Selection of Patients for Treatment of FADS1-Mediated Diseases or Disorders Using FADS-1 Inhibitors

Abstract

The present disclosure provides techniques for assessing FADS1 activity in a patient. Also provided are techniques for determining the appropriateness of treating a patient with a FADS1-modulating (e.g., inhibiting) compound. This determination can be made by analyzing one or more biological indicators of a FADS1-mediated disease or disorder in the subject. The one or more biological indicators can include one or more of the following in the subject: ratios of polyunsaturated fatty acids ("PUFAs"), the relative abundance of one or more cell types, the relative abundance of one or more differentially expressed genes ("DEGs") (or gene signatures of such DEGs, e.g., RNA), and / or the relative abundance of one or more metabolites. Also disclosed are methods of using FADS1 inhibitors in methods for treating metabolic disorders and obesity.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 384,862, filed November 23, 2022, and U.S. Provisional Patent Application No. 63 / 592,804, filed October 24, 2023. Each of the foregoing applications is incorporated herein by reference in its entirety for all purposes.

[0002] The present disclosure provides techniques for determining fatty acid desaturase 1 ("FADS1") activity levels in a subject using one or more biomarkers. Also disclosed are methods of using FADS1 inhibitors in the treatment of FADS1-mediated metabolic disorders and obesity in a subject in need of such treatment. In some embodiments, the subject in need of treatment is a subject with one or more biomarkers of a FADS1-mediated disorder or a FADS1-mediated disorder. In some embodiments, the subject in need of treatment is a subject with elevated FADS1 activity compared to a healthy population. [Background technology]

[0003] Polyunsaturated fatty acids ("PUFAs") perform important physiological functions in the human body. PUFAs serve as an energy source and structural components of cell membranes. PUFAs also regulate genes and are biosynthetic precursors for other physiologically relevant biomolecules, such as eicosanoids and endocannabinoids. Eicosanoids are signaling molecules with multiple functions that regulate, among other things, human inflammatory responses. Endocannabinoids (e.g., N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG)) are endogenous ligands of cannabinoid receptors that have been demonstrated to play roles in food intake and energy balance.

[0004] The relevant portion of the metabolic pathway for one particular PUFA, linoleic acid ("LA"), which leads to the formation of, among other things, anti- and pro-inflammatory eicosanoids and endocannabinoids, is shown in Figure 1(d). The desaturase enzymes that catalyze certain steps in the conversion of LA to dihomo-gamma-linolenic acid ("DGLA") and arachidonic acid ("AA") are delta-6-desaturase ("D6D"; encoded by the gene fatty acid desaturase 2 ("FADS2")) and delta-5-desaturase ("D5D"; encoded by the gene fatty acid desaturase 1 ("FADS1")). Selective inhibition of D5D activity increases the amount of DGLA while decreasing the amount of AA produced. Such pharmacological intervention could result in, for example, a decrease in downstream production of pro-inflammatory eicosanoids and endocannabinoids and an increase in anti-inflammatory eicosanoids, both of which could improve overall inflammation-related conditions and energy balance, particularly in subjects with high LA intake, such as those exposed to a Western diet.

[0005] The FADS1-3 locus has been linked to many metabolic traits, including fasting blood glucose, plasma lipids, and body weight, in human genome-wide association studies. In addition to human genetic evidence supporting the role of FADS1 / D5D in metabolic disorders, FADS1 knockout ("KO") mice also exhibit a phenotype that provides protection from diet-induced obesity, including lower body fat content, improved glycemic control, and reduced circulating lipid levels. Furthermore, FADS1 KO mice exhibit resistance to the development of arterial atherosclerotic plaques.

[0006] Desaturase enzyme activity is associated with a variety of diseases, particularly metabolic and cardiovascular diseases such as obesity, diabetes, nonalcoholic steatohepatitis ("NASH"), dyslipidemia, and coronary artery disease. Thus, pharmacological inhibition of D5D is of interest for treating metabolic, cardiovascular, and other diseases. Summary of the Invention [Means for solving the problem]

[0007] One aspect of the present disclosure provides a method for treating FADS1-mediated disease or disorder in a subject in need of treatment, comprising: receiving information comparing the level of biological indicator of FADS1-mediated disease from subject with a reference level of biological indicator, wherein the biological indicator is the ratio of AA to DGLA; and when the level of biological indicator of subject is higher than the reference level of biological indicator, administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject.Another aspect of the present disclosure provides a method for detecting FADS1-mediated disease or disorder in a subject, comprising: receiving information comparing the level of biological indicator of FADS1-mediated disease from subject with a reference level of biological indicator, wherein the biological indicator is the ratio of AA to DGLA. Another aspect of the present disclosure provides a FADS1 inhibitor compound for use in a method for treating a subject in need of treatment having a FADS1-mediated disease or disorder, the method comprising receiving information comparing the level of a biological indicator of a FADS1-mediated disease from the subject with a reference level of the biological indicator, the biological indicator being a ratio of AA to DGLA; and administering a therapeutically effective amount of the FADS1 inhibitor compound to the subject if the level of the biological indicator in the subject is higher than the reference level of the biological indicator.

[0008] Another embodiment of the present disclosure provides a method for treating a FADS1-mediated disease or disorder in a subject in need of treatment, comprising administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject when the subject has an AA to DGLA ratio of about 5:1 or greater. Another embodiment of the present disclosure provides a method for treating a FADS1-mediated disease or disorder in a subject in need of treatment, comprising administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject when the subject has an AA to DGLA ratio of about 6:1 or greater. Another embodiment of the present disclosure provides a method for treating a FADS1-mediated disease or disorder in a subject in need of treatment, comprising administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject when the subject has an AA to DGLA ratio of about 7:1 or greater. Another embodiment of the present disclosure provides a method for treating a FADS1-mediated disease or disorder in a subject in need of treatment, comprising administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject when the subject has an AA to DGLA ratio of about 15:2 or greater. Another embodiment of the present disclosure provides a method for treating a FADS1-mediated disease or disorder in a subject in need of treatment, comprising administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject when the subject has an AA to DGLA ratio of about 8:1 or greater. Another embodiment of the present disclosure provides a method for treating a FADS1-mediated disease or disorder in a subject in need of treatment, comprising administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject when the subject has an AA to DGLA ratio of about 17:2 or greater. Another embodiment of the present disclosure provides a method for treating a FADS1-mediated disease or disorder in a subject in need of treatment, comprising administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject when the subject has an AA to DGLA ratio of about 9:1 or greater.

[0009] Another aspect of the present disclosure provides a method for treating a FADS1-mediated disease or disorder in a subject in need of treatment, comprising: receiving information comparing the level of a biological indicator of a FADS1-mediated disease from the subject with a reference level of the biological indicator, wherein the biological indicator is a measured level of a PUFA; and administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject if the subject is determined to be a subject who will benefit from treatment with a FADS1 inhibitor compound, as determined by the subject's level of the biological indicator compared to the reference level of the biological indicator. Another aspect of the present disclosure provides a method for treating a FADS1-mediated disease or disorder in a subject in need of treatment, comprising: administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject if the subject's level of a biological indicator of a FADS1-mediated disease is higher than the reference level of the biological indicator, wherein the biological indicator is a measured level of a PUFA. Another aspect of the present disclosure provides a method for detecting a FADS1-mediated disease or disorder in a subject, comprising: receiving information comparing the level of a biological indicator of a FADS1-mediated disease from the subject with a reference level of the biological indicator, wherein the biological indicator is a measured level of a PUFA. Another aspect of the present disclosure provides a FADS1 inhibitor compound for use in a method for treating a subject in need of treatment for a FADS1-mediated disease or disorder, the method comprising: receiving information comparing the level of a biological indicator of a FADS1-mediated disease from the subject with a reference level of the biological indicator, the biological indicator being a measured level of a PUFA; and administering a therapeutically effective amount of the FADS1 inhibitor compound to the subject if the subject is determined to be a subject who would benefit from treatment with the FADS1 inhibitor compound, as determined by the subject's level of the biological indicator compared to the reference level of the biological indicator. In some embodiments, the PUFA is linoleic acid, arachidonic acid, gamma-linoleic acid, adrenic acid, dihomo-gamma-linolenic acid, docosapentanoic acid n-6, alpha-linolenic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, or a combination thereof.

[0010] Another aspect of the present disclosure provides a method for treating a FADS1-mediated disease or disorder in a subject in need of treatment, the method comprising: receiving information comparing the level of a biological indicator of a FADS1-mediated disease from the subject with a reference level of the biological indicator, where the biological indicator is a measured level of a metabolite; and, if the subject is determined to be a subject who would benefit from treatment with a FADS1 inhibitor compound, as determined by the subject's level of the biological indicator compared to the reference level of the biological indicator, administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject. Another aspect of the present disclosure provides a method for treating a FADS1-mediated disease or disorder in a subject in need of treatment, the method comprising: administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject when the level of the biological indicator of a FADS1-mediated disease is higher than the reference level of the biological indicator, where the biological indicator is a measured level of a metabolite. Another aspect of the present disclosure provides a method for detecting a FADS1-mediated disease or disorder in a subject, the method comprising receiving information comparing the level of a biological indicator of a FADS1-mediated disease from the subject with a reference level of the biological indicator, where the biological indicator is a measured level of a metabolite. Another aspect of the present disclosure provides a FADS1 inhibitor compound for use in a method for treating a subject having a FADS1-mediated disease or disorder in need of treatment, the method comprising receiving information comparing the level of a biological indicator of a FADS1-mediated disease from the subject with a reference level of the biological indicator, where the biological indicator is a measured level of a metabolite; and administering a therapeutically effective amount of the FADS1 inhibitor compound to the subject if the subject is determined to be a subject who would benefit from treatment with the FADS1 inhibitor compound, as determined by the subject's level of the biological indicator compared to the reference level of the biological indicator. In some embodiments, the metabolite is: cholesterol, free cholesterol, total cholesterol, cholesterol ester C20:4, malate, alpha-ketoglutarate, mannose, glucose, erythrodihydrosphingosine (d18:0),5-O-methylsphingosine (d18:1), erythrophingosine (d18:1), 3-O-methylsphingosine (d18:1), threosphingosine (d18:1), 1-hydroxy-2-amino-(cis, trans)-3,5-octadecadiene, 4-hydroxysphinganine (t18:0, phytosphingosine), sphingomyelin (d18:1, C23:0), sphingomyelin (d18:1, C24:0), ceramide (d18:1, C24:0), thromboxane B2, delta-12-prostaglandin D2, prostaglandin B Prostaglandin E2, prostaglandin D2, 12-hydroxyheptadecatrienoic acid (C17:[5,8,10]3), 14,15-dihydroxyeicosatrienoic acid (C20:cis[5,8,11]3), 11-hydroxyeicosatetraenoic acid (C20:cis[5,8,12,14]4), 13-hydroxyoctadecadienoic acid (13-HODE) (C18:cis[9]trans

[11] 2), arachidonic acid (C20:cis[5,8,11,14]4), docosahexaenoic acid (C22:cis[4,7,10,13,16,19]6), dihydroxyeicosatetraenoic acid (C20:cis[5,8,12,14]4), and cis[4,7,10,13,16,19]6. Homo-gamma-linolenic acid (C20:cis[8,11,14]3), gamma-linolenic acid (C18:cis[6,9,12]3), docosapentaenoic acid (C22:cis[7,10,13,16,19]5), eicosapentaenoic acid (C20:cis[5,8,11,14,17]5), docosatetraenoic acid (C22:cis[7,10,13,16]4), stearic acid (C18:0), tryptophan, kynurenic acid, xanthurenic acid, histidine, leucine, isoleucine, valine, 3-hydroxyisobutyrate, glutamate, threonine, cysteine In, sarcosine, plasma triglycerides, taurochenodeoxycholic acid, taurocholic acid, lysophosphatidylcholine (C18:0), lysophosphatidylcholine (C20:4), lysophosphatidylcholine (C17:0), lysophosphatidylethanolamine (C22:5), phosphatidylcholine (C18:0, C22:6), phosphatidylcholine (C18:0, C20:3), phosphatidylcholine (C18:1, C18:2), phosphatidylcholine (C16:1, C18:2), phosphatidylcholine (C18:0, C18:2),Phosphatidylcholine (C16:0, C20:5), phosphatidylcholine (C16:0, C16:0), glycerol-3 phosphate, choline plasmalogen (C18, C20:4), myo-inositol, myo-inositol phospholipid, glycerol phosphate, phospholipid fraction, or a combination of the foregoing.

[0011] Another aspect of the present disclosure provides a method of treating a FADS1-mediated disease or disorder in a subject in need of treatment, the method comprising: receiving information comparing the level of a biological indicator of a FADS1-mediated disease from the subject with a reference level of the biological indicator, where the biological indicator is a measured level of a differentially expressed gene ("DEG"); and, if the subject is determined to be a subject who would benefit from treatment with a FADS1 inhibitor compound, as determined by the subject's level of the biological indicator compared to the reference level of the biological indicator, administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject. Another aspect of the present disclosure provides a method of treating a FADS1-mediated disease or disorder in a subject in need of treatment, the method comprising: administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject when the level of the biological indicator of a FADS1-mediated disease is higher than the reference level of the biological indicator, where the biological indicator is a measured level of a DEG. Another aspect of the present disclosure provides a method for detecting a FADS1-mediated disease or disorder in a subject, the method comprising receiving information comparing the level of a biological indicator of a FADS1-mediated disease from the subject with a reference level of the biological indicator, where the biological indicator is a measured level of a DEG. Another aspect of the present disclosure provides a FADS1 inhibitor compound for use in a method for treating a subject having a FADS1-mediated disease or disorder in need of treatment, the method comprising receiving information comparing the level of a biological indicator of a FADS1-mediated disease from the subject with a reference level of the biological indicator, where the biological indicator is a measured level of a DEG; and administering a therapeutically effective amount of the FADS1 inhibitor compound to the subject if the subject is determined to be a subject who would benefit from treatment with the FADS1 inhibitor compound, as determined by the subject's level of the biological indicator compared to the reference level of the biological indicator. In some embodiments, the DEGs are: Serpinb1a, Gna14, Serpina3m, Hsd11b1, Cyp2c29, Akr1d1, Aldh1a1, Mmp19, Gyp27a1, Tymp, Elovl2, Chkb, H2afj, Tnfaip8l1,Tmem86a、Sel1l3、Agap2、4833411C07Rik、Elov4、Fat3、Eef1a2、Atp7a、Rgs2、Cenpe、Mfap2、Mlki67、Ctsh、Trub2、Ubc、H6pd、Eepd1、Acss2、Aacs、Gm36827、Man2a2、Nudt18、Plagl1、TM4sf19、Atp6v0d2、Gm20056、Trem2、Il1rn、Mmp12、Cdk18、Efr3b、Tagln2、Lurap1、Cp、I17rb、B230303O12Rik、Cfd、Sult1e1、Tdo2、Cyp2b9、Hao2、Cyp2b13、Cyp2a22、Acnat2、Ildr2、Rpl10a-ps1、Tm6sf2、Fitm1、Lpar1、C6、Cmah、Lbp、Arsg、Glra3、Lad1、A730063M14Rik、Ly6f、Foxi1、Crygc、Defb28、Wfdc9、Phlda2、Aqp6、Gm16411、Adam7、Ppp2r5b、Slc6a7、Gpr50、Ahnak2、S100a6、Mmp14、Htr2b、Hpgds、Gm18537、Pclo、Adrb3、Gm38394、AC154232.2、Cadps、Adgrb2、Gm45470、Sdr9c7、Dsg1c、Slc17a1、Ces1c、Gss、1810008I18Rik、Tlcd1、Snrk、Akr1c20、Gm19950、Ttr、Cbfa2t3、Acat2、Pmvk、Abcd3、Acacb、Arhgap27、Rnase9、Wfdc8、Ighv9-2、DerI3、Acap1、Ccl19、Tcf7、Xkrx、Trim46、Zfp369、Zfp871、Pcdhb21、Gm14288、Uprt、Atm、Dchs2、Cped1、Gm38357、Cck、Ckap2、Gm4419、1600015I10Rik、Sez6I2、Prnd、Gm16702、S100a8、Pcdh12、Malat1、Kcnq1ot1、ArI4c、Gm42549、Gm37310、Gm37776、Atp2a1、Ckm、Tnnt3、Adipoq、Fabp4、Lep、Retn、Hoxc8、Hoxc9、Cebpa、Dgat1、Dgat2、Elovl3、Fas、Scd1、Srebf1、Hilpda、Lipe、Mgll、Plin1、Plin4, Pnpla2, Pnpla3, Ldah, Cs, Gckr, Me1, Pck1, Pdk4, Irs1, Acaa1a, Acads, Acox1, Cpt1a, Cpt1b, Hadhb, Ehhadh, Ppara, Ppargc1a, Cyp4a12a, Cyp4a12b, Cyp2e1, Adgre1, Agtr1a, Ccl2, Cd14, Cd68, Il1b, Tnf, or a combination thereof.

[0012] Another aspect of the present disclosure provides a method of treating a FADS1-mediated disease or disorder in a subject in need of treatment, the method comprising: receiving information comparing the level of a biological indicator of a FADS1-mediated disease from the subject with a reference level of the biological indicator, where the biological indicator is a measured level of a cell type; and, if the subject is determined to be a subject who would benefit from treatment with a FADS1 inhibitor compound, as determined by the subject's level of the biological indicator compared to the reference level of the biological indicator, administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject. Another aspect of the present disclosure provides a method of treating a FADS1-mediated disease or disorder in a subject in need of treatment, the method comprising: administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject when the level of the biological indicator of a FADS1-mediated disease is higher than the reference level of the biological indicator, where the biological indicator is a measured level of a cell type. Another aspect of the present disclosure provides a method for detecting a FADS1-mediated disease or disorder in a subject, the method comprising receiving information comparing the level of a biological indicator of a FADS1-mediated disease from the subject with a reference level of the biological indicator, where the biological indicator is a measured level of a cell type. Another aspect of the present disclosure provides a FADS1 inhibitor compound for use in a method for treating a subject having a FADS1-mediated disease or disorder in need of treatment, the method comprising receiving information comparing the level of a biological indicator of a FADS1-mediated disease from the subject with a reference level of the biological indicator, where the biological indicator is a measured level of a cell type; and administering a therapeutically effective amount of the FADS1 inhibitor compound to the subject if the subject is determined to be a subject who would benefit from treatment with the FADS1 inhibitor compound, as determined by the subject's level of the biological indicator compared to the reference level of the biological indicator.In some embodiments, the cell type is an adipocyte ("Adipo"), a B cell ("Bcell"), an endothelial cell ("Endo"), a hepatocyte ("Hep"), a Kupffer cell ("Kupff"), a myeloid cell ("Myel"), a natural killer cell ("NK"), a T cell ("Tcell"), or a combination of the foregoing.

[0013] As disclosed elsewhere herein, some embodiments relate to treating a FADS1-mediated disease in a subject in need thereof. Some embodiments disclosed herein relate to selecting patients for treatment using FADS1 inhibition (e.g., by administering a FADS1 inhibitor). In some embodiments, during the selection process, subjects more likely to respond favorably to the treatment are selected for treatment. In some embodiments, patients more likely to be successfully treated are then treated, for example, with a FADS1-modulating compound (e.g., a FADS1 inhibitor compound). In some embodiments, the selection is based on patient data collected prior to administration of the FADS1 inhibitor. In some embodiments, the patient data is related to measuring one or more biological indicators of FADS1 activity (e.g., increased FADS1 activity). In some embodiments, the selection is based on patient data collected prior to, concurrent with, and / or after administration of the FADS1 inhibitor. In some embodiments, a FADS1-mediated disease or disorder is treated by inhibiting the FADS1 enzyme using one or more methods disclosed herein.

[0014] Some embodiments disclosed herein provide a method for identifying a subject with increased FADS1 activity. In some embodiments, the method comprises measuring one or more biological indicators of a FADS1-mediated disease or disorder in the subject. In some embodiments, the one or more biological indicators include one or more of the following in the subject: the ratio of PUFAs, the relative abundance of one or more cell types, the relative abundance of one or more DEGs (or gene signatures, e.g., RNA, for such DEGs), and / or the relative abundance of one or more metabolites. In some embodiments, the method further comprises administering a FADS1 inhibitor compound to the subject.

[0015] Some embodiments disclosed herein provide a method for identifying a subject in need of treatment with a FADS1 inhibitor compound. In some embodiments, the method comprises measuring one or more biological indicators of a FADS1-mediated disease or disorder in the subject. In some embodiments, the one or more biological indicators comprise, consist of, or consist essentially of one or more of the following in the subject: the ratio of PUFAs, the relative abundance of one or more cell types, the relative abundance of one or more DEGs or gene signatures, and / or the relative abundance of one or more metabolites. In some embodiments, the method further comprises administering a FADS1 inhibitor compound to the subject.

[0016] Some embodiments disclosed herein provide methods for reducing body weight, reducing body mass index, treating obesity, treating metabolic disorders, treating cardiovascular disorders, treating diabetes, treating dyslipidemia, and / or treating non-alcoholic steatohepatitis ("NASH") in a subject. In some embodiments, the method includes measuring one or more biological indicators of a FADS1-mediated disease or disorder in the subject. In some embodiments, the one or more biological indicators include, consist of, or consist essentially of one or more of the following in the subject: a ratio of PUFAs, a relative abundance of one or more cell types, a relative abundance of one or more DEGs or gene signatures, and / or a relative abundance of one or more metabolites. In some embodiments, the method further includes administering a FADS1 inhibitor compound to the subject.

[0017] In some embodiments, as disclosed herein, the method disclosed herein further comprises administering a FADS1 inhibitor compound to a subject.In some embodiments, the method disclosed herein further comprises administering a dose of labeled DGLA to a subject, and then measuring the ratio of labeled AA to labeled DGLA.In some embodiments, the ratio of labeled AA to labeled DGLA allows for calculation of the inhibitor concentration achieved using a FADS1 inhibitor.In some embodiments, the inhibitor concentration achieved using a FADS1 inhibitor is used to calculate the appropriate inhibitor dose for the subject.

[0018] Another aspect of the present disclosure provides a method for measuring the ratio of AA to DGLA in a subject, wherein AA is isotopically labeled and DGLA is isotopically labeled, and the ratio of AA to DGLA is measured by administering a dose of labeled DGLA to the subject and then measuring the ratio of labeled AA to labeled DGLA.

[0019] Another aspect of the present disclosure is a compound having the following structure: [ka] and providing a compound represented by the formula: where each "*" symbol represents: 13 indicates positions that can be isotopically enriched with C, and at least one "*" position is 13 It is isotopically enriched with C.

[0020] Another aspect of the present disclosure is a compound having the following structure: [ka] and providing a compound represented by the formula: where each "*" symbol represents: 13 indicates positions that can be isotopically enriched with C, and at least one "*" position is 13 It is isotopically enriched with C.

[0021] Another aspect of the present disclosure is a compound having the following structure: [ka] and providing a compound represented by the formula: wherein X is a halogen; and each "*" symbol represents 13 indicates positions that can be isotopically enriched with C, and at least one "*" position is 13 It is isotopically enriched with C.

[0022] Another aspect of the present disclosure is a compound having the following structure: [ka] A method for producing a compound represented by the formula: [ka] with KC*N, where each "*" symbol represents: 13 indicates positions that can be isotopically enriched with C, and at least one "*" position is 13It is isotopically enriched with C and X is a suitable leaving group. [Brief explanation of the drawings]

[0023] [Figure 1A] Figure 1(a) shows data demonstrating increased FADS1 activity in human and rodent models of obesity. Figure 1(a) shows a flow chart illustrating the n-3 PUFA pathway and the n-6 PUFA pathway. As shown, FADS1 mediates the D5D of n-6 PUFAs from DGLA to AA and the D5D of n-3 PUFAs from eicosatetraenoic acid ("ETA") to eicosapentaenoic acid ("EPA"). Figure 1(b) shows a comparison of plasma AA / DGLA ratios as a surrogate for FADS1 activity in lean, overweight, and obese men (n = 8-41 / group). Data are presented as minimum to maximum. Figure 1(c) shows a comparison of the AA / DGLA ratio as a surrogate for FADS1 activity in lean and high-fat diet ("HFD")-induced obese ("DIO") male C57Bl / 6 mice on a 12-week HFD. n = 8 / group. Figure 1(b,c) t-test. *P<0.05, ****P<0.00001, respectively. [Figure 1B] Figure 1(a) shows data demonstrating increased FADS1 activity in human and rodent models of obesity. Figure 1(a) shows a flow chart illustrating the n-3 PUFA pathway and the n-6 PUFA pathway. As shown, FADS1 mediates the D5D of n-6 PUFAs from DGLA to AA and the D5D of n-3 PUFAs from eicosatetraenoic acid ("ETA") to eicosapentaenoic acid ("EPA"). Figure 1(b) shows a comparison of plasma AA / DGLA ratios as a surrogate for FADS1 activity in lean, overweight, and obese men (n = 8-41 / group). Data are presented as minimum to maximum. Figure 1(c) shows a comparison of the AA / DGLA ratio as a surrogate for FADS1 activity in lean and high-fat diet ("HFD")-induced obese ("DIO") male C57Bl / 6 mice on a 12-week HFD. n = 8 / group. Figure 1(b,c) t-test. *P<0.05, ****P<0.00001, respectively. [Figure 1C]Figure 1(a) shows data demonstrating increased FADS1 activity in human and rodent models of obesity. Figure 1(a) shows a flow chart illustrating the n-3 PUFA pathway and the n-6 PUFA pathway. As shown, FADS1 mediates the D5D of n-6 PUFAs from DGLA to AA and the D5D of n-3 PUFAs from eicosatetraenoic acid ("ETA") to eicosapentaenoic acid ("EPA"). Figure 1(b) shows a comparison of plasma AA / DGLA ratios as a surrogate for FADS1 activity in lean, overweight, and obese men (n = 8-41 / group). Data are presented as minimum to maximum. Figure 1(c) shows a comparison of the AA / DGLA ratio as a surrogate for FADS1 activity in lean and high-fat diet ("HFD")-induced obese ("DIO") male C57Bl / 6 mice on a 12-week HFD. n = 8 / group. Figure 1(b,c) t-test. *P<0.05, ****P<0.00001, respectively. [Figure 1D] FIG. 1 is a schematic diagram showing the metabolic pathway of one particular PUFA, LA, which leads to the formation of anti-inflammatory and pro-inflammatory eicosanoids and endocannabinoids, among others. [Figure 2A]These data support the finding that Fads1 KO mice are resistant to HFD-induced obesity and have an improved metabolic profile. Figure 2(a) shows a comparison of age-matched WT and Fads1 KO mice on a 12-week HFD. The data demonstrate that Fads1 KO mice are resistant to HFD-induced weight gain. Figure 2(b) shows that Fads1 KO mice have lower fat mass compared to their WT littermates, and Figure 2(c) shows that Fads1 KO mice have lower lean mass compared to their WT littermates. Figure 2(d) shows that food intake measured at 7 weeks was not significantly different in Fads1 KO mice compared to WT mice. Figure 2(e) shows that Fads1 KO mice have lower insulin levels compared to WT mice. Figure 2(f) shows that Fads1 KO mice have improved glucose tolerance during a GTT compared to WT mice. Figure 2(g) shows that Fads1 KO mice have lower cholesterol than WT mice. Figure 2(h) shows that no differences were found in plasma triglyceride levels (n = 8-9 / group). Data are shown as mean ± SEM. (a-c) Two-way ANOVA with Sidak's test for multiple comparisons; (d-h) t-test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.00001. [Figure 2B]These data support the finding that Fads1 KO mice are resistant to HFD-induced obesity and have an improved metabolic profile. Figure 2(a) shows a comparison of age-matched WT and Fads1 KO mice on a 12-week HFD. The data demonstrate that Fads1 KO mice are resistant to HFD-induced weight gain. Figure 2(b) shows that Fads1 KO mice have lower fat mass compared to their WT littermates, and Figure 2(c) shows that Fads1 KO mice have lower lean mass compared to their WT littermates. Figure 2(d) shows that food intake measured at 7 weeks was not significantly different in Fads1 KO mice compared to WT mice. Figure 2(e) shows that Fads1 KO mice have lower insulin levels compared to WT mice. Figure 2(f) shows that Fads1 KO mice have improved glucose tolerance during a GTT compared to WT mice. Figure 2(g) shows that Fads1 KO mice have lower cholesterol than WT mice. Figure 2(h) shows that no differences were found in plasma triglyceride levels (n = 8-9 / group). Data are shown as mean ± SEM. (a-c) Two-way ANOVA with Sidak's test for multiple comparisons; (d-h) t-test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.00001. [Figure 2C]These data support the finding that Fads1 KO mice are resistant to HFD-induced obesity and have an improved metabolic profile. Figure 2(a) shows a comparison of age-matched WT and Fads1 KO mice on a 12-week HFD. The data demonstrate that Fads1 KO mice are resistant to HFD-induced weight gain. Figure 2(b) shows that Fads1 KO mice have lower fat mass compared to their WT littermates, and Figure 2(c) shows that Fads1 KO mice have lower lean mass compared to their WT littermates. Figure 2(d) shows that food intake measured at 7 weeks was not significantly different in Fads1 KO mice compared to WT mice. Figure 2(e) shows that Fads1 KO mice have lower insulin levels compared to WT mice. Figure 2(f) shows that Fads1 KO mice have improved glucose tolerance during a GTT compared to WT mice. Figure 2(g) shows that Fads1 KO mice have lower cholesterol than WT mice. Figure 2(h) shows that no differences were found in plasma triglyceride levels (n = 8-9 / group). Data are shown as mean ± SEM. (a-c) Two-way ANOVA with Sidak's test for multiple comparisons; (d-h) t-test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.00001. [Figure 2D]These data support the finding that Fads1 KO mice are resistant to HFD-induced obesity and have an improved metabolic profile. Figure 2(a) shows a comparison of age-matched WT and Fads1 KO mice on a 12-week HFD. The data demonstrate that Fads1 KO mice are resistant to HFD-induced weight gain. Figure 2(b) shows that Fads1 KO mice have lower fat mass compared to their WT littermates, and Figure 2(c) shows that Fads1 KO mice have lower lean mass compared to their WT littermates. Figure 2(d) shows that food intake measured at 7 weeks was not significantly different in Fads1 KO mice compared to WT mice. Figure 2(e) shows that Fads1 KO mice have lower insulin levels compared to WT mice. Figure 2(f) shows that Fads1 KO mice have improved glucose tolerance during a GTT compared to WT mice. Figure 2(g) shows that Fads1 KO mice have lower cholesterol than WT mice. Figure 2(h) shows that no differences were found in plasma triglyceride levels (n = 8-9 / group). Data are shown as mean ± SEM. (a-c) Two-way ANOVA with Sidak's test for multiple comparisons; (d-h) t-test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.00001. [Figure 2E]These data support the finding that Fads1 KO mice are resistant to HFD-induced obesity and have an improved metabolic profile. Figure 2(a) shows a comparison of age-matched WT and Fads1 KO mice on a 12-week HFD. The data demonstrate that Fads1 KO mice are resistant to HFD-induced weight gain. Figure 2(b) shows that Fads1 KO mice have lower fat mass compared to their WT littermates, and Figure 2(c) shows that Fads1 KO mice have lower lean mass compared to their WT littermates. Figure 2(d) shows that food intake measured at 7 weeks was not significantly different in Fads1 KO mice compared to WT mice. Figure 2(e) shows that Fads1 KO mice have lower insulin levels compared to WT mice. Figure 2(f) shows that Fads1 KO mice have improved glucose tolerance during a GTT compared to WT mice. Figure 2(g) shows that Fads1 KO mice have lower cholesterol than WT mice. Figure 2(h) shows that no differences were found in plasma triglyceride levels (n = 8-9 / group). Data are shown as mean ± SEM. (a-c) Two-way ANOVA with Sidak's test for multiple comparisons; (d-h) t-test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.00001. [Figure 2F]These data support the finding that Fads1 KO mice are resistant to HFD-induced obesity and have an improved metabolic profile. Figure 2(a) shows a comparison of age-matched WT and Fads1 KO mice on a 12-week HFD. The data demonstrate that Fads1 KO mice are resistant to HFD-induced weight gain. Figure 2(b) shows that Fads1 KO mice have lower fat mass compared to their WT littermates, and Figure 2(c) shows that Fads1 KO mice have lower lean mass compared to their WT littermates. Figure 2(d) shows that food intake measured at 7 weeks was not significantly different in Fads1 KO mice compared to WT mice. Figure 2(e) shows that Fads1 KO mice have lower insulin levels compared to WT mice. Figure 2(f) shows that Fads1 KO mice have improved glucose tolerance during a GTT compared to WT mice. Figure 2(g) shows that Fads1 KO mice have lower cholesterol than WT mice. Figure 2(h) shows that no differences were found in plasma triglyceride levels (n = 8-9 / group). Data are shown as mean ± SEM. (a-c) Two-way ANOVA with Sidak's test for multiple comparisons; (d-h) t-test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.00001. [Figure 2G]These data support the finding that Fads1 KO mice are resistant to HFD-induced obesity and have an improved metabolic profile. Figure 2(a) shows a comparison of age-matched WT and Fads1 KO mice on a 12-week HFD. The data demonstrate that Fads1 KO mice are resistant to HFD-induced weight gain. Figure 2(b) shows that Fads1 KO mice have lower fat mass compared to their WT littermates, and Figure 2(c) shows that Fads1 KO mice have lower lean mass compared to their WT littermates. Figure 2(d) shows that food intake measured at 7 weeks was not significantly different in Fads1 KO mice compared to WT mice. Figure 2(e) shows that Fads1 KO mice have lower insulin levels compared to WT mice. Figure 2(f) shows that Fads1 KO mice have improved glucose tolerance during a GTT compared to WT mice. Figure 2(g) shows that Fads1 KO mice have lower cholesterol than WT mice. Figure 2(h) shows that no differences were found in plasma triglyceride levels (n = 8-9 / group). Data are shown as mean ± SEM. (a-c) Two-way ANOVA with Sidak's test for multiple comparisons; (d-h) t-test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.00001. [Figure 2H]These data support the finding that Fads1 KO mice are resistant to HFD-induced obesity and have an improved metabolic profile. Figure 2(a) shows a comparison of age-matched WT and Fads1 KO mice on a 12-week HFD. The data demonstrate that Fads1 KO mice are resistant to HFD-induced weight gain. Figure 2(b) shows that Fads1 KO mice have lower fat mass compared to their WT littermates, and Figure 2(c) shows that Fads1 KO mice have lower lean mass compared to their WT littermates. Figure 2(d) shows that food intake measured at 7 weeks was not significantly different in Fads1 KO mice compared to WT mice. Figure 2(e) shows that Fads1 KO mice have lower insulin levels compared to WT mice. Figure 2(f) shows that Fads1 KO mice have improved glucose tolerance during a GTT compared to WT mice. Figure 2(g) shows that Fads1 KO mice have lower cholesterol than WT mice. Figure 2(h) shows that no differences were found in plasma triglyceride levels (n = 8-9 / group). Data are shown as mean ± SEM. (a-c) Two-way ANOVA with Sidak's test for multiple comparisons; (d-h) t-test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.00001. [Figure 3A]Data confirm that HFD-induced obese Fads1 KO mice have a lower respiratory exchange ratio (PER) and increased dark-cycle energy expenditure. Fads1 KO and WT mice were exposed to an HFD for 12 weeks (n = 24 mice / group). Figure 3(a, b) shows oxygen consumption in the two groups, Figure 3(c, d) shows carbon dioxide production in the two groups, Figure 3(e, f) shows PER measurements in the two groups, and Figure 3(g, h) shows activity measurements obtained at 0, 6, and 12 weeks of HFD feeding in the two groups. In Figure 3(a, c, e, g), each data point represents a running average of six time points, with the dark cycle (6 PM–6 AM) indicated by a bordered box. In Figure 3(b, d, f, h), measurements were averaged and displayed as the mean ± SEM for each day or night over time. Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. Figure 3(i-l) shows plots of light and dark cycle energy expenditure (kcal / hr) against body weight after 6 and 12 weeks of HFD feeding (least squares multiple linear regression model including body weight and genotype). [Figure 3B]Data confirm that HFD-induced obese Fads1 KO mice have a lower respiratory exchange ratio (PER) and increased dark-cycle energy expenditure. Fads1 KO and WT mice were exposed to an HFD for 12 weeks (n = 24 mice / group). Figure 3(a, b) shows oxygen consumption in the two groups, Figure 3(c, d) shows carbon dioxide production in the two groups, Figure 3(e, f) shows PER measurements in the two groups, and Figure 3(g, h) shows activity measurements obtained at 0, 6, and 12 weeks of HFD feeding in the two groups. In Figure 3(a, c, e, g), each data point represents a running average of six time points, with the dark cycle (6 PM–6 AM) indicated by a bordered box. In Figure 3(b, d, f, h), measurements were averaged and displayed as the mean ± SEM for each day or night over time. Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. Figure 3(i-l) shows plots of light and dark cycle energy expenditure (kcal / hr) against body weight after 6 and 12 weeks of HFD feeding (least squares multiple linear regression model including body weight and genotype). [Figure 3C]Data confirm that HFD-induced obese Fads1 KO mice have a lower respiratory exchange ratio (PER) and increased dark-cycle energy expenditure. Fads1 KO and WT mice were exposed to an HFD for 12 weeks (n = 24 mice / group). Figure 3(a, b) shows oxygen consumption in the two groups, Figure 3(c, d) shows carbon dioxide production in the two groups, Figure 3(e, f) shows PER measurements in the two groups, and Figure 3(g, h) shows activity measurements obtained at 0, 6, and 12 weeks of HFD feeding in the two groups. In Figure 3(a, c, e, g), each data point represents a running average of six time points, with the dark cycle (6 PM–6 AM) indicated by a bordered box. In Figure 3(b, d, f, h), measurements were averaged and displayed as the mean ± SEM for each day or night over time. Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. Figure 3(i-l) shows plots of light and dark cycle energy expenditure (kcal / hr) against body weight after 6 and 12 weeks of HFD feeding (least squares multiple linear regression model including body weight and genotype). [Figure 3D]Data confirm that HFD-induced obese Fads1 KO mice have a lower respiratory exchange ratio (PER) and increased dark-cycle energy expenditure. Fads1 KO and WT mice were exposed to an HFD for 12 weeks (n = 24 mice / group). Figure 3(a, b) shows oxygen consumption in the two groups, Figure 3(c, d) shows carbon dioxide production in the two groups, Figure 3(e, f) shows PER measurements in the two groups, and Figure 3(g, h) shows activity measurements obtained at 0, 6, and 12 weeks of HFD feeding in the two groups. In Figure 3(a, c, e, g), each data point represents a running average of six time points, with the dark cycle (6 PM–6 AM) indicated by a bordered box. In Figure 3(b, d, f, h), measurements were averaged and displayed as the mean ± SEM for each day or night over time. Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. Figure 3(i-l) shows plots of light and dark cycle energy expenditure (kcal / hr) against body weight after 6 and 12 weeks of HFD feeding (least squares multiple linear regression model including body weight and genotype). [Figure 3E]Data confirm that HFD-induced obese Fads1 KO mice have a lower respiratory exchange ratio (PER) and increased dark-cycle energy expenditure. Fads1 KO and WT mice were exposed to an HFD for 12 weeks (n = 24 mice / group). Figure 3(a, b) shows oxygen consumption in the two groups, Figure 3(c, d) shows carbon dioxide production in the two groups, Figure 3(e, f) shows PER measurements in the two groups, and Figure 3(g, h) shows activity measurements obtained at 0, 6, and 12 weeks of HFD feeding in the two groups. In Figure 3(a, c, e, g), each data point represents a running average of six time points, with the dark cycle (6 PM–6 AM) indicated by a bordered box. In Figure 3(b, d, f, h), measurements were averaged and displayed as the mean ± SEM for each day or night over time. Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. Figure 3(i-l) shows plots of light and dark cycle energy expenditure (kcal / hr) against body weight after 6 and 12 weeks of HFD feeding (least squares multiple linear regression model including body weight and genotype). [Figure 3F]Data confirm that HFD-induced obese Fads1 KO mice have a lower respiratory exchange ratio (PER) and increased dark-cycle energy expenditure. Fads1 KO and WT mice were exposed to an HFD for 12 weeks (n = 24 mice / group). Figure 3(a, b) shows oxygen consumption in the two groups, Figure 3(c, d) shows carbon dioxide production in the two groups, Figure 3(e, f) shows PER measurements in the two groups, and Figure 3(g, h) shows activity measurements obtained at 0, 6, and 12 weeks of HFD feeding in the two groups. In Figure 3(a, c, e, g), each data point represents a running average of six time points, with the dark cycle (6 PM–6 AM) indicated by a bordered box. In Figure 3(b, d, f, h), measurements were averaged and displayed as the mean ± SEM for each day or night over time. Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. Figure 3(i-l) shows plots of light and dark cycle energy expenditure (kcal / hr) against body weight after 6 and 12 weeks of HFD feeding (least squares multiple linear regression model including body weight and genotype). [Figure 3G]Data confirm that HFD-induced obese Fads1 KO mice have a lower respiratory exchange ratio (PER) and increased dark-cycle energy expenditure. Fads1 KO and WT mice were exposed to an HFD for 12 weeks (n = 24 mice / group). Figure 3(a, b) shows oxygen consumption in the two groups, Figure 3(c, d) shows carbon dioxide production in the two groups, Figure 3(e, f) shows PER measurements in the two groups, and Figure 3(g, h) shows activity measurements obtained at 0, 6, and 12 weeks of HFD feeding in the two groups. In Figure 3(a, c, e, g), each data point represents a running average of six time points, with the dark cycle (6 PM–6 AM) indicated by a bordered box. In Figure 3(b, d, f, h), measurements were averaged and displayed as the mean ± SEM for each day or night over time. Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. Figure 3(i-l) shows plots of light and dark cycle energy expenditure (kcal / hr) against body weight after 6 and 12 weeks of HFD feeding (least squares multiple linear regression model including body weight and genotype). [Figure 3H]Data confirm that HFD-induced obese Fads1 KO mice have a lower respiratory exchange ratio (PER) and increased dark-cycle energy expenditure. Fads1 KO and WT mice were exposed to an HFD for 12 weeks (n = 24 mice / group). Figure 3(a, b) shows oxygen consumption in the two groups, Figure 3(c, d) shows carbon dioxide production in the two groups, Figure 3(e, f) shows PER measurements in the two groups, and Figure 3(g, h) shows activity measurements obtained at 0, 6, and 12 weeks of HFD feeding in the two groups. In Figure 3(a, c, e, g), each data point represents a running average of six time points, with the dark cycle (6 PM–6 AM) indicated by a bordered box. In Figure 3(b, d, f, h), measurements were averaged and displayed as the mean ± SEM for each day or night over time. Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. Figure 3(i-l) shows plots of light and dark cycle energy expenditure (kcal / hr) against body weight after 6 and 12 weeks of HFD feeding (least squares multiple linear regression model including body weight and genotype). [Figure 3I]Data confirm that HFD-induced obese Fads1 KO mice have a lower respiratory exchange ratio (PER) and increased dark-cycle energy expenditure. Fads1 KO and WT mice were exposed to an HFD for 12 weeks (n = 24 mice / group). Figure 3(a, b) shows oxygen consumption in the two groups, Figure 3(c, d) shows carbon dioxide production in the two groups, Figure 3(e, f) shows PER measurements in the two groups, and Figure 3(g, h) shows activity measurements obtained at 0, 6, and 12 weeks of HFD feeding in the two groups. In Figure 3(a, c, e, g), each data point represents a running average of six time points, with the dark cycle (6 PM–6 AM) indicated by a bordered box. In Figure 3(b, d, f, h), measurements were averaged and displayed as the mean ± SEM for each day or night over time. Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. Figure 3(i-l) shows plots of light and dark cycle energy expenditure (kcal / hr) against body weight after 6 and 12 weeks of HFD feeding (least squares multiple linear regression model including body weight and genotype). [Figure 3J]Data confirm that HFD-induced obese Fads1 KO mice have a lower respiratory exchange ratio (PER) and increased dark-cycle energy expenditure. Fads1 KO and WT mice were exposed to an HFD for 12 weeks (n = 24 mice / group). Figure 3(a, b) shows oxygen consumption in the two groups, Figure 3(c, d) shows carbon dioxide production in the two groups, Figure 3(e, f) shows PER measurements in the two groups, and Figure 3(g, h) shows activity measurements obtained at 0, 6, and 12 weeks of HFD feeding in the two groups. In Figure 3(a, c, e, g), each data point represents a running average of six time points, with the dark cycle (6 PM–6 AM) indicated by a bordered box. In Figure 3(b, d, f, h), measurements were averaged and displayed as the mean ± SEM for each day or night over time. Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. Figure 3(i-l) shows plots of light and dark cycle energy expenditure (kcal / hr) against body weight after 6 and 12 weeks of HFD feeding (least squares multiple linear regression model including body weight and genotype). [Figure 3K]Data confirm that HFD-induced obese Fads1 KO mice have a lower respiratory exchange ratio (PER) and increased dark-cycle energy expenditure. Fads1 KO and WT mice were exposed to an HFD for 12 weeks (n = 24 mice / group). Figure 3(a, b) shows oxygen consumption in the two groups, Figure 3(c, d) shows carbon dioxide production in the two groups, Figure 3(e, f) shows PER measurements in the two groups, and Figure 3(g, h) shows activity measurements obtained at 0, 6, and 12 weeks of HFD feeding in the two groups. In Figure 3(a, c, e, g), each data point represents a running average of six time points, with the dark cycle (6 PM–6 AM) indicated by a bordered box. In Figure 3(b, d, f, h), measurements were averaged and displayed as the mean ± SEM for each day or night over time. Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. Figure 3(i-l) shows plots of light and dark cycle energy expenditure (kcal / hr) against body weight after 6 and 12 weeks of HFD feeding (least squares multiple linear regression model including body weight and genotype). [Figure 3L]Data confirm that HFD-induced obese Fads1 KO mice have a lower respiratory exchange ratio (PER) and increased dark-cycle energy expenditure. Fads1 KO and WT mice were exposed to an HFD for 12 weeks (n = 24 mice / group). Figure 3(a, b) shows oxygen consumption in the two groups, Figure 3(c, d) shows carbon dioxide production in the two groups, Figure 3(e, f) shows PER measurements in the two groups, and Figure 3(g, h) shows activity measurements obtained at 0, 6, and 12 weeks of HFD feeding in the two groups. In Figure 3(a, c, e, g), each data point represents a running average of six time points, with the dark cycle (6 PM–6 AM) indicated by a bordered box. In Figure 3(b, d, f, h), measurements were averaged and displayed as the mean ± SEM for each day or night over time. Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. Figure 3(i-l) shows plots of light and dark cycle energy expenditure (kcal / hr) against body weight after 6 and 12 weeks of HFD feeding (least squares multiple linear regression model including body weight and genotype). [Figure 4A]Figure 4(a) shows RNA-seq analysis of liver, epididymal (EPI) white adipose tissue (WAT), and inguinal (ING) WAT from Fads1 KO mice and WT mice at 12 weeks of HFD feeding. Figure 4(a) shows a volcano plot representing DEGs in liver, EPI WAT, and ING WAT from Fads1 KO mice and WT mice. Genes with Benjamini-Hochberg (BH)-adjusted P values ​​of less than 0.01 and fold changes of 2 or greater or 0.5 or less are color-coded. Figure 4(b) shows the average cellular composition in liver, EPI WAT, and ING WAT from Fads1 KO and WT mice analyzed by SCDC using scRNA-seq from the corresponding mouse organs as a reference. Cell types are abbreviated as follows: adipocytes ("Adipo"), B cells ("Bcell"), endothelial cells ("Endo"), hepatocytes ("Hep"), Kupffer cells ("Kupff"), myeloid cells ("Myel"), natural killer ("NK"), and T cells ("Tcell"). Kyoto Encyclopedia of Genes and Genomes ("KEGG") analysis of differentially altered metabolic pathways in liver and epithelial WAT of Fads1 KO mice compared to WT mice is shown in Figure 4(c) and Figure 4(d), respectively, showing the number of unique genes whose expression was significantly altered in each pathway (n = 4–8 / group). [Figure 4B]Figure 4(a) shows RNA-seq analysis of liver, epididymal (EPI) white adipose tissue (WAT), and inguinal (ING) WAT from Fads1 KO mice and WT mice at 12 weeks of HFD feeding. Figure 4(a) shows a volcano plot representing DEGs in liver, EPI WAT, and ING WAT from Fads1 KO mice and WT mice. Genes with Benjamini-Hochberg (BH)-adjusted P values ​​of less than 0.01 and fold changes of 2 or greater or 0.5 or less are color-coded. Figure 4(b) shows the average cellular composition in liver, EPI WAT, and ING WAT from Fads1 KO and WT mice analyzed by SCDC using scRNA-seq from the corresponding mouse organs as a reference. Cell types are abbreviated as follows: adipocytes ("Adipo"), B cells ("Bcell"), endothelial cells ("Endo"), hepatocytes ("Hep"), Kupffer cells ("Kupff"), myeloid cells ("Myel"), natural killer ("NK"), and T cells ("Tcell"). Kyoto Encyclopedia of Genes and Genomes ("KEGG") analysis of differentially altered metabolic pathways in liver and epithelial WAT of Fads1 KO mice compared to WT mice is shown in Figure 4(c) and Figure 4(d), respectively, showing the number of unique genes whose expression was significantly altered in each pathway (n = 4–8 / group). [Figure 4C]Figure 4(a) shows RNA-seq analysis of liver, epididymal (EPI) white adipose tissue (WAT), and inguinal (ING) WAT from Fads1 KO mice and WT mice at 12 weeks of HFD feeding. Figure 4(a) shows a volcano plot representing DEGs in liver, EPI WAT, and ING WAT from Fads1 KO mice and WT mice. Genes with Benjamini-Hochberg (BH)-adjusted P values ​​of less than 0.01 and fold changes of 2 or greater or 0.5 or less are color-coded. Figure 4(b) shows the average cellular composition in liver, EPI WAT, and ING WAT from Fads1 KO and WT mice analyzed by SCDC using scRNA-seq from the corresponding mouse organs as a reference. Cell types are abbreviated as follows: adipocytes ("Adipo"), B cells ("Bcell"), endothelial cells ("Endo"), hepatocytes ("Hep"), Kupffer cells ("Kupff"), myeloid cells ("Myel"), natural killer ("NK"), and T cells ("Tcell"). Kyoto Encyclopedia of Genes and Genomes ("KEGG") analysis of differentially altered metabolic pathways in liver and epithelial WAT of Fads1 KO mice compared to WT mice is shown in Figure 4(c) and Figure 4(d), respectively, showing the number of unique genes whose expression was significantly altered in each pathway (n = 4–8 / group). [Figure 4D]Figure 4(a) shows RNA-seq analysis of liver, epididymal (EPI) white adipose tissue (WAT), and inguinal (ING) WAT from Fads1 KO mice and WT mice at 12 weeks of HFD feeding. Figure 4(a) shows a volcano plot representing DEGs in liver, EPI WAT, and ING WAT from Fads1 KO mice and WT mice. Genes with Benjamini-Hochberg (BH)-adjusted P values ​​of less than 0.01 and fold changes of 2 or greater or 0.5 or less are color-coded. Figure 4(b) shows the average cellular composition in liver, EPI WAT, and ING WAT from Fads1 KO and WT mice analyzed by SCDC using scRNA-seq from the corresponding mouse organs as a reference. Cell types are abbreviated as follows: adipocytes ("Adipo"), B cells ("Bcell"), endothelial cells ("Endo"), hepatocytes ("Hep"), Kupffer cells ("Kupff"), myeloid cells ("Myel"), natural killer ("NK"), and T cells ("Tcell"). Kyoto Encyclopedia of Genes and Genomes ("KEGG") analysis of differentially altered metabolic pathways in liver and epithelial WAT of Fads1 KO mice compared to WT mice is shown in Figure 4(c) and Figure 4(d), respectively, showing the number of unique genes whose expression was significantly altered in each pathway (n = 4–8 / group). [Figure 5A]Fads1 knockout mice on a high-fat diet exhibit altered metabolic gene expression, elevated adiponectin levels, and reduced inflammatory markers in adipose tissue. Figure 5(a) shows a comparison of metabolic gene expression changes in EPI WAT, ING WAT, and liver of Fads1 KO mice compared with WT littermates. Genes with Benjamini-Hochberg adjusted P values ​​less than 0.01 and fold changes of 2 or greater or 0.5 or less are color-coded. Figure 5(b) shows a comparison of adiponectin, leptin, PAI-1, and MCP-1 levels in plasma, EPI WAT, and ING WAT between WT and Fads1 KO mice. (a-b) Data are presented from minimum to maximum. n = 3-8 per group. t-test *P < 0.05, **P < 0.01, ***P < 0.001. [Figure 5B] Fads1 knockout mice on a high-fat diet exhibit altered metabolic gene expression, elevated adiponectin levels, and reduced inflammatory markers in adipose tissue. Figure 5(a) shows a comparison of metabolic gene expression changes in EPI WAT, ING WAT, and liver of Fads1 KO mice compared with WT littermates. Genes with Benjamini-Hochberg adjusted P values ​​less than 0.01 and fold changes of 2 or greater or 0.5 or less are color-coded. Figure 5(b) shows a comparison of adiponectin, leptin, PAI-1, and MCP-1 levels in plasma, EPI WAT, and ING WAT between WT and Fads1 KO mice. (a-b) Data are presented from minimum to maximum. n = 3-8 per group. t-test *P < 0.05, **P < 0.01, ***P < 0.001. [Figure 6A]Fads1 KO mice exhibit altered fatty acid composition in plasma lipid subfractions. Figure 6(a) shows the fatty acid concentration of whole plasma and each of the four major lipid subfractions (phospholipids, free fatty acids, cholesterol esters, and triglycerides) in HFD WT and Fads1 KO mice. Figure 6(b) shows the fatty acid composition of whole plasma and each of the four lipid subfractions in plasma in WT and Fads1 KO mice. (a-b) n = 3 samples per genotype (each sample pooled from two mice). (a) Data are shown from minimum to maximum. t-test *P<0.05, **P<0.01, ***P<0.001. [Figure 6B] Fads1 KO mice exhibit altered fatty acid composition in plasma lipid subfractions. Figure 6(a) shows the fatty acid concentration of whole plasma and each of the four major lipid subfractions (phospholipids, free fatty acids, cholesterol esters, and triglycerides) in HFD WT and Fads1 KO mice. Figure 6(b) shows the fatty acid composition of whole plasma and each of the four lipid subfractions in plasma in WT and Fads1 KO mice. (a-b) n = 3 samples per genotype (each sample pooled from two mice). (a) Data are shown from minimum to maximum. t-test *P<0.05, **P<0.01, ***P<0.001. [Figure 7A-1]Metabolic analysis of Fads1 KO mice compared with WT mice on an HFD is shown. Figure 7(a) shows a comparison of plasma metabolite profiles between Fads1 KO and WT mice after 11 weeks of HFD feeding. The ratio of Fads1 KO metabolite levels to WT is shown. Only metabolites with ratios ≥ 1.15 or ≤ 0.85 and P values ​​≤ 0.05 are shown; n = 4–6 per group. t-test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.00001. Figure 7(b) shows a heatmap of the top affected IPA disease and biological functions based on the metabolite profiles of Fads1 KO mice compared with WT mice on an HFD. Figure 7(c) shows a heatmap comparing the changes in common and distinct disease and biological functions in the plasma metabolome and transcriptome of the liver, EPI WAT, and ING WAT of Fads1 KO mice compared with WT mice. In Figure 7 (b-c), only diseases and biological functions with p-values ​​less than 0.05 are shown. [Figure 7A-2] Metabolic analysis of Fads1 KO mice compared with WT mice on an HFD is shown. Figure 7(a) shows a comparison of plasma metabolite profiles between Fads1 KO and WT mice after 11 weeks of HFD feeding. The ratio of Fads1 KO metabolite levels to WT is shown. Only metabolites with ratios ≥ 1.15 or ≤ 0.85 and P values ​​≤ 0.05 are shown; n = 4–6 per group. t-test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.00001. Figure 7(b) shows a heatmap of the top affected IPA disease and biological functions based on the metabolite profiles of Fads1 KO mice compared with WT mice on an HFD. Figure 7(c) shows a heatmap comparing the changes in common and distinct disease and biological functions in the plasma metabolome and transcriptome of the liver, EPI WAT, and ING WAT of Fads1 KO mice compared with WT mice. In Figure 7 (b-c), only diseases and biological functions with p-values ​​less than 0.05 are shown. [Figure 7B]Metabolic analysis of Fads1 KO mice compared with WT mice on an HFD is shown. Figure 7(a) shows a comparison of plasma metabolite profiles between Fads1 KO and WT mice after 11 weeks of HFD feeding. The ratio of Fads1 KO metabolite levels to WT is shown. Only metabolites with ratios ≥ 1.15 or ≤ 0.85 and P values ​​≤ 0.05 are shown; n = 4–6 per group. t-test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.00001. Figure 7(b) shows a heatmap of the top affected IPA disease and biological functions based on the metabolite profiles of Fads1 KO mice compared with WT mice on an HFD. Figure 7(c) shows a heatmap comparing the changes in common and distinct disease and biological functions in the plasma metabolome and transcriptome of the liver, EPI WAT, and ING WAT of Fads1 KO mice compared with WT mice. In Figure 7 (b-c), only diseases and biological functions with p-values ​​less than 0.05 are shown. [Figure 7C] Metabolic analysis of Fads1 KO mice compared with WT mice on an HFD is shown. Figure 7(a) shows a comparison of plasma metabolite profiles between Fads1 KO and WT mice after 11 weeks of HFD feeding. The ratio of Fads1 KO metabolite levels to WT is shown. Only metabolites with ratios ≥ 1.15 or ≤ 0.85 and P values ​​≤ 0.05 are shown; n = 4–6 per group. t-test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.00001. Figure 7(b) shows a heatmap of the top affected IPA disease and biological functions based on the metabolite profiles of Fads1 KO mice compared with WT mice on an HFD. Figure 7(c) shows a heatmap comparing the changes in common and distinct disease and biological functions in the plasma metabolome and transcriptome of the liver, EPI WAT, and ING WAT of Fads1 KO mice compared with WT mice. In Figure 7 (b-c), only diseases and biological functions with p-values ​​less than 0.05 are shown. [Figure 8A]These data demonstrate that a FADS1 small molecule inhibitor reduced body weight and improved metabolic parameters in DIO mice. Compound A (Figure 8(a)) is a FADS1 inhibitor with over 1200-fold selectivity for human FADS1 over human FADS2, as determined in FADS1 and FADS2 cell-based assays, as shown in Figure 8(b). Similar efficacy was observed in the mouse FADS1 cell-based assay (Figure 8(b)) and in Figure 8(c), which provides a mouse in vivo FADS1 potency assay. Treatment with 10 mg / kg and 30 mg / kg of Compound A once daily for 54 days in DIO mice reduced body weight (Figure 8(d)) and in vivo residual hepatic FADS1 activity (Figure 8(e)), but did not affect food intake (Figure 8(f)). Treatment with Compound A reduced insulin levels (Figure 8(g)), cholesterol levels (Figure 8(h)), and triglyceride levels (Figure 8(i)) (n=7-10 / group). Data are shown as mean ± SEM. Figure 8(d) Two-way ANOVA with Sidak's test for multiple comparisons; Figure 8(e-i) One-way ANOVA with Dunnett's test for multiple comparisons. *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. ANOVA, analysis of variance; DIO, diet-induced obesity; FADS1, fatty acid desaturase 1; FADS2, fatty acid desaturase 2; MW, molecular weight; POC, percentage of control; SEM, standard error of the mean. [Figure 8B]These data demonstrate that a FADS1 small molecule inhibitor reduced body weight and improved metabolic parameters in DIO mice. Compound A (Figure 8(a)) is a FADS1 inhibitor with over 1200-fold selectivity for human FADS1 over human FADS2, as determined in FADS1 and FADS2 cell-based assays, as shown in Figure 8(b). Similar efficacy was observed in the mouse FADS1 cell-based assay (Figure 8(b)) and in Figure 8(c), which provides a mouse in vivo FADS1 potency assay. Treatment with 10 mg / kg and 30 mg / kg of Compound A once daily for 54 days in DIO mice reduced body weight (Figure 8(d)) and in vivo residual hepatic FADS1 activity (Figure 8(e)), but did not affect food intake (Figure 8(f)). Treatment with Compound A reduced insulin levels (Figure 8(g)), cholesterol levels (Figure 8(h)), and triglyceride levels (Figure 8(i)) (n=7-10 / group). Data are shown as mean ± SEM. Figure 8(d) Two-way ANOVA with Sidak's test for multiple comparisons; Figure 8(e-i) One-way ANOVA with Dunnett's test for multiple comparisons. *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. ANOVA, analysis of variance; DIO, diet-induced obesity; FADS1, fatty acid desaturase 1; FADS2, fatty acid desaturase 2; MW, molecular weight; POC, percentage of control; SEM, standard error of the mean. [Figure 8C]These data demonstrate that a FADS1 small molecule inhibitor reduced body weight and improved metabolic parameters in DIO mice. Compound A (Figure 8(a)) is a FADS1 inhibitor with over 1200-fold selectivity for human FADS1 over human FADS2, as determined in FADS1 and FADS2 cell-based assays, as shown in Figure 8(b). Similar efficacy was observed in the mouse FADS1 cell-based assay (Figure 8(b)) and in Figure 8(c), which provides a mouse in vivo FADS1 potency assay. Treatment with 10 mg / kg and 30 mg / kg of Compound A once daily for 54 days in DIO mice reduced body weight (Figure 8(d)) and in vivo residual hepatic FADS1 activity (Figure 8(e)), but did not affect food intake (Figure 8(f)). Treatment with Compound A reduced insulin levels (Figure 8(g)), cholesterol levels (Figure 8(h)), and triglyceride levels (Figure 8(i)) (n=7-10 / group). Data are shown as mean ± SEM. Figure 8(d) Two-way ANOVA with Sidak's test for multiple comparisons; Figure 8(e-i) One-way ANOVA with Dunnett's test for multiple comparisons. *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. ANOVA, analysis of variance; DIO, diet-induced obesity; FADS1, fatty acid desaturase 1; FADS2, fatty acid desaturase 2; MW, molecular weight; POC, percentage of control; SEM, standard error of the mean. [Figure 8D]These data demonstrate that a FADS1 small molecule inhibitor reduced body weight and improved metabolic parameters in DIO mice. Compound A (Figure 8(a)) is a FADS1 inhibitor with over 1200-fold selectivity for human FADS1 over human FADS2, as determined in FADS1 and FADS2 cell-based assays, as shown in Figure 8(b). Similar efficacy was observed in the mouse FADS1 cell-based assay (Figure 8(b)) and in Figure 8(c), which provides a mouse in vivo FADS1 potency assay. Treatment with 10 mg / kg and 30 mg / kg of Compound A once daily for 54 days in DIO mice reduced body weight (Figure 8(d)) and in vivo residual hepatic FADS1 activity (Figure 8(e)), but did not affect food intake (Figure 8(f)). Treatment with Compound A reduced insulin levels (Figure 8(g)), cholesterol levels (Figure 8(h)), and triglyceride levels (Figure 8(i)) (n=7-10 / group). Data are shown as mean ± SEM. Figure 8(d) Two-way ANOVA with Sidak's test for multiple comparisons; Figure 8(e-i) One-way ANOVA with Dunnett's test for multiple comparisons. *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. ANOVA, analysis of variance; DIO, diet-induced obesity; FADS1, fatty acid desaturase 1; FADS2, fatty acid desaturase 2; MW, molecular weight; POC, percentage of control; SEM, standard error of the mean. [Figure 8E]These data demonstrate that a FADS1 small molecule inhibitor reduced body weight and improved metabolic parameters in DIO mice. Compound A (Figure 8(a)) is a FADS1 inhibitor with over 1200-fold selectivity for human FADS1 over human FADS2, as determined in FADS1 and FADS2 cell-based assays, as shown in Figure 8(b). Similar efficacy was observed in the mouse FADS1 cell-based assay (Figure 8(b)) and in Figure 8(c), which provides a mouse in vivo FADS1 potency assay. Treatment with 10 mg / kg and 30 mg / kg of Compound A once daily for 54 days in DIO mice reduced body weight (Figure 8(d)) and in vivo residual hepatic FADS1 activity (Figure 8(e)), but did not affect food intake (Figure 8(f)). Treatment with Compound A reduced insulin levels (Figure 8(g)), cholesterol levels (Figure 8(h)), and triglyceride levels (Figure 8(i)) (n=7-10 / group). Data are shown as mean ± SEM. Figure 8(d) Two-way ANOVA with Sidak's test for multiple comparisons; Figure 8(e-i) One-way ANOVA with Dunnett's test for multiple comparisons. *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. ANOVA, analysis of variance; DIO, diet-induced obesity; FADS1, fatty acid desaturase 1; FADS2, fatty acid desaturase 2; MW, molecular weight; POC, percentage of control; SEM, standard error of the mean. [Figure 8F]These data demonstrate that a FADS1 small molecule inhibitor reduced body weight and improved metabolic parameters in DIO mice. Compound A (Figure 8(a)) is a FADS1 inhibitor with over 1200-fold selectivity for human FADS1 over human FADS2, as determined in FADS1 and FADS2 cell-based assays, as shown in Figure 8(b). Similar efficacy was observed in the mouse FADS1 cell-based assay (Figure 8(b)) and in Figure 8(c), which provides a mouse in vivo FADS1 potency assay. Treatment with 10 mg / kg and 30 mg / kg of Compound A once daily for 54 days in DIO mice reduced body weight (Figure 8(d)) and in vivo residual hepatic FADS1 activity (Figure 8(e)), but did not affect food intake (Figure 8(f)). Treatment with Compound A reduced insulin levels (Figure 8(g)), cholesterol levels (Figure 8(h)), and triglyceride levels (Figure 8(i)) (n=7-10 / group). Data are shown as mean ± SEM. Figure 8(d) Two-way ANOVA with Sidak's test for multiple comparisons; Figure 8(e-i) One-way ANOVA with Dunnett's test for multiple comparisons. *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. ANOVA, analysis of variance; DIO, diet-induced obesity; FADS1, fatty acid desaturase 1; FADS2, fatty acid desaturase 2; MW, molecular weight; POC, percentage of control; SEM, standard error of the mean. [Figure 8G]These data demonstrate that a FADS1 small molecule inhibitor reduced body weight and improved metabolic parameters in DIO mice. Compound A (Figure 8(a)) is a FADS1 inhibitor with over 1200-fold selectivity for human FADS1 over human FADS2, as determined in FADS1 and FADS2 cell-based assays, as shown in Figure 8(b). Similar efficacy was observed in the mouse FADS1 cell-based assay (Figure 8(b)) and in Figure 8(c), which provides a mouse in vivo FADS1 potency assay. Treatment with 10 mg / kg and 30 mg / kg of Compound A once daily for 54 days in DIO mice reduced body weight (Figure 8(d)) and in vivo residual hepatic FADS1 activity (Figure 8(e)), but did not affect food intake (Figure 8(f)). Treatment with Compound A reduced insulin levels (Figure 8(g)), cholesterol levels (Figure 8(h)), and triglyceride levels (Figure 8(i)) (n=7-10 / group). Data are shown as mean ± SEM. Figure 8(d) Two-way ANOVA with Sidak's test for multiple comparisons; Figure 8(e-i) One-way ANOVA with Dunnett's test for multiple comparisons. *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. ANOVA, analysis of variance; DIO, diet-induced obesity; FADS1, fatty acid desaturase 1; FADS2, fatty acid desaturase 2; MW, molecular weight; POC, percentage of control; SEM, standard error of the mean. [Figure 8H]These data demonstrate that a FADS1 small molecule inhibitor reduced body weight and improved metabolic parameters in DIO mice. Compound A (Figure 8(a)) is a FADS1 inhibitor with over 1200-fold selectivity for human FADS1 over human FADS2, as determined in FADS1 and FADS2 cell-based assays, as shown in Figure 8(b). Similar efficacy was observed in the mouse FADS1 cell-based assay (Figure 8(b)) and in Figure 8(c), which provides a mouse in vivo FADS1 potency assay. Treatment with 10 mg / kg and 30 mg / kg of Compound A once daily for 54 days in DIO mice reduced body weight (Figure 8(d)) and in vivo residual hepatic FADS1 activity (Figure 8(e)), but did not affect food intake (Figure 8(f)). Treatment with Compound A reduced insulin levels (Figure 8(g)), cholesterol levels (Figure 8(h)), and triglyceride levels (Figure 8(i)) (n=7-10 / group). Data are shown as mean ± SEM. Figure 8(d) Two-way ANOVA with Sidak's test for multiple comparisons; Figure 8(e-i) One-way ANOVA with Dunnett's test for multiple comparisons. *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. ANOVA, analysis of variance; DIO, diet-induced obesity; FADS1, fatty acid desaturase 1; FADS2, fatty acid desaturase 2; MW, molecular weight; POC, percentage of control; SEM, standard error of the mean. [Figure 8I]These data demonstrate that a FADS1 small molecule inhibitor reduced body weight and improved metabolic parameters in DIO mice. Compound A (Figure 8(a)) is a FADS1 inhibitor with over 1200-fold selectivity for human FADS1 over human FADS2, as determined in FADS1 and FADS2 cell-based assays, as shown in Figure 8(b). Similar efficacy was observed in the mouse FADS1 cell-based assay (Figure 8(b)) and in Figure 8(c), which provides a mouse in vivo FADS1 potency assay. Treatment with 10 mg / kg and 30 mg / kg of Compound A once daily for 54 days in DIO mice reduced body weight (Figure 8(d)) and in vivo residual hepatic FADS1 activity (Figure 8(e)), but did not affect food intake (Figure 8(f)). Treatment with Compound A reduced insulin levels (Figure 8(g)), cholesterol levels (Figure 8(h)), and triglyceride levels (Figure 8(i)) (n=7-10 / group). Data are shown as mean ± SEM. Figure 8(d) Two-way ANOVA with Sidak's test for multiple comparisons; Figure 8(e-i) One-way ANOVA with Dunnett's test for multiple comparisons. *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. ANOVA, analysis of variance; DIO, diet-induced obesity; FADS1, fatty acid desaturase 1; FADS2, fatty acid desaturase 2; MW, molecular weight; POC, percentage of control; SEM, standard error of the mean. [Figure 9A]Figure 9 shows indirect calorimetry data from Compound A-treated DIO mice or vehicle-treated mice. Figure 9(a) shows a comparison of body weight, Figure 9(b) shows energy expenditure across the light-dark cycle versus body weight, Figures 9(c,d) show oxygen consumption, Figures 9(e,f) show carbon dioxide production, Figures 9(g,h) show PER, and Figures 9(i,j) show activity. DIO mice were treated with vehicle or Compound A (30 mg / kg) for 42 days, and measurements were taken at the indicated time points. In Figures 9(c,e,g,i), each data point represents a 3-day moving average, with the dark cycle (6 PM - 6 AM) indicated by a bordered box. Measurements in Figures 9(d,f,h,j) were averaged and displayed as the mean ± SEM for each day or night over time. Figure 9(b) shows a least-squares multiple linear regression model including body weight and treatment. Figure 9 (a, d, f, h, j) Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. n=10-11 mice / group. [Figure 9B] Figure 9 shows indirect calorimetry data from Compound A-treated DIO mice or vehicle-treated mice. Figure 9(a) shows a comparison of body weight, Figure 9(b) shows energy expenditure across the light-dark cycle versus body weight, Figures 9(c,d) show oxygen consumption, Figures 9(e,f) show carbon dioxide production, Figures 9(g,h) show PER, and Figures 9(i,j) show activity. DIO mice were treated with vehicle or Compound A (30 mg / kg) for 42 days, and measurements were taken at the indicated time points. In Figures 9(c,e,g,i), each data point represents a 3-day moving average, with the dark cycle (6 PM - 6 AM) indicated by a bordered box. Measurements in Figures 9(d,f,h,j) were averaged and displayed as the mean ± SEM for each day or night over time. Figure 9(b) shows a least-squares multiple linear regression model including body weight and treatment. Figure 9 (a, d, f, h, j) Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. n=10-11 mice / group. [Figure 9C]Figure 9 shows indirect calorimetry data from Compound A-treated DIO mice or vehicle-treated mice. Figure 9(a) shows a comparison of body weight, Figure 9(b) shows energy expenditure across the light-dark cycle versus body weight, Figures 9(c,d) show oxygen consumption, Figures 9(e,f) show carbon dioxide production, Figures 9(g,h) show PER, and Figures 9(i,j) show activity. DIO mice were treated with vehicle or Compound A (30 mg / kg) for 42 days, and measurements were taken at the indicated time points. In Figures 9(c,e,g,i), each data point represents a 3-day moving average, with the dark cycle (6 PM - 6 AM) indicated by a bordered box. Measurements in Figures 9(d,f,h,j) were averaged and displayed as the mean ± SEM for each day or night over time. Figure 9(b) shows a least-squares multiple linear regression model including body weight and treatment. Figure 9 (a, d, f, h, j) Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. n=10-11 mice / group. [Figure 9D] Figure 9 shows indirect calorimetry data from Compound A-treated DIO mice or vehicle-treated mice. Figure 9(a) shows a comparison of body weight, Figure 9(b) shows energy expenditure across the light-dark cycle versus body weight, Figures 9(c,d) show oxygen consumption, Figures 9(e,f) show carbon dioxide production, Figures 9(g,h) show PER, and Figures 9(i,j) show activity. DIO mice were treated with vehicle or Compound A (30 mg / kg) for 42 days, and measurements were taken at the indicated time points. In Figures 9(c,e,g,i), each data point represents a 3-day moving average, with the dark cycle (6 PM - 6 AM) indicated by a bordered box. Measurements in Figures 9(d,f,h,j) were averaged and displayed as the mean ± SEM for each day or night over time. Figure 9(b) shows a least-squares multiple linear regression model including body weight and treatment. Figure 9 (a, d, f, h, j) Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. n=10-11 mice / group. [Figure 9E]Figure 9 shows indirect calorimetry data from Compound A-treated DIO mice or vehicle-treated mice. Figure 9(a) shows a comparison of body weight, Figure 9(b) shows energy expenditure across the light-dark cycle versus body weight, Figures 9(c,d) show oxygen consumption, Figures 9(e,f) show carbon dioxide production, Figures 9(g,h) show PER, and Figures 9(i,j) show activity. DIO mice were treated with vehicle or Compound A (30 mg / kg) for 42 days, and measurements were taken at the indicated time points. In Figures 9(c,e,g,i), each data point represents a 3-day moving average, with the dark cycle (6 PM - 6 AM) indicated by a bordered box. Measurements in Figures 9(d,f,h,j) were averaged and displayed as the mean ± SEM for each day or night over time. Figure 9(b) shows a least-squares multiple linear regression model including body weight and treatment. Figure 9 (a, d, f, h, j) Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. n=10-11 mice / group. [Figure 9F] Figure 9 shows indirect calorimetry data from Compound A-treated DIO mice or vehicle-treated mice. Figure 9(a) shows a comparison of body weight, Figure 9(b) shows energy expenditure across the light-dark cycle versus body weight, Figures 9(c,d) show oxygen consumption, Figures 9(e,f) show carbon dioxide production, Figures 9(g,h) show PER, and Figures 9(i,j) show activity. DIO mice were treated with vehicle or Compound A (30 mg / kg) for 42 days, and measurements were taken at the indicated time points. In Figures 9(c,e,g,i), each data point represents a 3-day moving average, with the dark cycle (6 PM - 6 AM) indicated by a bordered box. Measurements in Figures 9(d,f,h,j) were averaged and displayed as the mean ± SEM for each day or night over time. Figure 9(b) shows a least-squares multiple linear regression model including body weight and treatment. Figure 9 (a, d, f, h, j) Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. n=10-11 mice / group. [Figure 9G]Figure 9 shows indirect calorimetry data from Compound A-treated DIO mice or vehicle-treated mice. Figure 9(a) shows a comparison of body weight, Figure 9(b) shows energy expenditure across the light-dark cycle versus body weight, Figures 9(c,d) show oxygen consumption, Figures 9(e,f) show carbon dioxide production, Figures 9(g,h) show PER, and Figures 9(i,j) show activity. DIO mice were treated with vehicle or Compound A (30 mg / kg) for 42 days, and measurements were taken at the indicated time points. In Figures 9(c,e,g,i), each data point represents a 3-day moving average, with the dark cycle (6 PM - 6 AM) indicated by a bordered box. Measurements in Figures 9(d,f,h,j) were averaged and displayed as the mean ± SEM for each day or night over time. Figure 9(b) shows a least-squares multiple linear regression model including body weight and treatment. Figure 9 (a, d, f, h, j) Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. n=10-11 mice / group. [Figure 9H] Figure 9 shows indirect calorimetry data from Compound A-treated DIO mice or vehicle-treated mice. Figure 9(a) shows a comparison of body weight, Figure 9(b) shows energy expenditure across the light-dark cycle versus body weight, Figures 9(c,d) show oxygen consumption, Figures 9(e,f) show carbon dioxide production, Figures 9(g,h) show PER, and Figures 9(i,j) show activity. DIO mice were treated with vehicle or Compound A (30 mg / kg) for 42 days, and measurements were taken at the indicated time points. In Figures 9(c,e,g,i), each data point represents a 3-day moving average, with the dark cycle (6 PM - 6 AM) indicated by a bordered box. Measurements in Figures 9(d,f,h,j) were averaged and displayed as the mean ± SEM for each day or night over time. Figure 9(b) shows a least-squares multiple linear regression model including body weight and treatment. Figure 9 (a, d, f, h, j) Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. n=10-11 mice / group. [Figure 9I]Figure 9 shows indirect calorimetry data from Compound A-treated DIO mice or vehicle-treated mice. Figure 9(a) shows a comparison of body weight, Figure 9(b) shows energy expenditure across the light-dark cycle versus body weight, Figures 9(c,d) show oxygen consumption, Figures 9(e,f) show carbon dioxide production, Figures 9(g,h) show PER, and Figures 9(i,j) show activity. DIO mice were treated with vehicle or Compound A (30 mg / kg) for 42 days, and measurements were taken at the indicated time points. In Figures 9(c,e,g,i), each data point represents a 3-day moving average, with the dark cycle (6 PM - 6 AM) indicated by a bordered box. Measurements in Figures 9(d,f,h,j) were averaged and displayed as the mean ± SEM for each day or night over time. Figure 9(b) shows a least-squares multiple linear regression model including body weight and treatment. Figure 9 (a, d, f, h, j) Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. n=10-11 mice / group. [Figure 9J] Figure 9 shows indirect calorimetry data from Compound A-treated DIO mice or vehicle-treated mice. Figure 9(a) shows a comparison of body weight, Figure 9(b) shows energy expenditure across the light-dark cycle versus body weight, Figures 9(c,d) show oxygen consumption, Figures 9(e,f) show carbon dioxide production, Figures 9(g,h) show PER, and Figures 9(i,j) show activity. DIO mice were treated with vehicle or Compound A (30 mg / kg) for 42 days, and measurements were taken at the indicated time points. In Figures 9(c,e,g,i), each data point represents a 3-day moving average, with the dark cycle (6 PM - 6 AM) indicated by a bordered box. Measurements in Figures 9(d,f,h,j) were averaged and displayed as the mean ± SEM for each day or night over time. Figure 9(b) shows a least-squares multiple linear regression model including body weight and treatment. Figure 9 (a, d, f, h, j) Two-way ANOVA with Sidak's test for multiple comparisons; *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. n=10-11 mice / group. [Figure 10A-1]Figure 10 shows RNA-seq analysis of age-matched Fads1 KO and WT DIO mice treated with vehicle or 30 mg / kg Compound A for 54 days. Figure 10(a) shows a radar chart of commonly altered genes in liver, EPI WAT, and ING WAT of Fads1 KO mice treated with Compound A compared to WT vehicle-treated mice. Figure 10(b) shows the average cellular composition in liver, EPI, and ING WAT of Fads1 KO, WT + Compound A, and WT mice by SCDC analysis using scRNA-seq of the corresponding mouse organs as a reference. Cell types are abbreviated as follows: Adipo, Bcell, Endo, Hep, Kupff, Myel, NK, and Tcell. Ingenuity Pathway Analysis ("IPA") analysis identified common and unique pathways affected by Fads1 KO or inhibition in Figure 10(c) EPI WAT and Figure 10(d) liver; n=6-9 / group. [Figure 10A-2] Figure 10 shows RNA-seq analysis of age-matched Fads1 KO and WT DIO mice treated with vehicle or 30 mg / kg Compound A for 54 days. Figure 10(a) shows a radar chart of commonly altered genes in liver, EPI WAT, and ING WAT of Fads1 KO mice treated with Compound A compared to WT vehicle-treated mice. Figure 10(b) shows the average cellular composition in liver, EPI, and ING WAT of Fads1 KO, WT + Compound A, and WT mice by SCDC analysis using scRNA-seq of the corresponding mouse organs as a reference. Cell types are abbreviated as follows: Adipo, Bcell, Endo, Hep, Kupff, Myel, NK, and Tcell. Ingenuity Pathway Analysis ("IPA") analysis identified common and unique pathways affected by Fads1 KO or inhibition in Figure 10(c) EPI WAT and Figure 10(d) liver; n=6-9 / group. [Figure 10B]Figure 10 shows RNA-seq analysis of age-matched Fads1 KO and WT DIO mice treated with vehicle or 30 mg / kg Compound A for 54 days. Figure 10(a) shows a radar chart of commonly altered genes in liver, EPI WAT, and ING WAT of Fads1 KO mice treated with Compound A compared to WT vehicle-treated mice. Figure 10(b) shows the average cellular composition in liver, EPI, and ING WAT of Fads1 KO, WT + Compound A, and WT mice by SCDC analysis using scRNA-seq of the corresponding mouse organs as a reference. Cell types are abbreviated as follows: Adipo, Bcell, Endo, Hep, Kupff, Myel, NK, and Tcell. Ingenuity Pathway Analysis ("IPA") analysis identified common and unique pathways affected by Fads1 KO or inhibition in Figure 10(c) EPI WAT and Figure 10(d) liver; n=6-9 / group. [Figure 10C] Figure 10 shows RNA-seq analysis of age-matched Fads1 KO and WT DIO mice treated with vehicle or 30 mg / kg Compound A for 54 days. Figure 10(a) shows a radar chart of commonly altered genes in liver, EPI WAT, and ING WAT of Fads1 KO mice treated with Compound A compared to WT vehicle-treated mice. Figure 10(b) shows the average cellular composition in liver, EPI, and ING WAT of Fads1 KO, WT + Compound A, and WT mice by SCDC analysis using scRNA-seq of the corresponding mouse organs as a reference. Cell types are abbreviated as follows: Adipo, Bcell, Endo, Hep, Kupff, Myel, NK, and Tcell. Ingenuity Pathway Analysis ("IPA") analysis identified common and unique pathways affected by Fads1 KO or inhibition in Figure 10(c) EPI WAT and Figure 10(d) liver; n=6-9 / group. [Figure 10D]Figure 10 shows RNA-seq analysis of age-matched Fads1 KO and WT DIO mice treated with vehicle or 30 mg / kg Compound A for 54 days. Figure 10(a) shows a radar chart of commonly altered genes in liver, EPI WAT, and ING WAT of Fads1 KO mice treated with Compound A compared to WT vehicle-treated mice. Figure 10(b) shows the average cellular composition in liver, EPI, and ING WAT of Fads1 KO, WT + Compound A, and WT mice by SCDC analysis using scRNA-seq of the corresponding mouse organs as a reference. Cell types are abbreviated as follows: Adipo, Bcell, Endo, Hep, Kupff, Myel, NK, and Tcell. Ingenuity Pathway Analysis ("IPA") analysis identified common and unique pathways affected by Fads1 KO or inhibition in Figure 10(c) EPI WAT and Figure 10(d) liver; n=6-9 / group. [Figure 11A] Figure 11(a) shows that no differences in FADS2 activity were observed in obese humans and mice. Although higher FADS1 levels were observed in HFD-induced obese mice, the observed FADS2 activity was not elevated. Figure 11(a) shows that no differences were observed in plasma GLA / LA ratios, a surrogate marker of FADS2 n-6 activity, in overweight or obese men compared with lean subjects (n = 8-41 / group). Figure 11(b) also shows that no differences were observed in plasma GLA / LA ratios in DIO mice fed a HFD for 12 weeks (n = 7-8 / group). Figure 11(c) shows that SC-26196 is a FADS2-specific inhibitor that does not affect FADS1 activity, as demonstrated by in vitro human FADS1, FADS2, and mouse FADS1 activity assays. Figure 11(a,b) shows data presented as minimum to maximum; t-test. Figure 11(c-d) n=4-8 / group; data are shown as mean ± SEM. [Figure 11B]Figure 11(a) shows that no differences in FADS2 activity were observed in obese humans and mice. Although higher FADS1 levels were observed in HFD-induced obese mice, the observed FADS2 activity was not elevated. Figure 11(a) shows that no differences were observed in plasma GLA / LA ratios, a surrogate marker of FADS2 n-6 activity, in overweight or obese men compared with lean subjects (n = 8-41 / group). Figure 11(b) also shows that no differences were observed in plasma GLA / LA ratios in DIO mice fed a HFD for 12 weeks (n = 7-8 / group). Figure 11(c) shows that SC-26196 is a FADS2-specific inhibitor that does not affect FADS1 activity, as demonstrated by in vitro human FADS1, FADS2, and mouse FADS1 activity assays. Figure 11(a,b) shows data presented as minimum to maximum; t-test. Figure 11(c-d) n=4-8 / group; data are shown as mean ± SEM. [Figure 11C] Figure 11(a) shows that no differences in FADS2 activity were observed in obese humans and mice. Although higher FADS1 levels were observed in HFD-induced obese mice, the observed FADS2 activity was not elevated. Figure 11(a) shows that no differences were observed in plasma GLA / LA ratios, a surrogate marker of FADS2 n-6 activity, in overweight or obese men compared with lean subjects (n = 8-41 / group). Figure 11(b) also shows that no differences were observed in plasma GLA / LA ratios in DIO mice fed a HFD for 12 weeks (n = 7-8 / group). Figure 11(c) shows that SC-26196 is a FADS2-specific inhibitor that does not affect FADS1 activity, as demonstrated by in vitro human FADS1, FADS2, and mouse FADS1 activity assays. Figure 11(a,b) shows data presented as minimum to maximum; t-test. Figure 11(c-d) n=4-8 / group; data are shown as mean ± SEM. [Figure 12]Inhibition of FADS2 activity by SC-26196 affects not only the plasma GLA / LA ratio but also the plasma AA / DGLA ratio in DIO mice. Figure 12 One-way ANOVA with Dunnett's test for multiple comparisons, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. [Figure 13A]Figure 13 shows that Compound A-treated DIO mice exhibited altered metabolic gene expression, elevated adiponectin levels, and decreased inflammatory markers. Comparisons of metabolic gene expression are shown in Figure 13(a) liver, Figure 13(b) EPI WAT, and Figure 13(c) ING WAT of vehicle-treated WT DIO mice (WT), Compound A (30 mg / kg)-treated WT DIO mice (WT+A), and vehicle-treated Fads1 KO DIO mice (KO). n = 6-9 per group. IPA analysis of the top predicted upstream regulators is shown in Figure 13(d) liver and Figure 13(e) EPI WAT of Compound A-treated WT DIO mice (WT+A) and Fads1 KO DIO mice (KO) compared to vehicle-treated WT DIO mice (WT); predicted upstream regulators with overlapping P values ​​< 0.01 and activation z-scores are shaded. Figure 13(f) shows a comparison of adiponectin, leptin, PAI-1, and MCP-1 levels in plasma, EPI WAT, and ING WT in WT, Compound A-treated WT, and Fads1 KO DIO mice (n=7-9 / group). Figure 13(a-c,f) Data are presented from minimum to maximum. One-way ANOVA with Dunnett's test for multiple comparisons compared to vehicle-treated WT. *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. Figure 13(g) shows a volcano plot representing DEGs in the Fads1 KO compared to WT and the 30 mg / kg Compound A-treated (WT+A) group compared to vehicle-treated WT (WT) in the liver, EPI, and ING WAT of diet-induced obese mice. The number of genes with Benjamini-Hochberg adjusted P values ​​<0.01 and fold changes ≥2 or ≤0.5 are color-coded and shown in Venn diagram format representing the number of uniquely or similarly altered genes in the liver and adipose tissue of the Fads1 KO compared to WT or WT+A compared to WT cohorts. Figure 13(h) shows a comparison of hepatic PAI-1 and MCP-1 levels in WT, Compound A-treated WT, and Fads1 KO DIO mice. [Figure 13B]Figure 13 shows that Compound A-treated DIO mice exhibited altered metabolic gene expression, elevated adiponectin levels, and decreased inflammatory markers. Comparisons of metabolic gene expression are shown in Figure 13(a) liver, Figure 13(b) EPI WAT, and Figure 13(c) ING WAT of vehicle-treated WT DIO mice (WT), Compound A (30 mg / kg)-treated WT DIO mice (WT+A), and vehicle-treated Fads1 KO DIO mice (KO). n = 6-9 per group. IPA analysis of the top predicted upstream regulators is shown in Figure 13(d) liver and Figure 13(e) EPI WAT of Compound A-treated WT DIO mice (WT+A) and Fads1 KO DIO mice (KO) compared to vehicle-treated WT DIO mice (WT); predicted upstream regulators with overlapping P values ​​< 0.01 and activation z-scores are shaded. Figure 13(f) shows a comparison of adiponectin, leptin, PAI-1, and MCP-1 levels in plasma, EPI WAT, and ING WT in WT, Compound A-treated WT, and Fads1 KO DIO mice (n=7-9 / group). Figure 13(a-c,f) Data are presented from minimum to maximum. One-way ANOVA with Dunnett's test for multiple comparisons compared to vehicle-treated WT. *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. Figure 13(g) shows a volcano plot representing DEGs in the Fads1 KO compared to WT and the 30 mg / kg Compound A-treated (WT+A) group compared to vehicle-treated WT (WT) in the liver, EPI, and ING WAT of diet-induced obese mice. The number of genes with Benjamini-Hochberg adjusted P values ​​<0.01 and fold changes ≥2 or ≤0.5 are color-coded and shown in Venn diagram format representing the number of uniquely or similarly altered genes in the liver and adipose tissue of the Fads1 KO compared to WT or WT+A compared to WT cohorts. Figure 13(h) shows a comparison of hepatic PAI-1 and MCP-1 levels in WT, Compound A-treated WT, and Fads1 KO DIO mice. [Figure 13C]Figure 13 shows that Compound A-treated DIO mice exhibited altered metabolic gene expression, elevated adiponectin levels, and decreased inflammatory markers. Comparisons of metabolic gene expression are shown in Figure 13(a) liver, Figure 13(b) EPI WAT, and Figure 13(c) ING WAT of vehicle-treated WT DIO mice (WT), Compound A (30 mg / kg)-treated WT DIO mice (WT+A), and vehicle-treated Fads1 KO DIO mice (KO). n = 6-9 per group. IPA analysis of the top predicted upstream regulators is shown in Figure 13(d) liver and Figure 13(e) EPI WAT of Compound A-treated WT DIO mice (WT+A) and Fads1 KO DIO mice (KO) compared to vehicle-treated WT DIO mice (WT); predicted upstream regulators with overlapping P values ​​< 0.01 and activation z-scores are shaded. Figure 13(f) shows a comparison of adiponectin, leptin, PAI-1, and MCP-1 levels in plasma, EPI WAT, and ING WT in WT, Compound A-treated WT, and Fads1 KO DIO mice (n=7-9 / group). Figure 13(a-c,f) Data are presented from minimum to maximum. One-way ANOVA with Dunnett's test for multiple comparisons compared to vehicle-treated WT. *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. Figure 13(g) shows a volcano plot representing DEGs in the Fads1 KO compared to WT and the 30 mg / kg Compound A-treated (WT+A) group compared to vehicle-treated WT (WT) in the liver, EPI, and ING WAT of diet-induced obese mice. The number of genes with Benjamini-Hochberg adjusted P values ​​<0.01 and fold changes ≥2 or ≤0.5 are color-coded and shown in Venn diagram format representing the number of uniquely or similarly altered genes in the liver and adipose tissue of the Fads1 KO compared to WT or WT+A compared to WT cohorts. Figure 13(h) shows a comparison of hepatic PAI-1 and MCP-1 levels in WT, Compound A-treated WT, and Fads1 KO DIO mice. [Figure 13D]Figure 13 shows that Compound A-treated DIO mice exhibited altered metabolic gene expression, elevated adiponectin levels, and decreased inflammatory markers. Comparisons of metabolic gene expression are shown in Figure 13(a) liver, Figure 13(b) EPI WAT, and Figure 13(c) ING WAT of vehicle-treated WT DIO mice (WT), Compound A (30 mg / kg)-treated WT DIO mice (WT+A), and vehicle-treated Fads1 KO DIO mice (KO). n = 6-9 per group. IPA analysis of the top predicted upstream regulators is shown in Figure 13(d) liver and Figure 13(e) EPI WAT of Compound A-treated WT DIO mice (WT+A) and Fads1 KO DIO mice (KO) compared to vehicle-treated WT DIO mice (WT); predicted upstream regulators with overlapping P values ​​< 0.01 and activation z-scores are shaded. Figure 13(f) shows a comparison of adiponectin, leptin, PAI-1, and MCP-1 levels in plasma, EPI WAT, and ING WT in WT, Compound A-treated WT, and Fads1 KO DIO mice (n=7-9 / group). Figure 13(a-c,f) Data are presented from minimum to maximum. One-way ANOVA with Dunnett's test for multiple comparisons compared to vehicle-treated WT. *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. Figure 13(g) shows a volcano plot representing DEGs in the Fads1 KO compared to WT and the 30 mg / kg Compound A-treated (WT+A) group compared to vehicle-treated WT (WT) in the liver, EPI, and ING WAT of diet-induced obese mice. The number of genes with Benjamini-Hochberg adjusted P values ​​<0.01 and fold changes ≥2 or ≤0.5 are color-coded and shown in Venn diagram format representing the number of uniquely or similarly altered genes in the liver and adipose tissue of the Fads1 KO compared to WT or WT+A compared to WT cohorts. Figure 13(h) shows a comparison of hepatic PAI-1 and MCP-1 levels in WT, Compound A-treated WT, and Fads1 KO DIO mice. [Figure 13E]Figure 13 shows that Compound A-treated DIO mice exhibited altered metabolic gene expression, elevated adiponectin levels, and decreased inflammatory markers. Comparisons of metabolic gene expression are shown in Figure 13(a) liver, Figure 13(b) EPI WAT, and Figure 13(c) ING WAT of vehicle-treated WT DIO mice (WT), Compound A (30 mg / kg)-treated WT DIO mice (WT+A), and vehicle-treated Fads1 KO DIO mice (KO). n = 6-9 per group. IPA analysis of the top predicted upstream regulators is shown in Figure 13(d) liver and Figure 13(e) EPI WAT of Compound A-treated WT DIO mice (WT+A) and Fads1 KO DIO mice (KO) compared to vehicle-treated WT DIO mice (WT); predicted upstream regulators with overlapping P values ​​< 0.01 and activation z-scores are shaded. Figure 13(f) shows a comparison of adiponectin, leptin, PAI-1, and MCP-1 levels in plasma, EPI WAT, and ING WT in WT, Compound A-treated WT, and Fads1 KO DIO mice (n=7-9 / group). Figure 13(a-c,f) Data are presented from minimum to maximum. One-way ANOVA with Dunnett's test for multiple comparisons compared to vehicle-treated WT. *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. Figure 13(g) shows a volcano plot representing DEGs in the Fads1 KO compared to WT and the 30 mg / kg Compound A-treated (WT+A) group compared to vehicle-treated WT (WT) in the liver, EPI, and ING WAT of diet-induced obese mice. The number of genes with Benjamini-Hochberg adjusted P values ​​<0.01 and fold changes ≥2 or ≤0.5 are color-coded and shown in Venn diagram format representing the number of uniquely or similarly altered genes in the liver and adipose tissue of the Fads1 KO compared to WT or WT+A compared to WT cohorts. Figure 13(h) shows a comparison of hepatic PAI-1 and MCP-1 levels in WT, Compound A-treated WT, and Fads1 KO DIO mice. [Figure 13F]Figure 13 shows that Compound A-treated DIO mice exhibited altered metabolic gene expression, elevated adiponectin levels, and decreased inflammatory markers. Comparisons of metabolic gene expression are shown in Figure 13(a) liver, Figure 13(b) EPI WAT, and Figure 13(c) ING WAT of vehicle-treated WT DIO mice (WT), Compound A (30 mg / kg)-treated WT DIO mice (WT+A), and vehicle-treated Fads1 KO DIO mice (KO). n = 6-9 per group. IPA analysis of the top predicted upstream regulators is shown in Figure 13(d) liver and Figure 13(e) EPI WAT of Compound A-treated WT DIO mice (WT+A) and Fads1 KO DIO mice (KO) compared to vehicle-treated WT DIO mice (WT); predicted upstream regulators with overlapping P values ​​< 0.01 and activation z-scores are shaded. Figure 13(f) shows a comparison of adiponectin, leptin, PAI-1, and MCP-1 levels in plasma, EPI WAT, and ING WT in WT, Compound A-treated WT, and Fads1 KO DIO mice (n=7-9 / group). Figure 13(a-c,f) Data are presented from minimum to maximum. One-way ANOVA with Dunnett's test for multiple comparisons compared to vehicle-treated WT. *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. Figure 13(g) shows a volcano plot representing DEGs in the Fads1 KO compared to WT and the 30 mg / kg Compound A-treated (WT+A) group compared to vehicle-treated WT (WT) in the liver, EPI, and ING WAT of diet-induced obese mice. The number of genes with Benjamini-Hochberg adjusted P values ​​<0.01 and fold changes ≥2 or ≤0.5 are color-coded and shown in Venn diagram format representing the number of uniquely or similarly altered genes in the liver and adipose tissue of the Fads1 KO compared to WT or WT+A compared to WT cohorts. Figure 13(h) shows a comparison of hepatic PAI-1 and MCP-1 levels in WT, Compound A-treated WT, and Fads1 KO DIO mice. [Figure 13G]Figure 13 shows that Compound A-treated DIO mice exhibited altered metabolic gene expression, elevated adiponectin levels, and decreased inflammatory markers. Comparisons of metabolic gene expression are shown in Figure 13(a) liver, Figure 13(b) EPI WAT, and Figure 13(c) ING WAT of vehicle-treated WT DIO mice (WT), Compound A (30 mg / kg)-treated WT DIO mice (WT+A), and vehicle-treated Fads1 KO DIO mice (KO). n = 6-9 per group. IPA analysis of the top predicted upstream regulators is shown in Figure 13(d) liver and Figure 13(e) EPI WAT of Compound A-treated WT DIO mice (WT+A) and Fads1 KO DIO mice (KO) compared to vehicle-treated WT DIO mice (WT); predicted upstream regulators with overlapping P values ​​< 0.01 and activation z-scores are shaded. Figure 13(f) shows a comparison of adiponectin, leptin, PAI-1, and MCP-1 levels in plasma, EPI WAT, and ING WT in WT, Compound A-treated WT, and Fads1 KO DIO mice (n=7-9 / group). Figure 13(a-c,f) Data are presented from minimum to maximum. One-way ANOVA with Dunnett's test for multiple comparisons compared to vehicle-treated WT. *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. Figure 13(g) shows a volcano plot representing DEGs in the Fads1 KO compared to WT and the 30 mg / kg Compound A-treated (WT+A) group compared to vehicle-treated WT (WT) in the liver, EPI, and ING WAT of diet-induced obese mice. The number of genes with Benjamini-Hochberg adjusted P values ​​<0.01 and fold changes ≥2 or ≤0.5 are color-coded and shown in Venn diagram format representing the number of uniquely or similarly altered genes in the liver and adipose tissue of the Fads1 KO compared to WT or WT+A compared to WT cohorts. Figure 13(h) shows a comparison of hepatic PAI-1 and MCP-1 levels in WT, Compound A-treated WT, and Fads1 KO DIO mice. [Figure 13H]Figure 13 shows that Compound A-treated DIO mice exhibited altered metabolic gene expression, elevated adiponectin levels, and decreased inflammatory markers. Comparisons of metabolic gene expression are shown in Figure 13(a) liver, Figure 13(b) EPI WAT, and Figure 13(c) ING WAT of vehicle-treated WT DIO mice (WT), Compound A (30 mg / kg)-treated WT DIO mice (WT+A), and vehicle-treated Fads1 KO DIO mice (KO). n = 6-9 per group. IPA analysis of the top predicted upstream regulators is shown in Figure 13(d) liver and Figure 13(e) EPI WAT of Compound A-treated WT DIO mice (WT+A) and Fads1 KO DIO mice (KO) compared to vehicle-treated WT DIO mice (WT); predicted upstream regulators with overlapping P values ​​< 0.01 and activation z-scores are shaded. Figure 13(f) shows a comparison of adiponectin, leptin, PAI-1, and MCP-1 levels in plasma, EPI WAT, and ING WT in WT, Compound A-treated WT, and Fads1 KO DIO mice (n=7-9 / group). Figure 13(a-c,f) Data are presented from minimum to maximum. One-way ANOVA with Dunnett's test for multiple comparisons compared to vehicle-treated WT. *P<0.05, **P<0.01, ***P<0.001, ****P<0.00001. Figure 13(g) shows a volcano plot representing DEGs in the Fads1 KO compared to WT and the 30 mg / kg Compound A-treated (WT+A) group compared to vehicle-treated WT (WT) in the liver, EPI, and ING WAT of diet-induced obese mice. The number of genes with Benjamini-Hochberg adjusted P values ​​<0.01 and fold changes ≥2 or ≤0.5 are color-coded and shown in Venn diagram format representing the number of uniquely or similarly altered genes in the liver and adipose tissue of the Fads1 KO compared to WT or WT+A compared to WT cohorts. Figure 13(h) shows a comparison of hepatic PAI-1 and MCP-1 levels in WT, Compound A-treated WT, and Fads1 KO DIO mice. [Figure 14A]Figure 14 shows data demonstrating that FADS1 inhibition reduced endocannabinoid levels in liver and adipose tissue. Comparison of endocannabinoid, 2-arachidonyl-glycerol ("2-AG"), and anandamide ("AEA") levels in liver (Figure 14(a)) and ING WAT (Figure 14(b)) of vehicle-treated WT DIO mice (WT), Compound A (30 mg / kg)-treated WT DIO mice (WT+A), and vehicle-treated Fads1 KO DIO mice (KO) (data shown from minimum to maximum; n=8-6 / group). One-way ANOVA with Dunnett's test for multiple comparisons. *P<0.05, **P<0.01, ***P<0.001. [Figure 14B] Figure 14 shows data demonstrating that FADS1 inhibition reduced endocannabinoid levels in liver and adipose tissue. Comparison of endocannabinoid, 2-arachidonyl-glycerol ("2-AG"), and anandamide ("AEA") levels in liver (Figure 14(a)) and ING WAT (Figure 14(b)) of vehicle-treated WT DIO mice (WT), Compound A (30 mg / kg)-treated WT DIO mice (WT+A), and vehicle-treated Fads1 KO DIO mice (KO) (data shown from minimum to maximum; n=8-6 / group). One-way ANOVA with Dunnett's test for multiple comparisons. *P<0.05, **P<0.01, ***P<0.001. [Figure 15A]Figure 15(a) shows that FADS1 inhibition increased the expression of PPARα target genes, without significantly affecting hepatic triglyceride content and steatosis-related genes. Figure 15(b) shows a comparison of hepatic triglyceride levels in WT and Fads1 KO mice fed a chow diet (Figure 15(a)) or HFD (Figure 15(b)) for 12 weeks (n=4-8 / group). Figure 15(c) shows a comparison of hepatic triglyceride levels in vehicle-treated Fads1 KO and WT DIO mice after 8 weeks of vehicle or 10 or 30 mg / kg Compound A treatment (n=8 / group). Data are presented as minimum to maximum (n=8 / group). Figure 15(d) shows liver histological evaluation of WT DIO mice and age-matched vehicle-treated Fads1 KO DIO mice treated with vehicle or Compound A for 24 days. Compound A (10 mg / kg)-treated WT DIO mice and Fads1 KO DIO mice had similar or smaller vacuoles (H&E staining) and reduced lipid content (Oil-red-O staining) compared with WT vehicle DIO mice, suggesting that compound A treatment or loss of Fads1 expression did not exacerbate fatty liver disease (n=3 / group). Representative images are shown. Hepatic gene expression of fatty liver-related genes is shown in Figure 15(e), and PPARα target genes in Fads1 KO mice compared with WT littermates after 8 weeks of HFD are shown in Figure 15(f). Genes with a BH-adjusted P value of less than 0.01 and a fold change of 2 or greater or less than 0.5 are color-coded. n=4-6 / group. Figure 15(a,b) t-test; Figure 15(c) One-way ANOVA with Dunnett's test for multiple comparisons. [Figure 15B]Figure 15(a) shows that FADS1 inhibition increased the expression of PPARα target genes, without significantly affecting hepatic triglyceride content and steatosis-related genes. Figure 15(b) shows a comparison of hepatic triglyceride levels in WT and Fads1 KO mice fed a chow diet (Figure 15(a)) or HFD (Figure 15(b)) for 12 weeks (n=4-8 / group). Figure 15(c) shows a comparison of hepatic triglyceride levels in vehicle-treated Fads1 KO and WT DIO mice after 8 weeks of vehicle or 10 or 30 mg / kg Compound A treatment (n=8 / group). Data are presented as minimum to maximum (n=8 / group). Figure 15(d) shows liver histological evaluation of WT DIO mice and age-matched vehicle-treated Fads1 KO DIO mice treated with vehicle or Compound A for 24 days. Compound A (10 mg / kg)-treated WT DIO mice and Fads1 KO DIO mice had similar or smaller vacuoles (H&E staining) and reduced lipid content (Oil-red-O staining) compared with WT vehicle DIO mice, suggesting that compound A treatment or loss of Fads1 expression did not exacerbate fatty liver disease (n=3 / group). Representative images are shown. Hepatic gene expression of fatty liver-related genes is shown in Figure 15(e), and PPARα target genes in Fads1 KO mice compared with WT littermates after 8 weeks of HFD are shown in Figure 15(f). Genes with a BH-adjusted P value of less than 0.01 and a fold change of 2 or greater or less than 0.5 are color-coded. n=4-6 / group. Figure 15(a,b) t-test; Figure 15(c) One-way ANOVA with Dunnett's test for multiple comparisons. [Figure 15C]Figure 15(a) shows that FADS1 inhibition increased the expression of PPARα target genes, without significantly affecting hepatic triglyceride content and steatosis-related genes. Figure 15(b) shows a comparison of hepatic triglyceride levels in WT and Fads1 KO mice fed a chow diet (Figure 15(a)) or HFD (Figure 15(b)) for 12 weeks (n=4-8 / group). Figure 15(c) shows a comparison of hepatic triglyceride levels in vehicle-treated Fads1 KO and WT DIO mice after 8 weeks of vehicle or 10 or 30 mg / kg Compound A treatment (n=8 / group). Data are presented as minimum to maximum (n=8 / group). Figure 15(d) shows liver histological evaluation of WT DIO mice and age-matched vehicle-treated Fads1 KO DIO mice treated with vehicle or Compound A for 24 days. Compound A (10 mg / kg)-treated WT DIO mice and Fads1 KO DIO mice had similar or smaller vacuoles (H&E staining) and reduced lipid content (Oil-red-O staining) compared with WT vehicle DIO mice, suggesting that compound A treatment or loss of Fads1 expression did not exacerbate fatty liver disease (n=3 / group). Representative images are shown. Hepatic gene expression of fatty liver-related genes is shown in Figure 15(e), and PPARα target genes in Fads1 KO mice compared with WT littermates after 8 weeks of HFD are shown in Figure 15(f). Genes with a BH-adjusted P value of less than 0.01 and a fold change of 2 or greater or less than 0.5 are color-coded. n=4-6 / group. Figure 15(a,b) t-test; Figure 15(c) One-way ANOVA with Dunnett's test for multiple comparisons. [Figure 15D]Figure 15(a) shows that FADS1 inhibition increased the expression of PPARα target genes, without significantly affecting hepatic triglyceride content and steatosis-related genes. Figure 15(b) shows a comparison of hepatic triglyceride levels in WT and Fads1 KO mice fed a chow diet (Figure 15(a)) or HFD (Figure 15(b)) for 12 weeks (n=4-8 / group). Figure 15(c) shows a comparison of hepatic triglyceride levels in vehicle-treated Fads1 KO and WT DIO mice after 8 weeks of vehicle or 10 or 30 mg / kg Compound A treatment (n=8 / group). Data are presented as minimum to maximum (n=8 / group). Figure 15(d) shows liver histological evaluation of WT DIO mice and age-matched vehicle-treated Fads1 KO DIO mice treated with vehicle or Compound A for 24 days. Compound A (10 mg / kg)-treated WT DIO mice and Fads1 KO DIO mice had similar or smaller vacuoles (H&E staining) and reduced lipid content (Oil-red-O staining) compared with WT vehicle DIO mice, suggesting that compound A treatment or loss of Fads1 expression did not exacerbate fatty liver disease (n=3 / group). Representative images are shown. Hepatic gene expression of fatty liver-related genes is shown in Figure 15(e), and PPARα target genes in Fads1 KO mice compared with WT littermates after 8 weeks of HFD are shown in Figure 15(f). Genes with a BH-adjusted P value of less than 0.01 and a fold change of 2 or greater or less than 0.5 are color-coded. n=4-6 / group. Figure 15(a,b) t-test; Figure 15(c) One-way ANOVA with Dunnett's test for multiple comparisons. [Figure 15E]Figure 15(a) shows that FADS1 inhibition increased the expression of PPARα target genes, without significantly affecting hepatic triglyceride content and steatosis-related genes. Figure 15(b) shows a comparison of hepatic triglyceride levels in WT and Fads1 KO mice fed a chow diet (Figure 15(a)) or HFD (Figure 15(b)) for 12 weeks (n=4-8 / group). Figure 15(c) shows a comparison of hepatic triglyceride levels in vehicle-treated Fads1 KO and WT DIO mice after 8 weeks of vehicle or 10 or 30 mg / kg Compound A treatment (n=8 / group). Data are presented as minimum to maximum (n=8 / group). Figure 15(d) shows liver histological evaluation of WT DIO mice and age-matched vehicle-treated Fads1 KO DIO mice treated with vehicle or Compound A for 24 days. Compound A (10 mg / kg)-treated WT DIO mice and Fads1 KO DIO mice had similar or smaller vacuoles (H&E staining) and reduced lipid content (Oil-red-O staining) compared with WT vehicle DIO mice, suggesting that compound A treatment or loss of Fads1 expression did not exacerbate fatty liver disease (n=3 / group). Representative images are shown. Hepatic gene expression of fatty liver-related genes is shown in Figure 15(e), and PPARα target genes in Fads1 KO mice compared with WT littermates after 8 weeks of HFD are shown in Figure 15(f). Genes with a BH-adjusted P value of less than 0.01 and a fold change of 2 or greater or less than 0.5 are color-coded. n=4-6 / group. Figure 15(a,b) t-test; Figure 15(c) One-way ANOVA with Dunnett's test for multiple comparisons. [Figure 15F]Figure 15(a) shows that FADS1 inhibition increased the expression of PPARα target genes, without significantly affecting hepatic triglyceride content and steatosis-related genes. Figure 15(b) shows a comparison of hepatic triglyceride levels in WT and Fads1 KO mice fed a chow diet (Figure 15(a)) or HFD (Figure 15(b)) for 12 weeks (n=4-8 / group). Figure 15(c) shows a comparison of hepatic triglyceride levels in vehicle-treated Fads1 KO and WT DIO mice after 8 weeks of vehicle or 10 or 30 mg / kg Compound A treatment (n=8 / group). Data are presented as minimum to maximum (n=8 / group). Figure 15(d) shows liver histological evaluation of WT DIO mice and age-matched vehicle-treated Fads1 KO DIO mice treated with vehicle or Compound A for 24 days. Compound A (10 mg / kg)-treated WT DIO mice and Fads1 KO DIO mice had similar or smaller vacuoles (H&E staining) and reduced lipid content (Oil-red-O staining) compared with WT vehicle DIO mice, suggesting that compound A treatment or loss of Fads1 expression did not exacerbate fatty liver disease (n=3 / group). Representative images are shown. Hepatic gene expression of fatty liver-related genes is shown in Figure 15(e), and PPARα target genes in Fads1 KO mice compared with WT littermates after 8 weeks of HFD are shown in Figure 15(f). Genes with a BH-adjusted P value of less than 0.01 and a fold change of 2 or greater or less than 0.5 are color-coded. n=4-6 / group. Figure 15(a,b) t-test; Figure 15(c) One-way ANOVA with Dunnett's test for multiple comparisons. [Figure 16A]Compound A-treated DIO mice exhibit altered fatty acid composition in plasma lipid subfractions compared with vehicle-treated DIO mice. Figure 16(a) shows the total plasma fatty acid concentration and the fatty acid concentration of each of the four major lipid subfractions (phospholipids, free fatty acids, cholesterol esters, and triglycerides) of WT DIO mice treated with vehicle (AT) or 30 mg / kg Compound A (WT+A) for 54 days. Figure 16(b) shows the total plasma fatty acid concentration and the fatty acid concentration of each of the four plasma lipid subfractions of vehicle-treated (WT) and 30 mg / kg Compound A-treated WT DIO mice (WT+A). (a-b) n=3 samples per group (each sample pooled from two mice). (a) Data are presented as minimum to maximum. t-test *P<0.05, **P<0.01, ***P<0.001. [Figure 16B] Compound A-treated DIO mice exhibit altered fatty acid composition in plasma lipid subfractions compared with vehicle-treated DIO mice. Figure 16(a) shows the total plasma fatty acid concentration and the fatty acid concentration of each of the four major lipid subfractions (phospholipids, free fatty acids, cholesterol esters, and triglycerides) of WT DIO mice treated with vehicle (AT) or 30 mg / kg Compound A (WT+A) for 54 days. Figure 16(b) shows the total plasma fatty acid concentration and the fatty acid concentration of each of the four plasma lipid subfractions of vehicle-treated (WT) and 30 mg / kg Compound A-treated WT DIO mice (WT+A). (a-b) n=3 samples per group (each sample pooled from two mice). (a) Data are presented as minimum to maximum. t-test *P<0.05, **P<0.01, ***P<0.001. [Figure 17A] Figure 17a shows data on the percent conversion of 13C5-DGLA to 13C5-AA for each of compounds B through E, as measured using plasma-derived 13C5-DGLA and 13C5-AA. Figure 17b shows the percent inhibition for each of compounds B through E, as measured using plasma-derived 13C5-DGLA and 13C5-AA. A dose-response curve was generated for compound F and is shown in Figure 17c. [Figure 17B] Figure 17a shows data on the percent conversion of 13C5-DGLA to 13C5-AA for each of compounds B through E, as measured using plasma-derived 13C5-DGLA and 13C5-AA. Figure 17b shows the percent inhibition for each of compounds B through E, as measured using plasma-derived 13C5-DGLA and 13C5-AA. A dose-response curve was generated for compound F and is shown in Figure 17c. [Figure 17C] Figure 17a shows data on the percent conversion of 13C5-DGLA to 13C5-AA for each of compounds B through E, as measured using plasma-derived 13C5-DGLA and 13C5-AA. Figure 17b shows the percent inhibition for each of compounds B through E, as measured using plasma-derived 13C5-DGLA and 13C5-AA. A dose-response curve was generated for compound F and is shown in Figure 17c. DETAILED DESCRIPTION OF THE INVENTION

[0024] Chronic and persistent inflammation contributes to the disease pathology of obesity and its co-morbidities. FADS1 is a key enzyme in the synthesis of AA from DGLA. AA is a precursor of many pro-inflammatory eicosanoids. Meanwhile, DGLA is a precursor of several anti-inflammatory eicosanoids. Some embodiments disclosed herein relate to the treatment of FADS1-mediated diseases, conditions, and / or disorders. In some embodiments, the method includes selecting a subject suffering from a FADS1-mediated disease or disorder. In some embodiments, the subject is selected for treatment based on the level of FADS1 activity in the subject. In some embodiments, the subject has elevated FADS1 activity. In some embodiments, if the subject has elevated FADS1 activity, the method includes administering a FADS1 inhibitor to the subject. In some embodiments, the subject's FADS1 activity is measured before, during, or after treatment. In some embodiments, the subject's FADS1 activity is indicated by the subject's AA / DGLA ratio (or other biological indicators disclosed elsewhere herein). In some embodiments, the FADS1 activity level in the subject is compared to the FADS1 activity level in a subject (or population of subjects) that does not have a FADS1-mediated disease or disorder. In some embodiments, FADS1 activity, as indicated by the AA / DGLA ratio (or other biological indicators disclosed elsewhere herein), is elevated in obese subjects (e.g., humans). Inhibition of FADS1 activity can alleviate obesity and its metabolic comorbidities. U.S. Patent Application Publication Nos. 2021 / 0171529 and 2021 / 0188874 describe a family of FADS1 inhibitor compounds as agents for treating metabolic or cardiovascular disorders.

[0025] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. Features disclosed under one heading (e.g., compositions) may be used in combination with features disclosed under another heading (methods of making or methods of treating).

[0026] definition The following definitions are provided to facilitate understanding of the scope of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0027] The term "pharmaceutically acceptable," as used herein, refers to generally accepted for use in subjects, particularly humans.

[0028] The term "pharmaceutically acceptable excipient," as used herein, refers to a wide variety of ingredients that can be combined with the compounds or salts disclosed herein to prepare pharmaceutical compositions or formulations. Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherents, glidants, disintegrants, flavoring agents, coating agents, binders, sweeteners, lubricants, adsorbents, preservatives, etc.

[0029] The term "pharmaceutically acceptable salt" refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound and is not biologically or otherwise undesirable for its end use. Pharmaceutically acceptable salts include, for example, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid) or organic acids (e.g., acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid). Pharmaceutically acceptable salts also include, for example, salts formed when an acidic proton present in the parent compound is replaced by either a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion) or an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine). Furthermore, the salts of the compounds described herein can exist in either hydrated or anhydrous form, or as solvates with other solvent molecules.

[0030] The term "patient" or "subject," as used herein, refers to humans and mammals, including, but not limited to, primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In one embodiment, the subject is a human.

[0031] The term "therapeutically effective amount," as used herein, refers to an amount of a compound disclosed herein that will elicit the biological or medical response of a tissue, system, or subject desired by a researcher, veterinarian, physician, or other clinician.

[0032] As used herein, the term "relative abundance" refers to the comparison of the abundance of a particular feature in a test subject (e.g., a subject in need of treatment) to the abundance of the same feature in a non-test subject, or a population of non-test subjects. The non-test subject, or a population of non-test subjects, may include healthy subjects and / or subjects not in need of treatment.

[0033] As used herein, the term "healthy subject" refers to an individual who has the average characteristics of a population of healthy individuals. Health has its plain and ordinary meaning and includes subjects who lack one, more, or all FADS1-mediated diseases and / or disorders. A healthy population can be a population including individuals with a body mass index of less than about 25, about 22.5, or about 20. A healthy population can be a population including individuals with a body mass index of greater than about 18.5. A healthy population can be a population including individuals who are free of obesity, metabolic disorders, cardiovascular disease, diabetes, dyslipidemia, and / or NASH.

[0034] The term "isotopomer" refers to a species that differs in chemical structure from a specific compound of this invention only in its isotopic composition.

[0035] Disclosed herein are isotopically enriched compounds. It will be recognized that in the synthetically labeled compounds disclosed herein, there will be some variation in natural isotopic abundance depending on the origin of the chemicals used in synthesis. Therefore, preparations of labeled compounds will contain small amounts of labeled isotopes. In the labeled compounds disclosed herein, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "C" or "carbon," or is not designated, this position is understood to have carbon at its natural abundance isotopic composition. Similarly, unless otherwise specified, when a position is designated as " 13 When a position is specifically designated as "C" or "isotopically enriched," the position is 13at abundances at least 100-fold higher than the natural abundance of C 13 It is understood to have C.

[0036] The term "isotopic enrichment factor," as used herein, means the ratio between the isotopic abundance and the natural abundance of a specified isotope. In some embodiments, compounds of the present invention contain at least one isotope of each specified isotope. 13 In some embodiments, the isotopic enrichment factor for C atoms is about 100 or more, 500 or more, 1000 or more, 1500 or more, 2000 or more, 2500 or more, 3000 or more, 4000 or more, 5000 or more, or a range including and / or spanning the aforementioned values. In some embodiments, the isotopically enriched compounds of the invention have each designated 13 The isotopic enrichment factor for C atoms is about 100 or more, 500 or more, 1000 or more, 1500 or more, 2000 or more, 2500 or more, 3000 or more, 4000 or more, 5000 or more, or a range including and / or spanning the aforementioned values.

[0037] The term "halogen," as used herein, refers to -F, -Cl, -Br, or -I.

[0038] As known to those skilled in the art, certain compounds disclosed herein can exist in one or more tautomeric forms. Because a chemical structure may be used to represent only one tautomeric form, for convenience, reference to a compound of a given structural formula will be understood to include other tautomeric forms of that structural formula.

[0039] When referring to numerical values, the term "or a range including and / or spanning the stated values" (and variations thereof) is intended to include any range including or spanning the stated values. By way of example, if a value is expressed as "20, 30, 40, 50, or a range including and / or spanning the stated values," this includes each specific value provided (e.g., 20, 30, 40, and / or 50), or any range spanning or including any two values ​​provided (e.g., 20-50, 20-40, 20-30, 30-50, 30-40, or 40-50).

[0040] The following description provides background and examples, but should not be construed to limit the scope of the invention, which is covered by the claims of this specification or any other application claiming priority to this specification. No single element or collection of elements is necessary or essential. Any feature, structure, component, material, step, or method described and / or illustrated in any embodiment herein can be used with, or in place of, any feature, structure, component, material, step, or method described and / or illustrated in any other embodiment herein.

[0041] Introduction Dietary intake and endogenous synthesis of PUFAs, as well as their physiological regulation, affect human health and disease. Omega-3 (n-3) and omega-6 (n-6) fatty acids ("FAs"), the two major types of PUFAs, can be ingested or endogenously synthesized from primary precursors (n-3 alpha-linolenic acid ("ALA") or n-6 LA), which are essential FAs that mammals cannot synthesize. These FAs are metabolized sequentially by fatty acid desaturases and fatty acid elongases. The first rate-limiting enzyme is FADS2, which desaturates the sixth carbon of LA or ALA, converting them to gamma-linolenic acid ("GLA") or stearidonic acid, respectively, and is therefore also known as D6D (Figure 1(a)). Subsequent elongation of GLA and stearidonic acid produces DGLA and ETA, respectively (Figure 1(a)). DGLA and ETA are desaturated by FADS1, also known as D5D because it desaturates the fifth carbon of the fatty acid chain; the respective products of FADS1 enzymatic action are n-6 AA and n-3 EPA acids (Figure 1(a)). Both AA and EPA are extensively metabolized by enzymes such as cyclooxygenase and lipoxygenase to form bioactive eicosanoids, such as prostaglandins, thromboxanes, and leukotrienes. These eicosanoids play important roles in metabolism and inflammation; AA-derived eicosanoids are primarily pro-inflammatory, while EPA-derived eicosanoids are anti-inflammatory.

[0042] Obesity and its associated comorbidities have become a global public health concern. The increasing prevalence of obesity over the past few decades is partly attributable to a Westernized diet with a high n-6 to n-3 ratio (approximately 10:1 to 20:1). This high ratio may contribute to the development of inflammation, cardiovascular disease, cancer, and autoimmune diseases. Excess n-6 PUFAs, such as AA, can lead to excess pro-inflammatory eicosanoids and other oxylipins. Obesity and metabolic disorders may, in part, be the result of inflammatory damage mediated by excess eicosanoids. Humans depend on the consumption and production of PUFAs via FADS2 and FADS1, encoded by the FADS2 and FADS1 genes, respectively. Differential expression of FADS1 by different alleles at the FADS locus has enabled the identification of numerous associations with traits and diseases from genome-wide association studies (GWAS). Notably, the strongest association of the FADS locus to date is with AA concentrations (P = 3 × 10 -971 ), more specifically, the association with AA / DGLA concentrations (P = 2 × 10 -361 ). The minor C alleles of the FADS1 single nucleotide polymorphisms ("SNPs") rs174556 and rs174547 are associated with reduced FADS1 activity and reduced body weight or waist circumference. In addition, improved metabolic phenotypes have been observed in Fads1 KO mice when fed a normal diet or an HFD. Taken together, the phenotypes associated with FADS1 in both humans and mice suggest that reduced FADS1 activity may have therapeutic value in the treatment of obesity and related metabolic comorbidities.

[0043] In view of the foregoing, some embodiments provided herein relate to methods for determining whether a subject is a candidate for treatment with a FADS1 inhibitor compound. In some embodiments, the candidate for treatment with a FADS1 inhibitor compound may be a subject suffering from or at risk of suffering from a FADS1-mediated disorder or disease. In some embodiments, the method includes determining the level of a biological indicator in a biological sample from the subject. In some embodiments, the level of the biological indicator provides information about whether the patient is suffering from or at risk of suffering from a FADS1-mediated disease or disorder. In some embodiments, the level of the biological indicator is compared to a reference level of the biological indicator from a different subject (or a population of subjects) that is not suffering from (or at risk of developing) a FADS1-mediated disease or condition. In some embodiments, if the level of the biological indicator in the subject indicates that the subject is a candidate for treatment with a FADS1 inhibitor compound (e.g., suffering from or at risk of suffering from a FADS1-mediated condition), the subject is administered a FADS1 inhibitor compound. In some embodiments, the biological indicator is one or more PUFAs (or a ratio of PUFAs). In some embodiments, the biological indicator is the relative abundance of one or more cell types in the subject. In some embodiments, the biological indicator is the relative abundance of one or more DEGs. In some embodiments, the biological indicator is the relative abundance of one or more metabolites. In some embodiments, the FADS1 inhibitor compound is a FADS1 inhibitory small molecule. In some embodiments, inhibiting FADS1 limits and / or reduces AA availability and the production of pro-inflammatory eicosanoids.

[0044] Methods of treating and FADS1 inhibitor compounds for use in treatment Provided herein as embodiment 1 is a method of treating a FADS1-mediated disease or disorder in a subject in need thereof, comprising: receiving information comparing the level of a biological indicator of a FADS1-mediated disease from the subject to a reference level of the biological indicator; The biological indicator is the ratio of arachidonic acid (AA) to dihomo-gamma-linolenic acid (DGLA); and administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject when the level of the biological indicator in the subject is greater than the baseline level of the biological indicator. The method includes:

[0045] Provided herein as embodiment 2 is a FADS1 inhibitor compound for use in a method of treating a subject in need thereof having a FADS1-mediated disease or disorder, the method comprising: receiving information comparing the level of a biological indicator of a FADS1-mediated disease from the subject to a reference level of the biological indicator; The biological indicator is the ratio of arachidonic acid (AA) to dihomo-gamma-linolenic acid (DGLA); and administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject when the level of the biological indicator in the subject is greater than the baseline level of the biological indicator. and FADS1 inhibitor compounds comprising:

[0046] Provided herein as embodiment 3 is a method or compound according to embodiment 1 or 2, wherein the reference level of the biological indicator is a ratio of AA to DGLA of about 5:1 or greater.

[0047] Provided herein as embodiment 4 is a method or compound according to embodiment 1 or 2, wherein the reference level of the biological indicator is a ratio of AA to DGLA of about 6:1 or greater.

[0048] Provided herein as embodiment 5 is a method or compound according to embodiment 1 or 2, wherein the reference level of the biological indicator is a ratio of AA to DGLA of about 7:1 or greater.

[0049] Provided herein as embodiment 6 is the method or compound of embodiment 1 or 2, wherein the reference level of the biological indicator is a ratio of AA to DGLA that is greater than or equal to about 15:2.

[0050] Provided herein as embodiment 7 is the method or compound of embodiment 1 or 2, wherein the reference level of the biological indicator is a ratio of AA to DGLA that is greater than or equal to about 8:1.

[0051] Provided herein as embodiment 8 is a method or compound according to embodiment 1 or 2, wherein the reference level of the biological indicator is a ratio of AA to DGLA of about 17:2 or greater.

[0052] Provided herein as embodiment 9 is a method or compound according to embodiment 1 or 2, wherein the reference level of the biological indicator is a ratio of AA to DGLA of about 9:1 or greater.

[0053] Provided herein as embodiment 10 is a method of treating a FADS1-mediated disease or disorder in a subject in need thereof, comprising: receiving information comparing a level of a biological indicator of a FADS1-mediated disease from the subject to a reference level of the biological indicator; receiving, wherein the biological indicator is a measured level of linoleic acid, gamma-linoleic acid, adrenic acid, docosapentanoic acid n-6, alpha-linolenic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, or a combination of the foregoing; and administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject upon determining that the subject is a subject who would benefit from treatment with the FADS1 inhibitor compound, as determined by the subject's level of the biological indicator compared to a baseline level of the biological indicator. The method includes:

[0054] Provided herein as embodiment 11 is a FADS1 inhibitor compound for use in a method of treating a subject in need thereof having a FADS1-mediated disease or disorder, the method comprising: receiving information comparing a level of a biological indicator of a FADS1-mediated disease from the subject to a reference level of the biological indicator; receiving, wherein the biological indicator is a measured level of linoleic acid, gamma-linoleic acid, adrenic acid, docosapentanoic acid n-6, alpha-linolenic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, or a combination of the foregoing; and administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject upon determining that the subject is a subject who would benefit from treatment with the FADS1 inhibitor compound, as determined by the subject's level of the biological indicator compared to a baseline level of the biological indicator. and FADS1 inhibitor compounds comprising:

[0055] Provided herein as embodiment 12 is a method or compound according to embodiment 10 or 11, wherein the subject is determined to be a subject who would benefit from treatment with a FADS1 inhibitor compound if the level of the biological indicator in the subject is higher than a reference level of the biological indicator.

[0056] Provided herein as embodiment 13 is a method or compound according to embodiment 10 or 11, wherein the subject is determined to be a subject who would benefit from treatment with a FADS1 inhibitor compound if the subject's level of the biological indicator is lower than a reference level of the biological indicator.

[0057] Provided herein as embodiment 14 is a method of treating a FADS1-mediated disease or disorder in a subject in need thereof, comprising: receiving information comparing a level of a biological indicator of a FADS1-mediated disease from the subject to a reference level of the biological indicator; Biological indicators included plasma cholesterol, free cholesterol, total cholesterol, cholesterol ester C20:4, malate, alpha-ketoglutarate, mannose, glucose, erythrodihydrosphingosine (d18:0), 5-O-methylsphingosine (d18:1), erythrophingosine (d18:1), 3-O-methylsphingosine (d18:1), threosphingosine (d18:1), 1-hydroxy-2-amino-(cis, trans)-3,5-octadecadiene, 4-hydroxysphinganine (t18:0), and erythrodihydrosphingosine (d18:0). , phytosphingosine), sphingomyelin (d18:1, C23:0), sphingomyelin (d18:1, C24:0), ceramide (d18:1, C24:0), thromboxane B2, delta-12-prostaglandin D2, prostaglandin E2, prostaglandin D2, 12-hydroxyheptadecatrienoic acid (C17:[5,8,10]3), 14,15-dihydroxyeicosatrienoic acid (C20:cis[5,8,11]3), 11-hydroxyeicosatetraenoic acid (C20:cis[5,8,12,14]4), 13-hydroxy 13-HEXADECANOIC ACID (C18:cis[9]trans

[11] 2), arachidonic acid (C20:cis[5,8,11,14]4), docosahexaenoic acid (C22:cis[4,7,10,13,16,19]6), dihomo-gamma-linolenic acid (C20:cis[8,11,14]3), gamma-linolenic acid (C18:cis[6,9,12]3), docosapentaenoic acid (C22:cis[7,10,13,16,19]5), eicosapentaenoic acid (C20:cis[5,8,11,14,17]5), docosatetraenoic acid (C22:cis[7,10,13,16,19]5). [7,10,13,16]4), stearic acid (C18:0), tryptophan, kynurenic acid, xanthurenic acid, histidine, leucine, isoleucine, valine, 3-hydroxyisobutyrate, glutamate, threonine, cysteine, sarcosine, plasma triglycerides, taurochenodeoxycholic acid, taurocholic acid, lysophosphatidylcholine (C18:0), lysophosphatidylcholine (C20:4), lysophosphatidylcholine (C17:0), lysophosphatidylethanolamine (C22:5), phosphatidylcholine (C18:0,receiving a measured level of phosphatidylcholine (C18:0, C20:3), phosphatidylcholine (C18:1, C18:2), phosphatidylcholine (C16:1, C18:2), phosphatidylcholine (C18:0, C18:2), phosphatidylcholine (C16:0, C20:5), phosphatidylcholine (C16:0, C16:0), glycerol-3 phosphate, choline plasmalogen (C18, C20:4), myo-inositol, myo-inositol phospholipids, glycerol phosphate, phospholipid fractions, or a combination of the foregoing; and administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject upon determining that the subject is a subject who would benefit from treatment with the FADS1 inhibitor compound, as determined by the subject's level of the biological indicator compared to a baseline level of the biological indicator. The method includes:

[0058] Provided herein as embodiment 15 is a FADS1 inhibitor compound for use in a method of treating a FADS1-mediated disease or disorder in a subject in need thereof, the method comprising: receiving information comparing a level of a biological indicator of a FADS1-mediated disease from the subject to a reference level of the biological indicator; Biological indicators included plasma cholesterol, free cholesterol, total cholesterol, cholesterol ester C20:4, malate, alpha-ketoglutarate, mannose, glucose, erythrodihydrosphingosine (d18:0), 5-O-methylsphingosine (d18:1), erythrophingosine (d18:1), 3-O-methylsphingosine (d18:1), threosphingosine (d18:1), 1-hydroxy-2-amino-(cis, trans)-3,5-octadecadiene, 4-hydroxysphinganine (t18:0), and erythrodihydrosphingosine (d18:0). , phytosphingosine), sphingomyelin (d18:1, C23:0), sphingomyelin (d18:1, C24:0), ceramide (d18:1, C24:0), thromboxane B2, delta-12-prostaglandin D2, prostaglandin E2, prostaglandin D2, 12-hydroxyheptadecatrienoic acid (C17:[5,8,10]3), 14,15-dihydroxyeicosatrienoic acid (C20:cis[5,8,11]3), 11-hydroxyeicosatetraenoic acid (C20:cis[5,8,12,14]4), 13-hydroxy 13-HEXADECANOIC ACID (C18:cis[9]trans

[11] 2), arachidonic acid (C20:cis[5,8,11,14]4), docosahexaenoic acid (C22:cis[4,7,10,13,16,19]6), dihomo-gamma-linolenic acid (C20:cis[8,11,14]3), gamma-linolenic acid (C18:cis[6,9,12]3), docosapentaenoic acid (C22:cis[7,10,13,16,19]5), eicosapentaenoic acid (C20:cis[5,8,11,14,17]5), docosatetraenoic acid (C22:cis[7,10,13,16,19]5). [7,10,13,16]4), stearic acid (C18:0), tryptophan, kynurenic acid, xanthurenic acid, histidine, leucine, isoleucine, valine, 3-hydroxyisobutyrate, glutamate, threonine, cysteine, sarcosine, plasma triglycerides, taurochenodeoxycholic acid, taurocholic acid, lysophosphatidylcholine (C18:0), lysophosphatidylcholine (C20:4), lysophosphatidylcholine (C17:0), lysophosphatidylethanolamine (C22:5), phosphatidylcholine (C18:0,receiving a measured level of phosphatidylcholine (C18:0, C20:3), phosphatidylcholine (C18:1, C18:2), phosphatidylcholine (C16:1, C18:2), phosphatidylcholine (C18:0, C18:2), phosphatidylcholine (C16:0, C20:5), phosphatidylcholine (C16:0, C16:0), glycerol-3 phosphate, choline plasmalogen (C18, C20:4), myo-inositol, myo-inositol phospholipids, glycerol phosphate, phospholipid fractions, or a combination of the foregoing; and administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject upon determining that the subject is a subject who would benefit from treatment with the FADS1 inhibitor compound, as determined by the subject's level of the biological indicator compared to a baseline level of the biological indicator. and ADS1 inhibitor compounds comprising:

[0059] Provided herein as embodiment 16 is a method or compound according to embodiment 14 or 15, wherein the subject is determined to be a subject that would benefit from treatment with a FADS1 inhibitor compound if the level of the biological indicator in the subject is higher than a reference level of the biological indicator.

[0060] As embodiment 17, provided herein is a method for treating a disease, the method comprising administering to a patient a biological indicator selected from the group consisting of plasma cholesterol, free cholesterol, total cholesterol, cholesterol ester C20:4, mannose, glucose, erythrodihydrosphingosine (d18:0), 5-O-methylsphingosine (d18:1), erythrophingosine (d18:1), 3-O-methylsphingosine (d18:1), threosphingosine (d18:1), 1-hydroxy-2-amino-(cis,trans)-3,5-octadecadiene, 4-hydroxysphinganine (t18:0, phytosphingosine), sphingomyelin (d18:1, C23:0), sphingomyelin (d18:1, C24:0), ceramide (d18:1, C24:0), thromboxane B2, delta-12-prostaglandin D2, prostaglandin E2, prostaglandin D2, 12-hydroxyheptadecatrienoic acid (C17:[5,8,10]3), 14,15-dihydroxyeicosatrienoic acid (C20:cis[5,8,11]3), 11-hydroxy Eicosatetraenoic acid (C20: cis[5,8,12,14]4), 13-hydroxyoctadecadienoic acid (13-HODE) (C18: cis[9]trans

[11] 2), arachidonic acid (C20: cis[5,8,11,14]4), docosahexaenoic acid (C22: cis[4,7,10,13,16,19]6), docosapentaenoic acid (C22: cis[7,10,13,16,19]5), eicosapentaenoic acid (C20: cis[5,8,11,14,17]5), docosatetraenoic acid (C22: cis[7,10, 13,16]4), stearic acid (C18:0), cysteine, plasma triglycerides, taurochenodeoxycholic acid, taurocholic acid, lysophosphatidylcholine (C18:0), lysophosphatidylcholine (C20:4), lysophosphatidylcholine (C17:0), phosphatidylcholine (C18:0, C22:6), phosphatidylcholine (C18:0, C20:3), phosphatidylcholine (C18:0, C18:2), phosphatidylcholine (C16:0, C20:5), choline plasmalogen (C18,C20:4), myo-inositol, myo-inositol phospholipid, glycerol phosphate, phospholipid fraction, or a combination thereof.

[0061] Provided herein as embodiment 18 is a method or compound according to embodiment 14 or 15, wherein the subject is determined to be a subject that would benefit from treatment with a FADS1 inhibitor compound if the level of the biological indicator in the subject is lower than a reference level of the biological indicator.

[0062] As embodiment 19, provided herein is the method or compound of any one of embodiments 14-15, and 18, wherein the biological indicator is malate, alpha-ketoglutarate, dihomo-gamma-linolenic acid (C20:cis[8,11,14]3), gamma-linolenic acid (C18:cis[6,9,12]3), tryptophan, kynurenic acid, xanthurenic acid, histidine, leucine, isoleucine, valine, 3-hydroxyisobutyrate, glutamate, threonine, sarcosine, lysophosphatidylethanolamine (C22:5), phosphatidylcholine (C18:1, C18:2), phosphatidylcholine (C16:1, C18:2), phosphatidylcholine (C16:0, C16:0), glycerol-3 phosphate, or a combination thereof.

[0063] Provided herein as embodiment 20 is a method of treating a FADS1-mediated disease or disorder in a subject in need thereof, comprising: receiving information comparing the level of a biological indicator of a FADS1-mediated disease from the subject to a reference level of the biological indicator; The biological indicator is the measured level of differentially expressed genes (DEGs), DEGは、Serpinb1a、Gna14、Serpina3m、Hsd11b1、Cyp2c29、Akr1d1、Aldh1a1、Mmp19、Gyp27a1、Tymp、Elovl2、Chkb、H2afj、Tnfaip8l1、Tmem86a、Sel1l3、Agap2、4833411C07Rik、Elov4、Fat3、E ef1a2、Atp7a、Rgs2、Cenpe、Mfap2、Mlki67、Ctsh、Trub2、Ubc、H6pd、Eepd1、Acss2、Aacs、Gm368 27、Man2a2、Nudt18、Plagl1、TM4sf19、Atp6v0d2、Gm20056、Trem2、Il1rn、Mmp12、Cdk18、Efr3b 、Tagln2、Lurap1、Cp、I17rb、B230303O12Rik、Cfd、Sult1e1、Tdo2、Cyp2b9、Hao2、Cyp2b13、Cyp 2a22、Acnat2、Ildr2、Rpl10a-ps1、Tm6sf2、Fitm1、Lpar1、C6、Cmah、Lbp、Arsg、Glra3、Lad1、A7 30063M14Rik、Ly6f、Foxi1、Crygc、Defb28、Wfdc9、Phlda2、Aqp6、Gm16411、Adam7、Ppp2r5b、Sl c6a7、Gpr50、Ahnak2、S100a6、Mmp14、Htr2b、Hpgds、Gm18537、Pclo、Adrb3、Gm38394、AC154232.2, Cadps, Adgrb2, Gm45470, Sdr9c7, Dsg1c, Slc17a1, Ces1c, Gss, 1810008I18Rik, Tlcd1, Snrk, Akr1c 20, Gm19950, Ttr, Cbfa2t3, Acat2, Pmvk, Abcd3, Acacb, Arhgap27, Rnase9, Wfdc8, Ighv9-2, DerI3, Aca p1, Ccl19, Tcf7, Xkrx, Trim46, Zfp369, Zfp871, Pcdhb21, Gm14288, Uprt, Atm, Dchs2, Cped1, Gm38357, Cck, Ckap2, Gm4419, 1600015I10Rik, Sez6I2, Prnd, Gm16702, S100a8, Pcdh12, Malat1, Kcnq1ot1, ArI4 c, Gm42549, Gm37310, Gm37776, Atp2a1, Ckm, Tnnt3, Adipoq, Fabp4, Lep, Retn, Hoxc8, Hoxc9, Cebpa, D gat1, Dgat2, Elovl3, Fas, Scd1, Srebf1, Hilpda, Lipe, Mgll, Plin1, Plin4, Pnpla2, Pnpla3, Ldah, Cs, receiving Gckr, Me1, Pck1, Pdk4, Irs1, Acaa1a, Acads, Acox1, Cpt1a, Cpt1b, Hadhb, Ehhadh, Ppara, Ppargc1a, Cyp4a12a, Cyp4a12b, Cyp2e1, Adgre1, Agtr1a, Ccl2, Cd14, Cd68, Il1b, Tnf, or a combination of the foregoing; and administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject upon determining that the subject is a subject who would benefit from treatment with the FADS1 inhibitor compound, as determined by the subject's level of the biological indicator compared to a baseline level of the biological indicator. The method includes:

[0064] Provided herein as embodiment 21 is a FADS1 inhibitor compound for use in a method of treating a subject in need thereof having a FADS1-mediated disease or disorder, the method comprising: receiving information comparing a level of a biological indicator of a FADS1-mediated disease from the subject to a reference level of the biological indicator; The biological indicator is the measured level of differentially expressed genes (DEGs), DEGは、Serpinb1a、Gna14、Serpina3m、Hsd11b1、Cyp2c29、Akr1d1、Aldh1a1、Mmp19、Gyp27a1、Tymp、Elovl2、Chkb、H2afj、Tnfaip8l1、Tmem86a、Sel1l3、Agap2、4833411C07Rik、Elov4、Fat3、E ef1a2、Atp7a、Rgs2、Cenpe、Mfap2、Mlki67、Ctsh、Trub2、Ubc、H6pd、Eepd1、Acss2、Aacs、Gm368 27、Man2a2、Nudt18、Plagl1、TM4sf19、Atp6v0d2、Gm20056、Trem2、Il1rn、Mmp12、Cdk18、Efr3b 、Tagln2、Lurap1、Cp、I17rb、B230303O12Rik、Cfd、Sult1e1、Tdo2、Cyp2b9、Hao2、Cyp2b13、Cyp 2a22、Acnat2、Ildr2、Rpl10a-ps1、Tm6sf2、Fitm1、Lpar1、C6、Cmah、Lbp、Arsg、Glra3、Lad1、A7 30063M14Rik、Ly6f、Foxi1、Crygc、Defb28、Wfdc9、Phlda2、Aqp6、Gm16411、Adam7、Ppp2r5b、Sl c6a7、Gpr50、Ahnak2、S100a6、Mmp14、Htr2b、Hpgds、Gm18537、Pclo、Adrb3、Gm38394、AC154232.2, Cadps, Adgrb2, Gm45470, Sdr9c7, Dsg1c, Slc17a1, Ces1c, Gss, 1810008I18Rik, Tlcd1, Snrk, Akr1c 20, Gm19950, Ttr, Cbfa2t3, Acat2, Pmvk, Abcd3, Acacb, Arhgap27, Rnase9, Wfdc8, Ighv9-2, DerI3, Aca p1, Ccl19, Tcf7, Xkrx, Trim46, Zfp369, Zfp871, Pcdhb21, Gm14288, Uprt, Atm, Dchs2, Cped1, Gm38357, Cck, Ckap2, Gm4419, 1600015I10Rik, Sez6I2, Prnd, Gm16702, S100a8, Pcdh12, Malat1, Kcnq1ot1, ArI4 c, Gm42549, Gm37310, Gm37776, Atp2a1, Ckm, Tnnt3, Adipoq, Fabp4, Lep, Retn, Hoxc8, Hoxc9, Cebpa, D gat1, Dgat2, Elovl3, Fas, Scd1, Srebf1, Hilpda, Lipe, Mgll, Plin1, Plin4, Pnpla2, Pnpla3, Ldah, Cs, receiving Gckr, Me1, Pck1, Pdk4, Irs1, Acaa1a, Acads, Acox1, Cpt1a, Cpt1b, Hadhb, Ehhadh, Ppara, Ppargc1a, Cyp4a12a, Cyp4a12b, Cyp2e1, Adgre1, Agtr1a, Ccl2, Cd14, Cd68, Il1b, Tnf, or a combination of the foregoing; and administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject upon determining that the subject is a subject who would benefit from treatment with the FADS1 inhibitor compound, as determined by the subject's level of the biological indicator compared to a baseline level of the biological indicator. and FADS1 inhibitor compounds comprising:

[0065] Provided herein as embodiment 22 is a method or compound according to embodiment 20 or 21, wherein the subject is determined to be a subject who would benefit from treatment with a FADS1 inhibitor compound if the subject's biological indicator level is higher than a reference level of the biological indicator.

[0066] Provided herein as embodiment 23 is the method or compound of any one of embodiments 20-22, wherein the DEG is Serpinb1a, Gna14, Serpina3m, Hsd11b1, Cyp2c29, Hsd11b1, Akr1d1, Aldh1a1, or a combination thereof.

[0067] Provided herein as embodiment 24 is the method or compound of any one of embodiments 20-23, wherein the DEG is Elov4, Fat3, Eef1a2, Atp7a, Rgs2, Cenpe, Mfap2, Mlki67, Ctsh, or a combination thereof.

[0068] Provided herein as embodiment 25 is the method or compound of any one of embodiments 20-24, wherein the DEG is TM4sf19, Atp6v0d2, Gm20056, Trem2, Il1rn, Mmp12, Cdk18, Efr3b, Tagln2, or a combination thereof.

[0069] Provided herein as embodiment 26 is the method or compound of any one of embodiments 20-25, wherein the DEG is Cyp2b9, Fads1, Hao2, Cyp2b13, Cyp2a22, Acnat2, Ildr2, Rpl10a-ps1, Tm6sf2, or a combination thereof.

[0070] Provided herein as embodiment 27 is the method or compound of any one of embodiments 20-26, wherein the DEG is Ly6f, Foxil, Crygc, Defb28, Wfdc9, Phlda2, Aqp6, Gm16411, Adam7, or a combination thereof.

[0071] Provided herein as embodiment 28 is the method or compound of any one of embodiments 20-27, wherein the DEG is Slc6a7, Gpr50, Ahnak2, S100a6, Mmp14, Htr2b, Hpgds, Mfap2, or a combination thereof.

[0072] Provided herein as embodiment 29 is a method or compound according to any one of embodiments 20-28, wherein the DEG is Sdr9c7, Dsg1c, Slc17a1, Acnat2, Ces1c, Gss, Hsd11b1, or a combination thereof.

[0073] Provided herein as embodiment 30 is the method or compound of any one of embodiments 20-29, wherein the DEG is Adam7, Rnase9, Wfdc8, Ighv9-2, DerI3, Acap1, Ccl19, Tcf7, Xkrx, Trim46, or a combination thereof.

[0074] Provided herein as embodiment 31 is the method or compound of any one of embodiments 20-30, wherein the DEG is Cck, Ckap2, Gm4419, 1600015I10Rik, Sez6I2, Prnd, Gm16702, S100a8, or a combination thereof.

[0075] Provided herein as embodiment 32 is a method or compound according to embodiment 20 or 21, wherein the subject is determined to be a subject that would benefit from treatment with a FADS1 inhibitor compound if the subject's biological indicator level is lower than a reference level of the biological indicator.

[0076] Provided herein as embodiment 33 is the method or compound of any one of embodiments 20-21 and 32, wherein the DEG is Tmem86a, Elovl2, Agap2, Chkb, Tnfaip8l1, H2afj, Sel1l3, 4833411C07Rik, or a combination thereof.

[0077] Provided herein as embodiment 34 is the method or compound of any one of embodiments 20-21 and 32-33, wherein the DEG is Trub2, Ubc, H6pd, Eepd1, Acss2, Aacs, Gm36827, Man2a2, Nudt18, Plagl1, or a combination thereof.

[0078] Provided herein as embodiment 35 is the method or compound of any one of embodiments 20-21 and 32-34, wherein the DEG is Lurap1, Cp, I17rb, B230303O12Rik, Cfd, Sult1e1, Tdo2, or a combination thereof.

[0079] Provided herein as embodiment 36 is the method or compound of any one of embodiments 20-21 and 32-34, wherein the DEG is Fitm1, Tmem86a, Agap2, Lpar1, C6, Cmah, Lbp, Arsg, Glra3, Lad1, A730063M14Rik, or a combination thereof.

[0080] Provided herein as embodiment 37 are methods or compounds according to any one of embodiments 20-21 and 32-34, wherein the DEG is Ppp2r5b.

[0081] Provided herein as embodiment 38 is the method or compound of any one of embodiments 20-21 and 32-34, wherein the DEG is Gm18537, Aacs, Pclo, Adrb3, Gm38394, AC154232.2, Cadps, Adgrb2, Gm45470, or a combination thereof.

[0082] Provided herein as embodiment 39 is the method or compound of any one of embodiments 20-21 and 32-34, wherein the DEG is 1810008I18Rik, Tlcd1, Snrk, Akr1c20, Gm19950, Ttr, Cbfa2t3, Acat2, Pmvk, Abcd3, Acss2, Acacb, Arhgap27, or a combination thereof.

[0083] Provided herein as embodiment 40 is the method or compound of any one of embodiments 20-21 and 32-34, wherein the DEG is Zfp369, Zfp871, Pcdhb21, Adrb3, Gm14288, Uprt, Atm, Dchs2, Cped1, Gm38357, or a combination thereof.

[0084] Provided herein as embodiment 41 is the method or compound of any one of embodiments 20-21 and 32-34, wherein the DEG is Pcdh12, Malat1, Kcnq1ot1, ArI4c, Gm38394, Gm42549, AC154232.2, Gm37310, Gm37776, Atp2a1, Ckm, Tnnt3, or a combination thereof.

[0085] Provided herein as embodiment 42 is a method or compound according to any one of embodiments 20-41, wherein the DEG is Mmp19, Gyp27a1, Tymp, or a combination thereof.

[0086] Provided herein as embodiment 43 are DEGs, including Adipoq, Fabp4, Lep, Retn, Hoxc8, Hoxc9, Cebpa, Dgat1, Dgat2, Elovl3, Fas, Scd1, Srebf1, Adrb3, Hilpda, Lipe, Mgll, Plin1, Plin4, Pnpla2, Pnpla3, Ldah, Cs, Gckr, Me1, Pck1, Pdk4 , Irs1, Acaa1a, Acads, Acox1, Cpt1a, Cpt1b, Hadhb, Ehhadh, Ppara, Ppargc1a, Cyp4a12a, Cyp4a12b, Cyp2e1, Adgre1, Agtr1a, Ccl2, Cd14, Cd68, Il1b, Tm6sf2, Tnf, or a combination thereof.

[0087] Provided herein as embodiment 44 is a method or compound of any one of embodiments 20-43, wherein the DEG is one disclosed in Figure 4a, Figure 5a, Figure 10a, Figure 13a, Figure 13g, Figure 15e, Figure 15f, or a combination of DEGs disclosed above. For example, in some embodiments, the DEG is one disclosed in Figure 4a. In some embodiments, the DEG is one disclosed in Figure 5a. In some embodiments, the DEG is one disclosed in Figure 10a. In some embodiments, the DEG is one disclosed in Figure 13a. In some embodiments, the DEG is one disclosed in Figure 13g. In some embodiments, the DEG is one disclosed in Figure 15e. In some embodiments, the DEG is one disclosed in Figure 15f. In some embodiments, the DEG is one disclosed above or a combination of DEGs disclosed above. In some embodiments, the DEG is one disclosed in any other figure provided herein.

[0088] Provided herein as embodiment 45 is a method of treating a FADS1-mediated disease or disorder in a subject in need thereof, comprising: receiving information comparing a level of a biological indicator of a FADS1-mediated disease from the subject to a reference level of the biological indicator; receiving the biological indicator, wherein the biological indicator is a measured level of one or more cell types in the subject, the cell types being adipocytes (Adipo), B cells (Bcell), endothelial cells (Endo), hepatocytes (Hep), Kupffer cells (Kupff), myeloid cells (Myel), natural killer cells (NK), T cells (Tcell), or a combination thereof; and administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject upon determining that the subject is a subject who would benefit from treatment with the FADS1 inhibitor compound, as determined by the subject's level of the biological indicator compared to a baseline level of the biological indicator. The method includes:

[0089] Provided herein as embodiment 46 is a FADS1 inhibitor compound for use in a method of treating a subject in need thereof having a FADS1-mediated disease or disorder, the method comprising: receiving information comparing a level of a biological indicator of a FADS1-mediated disease from the subject to a reference level of the biological indicator; receiving the biological indicator, wherein the biological indicator is a measured level of one or more cell types in the subject, the cell types being adipocytes (Adipo), B cells (Bcell), endothelial cells (Endo), hepatocytes (Hep), Kupffer cells (Kupff), myeloid cells (Myel), natural killer cells (NK), T cells (Tcell), or a combination thereof; and administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject upon determining that the subject is a subject who would benefit from treatment with the FADS1 inhibitor compound, as determined by the subject's level of the biological indicator compared to a baseline level of the biological indicator. and FADS1 inhibitor compounds comprising:

[0090] Provided herein as embodiment 47 is a method or compound according to embodiment 45 or 46, wherein the subject is determined to be a subject who would benefit from treatment with a FADS1 inhibitor compound if the subject's biological indicator level is higher than a reference level of the biological indicator.

[0091] Provided herein as embodiment 48 are methods or compounds according to any one of embodiments 45-46 and 47, wherein the cell type is Adipo, Myel, or a combination thereof.

[0092] Provided herein as embodiment 49 is a method or compound according to embodiment 45 or 46, wherein the subject is determined to be a subject that would benefit from treatment with a FADS1 inhibitor compound if the subject's biological indicator level is lower than the reference level of the biological indicator.

[0093] Provided herein as embodiment 50 is a method or compound according to any one of embodiments 45-46 and 49, wherein the cell type is Bcell, Endo, NK, Tcell, or a combination thereof.

[0094] Provided herein as embodiment 51 are methods or compounds according to any one of embodiments 1-50, wherein the FADS1-mediated disease or disorder is obesity, a metabolic disorder, a cardiovascular disorder, diabetes, dyslipidemia, non-alcoholic steatohepatitis (NASH), or any combination thereof. For example, in some embodiments, the FADS1-mediated disease or disorder is obesity. In some embodiments, the FADS1-mediated disease or disorder is a metabolic disorder. In some embodiments, the FADS1-mediated disease or disorder is a cardiovascular disorder. In some embodiments, the FADS1-mediated disease or disorder is diabetes. In some embodiments, the FADS1-mediated disease or disorder is dyslipidemia. In some embodiments, the FADS1-mediated disease or disorder is non-alcoholic steatohepatitis (NASH).

[0095] Provided herein as embodiment 52 is a method or compound according to any one of embodiments 1 to 51, wherein the reference level of the biological indicator is the average amount of the biological indicator in a population of healthy subjects.

[0096] Provided herein as embodiment 53 is a method or compound according to any one of embodiments 1 to 52, wherein the reference level of the biological indicator is the average amount of the biological indicator in a population of subjects who do not have a FADS1-mediated disease.

[0097] Provided herein as embodiment 54 is a method or compound according to any one of embodiments 1 to 53, wherein the reference level of the biological indicator is the average amount of the biological indicator in a population of subjects with a body mass index (BMI) of 25.0 or greater.

[0098] Provided herein as embodiment 55 is a method or compound according to any one of embodiments 1 to 53, wherein the reference level of the biological indicator is the average amount of the biological indicator in a population of subjects with a body mass index (BMI) of 30.0 or greater.

[0099] Provided herein as embodiment 56 is the method or compound of any one of embodiments 1 to 55, wherein the reference level of the biological marker is the average amount of the biological marker in a population of subjects with a body fat percentage of 19% or less.

[0100] Provided herein as embodiment 57 is the method or compound of embodiment 56, wherein the reference level of the biological indicator is from a population of males and the subject is male.

[0101] Provided herein as embodiment 58 is the method or compound of any one of embodiments 1 to 55, wherein the reference level of the biological marker is the average amount of the biological marker in a population of subjects with a body fat percentage of 32% or less.

[0102] Provided herein as embodiment 59 is the method or compound of embodiment 58, wherein the reference level of the biological indicator is derived from a population of females and the subject is female.

[0103] Provided herein as embodiment 60 is a method or compound of any one of embodiments 1-59, wherein the level of the biological indicator of a FADS1-mediated disease from the subject is quantified using a sample collected from the subject, wherein the sample is blood, plasma, or a tissue biopsy. For example, in some embodiments, the level of the biological indicator of a FADS1-mediated disease from the subject is determined using a blood sample from the subject. In some embodiments, the level of the biological indicator of a FADS1-mediated disease from the subject is determined using a plasma sample from the subject. In some embodiments, the level of the biological indicator of a FADS1-mediated disease from the subject is determined using a tissue sample from the subject. In some embodiments, the tissue sample is collected as a biopsy. In some embodiments, the blood sample or plasma sample is collected using a needle.

[0104] Provided herein as embodiment 61 is a method or compound according to embodiment 60, wherein the tissue is adipose tissue or organ tissue. For example, in some embodiments, an adipose tissue sample is obtained from the subject.

[0105] As disclosed elsewhere herein, some embodiments relate to methods of determining and / or predicting whether a subject is a candidate for treatment (e.g., will respond to treatment) with a FADS1 inhibitor compound. In some embodiments, whether a subject is a candidate for treatment is related to the activity of the FADS1 enzyme in the subject. As disclosed elsewhere herein, treatment with a FADS1 inhibitor may be beneficial if FDAS1 activity is increased in the subject compared to healthy subjects and / or compared to subjects lacking a FADS1-mediated condition (e.g., a disease or disorder). In some embodiments, methods are provided for identifying a subject having FADS1 activity. In some embodiments, methods are provided for measuring or approximating the level of FADS1 activity in a subject. In some embodiments, methods are provided for determining whether a subject is in need of treatment with a FADS1 inhibitor, as disclosed elsewhere herein. In some embodiments, identifying a subject suffering from a FADS1-mediated condition, identifying a subject with increased FADS1 activity (compared to healthy subjects), and / or identifying a subject in need of treatment with a FADS1 inhibitor compound can be performed by analyzing the relative abundance and / or ratio of one or more biological indicators (e.g., biological markers) of a FADS1-mediated disease or disorder in a subject. Thus, provided herein are biological markers (e.g., biomarkers) that can be measured and / or compared. Some embodiments disclosed herein relate to methods of selecting a subject for treatment with a FADS1 inhibitor compound based on the presence or relative abundance of one or more biological indicators.

[0106] Advantageously, treatment regimens can be optimized for individuals according to individual patient information and characteristics. For example, the administration of a FADS1 inhibitor compound can be initiated or not initiated based on the level of a biological indicator in a patient. Because healthy subjects have one or more biological indicators that have different relative abundances (e.g., decreased or increased) compared with subjects who need treatment with a FADS1 inhibitor compound (e.g., treatment candidates), the patient selection process can be performed by measuring biological indicators in treatment candidates. During the selection process, the biological indicator levels in treatment candidates can be compared (e.g., before treatment) with biological indicator levels from healthy subjects or from other subjects who have been successfully treated. If the relative abundances of these biological indicators indicate that the subject may or will benefit from treatment (e.g., with a FADS1 inhibitor compound), or if a FADS1 disease or disorder exists or may develop, the subject can be selected for treatment.

[0107] Once treatment is selected, a FADS1 inhibitor compound may be administered to the patient, as described elsewhere herein. If these biological indicator levels indicate that the subject will not benefit from treatment or is unlikely to be treated successfully, the subject may be excluded from treatment.

[0108] As disclosed elsewhere herein, in some embodiments, biological indicators may be extracted from or measured in samples taken from a subject before, during, and / or after treatment. In some embodiments, the sample is a tissue sample (e.g., from the liver, organs, or blood). In some embodiments, the sample is taken via tissue biopsy or collected using a syringe (e.g., to collect a blood or plasma sample). In some embodiments, the sample is a bodily fluid (e.g., urine, saliva, plasma, etc.).

[0109] In some embodiments, the relative abundance of one, two, three, four, five, six, seven, eight, or more biological indicators may be used to assess whether a subject has increased FADS1 activity and / or is a candidate for treatment with a FADS1 inhibitor compound. Any combination of the various biological indicators disclosed herein may be used (e.g., in the patient selection process).

[0110] In some embodiments, the biological indicator may include one or more SNPs in the FADS1 gene. In some embodiments, the subject in need of treatment is one that lacks the rs174556 and / or rs7115739 SNPs of FADS1.

[0111] As disclosed elsewhere herein, in some embodiments, the biological indicator, or at least one of the biological indicators, is the ratio of PUFA in a subject. In some embodiments, the PUFA ratio comprises or consists of the ratio of AA to DGLA. In some embodiments, the ratio of AA to DGLA in a subject in need of treatment is about 4:1 or more, 9:2 or more, 5:1 or more, 11:2 or more, 6:1 or more, 7:1 or more, 8:1 or more, 10:1 or more, or ranges including and / or ranging from the aforementioned values. In some embodiments, the ratio of AA to DGLA in a subject in need of treatment is about 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, or ranges including and / or ranging from the aforementioned values, higher than the ratio in a healthy patient. For example, if the ratio of AA to DGLA in a healthy individual is 4, a 10% higher value is 4.4.

[0112] As disclosed elsewhere herein, in some embodiments, the biological indicator, or at least one of the biological indicators, is one or more cell types. In some embodiments, the cell types include one or more of adipocytes ("Adipo"), B cells ("Bcell"), endothelial cells ("Endo"), hepatocytes ("Hep"), Kupffer ("Kupff"), myeloid ("Myel"), natural killer ("NK"), T cells ("Tcell"), or any combination of the foregoing. In some embodiments, the relative abundance of at least one cell type in a subject in need of treatment is increased (e.g., compared to a healthy subject and / or a subject not in need of treatment). In some embodiments, the relative abundance of a cell type (e.g., from a sample) is increased by about 10% or more, 20% or more, 30% or more, 50% or more, 75% or more, 100% or more, 150% or more, 200% or more, 250% or more, 300% or more, 350% or more, 400% or more, 500% or more, or by a range including and / or spanning the aforementioned values. By way of example, if the relative abundance is increased by 200%, this is a 2-fold increase, that is, two times more relative abundance. In some embodiments, the relative abundance of a cell type (e.g., from a sample) is increased by about 1.1-fold or more, 1.2-fold or more, 1.3-fold or more, 1.5-fold or more, 1.75-fold or more, 2-fold or more, 2.5-fold or more, 3-fold or more, 3.5-fold or more, 4-fold or more, 5-fold or more, 10-fold or more, 15-fold or more, 20-fold or more, 40-fold or more, or by a range including and / or spanning the aforementioned values. In some embodiments, the relative abundance of at least one cell type in the subject is decreased. In some embodiments, the relative abundance of a cell type (e.g., from a sample) is decreased by about 2.5% or more, 5% or more, 10% or more, 20% or more, 30% or more, 50% or more, 75% or more, 90% or more, 92.5% or more, 95% or more, 97.5% or more, 99% or more, 99.5% or more, or by a range including and / or spanning the aforementioned values.In some embodiments, the relative abundance of a cell type (e.g., from a sample) is reduced by about 1.5-fold or more, 2-fold or more, 4-fold or more, 5-fold or more, 10-fold or more, 15-fold or more, 20-fold or more, 40-fold or more, or by a range including and / or spanning the aforementioned values. By way of example, if the relative abundance is reduced by 90%, this is a 10-fold reduction, where the relative abundance is 10-fold less (because the relative abundance is 10% of the reference abundance).

[0113] As disclosed elsewhere herein, in some embodiments, the biological indicator, or at least one of the biological indicators, is one or more metabolites. In some embodiments, the metabolites include one or more of the following: plasma cholesterol, free cholesterol, total cholesterol, cholesterol esters, malate, alpha-ketoglutarate, mannose, glucose, erythrone dihydrosphingosine, 5-O-methylsphingosine, threosphingosine, 1-hydroxy-2-amino-(cis,trans)-3,5-octadecadiene, 4-hydroxysphinganine, thromboxane B2, delta-12-prostaglandin D2, prostaglandin E2, prostaglandin D2, 12-hydroxyheptadecatrienoic acid, 14,15-dihydro ... delta-12-prostaglandin D2, delta-12-prostaglandin D2, delta-12-prostaglandin D2, delta-12-prostaglandin D2, delta-12-prostaglandin D2 In some embodiments, the relative abundance of at least one metabolite in a subject is increased (e.g., compared to a healthy subject and / or a subject not in need of treatment). In some embodiments, the relative abundance of a metabolite (e.g., from a sample) is increased by about 10% or more, 20% or more, 30% or more, 50% or more, 75% or more, 100% or more, 200% or more, 300% or more, 500% or more, 700% or more, 1000% or more, or by a range including and / or spanning the aforementioned values.In some embodiments, the relative abundance of a metabolite (e.g., from a sample) is increased by about 1.1-fold or more, 1.2-fold or more, 1.3-fold or more, 1.5-fold or more, 1.75-fold or more, 2-fold or more, 2.5-fold or more, 3-fold or more, 4-fold or more, 5-fold or more, 7-fold or more, 10-fold or more, 20-fold or more, or by a range including and / or spanning the aforementioned values. In some embodiments, the relative abundance of at least one metabolite in a subject is decreased. In some embodiments, the relative abundance of a metabolite (e.g., from a sample) is decreased by about 10% or more, 20% or more, 30% or more, 50% or more, 75% or more, 80% or more, 90% or more, 95% or more, or by a range including and / or spanning the aforementioned values. In some embodiments, the relative abundance of a metabolite (e.g., from a sample) is decreased by about 1.5-fold or more, 2-fold or more, 4-fold or more, 5-fold or more, 8-fold or more, 10-fold or more, 20-fold or more, or by a range including and / or spanning the aforementioned values.

[0114] As disclosed elsewhere herein, in some embodiments, the biological indicator, or at least one of the biological indicators, is one or more DEGs. In some embodiments, the DEGs include one or more of the following: Serpinb1a, Gna14, Serpina3m, Hsd11b1, Cyp2c29, Hsd11b1, Akr1d1, Aldh1a1, Mmp19, Gyp27a1, Tymp, Elovl2, Chkb, H2afj, Tnfaip8l1, Tmem86a, Sel1l3, Agap2, 4833 411C07Rik, Elov4, Fat3, Eef1a2, Atp7a, Rgs2, Cenpe, Mfap2, Mlki67, Ctsh, Trub2, Ubc, H6pd, Eepd1, Acs s2, Aacs, Gm36827, Man2a2, Nudt18, Plagl1, TM4sf19, Atp6v0d2, Gm20056, Trem2, Il1rn, Mmp12, Cdk18, E fr3b, Tagln2, Lurap1, Cp, I17rb, B230303O12Rik, Cfd, Sult1e1, Tdo2, Cyp2b9, Fads1, Hao2, Cyp2b13, Cy p2a22, Acnat2, Ildr2, Rpl10a-ps1, Tm6sf2, Fitm1, Tmem86a, Agap2, Lpar1, C6, Cmah, Lbp, Arsg, Glra3, L ad1, A730063M14Rik, Ly6f, Foxi1, Crygc, Defb28, Wfdc9, Phlda2, Aqp6, Gm16411, Adam7, Ppp2r5b, Slc6a 7, Gpr50, Ahnak2, S100a6, Mmp14, Htr2b, Hpgds, Mfap2, Gm18537, Aacs, Pclo, Adrb3, Gm38394, AC154232.2, Cadps, Adgrb2, Gm45470, Sdr9c7, Dsg1c, Slc17a1, Acnat2, Ces1c, Gss, Hsd11b1, 1810008I18Rik, Tlcd1, Snrk, Akr1c20, Gm19950, Ttr, Cbfa2t3, Acat2, Pmvk, Abcd3, Acss2, Acacb, Arhgap27, Adam7, Rnase9, Wfdc8, Ighv9-2, DerI3, Acap1, Ccl19, Tcf7, Xkrx, Trim46, Zfp369, Zfp871, Pcdhb21, Adrb3, Gm14288, Uprt, Atm, Dchs2, Cped1, Gm38357, Cck, Ckap2, Gm4419, 160 0015I10Rik, Sez6I2, Prnd, Gm16702, S100a8, Pcdh12, Malat1, Kcnq1ot1, ArI4c, Gm38394, Gm42549, AC154232.2, Gm37310, G m37776, Atp2a1, Ckm, Tnnt3, Serpinb1a, Gna14, Serpina3m, Hsd11b1, Cyp2c29, Hsd11b1, Akr1d1, Aldh1a1, Mmp19, Adipoq, Fabp4, Lep, Retn, Hoxc8, Hoxc9, Cebpa, Dgat1, Dgat2, Elovl3, Fads1, Fads2, Fas, Scd1, Srebf1, Adrb3, Hilpda, Lipe, Mgll, Plin1, Plin4, Pnpla2, Pnpla3, Ldah, Cs, Gckr, Mel, Pck1, Pdk4, Irs1, Acaa1a, Acads, Acox1, Cpt1a, Cpt1b, Hadhb, Ehhadh, Ppara, Ppargc1a, Cyp4a12a, Cyp4a12b, Cyp2e1, Adgre1, Agtr1a, Ccl2, Cd14, Cd68, Il1b, Tm6sf2, Tnf, or any combination thereof. In some embodiments, the DEGs include one or more of those shown in Figure 4a, Figure 5a, Figure 10a, Figure 13a, Figure 13g, Figure 15e, Figure 15f, or any one or more of the combinations of DEGs disclosed above. In some embodiments, DEGs are measured using RNA-seq analysis, as disclosed elsewhere herein.

[0115] In some embodiments, the relative abundance of at least one DEG in a subject is increased (e.g., compared to a healthy subject and / or a subject not in need of treatment). In some embodiments, the relative abundance of DEGs (e.g., from a sample) is increased by about 2-fold or more, 3-fold or more, 4-fold or more, 5-fold or more, 10-fold or more, 20-fold or more, 30-fold or more, 40-fold or more, 50-fold or more, 75-fold or more, 100-fold or more, 150-fold or more, 200-fold or more, 1000-fold or more, 100,000-fold or more, 200,000-fold or more, or by a range of factors including and / or spanning the aforementioned values. In some embodiments, the relative abundance of at least one DEG in a subject is decreased. In some embodiments, the relative abundance of DEGs (e.g., from a sample) is decreased by about 2-fold or more, 3-fold or more, 4-fold or more, 5-fold or more, 10-fold or more, 20-fold or more, 30-fold or more, 40-fold or more, 50-fold or more, 75-fold or more, 100-fold or more, 150-fold or more, 200-fold or more, 1000-fold or more, 100,000-fold or more, 200,000-fold or more, or is decreased by a range including and / or spanning the aforementioned values.

[0116] As disclosed elsewhere herein, some embodiments provide methods of treatment. In some embodiments, the subject being treated suffers from a FADS1-mediated disease or disorder (e.g., a disease or disorder that can be treated through modulation of the FADS1 enzyme). In some embodiments, a biological indicator of FADS1 activity is measured in the subject before, concurrently with, or after administration of a FADS1 inhibitor compound. In some embodiments, the FADS1-mediated disease or disorder is one or more of increased body mass index, obesity, metabolic disorders, cardiovascular disorders, diabetes, dyslipidemia, and / or nonalcoholic steatohepatitis (NASH). The scope of methods and uses provided in this disclosure should be understood to encompass methods and uses using all compounds disclosed herein. In addition to being useful for human treatment, the compounds provided herein may be useful for veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, etc. For example, animals including horses, dogs, and cats may be treated with the compounds provided herein.

[0117] In some embodiments, the compounds disclosed herein, or pharmaceutical compositions comprising such compounds, are provided for use in reducing the body weight of a subject. In some embodiments, the compounds, or pharmaceutical compositions comprising such compounds, are provided for use in reducing the body mass index of a subject. In some embodiments, the compounds, or pharmaceutical compositions comprising such compounds, are provided for use in treating a metabolic disorder. In some embodiments, the compounds, or pharmaceutical compositions comprising such compounds, are provided for use in treating a cardiovascular disorder. In some embodiments, the compounds, or pharmaceutical compositions comprising such compounds, are provided for use in treating diabetes. In some embodiments, the compounds, or pharmaceutical compositions comprising such compounds, are provided for use in treating obesity. In some embodiments, the compounds, or pharmaceutical compositions comprising such compounds, are provided for use in treating dyslipidemia. In some embodiments, the compounds, or pharmaceutical compositions comprising such compounds, are provided for use in treating non-alcoholic steatohepatitis (NASH).

[0118] In some embodiments, the compounds, or pharmaceutical compositions comprising such compounds, are used in the preparation of a medicament for reducing the body weight or body mass index of a subject. In some embodiments, the compounds, or pharmaceutical compositions comprising such compounds, are used in the preparation of a medicament for treating a metabolic or cardiovascular disorder. In some embodiments, the compounds, or pharmaceutical compositions comprising such compounds, are used in the preparation of a medicament for treating diabetes, obesity, dyslipidemia, or non-alcoholic steatohepatitis (NASH).

[0119] In some embodiments, the compounds, or pharmaceutical compositions comprising such compounds, are used in methods for reducing body weight and / or reducing body mass index in a subject in need thereof. In some embodiments, the compounds, or pharmaceutical compositions comprising such compounds, are used in methods for treating a metabolic disorder and / or a cardiovascular disorder in a subject in need thereof. In some embodiments, the compounds, or pharmaceutical compositions comprising such compounds, are used in methods for treating diabetes, obesity, dyslipidemia, and / or non-alcoholic steatohepatitis (NASH) in a subject in need thereof. In some embodiments, the compounds, or pharmaceutical compositions comprising such compounds, are used in methods for reducing waist-to-hip ratio (WHR) in a subject in need thereof. In some embodiments, the method comprises administering a therapeutically effective amount of the compound or composition to the subject.

[0120] Provided herein as further embodiments are methods for lowering blood glucose in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition comprising such a compound. In some embodiments, the methods reduce blood glucose by 10% or more. In some embodiments, the methods reduce blood glucose by 15% or more. In some embodiments, the methods reduce blood glucose by 20% or more. In some embodiments, the methods reduce blood glucose by 25% or more. In some embodiments, the methods reduce blood glucose by 30% or more. In some embodiments, the methods reduce blood glucose by 35% or more. In some embodiments, the methods reduce blood glucose by 40% or more. In some embodiments, the methods reduce blood glucose by 50% or more. In some embodiments, the methods reduce blood glucose with minimal impact on food intake / appetite. In some embodiments, the methods reduce blood glucose without having an impact on food intake / appetite.

[0121] Provided herein as further embodiments are methods for lowering insulin in a subject in need thereof, comprising administering to the subject the compound or a pharmaceutical composition comprising such a compound. In some embodiments, the methods lower insulin by 50% or more. In some embodiments, the methods lower insulin by 60% or more. In some embodiments, the methods lower insulin by 70% or more. In some embodiments, the methods lower insulin by 80% or more. In some embodiments, the methods lower blood insulin by 85% or more. In some embodiments, the methods lower insulin by 86% or more. In some embodiments, the methods lower insulin by 87% or more. In some embodiments, the methods lower insulin by 88% or more. In some embodiments, the methods lower insulin by 89% or more. In some embodiments, the methods lower insulin by 90% or more. In some embodiments, the methods lower insulin by 91% or more. In some embodiments, the methods lower insulin with minimal impact on food intake / appetite. In some embodiments, the methods lower insulin without having an impact on food intake / appetite.

[0122] Provided herein as further embodiments are methods for lowering cholesterol in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition comprising such a compound. In some embodiments, the methods lower cholesterol by 10% or more. In some embodiments, the methods lower cholesterol by 15% or more. In some embodiments, the methods lower cholesterol by 20% or more. In some embodiments, the methods lower cholesterol by 30% or more. In some embodiments, the methods lower cholesterol by 31% or more. In some embodiments, the methods lower cholesterol by 32% or more. In some embodiments, the methods lower cholesterol by 33% or more. In some embodiments, the methods lower cholesterol by 34% or more. In some embodiments, the methods lower cholesterol by 35% or more. In some embodiments, the methods lower blood cholesterol by 36% or more. In some embodiments, the methods lower cholesterol by 37% or more. In some embodiments, the methods lower cholesterol by 38% or more. In some embodiments, the methods lower cholesterol by 39% or more. In some embodiments, the methods lower cholesterol while minimizing the impact on food intake / appetite. In some embodiments, the methods lower cholesterol without having an effect on food intake / appetite.

[0123] Provided herein as further embodiments are methods for lowering LDL in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition comprising such a compound. In some embodiments, the methods lower low-density lipoprotein (LDL) by 10% or more. In some embodiments, the methods lower LDL by 20% or more. In some embodiments, the methods lower LDL by 21% or more. In some embodiments, the methods lower LDL by 22% or more. In some embodiments, the methods lower LDL by 23% or more. In some embodiments, the methods lower LDL by 24% or more. In some embodiments, the methods lower LDL by 25% or more. In some embodiments, the methods lower LDL by 26% or more. In some embodiments, the methods lower blood LDL by 27% or more. In some embodiments, the methods lower LDL with minimal impact on food intake / appetite. In some embodiments, the methods lower LDL without having an impact on food intake / appetite.

[0124] Provided herein as a further embodiment is a method for lowering triglycerides in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition comprising such a compound. In some embodiments, the method lowers triglycerides by 30% or more. In some embodiments, the method lowers triglycerides by 40% or more. In some embodiments, the method lowers triglycerides by 50% or more. In some embodiments, the method lowers triglycerides by 51% or more. In some embodiments, the method lowers triglycerides by 52% or more. In some embodiments, the method lowers triglycerides by 53% or more. In some embodiments, the method lowers triglycerides by 54% or more. In some embodiments, the method lowers triglycerides by 55% or more. In some embodiments, the method lowers blood triglycerides by 56% or more. In some embodiments, the method lowers triglycerides by 57% or more. In some embodiments, the methods lower triglycerides with minimal impact on food intake / appetite. In some embodiments, the methods lower triglycerides without having an impact on food intake / appetite.

[0125] Provided herein as further embodiments are methods for reducing body fat mass in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition comprising such a compound. In some embodiments, the methods reduce the subject's body fat mass by 30% or more. In some embodiments, the methods reduce the subject's body fat mass by 40% or more. In some embodiments, the methods reduce the subject's body fat mass by 45% or more. In some embodiments, the methods reduce the subject's body fat mass by 50% or more. In some embodiments, the methods reduce the subject's body fat mass by 55% or more. In some embodiments, the methods reduce the subject's blood body fat mass by 60% or more. In some embodiments, the methods reduce the subject's body fat mass by 65% ​​or more. In some embodiments, the methods reduce the subject's body fat mass by 70% or more. In some embodiments, the methods reduce the subject's body fat mass by 75% or more. In some embodiments, the methods reduce the subject's body fat mass with minimal impact on food intake / appetite. In some embodiments, the methods reduce the subject's body fat mass without having an impact on food intake / appetite.

[0126] As a further embodiment, provided herein is a method for increasing adiponectin in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or a pharmaceutical composition comprising such a compound.

[0127] As a further embodiment, provided herein is a method for lowering leptin in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or a pharmaceutical composition comprising such a compound.

[0128] As a further embodiment, provided herein is a method of reducing resistance in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or a pharmaceutical composition comprising such a compound.

[0129] The various method steps described above can be performed in an alternate sequence or order to achieve desirable results.

[0130] In addition, the treatment results of the methods disclosed herein provide further opportunities to optimize the administration regimen for patients.For example, if the treatment results (for example, weight loss, reduction of dyslipidemia, etc.) after a treatment period (for example, 2 months or more, 6 months or more, etc.) are lower than expected, the administration of FADS1 inhibitor can be increased.If the downstream results (for example, weight loss, reduction of dyslipidemia, etc.) after a treatment period (for example, 2 months or more, 6 months or more, etc.) are higher than expected or desired, the administration of FADS1 inhibitor can be maintained or reduced.

[0131] FADS1 inhibitor compounds In some embodiments, a method for treating a FADS1-mediated disease or disorder is carried out by administering a compound disclosed herein (e.g., a FADS1 inhibitory compound), a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer to a subject in need of treatment.

[0132] Provided herein as embodiment 62 is the method or compound of any one of embodiments 1 to 61, wherein the FADS1 inhibitor compound is: 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 3-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-3,7-bis(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-Fluoro-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-chloro-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-(Methoxymethyl)-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-Cyclopropyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-Cyclopropyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2,3-Dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-3H,7H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2,3-Dimethyl-5-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-3H,7H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 7-ethyl-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 1,2-dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-1H,7H-pyrazolo[1,5-a]pyrimidin-7-one; 1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-1H,7H-pyrazolo[1,5-a]pyrimidin-7-one; 1,3-Dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-1H,7H-pyrazolo[1,5-a]pyrimidin-7-one; 3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H,6H,7H,8H-pyrrolo[1,2-a]pyrimidin-4-one; 2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H,6H,7H,8H-pyrrolo[1,2-a]pyrimidin-4-one; 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-2H,3H,5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 6-{1-[(2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-2-methyl-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-2H,3H,5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 8-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-9-(trifluoromethyl)-6,10-diazatricyclo[4.4.0.0 2 , 4 ]deca-1(10),8-dien-7-one; 6-{1-[(3,3-difluorocyclobutyl)methyl]-1H-pyrazol-4-yl}-2-methyl-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-[1,2,4]triazolo[4,3-a]pyrimidin-5-one; 3-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-3H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidin-7-one; 2-methyl-6-{1-[(oxetan-3-yl)methyl]-1H-pyrazol-4-yl}-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-3-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-(hydroxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-(hydroxymethyl)-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-chloro-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(propan-2-yl)-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione; 1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 3-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-3H,7H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]oxazolo[3,2-a]pyrimidin-5-one; 2-methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 7-Ethoxy-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-(Methoxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-Methoxy-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 3-chloro-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-(hydroxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-(hydroxymethyl)-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione; 2-chloro-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-chloro-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Cyclopropyl-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-chloro-1-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-Dimethyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-dimethyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-(Methoxymethyl)-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-Ethyl-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(2-Methoxyethyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(propan-2-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-{1-[(2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-1,2-dimethyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-{1-[(3,3-difluorocyclobutyl)methyl]-1H-pyrazol-4-yl}-1,2-dimethyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-1,2-dimethyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(cyclopropylmethyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-(Methoxymethyl)-1-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(2-hydroxypropyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-dimethyl-6-{1-[(oxetan-3-yl)methyl]-1H-pyrazol-4-yl}-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(cyclopropylmethyl)-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-[2-(dimethylamino)ethyl]-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(cyclopropylmethyl)-2-methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-[2-(dimethylamino)ethyl]-2-methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-3-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methoxy-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methoxy-1-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-{1-[(2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-( 2 H3) methyl-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-( 2 H3) methyl-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(2-hydroxyethyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; Methyl 2-methyl-5-oxo-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidine-1-carboxylate; 1-[(2,2-difluorocyclopropyl)methyl]-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-[(3,3-difluorocyclobutyl)methyl]-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(2-hydroxyethyl)-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-[2-(dimethylamino)ethyl]-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(prop-2-yn-1-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-{2-methyl-5-oxo-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-1-yl}acetonitrile; 2-[2-methyl-5-oxo-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-1-yl]acetonitrile; 1-(2-hydroxy-2-methylpropyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-[2-(1-hydroxycyclopropyl)ethyl]-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-1-[(oxetan-3-yl)methyl]-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-1-(oxetan-3-yl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidine-5-thione; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyridin-2-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-1-(pyridin-2-yl)-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyrazin-2-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-1-(6-methylpyridin-2-yl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-1-(1-methyl-1H-pyrazol-4-yl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyridin-3-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-phenyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(6-chloropyridin-2-yl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyridin-4-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(1H-pyrazol-4-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-(Fluoromethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-[(Dimethylamino)methyl]-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 6-(1-{[(1R)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-(1-{[(1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-(1-{[(1R)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-1,2-dimethyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-(1-{[(1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-1,2-dimethyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-(1-{[(1R)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 6-(1-{[(1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; (2R)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-2H,3H,5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; (2S)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-2H,3H,5H,6H,7H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 1-{[(1R)-2,2-difluorocyclopropyl]methyl}-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-{[(1S)-2,2-difluorocyclopropyl]methyl}-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; (2R)-2-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenoxy)propanenitrile; (2R)-2-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-3-yl)phenoxy)propanenitrile; (2S)-2-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenoxy)propanenitrile; (2S)-2-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-3-yl)phenoxy)propanenitrile; (4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)-1H-pyrazol-1-yl)acetonitrile; (4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenoxy)acetonitrile; (4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenyl)acetonitrile; (4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-3-yl)phenoxy)acetonitrile; (4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-8-yl)acetonitrile; 1-(chloromethyl)-7-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-8-(trifluoromethyl)-1H,2H,6H-pyrimido[1,2-a][1,3]diazine-2,6-dione; 1-(Fluoromethyl)-7-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-8-(trifluoromethyl)-1H,2H,6H-[1,3]diazino[1,2-a]pyrimidine-2,6-dione; 1-(methyl-d3)-7-(4-(2,2,2-trifluoroethoxy)phenyl)-8-(trifluoromethyl)-2H-pyrimido[1,2-a]pyrimidine-2,6(1H)-dione; 1-methyl-7-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-8-(trifluoromethyl)-1H,2H,6H-[1,3]diazino[1,2-a]pyrimidine-2,6-dione; 2-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenoxy)-2-methylpropanenitrile; 2-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenoxy)propanenitrile; 2-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-3-yl)phenoxy)propanenitrile; 2-(Difluoromethyl)-3-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one; 2-(Difluoromethyl)-4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile; 2-(Difluoromethyl)-8-methoxy-3-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-(Difluoromethyl)-8-methoxy-3-(1-(4,4,4-trifluorobutyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-(Difluoromethyl)-8-methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-(Difluoromethyl)-8-methoxy-3-(6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-(Fluoromethyl)-4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile; 2-(Fluoromethyl)-8-methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H,6H,7H,9H-pyrimido[2,1-c][1,4]oxazin-4-one; 2,8-Dimethoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-Cyclopropyl-8-methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-Ethoxy-8-methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-ethoxy-8-methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 2-Ethyl-8-methoxy-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-Ethyl-8-methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-Ethyl-8-methoxy-3-(6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-4,8(1H)-dione; 3-(1-(2,2-difluoropropyl)-1H-pyrazol-4-yl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-{[(1R)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-{[(1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-benzofuran-2-yl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-cyclopropyl-1H-pyrazol-4-yl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-phenyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-propyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 3-(2-fluoro-4-(trifluoromethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(2-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 3-(4-(((1R)-2,2-difluorocyclopropyl)methoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(((1S)-2,2-difluorocyclopropyl)methoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-((2,2-difluorocyclopropyl)methoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-4,8(1H)-dione; 3-(4-(2,2,2-trifluoroethoxy)phenyl)-2,8-bis(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(2,2-difluoroethoxy)-2-fluorophenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(2,2-difluoroethoxy)phenyl)-8-(methyloxy-d3)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(2,2-difluoroethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(2,2-difluoropropoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(2-fluoroethoxy)phenyl)-8-(methyloxy-d3)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(2-fluoroethoxy)phenyl)-8-(methyloxy-d3)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 3-(4-(2-fluoroethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(2-fluoroethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 3-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)-1H-pyrazol-1-yl)propanenitrile; 3-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenyl)propanenitrile; 3-(4-(cyclopropylmethoxy)-2-fluorophenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(cyclopropylmethoxy)phenyl)-8-(methyloxy-d3)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(cyclopropylmethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(cyclopropylmethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 3-(4-(difluoromethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(5-(2,2,2-trifluoroethoxy)-2-pyridinyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H,6H,7H,9H-pyrimido[2,1-c][1,4]oxazin-4-one; 3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 3-[5-iodo-1-(2,2,3,3,3-pentafluoropropyl)-1H-1,2,3-triazol-4-yl]-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-{1-[(2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-7-fluoro-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-{1-[(2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-{1-[(2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 3-{1-[(3,3-difluorocyclobutyl)methyl]-1H-pyrazol-4-yl}-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-{1-[(3,3-difluorocyclobutyl)methyl]-1H-pyrazol-4-yl}-8-methoxy-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 3-{1-[(3,3-difluorocyclobutyl)methyl]-1H-pyrazol-4-yl}-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 3-Fluoro-1-methyl-7-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-8-(trifluoromethyl)-1H,2H,6H-[1,3]diazino[1,2-a]pyrimidine-2,6-dione; 4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile; 4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxylic acid; 4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile; 4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxamide; 4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxylic acid; 4-oxo-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-7-carbonitrile; 7-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-8-(trifluoromethyl)-2H-pyrimido[1,2-a]pyrimidine-2,6(1H)-dione; 7-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-8-(trifluoromethyl)-2H-pyrimido[1,2-a]pyrimidine-2,6(1H)-dione; 7-(4-(2,2,2-trifluoroethoxy)phenyl)-8-(trifluoromethyl)-2H-pyrimido[1,2-a]pyrimidine-2,6(1H)-dione; 7-(4-(2-fluoroethoxy)phenyl)-8-(trifluoromethyl)-2H-pyrimido[1,2-a]pyrimidine-2,6(1H)-dione; 7-(Methoxymethyl)-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7,8-Dimethyl-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H-pyrimido[1,2-b]pyridazin-4-one; 7,8-dimethyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7,9-dimethyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 7-chloro-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 7-chloro-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 7-chloro-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-chloro-8-methoxy-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 7-chloro-8-methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-[1,3]diazino[1,2-a]pyrimidin-4-one; 7-chloro-8-methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-chloro-8-methyl-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 7-chloro-8-methyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-chloro-8-methyl-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-Cyclopropyl-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 7-Cyclopropyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-Fluoro-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 7-Fluoro-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-Fluoro-8-hydroxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-Fluoro-8-methoxy-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 7-Fluoro-8-methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-[1,3]diazino[1,2-a]pyrimidin-4-one; 7-Fluoro-8-methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-Fluoro-8-methoxy-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-Fluoro-8-methyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-Methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-[1,3]diazino[1,2-a]pyrimidin-4-one; 7-Methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 7-Methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-Methyl-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H-pyrimido[1,2-b]pyridazin-4-one; 7-methyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-[1,3]diazino[1,2-a]pyrimidin-4-one; 7-methyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 7-methyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-methyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-((1R)-1-hydroxyethyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((1R)-1-hydroxyethyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((1S)-1-hydroxyethyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((1S)-1-hydroxyethyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((dimethylamino)methyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Methyloxy-d3)-2-(trifluoromethyl)-3-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((methylsulfanyl)methoxy)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((R)-ethylsulfinyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((R)-Methylsulfinyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((R)-Methylsulfinyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((S)-Ethylsulfinyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((S)-Methylsulfinyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((S)-Methylsulfinyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(1,3-oxazol-2-yl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(1-hydroxyethyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(1-hydroxyethyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(2-hydroxypropan-2-yl)-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(2-methyl-2-oxetanyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(2-propanyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(3-azetidinyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(aminomethyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(1-azetidinyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(chloromethoxy)-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(chloromethoxy)-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-(Difluoromethoxy)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Difluoromethyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Dimethylamino)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Dimethylamino)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Ethylsulfinyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Fluoromethoxy)-2-(trifluoromethyl)-3-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Fluoromethoxy)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Fluoromethoxy)-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Fluoromethoxy)-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-(Fluoromethyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Fluoromethyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(hydroxymethyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(hydroxymethyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Methoxymethyl)-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Methylamino)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Methylamino)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Methylamino)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 8-(methyl-d3)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Methyloxy-d3)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Methyloxy-d3)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 8-(Methyloxy-d3)-3-(1-(4,4,4-trifluorobutyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Methyloxy-d3)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Methyloxy-d3)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 8-(Methyloxy-d3)-3-(6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Methylsulfanyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Methylsulfanyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Methylsulfinyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Methylsulfinyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(Methylsulfonyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-acetyl-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-amino-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-amino-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-amino-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 8-chloro-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-chloro-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Cyclopropyl-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Cyclopropyl-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-ethenyl-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Ethoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-ethyl-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Fluoro-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Hydroxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-Methoxy-2-(trifluoromethyl)-3-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-2-(trifluoromethyl)-3-(1-(3,3,3-trifluoropropyl)-1H-imidazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-2-(trifluoromethyl)-3-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-2-(trifluoromethyl)-3-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 8-Methoxy-2-(trifluoromethyl)-3-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-2-(trifluoromethyl)-3-(4-(3,3,3-trifluoropropyl)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H-pyrimido[1,2-b]pyridazin-4-one; 8-Methoxy-2-(trifluoromethyl)-3-[3-(3,3,3-trifluoropropyl)-1,2-oxazol-5-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-2-(trifluoromethyl)-3-[4-(3,3,3-trifluoropropyl)-1H-imidazol-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-2-(trifluoromethyl)-3-[5-(3,3,3-trifluoropropyl)-1,3-thiazol-2-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-2-methyl-3-(4-(2,2,2-trifluoroethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(1-(4,4,4-trifluorobutyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(1-(4,4,4-trifluorobutyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(1-phenyl-1H-pyrazol-3-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(1-phenyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(1-propyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(2-methyl-4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(2-phenyl-1,3-oxazol-5-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(3-phenyl-1,2-oxazol-5-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(4-(2,2,2-trifluoroethoxy)-2-(trifluoromethyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(4-(2,2,3,3,3-pentafluoropropoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(4-(2,2,3,3-tetrafluoropropoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(4-(trifluoromethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(4-(trifluoromethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(4-propylphenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(5-propyl-1,2-oxazol-3-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(6-propyl-3-pyridinyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-1,2,3-triazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-3-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-[1,3]diazino[1,6-a]pyrimidin-4-one; 8-Methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-Methoxy-3-[2-(2,2,2-trifluoroethoxy)-1,3-thiazol-5-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-[1,3]diazino[1,2-a]pyrimidin-4-one; 8-Methoxy-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-Methoxy-3-[2-(2,2,3,3,3-pentafluoropropoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-[3-(2,2,3,3,3-pentafluoropropyl)-1,2-oxazol-5-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-[4-(2,2,2-trifluoroethoxy)-1,3-thiazol-2-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-[5-(2,2,2-trifluoroethoxy)-1,3-thiazol-2-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-{1-[(oxetan-3-yl)methyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-6-methyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methyl-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H-pyrimido[1,2-b]pyridazin-4-one; 8-methyl-2-(trifluoromethyl)-3-[5-(3,3,3-trifluoropropyl)-1,2,4-oxadiazol-3-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 8-methyl-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-methyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H,6H,7H,8H,9H-pyrimido[1,2-a]pyrazin-4-one; 8-methyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-methyl-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-methyl-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 9-chloro-8-methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 9-Fluoro-8-methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 9-methyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; Methyl 4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxylate; Methyl(4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-8-yl)carbamyl fluoride; N-(4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-8-yl)acetamide; N-(4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-8-yl)acetamide; N,N-Dimethyl-4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxamide; N-ethyl-4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxamide; N-methyl-4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxamide; or N-methyl-4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxamide; or A pharmaceutically acceptable salt of any of the foregoing.

[0133] Provided herein as embodiment 63 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0134] Provided herein as embodiment 64 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0135] Provided herein as embodiment 65 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0136] Provided herein as embodiment 66 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0137] Provided herein as embodiment 67 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0138] Provided herein as embodiment 68 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0139] Provided herein as embodiment 69 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0140] Provided herein as embodiment 70 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0141] Provided herein as embodiment 71 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0142] Provided herein as embodiment 72 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0143] Provided herein as embodiment 73 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0144] Provided herein as embodiment 74 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0145] Provided herein as embodiment 75 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0146] Provided herein as embodiment 76 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0147] Provided herein as embodiment 77 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0148] Provided herein as embodiment 78 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0149] Provided herein as embodiment 79 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0150] Provided herein as embodiment 80 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0151] Provided herein as embodiment 81 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0152] Provided herein as embodiment 82 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0153] Provided herein as embodiment 83 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0154] Provided herein as embodiment 84 is a FADS1 inhibitor compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0155] Provided herein as embodiment 85 is the method or compound of any one of embodiments 1 to 84, wherein the FADS1 inhibitor compound is a free base.

[0156] Patient response and labeled DGLA Also disclosed herein are methods for evaluating, analyzing, and / or adjusting the dosing regimen for patients who have been treated with a FADS1 inhibitor compound or who are currently undergoing a treatment regimen. One or more methods disclosed herein can be used to test the level of inhibition produced by a dose of a FADS1 inhibitor compound compared to the maximum inhibition level (e.g., IC level). If the inhibitory concentration level is lower than the target level and / or desired level, the dose can be adjusted (e.g., adjusted upward). If the inhibitory concentration level is equal to or greater than the target level, the dose can be adjusted downward or maintained. For example, if the target therapeutic dose is an inhibitory concentration equal to or greater than 90% of the maximum inhibitory concentration (IC90) and the actual dose produces 50% inhibition (e.g., IC50), the dose of the FADS1 inhibitor can be increased (by increasing the dose or increasing the frequency of administration). In some embodiments, the target therapeutic inhibitory concentration is greater than or equal to about 70% (e.g., IC70), 80% (e.g., IC80), 90% (e.g., IC90), 95% (e.g., IC95), 97.5% (e.g., IC97.5), 99% (e.g., IC99), 99.9% (e.g., IC99.9), 100% (IC100), or a range including and / or spanning the aforementioned values. In some embodiments, the measured and / or actual inhibitory concentration at an administered dose is greater than or equal to about 10% (e.g., IC10), 20% (e.g., IC20), 30% (e.g., IC30), 40% (e.g., IC40), 50% (e.g., IC50), 60% (e.g., IC60), 70% (e.g., IC70), 80% (e.g., IC80), 90% (e.g., IC90), or a range including and / or spanning the aforementioned values. In some embodiments, the dose may be increased if the actual inhibitory concentration is less than or equal to about 10% (e.g., IC), 20% (e.g., IC), 30% (e.g., IC), 50% (e.g., IC), 60% (e.g., IC), 70% (e.g., IC), 80% (e.g., IC), 90% (e.g., IC), 95% (e.g., IC) of the maximum inhibitory concentration, or a range including and / or spanning the aforementioned values. In some embodiments, if the inhibitory concentration is below the desired concentration, the dose is increased by about 5%, 10%, 15%, 20%, 30%, 50%, 75%, 100%, 200% or more, or by a range including and / or spanning the aforementioned values. In some embodiments, if the inhibitory concentration is below the desired concentration, the dosing frequency is doubled. In some embodiments, both the dose and the dosing frequency may be increased.

[0157] In some embodiments, to measure the inhibitory concentration achieved by a particular FADS1 inhibitory compound, a labeled DGLA molecule may be administered to a subject (e.g., orally, intravascularly, intravenously, intraarterially, intraperitoneally, subcutaneously, etc.). After a certain period of time, a sample is taken from the subject as disclosed elsewhere herein. The amount of labeled AA and labeled DGLA in the sample may then be determined. The amounts of labeled AA and labeled DGLA may be used to calculate the inhibitory concentration (e.g., using the methods disclosed in the Examples section). In some embodiments, the sample is a tissue biopsy or a blood sample (e.g., a plasma sample). In some embodiments, the period from administration of labeled DGLA to sample collection is about 30 minutes or more, 45 minutes or more, 1 hour or more, 2 hours or more, 3 hours or more, 4 hours or more, 6 hours or more, 8 hours or more, 10 hours or more, 12 hours or more, 16 hours or more, 18 hours or more, 24 hours or more, or a range including and / or spanning the aforementioned values.

[0158] In some embodiments, the FADS1 inhibitor compound is administered to a subject before, simultaneously with, or after the administration of a labeled DGLA molecule (e.g., an isotopic derivative of DGLA). In some embodiments, the period between the administration of the FADS1 inhibitor and the administration of labeled DGLA is about 30 minutes or more, 45 minutes or more, 1 hour or more, 2 hours or more, 3 hours or more, 4 hours or more, 6 hours or more, 8 hours or more, 10 hours or more, 12 hours or more, 16 hours or more, 18 hours or more, 24 hours or more, or a range including and / or spanning the aforementioned values.

[0159] In some embodiments, the labeled DGLA is 13 In some embodiments, the labeled DGLA is isotopically enriched with C at two or more positions. 13 In some embodiments, the labeled DGLA is isotopically enriched with C atoms. 13In some embodiments, the labeled DGLA is isotopically enriched with C atoms. 13 In some embodiments, the labeled DGLA is isotopically enriched with C atoms. 13 In some embodiments, the labeled DGLA is isotopically enriched with C atoms. In some embodiments, the labeled DGLA is isotopically enriched at about 1 or more positions, 2 or more positions, 3 or more positions, 4 or more positions, 5 or more positions, 6 or more positions, 7 or more positions, 8 or more positions, 9 or more positions, 10 or more positions, 11 or more positions, 12 or more positions, 13 or more positions, 14 or more positions, 15 or more positions, 16 or more positions, 17 or more positions, 18 or more positions, 19 or more positions, 20 or more positions. 13 In some embodiments, the labeled DGLA comprises DGLA isotopically enriched at C atoms or at positions in the range including and / or spanning the aforementioned values. 13 Contains DGLA that is uniformly isotopically enriched with C atoms.

[0160] In some embodiments, the labeled DGLA has the following structure: [ka] wherein each "*" symbol represents: 13 indicates positions that can be isotopically enriched with C, and at least one "*" position is 13 In some embodiments, the compound is isotopically enriched with C. 13 C w -DGLA, where "w" is 13 The "*" is the number of positions that are isotopically enriched with C. In some embodiments, "w" is 1, 2, 3, 4, or 5 or more. For example, if w is 2, then two "*" symbols represent: 13 In some embodiments, two or more "*" symbols represent positions that are isotopically enriched with C.13 In some embodiments, three or more "*" symbols represent positions that are isotopically enriched with C. 13 In some embodiments, four or more "*" symbols represent positions that are isotopically enriched with C. 13 In some embodiments, five or more "*" symbols represent positions that are isotopically enriched with C. 13 C denotes positions that are isotopically enriched.

[0161] In some embodiments, measurements of biological indicators disclosed elsewhere herein may be incorporated into methods of treatment and methods of use disclosed elsewhere herein. In some embodiments, measurements of biological indicators and / or patient selection steps disclosed elsewhere herein are used in methods of reducing a subject's weight, reducing body mass index, treating obesity, treating a metabolic disorder, treating a cardiovascular disorder, treating diabetes, treating obesity, treating dyslipidemia, and / or treating nonalcoholic steatohepatitis (NASH). Methods and uses into which the measurement and selection steps described in this section may be incorporated are described elsewhere herein.

[0162] Provided herein as embodiment 86 is a method for measuring a ratio of arachidonic acid (AA) to dihomo-gamma-linolenic acid (DGLA) in a subject, comprising: AA is isotopically labeled and DGLA is isotopically labeled, measuring the ratio of AA to DGLA by administering a dose of labeled DGLA to the subject and then measuring the ratio of labeled AA to labeled DGLA; It is a method.

[0163] Provided herein as embodiment 87 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of DGLA, the method ... 13 87. The method of embodiment 86, comprising DGLA isotopically enriched with C.

[0164] Provided herein as embodiment 88 is a labeled DGLA having at least two carbon positions 13 88. The method of embodiment 87, comprising DGLA isotopically enriched with C atoms. For example, in some embodiments, the labeled DGLA is isotopically enriched with C atoms at two carbon positions. 13 In some embodiments, the labeled DGLA is isotopically enriched with C atoms. 13 It is DGLA that is isotopically enriched with C atoms.

[0165] Provided herein as embodiment 89 is a labeled DGLA having three or more carbon positions. 13 88. The method of embodiment 87, comprising DGLA isotopically enriched with C atoms. For example, in some embodiments, the labeled DGLA is isotopically enriched with C atoms at three carbon positions. 13 In some embodiments, the labeled DGLA is isotopically enriched with C atoms. 13 It is DGLA that is isotopically enriched with C atoms.

[0166] Provided herein as embodiment 90 is a labeled DGLA having four or more carbon positions. 13 88. The method of embodiment 87, comprising DGLA isotopically enriched with C atoms. For example, in some embodiments, the labeled DGLA is isotopically enriched with C atoms at four carbon positions. 13 In some embodiments, the labeled DGLA is isotopically enriched with C atoms. 13 It is DGLA that is isotopically enriched with C atoms.

[0167] Provided herein as embodiment 91 is a labeled DGLA having 5 or more carbon positions. 1388. The method of embodiment 87, comprising DGLA isotopically enriched with C atoms. For example, in some embodiments, the labeled DGLA is isotopically enriched with C atoms at five carbon positions. 13 In some embodiments, the labeled DGLA is isotopically enriched with C atoms. 13 It is DGLA that is isotopically enriched with C atoms.

[0168] Provided herein as embodiment 92 is a method for producing a labeled DGLA comprising: [ka] 92. The method of any one of embodiments 86-91, wherein the carbon atom is a carbon atom, and the carbon atom is a carbon atom. 13 In some embodiments, three or more "*" symbols represent positions that are isotopically enriched with C. 13 In some embodiments, four or more "*" symbols represent positions that are isotopically enriched with C. 13 In some embodiments, each of the five "*" symbols represents a position that is isotopically enriched with 13 C denotes positions that are isotopically enriched.

[0169] Provided herein as embodiment 93 is a method according to any one of embodiments 86-92, wherein a dose of a FADS1 inhibitor compound is administered to the subject prior to, concurrently with, or after administration of a labeled dose of DGLA to the subject.

[0170] Provided herein as embodiment 94 is the method of embodiment 92, in which the conversion of labeled DGLA to labeled AA is used to measure and / or calculate the level of inhibition of the FADS1 enzyme by the FADS1 inhibitor compound at the dose provided to the patient.

[0171] Provided herein as embodiment 95 is the method of embodiment 94, further comprising comparing the measured level of inhibition by the FADS1 inhibitor compound at the dose provided to the patient with a desired level of inhibition of FADS1.

[0172] Provided herein as embodiment 96 is the method of embodiment 95, further comprising determining an adjusted dose of the FADS1 inhibitor for the subject based on a comparison of the measured level of inhibition of FADS1 with a desired level.

[0173] Provided herein as embodiment 97 is the method of embodiment 96, further comprising administering to the subject a titration dose of a FADS1 inhibitor.

[0174] Provided herein as embodiment 98 is a compound having the following structure: [ka] is a compound represented by During the ceremony, Each "*" symbol represents 13 indicates positions that can be isotopically enriched with C, At least one "*" position must be 13 isotopically enriched with C, It is a compound.

[0175] Provided herein as embodiment 99 is a compound having the following structure: [ka] is a compound represented by During the ceremony, Each "*" symbol represents 13 indicates positions that can be isotopically enriched with C, At least one "*" position must be 13 isotopically enriched with C, It is a compound.

[0176] Provided herein as embodiment 100 is a compound having the following structure: [ka] is a compound represented by During the ceremony, X is a halogen; Each "*" symbol represents 13 indicates positions that can be isotopically enriched with C, At least one "*" position must be 13 isotopically enriched with C, It is a compound.

[0177] Provided herein as embodiment 101 is that at least two "*" positions are: 13 The compound of any one of embodiments 98-100, wherein the compound is isotopically enriched with C.

[0178] Provided herein as embodiment 102 is at least three "*" positions: 13 The compound of any one of embodiments 98-100, wherein the compound is isotopically enriched with C.

[0179] Provided herein as embodiment 103 is at least four "*" positions: 13 The compound of any one of embodiments 98-100, wherein the compound is isotopically enriched with C.

[0180] Provided herein as embodiment 104 is that all five "*" positions are 13 The compound of any one of embodiments 98-100, wherein the compound is isotopically enriched with C.

[0181] Provided herein as embodiment 105 is a compound of any one of embodiments 98-104, wherein each isotopically enriched position is enriched by 100-fold or more. For example, the isotopic enrichment factor at the labeled position is 100 or more.

[0182] Provided herein as embodiment 106 is a compound of any one of embodiments 98-104, wherein each isotopically enriched position is enriched by 500-fold or more. For example, the isotopic enrichment factor at the labeled position is 500 or more.

[0183] Provided herein as embodiment 107 is a compound of any one of embodiments 98-104, wherein each isotopically enriched position is enriched by 1000-fold or more. For example, the isotopic enrichment factor at the labeled position is 1000 or more.

[0184] Methods for producing labeled DGLA Some embodiments disclosed herein provide methods for producing labeled DGLA. In some embodiments, DGLA is prepared by the method disclosed elsewhere herein. 13 Labeled with C. Excessively low 13 It has been found that C-atom labeled DGLA provides insufficient signal for measuring the ratio of labeled DGLA to labeled AA (e.g., for pharmacodynamic analysis). Advantageously, multiple (e.g., 2, 3, 4, or 5) 13 It has been found that C-labeled DGLA provides a sufficient signal to allow calculation of inhibitory concentration values ​​(e.g., as a measure of direct response by differentiation from endogenous DGLA and AA levels). 13 It has been found that DGLA labeled with a C label provides a sufficient signal to allow calculation of inhibitory concentration values. 13 C-labeled DGLA (e.g., dihomo-gamma-linoleic acid 1,2,3,4,5- 13 C) was prepared.

[0185] The scheme below (Scheme 1) provides one example route for the synthesis of DGLA, although others will be readily apparent based on the present disclosure: Scheme 1. [ka] Each "*" symbol represents 13 indicates positions that can be isotopically enriched with C, and at least one "*" position is 13 In some embodiments, y is 1, 2, 3, or 4 or more. For example, when y is 2, the two "*" symbols represent: 13 C represents the position isotopically enriched ([ 13 C2]). In some embodiments, at least two "*" symbols are 13 In some embodiments, at least three "*" symbols represent positions that are isotopically enriched with 13 In some embodiments, at least four "*" symbols represent positions that are isotopically enriched with 13 C represents a position that is isotopically enriched. In some embodiments, the structure [ 13 C w ]-14 and [ 13 C w ]-15, each of the five "*" symbols 13 C denotes positions that are isotopically enriched.

[0186] The scheme below (Scheme 2) provides another exemplary route for the synthesis of DGLA, where each "*" represents 13 It is isotopically enriched with C. Scheme 2. [ka]

[0187] In some embodiments, 13 C w -DGLA (represented by the structure below): [ka] The method for producing the compound [ka] with KC*N, wherein each "*" symbol represents 13 indicates positions that can be isotopically enriched with C, and at least one "*" position is 13 In some embodiments, X is isotopically enriched with C, and X is a suitable leaving group. In some embodiments, X is a halogen. In some embodiments, X is Br. In some embodiments, 13 C w -At least two "*" symbols on the DGLA 13 C represents a position that is isotopically enriched. 13 C w -At least three "*" symbols on the DGLA 13 C represents a position that is isotopically enriched. 13 C w -At least four "*" symbols on the DGLA 13 C represents a position that is isotopically enriched. 13 C w -All five "*" symbols on DGLA 13 C denotes positions that are isotopically enriched.

[0188] Labeled 1,4-butanediol (e.g., 1,4-butanediol- 13 C4) is commercially available. This can be synthesized using the following synthesis scheme (Scheme 3) to obtain the compound [ 13 C4]-8: Scheme 3. [ka]

[0189] Provided herein as embodiment 108 is a compound having the following structure: [ka] A method for producing a compound represented by the formula: [ka] with KC*N, During the ceremony, Each "*" symbol represents 13 indicates positions that can be isotopically enriched with C, and at least one "*" position is 13 isotopically enriched with C; X is a suitable leaving group; In some embodiments, two or more "*" symbols are 13 In some embodiments, three or more "*" symbols represent positions that are isotopically enriched with C. 13 In some embodiments, four or more "*" symbols represent positions that are isotopically enriched with C. 13 In some embodiments, each of the five "*" symbols represents a position that is isotopically enriched with 13 C denotes positions that are isotopically enriched.

[0190] Provided herein as embodiment 109 is the method of embodiment 108, wherein X is halogen.

[0191] Provided herein as embodiment 110 is the method of embodiment 109, wherein X is Br.

[0192] Formulation and Route of Administration In the described uses, although it may be possible to administer the compounds disclosed herein alone, the administered compounds are usually present as active ingredients in pharmaceutical compositions. Thus, in one embodiment, provided herein is a pharmaceutical composition comprising a compound disclosed herein in combination with one or more pharmaceutically acceptable excipients, such as diluents, carriers, adjuvants, and optionally other active ingredients. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein (e.g., a FADS1 inhibitor compound).

[0193] The compounds disclosed herein can be administered by any suitable route in the form of a pharmaceutical composition adapted to such route and in a dose effective for the intended treatment. The compounds and compositions presented herein can be administered in dosage unit formulations containing conventional pharmaceutically acceptable excipients, for example, orally, mucosally, topically, transdermally, rectally, pulmonary, parenterally, intranasally, intravascularly, intravenously, intraarterially, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, intravaginally, or by infusion techniques.

[0194] The pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, mini-tablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drop, injectable solution, emulsion, microemulsion, ointment, aerosol, aqueous suspension, or oily suspension. The pharmaceutical composition is typically made in the form of a dosage unit containing a particular amount of the active ingredient.

[0195] Enumerated Embodiments Provided herein as embodiment A.1 is a method for identifying a subject having increased fatty acid desaturase 1 (FADS1) activity, comprising: Measuring one or more biological indicators of a FADS1-mediated disease or disorder in a subject. Including, The one or more biological indicators comprise, consist of, or consist essentially of one or more of: ratios of polyunsaturated fatty acids ("PUFAs"), relative abundance of one or more cell types, relative abundance of one or more differentially expressed genes (DEGs) or gene signatures, and / or relative abundance of one or more metabolites in the subject; It is a method.

[0196] Provided herein as embodiment A.2 is a method of identifying a subject in need of treatment with a FADS1 inhibitor compound, comprising: Measuring one or more biological indicators of a FADS1-mediated disease or disorder in a subject. Including, The one or more biological indicators comprise, consist of, or consist essentially of one or more of: ratios of polyunsaturated fatty acids ("PUFAs"), relative abundance of one or more cell types, relative abundance of one or more differentially expressed genes (DEGs) or gene signatures, and / or relative abundance of one or more metabolites in the subject; It is a method.

[0197] Provided herein as embodiment A.3 is a method of reducing weight, reducing body mass index, treating obesity, treating a metabolic disorder, treating a cardiovascular disorder, treating diabetes, treating dyslipidemia, and / or treating non-alcoholic steatohepatitis (NASH) in a subject, comprising: Measuring one or more biological indicators of a FADS1-mediated disease or disorder in a subject. Including, The one or more biological indicators comprise, consist of, or consist essentially of one or more of: ratios of polyunsaturated fatty acids ("PUFAs"), relative abundance of one or more cell types, relative abundance of one or more differentially expressed genes (DEGs) or gene signatures, and / or relative abundance of one or more metabolites in the subject; It is a method.

[0198] Provided herein as Embodiment A.4 is the method of any one of Embodiments A.1-A.3, further comprising administering to the subject a FADS1 inhibitor compound.

[0199] Provided herein as embodiment A.5 is the method of any one of embodiments A.1-A.4, wherein the ratio of PUFAs comprises or consists of a ratio of arachidonic acid (AA) to dihomo-gamma-linolenic acid (DGLA).

[0200] Provided herein as embodiment A.6 is the method of embodiment A.5, in which the ratio of AA to DGLA is about 5:1 or greater.

[0201] Provided herein as embodiment A.7 is the method of embodiment A.5, wherein the ratio of AA to DGLA is about 6:1 or greater.

[0202] Provided herein as embodiment A.8 is the method of embodiment A.5, in which the ratio of AA to DGLA is about 7:1 or greater.

[0203] Provided herein as embodiment A.9 is a method according to any one of embodiments A.1 to A.8, wherein the one or more cell types include adipocytes (Adipo), B cells (Bcell), endothelial cells (Endo), hepatocytes (Hep), Kupffer cells (Kupff), myeloid cells (Myel), natural killer (NK), T cells (Tcell), or any combination of the foregoing.

[0204] Provided herein as embodiment A.10 is the method of embodiment A.9, wherein the relative abundance of at least one cell type in the subject is increased.

[0205] Provided herein as embodiment A.11 is the method of embodiment A.9 or A.10, wherein the relative abundance of at least one cell type in the subject is decreased.

[0206] Provided herein as embodiment A.12 is the method of claim 1, wherein the one or more metabolites are selected from the group consisting of plasma cholesterol, free cholesterol, total cholesterol, cholesterol esters, malate, alpha-ketoglutarate, mannose, glucose, erythrone dihydrosphingosine, 5-O-methylsphingosine, threosphingosine, 1-hydroxy-2-amino-(cis,trans)-3,5-octadecadiene, 4-hydroxysphinganine, thromboxane B2, delta-12-prostaglandin D2, prostaglandin E2, prostaglandin D2, 12-hydroxyheptadecatrienoic acid, 14,15-dihydroxyeicosatrienoic acid, 11-hydroxyeicosatetraenoic acid, and the like. , 13-hydroxyoctadecadienoic acid, arachidonic acid, docosahexaenoic acid, dihomo-gamma-linolenic acid, gamma-linolenic acid, docosapentaenoic acid, eicosapentaenoic acid, docosatetraenoic acid, stearic acid, tryptophan, histidine, valine, threonine, cysteine, kynurenic acid, taurochenodeoxycholic acid, taurocholic acid, plasma triglycerides, plasmalogens, choline plasmalogens, myo-inositol phospholipids, glycerol phosphate, phosphate, lysophosphatidylcholine, lysophosphatidylethanolamine, and / or phosphatidylcholine.

[0207] Provided herein as embodiment A.13 is the method of embodiment A.12, wherein the relative abundance of at least one metabolite in the subject is increased.

[0208] Provided herein as embodiment A.14 is the method of embodiment A.12 or A.13, wherein the relative abundance of at least one metabolite in the subject is decreased.

[0209] Provided herein as embodiment A.15 is the method of any one of embodiments A.1-A.14, wherein the DEGs include one or more of Serpinb1a, Gna14, Serpina3m, Hsd11b1, Cyp2c29, Hsd11b1, Akr1d1, Aldh1a1, Mmp19, or any combination of the foregoing.

[0210] Provided herein as embodiment A.16 is the method of any one of embodiments A.1-A.15, wherein the DEGs include one or more of Gyp27a1, Tymp, Elovl2, Chkb, H2afj, Tnfaip8l1, Tmem86a, Sel1l3, Agap2, 4833411C07Rik, or any combination of the foregoing.

[0211] Provided herein as embodiment A.17 is the method of any one of embodiments A.1-A.16, wherein the DEGs include one or more of Elov4, Fat3, Eef1a2, Atp7a, Rgs2, Cenpe, Mfap2, Mlki67, Ctsh, or any combination of the foregoing.

[0212] Provided herein as embodiment A.18 is the method of any one of embodiments A.1-A.17, wherein the DEGs include one or more of Trub2, Ubc, H6pd, Eepd1, Acss2, Aacs, Gm36827, Man2a2, Nudt18, Plagl1, or any combination of the foregoing.

[0213] Provided herein as embodiment A.19 is the method of any one of embodiments A.1-A.18, wherein the DEGs include one or more of TM4sf19, Atp6v0d2, Gm20056, Trem2, Il1rn, Mmp12, Cdk18, Efr3b, Tagln2, or any combination of the foregoing.

[0214] Provided herein as embodiment A.20 is the method of any one of embodiments A.1-A.19, wherein the DEGs include one or more of Lurap1, Cp, I17rb, B230303O12Rik, Cfd, Sult1e1, Tdo2, or any combination of the foregoing.

[0215] Provided herein as embodiment A.21 is the method of any one of embodiments A.1-A.20, wherein the DEGs include one or more of Cyp2b9, Fads1, Hao2, Cyp2b13, Cyp2a22, Acnat2, Ildr2, Rpl10a-ps1, Tm6sf2, or any combination of the foregoing.

[0216] Provided herein as embodiment A.22 is a method according to any one of embodiments A.1 to A.21, wherein the DEGs include one or more of Fitm1, Tmem86a, Agap2, Lpar1, C6, Cmah, Lbp, Arsg, Glra3, Lad1, A730063M14Rik, or any combination of the foregoing.

[0217] Provided herein as embodiment A.23 is a method according to any one of embodiments A.1-A.22, wherein the DEGs include one or more of Ly6f, Foxil, Crygc, Defb28, Wfdc9, Phlda2, Aqp6, Gm16411, Adam7, or any combination of the foregoing.

[0218] Provided herein as embodiment A.24 is the method of any one of embodiments A.1-A.23, wherein the DEG includes Ppp2r5b.

[0219] Provided herein as embodiment A.25 is the method of any one of embodiments A.1-A.24, wherein the DEGs include one or more of Slc6a7, Gpr50, Ahnak2, S100a6, Mmp14, Htr2b, Hpgds, Mfap2, or any combination of the foregoing.

[0220] Provided herein as embodiment A.26 is the method of any one of embodiments A.1-A.25, wherein the DEGs include one or more of Gm18537, Aacs, Pclo, Adrb3, Gm38394, AC154232.2, Cadps, Adgrb2, Gm45470, or any combination of the foregoing.

[0221] Provided herein as embodiment A.27 is a method according to any one of embodiments A.1 to A.26, wherein the DEGs include one or more of Sdr9c7, Dsg1c, Slc17a1, Acnat2, Ces1c, Gss, Hsd11b1, or any combination of the foregoing.

[0222] Provided herein as embodiment A.28 is the method of any one of embodiments A.1-A.27, wherein the DEGs include one or more of 1810008I18Rik, Tlcd1, Snrk, Akr1c20, Gm19950, Ttr, Cbfa2t3, Acat2, Pmvk, Abcd3, Acss2, Acacb, Arhgap27, or any combination of the foregoing.

[0223] Provided herein as embodiment A.29 is the method of any one of embodiments A.1-A.28, wherein the DEGs include one or more of Adam7, Rnase9, Wfdc8, Ighv9-2, DerI3, Acap1, Ccl19, Tcf7, Xkrx, Trim46, or any combination of the foregoing.

[0224] Provided herein as embodiment A.30 is the method of any one of embodiments A.1-A.29, wherein the DEGs include one or more of Zfp369, Zfp871, Pcdhb21, Adrb3, Gm14288, Uprt, Atm, Dchs2, Cped1, Gm38357, or any combination of the foregoing.

[0225] Provided herein as embodiment A.31 is the method of any one of embodiments A.1-A.30, wherein the DEGs include one or more of Cck, Ckap2, Gm4419, 1600015I10Rik, Sez6I2, Prnd, Gm16702, S100a8, or any combination of the foregoing.

[0226] Provided herein as embodiment A.32 is the method of any one of embodiments A.1-A.31, wherein the DEGs include one or more of Pcdh12, Malat1, Kcnq1ot1, ArI4c, Gm38394, Gm42549, AC154232.2, Gm37310, Gm37776, Atp2a1, Ckm, Tnnt3, or any combination of the foregoing.

[0227] Provided herein as embodiment A.33 is that the DEG is selected from the group consisting of Serpinb1a, Gna14, Serpina3m, Hsd11b1, Cyp2c29, Hsd11b1, Akr1d1, Aldh1a1, Mmp19, or any combination thereof, Adipoq, Fabp4, Lep, Retn, Hoxc8, Hoxc9, Cebpa, Dgat1, Dgat2, Elovl3, Fads1, Fads2, Fas, Scd1, Srebf1, Adrb3, Hilpda, Lipe, Mgll, Plin1, Plin2, Plin3, Plin4, Plin5, Plin6, Plin7, Plin8, Plin9, Plin10, Plin11, Plin12, Plin13, Plin14, Plin15, Plin16, Plin17, Plin18, Plin19, Plin19, Plin19, Plin19, Plin19, Plin19, Plin20, Plin19, Plin21, Plin19, Plin19, Plin22, Plin19, Plin23, Plin19, Plin24, Plin19, Plin19, Plin25, Plin19, Plin26, Plin19, Plin27, Plin19, Plin28, Plin19, Plin29, Plin30, Plin19, Plin29, Plin19, Plin29, Plin19, Plin20, Plin19, Plin21, Plin19, Plin21, Plin19, Plin21, Plin19, Plin22, Plin19, Plin23, Plin19, Plin24, Plin19, Plin25, Plin19, Plin26, Plin27, Plin19, P The method of any one of embodiments A.1 to A.32, comprising one or more of: in4, Pnpla2, Pnpla3, Ldah, Cs, Gckr, Me1, Pck1, Pdk4, Irs1, Acaa1a, Acads, Acox1, Cpt1a, Cpt1b, Hadhb, Ehhadh, Ppara, Ppargc1a, Cyp4a12a, Cyp4a12b, Cyp2e1, Adgre1, Agtr1a, Ccl2, Cd14, Cd68, Il1b, Tm6sf2, Tnf, or any combination of the foregoing.

[0228] Provided herein as embodiment A.34 is a method according to any one of embodiments A.1-A.33, wherein the DEGs include one or more DEGs disclosed in any one or more of Figures 4a, 5a, 10a, and / or 13a.

[0229] Provided herein as embodiment A.35 is the method of any one of embodiments A.1-A.34, wherein the relative abundance of at least one DEG in the subject is upregulated.

[0230] Provided herein as embodiment A.36 is the method of embodiment A.35, wherein at least one up-regulated DEG is up-regulated by two-fold or more.

[0231] Provided herein as embodiment A.37 is a method of any one of embodiments A.1-A.36, wherein the relative abundance of at least one DEG in the subject is downregulated.

[0232] Provided herein as embodiment A.38 is the method of embodiment A.37, wherein at least one down-regulated DEG is down-regulated by 2-fold or more.

[0233] Provided herein as embodiment A.39 is an edible soluble fiber composition, wherein the ratio of PUFAs comprises or consists of a ratio of labeled DGLA and labeled AA; The ratio of DGLA to AA is measured by administering a dose of labeled DGLA to a subject and then measuring the ratio of labeled AA to labeled DGLA. A method according to any one of embodiments A.1 to A.38.

[0234] Provided herein as embodiment A.40 is the method of embodiment A.39, in which the labeled DGLA comprises DGLA that is isotopically enriched with 13C labeling.

[0235] Provided herein as embodiment A.41 is the method of embodiment A.40, in which the labeled DGLA comprises DGLA isotopically enriched with 13C atoms at two or more positions.

[0236] Provided herein as embodiment A.42 is the method of embodiment A.40, in which the labeled DGLA comprises DGLA isotopically enriched with 13C atoms at three or more positions.

[0237] Provided herein as embodiment A.43 is the method of embodiment A.40, in which the labeled DGLA comprises DGLA isotopically enriched with 13C atoms at four or more positions.

[0238] Provided herein as embodiment A.44 is the method of embodiment A.40, in which the labeled DGLA comprises DGLA isotopically enriched with 13C atoms at five or more positions.

[0239] Provided herein as embodiment A.45 is the method of embodiment A.40, in which the labeled DGLA comprises DGLA that is uniformly isotopically enriched with 13C atoms.

[0240] Provided herein as embodiment A.46 is a method for producing a labeled DGLA comprising: [ka] The method of any one of embodiments A.39 to A.44, including labeling at one, more than one, or all of the locations indicated.

[0241] Provided herein as embodiment A.47 is a method according to any one of embodiments A.39 to A.46, wherein a dose of a FADS1 inhibitor compound is administered to the subject before, simultaneously with, or after administration of a labeled dose of DGLA to the subject.

[0242] Provided herein as embodiment A.48 is the method of embodiment A.46, in which the conversion of labeled DGLA to labeled AA is used to measure and / or calculate the level of inhibition of the FADS1 enzyme by the FADS1 inhibitor compound at the dose provided to the patient.

[0243] Provided herein as embodiment A.49 is the method of embodiment A.48, further comprising comparing the measured level of inhibition by the FADS1 inhibitor compound at the dose provided to the patient with the desired level of inhibition of FADS1.

[0244] Provided herein as embodiment A.50 is the method of embodiment A.49, further comprising determining an adjusted dose of the FADS1 inhibitor for the subject based on a comparison of the measured level of inhibition of FADS1 with a desired level.

[0245] Provided herein as embodiment A.51 is the method of embodiment A.50, further comprising administering to the subject a titration dose of a FADS1 inhibitor.

[0246] Provided herein as embodiment A.52 is a compound having the following structure: [ka] A compound represented by the formula: During the ceremony, Each "*" symbol indicates a position that can be isotopically enriched with 13C; At least one "*" position is isotopically enriched with 13C, It is a compound.

[0247] Provided herein as embodiment A.53 is a compound having the following structure: [ka] A compound represented by the formula: During the ceremony, Each "*" symbol indicates a position that can be isotopically enriched with 13C; At least one "*" position is isotopically enriched with 13C, It is a compound.

[0248] Provided herein as embodiment A.54 is a compound having the following structure: [ka] A compound represented by the formula: During the ceremony, X is a halogen; Each "*" symbol indicates a position that can be isotopically enriched with 13C; At least one "*" position is isotopically enriched with 13C, It is a compound.

[0249] Provided herein as embodiment A.55 is the method of any one of embodiments A.52-A.54, wherein at least two "*" positions are isotopically enriched with 13C.

[0250] Provided herein as embodiment A.56 is the method of any one of embodiments A.52-A.54, wherein at least three "*" positions are isotopically enriched with 13C.

[0251] Provided herein as embodiment A.57 is the method of any one of embodiments A.52-A.54, wherein at least four "*" positions are isotopically enriched with 13C.

[0252] Provided herein as embodiment A.58 is the method of any one of embodiments A.52-A.54, wherein at least five "*" positions are isotopically enriched with 13C.

[0253] Provided herein as embodiment A.59 is a compound having the following structure: [ka] A method for producing a compound represented by the formula: The following compounds [ka] with KC*N, During the ceremony, Each "*" symbol indicates a position that can be isotopically enriched with 13C, and at least one "*" position is isotopically enriched with 13C; X is a suitable leaving group; It is a method.

[0254] Provided herein as Embodiment A.60 is the method of Embodiment A.59, wherein X is a halogen.

[0255] Provided herein as Embodiment A.61 is the method of Embodiment A.60, wherein X is Br.

[0256] The following examples are presented to illustrate various embodiments of the present disclosure and are not intended to limit the disclosure in any way. Those skilled in the art will readily appreciate that the present disclosure is well adapted to carry out the objects and obtain the objects and advantages of the disclosure as well as those inherent therein. Those skilled in the art will recognize modifications in the examples and other uses that fall within the spirit of the present disclosure as defined by the scope of the claims. [Example]

[0257] This section provides specific examples of compounds of formula (I) and methods for their preparation.

[0258] Materials and Methods Provided below are exemplary materials and methods used in the accompanying examples. reagent List of Chemical Abbreviations

[0259] [Table 1]

[0260] FADS1 (NM_013402) and FADS2 (NM_004265) BacMam reagents were generally produced by Department of Biologics, Amgen (Thousand Oaks, CA). 13 C1-C5] arachidonic acid ( 13 C5-AA), alpha-linolenic acid-d14 (ALA-d14), anandamide-d8 (AEA-d8), and polyunsaturated fatty acid standards were purchased from Cayman Chemical (Ann Arbor, MI). 13 C1-C5]8,11,14-eicosatrienoic acid ( 13 C5-DGLA) was custom synthesized by Curachem (Korea). 13 C 18 ] Linoleic acid ( 13 C 18 -LA) was purchased from IsoSciences (Ambler, PA).

[0261] Human plasma samples All human specimens were collected with appropriate informed consent in accordance with all applicable laws and regulations and under the approval of the institution-specific ethical review board. In all cases, the material obtained exceeded standard clinical examination and standard of care. Patient identities and protected health information / identifying information were removed from tissue and clinical data before submission. Inclusion criteria were set as subjects free of cancer, cardiovascular disease, and autoimmune disease.

[0262] Compound A FADS1 small molecule inhibitor "Compound A," 8-methoxy-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, was synthesized according to the reaction steps described in WO 2021 / 108404 A1. Compound A was dissolved in dimethyl sulfoxide (DMSO) for in vitro activity assays and formulated in 2% hydroxypropylmethylcellulose (HPMC), 1% Tween 80 for mouse studies.

[0263] Mouse model and care Mice were housed in an internationally accredited AAALAC facility. Animals were cared for in accordance with the Guide for the Care and Use of Laboratory Animals, 8th Edition. Mice were housed in individually ventilated cage (IVC) systems (Innorack, Innovive or Greenline, Tecniplast) on irradiated corncob bedding (Envigo Teklad 7097). Lighting in the animal housing room was maintained on a 12:12-h light:dark cycle, and ambient temperature and humidity ranged from 68 to 79°F and 30 to 70%, respectively. Animals had free access to food and reverse osmosis (RO) chlorinated (2-3 ppm) water via an automated watering system. Male AGN-rFADS1KO knockout (Fads1 KO; Fads1 Gt(IST11525H2)Tigm, gene trap IST11525H2, Texas A&M Institute for Genomic Medicine) and WT C57BL / 6 mice were housed at Charles River Laboratories (Hollister, CA) or Jackson Laboratories (Bar Harbor, Maine). Only male mice were used in the study to avoid confounding effects of female estrous cycles. Mice were fed a standard diet (5066; LabDiet; St. Louis, MA) supplied by Charles River until 5–8 weeks of age. After arrival and 1–2 weeks of acclimation, DIO mice were maintained on an HFD (60 kcal% fat, D12492 Research Diets, New Brunswick, NJ) for 12 weeks or until indicated. Lean controls were fed a standard diet (Envigo Teklad Global Soy Protein-Free Extruded Rodent Diet 2020X, Indianapolis, IN).

[0264] Fads1 KO mouse phenotyping study Fads1 KO and WT mice were fed an HFD for 12 weeks. Weekly body weight and weekly measurements of fat and lean body composition (EchoMRI, Houston, TX) were recorded throughout the study. Food intake was measured at week 7 on the HFD. After a 12-hour fast on the HFD at week 7, an intraperitoneal (IP) GTT was performed using 2 g / kg glucose. Retroorbital blood was collected after a 4-hour fast on the day mice were switched to the HFD and at weeks 6 and 12 of the diet. At the end of the 12-week study, mice were euthanized by conscious decapitation, and plasma, liver, EPI, and ING WAT tissues were collected.

[0265] Chronic FADS1 inhibition study in DIO mice WT DIO mice were randomized and administered vehicle (2% HPMC, 1% Tween 80) or a dose of Compound A (10 mg / kg or 30 mg / kg) by PO gavage daily for 54 days. Body weights were measured daily and used for dose calculations. At baseline and on day 46, 4-hour fasted retro-orbital blood samples were collected and used for insulin, cholesterol, and triglyceride analysis. Average 3-day food consumption was measured on days 39-41. All animals received 2 mM HCl by IP injection 23.5 hours after the last PO gavage of various treatments. 13 0.1 ml of C5-DGLA was administered to allow a 30-minute exposure before necropsy to determine residual in vivo FADS1 activity.

[0266] Indirect calorimetry test Prior to the start of the HFD-feeding phase, and again at weeks 6 and 12 on the HFD, 24 Fads1 KO mice and 24 WT mice were placed in a Comprehensive Laboratory Animal Monitoring System (CLAMS; Columbus Instruments, Columbus, Ohio—Oxymax Model 2018, 0233-004M, Oxymax for Windows v5.53 software, Hardware configuration 190395). After 12 weeks of HFD, WT animals were randomized into two groups based on body weight, oxygen consumption, carbon dioxide production, age, and PER while still in the system (after a 96-hour baseline measurement): vehicle (2% HPMC, 1% Tween 80) and Compound A at 30 mg / kg. Body weight was measured daily, and food consumption was measured every other week. Animals were placed in the CLMS again on days 17-21 and 38-42. During this period, oxygen consumption (VO2), carbon dioxide production (VCO2), PER, and energy expenditure (HEAT) were measured. For simplicity, data are presented for light-on (light) and light-off (dark) cycles (12 hours on and 12 hours off, respectively).

[0267] Measurement of plasma lipids, glucose, and insulin Mice were conscious and bled from the retro-orbital sinus into EDTA plasma tubes. Plasma lipids were measured using an Olympus AU400e Chemistry Analyzer (Olympus America, Center Valley, PA). Plasma insulin was measured using an ALPCO Mouse Broad-Range Insulin ELISA (Alpco, Salem, NH). Blood glucose was measured using an AlphaTRAK blood glucose meter (Zoetis, Parsippany, NJ).

[0268] RNA-Seq analysis RNA was extracted using the Qiagen RNeasy 96 Universa kit (QIAGEN, Germantown, MD). The concentration and quality of the isolated RNA samples were assessed using an Agilent 4200 TapeStation system to determine an RNA integrity index of >9.1. Adipose or liver RNA (250 ng) was used to prepare cDNA libraries using a protocol modified from the Illumina TruSeq Stranded mRNA kit (Illumina, San Diego, CA). Briefly, polyA +After RNA selection, fragmentation, and priming, the fragmented RNA was transcribed into cDNA in a reverse transcription reaction using SuperScript™ II (Thermo Fisher Scientific-Invitrogen™, Waltham, MA) and RNase-out (Thermo Fisher Scientific-Invitrogen™, Waltham, MA). The products of the single-stranded cDNA synthesis reaction were then converted to double-stranded cDNA and subjected to end repair, A-tailing, and adapter ligation according to the manufacturer's instructions. The constructed library was amplified and barcoded using the following PCR program: a denaturation step at 98°C for 30 seconds, 15 cycles of 95°C for 10 seconds, 60°C for 30 seconds, and 72°C for 30 seconds, and an extension cycle at 72°C for 5 minutes, followed by a 4°C hold. Libraries were sequenced by Illumina HiSeq4000 with read lengths of 100 nt or 150 nt to a minimum depth of 30 million paired-end reads.

[0269] RNA-Seq sequencing reads from mouse samples were aligned and processed using the OSA aligner implemented in the OmicSoft Array Suite (QIAGEN OmicSoft, Cary, NC) based on mouse genome version GRCm38 and gene model GENCODE v19. Quantification of read counts was performed at the gene level based on the OmicSoft implementation of RSEM. Downstream analysis using this read count output was performed according to the standard RNA-seq workflow in the DESeq2 R / Bioconductor package. Briefly, raw read counts were transformed and normalized using the variance-stabilizing transformation (VST) method. Principal component analysis (PCA) was performed using the plotPCA function using the top 1000 variable genes. Differential expression analysis based on the negative binomial distribution was performed using the DESeq function.

[0270] Gene expression was expressed as normalized fragments per kilobase per million reads (FPKM). FPKM values ​​were further normalized by modifying the commonly used upper quartile method, which sets FPKM at a value of 10 at the 70th percentile. Lowly expressed genes with FPKM ≥ 1 and fewer than five samples were excluded. Genes with a Benjamini-Hochberg (BH) adjusted P value < 0.01 and a fold change ≥ 2 or ≤ 0.5 were selected as DEGs. Volcano plots of differential expression analysis results were generated using the EnhancedVolcano R package (github.com / kevinblighe / EnhancedVolcano).

[0271] Selected DEGs were annotated with standard pathway and toxicity lists by IPA (QIAGEN, Redwood City, CA). Gene expression enrichment in Gene Ontology (GO), KEGG, was analyzed using the Cluster Profiler R package with default parameters.

[0272] Deconvolution analysis was performed using MuSiC software v0.2.0 to estimate the relative abundance of cell types in each mouse bulk tissue sample. The Tabula Muris single-cell RNA-seq dataset was used as the baseline for the MuSiC algorithm. This analysis was performed separately for each tissue type, including epithelial, ingestible tissue (EPI), and liver.

[0273] Measurement of plasma PUFAs In a 96-well plate, 10 μL of plasma or PUFA standard diluted in a surrogate matrix (60 g / L bovine serum albumin in Dulbecco's phosphate-buffered saline [DPBS]) was added to the wells of a 96-well plate containing 10 μL of ALA-d as an internal standard. 14The mixture was mixed with 10 μL of 2N NaOH. For subsequent saponification, 100 μL of 2N NaOH was added to the mixture at 65°C for 1 hour. The mixture was then acidified with 50 μL of formic acid, followed by two sequential 500 μL hexane extractions. The organic extracts from the two extractions were combined, and the solvent was evaporated under nitrogen gas. The extract was then resuspended in 250 μL of 90% methanol and analyzed by liquid chromatography / tandem mass spectrometry (LC-MS / MS) using ALA-d as an internal standard. 14 The following PUFAs were analyzed using the Analyst software (SCIEX, Framingham, MA): LA, GLA, DGLA, and AA. PUFA peak areas were quantified using Analyst software (SCIEX, Framingham, MA).

[0274] Tissue protein extraction and biomarker analysis of tissue and plasma samples Frozen liver and adipose tissue samples were pulverized using stainless steel Bessman Tissue Pulverizers (Spectrum Laboratory Products, Gardena, CA) according to the manufacturer's instructions, and the resulting tissue powders were stored in cryotubes at -80°C until extraction. A portion of each powdered tissue sample was extracted using an in-house protein extraction buffer (50 mM Tris buffer, pH 7.4, 0.1 M NaCl, and 0.1% Triton X-100) containing a protease inhibitor cocktail (Millipore Sigma, Burlington, MA). Samples were homogenized in a MagNA Lyser (Roche Diagnostics, Indianapolis, IN) at 6500 rpm for 30 seconds, placed at 4°C for 30 minutes, and then centrifuged in a refrigerated μ-centrifuge at 10,000 rpm for 10 minutes. The resulting supernatant was transferred to a clean 1.5 ml microfuge tube and centrifuged again at 14,000 rpm for 15 minutes. The final supernatant was aliquoted into labeled cluster tubes and stored at −80°C after measuring protein concentration using a standard BCA protein assay (Thermo Fisher Scientific, Waltham, MA).

[0275] Separate aliquots of tissue protein extracts and peripheral plasma samples were used to quantify the levels of various analytes. Multiple adipokines and hormones (MCP-1, leptin, insulin, and PAI-1) were assessed using a multiplex mouse-specific Luminex assay, and adiponectin was assessed using a singlex mouse-specific Luminex assay (Millipore Sigma, Burlington, MA). All commercial assays were performed according to the manufacturer's instructions. Data were acquired using FlexMap 3D (Luminex Corporation, Austin, TX). Tissue protein expression levels were normalized per mg of total protein.

[0276] Plasma metabolomics analysis Plasma samples from male Fads1 KO mice (n = 4) and their WT littermates (n = 6) fed a HFD for 11 weeks were processed and analyzed for metabolomics analysis at Metanomics Health (Germany) using the MxP Broad Profiling and MxP Eicosanoid platforms.

[0277] Measurement of liver triglycerides Liver total lipids were homogenized and extracted using a 2:1 chloroform / methanol solution. The extracted lipids were dried under nitrogen gas and suspended in 90% isopropanol, 10% Triton X-100 solution. Liver triglyceride levels (mg / g tissue) were determined using total triglyceride measurement kits from Wako Diagnostics (Richmond, VA) and Sigma-Aldrich (Burlington, MA).

[0278] Tissue endocannabinoid measurements Approximately 200 mg of tissue was used per sample for endocannabinoid extraction. To each frozen tissue sample, 10 μl of ice-cold 100 mM butylated hydroxytoluene (BHT; methanol solution) and 0.5 ml of 100 nM AED-d8 (aqueous solution) were added. The BHT-containing tissue sample solution was immediately homogenized using a TissueLyser (QIAGEN, Germantown, MD) at 30 Hz for 3 minutes, followed by the addition of two successive 1.25 ml portions of ice-cold ethyl acetate:hexane (9:1) extraction solution. The pooled extract was completely dried under nitrogen gas. The dried sample was redissolved in 80% acetonitrile and subjected to LC / MS analysis. 10 μl of the sample was injected onto a Kinetex C18 2.1 x 100 mm, 2.6 μm column (Phenomenex, Torrance, CA). Mobile phase A was 0.2% acetic acid in water, and mobile phase B was 0.1% formic acid in acetonitrile. The LC gradient was a 7-min method at a flow rate of 0.2 ml / min, consisting of an isocratic period from 0 to 1 min at 75% B, followed by a gradient from 75 to 100% B from 1 to 4 min and from 100 to 75% B from 4 to 7 min. Analyte peak areas were quantified using Analyst software (SCIEX, Framingham MA).

[0279] 13 C5-DGLA([ 13 Preparation of C5]-15) [ 13 Synthesis of C4]-2 [ka] A 500 mL flask was charged with NaH (2.20 g, 55.0 mmol). The NaH was washed with hexane (decantation, twice), and then THF (50 mL) was added. The resulting suspension was cooled to 0° C. [ 13A solution of C4]-1 (4.70 g, 50.0 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature. After vigorously stirring at room temperature for 2 h, the reaction mixture was recooled to 0 °C, and TBDPS-Cl (13.7 g, 50.0 mmol) was added dropwise. It was then allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched with 10% aqueous K2CO3 solution (ca. 30 mL), extracted with Et2O, dried over Na2SO4, filtered, and evaporated. The product was purified by column chromatography on SiO2 (EtOAc:hexane = 1:4) to give [ 13 C4]-2 (16.1 g, 97%) was obtained. 1 H NMR (chloroform-d) δ:7.67(4H,br m),7.4(6H,br m),4.12(1H,br s),3.85(2H,br d),3.49(2H,br d),1.81(2H,br m),1.50(2H,br m),1.06(9H,s).

[0280] [ 13 Synthesis of C4]-3 [ka] A solution of oxalyl chloride (5.47 mL, 62.9 mmol) in DCM (15 mL) was placed in a nitrogen-purged 500 mL flask. The flask was cooled to -78°C. A solution of DMSO (4.47 mL, 62.9 mmol) in DCM (20 mL) was added dropwise, and the resulting mixture was stirred at -78°C for an additional 30 minutes. Then, [ 13 A solution of C4]-2 (16.1 g, 48.4 mmol) was added dropwise. The resulting mixture was stirred at -78 °C for an additional 30 min. At this time, TEA (17.5 mL, 126 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature. After stirring at room temperature overnight, the reaction mixture was quenched by the addition of water (30 mL), extracted with DCM, dried over Na2SO4, and filtered. The product was purified by column chromatography on SiO2 (5% EtOAc in Hex) to give [ 13 C4]-3 (11.2 g, 70%) was obtained. 1H NMR(chloroform-d)δ:9.75(1H,dd),7.67(4H,br m),7.4(6H,br m),3.86(1H,br m),3.50(1H,br m),2.70(1H,br m),2.38(1H,br m),2.04(1H,br m),1.72(1H,br m),1.06(s,9H).

[0281] [ 13 Synthesis of C4]-5.1 [ka] A solution of phosphonium 4.1 (17.5 g, 36.1 mmol) in THF (60 mL) was cooled to -78 °C, and KHMDS (37.7 mL, 37.7 mmol) was added dropwise. After stirring at -78 °C for 10 min, the reaction mixture was allowed to warm to room temperature. After stirring for 30 min, the reaction mixture was cooled again to -78 °C. [ 13 A solution of C4]-3 (11.2 g, 33.9 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature. After stirring overnight at room temperature, the reaction mixture was quenched by the addition of water (30 mL), stirred for 15 min, and then extracted with Et2O, dried over Na2SO4, and filtered. Column chromatography on SiO2 (EtOAc:hexane = 1:9) gave [ 13 C4]-5.1 (14.4 g, 93%) was obtained. 1 H NMR (chloroform-d) δ:7.66(4H,br m),7.40(6H,br m),6.62(1H,br m),5.40(2H,br m),5.15(1H,br m),4.58(br m),3.84(2H,br m),3.71(1H,br m),3.49(br m),3.38(br m),2.34(br m),1.98(br m),1.78-1.65(br m),1.60-1.21(br m),1.06(s,9H).

[0282] [ 13 Synthesis of C4]-6.1 [ka] In a 500 mL flask, 13 C4]-5.1 (14.4 g, 31.4 mmol), 150 mL of EtOH, and 0.5 g of Pd / C were added. The reaction mixture was hydrogenated at 1 atm of H2 (balloon) at room temperature overnight. After filtration through Celite and subsequent evaporation, the crude product was used in the next step without further purification. 13 C4]-6.1: 13.6 g (94%). 1 H NMR (chloroform-d) δ:7.66(6H,br m),7.38(8H,br m),4.57(br m),3.84(2H,br m),3.72(1H,br m),3.48(br m),3.37(br m),1.90-1.21(br m),1.06(s,9H).

[0283] [ 13 Synthesis of C4]-7 [ka] Crude [ 13 To a solution of C4]-6.1 (13.6 g, 29.6 mmol) was added TsOH (1.23 g, 6.47 mmol), and the reaction mixture was stirred at room temperature for 3 h. Saturated aqueous NaHCO3 (50 mL) was then added. The resulting mixture was extracted with Et2O, dried over Na2SO4, and filtered. Chromatography on SiO2 (EtOAc:hexane = 1:9) gave [ 13 C4]-7 (6.53 g, 59%) was obtained. 1 H NMR (chloroform-d) δ:7.66(4H,br m),7.38(6H,br m),3.83(1H,br m),3.63(2H,br m),3.48(1H,br m),1.7-1.11(11H,br m),1.06(s,9H).

[0284] [ 13 Synthesis of C4]-8 [ka] obtained. 1H NMR (chloroform-d) δ: 9.75(1H,s),7.66(4H,br m),7.38(6H,br m),3.83(1H,br m),3.47(1H,br m),2.40(2H,br m),1.7-1.11(8H,br m),1.06(s,9H).

[0285] A-[ 13 Synthesis of C4]-11 [ka] A solution of phosphonium 10 (9.99 g, 19.7 mmol) in THF (100 mL) was cooled to −78° C. and NaHMDS (19.7 mL, 19.7 mmol) was added dropwise. After stirring at −78° C. for 1.5 h, the aldehyde [ 13 A solution (30 mL) of C4]-8 (5.73 g, 15.4 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature. After stirring at room temperature for 2 h, the reaction mixture was quenched by adding aqueous NH4Cl, extracted with Et2O, dried over Na2SO4, filtered, and evaporated. Column chromatography on SiO2 (1% EtOAc in hexane) gave [ 13 C4]11 (4.63 g, 58%) was obtained. 1 H NMR(chloroform-d)δ:7.66(4H,br m),7.38(6H,br m),5.36(5H,m),3.82(1H,br m),3.47(1H,br m),2.80(3H,br m),2.04(4H,br m),1.7-1.11(15H,br m),1.04(s,9H),0.88(4H,br m).

[0286] [ 13 Synthesis of C4]-12 [ka] in THF (50 mL) 13To a solution of C4]-11 (4.63 g, 8.89 mmol) was added a solution of TBAF (13.3 mL, 13.3 mmol) in THF. After stirring at room temperature for 3 h, the reaction mixture was quenched with water, extracted with Et2O, dried over Na2SO4, filtered, and evaporated. Column chromatography on SiO2 (EtOAc:hexane = 1:9) gave [ 13 C4]-12 (2.36 g, 94%) was obtained. 1 H NMR(chloroform-d)δ:5.36(5H,br m),4.11(1H,br s),3.81(1H,br m),3.47(1H,br m),2.81(3H,br m),2.04(4H,br m),1.7-1.11(16H,br m),0.88(3H,br m).

[0287] [ 13 Synthesis of C4]-13 [ka] in DCM (30 mL) 13 A solution of C4]-12 (2.36 g, 8.35 mmol) was cooled to 0 °C, and CBr4 (3.73 g, 11.3 mmol) was added in one portion. After 5 min at 0 °C, a solution of PPh3 (2.84 g, 10.8 mmol) in DCM (10 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was poured into a mixture of ETOAc:hexane (300 mL, 1:9), and the resulting suspension was filtered through Celite. Column chromatography on SiO2 (Hex) revealed [ 13 C4]-13 (2.58 g, 89%) was obtained. 1 H NMR(chloroform-d)δ:5.36(5H,br m),3.59(1H,br m),3.21(1H,br m),2.81(3H,br m),2.05(4H,br m),1.7-1.11(16H,br m),0.88(3H,br m).

[0288] [ 13 Synthesis of C5]-14 [ka] in DMSO (20 mL) 13 C4]-14 (2.58 g, 7.47 mmol) and [ 13 A solution of [C]KCN (0.64 g, 9.68 mmol) was stirred overnight at 50 °C. The reaction mixture was then poured into water and extracted with EtOAc. The combined organic layers were washed with water, dried over Na2SO4, and filtered. Column chromatography on SiO2 (2% EtOAc in Hex) gave [ 13 C5]-14 (2.08 g, 95%) was obtained. 1 H NMR (chloroform-d) δ:5.37(5H,br m),2.81(3H,br m),2.50(1H,br s),2.17-2.05(5H,br m),1.82(1H,br m),1.7-1.11(15H,br m),0.89(3H,br m).

[0289] [ 13 Synthesis of C5]-15 [ka] in an EtOH / water mixture (30 mL, 4 / 1) 13 A solution of C5]-14 (2.08 g, 7.11 mmol) and NaOH (1.14 g, 28.50 mmol) was heated at 100 °C for 20 h. The reaction mixture was evaporated, dissolved in water, and 1N aqueous HCl was added to make an acidic solution (pH approx. 2). The product was extracted with DCM, dried over Na2SO4, and filtered. Column chromatography on SiO2 (EtOAc:Hex=3:7) gave [ 13 C5]-15 (2.06 g, 93%) was obtained. After two successive MPLC (medium pressure liquid chromatography) purifications (Wakogel, mobile phase - water / acetonitrile / acetic acid = 10 / 90 / 0.1, RT), [ 13 C5]-15 300 mg was obtained. 1H NMR(chloroform-d)δ:5.97(br m,6H),2.81(br m,4H),2.51(br m,2H),2.18(br m,2H),2.05(br m,4H),1.80(br m,1H),1.54(br m,4H),1.49(br m,4H),1.30(br m,4H),1.19(br m,2H),0.89(br m,1H),m / z=310.39.

[0290] overview The following examples provide additional ...

Claims

1. 1. A method of treating a FADS1-mediated disease or disorder in a subject in need thereof, comprising: receiving information comparing a level of a biological indicator of a FADS1-mediated disease from the subject to a reference level of the biological indicator; receiving, wherein the biological indicator is the ratio of arachidonic acid (AA) to dihomo-gamma-linolenic acid (DGLA); and administering a therapeutically effective amount of a FADS1 inhibitor compound to the subject when the level of the biological indicator in the subject is higher than a baseline level of the biological indicator. A method comprising:

2. 2. The method of claim 1, wherein the reference level of the biological indicator is a ratio of AA to DGLA that is greater than or equal to about 5:

1.

3. 2. The method of claim 1, wherein the reference level of the biological indicator is a ratio of AA to DGLA that is greater than or equal to about 6:

1.

4. 2. The method of claim 1, wherein the reference level of the biological indicator is a ratio of AA to DGLA that is greater than or equal to about 7:

1.

5. 1. A method of treating a FADS1-mediated disease or disorder in a subject in need thereof, comprising: receiving information comparing a level of a biological indicator of a FADS1-mediated disease from the subject to a reference level of the biological indicator; receiving, wherein the biological indicator is a measured level of linoleic acid, gamma-linoleic acid, adrenic acid, docosapentanoic acid n-6, alpha-linolenic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, or a combination of the foregoing; and administering a therapeutically effective amount of the FADS1 inhibitor compound to the subject upon determining that the subject is a subject who would benefit from treatment with the FADS1 inhibitor compound, as determined by the subject's level of the biological indicator compared to a baseline level of the biological indicator. A method comprising:

6. The method of claim 5, wherein the subject is determined to be a subject who would benefit from treatment with the FADS1 inhibitor compound if the level of the biological indicator of the subject is higher than the reference level of the biological indicator.

7. The method of claim 5, wherein the subject is determined to be a subject who would benefit from treatment with the FADS1 inhibitor compound if the level of the biological indicator of the subject is lower than the reference level of the biological indicator.

8. 1. A method of treating a FADS1-mediated disease or disorder in a subject in need thereof, comprising: receiving information comparing a level of a biological indicator of a FADS1-mediated disease from the subject to a reference level of the biological indicator; The biological indicators include plasma cholesterol, free cholesterol, total cholesterol, cholesterol ester C20:4, malate, alpha-ketoglutarate, mannose, glucose, erythrodihydrosphingosine (d18:0), 5-O-methylsphingosine (d18:1), erythrophingosine (d18:1), 3-O-methylsphingosine (d18:1), threosphingosine (d18:1), 1-hydroxy-2-amino-(cis,trans)-3,5-octadecadiene, 4-hydroxysphinganine (t18:1), threosphingosine (t ...threosphingosine (t18:1), threosphingosine (t18:1), threosphingosine (t18:1), threosphingosine (t18:1), threosphingosine (t18:1), threosphingosine (t18:1), threosphingosine (t :0, phytosphingosine), sphingomyelin (d18:1, C23:0), sphingomyelin (d18:1, C24:0), ceramide (d18:1, C24:0), thromboxane B2, delta-12-prostaglandin D2, prostaglandin E2, prostaglandin D2, 12-hydroxyheptadecatrienoic acid (C17:[5,8,10]3), 14,15-dihydroxyeicosatrienoic acid (C20:cis[5,8,11]3), 11-hydroxyeicosatetraenoic acid (C20:cis[5,8,12,14]4), 13-hydroxyheptadecatrienoic acid (C17:[5,8,10]3), 14,15-dihydroxyeicosatrienoic acid (C20:cis[5,8,12,14]4), Hydroxyoctadecadienoic acid (13-HODE) (C18: cis[9]trans[11]2), arachidonic acid (C20: cis[5,8,11,14]4), docosahexaenoic acid (C22: cis[4,7,10,13,16,19]6), dihomo-gamma-linolenic acid (C20: cis[8,11,14]3), gamma-linolenic acid (C18: cis[6,9,12]3), docosapentaenoic acid (C22: cis[7,10,13,16,19]5), eicosapentaenoic acid (C20: cis[5,8,11,14,17]5), docosatetraenoic acid (C22: Cis[7,10,13,16]4), stearic acid (C18:0), tryptophan, kynurenic acid, xanthurenic acid, histidine, leucine, isoleucine, valine, 3-hydroxyisobutyrate, glutamate, threonine, cysteine, sarcosine, plasma triglycerides, taurochenodeoxycholic acid, taurocholic acid, lysophosphatidylcholine (C18:0), lysophosphatidylcholine (C20:4), lysophosphatidylcholine (C17:0), lysophosphatidylethanolamine (C22:5), phosphatidylcholine (C18:0,receiving a measured level of phosphatidylcholine (C18:0, C20:3), phosphatidylcholine (C18:1, C18:2), phosphatidylcholine (C16:1, C18:2), phosphatidylcholine (C18:0, C18:2), phosphatidylcholine (C16:0, C20:5), phosphatidylcholine (C16:0, C16:0), glycerol-3 phosphate, choline plasmalogen (C18, C20:4), myo-inositol, myo-inositol phospholipids, glycerol phosphate, phospholipid fractions, or a combination of the foregoing; and administering a therapeutically effective amount of the FADS1 inhibitor compound to the subject upon determining that the subject is a subject who would benefit from treatment with the FADS1 inhibitor compound, as determined by the subject's level of the biological indicator compared to a baseline level of the biological indicator. A method comprising:

9. The method of claim 8, wherein the subject is determined to be a subject who would benefit from treatment with the FADS1 inhibitor compound if the level of the biological indicator of the subject is higher than the reference level of the biological indicator.

10. The method of claim 8, wherein the subject is determined to be a subject who would benefit from treatment with the FADS1 inhibitor compound if the level of the biological indicator of the subject is lower than the reference level of the biological indicator.

11. 1. A method of treating a FADS1-mediated disease or disorder in a subject in need thereof, comprising: receiving information comparing a level of a biological indicator of a FADS1-mediated disease from the subject to a reference level of said biological indicator; The biological indicator is a measured level of differentially expressed genes (DEGs); The DEG is Serpinb1a, Gna14, Serpina3m, Hsd11b1, Cyp2c29, Akr1d1, Aldh1a1, Mmp19, Gyp27a1, Tymp, Elovl2, Chkb, H2afj, Tnfaipl1, Tmem86a, Selll3, Agap2, 4833411C07Rik, Elov4, Fat3, Eef1a2, Atp7a, Rgs2, Cenpe, Mfap2, Mlki67, Ctsh, Trub2, Ubc, H6pd, Eepd1, Acss2, Aacs, Gm36827, Man2a2, Nudt18, Plagl1, TM4sf19, Atp6v0d2, Gm20056, Trem2, Il1rn, Mmp12, Cdk18, Efr3b, Tagln2, Lurap1, Cp, I17rb, B230303O12Rik, Cfd, Sult1e1, Tdo2, Cyp2b9, Hao2, Cyp2b13, Cyp2a22, Acnat2, Ildr2, Rpl10a-ps1, Tm6sf2, Fitm1, Lpar1, C6, Cmah, Lbp, Arsg, Glra3, Lad1, A730063M14Rik, Ly6f, Foxi1, Crygc, Defb28, Wfdc9, Phlda2, Aqp6, Gm16411, Adam7, Ppp2r5b, Slc6a7, Gpr50, Ahnak2, S100a6, Mmp14, Htr2b, Hpgds, Gm18537, Pclo, Adrb3, Gm38394, AC154232.2, Cadps, Adgrb2, Gm45470, Sdr9c7, Dsg1c, Slc17a1, Ces1c, Gss, 1810008I18Rik, Tlcd1, Snrk, Akr1c20, Gm19950, Ttr, Cbf2t3, Acat2, Pmvk, Abcd3, Acacb, Arhgap27, Rnase9, Wfdc8, Ighv9-2, DerI3, Acap1, Ccl19, Tcf7, Xkrx, Trim46, Zfp369, Zfp871, Pcdhb21, Gm14288, Uprt, Atm, Dchs2, Cped1, Gm38357, Cck, Ckap2, Gm4419, 1600015I10Rik, Sez6I2, Prnd, Gm16702, S100a8, Pcdh12, Malat1, Kcnq1ot1, ArI4c, Gm42549, Gm37310, Gm37776, Atp2a1,Ckm, Tnnt3, Adipoq, Fabp4, Lep, Retn, Hoxc8, Hoxc9, Cebpa, Dgat1, Dgat2, Elovl3, Fas, Scd 1, Srebf1, Hilpda, Lipe, Mgll, Plin1, Plin4, Pnpla2, Pnpla3, Ldah, Cs, Gckr, Me1, Pck1, Pdk 4, Irs1, Acaa1a, Acads, Acox1, Cpt1a, Cpt1b, Hadhb, Ehhadh, Ppara, Ppargc1a, Cyp4a12a, Cyp4a12b, Cyp2e1, Adgre1, Agtr1a, Ccl2, Cd14, Cd68, Il1b, Tnf, or a combination thereof; and administering a therapeutically effective amount of the FADS1 inhibitor compound to the subject upon determining that the subject is a subject who would benefit from treatment with the FADS1 inhibitor compound, as determined by the subject's level of the biological indicator compared to a baseline level of the biological indicator. A method comprising:

12. The method of claim 11, wherein the subject is determined to be a subject who would benefit from treatment with the FADS1 inhibitor compound if the level of the biological indicator of the subject is higher than the reference level of the biological indicator.

13. The method of claim 11, wherein the subject is determined to be a subject who would benefit from treatment with the FADS1 inhibitor compound if the level of the biological indicator of the subject is lower than the reference level of the biological indicator.

14. 12. The method of claim 11, wherein the DEG is one disclosed in Figures 4a, 5a, 10a, 13a, 13g, 15e, 15f, or a combination of the DEGs disclosed above.

15. 1. A method of treating a FADS1-mediated disease or disorder in a subject in need thereof, comprising: receiving information comparing a level of a biological indicator of a FADS1-mediated disease from the subject to a reference level of the biological indicator; receiving, wherein the biological indicator is a measured level of a cell type in the subject, the cell type being adipocytes (Adipo), B cells (Bcell), endothelial cells (Endo), hepatocytes (Hep), Kupffer cells (Kupff), myeloid cells (Myel), natural killer cells (NK), T cells (Tcell), or a combination thereof; and administering a therapeutically effective amount of the FADS1 inhibitor compound to the subject upon determining that the subject is a subject who would benefit from treatment with the FADS1 inhibitor compound, as determined by the subject's level of the biological indicator compared to a baseline level of the biological indicator. A method comprising:

16. The method of claim 15, wherein the subject is determined to be a subject who would benefit from treatment with the FADS1 inhibitor compound if the level of the biological indicator of the subject is higher than the reference level of the biological indicator.

17. The method of claim 15, wherein the subject is determined to be a subject who would benefit from treatment with the FADS1 inhibitor compound if the level of the biological indicator of the subject is lower than the reference level of the biological indicator.

18. 18. The method of any one of claims 1 to 17, wherein the FADS1-mediated disease or disorder is obesity, a metabolic disorder, a cardiovascular disorder, diabetes, dyslipidemia, non-alcoholic steatohepatitis (NASH), or any combination thereof.

19. The method according to any one of claims 1 to 18, wherein the reference level of the biological indicator is the average amount of the biological indicator in a population of healthy subjects.

20. The method of any one of claims 1 to 19, wherein the reference level of the biological indicator is the average amount of the biological indicator in a population of subjects not having a FADS1-mediated disease.

21. The method according to any one of claims 1 to 20, wherein the reference level of the biological indicator is the average amount of the biological indicator in a population of subjects having a body mass index (BMI) of 25.0 or greater.

22. The method according to any one of claims 1 to 20, wherein the reference level of the biological indicator is the average amount of the biological indicator in a population of subjects with a body mass index (BMI) of 30.0 or greater.

23. The method of any one of claims 1 to 22, wherein the level of a biological indicator of a FADS1-mediated disease from the subject is quantified using a sample taken from the subject, the sample being blood, plasma, or a tissue biopsy.

24. 24. The method of claim 23, wherein the tissue is adipose tissue or organ tissue.

25. the FADS1 inhibitor compound 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 3-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-3,7-bis(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-fluoro-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-chloro-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-(methoxymethyl)-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-cyclopropyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-cyclopropyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2,3-dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-3H,7H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2,3-dimethyl-5-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-3H,7H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 7-ethyl-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 1,2-dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-1H,7H-pyrazolo[1,5-a]pyrimidin-7-one; 1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-1H,7H-pyrazolo[1,5-a]pyrimidin-7-one; 1,3-dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-1H,7H-pyrazolo[1,5-a]pyrimidin-7-one; 3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H,6H,7H,8H-pyrrolo[1,2-a]pyrimidin-4-one; 2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H,6H,7H,8H-pyrrolo[1,2-a]pyrimidin-4-one; 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-2H,3H,5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 6-{1-[(2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-2-methyl-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-2H,3H,5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 8-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-9-(trifluoromethyl)-6,10-diazatricyclo[4.4.0.0 ２ , ４ ]deca-1(10),8-dien-7-one; 6-{1-[(3,3-difluorocyclobutyl)methyl]-1H-pyrazol-4-yl}-2-methyl-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-[1,2,4]triazolo[4,3-a]pyrimidin-5-one; 3-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-3H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidin-7-one; 2-methyl-6-{1-[(oxetan-3-yl)methyl]-1H-pyrazol-4-yl}-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-3-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-(hydroxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-(hydroxymethyl)-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-chloro-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(propan-2-yl)-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione; 1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 3-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-3H,7H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]oxazolo[3,2-a]pyrimidin-5-one; 2-methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 7-ethoxy-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-(methoxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-Methoxy-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 3-chloro-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-(hydroxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-(hydroxymethyl)-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione; 2-chloro-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-chloro-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-cyclopropyl-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-chloro-1-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-dimethyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-dimethyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-(methoxymethyl)-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-ethyl-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(2-methoxyethyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(propan-2-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-{1-[(2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-1,2-dimethyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-{1-[(3,3-difluorocyclobutyl)methyl]-1H-pyrazol-4-yl}-1,2-dimethyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-1,2-dimethyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(cyclopropylmethyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-(methoxymethyl)-1-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(2-hydroxypropyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-dimethyl-6-{1-[(oxetan-3-yl)methyl]-1H-pyrazol-4-yl}-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(cyclopropylmethyl)-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-[2-(dimethylamino)ethyl]-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(cyclopropylmethyl)-2-methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-[2-(dimethylamino)ethyl]-2-methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-3-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methoxy-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methoxy-1-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-{1-[(2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-( ２ H ３ ) methyl-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-( ２ H ３ ) methyl-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(2-hydroxyethyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; Methyl 2-methyl-5-oxo-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidine-1-carboxylate; 1-[(2,2-difluorocyclopropyl)methyl]-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-[(3,3-difluorocyclobutyl)methyl]-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(2-hydroxyethyl)-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-[2-(dimethylamino)ethyl]-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(prop-2-yn-1-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-{2-methyl-5-oxo-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-1-yl}acetonitrile; 2-[2-methyl-5-oxo-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-1-yl]acetonitrile; 1-(2-hydroxy-2-methylpropyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-[2-(1-hydroxycyclopropyl)ethyl]-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-1-[(oxetan-3-yl)methyl]-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-1-(oxetan-3-yl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidine-5-thione; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyridin-2-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-1-(pyridin-2-yl)-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyrazin-2-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-1-(6-methylpyridin-2-yl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-1-(1-methyl-1H-pyrazol-4-yl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyridin-3-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-phenyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(6-chloropyridin-2-yl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyridin-4-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(1H-pyrazol-4-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-(fluoromethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-[(dimethylamino)methyl]-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 6-(1-{[(1R)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-(1-{[(1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-(1-{[(1R)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-1,2-dimethyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-(1-{[(1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-1,2-dimethyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-(1-{[(1R)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 6-(1-{[(1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; (2R)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-2H,3H,5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; (2S)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-2H,3H,5H,6H,7H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 1-{[(1R)-2,2-difluorocyclopropyl]methyl}-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-{[(1S)-2,2-difluorocyclopropyl]methyl}-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; (2R)-2-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenoxy)propanenitrile; (2R)-2-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-3-yl)phenoxy)propanenitrile; (2S)-2-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenoxy)propanenitrile; (2S)-2-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-3-yl)phenoxy)propanenitrile; (4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)-1H-pyrazol-1-yl)acetonitrile; (4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenoxy)acetonitrile; (4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenyl)acetonitrile; (4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-3-yl)phenoxy)acetonitrile; (4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-8-yl)acetonitrile; 1-(chloromethyl)-7-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-8-(trifluoromethyl)-1H,2H,6H-pyrimido[1,2-a][1,3]diazine-2,6-dione; 1-(fluoromethyl)-7-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-8-(trifluoromethyl)-1H,2H,6H-[1,3]diazino[1,2-a]pyrimidine-2,6-dione; 1-(methyl-d ３ )-7-(4-(2,2,2-trifluoroethoxy)phenyl)-8-(trifluoromethyl)-2H-pyrimido[1,2-a]pyrimidine-2,6(1H)-dione; 1-methyl-7-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-8-(trifluoromethyl)-1H,2H,6H-[1,3]diazino[1,2-a]pyrimidine-2,6-dione; 2-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenoxy)-2-methylpropanenitrile; 2-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenoxy)propanenitrile; 2-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-3-yl)phenoxy)propanenitrile; 2-(difluoromethyl)-3-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one; 2-(difluoromethyl)-4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile; 2-(difluoromethyl)-8-methoxy-3-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-(difluoromethyl)-8-methoxy-3-(1-(4,4,4-trifluorobutyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-(difluoromethyl)-8-methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-(difluoromethyl)-8-methoxy-3-(6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-(fluoromethyl)-4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile; 2-(fluoromethyl)-8-methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H,6H,7H,9H-pyrimido[2,1-c][1,4]oxazin-4-one; 2,8-dimethoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-cyclopropyl-8-methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-ethoxy-8-methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-ethoxy-8-methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 2-ethyl-8-methoxy-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-ethyl-8-methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-ethyl-8-methoxy-3-(6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-4,8(1H)-dione; 3-(1-(2,2-difluoropropyl)-1H-pyrazol-4-yl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-{[(1R)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-{[(1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-benzofuran-2-yl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-cyclopropyl-1H-pyrazol-4-yl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-phenyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(1-propyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 3-(2-fluoro-4-(trifluoromethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(2-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 3-(4-(((1R)-2,2-difluorocyclopropyl)methoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(((1S)-2,2-difluorocyclopropyl)methoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-((2,2-difluorocyclopropyl)methoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-4,8(1H)-dione; 3-(4-(2,2,2-trifluoroethoxy)phenyl)-2,8-bis(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(2,2-difluoroethoxy)-2-fluorophenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(2,2-difluoroethoxy)phenyl)-8-(methyloxy-d ３ )-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(2,2-difluoroethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(2,2-difluoropropoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(2-fluoroethoxy)phenyl)-8-(methyloxy-d ３ )-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(2-fluoroethoxy)phenyl)-8-(methyloxy-d ３ )-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 3-(4-(2-fluoroethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(2-fluoroethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 3-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)-1H-pyrazol-1-yl)propanenitrile; 3-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenyl)propanenitrile; 3-(4-(cyclopropylmethoxy)-2-fluorophenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(cyclopropylmethoxy)phenyl)-8-(methyloxy-d ３ )-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(cyclopropylmethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(4-(cyclopropylmethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 3-(4-(difluoromethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(5-(2,2,2-trifluoroethoxy)-2-pyridinyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-(6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H,6H,7H,9H-pyrimido[2,1-c][1,4]oxazin-4-one; 3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 3-[5-iodo-1-(2,2,3,3,3-pentafluoropropyl)-1H-1,2,3-triazol-4-yl]-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-{1-[(2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-7-fluoro-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-{1-[(2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-{1-[(2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 3-{1-[(3,3-difluorocyclobutyl)methyl]-1H-pyrazol-4-yl}-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 3-{1-[(3,3-difluorocyclobutyl)methyl]-1H-pyrazol-4-yl}-8-methoxy-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 3-{1-[(3,3-difluorocyclobutyl)methyl]-1H-pyrazol-4-yl}-8-methyl-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 3-fluoro-1-methyl-7-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-8-(trifluoromethyl)-1H,2H,6H-[1,3]diazino[1,2-a]pyrimidine-2,6-dione; 4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile; 4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxylic acid; 4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile; 4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxamide; 4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxylic acid; 4-oxo-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-7-carbonitrile; 7-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-8-(trifluoromethyl)-2H-pyrimido[1,2-a]pyrimidine-2,6(1H)-dione; 7-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-8-(trifluoromethyl)-2H-pyrimido[1,2-a]pyrimidine-2,6(1H)-dione; 7-(4-(2,2,2-trifluoroethoxy)phenyl)-8-(trifluoromethyl)-2H-pyrimido[1,2-a]pyrimidine-2,6(1H)-dione; 7-(4-(2-fluoroethoxy)phenyl)-8-(trifluoromethyl)-2H-pyrimido[1,2-a]pyrimidine-2,6(1H)-dione; 7-(methoxymethyl)-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7,8-dimethyl-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H-pyrimido[1,2-b]pyridazin-4-one; 7,8-dimethyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 7,9-dimethyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 7-chloro-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 7-chloro-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 7-chloro-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-chloro-8-methoxy-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 7-chloro-8-methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-[1,3]diazino[1,2-a]pyrimidin-4-one; 7-chloro-8-methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-chloro-8-methyl-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 7-chloro-8-methyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-chloro-8-methyl-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-cyclopropyl-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 7-cyclopropyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-fluoro-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 7-fluoro-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-fluoro-8-hydroxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-fluoro-8-methoxy-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 7-fluoro-8-methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-[1,3]diazino[1,2-a]pyrimidin-4-one; 7-fluoro-8-methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-fluoro-8-methoxy-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-fluoro-8-methyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-Methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-[1,3]diazino[1,2-a]pyrimidin-4-one; 7-Methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 7-Methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-methyl-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H-pyrimido[1,2-b]pyridazin-4-one; 7-methyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-[1,3]diazino[1,2-a]pyrimidin-4-one; 7-methyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 7-methyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-methyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-((1R)-1-hydroxyethyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((1R)-1-hydroxyethyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((1S)-1-hydroxyethyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((1S)-1-hydroxyethyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((dimethylamino)methyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(methyloxy-d ３ )-2-(trifluoromethyl)-3-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((methylsulfanyl)methoxy)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((R)-ethylsulfinyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((R)-methylsulfinyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((R)-methylsulfinyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((S)-ethylsulfinyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((S)-methylsulfinyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-((S)-methylsulfinyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(1,3-oxazol-2-yl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(1-hydroxyethyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(1-hydroxyethyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(2-hydroxypropan-2-yl)-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(2-methyl-2-oxetanyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(2-propanyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(3-azetidinyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(aminomethyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(1-azetidinyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(chloromethoxy)-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(chloromethoxy)-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-(difluoromethoxy)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(difluoromethyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(dimethylamino)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(dimethylamino)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(ethylsulfinyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(fluoromethoxy)-2-(trifluoromethyl)-3-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(fluoromethoxy)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(fluoromethoxy)-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(fluoromethoxy)-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-(fluoromethyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(fluoromethyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(hydroxymethyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(hydroxymethyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(methoxymethyl)-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(methylamino)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(methylamino)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(methylamino)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 8-(methyl-d ３ )-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(methyloxy-d ３ )-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(methyloxy-d ３ )-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 8-(methyloxy-d ３ )-3-(1-(4,4,4-trifluorobutyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(methyloxy-d ３ )-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(methyloxy-d ３ )-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 8-(methyloxy-d ３ )-3-(6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(methylsulfanyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(methylsulfanyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(methylsulfinyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(methylsulfinyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-(methylsulfonyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-acetyl-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-amino-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-amino-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-amino-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 8-chloro-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-chloro-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-cyclopropyl-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-cyclopropyl-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-ethenyl-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-ethoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-ethyl-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-fluoro-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-hydroxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-Methoxy-2-(trifluoromethyl)-3-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-2-(trifluoromethyl)-3-(1-(3,3,3-trifluoropropyl)-1H-imidazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-2-(trifluoromethyl)-3-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-2-(trifluoromethyl)-3-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 8-Methoxy-2-(trifluoromethyl)-3-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-2-(trifluoromethyl)-3-(4-(3,3,3-trifluoropropyl)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H-pyrimido[1,2-b]pyridazin-4-one; 8-Methoxy-2-(trifluoromethyl)-3-[3-(3,3,3-trifluoropropyl)-1,2-oxazol-5-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-2-(trifluoromethyl)-3-[4-(3,3,3-trifluoropropyl)-1H-imidazol-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-2-(trifluoromethyl)-3-[5-(3,3,3-trifluoropropyl)-1,3-thiazol-2-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-2-methyl-3-(4-(2,2,2-trifluoroethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(1-(4,4,4-trifluorobutyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(1-(4,4,4-trifluorobutyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(1-phenyl-1H-pyrazol-3-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(1-phenyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(1-propyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(2-methyl-4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(2-phenyl-1,3-oxazol-5-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(3-phenyl-1,2-oxazol-5-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(4-(2,2,2-trifluoroethoxy)-2-(trifluoromethyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(4-(2,2,3,3,3-pentafluoropropoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(4-(2,2,3,3-tetrafluoropropoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(4-(trifluoromethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(4-(trifluoromethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(4-propylphenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(5-propyl-1,2-oxazol-3-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-(6-propyl-3-pyridinyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-1,2,3-triazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-3-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-[1,3]diazino[1,6-a]pyrimidin-4-one; 8-Methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-Methoxy-3-[2-(2,2,2-trifluoroethoxy)-1,3-thiazol-5-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-[1,3]diazino[1,2-a]pyrimidin-4-one; 8-Methoxy-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-Methoxy-3-[2-(2,2,3,3,3-pentafluoropropoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-[3-(2,2,3,3,3-pentafluoropropyl)-1,2-oxazol-5-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-[4-(2,2,2-trifluoroethoxy)-1,3-thiazol-2-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-[5-(2,2,2-trifluoroethoxy)-1,3-thiazol-2-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-3-{1-[(oxetan-3-yl)methyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-Methoxy-6-methyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-methyl-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H-pyrimido[1,2-b]pyridazin-4-one; 8-methyl-2-(trifluoromethyl)-3-[5-(3,3,3-trifluoropropyl)-1,2,4-oxadiazol-3-yl]-4H-pyrido[1,2-a]pyrimidin-4-one; 8-methyl-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 8-methyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H,6H,7H,8H,9H-pyrimido[1,2-a]pyrazin-4-one; 8-methyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-methyl-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one; 8-methyl-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one, 9-chloro-8-methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 9-fluoro-8-methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 9-methyl-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; Methyl 4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxylate; Methyl(4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-8-yl)carbamyl fluoride; N-(4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-8-yl)acetamide; N-(4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-8-yl)acetamide; N,N-dimethyl-4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxamide; N-ethyl-4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxamide; N-methyl-4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxamide; or N-methyl-4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxamide; or A pharmaceutically acceptable salt of any of the foregoing The method according to any one of claims 1 to 24, wherein

26. 26. The method of any one of claims 1 to 25, wherein the FADS1 inhibitor compound is a free base.

27. 1. A method for measuring the ratio of arachidonic acid (AA) to dihomo-gamma-linolenic acid (DGLA) in a subject, comprising: the AA is isotopically labeled, the DGLA is isotopically labeled, measuring the ratio of AA to DGLA by administering a dose of labeled DGLA to the subject and then measuring the ratio of labeled AA to labeled DGLA; method.

28. The labeled DGLA is １３ 28. The method of claim 27, comprising DGLA that is isotopically enriched with C.

29. The labeled DGLA has five or more carbon positions １３ 29. The method of claim 28, comprising DGLA that is isotopically enriched with C atoms.

30. The labeled DGLA is: 【Chemistry 1】 30. The method of any one of claims 27 to 29, wherein one, more than one, or all of the carbons indicated by "*" in

31. 31. The method of any one of claims 27 to 30, wherein the subject is administered a dose of a FADS1 inhibitor compound before, simultaneously with, or after administration of the labeled dose of DGLA to the subject.

32. The following structure: 【Chemistry 2】 A compound represented by the formula: During the ceremony, Each "*" symbol represents １３ indicates positions that can be isotopically enriched with C, At least one "*" position １３ isotopically enriched with C, compound.

33. At least five "*" positions are １３ 33. The compound of claim 32, which is isotopically enriched with C.

34. 34. The compound of claim 32 or 33, wherein each isotopically enriched position is enriched by a factor of 1000 or more.

35. The following structure: 【Transformation 3】 A method for producing a compound represented by the formula: 【Chemistry 4】 with KC*N, During the ceremony, Each "*" symbol represents １３ indicates positions that can be isotopically enriched with C, and at least one "*" position is １３ isotopically enriched with C, X is a halogen; method.

Images