Heterocyclic Compounds as Delta-5 Desaturase Inhibitors and Methods of Use

Abstract

To provide compounds useful for the inhibition of Delta-5 Desaturase.SOLUTION: There is provided a compound of Formula I or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where R1 is O, S or NH, R2 is a substituted benzene ring or a 5-membered heteroaryl, R4 is C1-3 alkyl or the like, and a group indicated with dashed lines forms a 5-membered ring with N and C.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 939,821, filed on November 25, 2019, the entire disclosure of which is incorporated herein by reference.

[0002] The present disclosure provides compounds useful for inhibiting delta - 5 desaturase ( "D5D"). The present disclosure also provides pharmaceutical compositions containing the compounds, uses of the compounds, and compositions for treating, for example, metabolic diseases or cardiovascular diseases. Further, the present disclosure provides intermediates useful for the synthesis of compounds of formula I.

Background Art

[0003] Polyunsaturated fatty acids ( "PUFA") play important physiological functions in the human body. Kroeger J and Schulze MB, 2012, page 4. PUFA function as an energy source and a component of cell membranes. Ibid. Also, PUFA regulate genes and serve as biosynthetic precursors for other physiologically relevant biomolecules such as eicosanoids and endogenous cannabinoids. Ibid. Di Marzo V and Matias I, 2005, page 585.

[0004] Eicosanoids are signaling molecules with multiple functions, and in particular, they regulate the human inflammatory response. Harizi H et al., 2008. Endogenous cannabinoids (N - arachidonoylethanolamine (anandamide), and 2 - arachidonoylglycerol (2 - AG) are endogenous ligands of cannabinoid receptors that have been established to have roles 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] In particular, a relevant part of the metabolic pathway of a specific PUFA, linoleic acid ("LA"), which results in the formation of anti-inflammatory and pro-inflammatory eicosanoids and endogenous cannabinoids, is shown in the above scheme.

[0008] The desaturase enzymes that catalyze specific steps in the conversion of LA to AA are delta-6 desaturase ("D6D"; encoded by the fatty acid desaturase 2 ("FADS2") gene) and delta-5 desaturase ("D5D"; encoded by the fatty acid desaturase 1 ("FADS1") gene). Yashiro H et al., 2016, page 2 / 18. By selectively inhibiting D5D activity, the amount of DGLA increases while the amount of AA produced decreases. Such pharmacological intervention would result in, for example, reducing the downstream production of pro-inflammatory eicosanoids and endogenous cannabinoids and enhancing anti-inflammatory eicosanoids, both of which can overall improve symptoms related to inflammation and improve the energy balance. Yashiro H et al., 2016, page 3 / 18. Di Marzo V and Matias I, 2005, page 585. This is particularly relevant for subjects with a high intake of LA, such as humans exposed to Western-style diets. Yashiro H et al., 2016, page 3 / 18.

[0009] The FADS1-3 loci have been associated with many metabolic traits in genome-wide association studies, including fasting glucose, plasma lipids, and body weight. Fumagalli M et al., 2015. Willer CJ et al., 2013. Dupuis J et al., 2010. Increases or elevations in each of these metabolic traits have been associated with the FADS1-3 loci and also 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 evidence from human genes supporting the role of FADS1 / D5D in metabolic disease, FADS1 knockout ("KO") mice also exhibit a phenotype protected from diet-induced obesity, including low body fat content, improved glucose control, and reduced lipid levels in circulating blood. Powell DR et al., 2016, page 197. In addition, FADS1 KO mice are resistant to the development of atherosclerotic plaques. Ibid.

[0011] Desaturase enzyme activity has been linked to various diseases, particularly metabolic and cardiovascular diseases such as obesity, diabetes, non-alcoholic steatohepatitis ("NASH"), dyslipidemia, and coronary artery disease. Tosi F et al., 2014; Kroeger J and Schulze MB, 2012; and Merino DM et al., 2010. Thus, pharmacological inhibition of D5D is a target for the purpose of treating metabolic, cardiovascular, and other diseases. Powell DR et al., 2016, page 197.

[0012] Although there have been some advancements in the field of small molecule therapies (e.g., Miyahisa I et al., 2016; Yashiro H et al., 2016; and Baugh SD et al., 2015), considering the significant and ongoing societal burden caused by, for example, 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), there remains a need for inhibitors of D5D that may be suitable for use as therapeutic agents.

Prior Art Documents

Non-Patent Documents

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Summary of the Invention

Means for Solving the Problems

[0014] First, in this specification, a compound of formula I

Chemical Formula

Chemical Formula

Chemical formula

Chemical formula

[0015] Second, the present specification provides 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 compound of formula I as described above herein, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition for use in reducing the body weight of a subject or for use in reducing the body mass index of a subject.

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

[0018] Fifth, the present specification provides a compound of formula I as described above herein, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition 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] Hereinafter, embodiments of the present disclosure will be referred to in detail. It will be understood that while specific embodiments of the present disclosure are described, the present disclosure is not intended to be limited to those described embodiments. On the contrary, references to embodiments of the present disclosure are intended to encompass alternative forms, modifications, and equivalents that may fall within the spirit and scope of the present disclosure as defined by the appended claims.

Mode for Carrying Out the Invention

[0020] As Embodiment 1, the present specification discloses a compound of formula I

Chemical formula

Chemical formula

Chemical Formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0021] As Embodiment 2, herein provided is a compound described in Embodiment 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein the compound is 1,3,3-trimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyrimidin-5-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; or not 2-[(methylamino)methyl]-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one.

[0022] As Embodiment 3, herein provided is a compound described in Embodiment 1 or Embodiment 2, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein x, y, and z are independently selected from CR, N, and NR''.

[0023] As Embodiment 4, herein provided is a compound described in Embodiment 1 or Embodiment 2, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein x, y, and z are independently selected from CR, N, and S.

[0024] As Embodiment 5, this specification provides the compound described in Embodiment 1 or Embodiment 2, or its tautomer, or a pharmaceutically acceptable salt of the compound or the tautomer, where

Chemical formula

Chemical formula

[0025] As Embodiment 6, this specification provides the compound described in Embodiment 1 or Embodiment 2, or its tautomer, or a pharmaceutically acceptable salt of the compound or the tautomer, where

Chemical formula

Chemical formula

[0026] As Embodiment 7, this specification provides the compound described in Embodiment 1 or Embodiment 2, or its tautomer, or a pharmaceutically acceptable salt of the compound or the tautomer, where

Chemical formula

Chemical formula

[0027] As Embodiment 8, this specification provides the compound described in any one of Embodiments 1 to 7, or its tautomer, or a pharmaceutically acceptable salt of the compound or the tautomer, where When present, each of R and R’ is independently selected from H, halogen, -COO(C 1~4 alkyl), C 1~4 alkyl, -(CH2) m (C 3~5 cycloalkyl), -CH2(C 3~5 heterocycloalkyl), C 1~4 deuterated alkyl, C 3~5 cycloalkyl, C 3~4 heterocycloalkyl, C 2~4 alkynyl, C 1~4 alkoxy, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl; C 1~4 alkyl groups are optionally substituted with 1 to 4 F or with substituents selected from -OH, -CN, C 1~4 alkoxy, C 1~4 alkylamino, and diC 1~4 alkylamino; and -(CH2) m (C 3~5 cycloalkyl), 5-membered heteroaryl, and 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, -OH, and C 1~4 alkyl.

[0028] As Embodiment 9, provided herein are the compounds described in any one of Embodiments 1 to 7, or their tautomers, or pharmaceutically acceptable salts of said compounds or said tautomers, wherein when present, each of R and R’ is independently selected from H, halogen, C 1~4 alkyl, C 1~4 deuterated alkyl, and C 1~4 alkoxy; C 1~4 alkyl groups are optionally substituted with substituents selected from -OH and -CN.

[0029] As Embodiment 10, the present specification provides a compound described in any one of Embodiments 1 to 7, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where when present, R and R' are each independently selected from H and C 1~4 alkyl.

[0030] As Embodiment 11, the present specification provides a compound described in any one of Embodiments 1 to 7, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where when present, R and R' are each independently selected from H, F, Cl, -COOMe, methyl, ethyl, isopropyl, fluoromethyl, trifluoromethyl, -CH2OH, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, -CH2CN, 2-hydroxypropyl, -CH2OCH3, -CH2CH2OCH3, methylaminomethyl, dimethylaminomethyl, 2-(dimethylamino)ethyl, cyclopropylmethyl, (2,2-difluorocyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, (1-hydroxycyclopropyl)ethyl, -CD3, cyclopropyl, (oxetan-3-yl)methyl, oxetan-3-yl, prop-2-yn-1-yl, methoxy, phenyl, pyrazolyl, 1-methyl-pyrazol-4-yl, pyridinyl, pyrazinyl, pyrimidinyl, 6-methylpyridin-2-yl, and 6-chloropyridin-2-yl.

[0031] As Embodiment 12, the present specification provides a compound described in any one of Embodiments 1 to 7, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where when present, R and R' are each independently selected from H, Cl, methyl, -CH2OH, 2-hydroxyethyl, -CH2CN, -CD3, and methoxy.

[0032] As Embodiment 13, the present specification provides a compound described in any one of Embodiments 1 to 7, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where when present, each of R and R’ is independently selected from H and methyl.

[0033] As Embodiment 14, the present specification provides a compound described in any one of Embodiments 1 to 13, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where when present, each R’’ is independently selected from H, -COO(C 1~4 alkyl), C 1~4 alkyl, -(CH2) m (C 3~5 cycloalkyl), -CH2(C 3~5 heterocycloalkyl), C 1~4 deuterated alkyl, C 3~5 cycloalkyl, C 3~4 heterocycloalkyl, C 2~4 alkynyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl; C 1~4 the alkyl group is optionally substituted with 1 to 4 F atoms, or is optionally substituted with a substituent selected from -OH, -CN, C 1~4 alkoxy, C 1~4 alkylamino, and diC 1~4 alkylamino; and -(CH2) m (C 3~5 cycloalkyl), 5-membered heteroaryl, and 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, -OH, and C 1~4 alkyl.

[0034] As Embodiment 15, the present specification provides a compound described in any one of Embodiments 1 to 13, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where when present, each R’’ is independently selected from H, C1~4 alkyl, and C 1~4 independently selected from deuterated alkyl; C 1~4 The alkyl group is optionally substituted with a substituent selected from -OH and -CN.

[0035] As Embodiment 16, provided herein is a compound according to any one of Embodiments 1 to 13, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein, when present, each R'' is independently selected from H and C 1~4 alkyl.

[0036] As Embodiment 17, provided herein is a compound according to any one of Embodiments 1 to 13, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein, when present, each R'' is independently selected from H, -COOMe, methyl, ethyl, isopropyl, fluoromethyl, trifluoromethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, -CH2CN, 2-hydroxypropyl, -CH2OCH3, -CH2CH2OCH3, dimethylaminomethyl, 2-(dimethylamino)ethyl, cyclopropylmethyl, (2,2-difluorocyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, (1-hydroxycyclopropyl)ethyl, -CD3, cyclopropyl, (oxetan-3-yl)methyl, oxetan-3-yl, prop-2-yn-1-yl, phenyl, pyrazolyl, 1-methyl-pyrazol-4-yl, pyridinyl, pyrazinyl, pyrimidinyl, 6-methylpyridin-2-yl, and 6-chloropyridin-2-yl.

[0037] As Embodiment 18, provided herein is a compound according to any one of Embodiments 1 to 13, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein, when present, each R'' is independently selected from H, methyl, 2-hydroxyethyl, -CH2CN, and -CD3.

[0038] As Embodiment 19, the present specification provides a compound described in any one of Embodiments 1 to 13, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein, when present, each R″ is independently selected from H and methyl.

[0039] As Embodiment 20, the present specification provides a compound described in any one of Embodiments 1 to 19, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein, when present, R of the first CR or CRR′ group and R of the second CR or CRR′ group form cyclopropyl together with the atom to which they are attached.

[0040] As Embodiment 21, the present specification provides a compound described in any one of Embodiments 1 to 20, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein, R 1 is O or S.

[0041] As Embodiment 22, the present specification provides a compound described in any one of Embodiments 1 to 20, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein, R 1 is O.

[0042] As Embodiment 23, the present specification provides a compound described in any one of Embodiments 1 to 22, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein, R 2 is

Chemical formula

[0043] As Embodiment 24, this specification provides a compound described in any one of Embodiments 1 to 22, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where R 2 is

Chemical formula

[0044] As Embodiment 25, this specification provides a compound described in any one of Embodiments 1 to 22, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where R 2 is

Chemical formula

[0045] As Embodiment 26, this specification provides a compound described in any one of Embodiments 1 to 22, 24, and 25, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where A is bonded to the bicyclic core via a C atom, and R 3 is bonded via an N atom.

[0046] As Embodiment 27, this specification provides a compound described in any one of Embodiments 1 to 22, 24, and 25, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where A is bonded to the bicyclic core via an N atom, and R 3 is bonded via a C atom.

[0047] As Embodiment 28, this specification provides a compound described in any one of Embodiments 1 to 22, 24, and 25, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where A is bonded to the bicyclic core via a C atom, and R 3is bonded via a C atom.

[0048] As Embodiment 29, the present specification provides a compound described in any one of Embodiments 1 to 22, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where R 2 is

Chemical formula

[0049] As Embodiment 30, the present specification provides a compound described in any one of Embodiments 1 to 22, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where R 2 is

Chemical formula

[0050] As Embodiment 31, the present specification provides a compound described in any one of Embodiments 1 to 30, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where R 2 portion

Chemical formula

[0051] As Embodiment 32, the present specification provides a compound described in any one of Embodiments 1 to 30, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where R 2 portion

Chemical formula

[0052] As Embodiment 33, the present specification provides a compound described in any one of Embodiments 1 to 30, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where R 2 portion

Chemical Formula

[0053] As Embodiment 34, the present specification provides a compound described in any one of Embodiments 1 to 33, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where R 3 is C 1~6 alkyl, C 2~6 alkoxy, -CH2(C 3~5 cycloalkyl), -OCH2(C 3~5 cycloalkyl), -CH2(C 3~5 heterocycloalkyl), or phenyl; C 1~6 alkyl, C 2~6 alkoxy, -CH2(C 3~5 cycloalkyl), and -OCH2(C 3~5 cycloalkyl) groups are optionally substituted with 1 to 9 halogen atoms and optionally substituted with -CN, and phenyl is optionally substituted with one halogen substituent.

[0054] As Embodiment 35, the present specification provides a compound described in any one of Embodiments 1 to 33, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where R 3 is C 1~6 alkyl, C 2~6 alkoxy, -CH2(C 3~5 cycloalkyl), or -CH2(C 3~5 heterocycloalkyl); C 1~6 alkyl, C2~6 Alkoxy, and -CH2(C 3~5 cycloalkyl) groups are optionally substituted with 1 to 9 halogen atoms.

[0055] As Embodiment 36, the present specification provides a compound described in any one of Embodiments 1 to 33, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein R 3 is C 1~6 alkyl, C 2~6 alkoxy, -CH2(C 3~5 cycloalkyl), or -CH2(C 3~5 heterocycloalkyl); C 1~6 alkyl, C 2~6 alkoxy, and -CH2(C 3~5 cycloalkyl) groups are substituted with 2 to 5 halogen atoms.

[0056] As Embodiment 37, the present specification provides a compound described in any one of Embodiments 1 to 33, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the 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, -OCH2CN, -OC(CH3)2CN, difluoromethoxy, trifluoromethoxy, -OCH(CN)CH3, 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, (oxetan-3-yl)methyl, phenyl, 3-fluorophenyl, or 4-fluorophenyl.

[0057] As Embodiment 38, this specification provides a compound described in any one of Embodiments 1 to 33, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where R 3 is 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 2,2,2-trifluoroethoxy, or (2,2-difluorocyclopropyl)methyl.

[0058] As Embodiment 39, this specification provides a compound described in any one of Embodiments 1 to 30 and 32 to 38, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where R 3’ is independently halogen or C 1~4 alkyl.

[0059] As Embodiment 40, this specification provides a compound described in any one of Embodiments 1 to 30 and 32 to 38, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where R 3’ is independently F or methyl.

[0060] As Embodiment 41, this specification provides a compound described in any one of Embodiments 1 to 40, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where R 4 is C 1~3 alkyl, C 1~4 haloalkyl, C 1~4 alkoxy, or C 3~5 cycloalkyl.

[0061] As Embodiment 42, this specification provides a compound described in any one of Embodiments 1 to 40, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where R 4 is C 1~4It is a haloalkyl.

[0062] As Embodiment 43, this specification provides a compound described in any one of Embodiments 1 to 40, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein R 4 is methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, or cyclopropyl.

[0063] As Embodiment 44, this specification provides a compound described in any one of Embodiments 1 to 40, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein R 4 is trifluoromethyl.

[0064] As Embodiment 45, this specification provides a compound described in any one of Embodiments 1 to 44, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein n is 0.

[0065] As Embodiment 46, this specification provides a compound described in any one of Embodiments 1 to 44, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein n is 1.

[0066] As Embodiment 47, this specification provides a compound described in any one of Embodiments 1 to 44, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein n is 2.

[0067] As Embodiment 48, this specification provides a compound described in any one of Embodiments 1 to 47, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein m is 1.

[0068] As Embodiment 49, this specification provides a compound described in any one of Embodiments 1 to 47, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, where m is 2.

[0069] As Embodiment 50, this specification provides a compound described in Embodiment 1, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, and the compound is 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 3-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-3,7-bis(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-Fluoro-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 7-(Trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-Chloro-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-(Methoxymethyl)-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-Cyclopropyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-Cyclopropyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2,3-Dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-3H,7H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2,3-Dimethyl-5-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-3H,7H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 7-Ethyl-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 1,2-Dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-1H,7H-pyrazolo[1,5-a]pyrimidin-7-one; 1-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-1H,7H-pyrazolo[1,5-a]pyrimidin-7-one; 1,3-Dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-1H,7H-pyrazolo[1,5-a]pyrimidin-7-one; 3-[1-(2,2,3,3,3-Pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H,6H,7H,8H-pyrrolo[1,2-a]pyrimidin-4-one; 2-Methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-(Trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H,6H,7H,8H-pyrrolo[1,2-a]pyrimidin-4-one; 6-[1-(2,2,3,3,3-Pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-2H,3H,5H-[1,3]thiadiazolo[3,2-a]pyrimidin-5-one; 6-{1-[(2,2-Difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-2-methyl-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-2H,3H,5H-[1,3]thiadiazolo[3,2-a]pyrimidin-5-one; 8-[1-(2,2,3,3,3-Pentafluoropropyl)-1H-pyrazol-4-yl]-9-(trifluoromethyl)-6,10-diazatricyclo[4.4.0.0 2 , 4 deca-1(10),8-dien-7-one; 6-{1-[(3,3-Difluorocyclobutyl)methyl]-1H-pyrazol-4-yl}-2-methyl-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 1-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-[1,2,4]triazolo[4,3-a]pyrimidin-5-one; 3-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-3H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidin-7-one; 2-Methyl-6-{1-[(oxetan-3-yl)methyl]-1H-pyrazol-4-yl}-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-3-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 6-[4-(2,2,2-Trifluoroethoxy)phenyl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-(Hydroxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-(Hydroxymethyl)-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-Chloro-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(propan-2-yl)-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione; 1-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 3-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-3H,7H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]oxazolo[3,2-a]pyrimidin-5-one; 2-Methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 7-Ethoxy-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-(Methoxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-Methoxy-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 3-chloro-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-(hydroxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-(hydroxymethyl)-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione; 2-chloro-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-chloro-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-cyclopropyl-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-chloro-1-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-Dimethyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-Dimethyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-(Methoxymethyl)-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-Ethyl-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(2-Methoxyethyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(propan-2-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-{1-[(2,2-Difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-1,2-dimethyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-{1-[(3,3-Difluorocyclobutyl)methyl]-1H-pyrazol-4-yl}-1,2-dimethyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-[1-(Cyclopropylmethyl)-1H-pyrazol-4-yl]-1,2-dimethyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(Cyclopropylmethyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-(Methoxymethyl)-1-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(2-Hydroxypropyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-Dimethyl-6-{1-[(oxetan-3-yl)methyl]-1H-pyrazol-4-yl}-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(Cyclopropylmethyl)-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-[2-(Dimethylamino)ethyl]-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(Cyclopropylmethyl)-2-methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-[2-(Dimethylamino)ethyl]-2-methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-Dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-3-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methoxy-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methoxy-1-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-{1-[(2,2-Difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-( 2 H3)methyl-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-( 2 H3)methyl-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(2-Hydroxyethyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; Methyl 2-methyl-5-oxo-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidine-1-carboxylate; 1-[(2,2-Difluorocyclopropyl)methyl]-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-[(3,3-Difluorocyclobutyl)methyl]-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(2-Hydroxyethyl)-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-[2-(Dimethylamino)ethyl]-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(prop-2-yn-1-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-{2-Methyl-5-oxo-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-1-yl}acetonitrile; 2-[2-Methyl-5-oxo-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-1-yl]acetonitrile; 1-(2-Hydroxy-2-methylpropyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-[2-(1-Hydroxycyclopropyl)ethyl]-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methyl-1-[(oxetan-3-yl)methyl]-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methyl-1-(oxetan-3-yl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-Dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidine-5-thione; 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyridin-2-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methyl-1-(pyridin-2-yl)-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyrazin-2-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methyl-1-(6-methylpyridin-2-yl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methyl-1-(1-methyl-1H-pyrazol-4-yl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyridin-3-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-phenyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(6-Chloropyridin-2-yl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyridin-4-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(1H-pyrazol-4-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-(Fluoromethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-[(Dimethylamino)methyl]-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 6-(1-{[(1R)-2,2-Difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-(1-{[(1S)-2,2-Difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-(1-{[(1R)-2,2-Difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-1,2-dimethyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-(1-{[(1S)-2,2-Difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-1,2-dimethyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 6-(1-{[(1R)-2,2-Difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 6-(1-{[(1S)-2,2-Difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; (2R)-2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-2H,3H,5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; (2S)-2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-2H,3H,5H,6H,7H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 1-{[(1R)-2,2-Difluorocyclopropyl]methyl}-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; or 1-{[(1S)-2,2-Difluorocyclopropyl]methyl}-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one.

[0070] As Embodiment 51, provided herein are the compounds described in Embodiment 1, or their tautomers, or pharmaceutically acceptable salts of said compounds or said tautomers, and the compounds are 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-Methoxy-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-(Hydroxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 2-Chloro-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-Dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-Dimethyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1,2-Dimethyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-Methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-( 2 H3)methyl-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 1-(2-Hydroxyethyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; 2-{2-Methyl-5-oxo-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-1-yl}acetonitrile; 2-[2-Methyl-5-oxo-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-1-yl]acetonitrile; 6-(1-{[(1R)-2,2-Difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; or 6-(1-{[(1S)-2,2-Difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one.

[0071] In Embodiment 52, provided herein is the compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is [Chemical formula] as follows.

[0072] In Embodiment 53, provided herein is the compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is [Chemical formula] as follows.

[0073] In Embodiment 54, provided herein is the compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is [Chemical formula] as follows.

[0074] In Embodiment 55, provided herein is the compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is [Chemical formula] as follows.

[0075] As Embodiment 56, the present specification provides the compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, and the compound is

Chemical formula

[0076] As Embodiment 57, the present specification provides the compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, and the compound is

Chemical formula

[0077] As Embodiment 58, the present specification provides the compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, and the compound is

Chemical formula

[0078] As Embodiment 59, the present specification provides the compound described in Embodiment 1, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, and the compound is

Chemical formula

[0079] As Embodiment 60, the present specification provides the compound described in Embodiment 1, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, and the compound is

Chemical formula

[0080] As Embodiment 61, this specification provides the compound described in Embodiment 1, or its tautomer, or a pharmaceutically acceptable salt of the compound or the tautomer, and the compound is [Chemical formula] as follows.

[0081] As Embodiment 62, this specification provides the compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, and the compound is [Chemical formula] as follows.

[0082] As Embodiment 63, this specification provides the compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, and the compound is [Chemical formula] as follows.

[0083] As Embodiment 64, this specification provides the compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, and the compound is [Chemical formula] as follows.

[0084] As Embodiment 65, this specification provides the compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, and the compound is [Chemical formula] as follows.

[0085] As Embodiment 66, this specification provides the compound described in Embodiment 1, or its tautomer, or a pharmaceutically acceptable salt of the compound or the tautomer, and the compound is [Chemical formula] It is.

[0086] As Embodiment 67, in the present specification, there is provided a compound described in Embodiment 1, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, and the compound is

Chemical formula

[0087] The foregoing description is merely a summary of certain aspects of the present disclosure and is in no way intended, nor should it be construed, to limit the present disclosure.

[0088] Formulations, and Routes of Administration In the uses described, it may be possible to administer the compounds disclosed herein alone, but the compounds to be administered will usually be present as the active ingredient in a pharmaceutical composition. Thus, in one embodiment, the present specification provides a pharmaceutical composition comprising a compound disclosed herein in combination with one or more pharmaceutically acceptable excipients such as diluents, carriers, adjuvants, etc. and, if desired, 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 GD Tovey, Royal Society of Chemistry, 2018. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein.

[0089] The compounds disclosed herein can be administered by any suitable route of administration, in the form of a pharmaceutical composition adapted to such a route and in an amount effective for the intended treatment. The compounds and compositions presented herein are, for example, in unit dosage forms containing conventional pharmaceutically acceptable excipients and can be administered orally, mucosally, topically, transdermally, rectally, by inhalation, parenterally, intranasally, intravascularly, intravenously, intraarterially, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternal, intravaginally, or by infusion techniques.

[0090] The pharmaceutical composition can be, for example, in the form of tablets, chewable tablets, minitablets, caplets, pills, beads, hard capsules, soft capsules, gelatin capsules, granules, powders, lozenges, patches, creams, gels, sachets, microneedle arrays, syrups, flavored syrups, juices, drops, injections, emulsions, microemulsions, ointments, aerosols, aqueous suspensions, or oily suspensions. The pharmaceutical composition is typically prepared in the form of dosage units containing a specific amount of the active ingredient.

[0091] As Embodiment 68, provided herein is a pharmaceutical composition comprising the compound described in any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, and a pharmaceutically acceptable excipient.

[0092] As Embodiment 69, provided herein is the compound described in any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, or the pharmaceutical composition described in Embodiment 68 for use as a medicament.

[0093] Furthermore, the present disclosure encompasses pharmaceutical compositions comprising a mixture of any of the compounds disclosed herein and one or more other active agents disclosed herein.

[0094] Method of Use As described herein (see the section entitled "Definitions"), the compounds described herein are to be understood to include all stereoisomers, tautomers, or pharmaceutically acceptable salts of any of the foregoing or solvates of any of the foregoing. Accordingly, the methods and uses provided in this disclosure are to be understood to encompass methods and uses employing all such forms as well.

[0095] In addition to being useful for the treatment of humans, the compounds provided herein may be useful for veterinary treatment of companion animals, exotic animals, and livestock, including mammals, rodents, etc. For example, animals including horses, dogs, and cats may be treated with the compounds provided herein.

[0096] In Embodiment 70, provided herein is a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to Embodiment 68, for use in reducing the body weight of a subject.

[0097] In Embodiment 71, provided herein is a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to Embodiment 68, for use in reducing the body mass index of a subject.

[0098] In Embodiment 72, provided herein is a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to Embodiment 68, for use in the treatment of metabolic diseases.

[0099] In Embodiment 73, provided herein is a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to Embodiment 68, for use in the treatment of cardiovascular diseases.

[0100] As Embodiment 74, the present specification provides a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, or a pharmaceutical composition according to Embodiment 68 for use in the treatment of diabetes.

[0101] As Embodiment 75, the present specification provides a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, or a pharmaceutical composition according to Embodiment 68 for use in the treatment of obesity.

[0102] As Embodiment 76, the present specification provides a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, or a pharmaceutical composition according to Embodiment 68 for use in the treatment of dyslipidemia.

[0103] As Embodiment 77, the present specification provides a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, or a pharmaceutical composition according to Embodiment 68 for use in the treatment of non-alcoholic steatohepatitis (NASH).

[0104] As Embodiment 79, the present specification provides the use of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, or a pharmaceutical composition according to Embodiment 68 in the preparation of a medicament for reducing the body weight or body mass index of a subject.

[0105] As Embodiment 80, the present specification provides the use of the compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, or the pharmaceutical composition according to Embodiment 68, in the preparation of a medicament for treating a metabolic disease or a cardiovascular disease.

[0106] As Embodiment 81, the present specification provides the use of the compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, or the pharmaceutical composition according to Embodiment 68, in the preparation of a medicament for treating diabetes, obesity, dyslipidemia, or non-alcoholic steatohepatitis (NASH).

[0107] As Embodiment 82, the present specification provides a method for reducing the body weight or body mass index of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.

[0108] As Embodiment 83, the present specification provides a method for treating a metabolic disease or a cardiovascular disease of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.

[0109] As Embodiment 84, the present specification provides a method for treating diabetes, obesity, dyslipidemia, or non-alcoholic steatohepatitis (NASH) of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.

[0110] As a further embodiment, provided herein is a method of reducing the waist-hip ratio (WHR) of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer. As a further embodiment, provided herein is the use of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, or a pharmaceutical composition according to Embodiment 68, in the preparation of a medicament for reducing the waist-hip ratio (WHR) of a subject. As a further embodiment, provided herein is a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, or a pharmaceutical composition according to Embodiment 68, for use in reducing the waist-hip ratio (WHR) of a subject.

[0111] As a further embodiment, provided herein is a method of reducing blood glucose in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, or a pharmaceutical composition according to Embodiment 68. 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 while minimizing the effect on food intake / appetite. In some embodiments, the method reduces blood glucose without affecting food intake / appetite.

[0112] As a further embodiment, provided herein is a method for reducing insulin in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, or a pharmaceutical composition according to Embodiment 68. In some embodiments, the method reduces insulin by 50% or more. In some embodiments, the method reduces insulin by 60% or more. In some embodiments, the method reduces insulin by 70% or more. In some embodiments, the method reduces insulin by 80% or more. In some embodiments, the method reduces blood insulin by 85% or more. In some embodiments, the method reduces insulin by 86% or more. In some embodiments, the method reduces insulin by 87% or more. In some embodiments, the method reduces insulin by 88% or more. In some embodiments, the method reduces insulin by 89% or more. In some embodiments, the method reduces insulin by 90% or more. In some embodiments, the method reduces insulin by 91% or more. In some embodiments, the method reduces insulin while minimizing the effect on food intake / appetite. In some embodiments, the method reduces insulin without affecting food intake / appetite.

[0113] As a further embodiment, the present specification provides a method for reducing cholesterol in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, or a pharmaceutical composition according to Embodiment 68. In some embodiments, the method reduces cholesterol by 10% or more. In some embodiments, the method reduces cholesterol by 15% or more. In some embodiments, the method reduces cholesterol by 20% or more. In some embodiments, the method reduces cholesterol by 30% or more. In some embodiments, the method reduces cholesterol by 31% or more. In some embodiments, the method reduces cholesterol by 32% or more. In some embodiments, the method reduces cholesterol by 33% or more. In some embodiments, the method reduces cholesterol by 34% or more. In some embodiments, the method reduces cholesterol by 35% or more. In some embodiments, the method reduces blood cholesterol by 36% or more. In some embodiments, the method reduces cholesterol by 37% or more. In some embodiments, the method reduces cholesterol by 38% or more. In some embodiments, the method reduces cholesterol by 39% or more. In some embodiments, the method reduces cholesterol while minimizing the effect on food intake / appetite. In some embodiments, the method reduces cholesterol without affecting food intake / appetite.

[0114] As a further embodiment, the present specification provides a method for reducing LDL in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, or a pharmaceutical composition according to Embodiment 68. In some embodiments, the method reduces low density lipoprotein (LDL) by 10% or more. In some embodiments, the method reduces LDL by 20% or more. In some embodiments, the method reduces LDL by 21% or more. In some embodiments, the method reduces LDL by 22% or more. In some embodiments, the method reduces LDL by 23% or more. In some embodiments, the method reduces LDL by 24% or more. In some embodiments, the method reduces LDL by 25% or more. In some embodiments, the method reduces LDL by 26% or more. In some embodiments, the method reduces blood LDL by 27% or more. In some embodiments, the method reduces LDL while minimizing the effect on food intake / appetite. In some embodiments, the method reduces LDL without affecting food intake / appetite.

[0115] As a further embodiment, provided herein is a method for reducing triglycerides in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to Embodiment 68. In some embodiments, the method reduces triglycerides by 30% or more. In some embodiments, the method reduces triglycerides by 40% or more. In some embodiments, the method reduces triglycerides by 50% or more. In some embodiments, the method reduces triglycerides by 51% or more. In some embodiments, the method reduces triglycerides by 52% or more. In some embodiments, the method reduces triglycerides by 53% or more. In some embodiments, the method reduces triglycerides by 54% or more. In some embodiments, the method reduces triglycerides by 55% or more. In some embodiments, the method reduces blood triglycerides by 56% or more. In some embodiments, the method reduces triglycerides by 57% or more. In some embodiments, the method reduces triglycerides while minimizing the effect on food intake / appetite. In some embodiments, the method reduces triglycerides without affecting food intake / appetite.

[0116] As a further embodiment, provided herein is a method for reducing the body fat mass of a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to Embodiment 68. In some embodiments, the method reduces the body fat mass of the subject by 30% or more. In some embodiments, the method reduces the body fat mass of the subject by 40% or more. In some embodiments, the method reduces the body fat mass of the subject by 45% or more. In some embodiments, the method reduces the body fat mass of the subject by 50% or more. In some embodiments, the method reduces the body fat mass of the subject by 55% or more. In some embodiments, the method reduces the blood body fat mass of the subject by 60% or more. In some embodiments, the method reduces the body fat mass of the subject by 65% or more. In some embodiments, the method reduces the body fat mass of the subject by 70% or more. In some embodiments, the method reduces the body fat mass of the subject by 75% or more. In some embodiments, the method reduces the body fat mass of the patient while minimizing the effect on food intake / appetite. In some embodiments, the method reduces the body fat mass of the patient without affecting food intake / appetite.

[0117] As a further embodiment, provided herein is a method for increasing the adiponectin of a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to Embodiment 68.

[0118] As a further embodiment, provided herein is a method for reducing the leptin of a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to Embodiment 68.

[0119] As a further embodiment, provided herein is a method of reducing resistin in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to Embodiment 68.

[0120] Combination Provided herein is a further embodiment that is a pharmaceutical composition comprising a compound according to any one of Embodiments 1 to 67 and one or more other active agents. In some embodiments, the one or more active agents include, but are not limited to, omega-3 fatty acid sources. In some embodiments, the one or more active agents include, but are not limited to, nutritional supplements of omega-3 fatty acids. In some embodiments, the one or more active agents include, but are not limited to, omega-3 carboxylic acids (e.g., Epanova®), omega-3 fatty acid ethyl esters (e.g., Lovaza® or Omtryg®), or ethyl eicosapentaenoate (e.g., Vascepa®).

[0121] As a further embodiment, provided herein is a method of treating diabetes, obesity, dyslipidemia, or non-alcoholic steatohepatitis (NASH) in a subject in need thereof, the method comprising administering, in combination with one or more other active agents, a therapeutically effective amount of a compound according to any one of embodiments 1 to 67, or a tautomer thereof, or a combination of a pharmaceutically acceptable salt of said compound or said tautomer. In some embodiments, the one or more active agents include, but are not limited to, omega-3 fatty acid sources. In some embodiments, the one or more active agents include, but are not limited to, nutritional supplements of omega-3 fatty acids. In some embodiments, the one or more active agents include, but are not limited to, omega-3 carboxylic acids (e.g., Epanova®), omega-3 fatty acid ethyl esters (e.g., Lovaza® or Omtryg®), or ethyl eicosapentaenoate (e.g., Vascepa®).

[0122] As a further embodiment, provided herein is a method of reducing body weight or body mass index in a subject in need thereof, the method comprising administering, in combination with one or more other active agents, a therapeutically effective amount of a compound according to any one of embodiments 1 to 67, or a tautomer thereof, or a combination of a pharmaceutically acceptable salt of said compound or said tautomer. In some embodiments, the one or more active agents include, but are not limited to, omega-3 fatty acid sources. In some embodiments, the one or more active agents include, but are not limited to, nutritional supplements of omega-3 fatty acids. In some embodiments, the one or more active agents include, but are not limited to, omega-3 carboxylic acids (e.g., Epanova®), omega-3 fatty acid ethyl esters (e.g., Lovaza® or Omtryg®), or ethyl eicosapentaenoate (e.g., Vascepa®).

[0123] As a further embodiment, provided herein is a method for treating a metabolic disorder or a cardiovascular disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a combination of a pharmaceutically acceptable salt of the compound or the tautomer, in combination with one or more other active agents. In some embodiments, the one or more active agents include, but are not limited to, omega-3 fatty acid sources. In some embodiments, the one or more active agents include, but are not limited to, omega-3 fatty acid nutraceuticals. In some embodiments, the one or more active agents include, but are not limited to, omega-3 carboxylic acids (e.g., Epanova®), omega-3 fatty acid ethyl esters (e.g., Lovaza® or Omtryg®), or ethyl eicosapentaenoate (e.g., Vascepa®).

[0124] As a further embodiment, provided herein is a method for reducing the waist-to-hip ratio (WHR) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a combination of a pharmaceutically acceptable salt of the compound or the tautomer, in combination with one or more other active agents.

[0125] As a further embodiment, provided herein is a method for reducing blood glucose in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a combination of a pharmaceutically acceptable salt of the compound or the tautomer, in combination with one or more other active agents.

[0126] As a further embodiment, provided herein is a method for reducing insulin in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a combination of a pharmaceutically acceptable salt of said compound or said tautomer, in combination with one or more other active agents.

[0127] As a further embodiment, provided herein is a method for reducing cholesterol in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a combination of a pharmaceutically acceptable salt of said compound or said tautomer, in combination with one or more other active agents.

[0128] As a further embodiment, provided herein is a method for reducing LDL in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a combination of a pharmaceutically acceptable salt of said compound or said tautomer, in combination with one or more other active agents.

[0129] As a further embodiment, provided herein is a method for reducing triglycerides in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a combination of a pharmaceutically acceptable salt of said compound or said tautomer, in combination with one or more other active agents.

[0130] As a further embodiment, provided herein is a method for reducing body fat mass in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a combination of a pharmaceutically acceptable salt of said compound or said tautomer, in combination with one or more other active agents.

[0131] As a further embodiment, provided herein is a method for increasing adiponectin in a subject in need thereof, the method comprising administering, in combination with one or more other active agents, a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a combination of a pharmaceutically acceptable salt of the compound or the tautomer.

[0132] As a further embodiment, provided herein is a method for decreasing leptin in a subject in need thereof, the method comprising administering, in combination with one or more other active agents, a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a combination of a pharmaceutically acceptable salt of the compound or the tautomer.

[0133] As a further embodiment, provided herein is a method for decreasing resistin in a subject in need thereof, the method comprising administering, in combination with one or more other active agents, a therapeutically effective amount of a compound according to any one of Embodiments 1 to 67, or a tautomer thereof, or a combination of a pharmaceutically acceptable salt of the compound or the tautomer.

[0134] In some embodiments, one or more active agents of the combinations described herein, or methods using these combinations described herein, include, but are not limited to, omega-3 carboxylic acids (e.g., Epanova®), omega-3 fatty acid ethyl esters (e.g., Lovaza® or Omtryg®), or ethyl eicosapentaenoate (e.g., Vascepa®).

[0135] Definitions The following definitions are provided to facilitate understanding of the scope of the present disclosure.

[0136] Unless otherwise indicated, all numbers expressing amounts of ingredients, reaction conditions, and the like used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the standard deviation found in their respective test measurements.

[0137] As used herein, when any variable element occurs more than once in a chemical formula, its definition at each occurrence is independent of its definition at every other occurrence. Where chemical structures and chemical names are in conflict, the chemical structure determines the identity of the compound.

[0138] Stereoisomers The compounds of the present disclosure may, for example, contain 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 includes all possible stereoisomers of the exemplified compounds, including stereochemically pure forms (e.g., geometrically pure, enantiomerically pure, diastereomerically pure, and atropisomerically pure) and mixtures of stereoisomers of any chemical structure (in whole or in part) disclosed herein (e.g., mixtures of geometric isomers, enantiomers, diastereomers, and atropisomers, or mixtures of any of the foregoing), unless the stereochemistry is specifically defined.

[0139] If the stereochemistry of a structure or a part of the structure is not indicated, for example, by a thick line or a dashed line, this structure or part of the structure should be interpreted as encompassing all of its stereoisomers. If the stereochemistry of a structure or a part of the structure is indicated, for example, by a thick line or a dashed line, this structure or part of the structure should be interpreted as encompassing only the indicated stereoisomer. A bond drawn as a wavy line indicates that both stereoisomers are included. This wavy line should not be confused with a wavy line drawn perpendicular to the bond (indicating the point at which the group is attached to the remainder of the molecule).

[0140] As used herein, the terms "stereoisomer" or "stereoisomerically pure" compound refer to one stereoisomer (e.g., geometric isomers, enantiomers, diastereomers, and atropisomers) of a compound that is substantially free of other stereoisomers of the 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 the 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 less than about 20% by weight of the other stereoisomers, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers.

[0141] This disclosure also encompasses pharmaceutical compositions containing the stereoisomerically pure forms of any compound disclosed herein, and the use of the stereoisomerically pure forms. Further, this disclosure also encompasses pharmaceutical compositions containing mixtures of stereoisomers of any compound disclosed herein and the use of said pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof may be synthesized according to methods well known in the art and methods disclosed herein. Mixtures of stereoisomers may 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).

[0142] Tautomers As is known to those skilled in the art, certain compounds disclosed herein may exist in one or more tautomeric forms. Since one chemical structure can be used only to represent one tautomeric form, for convenience, reference to a compound of a given structural formula is to be understood to include other tautomers of said structural formula. For example, the following illustrate tautomers of a compound of Formula I, wherein x, y, and z are N, C, and C, respectively. [Chemical Formula]

[0143] Accordingly, the scope of this disclosure is to be understood to encompass all tautomeric forms of the compounds disclosed herein.

[0144] Isotope-labeled compound Furthermore, within the scope of the present disclosure are all pharmaceutically acceptable isotope-labeled compounds of the compounds disclosed herein, such as the compounds of Formula I, wherein one or more atoms are replaced with atoms having the same atomic number but a different atomic mass or mass number than the atomic mass or mass number commonly found in nature. Examples of isotopes suitable for incorporation into the compounds disclosed herein include 2 H and 3 H, etc., of hydrogen, 11 C, 13 C and 14 C, etc., of carbon, 36 Cl, etc., of chlorine, 18 F, etc., of fluorine, 123 I and 125 I, etc., of iodine, 13 N and 15 N, etc., of nitrogen, 15 O, 17 O and 18 O, etc., of oxygen, 32 P, etc., of phosphorus and 35 S, etc., of sulfur. Certain isotope-labeled compounds of Formula I, for example those incorporating radioactive isotopes, are useful in the study of the tissue distribution of drugs and / or substrates. Tritium ([[]] 3 H) and carbon-14 ([[]] 14 C) of radioactive isotopes are particularly useful for this purpose considering their ease of incorporation and ease of detection means. Substitution with isotopes such as deuterium ([[]] 2 H or D) may be preferred in some situations because specific therapeutic advantages resulting from increased metabolic stability, such as an extended in vivo half-life or a reduced required dose, can be obtained. 11 C, 18 F, 15 O and 13Substitution with a positron-emitting isotope such as N can be useful, for example, in positron emission tomography (PET) studies to examine target occupancy. Isotopically labeled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those of ordinary skill in the art or by processes similar to those described in the appended general synthetic schemes and examples using appropriate isotopically labeled reagents in place of the conventionally used unlabeled reagents.

[0145] Solvate As described above, the compounds disclosed herein, as well as their stereoisomers, tautomers, and isotopically labeled forms, or pharmaceutically acceptable salts of any of the foregoing, may exist in solvated or unsolvated forms.

[0146] As used herein, the term "solvate" refers to a molecular complex comprising a compound described herein or a pharmaceutically acceptable salt thereof, and a stoichiometric or non-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules. When the solvent is water, the solvate is referred to as a "hydrate".

[0147] Accordingly, the scope of the present disclosure is to be understood to encompass all solvates of the compounds disclosed herein, as well as their stereoisomers, tautomers, and isotopically labeled forms, or pharmaceutically acceptable salts of any of the foregoing.

[0148] Various Definitions In this section, additional terms used to describe the scope of the compounds, compositions, and uses disclosed herein are defined.

[0149] As used herein, "C 1~3 alkyl", "C 1~4 alkyl", "C 2~6 alkyl", and "C 1~6 alkyl" refer to straight-chain or branched-chain hydrocarbons containing 1-3, 1-4, 2-6, and 1-6 carbon atoms, respectively. C 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, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, and hexyl.

[0150] As used herein, the term "C 2~4 alkenyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms having at least one carbon-carbon double bond. The alkenyl group includes both straight-chain and branched-chain moieties. C 2~4 Representative examples of alkenyl include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, and butenyl.

[0151] As used herein, the term "C 2~4 alkynyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms having at least one carbon-carbon triple bond. This term includes both straight-chain and branched-chain moieties. C 3~6 Representative examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, and 3-butynyl.

[0152] As used herein, the term "C 1~4 alkylamino" or "C 1~6 alkylamino" refers to -NHR*, where R* represents C 1~4 alkyl and C 1~6 alkyl, respectively, as defined herein. C 1~4 Representative examples of alkylamino or C 1~6 alkylamino include, but are not limited to, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, and -NHCH(CH3)2.

[0153] As used herein, the term "C 3~5 cycloalkyl" refers to a saturated carbocyclic molecule having a cyclic skeleton with 3 to 5 carbons. C 3~5Representative examples of cycloalkyl include, but are not limited to, cyclopropyl and cyclobutyl.

[0154] When used herein as a prefix for another term of a chemical group, the term "deuterium" refers to the modification of a chemical group in which one or more hydrogen atoms are replaced by deuterium ("D" or " 2 H"). For example, the term "C 1~4 deuterium alkyl" refers to C 1~4 alkyl as defined herein in which one or more hydrogen atoms are replaced by D. 1~4 Representative examples of C

[0155] deuterium alkyl include, but are not limited to, -CH2D, -CHD2, -CD3, -CH2CD3, -CDHCD3, -CD2CD3, -CH(CD3)2, -CD(CHD2)2, and -CH(CH2D)(CD3). 1~4 When used herein, the term "diC 1~6 alkylamino" or "diC 1~4 alkylamino" refers to -NR*R**, where R* and R** each independently represent C 1~6 alkyl as defined herein. Representative examples of diC 1~4 alkylamino or diC 1~6 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.

[0156] When used herein, the term "C 1~4 alkoxy" or "C 2~6 alkoxy" refers to -OR # , where R # represents C 1~4 alkyl group or C 2~6 alkyl group as defined herein. 1~4Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy. C 2~6 Representative examples of alkoxy include, but are not limited to, ethoxy, propoxy, isopropoxy, and butoxy.

[0157] As used herein, the term "halogen" refers to -F, -Cl, -Br, or -I.

[0158] When used herein as a prefix to another term of a chemical group, the term "halo" refers to a modification of a chemical group in which one or more hydrogen atoms are replaced by halogen as defined herein. The halogen is independently selected each time it appears. For example, the term "C 1~4 "haloalkyl" refers to a C 1~4 alkyl as defined herein in which one or more hydrogen atoms are replaced by halogen. 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).

[0159] As used herein, the term "5-membered heteroaryl" or "6-membered heteroaryl" refers to a 5- or 6-membered carbocyclic ring containing two or three double bonds and containing, instead of one or more ring carbon atoms, one ring heteroatom selected from N, S, and O, and optionally one or two additional ring N atoms. Representative examples of 5-membered heteroaryl include, but are not limited to, furyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and oxazolyl. Representative examples of 6-membered heteroaryl include, but are not limited to, pyridyl, pyrimidyl, pyrazyl, and pyridazyl.

[0160] As used herein, "C 3~5"heterocycloalkyl" or "C" 3~4 The term "heterocycloalkyl" refers to a saturated carbocyclic molecule having a cyclic skeleton of 3 to 5 carbons or 3 to 4 carbons, wherein one carbon atom is replaced by a heteroatom selected from N, O, and S. C 3~5 Representative examples of heterocycloalkyl include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, and pyrrolidinyl. C 3~4 Representative examples of heterocycloalkyl include, but are not limited to, aziridinyl, azetidinyl, and oxetanyl.

[0161] As used herein, the phrase "a 5-membered ring in which the ring is unsaturated, partially saturated, or saturated aromatic" in the context of Formula I refers to

Chemical formula

[0162] As used herein, the term "pharmaceutically acceptable" refers to being generally recognized for use in a subject, particularly a human.

[0163] As used herein, the term "pharmaceutically acceptable salt" refers to salts of compounds that are pharmaceutically acceptable and have 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, phosphoric acid, etc.; or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, etc.; or (2) salts formed when the acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion; or when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, etc. Further examples of such salts can be found in Berge et al., J. Pharm. Sci. 66(1):1-19(1977). Also, see Stahl et al., Pharmaceutical Salts: Properties, Selection, and Use, 2 nd Revised Edition(2011).

[0164] As used herein, the term "pharmaceutically acceptable excipient" refers to a wide range of components that can be combined with the compounds or salts disclosed herein to prepare a pharmaceutical composition or formulation. Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-adhesives, glidants, disintegrants, flavoring agents, coating agents, binders, sweeteners, lubricants, adsorbents, preservatives.

[0165] As used herein, the term "subject" refers to humans and animals, including, but not limited to, primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In one embodiment, the subject is a human.

[0166] As used herein, the term "therapeutically effective amount" refers to the amount of a compound disclosed herein that elicits a biological or medical response in a tissue, system, or subject as determined by a researcher, veterinarian, medical doctor, or other clinician.

[0167] As used herein, the term "body mass index" ("BMI") can be calculated, for example, by measuring a subject's weight in kilograms and dividing by the square of the height in meters. See, for example, https: / / www.cdc.gov / healthyweight / assessing / bmi / index.html (last accessed Nov. 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 has a healthy weight or will respond to weight loss treatment.

[0168] General Synthetic Procedures 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 may also be synthesized by alternative routes using alternative synthetic strategies, as will be understood by those skilled in the art. It will be understood that the general synthetic procedures and the specific examples provided herein are merely illustrative and should in no way be construed as limiting the scope of the disclosure.

[0169] Generally, the compounds of formula I can be synthesized according to the following scheme. Any variables used in the following scheme are variables defined for formula I unless otherwise noted. All starting materials are either commercially available from, for example, Merck Sigma - Aldrich Inc., Fluorochem Ltd, and Enamine Ltd., or are known in the art, and may be synthesized by using known procedures with ordinary techniques. The starting materials can also be synthesized via the procedures disclosed herein. Suitable reaction conditions such as solvents, reaction temperatures, and reagents for the schemes described in this section can be found in the examples provided herein.

[0170]

Chemical formula

[0171]

Chemical formula

[0172]

Chemical formula

[0173]

Chemical formula

[0174]

Chemical formula

[0175]

Chemical formula

[0176]

Chemical formula

Chemical formula

[0177]

Chem.

Chem.

[0178]

Chem.

[0179] As will be understood by those skilled in the art, the above synthetic schemes and representative examples are not intended to include an exhaustive list of all means by which the compounds described and claimed in this application can be synthesized. Further methods will be apparent to those skilled in the art. In addition, the various synthetic steps described above may be carried out in an alternative order or sequence to obtain the desired compound.

[0180] The methods for purifying the compounds described herein are known in the art and include, for example, crystallization, chromatography (e.g., liquid and gas phase), extraction, distillation, trituration, and reverse phase HPLC.

[0181] The present disclosure further encompasses "intermediate" compounds that include structures generated from the described synthetic procedures, whether isolated before obtaining the final desired compound or generated in situ and not isolated. These intermediates are included within the scope of the present disclosure. Exemplary embodiments of such intermediate compounds are described below.

[0182] As Embodiment 84, herein, a compound of Formula I-1

Chemical Formula

[0183] As Embodiment 85, herein, a compound of Embodiment 84 is provided, where X is H.

[0184] As Embodiment 86, the present specification provides the compound of Embodiment 84, where X is Br.

[0185] As Embodiment 87, the present specification provides the compound of any one of Embodiments 84 to 86, where R 1 is O.

[0186] As Embodiment 88, the present specification provides the compound of any one of Embodiments 84 to 87, where R is methyl.

[0187] As Embodiment 89, the present specification provides the compound of any one of Embodiments 84 to 87, where R is methoxy.

[0188] As Embodiment 90, the present specification provides the compound of any one of Embodiments 84 to 87, where R is hydroxymethyl.

[0189] As Embodiment 91, the present specification provides the compound of Formula I-2

Chemical formula

[0190] As Embodiment 92, the present specification provides the compound of Embodiment 91, or a tautomer thereof, where X is H.

[0191] As Embodiment 93, the present specification provides the compound of Embodiment 91, or a tautomer thereof, where X is Br.

[0192] As Embodiment 94, the present specification provides the compound of any one of Embodiments 91 to 93, or a tautomer thereof, where R 1 is O.

[0193] As Embodiment 95, the present specification provides the compound of any one of Embodiments 93 to 94, or a tautomer thereof, where R is H.

[0194] As Embodiment 96, the present specification provides the compound of any one of Embodiments 93 to 94, or a tautomer thereof, where R is Cl.

[0195] As Embodiment 97, the present specification provides the compound of any one of Embodiments 93 to 94, or a tautomer thereof, where R is hydroxymethyl.

[0196] As Embodiment 98, the present specification provides the compound of any one of Embodiments 93 to 94, or a tautomer thereof, where R is methyl.

[0197] As Embodiment 99, the present specification provides the compound of any one of Embodiments 91 to 98, or a tautomer thereof, where R’’ is H.

[0198] As Embodiment 100, the present specification provides the compound of any one of Embodiments 91 to 98, or a tautomer thereof, where R’’ is methyl.

[0199] As Embodiment 101, this specification provides any one compound of Embodiments 91 to 98, or a tautomer thereof, where R’’ is CD3.

[0200] As Embodiment 102, this specification provides any one compound of Embodiments 91 to 98, or a tautomer thereof, where R’’ is -CH2CH2OH.

[0201] As Embodiment 103, this specification provides any one compound of Embodiments 91 to 98, or a tautomer thereof, where R’’ is -CH2CN.

[0202] As Embodiment 104, this specification provides a compound that is 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole.

Examples

[0203] In this section, specific examples of the compound of Formula I and its preparation method are provided.

[0204] List of Abbreviations

[0205]

Table 2

[0206]

Table 3

[0207]

Table 4

[0208] General Analytical and Purification Methods In this section, descriptions of the general analytical and purification methods used to prepare the specific compounds provided in this specification are provided.

[0209] Chromatography: Unless otherwise indicated, the residue containing the crude product was purified by passing it through a silica gel column of the Biotage trademark pre-packed with either flash silica (SiO2) or reverse-phase flash silica (C18), and eluting from the column with the indicated solvent gradient. For example, the notation (330 g of SiO2, 0 - 40% EtOAc / hexane) means that the product was obtained by eluting from a column packed with 330 grams of silica with a solvent gradient of 0% - 40% EtOAc in hexane.

[0210] Preparative HPLC: When so indicated, the compounds described herein were purified by reverse-phase HPLC using a Waters Fractionlynx semi-preparative HPLC-MS system using one of the following two HPLC columns: (a) Phenominex Gemini column (5 micron, C18, 150×30 mm) or (b) Waters X-select CSH column (5 micron, C18, 100×30 mm).

[0211] Typical runs for passing through the instrument include: a linear gradient of 10% (v / v) - 100% MeCN (0.1% v / v formic acid) in water (0.1% formic acid), eluting at 45 mL / min over 10 minutes, and the conditions can be varied to achieve optimal separation.

[0212] Proton NMR spectrum: Unless otherwise indicated, all 1 H NMR spectra were collected on a Bruker NMR instrument at 300, 400 or 500 MHz. When characterized in this way, all observed protons are reported as parts per million (ppm) downfield from tetramethylsilane (TMS) using the internal solvent peak as a reference.

[0213] Mass spectrum (MS) Unless otherwise indicated, all mass spectral data for starting materials, intermediates and / or exemplified compounds are reported as mass / charge (m / z) with [M+H] + the molecular ion. The reported molecular ions were obtained by electrospray detection (commonly referred to as ESI MS) using a Waters Acquity UPLC / MS system. As will be understood by those skilled in the art, compounds having isotopic atoms such as bromine etc. are usually reported according to the detected isotope pattern.

[0214] Name of the compound The compounds disclosed and described herein are named using the IUPAC naming function provided by JChem for Excel 18.22.1.7 of ChemAxon Ltd.

[0215] Specific examples In this section, procedures for synthesizing specific examples of the compounds provided herein are provided. All starting materials are either commercially available from Merck Sigma-Aldrich Inc., Fluorochem Ltd or Enamine Ltd unless otherwise noted, or are known in the art and may be synthesized using known procedures using ordinary techniques.

[0216] Synthesis of intermediates: Intermediate 1A 6-Bromo-7-(trifluoromethyl)-[1,3]thiazolo[3,2-a]pyrimidin-5-one

Chemical formula

[0217] Step 1: 7-(Trifluoromethyl)-[1,3]thiazolo[3,2-a]pyrimidin-5-one A reaction mixture of 2-thiazolamine (1.0 g, 9.99 mmol), ethyl 4,4,4-trifluoroacetoacetate (7.3 mL, 49.93 mmol) and bismuth(III) trichloride (0.31 g, 1.0 mmol) was heated at 120 °C for 14 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (C18, 20 - 80% acetonitrile / 0.1% formic acid in water) to afford 7-(trifluoromethyl)-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.53 g, 2.4 mmol, 24% yield) as an off-white solid. LC / MS (ESI + ) m / z = 221.0 [M+H] + .

[0218] Step 2: 6-Bromo-7-(trifluoromethyl)-[1,3]thiazolo[3,2-a]pyrimidin-5-one N-Bromosuccinimide (420 mg, 2.36 mmol) was added to a stirred solution of 7-(trifluoromethyl)-[1,3]thiazolo[3,2-a]pyrimidin-5-one (520 mg, 2.36 mmol) in CH3CN (16.3 mL). The reaction mixture was stirred at room temperature for 20 h and then concentrated under reduced pressure. The residue was diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 6-bromo-7-(trifluoromethyl)-[1,3]thiazolo[3,2-a]pyrimidin-5-one (654 mg, 2.19 mmol, 93% yield) as a pale yellow solid. LC / MS (ESI + ) m / z = 299.0 / 301.0 [M+H] + .

[0219] Intermediates 1B - 1M listed in Table 2 below were prepared as follows according to the procedures described for Steps 1 and 2 of Intermediate 1A above.

[0220]

Table 5

[0221]

Table 6

[0222]

Table 7

[0223] Intermediate 2A 6-Bromo-2-(methoxymethyl)-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one

Chemical formula

[0224] Step 1: 2-(Methoxymethyl)-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one A mixture of 5-(methoxymethyl)-1,3,4-thiadiazol-2-amine (1.50 g, 10.33 mmol, Enamine), ethyl 4,4,4-trifluoro-3-oxobutanoate (8.47 mL, 51.66 mmol), and bismuth(III) trichloride (190 mg, 1.03 mmol) was heated at 120 °C for 18 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 10 - 50% EtOAc / cyclohexane) to give 2-(methoxymethyl)-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (1.04 g, 3.92 mmol, 38% yield) as a yellow solid. LC / MS (ESI + ) m / z = 266.1 [M+H] + .

[0225] Step 2: 6-Bromo-2-(methoxymethyl)-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one A solution of 2-(methoxymethyl)-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (600 mg, 2.24 mmol) and N-bromosuccinimide (598 mg, 3.36 mmol) in MeCN (7.2 mL) was heated at 80 °C for 16 h. Further, N-bromosuccinimide (100 mg, 0.56 mmol) was added and heating was continued for 6 h. The reaction mixture was concentrated, dissolved in EtOAc, and subsequently washed with saturated aqueous Na2S2O3, NaHCO3 and brine. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 30 - 60% EtOAc / cyclohexane) to give 6-bromo-2-(methoxymethyl)-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (350 mg, 1.02 mmol, 45% yield) as a yellow solid. LC / MS (ESI + ) m / z = 344.0 / 346.0 [M+H] + .

[0226] Intermediate 3A 6-Bromo-2-methyl-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one

Chemical Structure

[0227] Step 1: 2-Methyl-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one Ethyl 4,4,4-trifluoro-3-oxobutanoate (33.14 mL, 225.36 mmol) and indium(III) trifluoromethanesulfonate (5.31 g, 9.39 mmol) were added to a suspension of 5-methyl-1,3,4-thiadiazol-2-amine (21.63 g, 187.8 mmol, Enamine) in toluene (210 mL). The reaction mixture was heated at 95 °C for 24 h, then cooled to room temperature and filtered under vacuum. The solid was discarded and the solution was concentrated under reduced pressure. The residue was partitioned between EtOAc (600 mL) and water (600 mL), and the two phases were separated. The organic layer was washed with water (600 mL) and concentrated under reduced pressure. Cyclohexane (100 mL) was added to the residue, and the resulting precipitate was filtered, washed with cyclohexane and dried under vacuum to give 2-methyl-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (24.1 g, 102.47 mmol, 55% yield) as an off-white solid. LC / MS (ESI + ) m / z = 236.0 [M+H] + .

[0228] Step 2: 6-Bromo-2-methyl-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one N-Bromosuccinimide (20.06 g, 112.72 mmol) was added to a stirred suspension of 2-methyl-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (24.1 g, 102.47 mmol) in MeCN (206.6 mL). The mixture was heated at 70 °C overnight. After cooling to room temperature, saturated aqueous NaHCO3 (200 mL) and water (800 mL) were slowly added to the reaction mixture. The suspension was stirred at room temperature for 1 h, and the resulting solid was then filtered under vacuum, washed with water (50 mL) and dried under high vacuum to give 6-bromo-2-methyl-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (25.47 g, 81.09 mmol, 79% yield). LC / MS (ESI + ) m / z = 313.9 / 316.0 [M+H] + .

[0229] Intermediate 4A 6-Bromo-2-methoxy-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one

Chemical formula

[0230] Step 1: 2-Methoxy-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one A mixture of 5-methoxy-1,3,4-thiadiazol-2-amine (1.7 g, 12.96 mmol, Enamine), ethyl 4,4,4-trifluoro-3-oxobutanoate (9.47 mL, 64.81 mmol) and indium(III) trifluoromethanesulfonate (728.5 mg, 1.3 mmol) in toluene (50 mL) and 1,4-dioxane (5 mL) was heated at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (C18, 3 - 100% acetonitrile / water with 0.1% formic acid) to give 2-methoxy-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (548 mg, 2.18 mmol, 17% yield) as a white solid. LC / MS (ESI + ) m / z = 252.0 [M+H] + .

[0231] Step 2: 6-Bromo-2-methoxy-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one 2-Methoxy-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (548.0 mg, 2.18 mmol) and N-bromosuccinimide (582.43 mg, 3.27 mmol) in MeCN (10 mL) were heated at 80 °C for 48 h. After cooling to room temperature, the mixture was diluted with EtOAc and subsequently washed with saturated aqueous solutions of Na2S2O3 and NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (SiO2, 0 - 80% EtOAc / cyclohexane) to give 6-bromo-2-methoxy-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (577 mg, 1.75 mmol, 80% yield) as a white solid. LC / MS (ESI + ) m / z = 329.9 / 332.0 [M+H] + .

[0232] The intermediate 4B listed in Table 3 below was prepared as follows according to the procedures described for Steps 1 and 2 of the above intermediate 4A.

[0233]

Table 8

[0234] Intermediate 5A 6-Bromo-3-methyl-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-one

Chemical Structure

[0235] Step 1: 5-(Trifluoromethyl)-3H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one Ethyl 4,4,4-trifluoro-3-oxobutanoate (2.09 mL, 14.27 mmol) was added to a solution of 4H-1,2,4-triazole-3-amine (1.0 g, 11.89 mmol) in acetic acid (9 mL). The reaction mixture was heated to reflux for 4 h. After cooling to room temperature, the precipitate was filtered, washed with Et2O and dried to give 5-(trifluoromethyl)-3H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one (910 mg, 4.458 mmol, 37% yield) as a white solid. LC / MS (ESI + ) m / z = 205.0 [M+H] + .

[0236] Step 2: 3-Methyl-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-one Potassium carbonate (731 mg, 5.29 mmol) was added to a stirred solution of 5-(trifluoromethyl)-3H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one (900.0 mg, 4.41 mmol) in DMF (30 mL). After 10 min, iodomethane (0.3 mL, 4.85 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2; 40 - 100% EtOAc / cyclohexane) to give 3-methyl-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-one (130 mg, 0.6 mmol, 14% yield) as a yellow solid. LC / MS (ESI + ) m / z = 219.1 [M+H] + .

[0237] Step 3: 6-Bromo-3-methyl-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-one The title compound was prepared using the procedure described for Step 2 of Intermediate 1-A with the following modifications: The reaction was carried out using 3-methyl-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-one, and the mixture was heated at 80 °C for 2 hours. LC / MS (ESI + ) m / z = 297.1 / 299.1 [M+H] + .

[0238] Intermediate 5B listed in Table 4 was prepared as follows according to the procedure described for Steps 1, 2, and 3 of Intermediate 5A above.

[0239]

Table 9

[0240] Intermediate 6A 3-bromo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidin-4-one

Chem.

[0241] Step 1: 2-(trifluoromethyl)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidin-4-one A reaction mixture of 3,4-dihydro-2H-pyrrol-5-amine hydrochloride (1.0 g, 8.29 mmol), ethyl 4,4,4-trifluoroacetoacetate (6.1 mL, 41.47 mmol), bis(III)bismuth trichloride (0.26 g, 0.83 mmol), and N,N-diisopropylethylamine (1.44 mL, 8.29 mmol) was heated at 120 °C for 3 h. The reaction mixture was cooled to room temperature, washed with water, and extracted with EtOAc (2×). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 0 - 70% EtOAc / cyclohexane, then C18, 2 - 50% acetonitrile / 0.1% formic acid in water) to give 2-(trifluoromethyl)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidin-4-one (440 mg, 2.16 mmol, 26% yield) as a white solid. LC / MS (ESI + ) m / z = 205.0 [M+H] + .

[0242] Step 2: 3-Bromo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidin-4-one A suspension of 2-(trifluoromethyl)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidin-4-one (375 mg, 1.84 mmol) in water (15 mL) and HCl (2N solution in water, 0.92 mL, 1.84 mmol) was stirred at room temperature for 1 h. N-Bromosuccinimide (409 mg, 2.3 mmol) was added and stirring was continued overnight. Further N-bromosuccinimide (490 mg, 2.75 mmol) was added and stirring was continued for 24 h. The reaction mixture was cooled to 0 °C, treated with 1N aqueous NaOH solution (to pH 8), and extracted with DCM. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 0 - 70% EtOAc / cyclohexane) to give 3-bromo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidin-4-one (190 mg, 0.67 mmol, 37% yield) as an off-white solid. LC / MS (ESI+ ) m / z = 283.0 / 285.0 [M+H] + .

[0243] Intermediate 7A 3-Bromo-2-(trifluoromethyl)-6,6a,7,7a-tetrahydrocyclopropa[1,2]pyrrolo[4,5-a]pyrimidin-4-one [Chemical Structure]

[0244] Step 1: tert-Butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate A mixture of 3-azabicyclo[3.1.0]hexane hydrochloride (2.5 g, 20.9 mmol), triethylamine (6.1 mL, 43.9 mmol), and di-tert-butyl dicarbonate (5 g, 23 mmol) in anhydrous DCM (41.7 mL) was stirred at room temperature for 3 hours. Saturated aqueous NH4Cl was added, the two phases were separated, and the aqueous phase was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (3.83 g, 20.9 mmol, 100% yield) as a brown oil. LC / MS (ESI + ) m / z = 184.0 [M+H] + .

[0245] Step 2: tert-Butyl 4-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate Ruthenium(IV) oxide hydrate (32.2 mg, 0.21 mmol) was added to a 10% solution of sodium periodate (16.8 g, 78.74 mmol) in water (168 mL). After stirring at room temperature for 20 minutes, a solution of tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (3.83 g, 20.9 mmol) in EtOAc (56 mL) was added, and the resulting reaction mixture was stirred vigorously at room temperature for 16 hours. The mixture was diluted with water and extracted with EtOAc (2×). Isopropyl alcohol (20 mL) was added to the combined organic phases, and the mixture was stirred at room temperature for 3 hours, after which the precipitate was filtered off. The filtrate was washed with brine, dried over Na2SO4, filtered, and carefully concentrated under reduced pressure to give tert-butyl 4-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (4.1 g, 20.9 mmol, 100% yield) as a brown oil. LC / MS (ESI + ) m / z = 198.3 [M+H] + .

[0246] Step 3: 3-Azabicyclo[3.1.0]hexan-4-one A solution of tert-butyl 4-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (4.1 g, 20.9 mmol) and trifluoroacetic acid (3.81 mL, 49.74 mmol) in DCM (15 mL) was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM (3×). The organic phase was dried over Na2SO4, filtered, and carefully concentrated under reduced pressure to give 3-azabicyclo[3.1.0]hexan-4-one (1.5 g, 15.44 mmol, 74% yield) as a yellow oil. 1 1H NMR (400 MHz, DMSO-d6) δ 7.03 (br.s., 1H), 3.37 - 3.32 (m, 1H), 3.14 (d, J = 10.3 Hz, 1H), 1.90 (dq, J = 4.4, 5.9 Hz, 1H), 1.62 (tddd, J = 1.5, 3.1, 5.8, 8.6 Hz, 1H), 1.01 (dt, J = 4.0, 8.0 Hz, 1H), 0.45 (q, J = 4.0 Hz, 1H).

[0247] Step 4: 3-Azabicyclo[3.1.0]hexane-4-thione A mixture of 3-azabicyclo[3.1.0]hexan-4-one (500 mg, 5.15 mmol) and Lawesson's reagent (1.25 g, 3.09 mmol) in THF (5.7 ml) was heated to reflux for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (SiO2, 0 - 50% EtOAc / cyclohexane) to give 3-azabicyclo[3.1.0]hexane-4-thione (450 mg, 3.98 mmol, 77% yield). 1 H NMR (400 MHz, DMSO-d6) δ 0.33 - 0.46 (m, 1H) 1.10 - 1.26 (m, 1H) 2.04 (m, 1H) 2.22 - 2.32 (m, 1H) 3.46 (d, J = 12.54 Hz, 1H) 3.65 (dd, J = 12.54, 6.16 Hz, 1H) 9.40 - 9.63 (m, 1H).

[0248] Step 5: 4-Methylsulfanyl-3-azabicyclo[3.1.0]hex-3-ene A mixture of 3-azabicyclo[3.1.0]hexane-4-thione (425 mg, 3.76 mmol), sodium carbonate (438 mg, 4.13 mmol) and iodomethane (0.26 ml, 4.13 mmol) in DMF (18.8 ml) was stirred at room temperature for 5 h. The mixture was partitioned between water and EtOAc and extracted with EtOAc (3×). The combined organic phases were dried over Na2SO4, filtered and carefully concentrated under reduced pressure to give 4-methylsulfanyl-3-azabicyclo[3.1.0]hex-3-ene (475 mg, 3.76 mmol, 100% yield) as a yellowish oil, which was used without further purification in the next step. LC / MS (ESI + ) m / z = 127.9 [M + H] + .

[0249] Step 6: 3-Azabicyclo[3.1.0]hex-3-en-4-amine hydrochloride A mixture of 4-methylsulfanyl-3-azabicyclo[3.1.0]hex-3-ene (475 mg, 3.76 mmol) and ammonium chloride (221 mg, 4.13 mmol) in absolute ethanol (9 ml) was heated to reflux for 6 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum to give crude 3-azabicyclo[3.1.0]hex-3-ene-4-amine hydrochloride (500 mg, 3.76 mmol, 100% yield). 1 H NMR (400 MHz, DMSO-d6) δ 0.62 - 0.69 (m, 1H) 1.34 (m, 1H) 2.16 - 2.26 (m, 1H) 2.34 (m, 1H) 3.47 - 3.55 (m, 1H) 3.66 (m, 1H) 8.31 - 9.81 (m, 3H).

[0250] Step 7: 2-(Trifluoromethyl)-6,6a,7,7a-tetrahydrocyclopropa[1,2]pyrrolo[4,5-a]pyrimidin-4-one The title compound was prepared using the procedure described for Step 1 of Intermediate 6A with the following modifications: The reaction was carried out with 3-azabicyclo[3.1.0]hex-3-ene-4-amine hydrochloride, DIPEA and ethyl 4,4,4-trifluoro-3-oxobutanoate. LC / MS (ESI + ) m / z = 217.0 [M + H] + .

[0251] Step 8: 3-Bromo-2-(trifluoromethyl)-6,6a,7,7a-tetrahydrocyclopropa[1,2]pyrrolo[4,5-a]pyrimidin-4-one The title compound was prepared using the procedure described for Step 2 of Intermediate 6A with the following modifications: The reaction was carried out with 2-(trifluoromethyl)-6,6a,7,7a-tetrahydrocyclopropa[1,2]pyrrolo[4,5-a]pyrimidin-4-one. LC / MS (ESI + ) m / z = 295.0 / 297.0 [M + H] + .

[0252] Intermediate 8A 6-Bromo-2-methyl-7-(trifluoromethyl)-2,3-dihydro-[1,3]thiazolo[3,2-a]pyrimidin-5-one [Chemical formula]

[0253] Step 1: 5-Methyl-4,5-dihydro-1,3-thiazol-2-amine A 3N HCl aqueous solution (30.0 mL, 103.5 mmol) of prop-2-enylthiourea (2.0 g, 17.21 mmol) was heated at 70 °C for 16 h. After cooling to room temperature, the mixture was evaporated under reduced pressure. The crude material was purified by strong cation exchange chromatography to give 5-methyl-4,5-dihydro-1,3-thiazol-2-amine (1.67 g, 14.37 mmol, 84% yield) as a colorless oil. LC / MS (ESI + ) m / z = 116.9 [M+H] + .

[0254] Step 2: 2-Methyl-7-(trifluoromethyl)-2,3-dihydro-[1,3]thiazolo[3,2-a]pyrimidin-5-one The title compound was prepared using the procedure described for Step 1 of Intermediate 1A with the following modifications: The reaction was carried out using 5-methyl-4,5-dihydro-1,3-thiazol-2-amine and ethyl 4,4,4-trifluoro-3-oxobutanoate, and the reaction mixture was heated at 100 °C for 24 h. LC / MS (ESI + ) m / z = 237.0 [M+H] + .

[0255] Step 3: 6-Bromo-2-methyl-7-(trifluoromethyl)-2,3-dihydro-[1,3]thiazolo[3,2-a]pyrimidin-5-one The title compound was prepared with the following modifications using the procedure described for step 2 of Intermediate 1A: The reaction was carried out with 2-methyl-7-(trifluoromethyl)-2,3-dihydro-[1,3]thiazolo[3,2-a]pyrimidin-5-one, and the reaction mixture was heated at 80 °C for 20 h. LC / MS (ESI + ) m / z = 315.1 / 317.1 [M+H] + .

[0256] Intermediate 9A 6-Bromo-7-ethoxy-2-methyl-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one

Chemical formula

[0257] Step 1: 7-Hydroxy-2-methyl-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one Malonyldichloride (0.84 mL, 8.68 mmol) was added dropwise to a solution of 5-methyl-1,3,4-thiadiazol-2-amine (1 g, 8.68 mmol, Enamine) in DCE (8.2 mL) cooled to 0 °C. The reaction mixture was brought to room temperature and stirred for 48 h. The suspension was filtered, washed with DCM (3×30 mL) and water (2×20 mL), and dried under vacuum to give 7-hydroxy-2-methyl-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (950 mg, 5.19 mmol, 60% yield). LC / MS (ESI + ) m / z = 183.9 [M+H] + .

[0258] Step 2: 7-Ethoxy-2-methyl-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one Iodoethane (625.79 mg, 4.01 mmol) was added to a solution of 7-hydroxy-2-methyl-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (700.0 mg, 3.82 mmol) in DMF (18.67 mL). The reaction mixture was heated at 65 °C for 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 0 - 10% MeOH / DCM) to afford 7-ethoxy-2-methyl-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (306 mg, 1.45 mmol, 38% yield). LC / MS (ESI + ) m / z = 212.0 [M+H] + .

[0259] Step 3: 6-Bromo-7-ethoxy-2-methyl-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one The title compound was prepared using the procedure described for the synthesis of Intermediate 1A in Step 2 with the following modifications: The reaction was carried out with 7-ethoxy-2-methyl-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one. LC / MS (ESI + ) m / z = 289.9 / 291.9 [M+H] + .

[0260] Intermediate 10A 6-Bromo-1-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0261] Step 1: 7-(Trifluoromethyl)-1H-imidazo[1,2-a]pyrimidin-5-one 2-Bromo-1,1-diethoxyethane (4.4 g, 22.33 mmol) was added to a stirred solution of 2-amino-6-(trifluoromethyl)-1H-pyrimidin-4-one (2.0 g, 11.17 mmol) and potassium carbonate (3.86 g, 27.92 mmol) in DMF (16 mL) at room temperature. The reaction mixture was heated at 80 °C for 16 h, then cooled to room temperature and partitioned between water and EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in acetic acid (10.66 mL, 186.33 mmol) and heated at 120 °C for 1 h. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc (2×). The organic phase was slowly added to a stirred saturated aqueous solution of NaHCO3. The two phases were separated, the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography (SiO2, 0 - 60% EtOAc / cyclohexane) to afford 7-(trifluoromethyl)-1H-imidazo[1,2-a]pyrimidin-5-one (580 mg, 2.86 mmol, 26% yield). LC / MS (ESI + ) m / z = 204.2 [M+H] + .

[0262] Step 2: 1-Methyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one The title compound was prepared using the procedure described for Step 2 of Intermediate 5A with the following modifications: The reaction was carried out using 7-(trifluoromethyl)-1H-imidazo[1,2-a]pyrimidin-5-one. LC / MS (ESI + ) m / z = 218.2 [M+H] + .

[0263] Step 3: 6-Bromo-1-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one The title compound was prepared with the following modifications using the procedure described for the synthesis of Intermediate 1A, Step 2: The reaction was carried out with 1-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one. LC / MS (ESI + ) m / z = 296.2 / 298.2 [M+H] + .

[0264] Intermediate 11A 6-Bromo-7-(trifluoromethyl)-2,3-dihydro-[1,3]thiazolo[3,2-a]pyrimidin-5-one

Chemical Structure

[0265] Step 1: 7-(Trifluoromethyl)-2,3-dihydro-[1,3]thiazolo[3,2-a]pyrimidin-5-one 1,2-Dibromoethane (105.35 mg, 0.560 mmol) was added to a stirred solution of 2-sulfanyl-4-(trifluoromethyl)-1H-pyrimidin-6-one (100.0 mg, 0.51 mmol) and triethylamine (0.14 mL, 1.02 mmol) in THF (3 mL). After stirring at room temperature for 24 h, the reaction mixture was heated at 60 °C for 5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc and washed with water. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 7-(trifluoromethyl)-2,3-dihydro-[1,3]thiazolo[3,2-a]pyrimidin-5-one (110 mg, 0.5 mmol, 97% yield) as a pale yellow oil. LC / MS (ESI + ) m / z = 223.1 [M+H] + .

[0266] Step 2: 6-Bromo-7-(trifluoromethyl)-2,3-dihydro-[1,3]thiazolo[3,2-a]pyrimidin-5-one The title compound was prepared with the following modifications using the procedure described for step 2 of Intermediate 1A: The reaction was carried out with 7-(trifluoromethyl)-2,3-dihydro-[1,3]thiazolo[3,2-a]pyrimidin-5-one. LC / MS (ESI + ) m / z = 301.1 / 303.1 [M+H] + .

[0267] Intermediate 12A 6-Bromo-2-methyl-7-(trifluoromethyl)-[1,3]oxazolo[3,2-a]pyrimidin-5-one

Chemical Structure

[0268] Step 1: 6-(Trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyrimidine-2,4-dione Sodium hydride (60% in mineral oil, 55.50 mg, 1.39 mmol) was added to a solution of 6-(trifluoromethyl)uracil (250 mg, 1.39 mmol) and lithium bromide (122 mg, 1.39 mmol) in anhydrous NMP (4.8 mL). The mixture was stirred at room temperature for 30 minutes, followed by the addition of 2-(chloromethoxy)ethyl-trimethylsilane (0.25 mL, 1.39 mmol). After stirring at room temperature for 4 hours, the mixture was diluted with 10% aqueous Na2CO3 and extracted with EtOAc (2×). The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 10 - 30% EtOAc / cyclohexane) to give 6-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyrimidine-2,4-dione (165 mg, 0.53 mmol, 38% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ -0.02 (s, 9H), 0.89 - 0.85 (m, 2H), 3.66 - 3.61 (m, 2H), 5.21 (s, 2H), 6.31 (d, J = 2.1 Hz, 1H), 12.00 - 11.94 (m, 1H).

[0269] Step 2: 3-(2-Oxopropyl)-6-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyrimidine-2,4-dione 1-Chloro-2-propanone (0.02 mL, 0.27 mmol) was added to a suspension of 6-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyrimidine-2,4-dione (70 mg, 0.23 mmol) and cesium carbonate (148 mg, 0.45 mmol) in NMP (1 mL). The reaction mixture was stirred at room temperature for 16 h, then diluted with EtOAc and washed with brine (3×). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 10 - 30% EtOAc / cyclohexane) to give 3-(2-oxopropyl)-6-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyrimidine-2,4-dione (74 mg, 0.2 mmol, 90% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ -0.02 (s, 9H), 0.89 - 0.84 (m, 2H), 2.22 (s, 3H), 3.64 - 3.60 (m, 2H), 4.75 (s, 2H), 5.29 (s, 2H), 6.55 (s, 1H).

[0270] Step 3: 3-(2-Oxopropyl)-6-(trifluoromethyl)-1H-pyrimidine-2,4-dione A solution of 3-(2-oxopropyl)-6-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyrimidine-2,4-dione (72 mg, 0.2 mmol) in TFA (0.5 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to give 3-(2-oxopropyl)-6-(trifluoromethyl)-1H-pyrimidine-2,4-dione (45 mg, 0.19 mmol, 97% yield), which was used in the next step without further purification. LC / MS (ESI + ) m / z = 237.1 [M+H] + .

[0271] Step 4: 2-Methyl-7-(trifluoromethyl)-[1,3]oxazolo[3,2-a]pyrimidin-5-one A mixture of trimethylsilyl polyphosphate (2 mL) and 3-(2-oxopropyl)-6-(trifluoromethyl)-1H-pyrimidine-2,4-dione (45 mg, 0.19 mmol) was heated at 160 °C for 6 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with DCM (3×). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-methyl-7-(trifluoromethyl)-[1,3]oxazolo[3,2-a]pyrimidin-5-one (42 mg, 0.19 mmol, 100% yield) as a yellow solid. LC / MS (ESI + ) m / z = 219.1 [M+H] + .

[0272] Step 5: 6-Bromo-2-methyl-7-(trifluoromethyl)-[1,3]oxazolo[3,2-a]pyrimidin-5-one The title compound was prepared using the procedure described for Step 2 of Intermediate 1A with the following modifications: The reaction was carried out using 2-methyl-7-(trifluoromethyl)-[1,3]oxazolo[3,2-a]pyrimidin-5-one. LC / MS (ESI + ) m / z = 297.0 / 299.0 [M+H] + .

[0273] Intermediate 13A 7-(Trifluoromethyl)-1,3-dihydroimidazo[1,2-a]pyrimidine-2,5-dione

Chemical Structure

[0274] Step 1: 7-(Trifluoromethyl)-1,3-dihydroimidazo[1,2-a]pyrimidine-2,5-dione 2-Chloroacetyl chloride (1.96 mL, 24.57 mmol) was added dropwise to a stirred solution of 2-amino-6-(trifluoromethyl)-1H-pyrimidin-4-one (2.0 g, 11.17 mmol) in DMF (13 mL) at room temperature. The resulting mixture was heated at 50 °C for 3 h and stirred overnight at room temperature. Potassium carbonate (4.63 g, 33.5 mmol) was added and the suspension was stirred at 50 °C for 2 h. After cooling to room temperature, the mixture was diluted with water, treated with 1 M aqueous HCl until pH = 4, and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0 - 5% MeOH / DCM) to afford 7-(trifluoromethyl)-1,3-dihydroimidazo[1,2-a]pyrimidine-2,5-dione (1.31 g, 5.98 mmol, 54% yield). LC / MS (ESI + ) m / z = 220.2 [M+H] + .

[0275] Intermediate 14A 7-(Trifluoromethyl)-1,3-dihydroimidazo[1,2-a]pyrimidine-2,5-dione

Chemical Structure

[0276] Step 1: 6-Bromo-7-(trifluoromethyl)-1,3-dihydroimidazo[1,2-a]pyrimidine-2,5-dione A mixture of 7-(trifluoromethyl)-1,3-dihydroimidazo[1,2-a]pyrimidine-2,5-dione (Intermediate 13A, 700 mg, 3.19 mmol) and N-bromosuccinimide (682 mg, 3.83 mmol) in DMF (13 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 10% MeOH / DCM) to give 6-bromo-7-(trifluoromethyl)-1,3-dihydroimidazo[1,2-a]pyrimidine-2,5-dione (708 mg, 2.38 mmol, 59% yield). LC / MS (ESI + ) m / z = 296.1 / 298.1 [M-H] - .

[0277] Intermediate 15A 6-Bromo-1-methyl-7-(trifluoromethyl)-3H-imidazo[1,2-a]pyrimidine-2,5-dione

Chemical Structure

[0278] Step 1: 1-Methyl-7-(trifluoromethyl)-3H-imidazo[1,2-a]pyrimidine-2,5-dione Iodomethane (1.79 mL, 28.73 mmol) was added to a stirred suspension of 7-(trifluoromethyl)-1,3-dihydroimidazo[1,2-a]pyrimidine-2,5-dione (Intermediate 13A, 5.3 g, 23.95 mmol) and potassium carbonate (3.97 g, 28.73 mmol) in DMF (100 mL). The mixture was stirred at room temperature for 1.5 h and then partitioned between water and EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0 - 30% EtOAc / cyclohexane) to give 1-methyl-7-(trifluoromethyl)-3H-imidazo[1,2-a]pyrimidine-2,5-dione (3.18 g, 13.64 mmol, 57% yield). LC / MS (ESI+ ) m / z = 234.2 [M+H] + .

[0279] Step 2: 6-Bromo-1-methyl-7-(trifluoromethyl)-3H-imidazo[1,2-a]pyrimidine-2,5-dione The title compound was prepared using the procedure described for Step 2 of Intermediate 14A with the following modifications: The reaction was carried out with 1-methyl-7-(trifluoromethyl)-3H-imidazo[1,2-a]pyrimidine-2,5-dione and the mixture was heated at 50 °C for 1 h. LC / MS (ESI + ) m / z = 310.1 / 312.2 [M-H] - .

[0280] Intermediate 16A 6-Bromo-1-propan-2-yl-7-(trifluoromethyl)-3H-imidazo[1,2-a]pyrimidine-2,5-dione

Chemical Structure

[0281] Step 1: 1-Propan-2-yl-7-(trifluoromethyl)-3H-imidazo[1,2-a]pyrimidine-2,5-dione Sodium hydride (60% in mineral oil, 54.80 mg, 1.37 mmol) was added to a stirred solution of 7-(trifluoromethyl)-1,3-dihydroimidazo[1,2-a]pyrimidine-2,5-dione (Intermediate 13A, 300.0 mg, 1.37 mmol) in anhydrous DMF (2.7 mL) at 0 °C. The mixture was stirred at room temperature for 10 minutes, then 2-iodopropane (0.15 mL, 1.51 mmol) was added and the mixture was heated at 70 °C for 2 hours. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0 - 25% EtOAc / cyclohexane) to give 1-propan-2-yl-7-(trifluoromethyl)-3H-imidazo[1,2-a]pyrimidine-2,5-dione (78 mg, 0.30 mmol, 22% yield). LC / MS (ESI + ) m / z = 262.3 [M+H] + .

[0282] Step 2: 6-Bromo-1-propan-2-yl-7-(trifluoromethyl)-3H-imidazo[1,2-a]pyrimidine-2,5-dione The title compound was prepared using the procedure described for Step 2 of Intermediate 14A with the following modifications: The reaction was carried out with 1-propan-2-yl-7-(trifluoromethyl)-3H-imidazo[1,2-a]pyrimidine-2,5-dione and the mixture was heated at 50 °C for 3 hours. LC / MS (ESI + ) m / z = 338.2 / 340.1 [M-H].

[0283] Intermediate 17A 6-Bromo-1,3,3-trimethyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidine-2,5-dione

Chemical Structure

[0284] Step 1: 3-Methyl-7-(trifluoromethyl)-1,3-dihydroimidazo[1,2-a]pyrimidine-2,5-dione The title compound was prepared using the procedure described for Step 1 of Intermediate 14A with the following modifications: The reaction was carried out with 2-amino-6-(trifluoromethyl)-1H-pyrimidin-4-one and 2-chloropropanoyl chloride. LC / MS (ESI + ) m / z = 234.2 [M+H] + .

[0285] Step 2: 1,3,3-Trimethyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidine-2,5-dione Iodomethane (70 μL, 1.16 mmol) was added to a stirred suspension of 3-methyl-7-(trifluoromethyl)-1,3-dihydroimidazo[1,2-a]pyrimidine-2,5-dione (225.0 mg, 0.970 mmol) and potassium carbonate (160 mg, 1.16 mmol) in DMF (4 mL). The mixture was stirred at room temperature for 1.5 h and then diluted with water and extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0 - 40% EtOAc / cyclohexane) to give 1,3,3-trimethyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidine-2,5-dione (90 mg, 0.35 mmol, 36% yield). LC / MS (ESI + ) m / z = 262.2 [M+H] + .

[0286] Step 3: 6-Bromo-1,3,3-trimethyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidine-2,5-dione A solution of 1,3,3-trimethyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidine-2,5-dione (90 mg, 0.34 mmol) and N-bromosuccinimide (80 mg, 0.45 mmol) in MeCN (4 mL) was heated at 80 °C for 2 h. Further, N-bromosuccinimide (80 mg, 0.45 mmol) was added and heating was continued overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and purified by flash chromatography (SiO2, 0 - 40% EtOAc / cyclohexane) to give 6-bromo-1,3,3-trimethyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidine-2,5-dione (55 mg, 0.16 mmol, 47% yield). LC / MS(ESI + ) m / z = 340.2 / 342.2 [M+H] + .

[0287] Intermediate 18A 6-Bromo-2-methyl-7-(trifluoromethyl)-1H-imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0288] Step 1: 2-Amino-5-bromo-3-prop-2-ynyl-6-(trifluoromethyl)pyrimidin-4-one Molecular bromine (1.76 mL, 34.28 mmol) was added dropwise to a stirred suspension of 2-amino-4-hydroxy-6-(trifluoromethyl)pyrimidine (6.14 g, 34.28 mmol) in MeCN (61.4 mL). After the addition was complete, potassium carbonate (9.48 g, 68.57 mmol) was added all at once, and then 3-bromo-1-propyne (3.05 mL, 27.43 mmol) was added 5 minutes later. The reaction mixture was heated at 80 °C for 3 hours, then cooled to room temperature and stirred for 16 hours. Further, 3-bromo-1-propyne (0.150 mL, 0.35 mmol) was added, and the mixture was heated at 80 °C for 5 hours. After cooling to room temperature, DCM (20 mL) was added, and the mixture was stirred at room temperature for 2 minutes. The resulting precipitate was filtered off and washed with DCM (20 mL) and discarded. The filtrate was evaporated under reduced pressure to give 2-amino-5-bromo-3-prop-2-ynyl-6-(trifluoromethyl)pyrimidin-4-one (8.05 g, 27.19 mmol, 79% yield) as a slightly orange solid. This was used in the next step without further purification. LC / MS (ESI + ) m / z = 295.9 [M+H] + .

[0289] Step 2: 6-Bromo-2-methyl-7-(trifluoromethyl)-1H-imidazo[1,2-a]pyrimidin-5-one Potassium carbonate (4.9 g, 35.47 mmol) was added to a stirred solution of 2-amino-5-bromo-3-prop-2-ynyl-6-(trifluoromethyl)pyrimidin-4-one (7.0 g, 23.65 mmol) in MeCN (70 mL). The mixture was heated at 80 °C for 4 hours and stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure, DCM (70 mL) was added, and the mixture was stirred at room temperature for 15 minutes. The resulting precipitate was filtered off and washed with DCM (50 mL). The obtained solid was triturated with HCl (1 M aqueous solution, 90 mL), filtered, washed with H2O (15 mL), and dried under vacuum to give 6-bromo-2-methyl-7-(trifluoromethyl)-1H-imidazo[1,2-a]pyrimidin-5-one (5.95 g, 20.1 mmol, 85% yield). LC / MS (ESI + ) m / z = 296.1 [M+H]+ .

[0290] Intermediate 19A 6-Bromo-1,2-dimethyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0291] Step 1: 6-Bromo-1,2-dimethyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one Potassium carbonate (840.4 mg, 6.08 mmol) was added to a stirred solution of 6-bromo-2-methyl-7-(trifluoromethyl)-1H-imidazo[1,2-a]pyrimidin-5-one (Intermediate 18A, 1.5 g, 5.07 mmol) in DMF (50 mL). After 10 minutes, iodomethane (0.35 mL, 5.57 mmol) was added. The mixture was stirred at room temperature for 4 hours, then diluted with EtOAc and washed with ice water (×2) and brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0 - 20% EtOAc / DCM) to give 6-bromo-1,2-dimethyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one (1.38 g, 4.45 mmol, 88% yield). LC / MS (ESI + ) m / z = 310.0 / 311.9 [M+H] + .

[0292] Intermediates 19B - 19D listed in Table 5 below were prepared as follows according to the procedure described for Step 1 of Intermediate 19A above.

[0293]

Table 10

[0294] Intermediate 20A 6-Bromo-2-(methoxymethyl)-1-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one [Chemical formula]

[0295] Step 1: 2-Amino-5-bromo-4-(trifluoromethyl)-1H-pyrimidin-6-one A solution of 2-amino-4-(trifluoromethyl)-1H-pyrimidin-6-one (2.5 g, 13.96 mmol) and N-bromosuccinimide (2.61 g, 14.66 mmol) in MeCN (25 mL) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, diluted with EtOAc, and washed with water, saturated aqueous NaHCO3, and saturated aqueous Na2S2O3. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give 2-amino-5-bromo-4-(trifluoromethyl)-1H-pyrimidin-6-one (1.75 g, 6.78 mmol, 49% yield) as a yellow solid. LC / MS (ESI + ) m / z = 258.0 / 260.0 [M+H] + .

[0296] Step 2: 6-Bromo-2-(methoxymethyl)-7-(trifluoromethyl)-1H-imidazo[1,2-a]pyrimidin-5-one Sodium hydride (60% in mineral oil, 151 mg, 3.78 mmol) was added to a solution of 2-amino-5-bromo-4-(trifluoromethyl)-1H-pyrimidin-6-one (750 mg, 2.91 mmol) in anhydrous DMF (12 mL). Then, 1-chloro-3-methoxypropan-2-one (463 mg, 3.78 mmol, Enamine) was added after 15 minutes. The reaction mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was dissolved in toluene (10 mL). p-Toluenesulfonic acid hydrate (55 mg, 0.29 mmol) was added and the mixture was heated at 75 °C for 1 hour. After cooling to room temperature, the mixture was treated with saturated aqueous NaHCO3 and extracted with EtOAc (3×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (C18, 3 - 45% MeCN / water with 0.1% formic acid) to give 6-bromo-2-(methoxymethyl)-7-(trifluoromethyl)-1H-imidazo[1,2-a]pyrimidin-5-one (312 mg, 0.96 mmol, 33% yield) as a pale yellow solid. LC / MS (ESI + ) m / z = 326.0 / 328.0 [M+H] + .

[0297] Step 3: 6-Bromo-2-(methoxymethyl)-1-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one The title compound was prepared using the procedure described for Step 3 of Intermediate 19A with the following modifications: The reaction was carried out with 6-bromo-2-(methoxymethyl)-7-(trifluoromethyl)-1H-imidazo[1,2-a]pyrimidin-5-one. LC / MS (ESI + ) m / z = 340.0 / 342.0 [M+H] + .

[0298] Intermediate 21A 6-Bromo-2-methyl-7-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazo[1,2-a]pyrimidin-5-one

Chem.

[0299] Step 1: 6-Bromo-2-methyl-7-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazo[1,2-a]pyrimidin-5-one Sodium hydride (60% in mineral oil, 243 mg, 6.08 mmol) was added to a stirred solution of 6-bromo-2-methyl-7-(trifluoromethyl)-1H-imidazo[1,2-a]pyrimidin-5-one (Intermediate 18A, 1.5 g, 5.07 mmol) in anhydrous DMF (50.7 mL) at 0 °C. After 15 minutes at 0 °C, 2-(chloromethoxy)ethyl-trimethylsilane (1.17 mL, 6.59 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was treated with saturated aqueous NH4Cl and extracted with EtOAc. The organic phase was washed with ice water and brine. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 0 - 50% EtOAc / cyclohexane) to give 6-bromo-2-methyl-7-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazo[1,2-a]pyrimidin-5-one (1.8 g, 4.22 mmol, 83% yield). LC / MS (ESI + ) m / z = 426.0 / 428.0 [M+H] + .

[0300] Intermediates 21B - 21C listed in Table 6 were prepared as follows according to the procedure described for Step 1 of Intermediate 21A above.

[0301]

Table 11

[0302] Intermediate 22A 6-Bromo-1-(2-hydroxypropyl)-2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one

Chem.

[0303] Step 1: 6-Bromo-2-methyl-1-(2-oxopropyl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one The title compound was prepared using the procedure described for Intermediate 21A with the following modifications: The reaction was carried out with 6-bromo-2-methyl-7-(trifluoromethyl)-1H-imidazo[1,2-a]pyrimidin-5-one (Intermediate 18A) and 1-chloro-2-propanone. LC / MS (ESI + ) m / z = 352.0 / 354.0 [M+H] + .

[0304] Step 2: 6-Bromo-1-(2-hydroxypropyl)-2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one NaBH4 (10.7 mg, 0.28 mmol) was added to a solution of 6-bromo-2-methyl-1-(2-oxopropyl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one (100.0 mg, 0.280 mmol) in methanol (2.8 mL) cooled to 0 °C. The mixture was stirred at 0 °C for 1 h, then quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (SiO2, 0 - 100% EtOAc / cyclohexane) to give 6-bromo-1-(2-hydroxypropyl)-2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one (67 mg, 0.19 mmol, 67% yield). LC / MS (ESI + ) m / z = 354.0 / 356.0 [M+H] + .

[0305] Intermediate 23A 6-Bromo-2-methoxy-1-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0306] Step 1: Methyl N-(5-bromo-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl)-2-chloroacetimidate A mixture of 2-amino-5-bromo-4-(trifluoromethyl)-1H-pyrimidin-6-one (1 g, 3.88 mmol) and 2-chloro-1,1,1-trimethoxyethane (3.0 mL, 22.26 mmol) in MeCN (10 mL) was heated at 100 °C for 16 h. After cooling to room temperature, the mixture was evaporated under reduced pressure to give methyl N-(5-bromo-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl)-2-chloroacetimidate (1.35 g, 3.88 mmol). The crude product was used in the next step without further purification. LC / MS (ESI + ) m / z = 348.0 / 350.0 / 351.9 [M+H] + .

[0307] Step 2: 6-Bromo-2-methoxy-1-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one The crude methyl N-(5-bromo-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl)-2-chloroacetimidate (1.35 g, 3.88 mmol) was suspended in NMP (13 mL), and tetrabutylammonium iodide (143.2 mg, 0.39 mmol) and cesium carbonate (2.53 g, 7.75 mmol) were added. The resulting mixture was heated at 100 °C for 1 h and then cooled to room temperature. MeI (0.27 mL, 4.26 mmol) was added and the reaction was stirred at 40 °C for 16 h. The mixture was treated with H2O and extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 0 - 60% EtOAc / cyclohexane) to give 6-bromo-2-methoxy-1-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one. LC / MS (ESI+ ) m / z = 326.0 / 328.0 [M+H] + .

[0308] Intermediate 24A 1-(2,2,3,3,3-Pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole

Chemical Structure

[0309] Step 1: 1-(2,2,3,3,3-Pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)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 at 80 °C for 12 h. The reaction mixture was cooled to room temperature and partitioned between water and EtOAc. The organic layer was dried over Na2SO4, filtered, and adsorbed onto a pad of silica gel. Purification by flash chromatography (SiO2; 0 - 60% EtOAc / heptane) gave 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (289 mg, 0.9 mmol, 34% yield), which was carried on to the next reaction without further purification. 1 1H NMR (400 MHz, CDCl3) δ 1.32 (s, 16H) 4.75 (t, J = 14.10 Hz, 2H) 7.80 (s, 1H) 7.84 (s, 1H).

[0310] Intermediate 25A 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3,3,3-trifluoropropyl)pyrazole

Chemical Structure

[0311] 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 at 80 °C for 12 h. The reaction mixture was cooled to room temperature and filtered through a pad of celite with EtOAc. The filtrate was washed with brine, the organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0 - 60% EtOAc / heptane) to afford 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 (400 MHz, CDCl3) δ 1.32 (s, 13H) 2.74 (dt, J = 10.37, 7.36 Hz, 2H) 4.37 (t, J = 7.36 Hz, 2H) 7.71 (s, 1H) 7.81 (s, 1H).

[0312] Intermediate 26A Potassium trifluoro-[1-(2,2,3,3,3-pentafluoropropyl)pyrazol-4-yl]boranuide [Chemical formula]

[0313] Step 1: Potassium trifluoro-[1-(2,2,3,3,3-pentafluoropropyl)pyrazol-4-yl]boranuide 1-(2,2,3,3,3-Pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (Intermediate 24A, 1.0 g, 3.07 mmol) and potassium hydrogen fluoride (0.79 g, 10.12 mmol) in a mixture of acetone (15 mL) and water (5 mL) were 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 the undissolved salts. The solvent was evaporated, the residue was redissolved in hot acetone, cooled to room temperature and left 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]boranuide (270 mg, 0.88 mmol, 29% yield). 1 H NMR (400 MHz, DMSO-d6) δ 4.98 (t, J = 15.30 Hz, 2H), 7.03 - 7.33 (m, 2H).

[0314] Intermediate 27A 1-[(2,2-Difluorocyclopropyl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole

Chemical formula

[0315] 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 room temperature, filtered, and washed with MeCN. The filtrate was concentrated under reduced pressure and purified by flash chromatography (SiO2, 0–50% EtOAc / cyclohexane) to afford 1-[(2,2-difluorocyclopropyl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (460 mg, 1.62 mmol, 31% yield) as a colorless oil. LC / MS (ESI + ) m / z = 285.2 [M+H] + .

[0316] Intermediate 28A 1-[(3,3-Difluorocyclobutyl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole

Chem.

[0317] 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 room temperature for 18 h, then filtered and washed with EtOAc. The filtrate was washed with brine (2×), dried over Na2SO4, filtered, concentrated under reduced pressure, and 1-[(3,3-difluorocyclobutyl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (270 mg, 0.9 mmol, 88% yield) was obtained as a colorless oil. LC / MS (ESI + ) m / z = 299.1 [M+H] + .

[0318] Intermediate 29A 1-(Cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole

Chemical Structure

[0319] Step 1: 1-(Cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole 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) under a nitrogen atmosphere at 0 °C. The reaction mixture was warmed to room temperature and stirred for 24 h. The mixture was concentrated under reduced pressure, cyclohexane was added, and the resulting precipitate was filtered. 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 (1.78 g, 7.17 mmol, 70% yield) as a white solid. LC / MS (ESI + ) m / z = 249.1 [M+H] + .

[0320] Intermediate 30A 1-(2,2,3,3,3-pentafluoropropyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole [Chemical Structure]

[0321] 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 room temperature and partitioned between water and EtOAc. The organic phase was dried over Na2SO4, 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 carried on to the next reaction without further purification. LC / MS (ESI + ) m / z = 327.2 [M+H] + .

[0322] Intermediate 31A 4,4,5,5-Tetramethyl-2-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,2-dioxaborolane

Chemical formula

[0323] 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 room temperature, the mixture was partitioned between water and EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 50% EtOAc / cyclohexane) gave 1-bromo-4-(2,2,2-trifluoroethoxy)benzene (10.9 g, 42.73 mmol, 74% yield). 11H NMR (400 MHz, DMSO-d6) δ 4.78 (q, J = 8.88 Hz, 2H), 7.02 - 7.08 (m, 2H), 7.48 - 7.56 (m, 2H).

[0324] 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 purged with nitrogen for 5 minutes and then heated at 110 °C for 4 hours. After cooling to room temperature, 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 (SiO2, 0 - 3% EtOAc / cyclohexane) to give 4,4,5,5 - tetramethyl - 2 - [4 - (2,2,2 - trifluoroethoxy)phenyl] - 1,3,2 - dioxaborolane (2.76 g, 9.13 mmol, 47% yield) as a colorless oil. LC / MS (ESI + ) m / z = 303.1 [M + H] + .

[0325] Intermediate 32A 1 - (Oxetan - 3 - ylmethyl) - 4 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)pyrazole

Chemical Structure

[0326] 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 minutes. After cooling to room temperature, 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 (270 mg, 1 mmol, 100% yield) as a brown oil. LC / MS (ESI + ) m / z = 265.0 [M+H] + .

[0327] Intermediate 33A Trimethyl-[2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methoxy]ethyl]silane [Chemical Structure]

[0328] Step 1: Trimethyl-[2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methoxy]ethyl]silane Sodium hydride (60% in mineral oil, 309 mg, 7.73 mmol) was added to a stirred solution of 4-pyrazoleboronic acid pinacol ester (1 g, 5.15 mmol) in anhydrous DMF (10 mL) at 0 °C. The mixture was stirred at 0 °C for 5 minutes and then at room temperature for 30 minutes. The mixture was cooled again to 0 °C and 2-(chloromethoxy)ethyl-trimethylsilane (1.19 mL, 6.7 mmol) was added. The reaction was left to reach room temperature and stirred for 4 hours, then poured into saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and evaporated. The crude material was purified by flash chromatography (SiO2, 0 - 20% EtOAc / cyclohexane) to give trimethyl-[2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methoxy]ethyl]silane (830 mg, 2.56 mmol, 50% yield) as a colorless oil. LC / MS (ESI + ) m / z = 325.3 [M+H] + .

[0329] Intermediate 34A [1-(2-Bromoethyl)cyclopropyl]oxy-tert-butyl-dimethylsilane

Chemical Structure

[0330] Step 1: 1-(2-Bromoethyl)cyclopropan-1-ol Titanium(IV) isopropoxide (3.14 g, 11.05 mmol) was added to a solution of ethyl 3-bromopropionate (2.0 g, 11.05 mmol) in anhydrous THF (40 mL). The mixture was cooled to -5 °C, and then ethylmagnesium bromide (1 M solution in THF, 24.3 mL, 24.31 mmol) was added dropwise over 2 hours while maintaining a temperature below 4 °C. The reaction mixture was stirred at room temperature for 2 hours, then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 0 - 50% EtOAc / cyclohexane) to give 1-(2-bromoethyl)cyclopropan-1-ol (417 mg, 2.53 mmol, 23% yield) as a brown oil. 1 1H NMR (400 MHz, CDCl3) δ 0.61 - 0.53 (m, 2H), 0.88 - 0.81 (m, 2H), 1.99 (s, 1H), 2.15 (tt, J = 7.1, 0.6 Hz, 2H), 3.65 (t, J = 7.2 Hz, 2H).

[0331] Step 2: [1-(2-bromoethyl)cyclopropyl]oxy-tert-butyl-dimethylsilane tert-Butyl-chloro-dimethylsilane (685.5 mg, 4.55 mmol) was added portionwise at 0 °C to a mixture of 1-(2-bromoethyl)cyclopropan-1-ol (417 mg, 2.53 mmol) and imidazole (344.0 mg, 5.05 mmol) in DCM (10 mL). The mixture was stirred overnight at room temperature, then partitioned between water and DCM. The phases were separated, the organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100% cyclohexane) to give [1-(2-bromoethyl)cyclopropyl]oxy-tert-butyl-dimethylsilane (536 mg, 1.92 mmol, 76% yield) as a colorless oil. 11H NMR (400 MHz, CDCl3) δ -0.12 (s, 6H), 0.54 - 0.48 (m, 2H), 0.80 - 0.73 (m, 2H), 0.87 (s, 9H), 2.06 (ddt, J = 8.1, 7.5, 0.7 Hz, 2H), 3.63 - 3.55 (m, 2H).

[0332] Synthesis of Examples: Method 1 Example 1: 6-[1-(2,2,3,3,3-Pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

Chemical Structure

[0333] Step 1: 6-[1-(2,2,3,3,3-Pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one A screw-cap vial was charged with 6-bromo-7-(trifluoromethyl)-[1,3]thiazolo[3,2-a]pyrimidin-5-one (Intermediate 1A, 100 mg, 0.33 mmol), 1,4-dioxane (5.5 ml), water (0.55 ml), cesium carbonate (274 mg, 0.84 mmol), 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (Intermediate 24A, 142 mg, 0.43 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (27 mg, 0.07 mmol), and tris(dibenzylideneacetone)dipalladium(0) (31 mg, 0.033 mmol). The mixture was purged with nitrogen for 10 minutes and then heated at 90 °C for 2 hours. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated under reduced pressure and purified by flash chromatography (SiO2, 20 - 100% EtOAc / cyclohexane) to give 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (95 mg, 0.23 mmol, 68% yield) as a white solid. LC / MS(ESI + ) m / z = 419.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 5.04 Hz, 1H), 8.00 (s, 1H), 7.72 (d, J = 4.82 Hz, 1H), 7.64 (s, 1H), 5.27 (t, J = 15.02 Hz, 2H).

[0334] Example 2: 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one

Chemical Structure

[0335] Step 1: 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one A screw-cap vial was charged with 6-bromo-2-methyl-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (Intermediate 3A, 1.63 g, 5.19 mmol), 1,4-dioxane (15 mL), water (3 mL), cesium carbonate (4.25 g, 12.97 mmol), 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (Intermediate 24A, 3.38 g, 10.37 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (639 mg, 1.56 mmol), and tris(dibenzylideneacetone)dipalladium(0) (475 mg, 0.52 mmol). The mixture was purged with nitrogen for 10 minutes and then heated at 90 °C for 5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude material was purified by flash chromatography (C18, 3 - 80% MeCN / water with 0.1% formic acid, then SiO2, 10 - 90% EtOAc / cyclohexane) to give 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (1.10 g, 2.55 mmol, 49% yield) as a white solid. LC / MS (ESI + ) m / z = 434.17 [M+H] + . 1 1H NMR (500 MHz, DMSO-d6) δ 2.77 (s, 3H), 5.29 (t, J = 15.0 Hz, 2H), 7.66 (s, 1H), 8.05 (s, 1H).

[0336] Alternatively, Example 2 may be prepared as follows: A screw-cap vial was charged with 6-bromo-2-methyl-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (Intermediate 3A, 105 mg, 0.33 mmol), 1,4-dioxane (0.8 mL), water (0.2 mL), cesium carbonate (329 mg, 1.00 mmol), 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (Intermediate 24A, 171 mg, 0.52 mmol), and chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (34 mg, 0.04 mmol). The mixture was purged with nitrogen for 10 minutes and then heated at 110 °C for 50 minutes. After cooling to room temperature, the mixture was partitioned between water and EtOAc. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 50–100% EtOAc / cyclohexane) to give 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (108 mg, 0.25 mmol, 75% yield). LC / MS (ESI + ) m / z = 434.1 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 2.77 (s, 3H), 5.29 (t, J = 15.0 Hz, 2H), 7.66 (s, 1H), 8.05 (s, 1H).

[0337] Example 3: 1-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione

Chemical Structure

[0338] Step 1: 1-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione A screw-cap vial was charged with 6-bromo-1-methyl-7-(trifluoromethyl)-3H-imidazo[1,2-a]pyrimidine-2,5-dione (Intermediate 15A, 1.12 g, 3.34 mmol), 1,4-dioxane (35 mL), water (3.5 mL), cesium carbonate (2.74 g, 8.35 mmol), 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (Intermediate 24A, 2.18 g, 6.68 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (274 mg, 0.67 mmol), and tris(dibenzylideneacetone)dipalladium(0) (306 mg, 0.33 mmol). The mixture was purged with nitrogen for 10 minutes and then heated at 80 °C for 2 hours. After cooling to room temperature, the mixture was filtered through a pad of celite with EtOAc. The filtrate was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 0–50% EtOAc / cyclohexane, then C18, 0–70% acetonitrile / water) to give 1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione (445 mg, 1.03 mmol, 31% yield) as a white solid. LC / MS (ESI + ) m / z = 432.7 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 3.12 (s, 3H), 4.55 (s, 2H), 5.27 (t, J = 14.96 Hz, 2H), 7.61 (s, 1H), 8.00 (s, 1H).

[0339] Examples 4-36 listed in Table 7 below were prepared according to the procedure described in Step 1 of Method 1 above, as follows.

[0340] [Table 12]

[0341] [Table 13]

[0342] [Table 14]

[0343] [Table 15]

[0344] [Table 16]

[0345] [Table 17]

[0346] [Table 18]

[0347] [Table 19]

[0348] [Table 20]

[0349] [Table 21]

[0350]

Table 22

[0351]

Table 23

[0352]

Table 24

[0353]

Table 25

[0354]

Table 26

[0355]

Table 27

[0356]

Table 28

[0357] Method 2 Example 37: 1-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chem.

[0358] Step 1: 1-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one A microwave vial was charged with 6-bromo-1-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one (Intermediate 10A, 50 mg, 0.17 mmol), MeCN (2.3 mL), sodium carbonate (1 M solution in water, 0.42 mL, 0.42 mmol), potassium trifluoro-[1-(2,2,3,3,3-pentafluoropropyl)pyrazol-4-yl]boranuide (Intermediate 26A, 77.50 mg, 0.25 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12.40 mg, 0.02 mmol). The mixture was purged with nitrogen for 10 minutes, followed by microwave irradiation at 120 °C for 30 minutes. The reaction mixture was cooled to room temperature and filtered through a pad of celite with EtOAc. The filtrate was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0 - 100% EtOAc / cyclohexane, then C18, 0 - 70% MeCN in water) to give 1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (42 mg, 0.10 mmol, 44% yield) as a white solid. LC / MS (ESI + ) m / z = 416.4 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 3.74 (s, 3H), 5.24 (t, J = 14.96 Hz, 2H), 7.56 (s, 1H), 7.72 - 7.78 (m, 1H), 7.78 - 7.83 (m, 1H), 7.88 (s, 1H).

[0359] Examples 38 - 39 listed in Table 8 below were prepared as follows according to the procedure described in Step 1 of Method 2 above.

[0360]

Table 29

[0361] Method 3 Example 40: 2-Methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one

Chemical Structure

[0362] Step 1: 2-Methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one A screw-cap vial was charged with 6-bromo-2-methyl-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (Intermediate 3A, 200 mg, 0.64 mmol), 1,4-dioxane (1.8 mL), water (0.36 mL), cesium carbonate (622 mg, 1.91 mmol), 4,4,5,5-tetramethyl-2-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,2-dioxaborolane (Intermediate 31A, 385 mg, 1.27 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (70 mg, 0.10 mmol). The mixture was purged with nitrogen for 10 minutes and then heated at 95 °C for 45 minutes. 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 purified by flash chromatography (SiO2, 0 - 100% EtOAc / cyclohexane, then C18, 0 - 50% acetonitrile / water with 0.1% formic acid) to give 2-methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (140 mg, 0.34 mmol, 54% yield). LC / MS (ESI + ) m / z = 410.0 [M+H]+ . 1H NMR (500 MHz, DMSO-d6) δ 2.77 (s, 3H), 4.82 (q, J = 8.9 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H).

[0363] Method 4 Example 41: 7-Ethoxy-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one

Chemical Structure

[0364] Step 1: 7-Ethoxy-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one A screw-cap vial was charged with 6-bromo-7-ethoxy-2-methyl-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (Intermediate 9A, 40.0 mg, 0.140 mmol), 1,4-dioxane (1.4 mL), water (0.28 mL), cesium carbonate (135 mg, 0.41 mmol), 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (Intermediate 24A, 89.91 mg, 0.280 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (9.8 mg, 0.01 mmol). The mixture was purged with nitrogen for 10 minutes and then heated at 100 °C for 30 minutes. 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 purified by flash chromatography (C18, 0 - 50% acetonitrile / water with 0.1% formic acid) to give 7-ethoxy-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (21 mg, 0.051 mmol, 37% yield). LC / MS(ESI + ) m / z = 410.4 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 1.42 (t, J = 7.0 Hz, 3H), 2.73 (s, 3H), 4.50 (q, J = 7.0 Hz, 2H), 5.28 (t, J = 15.1 Hz, 2H), 8.23 (s, 1H), 8.52 (s, 1H).

[0365] Method 5 Example 42: 2-(Methoxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one

Chemical Structure

[0366] Step 1: 2-(Methoxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one A screw-cap vial was charged with 6-bromo-2-(methoxymethyl)-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (Intermediate 2A, 295 mg, 0.86 mmol), 1,4-dioxane (4.7 mL), water (1.2 mL), cesium carbonate (843 mg, 2.57 mmol), 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (Intermediate 24A, 608 mg, 1.71 mmol), and chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (100 mg, 0.13 mmol). The mixture was purged with nitrogen for 10 minutes and then heated at 110 °C for 1.5 hours. After cooling to room temperature, the mixture was partitioned between water and EtOAc and extracted with EtOAc (2×). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 30 - 80% EtOAc / cyclohexane, then C18, 20 - 80% acetonitrile / water with 0.1% formic acid) to give 2-(methoxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (224 mg, 0.48 mmol, 48% yield) as a white solid. LC / MS (ESI + ) m / z = 464.1 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 3.46 (s, 3H), 4.88 (s, 2H), 5.30 (t, J = 15.10 Hz, 2H), 7.67 (s, 1H), 8.06 (s, 1H).

[0367] Method 6 Example 43: 2-Methoxy-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one

Chemical formula

[0368] Step 1: 2-Methoxy-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one A mixture of 1,2-dimethoxyethane (12.4 mL), ethanol (7.4 mL), and water (2.5 mL) was purged with nitrogen for 10 minutes. 6-Bromo-2-methoxy-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (Intermediate 4A, 121 mg, 0.36 mmol), 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (Intermediate 24A, 176 mg, 0.54 mmol), potassium dihydrogen phosphate (50.5 mg, 0.37 mmol), and tripotassium phosphate (79.4 mg, 0.37 mmol) were added, and the mixture was purged with nitrogen for 10 minutes. [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (23.5 mg, 0.04 mmol) was added, and the reaction mixture was stirred at 40 °C overnight. Additionally, 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (Intermediate 24A, 176 mg, 0.54 mmol), [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (23.5 mg, 0.04 mmol), potassium dihydrogen phosphate (50.5 mg, 0.37 mmol), and tripotassium phosphate (79.4 mg, 0.37 mmol) were added, and stirring was continued for 48 hours. The reaction mixture was partitioned between EtOAc and H2O, the phases were separated, the organic phase was dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography (SiO2, 0 - 80% EtOAc / cyclohexane) to give 2-methoxy-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (14 mg, 0.031 mmol, 9% yield) as a white solid. LC / MS (ESI + ) m / z = 449.9 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 4.23 (s, 3H), 5.29 (t, J = 15.0 Hz, 2H), 7.66 (s, 1H), 8.04 (s, 1H).

[0369] Method 7 Example 44: 3-Chloro-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0370] Step 1: 3-Chloro-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one A solution of 1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (Example 37, 24.9 mg, 0.06 mmol) and N-chlorosuccinimide (9.6 mg, 0.07 mmol) in DMF (0.6 mL) was heated at 80 °C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0 - 50% EtOAc / cyclohexane) to give 3-chloro-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (9.3 mg, 0.021 mmol, 34% yield). LC / MS (ESI + ) m / z = 450.4 / 452.3 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 3.65 (s, 3H), 5.24 (t, J = 14.82 Hz, 2H), 7.54 (s, 1H), 7.87 (s, 1H), 7.90 (s, 1H).

[0371] Method 8 Example 45: 2-(Hydroxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one [Chemical formula]

[0372] Step 1: 2-(Hydroxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one Boron tribromide (1 M solution in DCM, 1.9 mL, 1.9 mmol) was added dropwise to a stirred solution of 2-(methoxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (Example 42, 220 mg, 0.47 mmol) in anhydrous DCM (43 mL) cooled to 0 °C. The reaction mixture was stirred at 0 °C for 4 hours and then at room temperature overnight. The solution was cooled to 0 °C, treated with saturated aqueous NaHCO3 and brine, and extracted with DCM (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 50 - 70% EtOAc / cyclohexane, then C18, 5 - 50% acetonitrile / 0.1% formic acid in water) to give 2-(hydroxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (160 mg, 0.36 mmol, 75% yield) as a white solid. LC / MS (ESI + ) m / z = 450.4 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 4.87 (d, J = 5.7 Hz, 2H), 5.30 (t, J = 15.0 Hz, 2H), 6.68 (t, J = 5.9 Hz, 1H), 7.67 (s, 1H), 8.06 (s, 1H).

[0373] Example 46: 2-(Hydroxymethyl)-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one

Chemical Structure

[0374] Step 1: 2-(Hydroxymethyl)-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one The title compound was prepared using the procedure described for Step 1 of Example 45 with the following modifications: The reaction was carried out with 2-(methoxymethyl)-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (Example 10). The product was purified by flash chromatography (C18, 5 - 40% acetonitrile / 0.1% formic acid in water, followed by SiO2, 70% EtOAc / cyclohexane). LC / MS (ESI + ) m / z = 414.1 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 2.80 - 3.06 (m, 2H), 4.47 (t, J = 6.8 Hz, 2H), 4.87 (d, J = 5.3 Hz, 2H), 6.67 (t, J = 5.6 Hz, 1H), 7.57 (s, 1H), 8.02 (s, 1H).

[0375] Method 9 Example 47: 6-[1-(2,2,3,3,3-Pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione [Chemical formula]

[0376] Step 1: 6-[1-(2,2,3,3,3-Pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione A screw-cap vial was charged with 6-bromo-7-(trifluoromethyl)-1,3-dihydroimidazo[1,2-a]pyrimidine-2,5-dione (Intermediate 14A, 700 mg, 1.9 mmol), 1,2-dimethoxyethane (24 mL), water (3.7 mL), 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (Intermediate 24A, 1.55 g, 4.75 mmol), sodium carbonate (604 mg, 5.7 mmol), and tetrakis(triphenylphosphine)palladium(0) (329 mg, 0.29 mmol). The reaction mixture was purged with nitrogen for 10 minutes and then heated at 100 °C for 6 hours. After cooling to room temperature, the mixture was diluted with water, treated with 1 M aqueous HCl until pH = 4, and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (C18, 0 - 40% MeCN / 0.1% formic acid in water) to give 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione (152 mg, 0.36 mmol, 19% yield) as a white solid. LC / MS (ESI + ) m / z = 418.6 [M + H] + . 11H NMR (500 MHz, DMSO-d6) δ 12.51 (br.s., 1H), 7.97 (s, 1H), 7.59 (s, 1H), 5.26 (t, J = 14.96 Hz, 2H), 4.48 (s, 2H).

[0377] Method 11 Example 48: 2-Chloro-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0378] Step 1: 2-Chloro-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one A mixture of phosphoryl chloride (V) (2.18 mL, 23.35 mmol) and 1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione (Example 3, 95.0 mg, 0.22 mmol) was heated at 150 °C for 3 days. After cooling to room temperature, the mixture was poured into ice water and extracted with EtOAc (2×). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 0 - 50% EtOAc / cyclohexane) to give 2-chloro-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (19 mg, 0.04 mmol, 19% yield). LC / MS (ESI + ) m / z = 450.3 / 452.3 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 3.67 (s, 3H), 5.25 (t, J = 14.91 Hz, 2H), 7.57 (s, 1H), 7.90 (s, 1H), 8.13 (s, 1H).

[0379] Example 49: 2-Chloro-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0380] Step 1: 2-Chloro-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one The title compound was prepared using the procedure described for Step 1 of Example 48 with the following modifications: The reaction was carried out with 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidin-2,5-dione (Example 47), and the mixture was heated at 90 °C for 5 hours. The product was purified by flash chromatography (C18, 0 - 60% acetonitrile / 0.1% formic acid in water). LC / MS (ESI + ) m / z = 436.0 / 438.0 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 5.23 (t, J = 14.9 Hz, 2H), 7.55 (s, 1H), 7.75 - 7.90 (m, 2H).

[0381] Method 11 Example 50: 2-Cyclopropyl-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chem.

[0382] Step 1: 2-Cyclopropyl-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one A screw-cap vial was charged with 2-chloro-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (Example 48, 20 mg, 0.04 mmol), THF (2.5 mL), tripotassium phosphate (18.9 mg, 0.09 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18.7 mg, 0.11 mmol), and bis(triphenylphosphine)palladium(II) dichloride (3.1 mg, 0.004 mmol). The mixture was purged with nitrogen and heated at 75 °C overnight. Further, 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18.7 mg, 0.11 mmol), tripotassium phosphate (18.9 mg, 0.09 mmol), and bis(triphenylphosphine)palladium(II) dichloride (3.1 mg, 0.004 mmol) were added and heating was continued for 7 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with water and brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (C18, 5 - 55% MeCN / water with 0.1% formic acid), followed by HPLC (40 / 60% v / v n-hexane / ethanol) to give 2-cyclopropyl-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (1 mg, 0.002 mmol, 5% yield) as a white solid. LC / MS (ESI + ) m / z = 456.1 [M+H] + . 11H NMR (500 MHz, CDCl3) δ 0.78 - 0.83 (m, 2H), 1.11 - 1.12 (m, 1H), 1.11 - 1.18 (m, 1H), 1.76 - 1.86 (m, 1H), 3.85 (s, 3H), 4.79 (t, J = 13.9 Hz, 2H), 7.28 (d, J = 1.1 Hz, 1H), 7.68 - 7.75 (m, 2H).

[0383] Method 12 Example 51: 2-Chloro-1-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0384] Step 1: 1-Methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)pyrazol-4-yl]-3H-imidazo[1,2-a]pyrimidine-2,5-dione The title compound was prepared using the procedure described in Step 1 of Example 3 with the following modifications: The reaction was carried out with 6-bromo-1-methyl-7-(trifluoromethyl)-3H-imidazo[1,2-a]pyrimidine-2,5-dione (Intermediate 15A) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3,3,3-trifluoropropyl)pyrazole (Intermediate 25A). LC / MS (ESI + ) m / z = 396.1 [M + H] + .

[0385] Step 2: 2-Chloro-1-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one The title compound was prepared using the procedure described in Step 1 of Example 48 with the following modifications: The reaction was carried out with 1-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)pyrazol-4-yl]-3H-imidazo[1,2-a]pyrimidine-2,5-dione, and the mixture was stirred at 160 °C for 24 h. The product was purified by flash chromatography (SiO2, 0 - 50% EtOAc / cyclohexane, then C18, 0 - 60% acetonitrile / water). LC / MS (ESI + ) m / z = 414.1 / 416.0 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 2.88 (qt, J = 11.2, 6.8 Hz, 2H), 3.66 (s, 3H), 4.43 (t, J = 6.7 Hz, 2H), 7.47 (s, 1H), 7.86 (s, 1H), 8.11 (s, 1H).

[0386] Method 13 Example 52: 1,2-Dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0387] Step 1: 1,2-Dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one A screw-cap vial was charged with 6-bromo-1,2-dimethyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one (Intermediate 19A, 355 mg, 1.14 mmol), acetonitrile (14.2 mL), water (3.6 mL), sodium carbonate (303.4 mg, 2.86 mmol), 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (Intermediate 24A, 560 mg, 1.72 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (84 mg, 0.11 mmol). The mixture was purged with nitrogen for 10 minutes and then heated at 110 °C for 1 hour. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (SiO2, 0 - 100% EtOAc / cyclohexane, then C18, 0 - 50% MeCN / water) to give 1,2-dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (155 mg, 0.36 mmol, 32% yield) as a white solid. LC / MS (ESI + ) m / z = 430.3 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 2.38 (d, J = 1.1 Hz, 3H), 3.65 (s, 3H), 5.24 (t, J = 15.0 Hz, 2H), 7.54 - 7.57 (m, 1H), 7.58 - 7.62 (m, 1H), 7.88 (s, 1H).

[0388] Example 53: 1,2-Dimethyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0389] Step 1: 1,2-Dimethyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one A screw-cap vial was charged with 6-bromo-1,2-dimethyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one (Intermediate 19A, 100 mg, 0.32 mmol), acetonitrile (4 mL), water (1 mL), sodium carbonate (85.5 mg, 0.81 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3,3,3-trifluoropropyl)pyrazole (Intermediate 25A, 140 mg, 0.48 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (23.70 mg, 0.03 mmol). The mixture was purged with nitrogen for 10 minutes and then heated at 110 °C for 6 hours. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (SiO2, 0 - 100% EtOAc / cyclohexane, then C18, 0 - 50% MeCN / water) to give 1,2-dimethyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one (30 mg, 0.076 mmol, 24% yield) as a white solid. LC / MS (ESI + ) m / z = 394.1 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 2.37 (d, J = 1.1 Hz, 3H), 2.88 (qt, J = 11.2, 6.8 Hz, 2H), 3.64 (s, 3H), 4.42 (t, J = 6.9 Hz, 2H), 7.45 (s, 1H), 7.58 (q, J = 0.8 Hz, 1H), 7.84 (s, 1H).

[0390] Example 54: 1,2-Dimethyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one [Chemical formula]

[0391] Step 1: 1,2-Dimethyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one A screw-cap vial was charged with 6-bromo-1,2-dimethyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one (Intermediate 19A, 60 mg, 0.19 mmol), acetonitrile (2.4 mL), water (0.6 mL), sodium carbonate (51.3 mg, 0.48 mmol), 4,4,5,5-tetramethyl-2-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,2-dioxaborolane (Intermediate 31A, 58.5 mg, 0.19 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.2 mg, 0.02 mmol). The mixture was purged with nitrogen for 10 minutes and then heated at 110 °C for 1 hour. After cooling to room temperature, the mixture was filtered through a pad of celite with EtOAc. The filtrate was concentrated under reduced pressure and purified by flash chromatography (SiO2, 0 - 10% EtOAc / cyclohexane, then C18, 0 - 50% MeCN / water with 0.1% formic acid) to give 1,2-dimethyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (27 mg, 0.067 mmol, 34% yield) as a white solid. LC / MS (ESI + ) m / z = 406.1 [M+H] + . 11H NMR (500 MHz, DMSO-d6) δ 2.38 (s, 3H), 3.66 (s, 3H), 4.80 (q, J = 8.9 Hz, 2H), 7.03 - 7.11 (m, 2H), 7.18 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 1.1 Hz, 1H).

[0392] Examples 55 to 70 listed in Table 9 below were prepared as follows according to the procedure described in Step 1 of Method 13 above.

[0393] [Table 30]

[0394] [Table 31]

[0395] [Table 32]

[0396] [Table 33]

[0397] [Table 34]

[0398] [Table 35]

[0399] [Table 36]

[0400] [Table 37]

[0401] Method 15 Example 71: 2-Methoxy-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0402] Step 1: 2-Methoxy-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one A screw-cap vial was charged with 6-bromo-2-methoxy-1-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one (Intermediate 23A, 70 mg, 0.21 mmol), 1,4-dioxane (1.75 mL), water (0.35 mL), cesium carbonate (210 mg, 0.64 mmol), 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (Intermediate 24A, 140 mg, 0.43 mmol), and (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride (16 mg, 0.02 mmol). The mixture was purged with nitrogen for 10 minutes and then heated at 100 °C for 20 minutes. After cooling to room temperature, the mixture was filtered through a pad of celite with EtOAc. The filtrate was concentrated under reduced pressure and purified by flash chromatography (SiO2, 0 - 60% MeCN / DCM) to give 2-methoxy-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (40 mg, 0.09 mmol, 42% yield) as a white solid. LC / MS (ESI + ) m / z = 446.1 [M + H]+ . 1 1H NMR (500 MHz, DMSO-d6) δ 3.53 (s, 3H), 4.03 (s, 3H), 5.24 (t, J = 15.0 Hz, 2H), 7.30 (s, 1H), 7.57 (s, 1H), 7.89 (s, 1H).

[0403] Example 72: 2-Methoxy-1-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0404] Step 1: 2-Methoxy-1-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one The title compound was prepared using the procedure described for Step 1 of Example 71 with the following modifications: The reaction was carried out with 6-bromo-2-methoxy-1-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one (Intermediate 23A) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3,3,3-trifluoropropyl)pyrazole (Intermediate 25A). Purification was by flash chromatography (SiO2, 0 - 60% MeCN / DCM, then SiO2, 20% EtOAc in cyclohexane). LC / MS (ESI + ) m / z = 410.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 2.88 (qt, J = 11.2, 6.7 Hz, 2H), 3.52 (s, 3H), 4.03 (s, 3H), 4.43 (t, J = 6.8 Hz, 2H), 7.28 (s, 1H), 7.46 (s, 1H), 7.84 (s, 1H).

[0405] Method 15 Example 73: 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0406] Step 1: 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)pyrazol-4-yl]-7-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazo[1,2-a]pyrimidin-5-one A screw-cap vial was charged with 6-bromo-2-methyl-7-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazo[1,2-a]pyrimidin-5-one (Intermediate 21A, 3 g, 7.04 mmol), 1,4-dioxane (100 mL), sodium carbonate (1 M aqueous solution, 21.11 mL, 21.11 mmol), 1-(2,2,3,3,3-pentafluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (Intermediate 24A, 4.59 g, 14.07 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (516 mg, 0.7 mmol). The mixture was purged with nitrogen for 10 minutes and heated at 110 °C for 3 hours. After cooling to room temperature, the mixture was filtered through a pad of celite with EtOAc. The filtrate was washed with water and brine, dried over Na2SO4, filtered, and evaporated under vacuum. The crude material was purified by flash chromatography (SiO2, 0 - 60% EtOAc / cyclohexane, then C18, 0 - 80% MeCN / water) to give 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)pyrazol-4-yl]-7-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazo[1,2-a]pyrimidin-5-one (2.17 g, 3.978 mmol, 57% yield). LC / MS (ESI + ) m / z = 546.0 [M+H] + .

[0407] Step 2: 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one TFA (42 mL, 3.94 mmol) was added to a stirred solution of 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)pyrazol-4-yl]-7-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazo[1,2-a]pyrimidin-5-one (2.17 g, 3.94 mmol) in DCM (42 mL) cooled to 0 °C. The mixture was stirred at room temperature for 6 h and then concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and evaporated under vacuum. Et2O was added and the precipitate was collected by filtration and dried under vacuum to give 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (1.34 g, 3.23 mmol, 82% yield) as a white solid. LC / MS (ESI + ) m / z = 416.0 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 2.31 (d, J = 1.4 Hz, 3H), 5.23 (t, J = 15.0 Hz, 2H), 7.48 (d, J = 1.1 Hz, 1H), 7.55 (s, 1H), 7.86 (s, 1H), 13.23 (br s, 1H).

[0408] Example 74: 2-Methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0409] Step 1: 2-Methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)pyrazol-4-yl]-1-(2-trimethylsilylethoxymethyl)imidazo[1,2-a]pyrimidin-5-one A screw-cap vial was charged with 6-bromo-2-methyl-7-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazo[1,2-a]pyrimidin-5-one (Intermediate 21A, 1.11 g, 2.6 mmol), 1,4-dioxane (20 mL), water (7.8 mL), sodium carbonate (827.9 mg, 7.81 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3,3,3-trifluoropropyl)pyrazole (Intermediate 25A, 1.51 g, 5.21 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (191 mg, 0.26 mmol). The mixture was purged with nitrogen for 10 minutes and then heated at 100 °C for 3 hours. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over Na2SO4, filtered, and evaporated in vacuo. The crude material was purified by flash chromatography (SiO2, 0 - 60% EtOAc / cyclohexane) to give 2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)pyrazol-4-yl]-1-(2-trimethylsilylethoxymethyl)imidazo[1,2-a]pyrimidin-5-one (502 mg, 0.99 mmol, 38% yield). LC / MS (ESI + ) m / z = 510.2 [M+H] + .

[0410] Step 2: 2-Methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one TFA (2.0 mL, 0 mmol) was added to a stirred solution of 2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)pyrazol-4-yl]-1-(2-trimethylsilylethoxymethyl)imidazo[1,2-a]pyrimidin-5-one (502 mg, 0.99 mmol) in DCM (10 mL) cooled to 0 °C. The mixture was stirred overnight at room temperature, then diluted with EtOAc and washed with water and brine. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 0 - 100% EtOAc / cyclohexane, then C18, 0 - 50% MeCN / 0.1% formic acid in water) to give 2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one (225 mg, 0.59 mmol, 61% yield) as a white solid. LC / MS (ESI + ) m / z = 380.1 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 2.31 (s, 3H), 2.80 - 2.94 (m, 2H), 4.42 (t, J = 6.8 Hz, 2H), 7.38 - 7.49 (m, 2H), 7.81 (s, 1H), 13.21 (br s, 1H).

[0411] Example 75: 2-Methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0412] Step 1: 2-Methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazo[1,2-a]pyrimidin-5-one A screw-cap vial was charged with 6-bromo-2-methyl-7-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazo[1,2-a]pyrimidin-5-one (Intermediate 21A, 200 mg, 0.46 mmol), 1,4-dioxane (3.6 mL), water (2.0 mL), cesium carbonate (449.4 mg, 1.38 mmol), 4,4,5,5-tetramethyl-2-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,2-dioxaborolane (Intermediate 31A, 278 mg, 0.920 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (33.80 mg, 0.05 mmol). The mixture was purged with nitrogen for 10 minutes and then heated at 110 °C for 30 minutes. After cooling to room temperature, the mixture was filtered through a pad of celite with EtOAc. The filtrate was concentrated under reduced pressure and purified by flash chromatography (SiO2, 0 - 50% EtOAc / cyclohexane) to give 2-methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazo[1,2-a]pyrimidin-5-one (160 mg, 0.31 mmol, 67% yield). LC / MS (ESI + ) m / z = 522.0 [M+H] + .

[0413] Step 2: 2-Methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one TFA (4.2 mL, 54.54 mmol) was added to a stirred solution of 2-methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazo[1,2-a]pyrimidin-5-one (165 mg, 0.32 mmol) in DCM (3.1 mL) cooled to 0 °C. The mixture was stirred at room temperature for 3 hours and then evaporated under reduced pressure and purified by flash chromatography (C18, 0 - 50% MeCN / 0.1% formic acid in water) to give 2-methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (52 mg, 0.13 mmol, 42% yield) as a white solid. LC / MS (ESI + ) m / z = 392.0 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 2.31 (d, J = 1.1 Hz, 3H), 4.80 (q, J = 9.1 Hz, 2H), 7.06 (br d, J = 8.7 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 7.46 (s, 1H), 13.13 (br s, 1H).

[0414] Example 76: 6-{1-[(2,2-Difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical formula

[0415] Step 1: 6-[1-[(2,2-Difluorocyclopropyl)methyl]pyrazol-4-yl]-2-methyl-7-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazo[1,2-a]pyrimidin-5-one A screw-cap vial was charged with 6-bromo-2-methyl-7-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazo[1,2-a]pyrimidin-5-one (Intermediate 21A, 130 mg, 0.30 mmol), 1,4-dioxane (5 mL), sodium carbonate (1 M aqueous solution, 0.91 mL, 0.91 mmol), 1-[(2,2-difluorocyclopropyl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (Intermediate 27A, 173 mg, 0.61 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22 mg, 0.03 mmol). The mixture was purged with nitrogen for 10 minutes and then heated at 100 °C for 3 hours. After cooling to room temperature, the mixture was filtered through a pad of celite with EtOAc. The filtrate was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 0 - 60% EtOAc / cyclohexane) to give 6-[1-[(2,2-difluorocyclopropyl)methyl]pyrazol-4-yl]-2-methyl-7-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazo[1,2-a]pyrimidin-5-one (92 mg, 0.18 mmol, 60% yield). LC / MS (ESI + ) m / z = 504.1 [M+H] + .

[0416] Step 2: 6-{1-[(2,2-Difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one TFA (0.5 mL, 31.49 mmol) was added to a stirred solution of 6-[1-[(2,2-difluorocyclopropyl)methyl]pyrazol-4-yl]-2-methyl-7-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazo[1,2-a]pyrimidin-5-one (92 mg, 0.18 mmol) in DCM (2 mL) cooled to 0 °C. The mixture was stirred overnight at room temperature, followed by the addition of 0.1 mL of water and stirring was continued for 3 h. The mixture was diluted with DCM, washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0 - 100% EtOAc / cyclohexane, then C18, 0 - 50% MeCN / water with 0.1% formic acid) to afford 6-{1-[(2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (25 mg, 0.07 mmol, 37% yield) as a white solid. LC / MS (ESI + ) m / z = 374.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 1.48 (dtd, J = 13.5, 7.7, 7.7, 3.9 Hz, 1H), 1.68 (tdd, J = 12.0, 12.0, 7.7, 4.9 Hz, 1H), 2.17 - 2.29 (m, 1H), 2.31 (s, 3H), 4.28 (d, J = 7.7 Hz, 2H), 7.45 (s, 2H), 7.78 (s, 1H), 13.20 (br s, 1H).

[0417] Method 16 Example 77: 1-( 2 H3)methyl-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical formula

[0418] Step 1: 1-( 21-(Trimethylsilyl)methyl-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one Sodium hydride (60% in mineral oil, 8.7 mg, 0.22 mmol) was added to a stirred solution of 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (Example 73, 75 mg, 0.18 mmol) in anhydrous DMF (1.9 mL) cooled to 0 °C. The mixture was stirred at room temperature for 15 minutes, followed by the addition of trideutero(iodo)methane (12 μL, 0.20 mmol), and the reaction mixture was stirred at room temperature for 1 hour. Saturated aqueous NH4Cl was added, and the mixture was extracted with EtOAc. The organic phase was washed with brine (2×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (C18, 5 - 80% MeCN / water with 0.1% formic acid) to give 1-( 2 1-(Trimethylsilyl)methyl-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (43 mg, 0.099 mmol, 55% yield) as a white solid. LC / MS (ESI + ) m / z = 433.1 [M+H] + . 1 1H NMR (500 MHz, DMSO-d6) δ 2.38 (d, J = 1.1 Hz, 3H), 5.23 (t, J = 14.8 Hz, 2H), 7.56 (s, 1H), 7.60 (q, J = 0.9 Hz, 1H), 7.82 - 7.95 (m, 1H).

[0419] Example 78: 1-( 2 1-(Trimethylsilyl)methyl-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0420] Step 1: 1-( 2 H3)methyl-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one The title compound was prepared using the procedure described in Step 1 of Example 77 with the following modifications: The reaction was carried out with 2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one (Example 74), and the reaction mixture was stirred at room temperature for 4 hours. It was purified by flash chromatography (SiO2, 0 - 100% EtOAc / cyclohexane). LC / MS (ESI + ) m / z = 397.1 [M+H] + . 1 1H NMR (500 MHz, DMSO-d6) δ 2.37 (s, 3H), 2.80 - 2.99 (m, 2H), 4.43 (t, J = 6.7 Hz, 2H), 7.45 (s, 1H), 7.58 (d, J = 1.4 Hz, 1H), 7.84 (s, 1H).

[0421] Example 79: 1-(2-Hydroxyethyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0422] Step 1: 1-(2-Hydroxyethyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one Sodium hydride (60% in mineral oil, 12 mg, 0.29 mmol) was added to a stirred solution of 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (Example 73, 100 mg, 0.24 mmol) in anhydrous DMF (4 mL) cooled to 0 °C. After stirring at room temperature for 15 minutes, 2-bromoethanol (0.1 mL, 1.44 mmol) was added and the mixture was heated at 70 °C for 16 hours. Saturated aqueous NH4Cl was added and the mixture was extracted with EtOAc. The organic phase was washed with brine (2×), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 10 - 70% EtOAc / cyclohexane, then C18, 5 - 80% MeCN / 0.1% formic acid in water) to give 1-(2-hydroxyethyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (36 mg, 0.08 mmol, 33% yield) as a white solid. LC / MS (ESI + ) m / z = 460.0 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6) δ 2.41 (d, J = 1.0 Hz, 3H), 3.75 (q, J = 5.6 Hz, 2H), 4.17 (t, J = 5.4 Hz, 2H), 4.96 (t, J = 5.8 Hz, 1H), 5.24 (t, J = 15.0 Hz, 2H), 7.56 (s, 1H), 7.59 (m, J = 1.3 Hz, 1H), 7.88 (s, 1H).

[0423] Examples 80 - 85 listed in Table 10 below were prepared as follows according to the procedure described in Step 1 of Method 16 above.

[0424]

Table 38

[0425]

Table 39

[0426]

Table 40

[0427] Method 17 Example 86: 2-{2-Methyl-5-oxo-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-1-yl}acetonitrile

Chem.

[0428] Step 1: 2-{2-Methyl-5-oxo-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-1-yl}acetonitrile Iodoacetonitrile (18 μL, 0.24 mmol) was added to a stirred solution of 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (Example 73, 100 mg, 0.22 mmol) and cesium carbonate (144 mg, 0.44 mmol) in DMF (1.85 mL) cooled to 0 °C. The reaction mixture was stirred at room temperature overnight and then diluted with ice water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 0 - 100% EtOAc / cyclohexane) to give 2-{2-methyl-5-oxo-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-1-yl}acetonitrile (40 mg, 0.09 mmol, 40% yield) as a white solid. LC / MS (ESI + ) m / z = 455.2 [M+H] + . 1 1H NMR (500 MHz, DMSO-d6) δ 2.44 (d, J = 1.1 Hz, 3H), 5.25 (t, J = 15.0 Hz, 2H), 5.43 (s, 2H), 7.58 (s, 1H), 7.67 (q, J = 1.4 Hz, 1H), 7.91 (s, 1H).

[0429] Example 87: 2-[2-Methyl-5-oxo-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-1-yl]acetonitrile

Chemical Structure

[0430] Step 1: 2-[2-Methyl-5-oxo-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-1-yl]acetonitrile Iodoacetonitrile (13 μL, 0.17 mmol) was added to a stirred solution of 2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one (Example 74, 60 mg, 0.16 mmol) and cesium carbonate (103 mg, 0.32 mmol) in DMF (1.2 mL) cooled to 0 °C. The reaction mixture was stirred at room temperature overnight, then quenched with 0.5 M aqueous HCl and extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude material was purified by flash chromatography [SiO2, 0 - 5% (0.1% formic acid in MeCN) / DCM] to give 2-[2-methyl-5-oxo-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-1-yl]acetonitrile (40 mg, 0.096 mmol, 60% yield) as a white solid. LC / MS (ESI + ) m / z = 419.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 2.44 (d, J = 1.4 Hz, 3H), 2.88 (qt, J = 11.2, 6.7 Hz, 2H), 4.44 (t, J = 6.7 Hz, 2H), 5.42 (s, 2H), 7.48 (s, 1H), 7.65 (q, J = 1.2 Hz, 1H), 7.87 (s, 1H).

[0431] Example 88: 1-(2-Hydroxy-2-methylpropyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0432] Step 1: 1-(2-Hydroxy-2-methylpropyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one The title compound was prepared using the procedure described in Step 1 of Example 86 with the following modifications: The reaction was carried out with 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (Example 73), potassium carbonate, and 2,2-dimethyloxirane, and the mixture was heated at 110 °C for 16 hours. The product was purified by flash chromatography (SiO2, 80 - 100% EtOAc / cyclohexane, then C18, 0 - 100% acetonitrile / 0.1% formic acid in water). LC / MS (ESI + ) m / z = 488.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 1.18 (s, 6H), 2.44 (d, J = 1.2 Hz, 3H), 4.05 (s, 2H), 4.85 (s, 1H), 5.23 (t, J = 15.0 Hz, 2H), 7.57 (s, 1H), 7.60 (d, J = 1.2 Hz, 1H), 7.89 (s, 1H).

[0433] Example 89: 1-[2-(1-Hydroxycyclopropyl)ethyl]-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0434] Step 1: 1-[2-[1-[tert-Butyl(dimethyl)silyl]oxycyclopropyl]ethyl]-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)pyrazol-4-yl]-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one The title compound was prepared using the procedure described in Step 1 of Example 86 with the following modifications: The reaction was carried out with 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (Example 73), potassium carbonate, and [1-(2-bromoethyl)cyclopropyl]oxy-tert-butyl-dimethylsilane (Intermediate 34A), and the mixture was heated at 80 °C for 16 hours. The product was purified by flash chromatography (SiO2, 0 - 40% EtOAc / cyclohexane). LC / MS (ESI + ) m / z = 614.2 [M+H] + .

[0435] Step 2: 1-[2-(1-Hydroxycyclopropyl)ethyl]-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one 1-[2-[1-[tert-Butyl(dimethyl)silyl]oxycyclopropyl]ethyl]-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)pyrazol-4-yl]-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-one (134 mg, 0.22 mmol) and tetrabutylammonium fluoride (1 M in THF, 0.66 mL, 0.66 mmol) in anhydrous THF (5 mL) were stirred at room temperature for 30 minutes. Water was added and the mixture was extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography (SiO2, 10 - 100% EtOAc / cyclohexane) to give 1-[2-(1-hydroxycyclopropyl)ethyl]-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (65 mg, 0.13 mmol, 60% yield) as a white solid. LC / MS(ESI + ) m / z = 500.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 0.21 - 0.28 (m, 2H), 0.47 - 0.55 (m, 2H), 1.91 (t, J = 6.9 Hz, 2H), 2.43 (d, J = 1.4 Hz, 3H), 4.30 (t, J = 6.9 Hz, 2H), 5.18 - 5.31 (m, 3H), 7.57 (s, 1H), 7.60 (d, J = 1.4 Hz, 1H), 7.88 (s, 1H).

[0436] Method 18 Example 90: 2-Methyl-1-[(oxetan-3-yl)methyl]-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0437] Step 1: 2-Methyl-1-[(oxetan-3-yl)methyl]-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one A microwave vial was charged with 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (Example 73, 50 mg, 0.12 mmol), 1,4-dioxane (0.5 mL), oxetan-3-ylmethanol (13 mg, 0.14 mmol), and 2-tributylphosphoranylideneacetonitrile (58 mg, 0.24 mmol). The solution was purged with nitrogen for 5 minutes, followed by microwave irradiation at 150 °C for 1 hour. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (2×). The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The crude material was purified by flash chromatography (SiO2, 10 - 40% EtOAc / cyclohexane, then C18, 20 - 100% MeCN / 0.1% formic acid in water) to give 2-methyl-1-[(oxetan-3-yl)methyl]-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (13 mg, 0.027 mmol, 22% yield) as a white solid. LC / MS (ESI + ) m / z = 486.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 2.38 (d, J = 0.9 Hz, 3H), 3.40 - 3.54 (m, 1H), 4.44 (d, J = 7.3 Hz, 2H), 4.52 (t, J = 6.2 Hz, 2H), 4.63 (dd, J = 7.7, 6.3 Hz, 2H), 5.23 (t, J = 15.0 Hz, 2H), 7.56 (s, 1H), 7.59 (br q, J = 1.3 Hz, 1H), 7.88 (s, 1H).

[0438] Example 91: 2-Methyl-1-(oxetan-3-yl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chem.

[0439] Step 1: 2-Methyl-1-(oxetan-3-yl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one The title compound was prepared using the procedure described in Step 1 of Example 90 with the following modifications: The reaction was carried out with 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (Example 73) and 3-oxetanol. Purified by flash chromatography (SiO2, 80 - 100% EtOAc / cyclohexane). LC / MS (ESI + ) m / z = 472.0 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6) δ 2.41 (d, J = 1.0 Hz, 3H), 4.89 (dd, J = 8.1, 7.1 Hz, 2H), 5.24 (t, J = 15.0 Hz, 2H), 5.35 (t, J = 6.9 Hz, 2H), 5.68 (quin, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.62 (br q, J = 1.0 Hz, 1H), 7.90 (s, 1H).

[0440] Method 19 Example 92: 1,2-Dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidine-5-thione

Chem.

[0441] Step 1: 1,2-Dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidine-5-thione A mixture of 1,2-dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidine-5-one (Example 52, 70 mg, 0.16 mmol) and Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-dithione, 78.4 mg, 0.2 mmol) in THF (0.58 mL) was heated to reflux for 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (C18, 0 - 100% MeCN / 0.1% formic acid in water, then SiO2, 0 - 60% EtOAc / cyclohexane) to give 1,2-dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidine-5-thione (22 mg, 0.05 mmol, 31% yield) as a yellow solid. LC / MS (ESI + ) m / z = 446.0 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 2.48 (d, J = 0.8 Hz, 3H), 3.76 (s, 3H), 5.24 (t, J = 14.7 Hz, 2H), 7.51 (s, 1H), 7.81 (s, 1H), 8.12 - 8.17 (m, 1H).

[0442] Method 20 Example 93: 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyridin-2-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidine-5-one

Chem.

[0443] Step 1: 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyridin-2-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one A screw-cap vial was charged with 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (Example 73, 200 mg, 0.47 mmol), toluene (2.6 mL), potassium carbonate (161 mg, 1.17 mmol), 2-iodopyridine (75 μL, 0.7 mmol), copper(I) iodide (22.2 mg, 0.12 mmol), and N,N'-dimethylethylenediamine (25.14 μL, 0.23 mmol). The mixture was purged with a nitrogen flow for 5 minutes and then heated at 120 °C for 16 hours. Further, 2-iodopyridine (50 μL, 0.47 mmol), copper(I) iodide (18 mg, 0.09 mmol), and N,N'-dimethylethylenediamine (19 μL, 0.18 mmol) were added and heating was continued for 24 hours. After cooling to room temperature, the mixture was filtered through a pad of celite with EtOAc. The filtrate was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (SiO2, 10 - 50% EtOAc / cyclohexane, then C18, 10 - 80% MeCN / water with 0.1% formic acid) to give 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyridin-2-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (34 mg, 0.07 mmol, 15% yield) as a white solid. LC / MS (ESI + ) m / z = 493.1 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 2.36 (s, 3H), 5.25 (t, J = 14.9 Hz, 2H), 7.59 - 7.67 (m, 2H), 7.80 (d, J = 1.1 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.93 (s, 1H), 8.18 (td, J = 7.8, 2.0 Hz, 1H), 8.67 - 8.74 (m, 1H).

[0444] Examples 94 to 96 listed in Table 11 below were prepared as follows according to the procedure described in Step 1 of Method 20 above.

[0445]

Table 41

[0446] Method 21 Example 97: 2-Methyl-1-(1-methyl-1H-pyrazol-4-yl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical formula

[0447] Step 1: 2-Methyl-1-(1-methyl-1H-pyrazol-4-yl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one Triethylamine (48 μL, 0.34 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (38.7 mg, 0.19 mmol), and copper(II) trifluoromethanesulfonate (56.0 mg, 0.16 mmol) were added to a solution of 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (Example 73, 70 mg, 0.16 mmol) in DMF (3.2 mL). The mixture was stirred at room temperature for 16 h in the presence of air, then diluted with EtOAc and washed with 10% aqueous NH4OH and brine. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 30 - 70% EtOAc / cyclohexane, then C18, 5 - 80% acetonitrile / 0.1% formic acid in water) to give 2-methyl-1-(1-methyl-1H-pyrazol-4-yl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (25 mg, 0.05 mmol, 33% yield) as a white solid. LC / MS (ESI + ) m / z = 496.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 2.25 (d, J = 1.0 Hz, 3H), 3.95 (s, 3H), 5.24 (t, J = 15.0 Hz, 2H), 7.58 (s, 1H), 7.74 (q, J = 1.2 Hz, 1H), 7.81 (s, 1H), 7.90 (s, 1H), 8.21 (s, 1H).

[0448] Examples 98 - 102 listed in Table 12 were prepared as follows according to the procedure described in Step 1 of Method 21 above.

[0449]

Table 42

[0450]

Table 43

[0451]

Table 44

[0452] Method 22 Example 103: 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(1H-pyrazol-4-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical formula

[0453] Step 1: 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)pyrazol-4-yl]-7-(trifluoromethyl)-1-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]imidazo[1,2-a]pyrimidin-5-one The title compound was prepared using the procedure described in Step 1 of Example 97 with the following modifications: The reaction was carried out with 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (Example 73) and trimethyl-[2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methoxy]ethyl]silane (Intermediate 33A), and the mixture was stirred at room temperature for 16 hours in the presence of air. The product was purified by flash chromatography (SiO2, 30 - 70% EtOAc / cyclohexane). LC / MS (ESI + ) m / z = 612.4 [M+H] + .

[0454] Step 2: 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(1H-pyrazol-4-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one The title compound was prepared using the procedure described in Step 2 of Example 73 with the following modifications: The reaction was carried out with 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)pyrazol-4-yl]-7-(trifluoromethyl)-1-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]imidazo[1,2-a]pyrimidin-5-one, and the mixture was stirred at room temperature for 24 hours. The product was purified by flash chromatography (C18, 5 - 80% acetonitrile / 0.1% ammonia in water). LC / MS (ESI + ) m / z = 482.1 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 2.26 (d, J = 1.1 Hz, 3H), 5.25 (t, J = 15.0 Hz, 2H), 7.58 (s, 1H), 7.66 - 8.50 (m, 2H), 7.75 (d, J = 1.4 Hz, 1H), 7.91 (s, 1H), 13.40 (br s, 1H).

[0455] Method 23 Example 104: 2-(Fluoromethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one

Chemical Structure

[0456] Step 1: 2-(Fluoromethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one 2-(Hydroxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (Example 45, 55.0 mg, 0.12 mmol) was added to a stirred solution of diethylaminosulfur trifluoride (20 μL, 0.16 mmol) in anhydrous DCM (1 mL) at -78 °C. The reaction mixture was left to reach room temperature over 10 h and was subsequently partitioned between DCM and water. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (C18, 40 - 80% acetonitrile / 0.1% formic acid in water) to give 2-(fluoromethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (15 mg, 0.033 mmol, 27% yield) as a white solid. LC / MS (ESI+) m / z = 452.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 5.30 (t, J = 15.0 Hz, 2H), 5.91 (d, J = 45.6 Hz, 2H), 7.68 (s, 1H), 8.08 (s, 1H).

[0457] Method 24 Example 105: 2-[(Dimethylamino)methyl]-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one

Chemical Structure

[0458] Step 1: [5-Oxo-6-[1-(2,2,3,3,3-pentafluoropropyl)pyrazol-4-yl]-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl]methyl methanesulfonate N,N-Diisopropylethylamine (87 μL, 0.50 mmol) and methanesulfonyl chloride (16 μL, 0.20 mmol) were successively added to a solution of 2-(hydroxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (Example 45, 75.0 mg, 0.17 mmol) in DCM (1.25 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h, followed by the addition of 10% aqueous NaHCO3. The phases were separated, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give [5-oxo-6-[1-(2,2,3,3,3-pentafluoropropyl)pyrazol-4-yl]-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl]methyl methanesulfonate (88 mg, 0.17 mmol, 100% yield), which was carried on to the next step without further purification. LC / MS (ESI+) m / z = 528.2 [M+H] + .

[0459] Step 2: 2-[(Dimethylamino)methyl]-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one N-Methylmethanamine (2M solution in THF, 0.42 mL, 0.83 mmol) was added to a stirred solution of [[5-oxo-6-[1-(2,2,3,3,3-pentafluoropropyl)pyrazol-4-yl]-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl]methyl methanesulfonate (88.0 mg, 0.17 mmol) in anhydrous THF (0.7 mL) at room temperature. The reaction mixture was heated at 75 °C for 16 h, then cooled to room temperature, diluted with DCM and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 50 - 80% EtOAc / cyclohexane, then SiO2, 20 - 50% EtOAc / cyclohexane) to give 2-[(dimethylamino)methyl]-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (20 mg, 0.042 mmol, 25% yield) as a white solid. LC / MS (ESI+) m / z = 477.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 2.35 (s, 6H), 3.88 (s, 2H), 5.30 (t, J = 15.0 Hz, 2H), 7.66 (s, 1H), 8.05 (s, 1H).

[0460] Example 106: 2-[(Methylamino)methyl]-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one

Chemical Structure

[0461] Step 1: [[5-oxo-6-[1-(2,2,3,3,3-pentafluoropropyl)pyrazol-4-yl]-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl]methyl methanesulfonate The title compound was prepared using the procedure described in Step 1 of Example 105. LC / MS (ESI+) m / z = 528.2 [M+H] + .

[0462] Step 2: 2-[(Methylamino)methyl]-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one The title compound was prepared using the procedure described in Step 2 of Example 105 with the following modifications: The reaction was carried out with [5-oxo-6-[1-(2,2,3,3,3-pentafluoropropyl)pyrazol-4-yl]-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl]methyl methanesulfonate and methylamine (2 M solution in THF), and the reaction mixture was stirred at room temperature for 48 h. Purification was by flash chromatography (SiO2, 50 - 100% EtOAc / cyclohexane, then SiO2, 80 - 100% EtOAc / cyclohexane). LC / MS (ESI + ) m / z = 463.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 2.83 (d, J = 4.7 Hz, 3H), 3.77 (s, 2H), 5.27 (t, J = 14.9 Hz, 2H), 7.65 (s, 1H), 7.72 (s, 1H), 8.02 (s, 1H).

[0463] Method 25 Examples 107 and 108: 6-(1-{[(1R)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one and 6-(1-{[(1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one

Chemical Structure

[0464] Step 1: 6-(1-{[(1R)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one and 6-(1-{[(1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one A racemic mixture of 6-{1-[(2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one (Example 76, 19 mg, 0.05 mmol) was purified by chiral SFC (Chiralcel OD-H column, 25×0.46 cm, 5 μm, 10% (EtOH + 0.1% isopropylamine) / CO2, flow rate 2.5 ml / min, 120 bar), and the following two peaks were obtained: the first eluting isomer (5.5 mg, 0.015 mmol), and the second eluting isomer (6 mg, 0.016 mmol). The stereochemistry of the isomers was arbitrarily assigned to 6-(1-{[(1R)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one as the first eluting isomer and 6-(1-{[(1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one as the second eluting isomer. First eluting isomer: LC / MS (ESI + ) m / z = 374.1 [M+H] + ; 11H NMR (500 MHz, methanol-d4) δ 1.40 (dtd, J = 13.4, 7.8, 7.8, 3.8 Hz, 1H), 1.55 - 1.66 (m, 1H), 2.22 (ddq, J = 13.0, 11.4, 7.5, 7.5, 7.5 Hz, 1H), 2.38 (d, J = 1.1 Hz, 3H), 4.25 - 4.41 (m, 2H), 7.39 (d, J = 1.1 Hz, 1H), 7.52 (s, 1H), 7.70 (s, 1H). The isomer eluting second: LC / MS (ESI+) m / z = 374.1 [M+H] + ; 1 1H NMR (500 MHz, methanol-d4) δ 1.36 - 1.46 (m, 1H), 1.56 - 1.66 (m, 1H), 2.22 (ddq, J = 13.1, 11.5, 7.5, 7.5, 7.5 Hz, 1H), 2.38 (s, 3H), 4.18 - 4.46 (m, 2H), 7.39 (d, J = 1.1 Hz, 1H), 7.52 (s, 1H), 7.70 (s, 1H).

[0465] Examples 109 to 116 listed in Table 13 below were obtained as follows according to the procedure described in Step 1 of Method 25 above.

[0466]

Table 45

[0467]

Table 46

[0468]

Table 47

[0469]

Table 48

[0470]

Table 49

[0471]

Table 50

[0472]

Table 51

[0473]

Table 52

[0474]

Table 53

[0475]

Table 54

[0476]

Table 55

[0477] Biological evaluation In this section, the biological evaluation of the specific examples provided in this specification is provided. See Tables 15 - 18.

[0478] In vitro measurement of delta-5-desaturase inhibitory activity using mass spectrometry assays of DGLA-CoA and arachidonyl-CoA Membrane specimens of HEK293 6E cells overexpressing D5D with a total protein concentration of 5.6 mg / mL were prepared. The stock D5D membrane specimens were diluted in D5D assay buffer (containing 25 mM 2-amino-2-(hydroxymethyl)-1,3-propanediol, pH 7.5, 10 mM MgCl2, 1 mM octyl glucoside (SigmaAldrich O-8001), 1 mM tris(2-carboxyethyl)phosphine hydrochloride (SigmaAldrich 646547)) and added to assay plates containing serially diluted test compounds such that the final D5D membrane concentration was 10 μg / mL. To 15 μL of this D5D specimen, 15 μL of substrate solution (0.25 mM NADH (nicotinamide adenine dinucleotide, Roche Diag. 10107735001), 0.25 mM adenosine triphosphate (SigmaAldrich A-3377), 0.05 mM coenzyme A hydrate (SigmaAldrich C-4282), and 0.01 mM DGLA (dihomo-γ-linolenic acid, Sigma E-4504)) in the same D5D assay buffer was added. After incubation for 1 hour at ambient temperature, acetonitrile (30 μL) was added to quench the reaction and the plate was centrifuged at 3,000 rpm for 10 minutes. Mass spectrometry was performed using a Rapidfire 360 SPE system coupled to an ABSciex API4000 Triple Quadrupole mass spectrometer with ionization in negative mode (solvent A = 100% water; solvent B = 100% acetonitrile, each containing 5 mM ammonium acetate) using a C18 SPE cartridge (G9203-80105). DGLA-CoA and arachidonoyl-CoA were detected by multiple reaction monitoring (MRM) of the divalent parent ions with m / z of 526.6 and 525.6, respectively.

[0479] The inhibition rate (%) was expressed as a percentage of the maximum inhibition value obtained in the absence of the enzyme according to the following formula: % inhibition = 100 - (100 * (Sx - Sc) / (So - Sc)). Sx is the value from the unknown sample, So is the value from DMSO alone, and Sc is the value from the wells without the enzyme. In the case of CRC analysis, the inhibition rate (%) was analyzed using XLfit (IDBS, Guilford, UK) by a four-parameter logistic model or a sigmoid dose-response model. The potency of the test item was expressed as the IC50 nM corresponding to the concentration of the test item capable of inhibiting 50% of the maximum reaction of the enzyme. IC 50 values were the mean values measured by at least two independent runs.

[0480] The results presented in Table 15 were generated by the in vitro assay described above. Using this assay, any of the compounds described herein can be tested to evaluate and characterize the ability of the compound to inhibit D5D.

[0481]

Table 56

[0482]

Table 57

[0483]

Table 58

[0484]

Table 59

[0485] In Vivo Measurement of Delta-5-Desaturase Inhibitory Activity Diet-induced obesity (DIO; Jackson Laboratories strain #3800050) mice were used to screen the pharmacodynamic (PD) activity of test compounds. Generally, test compounds formulated in a solvent of 2% hydroxypropyl methylcellulose (HPMC) and 1% Tween 80 were administered to 14- to 24-week-old DIO mice. For the PD test, animals were force-fed orally at a single dose (30 mg / kg) based on body weight. For PUFA analysis, plasma collection was included in the necropsy. 10 μl of plasma or standard diluted in an alternative matrix (65 g / l bovine serum albumin in Dulbecco's phosphate-buffered saline) was mixed with 10 μl of internal standard (100 μM α-linolenic acid-d 14 (ALA-d 14 , Cayman Chemical) in a 96-well plate. 100 μl of 2N NaOH was added to the mixture, which was then saponified at 65 °C for 1 hour. Subsequently, the mixture was acidified with 50 μl of formic acid and then extracted twice successively with hexane. Hexane (500 μl) was added and the mixture was mixed thoroughly by vortexing, and then centrifuged at 4,000 rpm for 15 minutes. The hexane phase was transferred to a new 1 ml 96-well plate and the remaining aqueous layer was extracted with hexane. The organic extracts were combined and the solvent was removed by placing the plate under nitrogen gas at 55 °C. 250 μl of 90% methanol was added to the plate and then vortexed for 2 minutes. 200 μl of the sample was transferred to a new 96-well polypropylene plate. As the internal standard, ALA-d 14To track PUFA: arachidonic acid (AA) and dihomo-γ-linolenic acid (DGLA) using [the method], samples were analyzed by LC-MS / MS. Description of the LC-MS / MS method: 5 μl of the sample was injected into a Poroshell 120 EC-C18 3.0×50 mm, 1.9 μm id column. The mobile phase consisted of 20% acetonitrile containing 5 mM ammonium acetate for mobile phase A and 99.8% acetonitrile containing 2 mM ammonium acetate for mobile phase B. The LC gradient was a method with a flow rate of 0.5 mL / min and a length of 11.30 minutes, consisting of 0% B to 45% B from 0 to 2.25 minutes, then 45% B to 71% B from 6.0 to 9.5 minutes, and then 71% to 95% B from 9.5 to 9.6 minutes. The system was then maintained at 95% B from 9.6 minutes to 10.10 minutes and returned to 0% B from 10.20 minutes to 11.30 minutes at the end of the method. The peak area of PUFA was quantified using SCIEX Analyst software. To measure the degree of D5D inhibition, the AA / DGLA ratio, which is the product / substrate ratio, was calculated by dividing the AA content (retention time 8.25 minutes) by the DGLA content (retention time 9.31 minutes). The relative decrease in the AA / DGLA ratio of the test compound-administered group compared to the solvent-administered group was calculated and used as an indicator for the degree of D5D inhibition.

[0486] Using this procedure, it was shown that the compounds provided herein inhibited D5D enzyme activity in vivo by altering polyunsaturated fatty acids (PUFA).

[0487] Using the specific compounds described herein in the in vivo protocol described above, the results shown in Table 16 were obtained.

[0488]

Table 60

[0489] Evaluation of D5D inhibitors in diet-induced obesity (DIO) mice Male C57BL / 6J DIO mice (Jackson Laboratories, stock number: 380050) were fed a high-fat diet (Research Diets, Inc, D12492) for 12 weeks. All animals were given free access to water and solid samples. Three days before the start of the experiment, the animals were acclimated to oral administration. The animals were randomized into groups of 8 - 10 animals per group based on body weight, body fat mass, fat-free mass, and blood glucose concentration. The following were orally administered to the animals twice a day: solvent (2% hydroxypropyl methylcellulose and 1% Tween 80 in water), Example 2 at 10 mg / kg or 30 mg / kg (formulated in 2% hydroxypropyl methylcellulose and 1% Tween 80 in water), Example 45 at 3 mg / kg or 10 mg / kg (formulated in 2% hydroxypropyl methylcellulose and 1% Tween 80 in water). As shown in Table 17 and Table 18, the average (Example 2) food intake over 3 days, or the average daily (Example 45) food intake, was measured at the specified time. Body composition (EchoMRI) was measured on day 78 for Example 2 and on day 22 for Example 45. In Example 2, blood sampling was performed on day 81 without fasting; blood glucose was measured immediately, and plasma samples were generated from the remaining blood for measuring DGLA and AA concentrations. Blood sampling was performed at 4-hour fasting on day 84, and plasma samples were generated from the blood for measuring cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, insulin, and adipokine (adiponectin, leptin, and resistin) levels. In Example 45, blood samples at 4-hour fasting were collected on day 25, blood glucose was measured immediately, and plasma samples were generated from the remaining blood for measuring cholesterol, triglyceride, LDL cholesterol, insulin, DGLA, and AA concentrations. At the end of the test, the weights of the liver, epididymal white adipose tissue, inguinal white adipose tissue, and mesenteric (Example 2 only) white adipose tissue were recorded. The data were analyzed using GraphPad Prism v 7.04. All data are shown in Table 17 and Table 18.

[0490] The D5D inhibitor resulted in a dose-dependent decrease in body weight over the course of the experiment compared to the vehicle control group (Tables 17 and 18). The weights of the sciatic nerve, epididymis, and mesenteric white adipose tissue (WAT) at necropsy decreased, and the body fat mass uniformly decreased. The D5D inhibitor caused a decrease in plasma cholesterol and triglycerides, as well as a decrease in both blood glucose and plasma insulin levels. Evidence of target binding was demonstrated by the observed increase in plasma DGLA and decrease in plasma AA.

[0491]

Table 61

[0492]

Table 62

[0493] References Baugh SD et al., Design, synthesis, and in vivo activity of novel inhibitors of delta-5 desaturase for the treatment of metabolic syndrome, Bioorg. Med. Chem. Lett. 25(18):3836-3839 (2015). Chopra M et al., A global response to a global problem: the epidemic of overnutrition, Bull. World Health Organ. 80:952-958 (2002). Di Marzo V and Matias I, Endocannabinoid control of food intake and energy balance, Nat. Neurosci. 8(5):585-589 (2005). Dupuis J, New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk, Nat. Genet. 42(2):105-116 (2010). Fumagalli M et al., Greenlandic Inuit show genetic signatures of diet and climate adaptation, Science 349(6254):1343-1347 (2015). Haidar YM and Cosman BC, Obesity epidemiology, Clin. Colon Rectal Surg. 24:205-210 (2011). Harizi H et al., Arachidonic-acid-derived eicosanoids: roles in biology and immunopathology, Trends Mol. Med. 14(10):461-469 (2008). Kroeger J and Schulze MB, Recent insights into the relation of delta5 desaturase and delta6 desaturase activity to the development of type 2 diabetes, Curr. Opin. Lipidol. 23(1):4-10 (2012). Mendis S et al., World Health Organization (WHO) and International Society of Hypertension (ISH) risk prediction charts: assessment of cardiovascular risk for prevention and control of cardiovascular disease in low and middle-income countries, J. Hypertens. 25:1578-1582 (2007). Merino DM et al., Genetic variation in lipid desaturases and its impact on the development of human disease, Lipids Health Dis. 9:63 (2010). Merino DM et al., Polymorphisms in FADS1 and FADS2 alter desaturase activity in young Caucasian and Asian adults, Mol. Genet. Metab. 103(2):171-178 (2011). Miyahisa I et al., T-3364366 Targets the Desaturase Domain of Delta-5 Desaturase with Nanomolar Potency and a Multihour Residence Time, ACS Med. Chem. Lett. 7(9):868-872 (2016). Monteiro CA et al., Socioeconomic status and obesity in adult populations of developing countries: a review. Bull. World Health Organ. 82:940-946 (2004). Obukowicz MG et al., Novel, selective delta6 or delta5 fatty acid desaturase inhibitors as antiinflammatory agents in mice, J. Pharmacol. Exp. Ther. 287(1):157-166 (1998). Powell DR et al., Fatty acid desaturase 1 knockout mice are lean with improved glycemic control and decreased development of atheromatous plaque, Diabetes Metab. Syndr. Obes. 9:185-199 (2016). Tosi F et al., Delta-5 and delta-6 desaturases: crucial enzymes in polyunsaturated fatty acid-related pathways with pleiotropic influences in health and disease, Adv. Exp. Med. Biol. 824:61-81 (2014). Willer CJ et al., Discovery and refinement of loci associated with lipid levels, Nat. Genet. 45(11):1274-1283 (2013). Yashiro H et al., A Novel Selective Inhibitor of Delta-5 Desaturase Lowers Insulin Resistance and Reduces Body Weight in Diet-Induced Obese C57BL / 6J Mice, PLoS One 11(11):e0166198 (2016).

[0494] All references cited in this specification, such as scientific papers or patent application publications, are hereby incorporated by reference in their entirety for all purposes to the same extent as if each reference were specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

Claims

1. A compound of formula I 【Chemical 1】 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein [Chemical 2] is [Chemical 3] ; R and R' are each independently selected from H, halogen, -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, -(CH ２ ) ｍ (C ３～５ cycloalkyl), -CH ２ (C ３～５ heterocycloalkyl), C １～４ deuterated alkyl, C ３～５ cycloalkyl, C ３～４ heterocycloalkyl, C ２～４ alkenyl, C ２～４ alkynyl, C １～４ alkoxy, C １～４ deuterated alkoxy, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl; Said C １～４ The alkyl group is optionally substituted with 1 to 4 Fs, or is optionally substituted with a substituent selected from -OH, -CN, C １～４ alkoxy, -NH ２ , C １～４ alkylamino, di-C １～４ alkylamino, and -S(O) ｎ (C １～４ alkyl); Said C １～４ The alkoxy group is optionally substituted with 1 to 4 independently selected halogens, or is optionally substituted with a substituent selected from -OH, -CN, C １～４ alkoxy, -NH ２ , C １～４ alkylamino, di-C １～４ alkylamino, and -S(O) ｎ (C １～４ alkyl); The foregoing -CH ２ (C ３～５ cycloalkyl), C ３～４ heterocycloalkyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents 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); and When present, R of the first CR or CRR' group and R of the second CR or CRR' group, together with the atoms to which they are attached, form a C ３～５ carbocyclic ring; Each R'' is independently selected from H, -OH, -CO(C １～４ alkyl), -S(O) ｎ (C １～４ alkyl), -COO(C １～４ alkyl), -CONH ２ , -CONH(C １～４ alkyl), -CO(diC １～４ alkylamino), C １～４ alkyl, -(CH ２ ) ｍ (C ３～５ cycloalkyl), -CH ２ (C ３～５ heterocycloalkyl), C １～４ deuterated alkyl, C ３～５ cycloalkyl, C ３～４ heterocycloalkyl, C ２～４ alkenyl, C ２～４ alkynyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl; Said C １～４ The alkyl group is optionally substituted with 1 to 4 Fs, or is optionally substituted with a substituent selected from -OH, -CN, C １～４ alkoxy, -NH ２ , C １～４ alkylamino, di-C １～４ alkylamino, and -S(O) ｎ (C １～４ alkyl); and The foregoing -(CH ２ ) ｍ (C ３～５ cycloalkyl), C ３～４ heterocycloalkyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents 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 O or NH; R ２ is [Chemical Formula 4] ; wherein ring A is a 5-membered heteroaryl containing one heteroatom selected from N, S, and O, and optionally one or two additional N atoms, the remaining ring atoms of said 5-membered heteroaryl being carbon, i) Ring A is attached to the bicyclic core via a C atom, and R ３ is attached via an N atom; or ii) Ring A is attached to the bicyclic core via an N atom, and R ３ is attached via a C atom; or iii) Ring A is bonded to the bicyclic core via a C atom, and R ３ is bonded via a C atom; and R ２ portion [Chemical Formula 5] further comprises one or two independently selected substituents R ３’ optionally substituted with; R ３ is C １～６ alkyl, C ２～６ alkoxy, C １～６ alkylamino, di-C 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; said C １～６ alkyl, C ３～５ cycloalkyl, C ２～６ alkoxy, C １～６ alkylamino, di-C 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 cycloalkyl) groups are optionally substituted with 1 to 9 halogen atoms and optionally substituted with -CN, and said phenyl is optionally substituted with 1 to 3 substituents selected from halogen, C １～４ alkyl, C １～４ haloalkyl, C １～４ alkoxy, and C １～４ haloalkoxy; R ３ ' is 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 cyclohaloalkyl; n is 0, 1, or 2; and m is 1 or 2; provided that （１） 【Chemical Formula 6】 is not 【Chemical Formula 7】 In the case of R ２ is 【Chemical 8】 , and R2 is not 【Chemical Formula 9】 (wherein R3 is CF3), and R2 is not 【Chemical Formula 10】 (wherein R3 is methyl), （２） 【Chemical 11】 is not 【Chemical 12】 In the case of R ２ is 【Chemical 13】 , （３） 【Chemical 14】 is not 【Chemical 15】 In the case of R ２ is 【Chemical 16】 ; and When any of R, R', or R'' is phenyl, R ３ is not unsubstituted C １～６ alkyl, and R ３ is not C １～２ alkoxy a compound or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

2. A compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is 1,3,3-trimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyrimidin-5-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; or not 2-[(methylamino)methyl]-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one, a compound or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

3. A compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein When present, each of R and R' is independently selected from H, halogen, -COO(C １～４ alkyl), C １～４ alkyl, -(CH ２ ) ｍ (C ３～５ cycloalkyl), -CH ２ (C ３～５ heterocycloalkyl), C １～４ deuterated alkyl, C ３～５ cycloalkyl, C ３～４ heterocycloalkyl, C ２～４ alkynyl, C １～４ alkoxy, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl; Said C １～４ The alkyl group is optionally substituted with 1 to 4 Fs, or is optionally substituted with a substituent selected from -OH, -CN, C １～４ alkoxy, C １～４ alkylamino, and diC １～４ alkylamino; and The foregoing -(CH ２ ) ｍ (C ３～５ cycloalkyl), a 5-membered heteroaryl, and a 6-membered heteroaryl group are optionally substituted with 1 to 4 substituents independently selected from halogen, -OH, and C １～４ alkyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

4. When present, each R″ is independently selected from H, —COO(C １～４ alkyl), C １～４ alkyl, —(CH ２ 2)n ｍ C(═O)O—(CH ３～５ 2)n ２ C(═O)O—(CH ３～５ 2)n １～４ —CH2—(CH ３～５ 2)n ３～４ —CH2—(CH ２～４ 2)n—, —CH2—C≡C—(CH2)n—, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl; Said C １～４ The alkyl group is optionally substituted with 1 to 4 Fs, or is optionally substituted with a substituent selected from -OH, -CN, C １～４ alkoxy, C １～４ alkylamino, and diC １～４ alkylamino; and The foregoing -(CH ２ ) ｍ (C ３～５ cycloalkyl), a 5-membered heteroaryl, and a 6-membered heteroaryl group are optionally substituted with 1 to 4 substituents independently selected from halogen, -OH, and C １～４ alkyl, the compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

5. When present, R of the first CR or CRR' group and R of the second CR or CRR' group form a cyclopropyl together with the atoms to which they are attached. A compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

6. R １ The compound according to claim 1, wherein R is O or S, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

7. R ２ is 【Chemical 17】 The compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein A is a 5-membered heteroaryl containing 2 N atoms.

8. R ２ is 【Chemical Formula 18】 The compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

9. R ３ is C １～６ alkyl, C ２～６ alkoxy, -CH ２ (C ３～５ cycloalkyl), -OCH ２ (C ３～５ cycloalkyl), -CH ２ (C ３～５ heterocycloalkyl), or phenyl; said C １～６ alkyl, C ２～６ alkoxy, -CH ２ (C ３～５ cycloalkyl), and -OCH ２ (C ３～５ cycloalkyl) groups are optionally substituted with 1 to 9 halogen atoms and optionally substituted with -CN, and said phenyl is optionally substituted with 1 halogen substituent, a compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

10. R ３ is C １～６ alkyl, C ２～６ alkoxy, -CH ２ (C ３～５ cycloalkyl), or -CH ２ (C ３～５ heterocycloalkyl); wherein said C １～６ alkyl, C ２～６ alkoxy, and -CH ２ (C ３～５ cycloalkyl) groups are optionally substituted with 1 to 9 halogen atoms, the compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

11. R ４ is C １～３ alkyl, C １～４ haloalkyl, C １～４ alkoxy, or C ３～５ The compound according to claim 1, wherein R is cycloalkyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

12. The compound is 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione; 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 3-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-3,7-bis(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-fluoro-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-chloro-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2,3-Dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-3H,7H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2,3-Dimethyl-5-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-3H,7H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 1,2-Dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-1H,7H-pyrazolo[1,5-a]pyrimidin-7-one; 1-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-1H,7H-pyrazolo[1,5-a]pyrimidin-7-one; 1,3-Dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-1H,7H-pyrazolo[1,5-a]pyrimidin-7-one; 3-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)-4H,6H,7H,8H-pyrrolo[1,2-a]pyrimidin-4-one; 2-(Trifluoromethyl)-3-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-4H,6H,7H,8H-pyrrolo[1,2-a]pyrimidin-4-one; 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-2H,3H,5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-2H,3H,5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 8-[1-(2,2,3,3,3-Pentafluoropropyl)-1H-pyrazol-4-yl]-9-(trifluoromethyl)-6,10-diazatricyclo[4.4.0.0 ２ , ４ deca-1(10),8-dien-7-one; 1-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-[1,2,4]triazolo[4,3-a]pyrimidin-5-one; 3-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-3H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidin-7-one; 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-3-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; 6-[4-(2,2,2-Trifluoroethoxy)phenyl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-(Hydroxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-(Hydroxymethyl)-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 2-Chloro-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(propan-2-yl)-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione; 3-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-3H,7H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3]oxazolo[3,2-a]pyrimidin-5-one; 6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,2H,3H,5H-imidazo[1,2-a]pyrimidine-2,5-dione; 2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-phenyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one; (2R)-2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-2H,3H,5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one; or (2S)-2-Methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-2H,3H,5H,6H,7H-[1,3]thiazolo[3,2-a]pyrimidin-5-one The compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable excipient.

14. The compound according to any one of claims 1 to 12, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or the pharmaceutical composition according to claim 13, for use as a medicament.

15. The compound according to any one of claims 1 to 12, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or the pharmaceutical composition according to claim 13, for use in reducing the body weight of a subject.

16. The compound according to any one of claims 1 to 12, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or the pharmaceutical composition according to claim 13, for use in reducing the obesity index of a subject.

17. The compound according to any one of claims 1 to 12, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or the pharmaceutical composition according to claim 13, for use in the treatment of metabolic diseases.

18. The compound according to any one of claims 1 to 12, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or the pharmaceutical composition according to claim 13, for use in the treatment of cardiovascular diseases.

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