Metalloenzyme inhibitors and uses thereof

Abstract

Provided are compounds that inhibit histone deacetylase (HDAC) enzymes and compositions thereof. Also provided are uses of the HDAC enzyme inhibitors in prevention or treatment of diseases or conditions ameliorated by inhibiting HDAC activity.

Description

[0001] GIVT-0002PCTUS

[0002] METALLOENZYME INHIBITORS AND USES THEREOF

[0003] BACKGROUND

[0004] Technical Field

[0005] The present disclosure relates to compounds that inhibit histone deacetylase (HD AC) enzymes and preparations thereof. The present disclosure also provides uses of the HD AC enzyme inhibitors of the present disclosure in treatment of diseases or conditions ameliorated by inhibiting HD AC activity. Further, the pharmaceutical compositions comprising the HD AC enzyme inhibitors of the present disclosure are provided for treatment of glioma, neurodegenerative diseases such as Huntington’s diseases (HD), Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), and tissue lesions such as idiopathic pulmonary fibrosis (IPF) and kidney fibrosis, via inhibition of HD AC, such as HDAC6.

[0006] Description of Related Art

[0007] Histone deacetylases (HDACs) catalyze the deacetylation of histone and non-histone proteins and play important roles in epigenetic regulation. There are currently eighteen known HDACs that are organized into three classes: class I HDACs (e.g., HDAC1, HDAC2, HDAC3, HDAC8, and HDAC11), which are mainly localized to the nucleus; class II HDACs (e.g., HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HD AC 10), which shuttle between the nucleus and the cytoplasm; and class III HDACs (SIRT1 -7), which are localized in various cellular organelles. Class II HDACs are further characterized as class Ila HDACs and class lib HDACs.

[0008] It has been found that HDAC6 inhibition in vivo decreases the severity of colitis in the dextran sodium sulphate-induced colitis mouse model and the CD4+CD62Lhlghadoptive transfer model of colitis. In addition, inhibition of HDAC6 with a subtherapeutic dose of rapamycin leads to prolonged cardiac allograft survival. Thus, an orally available small molecule selective inhibitor of class II HD AC activity (e.g., HDAC6, HDAC7, or HDAC9) is expected to modulate autoimmune diseases through expansion and enhancement of Treg activity. Due to these interactions, class Ila HDACs have been suggested to modulate the transcriptional repression of BCL6 and participate in B-cell activation and differentiation, inflammation, and cell-cycle regulation (Verdin et al., Trends in Genetics, 2003, 19: 286-293). HDAC6, a class lib HDAC, has been reported to participate in aggresomal protein degradation, making it a target for the treatment of B cell malignancies (Simms-Waldrip et al., Molecular Genetics and Metabolism, 2008, 94: 283-286). Accordingly, a small molecule selective inhibitor of HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, and / or HDAC9 is expected to be beneficial in the treatment of B-cell malignancies by targeting one or several of the above enzymes.GIVT-0002PCTUS

[0009] HDAC6 is expressed in most neurons and most abundantly in cerebellar Purkinje cells. The degeneration of this type of neuron is observed in patients with spinocerebellar ataxia type 1 (SCA1) or SCA7. HDAC6 is involved in regulating microtubule dynamics and protein degradation, and a defect in microtubule-based transport would contribute to the neuronal toxicity observed in Huntington’s disease (Kazantsev et al., Nature Reviews Drug Discovery, 2008, 7: 854-868). Additionally, HDAC6 activity has been shown to be required for autophagic degradation of aggregated huntingtin, suggesting a role in protecting cells from polyQ toxicity (Iwata, et al., Journal of Biological Chemistry, 2005, 280: 40282-40292). Accordingly, a small molecule selective inhibitor of HDAC6 activity is expected to be beneficial in the treatment of neurodegenerative diseases.

[0010] Autosomal dominant polycystic kidney disease (ADPKD) is characterized by slowly progressive, bilateral kidney enlargement due to numerous fluid-filled cysts. ADPKD is caused by mutations in either PKD 1 or PKD2 genes, where disruption of their normal functions leads to excessive proliferation of the renal tubular epithelium causing cyst formation. Over twelve million people worldwide have ADPKD, making it amongst the most commonly known monogenic disorders. Fifty percent of ADPKD patients eventually develop end-stage renal disease (ESRD) by the age of 60, accounting for 10% and 5% of prevalent patients with ESRD in Europe and the United States, respectively. Unfortunately, treatment options for this life-threatening disorder are still limited and inadequate.

[0011] HDAC6 inhibitors have been suggested as one possible strategy to inhibit cyst growth. Unlike other HDACs that function in the nucleus, HDAC6 functions in the cytoplasm, where it regulates a number of biological processes including transcription, cell migration, proliferation, cell signaling, immune response, and protein degradation. Furthermore, HDAC6 is an a-tubulin deacetylase that regulates the stability of a-tubulin. Despite its role in these processes, mice lacking HDAC6 are viable and fertile with no gross morphological abnormalities, suggesting that HDAC6 is not an essential protein and that a selective HDAC6 inhibitor would have a favorable safety profile.

[0012] It also has been found that HDAC6 inhibition down-regulates cAMP levels, inhibiting cell proliferation and cAMP-activated cystic fibrosis transmembrane conductance regulator (CFTR) chloride currents in Madin-Darby Canine Kidney (MDCK) cells. HDAC6 inhibition also can inhibit cyst growth in vitro. Based on previous studies showing that cystic cholangiocytes in polycystic liver disease have abnormal cell cycle profiles and malfunctioning cilia, Gradilone and collaborators studied the role of HDAC6 in polycystic liver disease (PLD), which targets the epithelial lining of the biliary tree. It was found that expression of the HDAC6 protein is six times higher in cystic liver tissue and in cultured cholangiocytes isolated from both Polycystic Kidney (PCK) rats (an animal model of PLD) and humans with PLD. As in the studies of ADPKD, inhibition of HDAC6 activity by HDAC6GIVT-0002PCTUS

[0013] inhibitors decreases the proliferation of cystic cholangiocytes in a dose- and time-dependent manner and inhibits cyst growth in three-dimensional (3D) cultures.

[0014] Therefore, class II HD AC inhibitors have therapeutic potential in the studies and / or treatment of the various diseases or conditions described herein. Many of the known small-molecule HDAC inhibitors, however, inhibit all HDAC isoforms. It would thus be necessary to identify HDAC inhibitors that inhibit one or more but not all HDAC isoforms.

[0015] SUMMARY

[0016] In at least one embodiment, the present disclosure is directed to pyrimidinone derivatives, such as compounds having the structure represented by Formula I below:

[0017]

[0018] Formula I

[0019] or a pharmaceutically acceptable salt thereof,

[0020] wherein:

[0021] R1is hydrogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, (C6-Ci8)aryl(Ci-C6)alkyl, (C3-Ci8)heteroaryl(Ci-C6)alkyl, substituted (C6-Ci8)aryl(Ci-C6)alkyl, or (C6-Cis)aryl;

[0022] R2is one of the following moieties:

[0023]

[0024] GIVT-0002PCTUS

[0025]

[0026] R3is hydrogen, (Ci-C6)alkyl, (C3-C6)cycloalkyl, (C6-Ci8)aryl(Ci-C6)alkyl, (C3- Ci8)heteroaryl(Ci-C6)alkyl, substituted (C6-Ci8)aryl(Ci-C6)alkyl, or (C6-Cis)aryl; and

[0027] R4is hydrogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, (C6-Ci8)aryl(Ci-C6)alkyl, (C3-Ci8)heteroaryl(Ci-C6)alkyl, substituted (C6-Ci8)aryl(Ci-C6)alkyl, or (C6-Cis)aryl; or

[0028] wherein:

[0029] R1is one of the following moieties:

[0030]

[0031] R2is hydrogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, (C6-Ci8)aryl(Ci-C6)alkyl, (C3-Ci8)heteroaryl (Ci-Ce)alkyl, substituted (C6-Ci8)aryl(Ci-C6)alkyl, or (C6-Cis)aryl;

[0032] R3is hydrogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, (C6-Ci8)aryl(Ci-C6)alkyl, (C3-Ci8)heteroaryl (Ci-Ce)alkyl, substituted (C6-Ci8)aryl(Ci-C6)alkyl, or (C6-Cis)aryl; and

[0033] R4is hydrogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, (C6-Ci8)aryl(Ci-C6)alkyl, (C3-Ci8)heteroaryl (Ci-Ce)alkyl, substituted (C6-Ci8)aryl(Ci-C6)alkyl, or (Ce-Ci8)aryl.

[0034] In at least one embodiment, the present disclosure provides compounds having the structure represented by Formula I shown above, wherein:GIVT-0002PCTUS

[0035] R1is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, phenyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-(4-fluorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(2,6-dimethylphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, or isopropyl;

[0036] R2is one of the following moieties:

[0037]

[0038] R3is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, phenyl, substituted phenyl, benzyl, 2-phenylethyl, 3 -phenylpropyl, 2-(4-fluorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(2,6-dimethylphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, or isopropyl; and

[0039] R4is hydrogen, methyl, ethyl, propyl, or cyclopropyl; or

[0040] wherein:

[0041] R1is one of the following moieties:

[0042]

[0043] GIVT-0002PCTUS

[0044]

[0045] R2is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, phenyl, benzyl, 2 -phenyl ethyl, 3-phenylpropyl, 2-(4-fluorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(2,6-dimethylphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, or isopropyl;

[0046] R3is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, phenyl, substituted phenyl, benzyl, 2 -phenyl ethyl, 3 -phenylpropyl, 2-(4-fluorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(2,6-dimethylphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, or isopropyl; and

[0047] R4is hydrogen, methyl, ethyl, propyl, or cyclopropyl.

[0048] In at least one embodiment of the present disclosure, the compound is selected from the group consisting of:

[0049] l-(4-chlorophenethyl)-5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin- 2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0050] l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0051] l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0052] l-(4-chlorophenethyl)-5-(2-fluoro-3-methoxyphenyl)-3-((5-(5-(trifluoromethyl)- 1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0053] l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(2 -hydroxy ethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0054] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l-phenylpyrimidine-2,4(lH,3H)-dione,

[0055] 3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-l-(2,6-dimethylphenyl)-6-methylpyrimidine-2, 4-dione,

[0056] l-benzyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0057] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-l-(2,6-dimethylbenzyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0058] 3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-l-(2-phenylethyl)pyrimidine-2, 4-dione,GIVT-0002PCTUS

[0059] l-(2-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0060] 3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-l-[2-(2,6-dimethylphenyl)ethyl]-6-methylpyrimidine-2, 4-dione,

[0061] l-[2-(4-chlorophenyl)ethyl]-3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,

[0062] 3 -((5-(5-(difluorom ethyl)- 1 ,3 ,4-oxadiazol-2-yl)pyridin-2-yl)methyl)- 1 -(4-methoxyphenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0063] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l-(4- (trifluoromethyl)phenethyl)pyrimidine-2,4(lH,3H)-dione,

[0064] l-(2,6-dichlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0065] l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-5-(2-hydroxy ethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0066] l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-3-phenylpyrimidine-2,4(lH,3H)-dione,

[0067] 3-benzyl-l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0068] l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-(2,6-dimethylbenzyl)- 6-methylpyrimidine-2,4(lH,3H)-dione,

[0069] l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-3-(2-phenylethyl)pyrimidine-2, 4-dione,

[0070] 3-[2-(2-chlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,

[0071] l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-(2,6-dimethylphenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0072] 3-[2-(4-chlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,

[0073] l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-3-[2-(4-methoxyphenyl)ethyl]-6-methylpyrimidine-2, 4-dione,

[0074] l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-3-{2-[4- (trifluoromethyl)phenyl]ethyl}pyrimidine-2, 4-dione,

[0075] 3-[2-(2,6-dichlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,GIVT-0002PCTUS

[0076] l-(4-chlorophenethyl)-5-(2 -hydroxy ethyl)-6-methyl-3-((5-(5-(trifluoromethyl)- 1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,

[0077] l-(4-chlorophenethyl)-5-cyclopropyl-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)- 6-methylpyrimidine-2,4(lH,3H)-dione,

[0078] l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0079] 4-(2-(3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-2,4-di oxo-3, 4-dihydropyrimidin-l(2H)-yl)ethyl)benzonitrile,

[0080] 4-(2-(3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-6-methyl-2,4-dioxo-3,4-dihydropyrimidin- 1 (2H)-yl)ethyl)benzonitrile,

[0081] 3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-l-propylpyrimidine-2, 4-dione,

[0082] l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0083] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l,6-dimethylpyrimidine- 2,4(lH,3H)-dione,

[0084] l-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0085] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-ethyl-6-methylpyrimidine-2,4(lH,3H)-dione,

[0086] l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0087] 3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-l-(4-fluorophenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0088] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-(4-fluorophenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0089] l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-5- (2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0090] l-(4-chlorophenethyl)-5-(2-fluoro-3-methoxyphenyl)-6-methyl-3-((5-(5-(tri fluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,

[0091] l-(4-chlorophenethyl)-6-methyl-3-((5-(5-(tri fluoromethyl)- 1,2, 4-oxadiazol-3-yl)thi azol-2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,

[0092] l-(4-chlorophenethyl)-6-methyl-3-(4-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)benzyl)pyrimidine-2,4(lH,3H)-dione,GIVT-0002PCTUS

[0093] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-(2,6-dimethylphenethyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione, and 3 -((5-(5-(difluorom ethyl)- 1 ,3 ,4-oxadiazol-2-yl)pyridin-2-yl)methyl)- 1 -(2,6-dimethylphenethyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione.

[0094] In at least one embodiment of the present disclosure, the compound is selected from the group consisting of l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0095] 3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-l-[2-(2,6-dimethylphenyl)ethyl]-6-methylpyrimidine-2, 4-dione,

[0096] 3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-l-propylpyrimidine-2, 4-dione,

[0097] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l,6-dimethylpyrimidine-2,4(lH,3H)-dione,

[0098] l-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione, and

[0099] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-ethyl-6-methylpyrimidine-2,4(lH,3H)-dione.

[0100] In at least one embodiment of the present disclosure, the compound is selected from the group consisting of l-(4-chlorophenethyl)-5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0101] l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0102] l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0103] l-(4-chlorophenethyl)-5-(2-fluoro-3-methoxyphenyl)-3-((5-(5-(trifluoromethyl)- 1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0104] l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(2 -hydroxy ethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0105] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l-phenylpyrimidine-2,4(lH,3H)-dione,

[0106] 3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-l-(2,6-dimethylphenyl)-6-methylpyrimidine-2, 4-dione,

[0107] l-benzyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,GIVT-0002PCTUS

[0108] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-l-(2,6-dimethylbenzyl)- 6-methylpyrimidine-2,4(lH,3H)-dione,

[0109] 3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-l-(2-phenylethyl)pyrimidine-2, 4-dione,

[0110] l-(2-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0111] 3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-l-[2-(2,6-dimethylphenyl)ethyl]-6-methylpyrimidine-2, 4-dione,

[0112] l-[2-(4-chlorophenyl)ethyl]-3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,

[0113] 3 -((5-(5-(difluorom ethyl)- 1 ,3 ,4-oxadiazol-2-yl)pyridin-2-yl)methyl)- 1 -(4-methoxyphenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0114] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l-(4- (trifluoromethyl)phenethyl)pyrimidine-2,4(lH,3H)-dione,

[0115] l-(2,6-dichlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0116] l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-5-(2-hydroxy ethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0117] l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-3-phenylpyrimidine-2,4(lH,3H)-dione,

[0118] 3-benzyl-l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0119] l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-(2,6-dimethylbenzyl)- 6-methylpyrimidine-2,4(lH,3H)-dione,

[0120] l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-3-(2-phenylethyl)pyrimidine-2, 4-dione,

[0121] 3-[2-(2-chlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,

[0122] l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-(2,6-dimethylphenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0123] 3-[2-(4-chlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,

[0124] l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-3-[2-(4-methoxyphenyl)ethyl]-6-methylpyrimidine-2, 4-dione,GIVT-0002PCTUS

[0125] l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-3-{2-[4-(trifluoromethyl)phenyl]ethyl}pyrimidine-2, 4-dione,

[0126] 3-[2-(2,6-dichlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,

[0127] l-(4-chlorophenethyl)-5-(2 -hydroxy ethyl)-6-methyl-3-((5-(5-(trifluoromethyl)- 1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,

[0128] l-(4-chlorophenethyl)-5-cyclopropyl-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)- 6-methylpyrimidine-2,4(lH,3H)-dione,

[0129] l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0130] 4-(2-(3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-2,4-di oxo-3, 4-dihydropyrimidin-l(2H)-yl)ethyl)benzonitrile,

[0131] 4-(2-(3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-6-methyl-2,4-dioxo-3,4-dihydropyrimidin- 1 (2H)-yl)ethyl)benzonitrile,

[0132] 3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-l-propylpyrimidine-2, 4-dione,

[0133] l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0134] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l,6-dimethylpyrimidine- 2,4(lH,3H)-dione,

[0135] l-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0136] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-ethyl-6-methylpyrimidine-2,4(lH,3H)-dione,

[0137] l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0138] 3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-l-(4-fluorophenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0139] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-(4-fluorophenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0140] l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-5- (2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0141] l-(4-chlorophenethyl)-5-(2-fluoro-3-methoxyphenyl)-6-methyl-3-((5-(5-(tri fluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,GIVT-0002PCTUS

[0142] l-(4-chlorophenethyl)-6-methyl-3-((5-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)thiazol-2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,

[0143] l-(4-chlorophenethyl)-6-methyl-3-(4-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)benzyl)pyrimidine-2,4(lH,3H)-dione,

[0144] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-(2,6-dimethylphenethyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0145] 3 -((5-(5-(difluorom ethyl)- 1 ,3 ,4-oxadiazol-2-yl)pyridin-2-yl)methyl)- 1 -(2,6-dimethylphenethyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0146] l-(2,6-dimethylphenethyl)-6-methyl-3-((5-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)pyridin- 2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,

[0147] l-(4-fluorophenethyl)-6-methyl-3-(4-(5 -(trifluoromethyl)- 1,2, 4-oxadiazol-3-yl)benzyl)pyrimidine-2,4(lH,3H)-dione,

[0148] 5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl- 1-propylpyrimidine-2,4(lH,3H)-dione,

[0149] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(2-fluorophenyl)-6-methyl-l-propylpyrimidine-2,4(lH,3H)-dione,

[0150] l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-3-propylpyrimidine-2,4(lH,3H)-dione,

[0151] 5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-6-methyl-l-propylpyrimidine-2,4(lH,3H)-dione,

[0152] l-(4-fluorophenethyl)-5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0153] l-(4-fluorophenethyl)-5,6-dimethyl-3-((5-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)pyridin- 2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,

[0154] 3 -((5-(5-(difluorom ethyl)- 1 ,3 ,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)- 1 -(4-fluorophenethyl)-5,6-dimethylpyrimidine-2,4(lH,3H)-dione,

[0155] l-butyl-5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0156] 5-cyclopropyl-l-(2-cyclopropylethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin- 2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0157] 5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methyl-l-propylpyrimidine-2,4(lH,3H)-dione,

[0158] 5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-(2,6-dimethylphenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,GIVT-0002PCTUS

[0159] 5-cyclopropyl-l-(2-cyclopropylethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0160] 5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-isopropyl-6-methylpyrimidine-2,4(lH,3H)-dione,

[0161] 5-cyclopropyl-3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-ethyl- 1 -propylpyrimidine-2, 4-dione,

[0162] 5-cyclopropyl-3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-isopropyl-1 -propylpyrimidine-2, 4-dione,

[0163] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-5-(2-fluoro-3-methoxyphenyl)-l,6-dimethylpyrimidine-2,4(lH,3H)-dione,

[0164] 5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l-(oxetan-3-ylmethyl)pyrimidine-2,4(lH,3H)-dione,

[0165] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,

[0166] l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione, and

[0167] l-allyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione.

[0168] In at least one embodiment, the present disclosure relates to a composition comprising a therapeutically effective amount of the compound as described above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle thereof.

[0169] In at least one embodiment, the present disclosure relates to uses of the composition for prevention or treatment of a disease or a condition having a benefit from inhibition of histone deacetylase (HD AC).

[0170] In at least one embodiment, the present disclosure provides uses of the composition for prevention or treatment of a fibrosis, a kidney disease, or a liver disease in a subject in need thereof, wherein said subject is administered with an effective amount of the composition. In at least one embodiment of the present disclosure, the fibrosis is pulmonary fibrosis, idiopathic pulmonary fibrosis, hepatic fibrosis, renal fibrosis, or myelofibrosis. In at least one embodiment of the present disclosure, the kidney disease is at least one selected from the group consisting of polycystic kidney disease, autosomal dominant polycystic kidney disease, and autosomal recessive polycystic kidney disease.

[0171] In at least one embodiment, the present disclosure relates to uses of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in manufacture of a medicament for prevention or treatment of a disease or a condition having a benefit from inhibition of HD AC.GIVT-0002PCTUS

[0172] In at least one embodiment, the present disclosure relates to uses of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in manufacture of a medicament for prevention or treatment of a disease or a condition. In at least one embodiment of the present disclosure, the disease or the condition is a fibrosis, a kidney disease, or a liver disease. In at least one embodiment of the present disclosure, the fibrosis is pulmonary fibrosis, idiopathic pulmonary fibrosis, hepatic fibrosis, renal fibrosis, or myelofibrosis. In at least one embodiment of the present disclosure, the kidney disease is at least one selected from the group consisting of polycystic kidney disease, autosomal dominant polycystic kidney disease, and autosomal recessive polycystic kidney disease.

[0173] In at least one embodiment, the present disclosure relates to a method for preventing or treating a disease or a condition having a benefit from inhibition of HD AC in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In at least one embodiment of the present disclosure, the disease or the condition is a fibrosis, a kidney disease, or a liver disease. In at least one embodiment of the present disclosure, the fibrosis is pulmonary fibrosis, idiopathic pulmonary fibrosis, hepatic fibrosis, renal fibrosis, or myelofibrosis. In at least one embodiment of the present disclosure, the kidney disease is at least one selected from the group consisting of polycystic kidney disease, autosomal dominant polycystic kidney disease, and autosomal recessive polycystic kidney disease.

[0174] In at least one embodiment, the present disclosure relates to a composition of the present disclosure for use in prevention or treatment of a disease or a condition having a benefit from inhibition of HD AC in a subject in need thereof. In at least one embodiment of the present disclosure, the disease or the condition is a fibrosis, a kidney disease, or a liver disease. In at least one embodiment of the present disclosure, the fibrosis is pulmonary fibrosis, idiopathic pulmonary fibrosis, hepatic fibrosis, renal fibrosis, or myelofibrosis. In at least one embodiment of the present disclosure, the kidney disease is at least one selected from the group consisting of polycystic kidney disease, autosomal dominant polycystic kidney disease, and autosomal recessive polycystic kidney disease.

[0175] BRIEF DESCRIPTION OF THE DRAWINGS

[0176] The present disclosure can be more fully understood by reading the following detailed descriptions of the embodiments, with reference made to the accompanying drawings.

[0177] FIG. 1 shows body weight changes in Pkdl transgenic (Tg) and wild-type (WT) mice treated with Compound 18 (Cpd 18). Wild-type (WT) control mice (Group 1 (Gl), sham, n = 5) and Pkdl Tg mice (Group 2 (G2), vehicle, n = 6; Group 3 (G3), 10 mg / kg Cpd 18, n = 5; Group 4 (G4), 30 mg / kgGIVT-0002PCTUS

[0178] Cpd 18, n = 5; Group 5 (G5), 100 mg / kg Cpd 18, n = 5) were monitored for body weight throughout the 42-day treatment period. Data are presented as mean ± SD.

[0179] FIG. 2 shows the results of Compound 18 (Cpd 18) treatment in lowering the kidney -to-body weight ratio (KW / BW) in Pkdl miRNA transgenic mice. KW / BW (%) = (right kidney weight (mg) + left kidney weight (mg)) / body weight x 100%. * p < 0.05, 10 or 100 mg / kg Compound 18 vs. vehicle control using Student’s T-test.

[0180] FIG. 3 shows the results of Compound 18 (Cpd 18) treatment in lowering the serum BUN level in Pkdl miRNA transgenic mice. * p < 0.05, 10 or 30 mg / kg Compound 18 vs. vehicle control using Student’s T-test. ** p < 0.01, 100 mg / kg Compound 18 vs. vehicle control using Student’s T-test.

[0181] FIG.4. shows the representative images of hematoxylin and eosin (H&E) staining of kidney tissues from each mice group.

[0182] FIGs. 5A and 5B show the immunohistochemistry (IHC) staining results of PC-1 protein. FIG.

[0183] 5 A shows the percentage of PC-1 positive area in ADPKD mouse kidneys of each mice group, and FIG. 5B shows the representative images of the PC-1 positive area in ADPKD mouse kidneys of each mice group.

[0184] FIG. 6 shows the representative images of computed tomography (CT) scans of mice.

[0185] FIG. 7 shows the representative photomicrographs of a-smooth muscle actin (SMA) immunostaining and a-SMA-positive area and Masson’s tri chrome-stained lung sections from each mice group.

[0186] DETAILED DESCRIPTION

[0187] Definitions

[0188] The alternative definitions for the various groups and substituent groups of Formula I provided throughout the present specification are intended to describe each compound species disclosed herein, individually, as well as groups of one or more compound species. The scope of this disclosure includes any combination of these group and substituent group definitions.

[0189] As used herein, the term “alkyl” represents a saturated, straight, or branched hydrocarbon moiety. Exemplary alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, etc. The term “Ci-C4alkyl” refers to an alkyl containing from 1 to 4 carbon atoms. When the term “alkyl” is used in combination with other substituent groups, such as “arylalkyl,” the term “alkyl” is intended to encompass a divalent straight- or branched-chain hydrocarbon radical. For example, “arylalkyl” is intended to mean the radical alkylaryl, wherein the alkyl moiety thereof is a divalent straight- or branched-chain carbon radical. The aryl moiety thereof is as defined herein and is represented by the bonding arrangement present in a benzyl group (-CEE-phenyl).GIVT-0002PCTUS

[0190] As used herein, the term “cycloalkyl” refers to a non-aromatic, saturated, cyclic hydrocarbon ring. The term “Cs-Cscycloalkyl” refers to a non-aromatic cyclic hydrocarbon ring having from three to eight ring carbon atoms. Exemplary “Cs-Cscycloalkyl” groups useful in the present disclosure include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0191] As used herein, the term “alkoxy” refers to a group containing an alkyl radical attached through an oxygen linking atom. The term “Ci-C4alkoxy” refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom. Exemplary “(Ci-C4)alkoxy” groups useful in the present disclosure include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and s-butoxy.

[0192] As used herein, the term “aryl” represents a group or moiety comprising an aromatic, monocyclic, or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms and to which may be fused with one or more cycloalkyl rings. In addition, the terms alkyl, aryl, cycloalkyl, heteroaryl, etc. may be used to define a divalent substituent, such as a group bonded to two other groups. In this instance, such terms are intended to encompass divalent moieties. For example, “pentyl” is intended to represent a pentylene diradical, wherein the pentyl moiety is any one of a divalent straight (e g., -CH2CH2CH2CH2CH2-) or branched (e g. -CH2CH(CH3)CH2CH2-, -CH2CH2CH(CH2CH3)-, or-CH2CH2C(CH3)2-) chain 5-carbon radical.

[0193] Generally, in the compounds of this disclosure, heterocycloalkyl groups are 5-membered and / or 6-membered heterocycloalkyl groups, such as pyrrolidyl (or pyrrolidinyl), tetrahydrofuranyl, tetrahydrothienyl, dihydrofuranyl, oxazolinyl, thiazolinyl, pyrazolinyl, piperidyl (or piperidinyl), piperazinyl, morpholinyl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxanyl, tetrahydro-2H-l, 4-thiazinyl, 1,4-dioxanyl, 1,3-oxathianyl, and 1,3-dithianyl.

[0194] As used herein, the term “heteroaryl” represents a group or moiety comprising an aromatic monocyclic containing 5 to 10 ring atoms, including 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. This term is also intended to encompass heterocyclic groups containing nitrogen and / or sulfur where the nitrogen or sulfur heteroatoms are optionally oxidized. Illustrative examples of heteroaryls include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, isothiazolyl, furazanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl, and tetrazolyl.

[0195] Some of the heteroaryl groups present in the compounds of this disclosure are 5- to 6-membered monocyclic heteroaryl groups. Selected 5-membered heteroaryl groups contain one nitrogen, oxygen or sulfur ring heteroatom, and optionally contain 1, 2 or 3 additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1, 2, 3 or 4 nitrogen ring heteroatoms. Selected 5- or 6-membered heteroaryl groups include thienyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl,GIVT-0002PCTUS

[0196] isothiazolyl, furazanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and thiadiazolyl.

[0197] As used herein, the terms “halogen” and “halo” represent chloro, fluoro, bromo, or iodo substituents.

[0198] As used herein, the term “(Cm-Cn)” or “Cm-n,” wherein m and n are integers and n > m, means that all integer unit amounts within the range of m to n are specifically disclosed as part of the present disclosure. Thus, for the term “(Cm-Cn),” it means that Cm, Cm+i, Cm+2, ..., Cn-2, Cn-i, Cn, (Cm-Cm+i), (Cm_Cm+2), (Cm_Cm+3), • • • , (Cm_Cn-2), (Cm_Cn-l), (Cm_Cn); (Cm+l_Cm+2), (Cm+l_Cm+3), (Cm+l_Cm+4), • • • , (Cm+i_Cn-2), (Cm+i_Cn-i), (Cm+i_Cn), . ., (Cn-2_Cn-i), (Cn-2_Cn); and (Cn-i_Cn) are included as embodiments of this disclosure.

[0199] For the term “(Ci-Ce)” or “Ci-6,” it means that all integer unit amounts within the range of 1 to 6 are specifically disclosed as part of the present disclosure. Thus, Ci, C2, C3, C4, C5, Ce; (C1-C2), (Ci-C3), (C1-C4), (C1-C5), (Ci-C6); (C2-C3), (C2-C4), (C2-C5), (C2-C6); (C3-C4), (C3-C5), (C3-C6); (C4-C5), (C4-C6); and (Cs-Ce) units amounts are included as embodiments of this disclosure.

[0200] The term “treating” or “treatment” refers to administration of an effective amount of a therapeutic agent to a subject, who has a disease, or a symptom or predisposition toward such a disease, with the purpose to cure, alleviate, relieve, remedy, ameliorate, or prevent the disease, the symptoms thereof, or the predispositions theretoward.

[0201] The compounds represented by general formula I in the present disclosure may be prepared by the following schemes but not limited thereto:

[0202]

[0203] Scheme 1 "">

[0204]

[0205] Scheme 3

[0206] DFAA: difluoroacetic anhydride; AIBN: azobisisobutyronitrile; NBS: N-bromosuccinimide;

[0207] Pyr / Py: pyridine; TFAA: trifluoroacetic anhydrideGIVT-0002PCTUS

[0208]

[0209] GIVT-0002PCTUS

[0210] EXAMPLES

[0211] The following examples illustrate the present disclosure. These examples are not intended to limit the scope of the present disclosure but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present disclosure. While embodiments of the present disclosure are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the scope of the present disclosure.

[0212] Example 1 : Preparation of compound 1

[0213] Step 1: Synthesis of compound 5-bromo-l-(4-chlorophenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione

[0214]

[0215] To a solution of l-(4-chlorophenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione (2.0 g, 7.56 mmol) in dimethylformamide (DMF, 30 mL) stirred under nitrogen at 25°C was added Bn (1.57 g, 9.82 mmol). The reaction mixture was stirred at 65°C for 4 h. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (DCMMeOH = 20:1) to give the compound 5-bromo-l-(4-chlorophenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione (1.0 g, yield: 38.5%) as a white solid.

[0216] LCMS: retention time (r.t.) = 1.19 min, MS = 344.9 [M + H]+.

[0217] Step 2: Synthesis of compound 5-bromo-l-(4-chlorophenethyl)-6-methyl-3-((2- (trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(lH,3H)-dione

[0218]

[0219] GIVT-0002PCTUS

[0220] To a solution of 5-bromo-l-(4-chlorophenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione (1.9 g, 5.53 mmol) in acetonitrile (ACN, 20 mL) stirred under nitrogen at 25°C was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.67 g, 11.06 mmol). The reaction mixture was stirred at 30°C for 30min. Then, the reaction mixture was cooled to 0°C and added with 2-(trimethylsilyl)ethoxymethyl chloride (SEM-C1, 1.38 g, 8.29 mmol). The reaction mixture was stirred at 25°C for 16 h. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether (PE):ethyl acetate (EA) = 2:1) to give the compound 5-bromo-l-(4-chlorophenethyl)-6-methyl-3((2(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(lH,3H)-dione (1.9 g, yield: 72.5%) as a yellow oil.

[0221] 'H NMR (400 MHz, DMSO-t / 6) 6 7.38-7.36 (m, 2H), 7.29-7.27 (m, 2H), 5.26 (s, 2H), 4.09-4.03 (m, 2H), 3.59-3.55 (m, 2H), 2.90 (t, J= 7.6 Hz, 2H), 2.48 (s, 3H), 0.87-0.83 (m, 2H), 0.03 (s, 9H).

[0222] Step 3: Synthesis of compound l-(4-chlorophenethyl)-5-cyclopropyl-6-methyl-3-((2- (trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(lH,3H)-dione

[0223]

[0224] To a solution of 5-bromo-l-(4-chlorophenethyl)-6-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(lH,3H)-dione (1.0 g, 2.11 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.53 g, 3.17 mmol) and K3PO4 (1.11 g, 5.28 mmol) in dioxane / H2O (20 mL / 2 mL) stirred under nitrogen at 25°C was added dichlorobis(diphenylphosphinoferrocene)palladium (II) Pd(dppf)C12 (0.15 g, 0.21 mmol). The reaction mixture was stirred at 100°C for 16 h. The reaction mixture was cooled to room temperature (rt), quenched with saturated NH4CI, extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SC>4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 2:1) to give the compound l-(4-chlorophenethyl)-5-cyclopropyl-6-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(lH,3H)-dione (0.6 g, yield: 65.4%) as a yellow oil.

[0225] LCMS: r.t. = 1.59 min, MS = 435.1 [M + H]+.GIVT-0002PCTUS

[0226] Step 4: Synthesis of compound l-(4-chlorophenethyl)-5-cyclopropyl-6-methylpyrimidine-2,4(lH,3H)-dione

[0227]

[0228] A solution of l-(4-chlorophenethyl)-5-cyclopropyl-6-methyl-3-((2- (trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(lH,3H)-dione (700 mg, 1.61 mmol) in trifluoroacetic acid (TFA, 10 mL) under nitrogen was stirred at room temperature for 4 h. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and washed with H2O. The combined organic layer was washed with brine, dried over Na2SC>4, filtered, and concentrated to give the compound 1-(4-chlorophenethyl)-5-cyclopropyl-6-methylpyrimidine-2,4(lH,3H)-dione (400 mg, yield: 81.6%) as a yellow oil without further purification.

[0229] LCMS: r.t. = 1.20 min, MS = 305.0 [M + H]+.

[0230] Step 5: Synthesis of compound l-(4-chlorophenethyl)-5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione

[0231]

[0232] To a solution of l-(4-chlorophenethyl)-5-cyclopropyl-6-methylpyrimidine-2,4(lH,3H)-dione (150 mg, 0.49 mmol) and 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-l,3,4-oxadiazole (157 mg, 0.54 mmol) in N,N-dimethylformamide (DMF, 5 mL) stirred under nitrogen at room temperature was added K2CO3 (170 mg, 1.23 mmol). The reaction mixture was stirred at 30°C for 16 h. The reaction mixture was cooled to 0°C, quenched with saturated NH4CI, extracted with ethyl acetate. TheGIVT-0002PCTUS

[0233] combined organic layer was washed with brine, dried over Na2SC>4, filtered, and concentrated. The residue was purified by prep-HPLC to give the compound (Cpd 1) l-(4-chlorophenethyl)-5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione (155 mg, yield: 61.3%) as a white solid.

[0234] LCMS: r.t. = 1.235 min, MS = 514.0 [M + H]+. 'HNMR (400 MHz, DMSO ) 69.09 (d, J= 2.0 Hz, 1H), 8.39 (dd, J= 8.4 Hz, J= 2.4 Hz, 1H), 7.69-7.44 (m, 2H), 7.37-7.35 (m, 2H), 7.27-7.25 (m, 2H), 5.22 (s, 2H), 4.03 (t, J= 7.2 Hz, 2H), 2.89 (t, J= 7.2 Hz, 2H), 2.33 (s, 3H), 1.36-1.31 (m, 1H), 0.85-0.80 (m, 2H), 0.41-0.37 (m, 2H).

[0235] Following similar procedures above with appropriate chemicals substituted, l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione (Compound 4), l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione (Compound 5), and l-(4-chlorophenethyl)-5-(2-fluoro-3-methoxyphenyl)-3-((5-(5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione (Compound 6) were prepared.

[0236] Compound 4 is a white solid having the following structure:

[0237]

[0238] LCMS: r.t. = 1.377 min, MS = 598.0 [M + H]+. 'HNMR (400 MHz, DMSO ) 69.12 (d, J = 2.0 Hz, 1H), 8.41 (dd, J= 8.4 Hz, J= 2.0 Hz, 1H), 7.69-7.44 (m, 2H), 7.39-7.37 (m, 2H), 7.32-7.30 (m, 2H), 7.17-7.14 (m, 2H), 6.74-6.72 (m, 1H), 5.28 (d, J= 1.2 Hz, 2H), 4.09 (t, . / = 4,0 Hz, 2H), 3.84 (s, 3H), 2.96 (t, J = 7.6 Hz, 2H), 2.03 (m, 3H).

[0239] Compound 5 is a white solid having the following structure:GIVT-0002PCTUS

[0240]

[0241] (Compound 5).

[0242] LCMS: r.t. = 1.159 min, MS = 597.1 [M + H]+. 'H NMR (400 MHz, DMSO-t / r,) 6 8.04-8.02 (m, 2H), 7.67-7.42 (m, 3H), 7.29-7.26 (m, 2H), 7.18-7.14 (m, 2H), 6.78-6.74 (m, 1H), 5.13 (s, 2H), 4.13-4.08 (m, 2H), 3.86 (s, 3H), 2.98 (t, J= 7.2 Hz, 2H).

[0243] Compound 6 is a white solid having the following structure:

[0244]

[0245] (Compound 6).

[0246] LCMS: r.t. = 1.157 min, MS = 616.1 [M + H]+.XH NMR (400 MHz, DMSO-t / r,): 69.14 (s, 1H), 8.45-8.42 (m, 1H), 7.56 (d, J= 8.4 Hz, 2H), 7.39 (d, J= 8.0 Hz, 2H), 7.23 (d, J= 8.0 Hz, 2H), 7.17 (m, 2H), 6.75-6.73 (m, 1H), 5.29 (s, 2H), 4.13-4.08 (m, 2H), 3.34 (s, 3H), 2.97 (t, J= 5.6 Hz, 2H), 2.03 (s, 3H).

[0247] Example 2: Preparation of Compound 7

[0248] Step 1: Synthesis of compound l-(4-chlorophenethyl)-6-methyl-5-vinylpyrimidine-2,4(lH,3H)-dioneGIVT-0002PCTUS

[0249]

[0250] To a solution of l-(4-chlorophenethyl)-5-iodo-6-methylpyrimidine-2,4(lH,3H)-dione (12.0 g, 30.72 mmol), 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (9.46 g, 61.44 mmol) and K3PO4 (19.55 g, 92.16 mol) in dioxane / thO (100 mL / 10 mL) stirred under nitrogen at room temperature was added Pd(dppf)C12 (2.25 g, 3.07 mmol). The reaction mixture was stirred at 100°C for 16 h. The reaction mixture was cooled to room temperature, quenched with saturated NH4CI, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SC>4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to give the compound l-(4-chlorophenethyl)-6-methyl-5-vinylpyrimidine-2,4(lH,3H)-dione (4.5 g, yield: 50.4%) as an off-white solid.

[0251] LCMS: r.t. = 1.20 min, MS = 291.0 [M + H]+.

[0252] Step 2: Synthesis of compound l-(4-chlorophenethyl)-5-(2-hydroxyethyl)-6-methylpyrimidine-2,4(lH,3H)-dione

[0253]

[0254] To a solution of l-(4-chlorophenethyl)-6-methyl-5-vinylpyrimidine-2,4(lH,3H)-dione (1.5 g, 5.16 mmol) in tetrahydrofuran (THF, 20 mL) stirred under nitrogen at 0°C was added a solution of 0.5 M 9-borabicyclo[3.3.1]nonane (9-BBN, 83 mL, 41.5 mmol) in THF. The reaction mixture was stirred at 30°C for 16 h. Then, the reaction mixture was cooled to 0°C and added with 37% of H2O2 (20 mL). The reaction mixture was stirred at 25 °C for 3 h. To the reaction mixture was added 1 M NaOH (42 mL) and stirred at 25°C for 2 h. The reaction mixture was quenched with saturated NH4CI and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SC>4, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1)GIVT-0002PCTUS

[0255] to give the compound l-(4-chlorophenethyl)-5-(2-hydroxyethyl)-6-methylpyrimidine-2,4(lH,3H)-dione (1.0 g, yield: 62.9%) as an off-white solid.

[0256] LCMS: r.t. = 1.04 min, MS = 309.0 [M + H]+.

[0257] Step 3: Synthesis of compound l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(2-hydroxyethyl)-6-methylpyrimidine-2,4(lH,3H)-dione

[0258]

[0259] To a solution of l-(4-chlorophenethyl)-5-(2-hydroxyethyl)-6-methylpyrimidine-2,4(lH,3H)-dione (150 mg, 0.49 mmol) and 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-l,3,4-oxadiazole (82 mg, 0.53 mmol) in DMF (5 mL) stirred under nitrogen at room temperature was added K2CO3 (168 mg, 1.21 mmol). The reaction mixture was stirred at 25°C for 16 h. Then, the reaction mixture was cooled to 0°C, quenched with saturated NH4CI, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SC>4, filtered, and concentrated. The residue was purified by prep-HPLC to give the compound (Compound 7, Cpd 7) l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(2-hydroxyethyl)-6-methylpyrimidine-2,4(lH,3H)-dione (144 mg, yield: 57.2%) as a white solid.

[0260] LCMS: r.t. = 1.238 min, MS = 518.1 [M + H]+. 'HNMR (400 MHz, DMSO ) 69.09 (d, J= 2.0 Hz, 1H), 8.39 (dd, J= 8.4 Hz, J= 2.4 Hz, 1H), 7.69-7.44 (m, 2H), 7.37-7.35 (m, 2H), 7.28-7.26 (m, 2H), 5.24 (s, 2H), 4.59 (t, J= 5.2 Hz, 1H), 4.04 (t, J= 7.6 Hz, 2H), 3.38-3.35 (m, 2H), 2.89 (t, J = 7.6 Hz, 2H), 2.56-2.53 (m, 2H), 2.27 (m, 3H).

[0261] Following similar procedures above with appropriate chemicals substituted, 3-((5(5-(difluoromethyl)-l, 3, 4-oxadiazol -2 -yl)pyridin-2-yl)methyl)-6-methyl-l -phenylpyrimidine-2,4(lH,3H)-dione (120.0 mg, yield: 23.6%) (Compound 7a), 3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyri din-2 -yl}methyl)-l -(2, 6-dimethylphenyl)-6-methylpyrimidine-2, 4-dione (231.0GIVT-0002PCTUS

[0262] mg, yield: 20.2%) (Compound 7b), l-benzyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione (130.0 mg, yield: 33.0%) (Compound 7d), 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-l-(2,6-dimethyl-benzyl)-6-methylpyrimidine-2,4(lH,3H)-dione (145.1 mg, yield: 59.6%) (Compound 7e), 3-({5-[5-(difluoromethyl)- 1 ,3 ,4-oxadiazol-2-yl]pyridin-2-yl }methyl)-6-m ethyl- 1 -(2-phenylethyl)pyrimidine-2, 4-dione (135 mg, 51.52%) (Compound 7f), l-(2-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione (130.0 mg, yield: 61.4%) (Compound 7g), 3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-l-[2-(2,6-dimethylphenyl)ethyl]-6-methylpyrimidine-2, 4-dione (80.1 mg, yield: 28.7%) (Compound 7h), l-[2-(4-chlorophenyl)ethyl]-3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione (195 mg, 68.94%) (Compound 7i), 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyri din-2 -yl)methyl)-l-(4-methoxyphen-ethyl)-6-methylpyrimidine-2,4(lH,3H)-dione (100.3 mg, yield: 39.8%) (Compound 7j), 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l-(4-(trifluoromethyl)phenethyl)pyrimidine-2,4(lH,3H)-dione (110 mg, 36.33%) (Compound 7k), and l-(2,6-dichlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione (120 mg, 39.57%) (Compound 71) were prepared.

[0263] Compound 7a is a white solid having the following structure:

[0264]

[0265] (Compound 7a).

[0266] LCMS: purity 99.89% (r.t. = 1.170 min), MS = 412.0 [M + H]+. HRMS = 412.1218 [M + H]+. 'HNMR (400 MHz, DMSO-t / 6): 69.13 (s, 1H), 8.38 (d, J= 8.4 Hz, 1H), 7.71-7.40 (m, 7H), 5.92 (s, 1H), 5.22 (s, 2H), 1.87 (s, 3H).13C NMR (100 MHz, DMSO-t / 6) 6 164.15, 162.09, 160.95, 159.04(t), 153.40, 152.13, 147.69, 137.45, 135.83, 129.91, 129.53, 129.36, 121.86, 118.18, 107.07(t), 100.73, 45.61, 20.88.

[0267] Compound 7b is a white solid having the following structure:GIVT-0002PCTUS

[0268]

[0269] (Compound 7b).

[0270] LCMS: purity 97.67% (r.t. = 1.247 min), MS = 440.1 [M + H]+. HRMS: MS = 440.1527 [M + H]+. 'HNMR (400 MHz, DMSO-t / r,) 69.06 (d, J= 2.0 Hz, 1H), 8.40 (dd, J= 2.0 Hz, J= 8.4 Hz 1H), 7.70-7.44 (m, 2H), 7.28-7.21 (m, 3H), 5.99 (s, 1H), 5.27 (s, 2H), 2.10 (s, 6H), 1.79 (s, 3H).13C NMR (100 MHz, DMSO-t / e) 6 163.04, 161.05, 159.53, 157.95(t), 151.92, 149.96, 146.51, 135.21, 134.82, 134.39, 128.56, 128.01, 120.95, 117.18, 108.36, 105.99, 103.62, 100.15, 44.12, 18.44, 16.45.

[0271] Compound 7d is a white solid having the following structure:

[0272]

[0273] (Compound 7d).

[0274] LCMS: purity 99.81% (r.t. = 1.210 min), MS = 426.0 [M + H]+. HRMS = 426.1372 [M + H]+. 'HNMR (400 MHz, DMSO-t / 6): 69.12 (s, 1H), 8.39 (d, J= 8.4 Hz, 1H), 7.71-7.21 (m, 7H), 5.81 (s, 1H), 5.26 (s, 2H), 5.14 (s, 2H), 2.21 (s, 3H).13C NMR (100 MHz, DMSO-t / 6) 6 163.08, 160.67, 159.76, 157.98(t), 152.78, 151.63, 146.60, 136.17, 134.79, 128.21, 126.73, 125.36, 120.92, 117.16, 106.01(t), 100.17, 46.56, 44.53, 18.64.

[0275] Compound 7e is a white solid having the following structure:GIVT-0002PCTUS

[0276]

[0277] (Compound 7e).

[0278] LCMS: purity 98.82% (r.t. = 1.263 min), MS = 454.1 [M + H]+. HRMS = 454.1681 [M + H]+. 'H NMR (400 MHz, DMSO-t / 6): 6 9.06 (s, 1H), 8.39 (d, J = 8.4 Hz, 1H), 7.58 (t, J = 51.6 Hz, 1H), 7.53 (d, J= 8.4 Hz, 1H), 7.08-7.00 (m, 3H), 5.77 (s, 1H), 5.23 (d, J= 6.0 Hz, 4H), 2.22 (s, 6H), 2.08 (s, 3H).13C NMR (100 MHz, DMSO-t / 6): 6 163.06, 160.57, 159.70, 157.97(t), 153.33, 151.59, 146.47, 135.34, 134.69, 132.75, 128.51, 126.51, 120.96, 117.13, 106.00(t), 100.21, 44.51, 43.81, 19.24, 18.49.

[0279] Compound 7f is a white solid having the following structure:

[0280]

[0281] (Compound 7f).

[0282] LCMS: purity 98.17% (r.t. = 1.247 min), MS = 440.1 [M + H]+. HRMS = 440.1528 [M + H]+. 'HNMR (400 MHz, DMSO-t / 6): 6 9.13 (d, J= 2.4Hz, 1H), 8.45-8.41 (m, 1H), 7.71-7.43 (m, 2H), 7.38-7.25 (m, 5H), 5.70 (s, 1H), 5.26 (s, 2H), 4.01 (t, J= 10.0 Hz, 2H), 2.93 (t, J= 9.6 Hz, 2H), 2.16 (s, 3H).13C NMR (100 MHz, DMSO-t / r,) 6 163.08, 160.62, 159.85, 158.26(t), 152.79, 150.95, 146.58, 137.54, 134.79, 128.34, 127.95, 126.01, 120.13, 117.13, 108.36, 105.99, 103.62, 99.55, 45.64, 44.40, 33.19, 18.48.

[0283] Compound 7g is a white solid having the following structure:GIVT-0002PCTUS

[0284]

[0285] (Compound 7g).

[0286] LCMS: purity 99.74% (r.t. = 1.251 min), MS = 474.0 [M + H]+. HRMS = 474.1137 [M + H]+. 'HNMR (400 MHz, DMSO-t / 6): 69.13 (d, J= 1.6 Hz, 1H), 8.39 (dd, J= 2.4 Hz, 8.4 Hz, 1H), 7.58 (t, J= 51.2 Hz, 1H), 7.50 (d, J= 8.4 Hz, 1H), 7.45-7.43 (m, 1H), 7.37-7.27 (m, 3H), 5.68 (s, 1H), 5.21 (s, 2H), 4.02 (t, J= 7.2 Hz, 2H), 3.05 (t, J= 6.8 Hz, 2H), 2.10 (s, 3H).13C NMR (100 MHz, DMSO-t / 6): 6 164.14, 161.70, 160.90, 159.03(t), 153.62, 152.05, 147.64, 136.20, 135.83, 133.72, 132.10, 129.81, 129.27, 128.06, 121.94, 118.19, 107.06(t), 100.76, 45.49, 45.14, 32.03, 19.40.

[0287] Compound 7h is a white solid having the following structure:

[0288]

[0289] (Compound 7h).

[0290] LCMS: purity 99.52% (r.t. = 1.318 min), MS = 468.1 [M + H]+. HRMS = 468.1839 [M + H]+. 'H NMR (400 MHz, DMSO-t / 6): 6 9.10 (d, J= 2.0 Hz, 1H), 8.41-8.38 (m, 1H), 7.70-7.44 (m, 2H), 7.01 (s, 3H), 5.73 (s, 1H), 5.24 (s, 2H), 3.88 (t, J= 7.6 Hz, 2H), 2.94 (t, J= 7.6 Hz, 2H), 2.33 (s, 6H), 2.52 (s, 3H).13C NMR (100 MHz, DMSO-t / 6): 6 163.08, 160.62, 159.81, 157.96(t), 152.65, 151.23, 146.58, 136.03, 134.76, 133.94, 127.50, 125.84, 120.90, 117.12, 108.37, 105.99, 103.62, 99.71, 44.47, 43.27, 27.56, 18.89, 18.31.

[0291] Compound 7i is a white solid having the following structure:GIVT-0002PCTUS

[0292]

[0293] LCMS: purity 96.81% (r.t. = 1.301 min), MS = 474.0 [M + H]+. HRMS = 474.1140 [M + H]+. 'H NMR (400 MHz, DMSO-t / 6): 6 9.11 (d, J = 1.6 Hz, 1H), 8.41-8.39 (m, 1H), 7.70-7.45 (m, 2H), 7.39-7.37 (m, 2H), 7.27 (d, J= 8.4 Hz, 2H), 5.70 (s, 1H), 5.21 (s, 2H), 3.98 (t, J= 7.2 Hz, 2H), 2.90 (t, = 7.2Hz, 2H), 2.17 (s, 3H).13C NMR (100 MHz, DMSO-t / 6): 6 164.15, 161.68, 160.89, 159.03(t), 153.77, 152.00, 147.68, 137.64, 135.86, 131.73, 131.33, 128.93, 121.88, 118.19, 109.43, 107.06, 104.69, 100.71, 46.35, 45.47, 35.54, 19.60.

[0294] Compound 7j is a white solid having the following structure:

[0295]

[0296] (Compound 7j).

[0297] LCMS: purity 99.47% (r.t. = 1.214 min), MS = 470.1 [M + H]+. HRMS = 470.1637 [M + H]+. 'H NMR (400 MHz, DMSO-t / 6): 6 9.11 (s, 1H), 8.39 (d, J = 8.4 Hz, 1H), 7.57 (t, J = 51.6 Hz, 1H), 7.49 (d, J= 8.4 Hz, 1H), 7.15 (d, J= 7.6 Hz, 2H), 6.88 (d, J= 7.6 Hz, 2H), 5.67 (s, 1H), 5.22 (s, 2H), 3.94 (t, J= 4.2 Hz, 2H), 3.72 (s, 3H), 2.83 (t, J= 7.2 Hz, 2H), 2.13 (s, 3H).13C NMR (100 MHz, DMSO-t / r,): 6 163.08, 160.63, 159.86, 157.96(t), 157.42, 152.81, 150.94, 146.59, 134.78, 129.37, 129.32, 120.80, 117.11, 113.34, 105.99(t), 99.52, 54.42, 45.79, 44.40, 32.32, 18.52.

[0298] Compound 7k is a white solid having the following structure:GIVT-0002PCTUS

[0299]

[0300] (Compound 7k).

[0301] LCMS: purity 97.35% (r.t. = 1.286 min), MS = 508.0 [M + H]+. HRMS = 508.1404 [M + H]+. 'H NMR (400 MHz, DMSO-t / 6): 6 9.11 (d, J = 1.6 Hz, 1H), 8.41-8.38 (m, 1H), 7.70-7.44 (m, 6H), 5.71 (s, 1H), 5.21 (s, 2H), 4.03 (t, J = 7.2 Hz, 2H), 3.01 (t, J = 7.2 Hz, 2H), 2.20 (s, 3H).13C NMR (100 MHz, DMSO-t / r,): 6 164.14, 161.70, 160.88, 159.03(t), 153.73, 152.02, 147.67, 143.57, 135.85, 130.28, 125.82(q), 121.88, 118.17, 109.42, 107.04, 104.67, 100.77, 46.16, 45.47, 34.07, 19.54.

[0302] Compound 71 is a white solid having the following structure:

[0303]

[0304] (Compound 71).

[0305] LCMS: purity 99.48% (r.t. = 1.291 min), MS = 507.9 [M + H]+. HRMS = 508.0748 [M + H]+. 'H NMR (400 MHz, DMSO-t / 6): 6 9.08 (d, J= 1.6 Hz, 1H), 8.40-8.37 (m, 1H), 7.69-7.44 (m, 4H), 7.28 (t, J= 8.4 Hz, 1H), 5.69 (s, 1H), 5.16 (s, 2H), 4.08 (t, J= 6.4 Hz, 2H), 3.24 (t, J= 6.4 Hz, 2H), 2.09 (s, 3H).13C NMR (100 MHz, DMSO-t / 6): 6 164.13, 161.75, 160.88, 159.04(t), 153.45, 152.14, 147.61, 135.77, 135.58, 134.19, 130.07, 129.05, 121.93, 118.17, 109.43, 107.05, 104.68, 100.90, 45.55, 43.50, 30.00, 19.28.

[0306] Example 3 : Preparation of compound 8a

[0307] Step 1: Synthesis of compound 6-methyl-3-phenylpyrimidine-2,4(lH,3H)-dioneGIVT-0002PCTUS

[0308] <

[0309]

[0310] H H

[0311] A mixture of 6-methylpyrimidine-2,4(lH,3H)-dione (0.35 g, 2.8 mmol), diphenyliodonium tetrafluorob orate (1.03 g, 2.8 mmol), Cui (0.05 g, 0.28 mmol), andNaOAc (0.46 g, 5.6 mmol) in DMF (15 ml) was provided. The reaction mixture was stirred at about 40°C for 6 hours under N2 atmosphere. Then, the reaction mixture was cooled to 0°C, quenched with H2O (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (50 mL), dried over Na2SC>4, filtered, and concentrated. The residue was purified by flash column chromatography (DCM / MeOH = 10 / 1) to give the compound 6-methyl-3-phenylpyrimidine-2,4(lH,3H)-dione (120.0 mg, 21.4%) as an off-white solid.

[0312] LCMS: r.t. = 0.27 min, MS = 203.1 [M + H]+. 'HNMR (400 MHz, DMSO-t / 6): 8 11.25 (s, 1 H), 7.46-7.38 (m, 3 H), 7.19 (d, J= 7.6 Hz, 2H), 5.57 (s, 1 H), 2.09 (s, 3 H).

[0313] Step 2: Synthesis of l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-3-phenylpyrimidine-2,4(lH,3H)-dione (Compound 8a)

[0314]

[0315] 8a

[0316] A mixture of 6-methyl-3-phenylpyrimidine-2,4(lH,3H)-dione (120 mg, 0.59 mmol), K2CO3 (164.0 mg, 1.19 mmol), and 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-l,3,4-oxadiazole (189.3 mg, 0.65 mmol) in DMF (10 mL) was provided. The reaction mixture was stirred at 25°C for 16 hours. Then, the reaction mixture was cooled to 0°C, quenched with H2O (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (50 mL), dried over Na2SC>4, filtered, and concentrated. The residue was purified with prep-HPLC (Xbrige Cl 85 pm, 19 x 150 mm, 16 min - 30-80%B, A: H2O (0.1% NH4HCO3), B: ACN, UV: 214 nm; flow rate: 15 mL / min; gradient time (GT): 10 min) to give the compound (8a) l-((5-(5-(difluoromethyl)-l,3,4-GIVT-0002PCTUS

[0317] oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-3-phenylpyrimidine-2,4(lH,3H)-dione (102.0 mg, yield: 41.8%) as a white solid.

[0318] LCMS: purity 100.0% (r.t. = 1.131 min), MS = 412.0 [M + H]+. HRMS = 412.1213 [M + H]+. 'HNMR (400 MHz, DMSO-t / 6): 69.19 (s, 1H), 8.43 (d, J= 8.0 Hz, 1H), 7.71-7.37 (m, 5H), 7.21 (d, J= 7.6 Hz, 2H), 5.86 (s, 1H), 5.30 (s, 2H), 2.31 (s, 3H).13C NMR (100 MHz, DMSO-t / 6): 6 164.06, 161.95, 160.51, 158.81(t), 154.31, 152.38, 148.01, 136.24, 136.19, 129.32, 129.18, 128.57, 122.51, 118.60, 107.06(t), 101.48, 49.44, 20.14.

[0319] Following similar procedures above with appropriate chemicals substituted, the following compounds were further prepared.

[0320] Compound 8d:

[0321]

[0322] 3-benzyl-l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine- 2,4(lH,3H)-dione (109.0 mg, yield: 46.2%) as a white solid

[0323] LCMS: purity 99.88% (r.t. = 1.215 min), MS = 426.0 [M + H]+. HRMS = 426.1372 [M + H]+.XH NMR (400 MHz, DMSO-t / 6): 69.15 (s, 1H), 8.43 (d, = 8.0Hz, 1H), 7.65 (d, = 8.0Hz, 1H), 7.58 (t, J= 51.2 Hz, 1H), 7.31-7.21 (m, 5H), 5.81 (s, 1H), 5.30 (s, 2H), 4.98 (s, 2H), 2.25 (s, 3H).13C NMR (100 MHz, DMSO-t / r,): 6 164.04, 161.84, 160.43, 159.10(t), 154.05, 152.42, 147.95, 137.59, 136.16, 128.76, 127.86, 127.55, 122.51, 118.62, 107.04(t), 100.93, 49.37, 44.00, 20.02.

[0324] Compound 8e:GIVT-0002PCTUS

[0325]

[0326] l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-(2,6-dimethylbenzyl)-6- methylpyrimidine-2,4(lH,3H)-dione (170 mg, yield: 62.84%) as a white solid

[0327] LCMS: purity 98.05% (r.t. = 1.371 min), MS = 454.0 [M + H]+. HRMS = 454.1683 [M + H]+. 'H NMR (400 MHz, DMSO-t / 6): 6 9.10 (d, J= 2.0 Hz, 1H), 8.42-8.39 (m, 1H), 7.70-7.45 (m, 2H), 6.99-6.90 (m, 3H), 5.73 (s, 1H), 5.24 (s, 2H), 4.99 (s, 2H), 2.24 (s, 6H), 2.21 (s, 3H).13C NMR (100 MHz, DMSO-t / r,): 6 162.97, 160.98, 159.39, 158.02(t), 152.68, 151.13, 146.78, 136.39, 135.01, 132.89, 127.57, 125.99, 121.39, 117.49, 108.35, 105.98, 103.61, 99.77, 48.10, 19.32, 18.82.

[0328] Compound 8f:

[0329]

[0330] l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-3-(2- phenylethyl)pyrimidine-2, 4-dione (172.2 mg, yield:43.8%) as a white solid

[0331] LCMS: purity 98.71% (r.t. = 1.243 min), MS = 440.0 [M + H]+. HRMS = 440.1526 [M + H]+. 'HNMR (400 MHz, DMSO-t / r,) 6 9.16 (s, 1H), 8.44-8.42 (m, 1H), 7.71-7.46 (m, 2H), 7.30-7.17 (m, 5H), 5.73 (s, 1H), 5.28 (s, 2H), 4.00 (t, J= 7.2 Hz, 2H), 2.80 (t, J= 7.6 Hz, 2H), 2.23 (s, 3H).13C NMR (100 MHz, DMSO-t / e) 6 163.00, 160.62, 159.44, 157.02(t), 152.53, 151.11, 146.91, 137.85, 135.10, 128.02, 127.80, 125.70, 121.38, 117.52, 107.35, 105.97, 103.62, 99.90, 48.23, 41.07, 32.41, 18.89.

[0332] Compound 8g:GIVT-0002PCTUS

[0333]

[0334] 3-[2-(2-chlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6- methyl-pyrimidine-2, 4-dione (115 mg, yield: 39.62%) as a white solid

[0335] LCMS: purity 99.30% (r.t. = 1.277 min), MS = 474.0 [M + H]+. HRMS = 474.1139 [M + H]+.

[0336] 1HNMR(400MHz, DMSO-t / 6): 69.15(d, J= 1.6 Hz, 1H), 8.44-8.42 (m, 1H), 7.71-7.45 (m, 2H), 7.37 (d, J= 7.2 Hz, 1H), 7.24-7.20 (m, 3H), 5.70 (s, 1H), 5.25 (s, 2H), 4.00 (t, J= 7.2 Hz, 2H), 2.95 (t, J = 7.2 Hz, 2H), 2.23 (s, 3H).13CNMR(100MHz, DMSO-t / 6): 6162.99, 160.60, 159.41, 158.04(t), 152.51, 151.12, 146.89, 135.54, 135.07, 132.65, 130.51, 128.55, 127.69, 126.63, 121.391, 117.50, 108.35, 105.98, 99.84, 48.19, 30.16, 18.90.

[0337] Compound 8h:

[0338]

[0339] l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-(2,6-dimethylphenethyl)-6- methylpyrimidine-2,4(lH,3H)-dione (105.0 mg, yield: 37.7%) as a white solid

[0340] LCMS: purity 96.63% (r.t. = 1.315 min), MS = 468.1 [M + H]+. HRMS = 468.1843 [M + H]+. 'HNMR (400 MHz, DMSO-t / 6): 69.16 (s, 1H), 8.44 (d, J= 7.2 Hz, 1H), 7.65 (d, J= 7.6 Hz, 1H), 7.58 (t, J= 51.2 Hz, 1H), 6.98 (s, 3H), 5.78 (s, 1H), 5.33 (s, 2H), 3.87-3.78 (m, 2H), 2.86-2.76 (m, 2H), 2.35 (s, 6H), 2.25 (s, 3H).13CNMR(100MHz, DMSO-t / 6) 6163.00, 160.77, 159.43, 158.03(t), 152.73, 151.25, 146.93, 135.87, 135.13, 134.23, 127.29, 125.58, 121.43, 117.54, 105.99(t), 99.96, 48.22, 26.83, 18.92, 18.62.GIVT-0002PCTUS

[0341] Compound 8i:

[0342]

[0343] 3-[2-(4-chlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6- methylpyrimidine-2, 4-dione (235 mg, yield: 82.9%) as a white solid

[0344] LCMS: purity 99.58% (r.t. = 1.317 min), MS = 474.0 [M + H]+. HRMS = 474.1140 [M + H]+. 'H NMR (400 MHz, DMSO-t / 6): 6 9.16 (d, J= 1.6 Hz, 1H), 8.45-8.43 (m, 1H), 7.72-7.46 (m, 2H), 7.30 (d, J= 8.0 Hz, 2H), 7.18 (d, J= 8.4 Hz, 2H), 5.72 (s, 1H), 5.26 (s, 2H), 4.00 (t, J= 7.2 Hz, 2H), 2.81 (t, J= 7.2 Hz, 2H), 2.23 (s, 3H).13C NMR (100 MHz, DMSO-t / 6): 6 163.00, 160.62, 159.40, 158.03(t), 152.58, 151.09, 146.90, 136.90, 135.06, 130.28, 129.97, 127.65, 121.36, 117.51, 108.36, 105.99, 103.61, 99.85, 48.21, 40.79, 31.65, 18.91.

[0345] Compound 8j :

[0346]

[0347] l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-3-[2-(4-methoxyphenyl)ethyl]- 6-methylpyrimidine-2, 4-dione (172.3 mg, yield: 41.0%) as a white solid

[0348] LCMS: purity 99.20% (r.t. = 1.159 min), MS = 470.0 [M + H]+. HRMS = 470.1634 [M + H]+. 'H NMR (400 MHz, DMSO-t / 6): 6 9.15 (d, J= 1.6 Hz, 1H), 8.43-8.41 (m, 1H), 7.72-7.46 (m, 2H), 7.08 (d, J= 8.8 Hz, 2H), 6.84-6.81 (m, 2H), 5.73 (s, 1H), 5.26 (s, 2H), 3.96 (t, J= 7.6 Hz, 1H), 3.70 (s, 3H), 2.73 (t, J= 7.6 Hz, 1H), 2.23 (s, 3H).13C NMR (100 MHz, DMSO-t / 6): 6 164.06, 161.70,GIVT-0002PCTUS

[0349] 160.51, 159.38(t), 158.23, 153.53, 152.18, 147.95, 136.12, 130.73, 130.09, 122.38, 118.57, 114.25, 109.43, 107.05, 104.68, 100.98, 55.41, 49.29, 42.33, 32.57, 19.96.

[0350] Compound 8k:

[0351]

[0352] l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-3-{2-[4- (trifluoromethyl)-phenyl]ethyl}pyrimidine-2, 4-dione (184.4 mg, yield: 60.9%) as a white solid

[0353] LCMS: purity 99.01% (r.t. = 1.239 min), MS = 508.0 [M + H]+. HRMS = 508.1401 [M + H]+. 'H NMR (400 MHz, DMSO-t / 6): 6 9.15 (d, J= 1.6 Hz, 1H), 8.44-8.42 (m, 1H), 7.72-7.57 (m, 4H), 7.40 (d, J= 7.6 Hz, 2H), 5.74 (s, 1H), 5.26 (s, 2H), 4.05 (t, J= 6.8 Hz, 2H), 2.91 (t, J= 7.2 Hz, 2H), 2.23 (s, 3H).13C NMR (100 MHz, DMSO-t / 6): 6 162.98, 160.63, 159.39, 158.03(t), 152.66, 151.10, 146.89, 142.89, 135.05, 128.96, 124.57, 124.53, 124.50, 121.36, 117.50, 108.35, 105.98, 103.61, 99.83, 48.20, 40.65, 32.21, 18.91.

[0354] Compound 81:

[0355]

[0356] 3-[2-(2,6-dichlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2- yl}methyl)-6-methylpyrimidine-2, 4-dione (195.7 mg, yield: 32.3%) as a white solid

[0357] LCMS: purity 96.74% (r.t. = 1.159 min), MS = 507.9 [M + H]+. HRMS = 508.0750 [M + H]+.XH NMR (400 MHz, DMSO-t / 6): 69.14 (s, 1H), 8.44-8.42 (m, 1H), 7.71-7.46 (m, 2H), 7.35 (d, J= 8.0GIVT-0002PCTUS

[0358] Hz, 2H), 7.19-7.35 (m, 1H), 5.66 (s, 1H), 5.21 (s, 2H), 4.11 (t, J= 5.6 Hz, 2H), 3.16 (t, J= 5.6 Hz, 2H), 2.24 (s, 3H).13C NMR (100 MHz, DMSO-t / 6): 6 164.05, 161.74, 160.46, 157.51(t), 153.56, 152.28, 147.91, 136.08, 135.48, 134.96, 129.43, 128.68, 122.59, 118.57, 107.06, 104.69, 100.90, 49.26, 29.17, 20.00.

[0359] Compound 8:

[0360]

[0361] l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-5-(2-hydroxyethyl)-6- methylpyrimidine-2,4(lH,3H)-dione as a white solid

[0362] LCMS: r.t. = 1.294 min, MS = 517.0 [M + H]+. 'HNMR (400 MHz, DMSO ) 68.01 (d, J = 8.0 Hz, 2H), 7.54-7.41 (m, 3H), 7.36-7.34 (m, 2H), 7.26-7.24 (m, 2H), 5.09 (s, 2H), 4.58 (t, J= 6.6 Hz, 1H), 4.05 (t, J= 7.2 Hz, 2H), 3.40-3.37 (m, 2H), 2.89 (t, J= 7.6 Hz, 2H), 2.53 (t, J= 14.0 Hz, 2H), 2.88 (s, 3H).

[0363] Compound 9:

[0364]

[0365] l-(4-chlorophenethyl)-5-(2-hydroxyethyl)-6-methyl-3-((5-(5-(trifluoromethyl)-l,3,4-oxadiazol-2- yl)pyridin-2-yl)methyl)pyrimidine-2,4(lH,3H)-dione as a white solid

[0366] LCMS: r.t. = 1.297 min, MS = 536.0 [M + H]+. 'HNMR (400 MHz, DMSO ) 69.12 (d, J =GIVT-0002PCTUS

[0367] 2.0 Hz, 1H), 8.40-8.42 (m, 1H), 7.48 (d, J= 8.4 Hz, 1H), 7.36 (d, J= 8.0 Hz, 2H), 7.27 (d, J= 8.4 Hz, 2H), 5.25 (s, 2H), 4.61 (t, J= 5.6 Hz, 1H), 4.04 (t, J= 7.2 Hz, 2H), 3.35-3.38 (m, 2H), 2.89 (t, J= 7.2 Hz, 2H), 2.54 (t, J= 6.8 Hz, 2H), 2.27 (s, 3H).

[0368] Compound 10:

[0369]

[0370] l-(4-chlorophenethyl)-5-cyclopropyl-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-6- methylpyrimidine-2,4(lH,3H)-dione as a white solid

[0371] LCMS: r.t. = 1.103 min, MS = 513.0 [M + H]+.XH NMR (400 MHz, DMSO-t / 6) 68.01 (d, J = 8.4 Hz, 2H), 7.67-7.42 (m, 3H), 7.35-7.33 (m, 2H), 7.23-7.21 (m, 2H), 5.07 (s, 2H), 4.03 (t, J= 7.2 Hz, 2H), 2.89 (t, J= 7.2 Hz, 2H), 2.35 (s, 3H), 1.38-1.32 (m, 1H), 0.86-0.82 (m, 2H), 0.43-0.39 (m, 2H).

[0372] Compound 13:

[0373]

[0374] l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-6-methylpyrimidine- 2,4(lH,3H)-dione (600.00 mg, yield: 73.36%) as a white solidGIVT-0002PCTUS

[0375] LCMS: r.t. = 1.344 min, MS = 473.0 [M + H]+.XH NMR (400 MHz, DMSO ) 68.03 (d, J = 8.4 Hz, 2H), 7.55-7.42 (m, 3H), 7.36-7.33 (m, 2H), 7.25-7.22 (m, 2H), 5.70 (s, 1H), 5.06 (s, 2H), 4.01-3.97 (m, 2H), 2.90 (t, J = 7.2 Hz, 2H), 2.19 (s, 3H).

[0376] Compound 14:

[0377]

[0378] 4-(2-(3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)ethyl)benzonitrile (205 mg, yield: 75.1%) as a white solid

[0379] LCMS: r.t. = 1.198 min, MS = 465.1 [M + H]+.XH NMR (400 MHz, DMSO-t / 6) 69.11 (d, J = 1.6 Hz, 1H), 8.39 (dd, J= 8.0 Hz, J= 2.0 Hz, 1H), 7.78 (d, J= 8.4 Hz, 2H), 7.69-7.44 (m, 4H), 5.70 (s, 1H), 5.19 (s, 2H), 4.02 (t, J= 7.2 Hz, 2H), 3.00 (t, J= 7.2 Hz, 2H), 2.19 (s, 3H).13C NMR (100 MHz, DMSO-t / e) 6 163.07, 160.58, 159.78, 157.96(t), 152.61, 150.93, 146.61, 143.57, 134.76, 131.78, 129.50, 120.84, 118.22, 117.12, 108.84, 105.97(t), 99.73, 44.85, 44.40, 33.24, 18.51.

[0380] Compound 15:

[0381]

[0382] 4-(2-(3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-6-methyl-2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)ethyl)benzonitrile (150 mg, yield 46.78%) as a white solidGIVT-0002PCTUS

[0383] LCMS: r.t. = 1.256 min, MS = 464.0 [M + H]+. 'H NMR (400 MHz, DMSO-t / r,) 6 8.03-8.01 (m, 2H), 7.75-7.35 (m, 2H), 7.47-7.41 (m, 5H), 5.71 (s, 1H), 5.05 (s, 2H), 4.05-4.01 (m, 2H), 3.02-2.98 (m, 2H), 1.99 (s, 3H).

[0384] Compound 16:

[0385]

[0386] 3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-l-propylpyrimidine- 2,4-dione (220 mg, yield: 65.4%) as a white solid

[0387] LCMS: r.t. = 1.153 min, MS = 378.1 [M + H]+.XH NMR (400 MHz, DMSO-t / 6) 69.85 (d, J = 2.0 Hz, 1H), 8.37 (dd, J= 8.0 Hz, J= 2.0 Hz, 1H), 7.69-7.44 (m, 2H), 5.72 (s, 1H), 5.19 (s, 2H), 3.74 (t, J= 7.6 Hz, 2H), 2.32 (s, 3H), 1.63-1.54 (m, 2H), 0.87 (t, J= 7.2 Hz, 3H).

[0388] Compound 17:

[0389]

[0390] l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-6- methylpyrimidine-2,4(lH,3H)-dione (110 mg, yield: 29.7%) as a white solid

[0391] LCMS: r.t. = 1.150 min, MS = 491.0 [M + H]+. 'HNMR (400 MHz, DMSO-t / 6): 6 7.87 (d, J = 9.2 Hz, 2H), 7.55 (t, J= 50.8 Hz, 1H), 7.37-7.34 (m, 2H), 7.30-7.23 (m, 3H), 5.72 (s, 1H), 5.10 (s, 2H), 3.99 (t, J= 7.6 Hz, 2H), 2.92-2.87 (m, 2H), 2.20 (s, 3H).GIVT-0002PCTUS

[0392] Compound 18:

[0393] <

[0394]

[0395] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l,6-dimethylpyrimidine- 2,4(lH,3H)-dione (150 mg, yield: 62.50%) as a white solid

[0396] LCMS: r.t. = 1.086 min, MS = 356.0 [M + H]+. 'H NMR (400 MHz, DMSO-t / r,) 6 8.05 (m, 1H), 7.54 (t, J= 51.2 Hz, 1H), 5.76 (s, 1H), 5.37 (s, 2H), 3.34 (s, 3H), 2.29 (s, 3H).

[0397] Compound 19:

[0398]

[0399] l-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6- methylpyrimidine-2,4(lH,3H)-dione (110 mg, yield: 41.1%) as an off-white solid

[0400] LCMS: r.t. = 1.137 min, MS = 382.0 [M + H]+.1H NMR (400 MHz, DMSO-t / 6): 68.50 (s, 1H), 7.54 (t, J= 50.8 Hz, 1H), 5.74 (s, 1H), 5.33 (s, 2H), 2.92-2.87 (m, 1H), 2.38 (s, 3H), 1.07-1.03 (m, 2H), 0.91-0.83 (m, 2H).

[0401] Compound 20:GIVT-0002PCTUS

[0402]

[0403] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-ethyl-6-methylpyrimidine- 2,4(lH,3H)-dione (185.00 mg, yield: 77.23%) as a white solid

[0404] LCMS: r.t. = 1.132 min, MS = 370.0 [M + H]+. 'HNMR (400 MHz, DMSO-t / r,) 68.49 (s, 1H), 7.53 (t, J= 51.2 Hz, 1H), 5.75 (s, 1H), 5.37 (s, 2H), 3.88-3.83 (m, 2H), 2.32 (s, 3H), 1.17 (t, J= 7.2 Hz, 3H).

[0405] Compound 21:

[0406]

[0407] l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6- methylpyrimidine-2,4(lH,3H)-dione (201.7 mg, yield: 74.2%) as a brown solid

[0408] LCMS: r.t. = 1.164 min, MS = 480.0 [M + H]+. 'HNMR (400 MHz, DMSO-t / r,) 68.52 (s, 1H), 7.54 (t, J= 51.2 Hz, 1H), 7.36-7.34 (m, 2H), 7.27-7.25 (m, 2H), 5.72 (s, 1H), 5.38 (s, 2H), 3.99 (t, J = 7.2 Hz, 2H), 2.91 (t, J= 7.6 Hz, 2H), 2.18 (s, 3H).13C NMR (100 MHz, DMSO-t / r,) 6 170.04, 160.15, 159.17, 157.44(t), 153.22, 150.64, 144.70, 136.45, 130.66, 130.23, 127.82, 119.25, 105.87(t), 99.51, 45.38, 41.25, 32.44, 18.55.

[0409] Compound 22:GIVT-0002PCTUS

[0410]

[0411] 3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-l-(4-fluorophenethyl)-6-methylpyrimidine- 2,4(lH,3H)-dione (185 mg, yield: 67.1%) as a white solid

[0412] LCMS: r.t. = 1.238 min, MS = 457.0 [M+H]+. 'H NMR (400 MHz, DMSO-t / r,) 6 8.02 (d, J = 8.4 Hz, 2H), 7.67-7.42 (m, 3H), 7.26-7.22 (m, 2H), 7.14-7.09 (m, 2H), 5.69 (s, 1H), 5.07 (s, 2H), 3.97 (t, J= 7.6 Hz, 2H), 2.89 (t, J= 7.6 Hz, 2H), 2.18 (s, 3H).13C NMR (100 MHz, DMSO-t / 6) 6 184.58, 161.68, 160.64, 159.28, 157.69(t), 152.75, 150.93, 141.71, 133.60, 130.19, 130.12, 127.86, 126.63, 120.59, 114.73, 114.52, 106.06(t), 99.62, 45.47, 42.81, 32.37.

[0413] Compound 23 :

[0414]

[0415] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-(4-fluorophenethyl)-6- methylpyrimidine-2,4(lH,3H)-dione (202 mg, yield: 72.1%) as an off-white solid

[0416] LCMS: r.t. = 1.267 min, MS = 64.0 [M + H]+. 'HNMR (400 MHz, DMSO-t / r,) 68.51 (s, 1H), 7.54 (t, J= 51.2 Hz, 1H), 7.28-7.25 (m, 2H), 7.14-7.09 (m, 2H), 5.72 (s, 1H), 5.38 (s, 2H), 3.98 (t, J = 7.2 Hz, 2H), 2.90 (t, J= 7.2 Hz, 2H), 2.16 (s, 3H).13C NMR (100 MHz, DMSO-t / r,) 6 171.11, 162.77, 161.22, 160.24, 158.52(t), 154.32, 151.72, 145.75, 134.62, 131.30, 120.34, 115.80, 115.59, 106.94(t), 100.54, 46.69, 42.32, 33.35.

[0417] Compound 24:GIVT-0002PCTUS

[0418]

[0419] l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione (150 mg, yield: 68.95%) as a white solid

[0420] LCMS: r.t. = 1.366 min, MS = 603.9 [M + H]+. 'HNMR (400 MHz, DMSO-t / r,) 68.53 (s, 1H), 7.54 (t, = 51.2 Hz, 1H), 7.37-7.28 (m, 4H), 7.21-7.14 (m, 2H), 6.76-6.72 (m, 1H), 5.44 (s, 2H), 4.13-4.09 (m, 2H), 3.85 (s, 3H), 2.97 (t, J= 7.2 Hz, 2H), 2.05 (s, 3H).

[0421] Compound 25:

[0422]

[0423] l-(4-chlorophenethyl)-5-(2-fluoro-3-methoxyphenyl)-6-methyl-3-((5-(5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)pyrimidine-2,4(lH,3H)-dione (160 mg, yield: 51.17%) as a white solid

[0424] LCMS: r.t. = 1.190 min, MS = 622.1 [M + H]+. 'HNMR (400 MHz, DMSO-t / r,) 68.59 (s, 1H), 7.36 (d, J= 8.0 Hz, 2H), 7.29 (d, J= 8.4 Hz, 2H), 7.20-7.14 (m, 2H), 6.75-6.72 (m, 1H), 5.45 (s, 2H), 4.10-4.06 (m, 2H), 3.85 (s, 3H), 2.97 (t, J= 7.2 Hz, 2H), 2.05 (s, 3H).

[0425] Compound 26:GIVT-0002PCTUS

[0426]

[0427] l-(4-chlorophenethyl)-6-methyl-3-((5-(5-(tri fluoromethyl)- 1,2, 4-oxadiazol-3-yl)thi azol-2- yl)methyl)pyrimidine-2,4(lH,3H)-dione (140 mg, yield: 49.6%) as a white solid

[0428] LCMS: r.t. = 1.114 min, MS = 498.0 [M + H]+. 'HNMR (400 MHz, DMSO-t / r,) 68.51 (s, 1H), 7.35 (d, J= 8.4 Hz, 2H), 7.26 (d, J= 8.4 Hz, 2H), 5.72 (s, 1H), 5.38 (s, 2H), 3.99 (t, J= 7.2 Hz, 2H), 2.91 (t, J= 7.6 Hz, 2H), 2.17 (s, 3H).

[0429] Compound 27 :

[0430]

[0431] l-(4-chlorophenethyl)-6-methyl-3-(4-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)benzyl)pyrimidine- 2,4(lH,3H)-dione (200 mg, yield: 41.7%) as a white solid

[0432] LCMS: r.t. = 1.247 min, MS = 491.0 [M + H]+. 'H NMR (400 MHz, DMSO-t / r,) 6 8.04-8.02 (m, 2H), 7.46-7.44 (m, 2H), 7.37-7.35 (m, 2H), 7.25-7.23 (m, 2H), 5.70 (s, 1H), 5.06 (s, 2H), 3.68 (t, J= 7.2 Hz, 2H), 2.90 (t, J= 7.6 Hz, 2H), 2.19 (s, 3H).

[0433] Compound 28:GIVT-0002PCTUS

[0434]

[0435] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-(2,6-dimethylphenethyl)-5-(2- fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione (122 mg, yield: 60.1%) as a white solid

[0436] LCMS: r.t. = 1.132 min, MS = 598.1 [M + H]+. 'HNMR (400 MHz, DMSO-t / r,) 68.53 (s, 1H), 7.54 (t, J= 51.2 Hz, 1H), 7.18-7.17 (m, 2H), 7.01 (s, 3H), 6.78-6.75 (m, 1H), 5.47 (s, 2H), 4.01 (t, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.01 (t, J= 7.6 Hz, 2H), 2.34 (s, 6H), 2.11 (s, 3H).

[0437] Compound 29:

[0438]

[0439] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-l-(2,6-dimethylphenethyl)-5-(2- fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione (80 mg, yield: 25.9%) as a white solid

[0440] LCMS: r.t. = 1.308 min, MS = 592.1 [M + H]+.XH NMR (400 MHz, DMSO-t / r,) 6 9.11-9.10 (m, 1H), 8.40 (dd, J= 8.0 Hz, J= 2.0 Hz, 1H), 7.69-7.44 (m, 2H), 7.19-7.13 (m, 2H), 7.01 (s, 3H), 6.77-6.74 (m, 1H), 5.30 (s, 2H), 4.01 (t, J= 7.2 Hz, 2H), 3.84 (s, 3H), 3.00 (t, J= 7.6 Hz, 2H), 2.34 (s, 6H), 2.09 (s, 3H).

[0441] Compound 30:GIVT-0002PCTUS

[0442]

[0443] l-(2,6-dimethylphenethyl)-6-methyl-3-((5-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)pyridin-2- yl)methyl)pyrimidine-2,4(lH,3H)-dione (130.00 mg, yield: 55.33%) as a white solid

[0444] LCMS: r.t. = 1.414 min, MS = 486.1 [M + H]+. 'H NMR (400 MHz, DMSO-t / r,) 6 9.09-9.08 (m, 1H), 8.40-8.38 (m, 1H), 7.51 (d, J= 8.4 Hz, 1H), 7.01-7.00 (m, 3H), 5.72 (s, 1H), 5.23 (s, 2H), 3.88 (t, J= 8.0 Hz, 2H), 2.93 (t, J= 7.6 Hz, 2H), 2.32 (s, 6H), 2.24 (s, 3H).

[0445] Compound 31 :

[0446]

[0447] l-(4-fluorophenethyl)-6-methyl-3-(4-(5 -(trifluoromethyl)- 1, 2, 4-oxadiazol-3-yl)benzyl)pyrimidine- 2,4(lH,3H)-dione (180 mg, yield: 37.5%) as a white solid

[0448] LCMS: r.t. = 1.163 min, MS = 475.0 [M + H]+. 'H NMR (400 MHz, DMSO-t / r,) 6 8.04-8.02 (m, 2H), 7.47-7.45 (m, 2H), 7.26-7.23 (m, 2H), 7.15-7.10 (m, 2H), 5.70 (s, 1H), 5.07 (s, 2H), 3.97 (t, J= 7.6 Hz, 2H), 2.89 (t, J= 7.6 Hz, 2H), 2.18 (s, 3H).

[0449] Compound 32:GIVT-0002PCTUS

[0450]

[0451] 5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l- propylpyrimidine-2,4(lH,3H)-dione (110 mg, yield: 36.6%) as a white solid

[0452] LCMS: r.t. = 1.233 min, MS = 418.1 [M + H]+. 'HNMR (400 MHz, DMSO ) 69.07 (d, J = 1.6 Hz, 1H), 8.36 (dd, J= 8.4 Hz, J= 2.0 Hz, 1H), 7.69-7.43 (m, 2H), 5.20 (s, 2H), 3.78 (t, J = 7.6 Hz, 2H), 2.48 (s, 3H), 1.61-1.55 (m, 2H), 1.40-1.36 (m, 1H), 0.89-0.81 (m, 5H), 0.49-0.45 (m, 2H).

[0453] Compound 33:

[0454]

[0455] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(2-fluorophenyl)-6-methyl-l- propylpyrimidine-2,4(lH,3H)-dione (210 mg, yield: 46.8%) as a white solid

[0456] LCMS: r.t. = 1.291 min, MS = 472.1 [M + H]+. 'HNMR (400 MHz, DMSO ) 69.10 (d, J = 1.6 Hz, 1H), 8.39 (dd, J= 8.0 Hz, J= 2.0 Hz, 1H), 7.69-7.40 (m, 3H), 7.31-7.22 (m, 3H), 5.26 (s, 2H), 3.87 (t, J= 7.6 Hz, 2H), 2.19 (s, 3H), 1.68-1.63 (m, 2H), 0.91 (t, J= 7.2 Hz, 3H).

[0457] Compound 34:GIVT-0002PCTUS

[0458]

[0459] l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-3-propylpyrimidine- 2,4(lH,3H)-dione (108 mg, yield: 64.0%) as a white solid

[0460] LCMS: r.t= 1.162 min, MS = 378.0 [M + H]+.[HNMR (400 MHz, DMSO-t / r,) 69.13 (s, 1H), 8.43 (dd, J= 8.4 Hz, J= 2.0 Hz, 1H), 7.70-7.44 (m, 2H), 5.72 (s, 1H), 5.27 (s, 2H), 3.73 (t, J= 7.2 Hz, 2H), 2.21 (s, 3H), 1.53-1.48 (m, 2H), 0.82 (t, J= 7.2 Hz, 3H).

[0461] Compound 35:

[0462]

[0463] 5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-6-methyl-l- propylpyrimidine-2,4(lH,3H)-dione (45.00 mg, yield: 20.86%) as white solid

[0464] LCMS: r.t. = 1.624 min, MS = 419.1 [M + H]+. 'H NMR (400 MHz, CDC13) 6 9.29 (s, 2H), 6.93 (t, J= 51.6 Hz, 1H), 5.49 (s, 2H), 3.84 (t, J= 8.0 Hz, 2H), 2.50 (s, 3H), 1.72-1.65 (m, 2H), 1.45-1.41 (m, 1H), 0.98-0.95 (m, 4H), 0.87-0.83 (m, 2H), 0.56-0.53 (m, 1H).

[0465] Compound 36:GIVT-0002PCTUS

[0466]

[0467] l-(4-fluorophenethyl)-5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2- yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione (37.3 mg, yield: 21.8%) as an off-white solid

[0468] LCMS: r.t. = 1.283 min, MS = 499.0 [M + H]+. 'HNMR (400 MHz, DMSO-t / r,) 69.36 (s, 2H), 7.60 (t, J= 50.8 Hz, 1H), 7.30-7.26 (m, 2H), 7.14 (t, J= 8.4 Hz, 2H), 5.32 (s, 2H), 4.01 (t, J= 7.6 Hz, 2H), 2.88 (t, J= 7.2 Hz, 2H), 2.30 (s, 3H), 1.35-1.32 (m, 1H), 0.84-0.80 (m, 2H), 0.38-0.37 (m, 2H).

[0469] Compound 37:

[0470]

[0471] l-(4-fluorophenethyl)-5,6-dimethyl-3-((5-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)pyridin-2- yl)methyl)pyrimidine-2,4(lH,3H)-dione (145 mg, yield:60.48%) as an off-white solid

[0472] LCMS: r.t. = 1.279 min, MS = 490.0 [M + H]+. 'HNMR (400 MHz, DMSO-t / r,) 69.09 (s, 1H), 8.40-8.37 (m, 1H), 7.45 (d, J= 8.4 Hz, 1H), 7.28 (t, J= 8.0 Hz, 2H), 7.13 (t, J= 8.8 Hz, 2H), 5.24 (s, 2H), 4.04 (t, J= 7.2 Hz, 2H), 2.88 (t, J= 7.2 Hz, 2H), 2.24 (s, 3H), 1.89 (s, 3H).

[0473] Compound 38:GIVT-0002PCTUS

[0474]

[0475] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-l-(4-fluorophenethyl)-5,6- dimethylpyrimidine-2,4(lH,3H)-dione (100 mg, yield:37.0%) as an off-white solid

[0476] LCMS: r.t. = 1.565 min, MS = 473.1 [M + H]+. 'HNMR (400 MHz, DMSO-t / r,) 69.35 (s, 2H), 7.60 (t, J= 51.2 Hz, 1H), 7.31-7.27 (m, 2H), 7.14 (t, J= 9.2 Hz, 2H), 5.34 (s, 2H), 4.03 (t, J= 7.6 Hz, 2H), 2.88 (t, J= 8.0 Hz, 2H), 2.22 (s, 3H), 1.88 (s, 3H).

[0477] Compound 39:

[0478]

[0479] l-butyl-5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6- methylpyrimidine-2,4(lH,3H)-dione (217.3 mg, yield: 34.5%) as an off-white solid

[0480] LCMS: r.t. = 0.98 min, MS = 432.1 [M + H]+. 'HNMR (400 MHz, DMSO-t / 6) 69.08 (s, 1H), 8.36 (d, J= 8.0 Hz, 1H), 7.57 (t, J= 51.2 Hz, 2H), 5.19 (s, 2H), 3.82 (t, J= 7.6 Hz, 2H), 2.48 (s, 3H), 1.56-1.50 (m, 2H), 1.39-1.27 (m, 3H), 0.91-0.83 (m, 5H), 0.47 (d, J= 5.2 Hz, 2H).

[0481] Compound 40:GIVT-0002PCTUS

[0482]

[0483] 5-cyclopropyl-l-(2-cyclopropylethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2- yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione (110 mg, yield: 36.8%) as a white solid

[0484] LCMS: r.t. = 1.35 min, MS = 444.1 [M + H]+. 'HNMR (400 MHz, DMSO-t / 6) 69.07 (s, 1H), 8.38 (d, J= 8.0 Hz, 2H), 7.57 (t, J= 12.4 Hz, 1H), 7.45 (s, 1H), 2.19 (s, 2H), 3.91 (t, J= 7.2 Hz, 2H), 2.5 (s, 3H), 1.50-1.44 (m, 2 H), 1.39-1.37 (m, 1 H), 0.85-0.83 (m, 2H), 0.68-0.66 (m, 1H), 0.45-0.43 (m, 2H), 0.04-0.00 (m, 5H).

[0485] Compound 41:

[0486]

[0487] 5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methyl-l- propylpyrimidine-2,4(lH,3H)-dione (116 mg, yield: 38.0%) as a white solid

[0488] LCMS: r.t. = 1.319 min, MS = 424.1 [M + H]+. 'HNMR (400 MHz, DMSO-t / r,) 68.49 (s, 1H), 7.54 (t, J= 51.6 Hz, 1H), 5.37 (s, 2H), 3.79 (t, J= 8.0 Hz, 2H), 2.46 (s, 3H), 1.61-1.55 (m, 2H), 1.39-1.38 (m, 1H), 0.90-0.83 (m, 5H), 0.47 (d, J =4.8 Hz, 2H).

[0489] Compound 42:GIVT-0002PCTUS

[0490]

[0491] 5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-(2,6- dimethylphenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione (146.7 mg, yield: 56.9%) as an off-white solid

[0492] LCMS: r.t. = 1.267 min, MS = 514.0 [M + H]+. 'HNMR (400 MHz, DMSO-t / r,) 68.50 (s, 1H), 7.54 (t, J= 51.2 Hz, 1H), 6.99 (d, J= 9.6 Hz, 3H), 5.42 (s, 2H), 3.93 (t, J= 7.6 Hz, 2H), 2.93 (t, J = 8.0 Hz, 2H), 2.42 (s, 3H), 2.33 (s, 6H), 1.39-1.37 (m, 1H), 0.86 (d, J= 8.0 Hz, 2H), 0.43 (d, J= 4.8 Hz, 2H).

[0493] Compound 43 :

[0494]

[0495] 5-cyclopropyl-l-(2-cyclopropylethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2- yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione (106 mg, yield: 36.10 %) as a white solid

[0496] LCMS: r.t. = 1.37 min, MS = 449.13, 450.2 [M + H]+.[HNMR (400 MHz, DMSO-t / 6): 68.49 (s, 1H), 7.54 (t, J= 112 Hz, 1H), 5.37 (s, 2H), 3.93 (t, J= 7.2 Hz 2H), 2.49 (s, 3H), 1.50-1.42 (m, 2H), 1.42-1.38 (m, 1H), 0.87-0.85 (m, 2H), 0.70-0.68 (m, 1H), 0.47-0.45 (m, 2H), 0.39-0.37 (m, 2H), 0.03 (m, 5H).

[0497] Compound 44:GIVT-0002PCTUS

[0498]

[0499] 5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-isopropyl-6- methylpyrimidine-2,4(lH,3H)-dione (149.0 mg, yield: 48.9%) as a white solid

[0500] LCMS: r.t. = 1.56 min, MS = 424.1 [M + H]+. 'HNMR (400 MHz, DMSO-t / 6) 68.49 (s, 1H), 7.53 (t, J= 51.2 Hz, 1H), 5.35 (s, 2H), 4.57-4.43 (m, 1H), 2.47 (s, 3H), 1.44 (d, J= 6.8 Hz, 6H), 1.42-1.33 (m, 1H), 0.91-0.81 (m, 2H), 0.51-0.43 (m, 2H).

[0501] Compound 45:

[0502]

[0503] 5-cyclopropyl-3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-ethyl-l- propylpyrimidine-2, 4-dione (52.3 mg, yield: 9.6%) as a yellow solid

[0504] LCMS: r.t. = 2.09 min, MS = 432 [M + H]+. 'H NMR (400 MHz, DMSO-t / r,) 6 9.08 (s, 1H), 8.38-8.35 (m, 1H), 7.57 (s, 1H), 7.46-7.44 (m, 1H), 5.18 (s, 2H), 3.79-3.76 (m, 2H), 2.91-2.86 (m, 2H), 1.61-1.55 (m, 2H), 1.45-1.42 (m, 1H), 1.24-1.21 (m, 3H), 0.90-0.83 (m, 3H), 0.83-0.80 (m, 2H), 0.67-0.63 (m, 2H).

[0505] Compound 46:GIVT-0002PCTUS

[0506]

[0507] 5-cyclopropyl-3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-isopropyl-l- propylpyrimidine-2, 4-dione (100.2 mg, yield: 35.4%) as a yellow solid

[0508] LCMS: r.t. = 1.39 min, MS = 446 [M + H]+. 'H NMR (400 MHz, CDC13) 69.27 (s, 1H), 8.50-8.48 (m, 1H), 7.53-7.51 (m, 1H), 7.06-6.80 (m, 1H), 5.45 (s, 2H), 4.19-4.10 (m, 1H), 3.86-3.82 (m, 2H), 1.74-1.68 (m, 2H), 1.48-1.45 (m, 1H), 1.44 (s, 3H), 1.42 (s, 3H), 0.99-0.93 (m, 5H), 0.64-0.63 (m, 2H).

[0509] Compound 47 :

[0510]

[0511] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-5-(2-fluoro-3-methoxyphenyl)- l,6-dimethylpyrimidine-2,4(lH,3H)-dione (168.5 mg, yield: 61.9%) as a white solid

[0512] LCMS: r.t. = 1.281 min, MS = 480.1 [M + H]+.XH NMR (400 MHz, DMSO-t / r,) 68.52 (s, 1H), 7.54 (t, J= 51.2 Hz, 1H), 7.21-7.15 (m, 2H), 6.80-6.77 (m, 1H), 5.44 (s, 2H), 3.86 (s, 3H), 3.45 (s, 3H), 2.15 (s, 3H).

[0513] Compound 57:GIVT-0002PCTUS

[0514]

[0515] 5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l- (oxetan-3-ylmethyl)pyrimidine-2,4(lH,3H)-dione (89.5 mg, yield: 19.7%) as a white solid

[0516] LCMS: r.t. = 0.868 min, MS = 445.9 [M + H]+. 'HNMR (400 MHz, DMSO-t / r,) 69.07 (s, 1H), 8.36 (d, J= 6.8 Hz, 1H), 7.56 (t, J= 51.2 Hz, 1H), 7.47 (d, J= 6.8 Hz, 1H), 5.19 (s, 2H), 4.59-4.55 (m, 2H), 4.41-4.37 (m, 2H), 4.20-4.18(m, 2H), 3.31-3.17 (m, 1H), 2.44 (s, 3H), 1.37-1.35 (m, 1H), 0.84-0.83 (m, 2H), 0.49-0.47(m, 2H).

[0517] Compound 59:

[0518]

[0519] 3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine- 2,4(lH,3H)-dione (763.1 mg, yield: 16.5%) as a white solid

[0520] LCMS: r.t. = 1.264 min, MS = 342.0 [M + H]+. 'H NMR (400 MHz, DMSO-t / 6) 6 11.41 (s, 1H), 8.50 (s, 1H), 7.54 (t, J= 51.2 Hz, 1H), 5.59 (s, 1H), 5.32 (s, 2H), 2.08 (d, J= 5.6 Hz, 3H).

[0521] Compound 59-1:GIVT-0002PCTUS

[0522]

[0523] l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine- 2,4(lH,3H)-dione

[0524] LCMS: r.t. = 1.249 min, MS = 342.0 [M + H]+. 'H NMR (400 MHz, DMSO-t / r,) 6 11.44 (d, J = 1.6 Hz, 1H), 8.57 (s, 1H), 7.55 (t, J= 51.2 Hz, 1H), 5.60 (d, J= 1.2 Hz, 1H), 5.40 (s, 2H), 2.30 (s, 3H).

[0525] Compound 60-1:

[0526]

[0527] l-allyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine- 2,4(lH,3H)-dione (225.7 mg, yield: 67.3%) as a white solid

[0528] LCMS: r.t. = 1.413 min, MS = 382.4 [M + H]+. 'HNMR (400 MHz, DMSO-t / r,) 68.49 (s, 1H), 7.53 (t, J= 51.2 Hz, 1H), 5.95-5.87 (m, 1H), 5.79 (s, 1H), 5.38 (s, 2H), 5.19-5.16 (m, 1H), 5.10-5.05 (m, 1H), 4.50-4.49 (m, 2H), 2.27 (m, 3H).

[0529] Example 4: Enzymatic assay to evaluate HD AC inhibition activity of the compounds of the present disclosure

[0530] The IC50 values for the aforementioned compounds against HDACs were determined. HD AC 1 to 11 can be assayed by using acetylated 7-amino-4-methylcoumarin (AMC)-labeled peptide substrate. The substrate I, a fluorogenic peptide from p53 residues 379-382 (RHKKAc), was used for all HD AC 1 to 11 but not HD AC 8, which has a substrate II (RHKAcKAc), a fluorogenic diacyl peptide based on residues 379-382 of p53. The compounds were tested in 10-dose IC50 mode in duplicate with 3 -fold serial dilution starting at 10 pM.GIVT-0002PCTUS

[0531] Human HDAC1 (GenBank Accession No. NM 004964): Full length with C-terminal glutathione S-transferase (GST) tag, MW = 79.9 kDa.

[0532] Human HDAC2 (GenBank Accession No. Q92769): Full length with C-terminal His tag, MW = 60 kDa.

[0533] Human HDAC3 / NcoR2 (GenBank Accession No. NM 003883 for HDAC3, GenBank Accession No. NM_006312 for NcoR2): Complex of human HDAC3, full length with C-terminal His tag, MW = 49.7 kDa, and human NCOR2, N-terminal GST tag, MW = 39 kDa.

[0534] Human HDAC6 (GenBank Accession No. BC069243): Full length with N-terminal GST tag, MW = 159 kDa.

[0535] Human HD AC8 (GenBank Accession No. NM_018486): Full length, MW = 42 kDa, expressed expression system.

[0536] Human HDAC10 (GenBank Accession No. NM_032019): Amino acids 1-631 with N-terminal GST tag, MW = 96 kDa.

[0537] Human HD AC 11 (GenBank Accession No. BC009676) with N-terminal GST tag, MW = 66 kDa.

[0538] Control inhibitor for HD AC was trichostatin A (TSA): Biomol Cat. # GR309.

[0539] Human HDAC1, Human HDAC2, Human HDAC3 / NcoR2, Human HDAC6, Human HD AC 10, and Human HD AC 11 were all expressed by a baculovirus expression system in Spodoptera frugiperda clone 9 (Sf9) cells.

[0540] Reaction conditions were as follows: assay buffers include 50 mM Tris-HCl at pH 8.0, 137 mM NaCl, 2.7 mM KC1, and 1 mM MgCh. Before use, 1 mg / mL BSA was added. HDAC1: 75 nM; HDAC2: 5 nM; HDAC3: 2.3 nM; HDAC6: 13 nM; HDAC8: 119 nM; HDAC10: 781 nM; HDAC11: 781 nM. 50 pM HD AC substrates. 1% DMSO final. Incubation for 2 hours at 30°C.

[0541] Table 1. HD AC inhibition activity (IC50, nM)

[0542] > > > > > > > >

[0543]

[0544] GIVT-0002PCTUS

[0545] > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > >

[0546]

[0547] ND: not determined

[0548] Example 5: Treating autosomal dominant polycystic kidney (ADPKD) disease with one exemplary compound of the present disclosure in an ADPKD mouse model

[0549] Compound 18 (Cpd 18) is a highly selective histone deacetylase 6 (HDAC6) inhibitor. To evaluate the efficacy of Compound 18, 14-day-old Pkdl miRNA transgenic mice were administered 10, 30, or 100 mg / kg Compound 18 orally once daily for 42 days. Body weight was measured twice weekly. All Compound 18-treated and vehicle control mice gained weight over the study period, with no significant differences between groups at any time point (FIG. 1).

[0550] Kidney weight and serum blood urea nitrogen (BUN) levelGIVT-0002PCTUS

[0551] The animals in all groups were sacrificed after 42-day treatment, and the left and right kidneys were weighed. The kidney-to-body weight ratio (KW / BW) was significantly elevated in Pkdl transgenic mice compared with wild-type controls. In animals treated with Cpd 18 (10 and 100 mg / kg), the average kidney-to-body weight ratio (KW / BW) was significantly decreased compared with vehicle-treated transgenic mice (FIG. 2).

[0552] Serum blood urea nitrogen (BUN) levels were also measured to evaluate the kidney function. Serum BUN levels were significantly higher in vehicle-treated Pkdl transgenic mice compared with sham controls. Treatment with Cpd 18 at 10 and 100 mg / kg significantly reduced serum BUN levels relative to vehicle (FIG. 3).

[0553] Histopathological scores for inflammation, cyst formation, and fibrosis

[0554] The histological changes in kidneys were analyzed by hematoxylin and eosin (H&E) staining, and the cyst area was analyzed. The vehicle group (Group 2) exhibited significantly increased histopathological scores for inflammation, cyst formation, and fibrosis compared to the sham group (Group 1), confirming the successful establishment of ADPKD-related renal lesions in the transgenic model. Among Compound 18 treatment groups (Groups 3 to 5), 100 mg / kg Compound 18 (Group 5) demonstrated the most notable improvement, with statistically significant reductions in inflammation, cysts, and total histopathological scores compared to the vehicle group, suggesting a therapeutic effect (Table 2). Representative histological images of kidney sections from wild-type and Pkdl transgenic mice treated with Compound 18 are shown in FIG. 4.

[0555] Table 2. The semi-quantitative scores of the ADPKD lesions

[0556]

[0557] Data are presented as Mean ± SD.GIVT-0002PCTUS

[0558] * p < 0.05, Vehicle (Group 2) vs. sham (Group 1); unpaired Student’s / -test.

[0559] #p < 0.05, Vehicle (Group 2) vs. Compound 18 treated groups (Groups 3 to 5); one-way ANOVA followed by Dunnett’ s test.

[0560] Immunohistochemistry (IHC) staining of PC-1 protein

[0561] The vehicle group (Group 2) exhibited a significantly lower PC-1 immuno-positive area percentage (3.43 ± 1.52%) compared to the sham group (Group 1) (9.14 ± 1.38%, / ? < 0.05), indicating a marked reduction of PC-1 expression in the renal lesions of the ADPKD model. This supports successful disease induction and altered PC-1 expression in the transgenic animals (FIG. 5A).

[0562] Among Compound 18 treatment groups, 100 mg / kg Compound 18 (Group 5) showed a statistically significant increase in PC-1 positive area (7.60 ± 1.18%, p < 0.05) compared to the vehicle control group (Group 2), suggesting a dose-dependent restoration of PC-1 expression. This indicates that the Compound 18 ameliorates PC-1 dysregulation in ADPKD renal lesions. Representative IHC images of the kidney tissues were shown in FIG. 5B.

[0563] Example 6: Idiopathic pulmonary fibrosis (IPF) mouse model

[0564] Bleomycin (BLM)-induced pulmonary fibrosis is the most well-established disease model for IPF and widely used to investigate the efficacy and mechanism of therapeutic candidates. In this model, alveolar injury and interstitial inflammation / fibrosis were induced by intratracheal BLM administration. This study is to examine the effect of Compound 18 on lung fibrosis in BLM-induced pulmonary fibrosis model. Mice were induced to develop pulmonary fibrosis by single intratracheal administration of bleomycin hydrochloride (Nippon Kayaku, Japan) in saline at a dose of 3.0 mg / kg, in a volume of 50 L per animal using Microsprayer (Penn-Century, USA) under a mixture of medetomidine (0.75 mg / kg), midazolam (4 mg / kg), and butorphanol (5 mg / kg) anesthesia by intraperitoneal administration in a volume of 10 mL / kg. BLM-induced pulmonary fibrosis model mice were orally administered Compound 18 twice daily (5 mg / kg, 15 mg / kg, or 50 mg / kg) or nintedanib at a dose of 100 mg / kg from Day 0 to Day 20, sacrificed on Day 21, and the samples were analyzed for fibrotic markers.

[0565] Computed tomography (CT) evaluation on days 14 and 20

[0566] CT scans were performed on days 14 and 20. The mice were mounted on a holder and placed in the X-ray CT system (LCT-200, Aloka, Japan) under a mixture of medetomidine, midazolam, and butorphanol anesthesia. The images were converted into DICOM format and analyzed with HorosGIVT-0002PCTUS

[0567] (Horos Project, Switzerland). Two section slides (upper: forth dorsal vertebra; lower: seventh dorsal vertebra) were determined from each scan data set, and eight regions of interest (ROI) were defined in the following areas: the right upper anterior and posterior regions and the left upper anterior and posterior regions. The means of the intensity of the eight ROIs were defined as an individual’s level of lung density.

[0568] Table 3. Lung density at day 14 and day 20

[0569]

[0570] Low: 10 mg / kg / day; middle: 30 mg / kg / day; high: 100 mg / kg / day.

[0571] As shown in FIG. 6, the vehicle group showed a significant increase in lung density compared with the sham group. Lung density in the Compound 18 high dose and nintedanib groups was shown to decrease compared with the vehicle group.

[0572] Histological analysis

[0573] Right lung tissues prefixed in 10% neutral buffered formalin were embedded in paraffin and sectioned at 4 pm.

[0574] For Masson’s tri chrome staining, the sections were deparaffinized and rehydrated, followed by re-fixation with Bouin’s solution for 15 minutes. The sections were stained in Weigert’s iron hematoxylin working solution (FUJIFILM Wako Pure Chemical Corporation), Biebrich scarlet-acid fuchsin solution (Sigma-Aldrich), phosphotungstic / phosphomolybdic acid solution, aniline blue solution, and 1% acetic acid solution (Sigma- Aldrich). For quantitative analysis of lung fibrosis area, bright field images of Masson’s tri chrome-stained sections were randomly captured using a digital camera (DFC295; Leica, Germany) at 100-fold magnification, and the subpleural regions in 20GIVT-0002PCTUS

[0575] fields / mouse were evaluated according to the criteria for grading lung fibrosis (Ashcroft, T., et al., Journal of Clinical Pathology, 1988; 41:467-470). All sections were blindly analyzed by an experimenter. Report included one annotated photograph of representative sample from each group.

[0576] Table 4. Criteria for grading lung fibrosis

[0577]

[0578] For immunohistochemistry (IHC), the sections cut from paraffin blocks were put into slides and routinely dewaxed and rehydrated. Endogenous peroxidase activity was blocked using 0.3% H2O2 for 5 minutes. The slides were incubated with antigen retrieval reagent (RM102-H, LSI Medience Corporation, Japan) for 10 minutes at 121 °C prior to incubation with a 200-fold dilution of anti-a-SMA antibody overnight at 4°C, followed with a secondary antibody for 30 minutes at room temperature. Enzyme-substrate reactions were performed using 3,3’-diaminobenzidine (DAB) / H2O2 solution (Nichirei, Japan). For quantitative analysis of a-smooth muscle actin (SMA)-positive area, bright field images of a-SMA-immunostained sections were captured around the central vein using a digital camera (DFC295; Leica, Germany) at 200-fold magnification, and the positive areas in 5 fields / section were measured using ImageJ software (National Institute of Health, USA).

[0579] As shown in FIG. 7, the vehicle group showed a significant increase in the a-SMA-positive area compared with the sham control group. a-SMA-positive area in the Compound 18 high group (100 mg / kg / day) was shown to decrease compared with the vehicle group. The vehicle group showed a significant increase in the Ashcroft score compared with the sham control group. The Compound 18 high group (100 mg / kg / day) showed a significant decrease in the Ashcroft score compared with theGIVT-0002PCTUS

[0580] vehicle group. The Ashcroft score in the nintedanib group was shown to decrease compared with the vehicle group.

[0581] While some of the embodiments of the present disclosure have been described in detail in the above, it is, however, possible for those of ordinary skill in the art to make various modifications and changes to the embodiments shown without substantially departing from the teaching of the present disclosure. Such modifications and changes are encompassed in the scope of the present disclosure as set forth in the appended claims.

Claims

GIVT-0002PCTUSCLAIMSWhat is claimed is:

1. A compound having the structure below:Formula Ior a pharmaceutically acceptable salt thereof,wherein:R1is hydrogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, (C6-Ci8)aryl(Ci-C6)alkyl, (C3-Ci8)heteroaryl(Ci-C6)alkyl, substituted (C6-Ci8)aryl(Ci-C6)alkyl, or (C6-Cis)aryl;R2is one of the following moieties:R3is hydrogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, (C6-Ci8)aryl(Ci-C6)alkyl, (C3- Ci8)heteroaryl(Ci-C6)alkyl, substituted (C6-Ci8)aryl(Ci-C6)alkyl, or (C6-Cis)aryl; andR4is hydrogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, (C6-Ci8)aryl(Ci-C6)alkyl, (C3- Ci8)heteroaryl(Ci-C6)alkyl, substituted (C6-Ci8)aryl(Ci-C6)alkyl, or (C6-Cis)aryl; orwherein:R1is one of the following moieties:GIVT-0002PCTUSR2is hydrogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, (C6-Ci8)aryl(Ci-C6)alkyl, (C3- Ci8)heteroaryl(Ci-C6)alkyl, substituted (C6-Ci8)aryl(Ci-C6)alkyl, or (C6-Cis)aryl;R3is hydrogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, (C6-Ci8)aryl(Ci-C6)alkyl, (C3- Ci8)heteroaryl(Ci-C6)alkyl, substituted (C6-Ci8)aryl(Ci-C6)alkyl, or (C6-Cis)aryl; andR4is hydrogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, (C6-Ci8)aryl(Ci-C6)alkyl, (C3- Ci8)heteroaryl(Ci-C6)alkyl, substituted (C6-Ci8)aryl(Ci-C6)alkyl, or (Ce-Ci8)aryl.2 The compound of claim 1, wherein:R1is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, phenyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-(4-fluorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(2,6-dimethylphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, or isopropyl;R2is one of the following moieties:GIVT-0002PCTUSR3is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, phenyl, substituted phenyl, benzyl, 2-phenylethyl, 3 -phenylpropyl, 2-(4-fluorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(2,6-dimethylphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, or isopropyl; andR4is hydrogen, methyl, ethyl, propyl, or cyclopropyl; orwherein:R1is one of the following moieties:R2is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, phenyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-(4-fluorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(2,6-dimethylphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, or isopropyl;GIVT-0002PCTUSR3is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, phenyl, substituted phenyl, benzyl, 2 -phenyl ethyl, 3 -phenylpropyl, 2-(4-fluorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(2,6-dimethylphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, or isopropyl; andR4is hydrogen, methyl, ethyl, propyl, or cyclopropyl.

3. The compound of claim 2, wherein the compound is selected from the group consisting of:l-(4-chlorophenethyl)-5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin- 2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-5-(2-fluoro-3-methoxyphenyl)-3-((5-(5-(trifluoromethyl)- 1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(2 -hydroxy ethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l-phenylpyrimidine-2,4(lH,3H)-dione,3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-l-(2,6-dimethylphenyl)-6-methylpyrimidine-2, 4-dione,l-benzyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-l-(2,6-dimethylbenzyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-l-(2-phenylethyl)pyrimidine-2, 4-dione,l-(2-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-l-[2-(2,6-dimethylphenyl)ethyl]-6-methylpyrimidine-2, 4-dione,l-[2-(4-chlorophenyl)ethyl]-3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,3 -((5-(5-(difluorom ethyl)- 1 ,3 ,4-oxadiazol-2-yl)pyridin-2-yl)methyl)- 1 -(4-methoxyphenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,GIVT-0002PCTUS3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l-(4-(trifluoromethyl)phenethyl)pyrimidine-2,4(lH,3H)-dione,l-(2,6-dichlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-5-(2-hydroxyethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-3-phenylpyrimidine-2,4(lH,3H)-dione,3-benzyl-l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-(2,6-dimethylbenzyl)- 6-methylpyrimidine-2,4(lH,3H)-dione,l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-3-(2-phenylethyl)pyrimidine-2, 4-dione,3-[2-(2-chlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-(2,6-dimethylphenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-[2-(4-chlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-3-[2-(4-methoxyphenyl)ethyl]-6-methylpyrimidine-2, 4-dione,l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-3-{2-[4- (trifluoromethyl)phenyl]ethyl}pyrimidine-2, 4-dione,3-[2-(2,6-dichlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,l-(4-chlorophenethyl)-5-(2 -hydroxy ethyl)-6-methyl-3-((5-(5-(trifluoromethyl)- 1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-5-cyclopropyl-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)- 6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-6-methylpyrimidine-2,4(lH,3H)-dione,4-(2-(3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-2,4-di oxo-3, 4-dihydropyrimidin-l(2H)-yl)ethyl)benzonitrile,GIVT-0002PCTUS4-(2-(3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-6-methyl-2,4-dioxo-3,4-dihydropyrimidin- 1 (2H)-yl)ethyl)benzonitrile,3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-l-propylpyrimidine-2, 4-dione,l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l,6-dimethylpyrimidine- 2,4(lH,3H)-dione,l-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-ethyl-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-l-(4-fluorophenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-(4-fluorophenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-5-(2-fluoro-3-methoxyphenyl)-6-methyl-3-((5-(5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-6-methyl-3-((5-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)thiazol-2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-6-methyl-3-(4-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)benzyl)pyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-(2,6-dimethylphenethyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3 -((5-(5-(difluorom ethyl)- 1 ,3 ,4-oxadiazol-2-yl)pyridin-2-yl)methyl)- 1 -(2,6-dimethylphenethyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(2,6-dimethylphenethyl)-6-methyl-3-((5-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)pyridin- 2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,l-(4-fluorophenethyl)-6-methyl-3-(4-(5 -(trifluoromethyl)- 1,2, 4-oxadiazol-3-yl)benzyl)pyrimidine-2,4(lH,3H)-dione,GIVT-0002PCTUS5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l-propylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(2-fluorophenyl)-6-methyl-l-propylpyrimidine-2,4(lH,3H)-dione,l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-3-propylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-6-methyl-l-propylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl- 1-propylpyrimidine-2,4(lH,3H)-dione,l-(4-fluorophenethyl)-5,6-dimethyl-3-((5-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)pyridin- 2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,3 -((5-(5-(difluorom ethyl)- 1 ,3 ,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)- 1 -(4-fluorophenethyl)-5,6-dimethylpyrimidine-2,4(lH,3H)-dione,l-butyl-5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-l-(2-cyclopropylethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin- 2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methyl- 1-propylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-(2,6-dimethylphenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-l-(2-cyclopropylethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol- 2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-isopropyl-6-methylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-ethyl- 1 -propylpyrimidine-2, 4-dione,5-cyclopropyl-3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-isopropyl-1 -propylpyrimidine-2, 4-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-5-(2-fluoro-3-methoxyphenyl)-l,6-dimethylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l-(oxetan-3-ylmethyl)pyrimidine-2,4(lH,3H)-dione,GIVT-0002PCTUS3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine- 2,4(lH,3H)-dione,l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine- 2,4(lH,3H)-dione, andl-allyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione.

4. The compound of claim 3, wherein the compound is l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-l-[2-(2,6-dimethylphenyl)ethyl]-6-methylpyrimidine-2, 4-dione,3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-l-propylpyrimidine-2, 4-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l,6-dimethylpyrimidine- 2,4(lH,3H)-dione,l-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione, or3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-ethyl-6-methylpyrimidine-2,4(lH,3H)-dione.

5. The compound of claim 3, wherein the compound is l-(4-chlorophenethyl)-5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione, l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5- (2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-5-(2-fluoro-3-methoxyphenyl)-3-((5-(5-(trifluoromethyl)- 1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(2 -hydroxy ethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difhioromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l-phenylpyrimidine-2,4(lH,3H)-dione,3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-l-(2,6-dimethylphenyl)-6-methylpyrimidine-2, 4-dione,GIVT-0002PCTUSl-benzyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-l-(2,6-dimethylbenzyl)- 6-methylpyrimidine-2,4(lH,3H)-dione,3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-l-(2-phenylethyl)pyrimidine-2, 4-dione,l-(2-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-l-[2-(2,6-dimethylphenyl)ethyl]-6-methylpyrimidine-2, 4-dione,l-[2-(4-chlorophenyl)ethyl]-3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,3 -((5-(5-(difluorom ethyl)- 1 ,3 ,4-oxadiazol-2-yl)pyridin-2-yl)methyl)- 1 -(4-methoxyphenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l-(4- (trifluoromethyl)phenethyl)pyrimidine-2,4(lH,3H)-dione,l-(2,6-dichlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-5-(2-hydroxy ethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-3-phenylpyrimidine-2,4(lH,3H)-dione,3-benzyl-l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-(2,6-dimethylbenzyl)- 6-methylpyrimidine-2,4(lH,3H)-dione,l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-3-(2-phenylethyl)pyrimidine-2, 4-dione,3-[2-(2-chlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-(2,6-dimethylphenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-[2-(4-chlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,GIVT-0002PCTUSl-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-3-[2-(4-methoxyphenyl)ethyl]-6-methylpyrimidine-2, 4-dione,l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-3-{2-[4- (trifluoromethyl)phenyl]ethyl}pyrimidine-2, 4-dione,3-[2-(2,6-dichlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,l-(4-chlorophenethyl)-5-(2 -hydroxy ethyl)-6-methyl-3-((5-(5-(trifluoromethyl)- 1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-5-cyclopropyl-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)- 6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-6-methylpyrimidine-2,4(lH,3H)-dione,4-(2-(3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-2,4-di oxo-3, 4-dihydropyrimidin-l(2H)-yl)ethyl)benzonitrile,4-(2-(3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-6-methyl-2,4-dioxo-3,4-dihydropyrimidin- 1 (2H)-yl)ethyl)benzonitrile,3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-l-propylpyrimidine-2, 4-dione,l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l,6-dimethylpyrimidine- 2,4(lH,3H)-dione,l-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-ethyl-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-l-(4-fluorophenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-(4-fluorophenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,GIVT-0002PCTUSl-(4-chlorophenethyl)-5-(2-fluoro-3-methoxyphenyl)-6-methyl-3-((5-(5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-6-methyl-3-((5-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)thiazol-2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-6-methyl-3-(4-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)benzyl)pyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-(2,6-dimethylphenethyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3 -((5-(5-(difluorom ethyl)- 1 ,3 ,4-oxadiazol-2-yl)pyridin-2-yl)methyl)- 1 -(2,6-dimethylphenethyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(2,6-dimethylphenethyl)-6-methyl-3-((5-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)pyridin- 2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,l-(4-fluorophenethyl)-6-methyl-3-(4-(5 -(trifluoromethyl)- 1,2, 4-oxadiazol-3-yl)benzyl)pyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl- 1-propylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(2-fluorophenyl)-6-methyl-l-propylpyrimidine-2,4(lH,3H)-dione,l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-3-propylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-6-methyl-l-propylpyrimidine-2,4(lH,3H)-dione,l-(4-fluorophenethyl)-5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-fluorophenethyl)-5,6-dimethyl-3-((5-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)pyridin- 2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,3 -((5-(5-(difluorom ethyl)- 1 ,3 ,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)- 1 -(4-fluorophenethyl)-5,6-dimethylpyrimidine-2,4(lH,3H)-dione,l-butyl-5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-l-(2-cyclopropylethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin- 2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methyl-l-propylpyrimidine-2,4(lH,3H)-dione,GIVT-0002PCTUS5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-(2,6-dimethylphenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-l-(2-cyclopropylethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol- 2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-isopropyl-6-methylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-ethyl- 1 -propylpyrimidine-2, 4-dione,5-cyclopropyl-3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-isopropyl-1 -propylpyrimidine-2, 4-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-5-(2-fluoro-3-methoxyphenyl)-l,6-dimethylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l-(oxetan-3-ylmethyl)pyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine- 2,4(lH,3H)-dione,l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine- 2,4(lH,3H)-dione, orl-allyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione.

6. A composition comprising a therapeutically effective amount of the compound as claimed in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle thereof.

7. The composition of claim 6 for use in prevention or treatment of a disease or a condition having a benefit from inhibition of histone deacetylase (HD AC).

8. The composition for use of claim 7, wherein the disease or the condition is a fibrosis, a kidney disease, or a live disease.

9. The composition for use of claim 8, wherein the fibrosis is pulmonary fibrosis, idiopathic pulmonary fibrosis, hepatic fibrosis, renal fibrosis, or myelofibrosis.GIVT-0002PCTUS10. The composition for use of claim 8, wherein the kidney disease is at least one selected from the group consisting of polycystic kidney disease, autosomal dominant polycystic kidney disease, and autosomal recessive polycystic kidney disease.

11. The composition for use of any one of claims 7 to 10, wherein the composition comprises a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of:l-(4-chlorophenethyl)-5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin- 2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5- (2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-5-(2-fluoro-3-methoxyphenyl)-3-((5-(5-(trifluoromethyl)- 1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5- (2 -hydroxy ethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l-phenylpyrimidine-2,4(lH,3H)-dione,3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-l-(2,6-dimethylphenyl)-6-methylpyrimidine-2, 4-dione,l-benzyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-l-(2,6-dimethylbenzyl)- 6-methylpyrimidine-2,4(lH,3H)-dione,3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-l-(2-phenylethyl)pyrimidine-2, 4-dione,l-(2-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-l-[2-(2,6-dimethylphenyl)ethyl]-6-methylpyrimidine-2, 4-dione,l-[2-(4-chlorophenyl)ethyl]-3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,3 -((5-(5-(difluorom ethyl)- 1 ,3 ,4-oxadiazol-2-yl)pyridin-2-yl)methyl)- 1 -(4-methoxyphenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,GIVT-0002PCTUS3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l-(4-(trifluoromethyl)phenethyl)pyrimidine-2,4(lH,3H)-dione,l-(2,6-dichlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-5-(2-hydroxyethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-3-phenylpyrimidine-2,4(lH,3H)-dione,3-benzyl-l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-(2,6-dimethylbenzyl)- 6-methylpyrimidine-2,4(lH,3H)-dione,l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-3-(2-phenylethyl)pyrimidine-2, 4-dione,3-[2-(2-chlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-(2,6-dimethylphenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-[2-(4-chlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-3-[2-(4-methoxyphenyl)ethyl]-6-methylpyrimidine-2, 4-dione,l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-3-{2-[4- (trifluoromethyl)phenyl]ethyl}pyrimidine-2, 4-dione,3-[2-(2,6-dichlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,l-(4-chlorophenethyl)-5-(2 -hydroxy ethyl)-6-methyl-3-((5-(5-(trifluoromethyl)- 1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-5-cyclopropyl-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)- 6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-6-methylpyrimidine-2,4(lH,3H)-dione,4-(2-(3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-2,4-di oxo-3, 4-dihydropyrimidin-l(2H)-yl)ethyl)benzonitrile,GIVT-0002PCTUS4-(2-(3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-6-methyl-2,4-dioxo-3,4-dihydropyrimidin- 1 (2H)-yl)ethyl)benzonitrile,3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-l-propylpyrimidine-2, 4-dione,l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l,6-dimethylpyrimidine- 2,4(lH,3H)-dione,l-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-ethyl-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-l-(4-fluorophenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-(4-fluorophenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-5-(2-fluoro-3-methoxyphenyl)-6-methyl-3-((5-(5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-6-methyl-3-((5-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)thiazol-2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-6-methyl-3-(4-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)benzyl)pyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-(2,6-dimethylphenethyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3 -((5-(5-(difluorom ethyl)- 1 ,3 ,4-oxadiazol-2-yl)pyridin-2-yl)methyl)- 1 -(2,6-dimethylphenethyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(2,6-dimethylphenethyl)-6-methyl-3-((5-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)pyridin- 2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,l-(4-fluorophenethyl)-6-methyl-3-(4-(5 -(trifluoromethyl)- 1,2, 4-oxadiazol-3-yl)benzyl)pyrimidine-2,4(lH,3H)-dione,GIVT-0002PCTUS5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl- 1-propylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(2-fluorophenyl)-6-methyl-l-propylpyrimidine-2,4(lH,3H)-dione,l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-3-propylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-6-methyl-l-propylpyrimidine-2,4(lH,3H)-dione,l-(4-fluorophenethyl)-5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-fluorophenethyl)-5,6-dimethyl-3-((5-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)pyridin- 2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,3 -((5-(5-(difluorom ethyl)- 1 ,3 ,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)- 1 -(4-fluorophenethyl)-5,6-dimethylpyrimidine-2,4(lH,3H)-dione,l-butyl-5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-l-(2-cyclopropylethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin- 2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methyl- 1-propylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-(2,6-dimethylphenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-l-(2-cyclopropylethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol- 2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-isopropyl-6-methylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-ethyl- 1 -propylpyrimidine-2, 4-dione,5-cyclopropyl-3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-isopropyl-1 -propylpyrimidine-2, 4-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-5-(2-fluoro-3-methoxyphenyl)-l,6-dimethylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l-(oxetan-3-ylmethyl)pyrimidine-2,4(lH,3H)-dione,GIVT-0002PCTUS3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione, andl-allyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione.

12. A method for preventing or treating a disease or a condition having a benefit from inhibition of histone deacetylase (HD AC) in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a composition comprising the compound as claimed in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle thereof.

13. The method of claim 12, wherein the disease or the condition is a fibrosis, a kidney disease, or a live disease.

14. The method of claim 13, wherein the fibrosis is pulmonary fibrosis, idiopathic pulmonary fibrosis, hepatic fibrosis, renal fibrosis, or myelofibrosis.

15. The method of claim 13, wherein the kidney disease is at least one selected from the group consisting of polycystic kidney disease, autosomal dominant polycystic kidney disease, and autosomal recessive polycystic kidney disease.

16. The method of any one of claims 12 to 15, wherein the compound is selected from the group consisting of:l-(4-chlorophenethyl)-5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-5-(2-fluoro-3-methoxyphenyl)-3-((5-(5-(trifluoromethyl)- 1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(2 -hydroxy ethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,GIVT-0002PCTUS3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l-phenylpyrimidine-2,4(lH,3H)-dione,3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-l-(2,6-dimethylphenyl)- 6-methylpyrimidine-2, 4-dione,l-benzyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-l-(2,6-dimethylbenzyl)- 6-methylpyrimidine-2,4(lH,3H)-dione,3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-l-(2-phenylethyl)pyrimidine-2, 4-dione,l-(2-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-l-[2-(2,6-dimethylphenyl)ethyl]-6-methylpyrimidine-2, 4-dione,l-[2-(4-chlorophenyl)ethyl]-3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,3 -((5-(5-(difluorom ethyl)- 1 ,3 ,4-oxadiazol-2-yl)pyridin-2-yl)methyl)- 1 -(4-methoxyphenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l-(4- (trifluoromethyl)phenethyl)pyrimidine-2,4(lH,3H)-dione,l-(2,6-dichlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-5-(2-hydroxy ethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-3-phenylpyrimidine-2,4(lH,3H)-dione,3-benzyl-l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-(2,6-dimethylbenzyl)- 6-methylpyrimidine-2,4(lH,3H)-dione,l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-3-(2-phenylethyl)pyrimidine-2, 4-dione,3-[2-(2-chlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,GIVT-0002PCTUSl-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-(2,6-dimethylphenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-[2-(4-chlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-3-[2-(4-methoxyphenyl)ethyl]-6-methylpyrimidine-2, 4-dione,l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-3-{2-[4- (trifluoromethyl)phenyl]ethyl}pyrimidine-2, 4-dione,3-[2-(2,6-dichlorophenyl)ethyl]-l-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methylpyrimidine-2, 4-dione,l-(4-chlorophenethyl)-5-(2 -hydroxy ethyl)-6-methyl-3-((5-(5-(trifluoromethyl)- 1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-5-cyclopropyl-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)- 6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-6-methylpyrimidine-2,4(lH,3H)-dione,4-(2-(3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-2,4-di oxo-3, 4-dihydropyrimidin-l(2H)-yl)ethyl)benzonitrile,4-(2-(3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-6-methyl-2,4-dioxo-3,4-dihydropyrimidin- 1 (2H)-yl)ethyl)benzonitrile,3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-methyl-l-propylpyrimidine-2, 4-dione,l-(4-chlorophenethyl)-3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l,6-dimethylpyrimidine- 2,4(lH,3H)-dione,l-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-ethyl-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)benzyl)-l-(4-fluorophenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,GIVT-0002PCTUS3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-(4-fluorophenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-5- (2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-5-(2-fluoro-3-methoxyphenyl)-6-methyl-3-((5-(5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-6-methyl-3-((5-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)thiazol-2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,l-(4-chlorophenethyl)-6-methyl-3-(4-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)benzyl)pyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-(2,6-dimethylphenethyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,3 -((5-(5-(difluorom ethyl)- 1 ,3 ,4-oxadiazol-2-yl)pyridin-2-yl)methyl)- 1 -(2,6-dimethylphenethyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(2,6-dimethylphenethyl)-6-methyl-3-((5-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)pyridin- 2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,l-(4-fluorophenethyl)-6-methyl-3-(4-(5 -(trifluoromethyl)- 1,2, 4-oxadiazol-3-yl)benzyl)pyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl- 1-propylpyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(2-fluorophenyl)-6-methyl-l-propylpyrimidine-2,4(lH,3H)-dione,l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-3-propylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-6-methyl-l-propylpyrimidine-2,4(lH,3H)-dione,l-(4-fluorophenethyl)-5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,l-(4-fluorophenethyl)-5,6-dimethyl-3-((5-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)pyridin- 2-yl)methyl)pyrimidine-2,4(lH,3H)-dione,3 -((5-(5-(difluorom ethyl)- 1 ,3 ,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)- 1 -(4-fluorophenethyl)-5,6-dimethylpyrimidine-2,4(lH,3H)-dione,l-butyl-5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,GIVT-0002PCTUS5-cyclopropyl-l-(2-cyclopropylethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methyl- 1-propylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-(2,6-dimethylphenethyl)-6-methylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-l-(2-cyclopropylethyl)-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol- 2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-l-isopropyl-6-methylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-ethyl- 1 -propylpyrimidine-2, 4-dione,5-cyclopropyl-3-({5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]pyridin-2-yl}methyl)-6-isopropyl-1 -propylpyrimidine-2, 4-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-5-(2-fluoro-3-methoxyphenyl)-l,6-dimethylpyrimidine-2,4(lH,3H)-dione,5-cyclopropyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-methyl-l-(oxetan-3-ylmethyl)pyrimidine-2,4(lH,3H)-dione,3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine- 2,4(lH,3H)-dione,l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine- 2,4(lH,3H)-dione, andl-allyl-3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-6-methylpyrimidine-2,4(lH,3H)-dione.

17. A use of the composition of claim 6 for manufacture of a medicament for prevention or treatment of a disease or a condition having a benefit from inhibition of histone deacetylase (HD AC) in a subject in need thereof, wherein said subject is administered with an effective amount of the composition.

18. The use of claim 17, wherein the disease or the condition is a fibrosis, a kidney disease, or a liver disease.

19. The use of claim 18, wherein the fibrosis is pulmonary fibrosis, idiopathic pulmonary fibrosis, hepatic fibrosis, renal fibrosis, or myelofibrosis.GIVT-0002PCTUS20. The method of claim 18, wherein the kidney disease is at least one selected from the group consisting of polycystic kidney disease, autosomal dominant polycystic kidney disease, and autosomal recessive polycystic kidney disease.

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