Heterocyclic compounds as delta-5 desaturase inhibitors and methods of use

Abstract

The present disclosure provides compounds useful for inhibiting delta-5 desaturase ("D5D"), which have the general formula (I): The variables of formula (I) are defined herein. The disclosure also provides pharmaceutical compositions containing the compounds, uses of the compounds, and compositions for treating, for example, metabolic or cardiovascular disorders. Additionally, the disclosure provides intermediates useful in the synthesis of compounds of formula (I).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 939,819, filed November 25, 2019, which is incorporated by reference in its entirety.

[0002] The present disclosure provides compounds useful for inhibiting delta-5 desaturase ("D5D"). The disclosure also provides pharmaceutical compositions containing the compounds, uses of the compounds, and compositions for treating, for example, metabolic or cardiovascular disorders. Additionally, the disclosure provides intermediates useful for synthesizing compounds of Formula I. [Background technology]

[0003] Polyunsaturated fatty acids ("PUFAs") perform important physiological functions in the human body. Kroeger J and Schulze MB, 2012, page 4. PUFAs serve as a source of energy and structural components of cell membranes. Ibid. PUFAs also regulate genes and are biosynthetic precursors for other physiologically relevant biomolecules such as eicosanoids and endocannabinoids. Ibid. Di Marzo V and Matias I, 2005, page 585.

[0004] Eicosanoids are signaling molecules with multiple functions, among them regulating inflammatory responses in humans (Non-Patent Document 3). Endocannabinoids (N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG)) are endogenous ligands of cannabinoid receptors that have been demonstrated to play a role in food intake and energy balance. Di Marzo V and Matias I, 2005, page 585.

[0005] [Table 1]

[0006] Yashiro H et al.,2016,page 2 / 18. Obukowicz MG et al., 1998, page 158. Di Marzo V and Matias I, 2005, page 585.

[0007] The relevant portion of the metabolic pathway of a particular PUFA, linoleic acid ("LA"), which leads to the formation of, among other things, anti-inflammatory and pro-inflammatory eicosanoids and endocannabinoids, is shown in the scheme above.

[0008] The desaturase enzymes that catalyze specific steps in the conversion of LA into 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")) (Non-Patent Document 4). Selective inhibition of D5D activity increases the amount of DGLA while reducing the amount of AA produced. Such pharmacological intervention can result in, for example, a reduction in the downstream production of pro-inflammatory eicosanoids and endocannabinoids and an increase in anti-inflammatory eicosanoids, both of which can overall improve inflammation-related conditions and energy balance. Yashiro H et al., 2016, page 3 / 18. Di Marzo V and Matias I, 2005, page 585. This is particularly true in subjects with high LA intake, such as those exposed to a Western diet. Yashiro H et al.,2016,page 3 / 18.

[0009] The FADS1-3 loci have been associated with many metabolic traits, including fasting blood glucose, plasma lipids, and body weight, in human genome-wide association studies (Fumagalli M et al., 2015; Willer CJ et al., 2013; Dupuis J et al., 2010). Increases or augmentations of each metabolic trait associated with the FADS1-3 loci are also associated with increased D5D activity, as estimated by the AA:DGLA ratio (Fumagalli M et al., 2015; Merino DM et al., 2011).

[0010] In addition to human genetic evidence supporting a role for 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 blood glucose regulation, and reduced circulating lipid levels. Powell DR et al., 2016, page 197. Furthermore, FADS1 KO mice are resistant to the development of arterial atherosclerotic plaques. Ibid.

[0011] 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. Tosi F et al., 2014; Kroeger J and Schulze MB, 2012; and Merino DM et al., 2010. Therefore, pharmacological inhibition of D5D is of interest for treating metabolic, cardiovascular, and other diseases. Powell DR et al., 2016, page 197.

[0012] Despite some progress in the area of ​​small molecule therapeutics (e.g., Miyahisa I et al., 2016; Yashiro H et al., 2016; and Baugh SD et al., 2015), there remains a need for inhibitors of D5D that may be suitable for use as therapeutic agents, given the significant ongoing societal burden caused, for example, by metabolic and cardiovascular diseases (e.g., Haidar YM and Cosman BC, 2011; Mendis S et al., 2007; Chopra M et al., 2002; and Monteiro CA et al., 2004). [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Kroeger J and Schulze MB,2012,page 4 [Non-patent document 2] Di Marzo V and Matias I,2005,page 585 [Non-patent document 3] Harizi H et al., 2008 [Non-patent document 4] Yashiro H et al.,2016,page 2 / 18 [Non-Patent Document 5] Obukowicz MG et al., 1998, page 158 [Non-patent document 6] Yashiro H et al.,2016,page 3 / 18 [Non-Patent Document 7] Fumagalli M et al., 2015 [Non-patent document 8] Willer CJ et al., 2013 [Non-Patent Document 9] Dupuis J et al., 2010 [Non-Patent Document 10] Merino DM et al., 2011 [Non-Patent Document 11] Powell DR et al.,2016,page 197 [Non-Patent Document 12] Tosi F et al., 2014 [Non-Patent Document 13] Kroeger J and Schulze MB, 2012 [Non-Patent Document 14] Merino DM et al., 2010 [Non-Patent Document 15] Miyahisa I et al., 2016 [Non-Patent Document 16] Yashiro H et al., 2016 [Non-Patent Document 17] Baugh SD et al., 2015 [Non-Patent Document 18] Haidar YM and Cosman BC, 2011 [Non-Patent Document 19] Mendis S et al., 2007 [Non-Patent Document 20] Chopra M et al., 2002 [Non-Patent Document 21] Monteiro CA et al., 2004 Summary of the Invention [Means for solving the problem]

[0014] First, herein, a compound of formula I [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of the above compound or the above tautomer, wherein: 1) [ka] teeth, [ka] wherein optionally one of CRw, CRx, CRy, and CRz is N; or 2) [ka] teeth, [ka] or 3) [ka] teeth, [ka] and During the ceremony, R w is H, halogen, -CN, -CO(C 1~4 alkyl), -S(O) n (C 1~4 alkyl), -COOH, -COO(C 1~4 alkyl), -CONH2, -CONH(C 1~4 alkyl), -CO(diC 1~4 alkylamino), -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, -NH(COC 1~4 alkyl), -N(C 1~4 alkyl)C(=O)F, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 3~5 Cycloalkyl, C 3~4 Heterocycloalkyl, C 2~4 Alkenyl, C 1~4 deuteroalkoxy, or 5-membered heteroaryl, wherein C 1~4 Alkyl and C 3~4 The heterocycloalkyl group may optionally be independently selected from halogen, —OH, —CN, C 1~4 Alkoxy, C 1~4Alkyl, -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, and -S(O) n (C 1~4 alkyl), R y are H, F, Cl, -OH, -CN, -CO(C 1~4 alkyl), -S(O) n (C 1~4 alkyl), -COOH, -COO(C 1~4 alkyl), -CONH2, -CONH(C 1~4 alkyl), -CO(diC 1~4 alkylamino), -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, -NH(COC 1~4 alkyl), -N(C 1~4 alkyl)C(=O)F, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 3~5 Cycloalkyl, C 3~4 Heterocycloalkyl, C 2~4 Alkenyl, C 1~4 Alkoxy, C 1~4 deuteroalkoxy, or 5-membered heteroaryl, wherein C 1~4 Alkyl, C 3~4 Heterocycloalkyl, and C 1~4 The alkoxy group may optionally be independently selected from halogen, —OH, —CN, C 1~4 Alkoxy, C 1~4 Alkyl, -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, and -S(O) n (C 1~4 alkyl), R x and R z are independently H, halogen, -OH, -CN, -CO(C 1~4 alkyl), -S(O)(C 1~4 alkyl), -COOH, -COO(C 1~4 alkyl), -CONH2, -CONH(C1~4 alkyl), -CO(diC 1~4 alkylamino), -NH 2 , C 1~4 Alkylamino, DiC 1~4 Alkylamino, -NH(COC 1~4 alkyl), -N(C 1~4 alkyl)C(=O)F, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 3~5 Cycloalkyl, C 3~4 Heterocycloalkyl, C 2~4 Alkenyl, C 1~4 Alkoxy, C 1~4 deuteroalkoxy, or 5-membered heteroaryl, wherein C 1~4 Alkyl, C 3~4 Heterocycloalkyl, and C 1~4 The alkoxy group may optionally be independently selected from halogen, —OH, —CN, C 1~4 Alkoxy, C 1~4 Alkyl, -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, and -S(O) n (C 1~4 alkyl), R 1 is H, C 1~4 Alkyl, C 1~4 Haloalkyl, or C 1~4 is a deuteroalkyl; x is O, NH, or N(C 1~4 alkyl), R 2 teeth, [ka] or 2-benzofuranyl, wherein A is independently CH or N, wherein: [ka] teeth [ka] rather than and B is a 5-membered heteroaryl containing one heteroatom selected from N, S, and O, and optionally one or two additional N atoms, wherein i) B is attached to the bicyclic core via a C atom and R 3 is bonded through an N atom, or ii) B is attached to the bicyclic core via an N atom and R 3 is bonded via a C atom, or iii) B is attached to the bicyclic core via a C atom and R 3 is bonded through a C atom, During the ceremony, R 2 or 2-benzofuranyl [ka] The moiety optionally contains one or two independently selected substituents R 3’ is further replaced by R 3 is CH2CN, C 2~6 Alkyl, C 3~5 Cycloalkyl, C 1~3 Alkoxy, C 1~6 Alkylamino, DiC 1~6 Alkylamino, -S(O) n (C 1~6 alkyl), -CH2(C 3~5 cycloalkyl), -OCH2(C 3~5 cycloalkyl), -NHCH2(C 3~5 cycloalkyl), -S(O) n CH2(C 3~5 cycloalkyl), -CH2(C 3~5 heterocycloalkyl), or phenyl, wherein C 2~6 Alkyl, C 3~5 Cycloalkyl, C 1~3 Alkoxy, C 1~6 Alkylamino, DiC 1~6 Alkylamino, -S(O) n (C 1~6 alkyl), -CH2(C 3~5cycloalkyl), -OCH2(C 3~5 cycloalkyl), -NHCH2(C 3~5 cycloalkyl), and -S(O) n CH2(C 3~5 cycloalkyl) groups are optionally substituted with 1 to 9 halogen atoms and optionally substituted with -CN, wherein phenyl is optionally substituted with halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, and C 1~4 substituted with 1 to 3 substituents selected from haloalkoxy; R 3’ are independently halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or C 1~4 haloalkoxy, R 4 is C 1~3 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 3~5 Cycloalkyl, or C 3~5 is cyclohaloalkyl, n is 0, 1, or 2.

[0015] Second, provided herein is a pharmaceutical composition comprising a compound of Formula I, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable excipient.

[0016] Third, the present specification provides a method for use in reducing the weight of a subject, or Provided is a compound of formula I, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition as described herein above, for use in reducing the body mass index of a subject.

[0017] Fourth, provided herein is a compound of formula I, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition as described herein above, for use in the treatment of a metabolic disorder, or for use in the treatment of a cardiovascular disorder.

[0018] Fifth, provided herein is a compound of Formula I, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition as described herein above, for use in the treatment of a metabolic disorder, or for use in the treatment of diabetes, obesity, dyslipidemia, or non-alcoholic steatohepatitis (NASH).

[0019] Reference will now be made in detail to the embodiments of the present disclosure. While particular embodiments of the present disclosure will be described, it will be understood that it is not intended that the embodiments of the present disclosure be limited to these described embodiments. On the contrary, reference to the embodiments of the present disclosure is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the embodiments of the present disclosure as defined by the appended claims. DETAILED DESCRIPTION OF THE INVENTION

[0020] In embodiment 1, the present specification provides a compound of formula I: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of the above compound or the above tautomer, wherein: 1) [ka] teeth, [ka] wherein optionally one of CRw, CRx, CRy, and CRz is N; or 2) [ka] teeth, [ka] or 3) [ka] teeth, [ka] and During the ceremony, R w is H, halogen, -CN, -CO(C 1~4 alkyl), -S(O) n (C 1~4 alkyl), -COOH, -COO(C 1~4 alkyl), -CONH2, -CONH(C 1~4 alkyl), -CO(diC 1~4 alkylamino), -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, -NH(COC 1~4 alkyl), -N(C 1~4 alkyl)C(=O)F, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 3~5 Cycloalkyl, C 3~4 Heterocycloalkyl, C 2~4 Alkenyl, C 1~4 deuteroalkoxy, or 5-membered heteroaryl, wherein C 1~4 Alkyl and C 3~4 The heterocycloalkyl group may optionally be independently selected from halogen, —OH, —CN, C 1~4 Alkoxy, C 1~4 Alkyl, -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, and -S(O) n (C 1~4 alkyl), R yare H, F, Cl, -OH, -CN, -CO(C 1~4 alkyl), -S(O) n (C 1~4 alkyl), -COOH, -COO(C 1~4 alkyl), -CONH2, -CONH(C 1~4 alkyl), -CO(diC 1~4 alkylamino), -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, -NH(COC 1~4 alkyl), -N(C 1~4 alkyl)C(=O)F, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 3~5 Cycloalkyl, C 3~4 Heterocycloalkyl, C 2~4 Alkenyl, C 1~4 Alkoxy, C 1~4 deuteroalkoxy, or 5-membered heteroaryl, wherein C 1~4 Alkyl, C 3~4 Heterocycloalkyl, and C 1~4 The alkoxy group may optionally be independently selected from halogen, —OH, —CN, C 1~4 Alkoxy, C 1~4 Alkyl, -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, and -S(O) n (C 1~4 alkyl), R x and R z are independently H, halogen, -OH, -CN, -CO(C 1~4 alkyl), -S(O)(C 1~4 alkyl), -COOH, -COO(C 1~4 alkyl), -CONH2, -CONH(C 1~4 alkyl), -CO(diC 1~4 alkylamino), -NH 2 , C 1~4 Alkylamino, DiC 1~4 Alkylamino, -NH(COC 1~4 alkyl), -N(C1~4 alkyl)C(=O)F, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 3~5 Cycloalkyl, C 3~4 Heterocycloalkyl, C 2~4 Alkenyl, C 1~4 Alkoxy, C 1~4 deuteroalkoxy, or 5-membered heteroaryl, wherein C 1~4 Alkyl, C 3~4 Heterocycloalkyl, and C 1~4 The alkoxy group may optionally be independently selected from halogen, —OH, —CN, C 1~4 Alkoxy, C 1~4 Alkyl, -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, and -S(O) n (C 1~4 alkyl), R 1 is H, C 1~4 Alkyl, C 1~4 Haloalkyl, or C 1~4 is a deuteroalkyl; x is O, NH, or N(C 1~4 alkyl), R 2 teeth, [ka] or 2-benzofuranyl, wherein A is independently CH or N, and [ka] teeth [ka] Instead, B is a 5-membered heteroaryl containing one heteroatom selected from N, S, and O, and optionally one or two additional N atoms, wherein i) B is attached to the bicyclic core via a C atom and R3 is bonded through an N atom, or ii) B is attached to the bicyclic core via an N atom and R 3 is bonded via a C atom, or iii) B is attached to the bicyclic core via a C atom and R 3 is bonded through a C atom, During the ceremony, R 2 or 2-benzofuranyl [ka] The moiety optionally contains one or two independently selected substituents R 3’ is further replaced by R 3 is CH2CN, C 2~6 Alkyl, C 3~5 Cycloalkyl, C 1~3 Alkoxy, C 1~6 Alkylamino, DiC 1~6 Alkylamino, -S(O) n (C 1~6 alkyl), -CH2(C 3~5 cycloalkyl), -OCH2(C 3~5 cycloalkyl), -NHCH2(C 3~5 cycloalkyl), -S(O) n CH2(C 3~5 cycloalkyl), -CH2(C 3~5 heterocycloalkyl), or phenyl, wherein C 2~6 Alkyl, C 3~5 Cycloalkyl, C 1~3 Alkoxy, C 1~6 Alkylamino, DiC 1~6 Alkylamino, -S(O) n (C 1~6 alkyl), -CH2(C 3~5 cycloalkyl), -OCH2(C 3~5 cycloalkyl), -NHCH2(C 3~5 cycloalkyl), and -S(O) n CH2(C 3~5cycloalkyl) groups are optionally substituted with 1 to 9 halogen atoms and optionally substituted with -CN, wherein phenyl is optionally substituted with halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, and C 1~4 substituted with 1 to 3 substituents selected from haloalkoxy; R 3’ are independently halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or C 1~4 haloalkoxy, R 4 is C 1~3 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 3~5 Cycloalkyl, or C 3~5 is cyclohaloalkyl, n is 0, 1, or 2.

[0021] As embodiment 2, provided herein is a compound of embodiment 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is 3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H,6H,7H,9H-pyrimido[2,1-c][1,4]oxazin-4-one, 7-(azetidin-1-yl)-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-[(dimethylamino)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-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-cyclopropyl-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-fluoro-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-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-pyrimido[1,2-b]pyridazin-4-one, 7-methoxy-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one, 7-methyl-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrazino[1,2-a]pyrimidin-4-one, 7-methyl-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one, 8-methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-1,2,4-triazol-3-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 8-Methoxy-3-[3-(2,2,2-trifluoroethoxy)phenyl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, or Not methyl 4-oxo-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-7-carboxylate.

[0022] As embodiment 3, provided herein is a compound of embodiment 1 or embodiment 2, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein the compound of formula I is a compound of formula IA. [ka]

[0023] As embodiment 4, provided herein is a compound of embodiment 1 or embodiment 2, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein the compound of formula I is a compound of formula IB. [ka]

[0024] As embodiment 5, provided herein is a compound of embodiment 1 or embodiment 2, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein the compound of formula I is a compound of formula IC. [ka]

[0025] As embodiment 6, provided herein is a compound of any one of embodiments 1, 2, 4, and 5, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R w is H, halogen, -CN, -CO(C 1~4 alkyl), -S(O) n (C 1~4 alkyl), -CONH2, -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, -NH(COC 1~4 alkyl), -N(C 1~4 alkyl)C(=O)F, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 3~5Cycloalkyl, C 2~4 Alkenyl, C 1~4 deuteroalkoxy, or 5-membered heteroaryl, wherein C 1~4 The alkyl groups are optionally independently selected from halogen, —OH, —CN, C 1~4 Alkoxy, -NH2, and diC 1~4 and alkylamino.

[0026] As embodiment 7, provided herein is a compound of any one of embodiments 1, 2, 4, and 5, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R w is H, halogen, -CN, -CONH2, -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, or C 1~4 deuteroalkoxyl, wherein C 1~4 The alkyl groups are optionally independently selected from halogen, —OH, C 1~4 Alkoxy, -NH2, and diC 1~4 and alkylamino.

[0027] As embodiment 8, provided herein is a compound of any one of embodiments 1, 2, 4, and 5, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R w is H, F, Cl, -CN, -COMe, -SMe, -CONH, -NH, -NHMe, -N(CH), -NH(COCH), -N(CH)C(=O)F, methyl, ethyl, -CD, cyclopropyl, -CH=CH, -OCD, or 1,3-oxazol-2-yl, wherein the methyl group is optionally substituted with 1 to 3 substituents independently selected from F, Cl, -OH, -CN, methoxy, -NH, and -N(CH).

[0028] As embodiment 9, provided herein is a compound of any one of embodiments 1, 2, 4, and 5, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R w is H, F, Cl, —CN, —CONH2, —NH2, —NHMe, or —OCD3, wherein the methyl group is optionally substituted with 1 to 3 substituents independently selected from F, —OH, methoxy, —NH2, and —N(CH3)2.

[0029] As embodiment 10, provided herein is a compound of any one of embodiments 1, 2, 4, and 5, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R w is H, halogen, or C 1~4 It is alkyl.

[0030] As embodiment 11, provided herein is a compound of any one of embodiments 1, 2, 4, and 5, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R w is H, F, Cl, or methyl.

[0031] As embodiment 12, provided herein is a compound of any one of embodiments 1, 2, 4, and 5, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R w is H.

[0032] As embodiment 13, provided herein is a compound of any one of embodiments 1-12, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R x is H, halogen, -OH, -CN, -CO(C 1~4 alkyl), -S(O) n (C 1~4alkyl), -CONH2, -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, -NH(COC 1~4 alkyl), -N(C 1~4 alkyl)C(=O)F, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 3~5 Cycloalkyl, C 2~4 Alkenyl, C 1~4 Alkoxy, C 1~4 deuteroalkoxy, or 5-membered heteroaryl, wherein C 1~4 Alkyl and C 1~4 The alkoxy group may optionally be independently selected from halogen, —OH, —CN, C 1~4 Alkoxy, -NH2, and diC 1~4 and alkylamino.

[0033] As embodiment 14, provided herein is a compound of any one of embodiments 1-12, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R x is H, halogen, -OH, -CN, -CONH2, -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, C 1~4 Alkoxy or C 1~4 deuteroalkoxyl, wherein C 1~4 Alkyl and C 1~4 The alkoxy group may optionally be independently selected from halogen, —OH, C 1~4 Alkoxy, -NH2, and diC 1~4 and alkylamino.

[0034] As embodiment 15, provided herein is a compound of any one of embodiments 1-12, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R xis H, F, Cl, —OH, —CN, —COMe, —SMe, —CONH, —NH, —NHMe, —N(CH), —NH(COCH), —N(CH)C(═O)F, methyl, ethyl, —CD, cyclopropyl, —CH═CH, methoxy, ethoxy, —OCD, or 1,3-oxazol-2-yl, wherein the methyl and methoxy groups are optionally substituted with 1 to 3 substituents independently selected from F, Cl, —OH, —CN, methoxy, —NH, and —N(CH).

[0035] As embodiment 16, provided herein is a compound of any one of embodiments 1-12, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R x is H, F, Cl, —OH, —CN, —CONH2, —NH2, —NHMe, methoxy, ethoxy, or —OCD3, wherein the methyl and methoxy groups are optionally substituted with 1 to 3 substituents independently selected from F, —OH, methoxy, —NH2, and —N(CH3)2.

[0036] As embodiment 17, provided herein is a compound of any one of embodiments 1-12, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R x is H, halogen, -OH, -CN, -CO(C 1~4 alkyl), -S(O) n (C 1~4 alkyl), -CONH2, -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, -NH(COC 1~4 alkyl), -N(C 1~4 alkyl)C(=O)F, C 1~4 Alkyl, C 3~5 Cycloalkyl, C 2~4 Alkenyl, C 1~4 Alkoxy, C 1~4 deuteroalkoxy, or 5-membered heteroaryl, wherein C 1~4Alkyl and C 1~4 The alkoxy group may optionally be independently selected from halogen, —OH, —CN, C 1~4 Alkoxy, -NH2, and diC 1~4 and alkylamino.

[0037] As embodiment 18, provided herein is a compound of any one of embodiments 1-12, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R x is H, halogen, -OH, -CN, -CONH2, -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, C 1~4 Alkyl, C 1~4 Alkoxy or C 1~4 deuteroalkoxy, wherein C 1~4 Alkyl and C 1~4 The alkoxy group may optionally be independently selected from halogen, —OH, C 1~4 Alkoxy, -NH2, and diC 1~4 and alkylamino.

[0038] As embodiment 19, provided herein is a compound of any one of embodiments 1-12, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R x are H, -CN, -NH2, C 1~4 Alkoxy or C 1~4 It is a deuteroalkoxy.

[0039] As embodiment 20, there is provided herein a compound of any one of embodiments 1-12, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R xis H, F, Cl, —OH, —CN, —COMe, —SMe, —CONH, —NH, —NHMe, —NH(CH), —NH(COCH), —N(CH)C(═O)F, methyl, ethyl, cyclopropyl, —CH═CH, methoxy, ethoxy, —OCD, or 1,3-oxazol-2-yl, wherein the methyl and methoxy groups are optionally substituted with 1 to 4 substituents independently selected from F, Cl, —OH, —CN, methoxy, —NH, and —N(CH).

[0040] As embodiment 21, provided herein is a compound of any one of embodiments 1-12, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R x is H, F, Cl, —OH, —CN, —CONH2, —NH2, —NHMe, methyl, methoxy, ethoxy, or —OCD3, wherein the methyl and methoxy groups are optionally substituted with 1 to 4 substituents independently selected from F, —OH, methoxy, —NH2, and —N(CH3)2.

[0041] As embodiment 22, provided herein is a compound of any one of embodiments 1-12, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R x is H, —CN, —NH2, methoxy, or —OCD3.

[0042] As embodiment 23, there is provided herein a compound of any one of embodiments 1 to 22, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R y are H, F, Cl, -OH, -CN, -CO(C 1~4 alkyl), -S(O) n (C 1~4 alkyl), -CONH2, -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, -NH(COC1~4 alkyl), -N(C 1~4 alkyl)C(=O)F, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 3~5 Cycloalkyl, C 2~4 Alkenyl, C 1~4 Alkoxy, C 1~4 deuteroalkoxy, or 5-membered heteroaryl, wherein C 1~4 Alkyl and C 1~4 The alkoxy group may optionally be independently selected from halogen, —OH, —CN, C 1~4 Alkoxy, -NH2, and diC 1~4 and alkylamino.

[0043] As embodiment 24, there is provided herein a compound of any one of embodiments 1-22, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R y are H, F, Cl, -OH, -CN, -CONH2, -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, C 1~4 Alkoxy or C 1~4 deuteroalkoxyl, wherein C 1~4 Alkyl and C 1~4 The alkoxy group may optionally be independently selected from halogen, —OH, C 1~4 Alkoxy, -NH2, and diC 1~4 and alkylamino.

[0044] As embodiment 25, provided herein is a compound of any one of embodiments 1-22, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R yis H, F, Cl, —OH, —CN, —COMe, —SMe, —CONH, —NH, —NHMe, —N(CH), —NH(COCH), —N(CH)C(═O)F, methyl, ethyl, —CD, cyclopropyl, —CH═CH, methoxy, ethoxy, —OCD, or 1,3-oxazol-2-yl, wherein the methyl and methoxy groups are optionally substituted with 1 to 3 substituents independently selected from F, Cl, —OH, —CN, methoxy, —NH, and —N(CH).

[0045] As embodiment 26, provided herein is a compound of any one of embodiments 1-22, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R y is H, F, Cl, —OH, —CN, —CONH2, —NH2, —NHMe, methoxy, ethoxy, or —OCD3, wherein the methyl and methoxy groups are optionally substituted with 1 to 3 substituents independently selected from F, —OH, methoxy, —NH2, and —N(CH3)2.

[0046] As embodiment 27, provided herein is a compound of any one of embodiments 1-22, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R y are H, F, Cl, -CN, -COO(C 1~4 alkyl), C 1~4 Alkyl, C 3~5 Cycloalkyl, C 3~4 Heterocycloalkyl, or C 1~4 Alkoxy, wherein C 1~4 The alkyl groups are optionally independently C 1~4 Alkoxy and diC 1~4 and alkylamino.

[0047] As embodiment 28, there is provided herein a compound of any one of embodiments 1-22, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R y is H, F, Cl, —CN, —COOMe, methyl, cyclopropyl, azetidinyl, or methoxy, wherein the methyl group is optionally substituted with 1 to 3 substituents independently selected from methoxy and dimethylamino.

[0048] As embodiment 29, provided herein is a compound of any one of embodiments 1-22, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R y is H or Cl.

[0049] As embodiment 30, provided herein is a compound of any one of embodiments 1-4, and 6-29, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R z is H, halogen, -OH, -CN, -CO(C 1~4 alkyl), -S(O) n (C 1~4 alkyl), -CONH2, -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, -NH(COC 1~4 alkyl), -N(C 1~4 alkyl)C(=O)F, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 3~5 Cycloalkyl, C 2~4 Alkenyl, C 1~4 Alkoxy, C 1~4 deuteroalkoxy, or 5-membered heteroaryl, wherein C 1~4 Alkyl and C 1~4 The alkoxy group may optionally be independently selected from halogen, —OH, —CN, C 1~4 Alkoxy, -NH2, and diC 1~4and alkylamino.

[0050] As embodiment 31, provided herein is a compound of any one of embodiments 1-4, and 6-29, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R z is H, halogen, -OH, -CN, -CONH2, -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, C 1~4 Alkoxy or C 1~4 deuteroalkoxyl, wherein C 1~4 Alkyl and C 1~4 The alkoxy group may optionally be independently selected from halogen, —OH, C 1~4 Alkoxy, -NH2, and diC 1~4 and alkylamino.

[0051] As embodiment 32, provided herein is a compound of any one of embodiments 1-4, and 6-29, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R z is H, F, Cl, —OH, —CN, —COMe, —SMe, —CONH, —NH, —NHMe, —N(CH), —NH(COCH), —N(CH)C(═O)F, methyl, ethyl, —CD, cyclopropyl, —CH═CH, methoxy, ethoxy, —OCD, or 1,3-oxazol-2-yl, wherein the methyl and methoxy groups are optionally substituted with 1 to 3 substituents independently selected from F, Cl, —OH, —CN, methoxy, —NH, and —N(CH).

[0052] As embodiment 33, there is provided herein a compound of any one of embodiments 1-4, and 6-29, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R zis H, F, Cl, —OH, —CN, —CONH2, —NH2, —NHMe, methoxy, ethoxy, or —OCD3, wherein the methyl and methoxy groups are optionally substituted with 1 to 3 substituents independently selected from F, —OH, methoxy, —NH2, and —N(CH3)2.

[0053] As embodiment 34, provided herein is a compound of any one of embodiments 1-4, and 6-29, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R z is H or C 1~4 It is alkyl.

[0054] As embodiment 35, provided herein is a compound of any one of embodiments 1-4, and 6-29, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R z is H or methyl.

[0055] As embodiment 36, provided herein is a compound of any one of embodiments 1-4, and 6-29, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R z is H.

[0056] As embodiment 37, provided herein is a compound of embodiment 1 or embodiment 2, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein the compound of formula I is a compound of formula ID. [ka]

[0057] As embodiment 38, provided herein is a compound of embodiment 37, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R y are H, F, Cl, -OH, -CN, -CO(C 1~4 alkyl), -S(O) n (C 1~4 alkyl), -CONH2, -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, -NH(COC 1~4 alkyl), -N(C 1~4 alkyl)C(=O)F, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 3~5 Cycloalkyl, C 2~4 Alkenyl, C 1~4 Alkoxy, C 1~4 deuteroalkoxy, or 5-membered heteroaryl, wherein C 1~4 Alkyl and C 1~4 The alkoxy group may optionally be independently selected from halogen, —OH, —CN, C 1~4 Alkoxy, -NH2, and diC 1~4 and alkylamino.

[0058] As embodiment 39, provided herein is a compound of embodiment 37, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R y are H, F, Cl, -OH, -CN, -CONH2, -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, C 1~4 Alkoxy or C 1~4 deuteroalkoxyl, wherein C 1~4 Alkyl and C 1~4 The alkoxy group may optionally be independently selected from halogen, —OH, C 1~4 Alkoxy, -NH2, and diC 1~4 and alkylamino.

[0059] As embodiment 40, provided herein is a compound of embodiment 37, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R y is H, F, Cl, —OH, —CN, —COMe, —SMe, —CONH, —NH, —NHMe, —N(CH), —NH(COCH), —N(CH)C(═O)F, methyl, ethyl, —CD, cyclopropyl, —CH═CH, methoxy, ethoxy, —OCD, or 1,3-oxazol-2-yl, wherein the methyl and methoxy groups are optionally substituted with 1 to 3 substituents independently selected from F, Cl, —OH, —CN, methoxy, —NH, and —N(CH).

[0060] As embodiment 41, provided herein is a compound of embodiment 37, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R y is H, F, Cl, —OH, —CN, —CONH2, —NH2, —NHMe, methoxy, ethoxy, or —OCD3, wherein the methyl and methoxy groups are optionally substituted with 1 to 3 substituents independently selected from F, —OH, methoxy, —NH2, and —N(CH3)2.

[0061] As embodiment 42, provided herein is a compound of embodiment 37, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R y are H, F, Cl, -CN, -COO(C 1~4 alkyl), C 1~4 Alkyl, C 3~5 Cycloalkyl, C 3~4 Heterocycloalkyl, or C 1~4 Alkoxy, wherein C 1~4 The alkyl groups are optionally independently C 1~4 Alkoxy and diC 1~4 and alkylamino.

[0062] As embodiment 43, provided herein is a compound of embodiment 37, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R y is H, F, Cl, —CN, —COOMe, methyl, cyclopropyl, azetidinyl, or methoxy, wherein the methyl group is optionally substituted with 1 to 3 substituents independently selected from methoxy and dimethylamino.

[0063] As embodiment 44, provided herein is a compound of embodiment 37, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R y is H or Cl.

[0064] As embodiment 45, provided herein is a compound of any one of embodiments 37-44, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R z is H, halogen, -OH, -CN, -CO(C 1~4 alkyl), -S(O) n (C 1~4 alkyl), -CONH2, -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, -NH(COC 1~4 alkyl), -N(C 1~4 alkyl)C(=O)F, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 3~5 Cycloalkyl, C 2~4 Alkenyl, C 1~4 Alkoxy, C 1~4 deuteroalkoxy, or 5-membered heteroaryl, wherein C 1~4 Alkyl and C 1~4 The alkoxy group may optionally be independently selected from halogen, —OH, —CN, C 1~4 Alkoxy, -NH2, and diC 1~4and alkylamino.

[0065] As embodiment 46, there is provided herein a compound of any one of embodiments 37-44, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R z is H, halogen, -OH, -CN, -CONH2, -NH2, C 1~4 Alkylamino, DiC 1~4 Alkylamino, C 1~4 Alkoxy or C 1~4 deuteroalkoxyl, wherein C 1~4 Alkyl and C 1~4 The alkoxy group may optionally be independently selected from halogen, —OH, C 1~4 Alkoxy, -NH2, and diC 1~4 and alkylamino.

[0066] As embodiment 47, there is provided herein a compound of any one of embodiments 37-44, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R z is H, F, Cl, —OH, —CN, —COMe, —SMe, —CONH, —NH, —NHMe, —N(CH), —NH(COCH), —N(CH)C(═O)F, methyl, ethyl, —CD, cyclopropyl, —CH═CH, methoxy, ethoxy, —OCD, or 1,3-oxazol-2-yl, wherein the methyl and methoxy groups are optionally substituted with 1 to 3 substituents independently selected from F, Cl, —OH, —CN, methoxy, —NH, and —N(CH).

[0067] As embodiment 48, there is provided herein a compound of any one of embodiments 37-44, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R zis H, F, Cl, —OH, —CN, —CONH2, —NH2, —NHMe, methoxy, ethoxy, or —OCD3, wherein the methyl and methoxy groups are optionally substituted with 1 to 3 substituents independently selected from F, —OH, methoxy, —NH2, and —N(CH3)2.

[0068] As embodiment 49, provided herein is a compound of any one of embodiments 37-44, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R z is H, halogen, or C 1~4 It is alkyl.

[0069] As embodiment 50, there is provided herein a compound of any one of embodiments 37-44, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R z is H, F, Cl, or methyl.

[0070] As embodiment 51, there is provided herein a compound of any one of embodiments 37-44, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R z is H.

[0071] As embodiment 52, provided herein is a compound of any one of embodiments 37-51, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 1 is H, methyl, CH2F, or CD3.

[0072] As embodiment 53, there is provided herein a compound of any one of embodiments 37-51, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 1 is H.

[0073] As embodiment 54, provided herein is a compound of embodiment 1 or embodiment 2, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein the compound of formula I is a compound of formula IE. [ka]

[0074] As embodiment 55, provided herein is a compound of embodiment 54, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: x is O.

[0075] As embodiment 56, provided herein is a compound of embodiment 54, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: x is NH.

[0076] As embodiment 57, there is provided herein a compound of embodiment 54, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: x is N(C 1~4 alkyl).

[0077] As embodiment 58, provided herein is a compound of embodiment 54, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: x is NCH3.

[0078] As embodiment 59, there is provided herein a compound of any one of embodiments 1 to 58, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 2 teeth, [ka] is.

[0079] As embodiment 60, there is provided herein a compound of any one of embodiments 1 to 58, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 2 teeth, [ka] is.

[0080] As embodiment 61, there is provided herein a compound of any one of embodiments 1 to 58, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 2 teeth, [ka] is.

[0081] As embodiment 62, there is provided herein a compound of any one of embodiments 1 to 58, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 2 teeth, [ka] is.

[0082] As embodiment 63, there is provided herein a compound of any one of embodiments 1 to 58, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 2 teeth, [ka] is.

[0083] As embodiment 64, there is provided herein a compound of any one of embodiments 1 to 58, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 2 teeth, [ka] is.

[0084] As embodiment 65, there is provided herein a compound of any one of embodiments 1 to 58, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 2 teeth, [ka] where B is a 5-membered heteroaryl containing two N atoms.

[0085] As embodiment 66, provided herein is a compound of any one of embodiments 1 to 58, 64, and 65, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein B is attached to the bicyclic core through a C atom and R 3 is bonded through the N atom.

[0086] As embodiment 67, provided herein is a compound of any one of embodiments 1 to 58, 64, and 65, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein B is attached to the bicyclic core through an N atom and R 3 is bonded via a C atom.

[0087] As embodiment 68, there is provided herein a compound of any one of embodiments 1 to 58, 64, and 65, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein B is attached to the bicyclic core through a C atom and R 3is bonded via a C atom.

[0088] As embodiment 69, provided herein is a compound of any one of embodiments 1 to 58, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 2 teeth, [ka] is.

[0089] As embodiment 70, provided herein is a compound of any one of embodiments 1 to 58, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 2 teeth, [ka] is.

[0090] As embodiment 71, provided herein is a compound of any one of embodiments 1 to 58, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 2 is 2-benzofuranyl.

[0091] As embodiment 72, provided herein is a compound of any one of embodiments 1 to 71, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 2 or 2-benzofuranyl [ka] The moiety optionally contains one substituent R 3’ is further substituted with

[0092] As embodiment 73, there is provided herein a compound of any one of embodiments 1 to 71, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 3 or 2-benzofuranyl [ka] The moiety may contain one or two independently selected substituents R 3’ is not further substituted with

[0093] As embodiment 74, provided herein is a compound of any one of embodiments 1 to 70, 72, and 73, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 3 is C 2~6 Alkyl, C 1~3 Alkoxy, -CH2(C 3~5 cycloalkyl), -OCH2(C 3~5 cycloalkyl), or phenyl, wherein C 2~6 Alkyl, C 1~3 Alkoxy, -CH2(C 3~5 cycloalkyl), and -OCH2(C 3~5 The cycloalkyl) group is optionally substituted with 1 to 5 halogen atoms and optionally substituted with -CN, wherein the phenyl is optionally substituted with one halogen substituent.

[0094] As embodiment 75, provided herein is a compound of any one of embodiments 1 to 70, 72, and 73, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 3 is C 2~6 Alkyl, C 1~3 Alkoxy, or -OCH2(C 3~5 cycloalkyl), wherein C 2~6 Alkyl, C 1~3 Alkoxy, and -OCH2(C 3~5The cycloalkyl) group is optionally substituted with 1 to 5 halogen atoms and optionally substituted with -CN.

[0095] As embodiment 76, provided herein is a compound of any one of embodiments 1 to 70, 72, and 73, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 3 is C 2~6 Alkyl or C 1~3 Alkoxy, wherein C 2~6 Alkyl and C 1~3 The alkoxy group is optionally substituted with 3 to 5 halogen atoms.

[0096] As embodiment 77, provided herein is a compound of any one of embodiments 1 to 70, 72, and 73, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 3 is 2,2,2-trifluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 2,2,3,3,3-pentafluoropropyl, -OCHCN, -OC(CH)CN, difluoromethoxy, trifluoromethoxy, -OCH(CN)CH, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoropropoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, cyclopropylmethyl, (2,2-difluorocyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, cyclopropylmethoxy, (2,2-difluorocyclopropyl)methoxy, phenyl, 3-fluorophenyl, or 4-fluorophenyl.

[0097] As embodiment 78, provided herein is a compound of any one of embodiments 1 to 70, 72, and 73, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 3 is 2,2-difluoropropyl, 4,4,4-trifluorobutyl, 2,2,3,3,3-pentafluoropropyl, —OC(CH)CN, trifluoromethoxy, —OCH(CN)CH, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoropropoxy, cyclopropylmethoxy, or (2,2-difluorocyclopropyl)methoxy.

[0098] As embodiment 79, provided herein is a compound of any one of embodiments 1 to 70, 72, and 73, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 3 is 2,2,3,3,3-pentafluoropropyl or 2,2,2-trifluoroethoxy.

[0099] As embodiment 80, there is provided herein a compound of any one of embodiments 1 to 72, and 74 to 79, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 3’ are independently halogen or C 1~4 It is alkyl.

[0100] As embodiment 81, there is provided herein a compound of any one of embodiments 1 to 72, and 74 to 79, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 3’ is F or methyl.

[0101] As embodiment 82, there is provided herein a compound of any one of embodiments 1 to 81, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 4 is C 1~3 Alkyl, C 1~4 Haloalkyl, C1~4 Alkoxy or C 3~5 It is cycloalkyl.

[0102] As embodiment 83, there is provided herein a compound of any one of embodiments 1 to 81, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 4 is C 1~3 It is haloalkyl.

[0103] As embodiment 84, there is provided herein a compound of any one of embodiments 1 to 81, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 4 is methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, or cyclopropyl.

[0104] As embodiment 85, there is provided herein a compound of any one of embodiments 1 to 81, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 4 is ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, or cyclopropyl.

[0105] As embodiment 86, there is provided herein a compound of any one of embodiments 1 to 81, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 4 is trifluoromethyl.

[0106] As embodiment 87, provided herein is a compound of any one of embodiments 1 to 86, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: n is 0.

[0107] As embodiment 88, there is provided herein a compound of any one of embodiments 1 to 86, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: n is 1.

[0108] As embodiment 89, provided herein is a compound of any one of embodiments 1 to 86, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: n is 2.

[0109] As embodiment 90, provided herein is a compound of embodiment 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is (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.

[0110] As embodiment 91, provided herein is a compound of embodiment 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is (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, 2-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenoxy)-2-methylpropanenitrile, 2-(difluoromethyl)-8-methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(fluoromethyl)-8-methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-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-ethyl-8-methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-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-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[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-(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-((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-difluoroethoxy)-2-fluorophenyl)-8-methoxy-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-methoxy-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, 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-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxamide, 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-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-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, 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-((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-((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-(aminomethyl)-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-(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-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-(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-(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-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-ethoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-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-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-(2-methyl-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-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-(trifluoromethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrimido[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-[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-4-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one, 8-Methoxy-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, or 8-Methoxy-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one.

[0111] As embodiment 92, provided herein is a compound of embodiment 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is 4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile, 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-amino-3-(4-(2,2,2-trifluoroethoxy)phenyl)-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, or 8-Methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one.

[0112] As embodiment 93, provided herein is a compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] is.

[0113] As embodiment 94, provided herein is a compound of embodiment 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is [ka] is.

[0114] As embodiment 95, provided herein is a compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] is.

[0115] As embodiment 96, provided herein is a compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] is.

[0116] As embodiment 97, provided herein is a compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] is.

[0117] As embodiment 98, provided herein is a compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] is.

[0118] The foregoing merely summarizes certain aspects of the disclosure and is not intended, nor should it be construed, to limit the disclosure in any way.

[0119] Formulations and Routes of Administration In the disclosed use, although the compound disclosed herein can be administered alone, the compound administered will usually be present as an active ingredient in a pharmaceutical composition.Therefore, in one embodiment, the present invention provides a pharmaceutical composition comprising the compound disclosed herein in combination with one or more pharmaceutically acceptable excipients such as diluents, carriers, adjuvants, and optionally other active ingredients. See, for example, Remington: The Science and Practice of Pharmacy, Volume I and Volume II, twenty-second edition, edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vol. 1-3), Liberman et al., Eds., Marcel Dekker, New York, NY, 1992; Handbook of Pharmaceutical Excipients (3rd Ed.), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000; Pharmaceutical Formulation: The Science and Technology of Dosage Forms (Drug Discovery), first edition, edited by G. D. Tovey, Royal Society of Chemistry, 2018. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein.

[0120] The compound(s) disclosed herein can be administered by any suitable route of administration in the form of a pharmaceutical composition adapted to such route and in a dose effective for the intended treatment. The compounds and compositions provided herein can be administered, for example, orally, mucosally, topically, transdermally, rectally, pulmonary, parenterally, intranasally, intravascularly, intravenously, intraarterially, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, intravaginally, or by infusion techniques in dosage unit formulations containing conventional pharmaceutically acceptable excipients.

[0121] 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, drops, injectable solution, emulsion, microemulsion, ointment, aerosol, aqueous suspension, or oily suspension. Pharmaceutical compositions are typically made in the form of a dosage unit containing a particular amount of the active ingredient.

[0122] In embodiment 99, provided herein is a pharmaceutical composition comprising a compound of any one of embodiments 1-98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable excipient.

[0123] As embodiment 100, there is provided herein a compound of any one of embodiments 1 to 98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition of embodiment 99, for use as a medicament.

[0124] Additionally, the present disclosure encompasses pharmaceutical compositions comprising a mixture of any of the compounds disclosed herein with one or more other active agents disclosed herein.

[0125] How to use As described herein (see the section entitled "Definitions"), the compounds described herein are understood to include all stereoisomers, tautomers, or pharmaceutically acceptable salts of any of the above, or solvates of any of the above. Accordingly, the scope of methods and uses provided in this disclosure should be understood to encompass methods and uses employing all such forms.

[0126] 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 can be treated with the compounds provided herein.

[0127] As embodiment 101, there is provided herein a compound of any one of embodiments 1 to 98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition of embodiment 99, for use in reducing body weight.

[0128] As embodiment 102, provided herein is a compound of any one of embodiments 1 to 98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition of embodiment 99, for use in reducing the body mass index of a subject.

[0129] As embodiment 103, provided herein is a compound of any one of embodiments 1 to 98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition of embodiment 99, for use in treating a metabolic disorder.

[0130] As embodiment 104, provided herein is a compound of any one of embodiments 1 to 98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition of embodiment 99, for use in treating a cardiovascular disorder.

[0131] As embodiment 105, provided herein is a compound of any one of embodiments 1 to 98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition of embodiment 99, for use in treating diabetes.

[0132] As embodiment 106, there is provided herein a compound of any one of embodiments 1 to 98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition of embodiment 99, for use in treating obesity.

[0133] As embodiment 107, provided herein is a compound of any one of embodiments 1 to 98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition of embodiment 99, for use in treating dyslipidemia.

[0134] As embodiment 108, provided herein is a compound of any one of embodiments 1-98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition of embodiment 99, for use in treating nonalcoholic steatohepatitis (NASH).

[0135] As embodiment 109, provided herein is the use of a compound of any one of embodiments 1 to 98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition of embodiment 99, in the preparation of a medicament for reducing the body weight or body mass index of a subject.

[0136] As embodiment 110, provided herein is the use of a compound of any one of embodiments 1 to 98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition of embodiment 99, in the preparation of a medicament for treating a metabolic or cardiovascular disorder.

[0137] As embodiment 111, provided herein is the use of a compound of any one of embodiments 1 to 98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or the pharmaceutical composition of embodiment 99, in the preparation of a medicament for treating diabetes, obesity, dyslipidemia, or non-alcoholic steatohepatitis (NASH).

[0138] As embodiment 112, provided herein is a method of reducing body weight or body mass index in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0139] As embodiment 113, provided herein is a method of treating a metabolic or cardiovascular disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0140] As embodiment 114, provided herein is a method of treating diabetes, obesity, dyslipidemia, or non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0141] As a further embodiment, provided herein is a method of reducing waist-to-hip ratio (WHR) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. As a further embodiment, provided herein is the use of a compound of any one of embodiments 1-98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or the pharmaceutical composition of embodiment 99, in the preparation of a medicament for reducing waist-to-hip ratio (WHR) in a subject. As a further embodiment, provided herein is a compound of any one of embodiments 1-98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or the pharmaceutical composition of embodiment 99, for use in reducing waist-to-hip ratio (WHR) in a subject.

[0142] In further embodiments, provided herein are methods of lowering blood glucose in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or the pharmaceutical composition of embodiment 99. In some embodiments, the method reduces blood glucose by 10% or more. In some embodiments, the method reduces blood glucose by 15% or more. In some embodiments, the method reduces blood glucose by 20% or more. In some embodiments, the method reduces blood glucose by 25% or more. In some embodiments, the method reduces blood glucose with minimal impact on food intake / appetite. In some embodiments, the method reduces blood glucose without having an impact on food intake / appetite.

[0143] In further embodiments, provided herein are methods of lowering insulin in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or the pharmaceutical composition of embodiment 99. 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 while minimizing the impact on food intake / appetite. In some embodiments, the methods lower insulin without having an effect on food intake / appetite.

[0144] In further embodiments, provided herein are methods of lowering cholesterol in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or the pharmaceutical composition of embodiment 99. 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 method lowers cholesterol by 39% or more. In some embodiments, the method lowers cholesterol with minimal impact on food intake / appetite. In some embodiments, the method lowers cholesterol without having an impact on food intake / appetite.

[0145] In further embodiments, provided herein are methods of lowering LDL in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or the pharmaceutical composition of embodiment 99. 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 method lowers LDL without having an effect on food intake / appetite.

[0146] In further embodiments, provided herein are methods for lowering triglycerides in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or the pharmaceutical composition of embodiment 99. In some embodiments, the methods reduce triglycerides by 30% or more. In some embodiments, the methods reduce triglycerides by 40% or more. In some embodiments, the methods reduce triglycerides by 50% or more. In some embodiments, the methods reduce triglycerides by 51% or more. In some embodiments, the methods reduce triglycerides by 52% or more. In some embodiments, the methods reduce triglycerides by 53% or more. In some embodiments, the methods reduce triglycerides by 54% or more. In some embodiments, the methods reduce triglycerides by 55% or more. In some embodiments, the methods reduce blood triglycerides by 56% or more. In some embodiments, the method lowers triglycerides by 57% or more. In some embodiments, the method lowers triglycerides with minimal impact on food intake / appetite. In some embodiments, the method lowers triglycerides without having an impact on food intake / appetite.

[0147] In further embodiments, provided herein are methods of reducing body fat mass in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or the pharmaceutical composition of embodiment 99. 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 body fat mass in a subject with minimal impact on food intake / appetite, hi some embodiments, the methods reduce body fat mass in a subject without having an impact on food intake / appetite.

[0148] As a further embodiment, provided herein is a method of increasing adiponectin in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition of embodiment 99.

[0149] As a further embodiment, provided herein is a method of lowering leptin in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition of embodiment 99.

[0150] As a further embodiment, provided herein is a method of lowering resistin in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition of embodiment 99.

[0151] Use in combination In further embodiments, provided herein are pharmaceutical compositions comprising a compound of any one of embodiments 1-98 and one or more other active agents. In some embodiments, the one or more active agents include, but are not limited to, a source of omega-3 fatty acids. In some embodiments, the one or more active agents include, but are not limited to, an omega-3 fatty acid supplement. In some embodiments, the one or more active agents include, but are not limited to, an omega-3 carboxylic acid (e.g., Epanova®), an omega-3 acid ethyl ester (e.g., Lovaza® or Omtryg®), or icosapent ethyl (e.g., Vascepa®).

[0152] In further embodiments, provided herein are methods for treating diabetes, obesity, dyslipidemia, or non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a combination of pharmaceutically acceptable salts of said compounds or said tautomers, in combination with one or more other active agents. In some embodiments, the one or more active agents include, but are not limited to, a source of omega-3 fatty acids. In some embodiments, the one or more active agents include, but are not limited to, an omega-3 fatty acid supplement. In some embodiments, the one or more active agents include, but are not limited to, an omega-3 carboxylic acid (e.g., Epanova®), an omega-3 acid ethyl ester (e.g., Lovaza® or Omtryg®), or icosapent ethyl (e.g., Vascepa®).

[0153] In further embodiments, provided herein are methods for reducing the body weight or body mass index of a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a combination of pharmaceutically acceptable salts of said compounds or said tautomers, in combination with one or more other active agents. In some embodiments, the one or more active agents include, but are not limited to, a source of omega-3 fatty acids. In some embodiments, the one or more active agents include, but are not limited to, an omega-3 fatty acid supplement. In some embodiments, the one or more active agents include, but are not limited to, an omega-3 carboxylic acid (e.g., Epanova®), an omega-3 acid ethyl ester (e.g., Lovaza® or Omtryg®), or icosapent ethyl (e.g., Vascepa®).

[0154] In further embodiments, provided herein are methods for treating a metabolic or cardiovascular disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a combination of pharmaceutically acceptable salts of said compounds or said tautomers, in combination with one or more other active agents. In some embodiments, the one or more active agents include, but are not limited to, a source of omega-3 fatty acids. In some embodiments, the one or more active agents include, but are not limited to, an omega-3 fatty acid supplement. In some embodiments, the one or more active agents include, but are not limited to, an omega-3 carboxylic acid (e.g., Epanova®), an omega-3 acid ethyl ester (e.g., Lovaza® or Omtryg®), or icosapent ethyl (e.g., Vascepa®).

[0155] As a further embodiment, provided herein is a method of reducing waist-to-hip ratio (WHR) in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a combination of pharmaceutically acceptable salts of said compound or said tautomer, in combination with one or more other active agents.

[0156] As a further embodiment, provided herein is a method of lowering blood glucose in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a combination of pharmaceutically acceptable salts of said compound or said tautomer, in combination with one or more other active agents.

[0157] As a further embodiment, provided herein is a method of lowering insulin in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a combination of pharmaceutically acceptable salts of said compound or said tautomer, in combination with one or more other active agents.

[0158] As a further embodiment, provided herein is a method of lowering cholesterol in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a combination of pharmaceutically acceptable salts of said compound or said tautomer, in combination with one or more other active agents.

[0159] As a further embodiment, provided herein is a method of lowering LDL in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a combination of pharmaceutically acceptable salts of said compound or said tautomer, in combination with one or more other active agents.

[0160] As a further embodiment, provided herein is a method of lowering triglycerides in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a combination of pharmaceutically acceptable salts of said compound or said tautomer, in combination with one or more other active agents.

[0161] As a further embodiment, provided herein is a method for reducing body fat mass in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a combination of pharmaceutically acceptable salts of said compound or said tautomer, in combination with one or more other active agents.

[0162] As a further embodiment, provided herein is a method of increasing adiponectin in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a combination of pharmaceutically acceptable salts of said compound or said tautomer, in combination with one or more other active agents.

[0163] As a further embodiment, provided herein is a method of lowering leptin in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a combination of pharmaceutically acceptable salts of said compound or said tautomer, in combination with one or more other active agents.

[0164] As a further embodiment, provided herein is a method of lowering resistin in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of embodiments 1-98, or a tautomer thereof, or a combination of pharmaceutically acceptable salts of said compound or said tautomer, in combination with one or more other active agents.

[0165] In some embodiments, one or more active agents in the combinations described herein, or in the methods utilizing these combinations described herein, include, but are not limited to, omega-3 carboxylic acids (e.g., Epanova®), omega-3 acid ethyl esters (e.g., Lovaza® or Omtryg®), or icosapent ethyl (e.g., Vascepa®).

[0166] definition The following definitions are provided to facilitate understanding of the scope of the present disclosure.

[0167] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless otherwise indicated, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending on the standard deviation found in their respective testing measurements.

[0168] As used herein, when any variable occurs more than one time in a chemical formula, its definition at each occurrence is independent of its definition at every other occurrence. When the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0169] stereoisomer The compounds of the present disclosure may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with rotational hindrance, and thus may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers (E / Z)), enantiomers, diastereomers, and atropisomers. Accordingly, the scope of the present disclosure should be understood to encompass all possible stereoisomers of the exemplified compounds, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, diastereomerically pure, and atropisomerically pure), and mixtures of stereoisomers (e.g., mixtures of geometric isomers, enantiomers, diastereomers, and atropisomers, or mixtures of any of the above) of any chemical structure (in whole or in part) disclosed herein, unless the stereochemistry is specifically specified.

[0170]

[0013] When the stereochemistry of a structure or portion of a structure is not indicated, for example, with a bold or dashed line, the structure or portion of a structure is to be interpreted as encompassing all stereoisomers thereof. When the stereochemistry of a structure or portion of a structure is not indicated, for example, with a bold or dashed line, the structure or portion of a structure is to be interpreted as encompassing only the specified stereoisomer. A bond drawn with a wavy line indicates that both stereoisomers are encompassed. This wavy line should not be confused with a wavy line drawn perpendicular to a bond, which indicates the point at which a group is attached to the rest of the molecule.

[0171] As used herein, the term "stereoisomer" or "stereoisomerically pure" compound refers to one stereoisomer (e.g., geometric isomer, enantiomer, diastereomer, and atropisomer) of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the mirror-image enantiomer of that compound, and a stereoisomerically pure compound having two chiral centers will be substantially free of other enantiomers or diastereomers of that compound. A typical stereoisomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and about 20% by weight or less of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and about 10% by weight or less of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and about 5% by weight or less of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and about 3% by weight or less of other stereoisomers of the compound.

[0172] The present disclosure also encompasses pharmaceutical compositions containing stereoisomerically pure forms and the use of stereoisomerically pure forms of any compound disclosed herein. Additionally, the present disclosure also encompasses pharmaceutical compositions containing mixtures of stereoisomers of any compound disclosed herein and the use of such pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof can be synthesized according to methods well known in the art and disclosed herein. Mixtures of stereoisomers can be resolved using standard techniques, such as chiral columns or chiral resolving agents. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0173] tautomers As known to those skilled in the art, certain compounds disclosed herein may 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 tautomers of that structural formula. For example, the following are illustrative tautomers of compounds of Formula I, where w, y, and z are each CR w , C.R. y , and CR z and x is COH. [ka]

[0174] Therefore, the scope of the present disclosure should be understood to encompass all tautomeric forms of the compounds disclosed herein.

[0175] isotope labeled compounds Additionally, the scope of the present disclosure includes all pharmaceutically acceptable isotopically labeled compounds of the compounds disclosed herein, such as compounds of Formula I, in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds disclosed herein include: 2 H and 3 Hydrogen such as H 11 C. 13 C and 14 Carbon, such as C, 36 chlorine such as Cl, 18 Fluorine such as F, 123 I and 125 Iodine, such as I 13 N and 15 Nitrogen such as N 15 O. 17 O and 18 Oxygen, such as O 32 Phosphorus such as P, 35 Certain isotopically labeled compounds of Formula I, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 ( 14 Deuterium (C) is particularly useful for this purpose given its ease of incorporation and facile means of detection. 2 Substitution with isotopes such as H) may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be advantageous. 11 C. 18 F, 15 O and 13Substitution with positron-emitting isotopes, such as N, can be useful, for example, in positron emission tomography (PET) studies to determine target occupancy. Isotopically labeled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the accompanying general synthetic schemes and examples, in which suitable isotopically labeled reagents are substituted for conventionally used non-labeled reagents.

[0176] solvate As noted above, the compounds disclosed herein, as well as the stereoisomers, tautomers, and isotopically labeled forms thereof, or pharmaceutically acceptable salts of any of the foregoing, can exist in solvated or unsolvated forms.

[0177] As used herein, the term "solvate" refers to a molecular complex comprising a compound described herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solvent molecules, in a stoichiometric or non-stoichiometric amount. When the solvent is water, the solvate is referred to as a "hydrate."

[0178] Accordingly, the scope of the present disclosure should be understood to encompass all solvates of the compounds disclosed herein and their stereoisomers, tautomers, and isotopically labeled forms, or pharmaceutically acceptable salts of any of the foregoing.

[0179] Various definitions This section defines additional terms used to describe the scope of the compounds, compositions, and uses disclosed herein.

[0180] As used herein, the term "C 1~3 Alkyl," "C 1~4 Alkyl," "C 2~6 alkyl," and "C 1~6 "Alkyl" refers to a straight or branched chain hydrocarbon containing 1 to 3, 1 to 4, 2 to 6, and 1 to 6 carbon atoms, respectively. 1~3 Alkyl, C 1~4 Alkyl, C 2~6Alkyl or C 1~6 Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, and hexyl.

[0181] As used herein, the term "C 2~4 "Alkenyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms with at least one carbon-carbon double bond. Alkenyl groups include both straight-chain and branched-chain moieties. 2~4 Representative examples of alkenyl include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, and butenyl.

[0182] As used herein, the term "C 1~4 alkylamino" or "C 1~6 "Alkylamino" refers to -NHR*, where each R* is C 1~4 Alkyl and C 1~6 Represents alkyl. C 1~4 Alkylamino or C 1~6 Representative examples of alkylamino include, but are not limited to, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, and -NHCH(CH3)2.

[0183] As used herein, the term "C 3~5 "Cycloalkyl" refers to a saturated carbocyclic molecule whose cyclic backbone has 3 to 6 carbons. 3~5 Representative examples of cycloalkyl include, but are not limited to, cyclopropyl and cyclobutyl.

[0184] When used herein as a prefix to another term for a chemical group, the term "deutero" refers to a group in which one or more hydrogen atoms are replaced by deuterium ("D," "d," or 2 For example, the term "C 1~4"Deuteroalkyl" refers to a C, as defined herein, in which one or more hydrogen atoms are replaced with D. 1~4 Refers to alkyl. C 1~4 Representative examples of deuteroalkyl include, but are not limited to, -CH2D, -CHD2, -CD3, -CH2CD3, -CDHCD3, -CD2CD3, -CH(CD3)2, -CD(CHD2)2, and -CH(CH2D)(CD3).

[0185] As used herein, the term "diC 1~4 Alkylamino" or "DiC 1~6 "Alkylamino" refers to -NR*R**, where R* and R** are each independently C, as defined herein. 1~4 Alkyl and C 1~6 Represents alkyl. DiC 1~4 Alkylamino or diC 1~6 Representative examples of alkylamino include, but are not limited to, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -N(CH2CH2CH3)2, and -N(CH(CH3)2)2.

[0186] As used herein, the term "C 1~4 Alkoxy" or "C 1~3 "Alkoxy" refers to -OR, where R is as defined herein. # are C 1~4 Alkyl group or C 1~3 Represents an alkyl group. 1~4 Alkoxy or C 1~3 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0187] As used herein, the term "halogen" refers to -F, -Cl, -Br, or -I.

[0188] The term "halo," when used herein as a prefix to another term for a chemical group, refers to a modification of a chemical group in which one or more hydrogen atoms have been replaced with a halogen, as defined herein. Each occurrence of a halogen is independently selected. For example, the term "C 1~4 "Haloalkyl" refers to a C alkyl group, as defined herein, in which one or more hydrogen atoms are replaced with halogen. 1~4 Refers to alkyl. C 1~4 Representative examples of haloalkyl include, but are not limited to, -CH2F, -CHF2, -CF3, -CHFCl, -CH2CF3, -CFHCF3, -CF2CF3, -CH(CF3)2, -CF(CHF2)2, and -CH(CH2F)(CF3).

[0189] As used herein, the term "5-membered heteroaryl" refers to a 5-membered carbocyclic ring in which two double bonds contain one ring heteroatom selected from N, S, and O, and optionally one or two additional ring N atoms in place of one or more ring carbon atom(s). Representative examples of 5-membered heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and oxazolyl.

[0190] As used herein, the term "C 3~5 Heterocycloalkyl" or "C 3~4 "Heterocycloalkyl" refers to a saturated carbocyclic molecule having a cyclic backbone of 3 to 5 carbons or 3 to 4 carbons in which one carbon atom is replaced with a heteroatom selected from N, O, and S. 3~5 Heterocycloalkyl or C 3~4 Representative examples of heterocycloalkyl include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, and pyrrolidinyl.

[0191] As used herein, the term "pharmaceutically acceptable" refers to something that is recognized for use in subjects, generally, especially humans.

[0192] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or acid addition salts formed with organic acids such as 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, and methanesulfonic acid; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion; or when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and dicyclohexylamine. Further examples of such salts can be found in Berge et al., J. Pharm. Sci. 66(1):1-19 (1977). See also Stahl et al., Pharmaceutical Salts: Properties, Selection, and Use, 2nd Revised Edition (2011).

[0193] As used herein, the term "pharmaceutically acceptable excipient" 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, and preservatives.

[0194] As used herein, the term "subject" 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.

[0195] As used herein, the term "therapeutically effective amount" refers to an amount of a compound disclosed herein that elicits the biological or medical response in a tissue, system, or subject desired by a researcher, veterinarian, medical doctor, or other clinician.

[0196] As used herein, the term "body mass index" ("BMI") can be calculated, for example, by measuring a subject's weight in kilograms and dividing it by the square of their height in meters. See, for example, https: / / www.cdc.gov / healthyweight / assessing / bmi / index.html (last accessed November 4, 2019). BMI is an indicator of body fat mass in a subject, such as a human. BMI is used as a screening tool to identify whether a subject is at a healthy weight or will respond to weight loss treatment.

[0197] Synthesis procedure The compounds provided herein can be synthesized according to the procedures described in this section and the following sections. The synthetic methods described herein are merely exemplary, and the compounds disclosed herein can also be synthesized by alternative routes using alternative synthetic strategies as would be understood by one of ordinary skill in the art. It will be understood that the general synthetic procedures and specific examples provided herein are illustrative only and should not be construed as limiting the scope of the present disclosure in any way.

[0198] All starting materials are commercially available, for example, from Sigma-Aldrich Chemical Company, Inc., St. Louis, MO, USA, or can be synthesized by using known procedures using conventional techniques known in the art. Starting materials can also be synthesized via the procedures disclosed herein.

[0199] As will be appreciated by those of skill in the art, the representative examples are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Additional methods will be apparent to those skilled in the art. Additionally, the various synthetic steps described above can be performed in an alternate sequence or order to give the desired compounds.

[0200] Methods for purification of the compounds described herein are known in the art and include, for example, crystallization, chromatography (eg, liquid and gas phase), extraction, distillation, trituration, and reverse phase HPLC.

[0201] The present disclosure further encompasses "intermediate" compounds, including structures produced by the described synthetic procedures prior to obtaining the final desired compound, whether isolated or produced in situ and not isolated. These intermediates are included within the scope of the present disclosure. Exemplary embodiments of such intermediate compounds are shown below.

[0202] As embodiment 115, there is provided herein a compound, the compound comprising: N-(3-iodo-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-8-yl)acetamide, 8-bromo-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 8-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 8-hydroxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile, 3-iodo-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile, 3-bromo-8-methoxy-2-(trifluoromethyl)pyrimido[1,2-a]pyrimidin-4-one, 8-Methoxy-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one, or 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. [Example]

[0203] This section provides specific examples of compounds of Formula I and methods for making them.

[0204] List of abbreviations

[0205] [Table 2]

[0206] [Table 3]

[0207] [Table 4]

[0208] [Table 5]

[0209] General analytical and purification methods This section provides a description of the general analytical and purification methods used to prepare certain compounds provided herein.

[0210] Chromatography: Unless otherwise indicated, residues containing crude product were purified by passing the crude material or concentrate through either a Biotage or Isco brand silica gel column (pre-packed or separately packed with SiO) or reverse-phase flash silica (C18) and eluting the product from the column with the specified solvent gradient. For example, the description (330 g SiO, 0-40% EtOAc / Hexanes) means that the product was obtained by eluting a column packed with 330 grams of silica with a solvent gradient of 0% to 40% EtOAc in hexanes.

[0211] Preparative HPLC method: Where so designated, the compounds described herein were purified by reverse-phase HPLC using one of the following instruments: Shimadzu, Varian, Gilson, Agilent 1260 infinity, or Waters Fractionlynx, unless otherwise indicated, using one of the following HPLC columns: (a) Phenomenex Luna, or (b) Gemini column (5 micrometer or 10 micrometer, C18, 150 x 50 mm), or (c) Waters X-select CSH column (5 micrometer, C18, 100 x 30 mm).

[0212] A typical run through the instrument involved elution at 45 mL / min over 10 min with a linear gradient of 10% (v / v) to 100% MeCN (0.1% v / v TFA) in water (0.1% TFA), although conditions may be modified to achieve optimal separation.

[0213] Proton NMR spectrum: Unless otherwise indicated, all 1 H NMR spectra were collected at 300 MHz, 400 MHz, or 500 MHz on a Bruker NMR instrument. When so characterized, all observed protons are reported as parts per million (ppm) downfield from tetramethylsilane (TMS) or other internal standard in the appropriate solvent as specified.

[0214] Mass spectrum (MS) Unless otherwise indicated, all mass spectral data for starting materials, intermediates and / or exemplary compounds is given as [M+H] + The molecular ions are reported as mass / charge (m / z). The reported molecular ions were obtained using a PE SCIEX API 150EX MS instrument, an Agilent 1100 Series LC / MSD system, or a Waters Acquity UPLC / MS with electrospray detection (commonly referred to as ESI MS). As will be understood by those skilled in the art, compounds with isotopic atoms such as bromine are typically reported according to the detected isotopic pattern.

[0215] Compound name The compounds disclosed and described herein are named using IUPAC nomenclature rules as provided by Chem-Draw Professional 15.1.0.144 software, ACD / Labs software version 2015 from Advanced Chemistry Development Inc., or JChem for Excel 18.22.1.7 from ChemAxon Ltd.

[0216] Specific examples This section provides procedures for synthesizing specific examples of the compounds provided herein. All starting materials, unless otherwise noted, are commercially available from Sigma-Aldrich Chemical Company, Inc., St. Louis, MO, USA, or are known in the art and can be synthesized using known procedures using routine techniques.

[0217] Synthesis of intermediates Intermediate 1-A 3-Bromo-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-Methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A reaction mixture of 2-amino-4-methoxypyridine (3.91 g, 31.5 mmol, Oakwood Products, Inc.), ethyl 4,4,4-trifluoroacetoacetate (18.56 mL, 126 mmol), and bismuth(III) trichloride (1.091 mL, 15.75 mmol) was heated to 100 °C for 5 h. The reaction mixture was cooled to rt, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluent: 0-60% EtOAc / heptane) to give 8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (2.16 g, 8.9 mmol, 28% yield). LC / MS (ESI) + ) m / z = 245.2 [M+H] + .

[0218] Step 2: 3-Bromo-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A solution of bromine (8 μL, 0.16 mmol) in acetic acid (0.5 mL) was added dropwise to a solution of 8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (40 mg, 0.16 mmol) in acetic acid (1.2 mL) at rt. Upon completion of the addition, the reaction mixture was cooled to 0°C and diluted with EtOAc (5 mL) and water (2 mL). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluent: 5-50% EtOAc / heptane) to give 3-bromo-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a white solid (52 mg, 0.16 mmol, 98% yield). MS (ESI) + ) m / z=323.0[M+H] + . 1H NMR(400MHz,CDCl3)δ 8.97(d,J=7.82Hz,1H)7.05(d,J=2.74Hz,1H)6.98(dd,J=7.92,2.64Hz,1H)4.02(s,3H).

[0219] Intermediate 1-B 3-Iodo-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. [ka] Step 1: 8-Methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-A, Step 1.

[0220] Step 2: 3-Iodo-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. To a solution of 8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.22 g, 0.89 mmol) in acetonitrile (5 mL) was added N-iodosuccinimide (0.24 g, 1.1 mmol). The reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was concentrated in vacuo, and the crude residue was purified by silica gel chromatography (eluent: 100% DCM) to give 3-iodo-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.31 g, 0.84 mmol, 94% yield). LC / MS (ESI + ) m / z=370.9[M+H] + ,371.9[M+2H] + . 1 H NMR(400MHz,CDCl3)δ 8.98(d,J=7.82Hz,1H),7.06(d,J=2.74Hz,1H),6.97(dd,J=2.64,7.92Hz,1H),4.02(s,3H). 19 F NMR(376MHz,CDCl3)δ -67.21(s,3F).

[0221] Intermediate 1-C 3-Bromo-2-(difluoromethyl)-8-methoxy-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 2-(Difluoromethyl)-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one. A solution of 4-methoxypyridin-2-amine (3.75 g, 30.2 mmol, Combi-Blocks Inc.) and 4,4-difluoro-3-oxobutanoic acid ethyl ester (7.5 mL, 45 mmol, Combi-Blocks Inc.) in glacial acetic acid (25 mL, 433 mmol) was heated to reflux for 18 h. The reaction mixture was concentrated under reduced pressure and then partitioned between CHCl (50 mL) and 5 M NaOH (20 mL). The organic layer was extracted with CHCl (2×), and the combined organic layers were dried over NaSO. The filtrate was concentrated in vacuo. The crude residue was suspended in DCM (10 mL) and filtered. The filtrate was purified by silica gel chromatography (eluent: 0–35% (3:1 EtOAc / EtOH) / heptane) to give 2-(difluoromethyl)-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one as a solid (0.92 g, 4.1 mmol, 14% yield). 1 H NMR(400MHz,CDCl3)δ 8.95(d,J=7.9Hz,1H),6.97(d,J=2.5Hz,1H),6.88(dd,J=7.9,2.70Hz,1H),6.54(s,1H),6.43(m,1H),3.99(s,3H).

[0222] Step 2: 3-Bromo-2-(difluoromethyl)-8-methoxy-pyrido[1,2-a]pyrimidin-4-one. 1,3-Dibromo-5,5-dimethylhydantoin (0.81 g, 2.9 mmol) was added to a stirred suspension of 2-(difluoromethyl)-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one (0.92 g, 4.1 mmol) in DMF (7 mL) / DCM (4 mL) under a nitrogen atmosphere at −45° C. After 30 min, the reaction was treated with saturated aqueous NaHCO (20 mL) and EtOAc (25 mL), and after stirring for 15 min, the resulting precipitate was filtered off. The organic phase of the filtrate was separated, washed with brine (10 mL), and dried over Na SO . The filtrate was concentrated under reduced pressure. The crude material was suspended in DCM (5 mL). The solid was filtered off and dried to give 3-bromo-2-(difluoromethyl)-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one (0.73 g, 2.4 mmol, 59% yield) as a white solid. LC / MS (ESI + ) m / z=305.0[M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.96(d,J=7.88Hz,1H),7.07-7.08(m,1H),6.93(t,J=52Hz,1H),6.95(d,J=2.7Hz,1H),4.00(s,3H).

[0223] Intermediate 1-D Methyl 3-iodo-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxylate [ka] Step 1: Methyl 4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxylate. A pressure autoclave was charged with 8-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (10 g, 34 mmol, Intermediate 3-C), methanol (10 mL), DIPEA (30 mL, 171 mmol), and Pd(dppf)Cl (2.5 g, 3.1 mmol). The reaction mixture was heated to 70 °C under an atmosphere of carbon monoxide (70 psi pressure) for 20 h. The reaction mixture was cooled to rt and filtered through a pad of Celite. The Celite pad was washed with dichloromethane (3 × 50 mL). The combined filtrates were concentrated under reduced pressure. The residue was dissolved in water (100 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluent: 15% ethyl acetate / hexanes) to give methyl 4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxylate as a pale yellow solid (6.7 g, 72% yield). LC / MS (ESI + ) m / z = 273.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.07(d,J=7.4Hz,1H),8.20(d,J=1.9Hz,1H),7.73(dd,J=7.2,1.8Hz,1H),7.00(s,1H),3.96(s,3H).

[0224] Step 2: Methyl 3-iodo-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxylate. The title compound was prepared using the procedure described for Intermediate 1-B, Step 2, with the following modifications. Step 2 was carried out using methyl 4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxylate. LC / MS (ESI + ) m / z=398.9[M+H] + .

[0225] Intermediate 1-E 8-(Dimethylamino)-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-(Dimethylamino)-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A resealable vial was charged with 8-bromo-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.5 g, 1.2 mmol, Intermediate 3-I), DMF (5 mL), copper(I) iodide (52 mg, 0.28 mmol), and dimethylamine (0.66 mL, 1.3 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was cooled to rt, diluted with water, and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with ice-cold water (3 × 20 mL), dried over NaSO, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluent: 25-30% ethyl acetate / hexanes) to give 8-(dimethylamino)-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a solid (0.32 g, 0.84 mmol, 70% yield). LC / MS (ESI) + ) m / z = 384.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.74(d,J=8.1Hz,1H),7.20(dd,J=8.2,2.9Hz,1H),6.66(d,J=2.9Hz,1H),3.19(s,6H).

[0226] Intermediate 1-F 3-Iodo-8-(methylamino)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 3-Iodo-8-(methylamino)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-E, Step 1, with the following modifications: Step 1 was carried out with methylamine. LC / MS (ESI + ) m / z = 370.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.67(d,J=7.8Hz,1H),8.04(d,J=6.5Hz,1H),6.96-6.84(m,1H),6.48(s,1H),2.87(d,J=4.8Hz,3H).

[0227] Intermediate 1-G 8-Acetyl-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-Acetyl-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A pressure tube was charged with 8-bromo-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (2.5 g, 6.0 mmol, Intermediate 3-I), toluene (25 mL), and tributyl(1-ethoxyvinyl)stannane (2.2 g, 6.0 mmol). The reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of Pd(PPh3)4 (0.69 g, 0.6 mmol). The reaction mixture was heated to 105 °C for 1 hour. The reaction mixture was cooled to rt and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give a crude residue, which was dissolved in acetone (35 mL). The solution was cooled to 0 °C and treated with 10% aqueous HCl (17 mL). The reaction mixture was allowed to warm to rt and stirred for 30 minutes. The volatiles were removed under reduced pressure, and the remaining residue was diluted with water (20 mL) and extracted with dichloromethane (3 × 30 mL). The combined organic layers were dried over NaSO, and the filtrate was adsorbed onto a plug of silica gel. Purification by silica gel chromatography (eluent: 0-20% EtOAc / hexanes) gave 8-acetyl-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow solid (700 mg, 31% yield). LC / MS (ESI) + ) m / z=382.9[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.02(d,J=7.5Hz,1H),8.43(d,J=1.9Hz,1H),7.72(dd,J=7.4,2.0Hz,1H),2.74(s,3H).

[0228] Intermediate 1-H 3-Iodo-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile [ka] Step 1: 4-Oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile. A resealable vial was charged with 8-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.3 g, 1.0 mmol, Intermediate 3-C), zinc cyanide (0.12 g, 1.0 mmol), and Pd(PPh3)4 (0.12 g, 0.10 mmol). The vial was evacuated and backfilled with nitrogen. This procedure was repeated three times, followed by the addition of NMP (5 mL). The reaction mixture was heated to 90 °C. After 18 h, the reaction mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried over MgSO4, filtered, and adsorbed onto a plug of silica gel. Purification by silica gel chromatography (eluent: 0-10% (3:1 EtOAc / EtOH) / heptane) gave 4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile as a yellow solid (0.16 g, 0.66 mmol, 64% yield). LC / MS (ESI+) m / z = 240.0 [M+H] + . 1 H NMR(CDCl3,400MHz)δ 9.10(d,J=7.5Hz,1H),8.10(s,1H),7.28-7.33(m,1H),6.93(s,1H).

[0229] Step 2: 3-Iodo-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile. The title compound was prepared using the procedure described for Intermediate 1-B, Step 2, with the following modifications. Step 2 was carried out using 4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile. LC / MS (ESI + ) m / z = 366.0 [M+H]+. 1 H NMR(400MHz,CDCl3)δ 9.02(d,J=7.4Hz,1H),8.61(d,J=1.8Hz,1H),7.73(dd,J=7.4,1.9Hz,1H).

[0230] Intermediate 1-I 7-chloro-3-iodo-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 7-Chloro-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-A, Step 1, with the following modifications: Step 1 was carried out using 5-chloro-4-methoxypyridin-2-amine (prepared according to the procedure described in WO 2017 / 200825 A1). LC / MS (ESI + ) m / z = 279.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.04(1H,s)7.47(1H,s)6.70(1H,s)4.13(4H,s).

[0231] Step 2: 7-Chloro-3-iodo-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-B, Step 2, with the following modifications: Step 2 was carried out using 7-chloro-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. LC / MS (ESI + ) m / z = 405.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.03(1H,s)7.45(1H,s)4.13(3H,s).

[0232] Intermediate 1-J 2-(Difluoromethyl)-3-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile [ka] Step 1: 2-(Difluoromethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile. The title compound was prepared using the procedure described for Intermediate 1-A, Step 1, with the following modifications: Step 1 was carried out using 2-aminoisonicotinonitrile and 4,4-difluoro-3-oxobutanoic acid ethyl ester (Combi-Blocks Inc). LC / MS (ESI + ) m / z=222.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 6.77-7.09(t,1H)6.82(s,1H)7.59-7.67(d,1H)8.53(s,1H)8.97-9.07(d,1H).

[0233] Step 2: 2-(Difluoromethyl)-3-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile. The title compound was prepared using the procedure described for Intermediate 1-B, Step 2, with the following modifications. Step 2 was carried out using 2-(difluoromethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile. LC / MS (ESI + ) m / z = 348.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 6.96-7.29(t,1H)7.67(dd,1H)8.58(d,1H)9.00(dd,1H).

[0234] Intermediate 1-K 3-Iodo-8-(methylthio)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 4-(methylthio)pyridin-2-amine. Sodium thiomethoxide (65.4 g, 933 mmol, Chempure) was added to a solution of 4-chloropyridin-2-amine (20 g, 156 mmol, Combi-Blocks, Inc.) in water (300 mL) at rt. The reaction mixture was stirred at 100° C. for 2 days. The reaction mixture was quenched with water (300 mL) and extracted with EtOAc (2×250 mL). The combined organic layers were washed with brine (250 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 4-(methylthio)pyridin-2-amine as a yellow solid (18.0 g, 83% yield). The product was used in the next step without further purification. LC / MS (ESI + ) m / z = 141.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.72(d,J=5.5Hz,1H),6.36(dd,J=5.5,1.7Hz,1H),6.27(d,J=1.7Hz,1H),5.89(s,2H),2.41(s,3H).

[0235] Step 2: 8-(Methylthio)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-A, Step 1, with the following modifications: Step 1 was carried out with 4-(methylthio)pyridin-2-amine. LC / MS (ESI + ) m / z=261.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.80(dd,J=7.6,1.4Hz,1H),7.49(d,J=2.1Hz,1H),7.39(dt,J=7.6,1.8Hz,1H),6.70(d,J=1.4Hz,1H),2.69(d,J=1.6Hz,3H).

[0236] Step 3: 3-Iodo-8-(methylthio)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-B, Step 12, with the following modifications: Step 2 was carried out using 8-(methylthio)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. LC / MS (ESI + ) m / z = 386.9 [M+H]+. 1 H NMR(400MHz,DMSO-d6)δ 8.79(d,J=7.5Hz,1H),7.48-7.40(m,2H),2.69(s,3H).

[0237] Intermediate 1-L N-(3-iodo-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-8-yl)acetamide [ka] Step 1: N-(3-iodo-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-8-yl)acetamide. A resealable vial was charged with 8-bromo-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.1 g, 0.239 mmol, Intermediate 3-I), acetamide (19 mg, 0.32 mmol), cesium carbonate (0.16 g, 0.48 mmol), and dioxane (1 mL). The reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of Pd(dba) (11 mg, 0.012 mmol) and Xantphos (7 mg, 0.012 mmol). The reaction mixture was then heated to 80° C. for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluent: 50-70% ethyl acetate / hexanes) to give N-(3-iodo-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-8-yl)acetamide (0.035 g, 0.088 mmol, 37%) as a yellow solid. LC / MS (ESI) + ) m / z = 397.9 [M+H] + .

[0238] Intermediate 1-M 3-Iodo-8-isopropyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. [ka] Step 1: 8-Isopropyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. Isopropylmagnesium chloride (2 M in THF, 4.3 mL, 8.5 mmol) was added dropwise to a solution of 8-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (1.0 g, 3.4 mmol, Intermediate 3-C) and CoCl (0.22 g, 1.7 mmol) in benzene (10 mL) under a nitrogen atmosphere at rt. The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was diluted with 1.5 N aqueous HCl (5 mL) and extracted with ethyl acetate (2 × 25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluent: 0–40% EtOAc / hexanes) to give 8-isopropyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as an off-white solid (350 mg, 40% yield). LC / MS (ESI + ) m / z = 257.1 [M+H]+. 1 H NMR(400MHz,DMSO-d6)δ 8.95(dd,J=7.4,3.2Hz,1H),7.71-7.66(m,1H),7.50(dd,J=7.4,1.9Hz,1H),6.74(d,J=2.4Hz,1H),3.10(h,J=6.9Hz,1H),1.28(d,J=6.9Hz,6H).

[0239] Step 2: 3-Iodo-8-isopropyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-B, Step 2, with the following modifications: Step 2 was carried out using 8-isopropyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. LC / MS (ESI +) m / z=383.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.96(dd,J=7.3,2.8Hz,1H),7.72(d,J=2.0Hz,1H),7.56(dd,J=7.4,2.0Hz,1H),3.13(p,J=6.8Hz,1H),1.29(d,J=6.9Hz,6H).

[0240] Intermediate 1-N 3-Bromo-8-(methoxy-d3)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-(Methoxy-d3)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. Iodomethane-d3 (0.5 ml, 7.8 mmol) was added to a reaction mixture of 8-hydroxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.60 g, 2.6 mmol, Intermediate 1-Q) and cesium carbonate (1.3 g, 3.9 mmol) in DMF (14 ml) at 0 °C. The reaction mixture was stirred at rt. After 1 h, the reaction mixture was diluted with water and EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (eluent: 0-100% EtOAc / heptane) to give 8-(methoxy-d3)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as an off-white solid. LC / MS (ESI) + ) m / z=248.0[M+H] + . 1 H NMR(400MHz,CDCl3)δ 6.61(s,1H)6.91(dd,J=7.88,2.70Hz,1H)7.04(d,J=2.70Hz,1H)8.96(d,J=7.88Hz,1H).

[0241] Step 2: 3-Bromo-8-(methoxy-d3)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-C, Step 2, with the following modifications: Step 2 was carried out using 8-(methoxy-d3)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. LC / MS (ESI + ) m / z=326 / 328[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.25(dd,J=7.88,2.70Hz,1H)7.31(d,J=2.70Hz,1H)8.91(d,J=7.88Hz,1H).

[0242] Intermediate 1-O 3-Bromo-8-methoxy-2-(trifluoromethyl)pyrimido[1,2-a]pyrimidin-4-one [ka] Step 1-1 and Step 1-2: 3-Bromo-8-methoxy-2-(trifluoromethyl)pyrimido[1,2-a]pyrimidin-4-one. A reaction mixture of 4-methoxypyrimidin-2-amine (6.0 g, 48 mmol, Ark Pharm) and 4,4,4-trifluoro-3-oxobutanoic acid ethyl ester (26 mL, 144 mmol) in acetic acid (30 mL) was heated to reflux for 18 h. The reaction mixture was cooled to rt, and bromine (2.5 mL, 48 mmol) was added dropwise. Stirring was continued at rt for 1 h. The reaction mixture was concentrated in vacuo, and the residue was treated with water, saturated NaHCO3 solution, and EtOAc. The organic layer was separated and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluent: 0-50% EtOAc / heptane) to give 3-bromo-8-methoxy-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one (1.0 g, 3.2 mmol, 7% yield). LC / MS (ESI) + ) m / z = 324.0 / 326.0 [M+H] + .1 H NMR(400MHz,CDCl3)δ 9.07(d,J=7.63Hz,1H),6.82(d,J=7.63Hz,1H),4.23(s,3H).

[0243] Intermediate 1-P 3-Bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Steps 1 and 2 were carried out according to the synthesis procedure described in International Publication No. 2008097991. + ) m / z = 295.0 [M+H] + .

[0244] Intermediate 1-Q 8-Hydroxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-Hydroxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-A, Step 1, with the following modifications. Step 1 was carried out using 2-aminopyridin-4-ol (Combi-Blocks Inc.). LC / MS (ESI + ) m / z=231.0[M+H] + .

[0245] Intermediate 1-R 3-Bromo-8-(methoxy-d3)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one [ka] Step 1: 4-(Methoxy-d3)pyrimidin-2-amine. MeOH-d4 (0.41 mL, 10 mmol) was added dropwise to a suspension of sodium hydride (60% in mineral oil, 0.43 g, 10 mmol) in THF. The suspension was stirred for 10 min, and a solution of 2-amino-4-chloropyrimidine (1.0 g, 7.7 mmol, Asta Tech, Inc.) in THF was slowly added. After the addition was complete, the reaction mixture was stirred at rt for 12 h, diluted with water, and extracted with EtOAc. The organic phase was concentrated in vacuo to give 4-(methoxy-d3)pyrimidin-2-amine (0.81 g, 6.3 mmol, 82% yield). The crude product was used in the next step without further purification. LC / MS (ESI + ) m / z=129.2[M+H] + .

[0246] Step 2: 8-(Methoxy-d3)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-C, Step 1, with the following modifications: Step 1 was carried out using 4-(methoxy-d3)pyrimidin-2-amine (0.8 g, 6.3 mmol) and 4,4,4-trifluoro-3-oxobutanoic acid ethyl ester (1.85 mL, 12.6 mmol). LC / MS (ESI + ) m / z = 249.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 9.06(d,J=7.67Hz,1H),6.76(d,J=7.67Hz,1H),6.71(s,1H).

[0247] Step 3: 3-Bromo-8-(methoxy-d3)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-A, Step 2, with the following modifications: Step 2 was carried out using 8-(methoxy-d3)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one. LC / MS (ESI + ) m / z = 327.0 / 329.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 9.06(d,J=7.67Hz,1H),7.12(d,J=7.67Hz,1H).

[0248] Intermediate 1-S 3-Bromo-2-(fluoromethyl)-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 2-(Fluoromethyl)-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one. A reaction mixture of 2-amino-4-methoxypyridine (0.5 g, 4.0 mmol, Combi-Blocks, Inc.) and ethyl 4-fluoro-3-oxobutanoate (1.1 g, 7.3 mmol, HCH Pharma) was heated to 120 °C. After 20 min, methanesulfonic acid (0.5 mL, 8 mmol) was added. Heating was continued for 1 h. The reaction mixture was cooled to rt and treated with CHCl (20 mL) and water (40 mL). The pH was adjusted to pH = 14 by dropwise addition of 5 M NaOH solution. The organic phase was separated, washed with brine (5 mL), dried over MgSO, and then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluent: 0-40% (3:1 EtOAc / EtOH) / heptane) to give 2-(fluoromethyl)-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one as a white solid (40 mg, 0.19 mmol, 5% yield). LC / MS (ESI) + ) m / z=209.1[M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.93(d,J=7.46Hz,1H),6.77-6.83(m,2H),6.40-6.45(m,1H),5.28(t,J=46.60Hz,3H),3.96(s,3H).

[0249] Step 2: 3-Bromo-2-(fluoromethyl)-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-C, Step 2, with the following modifications: Step 2 was carried out using 2-(fluoromethyl)-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one. LC / MS (ESI + ) m / z = 287.0 / 289.0 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.95(d,J=7.88Hz,1H),7.07(d,J=2.49Hz,1H),6.91(dd,J=2.49,7.88Hz,1H),5.53(d,J=46.65Hz,2H),3.98-4.01(m,3H).

[0250] Intermediate 1-T 3-Bromo-2-ethyl-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 2-Ethyl-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-C, Step 1, with the following modifications. Step 1 was carried out using methyl 3-oxopentanoate (TCI America). LC / MS (ESI + ) m / z=205.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.90(dd,J=8.0,1.1Hz,1H),6.90-6.85(m,1H),6.77(ddd,J=7.9,2.7,1.1Hz,1H),6.19(d,J =1.1Hz,1H),3.96(d,J=1.2Hz,3H),2.67(qd,J=7.6,1.1Hz,2H),1.31(td,J=7.6,1.2Hz,3H).

[0251] Step 2: 3-Bromo-2-ethyl-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-C, Step 2, with the following modifications. Step 2 was carried out using 2-ethyl-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one. LC / MS (ESI + ) m / z = 283.0 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.89(t,J=7.7Hz,1H),6.86(dd,J=7.2,2.8Hz,1H),6.80(dq,J=7.8,2.7Hz,1 H),3.97(d,J=4.0Hz,3H),2.91(p,J=7.4Hz,2H),1.31(td,J=7.4,5.2Hz,3H).

[0252] Intermediate 1-U 3-Bromo-2-cyclopropyl-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 2-Cyclopropyl-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-S, Step 1, with the following modifications: Step 1 was carried out using methyl 3-cyclopropyl-3-oxopropanoate (Accela ChemBio Inc.). LC / MS (ESI + ) m / z=217.2[M+H] + .

[0253] Step 2: 3-Bromo-2-cyclopropyl-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-C, Step 2, with the following modifications. Step 2 was carried out using 2-cyclopropyl-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one. LC / MS (ESI + ) m / z = 295.0 / 297.0 [M+H] + .

[0254] Intermediate 1-V 3-Bromo-8-(difluoromethoxy)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-(Difluoromethoxy)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. Difluoromethyl trifluoromethanesulfonate (0.4 g, 2.2 mmol; prepared according to the procedure described by Levin et al., Journal of Fluorine Chemistry 130 (2009) 667-670) was added to a suspension of 8-hydroxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.1 g, 0.4 mmol, Intermediate 1-Q) and potassium hydroxide (0.29 g, 5.2 mmol) in acetonitrile (2 ml). The reaction mixture was stirred at rt for 10 minutes. The reaction was quenched by adding saturated ammonium chloride solution. The reaction mixture was diluted with EtOAc and water. The organic phase was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude residue was dissolved in EtOAc and treated with 1N NaOH. The organic layer was washed with additional 1N NaOH, followed by saturated ammonium chloride and brine. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to give 8-(difluoromethoxy)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.1 g, 0.36 mmol) (combined yield). MS (ESI + ) m / z=281.0[M+H] + .

[0255] Step 2: 3-Bromo-8-(difluoromethoxy)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-A, Step 2, with the following modifications: Step 2 was carried out using 8-(difluoromethoxy)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. LC / MS (ESI+ ) m / z=358.8[M+H] + . 1 H NMR(400MHz,CD2Cl2)δ 6.98-7.38(m,1H)7.38-7.42(m,1H)7.80(d,J=7.67Hz,1H)8.99(dd,J=7.26,1.04Hz,1H).

[0256] Intermediate 1-W 3-Bromo-8-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-Methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-C, Step 1, with the following modifications: Step 1 was carried out with methyl acetoacetate. LC / MS (ESI + ) m / z=191.2[M+H] + .

[0257] Step 2: 3-Bromo-8-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-C, Step 2, with the following modifications: Step 2 was carried out with 8-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. 1 H NMR(400MHz,CDCl3)δ 8.91(d,J=7.88Hz,1H),6.86(d,J=2.49Hz,1H),6.82(dd,J=7.88,2.70Hz,1H),3.97(s,3H),2.62(s,3H).

[0258] Intermediate 1-X 3-Bromo-8-cyclopropyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. [ka] Step 1: 8-Cyclopropyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-C, Step 1, with the following modifications: Step 1 was carried out using 4-cyclopropylpyridin-2-amine (ArkPharm). LC / MS (ESI + ) m / z=255.1[M+H] + .

[0259] Step 2: 3-Bromo-8-cyclopropyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-A, Step 2, with the following modifications. Step 2 was carried out using 8-cyclopropyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. LC / MS (ESI + ) m / z=332.9[M+H] + . 1 H NMR(CDCl3,400MHz)δ 8.98(d,J=7.5Hz,1H),7.44(d,J=1.9Hz,1H),7.02(dd,J=7.5,1.9Hz,1H),2.02-2.09(m,1H),1.28-1.35(m,2H),0.96-1.09(m,2H).

[0260] Intermediate 1-Y 8-Fluoro-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-Fluoro-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. Potassium fluoride (0.3 g, 5.2 mmol) was added to a solution of 8-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.5 g, 1.7 mmol, Intermediate 3-C) in DMSO (5 mL) under a nitrogen atmosphere. 18-Crown-6 (23 mg, 0.085 mmol) was added, and the resulting reaction mixture was heated at 100° C. for 6 h. The reaction mixture was cooled to rt and quenched by the addition of ice (10 g). Stirring was continued for 15 min, and the resulting precipitate was filtered off. The solid was washed with water (3×5 mL) and dried under reduced pressure to give 8-fluoro-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.3 g, 76% yield). LC / MS (ESI + ) m / z=233.1[M+H] + . 1 H NMR(400MHz,CDCl3)δ 9.15(dd,J=8.0,6.2Hz,1H),7.44(dd,J=8.5,2.8Hz,1H),7.14(ddd,J=8.6,6.2,2.8Hz,1H),6.77(s,1H).

[0261] Step 2: 8-Fluoro-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-B, Step 2, with the following modifications. Step 2 was carried out using 8-fluoro-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. LC / MS (ESI + ) m / z = 359.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.13-9.08(m,1H),7.86(dd,J=9.2,2.8Hz,1H),7.63-7.57(m,1H).

[0262] Intermediate 1-Z 3-iodo-8-(methyl-d3)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-(Methyl-d3)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. Cobalt(II) chloride (0.2 g, 1.5 mmol) was added to a solution of 8-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (1.0 g, 3.4 mmol, Intermediate 3-C) in benzene (15 mL) under a nitrogen atmosphere at room temperature. A separately prepared solution of magnesium turnings (0.33 g, 13.7 mmol) and trideuteromethyl iodide (0.15 g, 10.2 mmol) in diethyl ether (10 mL) was added dropwise at room temperature. The reaction mixture was heated to 75 °C for 2 h. The reaction mixture was cooled to room temperature and quenched by the addition of aqueous hydrochloric acid (1.5 N, 10 mL). After 10 min, the pH of the reaction mixture was adjusted to pH = 8 by adding NaHCO₃ followed by dilution with ethyl acetate (25 mL). The mixture was filtered through a pad of Celite and washed with ethyl acetate (3 x 5 mL). The organic layer was separated, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluent: 100% DCM) to give 8-(methyl-d)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.32 g, 40%) as a yellow solid. LC / MS (ESI + ) m / z=232.2[M+H] + . 1 H NMR(400MHz,CDCl3)δ 9.01(d,J=7.3Hz,1H),7.62(d,J=1.8Hz,1H),7.14(dd,J=7.3,1.9Hz,1H),6.74(s,1H).

[0263] Step 2: 3-Iodo-8-(methyl-d3)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-B, Step 2, with the following modifications: Step 2 was carried out using 8-(methyl-d3)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. LC / MS (ESI+ ) m / z=358.0[M+H] + . 1 H NMR(400MHz,CDCl3)δ 9.03(d,J=7.3Hz,1H),7.64(d,J=1.9Hz,1H),7.19(dd,J=7.3,1.8Hz,1H).

[0264] Intermediate 2-A 2-(4-((2,2-difluorocyclopropyl)methoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Step 1: 1-((2,2-difluorocyclopropyl)methoxy)-4-iodobenzene. DIAD (3.6 g, 18 mmol) was added dropwise to a stirred solution of 4-iodophenol (3.4 g, 15 mmol) and triphenylphosphine (4.7 g, 18 mmol) in tetrahydrofuran (34 mL) under a nitrogen atmosphere at 0 °C. After 10 min, (2,2-difluorocyclopropyl)methanol (1.5 g, 14 mmol) was added dropwise, and the reaction mixture was warmed to rt and stirred for an additional 16 h. The reaction was quenched by the addition of ice-water (100 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was adsorbed onto a plug of silica gel and purified by silica gel chromatography (eluent: 0–3% ethyl acetate / hexanes) to give 1-((2,2-difluorocyclopropyl)methoxy)-4-iodobenzene (1.8 g, 5.8 mmol, 42% yield). LC / MS (ESI + ) m / z=311.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.62-7.56(m,2H),6.84-6.78(m,2H),4.12(ddd,J=10.3,6.6,3.1Hz,1H),3.95(ddd,J=10.6 ,8.5,1.8Hz,1H),2.26-2.14(m,1H),1.71(tdd,J=12.1,7.9,4.8Hz,1H),1.50-1.41(m,1H).

[0265] Step 2: 2-(4-((2,2-difluorocyclopropyl)methoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A resealable vial was charged with 1-((2,2-difluorocyclopropyl)methoxy)-4-iodobenzene (1.6 g, 5.2 mmol), DMF (10 mL), bis(pinacolato)diboron (1.6 g, 6.2 mmol), and potassium acetate (2.0 g, 21 mmol). The reaction mixture was purged with nitrogen for 15 minutes, and Pd(dppf)Cl (0.38 g, 0.52 mmol) was added. The reaction mixture was heated to 90 °C for 16 hours. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluent: 0–5% ethyl acetate / hexane) to give 2-(4-((2,2-difluorocyclopropyl)methoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (950 mg, 60% yield). 1 H NMR(400MHz,DMSO-d6)δ 7.64-7.59(m,2H),6.97(dd,J=8.7,2.6Hz,2H),4.17(d,J=8.1Hz,1H),4.00(t,J=9. 2Hz,1H),2.25(s,1H),1.74(d,J=9.1Hz,1H),1.52-1.44(m,1H),1.30-1.27(m,12H).

[0266] Intermediate 2-B 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole [ka] Step 1: 5-Bromo-2-phenyloxazole. NBS (19 g, 106 mmol) and AIBN (0.67 g, 4.0 mmol, SpectroChem) were added sequentially to a solution of 2-phenyl-4,5-dihydrooxazole (6.0 g, 41 mmol, Arbor) in carbon tetrachloride (60 mL). The reaction mixture was heated to 85 °C for 2 h. The reaction mixture was cooled to rt and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluent: 0-5% ethyl acetate / hexane) to give 5-bromo-2-phenyloxazole (4.2 g, 46% yield). LC / MS (ESI + ) m / z=224.0[M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.05-7.99(m,2H),7.52-7.46(m,3H),7.13(d,J=1.4Hz,1H).

[0267] Step 2: 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole. n-Butyllithium (1.6 M in hexanes, 0.61 mL, 0.982 mmol) was added to a solution of 5-bromo-2-phenyloxazole (200 mg, 0.89 mmol) in tetrahydrofuran (6 mL) under a nitrogen atmosphere at −78°C. The reaction mixture was stirred at −78°C for 10 minutes, followed by the addition of triisopropyl borate (201 mg, 1.1 mmol). The reaction mixture was stirred at −78°C for 30 minutes and then allowed to warm to rt. After 30 minutes, 2,3-dimethylbutane-2,3-diol (127 mg, 1.1 mmol) and acetic acid (61 μL, 1.1 mmol) were added, and stirring was continued at rt for 1 hour. The reaction mixture was concentrated under reduced pressure to give a crude residue (400 mg), which was used without further purification.

[0268] Intermediate 2-C 2-(4-(2,2-difluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Step 1: 2-(4-(2,2-difluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A mixture of 4-hydroxyphenylboronic acid pinacol ester (1.0 g, 4.5 mmol), dimethyl sulfoxide (20 mL), cesium carbonate (2.2 g, 6.8 mmol), and 1,1-difluoro-2-iodoethane (1.2 mL, 13.6 mmol, Matrix) was heated to 75 °C for 2 h. The reaction mixture was diluted with EtOAc and water. The organic phase was separated, dried over NaSO, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (eluent: 0-50% EtOAc / heptane) to give 2-(4-(2,2-difluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.18 g, 4.15 mmol, 91% yield). LC / MS (ESI) + ) m / z=285[M+H] + . 1 H NMR(400MHz,CDCl3)δ 1.33(s,12H)4.11-4.31(m,2H)5.86-6.27(m,1H)6.91(d,J=8.71Hz,2H)7.77(d,J=8.71Hz,2H).

[0269] Intermediate 2-D 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3,3,3-trifluoropropyl)pyrazole [ka] Step 1: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3,3,3-trifluoropropyl)pyrazole. A resealable vial was charged with 4-pyrazoleboronic acid pinacol ester (500 mg, 2.6 mmol), acetonitrile (5 mL), cesium carbonate (1.7 g, 5.1 mmol), and 1,1,1-trifluoro-3-iodopropane (604 μL, 5.15 mmol, Oakwood). The reaction mixture was heated to 80° C. for 12 h. The reaction mixture was cooled to RT and filtered through a pad of Celite with EtOAc. The filtrate was washed with brine, and the organic phase was dried over sodium sulfate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: 0-60% EtOAc / heptane) to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole (137 mg, 0.47 mmol, 18% yield). 1 H NMR(400MHz,CDCl3)δ 1.32(s,13H)2.74(dt,J=10.37,7.36Hz,2H)4.37(t,J=7.36Hz,2H)7.71(s,1H)7.81(s,1H).

[0270] Intermediate 2-E 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4,4,4-trifluorobutyl)pyrazole [ka] Step 1: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4,4,4-trifluorobutyl)pyrazole. A resealable vial was charged with 4-pyrazoleboronic acid pinacol ester (500 mg, 2.58 mmol), acetonitrile (5 mL), potassium carbonate (0.53 g, 3.8 mmol), and 1,1,1-trifluoro-4-iodobutane (0.7 mL, 5.2 mmol, Oakwood). The reaction mixture was heated to 65°C for 12 hours. The reaction mixture was cooled to room temperature and partitioned between water and EtOAc. The organic phase was dried over sodium sulfate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: 0-60% EtOAc / heptane) to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4,4,4-trifluorobutyl)-1H-pyrazole (508 mg, 1.7 mmol, 65% yield). 1 H NMR(400MHz,CDCl3)δ 1.33(s,13H)1.99-2.11(m,2H)2.11-2.23(m,2H)4.22(t,J=6.46Hz,2H)7.69(s,1H)7.81(s,1H).

[0271] Intermediate 2-F 2-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Step 1: 1-Bromo-2-fluoro-4-(2,2,2-trifluoroethoxy)benzene. 2,2,2-Trifluoroethyl iodide (4.6 mL, 47 mmol, Oakwood Products, Inc.) was added to a mixture of 4-bromo-3-fluorophenol (3.0 g, 15 mmol, Apollo Scientific, Ltd.) and potassium carbonate (4.3 g, 31 mmol) in DMF (30 mL). The reaction mixture was heated to 100° C. for 12 hours. Additional 2,2,2-trifluoroethyl iodide (1.5 mL) was added and stirring was continued for 12 hours. The reaction mixture was cooled to room temperature and filtered through a pad of Celite with ethyl acetate. The filtrate was washed with water and brine and dried over Na2SO4. The filtrate was concentrated under reduced pressure and the crude residue was purified by silica gel chromatography (eluent: 0-20% ethyl acetate / heptane) to give 1-bromo-2-fluoro-4-(2,2,2-trifluoroethoxy)benzene (3.75 g, 13.7 mmol, 87% yield). 1 H NMR (CDCl3,400MHz): δ=7.48(dd,J=8.8,7.8Hz,1H),6.77(dd,J=9.8,2.7Hz,1H),6.67(ddd,J=8.9,2.9,1.2Hz,1H),4.34(q,J=8.0Hz,2H).

[0272] Step 2: 2-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A resealable vial was charged with 1-bromo-2-fluoro-4-(2,2,2-trifluoroethoxy)benzene (1.54 g, 5.64 mmol), bis(pinacolato)diboron (2.149 g, 8.46 mmol), potassium acetate (1.9 g, 19 mmol), and 1,4-dioxane (19 mL). The reaction mixture was purged with argon for 5 minutes, followed by the addition of Pd(dppf)Cl (0.46 g, 0.56 mmol, Strem). The reaction mixture was heated to 100° C. for 18 hours. The reaction mixture was cooled to room temperature and filtered through a pad of Celite with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude residue was purified by silica gel chromatography (eluent: 0–30% ethyl acetate / heptane) to give 2-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.37 g, 4.3 mmol, 76% yield). 1 H NMR (CDCl3,400MHz): δ=7.69(dd,J=8.3,7.1Hz,1H),6.72(dd,J=8.4,2.3Hz,1H),6.61(dd,J=10.6,2.3Hz,1H),4.35(q,J=8.0Hz,2H),1.34(s,12H).

[0273] Intermediate 2-G 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] Step 1: 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. A resealable vial was charged with 4-pyrazoleboronic acid pinacol ester (0.5 g, 2.6 mmol), potassium carbonate (0.7 g, 5 mmol), DMF (3 mL), and 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate (1.0 g, 3.5 mmol, Matrix Scientific). The reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was cooled to room temperature and partitioned between water (70 mL) and EtOAc (70 mL). The organic layer was dried over sodium sulfate, filtered, and adsorbed onto a pad of silica gel. Purification by silica gel chromatography (eluent: 0-60% EtOAc / heptane) gave 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (289 mg, 0.9 mmol, 34% yield), which was carried on to the next reaction without further purification. 1 H NMR(400MHz,CDCl3)δ 1.32(s,16H)4.75(t,J=14.10Hz,2H)7.80(s,1H)7.84(s,1H).

[0274] Intermediate 2-H 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile [ka] Step 1: 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile. 3-Bromo-propionitrile (2.1 g, 15 mmol, Combi-Blocks Inc.), sodium iodide (0.154 g, 1.03 mmol), and potassium carbonate (2.1 g, 15 mmol) were added sequentially to a suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 10.3 mmol, 1.0 eq.) in acetonitrile (20 mL). The reaction mixture was heated to 60° C. for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. The filtrate was concentrated under reduced pressure to give 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (2.5 g, 10.1 mmol, 98% yield) as a yellow liquid, which was used in the next step without further purification. LC / MS (ESI + ) m / z = 248.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.04(s,1H),7.65(s,1H),4.41(t,J=6.4Hz,2H),3.07(t,J=6.4Hz,2H),1.26(s,12H).

[0275] Intermediate 2-I 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetonitrile [ka] Step 1: 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetonitrile. The title compound was prepared using the procedure described for Intermediate 2-H, Step 1, with the following modifications: Step 1 was carried out using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 10 mmol, Combi-Blocks Inc.) and 2-bromoacetonitrile (4.95 g, 41.2 mmol, Spectrochem). LC / MS (ESI + ) m / z = 234.2 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.85(s,2H),5.10(s,2H),1.33(s,12H).

[0276] Intermediate 2-J 1-(2,2-Difluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] Step 1: 4-Bromo-1-(2,2-difluoropropyl)-1H-pyrazole. A solution of diethylaminosulfur trifluoride (0.84 mL, 6.3 mmol) in DCM (2 mL) was added dropwise to a solution of 1-(4-bromo-1H-pyrazol-1-yl)propan-2-one (0.33 g, 1.6 mmol, Enamine Ltd.) in DCM (10 mL) at −78° C. The reaction mixture was allowed to warm to room temperature over 12 h. The reaction mixture was cooled to 0° C. and quenched by the addition of 1N sodium thiosulfate (20 mL), followed by partitioning between EtOAc and water. The organic extract was washed with brine, dried over sodium sulfate, filtered, and adsorbed onto silica gel. Purification by silica gel chromatography (eluent: 0–100% EtOAc / heptane) afforded 4-bromo-1-(2,2-difluoropropyl)-1H-pyrazole (220 mg, 0.98 mmol, 61% yield). 1 H NMR(400MHz,CDCl3)δ 1.57(t,J=18.66Hz,3H)4.43(t,J=12.02Hz,2H)7.51(s,1H)7.53(s,1H).

[0277] Step 2: 1-(2,2-Difluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. A resealable vial was charged with 4-bromo-1-(2,2-difluoropropyl)-1H-pyrazole (0.31 g, 1.4 mmol), bis(acetonitrile)dichloropalladium(II) (11 mg, 0.04 mmol, Strem), and 2-dicyclohexylphosphino-2,6'-dimethoxy-1,1'-biphenyl (51 mg, 0.12 mmol, Strem). The vial was evacuated and backfilled with nitrogen. This procedure was repeated three times. Toluene (1.8 mL) was added, followed by pinacolborane (0.24 mL, 1.6 mmol) and triethylamine (0.48 mL, 3.4 mmol). Additional toluene (0.7 mL) was added. The reaction mixture was heated to 90°C for 12 hours. The reaction mixture was filtered through a plug of silica gel and concentrated under pressure. The crude residue was purified by silica gel chromatography (eluent: 0-50% EtOAc / heptane) to give 1-(2,2-difluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (164 mg, 0.6 mmol, 44% yield). 1 H NMR(400MHz,CDCl3)δ 1.33(s,12H)1.56(m,3H)4.47(t,J=12.02Hz,2H)7.79(s,1H)7.81(s,1H).

[0278] Intermediate 2-K 2-(Fluoromethyl)-3-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile [ka] Step 1: 2-(Fluoromethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile. Polyphosphoric acid (approximately 700 μL) was added to a suspension of ethyl 4-fluoro-3-oxobutanoate (0.4 g, 2.7 mmol, HCH Pharma) and 2-aminopyridine-4-carbonitrile (0.32 mg, 2.7 mmol, Fluorochem). The reaction mixture was heated to 90° C. for 6 hours. The reaction mixture was poured into 50 mL of water and extracted with EtOAc (2×). The organic layer was dried, filtered, and concentrated under reduced pressure. The residue was dissolved in THF (15 mL), and pyridine (0.3 mL, 4 mmol) was added, followed by trifluoroacetic anhydride (370 μL, 2.7 mmol). The resulting mixture was stirred at room temperature for 1 hour, then quenched with water and extracted with EtOAc. The organic layer was dried, filtered, and concentrated, and the residue was purified by silica gel chromatography (eluent: 50% EtOAc / cyclohexane) to give 2-(fluoromethyl)-4-oxopyrido[1,2-a]pyrimidine-8-carbonitrile (290 mg, 1.43 mmol, 53% yield). LC / MS (ESI + ) m / z = 204.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 5.34-5.61(d,2H)6.55-6.61(s,1H)7.46-7.60(d,1H)8.34-8.43(s,1H)8.93-9.01(d,1H).

[0279] Step 2: 2-(Fluoromethyl)-3-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile. The title compound was prepared using the procedure described for Intermediate 1-B, Step 2, with the following modifications. Step 2 was carried out using 2-(fluoromethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile. LC / MS (ESI + ) m / z=402.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 5.43-5.64(d,2H)7.64(d,J=7.48,1H)8.49-8.54(s,1H)8.96-9.03(d,1H).

[0280] Intermediate 2-L (2-Fluoro-4-(2,2,2-trifluoroethoxy)phenyl)boronic acid [ka] Step 1: (2-Fluoro-4-(2,2,2-trifluoroethoxy)phenyl)boronic acid. Sodium periodate (0.13 ml, 2.3 mmol) was added to a solution of 2-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.25 g, 0.78 mmol, Intermediate 2-F) in THF:water and concentrated under reduced pressure to give (2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)boronic acid. 1 H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H) 7.49-7.81 (m, 1H) 6.76-6.97 (m, 2H) 4.81 (q, J = 8.85 Hz, 2H). (1:1, 10 ml) and 1 N hydrochloric acid (5 ml). After 20 min, the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over magnesium sulfate.

[0281] Intermediate 2-M 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole [ka] Step 1: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole. 2,2,2-Trifluoroethyl triflate (0.37 mL, 2.6 mmol, Oakwood Products) was added to a mixture of 4-pyrazoleboronic acid pinacol ester (0.25 g, 1.3 mmol), potassium carbonate (0.27 g, 1.9 mmol), and acetonitrile (2.6 mL). The reaction mixture was heated to 65° C. for 12 hours. The reaction mixture was cooled to room temperature and partitioned between water (70 mL) and EtOAc (70 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography gave 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (133 mg, 0.48 mmol, 37% yield). 1 H NMR(400MHz,CD2Cl2)δ 1.30(s,13H)4.74(q,J=8.41Hz,2H)7.75(s,1H)7.79(s,1H).

[0282] Intermediate 2-N 2-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Step 1: 4-Bromo-2-chloro-1-(2,2,2-trifluoroethoxy)benzene. 1,1,1-Trifluoro-2-iodoethane (4.2 mL, 43 mmol, Oakwood Products, Inc.) was added to a mixture of 2-chloro-4-bromophenol (3.0 mL, 14 mmol) and potassium carbonate (4.0 g, 29 mmol) in DMF (30 mL). The reaction mixture was heated to 100 °C for 12 h. The reaction mixture was cooled to rt and filtered through a pad of Celite with EtOAc. The filtrate was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluent: 0-20% ethyl acetate / heptane) to give 4-bromo-2-chloro-1-(2,2,2-trifluoroethoxy)benzene (2.8 g, 9.7 mmol, 67% yield). 1 H NMR (CDCl3,400MHz): δ=7.55(d,J=2.3Hz,1H),7.36(dd,J=8.7,2.4Hz,1H),6.86(d,J=8.8Hz,1H),4.38(q,J=8.0Hz,2H).

[0283] Step 2: 2-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A mixture of 4-bromo-2-chloro-1-(2,2,2-trifluoroethoxy)benzene (1.7 g, 6.0 mmol), bis(pinacolato)diboron (2.3 g, 9.0 mmol), potassium acetate (2.1 g, 21 mmol), and Pd(dppf)Cl2 (0.49 g, 0.6 mmol, Strem) in dioxane (20 mL) was purged with argon for 5 minutes. The reaction mixture was heated to 110 °C for 12 hours. The reaction mixture was cooled to room temperature and filtered through a pad of Celite with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: 0-20% ethyl acetate / heptane) to give (1.38 g, 4.1 mmol, 68% yield). 1H NMR (CDCl3,400MHz): δ=7.77(d,J=1.6Hz,1H),7.59(dd,J=8.1,1.5Hz,1H),6.85(d,J=8.2Hz,1H),4.35(q,J=8.0Hz,2H),1.26(s,12H).

[0284] Intermediate 2-O 3-Bromo-2-fluoro-6-(2,2,2-trifluoroethoxy)pyridine [ka] Step 1: 3-Bromo-2-fluoro-6-(2,2,2-trifluoroethoxy)pyridine. 1,1,1-Trifluoro-2-iodoethane (0.76 ml, 7.8 mmol, Oakwood Chemical, Estill, SC, USA) was added to a mixture of 3-bromo-2-fluoro-6-hydroxypyridine (500 mg, 2.6 mmol, Combi-Blocks, San Diego, CA, USA) and potassium carbonate (0.72 g, 5.2 mmol) in DMF (5 ml) under an argon atmosphere. The reaction mixture was heated to 100 °C for 12 h. The reaction mixture was cooled to rt and filtered through a pad of Celite with EtOAc. The filtrate was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluent: 0-10% ethyl acetate / heptane) to give 3-bromo-2-fluoro-6-(2,2,2-trifluoroethoxy)pyridine (0.71 g, 0.91 mmol, 35% yield). LC / MS (ESI + ) m / z = 274.0 [M+H] + .

[0285] Intermediate 2-P 2-Bromo-5-(2,2,2-trifluoroethoxy)pyridine [ka] Step 1: 2-Bromo-5-(2,2,2-trifluoroethoxy)pyridine. A resealable vial was charged with 2,2,2-trifluoroethanol (0.42 mL, 5.7 mmol), potassium tert-butoxide (1 M in THF, 5.7 mL, 5.7 mmol), 2-bromo-5-fluoropyridine (1.0 g, 5.68 mmol), and THF (6 mL). The reaction mixture was heated to 70 °C for 60 h. The reaction mixture was cooled to ambient temperature and partitioned between water and EtOAc. The organic phase was dried over MgSO and concentrated in vacuo. The crude residue was purified by silica gel chromatography (eluent: 0-10% EtOAc / heptane) to give 2-bromo-5-(2,2,2-trifluoroethoxy)pyridine (150 mg, 0.59 mmol, 10% yield) as a solid. LC / MS (ESI + ) m / z=256.0[M+H] + .

[0286] Intermediate 2-Q 5-Bromo-3-fluoro-2-(2,2,2-trifluoroethoxy)pyridine [ka] Step 1: 5-Bromo-3-fluoro-2-(2,2,2-trifluoroethoxy)pyridine. 1,1,1-Trifluoro-2-iodoethane (2.3 ml, Oakwood Chemical, Estill, SC, USA) was added to a mixture of 5-bromo-3-fluoropyridin-2-ol (1.5 g, 7.8 mmol, Combi-Blocks, San Diego, CA, USA) and potassium carbonate (2.2 g, 15.6 mmol) in DMF (10 ml) under an argon atmosphere. The reaction was heated to 100 °C for 12 h. The reaction mixture was cooled to rt and filtered through a pad of Celite with EtOAc. The filtrate was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluent: 0-10% ethyl acetate / heptane) to give 5-bromo-3-fluoro-2-(2,2,2-trifluoroethoxy)pyridine (1.28 g, 4.67 mmol, 60% yield). LC / MS (ESI) +) m / z = 274.0 [M+H] + .

[0287] Intermediate 2-R 5-Bromo-2-(2,2,2-trifluoroethoxy)pyridine [ka] Step 1: 5-Bromo-2-(2,2,2-trifluoroethoxy)pyridine. The title compound was prepared using the procedure described for Intermediate 2-P, Step 1, with the following modifications: Step 1 was carried out with 5-bromo-2-fluoropyridine. LC / MS (ESI + ) m / z=255.8[M+H] + / 258.0[M+2] + .

[0288] Intermediate 2-S (2-methyl-4-(2,2,2-trifluoroethoxy)phenyl)boronic acid [ka] Step 1: 1-Bromo-2-methyl-4-(2,2,2-trifluoroethoxy)benzene. A vial was charged with 4-bromo-3-methylphenol (1 g, 5.4 mmol), 1,1,1-trifluoro-2-iodoethane (4.5 g, 21.4 mmol, Oakwood), DMF (5 mL), and cesium carbonate (3.5 g, 10.7 mmol). The reaction mixture was heated to 60 °C for 48 h. The reaction mixture was cooled to rt and partitioned between EtOAc and water. The organic phase was separated, washed with water and brine, and dried over MgSO. The filtrate was absorbed onto a pad of silica gel. Purification by silica gel chromatography (eluent: 0–10% (3:1 EtOAc / EtOH) / heptane) gave 1-bromo-2-methyl-4-(2,2,2-trifluoroethoxy)benzene (1.1 g, 4.1 mmol, 76% yield). 1H NMR(CDCl3,400MHz)δ 7.37(d,J=8.7Hz,1H),6.77(d,J=3.1Hz,1H),6.58(dd,J=8.7,3.1Hz,1H),4.24(q,J=8.2Hz,2H),2.31(s,3H).

[0289] Step 2: 4,4,5,5-tetramethyl-2-(2-methyl-4-(2,2,2-trifluoroethoxy)phenyl)-1,3,2-dioxaborolane. The title compound was prepared using the procedure described for Intermediate 2-N, Step 2, with the following modifications: Step 2 was carried out with 1-bromo-2-methyl-4-(2,2,2-trifluoroethoxy)benzene. 1 H NMR(CDCl3,400MHz)δ 7.74(br d,J=8.3Hz,1H),6.64-6.79(m,2H),4.29-4.40(m,2H),2.53(s,3H),1.31-1.38(m,12H).

[0290] Step 3: (2-methyl-4-(2,2,2-trifluoroethoxy)phenyl)boronic acid. The title compound was prepared using the procedure described for Intermediate 2-L, Step 1, with the following modifications: Step 1 was carried out using 4,4,5,5-tetramethyl-2-(2-methyl-4-(2,2,2-trifluoroethoxy)phenyl)-1,3,2-dioxaborolane. 1 H NMR(DMSO-d6,400MHz)δ 7.83(d,J=9.1Hz,1H),6.76-6.93(m,2H),4.73(q,J=8.9Hz,2H),2.61-2.65(m,3H).

[0291] Intermediate 2-T 8-chloro-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-Chloro-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. Concentrated hydrochloric acid (37%, 3.4 mL, 41 mmol) was added to a solution of 8-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (2.0 g, 6.8 mmol, Intermediate 3-C) in acetonitrile (16 mL). The resulting mixture was then subjected to microwave irradiation at 100 °C for 15 min. The mixture was slowly quenched with saturated NaHCO (200 mL) and extracted with EtOAc (2 × 200 mL). The combined organic extracts were dried over MgSO and concentrated under reduced pressure. Purification of the crude residue by silica gel chromatography (eluent: 0-100% EtOAc / heptane) afforded 8-chloro-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. LC / MS (ESI+) m / z = 249.1 [M+H] + . 1 H NMR(DMSO-d6)δ:8.97(d,J=7.7Hz,1H),8.10(d,J=2.1Hz,1H),7.55(dd,J=7.7,2.3Hz,1H),6.87(s,1H).

[0292] Step 2: 8-Chloro-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-B, Step 2, with the following modifications: Step 2 was carried out using 8-chloro-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. LC / MS (ESI+) m / z = 374.9 [M+H] + . 1 H NMR(DMSO-d6)δ 8.96(d,J=7.7Hz,1H),8.10(d,J=2.1Hz,1H),7.59(dd,J=7.7,2.3Hz,1H).

[0293] Intermediate 2-U 3-iodo-2-(trifluoromethyl)-8-vinyl-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Tributyl(vinyl)tin (0.90 g, 2.86 mmol) was added to a solution of 8-bromo-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (1.0 g, 2.38 mmol, Intermediate 3-I) in toluene (10 mL). The reaction mixture was purged with nitrogen for 10 minutes, and Pd(PPh3)4 (276 mg, 0.24 mmol) was added. The reaction mixture was heated to 110 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel chromatography (eluent: 0-10% ethyl acetate / hexanes) to give 3-iodo-2-(trifluoromethyl)-8-vinyl-4H-pyrido[1,2-a]pyrimidin-4-one (400 mg, 46% yield). LC / MS (ESI+) m / z = 367.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.93(d,J=7.5Hz,1H),7.91(d,J=1.8Hz,1H),7.79(dd,J=7.6,1.9Hz,1H),6. 96(dd,J=17.6,10.9Hz,1H),6.42(d,J=17.7Hz,1H),5.82(d,J=10.9Hz,1H).

[0294] Intermediate 2-V 3-Bromo-8-methyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-Methyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-O, step 1-1, with the following modifications: Step 1-1 was carried out using 2-amino-4-methylpyridine. LC / MS (ESI+) m / z=229.9 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.99(d,J=7.3Hz,1H),7.60(s,1H),7.14-7.09(m,1H),6.72(s,1H),2.54(s,3H).

[0295] Step 2: 3-Bromo-8-methyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-O, Step 1-2, with the following modifications: Step 1-2 was carried out using 8-methyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. LC / MS (ESI+) m / z = 307.0 [M+H] + .

[0296] Intermediate 2-W 3-Iodo-2,8-dimethoxy-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: Ethyl 3-((4-methoxypyridin-2-yl)amino)-3-oxopropanoate. A solution of ethyl malonyl chloride (3.9 ml, 30 mmol) in DCM (10 mL) was added dropwise to a solution of 2-amino-4-methoxylpyridine (2.5 g, 20 mmol, Combi-Blocks Inc.) in DCM (12 mL) and pyridine (18 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 40 min. Water (40 mL) was added, and the reaction mixture was stirred vigorously at rt for 3 min. Saturated aqueous sodium carbonate was added, and the organic layer was separated. The aqueous phase was extracted with DCM, and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography (eluent: 0–25% (3:1 EtOAc / EtOH) / heptane) to give ethyl 3-((4-methoxypyridin-2-yl)amino)-3-oxopropanoate (1.54 g, 6.5 mmol, 32% yield). 1 H NMR(400MHz,CDCl3)δ 9.45(br s,1H),8.09(d,J=5.80Hz,1H),7.80(s,1H),6.60(dd,J=2.28,5.80Hz,1H) ,4.25(q,J=7.05Hz,2H),3.86(s,3H),3.47(s,2H),1.31(t,J=7.15Hz,3H).

[0297] Step 2: 2-Chloro-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one. A mixture of ethyl 3-((4-methoxypyridin-2-yl)amino)-3-oxopropanoate (1.0 g, 4.3 mmol), phosphorus oxychloride (1.2 mL, 13.0 mmol), and polyphosphoric acid (0.17 mL, 4.3 mmol) was heated at 130° C. for 16 h. The reaction mixture was cooled to rt, followed by the addition of EtOH (4.3 mL). The reaction mixture was further heated at reflux for 30 min and then cooled to rt. The reaction mixture was partitioned between EtOAc and brine. The aqueous layer was back-extracted with EtOAc (×2), and the combined organic layers were dried over NaSO. The filtrate was concentrated in vacuo, and the residue was suspended in DCM (5 mL). The solid was filtered off and dried to give 2-chloro-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one as a solid (485 mg, 2.3 mmol, 53% yield). LC / MS (ESI + ) m / z=211.1[M+H] + .

[0298] Step 3: 2,8-Dimethoxy-4H-pyrido[1,2-a]pyrimidin-4-one. Sodium methoxide (25 wt% in MeOH, 0.33 ml, 1.5 mmol) was added dropwise to a solution of 2-chloro-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one (213 mg, 1.0 mmol) in acetonitrile (2 ml). The reaction mixture was stirred at rt for 2 h and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over NaSO. The filtrate was concentrated to give 2,8-dimethoxy-4H-pyrido[1,2-a]pyrimidin-4-one (172 mg, 0.83 mmol, 82% yield) as an off-white solid. LC / MS (ESI) + ) m / z=207.2[M+H] + .

[0299] Step 4: 3-Iodo-2,8-dimethoxy-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-B, Step 2, with the following modifications. Step 2 was carried out using 2,8-dimethoxy-4H-pyrido[1,2-a]pyrimidin-4-one. LC / MS (ESI + ) m / z = 333.0 [M+H] + .

[0300] Intermediate 2-X 2-Ethoxy-3-iodo-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 2-Ethoxy-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one. Sodium ethoxide (254 mg, 0.78 mmol) was added to a solution of 2-chloro-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one (150 mg, 0.71 mmol, Intermediate 2-W, prepared according to the method described for steps 1 and 2) in acetonitrile (2.3 mL). The reaction mixture was stirred at rt for 1 h and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over NaSO. The filtrate was concentrated, and the crude material was purified by silica gel chromatography (eluent: 0-25% (3:1 EtOAc / EtOH) / heptane) to give 2-ethoxy-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one as a white solid (85 mg, 0.39 mmol, 54% yield). LC / MS (ESI) + ) m / z=221.1[M+H] + .

[0301] Step 2: 2-Ethoxy-3-iodo-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-B, Step 2, with the following modifications. Step 2 was carried out using 2-ethoxy-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one. LC / MS (ESI + ) m / z = 347.0 [M+H] + .

[0302] Intermediate 2-Y 3-(4-hydroxy-2-(trifluoromethyl)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 3-(4-Hydroxy-2-(trifluoromethyl)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Method 4, Step 3, with the following modifications. Step 3 was carried out using 3-bromo-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.15 g, 0.46 mmol, Intermediate 1-A) and 4-hydroxy-2-(trifluoromethyl)phenylboronic acid (144 mg, 0.7 mmol, Aurum Pharmatech LLC). LC / MS (ESI + ) m / z = 404.9 [M+H] + . 1 H NMR(DMSO-d6,400MHz)δ 10.18-10.39(m,1H),8.88(d,J=7.9Hz,1H),7.31(d,J=2.7Hz,1H),7.14-7.23(m,3H),7.09(d,J=8.6Hz,1H),4.05(s,3H).

[0303] Intermediate 2-Z 3-(2-chloro-4-hydroxyphenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 3-(2-chloro-4-hydroxyphenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Method 4, Step 3, with the following modifications. Step 3 was carried out using 3-bromo-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (1 g, 3.1 mmol, Intermediate 1-A) and 2-chloro-4-hydroxyphenylboronic acid (800 mg, 4.6 mmol, Combi-Blocks Inc.). LC / MS (ESI + ) m / z = 371.0 [M+H] + . 1 H NMR(DMSO-d6,400MHz)δ 10.03(br s,1H),8.89(d,J=7.9Hz,1H),7.31(d,J=2.7Hz,1H),7.21(dd,J=7.9,2.9Hz,1H),7.12(d,J =8.3Hz,1H),6.93(d,J=2.3Hz,1H),6.79(dd,J=8.3,2.5Hz,1H),4.04(s,3H),3.30(s,3H).

[0304] Intermediate 3-A 3-(4-hydroxyphenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 3-(4-hydroxyphenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Method 4, Step 3, with the following modifications. Step 3 was carried out using 3-bromo-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (1 g, 3.1 mmol, Intermediate 1-A) and (4-hydroxyphenyl)boronic acid (0.63 g, 4.6 mmol, Combi-Blocks Inc.). LC / MS (ESI + ) m / z = 337.0 [M+H] + . 1H NMR(400MHz,CDCl3)δ 8.97(d,J=7.88Hz,1H),7.14(d,J=8.29Hz,2H),7.07(d,J=2.49Hz,1H),6.94(dd,J=2.70,7.88Hz,1H),6.79(d,J=8.50Hz,2H),6.47(br s,1H),4.00(s,3H).

[0305] Intermediate 3-B 3-(4-hydroxyphenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one [ka] Step 1: 3-(4-hydroxyphenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Method 1, Step 1, with the following modifications. Step 1 was carried out using 3-bromo-8-methoxy-2-(trifluoromethyl)pyrimido[1,2-a]pyrimidin-4-one (2.0 g, 6.2 mmol, Intermediate 1-O), (4-hydroxyphenyl)boronic acid (1.0 g, 7.4 mmol, Combi-Blocks Inc.). LC / MS (ESI + ) m / z = 338.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.60(s,1H),9.01(d,J=7.7Hz,1H),7.18-7.00(m,3H),6.83-6.78(m,2H),4.10(s,3H).

[0306] Intermediate 3-C 8-Bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-Bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-A, Step 1, with the following modifications: Step 1 was carried out using 4-bromopyridin-2-amine (Combi-Blocks Inc.). LC / MS (ESI + ) m / z = 294.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.88(d,J=7.6Hz,1H),8.26(d,J=2.2Hz,1H),7.66(dd,J=7.6,2.1Hz,1H),6.89(s,1H).

[0307] Intermediate 3-D 8-Cyclopropyl-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] 8-Bromo-3-iodo-2-(trifluoromethyl)pyrido[1,2-a]pyrimidin-4-one (150 mg, 0.36 mmol, Intermediate 3-I), Pd(PPh3)4 (41 mg, 0.04 mmol), cyclopropylboronic acid (61 mg, 0.72 mmol, Fluorochem), and potassium carbonate (100 mg, 0.72 mmol) were suspended in toluene (3 mL). The reaction mixture was heated to 100 °C for 24 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel chromatography (eluent: 0-30% EtOAc / cyclohexane) to give 8-cyclopropyl-3-iodo-2-(trifluoromethyl)pyrido[1,2-a]pyrimidin-4-one as a yellow solid (70 mg, 0.18 mmol, 51% yield). LC / MS (ESI) + ) m / z = 381.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 0.98-1.10(m,2H)1.30-1.41(m,2H)2.01-2.16(m,1H)7.00-7.08(d,1H)7.43-7.51(s,1H)8.96-9.04(d,1H).

[0308] Intermediate 3-E 8-(Azetidin-1-yl)-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] A resealable vial was charged with 8-bromo-3-iodo-2-(trifluoromethyl)pyrido[1,2-a]pyrimidin-4-one (100 mg, 0.24 mmol, Intermediate 3-I), azetidine hydrochloride (25 mg, 0.26 mmol), copper(I) iodide (11 mg, 0.06 mmol), potassium carbonate (40 mg, 0.29 mmol), and DMF (3 mL). The reaction mixture was heated to 80 °C for 1 h. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl and brine. The organic phase was dried and concentrated in vacuo. The crude residue was purified by silica gel chromatography (eluent: 70% EtOAc / cyclohexane) to give 8-(azetidin-1-yl)-3-iodo-2-(trifluoromethyl)pyrido[1,2-a]pyrimidin-4-one as a pale yellow solid (48 mg, 0.12 mmol, 51% yield). + ) m / z = 396.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 2.45-2.71(m,2H)4.06-4.42(br s,4H)6.28-6.39(d,1H)6.39-6.57(dd,1H)8.80-8.97(d,1H).

[0309] Intermediate 3-F Methyl 4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxylate [ka] Step 1: methyl 4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxylate. The title compound was prepared using the procedure described for Method 1, Step 1, with the following modifications: Step 1 was carried out using methyl 3-iodo-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxylate (0.47 g, 1.2 mmol, Intermediate 1-D), 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.50 g, 1.54 mmol, Intermediate 2-G). LC / MS (ESI + ) m / z = 471.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 9.11(d,J=7.5Hz,1H),8.46(s,1H),7.98(s,1H),7.91(s,1H),7.74(dd,J=7.6,1.8Hz,1H),4.85(t,J=13.9Hz,2H),4.06(s,3H).

[0310] Intermediate 3-G 8-(Ethylthio)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-(Ethylthio)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. Sodium ethanethiol (3.0 g, 36 mmol) was added to a solution of 8-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3.0 g, 12 mmol, Intermediate 3-C) in water (45 mL) at room temperature. The reaction mixture was heated to 100 °C for 48 h. The reaction mixture was cooled to rt and partitioned between water (200 mL) and EtOAc (500 mL). The combined organic layers were washed with brine (250 mL) and dried over sodium sulfate. The filtrate, concentrated under reduced pressure to give the crude material, was purified by silica gel chromatography (eluent: 0–25% ethyl acetate / hexane) to give 8-(ethylthio)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.4 g, 1.46 mmol, 12% yield). LC / MS(ESI+)m / z=275.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.81(d,J=7.6Hz,1H),7.55(d,J=2.1Hz,1H),7.36(dd,J=7.6,2.1Hz,1H),6 .69(s,1H),3.26(t,J=7.4Hz,2H),1.35(t,J=7.3Hz,3H),1.29-1.20(m,1H).

[0311] Step 2: 8-(Ethylthio)-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-B, Step 2, with the following modifications: Step 2 was carried out using 8-(ethylthio)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. LC / MS (ESI+) m / z = 401.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.80(dd,J=7.6,2.0Hz,1H),7.53(t,J=2.2Hz,1H),7.41(dt,J=7.6,2.2Hz,1H),3.27(qt,J=7.5,2.4Hz,2H),1.35(td,J=7.3,2.0Hz,3H).

[0312] Step 3: 8-(Ethylthio)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Method 1, Step 1, with the following modifications: Step 1 was carried out using 8-(ethylthio)-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.4 g, 1.0 mmol) and (4-(2,2,2-trifluoroethoxy)phenyl)boronic acid (0.29 g, 1.3 mmol, Combi-Blocks Inc.). LC / MS (ESI+) m / z = 449.0 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 8.77(dd,J=7.5,1.2Hz,1H),7.57-7.51(m,1H),7.38-7.32(m,1H),7.26(d,J=8.4Hz,2H), 7.15-7.09(m,2H),4.82(q,J=8.9Hz,2H),3.29-3.24(m,2H),1.36(td,J=7.3,1.2Hz,3H).

[0313] Intermediate 3-H 4-Oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carbaldehyde [ka] Step 1: 4-Oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carbaldehyde. A solution of DIBAL-H (1 M in DCM, 4 mL, 4 mmol) was added dropwise to a solution of methyl 4-oxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2-(trifluoromethyl)pyrido[1,2-a]pyrimidine-8-carboxylate (1.5 g, 3.36 mmol, Examples 1-36) in dichloromethane (30 mL) at -40 °C. Stirring was continued for 5 min, followed by the addition of 1 N aqueous HCl (20 mL). The reaction mixture was extracted with dichloromethane (2 × 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carbaldehyde (0.85 g, 1.3 mmol, 40% yield). The product was used without further purification. LC / MS (ESI+) m / z=417.1 [M+1] + .

[0314] Intermediate 3-I 8-Bromo-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-Bromo-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-B, Step 2, with the following modifications. Step 2 was carried out using 8-bromo-2-(trifluoromethyl)pyrido[1,2-a]pyrimidin-4-one. LC / MS (ESI + ) m / z = 419.0 [M+H] + .

[0315] Intermediate 3-J 8-Hydroxy-2-(trifluoromethyl)-3-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-Hydroxy-2-(trifluoromethyl)-3-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Method 10, Step 1, with the following modifications: Step 1 was carried out using 8-methoxy-2-(trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)pyrazol-4-yl]pyrido[1,2-a]pyrimidin-4-one (Examples 1-69). LC / MS (ESI + ) m / z = 393.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 2.82-3.01(m,2H)4.37-4.51(t,2H)6.87-6.96(s,1H)7.02-7.16(d,1H)7 .46-7.58(s,1H)7.89-7.96(s,1H)8.85-8.98(d,1H)12.19-12.29(s,1H).

[0316] Intermediate 3-K 9-Fluoro-3-iodo-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 3-Fluoro-4-methoxypyridin-2-amine. A mixture of 2-bromo-3-fluoro-4-methoxypyridine (400 mg, 1.94 mmol), L-proline (224 mg, 1.94 mmol), sodium azide (190 mg, 2.91 mmol), and copper(I) oxide (306 mg, 2.14 mmol) in DMSO (6 mL) was stirred at 100° C. for 10 h. The mixture was filtered, and the filtrate was directly purified by flash chromatography (C18 cartridge, 0.1% NH:ACN in water as eluent, 100% aqueous to 8:2) to give 3-fluoro-4-methoxypyridin-2-amine as a white solid (185 mg, 1.302 mmol, 67% yield). LC / MS (ESI +) m / z = 143.1 [M+H] + .

[0317] Step 2: 9-Fluoro-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-A, Step 1, with the following modifications: Step 1 was carried out with 3-fluoro-4-methoxypyridin-2-amine. LC / MS (ESI + ) m / z=263.3[M+H] + .

[0318] Step 3: 9-Fluoro-3-iodo-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-B, Step 2, with the following modifications: Step 2 was carried out using 9-fluoro-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. LC / MS (ESI + ) m / z=388.9[M+H] + .

[0319] Intermediate 3-L 3-Bromo-7-fluoro-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 2-Chloro-5-fluoropyridin-4-ol. To a solution of 2-chloro-5-fluoropyridine (11.6 mL, 114 mmol) in THF (120 mL) at −78° C. was added lithium diisopropylamide (2 M in THF, 65 mL, 130 mmol) dropwise. The mixture was allowed to warm to −60° C. over 3 h. The reaction was then cooled to −78° C. and trimethyl borate (25.4 mL, 228 mmol) was slowly added. The temperature was slowly raised to 0° C. and the mixture was stirred for 2 h. Acetic acid (19.6 mL, 342 mmol) was added at the same temperature, followed 20 min later by the dropwise addition of hydrogen peroxide (30% in water, 29 mL, 285 mmol). The reaction mixture was allowed to warm to rt and then stirred overnight. Saturated aqueous sodium thiosulfate solution was added to the reaction, and the mixture was extracted with EtOAc (×2) and DCM (×2). The aqueous phase was acidified to pH 5 / 6 with HCl 6M solution and further extracted with EtOAc (×2) and DCM. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The resulting crude was triturated with DCM and the solid was collected to give 2-chloro-5-fluoropyridin-4-ol (15.53 g, 105.3 mmol, 92% yield) as a white solid. LC / MS (ESI + ) m / z = 148.1 / 150.1 [M+H] + .

[0320] Step 2: 2-Chloro-5-fluoro-4-methoxypyridine. To 2-chloro-5-fluoropyridin-4-ol (15.53 g, 105.3 mmol) in DCM (300 mL) was added silver carbonate (62.4 g, 224.64 mmol) and iodomethane (6.99 mL, 112.32 mmol), and the mixture was stirred at rt overnight. The mixture was filtered, and the residue was washed with water (×2). The organic phase was dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was subsequently purified by flash column chromatography (SiO2, Cy:EtOAc as eluent, 100% Cy to 7:3) to give 2-chloro-5-fluoro-4-methoxypyridine as a white solid (5.36 g, 33.2 mmol, 32.5% yield). LC / MS (ESI) + ) m / z = 161.9 / 163.9 [M+H] + .

[0321] Step 3: 2-Chloro-5-fluoro-4-methoxypyridine. A mixture of 2-chloro-5-fluoro-4-methoxypyridine (5.36 g), carbamic acid tert-butyl ester (4.43 g, 37.8 mmol), and potassium triphosphate (10.17 g, 47.24 mmol) in 1,4-dioxane (200 mL) was degassed for 15 minutes, followed by the addition of Pd2dba3 (2.88 g, 3.15 mmol) and (5-diphenylphosphino-9,9-dimethyl-4-xanthenyl)-diphenylphosphine (3.64 g, 6.3 mmol), and the mixture was stirred at 100° C. for 15 hours. The mixture was filtered, and the residue was concentrated in vacuo. The resulting material was purified by flash chromatography (SiO, Cy:EtOAc as eluent, 100% Cy to 7:3) to give impure tert-butyl N-(5-fluoro-4-methoxypyridin-2-yl)carbamate, which was used directly in the following reaction. LC / MS (ESI + ) m / z = 187.3 [M-tBu+H] + .

[0322] Step 4: 5-Fluoro-4-methoxypyridin-2-amine. To crude tert-butyl N-(5-fluoro-4-methoxypyridin-2-yl)carbamate (8.3 g) in DCM (70 mL) was added trifluoroacetic acid (10 mL), and the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was loaded onto an SCX cartridge, washed with DCM and MeCN, and eluted with 10% ammonia in MeCN. The solvent was evaporated to give 5-fluoro-4-methoxypyridin-2-amine (2.16 g, 15.2 mmol) as a pale orange solid. LC / MS (ESI + ) m / z = 143.1 [M+H] + .

[0323] Step 5: 7-Fluoro-8-methoxy-2-(trifluoromethyl)pyrido[1,2-a]pyrimidin-4-one. A mixture of 5-fluoro-4-methoxypyridin-2-amine (2.16 g), 4,4,4-trifluoro-3-oxobutanoic acid ethyl ester (10.33 mL, 70.67 mmol), and bismuth trichloride (0.45 g, 1.41 mmol) was stirred at 120 °C for 24 h. The mixture was partitioned between EtOAc and water, and the organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by flash chromatography (SiO2, DCM:MeOH as eluent, 100% DCM to 95:5) followed by reverse-phase flash chromatography (C18, 0.1% aqueous HCOOH:acetonitrile, 100% aqueous to 1:1) to give 7-fluoro-8-methoxy-2-(trifluoromethyl)pyrido[1,2-a]pyrimidin-4-one as a white solid (1.94 g, 7.41 mmol, 52% yield). LC / MS (ESI + ) m / z=263.1[M+H] + .

[0324] Step 6: 3-Bromo-7-fluoro-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A mixture of N-bromosuccinimide (1.45 g, 8.16 mmol) and 7-fluoro-8-methoxy-2-(trifluoromethyl)pyrido[1,2-a]pyrimidin-4-one (1.94 g, 7.41 mmol) in MeCN (15 mL) was stirred at 80 °C for 1 h. The mixture was partitioned between EtOAc and water, and the organic phase was washed with saturated NaHCO and saturated NaSO solutions. The organic phase was then dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (SiO, Cy:EtOAc, 100% Cy to 7:3 as eluent) to give 3-bromo-7-fluoro-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a white solid (2.53 g, 7.40 mmol, quantitative yield). LC / MS (ESI) + ) m / z = 341.1 / 343.1 [M+H] + .

[0325] Intermediate 3-M 3-Bromo-8-methoxy-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one [ka] Step 1: tert-Butyl N-(5-methoxypyridazin-3-yl)carbamate. A solution of 3-chloro-5-methoxypyridazine (250 mg, 1.73 mmol, Combi-Blocks Inc.), carbamic acid tert-butyl ester (263 mg, 2.25 mmol), and cesium carbonate (794 mg, 2.42 mmol) in 1,4-dioxane (5 mL) was degassed with a stream of nitrogen for 10 minutes, followed by the addition of (5-diphenylphosphino-9,9-dimethyl-4-xanthenyl)-diphenylphosphine (150 mg, 0.260 mmol) and palladium(II) diacetate (27 mg, 0.12 mmol). The mixture was heated at 100° C. for 22 hours. The mixture was filtered, diluted with EtOAc, and washed twice with brine. The organic phase was dried, filtered, and concentrated in vacuo. The resulting material was purified by flash chromatography (SiO2, Cy:EtOAc, 50:50 from 100% Cy as eluent) to give tert-butyl N-(5-methoxypyridazin-3-yl)carbamate as a white solid (160 mg, 0.710 mmol, 41% yield). + ) m / z=226.2[M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.86(d,J=2.6Hz,1H),8.59(d,J=2.7Hz,1H),7.75(d,J=2.7Hz,1H),7.66(s,1H),6.96(d,J=2.6Hz,1H),3.96(s,1H),3.95(s,3H),1.56(s,9H).

[0326] Step 2: 5-Methoxypyridazin-3-amine. Trifluoroacetic acid (1.07 mL, 14.03 mmol) was added to a solution of tert-butyl N-(5-methoxypyridazin-3-yl)carbamate (158 mg, 0.700 mmol) in DCM (4 mL) at 0° C. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated to give the crude material, which was purified by SCX cartridge to give 5-methoxypyridazin-3-amine as a white solid (60 mg, 0.480 mmol, 68% yield). LC / MS (ESI + ) m / z=126.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.17(d,J=2.6Hz,1H),6.22(d,J=2.7Hz,3H),3.78(s,3H).

[0327] Step 3: 8-Methoxy-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one. A mixture of 5-methoxypyridazin-3-amine (85 mg, 0.68 mmol), 4,4,4-trifluoro-3-oxobutanoic acid ethyl ester (1.0 mL, 6.79 mmol), and bismuth trichloride (21 mg, 0.07 mmol) was stirred at 120 °C for 24 h. The mixture was diluted with water and extracted twice with EtOAc. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give the crude material, which was purified by flash chromatography (SiO2, Cy:EtOAc, 80:20 to 100% EtOAc as eluent) to give 8-methoxy-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one (80 mg, 0.33 mmol, 48% yield) as a pale yellow solid. LC / MS (ESI + ) m / z=246.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.80(d,J=2.9Hz,1H),7.58(d,J=2.9Hz,1H),6.83(s,1H),4.05(s,3H).

[0328] Step 4: 3-Bromo-8-methoxy-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one. A mixture of 8-methoxy-2-(trifluoromethyl)pyrimido[1,2-b]pyridazin-4-one (95 mg, 0.390 mmol) and 1-bromopyrrolidine-2,5-dione (103 mg, 0.58 mmol) in MeCN (3 mL) was stirred at room temperature for 18 hours, followed by 1 hour at 80 °C. The mixture was concentrated, dissolved in DCM, and then washed with saturated aqueous NaSO and saturated aqueous NaHCO, and brine. The organic phase was dried and concentrated to give 3-bromo-8-methoxy-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one as a yellow solid (112 mg, 0.346 mmol, 89% yield). LC / MS (ESI + ) m / z = 324.0 / 326.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.87(d,J=2.8Hz,1H),7.61(d,J=2.8Hz,1H),4.06(s,3H).

[0329] Intermediate 3-N 3-Iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] To a suspension of potassium (chloromethyl)trifluoroborate (156 mg, 1 mmol) in methanol (4 mL), sodium methoxide (52 mg, 0.95 mmol) was added, and the mixture was stirred at 70° C. for 4 hours, followed by evaporation of the solvent. The resulting crude material was redissolved in 1,4-dioxane (4 mL) and water (1 mL), followed by addition of cesium carbonate (157 mg, 0.48 mmol), 8-bromo-3-iodo-2-(trifluoromethyl)pyrido[1,2-a]pyrimidin-4-one (Intermediate 3-I, 100 mg, 0.24 mmol), and palladium triphenylphosphine (28 mg, 0.02 mmol), and the mixture was stirred at 90° C. overnight. After cooling, the mixture was diluted with EtOAc and washed with water. The organic phase was dried and evaporated, and the crude material was purified by flash chromatography (SiO, Cy / EtOAc 50:50) to give 3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow solid (62 mg, 0.182 mmol, 77% yield). LC / MS (ESI + ) m / z = 431.0 [M+H] + .

[0330] Intermediate 3-O 3-Bromo-7-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 7-Methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A mixture of 5-methoxypyridin-2-amine (1.0 g, 8.06 mmol, Fluorochem Ltd), 4,4,4-trifluoro-3-oxobutanoic acid ethyl ester (2.36 mL, 16.1 mmol), and polyphosphoric acid (19.3 g, 80.55 mmol) was stirred at 120 °C for 20 h and then cooled. The mixture was carefully added to saturated aqueous NaHCO (80 mL) at 0 °C, and the pH was adjusted to 7. The aqueous phase was then extracted with AcOEt (3 × 100 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give the crude material, which was purified by flash chromatography (SiO2, Cy:EtOAc, 90:10 to 80:20 as eluent) to give 7-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (1.66 g, 6.78 mmol, 84% yield) as a pale yellow solid. LC / MS (ESI + ) m / z=254.2[M+H] + . 1 H NMR(400MHz,CDCl3)δ 3.89-4.07(s,3H)6.80(s,1H)7.67(dd,1H)7.78(d,1H)8.62(d,1H).

[0331] Step 2: 3-Bromo-7-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A mixture of the resulting 7-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (400 mg, 1.64 mmol) and N-bromosuccinimide (321 mg, 1.8 mmol) in MeCN (10 mL) was stirred at room temperature for 5 h. The mixture was concentrated, dissolved in DCM, and subsequently washed with saturated aqueous NaSO and saturated aqueous NaHCO, and brine. The organic phase was dried, and the crude product was purified by column chromatography (SiO, Cy:EtOAc, 9:1 to 6:4) to give 3-bromo-7-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a white solid (466 mg, 1.44 mmol, 88% yield). LC / MS (ESI) +) m / z = 323.1 / 325.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 4.02(s,3H)7.70(dd,1H)7.80(d,1H)8.61(d,J 1H).

[0332] Intermediate 3-P 3-Bromo-8-(2-hydroxypropan-2-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-(2-Hydroxypropan-2-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A mixture of 2-(2-aminopyridin-4-yl)propan-2-ol (828 mg, 5.44 mmol, Combi-Blocks Inc), 4,4,4-trifluoro-3-oxobutanoic acid ethyl ester (3.98 mL, 27.2 mmol), and bismuth trichloride (172 mg, 0.54 mmol) was stirred at 120 °C for 24 h. The mixture was diluted with water and extracted twice with EtOAc. The organic phase was dried over NaSO, filtered, and concentrated in vacuo to give the crude material, which was purified by flash chromatography (SiO, Cy:EtOAc, 80:20 to 100% EtOAc as eluent) to give 8-(2-hydroxypropan-2-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (284 mg, 1.04 mmol, 19% yield). LC / MS (ESI) + ) m / z = 273.1 [M+H] + .

[0333] Step 2: 3-Bromo-8-(2-hydroxypropan-2-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A mixture of 8-(2-hydroxypropan-2-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (284 mg, 1.04 mmol) and N-bromosuccinimide (204 mg, 1.15 mmol) in MeCN (5 mL) was stirred at room temperature for 5 hours. The mixture was concentrated, dissolved in DCM, and subsequently washed with saturated aqueous NaSO and saturated aqueous NaHCO, and brine. The organic phase was dried and concentrated to give 3-bromo-8-(2-hydroxypropan-2-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow solid (335 mg, 0.95 mmol, 91% yield). LC / MS (ESI+) m / z = 381.1 / 383.1 [M+H]+. 1 H NMR(400MHz,DMSO-d6)δ 1.51(s,6H)5.66(s,1H)7.67-7.78(m,1H)7.80-7.90(m,1H)8.91-9.08(m,1H).

[0334] Intermediate 3-Q 3-Bromo-7-chloro-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 7-Chloro-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A mixture of 2-amino-5-chloropyridine (1250 mg, 9.72 mmol), 4,4,4-trifluoro-3-oxobutanoic acid ethyl ester (2.84 mL, 19.5 mmol), and bismuth trichloride (153 mg, 0.49 mmol) was heated at 120 °C for 18 hours. MeOH was added, and the precipitate was filtered under vacuum to give 7-chloro-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a pale yellow solid (753 mg, 3.03 mmol, 31% yield). LC / MS (ESI) + ) m / z = 249.1 / 251.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 9.04(d,J=2.3Hz,1H),8.20(dd,J=9.5,2.4Hz,1H),7.92(dd,J=9.5,0.7Hz,1H),6.93(s,1H).

[0335] Step 2: 3-Bromo-7-chloro-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A mixture of 7-chloro-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (753 mg, 3 mmol) and N-bromosuccinimide (800 mg, 4.5 mmol) in MeCN (20 mL) was stirred at 80 °C for 6 h. The mixture was concentrated, dissolved in DCM, and subsequently washed with saturated aqueous NaSO and saturated aqueous NaHCO, and brine. The organic phase was dried and concentrated to give 3-bromo-7-chloro-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow solid (989 mg, 3.02 mmol, quantitative yield). LC / MS (ESI+) m / z = 327.0 / 329.0 [M+H]+. 1 H NMR(400MHz,DMSO-d6)δ 7.96(d,J=9.46Hz,1H)8.23(dd,J=9.46,2.20Hz,1H)9.00-9.12(m,1H).

[0336] Intermediate 3-R 3-Bromo-8-(methoxymethyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-(Methoxymethyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A suspension of 4-(methoxymethyl)pyridin-2-amine (100 mg, 0.72 mmol, Enamine Ltd), bismuth(III) chloride (23 mg, 0.07 mmol), and 4,4,4-trifluoro-3-oxobutanoic acid ethyl ester (0.53 mL, 3.62 mmol) was stirred at 120 °C for 48 h. After cooling, the mixture was diluted with EtOAc and washed with water. The organic phase was dried and evaporated, and the crude material was purified by flash chromatography (SiO, Cy / EtOAc 1:1) to give 8-(methoxymethyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (70 mg, 0.27 mmol, 37% yield). 1 H NMR(400MHz,CDCl3)δ 9.07(d,1H),7.79(dq,1H),7.26(dd,1H),6.78(s,1H),4.62(d,2H),3.53(s,3H).

[0337] Step 2: 3-Bromo-8-(methoxymethyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. To a solution of 8-(methoxymethyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (70 mg, 0.27 mmol) in MeCN (3 mL) was added N-bromosuccinimide (53 mg, 0.30 mmol), and the mixture was stirred at RT for 3 h. The mixture was concentrated, diluted with EtOAc, and subsequently washed with NaSO and NaHCO. The organics were combined, dried, and evaporated to give 3-bromo-8-(methoxymethyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow solid (84 mg, 0.25 mmol, 92% yield). LC / MS (ESI+) m / z = 327.0 / 329.0 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 9.09(dd,1H),7.82(dq,1H),7.32(dd,1H),4.62(d,2H),3.54(s,3H).

[0338] Intermediates 3-S to 3-AF in Table 2 were prepared in the same manner as for intermediate 3-R.

[0339] [Table 6]

[0340] [Table 7]

[0341] [Table 8]

[0342] Intermediate 4-A 3-Bromo-8-methoxy-2-(trifluoromethyl)-4H-[1,3]diazino[1,6-a]pyrimidin-4-one [ka] Step 1: 2,2,2-trifluoro-N-(6-methoxypyrimidin-4-yl)acetamide. 6-Methoxy-4-pyrimidinamine (2.0 g, 15.98 mmol) was dissolved in DMF (106 mL) and sodium hydride (60% in oil, 1.28 g, 31.97 mmol) was added at room temperature. After 1 h, trifluoroacetic anhydride (5.37 g, 25.57 mmol) was added and the mixture was left to react at room temperature for 30 min. The reaction mixture was poured into cold water and extracted with EtOAc. The organic phase was washed with water, brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by flash chromatography (SiO2, eluted with cyclohexane:EtOAc 100:0 to 75:25) to give 2,2,2-trifluoro-N-(6-methoxypyrimidin-4-yl)acetamide (2.08 g, 9.41 mmol, 59% yield). LC / MS (ESI) + ) m / z=222.3[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 3.95(s,3H)7.36(s,1H)8.69(s,1H)12.38(br s,1H).

[0343] Step 2: Ethyl 4,4,4-trifluoro-3-[(6-methoxypyrimidin-4-yl)amino]but-2-enoate. 2,2,2-Trifluoro-N-(6-methoxypyrimidin-4-yl)acetamide (2.08 g, 9.41 mmol) was dissolved in toluene (23 mL). (Carbethoxymethylene)triphenylphosphorane (6.55 g, 18.81 mmol) was added, and the reaction was allowed to react at room temperature for 2 h, followed by 55 °C for 3 h. The solvent was removed in vacuo, and the crude material was purified by flash chromatography (SiO, eluting with cyclohexane:EtOAc 100:0 to 80:20) to give ethyl 4,4,4-trifluoro-3-[(6-methoxypyrimidin-4-yl)amino]but-2-enoate (671 mg, 2.30 mmol, 24.5% yield). LC / MS (ESI) + ) m / z = 292.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 1.03(t,3H)3.87(s,3H)3.95(q,2H)6.16(s,1H)6.25(d,1H)8.30(d,1H)9.55(br s,1H).

[0344] Step 3: 8-Methoxy-2-(trifluoromethyl)-4H-[1,3]diazino[1,6-a]pyrimidin-4-one. Ethyl 4,4,4-trifluoro-3-[(6-methoxypyrimidin-4-yl)amino]but-2-enoate (671 mg, 2.30 mmol) was repeatedly evaporated from a mixture of water (70 mL) and MeCN (40 mL) at 60 °C. The crude material was purified by flash chromatography (SiO, eluent cyclohexane:EtOAc 100:0 to 55:45) to give 8-methoxy-2-(trifluoromethyl)-4H-[1,3]diazino[1,6-a]pyrimidin-4-one (300 mg, 1.22 mmol, 53% yield). LC / MS (ESI) + ) m / z=246.3[M+H] + .

[0345] Step 4: 3-Bromo-8-methoxy-2-(trifluoromethyl)-4H-[1,3]diazino[1,6-a]pyrimidin-4-one. A mixture of the resulting 8-methoxy-2-(trifluoromethyl)-4H-[1,3]diazino[1,6-a]pyrimidin-4-one (300 mg, 1.22 mmol) and N-bromosuccinimide (240 mg, 1.35 mmol) in MeCN (9.5 mL) was stirred at room temperature for 5 h. The mixture was concentrated, dissolved in EtOAc, and subsequently washed with saturated aqueous NaSO and saturated aqueous NaHCO, and brine. The organic phase was dried and concentrated to give the crude product, which was purified by flash chromatography (SiO, eluent from cyclohexane:EtOAc 100:0 to 50:50) to give 3-bromo-8-methoxy-2-(trifluoromethyl)-4H-[1,3]diazino[1,6-a]pyrimidin-4-one as a yellow solid (153 mg, 0.47 mmol, 39% yield). LC / MS (ESI + ) m / z = 324.2 / 326.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 4.07(s,3H)7.13(m,1H)9.57-9.64(m,1H).

[0346] Intermediates 4-B to 4-I in Table 3 were prepared in the same manner as for intermediate 4-A.

[0347] [Table 9]

[0348] [Table 10]

[0349] Intermediate 4-J 3-Bromo-7-cyclopropyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 7-Bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A mixture of 5-bromo-2-pyridinamine (1250 mg, 7.23 mmol), 4,4,4-trifluoro-3-oxobutanoic acid ethyl ester (2.11 mL, 14.5 mmol), and bismuth trichloride (114 mg, 0.36 mmol) was heated at 120 °C for 18 h. The reaction was then cooled to RT, diluted with a distilled water / brine mixture, and extracted with EtOAc. The organic phase was then washed with brine (x2) and concentrated in vacuo. The mixture was purified by flash chromatography (SiO, EtOAc:Cy 3:97 to 25:75), followed by reverse-phase flash chromatography (C, HO + HCOOH 0.1%:MeCN Purification by LC / MS (ESI 97:3 to 40:60) gave 7-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (517 mg, 1.76 mmol, 24% yield) as a white solid. + ) m / z = 293.0 / 295.0 [M+H] + .

[0350] Step 2: 7-Cyclopropyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A mixture of 7-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (150 mg, 0.51 mmol), triphenylphosphine palladium (592 mg, 0.51 mmol), cyclopropylboronic acid (44 mg, 0.51 mmol), and potassium carbonate (71 mg, 0.51 mmol) was suspended in dry toluene (3 mL) in a sealable vial. The suspension was degassed using several vacuum / nitrogen cycles, then shaken and heated to 100 °C for 18 h. The mixture was cooled to RT, diluted with EtOAc, and washed with distilled water and brine. The organic phase was dried over Na SO and concentrated in vacuo. The mixture was then purified by flash chromatography (SiO, EtOAc:Cy 3:97 to 30:70) to give 7-cyclopropyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a white solid (110 mg, 0.43 mmol, 85% yield). LC / MS (ESI + ) m / z=255.1[M+H] + .

[0351] Step 3: 3-Bromo-7-cyclopropyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A mixture of 7-cyclopropyl-2-(trifluoromethyl)pyrido[1,2-a]pyrimidin-4-one (110 mg, 0.43 mmol) and N-bromosuccinimide (85 mg, 0.48 mmol) in MeCN (3 mL) was stirred at room temperature for 1.5 h. The mixture was diluted with DCM and subsequently washed with saturated aqueous NaSO and brine. The mixture was purified by flash chromatography (SiO, EtOAc:Cy 3:97 to 25:75) to give 3-bromo-7-cyclopropyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a white solid (130 mg, 0.39 mmol, 90% yield). LC / MS (ESI) + ) m / z = 333.1 / 335.1 [M+H] + .

[0352] Intermediate 4-K 7-(azetidin-1-yl)-3-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 7-(Azetidin-1-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A screw-cap vial was charged with 7-bromobromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (Intermediate 4-J, Step 1, 60 mg, 0.20 mmol), 1,4-dioxane (3 mL), cesium carbonate (67 mg, 0.20 mmol), azetidine (0.02 mL, 0.25 mmol), (5-diphenylphosphino-9,9-dimethyl-4-xanthenyl)-diphenylphosphine (12 mg, 0.02 mmol), and palladium(II) diacetate (2.3 mg, 0.010 mmol). The mixture was stirred in the screw-cap vial at 100 °C for 4 h, then cooled to rt, diluted with a mixture of water and brine, and extracted with EtOAc. The organic phase was dried and evaporated, and the crude material was purified by flash chromatography (SiO, Cy: EtOAc 95:5 to 60:40) followed by reverse-phase flash chromatography (C, HO + 0.1% HCOOH: MeCN 97:3 to 50:50) to give 7-(azetidin-1-yl)-2-(trifluoromethyl)pyrido[1,2-a]pyrimidin-4-one as a yellow solid (35 mg, 0.13 mmol, 63% yield). LC / MS (ESI) + ) m / z=270.1[M+H] + .

[0353] Step 2: 7-(Azetidin-1-yl)-3-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A mixture of 7-(azetidin-1-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (35 mg, 0.130 mmol) and N-bromosuccinimide (25 mg, 0.140 mmol) in MeCN (2.5 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo, diluted with EtOAc, and subsequently washed with saturated aqueous NaSO and NaHCO. The organic phase was dried and concentrated in vacuo. The mixture was purified by reverse-phase chromatography (C18, HO + HCOOH 0.1%:MeCN 97:3 to 50:50) to give 7-(azetidin-1-yl)-3-bromo2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (18 mg, 0.052 mmol, 40% yield) as a yellow solid. LC / MS (ESI + ) m / z = 348.0 / 350.0 [M+H] + .

[0354] Intermediate 4-L 3-Bromo-7-(methoxymethyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 7-(Bromomethyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A suspension of 7-methyl-2-(trifluoromethyl)pyrido[1,2-a]pyrimidin-4-one (Intermediate 3-X, Step 1, 500 mg, 2.19 mmol), N-bromosuccinimide (585 mg, 3.29 mmol), and 2,2'-azobis(2-methylpropionitrile) (36 mg, 0.220 mmol) in carbon tetrachloride (10 mL) was stirred at 80 °C for 7 h. The mixture was evaporated and the crude material was purified by flash chromatography (SiO, Cy / EtOAc 100:0 to 70:30) to give 7-(bromomethyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (130 mg, 0.423 mmol, 19% yield). LC / MS (ESI) +) m / z = 307.0 / 309.0 [M+H] + .

[0355] Step 2: 7-(Methoxymethyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. To a suspension of 7-(bromomethyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (60 mg, 0.20 mmol) in methanol (4 mL) was added sodium methoxide (11.6 mg, 0.21 mmol), and the mixture was stirred at rt for 3 days. The mixture was evaporated and the crude was purified by flash chromatography (SiO, Cy / EtOAc 100:0 to 70:30) to give 7-(methoxymethyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a white solid (34 mg, 0.132 mmol, 67% yield). LC / MS (ESI) + ) m / z = 259.1 [M+H] + .

[0356] Step 3: 3-Bromo-7-(methoxymethyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. To a solution of 7-(methoxymethyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (34 mg, 0.13 mmol) in MeCN (3 mL) was added N-bromosuccinimide (26 mg, 0.14 mmol), and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated, diluted with EtOAc, and washed with NaSO and NaHCO. The organic phases were combined, dried, and evaporated to give 3-bromo-7-(methoxymethyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (35 mg, 0.104 mmol, 79% yield). LC / MS (ESI) + ) m / z = 337.0 / 339.0 [M+H] + .

[0357] Intermediate 4-M 3-Bromo-7-[(dimethylamino)methyl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 3-Bromo-7-[(dimethylamino)methyl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A solution of 3-bromo-7-methyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (Intermediate 3-X, 30 mg, 0.090 mmol), N-bromosuccinimide (16 mg, 0.090 mmol), and 2,2'-azobis(2-methylpropionitrile) (1.5 mg, 0.010 mmol) in MeCN (3 mL) was shaken at rt for 2 h, then warmed to 80 °C and shaken at that temperature for 24 h. The mixture was evaporated and the crude was purified by flash chromatography (SiO, Cy / EtOAc 100:0 to 70:30) to give 3-bromo-7-(bromomethyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a pale yellow solid (15.5 mg, 0.040 mmol, 46% yield). LC / MS (ESI + ) m / z = 387.1 [M+H] + .

[0358] Step 2: 3-Bromo-7-[(dimethylamino)methyl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. To a solution of 3-bromo-7-(bromomethyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (15 mg, 0.040 mmol) in MeCN (1 mL) was added dimethylamine (2 M in MeOH, 0.05 mL, 0.100 mmol), and the mixture was stirred at rt for 1 h. The mixture was evaporated to give crude 3-bromo-7-[(dimethylamino)methyl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, which was used directly in the next step. LC / MS (ESI + ) m / z = 350.2 / 352.2 [M+H]+ .

[0359] Intermediate 4-N 8-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. 3-Bromo-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (Intermediate 1-A, 0.5 g, 1.55 mmol), bis(pinacolato)diboron (0.51 g, 2.01 mmol), potassium acetate (0.41 g, 4.18 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) DCM complex (63.4 mg, 0.08 mmol) were combined in toluene (10.0 mL) in a microwave vial and degassed for 10 minutes. The tube was sealed, and the reaction was stirred under microwave irradiation at 130 °C for 3 hours. Afterwards, the mixture was diluted with EtOAc, washed with water, dried, and evacuated. The residue was purified by flash chromatography (SiO, cyclohexane:EtOAc) to give 8-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (30 mg, 0.08 mmol, 5% yield). LC / MS (ESI + ) m / z = 371.4 [M+H] + .

[0360] Intermediate 4-O 3-Bromo-2-ethoxy-8-methoxypyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 2-Hydroxy-8-methoxypyrido[1,2-a]pyrimidin-4-one. 4-Methoxy-2-pyridinamine (3.0 g, 24.17 mmol) was dissolved in dry DCM (30 mL) and the solution was cooled to 0 °C. Under a nitrogen atmosphere, propanedioyl chloride (2.82 mL, 29.0 mmol) was added dropwise and the reaction was allowed to stir at room temperature for 48 h. The reaction was then filtered, washed with DCM, and the organic phase was dried and evaporated. The crude material was used as is in the following reaction.

[0361] Step 2: 2-Ethoxy-8-methoxypyrido[1,2-a]pyrimidin-4-one. The crude 2-hydroxy-8-methoxypyrido[1,2-a]pyrimidin-4-one from step 1 was suspended in DMF (3.0 mL) and cesium carbonate (373 mg, 1.14 mmol) was added. The mixture was degassed and stirred at room temperature for 10 minutes. Iodoethane (0.09 mL, 1.09 mmol) was added and the reaction was stirred at 65 °C overnight. Water was added and the mixture was extracted with EtOAc. The organic phase was dried and discarded. The crude product was purified by flash chromatography (SiO, cyclohexane: EtOAc) to give 2-ethoxy-8-methoxypyrido[1,2-a]pyrimidin-4-one (102 mg, 0.46 mmol, 44% yield). LC / MS (ESI + ) m / z=221.3[M+H] + .

[0362] Step 3: 3-Bromo-2-ethoxy-8-methoxypyrido[1,2-a]pyrimidin-4-one. 2-Ethoxy-8-methoxypyrido[1,2-a]pyrimidin-4-one (102 mg, 0.46 mmol) was dissolved in MeCN (5.0 mL). N-Bromosuccinimide (86.6 mg, 0.49 mmol) was added, and the mixture was stirred at room temperature overnight. The solvent was then removed, and the crude product was purified by flash chromatography (SiO, cyclohexane:EtOAc) to give 3-bromo-2-ethoxy-8-methoxypyrido[1,2-a]pyrimidin-4-one (44.0 mg, 0.15 mmol, 31% yield). LC / MS (ESI) + ) m / z = 301.0 / 302.0 [M+H] + .

[0363] Intermediate 4-P 3-Bromo-1-(2,2,3,3,3-pentafluoropropyl)-1,2,4-triazole [ka] 3-Bromo-1H-1,2,4-triazole (500.0 mg, 3.38 mmol), 2,2,3,3,3-pentafluoropropyl triflate (953.3 mg, 3.38 mmol), and cesium carbonate (1.10 g, 3.38 mmol) were suspended in MeCN (20 mL) and stirred at 60 °C for 2 h. The mixture was concentrated in vacuo, EtOAc was added, and the organic phase was washed with water. The solvent was removed to give the product, 3-bromo-1-(2,2,3,3,3-pentafluoropropyl)-1,2,4-triazole (865 mg, 3.09 mmol, 91% yield). 1 H NMR(500MHz,DMSO-d6)δ 5.41(t,J=15.23Hz,2H),8.75(s,1H).

[0364] Intermediate 4-Q [2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]boronic acid [ka] Step 1: 5-Bromo-2-(2,2,2-trifluoroethoxy)pyrimidine. To a solution of 2,2,2-trifluoroethanol (0.78 g, 7.75 mmol) in DMF (10 mL) at 0 °C was added 60% sodium hydride (0.31 g, 7.75 mmol). The mixture was allowed to reach rt for 15 min, followed by the addition of 5-bromo-2-chloropyrimidine (1.0 g, 5.17 mmol). The mixture was stirred at rt for 2 h. EtOAc and brine were added, the phases were separated, and the organic phase was dried over Na2SO4, filtered, and concentrated. The resulting crude was purified by flash chromatography (SiO2, Cy / EtOAc 95 / 5) to give 5-bromo-2-(2,2,2-trifluoroethoxy)pyrimidine as a colorless oil (893 mg, 3.47 mmol, 67% yield). LC / MS (ESI) + ) m / z = 257.1 / 259.1 [M+H] + .

[0365] Step 2: [2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]boronic acid. To a solution of 5-bromo-2-(2,2,2-trifluoroethoxy)pyrimidine (0.89 g, 3.46 mmol) in 1,4-dioxane (10 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.32 g, 5.19 mmol), potassium acetate (1030 mg, 10.39 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloride (complex with dichloromethane) (142 mg, 0.170 mmol). The mixture was degassed for 10 min and then stirred at 90 °C for 3 h. This was concentrated and purified by flash chromatography (C18, HO+0.1% HCOOH / CH3CN, 1:0 to 1:1) to give [2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]boronic acid as a white solid (514 mg, 2.32 mmol, 67% yield). 1 H NMR(400MHz,DMSO-d6)δ 4.97-5.00(m,1H)5.06(q,J=8.95Hz,2H)8.52(s,2H)8.89(s,2H).

[0366] Intermediate 4-R [2-(2,2,3,3,3-pentafluoropropoxy)pyrimidin-5-yl]boronic acid [ka] The title compound was prepared using the procedure described for Intermediate 4-Q, Steps 1 and 2, with the following modifications: Step 1 was carried out using 2,2,3,3,3-pentafluoropropan-1-ol. Step 1 LC / MS (ESI + ) m / z = 307.1 / 309.1 [M+H] + . Process 2 LC / MS(ESI + ) m / z = 273.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 5.16(t,J=13.20Hz,2H)8.47-8.55(m,2H)8.89(s,2H).

[0367] Intermediate 4-S Potassium trifluoro-[1-(2,2,3,3,3-pentafluoropropyl)pyrazol-4-yl]boranide [ka] Step 1: Potassium trifluoro-[1-(2,2,3,3,3-pentafluoropropyl)pyrazol-4-yl]boranide. A mixture of 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (Intermediate 2-G, 1.0 g, 3.07 mmol) and potassium bifluoride (0.79 g, 10.12 mmol) in acetone (15 mL) and water (5 mL) was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was suspended in hot acetone (25 mL) and filtered to remove undissolved salts. The solvent was evaporated, and the residue was redissolved in hot acetone, cooled to RT, and allowed to stand overnight. The crystallized product was collected, washed with cold acetone, and dried under vacuum to give potassium trifluoro-[1-(2,2,3,3,3-pentafluoropropyl)pyrazol-4-yl]boranide (270 mg, 0.88 mmol, 29% yield). 1 H NMR(400MHz,DMSO-d6)δ 4.98(t,J=15.30Hz,2H),7.03-7.33(m,2H).

[0368] Intermediate 4-T 1-[(2,2-difluorocyclopropyl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole [ka] Step 1: 1-[(2,2-difluorocyclopropyl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole. A resealable vial was charged with 4-pyrazoleboronic acid pinacol ester (1 g, 5.15 mmol), potassium carbonate (1.42 g, 10.3 mmol), acetonitrile (20 mL), and 2-(bromomethyl)-1,1-difluorocyclopropane (1.06 g, 6.18 mmol). The reaction mixture was heated at 80 °C for 4 h, then cooled to rt and filtered, rinsing with MeCN. The filtrate was concentrated under reduced pressure and purified by flash chromatography (SiO2, 0-50% EtOAc / cyclohexane) to give 1-[(2,2-difluorocyclopropyl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole as a colorless oil (460 mg, 1.62 mmol, 31% yield). LC / MS (ESI) + ) m / z=285.2[M+H] + .

[0369] Intermediate 4-U 1-(Cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole [ka] Step 1: 1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole. Under a nitrogen atmosphere at 0 °C, cyclopropanemethanol (0.89 g, 12.37 mmol) was added dropwise to a stirred solution of 4-pyrazoleboronic acid pinacol ester (2.0 g, 10.31 mmol), triphenylphosphine (2.7 g, 10.31 mmol), and DIAD (2.0 mL, 10.31 mmol) in THF (30 mL). The reaction mixture was warmed to rt and stirred for 24 h. The mixture was concentrated under reduced pressure, cyclohexane was added, and the resulting precipitate was filtered off. The filtrate was evaporated, and the crude material was purified by flash chromatography (SiO2, 0-50% EtOAc / cyclohexane) to give 1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole as a white solid (1.78 g, 7.17 mmol, 70% yield). LC / MS (ESI) + ) m / z = 249.1 [M+H] + .

[0370] Intermediate 4-V 1-[(3,3-difluorocyclobutyl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole [ka] Step 1: 1-[(3,3-difluorocyclobutyl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole. A solution of 3-(bromomethyl)-1,1-difluorocyclobutane (195 mg, 1.05 mmol) in DMF (0.6 mL) was added to a stirred suspension of 4-pyrazoleboronic acid pinacol ester (200 mg, 1.03 mmol) and cesium carbonate (537 mg, 1.65 mmol) in DMF (1.4 mL) at 0°C. The reaction mixture was stirred at rt for 18 h and then filtered, washing with EtOAc. The filtrate was washed with brine (2x), dried over NaSO, filtered, and concentrated under reduced pressure to give 1-[(3,3-difluorocyclobutyl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole as a colorless oil (270 mg, 0.9 mmol, 88% yield). LC / MS (ESI) + ) m / z = 299.1 [M+H] + .

[0371] Intermediate 4-W 4,4,5,5-tetramethyl-2-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,2-dioxaborolane [ka] Step 1: 1-Bromo-4-(2,2,2-trifluoroethoxy)benzene. 4-Methylbenzenesulfonic acid 2,2,2-trifluoroethyl ester (14.7 g, 57.9 mmol) was added to a stirred mixture of 4-bromophenol (10 g, 57.8 mmol) and potassium carbonate (39.9 g, 289 mmol) in DMF (80 mL) at 0 °C. The reaction mixture was heated at 110 °C for 16 h. After cooling to rt, the mixture was partitioned between water and EtOAc. The organic layer was dried over Na SO , filtered, and concentrated under reduced pressure. Purification by flash chromatography (SiO , 50% EtOAc / cyclohexane) gave 1-bromo-4-(2,2,2-trifluoroethoxy)benzene (10.9 g, 42.73 mmol, 74% yield). 1 H NMR(400MHz,DMSO-d6)δ 4.78(q,J=8.88Hz,2H),7.02-7.08(m,2H),7.48-7.56(m,2H).

[0372] Step 2: 4,4,5,5-tetramethyl-2-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,2-dioxaborolane. A mixture of 1-bromo-4-(2,2,2-trifluoroethoxy)benzene (5.0 g, 19.61 mmol), bis(pinacolato)diboron (5.48 g, 21.57 mmol), potassium acetate (5.77 g, 58.82 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (719 mg, 0.98 mmol) in 1,4-dioxane (50 ml) was degassed with nitrogen for 5 min and heated at 110° C. for 4 h. After cooling to rt, the mixture was filtered through a pad of Celite with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (SiO, 0-3% EtOAc / cyclohexane) to give 4,4,5,5-tetramethyl-2-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,2-dioxaborolane as a colorless oil (2.76 g, 9.13 mmol, 47% yield). LC / MS (ESI) + ) m / z=303.1 [M+H] + .

[0373] Intermediate 4-X 1-(Oxetan-3-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole [ka] Step 1: 1-(oxetan-3-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole. A microwave vial was charged with 4-pyrazoleboronic acid pinacol ester (194 mg, 1 mmol), oxetan-3-ylmethanol (88 mg, 1 mmol), 2-tributylphosphoranylideneacetonitrile (0.52 mL, 2 mmol), and 1,4-dioxane (3 mL). The resulting mixture was subjected to microwave irradiation at 150 °C for 45 min. After cooling to rt, the mixture was partitioned between water and EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 50-90% EtOAc / cyclohexane) to give 1-(oxetan-3-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole as a brown oil (270 mg, 1 mmol, 100% yield). LC / MS (ESI) + ) m / z=265.0[M+H] + .

[0374] Intermediate 4-Y 1-(2,2,3,3,3-pentafluoropropyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole [ka] Step 1: 1-(2,2,3,3,3-pentafluoropropyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole. A resealable vial was charged with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 5.15 mmol), sodium carbonate (1.09 g, 10.31 mmol), MeCN (5 mL), and 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate (1.32 mL, 7.99 mmol). The mixture was heated at 80° C. for 20 h, then cooled to rt and partitioned between water and EtOAc. The organic phase was dried over NaSO, filtered, and evaporated under reduced pressure to give 1-(2,2,3,3,3-pentafluoropropyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1 g, 3.07 mmol, 60% yield), which was used in the next reaction without further purification. LC / MS (ESI + ) m / z = 327.2 [M+H] + .

[0375] Intermediate 4-Z 9-chloro-3-iodo-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 9-Chloro-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-A, Step 1, with the following modifications: Step 1 was carried out using 3-chloro-4-methoxypyridin-2-amine (preparation described in WO2017197555). LC / MS (ESI + ) m / z = 279.0 / 281.0 [M+H] + .

[0376] Step 2: 9-Chloro-3-iodo-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Intermediate 1-B, Step 2, with the following modifications: Step 2 was carried out using 9-chloro-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. LC / MS (ESI + ) m / z = 404.9 / 406.9 [M+H] + .

[0377] Example Synthesis: Method 1 Example 1-1: 3-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenyl)propanenitrile. [ka] Step 1: 3-(4-(8-Methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenyl)propanenitrile. In a resealable vial, 3-bromo-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (Intermediate 1-A, 170 mg, 0.526 mmol), 4-(2-cyanoethyl)phenylboronic acid (138 mg, 0.789 mmol, Combi-Blocks Inc.), tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.026 mmol), 2-dicyclohexylphosphino-2,6'-dimethoxy-1,1'-biphenyl (22 mg, 0.053 mmol), and cesium carbonate (340 mg, 1.1 mmol) were charged. The vial was evacuated and backfilled with nitrogen. This procedure was repeated three times, followed by the addition of 1,4-dioxane (850 μL). The reaction mixture was heated to 90° C. and stirred for 12 hours. The reaction mixture was quenched with water (2 mL). The mixture was cooled and diluted with EtOAc (2 mL). The reaction mixture was filtered through a pad of silica gel. The organic phase was separated, washed with brine, dried over magnesium sulfate, filtered, and adsorbed onto silica gel. The crude product was purified by silica gel chromatography (eluent: 0-70% EtOAc / heptane) to give 3-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenyl)propanenitrile as a white solid. LC / MS (ESI + ) m / z = 374.0 [M+H] + . 1 H NMR(400MHz,CD2Cl2)δ 2.70(t,J=7.57Hz,2H)3.03(t,J=7.46Hz,2H)4.03(s,3H)6.86-7.01(m,1H)7.05(d,J=2.70Hz,1H)7.23-7.40(m,4H)8.91(d,J=7.88Hz,1H).

[0378] Examples 1-2 through 1-88 listed in Table 4 were prepared according to the procedure described in Method 1, Step 1 above, as follows.

[0379] [Table 11]

[0380]

Table 12

[0381]

Table 13

[0382]

Table 14

[0383]

Table 15

[0384] Table 16

[0385] Table 17

[0386] Table 18

[0387] Table 19

[0388] Table 20

[0389] Table 21

[0390] Table 22

[0391] [Table 23]

[0392] [Table 24]

[0393] [Table 25]

[0394] [Table 26]

[0395] Method 2 Example 2-1: 8-ethyl-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-Ethyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. Cobalt(II) chloride (0.400 g, 3.07 mmol) and a freshly prepared Grignard solution (prepared from magnesium turnings (0.67 g, 27 mmol) and iodoethane (0.56 mL, 6.8 mmol) in anhydrous diethyl ether (10 mL)) were added to a solution of 8-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (Intermediate 3-C, 2.0 g, 6.83 mmol) in benzene (15.0 mL) under a nitrogen atmosphere at rt. The reaction mixture was heated to 75 °C for 2 h. The reaction mixture was quenched with aqueous HCl (1.5 N, 10 mL). After 10 min, the pH of the reaction mixture was adjusted to pH 8 by adding aqueous NaHCO. The reaction mixture was extracted with ethyl acetate (2 × 25 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluent: 0-40% EtOAc / hexanes) to give 8-ethyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a pale yellow solid (0.4 g, 24% yield). LC / MS (ESI+) m / z = 243.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.96(d,J=7.3Hz,1H),7.74-7.67(m,1H),7.45(dd,J=7.2,2.0Hz,1H),6.76(s,1H),2.83(q,J=7.5Hz,2H),1.27(q,J=7.5Hz,3H).

[0396] Step 2: 8-Ethyl-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. NIS (0.84 g, 3.72 mmol, 3.0 eq.) was added to a solution of 8-ethyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.3 g, 1.239 mmol) in acetonitrile (6.0 mL). The reaction mixture was heated to 80°C for 48 hours and then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluent: 0-20% ethyl acetate / hexane) to give the compound 8-ethyl-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow solid (0.4 g, 88% yield). LC / MS (ESI+) m / z = 369.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.95(d,J=7.20Hz,1H),7.73(s,1H),7.50(dd,J=2.00,7.40Hz,1H),2.82(q,J=7.20Hz,2H),1.27(t,J=7.60Hz,3H).

[0397] Step 3: 8-Ethyl-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A resealable vial was charged with 8-ethyl-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.45 g, 1.2 mmol), 1,4-dioxane (5.0 mL), (4-(2,2,2-trifluoroethoxy)phenyl)boronic acid (0.325 g, 1.46 mmol, Combi-Blocks Inc.), and aqueous sodium carbonate (1.0 M, 2.5 mL, 2.445 mmol) at ambient temperature under a nitrogen atmosphere. The reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(PPh) (0.140 g, 0.122 mmol, Hindustan Platinum). The reaction mixture was stirred and heated to 95 °C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel chromatography (eluent: 0-5% methanol in dichloromethane) to give 8-ethyl-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a pale yellow solid (0.17 g, 32% yield). LC / MS (ESI+) m / z = 417.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.93(d,J=7.3Hz,1H),7.72(s,1H),7.44(dd,J=7.3,2.0Hz,1H),7.28(d,J=8.5Hz,2H), 7.16-7.08(m,2H),4.84(q,J=8.8Hz,2H),2.84(q,J=7.5Hz,2H),1.29(t,J=7.5Hz,3H).

[0398] Examples 2-2 to 2-9 listed in Table 5 were prepared according to the procedure described in Method 2, Step 3 above, as follows.

[0399] [Table 27]

[0400] [Table 28]

[0401] Method 3 Example 3-1: 2-Ethyl-8-methoxy-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 2-Ethyl-8-methoxy-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one. A resealable vial was charged with 3-bromo-2-ethyl-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one (9.0 g, 31.8 mmol, Intermediate 1-T), (1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)boronic acid (9.3 g, 38 mmol, Intermediate 2-G), potassium phosphate (10 g, 48 mmol), and 1,4-dioxane (70 mL). The reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of Pd(dppf)Cl (2.3 g, 3.2 mmol). The reaction mixture was heated to 95 °C for 16 hours. The reaction mixture was cooled to room temperature and filtered through a pad of Celite. The Celite was rinsed with ethyl acetate (2 × 250 mL), and the filtrate was concentrated under reduced pressure. The crude residue was adsorbed onto a plug of silica gel and purified by silica gel chromatography (eluent: 0-35% ethyl acetate / hexanes) to give 2-ethyl-8-methoxy-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one as a light orange solid (7.9 g, 19.6 mmol, 62% yield). LC / MS (ESI+) m / z = 403.1 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ 8.89-8.74(m,1H),8.10(s,1H),7.78(s,1H),7.07-6.92(m,2H),5.26(t, J=15.2Hz,2H),3.99(s,3H),2.71(q,J=7.5Hz,2H),1.21(t,J=7.5Hz,3H).

[0402] Example 3-2 listed in Table 6 was prepared according to the procedure described in Method 3, Step 1 above, as follows.

[0403] [Table 29]

[0404] Method 4 Example 4-1: 3-(4-(2,2,2-trifluoroethoxy)phenyl)-2,8-bis(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 2,8-Bis(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A solution of 4-(trifluoromethyl)pyridin-2-amine (2.5 g, 15.4 mmol, ArkPharm) and 4,4,4-trifluoroacetoacetic acid ethyl ester (3.4 mL, 23 mmol) in acetic acid (6 mL) was heated to 110 °C for 20 h. The reaction mixture was cooled to rt and neutralized with saturated bicarbonate solution. The reaction mixture was partitioned with EtOAc, and the aqueous layer was back-extracted with EtOAc. The combined organic phases were dried over MgSO, filtered, concentrated, and adsorbed onto a pad of silica gel. The crude residue was purified by silica gel chromatography (eluent: 0-10% (3:1 EtOAc in ethanol) / heptane) to give 2,8-bis(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a white solid (0.27 g, 0.97 mmol, 6% yield). LC / MS (ESI+) m / z = 283.0 [M+H] + .

[0405] Step 2: 3-Bromo-2,8-bis(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A solution of bromine (0.25 mL, 4.8 mmol) in acetic acid (1.382 mL) was added dropwise to a solution of 2,8-bis(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.27 g, 0.97 mmol) in acetic acid (3.5 mL) at rt. After 24 h, the reaction mixture was cooled to 0 °C and quenched by the dropwise addition of saturated thiosulfate solution (5 mL). The reaction mixture was partitioned between EtOAc and brine, and the aqueous layer was back-extracted three times with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The resulting solid was triturated with EtO to give 3-bromo-2,8-bis(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.35 g, 0.97 mmol, 99% yield) as a white solid. The product was carried on to the next step without further purification. LC / MS(ESI+)m / z=361.0[M+H] + . 1H NMR(400MHz,CDCl3)δ 9.17(d,J=7.5Hz,1H),8.10(s,1H),7.41(d,J=7.3Hz,1H).

[0406] Step 3: 3-(4-(2,2,2-trifluoroethoxy)phenyl)-2,8-bis(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A resealable vial was charged with SPhos palladacycle (0.012 mL, 0.017 mmol, Strem Chemicals, Inc.), cesium carbonate (0.173 g, 0.532 mmol, Strem Chemicals, Inc.), 3-bromo-2,8-bis(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.12 g, 0.332 mmol), and (4-(2,2,2-trifluoroethoxy)phenyl)boronic acid (0.110 g, 0.499 mmol, Combi-Blocks Inc.). The vial was evacuated and backfilled with nitrogen. This procedure was repeated three times, followed by the addition of 1,4-dioxane (1.6 mL). The reaction mixture was heated to 40 °C. After 2 h, the reaction mixture was partitioned between water and EtOAc. The organic phase was separated, washed with brine, dried over magnesium sulfate, filtered, and adsorbed onto a pad of silica gel. The crude product was purified by silica gel chromatography (eluent: 0-10% (3:1 EtOAc in ethanol) / heptane) to give 3-(4-(2,2,2-trifluoroethoxy)phenyl)-2,8-bis(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as an off-white solid (45 mg, 0.1 mmol, 30% yield). LC / MS (ESI+) m / z = 457.0 [M+H] + . 1 H NMR(DMSO-d6,500MHz)δ 9.08(d,J=7.5Hz,1H),8.36(s,1H),7.67(dd,J=7.5,1.9Hz,1H),7.28-7.31(m,J=8.7Hz,2H),7.14-7.17(m,2H),4.84(q,J=8.8Hz,2H).

[0407] Examples 4-2 to 4-3 listed in Table 7 were prepared according to the procedure described in Method 4, Step 1 above, as follows.

[0408] [Table 30]

[0409] Method 5 Example 5-1: 3-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 3-(2-Fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A resealable vial was charged with 2-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (218 mg, 0.68 mmol, Intermediate 2-F), Sphos palladacycle G3 (27 mg, 0.034 mmol, Strem), 3-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (100 mg, 0.34 mmol, Intermediate 1-P), and sodium carbonate (72 mg, 0.68 mmol). The vial was evacuated and backfilled with nitrogen. This procedure was repeated three times, followed by the addition of 1,4-dioxane (800 μL) and water (200 μL). The reaction mixture was heated to 85 °C. After 2 h, the reaction mixture was partitioned between water and EtOAc and filtered through a pad of silica gel. The filtrate was washed successively with 1N HCl (50 mL), saturated aqueous sodium bicarbonate (50 mL), and brine (50 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by SFC (IC, 150 × 21 mm, 5 μm, 10% (20 mM NH in MeOH) / CO, 80 g / min, 100 bar) to give 3-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a white solid (32 mg, 0.08 mmol, 23% yield). LC / MS (ESI+) m / z = 407.6 [M+H] + . 1H NMR(400MHz,CD2Cl2)δ 4.45(q,J=8.02Hz,2H)6.82(dd,J=10.76,2.54Hz,1H)6.86(dd,J=8.41,2.54Hz,1H)7.27(t,J= 8.41Hz,1H)7.31-7.38(m,1H)7.83(d,J=8.80Hz,1H)7.89-8.03(m,1H)9.07(d,J=7.24Hz,1H).

[0410] Examples 5-2 to 5-4 listed in Table 8 were prepared according to the procedure described in Method 5, Step 1 above, as follows.

[0411] [Table 31]

[0412] Method 6 Example 6-1: 8-amino-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-amino-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. 10% aqueous sodium hydroxide solution (0.8 mL, 1.92 mmol) was added to a solution of 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 (0.3 g, 0.64 mmol, Example 1-82) in methanol (10.0 mL) at rt. After 15 min, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a 5% solution of methanol in DCM (50 mL) and washed with water (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluent: 0-65% EtOAc / hexanes) to give 8-amino-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a pale yellow solid (0.165 g, 0.39 mmol, 60% yield). LC / MS (ESI) + ) m / z=428.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.72(dd,J=7.8,1.5Hz,1H),7.88(s,1H),7.57(s,1H),7.39(s,2H),6.88(dt,J=7.9,2.0Hz,1H),6.53(t,J=2.0Hz,1H),5.23(t,J=15.0Hz,2H).

[0413] Example 6-2, listed in Table 9, was prepared according to the procedure described in Method 6, Step 1 above, as follows.

[0414] [Table 32]

[0415] Method 7 Example 7-1: 3-(2-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 3-(2-Fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A solution of isopropylmagnesium chloride (2 M in THF, 0.5 mL, 1.1 mmol, Acros Organics, Geel, Belgium) was added dropwise to a solution of 3-iodo-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (Intermediate 1-B, 0.367 g, 0.992 mmol) in THF (1 mL) under a nitrogen atmosphere at 0° C. The reaction mixture was stirred at 0° C. for 15 min, followed by the dropwise addition of ZnCl (0.5 M in THF, 2.2 mL, 1.1 mmol). The reaction mixture was allowed to warm to rt over 1 h and then added to a solution of [(SIPr)PdCl] (47 mg, 0.04 mmol, Umicore Ag & Co. Kg., Rodenbacher, Germany) and 3-bromo-2-fluoro-6-(2,2,2-trifluoroethoxy)pyridine (Intermediate 2-O, 0.23 g, 0.83 mmol) in THF (1 mL) that had been aged for 20 min. The reaction mixture was then heated to 70 °C for 12 h. The reaction was cooled to rt, filtered through a pad of Celite, concentrated, and adsorbed onto a pad of silica gel. The crude residue was purified by silica gel chromatography (eluent: 0-40% (3:1 EtOAc / EtOH) / heptane) to give 3-(2-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a light yellow solid (0.17 g, 0.38 mmol, 46% yield). MS (ESI) + ) m / z = 438.1 [M+H] + . 19 F NMR(376MHz, CDCl3)δ-73.81(s,1F)-69.99(br d,J=1.74Hz,1F)-65.15(d,J=2.60Hz,1F). 1H NMR(400MHz,CDCl3)δ 3.90-4.13(m,3H)4.60-4.83(m,2H)6.72-6.89(m,1H)6.91-7.04(m,1H)7.04-7.17(m,1H)7.57-7.73(m,1H)8.88-9.06(m,1H).

[0416] Examples 7-2 to 7-6 listed in Table 10 were prepared according to the procedure described in Method 7, Step 1 above, as follows.

[0417] [Table 33]

[0418] Method 8 Example 8-1: 3-(4-(cyclopropylmethoxy)-2-fluorophenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 3-(2-Fluoro-4-hydroxyphenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Method 1, Step 1, with the following modifications. Step 1 was carried out using 2-fluoro-4-hydroxybenzeneboronic acid pinacol ester (Combi-Blocks Inc.). MS (ESI + ) m / z = 355.0 [M+H] + .

[0419] Step 2: 3-(4-(cyclopropylmethoxy)-2-fluorophenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A resealable vial was charged with 3-(2-fluoro-4-hydroxyphenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (309 mg, 0.87 mmol) and cesium carbonate (1.3 g, 3.9 mmol). The vial was evacuated and backfilled with nitrogen. This procedure was repeated three times, followed by the addition of DMF (4 mL) and (bromomethyl)cyclopropane (0.127 mL, 1.308 mmol). The reaction mixture was heated to 80° C. for 12 h. The reaction mixture was cooled to rt and filtered through a plug of Celite. The filtrate was extracted with EtOAc (100 mL), and the organic phase was washed successively with water (100 mL) and 1 M LiCl (100 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure. The crude residue was adsorbed onto a plug of silica gel and purified by silica gel chromatography (eluent: 0-40% EtOAc / heptane) to give 3-(4-(cyclopropylmethoxy)-2-fluorophenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a light yellow solid (184 mg, 0.45 mmol, 52% yield). MS (ESI) + ) m / z=409.0[M+H] + . 1 H NMR(400MHz,CD2Cl2)δ 0.33-0.41(m,2H)0.61-0.71(m,2H)1.23-1.39(m,1H)3.85(d,J=7.05Hz,2H)4.02(s,3H)6.72(dd,J=11.61,2.28Hz,1H)6.78 (dd,J=8.50,2.28Hz,1H)6.95(dd,J=7.88,2.70Hz,1H)7.06(d,J=2.49Hz,1H)7.16(t,J=8.50Hz,1H)8.92(d,J=7.88Hz,1H).

[0420] Examples 8-2 to 8-5 listed in Table 11 were prepared according to the procedure described in Method 8, Step 2 above, as follows.

[0421] [Table 34]

[0422] Method 9 Example 9-1: 8-Methoxy-3-(4-(2,2,3,3-tetrafluoropropoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 3-(4-hydroxyphenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described for Method 1, step 1, with the following modifications: Step 1 was carried out using 2-fluoro-4-hydroxybenzeneboronic acid pinacol ester (Combi-Blocks Inc.). MS (ESI + ) m / z = 337.0 [M+H] + .

[0423] Step 2: 4-(8-Methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenyl trifluoromethanesulfonate. A reaction mixture of 3-(4-hydroxyphenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.5 g, 1.5 mmol), pyridine (0.25 mL, 3.0 mmol), and dichloromethane (7 mL) was cooled to 0 °C, followed by the addition of trifluoromethanesulfonic anhydride (0.3 mL, 1.8 mmol). The reaction mixture was allowed to warm to RT and then stirred for an additional 2 h. The crude material was adsorbed onto silica gel and purified by silica gel chromatography (eluent: 0-30% (3:1 EtOAc / EtOH) / heptane) to give 4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenyl trifluoromethanesulfonate as a white solid (0.64 g, 1.36 mmol, 91% yield). MS (ESI) + ) m / z = 469.0 [M+H] + .

[0424] Step 3: 8-Methoxy-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The vial was charged with Pd(dppf)Cl (0.100 g, 0.136 mmol) and 4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenyl trifluoromethanesulfonate (0.64 g, 1.4 mmol). The vial was evacuated and backfilled with nitrogen. This procedure was repeated three times, followed by the addition of 1,4-dioxane (6.80 mL) and triethylamine (0.57 mL, 4.1 mmol). The reaction mixture was heated to 80° C. for 6 hours. The reaction mixture was cooled to rt, filtered through a pad of Celite, adsorbed to a pad of silica gel, and purified by silica gel chromatography (eluent: 0-30% (3:1 EtOAc / EtOH) / heptane) to give 8-methoxy-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.8 g, 1.8 mmol, 75% purity). The product was carried on to the next step without further purification. MS (ESI) + ) m / z = 447.0 [M+H] + .

[0425] Step 4: 3-(4-Bromophenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A reaction mixture of 8-methoxy-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.61 g, 1.36 mmol), copper(II) bromide (0.9 g, 4.1 mmol), water (1 mL), and methanol (6 mL) was heated at 90° C. for 5 h. The reaction mixture was cooled to rt and partitioned between EtOAc and water. The organic phase was washed with water and brine and adsorbed onto a pad of silica gel. The crude product was purified by silica gel chromatography (eluent: 10-30% 3:1 EtOAc / EtOH in heptane) to give 3-(4-bromophenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.34 g, 0.86 mmol, 90% purity). The product was carried on to the next step without further purification. MS (ESI) + ) m / z=398.9[M+H] + .

[0426] Step 5: 8-Methoxy-3-(4-(2,2,3,3-tetrafluoropropoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A resealable vial was charged with 3-(4-bromophenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (50 mg, 0.125 mmol), sodium tert-butoxide (17 mg, 0.175 mmol), and tBuBrettPhos palladacycle G3 (6 mg, 7.5 μmol). The vial was evacuated and backfilled with nitrogen. This procedure was repeated three times, followed by the addition of 1,4-dioxane (835 μL) and 2,2,3,3-tetrafluoro-1-propanol (33 μL, 0.38 mmol). The reaction mixture was heated to 60 °C for 2 h, filtered through a pad of silica gel, and extracted with EtOAc (60 mL). The organic phase was washed successively with saturated aqueous sodium bicarbonate (60 mL) and brine (60 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was adsorbed onto a plug of silica gel and purified by silica gel chromatography (eluent: 0-50% EtOAc / heptane) to give 8-methoxy-3-(4-(2,2,3,3-tetrafluoropropoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a light orange solid (23 mg, 0.05 mmol, 41% yield). MS (ESI) + ) m / z = 451.0 [M+H] + . 1 H NMR(400MHz,CD2Cl2)δ 4.03(s,3H)4.43(t,J=11.92Hz,2H)5.99-6.31(m,1H)6.94(dd,J=7.88,2.70Hz,1H)6 .99-7.04(m,2H)7.05(d,J=2.49Hz,1H)7.29(d,J=8.50Hz,2H)8.91(d,J=7.88Hz,1H).

[0427] Example 9-2, listed in Table 12, was prepared according to the procedure described in Method 9, Step 5 above, as follows.

[0428] [Table 35]

[0429] Method 10 Example 10-1: 3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-4,8(1H)-dione. [ka] Step 1: 3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-4,8(1H)-dione. A solution of 8-methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (1 g, 2.4 mmol, Example 1-44) in HBr (33% in acetic acid, 1.3 mL, 7.2 mmol) was heated to 110° C. for 2 days. The reaction mixture was cooled to rt, partitioned between EtOAc and water, and the aqueous layer was back-extracted with EtOAc (2×). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo to give a residue that was triturated with EtO (20 mL). The solid was filtered off and dried to give 3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-4,8(1H)-dione as a white solid (0.92 g, 2.3 mmol, 95% yield). MS (ESI + ) m / z = 404.9 [M+H] + . 1 H NMR(DMSO-d6,400MHz)δ 12.25(br s,1H),8.87(br d,J=6.8Hz,1H),7.23(br d,J=8.3Hz,2H),7.08(br d,J=8.7Hz,3H),6.88(br s,1H),4.80(q,J=8.8Hz,2H).

[0430] Examples 10-2 to 10-4 listed in Table 13 were prepared according to the procedure described in Method 10, Step 1 above, as follows.

[0431] [Table 36]

[0432] Method 11 Example 11-1: 1-(methyl-d3)-7-(4-(2,2,2-trifluoroethoxy)phenyl)-8-(trifluoromethyl)-2H-pyrimido[1,2-a]pyrimidine-2,6(1H)-dione [ka] Step 1: 1-(methyl-d3)-7-(4-(2,2,2-trifluoroethoxy)phenyl)-8-(trifluoromethyl)-2H-pyrimido[1,2-a]pyrimidine-2,6(1H)-dione. Deuterated iodomethane (0.07 mL, 1.1 mmol) was added to a suspension of 7-(4-(2,2,2-trifluoroethoxy)phenyl)-8-(trifluoromethyl)-2H-pyrimido[1,2-a]pyrimidine-2,6(1H)-dione (Example 10-3, 7.0 mg, 0.20 mmol) and cesium carbonate (0.12 g, 0.36 mmol) in DMF (2 mL). The reaction mixture was stirred at rt for 3 h, then diluted with water and extracted with EtOAc. The organic phase was separated, concentrated under reduced pressure, and purified by silica gel chromatography (eluent: 0-30% EtOAc / heptane) to give 1-(methyl-d3)-7-(4-(2,2,2-trifluoroethoxy)phenyl)-8-(trifluoromethyl)-2H-pyrimido[1,2-a]pyrimidine-2,6(1H)-dione (5 mg, 0.12 mmol, 67% yield). MS (ESI) + ) m / z=423.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.58(d,J=8.29Hz,1H),7.20-7.27(m,J=8.71Hz,2H),7.11-7.17(m,J=8.71Hz,2H),6.55(d,J=8.29Hz,1H),4.83(q,J=8.91Hz,2H).

[0433] Examples 11-2 to 11-3 listed in Table 14 were prepared according to the procedure described in Method 11, Step 1 above, as follows.

[0434] [Table 37]

[0435] Method 12 Example 12-1: N-methyl-4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxamide [ka] A solution of methyl 4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxylate (Example 1-36, 0.25 g, 0.56 mmol) in methylamine (2 M in THF, 2.5 mL, Spectrochem) was stirred at 0° C. for 1 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was treated with diethyl ether (15 mL) for 30 min. The solid was filtered off and dried to give N-methyl-4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxamide as an off-white solid (0.22 g, 88% yield). LC / MS (ESI + ) m / z = 446.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.05(dd,J=13.4,6.0Hz,2H),8.29(d,J=1.8Hz,1H),7.75(dd,J=7.4,1.9Hz,1H),7 .35-7.27(m,2H),7.19-7.08(m,2H),4.84(q,J=8.9Hz,2H),2.86(d,J=4.4Hz,3H).

[0436] Examples 12-2 to 12-5 listed in Table 15 were prepared according to the procedure described in Method 12, Step 1 above, as follows.

[0437] [Table 38]

[0438] Method 13 Examples 13-1 and 13-2: 8-(hydroxymethyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one and 8-(fluoromethyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-(hydroxymethyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A solution of borane (1.0 M in THF, 5.5 mL, 5.5 mmol) was added dropwise to a solution of 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 (Example 1-21, 0.5 g, 1.1 mmol) in THF (5.0 mL) under a nitrogen atmosphere at 0° C. After 10 min, the reaction mixture was warmed to rt and stirred for an additional 5 h. The reaction mixture was cooled to 0° C. and quenched by the addition of methanol (2 mL). The resulting solution was concentrated under reduced pressure, diluted with water (5 mL), and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine solution (5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluent: 0-55% EtOAc / hexanes) to give 8-(hydroxymethyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow solid (0.35 g, 72% yield). MS (ESI) + ) m / z = 443.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.97(d,J=7.3Hz,1H),8.05(s,1H),7.69(s,2H),7.43(dd,J=7.5,1.8Hz,1H),5.78(t,J=5.7Hz,1H),5.29(t,J=14.9Hz,2H),4.71(d,J=5.4Hz,2H).

[0439] Step 2: 8-(Fluoromethyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. DAST (0.1 mL, 0.75 mL) was added dropwise to a solution of 8-(hydroxymethyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (Example 13-1, 0.17 g, 0.37 mmol) in DCM (3.0 mL) under a nitrogen atmosphere at 0° C. The reaction mixture was warmed to rt and stirred for 1 h. The reaction mixture was cooled to 0° C. and quenched by adding 10% aqueous NaHCO (3 mL) and extracted with DCM (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluent: 0-35% EtOAc / hexanes) to give 8-(fluoromethyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow solid (0.12 g, 0.26 mmol, 70% yield). MS (ESI) + ) m / z = 445.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.03(d,J=7.3Hz,1H),8.08(s,1H),7.78(s,1H),7.72(s,1H),7.46(dd,J=7.4,1.8Hz,1H),5.71(dd,J=46.0Hz,1.3Hz,2H),5.31(t,J=15.0Hz,2H).

[0440] Examples 13-3 to 13-4 listed in Table 16 were prepared according to the procedures described in Method 13, steps 1 and 2 above, as follows.

[0441] [Table 39]

[0442] Method 14 Example 14-1: 8-(methylamino)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-chloro-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one. 7-(4-(2,2,2-trifluoroethoxy)phenyl)-8-(trifluoromethyl)-2H-pyrimido[1,2-a]pyrimidine-2,6(1H)-dione (0.43 g, 1.1 mmol, Example 10-3) was suspended in phosphorus oxychloride (5.0 mL) under a nitrogen atmosphere, and the resulting reaction mixture was heated to 110° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Residual POCl was removed by azeotropic distillation with toluene (3×5 mL) to give 8-chloro-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one as a solid. The product was carried on to the next step without further purification. MS (ESI) + ) m / z = 424.0 [M+H] + .

[0443] Step 2: 8-(Methylamino)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one. Methylamine (2.0 M in THF, 5.3 mL, 10.6 mmol) was added dropwise over 10 minutes to a solution of 8-chloro-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one (0.45 g, 1.1 mmol) in anhydrous THF (4.5 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was diluted with water (5 mL) and extracted with a mixture of methanol in DCM (ratio 1:9; 3×5 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluent: 100% (1.5% methanol in dichloromethane)) to give 8-(methylamino)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one (0.36 g) as an off-white solid. MS (ESI) + ) m / z = 419.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.81(t,J=4.8Hz,1H),8.67(dd,J=7.8,2.7Hz,1H),7.21(dd,J=9.1,2.6Hz,2H),7.15-7.05( m,2H),6.69(dd,J=7.8,2.6Hz,1H),4.82(qd,J=9.0,2.7Hz,2H),2.98(dd,J=4.9,2.6Hz,3H).

[0444] Example 14-2 listed in Table 17 was prepared according to the procedure described in Method 14, Step 2 above, as follows.

[0445] [Table 40]

[0446] Method 15 Example 15-1: 8-(Methylsulfinyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-(Methylsulfinyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. Oxone® (3.3 g, 5.3 mmol) was added to a solution of 8-(methylsulfanyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (2.3 g, 5.3 mmol, Example 1-35) in methanol (46 mL) and water (23 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The solvent was partially removed under reduced pressure, the pH of the crude residue was adjusted to approximately 7 by adding saturated NaHCO solution (50 mL), and the reaction mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluent: 0-90% EtOAc / hexanes) to give 8-(methylsulfinyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.90 g, 2.0 mmol, 38% yield. MS (ESI) + ) m / z = 451.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.09(d,J=7.4Hz,1H),8.05(d,J=1.7Hz,1H),7.72(dd,J=7.4,1.9Hz,1H), 7.33-7.25(m,2H),7.20-7.12(m,2H),4.85(q,J=8.8Hz,2H),2.97(s,3H).

[0447] Examples 15-4 and 15-7 listed in Table 18 were prepared according to the procedure described in Method 15, Step 1 above, as follows.

[0448] [Table 41]

[0449] Method 16 Example 16-1: (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 [ka] Step 1-1: (4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-8-yl)methyl methanesulfonate. Triethylamine (0.3 mL, 2.4 mmol) was added to a solution of 8-(hydroxymethyl)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (700 mg, 1.6 mmol, Example 13-1) in THF (7.0 mL) at 0° C., followed by the addition of mesyl chloride (160 μL, 2.1 mmol). The reaction mixture was allowed to warm to room temperature. After 1 h, the reaction mixture was cooled to 0° C., quenched with water (30 mL), and extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over potassium carbonate, filtered, and concentrated under reduced pressure to give the crude product (700 mg), which was used in the next step without further purification.

[0450] Step 1-2: (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. Potassium cyanide (186 mg, 2.9 mmol) was added to a solution of the crude product (700 mg) obtained in step 1-1 in DMF (7.0 mL) at rt. After 1 h, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by RP HPLC (Gemini NX C18, 250 × 19 mm, 5 μm, mobile phase A: 10 mM ammonium acetate in water, mobile phase B: acetonitrile, flow rate: 15 ml / min) to give (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 (55 mg) as a solid. LC / MS (ESI + ) m / z = 452.0 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 9.10(d,J=7.4Hz,1H),7.93(s,1H),7.86(d,J=11.4Hz,2H),7.22(dd,J=7.4,1.9Hz,1H),4.85(t,J=13.8Hz,2H),3.96(d,J=1.3Hz,2H).

[0451] Example 16-2 listed in Table 19 was prepared according to the procedure described in Method 16, Step 1 above, as follows.

[0452] [Table 42]

[0453] Method 17 Examples 17-1 and 17-2: 8-((methylsulfanyl)methoxy)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one and 8-(fluoromethoxy)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-((methylsulfanyl)methoxy)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A resealable vial was charged with 3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-4,8(1H)-dione (Example 10-1, 0.15 g, 0.37 mmol), sodium iodide (5 mg, 0.37 mmol), and DMF (1.0 mL). The reaction mixture was cooled to 0° C., and sodium hydride (8 mg, 0.34 mmol) was added. The reaction mixture was stirred at 0° C. for 30 minutes, followed by the addition of chloromethyl methyl sulfide (65 mg, 0.68 mmol). The reaction was allowed to warm to rt, and stirring was continued for 24 hours. The reaction mixture was quenched with MeOH and directly adsorbed onto a plug of silica gel. The crude material was purified by silica gel chromatography (eluent: 0-30% (3:1 EtOAc in EtOH) / heptane) to give 8-((methylsulfanyl)methoxy)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a white solid (Example 17-1, 74 mg, 0.16 mmol, 47% yield). LC / MS (ESI) + ) m / z=464.9[M+H] + . 1 H NMR(CDCl3,400MHz)δ 8.95(d,J=7.9Hz,1H),7.28-7.30(m,1H),7.08(d,J=2.5Hz,1H),6.91-7.03(m ,3H),5.29(s,2H),4.34-4.42(m,1H),4.38(d,J=8.1Hz,1H),2.30(s,3H).19F NMR(CDCl3,376MHz)δ -63.10(s,3F),-73.94(s,3F).

[0454] Step 2: 8-(Fluoromethoxy)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A solution of sulfuryl chloride (1 M in DCM, 43 μl, 0.43 mmol) was added to a solution of 8-((methylsulfanyl)methoxy)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (Example 17-1, 67 mg, 0.14 mmol) in dichloromethane (0.7 ml). The reaction mixture was stirred for 15 min and then concentrated under reduced pressure. The crude residue was dissolved in DCM (1 mL), followed by the addition of tetrabutylammonium fluoride (1 M in THF, 0.3 ml, 0.23 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with water and brine and then dried over MgSO4. The filtrate was concentrated in vacuo, and the residue was purified by RP HPLC (Xbridge Column, 100 × 19 mm, 10 μM, mobile phase A: 0.1% NH OH in water, mobile phase B: acetonitrile) to give 8-(fluoromethoxy)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a white solid (Example 17-2, 15 mg, 0.034 mmol, 24% yield). LC / MS (ESI + ) m / z = 437.1 [M+H] + . 1 H NMR(DMSO-d6,500MHz)δ 8.97- 8.92(m,1H),7.50-7.45(m,1H),7.24-7.34(m,3H),7.11-7.15(m,2H),6.23-6.03(m,2H),4.83(q,J=9.0Hz,2H). 19 F NMR(CDCl3,376MHz)δ -63.11(s,3F),-73.94(s,3F),-154.87(s,1F).

[0455] Example 17-3 in Table 20 was prepared according to the procedure described in Method 17, steps 1 and 2 above, as follows.

[0456] [Table 43]

[0457] Method 18 Examples 1-83 and 1-84: 3-(4-(((1R)-2,2-difluorocyclopropyl)methoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one and 3-(4-(((1S)-2,2-difluorocyclopropyl)methoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 3-(4-(((1R)-2,2-difluorocyclopropyl)methoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one and 3-(4-(((1S)-2,2-difluorocyclopropyl)methoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The racemic mixture of 3-(4-((2,2-difluorocyclopropyl)methoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (Example 1-4, 0.090 g, 0.21 mmol) was purified by SFC ((OJ-H, 250 × 20 mm, 5 μm), 35% MeOH / CO, 60 ml / min, 100 bar) to give two peaks: the first-eluting isomer (0.038 g, 0.09 mmol, 92% ee) and the second-eluting isomer (0.033 g, 0.08 mmol, 96% ee). The stereochemistry of the isomers was appropriately assigned to be 3-(4-(((1R)-2,2-difluorocyclopropyl)methoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as the first eluting isomer and 3-(4-(((1S)-2,2-difluorocyclopropyl)methoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as the second eluting isomer. First eluting isomer: LC / MS (ESI+) m / z = 427.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 1.47-1.55(m,1H)1.75(tdd,J=12.15,12.15,7.72,4.87Hz,1H)2.20-2.31(m,1H)4.04(s,4H)4.20(br s,1H)6.99-7.05(m,2H)7.15-7.28(m,4H)8.87(d,J=7.88Hz,1H).Second elution isomer: LC / MS(ESI+)m / z=427.1[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 1.46-1.55(m,1H)1.74(tdd,J=11.97,11.97,7.57,4.77Hz,1H)2.21-2.30(m,1H)4.03( s,4H)4.16-4.23(m,1H)7.01(d,J=8.71Hz,2H)7.14-7.28(m,4H)8.87(d,J=7.88Hz,1H).

[0458] The examples listed in Table 21 were obtained according to the procedure described in Method 18, Step 1 above as follows.

[0459] [Table 44]

[0460] [Table 45]

[0461] [Table 46]

[0462] [Table 47]

[0463] Example 18 3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-4,8(1H)-dione [ka] Step 1: 3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-4,8(1H)-dione. Boron tribromide (2.2 mL, 24 mmol) was added to a solution of 8-methoxy-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.70 g, 1.6 mmol, Example 1-68) in dichloromethane (10 mL) under a nitrogen atmosphere at 0° C. The reaction mixture was allowed to warm to room temperature and heated to 50° C. for 48 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluent: 0-40% EtOAc / hexanes) to give 3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-4,8(1H)-dione as a white solid (0.18 g, 27% yield). LC / MS (ESI) + ) m / z = 429.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 12.29(s,1H),8.92(d,J=7.9Hz,1H),7.97(s,1H),7.64(s,1H),7.11(dd,J=7.8,2.6Hz,1H),6.93(d,J=2.6Hz,1H),5.27(t,J=15.0Hz,2H).

[0464] Example 19 8-(Methylsulfonyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-(Methylsulfonyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. mCPBA (0.25 g, 1.0 mmol) was added to a solution of 8-(methylsulfanyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.2 g, 0.46 mmol, Example 1-35) in dichloromethane (4 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes and then warmed to rt. After 3 hours, the reaction mixture was diluted with dichloromethane (25 mL) and washed with saturated aqueous sodium bicarbonate (3×50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was suspended in diethyl ether. The solid was filtered off and dried to give 8-(methylsulfonyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow solid (0.10 g, 47% yield). LC / MS (ESI + ) m / z = 467.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.12(d,J=7.5Hz,1H),8.32(d,J=1.8Hz,1H),7.77(dd,J=7.5,2.0Hz,1H), 7.35-7.28(m,2H),7.21-7.12(m,2H),4.85(q,J=8.8Hz,2H),3.52(s,3H).

[0465] Example 20 3-(6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 3-(6-Fluoropyridin-3-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. The title compound was prepared using the procedure described in Method 1, Step 1, with the following modifications. Step 1 was carried out using 3-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (Intermediate 1-P) and 2-fluoropyridine-5-boronic acid (0.1 g, 0.8 mmol) (Frontier Scientific, Logan, UT, USA). LC / MS (ESI + ) m / z=310.1 [M+H] + .

[0466] Step 2: 3-(6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A resealable vial was charged with 2,2,2-trifluoroethanol (17 μL, 0.23 mmol), 2-methyl-2-propano potassium salt (0.23 mL, 0.23 mmol), 3-(6-fluoropyridin-3-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (7.0 mg, 0.20 mmol), and tetrahydrofuran (1.0 mL). The reaction mixture was heated to 70° C. for 2 hours. The reaction mixture was cooled to rt and partitioned between EtOAc and water. The organic phase was separated and dried over MgSO4. The filtrate was concentrated under reduced pressure, and the crude residue was purified by silica gel chromatography (eluent: 0-40% EtOAc / heptane) to give 3-(6-(2,2,2-trifluoroethoxy)-3-pyridinyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as an off-white solid (41 mg, 0.1 mmol, 50% yield). LC / MS (ESI) + ) m / z = 390.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 4.74-4.88(m,2H)6.94-7.03(m,1H)7.30-7.40(m,1H)7.63-7.73(m,1H)7.83-7.98(m,2H)8.09-8.18(m,1H)9.02-9.17(m,1H). 19F NMR(376MHz,CDCl3)δ -73.78(s,1 F)-62.82(s,1 F).

[0467] Example 21 (4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenoxy)acetonitrile [ka] Step 1: (4-(8-Methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenoxy)acetonitrile. A resealable vial was charged with 3-(4-hydroxyphenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (Intermediate 3-A, 85 mg, 0.25 mmol), cesium carbonate (124 mg, 0.38 mmol), cesium fluoride (57 mg, 0.38 mmol), 2-iodoacetonitrile (37 μL, 0.51 mmol), and dimethyl sulfoxide (1.3 mL). The reaction mixture was heated to 70° C. for 48 h. The reaction mixture was cooled to rt and diluted with EtOAc (50 mL) and water (50 mL). The organic phase was separated and washed with water (50 mL) and brine (50 mL). The combined aqueous extracts were extracted with EtOAc (3×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by RP HPLC (XSelect Column, 100 × 19 mm, 10 μm, mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile) to give (4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenoxy)acetonitrile as a solid (26 mg, 0.07 mmol, 27% yield). LC / MS (ESI + ) m / z = 376.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 4.04(s,3H)5.22(s,2H)7.07-7.15(m,2H)7.18(dd,J=7.88,2.70Hz,1H)7.25-7.34(m,3H)8.88(d,J=7.88Hz,1H).

[0468] Example 22 8-Methoxy-3-(4-(2,2,3,3,3-pentafluoropropoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] Step 1: 8-Methoxy-3-(4-(2,2,3,3,3-pentafluoropropoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one. A resealable vial was charged with 3-(4-hydroxyphenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (Intermediate 3-A, 66 mg, 0.2 mmol), potassium carbonate (49 mg, 0.36 mmol), and DMF (400 μL). The reaction mixture was stirred at rt for 1 h and then 2,2,3,3,3-pentafluoropropyl 4-methylbenzenesulfonate (60 mg, 0.2 mmol; synthesized according to the procedure described in U.S. Patent Application Publication No. 20070155726) was added. The reaction mixture was heated to 90° C. for 12 h. Additional potassium carbonate (49 mg, 0.36 mmol) was added, and the reaction mixture was heated to 120° C. for 12 h. The reaction mixture was cooled to rt and diluted with EtOAc (20 mL) and water (20 mL). The organic phase was separated, extracted with water (20 mL) and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by SFC (OD column, 150 × 21 mm, 5 μm, 35% (20 mM NH in MeOH) / CO, flow rate 50 g / min, 100 bar) to give 8-methoxy-3-(4-(2,2,3,3,3-pentafluoropropoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a solid (11 mg, 0.024 mmol, 12% yield). LC / MS (ESI) + ) m / z = 469.0 [M+H] + . 1 H NMR(400MHz,CD2Cl2)δ 1.56(br s,2H)3.42(s,1H)4.03(s,3H)4.52(td,J=12.44,0.83Hz,2H)6.94(dd,J=7.98,2.80Hz ,1H)7.00-7.03(m,1H)7.03-7.07(m,2H)7.30(d,J=8.71Hz,2H)8.91(d,J=7.88Hz,1H).

[0469] Example 23 Ethyl(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 [ka] Step 1: 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. A resealable vial was charged with 8-(methylamino)-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (Example 1-23, 100 mg, 0.23 mmol), tetramethylammonium trifluoromethanethiolate (51 mg, 0.3 mmol, synthesized as described in Scattolin T et al., Angew. Chem. Int. Ed. Engl. 56(1):221-224 (2017)), and a mixture of DCM:acetonitrile (1:1, 3 mL). The reaction mixture was stirred at rt for 1.5 hours, and additional tetramethylammonium trifluoromethanethiolate (52 mg, 0.3 mmol) was added. Stirring was continued for 36 hours. Silver(I) fluoride (172 mg, 1.36 mmol) was added, and the mixture was stirred for 40 minutes. The reaction mixture was filtered through a pad of Celite and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: 10-80% EtOAc / heptane) to give methyl (4-oxo-3-(1-(2,2,3,3,3-pentaflu...

Claims

1. Compounds of Formula I 【Chemistry 1】 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein: １） 【Chemistry 2】 teeth, 【Chemistry 3】 wherein optionally CR ｗ , C.R. ｘ , C.R. ｙ , and C.R. ｚ 1 of is N or 2) 【Chemistry 4】 teeth, 【Chemistry 5】 or 3) 【Chemistry 6】 teeth, 【Chemistry 7】 and During the ceremony, R ｗ is H, halogen, -CN, -CO(C １～４ alkyl), -S(O) ｎ (C １～４ alkyl), -COOH, -COO(C １～４ alkyl), -CONH ２ , -CONH(C １～４ Alkyl), -CO(diC １～４ alkylamino), -NH ２ , C １～４ Alkylamino, DiC １～４ Alkylamino, -NH(COC １～４ Alkyl), -N(C １～４ alkyl)C(=O)F,C １～４ Alkyl, C １～４ Deuteroalkyl, C ３～５ Cycloalkyl, C ３～４ Heterocycloalkyl, C ２～４ Alkenyl, C １～４ deuteroalkoxy, or 5-membered heteroaryl, １～４ Alkyl and C ３～４ The heterocycloalkyl group is optionally independently selected from halogen, —OH, —CN, C １～４ Alkoxy, C １～４ Alkyl, -NH ２ , C １～４ Alkylamino, DiC １～４ Alkylamino, and -S(O) ｎ (C １～４ alkyl), R ｙ is H, F, Cl, -OH, -CN, -CO(C １～４ alkyl), -S(O) ｎ (C １～４ alkyl), -COOH, -COO(C １～４ alkyl), -CONH ２ , -CONH(C １～４ Alkyl), -CO(diC １～４ alkylamino), -NH ２ , C １～４ Alkylamino, DiC １～４ Alkylamino, -NH(COC １～４ alkyl), -N(C １～４ alkyl)C(=O)F,C １～４ Alkyl, C １～４ Deuteroalkyl, C ３～５ Cycloalkyl, C ３～４ Heterocycloalkyl, C ２～４ Alkenyl, C １～４ Alkoxy, C １～４ deuteroalkoxy, or 5-membered heteroaryl, １～４ Alkyl, C ３～４ Heterocycloalkyl, and C １～４ The alkoxy group is optionally independently selected from halogen, —OH, —CN, C １～４ Alkoxy, C １～４ Alkyl, -NH ２ , C １～４ Alkylamino, DiC １～４ Alkylamino, and -S(O) ｎ (C １～４ alkyl), R ｘ and R ｚ are independently H, halogen, -OH, -CN, -CO(C １～４ alkyl), -S(O)(C １～４ alkyl), -COOH, -COO(C １～４ alkyl), -CONH ２ , -CONH(C １～４ Alkyl), -CO(diC １～４ alkylamino), -NH ２ , C １～４ Alkylamino, DiC １～４ Alkylamino, -NH(COC １～４ alkyl), -N(C １～４ alkyl)C(=O)F,C １～４ Alkyl, C １～４ Deuteroalkyl, C ３～５ Cycloalkyl, C ３～４ Heterocycloalkyl, C ２～４ Alkenyl, C １～４ Alkoxy, C １～４ deuteroalkoxy, or 5-membered heteroaryl, １～４ Alkyl, C ３～４ Heterocycloalkyl, and C １～４ The alkoxy group is optionally independently selected from halogen, —OH, —CN, C １～４ Alkoxy, C １～４ Alkyl, -NH ２ , C １～４ Alkylamino, DiC １～４ Alkylamino, and -S(O) ｎ (C １～４ alkyl), R １ is H, C １～４ Alkyl, C １～４ Haloalkyl, or C １～４ is a deuteroalkyl; x is O, NH, or N(C １～４ alkyl), R ２ teeth, 【Chemistry 8】 or 2-benzofuranyl, where A is independently CH or N, and 【Chemistry 9】 teeth 【Chemistry 10】 Instead, B is a 5-membered heteroaryl containing one heteroatom selected from N, S, and O, and optionally one or two additional N atoms, wherein B is attached to the bicyclic core via a C atom and R ３ is bonded through a N atom, B is attached to the bicyclic core via an N atom; R ３ is bonded via a C atom, or B is attached to the bicyclic core via a C atom; R ３ is bonded via a C atom, During the ceremony, R ２ of 【Chemistry 11】 The moiety or 2-benzofuranyl optionally contains one or two independently selected substituents R ３’ is further replaced by R ３ is CH ２ C.N., C. ２～６ Alkyl, C ３～５ Cycloalkyl, C １～３ Alkoxy, C １～６ Alkylamino, DiC １～６ Alkylamino, -S(O) ｎ (C １～６ alkyl), -CH ２ (C ３～５ Cycloalkyl), -OCH ２ (C ３～５ Cycloalkyl), -NHCH ２ (C ３～５ Cycloalkyl), -S(O) ｎ CH ２ (C ３～５ Cycloalkyl), -CH ２ (C ３～５ heterocycloalkyl), or phenyl, ２～６ Alkyl, C ３～５ Cycloalkyl, C １～３ Alkoxy, C １～６ Alkylamino, DiC １～６ Alkylamino, -S(O) ｎ (C １～６ alkyl), -CH ２ (C ３～５ Cycloalkyl), -OCH ２ (C ３～５ Cycloalkyl), -NHCH ２ (C ３～５ cycloalkyl), and -S(O) ｎ CH ２ (C ３～５ The cycloalkyl) group is optionally substituted with 1 to 9 halogen atoms and optionally substituted with -CN, wherein the phenyl is optionally substituted with halogen, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, and C １～４ substituted with 1 to 3 substituents selected from haloalkoxy; R ３’ are independently halogen, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy or C １～４ is haloalkoxy; R ４ is C １～３ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ３～５ Cycloalkyl, or C ３～５ is cyclohaloalkyl; n is 0, 1, or 2; However, the compound is 3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H,6H,7H,9H-pyrimido[2,1-c][1,4]oxazin-4-one, 7-(azetidin-1-yl)-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-[(dimethylamino)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-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-cyclopropyl-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-fluoro-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-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-pyrimido[1,2-b]pyridazin-4-one, 7-methoxy-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one, 7-methyl-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrazino[1,2-a]pyrimidin-4-one, 7-methyl-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one, 8-methoxy-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-1,2,4-triazol-3-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 8-Methoxy-3-[3-(2,2,2-trifluoroethoxy)phenyl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, or A compound that is not methyl 4-oxo-3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-7-carboxylate, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

2. 2. The compound of claim 1, wherein the compound of formula I is a compound of formula IA, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer. 【Chemistry 12】

3. 2. The compound of claim 1, wherein the compound of formula I is a compound of formula IB, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer. 【Chemistry 13】

4. 2. The compound of claim 1, wherein the compound of formula I is a compound of formula IC, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer. 【Chemistry 14】

5. R ｗ is H, halogen, -CN, -CO(C １～４ alkyl), -S(O) ｎ (C １～４ alkyl), -CONH ２ , -NH ２ , C １～４ Alkylamino, DiC １～４ Alkylamino, -NH(COC １～４ alkyl), -N(C １～４ alkyl)C(=O)F,C １～４ Alkyl, C １～４ Deuteroalkyl, C ３～５ Cycloalkyl, C ２～４ Alkenyl, C １～４ deuteroalkoxy, or 5-membered heteroaryl, １～４ The alkyl group is optionally independently selected from halogen, —OH, —CN, C １～４ Alkoxy, -NH ２ , and JiC １～４ 5. The compound of any one of claims 1, 3, and 4, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein said compound is substituted with one to four substituents selected from alkylamino.

6. R ｗ is H, halogen, -CN, -CONH ２ , -NH ２ , C １～４ Alkylamino, DiC １～４ Alkylamino, or C １～４ Deuteroalkoxyl, wherein １～４ The alkyl group is optionally independently selected from halogen, —OH, C １～４ Alkoxy, -NH ２ , and JiC １～４ 5. The compound of any one of claims 1, 3, and 4, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein said compound is substituted with one to four substituents selected from alkylamino.

7. R ｗ is H, F, Cl, -CN, -COMe, -SMe, -CONH ２ , -NH ２ , -NHMe, -N(CH ３ ) ２ , -NH(COCH ３ ), -N(CH ３ ) C(=O)F, methyl, ethyl, -CD ３ , cyclopropyl, -CH=CH ２ , -OCD ３ or 1,3-oxazol-2-yl, wherein the methyl groups are optionally independently selected from F, Cl, —OH, —CN, methoxy, —NH ２ , and -N(CH ３ ) ２ or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, according to any one of claims 1, 3, and 4, wherein said compound or said tautomer is substituted with 1 to 3 substituents selected from

8. R ｗ is H, F, Cl, -CN, -CONH ２ , -NH ２ , -NHMe, or -OCD ３ wherein the methyl groups are optionally independently selected from F, —OH, methoxy, —NH ２ , and -N(CH ３ ) ２ or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, according to any one of claims 1, 3, and 4, wherein said compound or said tautomer is substituted with 1 to 3 substituents selected from

9. R ｗ is H, halogen, or C １～４ 5. The compound of any one of claims 1, 3, and 4, wherein R is an alkyl group, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

10. R ｗ is H, F, Cl, or methyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

11. R ｗ is H, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

12. R ｘ is H, halogen, -OH, -CN, -CO(C １～４ alkyl), -S(O) ｎ (C １～４ alkyl), -CONH ２ , -NH ２ , C １～４ Alkylamino, DiC １～４ Alkylamino, -NH(COC １～４ Alkyl), -N(C １～４ alkyl)C(=O)F,C １～４ Alkyl, C １～４ Deuteroalkyl, C ３～５ Cycloalkyl, C ２～４ Alkenyl, C １～４ Alkoxy, C １～４ deuteroalkoxy, or 5-membered heteroaryl, １～４ Alkyl and C １～４ The alkoxy group is optionally independently selected from halogen, —OH, —CN, C １～４ Alkoxy, -NH ２ , and JiC １～４ 12. The compound of claim 1, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein said compound is substituted with one to four substituents selected from alkylamino.

13. R ｘ is H, halogen, -OH, -CN, -CONH ２ , -NH ２ , C １～４ Alkylamino, DiC １～４ Alkylamino, C １～４ Alkoxy or C １～４ Deuteroalkoxyl, wherein １～４ Alkyl and C １～４ The alkoxy group is optionally independently selected from halogen, —OH, C １～４ Alkoxy, -NH ２ , and JiC １～４ 12. The compound of claim 1, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein said compound is substituted with one to four substituents selected from alkylamino.

14. R ｘ is H, F, Cl, -OH, -CN, -COMe, -SMe, -CONH ２ , -NH ２ , -NHMe, -N(CH ３ ) ２ , -NH(COCH ３ ), -N(CH ３ ) C(=O)F, methyl, ethyl, -CD ３ , cyclopropyl, -CH=CH ２ , methoxy, ethoxy, -OCD ３ or 1,3-oxazol-2-yl, wherein the methyl and methoxy groups are optionally independently selected from F, Cl, —OH, —CN, methoxy, —NH ２ , and -N(CH ３ ) ２ or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

15. R ｘ is H, F, Cl, -OH, -CN, -CONH ２ , -NH ２ , -NHMe, methoxy, ethoxy, or -OCD ３ wherein the methyl and methoxy groups are optionally independently selected from F, —OH, methoxy, —NH ２ , and -N(CH ３ ) ２ or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

16. R ｘ is H, halogen, -OH, -CN, -CO(C １～４ alkyl), -S(O) ｎ (C １～４ alkyl), -CONH ２ , -NH ２ , C １～４ Alkylamino, DiC １～４ Alkylamino, -NH(COC １～４ alkyl), -N(C １～４ alkyl)C(=O)F,C １～４ Alkyl, C ３～５ Cycloalkyl, C ２～４ Alkenyl, C １～４ Alkoxy, C １～４ deuteroalkoxy, or 5-membered heteroaryl, １～４ Alkyl and C １～４ The alkoxy group is optionally independently selected from halogen, —OH, —CN, C １～４ Alkoxy, -NH ２ , and JiC １～４ 12. The compound of claim 1, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein said compound is substituted with one to four substituents selected from alkylamino.

17. R ｘ is H, halogen, -OH, -CN, -CONH ２ , -NH ２ , C １～４ Alkylamino, DiC １～４ Alkylamino, C １～４ Alkyl, C １～４ Alkoxy or C １～４ Deuteroalkoxy, wherein １～４ Alkyl and C １～４ The alkoxy group is optionally independently selected from halogen, —OH, C １～４ Alkoxy, -NH ２ , and JiC １～４ 12. The compound of claim 1, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein said compound is substituted with one to four substituents selected from alkylamino.

18. R ｘ is H, -CN, -NH ２ , C １～４ Alkoxy or C １～４ 12. The compound of any one of claims 1 to 11, which is deuteroalkoxy, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

19. R ｘ is H, F, Cl, -OH, -CN, -COMe, -SMe, -CONH ２ , -NH ２ , -NHMe, -NH(CH ３ ) ２ , -NH(COCH ３ ), -N(CH ３ ) C(=O)F, methyl, ethyl, cyclopropyl, -CH=CH ２ , methoxy, ethoxy, -OCD ３ or 1,3-oxazol-2-yl, wherein the methyl and methoxy groups are optionally independently selected from F, Cl, —OH, —CN, methoxy, —NH ２ , and -N(CH ３ ) ２ or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

20. R ｘ is H, F, Cl, -OH, -CN, -CONH ２ , -NH ２ , -NHMe, methyl, methoxy, ethoxy, or -OCD ３ wherein the methyl and methoxy groups are optionally independently selected from F, —OH, methoxy, —NH ２ , and -N(CH ３ ) ２ or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

21. R ｘ is H, -CN, -NH ２ , methoxy, or -OCD ３ 12. The compound of any one of claims 1 to 11, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

22. R ｙ is H, F, Cl, -OH, -CN, -CO(C １～４ alkyl), -S(O) ｎ (C １～４ alkyl), -CONH ２ , -NH ２ , C １～４ Alkylamino, DiC １～４ Alkylamino, -NH(COC １～４ alkyl), -N(C １～４ alkyl)C(=O)F,C １～４ Alkyl, C １～４ Deuteroalkyl, C ３～５ Cycloalkyl, C ２～４ Alkenyl, C １～４ Alkoxy, C １～４ deuteroalkoxy, or 5-membered heteroaryl, １～４ Alkyl and C １～４ The alkoxy group is optionally independently selected from halogen, —OH, —CN, C １～４ Alkoxy, -NH ２ , and JiC １～４ 22. The compound of any one of claims 1 to 21, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein said compound is substituted with one to four substituents selected from alkylamino.

23. R ｙ is H, F, Cl, -OH, -CN, -CONH ２ , -NH ２ , C １～４ Alkylamino, DiC １～４ Alkylamino, C １～４ Alkoxy or C １～４ Deuteroalkoxyl, wherein １～４ Alkyl and C １～４ The alkoxy group is optionally independently selected from halogen, —OH, C １～４ Alkoxy, -NH ２ , and JiC １～４ 22. The compound of any one of claims 1 to 21, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein said compound is substituted with one to four substituents selected from alkylamino.

24. R ｙ is H, F, Cl, -OH, -CN, -COMe, -SMe, -CONH ２ , -NH ２ , -NHMe, -N(CH ３ ) ２ , -NH(COCH ３ ), -N(CH ３ ) C(=O)F, methyl, ethyl, -CD ３ , cyclopropyl, -CH=CH ２ , methoxy, ethoxy, -OCD ３ or 1,3-oxazol-2-yl, wherein the methyl and methoxy groups are optionally independently selected from F, Cl, —OH, —CN, methoxy, —NH ２ , and -N(CH ３ ) ２ or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, according to any one of claims 1 to 21, substituted with 1 to 3 substituents selected from:

25. R ｙ is H, F, Cl, -OH, -CN, -CONH ２ , -NH ２ , -NHMe, methoxy, ethoxy, or -OCD ３ wherein the methyl and methoxy groups are optionally independently selected from F, —OH, methoxy, —NH ２ , and -N(CH ３ ) ２ or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, according to any one of claims 1 to 21, substituted with 1 to 3 substituents selected from:

26. R ｙ is H, F, Cl, -CN, -COO(C １～４ Alkyl), C １～４ Alkyl, C ３～５ Cycloalkyl, C ３～４ Heterocycloalkyl, or C １～４ Alkoxy, wherein the C １～４ The alkyl group is optionally independently selected from the group consisting of C １～４ Alkoxy and diC １～４ 22. The compound of any one of claims 1 to 21, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein said compound is substituted with one to four substituents selected from alkylamino.

27. R ｙ is H, F, Cl, -CN, -COOMe, methyl, cyclopropyl, azetidinyl, or methoxy, wherein the methyl group is optionally substituted with 1 to 3 substituents independently selected from methoxy and dimethylamino, or a tautomer thereof, or a pharma- ceutically acceptable salt of the compound or tautomer.

28. R ｙ is H or Cl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

29. R ｚ is H, halogen, -OH, -CN, -CO(C １～４ alkyl), -S(O) ｎ (C １～４ alkyl), -CONH ２ , -NH ２ , C １～４ Alkylamino, DiC １～４ Alkylamino, -NH(COC １～４ Alkyl), -N(C １～４ alkyl)C(=O)F,C １～４ Alkyl, C １～４ Deuteroalkyl, C ３～５ Cycloalkyl, C ２～４ Alkenyl, C １～４ Alkoxy, C １～４ deuteroalkoxy, or 5-membered heteroaryl, １～４ Alkyl and C １～４ The alkoxy group is optionally independently selected from halogen, —OH, —CN, C １～４ Alkoxy, -NH ２ , and JiC １～４ 29. The compound of any one of claims 1 to 3 and 5 to 28, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein said compound is substituted with one to four substituents selected from alkylamino.

30. R ｚ is H, halogen, -OH, -CN, -CONH ２ , -NH ２ , C １～４ Alkylamino, DiC １～４ Alkylamino, C １～４ Alkoxy or C １～４ Deuteroalkoxyl, wherein １～４ Alkyl and C １～４ The alkoxy group is optionally independently selected from halogen, —OH, C １～４ Alkoxy, -NH ２ , and JiC １～４ 29. The compound of any one of claims 1 to 3 and 5 to 28, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein said compound is substituted with one to four substituents selected from alkylamino.

31. R ｚ is H, F, Cl, -OH, -CN, -COMe, -SMe, -CONH ２ , -NH ２ , -NHMe, -N(CH ３ ) ２ , -NH(COCH ３ ), -N(CH ３ ) C(=O)F, methyl, ethyl, -CD ３ , cyclopropyl, -CH=CH ２ , methoxy, ethoxy, -OCD ３ or 1,3-oxazol-2-yl, wherein the methyl and methoxy groups are optionally independently selected from F, Cl, —OH, —CN, methoxy, —NH ２ , and -N(CH ３ ) ２ or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

32. R ｚ is H, F, Cl, -OH, -CN, -CONH ２ , -NH ２ , -NHMe, methoxy, ethoxy, or -OCD ３ wherein the methyl and methoxy groups are optionally independently selected from F, —OH, methoxy, —NH ２ , and -N(CH ３ ) ２ or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

33. R ｚ is H or C １～４ 29. The compound of any one of claims 1 to 3 and 5 to 28, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

34. R ｚ is H or methyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

35. R ｚ is H, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

36. 2. The compound of claim 1, wherein the compound of formula I is a compound of formula ID, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer. 【Chemistry 15】

37. R ｙ is H, F, Cl, -OH, -CN, -CO(C １～４ alkyl), -S(O) ｎ (C １～４ alkyl), -CONH ２ , -NH ２ , C １～４ Alkylamino, DiC １～４ Alkylamino, -NH(COC １～４ Alkyl), -N(C １～４ alkyl)C(=O)F,C １～４ Alkyl, C １～４ Deuteroalkyl, C ３～５ Cycloalkyl, C ２～４ Alkenyl, C １～４ Alkoxy, C １～４ deuteroalkoxy, or 5-membered heteroaryl, １～４ Alkyl and C １～４ The alkoxy group is optionally independently selected from halogen, —OH, —CN, C １～４ Alkoxy, -NH ２ , and JiC １～４ 37. The compound of claim 36, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein said compound is substituted with one to four substituents selected from alkylamino.

38. R ｙ is H, F, Cl, -OH, -CN, -CONH ２ , -NH ２ , C １～４ Alkylamino, DiC １～４ Alkylamino, C １～４ Alkoxy or C １～４ Deuteroalkoxyl, wherein １～４ Alkyl and C １～４ The alkoxy group is optionally independently selected from halogen, —OH, C １～４ Alkoxy, -NH ２ , and JiC １～４ 37. The compound of claim 36, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein said compound is substituted with one to four substituents selected from alkylamino.

39. R ｙ is H, F, Cl, -OH, -CN, -COMe, -SMe, -CONH ２ , -NH ２ , -NHMe, -N(CH ３ ) ２ , -NH(COCH ３ ), -N(CH ３ ) C(=O)F, methyl, ethyl, -CD ３ , cyclopropyl, -CH=CH ２ , methoxy, ethoxy, -OCD ３ or 1,3-oxazol-2-yl, wherein the methyl and methoxy groups are optionally independently selected from F, Cl, —OH, —CN, methoxy, —NH ２ , and -N(CH ３ ) ２ or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

40. R ｙ is H, F, Cl, -OH, -CN, -CONH ２ , -NH ２ , -NHMe, methoxy, ethoxy, or -OCD ３ wherein the methyl and methoxy groups are optionally independently selected from F, —OH, methoxy, —NH ２ , and -N(CH ３ ) ２ or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

41. R ｙ is H, F, Cl, -CN, -COO(C １～４ Alkyl), C １～４ Alkyl, C ３～５ Cycloalkyl, C ３～４ Heterocycloalkyl, or C １～４ Alkoxy, wherein the C １～４ The alkyl group is optionally independently selected from the group consisting of C １～４ Alkoxy and diC １～４ 37. The compound of claim 36, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein said compound is substituted with one to four substituents selected from alkylamino.

42. R ｙ is H, F, Cl, -CN, -COOMe, methyl, cyclopropyl, azetidinyl, or methoxy, wherein the methyl group is optionally substituted with 1 to 3 substituents independently selected from methoxy and dimethylamino, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

43. R ｙ is H or Cl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

44. R ｚ is H, halogen, -OH, -CN, -CO(C １～４ alkyl), -S(O) ｎ (C １～４ alkyl), -CONH ２ , -NH ２ , C １～４ Alkylamino, DiC １～４ Alkylamino, -NH(COC １～４ alkyl), -N(C １～４ alkyl)C(=O)F,C １～４ Alkyl, C １～４ Deuteroalkyl, C ３～５ Cycloalkyl, C ２～４ Alkenyl, C １～４ Alkoxy, C １～４ deuteroalkoxy, or 5-membered heteroaryl, １～４ Alkyl and C １～４ The alkoxy group is optionally independently selected from halogen, —OH, —CN, C １～４ Alkoxy, -NH ２ , and JiC １～４ 44. The compound of any one of claims 36 to 43, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein said compound is substituted with one to four substituents selected from alkylamino.

45. R ｚ is H, halogen, -OH, -CN, -CONH ２ , -NH ２ , C １～４ Alkylamino, DiC １～４ Alkylamino, C １～４ Alkoxy or C １～４ Deuteroalkoxyl, wherein １～４ Alkyl and C １～４ The alkoxy group is optionally independently selected from halogen, —OH, C １～４ Alkoxy, -NH ２ , and JiC １～４ 44. The compound of any one of claims 36 to 43, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein said compound is substituted with one to four substituents selected from alkylamino.

46. R ｚ is H, F, Cl, -OH, -CN, -COMe, -SMe, -CONH ２ , -NH ２ , -NHMe, -N(CH ３ ) ２ , -NH(COCH ３ ), -N(CH ３ ) C(=O)F, methyl, ethyl, -CD ３ , cyclopropyl, -CH=CH ２ , methoxy, ethoxy, -OCD ３ or 1,3-oxazol-2-yl, wherein the methyl and methoxy groups are optionally independently selected from F, Cl, —OH, —CN, methoxy, —NH ２ , and -N(CH ３ ) ２ or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

47. R ｚ is H, F, Cl, -OH, -CN, -CONH ２ , -NH ２ , -NHMe, methoxy, ethoxy, or -OCD ３ wherein the methyl and methoxy groups are optionally independently selected from F, —OH, methoxy, —NH ２ , and -N(CH ３ ) ２ or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

48. R ｚ is H, halogen, or C １～４ 44. The compound of any one of claims 36 to 43, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein R is an alkyl group.

49. R ｚ is H, F, Cl, or methyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

50. R ｚ is H, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

51. R １ is H, methyl, CH ２ F or CD ３ 51. The compound of any one of claims 36 to 50, wherein:

52. R １ is H, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

53. 2. The compound of claim 1, wherein the compound of formula I is a compound of formula IE, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer. 【Chemistry 16】

54. 54. The compound of claim 53, wherein x is O, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

55. 54. The compound of claim 53, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein x is NH.

56. x is N(C １～４ 54. The compound of claim 53, wherein R is H, R is H, R is H, R is H, R is H, R is H, R is H, R is H, R is H, R is H, R is H, R is H, R is H,

57. x is NCH ３ 54. The compound of claim 53, wherein:

58. R ２ teeth, 【Chemistry 17】 58. The compound of any one of claims 1 to 57, wherein:

59. R ２ teeth, 【Chemistry 18】 58. The compound of any one of claims 1 to 57, wherein:

60. R ２ teeth, 【Chemistry 19】 58. The compound of any one of claims 1 to 57, wherein:

61. R ２ teeth, 【Chemistry 20】 58. The compound of any one of claims 1 to 57, wherein:

62. R ２ teeth, 【Chemistry 21】 58. The compound of any one of claims 1 to 57, wherein:

63. R ２ teeth, 【Chemical 22】 58. The compound of any one of claims 1 to 57, wherein:

64. R ２ teeth, 【Chemistry 23】 and 58. The compound of any one of claims 1 to 57, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein B is a 5-membered heteroaryl containing two N atoms.

65. B is attached to the bicyclic core via a C atom; R ３ is attached through an N atom, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

66. B is attached to the bicyclic core via an N atom; R ３ is attached via a C atom, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

67. B is attached to the bicyclic core via a C atom; R ３ is attached via a C atom, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

68. R ２ teeth, 【Chemistry 24】 58. The compound of any one of claims 1 to 57, wherein:

69. R ２ teeth, 【Chemistry 25】 58. The compound of any one of claims 1 to 57, wherein:

70. R ２ is 2-benzofuranyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

71. R ２ of 【Chemistry 26】 The moiety or 2-benzofuranyl optionally contains one substituent R ３’ 71. The compound of any one of claims 1 to 70, further substituted by:

72. R ３ of 【Chemistry 27】 The moiety or 2-benzofuranyl may have one or two independently selected substituents R ３’ 71. The compound of any one of claims 1 to 70, which is not further substituted by, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

73. R ３ is C ２～６ Alkyl, C １～３ Alkoxy, -CH ２ (C ３～５ Cycloalkyl), -OCH ２ (C ３～５ cycloalkyl), or phenyl, ２～６ Alkyl, C １～３ Alkoxy, -CH ２ (C ３～５ cycloalkyl), and -OCH ２ (C ３～５ 73. The compound of any one of claims 1 to 69, 71, and 72, wherein the phenyl) group is optionally substituted with 1 to 5 halogen atoms and optionally substituted with -CN, wherein the phenyl is optionally substituted with one halogen substituent, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

74. R ３ is C ２～６ Alkyl, C １～３ Alkoxy or -OCH ２ (C ３～５ cycloalkyl), wherein ２～６ Alkyl, C １～３ Alkoxy, and -OCH ２ (C ３～５ 73. The compound of any one of claims 1 to 69, 71, and 72, wherein the (cycloalkyl) group is optionally substituted with 1 to 5 halogen atoms and optionally substituted with -CN, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

75. R ３ is C ２～６ Alkyl or C １～３ Alkoxy, wherein the C ２～６ Alkyl and C １～３ 73. The compound of any one of claims 1 to 69, 71, and 72, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein the alkoxy group is optionally substituted with 3 to 5 halogen atoms.

76. R ３ is 2,2,2-trifluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 2,2,3,3,3-pentafluoropropyl, -OCH ２ CN, -OC(CH ３ ) ２ CN, difluoromethoxy, trifluoromethoxy, -OCH(CN)CH ３ , 2-fluoroethoxy, 2,2,-difluoroethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoropropoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, cyclopropylmethyl, (2,2-difluorocyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, cyclopropylmethoxy, (2,2-difluorocyclopropyl)methoxy, phenyl, 3-fluorophenyl, or 4-fluorophenyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

77. R ３ is 2,2-difluoropropyl, 4,4,4-trifluorobutyl, 2,2,3,3,3-pentafluoropropyl, -OC(CH ３ ) ２ CN, trifluoromethoxy, -OCH(CN)CH ３ , 2-fluoroethoxy, 2,2,-difluoroethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoropropoxy, cyclopropylmethoxy, or (2,2-difluorocyclopropyl)methoxy, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

78. R ３ is 2,2,3,3,3-pentafluoropropyl or 2,2,2-trifluoroethoxy, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

79. R ３’ are independently halogen or C １～４ 80. The compound of any one of claims 1 to 71 and 73 to 78, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

80. R ３’ is F or methyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

81. R ４ is C １～３ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy or C ３～５ 81. The compound of any one of claims 1 to 80, wherein R is cycloalkyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

82. R ４ is C １～３ 81. The compound of any one of claims 1 to 80, which is haloalkyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

83. R ４ is methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, or cyclopropyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

84. R ４ is ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, or cyclopropyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

85. R ４ is trifluoromethyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

86. 86. The compound of any one of claims 1 to 85, wherein n is 0, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

87. 86. The compound of any one of claims 1 to 85, wherein n is 1, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

88. 86. The compound of any one of claims 1 to 85, wherein n is 2, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

89. The compound is (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 2. The compound of claim 1 which is N-methyl-4-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxamide, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

90. The compound is (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, 2-(4-(8-methoxy-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)phenoxy)-2-methylpropanenitrile, 2-(difluoromethyl)-8-methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(fluoromethyl)-8-methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-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-ethyl-8-methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-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-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-8-methoxy-2-(trifluoromethyl)-4H-pyrido[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-(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-((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-difluoroethoxy)-2-fluorophenyl)-8-methoxy-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-methoxy-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, 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-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carboxamide, 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-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-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, 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-((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-((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-(aminomethyl)-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-(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-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-(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-(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-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-ethoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-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-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-(2-methyl-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-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-(trifluoromethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrimido[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-[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-4-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one, 8-Methoxy-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, or 2. The compound of claim 1 which is 8-methoxy-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2-(trifluoromethyl)-4H-pyrimido[1,2-b]pyridazin-4-one, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

91. The compound is 4-oxo-3-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile, 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-amino-3-(4-(2,2,2-trifluoroethoxy)phenyl)-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, or 2. The compound of claim 1 which is 8-methoxy-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

92. The compound is 【Chemistry 28】 2. The compound of claim 1, wherein:

93. The compound is 【Chemical 29】 2. The compound of claim 1, wherein:

94. The compound is 【Chemistry 30】 2. The compound of claim 1, wherein:

95. The compound is 【Chemistry 31】 2. The compound of claim 1, wherein:

96. The compound is 【Chemistry 32】 2. The compound of claim 1, wherein:

97. The compound is 【Chemical 33】 2. The compound of claim 1, wherein:

98. 98. A pharmaceutical composition comprising a compound according to any one of claims 1 to 97, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, and a pharma- ceutically acceptable excipient.

99. A compound according to any one of claims 1 to 97, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to claim 98, for use as a medicament.

100. 98. A compound according to any one of claims 1 to 97, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to claim 98, for use in reducing body weight.

101. 98. A compound according to any one of claims 1 to 97, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to claim 98, for use in reducing the body mass index of a subject.

102. A compound according to any one of claims 1 to 97, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to claim 98, for use in the treatment of a metabolic disorder.

103. 98. A compound according to any one of claims 1 to 97, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to claim 98, for use in the treatment of a cardiovascular disorder.

104. 98. A compound according to any one of claims 1 to 97, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to claim 98, for use in the treatment of diabetes.

105. 98. A compound according to any one of claims 1 to 97, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to claim 98, for use in the treatment of obesity.

106. 98. A compound according to any one of claims 1 to 97, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to claim 98, for use in the treatment of dyslipidemia.

107. 98. A compound according to any one of claims 1 to 97, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to claim 98, for use in the treatment of non-alcoholic steatohepatitis (NASH).

108. 98. Use of a compound according to any one of claims 1 to 97, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to claim 98, in the preparation of a medicament for reducing the body weight or body mass index of a subject.

109. 98. Use of a compound according to any one of claims 1 to 97, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to claim 98, in the preparation of a medicament for treating a metabolic or cardiovascular disorder.

110. 98. Use of a compound according to any one of claims 1 to 97, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to claim 98, in the preparation of a medicament for the treatment of diabetes, obesity, dyslipidemia, or non-alcoholic steatohepatitis (NASH).

111. N-(3-iodo-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-8-yl)acetamide, 8-bromo-3-iodo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 8-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 8-hydroxy-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile, 3-iodo-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-8-carbonitrile, 3-bromo-8-methoxy-2-(trifluoromethyl)pyrimido[1,2-a]pyrimidin-4-one, 8-Methoxy-2-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one, or The compound is 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

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