-3-fluorophenyl)-2-oxoethyl)formamide

[0231] To a solution of N-(2-(4-chloro-3-fluorophenyl)-1-hydroxy-2-oxoethyl)formamide (90.0 g, 1 Eq, 389 mmol) in DCM (1000 mL) was added phosphorus pentachloride (80.9 g, 1.0 Eq, 389 mmol) under argon at 0°C. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum at 45 °C, and the resulting solid was triturated with 10% MTBE in hexanes (1.0 L), collected by vacuum filtration, and dried under vacuum to afford N-(1-chloro-2-(4-chloro-3-fluorophenyl)-2-oxoethyl)formamide (92 g, 0.37 mol, 95%) as a solid. This compound was directly used in the next step without further purification. N-(2-(4-chloro-3-fluorophenyl)-1-(4-cyclopropyl-2-oxopyrimidin-1(2H)-yl)-2-oxoethyl)formamide

[0232] In a 2 L multi-necked round bottom flask were combined 4-cyclopropylpyrimidin-2(1H)- one (45.0 g, 1 Eq, 331 mmol) and DMF (450 mL). Next, triethylamine (134 g, 184 mL, 4.0 Eq, 1.32 mol) was added, and the mixture was cooled to 0 °C. Finally, a solution of N-(1-chloro-2-(4- chloro-3-fluorophenyl)-2-oxoethyl)formamide (90.9 g, 1.1 Eq, 364 mmol) in DMF (500 mL) was added drop-wise over 1 hour, and the resulting reaction mixture was stirred at 25 °C for 2 hours. The excess solvent was evaporated under reduced pressure, and the obtained residue was poured into ice water (2 L). The resulting precipitated solid was collected by vacuum filtration, washed with 50% MTBE in hexanes (500 mL), washed with ethyl acetate (500 mL), and dried under vacuum to afford N-(2-(4-chloro-3-fluorophenyl)-1-(4-cyclopropyl-2-oxopyrimidin-1(2H)-yl)-2- oxoethyl)formamide (42.0 g, 120 mmol, 36.3%) as a solid.

[0233] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.66 (brs, 1H), 8.22 (s, 1H), 8.18 (d, J = 6.97 Hz, 1H), 7.74 - 7.93 (m, 2H), 7.68 (dd, J = 8.42, 1.84 Hz, 1H), 7.22 (brs, 1H), 6.58 (d, J = 6.97 Hz, 1H), 1.93 - 2.02 (m, 1H), 0.93 - 1.11 (m, 4 H). 1-(5-(4-chloro-3-fluorophenyl) oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one

[0234] In a 1 L 3 necked round bottom flask were combined triphenylphosphine (33.0 g, 2.0 Eq, 126 mmol) and DCM (500 mL). Iodine (23.9 g, 1.5 Eq, 94.4 mmol) was added portion-wise over an hour at room temperature. Next, TEA (25.5 g, 35.1 mL, 4.0 Eq, 252 mmol) was added, and the mixture was stirred for 10 minutes. Finally, N-(2-(4-chloro-3-fluorophenyl)-1-(4-cyclopropyl-2- oxopyrimidin-1(2H)-yl)-2-oxoethyl)formamide (22.0 g, 1 Eq, 62.9 mmol) was added portion-wise over 30 minutes, and the resulting reaction mixture was stirred for 1 hour at room temperature.The reaction mixture was diluted with DCM (300 mL), washed with aqueous sodium thiosulphate (3 x 500 mL), washed with brine (500 mL), and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude solid. This material was mixed with ethyl acetate (300 mL) and stirred for 1 hour at room temperature. The solid was collected by vacuum filtration, washed with ethyl acetate, and dried under reduced pressure to afford 1-(5-(4-chloro-3-fluorophenyl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one (8.3 g, 25 mmol, 39%) as a solid.

[0235] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (s, 1H), 8.08 (d, J = 6.97 Hz, 1H), 7.74 (t, J = 8.16 Hz, 1H), 7.47 (dd, J = 10.26, 1.97 Hz, 1H), 7.23 (dd, J = 8.42, 1.32 Hz, 1H), 6.67 (d, J = 6.97 Hz, 1H), 2.05 - 2.15 (m, 1H), 1.10 - 1.20 (m, 4H). 1-[5-(4-chloro-3-fluorophenyl)-2-(1-methyl-1,5-diaza-6-indanyl)-1,3-oxazol-4-yl]-4-cyclopropyl- 2(1H)-pyrimidinone [Compound 103]

[0236] In a 30 mL sealable tube, 1-(5-(4-chloro-3-fluorophenyl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one (150 mg, 1 Eq, 452 μmol), 6-bromo-1-methyl-2,3-dihydro-1H- pyrrolo[3,2-c]pyridine (193 mg, 2.0 Eq, 904 μmol), and toluene (5.0 mL) were combined, and the mixture was purged with argon for 5 minutes. Next, potassium carbonate (312 mg, 5.0 Eq, 2.26 mmol), di((3S,5S,7S)-adamantan-1-yl)(butyl)phosphane (32.4 mg, 0.2 Eq, 90.4 μmol), pivalic acid (23.1 mg, 0.5 Eq, 226 μmol), and CataxiumAPdG3 (65.9 mg, 0.2 Eq, 90.4 μmol) were added, and the mixture was purged with argon 5 minutes. Finally, the tube was sealed and heated to 105 °C for 16 hours. The reaction mixture was filtered through a pad of celite, and the celite pad was washed with 10% MeOH in DCM (20mL). The combined filtrate was concentrated to dryness, and the crude material was purified by normal phase flash chromatography (silica gel, 60-90% ethyl acetate in hexanes). The collected pure fractions were concentrated to give a solid material, and this solid was triturated with ethyl acetate, collected by vacuum filtration, and dried under reduced pressure to afford 1-[5-(4-chloro-3-fluorophenyl)-2-(1-methyl-1,5-diaza-6-indanyl)-1,3- oxazol-4-yl]-4-cyclopropyl-2(1H)-pyrimidinone (11 mg, 24 μmol, 5.2%) as a solid.

[0237] (+esi) [M+H]+= 464.2.

[0238] 1H-NMR (DMSO-d6, 400 MHz) δ 8.18 (d, 1H, J = 7.0 Hz), 8.12 (s, 1H), 7.77 (t, 1H, J = 8.1 Hz), 7.53 (dd, 1H, J = 2.0, 10.3 Hz), 7.30 (dd, 1H, J = 1.4, 8.4 Hz), 7.21 (s, 1H), 6.70 (d, 1H, J = 7.0 Hz), 3.56 (t, 2H, J = 8.7 Hz), 3.06 (t, 2H, J = 8.7 Hz), 2.90 (s, 3H), 2.1-2.2 (m, 1H), 1.1-1.2 (m, 4H).

[0239] The following compounds were prepared in an analogous manner from the appropriate starting materials using similar procedures. Compound (M+H)+Calc. Mass 103 464.2 463.9 104 422.4 422.847 105 437.2 436.874 106 438.5 437.862 107 440.3 439.834 108 441.1 440.837 109 452.3 451.845 110 453.5 452.873 111 452.5 452.873 112 452.3 452.873 113 455.5 454.864 114 465.2 464.884 115 468.3 467.888 116 470.4 469.879 117 471.4 470.863 118 485.3 484.865 119 485.5 484.865 120 485.5 484.865 Synthesis of Compound 121. 1-[5-(4-chloro-3-fluorophenyl)-2-(6-ethyl-4-methyl-2-pyridyl)-1,3- oxazol-4-yl]-4-cyclopropyl-2(1H)-pyrimidinone: 1-[5-(4-chloro-3-fluorophenyl)-2-(6-ethyl-4-methyl-2-pyridyl)-1,3-oxazol-4-yl]-4-cyclopropyl- 2(1H)-pyrimidinone [Compound 121]

[0240] In a 25 mL sealable tube, 1-(5-(4-chloro-3-fluorophenyl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one (100 mg, 1 Eq, 301 μmol), 2-bromo-6-ethyl-4-methylpyridine (296 mg, 51% Wt., 2.5 Eq, 754 μmol), and toluene (3.0 mL) were combined, and the mixture was purged with argon for 10 minutes. Next, K2CO3 (208 mg, 5.0 Eq, 1.51 mmol), diacetyl(oxo)palladium (12.6 mg, 0.2 Eq, 60.3 μmol), and dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphane (28.1 mg, 0.2 Eq, 60.3 μmol) were added, and the reaction mixture was purged with argon for 5 minutes. Finally, the vial was sealed, and the mixture was heated to 100 °C for 16 hours. The reaction mixture was concentrated under vacuum to afford crude material. The crude compound was purified by normal phase flash chromatography (silica gel, 100% ethyl acetate). The collected product from the purification gave 25 mg of a pale yellow solid. This material was triturated with MTBE to afford 9.1 mg of a beige colored solid. This material was further purified by preparative HPLC (C18 column, 10-100% MeCN in water with 0.1% FA) to afford 1-[5-(4-chloro-3-fluorophenyl)-2-(6-ethyl-4-methyl-2-pyridyl)-1,3-oxazol-4-yl]-4- cyclopropyl-2(1H)-pyrimidinone (5.0 mg, 11 μmol, 3.5%) as a solid.

[0241] (+esi) [M+H]+= 451.1

[0242] 1H NMR (DMSO-d6, 400 MHz) δ 8.18 (d, 1H, J = 7.0 Hz), 7.96 (s, 1H), 7.78 (t, 1H, J = 8.1 Hz), 7.59 (dd, 1H, J = 1.9, 10.2 Hz), 7.3-7.4 (m, 2H), 6.71 (d, 1H, J = 7.0 Hz), 2.82 (q, 2H, J = 7.6 Hz), 2.42 (s, 3H), 2.1-2.2 (m, 1H), 1.28 (t, 3H, J = 7.6 Hz), 1.2-1.2 (m, 4H).

[0243] The following compounds were prepared in an analogous manner from the appropriate starting materials using similar procedures. Compound (M+H)+Calc. Mass 121 451.1 450.901 122 409.3 408.82 123 412.4 411.824 124 423.3 422.847 125 424.2 423.835 126 424.4 423.835 127 426.0 425.851 128 426.0 425.851 129 428.9 428.876 130 433.1 432.842 131 437.0 436.874 132 437.4 436.874 133 438.0 437.862 134 438.0 437.862 135 439.1 438.846 136 439.4 438.846 137 438.3 438.846 138 438.3 438.846 139 440.0 439.834 140 440.0 439.834 141 441.0 440.837142 441.5 440.837 143 441.4 440.837 144 441.0 440.837 145 442.3 441.825 146 443.0 443.265 147 447.2 446.869 148 448.5 448.841 149 449.4 448.885 150 450.3 449.873 151 450.5 449.873 152 450.0 449.873 153 451.3 450.857 154 450.3 450.857 155 451.3 450.901 156 452.1 451.889 157 452.2 451.889 158 453.4 452.873 159 452.3 452.873 160 454.0 453.861 161 455.5 454.914 162 455.4 454.914 163 456.4 455.852 164 457.3 456.836 165 457.4 456.836 166 457.0 457.292 167 457.1 457.292 168 457.0 457.292 169 457.0 457.292 170 459.2 458.827 171 459.0 458.88 172 459.0 458.88 173 461.0 461.255 174 461.0 461.255 175 463.4 462.868 176 463.0 462.912 177 463.0 462.912 178 464.0 463.9 179 464.4 463.9 180 464.4 463.9 181 464.4 463.9 182 465.0 464.884 183 467.8 467.863 184 468.5 468.891 185 471.4 470.863 186 473.4 472.854 187 472.3 472.854188 473.4 472.854 189 473.4 472.907 190 473.0 473.291 191 472.3 473.291 192 475.1 474.826 193 475.4 474.826 194 477.0 476.817 195 477.0 477.71 196 492.3 491.91 197 507.0 506.843 377 463.1 462.87 Synthesis of compound 3771-(5-(4-chloro-3-fluorophenyl)-2-(1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one:

[0244] To a resealable vial were added 1-(5-(4-chloro-3-fluorophenyl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one (0.050 g, 1 Eq, 0.15 mmol), 3-bromo-1-methyl-1H-pyrazolo[4,3- b]pyridine (48 mg, 1.5 Eq, 0.23 mmol), pivalic acid (6.2 mg, 0.40 Eq, 60 μmol), Pd(OAc)2 (3.4 mg, 0.10 Eq, 15 μmol), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphane (14 mg, 0.20 Eq, 30 μmol), 4 angstrom molecular sieves (100 mg), K2CO3(62 mg, 3 Eq, 0.45 mmol), and toluene (2.0 mL). The vial was capped, purged with nitrogen for 5 minutes, and heated at 110 °C for 16 hours. The crude reaction was concentrated onto Celite and purified by normal phase chromatography (24 g silica gel column, 0-10% MeOH / DCM to afford 1-(5-(4-chloro-3- fluorophenyl)-2-(1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)oxazol-4-yl)-4-cyclopropylpyrimidin- 2(1H)-one (22.9 mg, 49.5 μmol, 33%) as a solid.

[0245] LCMS (M+H)+ = 463.1. LCAP % at 280 nm 97%.

[0246] 1H NMR (400 MHz, MeOD) δ 8.76 (d, J = 4.3 Hz, 1H), 8.28 (d, J = 7.9 Hz, 1H), 8.19 (d, J = 6.9 Hz, 1H), 7.67 – 7.56 (m, 3H), 7.40 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 7.0 Hz, 1H), 4.30 (s, 3H), 2.16 (d, J = 4.9 Hz, 1H), 1.39 – 1.25 (m, 4H).Compound (M+H)+Calc. Mass 377 463.1 462.87 Synthesis of Compound 198.1-[5-(4-chloro-3-fluorophenyl)-2-(4-cyclopropyl-2-pyrimidinyl)- 1,3-oxazol-4-yl]-4-cyclopropyl-2(1H)-pyrimidinone: 1-[5-(4-chloro-3-fluorophenyl)-2-(4-cyclopropyl-2-pyrimidinyl)-1,3-oxazol-4-yl]-4-cyclopropyl- 2(1H)-pyrimidinone [Compound 198]

[0247] To a degassed stirred solution of 1-(5-(4-chloro-3-fluorophenyl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one (100 mg, 1.0 Eq, 301 μmol) in DMF (6 mL) were added 2- bromo-4-cyclopropylpyrimidine (233 mg, 5.0 Eq, 1.51 mmol), Cs2CO3 (295 mg, 3.0 Eq, 904 μmol), CuI (28.7 mg, 0.5 Eq, 151 μmol), and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (73.9 mg, 0.3 Eq, 90.4 μmol). The reaction mixture was then degassed with argon for 5 minutes. The reaction mixture was then heated to 105 °C for 16 hours. The reaction was diluted with DCM (15 mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to afford crude material as a dark brown liquid. The crude product was purified by normal phase flash chromatography (24 g silica gel column, 85% EtOAc in hexanes) to afford 1-[5-(4-chloro-3-fluorophenyl)-2-(4-cyclopropyl-2-pyrimidinyl)-1,3-oxazol-4-yl]-4- cyclopropyl-2(1H)-pyrimidinone (19.7 mg, 42.8 μmol, 14.2%) as a solid.

[0248] (+esi) [M+H]+= 450.1

[0249] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.79 (d, J = 5.26 Hz, 1H), 8.16 (d, J = 6.84 Hz, 1H), 7.80 (t, J = 8.16 Hz, 1H), 7.60 (d, J = 5.13 Hz, 1H), 7.47 (dd, J = 10.06, 1.91 Hz, 1H), 7.33 (dd, J = 8.42, 1.45 Hz, 1H), 6.71 (d, J = 6.84 Hz, 1H), 2.22 - 2.31 (m, 1H), 2.07 - 2.18 (m, 1H), 1.10 - 1.25 (m, 8H).

[0250] The following compounds were prepared in an analogous manner from the appropriate starting materials using similar procedures. Compound (M+H)+Calc. Mass 198 450.1 449.873199 413.2 412.812 200 424.1 423.835 201 424.4 423.835 202 434.4 433.83 203 448 447.857 204 455.3 454.864 205 455.5 455.852 206 459.4 458.827 207 462 461.884 208 462 461.884 209 461 461.884 210 462 461.884 211 462 461.884 212 485 (M+Na)+462.872 213 464.4 463.9 214 472.3 471.851 215 478.1 477.805 216 482 482.302 217 482 482.302 218 486.4 485.878 Synthesis of Compound 219.1-[5-(4-chloro-3-fluorophenyl)-2-(2-ethynyl-4-pyridyl)-1,3-oxazol- 4-yl]-4-cyclopropyl-2(1H)-pyrimidinone: 1-(5-(4-chloro-3-fluorophenyl)-2-(2-chloropyridin-4-yl)oxazol-4-yl)-4-cyclopropylpyrimidin- 2(1H)-one

[0251] In a 100 mL sealable tube, 1-(5-(4-chloro-3-fluorophenyl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one (900 mg, 1 Eq, 2.71 mmol), toluene (27 mL), 2-chloro-4- iodopyridine (1.95 g, 3 Eq, 8.14 mmol), K2CO3 (1.50 g, 4 Eq, 10.9 mmol), pivalic acid (111 mg, 0.4 Eq, 1.09 mmol), bis(1-adamantyl)-butyl-phosphane (97.3 mg, 0.1 Eq, 271 μmol), and mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (198 mg,0.1 Eq, 271 μmol) were combined. The mixture was then purged with argon for 10 minutes. The tube was sealed and heated to 105 °C for 16 hours. The reaction mixture was diluted with hexanes and a solid precipitated. The solid was collected by filtration and mixed with 5% methanol in DCM. The remaining undissolved solid was removed by filtration, and the filtrate was evaporated under reduced pressure to yield crude material. This crude material was purified by normal phase flash chromatography (12 g silica gel column, 80% ethyl acetate in hexanes) to provide 1-(5-(4- chloro-3-fluorophenyl)-2-(2-chloropyridin-4-yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one (800 mg, 1.80 mmol, 66.5%) as a solid.

[0252] (+esi) [M+H]+= 443.1.

[0253] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.66 (dd, J = 5.13, 0.66 Hz, 1H), 8.29 - 8.31 (m, 1 H), 8.15 (d, J = 6.97 Hz, 1H), 8.09 (dd, J = 5.13, 1.45 Hz, 1H), 7.90 (dd, J = 10.33, 2.04 Hz, 1H), 7.77 (t, J = 8.09 Hz, 1H), 7.33 (dt, J = 8.42, 1.05 Hz, 1H), 6.72 (d, J = 6.97 Hz, 1H), 2.09 - 2.18 (m, 1H), 1.15 - 1.21 (m, 4H). 1-(5-(4-chloro-3-fluorophenyl)-2-(2-((trimethylsilyl)ethynyl)pyridin-4-yl)oxazol-4-yl)-4- cyclopropyl- pyrimidin-2(1H)-one

[0254] In a 100 mL sealable tube, 1-(5-(4-chloro-3-fluorophenyl)-2-(2-chloropyridin-4-yl)oxazol- 4-yl)-4-cyclopropylpyrimidin-2(1H)-one (900 mg, 1 Eq, 2.03 mmol), MeCN (30 mL), ethynyl- trimethyl-silane (997 mg, 1.42 mL, 5 Eq, 10.2 mmol), diisopropylamine (205 mg, 287 μL, 1 Eq, 2.03 mmol), triphenylphosphine (53.3 mg, 0.1 Eq, 203 μmol), CuI (19.3 mg, 0.05 Eq, 102 μmol), and palladium(II)bis(trifluoroacetate) (33.8 mg, 0.05 Eq, 102 μmol) were combined. The reaction mixture was purged with argon for 5 minutes, and the tube was sealed and heated to 70 °C for 3 hours. The reaction mixture was diluted with DCM, filtered through celite, and the celite pad was washed with DCM thoroughly. The combined filtrate was evaporated to yield crude solid. The crude compound was triturated with MTBE, collected by vacuum filtration, washed with MTBE, and dried to yield 1 g of crude solid. This solid was purified by normal phase flash chromatography (12 g silica gel, 80-90% DCM in hexanes) to give a still crude solid. This material was triturated with MTBE, collected by vacuum filtration, washed with MTBE, and dried under vacuum to yield 1-(5-(4-chloro-3-fluorophenyl)-2-(2-((trimethylsilyl)ethynyl)pyridin-4- yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one (520 mg, 1.03 mmol, 50.7%) as a solid.

[0255] (+esi) [M+H]+= 505.2

[0256] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (dd, J = 5.20, 0.72 Hz, 1 H), 8.25 - 8.27 (m, 1H), 8.15 (d, J = 6.97 Hz, 1H), 8.06 (dd, J = 5.13, 1.71 Hz, 1H), 7.90 (dd, J = 10.39, 1.97 Hz, 1H), 7.77 (t, J = 8.16 Hz, 1H), 7.34 (dd, J = 8.48, 1.51 Hz, 1H), 6.71 (d, J = 6.97 Hz, 1H), 2.09 - 2.18 (m, 1H), 1.14 - 1.22 (m, 4H), 0.29 (s, 8H). 1-[5-(4-chloro-3-fluorophenyl)-2-(2-ethynyl-4-pyridyl)-1,3-oxazol-4-yl]-4-cyclopropyl-2(1H)- pyrimidinone [Compound 219]

[0257] In a 100 mL round bottom flask, 1-(5-(4-chloro-3-fluorophenyl)-2-(2- ((trimethylsilyl)ethynyl)pyridin-4-yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one (519 mg, 1 Eq, 1.03 mmol) and methanol (10 mL) were combined and cooled to 0 °C. Potassium carbonate (213 mg, 1.5 Eq, 1.54 mmol) was added in one portion, and the resulting reaction mixture was stirred at room temperature for 20 minutes. Cold water was added to the reaction mixture, and the resulting solid was collected by vacuum filtration, washed with cold water, and dried to give a crude yellow solid. This solid was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting solid was triturated with ethanol, collected by vacuum filtration, washed with ethanol, and dried under reduced pressure to yield 1-[5-(4-chloro-3-fluorophenyl)-2-(2-ethynyl-4-pyridyl)-1,3-oxazol-4-yl]-4-cyclopropyl- 2(1H)-pyrimidinone (252 mg, 572 μmol, 55.6%) as a solid.

[0258] (+esi) [M+H]+= 433.2

[0259] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.80 (dd, J = 5.20, 0.86 Hz, 1H), 8.30 (dd, J = 1.64, 0.86 Hz, 1H), 8.15 (d, J = 6.97 Hz, 1H), 8.08 (dd, J = 5.20, 1.64 Hz, 1H), 7.89 (dd, J = 10.39, 1.97 Hz, 1H), 7.77 (t, J = 8.16 Hz, 1H), 7.33 (dt, J = 8.48, 1.02 Hz, 1H), 6.72 (d, J = 6.84 Hz, 1H), 4.55 (s, 1H), 2.09 - 2.17 (m, 1H), 1.15 - 1.21 (m, 4H)

[0260] The following compounds were prepared in an analogous manner from the appropriate starting materials using similar procedures. Compound (M+H)+Calc. Mass 219433.2 432.842 220433 432.842221451.1 450.832 222451.1 450.832Synthesis of Compound 223.1-[5-(4-chloro-3-fluorophenyl)-2-(2-methyl-1,3-thiazol-5-yl)-1,3- oxazol-4-yl]-4-cyclopropyl-2(1H)-pyrimidinone: 1-(2-chloro-5-(4-chloro-3-fluorophenyl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one

[0261] To a -78 °C suspension of 1-(5-(4-chloro-3-fluorophenyl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one (750 mg, 1 Eq, 2.26 mmol) in THF (18 mL) was added lithium bis(trimethylsilyl)amide (2.71 mL, 1 molar in THF, 1.2 Eq, 2.71 mmol) dropwise over 2 minutes. The reaction mixture was stirred at -78 °C one hour. The flask was transferred to a -40 °C bath, and the mixture was stirred for an additional 15 minutes. The reaction was returned to -78 °C and allowed to cool for 10 minutes. Then, perchloroethane (642 mg, 1.2 Eq, 2.71 mmol) was dissolved in 1 mL THF and added dropwise. The reaction mixture was then stirred for 15 minutes at temperature. The reaction was then transferred again to a -40 °C bath and stirred for 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride and stirred while warming to room temperature. The mixture was extracted with DCM (3 times). The organics were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by normal phase chromatography (40 g silica gel, 40-100% EtOAc in heptane) affording 1-(2-chloro-5-(4-chloro-3-fluorophenyl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one (575 mg, 1.57 mmol, 69.5%) as a solid.

[0262] LCMS: (M+H)+= 366.0

[0263] 1H NMR (400 MHz, DMSO) δ 8.06 (d, J = 7.0 Hz, 1H), 7.75 (t, J = 8.1 Hz, 1H), 7.49 (dd, J = 10.2, 2.0 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 7.0 Hz, 1H), 1.15 (d, J = 6.7 Hz, 4H). 1-[5-(4-chloro-3-fluorophenyl)-2-(2-methyl-1,3-thiazol-5-yl)-1,3-oxazol-4-yl]-4-cyclopropyl- 2(1H)-pyrimidinone [Compound 223]

[0264] A mixture of 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (33 mg, 1.2 Eq, 0.15 mmol), 1-(2-chloro-5-(4-chloro-3-fluorophenyl)oxazol-4-yl)-4-cyclopropylpyrimidin- 2(1H)-one (45 mg, 1 Eq, 0.12 mmol), Pd(dppf) (9.0 mg, 0.1 Eq, 12 μmol), and cesium carbonate (96 mg, 2.4 Eq, 0.29 mmol) in dioxane (1.3 mL) and water (0.2 mL) was stirred at 90 °C for 1.5 hours. The reaction mixture was cooled to room temperature, and the mixture was adsorbed ontosilica gel. This material was then and purified by column chromatography (12 g silica gel, 0-10% MeOH in DCM) to provide 1-[5-(4-chloro-3-fluorophenyl)-2-(2-methyl-1,3-thiazol-5-yl)-1,3- oxazol-4-yl]-4-cyclopropyl-2(1H)-pyrimidinone (11 mg, 26 μmol, 21%) as a white solid.

[0265] LCMS: (M+H)+= 429.0

[0266] 1H NMR (400 MHz, DMSO) δ 8.56 (s, 1H), 8.13 (d, J = 6.8 Hz, 1H), 7.76 (t, J = 8.3 Hz, 1H), 7.65 (d, J = 10.2 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 6.69 (d, J = 6.9 Hz, 1H), 2.78 (s, 3H), 2.12 (s, 1H), 1.16 (d, J = 5.2 Hz, 4H).

[0267] The following compounds were prepared in an analogous manner from the appropriate starting materials using similar procedures. Compound (M+H)+Mass 223 429 428.876 224 438.0 437.862 225 453 452.848 226 454.1 453.861 Synthesis of Compound 227.4-cyclopropyl-1-{2-(1-methyl-2-oxo-6-quinolyl)-5-[p- (trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-2(1H)-pyrimidinone: N-(1-hydroxy-2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)formamide

[0268] To a stirred solution of 2,2-dihydroxy-1-(4-(trifluoromethyl)phenyl)ethan-1-one (10.0 g, 1.0 Eq, 45.4 mmol) in 1,4-Dioxane (150 mL) was added formamide (2.46 g, 2.17 mL, 1.2 Eq, 54.5 mmol) and the resulting reaction mixture was heated at 90 °C for 8 h. The reaction was allowed to cool to room temperature and the dioxane was removed under reduced pressure. The resulting residue was poured into ice-cold water and the obtained precipitate was collected by vacuum filtration. The solid was dissolved in ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The obtained solid was triturated with MTBE (100 mL),filtered, washed with MTBE, and dried under reduced pressure to afford N-(1-hydroxy-2-oxo-2- (4-(trifluoromethyl)phenyl)ethyl)formamide (9.82 g, 39.7 mmol, 87.5%) as a solid.

[0269] 1H NMR (400 MHz, CHLOROFORM-d) d ppm 8.34 (s, 1 H), 8.24 (d, J = 8.07 Hz, 2 H), 7.80 (d, J = 8.31 Hz, 2 H), 6.91 (brs, 1 H), 6.59 (t, J = 6.60 Hz, 1 H), 4.61 (d, J = 5.87 Hz, 1 H). N-(1-(4-cyclopropyl-2-oxopyrimidin-1(2H)-yl)-2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl) formamide

[0270] To a solution of N-(1-hydroxy-2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)formamide (15.0 g, 1.00 Eq, 60.7 mmol) in DCM (500 mL) was added PCl5 (14.5 g, 1.15 Eq, 69.8 mmol) at 0 °C. The mixture was then allowed to warm to room temperature and stirred at temperature for 2 hours. The solvent was evaporated completely under vacuum. This crude material was triturated with hexanes and the solid collected by vacuum filtration. The resulting solid product N-(1-chloro-2- oxo-2-(4-(trifluoromethyl)phenyl)ethyl)formamide was dried under vacuum and used directly in the next step.

[0271] To a round bottom flask were added 4-cyclopropylpyrimidin-2(1H)-one (7.44 g, 0.90 Eq, 54.6 mmol), DMF (100 mL), and triethylamine (18.4 g, 25.4 mL, 3.00 Eq, 182 mmol). The mixture was then cooled to 0 °C and N-(1-chloro-2-oxo-2-(4- (trifluoromethyl)phenyl)ethyl)formamide (assuming 100% yield, 60.7 mmol) in DMF (50 mL) was added dropwise. The resulting reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was poured into ice water and extracted with EtOAc (2 x 500 mL). The combined organic layers were then washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide crude product. To this material was added ethyl acetate and the resulting solid was collected by filtration. The material was then washed with hexanes and dried under reduced pressure to yield N-(1-(4-cyclopropyl-2-oxopyrimidin-1(2H)-yl)- 2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)formamide (7.50 g, 20.5 mmol, 33 %) as a solid. This material was used directly in the next step.

[0272] LCMS : (+ESI)[M+1]= 366.2. 4-cyclopropyl-1-(5-(4-(trifluoromethyl)phenyl)oxazol-4-yl)pyrimidin-2(1H)-one

[0273] N-(1-(4-cyclopropyl-2-oxopyrimidin-1(2H)-yl)-2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl) formamide (7.50 g, 1 Eq, 20.5 mmol) was combined with Eaton’s reagent (7.5% phosphorus(V) oxide in methanesulfonic acid, 73.3 g, 48.8 mL, 15.0 Eq, 308 mmol) and the mixture was heated to 70 °C for 150 minutes. The reaction was then poured into ice and basified with solid sodiumbicarbonate. The aqueous mixture was then extracted with EtOAc (3 x 300 ml). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product. The crude material was purified by normal phase chromatography (40 g silica gel, 0-3% methanol in chloroform). The fractions containing product were evaporated under reduced pressure to yield 4-cyclopropyl-1-(5-(4- (trifluoromethyl)phenyl)oxazol-4-yl)pyrimidin-2(1H)-one (2.3 g, 6.5 mmol, 32 %) as a solid.

[0274] LCMS : (+ESI)[M+1]= 348.1.

[0275] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.67 - 8.81 (m, 1 H), 8.05 - 8.17 (m, 1 H), 7.84 - 7.93 (m, 2 H), 7.55 - 7.69 (m, 2 H), 6.60 - 6.72 (m, 1 H), 2.04 - 2.18 (m, 1 H), 1.08 - 1.22 (m, 4 H). 4-cyclopropyl-1-{2-(1-methyl-2-oxo-6-quinolyl)-5-[p-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}- 2(1H)-pyrimidinone [Compound 227]

[0276] To a resealable vial were added 4-cyclopropyl-1-(5-(4-(trifluoromethyl)phenyl)oxazol-4- yl)pyrimidin-2(1H)-one (30 mg, 1 Eq, 86 μmol), 6-bromo-1-methylquinolin-2(1H)-one (31 mg, 1.5 Eq, 0.13 mmol), PdOAc2 (1.9 mg, 0.10 Eq, 8.6 μmol), dicyclohexyl(2',6'-diisopropoxy- [1,1'- biphenyl]-2-yl)phosphane (8.1 mg, 0.20 Eq, 17 μmol), K2CO3 (36 mg, 3 Eq, 0.26 mmol), and toluene (1 mL). The reaction was capped and heated at 115 °C for 16 hours. The crude reaction was mixed with 1 mL of DMF and directly purified by reverse phase chromatography (C18 column, 10-100% MeCN in water with 0.1% TFA). This purification provided 4-cyclopropyl-1- {2-(1-methyl-2-oxo-6-quinolyl)-5-[p-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-2(1H)- pyrimidinone (8.5 mg, 17 μmol, 20 %) as a solid.

[0277] 1H NMR (400 MHz, CDCl3) δ 8.39 – 8.27 (m, 2H), 7.90 (d, J = 9.3 Hz, 1H), 7.73 (dq, J = 14.8, 7.7 Hz, 5H), 7.60 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 9.5 Hz, 1H), 6.51 (d, J = 6.9 Hz, 1H), 3.86 (s, 3H), 2.10 (dt, J = 8.1, 3.9 Hz, 1H), 1.51 – 1.43 (m, 2H), 1.35 (dt, J = 7.7, 3.5 Hz, 2H).

[0278] LCMS (M+H)+ = 505.1. LCAP % at 280 nm = 97.9%.

[0279] The following compounds were prepared in an analogous manner from the appropriate starting materials using similar procedures.Synthesis of Compound 2664-cyclopropyl-1-[2-(1-methylisoquinolin-6-yl)-5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl]- 1,2-dihydropyrimidin-2-one:

[0280] 6-Bromo-1-methylisoquinoline (1.77 g, 7.63 mmol, 1.5 eq), potassium carbonate (2.11 g, 15.3 mmol, 3.0 eq), pivalic acid (228 μl, 2.04 mmol, 0.4 eq), RuPhos (0.475 g, 1.02 mmol, 0.2 eq),and 4-cyclopropyl-1-{5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-1,2-dihydropyrimidin-2-one (1.9 g, 5.09 mmol, 1.0 eq) were placed in a reaction tube with toluene (51.3 mL). After degassing with Ar for 10 minutes, palladium(II) acetate (0.114 g, 0.509 mmol, 0.1 eq) was added. The reaction vessel was sealed, and the reaction mixture was stirred at 115 °C for 16 hours. The crude reaction was concentrated under vacuum. The residue was treated with brine, and the mixture was extracted with dichloromethane (3 times). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (0-10% MeOH in DCM) to give 4-cyclopropyl-1-[2-(1-methylisoquinolin- 6-yl)-5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl]-1,2-dihydropyrimidin-2-one (1.5 g, 3.07 mmol, 60%).

[0281] LC-MS: 2.10 min, [M+H]+= 489.2, 99.04% @ 220 nm.

[0282] 1H NMR (300 MHz, DMSO-d6) δ 8.82 (d, J = 1.7 Hz, 1H), 8.48 (d, J = 5.8 Hz, 1H), 8.45 – 8.38 (m, 1H), 8.32 (dd, J = 8.8, 1.8 Hz, 1H), 8.24 (d, J = 6.9 Hz, 1H), 7.97 – 7.86 (m, 3H), 7.86 – 7.77 (m, 2H), 6.74 (d, J = 6.9 Hz, 1H), 2.95 (s, 3H), 2.15 (qd, J = 6.8, 5.4 Hz, 1H), 1.27 – 1.11 (m, 4H).S (N-(1-hydroxy-2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)formamide

[0283] To a stirred solution of 2,2-dihydroxy-1-(4-(trifluoromethyl)phenyl)ethan-1-one (400 g, 1 Eq, 1.82 mol) in dioxane (3000 mL) was added formamide (205 g, 181 mL, 2.5 Eq, 4.54 mol), andthe resulting reaction mixture was heated to 90 °C for 3 hours. Then, the reaction mixture was allowed to cool to room temperature, and the excess solvent was evaporated under reduced pressure. The obtained residue was poured into ice water (3000 mL) and a solid precipitated. This material was collected by vacuum filtration, washed with hexanes (2000 mL), washed with 20% MTBE in hexanes (2000 mL), and dried under vacuum at 60 °C for 24 hours to afford N-(1- hydroxy-2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)formamide (340 g, 1.32 mol, 72.4%) as a solid.

[0284] 1H NMR (DMSO-d6, 400 MHz) δ 8.9-9.1 (m, 1H), 8.1-8.2 (m, 2H), 8.10 (d, 1H, J = 0.7 Hz), 7.92 (d, 2H, J = 8.3 Hz), 6.8-6.9 (m, 1H), 6.3-6.4 (m, 1H). N-(1-chloro-2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)formamide

[0285] To a solution of N-(1-hydroxy-2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)formamide (100 g, 1.0 Eq, 405 mmol) in DCM (1000 mL) was added PCl5 (92.7 g, 1.1 Eq, 445 mmol) at 0° C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to give a crude solid. The solid was triturated with 10% MTBE in hexanes (1.5 L), collected by vacuum filtration, and dried under vacuum to yield N-(1-chloro-2-oxo-2-(4- (trifluoromethyl)- phenyl)ethyl)formamide (100 g, 377 mmol, 93%) as a solid. This material was directly used in the next step without purification. N-(1-(4-cyclopropyl-2-oxopyrimidin-1(2H)-yl)-2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl) formamide

[0286] In a 2 L multi necked round bottom flask, 4-cyclopropylpyrimidin-2(1H)-one (49.6 g, 0.9 Eq, 364 mmol) and DMF (500 mL) were combined. Then, TEA (123 g, 169 mL, 3.0 Eq, 1.21 mol) was added, and the mixture was cooled to 0 °C. A solution of N-(1-chloro-2-oxo-2-(4- (trifluoromethyl)- phenyl)ethyl)formamide (100 g, 1.03 eq, 0.377 mol) in DMF (500 mL) was added drop-wise for 1 hour, and the resulting reaction mixture was stirred at 25 °C for 2 hours. At this time, the excess solvent was evaporated under reduced pressure, and the obtained residue was poured into ice water (2 L). The resulting solid was collected by vacuum filtration, washed with 50% MTBE in hexanes (500 mL), washed with ethyl acetate (500 mL), and dried under vacuum to afford N-(1-(4-cyclopropyl-2-oxopyrimidin-1(2H)-yl)-2-oxo-2-(4- (trifluoromethyl)phenyl)ethyl)formamide (50 g, 0.12 mol, 35%) as a solid.

[0287] (+ESI) [M+H]+= 366.2

[0288] 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.35 (s, 1 H), 7.94 - 8.00 (m, 2 H), 7.86 (d, J = 8.16 Hz, 2H), 7.68 (d, J = 8.29 Hz, 2H), 6.70 (d, J = 7.50 Hz, 1H), 6.33 (d, J = 6.84 Hz, 1H), 1.72 - 1.89 (m, 1H), 1.07 - 1.24 (m, 4H). 4-cyclopropyl-1-(5-(4-(trifluoromethyl)phenyl)oxazol-4-yl)pyrimidin-2(1H)-one

[0289] In a 1 L 3-necked round bottom flask, triphenylphosphine (40 g, 2.0 Eq, 0.15 mol) and DCM (600 mL) were combined. Then, iodine (39 g, 2.0 Eq, 0.15 mol) was added portion-wise over an hour at room temperature. Next, TEA (31 g, 43 mL, 4.0 Eq, 0.31 mol) was added over 10 minutes, and the resulting reaction mixture was stirred for 10 minutes. Finally, N-(1-(4- cyclopropyl-2-oxopyrimidin-1(2H)-yl)-2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)formamide (28 g, 1 Eq, 77 mmol) was added portion-wise over 30 minutes, and the resulting reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was diluted with DCM (300 mL), washed with aqueous sodium thiosulphate (3 x 500 mL), and washed with brine (500 mL). The layers were separated, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a crude solid. This material was taken up in ethyl acetate (300 mL) and stirred for 1 hour at room temperature. The resulting solid was collected by vacuum filtration. The solid was again taken up in ethyl acetate (300 mL), stirred for 1 hour at room temperature, and collected by vacuum filtration. The solid was then washed with ethyl acetate and dried under reduced pressure to yield 4-cyclopropyl-1-(5-(4-(trifluoromethyl)- phenyl)oxazol-4-yl)pyrimidin-2(1H)-one (15 g, 42 mmol, 55%) as a solid.

[0290] (+ESI) [M+H]+= 348.1

[0291] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (s, 1 H), 8.08 (d, J = 6.84 Hz, 1H), 7.06 (d, J = 7.76 Hz, 2H), 6.67 (d, J = 6.97 Hz, 1H), 2.18 (s, 3H), 2.07 - 2.14 (m, 1H) 1.12 - 1.18 (m, 4H). 4-cyclopropyl-1-{2-(6-fluoro-3-quinolyl)-5-[p-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-2(1H)- pyrimidinone [Compound 297]

[0292] In a 25 mL sealable tube, 4-cyclopropyl-1-(5-(4-(trifluoromethyl)phenyl)oxazol-4- yl)pyrimidin-2(1H)-one (100 mg, 1 Eq, 288 μmol), 3-bromo-6-fluoroquinoline (130 mg, 2.0 Eq, 576 μmol), and toluene (4 mL) were combined and purged with argon for 10 minutes. Then, K2CO3(199 mg, 5.0 Eq, 1.44 mmol) was added, and the argon purging was continued for a further 10 minutes. Next, diacetoxypalladium (12.9 mg, 0.2 Eq, 57.6 μmol) and dicyclohexyl(2',6'- diisopropoxy-[1,1'-biphenyl]-2-yl)phosphane (26.9 mg, 0.2 Eq, 57.6 μmol) were added, and the mixture was purged with argon for 5 more minutes. Finally, the tube was sealed and heated to 105°C for 16 hours. Upon cooling, the reaction mixture was filtered through celite with the aid of DCM (25 mL). The combined filtrate was concentrated under vacuum to afford crude material. The crude compound was purified by normal phase flash chromatography (silica gel, 60% EtOAc in hexanes) to afford 4-cyclopropyl-1-{2-(6-fluoro-3-quinolyl)-5-[p-(trifluoromethyl)phenyl]-1,3- oxazol-4-yl}-2(1H)-pyrimidinone (37.9 mg, 74.9 μmol, 26%) as a solid.

[0293] (+esi) [M+H]+= 493.0

[0294] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.55 (d, J = 1.97 Hz, 1H), 9.21 (d, J = 1.97 Hz, 1H), 8.19 - 8.25 (m, 2H), 8.03 (dd, J = 9.21, 2.76 Hz, 1H), 7.94 (d, J = 8.42 Hz, 2H), 7.79 - 7.88 (m, 3H), 6.74 (d, J = 6.84 Hz, 1H), 2.07 - 2.18 (m, 1H), 1.13 - 1.26 (m, 4H).

[0295] The following compounds were prepared in an analogous manner from the appropriate starting materials using similar procedures.o 1 p

[0296] In a 25 mL sealable tube, 4-cyclopropyl-1-(5-(4-(trifluoromethyl)phenyl)oxazol-4- yl)pyrimidin-2(1H)-one (100 mg, 1.0 Eq, 288 μmol), 3-bromo-8-chloroquinoline (105 mg, 1.5 Eq,432 μmol), K2CO3 (199 mg, 5.0 Eq, 1.44 mmol), and toluene (3 mL) were combined, and the mixture was purged with argon for 10 minutes. Then, PdCl2(dppf) (23.5 mg, 0.1 Eq, 28.8 μmol) and copper(I) iodide (11.0 mg, 0.2 Eq, 57.6 μmol) were added, and the mixture was purged with argon for 5 more minutes. Finally, the tube was sealed and heated to 105 °C for 24 hours. The crude reaction mixture was filtered through celite, and the celite was washed with DCM (2 x 20 mL). The combined filtrate was concentrated under vacuum to afford crude product. The crude compound was purified by normal phase flash chromatography (silica gel, 2% MeOH in CHCl3) to afford 1-{2-(8-chloro-3-quinolyl)-5-[p-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-4- cyclopropyl-2(1H)-pyrimidinone (13 mg, 25 μmol, 8.7%) as a solid.

[0297] (+esi) [M+H]+= 509.0.

[0298] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.67 (d, J = 2.24 Hz, 1H), 9.33 (d, J = 2.10 Hz, 1H), 8.21 - 8.27 (m, 2H), 8.11 (dd, J = 7.50, 1.05 Hz, 1 H), 7.95 (d, J = 8.42 Hz, 2H), 7.85 (d, J = 8.29 Hz, 2H), 7.75 (t, J = 7.89 Hz, 1H), 6.74 (d, J = 6.84 Hz, 1H), 2.11 - 2.19 (m, 1H), 1.14 - 1.22 (m, 4H).

[0299] The following compounds were prepared in an analogous manner from the appropriate starting materials using similar procedures.Synthesis of Compound 308.4-cyclopropyl-1-{2-(2-isoindolinyl)-5-[p-(trifluoromethyl)phenyl]- 1,3-oxazol-4-yl}-2(1H)-pyrimidinone:1-{2-chloro-5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-4-cyclopropyl-1,2-dihydropyrimidin- 2-one

[0300] To a -78 °C suspension of 4-cyclopropyl-1-(5-(4-(trifluoromethyl)phenyl)oxazol-4- yl)pyrimidin-2(1H)-one (1.88 g, 5.41 mmol, 1.0 eq) in THF (113 mL) was added a 1.0 M solution of LHMDS in THF (6.0 mL, 5.96 mmol, 1.1 eq) dropwise over 2 minutes. The reaction mixturewas stirred at -78 °C for one hour. At this time, the cooling bath was removed, and the mixture was stirred 15 minutes more. The mixture was again cooled to -78 °C and hexachloroethane (1.41 g, 5.96 mmol, 1.1 eq) was added. The reaction mixture was stirred 15 minutes and then the cooling bath was removed. The mixture warmed to room temperature and was and stirred for an additional 30 minutes. The solution was diluted with DCM and washed with saturated aqueous ammonium chloride. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (80g, 70-100% EtOAc in hexanes) to afford 1-{2-chloro-5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-4- cyclopropyl-1,2-dihydropyrimidin-2-one (1.40 g, 3.67 mmol, 67.7%) as a cream solid.

[0301] [M+Na]+Calculated = 404.04 (100.0%), 406.4 (32.0%); experimental = 404, 406

[0302] HPLC purity: 97 % @ 254 nm

[0303] 1H NMR (600 MHz, DMSO) δ ppm 8.08 (d, J = 6.9 Hz, 1H), 7.89 (m, 2H), 7.64 – 7.59 (m, 2H), 6.69 (d, J = 6.9 Hz, 1H), 2.11 (tt, J = 7.8, 4.8 Hz, 1H), 1.23 – 1.12 (m, 4H). 4-cyclopropyl-1-{2-(2-isoindolinyl)-5-[p-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-2(1H)- pyrimidinone [Compound 308]

[0304] To a vial were added 1-(2-chloro-5-(4-(trifluoromethyl)phenyl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one (50.0 mg, 1 Eq, 131 μmol), isoindoline∙HCl (18.7 mg, 1.2 Eq, 157 μmol), and potassium carbonate (54.3 mg, 3 Eq, 393 μmol). Isopropanol (1 mL) was added, and the resulting slurry was stirred at 150 °C for 30 minutes in a microwave reactor. The reaction was passed through a 50 μm syringe filter and purified by reverse phase HPLC (C18 column, 0- 60% MeCN in water with 0.1% TFA). The product containing fraction were combined and re- purified by silica gel column chromatography (0-100% EtOAc in heptane) to provide 4- cyclopropyl-1-{2-(2-isoindolinyl)-5-[p-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-2(1H)- pyrimidinone (6.2 mg, 13.3 μmol, 10%).

[0305] 1H NMR (400 MHz, DMSO) δ ppm 8.09 (d, J = 6.8 Hz, 1H), 7.80 (d, J = 8.2 Hz, 2H), 7.50 – 7.34 (m, 6H), 6.65 (d, J = 6.8 Hz, 1H), 4.94 (s, 4H), 2.15 – 2.08 (m, 1H), 1.30 – 1.13 (m, 4H).

[0306] LCMS (M+H)+= 465.2, LCAP % at 280 nm = 95%.S 1

[0307] To a slurry of 1-(4-fluorophenyl)-2,2-dihydroxyethan-1-one (10 g, 1.0 Eq, 59 mmol) in 1,4-dioxane (150 mL) was added formamide (5.3 g, 4.7 mL, 2 Eq, 0.12 mol) and the reaction mixture was heated at 90 °C for 16 hours. The reaction was concentrated and poured into water (300 mL). The resulting solid was filtered and rinsed with water (200 mL). The resulting solid material was dried in a 50 °C vacuum oven for 24 hours. This material was N-(2-(4-fluorophenyl)- 1-hydroxy-2-oxoethyl)formamide (8.7 g, 75% yield, 80% purity).

[0308] 1H NMR: (400 MHz, DMSO) δ 8.97 (d, J = 8.7 Hz, 1H), 8.15 – 8.03 (m, 3H), 7.38 (td, J = 8.7, 4.3 Hz, 2H), 6.77 (d, J = 7.1 Hz, 1H), 6.37 (t, J = 7.7 Hz, 1H). N-(1-(4-cyclopropyl-2-oxopyrimidin-1(2H)-yl)-2-(4-fluorophenyl)-2-oxoethyl)formamide

[0309] To a slurry of N-(2-(4-fluorophenyl)-1-hydroxy-2-oxoethyl)formamide (300 mg, 1 Eq, 1.52 mmol) in DCM (5 mL) was added PCl5(348 mg, 1.1 Eq, 1.67 mmol). The resulting homogeneous solution was stirred at 50 °C for 30 min. The mixture was cooled to room temperature, concentrated under reduced pressure, and dried in vacuo to give N-(1-chloro-2-(4- fluorophenyl)-2-oxoethyl)formamide. This crude material was used directly and is unstable to storage. To a solution of N-(1-chloro-2-(4-fluorophenyl)-2-oxoethyl)formamide in DMF (3 mL) was added triethylamine (462 mg, 0.63 mL, 3 Eq, 4.56 mmol) followed by solid 4- cyclopropylpyrimidin-2(1H)-one (228 mg, 1.1 Eq, 1.67 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. The reaction was concentrated to dryness and water (15 mL) was added. A solid precipitated after the addition of water and it was collected and dried in a 50 °C vacuum oven for 16 hours. This gave N-(1-(4-cyclopropyl-2-oxopyrimidin-1(2H)-yl)-2-(4-fluorophenyl)-2-oxoethyl)formamide (242 mg, 768 μmol, 50.4 %). This material was used directly in the next reaction. 4-cyclopropyl-1-(5-(4-fluorophenyl)oxazol-4-yl)pyrimidin-2(1H)-one

[0310] N-(1-(4-Cyclopropyl-2-oxopyrimidin-1(2H)-yl)-2-(4-fluorophenyl)-2-oxoethyl)formamide (120 mg, 1 Eq, 381 μmol) was suspended in Eaton's reagent (7.5% phosphorus(V) oxide in methanesulfonic acid, 3 mL) and the resulting material was heated to 60 °C for 2 hours. The reaction was mixed with 1 mL of MeOH and directly purified by reverse phase chromatography (C18 HPLC column, 10- 100% MeCN in water with 0.1% TFA). This purification provided 4- cyclopropyl-1-(5-(4-fluorophenyl)oxazol-4-yl)pyrimidin-2(1H)-one (60 mg, 0.20 mmol, 53 %).

[0311] 1H NMR: (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.87 (d, J = 7.0 Hz, 1H), 7.56 – 7.42 (m, 2H), 7.20 – 7.08 (m, 2H), 6.42 (d, J = 7.1 Hz, 1H), 2.21 (ddd, J = 7.7, 4.9, 2.9 Hz, 1H), 1.46 (ddd, J = 12.6, 6.1, 3.4 Hz, 4H). 4-cyclopropyl-1-[5-(p-fluorophenyl)-2-(1-methyl-6-isoquinolyl)-1,3-oxazol-4-yl]-2(1H)- pyrimidinone [Compound 309]

[0312] To a resealable vial were added 4-cyclopropyl-1-(5-(4-fluorophenyl)oxazol-4- yl)pyrimidin-2(1H)-one (30 mg, 1 Eq, 0.10 mmol), 6-bromo-1-methylisoquinoline (34 mg, 1.5 Eq, 0.15 mmol), pivalic acid (4.1 mg, 0.40 Eq, 40 μmol), Pd(OAc)2(2.3 mg, 0.10 Eq, 10 μmol), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphane (9.4 mg, 0.20 Eq, 20 μmol), and K2CO3 (42 mg, 3 Eq, 0.30 mmol). Toluene (1 mL) was then added, and the sealed vessel was heated at 115 °C for 16 hours. The crude reaction was cooled to room temperature and mixed with 1 mL of DMF. The mixture was then syringe filtered and directly purified by reverse phase chromatography (C18 HPLC column, 10-100% MeCN in water with 0.1% TFA). This purification provided 4-cyclopropyl-1-[5-(p-fluorophenyl)-2-(1-methyl-6-isoquinolyl)-1,3-oxazol-4-yl]-2(1H)- pyrimidinone (18 mg, 41 μmol, 41 %).

[0313] 1H NMR: (400 MHz, MeOD) δ 8.89 (s, 1H), 8.64 (q, J = 8.9 Hz, 2H), 8.44 (d, J = 6.5 Hz, 1H), 8.32 (d, J = 6.6 Hz, 1H), 7.90 (d, J = 6.9 Hz, 1H), 7.79 – 7.60 (m, 2H), 7.23 (t, J = 8.5 Hz, 2H), 6.65 (d, J = 7.0 Hz, 1H), 3.27 (s, 3H), 2.16 – 2.04 (m, 1H), 1.45 – 1.23 (m, 4H).

[0314] LCMS (ESI+): m / z 439.1 [M+H]+

[0315] HPLC: RT: 1.92 min

[0316] The following compounds were prepared in an analogous manner from the appropriate starting materials using similar procedures.Synthesis of 503, 4-cyclopropyl-1-(5-(4-fluorophenyl)-2-(2-methylbenzo[d]oxazol-6-yl)oxazol-4- yl)pyrimidin-2(1H)-one4-cyclopropyl-1-(5-(4-fluorophenyl)-2-(2-methylbenzo[d]oxazol-6-yl)oxazol-4-yl)pyrimidin- 2(1H)-one:

[0317] To a resealable vial were added 4-cyclopropyl-1-(5-(4-fluorophenyl)oxazol-4- yl)pyrimidin-2(1H)-one (0.050 g, 1 Eq, 0.17 mmol), 6-bromo-2-methylbenzo[d]oxazole (46 mg, 1.3 Eq, 0.22 mmol), CuBr(phenan)(PPh3) (9.9 mg, 0.1 Eq, 17 μmol), Pd(PPh3)4(19 mg, 0.1 Eq, 17 μmol), Cs2CO3(0.12 g, 2.2 Eq, 0.37 mmol), and toluene (3.0 mL). The vial was capped, purged with nitrogen for 5 minutes, and heated at 105 °C for 16 hours. The crude mixture was concentrated onto Celite and purified with normal phase column chromatography (24 g silica gel column, 0-5% MeOH / DCM) to afford crude product. This material was triturated in MeOH, and the resulting solid was collected and dried to afford 4-cyclopropyl-1-(5-(4-fluorophenyl)-2-(2-methylbenzo[d]oxazol-6-yl)oxazol-4-yl)pyrimidin-2(1H)-one (10.4 mg, 24.4 μmol, 14 %) as a solid.

[0318] LCMS (M+H)+= 429.1. LCAP % at 280 nm 95%.

[0319] 1H NMR (400 MHz, MeOD) δ 8.36 (d, J = 1.5 Hz, 1H), 8.18 (dd, J = 8.4, 1.6 Hz, 1H), 8.08 (d, J = 6.9 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.70 – 7.61 (m, 2H), 7.27 (t, J = 8.8 Hz, 2H), 6.73 (d, J = 6.9 Hz, 1H), 2.72 (s, 3H), 2.21 – 2.10 (m, 1H), 1.39 – 1.25 (m, 4H).Synthesis of 504, 4-cyclopropyl-1-(5-(4-fluorophenyl)-2-(1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)oxazol-4-yl)pyrimidin-2(1H)-one4-cyclopropyl-1-[5-(4-fluorophenyl)-2-{1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl}-1,3-oxazol- 4-yl]-1,2-dihydropyrimidin-2-one:

[0320] Under inert atmosphere, 4-cyclopropyl-1-[5-(4-fluorophenyl)-1,3-oxazol-4-yl]-1,2- dihydropyrimidin-2-one (0.56 g, 1.71 mmol, 1.0 eq), potassium carbonate (0.711 g, 5.14 mmol, 3.0 eq), bromo(1,10-phenanthroline)(triphenylphosphine)copper(I) (0.151 g, 0.257 mmol, 0.15 eq), RuPhos (0.16 g, 0.343 mmol, 0.2 eq), and 5-bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine (0.545 g, 2.57 mmol, 1.5 eq) were suspended in dioxane (11.2 mL). The resulting mixture was purged with Ar for 5 minutes prior to the addition of palladium(II) acetate (0.058 g, 0.257 mmol, 0.15 eq). The reaction vial was sealed, and the reaction mixture was stirred at 120 °C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and filtered through a pad of celite. The celite pad was washed with a mixture of dichloromethane and methanol (9 / 1, v / v). The filtrate was concentrated under reduced pressure to give the crude product which was purified via normal phase column chromatography (0-5% MeOH in DCM) to provide4-cyclopropyl-1-[5-(4-fluorophenyl)-2-{1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl}-1,3-oxazol-4- yl]-1,2-dihydropyrimidin-2-one (0.308 g, 0.72 mmol, 42%) as a solid.

[0321] LC-MS: 2.50 min, [M+H]+= 429.2, 98.4% @ 205 nm

[0322] 1H NMR (300 MHz, DMSO-d6) δ 9.36 (t, J = 1.1 Hz, 1H), 8.65 (d, J = 1.3 Hz, 1H), 8.38 (d, J = 0.8 Hz, 1H), 8.21 (d, J = 6.9 Hz, 1H), 7.60 (dd, J = 8.8, 5.3 Hz, 2H), 7.41 (t, J = 8.9 Hz, 2H), 6.70 (d, J = 6.9 Hz, 1H), 4.27 (s, 3H), 2.20 – 2.07 (m, 1H), 1.24 – 1.12 (m, 4H).Synthesis of 505, 6-(4-(4-cyclopropyl-2-oxopyrimidin-1(2H)-yl)-5-(4-fluorophenyl)oxazol-2-yl)- 2-methylisoindolin-1-one6-[4-(4-cyclopropyl-2-oxo-1,2-dihydropyrimidin-1-yl)-5-(4-fluorophenyl)-1,3-oxazol-2-yl]-2- methyl-2,3-dihydro-1H-isoindol-1-one:

[0323] Under inert atmosphere, 4-cyclopropyl-1-[5-(4-fluorophenyl)-1,3-oxazol-4-yl]-1,2- dihydropyrimidin-2-one (0.105 g, 0.336 mmol, 1.0 eq), potassium carbonate (0.139 g, 1.01 mmol, 3.0 eq), bromo(1,10-phenanthroline)(triphenylphosphine)copper(I) (0.03 g, 0.05 mmol, 0.15 eq), RuPhos (0.031 g, 0.067 mmol, 0.2 eq), and 6-bromo-2-methylisoindolin-1-one (0.099 g, 0.437 mmol, 1.3 eq) were suspended in dioxane (2.0 mL). The resulting mixture was purged with Ar for 5 minutes prior to the addition of palladium(II) acetate (0.011 g, 0.05 mmol, 0.15 eq). The reaction vial was sealed, and the reaction mixture was stirred for 1.5 hours at 120 °C. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and filtered through a pad of celite. The celite pad was washed with a mixture of dichloromethane and methanol (9 / 1, v / v). The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified via normal phase column chromatography (0-4% MeOH in DCM). Fractions containing the desired product were concentrated under reduced pressure. The residue was triturated withmethanol, collected by filtration, washed with methanol, and dried under vacuum to provide 6-[4- (4-cyclopropyl-2-oxo-1,2-dihydropyrimidin-1-yl)-5-(4-fluorophenyl)-1,3-oxazol-2-yl]-2-methyl- 2,3-dihydro-1H-isoindol-1-one (0.025 g, 0.056 mmol, 17%).

[0324] LC-MS: 2.53 min, [M+H]+= 443.2, 98.4% @ 210 nm.

[0325] 1H NMR (300 MHz, DMSO-d6) δ 8.45 – 8.28 (m, 2H), 8.19 (d, J = 6.9 Hz, 1H), 7.96 – 7.74 (m, 1H), 7.76 – 7.55 (m, 2H), 7.48 – 7.19 (m, 2H), 6.70 (d, J = 6.9 Hz, 1H), 4.59 (s, 2H), 3.12 (s, 3H), 2.17 – 1.93 (m, 1H), 1.41 – 0.92 (m, 4H). Compound (M+H)+Calc. Mass 505 443.2 442.45 Synthesis of 506, 4-cyclopropyl-1-(2-(4-(difluoromethyl)phenyl)-5-(4-fluorophenyl)oxazol-4- yl)pyrimidin-2(1H)-one4-cyclopropyl-1-(2-(4-(difluoromethyl)phenyl)-5-(4-fluorophenyl)oxazol-4-yl)pyrimidin- 2(1H)-one:

[0326] To a 25 mL sealable tube were added 4-cyclopropyl-1-(5-(4-fluorophenyl)oxazol-4- yl)pyrimidin-2(1H)-one (100 mg, 336 μmol, 1 Eq.), 1-bromo-4-(difluoromethyl)benzene (104 mg, 505 μmol, 1.5 Eq.), and toluene (5 mL). The mixture was purged with argon for 10 minutes. Then, potassium carbonate (139 mg, 1.01 mmol, 3 Eq.), bromo(1,10- phenanthroline)(triphenylphosphine)copper (20 mg, 34 μmol, 0.1 Eq.), and Pd(PPh3)4 (39 mg, 37 μmol, 0.1 Eq.) were added while purging with argon. Then, the tube was sealed and heated to 110 °C for 16 hours. The reaction mixture was cooled to ambient temperature, diluted with 5% methanol in DCM, and filtered. The filtrate was evaporated under reduced pressure. The resulting crude compound was purified by flash normal phase chromatography (12 g column, silica gel, 70- 90% EtOAc in hexanes) to yield 4-cyclopropyl-1-(2-(4-(difluoromethyl)phenyl)-5-(4- fluorophenyl)oxazol-4-yl)pyrimidin-2(1H)-one (90 mg, 208 µmol, 62%) as a solid.

[0327] LCMS: (+ESI)[M+H]+= 424.3.

[0328] 1H NMR (400 MHz, DMSO-d6) δ = 8.27 (br d, J = 8.2 Hz, 2H), 8.17 (d, J = 6.8 Hz, 1H), 7.80 (br d, J = 8.0 Hz, 2H), 7.63 (dd, J = 5.3, 8.9 Hz, 2H), 7.40 (br t, J = 8.8 Hz, 2H), 7.16 (t, J = 55.6 Hz, 1H), 6.69 (d, J = 7.0 Hz, 1H), 2.18 - 2.06 (m, 1H), 1.21 - 1.14 (m, 4H). Compound (M+H)+Calc. Mass 506 424.3 423.39 Synthesis of 507, 4-cyclopropyl-1-(5-(4-fluorophenyl)-2-(1-methyl-1H-indazol-5-yl)oxazol-4- yl)pyrimidin-2(1H)-one4-cyclopropyl-1-(5-(4-fluorophenyl)-2-(1-methyl-1H-indazol-6-yl)oxazol-4-yl)pyrimidin- 2(1H)-one:

[0329] To a 25 mL sealable tube were added 4-cyclopropyl-1-(5-(4-fluorophenyl)oxazol-4- yl)pyrimidin-2(1H)-one (58.5 mg, 197 μmol, 1 Eq.), 6-bromo-1-methyl-1H-indazole (62.3 mg, 295 μmol, 1.5 Eq.), and toluene (2 mL). The mixture was degassed with argon for 10 minutes. Then, potassium carbonate (109 mg, 787 μmol, 4 Eq.), Pd(PPh3)4 (23 mg, 20 μmol, 0.1 Eq.), and bromo(1,10-phenanthroline)(triphenylphosphine)- copper (17 mg, 29 μmol, 0.15 Eq.) were added while purging with argon. The tube was sealed, and the resulting reaction mixture was heated to 110 °C for 16 hours. The reaction mixture was cooled to ambient temperature, diluted with DCM, and^filtered. The filtrate was evaporated under reduced pressure to afford crude compound. The crude compound was purified by flash normal phase chromatography (12 g column, silica gel, 0- 100% EtOAc in hexanes). The fractions containing product were combined and concentrated under vacuum. The resulting compound was triturated with ethyl acetate, collected by vacuum filtration, and dried to afford 4-cyclopropyl-1-(5-(4-fluorophenyl)-2-(1-methyl-1H-indazol-6- yl)oxazol-4-yl)pyrimidin-2(1H)-one (55 mg, 124 µmol, 63%) as a solid.

[0330] (+ESI) [M+H]+= 428.0.

[0331] 1H NMR (400 MHz, DMSO-d6) δ = 8.62 (s, 1H), 8.26 (s, 1H), 8.20 (d, J = 6.8 Hz, 1H), 8.14 - 8.08 (m, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.62 (dd, J = 5.3, 8.7 Hz, 2H), 7.40 (br t, J = 8.9 Hz, 2H), 6.69 (d, J = 6.8 Hz, 1H), 4.12 (s, 3H), 2.17 - 2.07 (m, 1H), 1.21 - 1.14 (m, 4H). Compound (M+H)+Calc. Mass 507 428.0 427.44 Synthesis of 508, 4-cyclopropyl-1-(5-(4-fluorophenyl)-2-(1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)oxazol-4-yl)pyrimidin-2(1H)-one N N ONO NCui, K2CO3, pivalic acid NN O N Bis-(1-adamantyl)-butyl- Nphosphane, cataCXiumN p N Fd G3Br4-cyclopropyl-1-(5-(4-fluorophenyl)-2-(1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)oxazol-4- yl)pyrimidin-2(1H)-one:

[0332] To a 30 mL sealable tube were added 4-cyclopropyl-1-(5-(4-fluorophenyl)oxazol-4- yl)pyrimidin-2(1H)-one (100 mg, 336 μmol, 1 Eq.), 5-bromo-1-methyl-1H-pyrrolo[2,3-c]pyridine (106 mg, 505 μmol, 1.5 Eq.), potassium carbonate (232 mg, 1.68 mmol, 5 Eq.), and^toluene (5.0 mL). The reaction mixture was then degassed with argon for 10 minutes. Then, di((3S,5S,7S)- adamantan-1-yl)(butyl)phosphane (18 mg, 50 μmol, 0.15 Eq.), cataCXium Pd G3 (36 mg, 50μmol, 0.15 Eq.),^ copper(I) iodide (13 mg, 67 μmol, 0.2 Eq.), and pivalic acid (17 mg, 17 μmol, 0.05 Eq.) were added while purging with argon. The tube was sealed and heated to 110 °C for 16 hours. The reaction mixture was cooled to ambient temperature, diluted with DCM (50 mL), and filtered through a pad of Celite. The Celite cake was washed with DCM. The combined filtrate was concentrated under reduced pressure. The crude compound was purified by flash normal phase chromatography (12 g column, 0-10% MeOH in EtOAc). The fractions containing product were evaporated under reduced pressure and the obtained compound was triturated with ethyl acetate. The slurry was filtered and the solid dried under vacuum to afford 4-cyclopropyl-1-(5-(4- fluorophenyl)-2-(1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)oxazol-4-yl)pyrimidin-2(1H)-one (90 mg, 0.20 mmol, 61 %) as a solid.^

[0333] (+ESI)[M+H]+= 428.3.

[0334] 1H NMR (400 MHz, DMSO-d6) δ = 9.01 (s, 1H), 8.44 (d, J = 0.9 Hz, 1H), 8.21 (d, J = 6.8 Hz, 1H), 7.72 (d, J = 3.0 Hz, 1H), 7.58 (dd, J = 5.3, 8.9 Hz, 2H), 7.40 (t, J = 8.9 Hz, 2H), 6.70 - 6.68 (m, 2H), 4.00 (s, 3H), 2.18 - 2.09 (m, 1H), 1.17- 1.15 (m, J = 3.3 Hz, 4H). Compound (M+H)+Calc. Mass 508 428.3 427.44 Synthesis of 509, 4-cyclopropyl-1-(5-(4-fluorophenyl)-2-(1-(pyridin-3-yl)-1H-pyrazol-3- yl)oxazol-4-yl)pyrimidin-2(1H)-one4-cyclopropyl-1-(5-(4-fluorophenyl)-2-(1-(pyridin-3-yl)-1H-pyrazol-3-yl)oxazol-4- yl)pyrimidin-2(1H)-one

[0335] To a 25 mL sealable tube were added 4-cyclopropyl-1-(5-(4-fluorophenyl)-oxazol-4- yl)pyrimidin-2(1H)-one (100 mg, 336 μmol, 1 Eq.),^toluene (4.0 mL), 3-(3-bromo-1H-pyrazol-1- yl)pyridine (90.4 mg, 404 μmol, 1.2 Eq.), and potassium carbonate (139 mg, 1.01 mmol, 3 Eq.). The mixture was degassed with argon for 5 minutes. Then, dicyclohexylphosphino-2',6'- diisopropoxybiphenyl (15.7 mg, 33.6 μmol, 0.1 Eq.) and palladium acetate (7.5 mg, 33 μmol, 0.1 Eq.) were added under continuing argon purging which was then continued for 5 minutes. ^The tube was sealed, and the resulting reaction mixture was heated to 105 °C^for 16 hours. The reaction mixture was cooled and filtered through Celite. The filtrate was washed with DCM (20 mL). The filtrate was concentrated under vacuum and the crude compound was purified by flash normal phase chromatography (12 g column, 50-100% EtOAc in hexanes). The compound obtained was then triturated with ethyl acetate. This material was then further purified preparative HPLC (C18 column, 10-100% MeCN in water with 0.1% TFA) to afford 4-cyclopropyl-1-(5-(4-fluorophenyl)-2-(1-(pyridin-3-yl)-1H-pyrazol-3-yl)oxazol-4-yl)pyrimidin-2(1H)-one (9.5 mg, 21.5 µmol, 6.4%) as a solid.^

[0336] LCMS:^(+ESI)[M+H]+= 441.2

[0337] 1H NMR (400 MHz, DMSO-d6) δ = 9.23 (d, J = 2.5 Hz, 1H), 8.87 (d, J = 2.6 Hz, 1H), 8.63 (dd, J = 1.2, 4.7 Hz, 1H), 8.40 - 8.35 (m, 1H), 8.18 (d, J = 6.8 Hz, 1H), 7.64 (dd, J = 4.6, 8.3 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.45 - 7.37 (m, 2H), 7.29 (d, J = 2.6 Hz, 1H), 6.69 (d, J = 7.0 Hz, 1H), 2.16 - 2.08 (m, 1H), 1.21 - 1.14 (m, 4H). Compound (M+H)+Calc. Mass 509 441.2 440.44 Synthesis of 510, 4-cyclopropyl-1-(5-(4-fluorophenyl)-2-(1-methyl-1H-indazol-6-yl)oxazol-4- yl)pyrimidin-2(1H)-one4-cyclopropyl-1-(5-(4-fluorophenyl)-2-(1-methyl-1H-indazol-6-yl)oxazol-4-yl)pyrimidin- 2(1H)-one:

[0338] To a 25 mL sealable tube were added 4-cyclopropyl-1-(5-(4-fluorophenyl)oxazol-4- yl)pyrimidin-2(1H)-one (100 mg, 336 μmol, 1 Eq.), 6-bromo-1-methyl-1H-idazole (106 mg, 505 μmol, 1.5 Eq.), and toluene (4.0 mL). The mixture was degassed using argon for 10 minutes. Then, potassium carbonate (186 mg, 1.35 mmol, 4 Eq.), Pd(PPh3)4 (38.9 mg, 33.6 μmol, 0.1 Eq.), and bromo(1,10-phenanthroline)(triphenylphosphine)copper (39.4 mg, 67.3 μmol, 0.2 Eq.) were added while purging with argon. The tube was sealed, and the resulting mixture was heated to 110 °C for 16 hours. The reaction mixture was cooled to ambient temperature, diluted with 10% methanol in DCM, and filtered. The filtrate was concentrated under reduced pressure. The crude compound was purified by flash normal phase chromatography (4 g column, 50-100% EtOAc in hexanes). The fractions containing product were concentrated under vacuum. The resulting compound was triturated with ethyl acetate, collected by vacuum filtration, and dried undervacuum to afford 4-cyclopropyl-1-(5-(4-fluorophenyl)-2-(1-methyl-1H-indazol-6-yl)oxazol-4- yl)pyrimidin-2(1H)-one (55 mg, 124 µmol, 37%) as a solid.

[0339] (+ESI)[M+H]+= 428.0.

[0340] 1H NMR (400 MHz, DMSO-d6) δ = 8.47 (d, J = 0.9 Hz, 1H), 8.23 - 8.15 (m, 2H), 7.96 (dd, J = 0.8, 8.6 Hz, 1H), 7.86 (dd, J = 1.4, 8.5 Hz, 1H), 7.69 - 7.64 (m, 2H), 7.44 - 7.38 (m, 2H), 6.69 (d, J = 6.8 Hz, 1H), 4.19 (s, 3H), 2.16 - 2.09 (m, 1H), 1.20 - 1.16 (m, 4H). Compound (M+H)+Calc. Mass 510 428.0 427.44 Synthesis of 511, 6-(4-(4-cyclopropyl-2-oxopyrimidin-1(2H)-yl)-5-phenyloxazol-2-yl)-2-methyl- 3,4-dihydroisoquinolin-1(2H)-oneN-(1-hydroxy-2-oxo-2-phenylethyl)formamide:

[0341] Formamide (2.52 mL, 63.1 mmol, 1.1 eq) and 2,2-dihydroxy-1-phenylethanone (7.7 g, 57.4 mmol, 1.0 eq) were dissolved in dioxane (115 mL), and the mixture was heated to 110 °C for 8 hours. The crude reaction was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate and washed with sodium bicarbonate and water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was triturated with a hexane / ethyl acetate mixture (8 / 2 v / v), filtered, and washed with hexane to give, after drying, N-(1-hydroxy-2-oxo-2-phenylethyl)formamide (6.17 g, 27.5 mmol, 48%) as a solid.

[0342] 1H NMR (300 MHz, DMSO-d6) δ 8.96 (d, J = 8.8 Hz, 1H), 8.14 – 8.07 (m, 1H), 8.04 – 7.94 (m, 2H), 7.70 – 7.62 (m, 1H), 7.59 – 7.50 (m, 2H), 6.72 (dd, J = 7.0, 2.8 Hz, 1H), 6.44 – 6.34 (m, 1H). N-(1-chloro-2-oxo-2-phenylethyl)formamide

[0343] N-(1-Hydroxy-2-oxo-2-phenylethyl)formamide (6.15 g, 27.5 mmol, 1.0 eq) was dissolved in dichloromethane (123 mL). Phosphorus pentachloride (6.00 g, 28.8 mmol, 1.05 eq) was added, and the resulting mixture was stirred for 16 hours at room temperature. The crude reaction was reduced in volume to ¼ the original amount. Pentane (50 ml) was added, and the reaction mixture was stirred for 30 minutes. The resulting precipitate was collected by filtration and washed with pentane to give 5.97 g of a crude material. The crude material was dissolved in ethyl acetate and pentane was added. The resulting precipitate was collected, washed with pentane, and dried to afford N-(1-chloro-2-oxo-2-phenylethyl)formamide (2.97 g, 12.8 mmol, 47%) as a solid.

[0344] 1H NMR (400 MHz, DMSO-d6) δ 9.73 (d, J = 9.6 Hz, 1H), 8.26 – 8.22 (m, 1H), 8.08 – 8.04 (m, 2H), 7.75 – 7.68 (m, 1H), 7.60 – 7.56 (m, 2H), 7.41 (d, J = 9.6 Hz, 1H). N-[1-(4-cyclopropyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2-oxo-2-phenylethyl]formamide

[0345] 4-Cyclopropyl-1,2-dihydropyrimidin-2-one (1.35 g, 8.94 mmol, 0.7 eq) was dissolved in dimethylformamide (29.7 mL) and triethylamine (41.0 mL, 291 mmol, 10.0 eq) was added. The reaction mixture was stirred for 10 minutes at room temperature. Then, N-(1-chloro-2-oxo-2- phenylethyl)formamide (2.97 g, 12.8 mmol, 1.0 eq) was added and reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was quenched with water and extracted with isopropyl acetate (3 times). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude material was purified by normal phase column chromatography (0-5% MeOH in DCM) to give N-[1-(4- cyclopropyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2-oxo-2-phenylethyl]formamide (0.78 g, 2.02 mmol, 16%) as a solid.

[0346] 1H NMR (300 MHz, DMSO-d6) δ 9.63 (d, J = 8.3 Hz, 1H), 8.24 (s, 1H), 8.12 (d, J = 6.9 Hz, 1H), 7.88 – 7.81 (m, 2H), 7.70 – 7.63 (m, 1H), 7.57 – 7.50 (m, 2H), 7.29 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 6.9 Hz, 1H), 2.01 – 1.93 (m, 1H), 1.09 – 0.97 (m, 4H). 4-cyclopropyl-1-(5-phenyl-1,3-oxazol-4-yl)-1,2-dihydropyrimidin-2-one

[0347] Tris(4-methoxyphenyl)phosphine (1.42 g, 4.04 mmol, 2.0 eq), triethylamine (1.05 mL, 8.08 mmol, 4.0 eq), and solid iodine (0.769 g, 3.03 mmol, 1.5 eq) were dissolved indichloromethane (15.6 mL). After stirring at 0 °C for 5 minutes, N-[1-(4-cyclopropyl-2-oxo-1,2- dihydropyrimidin-1-yl)-2-oxo-2-phenylethyl]formamide (0.78 g, 2.02 mmol, 1.0 eq) was added. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with water and dichloromethane was added. The organic layer was washed with water (2 times), dried over sodium sulfate, and concentrated. The crude material was purified by normal phase column chromatography (0-5% MeOH in DCM). The fractions containing the desired product were combined and concentrated. An additional purification was performed by normal phase column chromatography (10-40% EtOAc in DCM) to provide 4-cyclopropyl-1-(5-phenyl- 1,3-oxazol-4-yl)-1,2-dihydropyrimidin-2-one (0.18 g, 0.637 mmol, 32%) as a solid.

[0348] UPLC-MS: 2.29 min, [M+H]+= 280.45, 99% @ 254 nm

[0349] 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.09 (d, J = 6.9 Hz, 1H), 7.57 – 7.35 (m, 5H), 6.64 (d, J = 6.9 Hz, 1H), 2.16 – 2.03 (m, 1H), 1.16 (dd, J = 8.1, 3.5 Hz, 4H). 6-[4-(4-cyclopropyl-2-oxo-1,2-dihydropyrimidin-1-yl)-5-phenyl-1,3-oxazol-2-yl]-2-methyl- 1,2,3,4-tetrahydroisoquinolin-1-one

[0350] 4-Cyclopropyl-1-(5-phenyl-1,3-oxazol-4-yl)-1,2-dihydropyrimidin-2-one (0.080 g, 0.272 mmol, 1.0 eq), potassium carbonate (0.113 g, 0.816 mmol, 3.0 eq), bromo(1,10- phenanthroline)(triphenylphosphine)copper(I) (0.024 g, 0.041 mmol, 0.15 eq), RuPhos (0.025 g, 0.054 mmol, 0.2 eq), and 6-bromo-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (0.098 g, 0.408 mmol, 1.5 eq) were suspended in dioxane (1.6 mL). The resulting mixture was purged with Ar for 5 minutes prior to the addition of palladium(II) acetate (0.0090 g, 0.041 mmol, 0.15 eq). The reaction vial was sealed, and the reaction mixture was stirred for 2.5 hours at 120 °C. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and filtered through a pad of celite. The celite pad was washed with a mixture of dichloromethane and methanol (9 / 1, v / v). The filtrate was concentrated under reduced pressure to give the crude product. The crude material was purified by normal phase column chromatography (0-5% MeOH in DCM) to afford 6-[4-(4-cyclopropyl-2-oxo-1,2-dihydropyrimidin-1-yl)-5-phenyl-1,3-oxazol-2- yl]-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-one (0.098 g, 0.218 mmol, 80%) as a white solid.

[0351] LC-MS: 2.22 min, [M+H]+= 439.1, 97.4% @ 210 nm

[0352] 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 6.8 Hz, 1H), 8.10 – 8.03 (m, 3H), 7.59 – 7.51 (m, 4H), 7.49 – 7.44 (m, 1H), 6.69 (d, J = 6.9 Hz, 1H), 3.62 (t, J = 6.7 Hz, 2H), 3.12 (t, J = 6.7 Hz, 2H), 3.07 (s, 3H), 2.17 – 2.10 (m, 1H), 1.22 – 1.13 (m, 4H).Compound (M+H)+Calc. Mass 511 439.1 438.49 Synthesis of Compound 320.1-[5-(4-chloro-3,5-difluorophenyl)-2-(4-methyl-2-pyridyl)-1,3- oxazol-4-yl]-4-cyclopropyl-2(1H)-pyrimidinone: 4-chloro-3,5-difluoro-N-methoxy-N-methylbenzamide

[0353] 4-Chloro-3,5-difluorobenzoic acid (24.8 g, 129 mmol, 1.0 eq) and N,N'- carbonyldiimidazole (31.3 g, 193 mmol, 1.5 eq) were dissolved in dichloromethane (496 mL) and stirred for 1 h at room temperature. Next, methoxy(methyl)amine hydrochloride (18.8 g, 193 mmol, 1.5 eq) was added and the mixture was stirred at room temperature for 16 hours. At this time, another portion of N,N'-carbonyldiimidazole (15.7 g, 96.6 mmol, 0.75 eq) as well as methoxy(methyl)amine hydrochloride (9.42 g, 96.6 mmol, 0.75 eq) were added and reaction was continued for another 2 hours. The crude reaction mixture was washed with saturated aqueous sodium bicarbonate (2 times). The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 4-chloro-3,5-difluoro-N-methoxy-N-methylbenzamide (13.5 g, 57.3 mmol, 44%) as a semisolid.

[0354] 1H NMR (300 MHz, DMSO-d6) δ 7.66 – 7.44 (m, 2H), 3.58 (s, 3H), 3.27 (s, 3H). 1-(4-chloro-3,5-difluorophenyl)ethan-1-one

[0355] 4-Chloro-3,5-difluoro-N-methoxy-N-methylbenzamide (13.5 g, 57.3 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (149 mL). The reaction mixture was cooled to 0° C andmethylmagnesium chloride solution (3 M in THF, 25.2 mL, 75.6 mmol, 1.32 eq) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with 250 mL of 0.1 M hydrochloric acid (aqueous) and extracted with dichloromethane (2 times). The organic layers were collected, dried over sodium sulfate and concentrated to give 1-(4-chloro-3,5-difluorophenyl)ethan-1-one (10.5 g, 55.1 mmol, 96%) as an oil.

[0356] 1H NMR (300 MHz, DMSO-d6) δ 7.91 – 7.82 (m, 2H), 2.62 (s, 3H). 1-(4-chloro-3,5-difluorophenyl)-2,2-dihydroxyethan-1-one

[0357] To a solution of 1-(4-chloro-3,5-difluorophenyl)ethan-1-one (5.49 g, 28.8 mmol, 1.0 eq) in dimethyl sulfoxide (41.3 mL) was added hydrobromic acid (48% in water, 6.99 g, 86.4 mmol, 3.0 eq) dropwise over 30 minutes. The resulting yellow solution was stirred at 60 °C for 16 hours. The reaction mixture was cooled to room temperature and slowly poured into ice mixed with sodium bicarbonate until neutral pH was achieved. The aqueous layer was extracted with ethyl acetate. The organic solution was dried over sodium sulfate and concentrated to give crude material. This material was purified via normal phase column chromatography (silica gel, DCM) to give 1-(4-chloro-3,5-difluorophenyl)-2,2-dihydroxyethan-1-one (3.44 g, 15.5 mmol, 54%) as a solid.

[0358] NMR confirmed the structure is a mixture of two forms; the aldehyde and the hydrate in a ratio of 1:1. (Characteristic signals from both forms observed). 1H NMR (300 MHz, DMSO-d6) δ 9.47 (s, 1H, aldehyde CH aldehyde form), 7.95 – 7.89 (m, 4H, aryl CH both forms), 7.09 (d, J = 6.8 Hz, 2H, 2 x OH hydrate form), 5.61 (t, J = 6.9 Hz, 1H, CH hydrate form). N-[2-(4-chloro-3,5-difluorophenyl)-1-hydroxy-2-oxoethyl]formamide

[0359] 1-(4-Chloro-3,5-difluorophenyl)-2,2-dihydroxyethan-1-one (3.44 g, 15.5 mmol, 1.0 eq) and formamide (0.678 mL, 17.0 mmol, 1.1 eq) were dissolved in dioxane (60.0 mL), and the reaction mixture was stirred at 100 °C for 2 hours. The reaction was allowed to cool to room temperature, and the dioxane was removed under reduced pressure. The crude material was purified via normal phase column chromatography (silica gel, 0-10% MeOH in DCM) to give N- [2-(4-chloro-3,5-difluorophenyl)-1-hydroxy-2-oxoethyl]formamide (2.11 g, 8.47 mmol, 55%) as a solid.

[0360] 1H NMR (300 MHz, DMSO-d6) δ 9.03 (d, J = 8.4 Hz, 1H), 8.09 (dd, J = 1.6, 0.8 Hz, 1H), 7.87 – 7.81 (m, 2H), 6.95 (d, J = 7.3 Hz, 1H), 6.30 (ddd, J = 8.2, 7.3, 0.8 Hz, 1H).N-(1-chloro-2-(4-chloro-3,5-difluorophenyl)-2-oxoethyl)formamide

[0361] N-[2-(4-Chloro-3,5-difluorophenyl)-1-hydroxy-2-oxoethyl]formamide (2.11 g, 8.47 mmol, 1.0 eq) was dissolved in dichloromethane (47.0 mL) and phosphorus pentachloride (1.94 g, 9.32 mmol, 1.1 eq) was added. The resulting mixture was stirred for 2 hours at 45 °C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford crude N-(1-chloro-2-(4-chloro-3,5-difluorophenyl)-2-oxoethyl)formamide (2.13 g, 7.95 mmol, 94%) which was used in the next step without further purification.

[0362] 1H NMR (300 MHz, DMSO-d6) δ 9.05 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.88 – 7.81 (m, 2H), 6.29 (d, J = 8.4 Hz, 1H). N-[2-(4-chloro-3,5-difluorophenyl)-1-(4-cyclopropyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2- oxoethyl]formamide

[0363] N-(1-Chloro-2-(4-chloro-3,5-difluorophenyl)-2-oxoethyl)formamide (2.13 g, 7.95 mmol, 1.3 eq) was added to a mixture of 4-cyclopropyl-1,2-dihydropyrimidin-2-one (0.85 g, 6.12 mmol, 1.0 eq) and triethylamine (4.26 mL, 30.6 mmol, 5.0 eq) in dimethylformamide (34.0 mL) at 0 °C. The reaction mixture was then stirred for 2 days at room temperature. The reaction mixture was diluted with brine and extracted with ethyl acetate (3 times). The organic layers were combined, dried over sodium sulfate, and concentrated. The resulting crude material was purified by normal phase column chromatography (silica gel, 0-10% MeOH in DCM) to give N-[2-(4-chloro-3,5- difluorophenyl)-1-(4-cyclopropyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2-oxoethyl]formamide (0.288 g, 0.783 mmol, 13%) as a solid.

[0364] 1H NMR (300 MHz, DMSO-d6) δ 9.62 (d, J = 8.0 Hz, 1H), 8.21 (t, J = 3.5 Hz, 2H), 7.75 (d, J = 7.6 Hz, 2H), 7.19 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 6.9 Hz, 1H), 1.98 (td, J = 8.1, 4.0 Hz, 1H), 1.12 – 0.92 (m, 4H). 1-[5-(4-chloro-3,5-difluorophenyl)-1,3-oxazol-4-yl]-4-cyclopropyl-1,2-dihydropyrimidin-2-one

[0365] N-[2-(4-Chloro-3,5-difluorophenyl)-1-(4-cyclopropyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2- oxoethyl]formamide (0.288 g, 0.783 mmol, 1.0 eq) was mixed with Eaton’s Reagent (7.5% phosphorus(V) oxide in methanesulfonic acid, 1.6 mL). The mixture was heated to 60 °C for 4 hours. The reaction mixture was quenched with saturated aqueous sodium carbonate. The aqueous solution was extracted with dichloromethane (3 times). The combined organic solution was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by normal phase column chromatography (silica gel, 0-5% MeOH in DCM)to afford 1-[5-(4-chloro-3,5-difluorophenyl)-1,3-oxazol-4-yl]-4-cyclopropyl-1,2- dihydropyrimidin-2-one (54.6 mg, 0.156 mmol, 20%) as a solid.

[0366] 1H NMR (300 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.09 (d, J = 6.9 Hz, 1H), 7.42 – 7.28 (m, 2H), 6.69 (d, J = 6.9 Hz, 1H), 2.15 – 2.08 (m, 1H), 1.20 – 1.12 (m, 4H). 1-[5-(4-chloro-3,5-difluorophenyl)-2-(4-methyl-2-pyridyl)-1,3-oxazol-4-yl]-4-cyclopropyl-2(1H)- pyrimidinone [Compound 320]

[0367] 1-[5-(4-Chloro-3,5-difluorophenyl)-1,3-oxazol-4-yl]-4-cyclopropyl-1,2-dihydropyrimidin- 2-one (27.3 mg, 0.078 mmol, 1.0 eq), 2-bromo-4-methylpyridine (0.013 g, 0.078 mmol, 1.0 eq), potassium carbonate (0.032 g, 0.234 mmol, 3.0 eq), and pivalic acid (0.004 g, 0.031 mmol, 0.4 eq) were placed in a reaction tube with anhydrous toluene (4.0 mL). The reaction mixture was sparged with argon for 10 minutes. RuPhos (0.003 g, 0.005 mmol, 0.07 eq) and RuPhos Pd G3 (0.005 g, 0.005 mmol, 0.07 eq) were then added, and the reaction tube was sealed and stirred for 2 days at 110 °C. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The layers were separated, and the water layer was back extracted with dichloromethane (2 times). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude material was purified by normal phase column chromatography (silica gel, 0-10% EtOAc in DCM). This gave impure material which was further purified by normal phase preparative TLC (200 uM thickness, 2% MeOH in DCM, eluting 3 times). The isolated product was treated with methanol, collected by vacuum filtration, and washed with diethyl ether to give 1-[5-(4-chloro-3,5-difluorophenyl)-2-(4-methyl-2-pyridyl)-1,3-oxazol-4-yl]- 4-cyclopropyl-2(1H)-pyrimidinone (4.8 mg, 0.011 mmol, 14%) as a solid.

[0368] 1H NMR: (400 MHz, DMSO-d6) δ 8.64 (d, J = 5.0 Hz, 1H), 8.20 – 8.13 (m, 2H), 7.50 – 7.41 (m, 3H), 6.73 (d, J = 7.0 Hz, 1H), 2.46 (s, 3H), 2.18 – 2.09 (m, 1H), 1.21 – 1.15 (m, 4H).

[0369] LCMS (ESI+): m / z 441.1 [M+H]+

[0370] RT: 1.69 min. LCAP = 98.3% pure at 220 nm.

[0371] The following compounds were prepared in an analogous manner from the appropriate starting materials using similar procedures. Compound (M+H)+Calc. Mass 320 441.1 440.837 321 455.1 454.864 322 455 454.864323 466 465.847 324 467 466.831 325 467 466.835 326 467 466.835 327 467 466.875 328 471 470.863 329 480 479.874 330 480 479.874 331 480 479.874 332 480 479.874 333 480 479.874 334 481.1 480.862 335 481.1 480.862 336 481.1 480.862 337 481 480.862 338 481.1 480.862 339 481.1 480.862 340 481.1 480.862 341 481.1 480.862 342 481.1 480.862 343 481.1 480.862 344 481.1 480.862 345 481.1 480.862 346 482 481.85 347 507 506.896 Synthesis of 512, 1-(5-(4-chloro-3,5-difluorophenyl)-2-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)oxazol- 4-yl)-4-cyclopropylpyrimidin-2(1H)-one1-(5-(4-chloro-3,5-difluorophenyl)-2-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one:

[0372] To a 25 mL sealable tube were added 1-(5-(4-chloro-3,5-difluorophenyl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one (200 mg, 572 μmol, 1 Eq.), 3-(4-bromo-1H-pyrazol-1- yl)pyridine (256 mg, 1.15 mmol, 2 Eq.), and toluene (4 mL). The mixture was then degassed using argon for 10 minutes. Then, potassium carbonate (237 mg 1.71 mmol, 3 Eq.), 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (80.0 mg, 171 μmol, 0.3 Eq.), Pd(OAc)2(38.5 mg, 171 μmol, 0.3 Eq.), and CuI (54.4 mg, 285 μmol, 0.5 Eq.) were added while purging with argon. The tube was then sealed, and the resulting reaction mixture was heated to 110 °C for 16 hours. The reaction mixture was diluted with DCM and filtered. The filtrate was evaporated under reduced pressure. The crude compound was purified by flash normal phase chromatography (12 g column, 0-10% MeOH in DCM). The fractions containing product were concentrated, and the resulting compound was triturated with ethyl acetate. The slurry was filtered and the solid was dried under vacuum to yield 1-(5-(4-chloro-3,5-difluorophenyl)-2-(1-(pyridin-3-yl)-1H-pyrazol-4- yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one (33 mg, 63 µmol, 11%) as a solid.

[0373] LCMS: (+ESI)[M+H]+= 493.2.

[0374] 1H NMR (400 MHz, DMSO-d6) δ = 9.52 (s, 1H), 9.23 (br s, 1H), 8.63 (br s, 1H), 8.54 (s, 1H), 8.37 (br d, J = 9.5 Hz, 1H), 8.16 (d, J = 7.0 Hz, 1H), 7.63 (dd, J = 4.7, 8.4 Hz, 1H), 7.43 (d, J = 7.9 Hz, 2H), 6.71 (d, J = 6.8 Hz, 1H), 2.18 - 2.08 (m, 1H), 1.25 - 1.11 (m, 4H). Compound (M+H)+Calc. Mass 512 493.2 492.87 Synthesis of 513, 1-(5-(4-chloro-3,5-difluorophenyl)-2-(1-(2,2-difluoroethyl)-1H-pyrazol-3- yl)oxazol-4-yl)-4-cyclopropylpyrimidin-2(1H)-one1-(5-(4-chloro-3,5-difluorophenyl)-2-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)oxazol-4-yl)-4- cyclopropyl pyrimidin-2(1H)-one:

[0375] To a 25 mL sealable tube were added 1-(5-(4-chloro-3,5-difluorophenyl)oxazol-4-yl)-4- cyclopropyl-pyrimidin-2(1H)-one (50 mg, 0.14 mmol, 1 Eq.), toluene (5 mL), 3-bromo-1-(2,2- difluoroethyl)-1H-pyrazole (30 mg, 0.14 mmol, 1 Eq.), and K2CO3 (59 mg, 0.43 mmol). The mixture was then purged with argon for 10 minutes. Then, mesylate[(di(1-adamantyl)-n- butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 14 μmol, 0.1 Eq.), bis(1- adamantyl)-butyl-phosphane (5.1 mg, 14 μmol, 0.1 Eq.), pivalic acid (5.8 mg, 57 μmol, 0.05 Eq.), and copper(I) iodide (2.7 mg, 14 μmol, 0.1 Eq.) were added while purging with argon. The tube was then sealed and heated to 105 °C for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated under vacuum. The crude compound was purified by flash normal phase chromatography (4 g column, 50-100% EtOAc in hexanes) to afford 1-(5-(4-chloro-3,5- difluorophenyl)-2-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)oxazol-4-yl)-4-cyclopropyl pyrimidin- 2(1H)-one (8.2 mg, 17 µmol, 12%) as a solid.

[0376] LCMS:^(+ESI)[M+H]+= 479.8.

[0377] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.15 (d, J = 6.97 Hz, 1H) 8.06 (d, J = 2.37 Hz, 1H) 7.38 (d, J = 7.76 Hz, 2H) 7.08 (d, J = 2.37 Hz, 1H) 6.71 (d, J = 6.97 Hz, 1H) 6.30 - 6.63 (m, 1H), 4.82 (td, J = 15.09, 3.35 Hz, 2H) 2.10 - 2.17 (m, 1H) 1.15 - 1.20 (m, 4H).^ Compound (M+H)+Calc. Mass 513 479.8 479.82Synthesis of Compound 348.4-cyclopropyl-1-[5-(3,5-difluoro-4-tolyl)-2-(4-methyl-2-pyridyl)- 1,3-oxazol-4-yl]-2(1H)-pyrimidinone: 1-(3,5-difluoro-4-methylphenyl)ethan-1-one

[0378] 1-(4-Chloro-3,5-difluorophenyl)ethan-1-one (4.65 g, 24.4 mmol, 1.0 eq), methylboronic acid (2.19 g, 36.6 mmol, 1.5 eq), and potassium phosphate tribasic monohydrate (11.2 g, 48.8 mmol, 2.0 eq) were suspended in tetrahydrofuran (75.0 mL). The resulting mixture was purged with argon for 5 minutes before adding bis(triphenylphosphine)palladium(II) chloride (1.71 g, 2.44 mmol, 0.1 eq). The reaction mixture was stirred for 18 hours at 70 °C. The reaction mixture was cooled to room temperature, and water was added. The aqueous solution was extracted with ethyl acetate (3 times). The combined organic solution was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by normal phase column chromatography (silica gel, 0-50% DCM in hexanes) to give 1-(3,5- difluoro-4-methylphenyl)ethan-1-one (3.05 g, 17.9 mmol, 73%).

[0379] 1H NMR (300 MHz, Chloroform-d) δ 7.45 (dd, J = 6.6, 1.3 Hz, 2H), 2.59 (s, 3H), 2.27 (t, J = 1.9 Hz, 3H). 1-(3,5-difluoro-4-methylphenyl)-2,2-dihydroxyethan-1-one

[0380] To a solution of 1-(3,5-difluoro-4-methylphenyl)ethan-1-one (2.88 g, 16.9 mmol, 1.0 eq) in dimethyl sulfoxide (23.7 mL) was added hydrobromic acid (48% in water, 4.11 g, 50.8 mmol, 3.0 eq) dropwise over 30 minutes. The resulting yellow solution was stirred at 60 °C for 5 hours. Themixture was cooled to room temperature, poured into ice, and stirred vigorously for 20 minutes. The resulting precipitate was collected by vacuum filtration, washed with water, and dried under reduced pressure to give 1-(3,5-difluoro-4-methylphenyl)-2,2-dihydroxyethan-1-one (2.49 g, 12.3 mmol, 73%).

[0381] 1H NMR (300 MHz, DMSO-d6) δ 7.70 – 7.51 (m, 2H), 2.22 (t, J = 1.9 Hz, 3H). (Signals from CH and OH groups were not observed). N-[2-(3,5-difluoro-4-methylphenyl)-1-hydroxy-2-oxoethyl]formamide

[0382] 1-(3,5-Difluoro-4-methylphenyl)-2,2-dihydroxyethan-1-one (2.49 g, 12.3 mmol, 1.0 eq) and formamide (0.54 mL, 13.5 mmol, 1.1 eq) were dissolved in dioxane (37.4 mL) and the reaction mixture was stirred at 100 °C for 3 hours. The dioxane was removed under reduced pressure, and the resulting solid was suspended in a mixture of hexanes and ethyl acetate (9 to 1). The solid precipitate was collected by vacuum filtration and dried to give N-[2-(3,5-difluoro-4- methylphenyl)-1-hydroxy-2-oxoethyl]formamide (1.33 g, 5.81 mmol, 47%).

[0383] 1H NMR (300 MHz, DMSO-d6) δ 9.00 (d, J = 8.6 Hz, 1H), 8.09 (d, J = 1.5 Hz, 1H), 7.76 – 7.48 (m, 2H), 6.87 (m, 1H), 6.30 (d, J = 8.6 Hz, 1H), 2.23 (t, J = 1.9 Hz, 3H). N-[1-chloro-2-(3,5-difluoro-4-methylphenyl)-2-oxoethyl]formamide

[0384] N-[2-(3,5-Difluoro-4-methylphenyl)-1-hydroxy-2-oxoethyl]formamide (1.33 g, 5.81 mmol, 1.0 eq) was dissolved in dichloromethane (29.6 mL) and phosphorus pentachloride (1.33 g, 6.39 mmol, 1.1 eq) was added. The resulting mixture was stirred for 18 hours at room temperature. At this time, the solvent was removed under reduced pressure. The resulting solid was suspended in hexanes, collected by vacuum filtration, washed with hexanes, and dried in vacuo to give N-[1- chloro-2-(3,5-difluoro-4-methylphenyl)-2-oxoethyl]formamide (1.44 g, 5.81 mmol, 100%).

[0385] 1H NMR (300 MHz, DMSO-d6) δ 9.01 (d, J = 8.6 Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.64 – 7.44 (m, 2H), 6.29 (d, J = 8.6 Hz, 1H), 2.23 (t, J = 1.9 Hz, 3H). N-[1-(4-cyclopropyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2-(3,5-difluoro-4-methylphenyl)-2- oxoethyl]formamide

[0386] A solution of 4-cyclopropyl-1,2-dihydropyrimidin-2-one (0.728 g, 5.24 mmol, 0.9 eq) and triethylamine (4.06 mL, 29.1 mmol, 5.0 eq) in dimethylformamide (62.0 mL) was cooled to 0 °C. N-[1-Chloro-2-(3,5-difluoro-4-methylphenyl)-2-oxoethyl]formamide (1.44 g, 5.81 mmol, 1.0 eq) was then added and the resulting mixture was stirred for 1 hour at room temperature. The volatiles were removed under reduced pressure. The resulting solid residue was suspended in water,collected by vacuum filtration, washed with water and diethyl ether, and dried in vacuo to give N- [1-(4-cyclopropyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2-(3,5-difluoro-4-methylphenyl)-2- oxoethyl]formamide (1.03 g, 2.954 mmol, 56%).

[0387] 1H NMR (300 MHz, DMSO-d6) δ 9.63 (d, J = 8.2 Hz, 1H), 9.07 – 8.00 (m, 2H), 7.49 (d, J = 6.9 Hz, 2H), 7.19 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 6.9 Hz, 1H), 2.20 (d, J = 1.9 Hz, 3H), 1.96 (td, J = 7.9, 4.0 Hz, 1H), 1.10 – 0.89 (m, 4H). 4-cyclopropyl-1-[5-(3,5-difluoro-4-methylphenyl)-1,3-oxazol-4-yl]-1,2-dihydropyrimidin-2-one

[0388] N-[1-(4-Cyclopropyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2-(3,5-difluoro-4-methylphenyl)- 2-oxoethyl]formamide (0.450 g, 1.30 mmol, 1.0 eq) was mixed with Eaton’s Reagent (7.5% phosphorus(V) oxide in methanesulfonic acid, 2.67 mL). The reaction mixture was then stirred at 60 °C for 4 hours. The reaction mixture was cooled to room temperature and diluted with dichloromethane. This mixture was then washed with saturated aqueous sodium bicarbonate. The organic solution was dried over sodium sulfate and concentrated under reduced pressure. This crude material was purified by normal phase column chromatography (silica gel, 0-2% MeOH in DCM) to afford 4-cyclopropyl-1-[5-(3,5-difluoro-4-methylphenyl)-1,3-oxazol-4-yl]-1,2- dihydropyrimidin-2-one (30.3 mg, 0.092 mmol, 7%).

[0389] 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.08 (d, J = 6.9 Hz, 1H), 7.06 (d, J = 7.1 Hz, 2H), 6.67 (d, J = 6.9 Hz, 1H), 2.18 (s, 3H), 2.14 – 2.06 (m, 1H), 1.20 – 1.06 (m, 4H). 4-cyclopropyl-1-[5-(3,5-difluoro-4-tolyl)-2-(4-methyl-2-pyridyl)-1,3-oxazol-4-yl]-2(1H)- pyrimidinone [Compound 348]

[0390] Under inert atmosphere, 4-cyclopropyl-1-[5-(3,5-difluoro-4-methylphenyl)-1,3-oxazol-4- yl]-1,2-dihydropyrimidin-2-one (30.3 mg, 0.092 mmol, 1.0 eq), potassium carbonate (0.038 g, 0.277 mmol, 3.0 eq), pivalic acid (0.004 g, 0.037 mmol, 0.4 eq), RuPhos (0.003 g, 0.006 mmol, 0.07 eq), and 2-Bromo-4-methylpyridine (0.016 g, 0.092 mmol, 1.0 eq) were suspended in anhydrous toluene (0.64 mL). The resulting mixture was purged with argon for 5 minutes prior to the addition of RuPhos Pd G3 (0.005 g, 0.006 mmol, 0.07 eq). The reaction flask was then sealed, and the mixture was stirred at 110 °C for 18 hours. Brine and dichloromethane were added to the cooled reaction mixture and the layers were separated. The aqueous layer was extracted with dichloromethane (3 times). The combined organic layers were dried over sodium sulfate and concentrated to give the crude product. This material was purified by preparative TLC (200 umsilica gel, 2:18:80 MeOH / hexane / DCM elution mixture) to give 4-cyclopropyl-1-[5-(3,5-difluoro- 4-tolyl)-2-(4-methyl-2-pyridyl)-1,3-oxazol-4-yl]-2(1H)-pyrimidinone (1.7 mg, 0.0040 mmol, 4%).

[0391] 1H NMR: (300 MHz, DMSO-d6) δ 8.64 (d, J = 4.9 Hz, 1H), 8.27 – 8.00 (m, 2H), 7.46 (d, J = 5.1 Hz, 1H), 7.17 (d, J = 7.2 Hz, 2H), 6.72 (d, J = 6.9 Hz, 1H), 2.46 (s, 3H), 2.21 (d, J = 1.9 Hz, 3H), 2.17 – 2.08 (m, 1H), 1.26 – 1.15 (m, 4H).

[0392] LCMS (ESI+): m / z 421.2 [M+H]+

[0393] RT: 2.76 min. LCAP = 88% pure at 220 nm.

[0394] The following compounds were prepared in an analogous manner from the appropriate starting materials using similar procedures. Compound (M+H)+Calc. Mass 348421.2420.419 349461.1460.444 350471.2470.479 351487486.478 Synthesis of 514, N-(2-(4-(4-cyclopropyl-2-oxopyrimidin-1(2H)-yl)-5-(3,5-difluoro-4- methylphenyl)oxazol-2-yl)-5-fluoropyridin-4-yl)acetamideN-(2-bromo-5-fluoropyridin-4-yl)acetamide:

[0395] 2-Bromo-5-fluoropyridin-4-amine, (0.300 g, 1.57 mmol, 1.0 eq) was suspended in dichloromethane (3.0 mL). Sodium bicarbonate (1.58 g, 18.8 mmol, 12.0 eq) was added, and the reaction mixture was cooled to 0 °C. Then, acetyl chloride (0.224 mL, 3.14 mmol, 2.0 eq) was added, and the reaction mixture was stirred at room temperature for 16 hours. The crude reaction was filtered, and the filtrate was concentrated to give, after drying, N-(2-bromo-5-fluoropyridin-4- yl)acetamide (0.116 g, 0.453 mmol, 29%).

[0396] LC-MS: 2.08 min, [M+H]+= 234.5, 91% @ 254 nm.N-{2-[4-(4-cyclopropyl-2-oxo-1,2-dihydropyrimidin-1-yl)-5-(3,5-difluoro-4-methylphenyl)- 1,3-oxazol-2-yl]-5-fluoropyridin-4-yl}acetamide:

[0397] 4-Cyclopropyl-1-[5-(3,5-difluoro-4-methylphenyl)-1,3-oxazol-4-yl]-1,2-dihydropyrimidin- 2-one (0.050 g, 0.149 mmol, 1.0 eq), N-(2-bromo-5-fluoropyridin-4-yl)acetamide (0.041 g, 0.161 mmol, 1.08 eq), and cesium carbonate (0.145 g, 0.446 mmol, 3.0 eq) were placed in a reaction vial and DMF (1.0 mL) was added. After degassing with Ar for 5 minutes, 1,1'- bis(diphenylphosphino)ferrocene dichloropalladium(II) (0.022 g, 0.03 mmol, 0.2 eq) and copper(I) iodide (0.006 g, 0.03 mmol, 0.2 eq) were added and the vial was sealed. The reaction was then stirred for 2 hours at 100 °C. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The celite was then washed with a mixture of dichloromethane / methanol (9 / 1, v / v)). The filtrate was concentrated under reduced pressure and the crude material was purified by normal phase chromatography (0-3% MeOH in DCM). Fractions containing the desired product were concentrated under reduced pressure. The combined product was triturated with methanol, collected by filtration, washed with methanol, and dried under reduced pressure to give N-{2-[4-(4-cyclopropyl-2-oxo-1,2-dihydropyrimidin-1-yl)-5-(3,5-difluoro-4-methylphenyl)- 1,3-oxazol-2-yl]-5-fluoropyridin-4-yl}acetamide (0.014 g, 0.028 mmol, 19%) as a white solid.

[0398] LC-MS: 3.42 min, [M+H]+= 482.2, 96.2% @ 205 nm.

[0399] 1H NMR (300 MHz, DMSO-d6) δ 10.49 (s, 1H), 9.08 (d, J = 6.3 Hz, 1H), 8.74 (d, J = 2.8 Hz, 1H), 8.16 (d, J = 6.9 Hz, 1H), 7.10 (d, J = 8.3 Hz, 2H), 6.71 (d, J = 6.9 Hz, 1H), 2.22 (s, 3H), 2.20 (s, 3H), 2.17 – 2.09 (m, 1H), 1.21 – 1.14 (m, 4H). Compound (M+H)+Calc. Mass 514482.2481.43Synthesis of 515, 5-(4-(4-cyclopropyl-2-oxopyrimidin-1(2H)-yl)-5-(3,5-difluoro-4- methylphenyl)oxazol-2-yl)-2-methylisoindolin-1-one 5-(4-(4-cyclopropyl-2-oxopyrimidin-1(2H)-yl)-5-(3,5-difluoro-4-methylphenyl)oxazol-2-yl)-2- methylisoindolin-1-one:

[0400] To a 25 mL sealable tube were added 4-cyclopropyl-1-(5-(3,5-difluoro-4- methylphenyl)oxazol-4-yl)pyrimidin-2(1H)-one (80 mg, 0.24 mmol, 1 Eq.), toluene (5 mL), 5- bromo-2-methyl-1-isoindolinone (66 mg, 0.29 mmol, 1.2 Eq.), and K2CO3 (0.10 g, 0.73 mmol, 3 Eq.). The mixture was then purged with argon for 10 minutes. Then, 2-dicyclohexylphosphino- 2',6'-diisopropoxybiphenyl (23 mg, 49 μmol, 0.2 Eq.), PdOAc2(11 mg, 49 μmol, 0.2 Eq.), pivalic acid (2.5 mg, 24 μmol, 0.1 Eq.), and copper(I) iodide (4.6 mg, 24 μmol, 0.1 Eq.) were added while purging with argon. The tube was then sealed, and the resulting reaction mixture was^heated to 105 °C for 16 h. The reaction mixture was cooled to an ambient temperature, diluted with 10% methanol in DCM, and filtered. The filtrate was concentrated under vacuum. The crude compound was then purified by flash normal phase chromatography (4 g column, 50-100% EtOAc in hexanes) to afford 5-(4-(4-cyclopropyl-2-oxopyrimidin-1(2H)-yl)-5-(3,5-difluoro-4- methylphenyl)oxazol-2-yl)-2-methylisoindolin-1-one (79 mg, 0.17 mmol, 69%) as a solid.

[0401] LCMS:^(+ESI) [M+H]+= 475.2.

[0402] 1H NMR (400 MHz, DMSO-d6) δ = 8.43 (s, 1H), 8.27 (dd, J = 1.3, 8.0 Hz, 1H), 8.18 (d, J = 6.8 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 7.8 Hz, 2H), 6.72 (d, J = 6.8 Hz, 1H), 4.59 (s, 2H), 3.12 (s, 3H), 2.20 (s, 3H), 2.16 - 2.11 (m, 1H), 1.21 - 1.15 (m, 4H). Compound (M+H)+Calc. Mass 515475.2474.47Synthesis of Compound 352.4-cyclopropyl-1-[5-(3-fluoro-4-tolyl)-2-(1-methyl-1H-1,2,6- triazainden-5-yl)-1,3-oxazol-4-yl]-2(1H)-pyrimidinone: 3-fluoro-N-methoxy-N,4-dimethylbenzamide

[0403] 3-Fluoro-4-methylbenzoic acid (50.0 g, 324 mmol, 1.0 eq) and N,N'-carbonyldiimidazole (78.9 g, 487 mmol, 1.5 eq) were dissolved in dichloromethane (1000 mL) and the resulting mixture was stirred for 2 hours at room temperature. Methoxy(methyl)amine hydrochloride (24.3 g, 249 mmol, 0.768 eq) was then added and the reaction mixture was stirred for additional 2 hours at room temperature. The crude mixture was washed with saturated aqueous sodium bicarbonate and 0.5 M aqueous hydrochloric acid. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 3-fluoro-N-methoxy-N,4-dimethylbenzamide (65.0 g, 297 mmol, 91%) as an oil.

[0404] 1H NMR (300 MHz, DMSO-d6) δ 7.39 – 7.30 (m, 3H), 3.55 (s, 3H), 3.26 (s, 3H), 2.28 (d, J = 2.0 Hz, 3H). 1-(3-fluoro-4-methylphenyl)ethan-1-one

[0405] 3-Fluoro-N-methoxy-N,4-dimethylbenzamide (65.0 g, 297 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (715 mL). The reaction mixture was cooled to 0 °C and methyl magnesium chloride (3 M in THF, 95.0 mL, 285 mmol, 0.961 eq) was added. Then, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with methanol, and the resulting homogeneous solution was concentrated under reduced pressure. The residue was partitioned between dichloromethane and 0.5 M aqueous hydrochloric acid. The layers were separated, and the aqueous layer was extracted with dichloromethane two times. Thecombined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give 1-(3-fluoro-4-methylphenyl)ethan-1-one (36.3 g, 238 mmol, 80%) as a colorless semisolid.

[0406] 1H NMR (300 MHz, DMSO-d6) δ 7.75 – 7.60 (m, 2H), 7.44 (td, J = 7.8, 0.9 Hz, 1H), 2.56 (s, 3H), 2.34 – 2.26 (m, 3H). 1-(3-fluoro-4-methylphenyl)-2,2-dihydroxyethan-1-one

[0407] A mixture of 1-(3-fluoro-4-methylphenyl)ethan-1-one (36.3 g, 238 mmol, 1.0 eq) and selenium dioxide (31.7 g, 286 mmol, 1.2 eq) in dioxane (145 mL) and water (36.3 mL) was stirred at 110 °C for 18 hours. The reaction mixture was diluted with dichloromethane and filtered through a pad of celite. The celite pad was washed with a mixture of dichloromethane and methanol (9 / 1, v / v). The filtrate was then concentrated under reduced pressure. The residue was boiled in water (15 volumes) for 2 hours. The hot water was decanted and cooled down in an ice bath. The resulting precipitate was collected by filtration, and the filtrate was used for an additional crystallization. This operation was repeated one more time. The two crystallization products were combined to give 1-(3-fluoro-4-methylphenyl)-2,2-dihydroxyethan-1-one (33.2 g, 180 mmol, 76%) as a white solid.

[0408] 1H NMR (300 MHz, DMSO-d6) δ 7.89 – 7.70 (m, 2H), 7.46 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 7.1 Hz, 2H), 5.63 (t, J = 7.0 Hz, 1H), 2.32 (d, J = 1.9 Hz, 3H). N-[2-(3-fluoro-4-methylphenyl)-1-hydroxy-2-oxoethyl]formamide

[0409] Formamide (3.29 mL, 82.5 mmol, 1.0 eq) and 1-(3-fluoro-4-methylphenyl)-2,2- dihydroxyethan-1-one (15.2 g, 82.5 mmol, 1.0 eq) were dissolved in dioxane (30.0 mL) and the resulting mixture was stirred at 100 °C for 3 hours. The dioxane was then removed under reduced pressure. The residue was dissolved in ethyl acetate, washed two times with saturated sodium bicarbonate solution, and washed with brine. The organic layer was then dried over sodium sulfate and concentrated under reduced pressure to give the crude product. This material was then triturated with (hexanes / EtOAc, 8 / 2 v / v), collected by filtration, and washed with diethyl ether to give N-[2-(3-fluoro-4-methylphenyl)-1-hydroxy-2-oxoethyl]formamide (11.8 g, 44.7 mmol, 54%) as a white solid.

[0410] 1H NMR (300 MHz, DMSO-d6) δ 8.97 (d, J = 8.7 Hz, 1H), 8.10 (dd, J = 1.7, 0.8 Hz, 1H), 7.79 – 7.60 (m, 2H), 7.56 – 7.41 (m, 1H), 6.78 (d, J = 7.2 Hz, 1H), 6.33 (ddd, J = 8.3, 7.3, 0.8 Hz, 1H), 2.32 (d, J = 2.0 Hz, 3H). N-[1-chloro-2-(3-fluoro-4-methylphenyl)-2-oxoethyl]formamide

[0411] N-[2-(3-Fluoro-4-methylphenyl)-1-hydroxy-2-oxoethyl]formamide (11.8 g, 44.7 mmol, 1.0 eq) was dissolved in dichloromethane (236 mL). Phosphorus pentachloride (6.52 g, 31.3 mmol, 0.7 eq) was added and the resulting mixture was stirred for 18 hours at room temperature. Pentane was added directly to the reaction mixture and a precipitate formed. This material was collected by vacuum filtration, washed with pentane, and dried under vacuum to give N-[1-chloro-2-(3-fluoro- 4-methylphenyl)-2-oxoethyl]formamide (12.4 g, 43.2 mmol, 97%) as a light yellow solid.

[0412] 1H NMR (300 MHz, DMSO-d6) δ 8.98 (d, J = 8.7 Hz, 1H), 8.10 (d, J = 1.5 Hz, 1H), 7.74 (dd, J = 7.8, 1.7 Hz, 1H), 7.69 (dd, J = 10.6, 1.7 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 6.33 (d, J = 8.8 Hz, 1H), 2.32 (d, J = 2.0 Hz, 3H). N-[1-(4-cyclopropyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2-(3-fluoro-4-methylphenyl)-2- oxoethyl]formamide

[0413] N-[1-Chloro-2-(3-fluoro-4-methylphenyl)-2-oxoethyl]formamide (12.4 g, 43.2 mmol, 1.0 eq) was added to a mixture of 4-cyclopropyl-1,2-dihydropyrimidin-2-one (9.59 g, 66.9 mmol, 0.6 eq) and anhydrous triethylamine (59.9 mL, 432 mmol, 10.0 eq) in DMF (124 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with brine and extracted with isopropyl acetate three times. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude product was then triturated with (EtOAc / pentane, 2 / 8, v / v) and the material was collected by vacuum filtration. This solid was then washed with pentane and dried under reduced pressure to give N-[1-(4-cyclopropyl- 2-oxo-1,2-dihydropyrimidin-1-yl)-2-(3-fluoro-4-methylphenyl)-2-oxoethyl]formamide (4.6 g, 14.0 mmol, 32%) as a solid.

[0414] 1H NMR (300 MHz, DMSO-d6) δ 9.63 (d, J = 8.3 Hz, 1H), 8.23 (s, 1H), 8.15 (d, J = 7.0 Hz, 1H), 7.64 – 7.53 (m, 2H), 7.46 (t, J = 7.7 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 6.58 (d, J = 6.9 Hz, 1H), 2.30 (d, J = 2.0 Hz, 3H), 1.97 (td, J = 8.1, 4.0 Hz, 1H), 1.14 – 0.90 (m, 4H). 4-cyclopropyl-1-[5-(3-fluoro-4-methylphenyl)-1,3-oxazol-4-yl]-1,2-dihydropyrimidin-2-one

[0415] Tris(4-methoxyphenyl)phosphine (9.84 g, 27.9 mmol, 2.0 eq) was dissolved in dichloromethane (92.0 mL). Anhydrous triethylamine (7.25 mL, 55.9 mmol, 4.0 eq) and iodine(5.32 g, 21.0 mmol, 1.5 eq) were added. Then, N-[1-(4-cyclopropyl-2-oxo-1,2-dihydropyrimidin- 1-yl)-2-(3-fluoro-4-methylphenyl)-2-oxoethyl]formamide (4.6 g, 14.0 mmol, 1.0 eq) was added to the reaction mixture in one portion, and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by normal phase chromatography (silica gel, 0-20% EtOAc in DCM) to give 4-cyclopropyl-1-[5-(3-fluoro-4-methylphenyl)-1,3-oxazol-4-yl]-1,2-dihydropyrimidin-2-one (2.4 g, 7.71 mmol, 55%) as a solid.

[0416] 1H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.08 (d, J = 6.9 Hz, 1H), 7.49 – 7.35 (m, 1H), 7.25 – 7.08 (m, 2H), 6.66 (d, J = 6.9 Hz, 1H), 2.26 (d, J = 1.9 Hz, 3H), 2.11 (tt, J = 7.3, 5.0 Hz, 1H), 1.22 – 1.02 (m, 4H). 4-cyclopropyl-1-[5-(3-fluoro-4-tolyl)-2-(1-methyl-1H-1,2,6-triazainden-5-yl)-1,3-oxazol-4-yl]- 2(1H)-pyrimidinone [Compound 352]

[0417] A reaction vial was charged with cesium carbonate (0.157 g, 0.482 mmol, 3.0 eq), 5- bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine (0.065 g, 0.308 mmol, 2.0 eq) and 4-cyclopropyl-1- [5-(3-fluoro-4-methylphenyl)-1,3-oxazol-4-yl]-1,2-dihydropyrimidin-2-one (0.050 g, 0.154 mmol, 1.0 eq), and anhydrous DMF (1.0 mL). The mixture was flushed with argon for 10 minutes. Then, copper(I) iodide (0.0030 g, 0.016 mmol, 0.1 eq) and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) (0.012 g, 0.016 mmol, 0.1 eq) were added. The reaction vial was sealed, and the reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and filtered through a pad of celite. The celite pad was washed with a mixture of dichloromethane and methanol (1 / 1, v / v). The combined organic solutions were concentrated under reduced pressure to give the crude product. The crude material was purified by normal phase column chromatography (silica gel, 0-3% MeOH in DCM). The fractions containing the desired product were concentrated and the residue was triturated with diethyl ether. The resulting solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give 4-cyclopropyl-1-[5-(3-fluoro-4-tolyl)-2-(1-methyl-1H-1,2,6- triazainden-5-yl)-1,3-oxazol-4-yl]-2(1H)-pyrimidinone (0.0080 g, 0.018 mmol, 12%) as a white solid.

[0418] LCMS: [M+H]+= 443.11, 97.4 % @ 215nm

[0419] 1H NMR (300 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.72 (s, 1H), 8.66 (d, J = 1.4 Hz, 1H), 8.20 (d, J = 6.9 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.32 – 7.18 (m, 2H), 6.71 (d, J = 6.9 Hz, 1H), 4.33 (s, 3H), 2.29 (d, J = 1.8 Hz, 3H), 2.19 – 2.09 (m, 1H), 1.19 (dd, J = 8.0, 3.0 Hz, 4H).

[0420] The following compounds were prepared in an analogous manner from the appropriate starting materials using similar procedures. Compound (M+H)+Calc. Mass 352 443.1 442.454 353 403.2 402.429 354 404.3 403.417 355 417.2 416.456 356 430.2 429.455 357 433.1 432.455 358 433.1 432.455 359 437 436.874 360 442.2 441.466 Synthesis of Compound 361.4-cyclopropyl-1-{2-[4-(difluoromethyl)-2-pyridyl]-5-(3-fluoro-4- tolyl)-1,3-oxazol-4-yl}-2(1H)-pyrimidinone:

[0421] η1-CH2=CH-CH2)PdCl(dppb) was prepared according to the method previously described by Doucet and co-workers (F. Derridj, S. Djebbar, O. Benali-Baitich and H. Doucet, Journal of Organometallic Chemistry, 2008, 693, 135-144) 4-cyclopropyl-1-{2-[4-(difluoromethyl)-2-pyridyl]-5-(3-fluoro-4-tolyl)-1,3-oxazol-4-yl}-2(1H)- pyrimidinone [Compound 361]

[0422] A reaction vial was charged with cesium carbonate (0.151 g, 0.463 mmol, 3.0 eq), η1- CH2=CH-CH2)PdCl(dppb) (0.010 g, 0.015 mmol, 0.1 eq), 4-cyclopropyl-1-[5-(3-fluoro-4- methylphenyl)-1,3-oxazol-4-yl]-1,2-dihydropyrimidin-2-one (0.050 g, 0.154 mmol, 1.0 eq), 2- bromo-4-(difluoromethyl)pyridine (0.048 g, 0.231 mmol, 1.5 eq), and diethyl carbonate (0.75 mL). The resulting mixture was briefly flushed with argon. The vial was then sealed, and the reaction mixture was stirred at 120 °C for 3 hours. At this time, an additional portion of 2-Bromo- 4-(difluoromethyl)pyridine (0.048 g, 0.231 mmol, 1.5 eq) was added and reaction mixture wasstirred for an additional 1 hour. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and filtered through a pad of celite. The celite pad was washed with a mixture of dichloromethane and methanol (8 / 2, v / v). The combined organic solutions were concentrated under reduced pressure to give the crude product. This crude material was purified by preparative HPLC (C18 column, 10-100% MeCN in water with 0.1% FA) to afford 4-cyclopropyl-1-{2-[4- (difluoromethyl)-2-pyridyl]-5-(3-fluoro-4-tolyl)-1,3-oxazol-4-yl}-2(1H)-pyrimidinone (0.0030 g, 0.007 mmol, 5%).

[0423] LCMS: [M+H]+= 439.2, 98.1% @ 205nm

[0424] 1H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J = 5.0 Hz, 1H), 8.36 (s, 1H), 8.18 (d, J = 6.9 Hz, 1H), 7.83 – 7.79 (m, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.38 – 7.09 (m, 3H), 6.71 (d, J = 6.9 Hz, 1H), 2.29 (d, J = 1.9 Hz, 3H), 2.18 – 2.10 (m, 1H), 1.22 – 1.14 (m, 4H).

[0425] The following compounds were prepared in an analogous manner from the appropriate starting materials using similar procedures. Compound (M+H)+Calc. Mass 361 439.2 438.409 362 403.2 402.429 363 404.2 403.417 364 417 416.456 365 419.1 418.428 366 419.2 418.428 367 421.2 420.419 368 421.2 420.419 369 429.2 428.467 370 429.2 428.467 371 430.2 429.455 372 437.2 436.874 373 454.4 454.408 374 457.1 456.399Synthesis of Compound 375.4-cyclopropyl-1-[2-(4,6-dimethyl-2-pyrimidinyl)-5-(3-fluoro-4- tolyl)-1,3-oxazol-4-yl]-2(1H)-pyrimidinone: 4-cyclopropyl-1-[2-(4,6-dimethyl-2-pyrimidinyl)-5-(3-fluoro-4-tolyl)-1,3-oxazol-4-yl]-2(1H)- pyrimidinone [Compound 375]

[0426] Under inert atmosphere, 4-cyclopropyl-1-[5-(3-fluoro-4-methylphenyl)-1,3-oxazol-4-yl]- 1,2-dihydropyrimidin-2-one (0.025 g, 0.080 mmol, 1.0 eq), 2-bromo-4,6-dimethylpyrimidine (0.022 g, 0.119 mmol, 1.5 eq), bromo(1,10-phenanthroline)(triphenylphosphine)copper(I) (0.005 g, 0.008 mmol, 0.1 eq), and cesium carbonate (0.052 g, 0.159 mmol, 2.0 eq) were dissolved in dioxane (0.25 mL). The mixture was purged with argon for 10 minutes before tetrakis(triphenylphosphine)palladium (0.009 g, 0.008 mmol, 0.1 eq) was added. The reaction tube was sealed, and the mixture was stirred for 3 hours at 90 °C. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and filtered through a pad of celite. The celite pad was washed with a mixture of dichloromethane and methanol (9 / 1, v / v). The combined organic mixture was concentrated under reduced pressure to give the crude product. The crude material was purified by normal phase column chromatography (silica gel, 0-3% MeOH in DCM). The fractions containing the desired product were combined and concentrated. The resulting crude material was additionally purified by preparative HPLC (C18 column, 10-100% MeCN in water with 0.1% FA) to give 4-cyclopropyl-1-[2-(4,6-dimethyl-2-pyrimidinyl)-5-(3-fluoro-4- tolyl)-1,3-oxazol-4-yl]-2(1H)-pyrimidinone (0.007 g, 0.017 mmol, 21%) as a white solid.

[0427] LCMS: [M+H]+= 418.2, 99.0 % @ 205nm

[0428] 1H NMR (300 MHz, Methanol-d4) δ 8.09 (d, J = 6.9 Hz, 1H), 7.46 – 7.35 (m, 3H), 7.32 (dd, J = 7.9, 1.7 Hz, 1H), 6.73 (d, J = 6.9 Hz, 1H), 2.63 (s, 6H), 2.34 (d, J = 2.0 Hz, 3H), 2.15 (td, J = 8.1, 4.0 Hz, 1H), 1.41 – 1.25 (m, 4H). Compound(M+H)+Calc. Mass 375418.2417.444Synthesis of Compound 376.4-cyclopropyl-1-{2-[6-(fluoromethyl)-5-methyl-2-pyridyl]-5-(3- fluoro-4-tolyl)-1,3-oxazol-4-yl}-2(1H)-pyrimidinone: 4-cyclopropyl-1-{2-[6-(fluoromethyl)-5-methyl-2-pyridyl]-5-(3-fluoro-4-tolyl)-1,3-oxazol-4-yl}- 2(1H)-pyrimidinone [Compound 376]

[0429] In a 30 mL sealable tube, 4-cyclopropyl-1-(5-(3-fluoro-4-methylphenyl)oxazol-4- yl)pyrimidin-2(1H)-one (100 mg, 1 Eq, 321 μmol), toluene (5.0 mL), 6-bromo-2-(fluoromethyl)- 3-methylpyridine (98.3 mg, 1.5 Eq, 482 μmol), potassium carbonate (222 mg, 5.0 Eq, 1.61 mmol), palladium diacetate (14.4 mg, 0.2 Eq, 64.2 μmol), and 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl (30.0 mg, 0.2 Eq, 64.2 μmol) were combined, and the resulting reaction mixture was purged with argon for 5 minutes. Then, the vial was sealed and heated to 105 °C for 16 hours. The reaction mixture was concentrated under vacuum to afford crude compound. This material was purified by normal phase flash chromatography (4 g silica column, 70-80% EtOAc in hexanes). The resulting off-white solid was triturated with MTBE (20 mL), collected by vacuum filtration, washed with hexanes, and dried under reduced pressure to afford 4-cyclopropyl-1-{2-[6- (fluoromethyl)-5-methyl-2-pyridyl]-5-(3-fluoro-4-tolyl)-1,3-oxazol-4-yl}-2(1H)-pyrimidinone (50 mg, 0.12 mmol, 36%) as a solid.

[0430] [+esi] [M+H]+= 435.4

[0431] 1H NMR (DMSO-d6, 400 MHz) δ 8.1-8.2 (m, 2H), 7.95 (d, 1H, J = 8.0 Hz), 7.46 (t, 1H, J = 8.0 Hz), 7.2-7.3 (m, 2H), 6.69 (d, 1H, J = 6.8 Hz), 5.5-5.8 (m, 2H), 2.5-2.5 (m, 3H), 2.28 (s, 3H), 2.13 (brs, 1H), 1.1-1.2 (m, 4H). Compound (M+H)+Calc. Mass 376 435.4 434.446Synthesis of Compound 378.1-{5-(4-chloro-3,5-difluorophenyl)-2-[1-(2-methoxyethyl)-1H- 1,2,6-triazainden-5-yl]-1,3-oxazol-4-yl}-4-cyclopropyl-2(1H)-pyrimidinone: 4-chloro-3,5-difluoro-N-methoxy-N-methylbenzamide

[0432] 4-Chloro-3,5-difluorobenzoic acid (50.0 g, 260 mmol, 1.0 eq) and N,N'- carbonyldiimidazole (63.2 g, 390 mmol, 1.5 eq) were dissolved in dichloromethane, and the resulting mixture was stirred for 4 hours at room temperature. Methoxy(methyl)amine hydrochloride (38.0 g, 390 mmol, 1.5 eq) was then added and the reaction mixture was stirred for additional 18 hours at room temperature. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution two times. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude material was purified by normal phase column chromatography (silica gel, 100% DCM) to give 4-chloro-3,5-difluoro-N-methoxy-N- methylbenzamide (53.0 g, 214 mmol, 82%) as a solid.

[0433] UPLC-MS: [M+H]+= 235.75, 99.0% 254 nm 1-(4-chloro-3,5-difluorophenyl)ethan-1-one

[0434] 4-Chloro-3,5-difluoro-N-methoxy-N-methylbenzamide (53.0 g, 214 mmol, 1.0 eq) was dissolved in anhydrous THF (583 mL). The reaction mixture was cooled to 0 °C and methylmagnesium chloride (3.0 M in THF, 94.0 mL, 282 mmol, 1.32 eq) was added. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with methanol, and the resulting homogeneous solution was concentrated under reduced pressure. The residue was partitioned between dichloromethane and 0.5 M aqueous hydrochloric acid solution.The layers were separated, and the aqueous layer was extracted with dichloromethane two times. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by normal phase column chromatography (silica gel, 50% EtOAc in hexanes) to give 1-(4-chloro-3,5-difluorophenyl)ethan- 1-one (18.9 g, 79.3 mmol, 37%).

[0435] 1H NMR (300 MHz, DMSO-d6) δ 7.89 – 7.78 (m, 2H), 2.61 (s, 3H). 1-(4-chloro-3,5-difluorophenyl)-2,2-dihydroxyethan-1-one

[0436] To a solution of 1-(4-chloro-3,5-difluorophenyl)ethan-1-one (18.9 g, 79.3 mmol, 1.0 eq) in dimethyl sulfoxide (132 mL) was added hydrobromic acid (48% in water, 40.1 g, 238 mmol, 3.0 eq). The reaction mixture was stirred at 60 °C for 18 hours. The mixture was cooled to room temperature, quenched with a saturated aqueous solution of sodium bicarbonate, and extracted with dichloromethane (x3). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude material was then dissolved in ethyl acetate and washed with brine (x2). The organic layer was dried over sodium sulfate and concentrated to give 1-(4-chloro-3,5-difluorophenyl)-2,2-dihydroxyethan-1-one (20.5 g, 73.7 mmol, 93%) as a yellow oil. This material was used directly in the next reaction. N-[2-(4-chloro-3,5-difluorophenyl)-1-hydroxy-2-oxoethyl]formamide

[0437] 1-(4-Chloro-3,5-difluorophenyl)-2,2-dihydroxyethan-1-one (20.5 g, 73.7 mmol, 1.0 eq) and formamide (4.41 mL, 111 mmol, 1.5 eq) were dissolved in dioxane (308 mL) and the reaction mixture was stirred at 100 °C for 2 hours. Upon cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. Hexanes was added, and the resulting precipitate was collected by vacuum filtration. This solid was washed with methanol to give N-[2-(4-chloro-3,5-difluorophenyl)-1-hydroxy-2-oxoethyl]formamide (10.9 g, 42.6 mmol, 58%) as a white solid.

[0438] 1H NMR (300 MHz, DMSO-d6) δ 9.03 (d, J = 8.4 Hz, 1H), 8.09 (dd, J = 1.6, 0.8 Hz, 1H), 7.87 – 7.80 (m, 2H), 6.96 (d, J = 7.2 Hz, 1H), 6.35 – 6.26 (m, 1H). N-[1-chloro-2-(4-chloro-3,5-difluorophenyl)-2-oxoethyl]formamide

[0439] N-[2-(4-Chloro-3,5-difluorophenyl)-1-hydroxy-2-oxoethyl]formamide (10.9 g, 42.6 mmol, 1.0 eq) was dissolved in dichloromethane (217 mL) and phosphorus pentachloride (6.21 g, 29.8 mmol, 0.7 eq) was added. The reaction mixture was then stirred for 18 hours at room temperature. Pentane was added directly to the reaction mixture and a precipitate formed. This solid wascollected by vacuum filtration, washed with pentane, and dried under vacuum to give N-[1-chloro- 2-(4-chloro-3,5-difluorophenyl)-2-oxoethyl]formamide (10.7 g, 39.9 mmol, 94%) as a yellow solid.

[0440] 1H NMR (300 MHz, DMSO-d6) δ 9.77 (d, J = 9.5 Hz, 1H), 8.23 (d, J = 1.2 Hz, 1H), 8.06 – 7.97 (m, 2H), 6.31 (d, J = 8.5 Hz, 1H). N-[2-(4-chloro-3,5-difluorophenyl)-1-(4-cyclopropyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2- oxoethyl]formamide

[0441] N-[1-Chloro-2-(4-chloro-3,5-difluorophenyl)-2-oxoethyl]formamide (10.7 g, 39.9 mmol, 1.0 eq) was added to a mixture of 4-cyclopropyl-1,2-dihydropyrimidin-2-one (4.23 g, 27.9 mmol, 0.7 eq) and triethylamine (27.8 mL, 200 mmol, 5.0 eq) in DMF (107 mL), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was triturated (EtOAc / Hex, 1 / 4, v / v) to give a solid. This material was collected by vacuum filtration, washed with methanol, and dried under reduced pressure to give N-[2-(4-chloro-3,5-difluorophenyl)-1-(4-cyclopropyl-2- oxo-1,2-dihydropyrimidin-1-yl)-2-oxoethyl]formamide (3.0 g, 7.83 mmol, 20%) as a solid. This material was used directly in the next reaction. 1-[5-(4-chloro-3,5-difluorophenyl)-1,3-oxazol-4-yl]-4-cyclopropyl-1,2-dihydropyrimidin-2-one

[0442] Tris(4-methoxyphenyl)phosphine (5.52 g, 15.7 mmol, 2.0 eq) was dissolved in dichloromethane (60.0 mL). Triethylamine (4.06 mL, 31.3 mmol, 4.0 eq) and N-[2-(4-chloro-3,5- difluorophenyl)-1-(4-cyclopropyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2-oxoethyl]formamide (3.0 g, 7.83 mmol, 1.0 eq) were added. Then, iodine (2.98 g, 11.7 mmol, 1.5 eq) was added in one portion and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by normal phase column chromatography (silica gel, 0-10% acetone in DCM). The fractions containing the desired product were combined and concentrated, and the resulting solid was triturated with methanol. This solid was collected by vacuum filtration, washed with cold methanol, and dried under reduced pressure to give 1-[5-(4-chloro-3,5-difluorophenyl)-1,3-oxazol-4-yl]-4-cyclopropyl-1,2-dihydropyrimidin- 2-one (1.35 g, 3.86 mmol, 49%) as a solid.

[0443] UPLC-MS: [M+H]+= 349.85100% @ 254nm1-{5-(4-chloro-3,5-difluorophenyl)-2-[1-(2-methoxyethyl)-1H-1,2,6-triazainden-5-yl]-1,3-oxazol- 4-yl}-4-cyclopropyl-2(1H)-pyrimidinone [Compound 378]

[0444] A reaction vial was charged with 1-[5-(4-chloro-3,5-difluorophenyl)-1,3-oxazol-4-yl]-4- cyclopropyl-1,2-dihydropyrimidin-2-one (50 mg, 0.142 mmol, 1.0 eq), 5-bromo-1-(2- methoxyethyl)-1H-pyrazolo[3,4-c]pyridine (0.042 g, 0.156 mmol, 1.1 eq), cesium carbonate (0.138 g, 0.425 mmol, 3.0 eq), copper(I) iodide (0.003 g, 0.014 mmol, 0.1 eq), 1,1'- bis(diphenylphosphino)ferrocene dichloropalladium(II) (0.01 g, 0.014 mmol, 0.1 eq), and DMF (1.0 mL). The vial was sealed, and the mixture was flushed with argon for 5 minutes. Then, the reaction mixture was stirred for 1 hour at 100 °C. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The celite pad was washed with dichloromethane and methanol. The combined filtrate was concentrated under reduced pressure, and the crude material was purified by normal phase column chromatography (silica gel, 0-6% MeOH in DCM). The fractions containing the desired product were collected, and the resulting material was repurified by preparative TLC (4:5:1 ether: DCM: acetone) to afford 1-{5-(4-chloro-3,5- difluorophenyl)-2-[1-(2-methoxyethyl)-1H-1,2,6-triazainden-5-yl]-1,3-oxazol-4-yl}-4- cyclopropyl-2(1H)-pyrimidinone (0.005 g, 0.009 mmol, 7%) as a solid.

[0445] LCMS: [M+H]+= 525.2, 97.9% @ 315 nm

[0446] 1H NMR (300 MHz, DMSO-d6) δ 9.36 (t, J = 1.1 Hz, 1H), 8.76 (d, J = 1.2 Hz, 1H), 8.42 (d, J = 0.8 Hz, 1H), 8.21 (d, J = 7.0 Hz, 1H), 7.51 – 7.40 (m, 2H), 6.74 (d, J = 7.0 Hz, 1H), 4.81 (t, J = 5.0 Hz, 2H), 3.82 (t, J = 5.0 Hz, 2H), 3.22 (s, 3H), 2.15 (p, J = 7.1 Hz, 1H), 1.19 (dd, J = 6.3, 3.5 Hz, 4H).

[0447] The following compounds were prepared in an analogous manner from the appropriate starting materials using similar procedures. Compound (M+H)+Calc. Mass 378 525.2 524.915 379 441.1 440.837 380 442.1 441.825 381 456.1 455.852 382 459.1 458.827 383 467 466.835 384 467 466.835 385 467 466.835 386 480 479.874387 481 480.862 388 495.1 494.807 Synthesis of Compound 389.1-[5-(4-chloro-3,5-difluorophenyl)-2-(2-cyclopropyl-4- pyrimidinyl)-1,3-oxazol-4-yl]-4-cyclopropyl-2(1H)-pyrimidinone: 1-[5-(4-chloro-3,5-difluorophenyl)-2-(2-cyclopropyl-4-pyrimidinyl)-1,3-oxazol-4-yl]-4- cyclopropyl-2(1H)-pyrimidinone [Compound 389]

[0448] A reaction vial was charged with 1-[5-(4-chloro-3,5-difluorophenyl)-1,3-oxazol-4-yl]-4- cyclopropyl-1,2-dihydropyrimidin-2-one (0.056 g, 0.159 mmol, 1.0 eq), 4-chloro-2- cyclopropylopyrimidine (0.049 g, 0.317 mmol, 2.0 eq), potassium carbonate (0.066 g, 0.476 mmol, 3.0 eq), pivalic acid (0.007 ml, 0.063 mmol, 0.4 eq) and toluene (1.88 mL). The reaction mixture was flushed with argon for 10 minutes. Then, RuPhos (0.005 g, 0.011 mmol, 0.07 eq) and RuPhos Pd G3 (0.009 g, 0.011 mmol, 0.07 eq) were added. The reaction vial was sealed, and the reaction mixture was stirred for 2 days at 110 °C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by normal phase column chromatography (silica gel, 10% MeOH in DCM). This gave impure product which was again purified by preparative TLC (Et2O / DCM / MeOH, 20 / 75 / 5, v / v / v). The resulting material was triturated with methanol, collected by vacuum filtration, washed with diethyl ether, and dried under reduced pressure to give 1-[5-(4-chloro-3,5-difluorophenyl)-2-(2-cyclopropyl-4- pyrimidinyl)-1,3-oxazol-4-yl]-4-cyclopropyl-2(1H)-pyrimidinone (0.006 g, 0.012 mmol, 8%) as a white solid.

[0449] LCMS: [M+H]+= 468.11, 96.4% @ 205 nm

[0450] 1H NMR (300 MHz, DMSO-d6) δ 8.94 (d, J = 5.2 Hz, 1H), 8.17 (d, J = 7.0 Hz, 1H), 8.07 (d, J = 5.1 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 6.74 (d, J = 7.0 Hz, 1H), 2.38 – 2.32 (m, 1H), 2.20 – 2.09 (m, 1H), 1.16 (dt, J = 16.3, 6.1 Hz, 8H).

[0451] The following compounds were prepared in an analogous manner from the appropriate starting materials using similar procedures. Compound (M+H)+Calc. Mass 389 468.1 467.863 390 456.1 455.852 391 456.1 455.852 392 472.2 471.851 393 525 524.833 Synthesis of Compound 394.1-[5-(4-chloro-3,5-difluorophenyl)-2-(6,7-dihydro-4H-5-oxa-1,7a- diazainden-2-yl)-1,3-oxazol-4-yl]-4-cyclopropyl-2(1H)-pyrimidinone: 1-[5-(4-chloro-3,5-difluorophenyl)-2-(6,7-dihydro-4H-5-oxa-1,7a-diazainden-2-yl)-1,3-oxazol-4- yl]-4-cyclopropyl-2(1H)-pyrimidinone [Compound 394]

[0452] In a 30 ml sealable tube, 1-(5-(4-chloro-3,5-difluorophenyl)oxazol-4-yl)-4- cyclopropylpyrimidin-2(1H)-one (50 mg, 1 Eq, 0.14 mmol), toluene (5 mL), 2-bromo-6,7- dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (58 mg, 2.0 Eq, 0.29 mmol), and potassium carbonate (99 mg, 5.0 Eq, 0.71 mmol) were combined, and the resulting reaction mixture was degassed with argon for 10 minutes. Then, di((3S,5S,7S)-adamantan-1-yl)(butyl)phosphane (10 mg, 0.2 Eq, 29 μmol), pivalic acid (7.3 mg, 0.5 Eq, 71 μmol), and CataxiumA PdG3 (21 mg, 0.2 Eq, 29 μmol) w...

Claims

CLAIMS:

1. A compound, or a salt or a hydrate or a solvate thereof, having a structure according to formula (II):(II) wherein X is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazolyl, or substituted or unsubstituted diazaindenyl; Z is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; Rais substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted C3-C6 cycloalkyl; and Rbis H, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, or unsubstituted C3-C6cycloalkyl.

2. The compound of claim 1, or a salt or a hydrate or a solvate thereof, wherein is, , , , , , or .

3. The compound of claim 1, or a salt or a hydrate or a solvate thereof, wherein4. The compound of a preceding claim, or a salt or a hydrate or a solvate thereof, wherein Xis wherein Rf, Rg, and Rh are each independently selected from the group consistingof H, halogen, C2-C4 alkenyl, unsubstituted C1-3 alkyl, C1-3 alkyl substituted with one or more halogen, unsubstituted C1-3alkoxy, and C1-3alkoxy substituted with one or more halogen, wherein at least one of Rf, Rg, and Rhis not H.

5. The compound of any one of claims 1-4, or a salt or a hydrate or a solvate thereof, wherein X is 4-(trifluoromethyl)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-chloro-3-fluorophenyl, 4- chloro-3,5-difluorophenyl, 3,5-difluorophenyl, 4-methyl-3,5-difluorophenyl, 3-chloro-(4- cyclopropyl)phenyl, 3-fluoro-(4-fluoromethyl)phenyl, 3-fluoro-(4-difluoromethyl)phenyl, 4- (difluoromethyl)phenyl, 4-(methyl)phenyl, 3,4-difluorophenyl, 3-fluoro-(4-methyl)phenyl, 3- fluoro-(4-methoxy)phenyl, 4-fluoro-5-methylpyridin-2-yl, 6-(trifluoromethyl)pyridin-3-yl, or 5- trifluoromethylpyridin-2-yl.

6. The compound of any one of claims 1-4, or a salt or a hydrate or a solvate thereof, wherein X is 4-(trifluoromethyl)phenyl, 4-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chloro-3,5- difluorophenyl, or 4-methyl-3,5-difluorophenyl.

7. The compound of a preceding claim, or a salt or a hydrate or a solvate thereof, wherein Z is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted azaindenyl, substituted or unsubstituted diazaindenyl, substituted or unsubstituted triazaindenyl, substituted or unsubstituted tetraazaindenyl, substituted or unsubstituted isoquinolyl, substituted or unsubstituted quinolyl, substituted or unsubstituted indazolyl, or substituted or unsubstituted pyrazolyl.

8. The compound of a preceding claim, or a salt or a hydrate or a solvate thereof, wherein Z is 1-methyl-1H-1,2,4-triazainden-3-yl, 1,4,7a-triaza-5-indenyl, 5-fluoro-4-methyl-2-pyridyl, 7- methyl-1,3,3a-triaza-2-indenyl, 1-methyl-1H-1,6-diazainden-5-yl, 1-methyl-1H-1,2,5-triazainden- 6-yl, 4-methyl-1,3,3a-triaza-2-indenyl, 7-methyl-1,3a-diaza-2-indenyl, 1-methyl-6-isoquinolyl, 6- (fluoromethyl)-5-methyl-2-pyridyl, 6-(fluoromethyl)-4-methyl-2-pyridyl, or 6-fluoro-4-methyl-2- pyridyl.

9. The compound of claim 1, or a salt or a hydrate or a solvate thereof, which is 1-[5-(4- chloro-3-fluorophenyl)-2-(1-methyl-1H-1,2,4-triazainden-3-yl)-1,3-oxazol-4-yl]-4-cyclopropyl- 2(1H)-pyrimidinone, 1-[2-(1,4,7a-triaza-5-indenyl)-5-(3,5-difluoro-4-tolyl)-1,3-oxazol-4-yl]-4- cyclopropyl-2(1H)-pyrimidinone, 4-cyclopropyl-1-[5-(3,5-difluoro-4-tolyl)-2-(5-fluoro-4-methyl- 2-pyridyl)-1,3-oxazol-4-yl]-2(1H)-pyrimidinone, 1-[5-(4-chloro-3,5-difluorophenyl)-2-(7-methyl- 1,3,3a-triaza-2-indenyl)-1,3-oxazol-4-yl]-4-cyclopropyl-2(1H)-pyrimidinone, 1-[5-(4-chloro-3,5- difluorophenyl)-2-(1-methyl-1H-1,6-diazainden-5-yl)-1,3-oxazol-4-yl]-4-cyclopropyl-2(1H)- pyrimidinone, 1-[5-(4-chloro-3,5-difluorophenyl)-2-(1-methyl-1H-1,2,5-triazainden-6-yl)-1,3- oxazol-4-yl]-4-cyclopropyl-2(1H)-pyrimidinone, 1-[5-(4-chloro-3,5-difluorophenyl)-2-(4-methyl- 1,3,3a-triaza-2-indenyl)-1,3-oxazol-4-yl]-4-cyclopropyl-2(1H)-pyrimidinone, 1-[5-(4-chloro-3,5- difluorophenyl)-2-(7-methyl-1,3a-diaza-2-indenyl)-1,3-oxazol-4-yl]-4-cyclopropyl-2(1H)- pyrimidinone, 4-cyclopropyl-1-{2-[6-(fluoromethyl)-5-methyl-2-pyridyl]-5-(3-fluoro-4-tolyl)-1,3- oxazol-4-yl}-2(1H)-pyrimidinone, 1-{5-(4-chloro-3-fluorophenyl)-2-[6-(fluoromethyl)-4-methyl- 2-pyridyl]-1,3-oxazol-4-yl}-4-cyclopropyl-2(1H)-pyrimidinone, 4-cyclopropyl-1-[2-(6-fluoro-4- methyl-2-pyridyl)-5-(3-fluoro-4-tolyl)-1,3-oxazol-4-yl]-2(1H)-pyrimidinone, or 1-[5-(4-chloro-3- fluorophenyl)-2-(6-fluoro-4-methyl-2-pyridyl)-1,3-oxazol-4-yl]-4-cyclopropyl-2(1H)- pyrimidinone.

10. The compound of claim 1, or a salt or a hydrate or a solvate thereof, which is 4- cyclopropyl-1-[5-(p-fluorophenyl)-2-(1-methyl-6-isoquinolyl)-1,3-oxazol-4-yl]-2(1H)- pyrimidinone.

11. The compound of claim 1, or a salt or a hydrate or a solvate thereof, which is 4- cyclopropyl-1-{2-(1-methyl-6-isoquinolyl)-5-[p-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-2(1H)- pyrimidinone.

12. A pharmaceutical formulation comprising: a) the compound of any one of claims 1-11, or a pharmaceutically acceptable salt or a hydrate or a solvate thereof; and b) a pharmaceutically acceptable excipient.

13. A method of inhibiting propagation of misfolded proteins, the method comprising contacting the misfolded proteins with the compound of any one of claims 1-11, or a pharmaceutically acceptable salt or a hydrate or a solvate thereof, thereby inhibiting propagation of the misfolded proteins.

14. The method of claim 13, wherein the misfolded proteins comprise tau and / or amyloid β.

15. The method of claim 13, wherein the misfolded proteins comprise α-synuclein.

16. A method of treating a disease in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-11, or a pharmaceutically acceptable salt or a hydrate or a solvate thereof, thereby treating the disease in the subject.

17. The method of claim 16, wherein the disease is associated with misfolded proteins.

18. A method of treating a neurodegenerative disease in a subject, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-11, or a pharmaceutically acceptable salt or a hydrate or a solvate thereof, thereby treating the neurodegenerative disease in the subject.

19. The method of claim 18, wherein the neurodegenerative disease is selected from the group consisting of Multiple System Atrophy, Parkinson’s Disease, and Alzheimer’s Disease.

20. A method of detecting a disease in a mammalian tissue, comprising: contacting the mammalian tissue with a labeled compound; and determining binding of the labeled compound to the mammalian tissue wherein the labeled compound is the compound of any one of claims 1-11, or a pharmaceutically acceptable salt or a hydrate or a solvate thereof, wherein one or more of its atoms is replaced with [2H], [3H], [11C], [18F], or [13N], thereby detecting the disease in the mammalian tissue.

21. The method of claim 20, wherein the disease is associated with misfolded proteins.

22. The method of claim 20, wherein the disease is a neurodegenerative disease.

23. The method of claim 22, wherein the neurodegenerative disease is selected from the group consisting of Multiple System Atrophy, Parkinson’s Disease, and Alzheimer’s Disease.

24. The method of claim 20, wherein the mammalian tissue has been separated from the mammal.

25. The method of claim 20, wherein the mammalian tissue is human brain tissue, and the disease is a neurodegenerative disease.

26. The method of claim 20, wherein the determining comprises performing positron emission tomography, imaging mass spectrometry, or magnetic resonance imaging on the mammalian sample.