Novel VDAC1 inhibitors

Abstract

The present invention relates to compounds of general formula I [Formula 1] JPEG2023535492000065.jpg5468 where R 1‐7 , Hy, and X are as defined in claim 1. Such compounds of general formula I bind to VDAC1 and are suitable for use in a method for treating diabetes or pre-diabetes in a subject in need thereof.

Description

[Technical Field]

[0001] The present invention relates to compounds of Formula I and / or II that are inhibitors of VDAC1 for treating prediabetes and diabetes, preventing the progression (worsening) of diabetic disease, and preventing the progression of prediabetes to diabetes. [Background technology]

[0002] Diabetes mellitus (Diabetes mellitus) is a serious metabolic disease that shortens life expectancy through cardiovascular and chronic kidney disease, as well as leading to stroke, peripheral neuropathy, and blindness. Approximately 12% of global healthcare costs are spent on diabetes. Diabetes is caused by insufficient insulin production from the pancreas or by the body's cells not responding appropriately to the insulin produced. There are two main types of diabetes: type 1 diabetes (T1D) and type 2 diabetes (T2D). T1D is a multifactorial endocrine and metabolic disorder most commonly seen in childhood, resulting in persistent hyperglycemia due to autoimmune destruction of insulin-producing beta cells in the pancreatic islets. T1D requires lifelong insulin therapy. Several studies have reported that beta cells (β cells) remain in the pancreatic islets of patients with T1D. Although up to 40–50% of these β cells may survive destruction, insulin secretion is insufficient to maintain normal blood glucose regulation. In vitro culture of pancreatic islets from patients with type 1 diabetes (T1D) at physiological glucose concentrations has been shown to improve glucose-stimulated insulin secretion in a time-dependent manner (Lupi R, et al. 2004. Diabetes / metabolism research and reviews, 5 20(3), 246-251; Krogvold L et al. 2015. Diabetes 64:2506-2512; Brissova M. et al. 2018 Cell Rep. 22:2667-2676). These results suggest that residual beta cells, although dysfunctional in vivo, can resume regulated insulin secretion after extraction from the hostile in vivo environment. Type 2 diabetes (T2D) is a global health problem associated with the obesity epidemic. Approximately 400 million people worldwide suffer from type 2 diabetes, and an estimated 320 million have prediabetes (Zimmet P and Alberti KG. 2016. Nature Rev Endo 10:616-622). Obesity-associated insulin resistance is compensated for by increased insulin secretion, maintaining euglycemia. Type 2 disease has a strong genetic component and most frequently develops in members of a diabetes-prone family who also share cumulative risk factors such as obesity, smoking, repeated pregnancies, and shift work.Obesity-associated diseases appear to develop when insulin secretion from pancreatic beta cells becomes unable to adapt to the increased insulin demands of this hormone-resistant organ. T2D develops several years after elevated fasting blood glucose (FBG) and / or impaired glucose tolerance (IGT), criteria that define prediabetes (Ligthart S, et al. 2016. Lancet Diabetes & 20 Endocrinology 4:44-51). Elevated mean blood glucose concentrations exert a detrimental effect on most cells in the body, including endothelial cells and beta cells, known as glucotoxicity (Hansen NW, et al. IUBMB Life 69:148-161, 2017; Weir GC et al. 2004 Diabetes 53, Suppl 3:S16-21). Glucose toxicity contributes to metabolic dysfunction in beta cells, a phenomenon that also exists in healthy individuals because glucose infusion attenuates glucose-stimulated insulin secretion (GSIS). Overt T2D, characterized by hyperglycemia, increased urination, and dry mouth, is often preceded by prediabetes, which often lasts approximately 7 years. Prediabetes is defined as elevated fasting blood glucose levels or an inability to lower blood glucose levels after an oral glucose load. T2D is reversible early after onset with lifestyle interventions aimed at weight loss and exercise (Al-Mrabeh et al., 2016. Diabetologia 59:1753-1759). However, such interventions demonstrate poor patient compliance.

[0003] In healthy cells, the multifunctional protein voltage-dependent anion channel (VDAC) is considered a master gatekeeper at the crossroads of metabolic and survival pathways, controlling the flux of metabolites and ions between mitochondria and the cytoplasm. Of the three VDAC isoforms, VDAC1 and VDAC2 mediate mitochondrial ADP / ATP exchange and calcium flux, while the function of VDAC3 is less clear (Shoshan-Barmatz V et al., 2015; Biochim. Biophys. Acta 1848:2547-2575; Shoshan-Barmatz V et al. Molecular aspects of medicine 31:227-285). VDAC1 has also been localized in cellular compartments other than mitochondria, such as the plasma membrane of various cells, the sarcoplasmic reticulum of skeletal muscle, the endoplasmic reticulum (ER) of rat cerebellum, and synaptosomes of Torpedo electric organ (De Pinto V et al., FEBS Lett. 2010, 584:1793-1799). In endothelial cells, VDAC1 is expressed on the plasma membrane even under physiological conditions (Li L et al. J Biol Chem. 2014, 289:32628-38). The mechanism underlying VDAC1 plasma membrane localization in specific cell types remains unclear. VDAC1 also plays an important role in apoptosis, mediating the release of apoptotic factors from mitochondria and interacting with anti-apoptotic regulators (Shoshan-Barmatz et al., 2015, ibid.; Shoshan-Barmatz et al., 2010, ibid.).

[0004] Mitochondrial proteome analysis revealed altered expression of VDAC and several other proteins involved in nutrient metabolism, ATP synthesis, cellular defense, glycoprotein folding, and mitochondrial DNA stability in clonal rat pancreatic β cells exposed to high glucose (Ahmed, M. et al., Islets 2010, 2:283-292). Under glucotoxic conditions, VDAC1 expression was upregulated, while VDAC2 expression was downregulated. In islets from human T2D organ donors, VDAC1 mRNA and protein were upregulated, whereas VDAC2 levels were downregulated (Zhang E. et al., 2019, Cell Metabolism 29:64-77). VDAC1 was mistargeted to the plasma membrane in β cells from T2D organ donors, and such translocation was recapitulated when islets from nondiabetic organ donors were cultured under glucotoxic conditions. Plasma membrane expression of VDAC1 has been shown to result in the loss of ATP, an essential binding factor for glucose-stimulated insulin secretion (GSIS). Acute exposure of T2D islets to antibodies against VDAC1 or the VDAC1 inhibitor N-(4-chlorophenyl)-4-hydroxy-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}butanamide (CAS number: 2086257-77-2) to prevent ATP loss restored GSIS. Inhibition of VDAC1 function in vitro does not affect insulin secretion or alter blood glucose levels in nondiabetic control mice (Zhang et al. Cell Metabolism, ibid.). Summary of the Invention

[0005] In a first aspect, the present invention provides compounds of general formula I [ka] where R 1 ~R 5 are hydrogen, halogens, CN, NO2, CF3, quaternary ammonium, COOH, COO‐C 1-6Alkyl, OCF3, SCF3, SO3‐C 1‐6 alkyl, wherein R 1 ~R 5 At least one of the is not hydrogen, R 6 is C 1‐3 -R 8 is selected from, where R 8 is selected from H, OH, SH, and NH2; R 7 are a) hydrogen, halogen, CN, C 1‐3 Alkyl, NO2, CONH2, NHCO‐C 1‐3 Alkyl, CF3, tertiary ammonium, COOH, COO‐C 1‐6 Alkyl, OC 1‐3 Alkyl, OCF3, SCF3, SO2‐C 1‐3 Alkyl, SO3‐C 1‐3 a) aryl substituted with one or more groups selected from alkyl, provided that at least one of said groups is not hydrogen; b) halogen, CN, C 1‐3 Alkyl, NO2, CONH2, NHCO‐C 1‐3 Alkyl, CF3, tertiary ammonium, COOH, COO‐C 1‐6 Alkyl, OC 1‐3 Alkyl, OCF3, SCF3, SO2‐C 1‐3 Alkyl, SO3‐C 1‐3 pyridyl optionally substituted with one or more groups selected from alkyl; c) halogen, CN, C 1‐3 Alkyl, NO2, CONH2, NHCO‐C 1‐3 Alkyl, CF3, tertiary ammonium, COOH, COO‐C 1‐6 Alkyl, OC 1‐3 Alkyl, OCF3, SCF3, SO2‐C 1‐3 Alkyl, SO3‐C 1‐3 pyrrolidinyl optionally substituted with one or more groups selected from alkyl; d) halogen, CN, C 1‐3 Alkyl, NO2, CONH2, NHCO‐C 1‐3 Alkyl, CF3, tertiary ammonium, COOH, COO‐C 1‐6 Alkyl, OC 1‐3Alkyl, OCF3, SCF3, SO2‐C 1‐3 Alkyl, SO3‐C 1‐3 e) pyrazolyl optionally substituted with one or more groups selected from halogen, CN, C 1‐3 Alkyl, NO2, CONH2, NHCO‐C 1‐3 Alkyl, CF3, tertiary ammonium, COOH, COO‐C 1‐6 Alkyl, OC 1‐3 Alkyl, OCF3, SCF3, SO2‐C 1‐3 Alkyl, SO3‐C 1‐3 thiazolyl optionally substituted with one or more groups selected from alkyl; f) halogen, CN, C 1‐3 Alkyl, NO2, CONH2, NHCO‐C 1‐3 Alkyl, CF3, tertiary ammonium, COOH, COO‐C 1‐6 Alkyl, OC 1‐3 Alkyl, OCF3, SCF3, SO2‐C 1‐3 Alkyl, SO3‐C 1‐3 C optionally substituted with one or more groups selected from alkyl 5‐7 Cycloalkyl; g) NHCONH2; h) CONH2, CON(CH3)2, CF3, and C 2‐4 C optionally substituted with a group selected from alkenes 1‐3 alkyl; X is -CONH- or -NHCO-, or X-R 7 are taken together to be CONR'R'', where R' and R'' together with the nitrogen form a) a single heterocycle having 4 to 7 ring atoms, 1 to 2 of which are selected from nitrogen and 0 to 2 of which are oxygen, the remaining ring atoms being carbon, optionally selected from oxo, OH, C 1‐3 a) a monoheterocyclic group substituted with a group selected from alkyl-CN, or b) a biheterocyclic group having 7 to 10 ring atoms, 1 to 4 of which are selected from nitrogen and the remaining ring atoms are carbon, optionally oxo, OH, C 1‐3 forming a mono- or biheterocyclic group selected from biheterocyclic groups substituted with a group selected from alkyl-CN, Hy is a) a single heterocycle having 4 to 7 ring atoms, in which 2 to 3 ring atoms are N, 0 to 1 ring atom are O, 0 to 1 ring atom are S, and the remaining ring atoms are carbon, provided that when the single heterocycle is piperazine, R 6 is not CHOH or X is not —CONH—, where the substituent R of formula I 1 ~R 5 The point of attachment of the single heterocycle to the phenyl ring having the R 6 and CH2‐X‐R 7 and b) a biheterocyclic group having fused first and second heterocycles, the biheterocyclic group having 6 to 12 ring atoms, 2-4 ring atoms being N, 0-2 ring atoms being O, 0-2 ring atoms being S, and the remaining ring atoms being carbon, wherein the first heterocycle is a biheterocyclic group having a substituent R 1 ~R 5 and the second heterocycle is attached to a phenyl ring having an R 6 and CH2‐X‐R 7 and c) a spiroheterocyclic group having first and second heterocycles connected and sharing one carbon atom, the spiroheterocyclic group having 6 to 12 ring atoms, 2-4 ring atoms being N, 0-2 ring atoms being O, 0-2 ring atoms being S, and the remaining ring atoms being carbon, wherein the first heterocycle is bonded to a substituent R of formula I. 1 ~R 5 and a second heterocycle is attached to a phenyl ring having R of formula I 6 and CH2‐X‐R 7 or d) a bond, e.g., sp 2 or sp 3 a first and second single heterocycle connected by a linker such as a hybrid bond, wherein each single heterocycle is independently selected from single heterocycles having 4 to 7 ring atoms, wherein 1 to 3 ring atoms are N, 0 to 1 ring atoms are O, 0 to 1 ring atoms are S, and the remaining ring atoms are carbon, and wherein the first single heterocycle is a substituent R of I; 1 ~R 5 and the second single heterocycle is attached to a phenyl ring having R6 and CH2‐X‐R 7 is attached to a carbon atom linked to It relates to a pharmaceutically acceptable salt or solvate thereof.

[0006] In embodiments, R 1 are halogens, CN, NO2, CF3, quaternary ammonium, COOH, COO‐C 1‐6 Alkyl, OCF3, SCF3, SO3‐C 1‐6 alkyl; R 2 ~R 5 is hydrogen.

[0007] In other embodiments, R 2 are halogens, CN, NO2, CF3, quaternary ammonium, COOH, COO‐C 1‐6 Alkyl, OCF3, SCF3, SO3‐C 1‐6 alkyl; R 1 , R 3 ~R 5 is hydrogen.

[0008] In a further embodiment, R 3 are halogens, CN, NO2, CF3, quaternary ammonium, COOH, COO‐C 1‐6 Alkyl, OCF3, SCF3, SO3‐C 1‐6 alkyl; R 1 , R 2 , R 4 ~R 5 is hydrogen, typically R 3 is OCF3.

[0009] In a further embodiment, R 4 are halogens, CN, NO2, CF3, quaternary ammonium, COOH, COO‐C 1‐6 Alkyl, OCF3, SCF3, SO3‐C 1‐6 alkyl; R 1 ~R 3 , R 5 is hydrogen.

[0010] In a further embodiment, R 5 are halogens, CN, NO2, CF3, quaternary ammonium, COOH, COO‐C 1‐6 Alkyl, OCF3, SCF3, SO3‐C 1‐6 alkyl; R 1 ~R 4 is hydrogen.

[0011] In a further embodiment, R 6 is C 1‐3 -R 8 is selected from, where R 8 is OH, typically CH2OH.

[0012] In a further embodiment, R 7 are a) hydrogen, halogen, CN, C 1‐3 Alkyl, NO2, CONH2, NHCO‐C 1‐3 Alkyl, CF3, tertiary ammonium, COOH, COO‐C 1‐6 Alkyl, OC 1‐3 Alkyl, OCF3, SCF3, SO2‐C 1‐3 Alkyl, SO3‐C 1‐3 a) phenyl substituted with one or more groups selected from alkyl, provided that at least one of said groups is not hydrogen, typically phenyl substituted with groups selected from halogen, CF, OCH, NHCOCH, CN, CH, and SOCH; b) pyridyl optionally substituted with one or more halogens; c) phenyl substituted with one or more NHCO-C 1‐3 d) pyrrolidinyl optionally substituted with one or more CONH groups; e) thiazolyl; f) cyclohexyl optionally substituted with one or more CN alkyl groups; g) NHCONH groups; and h) C substituted with a group selected from CON(CH), CF, and C alkene. 1-2 alkyl.

[0013] In an alternative embodiment, X-R 7are taken together as CONR'R'', where R' and R'' together with the nitrogen form a monoheterocyclic or biheterocyclic group selected from a) a monoheterocyclic group having 5 ring atoms, 1 to 2 of which are selected from nitrogen and the remaining ring atoms are carbon, optionally substituted with a group selected from oxo, OH, CH2-CN, or b) a biheterocyclic group having 9 to 10 ring atoms, 1 to 3 of which are selected from nitrogen and the remaining ring atoms are carbon. In a further embodiment, X is -CONH-. In another embodiment, X is -NHCO-.

[0014] In a further embodiment, Hy is a non-aromatic ring system selected from a) in which the single heterocycle has 6-7 ring atoms, where two are N and the remaining ring atoms are carbon, such as piperazine or homopiperazine.

[0015] In a further embodiment, Hy is a non-aromatic ring system selected from b) wherein the biheterocyclic group has 8 to 11 ring atoms, 1 to 2 of which are N, 0 to 1 of which are O, and the remaining ring atoms are carbon.

[0016] In a further embodiment, Hy is a non-aromatic ring system selected from c) wherein the spiroheterocyclic group has 8 to 11 ring atoms, 2-3 ring atoms are N, 0-1 ring atoms are O, and the remaining ring atoms are carbon.

[0017] In a further embodiment, Hy is a non-aromatic ring system selected from d), wherein a first and a second single heterocycle are connected by a bond, the first single heterocycle having 4 to 6 ring atoms, 1 to 2 of which are N, 0 to 1 of which are O, and the remaining ring atoms are carbon, and the second single heterocycle having 4 to 6 ring atoms, 1 to 2 of which are N, 0 to 1 of which are O, and the remaining ring atoms are carbon.

[0018] In a further embodiment, the compound of general formula I is a compound of formula II [ka] where R 1 ~R 5 are hydrogen, halogens, CN, NO2, CF3, quaternary ammonium, COOH, COO‐C 1‐6 Alkyl, OCF3, SCF3, SO3‐C 1‐6 alkyl, with the proviso that R 1 ~R 5 At least one of the is not hydrogen, R 6 is C 1‐3 -R 8 where R 8 is selected from H, OH, SH, and NH2; R 7 are a) hydrogen, halogen, CN, C 1‐3 Alkyl, NO2, CONH2, NHCO‐C 1‐3 Alkyl, CF3, tertiary ammonium, COOH, COO‐C 1‐6 Alkyl, OC 1‐3 Alkyl, OCF3, SCF3, SO2‐C 1‐3 Alkyl, SO3‐C 1‐3 a) aryl substituted with one or more groups selected from alkyl, provided that at least one of said groups is not hydrogen; b) halogen, CN, C 1‐3 Alkyl, NO2, CONH2, NHCO‐C 1‐3 Alkyl, CF3, tertiary ammonium, COOH, COO‐C 1‐6 Alkyl, OC 1‐3 Alkyl, OCF3, SCF3, SO2‐C 1‐3 Alkyl, SO3‐C 1‐3 c) pyridyl optionally substituted with one or more groups selected from alkyl, halogen, CN, C 1‐3 Alkyl, NO2, CONH2, NHCO‐C 1‐3 Alkyl, CF3, tertiary ammonium, COOH, COO‐C 1‐6 Alkyl, OC 1‐3 Alkyl, OCF3, SCF3, SO2‐C 1‐3 Alkyl, SO3‐C 1‐3pyrrolidinyl optionally substituted with one or more groups selected from alkyl; d) halogen, CN, C 1‐3 Alkyl, NO2, CONH2, NHCO‐C 1‐3 Alkyl, CF3, tertiary ammonium, COOH, COO‐C 1‐6 Alkyl, OC 1‐3 Alkyl, OCF3, SCF3, SO2‐C 1‐3 Alkyl, SO3‐C 1‐3 e) pyrazolyl optionally substituted with one or more groups selected from alkyl, halogen, CN, C 1‐3 Alkyl, NO2, CONH2, NHCO‐C 1‐3 Alkyl, CF3, tertiary ammonium, COOH, COO‐C 1‐6 Alkyl, OC 1‐3 Alkyl, OCF3, SCF3, SO2‐C 1‐3 Alkyl, SO3‐C 1‐3 f) thiazolyl optionally substituted with one or more groups selected from alkyl, halogen, CN, C 1‐3 Alkyl, NO2, CONH2, NHCO‐C 1‐3 Alkyl, CF3, tertiary ammonium, COOH, COO‐C 1‐6 Alkyl, OC 1‐3 Alkyl, OCF3, SCF3, SO2‐C 1‐3 Alkyl, SO3‐C 1‐3 C optionally substituted with one or more groups selected from alkyl 5‐7 Cycloalkyl; g) NHCONH2; h) CONH2, CON(CH3)2, CF3, and C 2‐4 C optionally substituted with a group selected from alkenes 1‐3 alkyl, X is -CONH- or -NHCO-, or X-R 7 are taken together to be CONR'R'', where R' and R'' together with the nitrogen form a) a monoheterocyclic ring having 4-7 ring atoms, 1-2 of which are selected from nitrogen and 0-2 of which are oxygen, the remaining ring atoms being carbon, optionally selected from oxo, OH, C 1‐3a) a monoheterocyclic group substituted with a group selected from alkyl-CN, or b) a biheterocyclic group having 7 to 10 ring atoms, 1 to 4 of which are selected from nitrogen and the remaining ring atoms are carbon, optionally oxo, OH, C 1‐3 a biheterocyclic group substituted with a group selected from alkyl-CN; [ka] is a non-aromatic heterocyclic ring system having a first and a second nitrogen as points of attachment, including: a) a single heterocyclic ring having 4-7 ring atoms, wherein 2-3 ring atoms are N, 0-1 ring atoms are O, 0-1 ring atoms are S, and the remaining ring atoms are carbon, provided that when the single heterocyclic ring is piperazine, R 6 is not CHOH or X is not -CONH- and the first nitrogen of the single heterocycle is a substituent R of formula I 1 ~R 5 and the second nitrogen of the single heterocycle is attached to a phenyl ring having the R 6 and CH2‐X‐R 7 and b) a biheterocyclic group having fused first and second heterocycles, the biheterocyclic group having 6 to 12 ring atoms, 2-4 ring atoms being N, 0-2 ring atoms being O, 0-2 ring atoms being S, and the remaining ring atoms being carbon, wherein the first nitrogen of the first heterocycle is bonded to a carbon atom linked to the substituent R of formula I. 1 ~R 5 and the second nitrogen of the second heterocycle is bonded to a phenyl ring having the R 6 and CH2‐X‐R 7 and c) a spiroheterocyclic group having first and second heterocycles connected and sharing one carbon atom, the spiroheterocyclic group having 6 to 12 ring atoms, 2 to 4 ring atoms being N, 0 to 2 ring atoms being O, 0 to 2 ring atoms being S, and the remaining ring atoms being carbon, wherein the first nitrogen of the first heterocycle is bonded to a substituent R of formula I. 1 ~R 5 and the second nitrogen of the second heterocycle is bonded to a phenyl ring having the R6 and CH2‐X‐R 7 or d) first and second single heterocycles connected by a linker such as a bond, each single heterocycle being independently selected from single heterocycles having 4 to 7 ring atoms, wherein 1 to 3 ring atoms are N, 0 to 1 ring atoms are O, 0 to 1 ring atoms are S, and the remaining ring atoms are carbon, and wherein the first nitrogen of the first single heterocycle is bonded to a substituent R of Formula I. 1 ~R 5 and the second nitrogen of the second heterocycle is bonded to a phenyl ring having the R 6 and CH2‐X‐R 7 is attached to a carbon atom linked to and pharmaceutically acceptable salts or solvates thereof.

[0019] In further embodiments, the compound of formula I is selected from one of the following: 4-chloro-N-(3-hydroxy-2-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}propyl)benzamide, N-(4-chlorophenyl)-5-hydroxy-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}pentanamide, N-(4-chlorophenyl)-4-hydroxy-3-{4-[4-(trifluoromethoxy)phenyl]-1,4-diazepan-1-yl}butanamide, N-(4-chlorophenyl)-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, N-(4-chlorophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(4-chlorophenyl)-4-hydroxy-3-(3-{1-[4-(trifluoromethoxy)phenyl]azetidin-3-yl}piperidin-1-yl)butanamide, N-(4-chlorophenyl)-4-hydroxy-3-{6-[4-(trifluoromethoxy)phenyl]-2,6-diazaspiro[3.4]octan-2-yl}butanamide, N-(4-chlorophenyl)-4-hydroxy-3-{1-[4-(trifluoromethoxy)phenyl]-octahydro-1H-pyrrolo[3,2-b]pyridin-4-yl}butanamide, N-(4-chlorophenyl)-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-octahydropyrrolo[3,4-c]pyrrol-2-yl}butanamide, N-(4-chlorophenyl)-4-hydroxy-3-{8-[4-(trifluoromethoxy)phenyl]-2,8-diazaspiro[5.5]undecan-2-yl}butanamide, N-[(dimethylcarbamoyl)methyl]-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 3-(4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide)pyrrolidine-1-carboxamide, N-[2-(dimethylcarbamoyl)ethyl]-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 5-(4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide)-1H-pyrazole-3-carboxamide, 4-hydroxy-N-(2,2,2-trifluoroethyl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}-N-[4-(trifluoromethyl)phenyl]butanamide, N-(5-chloropyridin-2-yl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-N-(3-methoxyphenyl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(4-acetamidophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(3-acetamidophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(4-cyanophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(2-chlorophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(3-chlorophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(4-fluorophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 1-(4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanoyl)imidazolidin-4-one, 4-hydroxy-N-(prop-2-en-1-yl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-1-(pyrazolidin-1-yl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butan-1-one, 4-hydroxy-1-(3-hydroxypyrrolidin-1-yl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butan-1-one, 2-[1-(4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanoyl)pyrrolidin-3-yl]acetonitrile, N-(3-chlorophenyl)-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, 4-hydroxy-N-(pyridin-3-yl)-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, 4-hydroxy-N-(1,2-thiazol-5-yl)-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, N-[(dimethylcarbamoyl)methyl]-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, N-(2-chlorophenyl)-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, 4-hydroxy-N-(1H-pyrazol-1-yl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(4-cyanophenyl)-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, 4-hydroxy-1-{1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butan-1-one, 4-hydroxy-N-[(1r,4r)-4-cyanocyclohexyl]-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(carbamoylamino)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-N-(pyridin-2-yl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-N-(pyridin-3-yl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}-N-(2,4,6-trimethylphenyl)butanamide, 4-hydroxy-N-(4-methanesulfonylphenyl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-1-{1H,4H,5H,6H,7H-pyrrolo[3,2-c]pyridin-5-yl}-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butan-1-one; or a pharmaceutically acceptable salt or solvate thereof. Each of the above-listed compounds or pharmaceutically acceptable salts or solvates thereof is an individual embodiment and may be the subject of one or more independent claims.

[0020] In further embodiments, the compound of formula I is selected from one of the following: 4-chloro-N-(3-hydroxy-2-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}propyl)benzamide, N-(4-chlorophenyl)-5-hydroxy-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}pentanamide, N-(4-chlorophenyl)-4-hydroxy-3-{4-[4-(trifluoromethoxy)phenyl]-1,4-diazepan-1-yl}butanamide, N-(4-chlorophenyl)-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, N-(4-chlorophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(4-chlorophenyl)-4-hydroxy-3-(3-{1-[4-(trifluoromethoxy)phenyl]azetidin-3-yl}piperidin-1-yl)butanamide, N-(4-chlorophenyl)-4-hydroxy-3-{6-[4-(trifluoromethoxy)phenyl]-2,6-diazaspiro[3.4]octan-2-yl}butanamide, N-(4-chlorophenyl)-4-hydroxy-3-{1-[4-(trifluoromethoxy)phenyl]-octahydro-1H-pyrrolo[3,2-b]pyridin-4-yl}butanamide, N-(4-chlorophenyl)-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-octahydropyrrolo[3,4-c]pyrrol-2-yl}butanamide, N-(4-chlorophenyl)-4-hydroxy-3-{8-[4-(trifluoromethoxy)phenyl]-2,8-diazaspiro[5.5]undecan-2-yl}butanamide, N-[(dimethylcarbamoyl)methyl]-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-[2-(dimethylcarbamoyl)ethyl]-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-N-(2,2,2-trifluoroethyl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}-N-[4-(trifluoromethyl)phenyl]butanamide, N-(5-chloropyridin-2-yl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-N-(3-methoxyphenyl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(4-acetamidophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(3-acetamidophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(4-cyanophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(2-chlorophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(3-chlorophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(4-fluorophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 1-(4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanoyl)imidazolidin-4-one, 4-hydroxy-N-(prop-2-en-1-yl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-1-(pyrazolidin-1-yl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butan-1-one, 4-hydroxy-1-(3-hydroxypyrrolidin-1-yl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butan-1-one, 2-[1-(4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanoyl)pyrrolidin-3-yl]acetonitrile, N-(3-chlorophenyl)-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, 4-hydroxy-N-(pyridin-3-yl)-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, 4-hydroxy-N-(1,2-thiazol-5-yl)-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, N-[(dimethylcarbamoyl)methyl]-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, N-(2-chlorophenyl)-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, 4-hydroxy-N-(1H-pyrazol-1-yl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(4-cyanophenyl)-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, 4-hydroxy-1-{1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butan-1-one, 4-hydroxy-N-[(1r,4r)-4-cyanocyclohexyl]-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(carbamoylamino)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-N-(pyridin-2-yl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-N-(pyridin-3-yl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}-N-(2,4,6-trimethylphenyl)butanamide, 4-hydroxy-N-(4-methanesulfonylphenyl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-Hydroxy-1-{1H,4H,5H,6H,7H-pyrrolo[3,2-c]pyridin-5-yl}-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butan-1-one; or a pharmaceutically acceptable salt or solvate thereof.

[0021] The compounds presented herein are meant to include all diastereomeric, enantiomeric, atropisomeric, and epimeric forms as well as the appropriate mixtures thereof.

[0022] In a second aspect, the invention relates to a compound of any one of the above aspects or embodiments for use as a medicament and in a method for treating diabetes or pre-diabetes, i.e. for use in the treatment of diabetes or pre-diabetes, in a subject in need thereof. Typically, the diabetes is type 2. A related aspect of the invention provides for the use of a compound of any one of the above aspects or embodiments in the manufacture of a medicament for treating diabetes or pre-diabetes.

[0023] In a third aspect, the present invention relates to a method for treating diabetes or prediabetes in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I or II.

[0024] In a fourth aspect, the present invention relates to a method for preventing the progression of diabetes and / or preventing the progression of prediabetes to diabetes and / or reversing diabetes and / or reversing diabetes by reversing beta cell dysfunction in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I or II.

[0025] To have sufficient ability to treat diabetes or prediabetes in a human subject, a compound of Formula I or II should have high affinity for VDAC1 and inhibit the function of VDAC1. In this regard, specific binding to VDAC1 can be measured in a microscale thermophoresis (MST) binding assay, typically the MST assay described herein, with a K of less than 15 μM (where μM means micromolar), e.g., less than 10 μM, e.g., less than 5 μM, and in a preferred embodiment, less than 1 μM. D value.

[0026] Further objects and advantages of the present invention will become apparent from the following description, and from the claims. [Brief explanation of the drawings]

[0027] [Figure 1] FIG. 1 shows the MST plot of the compound of Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0028] Detailed Description of the Invention The present invention relates to compounds of formula I that bind to the voltage-dependent anion channel type 1 (VDAC1) protein and their use in the treatment of diabetes or pre-diabetes.

[0029] Compounds that bind to VDAC1 can reduce the conductance of the VDAC1 channel, inhibit metabolite transport through VDAC1, and particularly inhibit VDAC1 that has translocated to the plasma membrane of pancreatic β cells.

[0030] In a first aspect, the present invention relates to compounds of general formula I [ka] where R 1 ~R 7 , Hy and X are as defined in claim 1.

[0031] In a preferred embodiment, R 3 are halogens, CN, NO2, CF3, quaternary ammonium, COOH, COO‐C 1‐6 Alkyl, OCF3, SCF3, SO3‐C 1‐6 alkyl; R 1 , R 2 , R 4 ~R 5 is hydrogen. In a further preferred embodiment, R 1 , R 2 , R 4 ~R 5 is hydrogen and R 3 is OCF3.

[0032] In a further embodiment, R 6 is C 1‐3 -R 8 where R 8is OH. In a preferred embodiment, R 6 is C 1‐2 -R 8 where R 8 is OH. Typically, R 6 is CH2CH2OH or CH2OH.

[0033] In a further embodiment, R 7 are halogens, CN, C 1‐3 Alkyl, NO2, CONH2, NHCO‐C 1‐3 Alkyl, CF3, tertiary ammonium, COOH, COO‐C 1‐6 Alkyl, OC 1‐3 Alkyl, OCF3, SCF3, SO2‐C 1‐3 Alkyl, SO3‐C 1‐3 alkyl, with the remaining substituents being hydrogen. 7 is phenyl substituted with one or two groups selected from halogen, CF3, OCH3, NHCOCH3, CN, CH3, and SO2CH3, for example, one group.

[0034] In a further embodiment, R 7 is pyridyl. In another embodiment, R 7 is pyridyl substituted with one or more halogens, for example, phenyl substituted with one halogen, for example, one Cl.

[0035] In a further embodiment, R 7 is pyrrolidinyl substituted with one or more CONH. In an exemplary embodiment, R 7 is pyrrolidinyl substituted with one CONH2.

[0036] In a further embodiment, R 7 is pyrazolyl. In a further embodiment, R 7 is pyrazolyl substituted with one or two CONH2, for example one CONH2.

[0037] In a further embodiment, R 7 is thiazolyl. In a further embodiment, R 7 is cyclohexyl substituted with one or two CN, for example, one CN.

[0038] In a further embodiment, R 7 is NHCONH2. In a further embodiment, R 7 is a C substituted with one group selected from CON(CH3)2, CF3, and C2 alkene; 1-2 In a further embodiment, R 7 is CH substituted with one group selected from CON(CH 3 ) 2 , CF 3 , and C 2 alkene. In another embodiment, R 7 is CH2CH2 substituted with one group selected from CON(CH3)2.

[0039] In one alternative embodiment, X-R 7 are taken together as CONR'R'', where R' and R'' together with the nitrogen form a monoheterocyclic group having five ring atoms, one to two of which are selected from nitrogen and the remaining ring atoms are carbon, optionally substituted with a group selected from oxo, OH, CH2-CN. In a further embodiment, R' and R'' together with the nitrogen form a monoheterocyclic group having five ring atoms, one to two of which are selected from nitrogen and the remaining ring atoms are carbon, e.g., imidazolidinyl, pyrazolidinyl, pyrrolidinyl. In a further embodiment, R' and R" together with the nitrogen form a monoheterocyclic group having 5 ring atoms, of which 1 to 2 are selected from nitrogen and the remaining ring atoms are carbon, substituted with 1 or 2 groups, e.g., oxo, OH, CH2-CN, typically imidazolidinyl substituted with 1 or 2 groups, e.g., oxo, or pyrrolidinyl substituted with 1 or 2 groups, e.g., OH, CH2-CN.

[0040] In another alternative embodiment, the X-R 7 are taken together to be CONR'R'', where R' and R'' together with the nitrogen form a biheterocyclic group having 9 ring atoms, of which 1 to 3 are selected from nitrogen, and the remaining ring atoms are carbon. In a further embodiment, R' and R'' together with the nitrogen form a biheterocyclic group having 9 ring atoms, of which 3 are selected from nitrogen, and the remaining ring atoms are carbon. Typically the biheterocyclic group is 1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridinyl, for example 1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl.

[0041] In a further embodiment, X is -CONH-. In another embodiment, X is -NHCO-. In a further embodiment, Hy is a non-aromatic ring system selected from a) in which the single heterocycle has 6 ring atoms, two of which are N, and the remaining ring atoms are carbon, such as piperazine, typically piperazin-1-yl. In another embodiment, Hy is a non-aromatic ring system selected from a) in which the single heterocycle has 7 ring atoms, two of which are N, and the remaining ring atoms are carbon, such as homopiperazine, typically 1,4-diazepan-1-yl.

[0042] In a further embodiment, Hy is a non-aromatic ring system selected from b) in which the biheterocyclic group has 8 ring atoms, of which 2 are N and the remaining ring atoms are carbon, such as 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole or octahydropyrrolo[3,4-c]pyrrole.

[0043] In a further embodiment, Hy is a non-aromatic ring system selected from b) in which the biheterocyclic group has 9 ring atoms, two of which are N and the remaining ring atoms are carbon, for example octahydro-1H-pyrrolo[3,2-b]pyridinyl.

[0044] In a further embodiment, Hy is a non-aromatic ring system selected from c) in which the spiroheterocyclic group has 8 ring atoms, where two ring atoms are N and the remaining ring atoms are carbon, for example 2,6-diazaspiro[3.4]octanyl. In a further embodiment, Hy is a non-aromatic ring system selected from c) in which the spiroheterocyclic group has 10 ring atoms, where two ring atoms are N, one ring atom is O, and the remaining ring atoms are carbon, for example 6-oxa-2,9-diazaspiro[4.5]decanyl.

[0045] In some embodiments, Hy is selected from a non-aromatic ring system selected from c), and in such circumstances, R 7 a) Hydrogen, halogens, CN, C 1‐3 Alkyl, NO2, CONH2, NHCO‐C 1‐3 Alkyl, CF3, tertiary ammonium, COOH, COO‐C 1‐6 Alkyl, OC 1‐3 Alkyl, OCF3, SCF3, SO2‐C 1‐3 Alkyl, SO3‐C 1‐3 a) aryl substituted with one or more groups selected from alkyl (provided that at least one of said groups is not hydrogen); b) halogen, CN, C 1‐3 Alkyl, NO2, CONH2, NHCO‐C 1‐3 Alkyl, CF3, tertiary ammonium, COOH, COO‐C 1‐6 Alkyl, OC 1‐3 Alkyl, OCF3, SCF3, SO2‐C 1‐3 Alkyl, SO3‐C 1‐3 c) pyridyl optionally substituted with one or more groups selected from alkyl, halogen, CN, C 1‐3 Alkyl, NO2, NHCO‐C 1‐3 Alkyl, CF3, tertiary ammonium, COOH, COO‐C 1‐6 Alkyl, OC 1‐3 Alkyl, OCF3, SCF3, SO2‐C 1‐3 Alkyl, SO3‐C 1‐3 pyrrolidinyl optionally substituted with one or more groups selected from alkyl; d) halogen, CN, C1‐3 Alkyl, NO2, NHCO‐C 1‐3 Alkyl, CF3, tertiary ammonium, COOH, COO‐C 1‐6 Alkyl, OC 1‐3 Alkyl, OCF3, SCF3, SO2‐C 1‐3 Alkyl, SO3‐C 1‐3 e) pyrazolyl optionally substituted with one or more groups selected from alkyl, halogen, CN, C 1‐3 Alkyl, NO2, CONH2, NHCO‐C 1‐3 Alkyl, CF3, tertiary ammonium, COOH, COO‐C 1‐6 Alkyl, OC 1‐3 Alkyl, OCF3, SCF3, SO2‐C 1‐3 Alkyl, SO3‐C 1‐3 f) thiazolyl optionally substituted with one or more groups selected from alkyl, halogen, CN, C 1‐3 Alkyl, NO2, CONH2, NHCO‐C 1‐3 Alkyl, CF3, tertiary ammonium, COOH, COO‐C 1‐6 Alkyl, OC 1‐3 Alkyl, OCF3, SCF3, SO2‐C 1‐3 Alkyl, SO3‐C 1‐3 C optionally substituted with one or more groups selected from alkyl 5‐7 Cycloalkyl; g) NHCONH2; h) CONH2, CON(CH3)2, CF3 and C 2‐4 C optionally substituted with a group selected from alkenes 1‐3 Preferably, it is selected from the group consisting of alkyl.

[0046] In a further embodiment, 3-(4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide)-pyrrolidine-1-carboxamide is discarded.

[0047] In a further embodiment, 5-(4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamido)-1H-pyrazole-3-carboxamide is discarded.

[0048] In a further embodiment, Hy is a non-aromatic ring system selected from c) in which the spiroheterocyclic group has 11 ring atoms, two ring atoms are N and the remaining ring atoms are carbon, e.g., 2,8-diazaspiro[5.5]undecanyl.

[0049] In a further embodiment, Hy is a non-aromatic ring system selected from d) wherein the first and second monoheterocyclic rings are connected by a bond, the first monoheterocyclic ring having 4 ring atoms, one of which is N and the remaining ring atoms are carbon, and the second monoheterocyclic ring having 6 ring atoms, one of which is N and the remaining ring atoms are carbon, e.g., azetidin-3-ylpiperidinyl.

[0050] In a further embodiment, the compound of general formula I is a compound of formula II: [ka] where R 1 ~R 7 and X are as defined in claim 1. All embodiments described above in connection with the ifrst aspect for compounds of formula I are also embodiments for compounds of formula II.

[0051] In Formula II [ka] is a particular embodiment of Hy as defined above and in claim 1, where there are two nitrogen atoms, designated the first nitrogen and the second nitrogen. The first nitrogen is a substituent R of formula II. 1 ~R 5 and the second nitrogen is defined as a nitrogen attached to a phenyl ring having R of formula II.6 and CH2‐X‐R 7 As a result, in this particular embodiment of Hy, one nitrogen of either the first and second single heterocycles connected by a linker, such as a single heterocycle, a double heterocycle, a spiro heterocycle, or a bond, is bonded to the substituent R of formula II. 1 ~R 5 and a second nitrogen of either of the first and second single heterocycles connected by a linker such as a single heterocycle, a double heterocycle, a spiro heterocycle, or a bond is R of formula II 6 and CH2‐X‐R 7 and the first and second nitrogens obviously cannot be the same, but the terms first and second nitrogen should not be construed to mean that the heterocycle cannot contain additional nitrogen (N), oxygen (O) and / or sulfur (S).

[0052] The IUPAC name and corresponding chemical structure of each compound are shown in the table below.

[0053] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13]

[0054] In a second aspect, the invention relates to a compound according to any one of the above aspects or embodiments for use as a medicament, and for use in a method for treating diabetes or pre-diabetes in a subject in need thereof. Typically, the diabetes is type 2. In preferred embodiments, the compound of formula I or II has a K in the MST assay of less than 15 μM, or less than 10 μM, for example less than 5 μM, for example less than 1 μM. D Connect to VDAC1 by value.

[0055] In a third aspect, the present invention relates to a method for treating diabetes or prediabetes in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I or II. In embodiments, treating diabetes or prediabetes comprises at least one of treating insulin resistance, such as insulin resistance in type 2 diabetes; inducing glucose-stimulated insulin secretion; improving glucose tolerance; restoring insulin secretion from pancreatic beta cells in a subject with diabetes; and preventing beta-cell dysfunction.

[0056] In a fourth aspect, the present invention relates to a method for preventing the progression of diabetes and / or preventing the progression of prediabetes to diabetes and / or reversing diabetes and / or reversing diabetes by reversing beta cell dysfunction in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I or II.

[0057] As used herein, the term "halogen" means Cl, F, I, or Br. As used herein, the term "quaternary ammonium" refers to NH4 + or N(CH3)4 + means a nitrogen having four valence bonds, such as As used herein, the term "C 1‐x "Alkyl" refers to a straight chain alkyl group containing 1 to x carbon atoms, e.g., C 1‐3 or C 1‐6 , for example, methyl, ethyl, propyl, butyl, pentyl or hexyl. As used herein, the term "C 5‐7 "Cycloalkyl" means a cyclic alkyl group containing 5 to 7 carbon atoms, such as cyclopentyl, cyclohexyl, or cycloheptyl. As used herein, the term "C 2‐4 "Alkenyl" means a straight chain alkenyl having 2 to 4 carbon atoms and containing one double bond, such as ethenyl. The term "oxo" as used herein means an oxygen atom having a double bond, also depicted as =O.

[0058] As used herein, the term "COO-C 1‐6 Alkyl, SO3‐C 1‐6 Alkyl, NHCO‐C 1‐3 Alkyl, OC 1‐3 Alkyl, SO2-C 1‐3 "Alkyl" means a group selected from COO, SO, NHCO, O or SO, and is defined as C 1‐x It means that alkyl is bonded. As used herein, the term "C 1‐3"Alkyl-CN" refers to a C alkyl group as defined above with C-N attached to one of the carbon atoms. 1‐x It means alkyl.

[0059] The term "aryl" as used herein means a monocyclic or bicyclic aromatic ring system containing 6 to 12 carbon atoms, such as phenyl or naphthyl. The term "single heterocycle" as used herein means one ring containing carbon atoms and at least one heteroatom such as N, O, or S.

[0060] As used herein, the term "biheterocyclic group" means two monoheterocyclic rings fused together and sharing two ring atoms, each containing a carbon atom and at least one heteroatom such as N, O, or S. The term "non-aromatic heterocyclic ring system" as used herein in reference to a single heterocycle, a double heterocycle, a spiro heterocycle, or a first and second single heterocycle connected by a linker such as a bond, means a saturated or partially unsaturated system, provided that none of the heterocycles is aromatic.

[0061] As used herein, the term "VDAC" refers to a highly conserved family of voltage-dependent anion channel proteins, known as mitochondrial porins. To date, three VDAC isoforms, VDAC type 1 (VDAC1), VDAC type 2 (VDAC2), and VDAC type 3 (VDAC3), encoded by three genes, are known. As used herein, the term "VDAC1" refers to mammalian VDAC1, particularly human VDAC1, which contains 283 amino acids (NP_003365) (Shoshan-Barmatz V et al., 2010. Molecular aspects of medicine 31:227-285).

[0062] When the compounds of Formula I or II and pharmaceutical compositions disclosed herein are used for the above treatments, a therapeutically effective amount of at least one compound is administered to a mammal in need of said treatment.

[0063] As used herein, the terms "treatment" and "treating" refer to the management and care of a patient for the purpose of combating a condition, such as a disease or disorder. This term is intended to encompass the full range of treatments for a given condition from which a patient is suffering, including the administration of active compounds to alleviate symptoms or complications, delay the progression of the disease, disorder, or condition, relieve or mitigate symptoms and complications, and / or cure or eliminate the disease, disorder, or condition, as well as to prevent the condition, where prevention is to be understood as the management and care of a patient to combat the disease, condition, or disorder and includes the administration of active compounds to prevent the onset of symptoms or complications. Treatment may be carried out in an acute or chronic manner. The patient to be treated is preferably a mammal; particularly a human, but may also include animals such as dogs, cats, cows, sheep, pigs, rats, mice, rabbits, and guinea pigs.

[0064] As used herein, the term "therapeutically effective amount" of a compound for use in the present invention means an amount sufficient to cure, alleviate, or partially arrest the clinical symptoms of a given disease and its complications. An amount sufficient to accomplish this is defined as a "therapeutically effective dose." Effective amounts for each purpose will depend on the severity of the disease or injury, as well as the weight and general condition of the subject. It will be appreciated that determining appropriate dosages can be accomplished using routine experimentation, by constructing a matrix of values, and testing different points within the matrix, all of which is within the ordinary skill of a trained physician or veterinarian.

[0065] In a further aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula I or II and optionally a pharmaceutically acceptable additive such as a carrier or excipient.

[0066] As used herein, "pharmaceutically acceptable excipients" is intended to include, but is not limited to, carriers, excipients, diluents, adjuvants, colorants, flavorings, preservatives, and the like that a person skilled in the art would consider using when formulating the compounds of the present invention to make pharmaceutical compositions.

[0067] The adjuvants, diluents, excipients and / or carriers that can be used in the compositions of the present invention must be pharmaceutically acceptable in the sense that they are compatible with the compound of Formula I or II and other ingredients of the pharmaceutical composition and are not harmful to the recipient. Preferably, the compositions should not contain materials that may cause adverse reactions, such as allergic reactions. Adjuvants, diluents, excipients and carriers that can be used in the pharmaceutical compositions of the present invention are well known to those skilled in the art.

[0068] As mentioned above, the compositions disclosed herein, particularly pharmaceutical compositions, may further comprise at least one pharmaceutically acceptable adjuvant, diluent, excipient, and / or carrier in addition to the compound of Formula I or II disclosed herein. In some embodiments, the pharmaceutical composition comprises 1 to 99% by weight of the at least one pharmaceutically acceptable adjuvant, diluent, excipient, and / or carrier and 1 to 99% by weight of the compound of Formula I or II disclosed herein. The total amount of the active ingredient and the pharmaceutically acceptable adjuvant, diluent, excipient, and / or carrier does not exceed 100% by weight of the composition, particularly the pharmaceutical composition.

[0069] In some embodiments, only one compound of Formula I or II as disclosed herein is used for the purposes discussed above. In some embodiments, two or more compounds of Formula I or II as disclosed herein are used in combination for the purposes discussed above.

[0070] The compositions described herein, particularly pharmaceutical compositions comprising the compounds, may be adapted for oral, intravenous, topical, intraperitoneal, nasal, buccal, sublingual, or subcutaneous administration, or for administration via the respiratory tract, for example, in the form of an aerosol or air-suspended fine powder. Thus, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, powder, nanoparticle, crystal, amorphous material, solution, transdermal patch, or suppository.

[0071] Further embodiments of the process are described in the experimental section of this specification, and each individual process as well as each starting material constitutes an embodiment that may form part of an embodiment.

[0072] The above embodiments should be construed as referring to any one of the aspects described herein (e.g., "methods for treatment," "pharmaceutical compositions," "compounds of Formula I or II for use as a medicament," "compounds of Formula I or II for use in a method," etc.) as well as any one of the embodiments described herein, unless it is explicitly stated that the embodiment relates to a particular aspect or embodiment of the invention.

[0073] All documents cited herein, including publications, patent applications, and patents, are incorporated by reference to the same extent as if each individual document was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.

[0074] All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way. Any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0075] As used in the context of describing the present invention, the terms "a" and "an" and "the" and similar reference words shall be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0076] As used herein, the term "and / or" is intended to refer to both alternatives as well as each alternative individually. For example, the phrase "xxx and / or yyy" means "xxx and yyy; xxx; or yyy," and all three alternatives are subject to separate embodiments.

[0077] The recitation of ranges of values ​​herein, unless otherwise indicated herein, is merely intended to serve as a shorthand method for referring individually to each separate value falling within the range, and each separate value is incorporated herein as if individually set forth herein. Unless otherwise specified, all exact values ​​provided herein represent the corresponding approximation (e.g., all exact exemplary values ​​provided with respect to a particular factor or measurement can also be considered to provide the corresponding approximate measurement, modified by "about" as appropriate).

[0078] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples provided herein, or exemplary language (e.g., "etc."), is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless specifically indicated. No language in this specification should be construed as indicating any element as essential to the practice of the invention unless expressly recited.

[0079] The citation and incorporation of patent documents herein is for convenience only and does not reflect any opinion regarding the validity, patentability and / or enforceability of such patent documents.

[0080] The description herein of any aspect or embodiment of the invention using terms such as "comprising," "having," "including," or "containing" in reference to an element or elements is intended to provide support for similar aspects or embodiments of the invention that "consist," "consist essentially of," or "substantially comprise" that particular element or elements, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood to also describe a composition consisting of that element, unless otherwise stated or clearly contradicted by context). The present invention includes all modifications and equivalents of the subject matter recited in the aspects or claims presented herein to the maximum extent permitted by applicable law.

[0081] The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of protection. The features disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realizing the invention in diverse forms thereof. [Example]

[0082] MST assay and data Microscale thermophoresis (MST) is a biophysical technique that measures the strength (affinity) of interactions between two molecules by detecting changes in fluorescence signal as a result of temperature changes induced by an IR laser. The magnitude of the change in fluorescence signal correlates with the degree of binding between the ligand and fluorescent target. This allows for highly sensitive quantitative analysis of intermolecular interactions in solution at the microliter scale. The MST signal consists of two major components: the TRIC effect and thermophoresis. TRIC stands for Temperature-Related Intensity-Change and describes how the fluorescence intensity of a fluorophore depends on the local temperature of the solution. For most fluorophores, fluorescence intensity decreases with increasing temperature. However, most importantly, the degree of temperature dependence is strongly related to the chemical environment of the fluorophore. This environment is sensitively affected by the binding of ligand molecules to fluorescently labeled target molecules (through conformational changes or the proximity of the ligand and dye). The second component of the MST signal, thermophoresis, describes the movement of molecules along a temperature gradient, resulting in a quantitative change in the local concentration of the target molecule. In MST, these target molecules are fluorescently labeled, allowing these concentration changes to be easily monitored by fluorescence measurements. The directional motion of such molecules depends on their size, charge, and hydration shell. When a ligand binds to a target molecule, at least one of these parameters changes, resulting in a change in the thermophoretic motion of the target-ligand complex compared to that of a single molecule. Thus, both TRIC and thermophoresis contribute to the overall MST signal, which is detected by fluorescence measurements. This robust physical principle and direct monitoring make MST applicable to determining the affinity and binding strength of almost any type of intermolecular interaction or modification of small molecules, proteins, peptides, DNA, sugars, or molecular complexes.

[0083] For a detailed description of the physical principles behind MST see Jerabek-Willemsen M, Andre T, Wanner A, Roth HM, Duhr S, Baaske P, Breitsprecher D (2014). "Microscale Thermophoresis: Interaction analysis and beyond". Journal of Molecular Structure 1077:101-113 and Jerabek-Willemsen M, Wienken CJ, Braun D, ​​Baaske P, Duhr S (2011). "Molecular interaction studies using microscale thermophoresis". Assay and Drug Development Technologies. 9(4):342-53.

[0084] Labeling of recombinant VDAC1 Reconstituted N-terminal His-GST-tagged E. coli recombinant human VDAC1 (hVDAC1) was buffer-exchanged into a protein labeling buffer because the primary amines in the Tris lyophilization buffer inhibit NHS-based labeling. The labeling buffer was as close as possible to the target protein storage buffer as described in the protein data sheet (LSBio LS-G25810). Tris was replaced with HEPES. PLURONIC® F-127 was added to 0.05% to increase protein recovery in the final dye removal step. The total volume of the labeling batch was 100 μL. The labeling time was 30 min. The labeling reaction was performed at room temperature. Unbound or unreacted dye was separated from the labeled protein using a gravity-flow gel filtration column (GE Healthcare, PD Minitrap G-25, GE28-9180-07). The final target buffer was as close as possible to the original protein storage buffer, again containing Tris instead of HEPES.

[0085] Assay Validation The first step in establishing the technical assay was the so-called "noise test." This test examined the intrinsic MST noise of the labeled target protein. Subsequently, a reference compound or positive control (CAS number: 2086257-77-2) was characterized to confirm its previously reported VDAC1 binding (Zhang et al. (2019) Preserving Insulin Secretion in Diabetes by Inhibiting VDAC1 Overexpression and Surface Translocation in β Cells. Cell Metabolism 29, 64-77.). Serial dilutions of the compound with CAS number: 2086257-77-2 were prepared to match the final buffer conditions of the reaction mixture (assay buffer). The highest and lowest ligand concentrations were 10.0 mM and 4.88 μM, respectively. A total of 12 dilution steps were prepared. Serial dilutions were prepared by mixing 0.1 μl of each dilution step with 9.9 μl of fluorescent target molecule (labeled VDAC1) for a total volume of 10 μL. The final reaction mixture, loaded into a premium-coated MST capillary, contained the respective amount of ligand (maximum concentration 100 μM, minimum concentration 41 nM) and a constant 5 nM fluorescent target molecule. Samples were analyzed at 25 °C using an NT. Automated instrument (Nanotemper Technologies, Munich) at 10% LED power and 40% laser power. To test the reproducibility of the established positive control, interactions were tested with labeled VDAC1 at 4°C for 0, 2, 4, and 6 h prior to assay sample preparation.

[0086] Screening assays Serial dilutions of compounds were prepared using a Labcyte Echo 550 acoustic nanoliter dispenser. 10 mM DMSO compound stocks were transferred to a Labcyte LP-0200 384-well plate ("source plate"). A decreasing volume series of compounds was dispensed into 12 adjacent wells (e.g., A1-A12) of a Greiner 784201 384-well plate ("destination plate"): 100, 50, 25, 12.5, 7.5, 2.5, 1.56, 0.78, 0.41, 0.20, 0.08, and 0.04 nL (volumes of 1 nL or less were dispensed from intermediate DMSO dilutions of compounds). DMSO backfills were then performed by filling each well to a total volume of 100 nL. The destination plate was heat-sealed and stored at room temperature until use.

[0087] In addition to the compound dilutions, a DMSO reference was prepared in a similar manner by dispensing a series of decreasing volumes of DMSO (same volumes as above) and backfilling to 100 nL with DMSO.

[0088] High-throughput compound screening was performed as follows: 100 μL of labeled VDAC1 stock was thawed and centrifuged (15 min, 21,000 x g, 4°C), and 90 μL of the supernatant was used. The thawed and centrifuged labeled VDAC1 stock was stored on ice for up to 6 hours. After 6 hours, a fresh labeled stock was thawed and centrifuged as described above. A positive control test for CAS number 2086257-77-2 was prepared as described above. A positive control for assay validation was performed every 6 hours after thawing a fresh labeled VDAC1 stock. A positive control was also performed after measuring the entire set of compounds. For screening compound examples 1-10, the labeled VDAC1 stock was diluted to 5.05 nM in assay buffer (see Table 1) and added to the pre-aliquoted compound plate. 10 μL of diluted VDAC1 stock was added per well using an Opentrons OT-2 liquid handling robot. Sample solutions were loaded into four 24-capillary chips at a time (capillaries for 8 ligands in a 12-data-point serial dilution) (premium-coated capillaries, Nanotemper Technologies, Munich, Germany). The loaded capillaries were incubated at room temperature for 10 minutes. Four capillary chips (8 ligands in total in a serial dilution) were loaded into an NT.Automated MST instrument (Nanotemper Technologies, Munich, Germany) and run using the settings shown in Table 1. A 12-data-point DMSO reference was also analyzed.

[0089] [Table 2]

[0090] Data analysis The tested ligand compounds were classified into binder, weak binder, and nonbinder categories. Data were analyzed using MO.AffinityAnalysis (version 2.2.6.5385, Nanotemper Technologies, Munich, Germany) and MO.ScreeningAnalysis (version 1.0.2.8057, Nanotemper Technologies, Munich, Germany). MST traces (fluorescence vs. time) were analyzed for the time intervals -3 to 0 s (laser off, "cold" time interval) and +1.5 to +2.5 s (laser on, "hot" time interval). Fnorm data were fitted to the KD model.

[0091] A 12-point DMSO blank control was included in the screen to classify the analyzed ligands into predefined categories. The noise of this blank control was 1.35 Fnorm units (2 STDE(Fnorm)). Therefore, classification of binders and weak binders required an Fnorm signal amplitude of at least >(2 noise) (>2.7).

[0092] A typical MST plot for Example 4 is shown in Figure 1 (the MST plot is for the compound of Example 4; K D 5.1 μM (S / N 20.1; dF norm 23.9).

[0093] [Table 3]

[0094] example Abbreviations used [Table 4]

[0095] 1.HPLC purification Purification was performed by HPLC (H2O-MeOH; Agilent 1260 Infinity system equipped with DAD and mass spectrometer. Waters Sunfire C18 OBD Prep Column, 100Å, 5 μm, 19mm x 100mm, with SunFire C18 Prep Guard cartridge, 100Å, 10 μm, 19mm x 10mm). The material was dissolved in 0.7mL DMSO. Flow: 30mL / min. The purity of the obtained fractions was confirmed via analytical LCMS. Spectra were recorded for each fraction obtained directly after chromatography in the form of a solution. The solvent was evaporated in a stream of N2 at 80°C. The fractions were unified based on the LCMS analysis after chromatography. The solid fraction was dissolved in 0.5mL MeOH and transferred to a pre-weighed labeled vial. The obtained solution was again evaporated under a stream of N2 at 80°C. After drying, the LCMS and 1 The product was characterized by 1 H NMR.

[0096] 2.Analysis method NMR Equipment specifications Bruker AVANCE DRX 500 Varian UNITYplus 400

[0097] LC / MS Equipment specifications Agilent 1100 Series LC / MSD system with DAD / ELSD and Agilent LC / MSD VL (G1956A), SL (G1956B) mass spectrometer. Agilent 1200 Series LC / MSD system with DAD / ELSD and Agilent LC / MSD SL(G6130A), SL(G6140A) mass spectrometer. All LC / MS data were acquired in positive / negative mode switching.

[0098] Column: Zorbax SB-C18 1.8 μm 4.6 x 15 mm High-Speed ​​Resolution Cartridge (PN821975-932) Mobile phase A - acetonitrile, 0.1% formic acid B-water (0.1% formic acid) Flow rate 3ml / min Gradient: 0 min - 100% B 0.01 min-100%B 1.5 minutes - 0%B 1.8 minutes - 0%B 1.81 minutes-100%B Injection volume 1μl Ionization mode: Atmospheric pressure chemical ionization (APCI) Scan range m / z 80‐1000

[0099] 3. Experiment Unless otherwise noted, all compounds were isolated as racemates.

[0100] Synthesis of 4-chloro-N-(3-hydroxy-2-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}propyl)benzamide Example 1 Step 1: Synthesis of 4-chloro-N-(prop-2-en-1-yl)benzamide [ka] Prop-2-en-1-amine (1.48 g, 25.97 mmol) was dissolved in CHCl (30 mL). 4-Chlorobenzoyl chloride (5.0 g, 28.57 mmol) and triethylamine (5.78 g, 57.13 mmol) were added, and the mixture was stirred at room temperature under nitrogen for 2 days. Next, aqueous NaOH (1 M, 30 mL) was added, and the mixture was extracted with CHCl (2 × 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (5:1 hexane / EtOAc, Rf = 0.10) to give 4-chloro-N-(prop-2-en-1-yl)benzamide (4.46 g, 22.8 mmol, 87.8% yield) as a yellow solid.

[0101] Step 2: Synthesis of 4-chloro-N-(2,3-dihydroxypropyl)benzamide [ka] To a stirred solution of 4-chloro-N-(prop-2-en-1-yl)benzamide (4.4 g, 22.49 mmol) in 2:1 acetonitrile / water solution (100 mL:50 mL) at 0 °C was added 4-methylmorpholin-4-ium-4-olate (5.27 g, 44.98 mmol), followed by tetraoxoosmium (114.35 mg, 449.79 μmol). The mixture was stirred at room temperature overnight. The reaction was quenched by the addition of sodium sulfite (25 g) and diluted with water (60 mL). The aqueous solution was then extracted with EtOAc (3 × 90 mL), and the combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give 4-chloro-N-(2,3-dihydroxypropyl)benzamide (4.45 g, 19.38 mmol, 86.2% yield) as a crystalline solid.

[0102] Step 3: Synthesis of N-{3-[(tert-butyldimethylsilyl)oxy]-2-hydroxypropyl}-4-chlorobenzamide [ka] 4-Chloro-N-(2,3-dihydroxypropyl)benzamide (3.92 g, 17.07 mmol) was suspended in CHCl (600 mL). tert-Butyl(chloro)dimethylsilane (2.86 g, 18.95 mmol) in CHCl (10 mL) was added under stirring, followed by triethylamine (2.07 g, 20.48 mmol) and N,N-dimethylpyridin-4-amine (83.41 mg, 682.71 μmol). The mixture was stirred for 36 h and then shaken with water (100 mL). The aqueous phase was washed with CHCl (70 mL), and the combined organic phases were combined, washed with brine (2 × 50 mL), and then dried over NaSO. The solution was concentrated under reduced pressure and the oily residue was purified by chromatography on silica gel (hexane / EtOAc 1 / 1, Rf = 0.42) to give N-3-[(tert-butyldimethylsilyl)oxy]-2-hydroxypropyl-4-chlorobenzamide (2.61 g, 7.59 mmol, 44.5% yield) as a colorless oil.

[0103] Step 4: Synthesis of N-{3-[(tert-butyldimethylsilyl)oxy]-2-oxopropyl}-4-chlorobenzamide [ka] To a solution of 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (493.73 mg, 1.16 mmol) in anhydrous dichloromethane (5 mL) was added a solution of N-3-[(tert-butyldimethylsilyl)oxy]-2-hydroxypropyl-4-chlorobenzamide (400.35 mg, 1.16 mmol) in anhydrous dichloromethane (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 12 h, then evaporated in vacuo to 1 / 3 of the original volume and applied to a silica-packed column. Elution with a 1 / 1 mixture of ethyl acetate and petroleum ether afforded N-3-[(tert-butyldimethyl)oxy]-2-oxypropyl-4-chlorobenzamide (400.0 mg, 1.17 mmol, 100.5% yield) as a colorless oil.

[0104] Step 5: Synthesis of 4-chloro-N-(3-hydroxy-2-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}propyl)benzamide [ka] 1-[4-(Trifluoromethoxy)phenyl]piperazine (345.89 mg, 1.4 mmol) was added to a solution of N-3-[(tert-butyldimethylsilyl)oxy]-2-oxopropyl-4-chlorobenzamide (400.24 mg, 1.17 mmol) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 15 min, followed by the addition of sodium cyanoborohydride (73.56 mg, 1.17 mmol). Stirring was continued for 48 h and then concentrated to dryness under reduced pressure. The residue was dissolved in CHCl (10 mL), 10% HCl (10 mL) was added, and the mixture was stirred at room temperature for 2 h. The CHCl was separated, and the aqueous layer was washed with CHCl (10 mL). The organic layers were combined, and the aqueous layer was triturated with solid NaHCO to pH = 8. The crude product was extracted with CHCl (3 × 15 mL). The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse preparative HPLC to give 4-chloro-N-(3-hydroxy-2-4-[4-(trifluoromethoxy)phenyl]piperazin-1-ylpropyl)benzamide (29.0 mg, 63.34 μmol, 5.4% yield). LC-MS (ESI-pos). [M+H] + =458.2 / 460.2

[0105] Synthesis Example 2 of N-(4-chlorophenyl)-5-hydroxy-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}pentanamide Step 1A: Synthesis of ethyl (2E)-5-(prop-2-en-1-yloxy)pent-2-enoate [ka] To a stirred suspension of sodium hydride (420.47 mg, 17.52 mmol) in THF (30 mL) at 0 °C was added ethyl 2-(diethylphosphono)acetate (3.93 g, 17.52 mmol). The reaction mixture was stirred for 15 min, and then a solution of 3-(allyloxy)propanal (2.0 g, 17.52 mmol) in THF (5 mL) was added. The mixture was stirred overnight at room temperature, after which the THF solution was evaporated in vacuo to give ethyl (2E)-5-(prop-2-en-1-yloxy)pent-2-enoate (3.1 g, 16.83 mmol, 96% yield) as a colorless oil, which was used in the next step without further purification.

[0106] Step 1B: Synthesis of tert-butyl 4-[4-(trifluoromethoxy)phenyl]piperazine-1-carboxylate [ka] To a solution of 1-bromo-4-(trifluoromethoxy)benzene (24.1 g, 100.0 mmol) in toluene (500 mL), tert-butylpiperazine-1-carboxylate (16.76 g, 90.0 mmol), tris((4E)-1,5-diphenylpenta-1,4-dien-3-one)dipalladium (2.29 g, 2.5 mmol), 1-[2-(diphenylphosphanyl)naphthalen-1-yl]naphthalen-2-yldiphenylphosphane (3.11 g, 5.0 mmol), and sodium tert-butoxide (19.22 g, 200.0 mmol) were added sequentially. The mixture was refluxed overnight under Ar atmosphere. The solvent was evaporated to give crude tert-butyl 4-[4-(trifluoromethoxy)phenyl]piperazine-1-carboxylate (63.0 g, 181.9 mmol, 181.9% yield) as a residue, which was used directly in the next step without further purification.

[0107] Step 2: Synthesis of ethyl 5-(prop-2-en-1-yloxy)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}pentanoate [ka] To a solution of ethyl (2E)-5-(prop-2-en-1-yloxy)pent-2-enoate (2.0 g, 10.86 mmol) in dry MeOH (10 mL) was added 1-[4-(trifluoromethoxy)phenyl]piperazine (2.67 g, 10.86 mmol), and the reaction mixture was stirred at room temperature overnight and then at reflux for 6 h. The reaction mixture was evaporated, and the crude product was purified by flash chromatography on silica (eluent DCM / EtOAC = 1 / 1, Rf = 0.65) to give ethyl 5-(prop-2-en-1-yloxy)-3-4-[4-(trifluoromethoxy)phenyl]piperazin-1-ylpentanoate (2.9 g, 6.74 mmol, 62.1% yield), which was used in the next step without further purification.

[0108] Step 3: Synthesis of 5-(prop-2-en-1-yloxy)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}pentanoic acid [ka] To a suspension of ethyl 5-(prop-2-en-1-yloxy)-3-4-[4-(trifluoromethoxy)phenyl]piperazin-1-ylpentanoate (2.9 g, 6.74 mmol) in MeOH and water (60 mL, 4 / 1) was added a solution of sodium hydroxide (480 mg, 12.0 mmol) in water (3 mL). The reaction mixture was stirred at room temperature for 2 h. After that, sodium hydrogen sulfate (1.52 g, 12.67 mmol) was added, and the reaction mixture was stirred for 1 h and evaporated to dryness. The crude product was dissolved in MTBE (100 mL), washed with water (3 x 25 ml), and evaporated to give 5-(prop-2-en-1-yloxy)-3-4-[4-(trifluoromethoxy)phenyl]piperazin-1-ylpentanoic acid (2.2 g, 5.47 mmol, 81.2% yield) as a yellow oil, which was used further without purification.

[0109] Step 4: Synthesis of N-(4-chlorophenyl)-5-(prop-2-en-1-yloxy)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}pentanamide [ka] To a stirred solution of 5-(prop-2-en-1-yloxy)-3-4-[4-(trifluoromethoxy)phenyl]piperazin-1-ylpentanoic acid (2.2 g, 5.47 mmol) in DCM (30 mL), oxalyl chloride (693.93 mg, 5.47 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was evaporated, the residue was dissolved in DCM (30 mL), and then 4-chloroaniline (697.46 mg, 5.47 mmol) and triethylamine (1.38 g, 13.67 mmol, 1.91 mL) were added, and stirring was continued at room temperature for 2 h. The reaction mixture was washed with water (3 × 30 mL) and evaporated. The crude product was purified by column chromatography (silica, eluent hexane / EtOAc = 1 / 1, Rf = 0.36) to give crude N-(4-chlorophenyl)-5-(prop-2-en-1-yloxy)-3-4-[4-(trifluoromethoxy)phenyl]piperazin-1-ylpentanamide (1.21 g, 2.36 mmol, 43.2% yield) as a yellow oil. The crude material was further purified by reverse-phase HPLC to give the pure title compound.

[0110] Step 5: Synthesis of N-(4-chlorophenyl)-5-hydroxy-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}pentanamide [ka] A mixture of N-(4-chlorophenyl)-5-(prop-2-en-1-yloxy)-3-4-[4-(trifluoromethoxy)phenyl]piperazin-1-ylpentanamide (511.0 mg, 998.12 μmol), 1,3-dimethyl-1,3-diazinan-2,4,6-trione (314.48 mg, 2.01 mmol), tetrakis(triphenylphosphine)palladium(0) (57.76 mg, 49.81 μmol), and dry THF (4 mL) was heated to 90 °C in a sealed tube under an argon atmosphere. After stirring at the same temperature for 24 h, the reaction mixture was poured into saturated aqueous Na2CO3 and extracted twice with EtOAc. The organic layer was washed with brine, dried over MgSO4, and evaporated in vacuo. The crude product was purified by reverse preparative HPLC to give N-(4-chlorophenyl)-5-hydroxy-3-4-[4-(trifluoromethoxy)phenyl]piperazin-1-ylpentanamide (151.9 mg, 321.89 μmol, 32% yield). LC-MS (ESI-pos): [M+H] + =472.2 / 474.2

[0111] Synthesis of starting materials In the following examples, the p-trifluoromethoxyphenylaminoyl starting materials were synthesized from commercially available 1-bromo-4-(trifluoromethoxy)benzene and the relevant amines in a manner similar to that described in Example 2, Step 1B. The relevant amines may be protected with cleavable protecting groups, such as tert-butyloxycarbamoyl, benzyloxycarbonyl, and the like. Alternatively, the p-trifluoromethoxyphenylaminoyl starting materials were synthesized from commercially available 1-bromo-4-(trifluoromethoxy)benzene and the relevant unprotected amines in a manner similar to that described in Example 2, Step 1B, after which the starting materials were purified by standard methods known to those skilled in the art, such as manual or automated silica chromatography.

[0112] Synthesis of N-(4-chlorophenyl)-4-hydroxy-3-{4-[4-(trifluoromethoxy)phenyl]-1,4-diazepan-1-yl}butanamide Example 3 Step 1: Synthesis of 4-{4-[4-(trifluoromethoxy)phenyl]-1,4-diazepan-1-yl}oxolan-2-one [ka] A mixture of 1-[4-(trifluoromethoxy)phenyl]-1,4-diazepane (5.2 g, 19.98 mmol) and 2,5-dihydrofuran-2-one (3.36 g, 39.96 mmol) in MeOH (12.5 mL) was stirred at room temperature overnight. The mixture was evaporated in vacuo. The crude product was purified by column chromatography on silica gel (CHCl / EtOAc = 1 / 1, Rf = 0.12) to give 4-4-[4-(trifluoromethoxy)phenyl]-1,4-diazepan-1-yloxolan-2-one (2.4 g, 6.97 mmol, 34.9% yield) as a yellow oil.

[0113] Step 2: Synthesis of N-(4-chlorophenyl)-4-hydroxy-3-{4-[4-(trifluoromethoxy)phenyl]-1,4-diazepan-1-yl}butanamide [ka] To a solution of 4-chloroaniline (254.87 mg, 2.0 mmol) in toluene (5 mL) was added trimethylaluminum (288.71 mg, 4.01 mmol). After stirring for 10 minutes, 4-4-[4-(trifluoromethoxy)phenyl]-1,4-diazepan-1-yloxolan-2-one (344.0 mg, 999.04 μmol) was added to the solution, and the resulting mixture was heated to 80 °C for 8 hours. After cooling to room temperature, the solvent was evaporated in vacuo, and the residue was purified by reverse preparative HPLC to give N-(4-chlorophenyl)-4-hydroxy-3-4-[4-(trifluoromethoxy)phenyl]-1,4-diazepan-1-ylbutanamide (38.6 mg, 81.8 μmol, 8% yield). LC-MS (ESI-pos): [M+H] + =472.0 / 474.0

[0114] Synthesis of N-(4-chlorophenyl)-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide Example 4 Step 1: Synthesis of tert-butyl 5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylate [ka] tert-Butyl 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylate hydrochloride (2.0 g, 8.11 mmol), tris(1,5-diphenylpenta-1,4-dien-3-one)dipalladium (206.2 mg, 225.18 μmol), 1-[2-(diphenylphosphanyl)naphthalen-1-yl]naphthalen-2-yldiphenylphosphane (280.43 mg, 450.37 μmol), and sodium tert-butoxide (2.6 g, 27.02 mmol) were subsequently added to a solution of 1-bromo-4-(trifluoromethoxy)benzene (2.17 g, 9.01 mmol) in toluene (70 mL). The mixture was degassed twice and refluxed overnight under Ar. The solvent was evaporated to give crude tert-butyl 5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylate (7.2 g, 19.44 mmol) as a residue, which was used directly in the next step without further purification.

[0115] Step 2: Synthesis of 2-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole [ka] A mixture of crude tert-butyl 5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylate (3.34 g, 9.01 mmol) (obtained in the previous step) in 45 mL of concentrated HCl and 30 mL of DCM was stirred at room temperature for 1.5 h. After phase separation, the DCM phase was discarded, and the aqueous phase was adjusted to pH ∼9 by adding Na2CO3. Then, 50 mL of DCM was added, followed by stirring for an additional 0.5 h. The DCM phase was collected, dried over Na2SO4, and concentrated in vacuo to give 2-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole (1.4 g, 5.18 mmol, 57.5% yield) as a white solid.

[0116] Step 3: Synthesis of 4-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}oxolan-2-one [ka] A mixture of 2-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole (1.4 g, 5.18 mmol) and 2,5-dihydrofuran-2-one (871.29 mg, 10.36 mmol) in MeOH (3.1 mL) was stirred at room temperature overnight. The mixture was evaporated in vacuo, and the residue was treated with water (20 mL), filtered, washed with water (2 × 20 mL) and hexane (30 mL), and dried to give 4-5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yloxolan-2-one (1.6 g, 4.52 mmol, 87.1% yield) as a yellow solid.

[0117] Step 4: Synthesis of N-(4-chlorophenyl)-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide [ka] To a solution of 4-chloroaniline (254.67 mg, 2.0 mmol) in benzene (8 mL) was added trimethylaluminum (287.8 mg, 3.99 mmol). After stirring for 10 min, 4-5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yloxolan-2-one (354.0 mg, 999.09 μmol) was added, and the resulting mixture was heated at 50 °C for 2.5 h. After cooling to room temperature, water (3 mL) and EtOAc (15 mL) were added, filtered, the solvent was evaporated in vacuo, and the residue was purified by reverse preparative HPLC to give N-(4-chlorophenyl)-4-hydroxy-3-5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-ylbutanamide (186.0 mg, 385.98 μmol, 38% yield). LC-MS (ESI-pos): [M+H] + =482.2 / 484.0

[0118] Step 4 was synthesized in the same manner as in Example 5 (Examples 29 to 34, 36 to 37, 42, and 44). [Table 5-1] [Table 5-2]

[0119] Synthesis of N-(4-chlorophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide Example 5 Step 1: Synthesis of tert-butyl 2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decane-9-carboxylate [ka] tert-Butyl 6-oxa-2,9-diazaspiro[4.5]decane-9-carboxylate (2.5 g, 10.32 mmol), tris(1,5-diphenylpenta-1,4-dien-3-one)dipalladium (262.43 mg, 286.59 μmol), 1-[2-(diphenylphosphanyl)naphthalen-1-yl]naphthalen-2-yldiphenylphosphane (356.9 mg, 573.17 μmol), and sodium tert-butoxide (2.2 g, 22.93 mmol) were subsequently added to a solution of 1-bromo-4-(trifluoromethoxy)benzene (2.76 g, 11.46 mmol) in toluene (55 mL). The mixture was refluxed overnight under Ar atmosphere. The solvent was evaporated to give crude tert-butyl 2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decane-9-carboxylate (7.1 g, 17.64 mmol) as a residue, which was used in the next step without any purification.

[0120] Step 2: Synthesis of 2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decane [ka] A solution of crude tert-butyl 2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decane-9-carboxylate (4.61 g, 11.46 mmol) (obtained in the previous step) in 45 mL of concentrated hydrochloric acid and 30 mL of DCM was stirred at room temperature for 1.5 h. After phase separation, the DCM phase was discarded, and the aqueous phase was evaporated to dryness in vacuo. The residue was dissolved in a mixture of 20 mL of NaOH (2.0 M). DCM (50 mL) was then added, and the mixture was stirred for an additional 0.5 h. The DCM phase was collected, dried over Na2SO4, and concentrated in vacuo to give 2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decane (2.3 g, 7.61 mmol, 66.4% yield) as a yellow oil.

[0121] Step 3: Synthesis of 4-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}oxolan-2-one [ka] A mixture of 2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decane (999.91 mg, 3.31 mmol) and 2,5-dihydrofuran-2-one (556.19 mg, 6.62 mmol) in MeOH (2.0 mL) was stirred at room temperature overnight. The mixture was evaporated in vacuo, and the residue was dissolved in MTBE (50 mL), washed with water (2 × 50 mL), brine (30 mL), and evaporated to give 4-2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yloxolan-2-one (920.0 mg, 2.38 mmol, 72% yield) as a brown oil.

[0122] Step 4: Synthesis of N-(4-chlorophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide [ka] To a solution of 4-chloroaniline (255.57 mg, 2.0 mmol) in benzene (8 mL) was added trimethylaluminum (288.82 mg, 4.01 mmol, 2.0 mL). After stirring for 10 min, 4-2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yloxolan-2-one (387.0 mg, 1.0 mmol) was added, and the resulting mixture was heated at 50 °C for 2.5 h. After cooling to room temperature, water (3 mL) and EtOAc (15 mL) were added, filtered, the solvent was evaporated in vacuo, and the residue was purified by reverse preparative HPLC to give N-(4-chlorophenyl)-4-hydroxy-3-2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-ylbutanamide (184.0 mg, 358.02 μmol, 35.7% yield). LC-MS (ESI-pos): [M+H] + =514.2 / 516.0.

[0123] Step 4 was synthesized in the same manner as in Example 5 (Examples 11 to 28, 35, 38 to 41, and 43). [Table 6-1] [Table 6-2] [Table 6-3]

[0124] Synthesis of N-(4-chlorophenyl)-4-hydroxy-3-(3-{1-[4-(trifluoromethoxy)phenyl]azetidin-3-yl}piperidin-1-yl)butanamide Example 6 Step 1: Synthesis of 3-{1-[4-(trifluoromethoxy)phenyl]azetidin-3-yl}piperidine [ka] Benzyl 3-1-[4-(trifluoromethoxy)phenyl]azetidin-3-ylpiperidine-1-carboxylate (4.2 g, 9.67 mmol) was dissolved in MeOH (50 mL), 10% Pd / C (300 mg) was added, and the reaction mixture was stirred overnight under an atmosphere of H2. The reaction mixture was filtered and evaporated under reduced pressure. The residue was treated with 10 N HCl (30 mL) and DCM (30 mL). The organic layer was diluted, the aqueous layer was washed with DCM (2 x 20 mL), and 6 N NaOH was added to pH 10. The crude product was extracted with DCM (3 x 40 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 3-1-[4-(trifluoromethoxy)phenyl]azetidin-3-ylpiperidine (800.0 mg, 2.66 mmol, 27.6% yield) as a brown oil.

[0125] Step 2: Synthesis of 4-(3-{1-[4-(trifluoromethoxy)phenyl]azetidin-3-yl}piperidin-1-yl)oxolan-2-one [ka] A mixture of 3-1-[4-(trifluoromethoxy)phenyl]azetidin-3-ylpiperidine (800.03 mg, 2.66 mmol) and 2,5-dihydrofuran-2-one (447.93 mg, 5.33 mmol) in MeOH (1.6 mL) was stirred at room temperature overnight. The mixture was evaporated in vacuo, and the residue was dissolved in MTBE (50 mL), washed with water (2 x 50 mL), brine (30 mL), and evaporated to give 4-(3-1-[4-(trifluoromethoxy)phenyl]azetidin-3-ylpiperidin-1-yl)oxolan-2-one (600.0 mg, 1.56 mmol, 58.6% yield, purity ~85%, mixture of diastereomers).

[0126] Step 3: Synthesis of N-(4-chlorophenyl)-4-hydroxy-3-(3-{1-[4-(trifluoromethoxy)phenyl]azetidin-3-yl}piperidin-1-yl)butanamide [ka] To a solution of 4-chloroaniline (398.69 mg, 3.13 mmol) in benzene (15 mL) was added trimethylaluminum (g, mol). After stirring for 10 minutes, 4-(3-1-[4-(trifluoromethoxy)phenyl]azetidin-3-ylpiperidin-1-yl)oxolan-2-one (600.0 mg, 1.56 mmol) was added to the solution, and the resulting mixture was heated to 50 °C for 2.5 hours. After cooling to room temperature, water (3 mL) and EtOAc (15 mL) were added, filtered, the solvent was evaporated in vacuo, and the residue was purified by reverse preparative HPLC to give N-(4-chlorophenyl)-4-hydroxy-3-(3-1-[4-(trifluoromethoxy)phenyl]azetidin-3-ylpiperidin-1-yl)butanamide (23.0 mg, 44.93 μmol, 3% yield). LC-MS (ESI-pos): [M+H] + =512.2 / 514.2

[0127] Synthesis of N-(4-chlorophenyl)-4-hydroxy-3-{6-[4-(trifluoromethoxy)phenyl]-2,6-diazaspiro[3.4]octan-2-yl}butanamide Example 7 Step 1: Synthesis of 4-{6-[4-(trifluoromethoxy)phenyl]-2,6-diazaspiro[3.4]octan-2-yl}oxolan-2-one [ka] A mixture of 6-[4-(trifluoromethoxy)phenyl]-2,6-diazaspiro[3.4]octane (1.6 g, 5.88 mmol) and 2,5-dihydrofuran-2-one (1.24 g, 14.69 mmol) in 10 mL of EtOH was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was dissolved in 50 mL of MTBE, washed with water (3 × 50 mL), brine (50 mL), and dried over sodium sulfate. The filtrate was concentrated under reduced pressure to give 4-6-[4-(trifluoromethoxy)phenyl]-2,6-diazaspiro[3.4]octan-2-yloxolan-2-one (800.0 mg, 75.0% purity, 1.68 mmol, 28.7% yield) as a yellow solid, which was used without further purification.

[0128] Step 2: Synthesis of N-(4-chlorophenyl)-4-hydroxy-3-{6-[4-(trifluoromethoxy)phenyl]-2,6-diazaspiro[3.4]octan-2-yl}butanamide [ka] To a stirred solution of 4-chloroaniline (446.62 mg, 3.5 mmol) in 8 mL of benzene under argon, trimethylaluminum (504.74 mg, 7.0 mmol, 3.5 mL) was added dropwise. After stirring for 10 min, 4-6-[4-(trifluoromethoxy)phenyl]-2,6-diazaspiro[3.4]octan-2-yloxolan-2-one (800.0 mg, 2.25 mmol) in 2 mL of benzene was added dropwise, and the mixture was stirred at 50 °C for 2 h. The mixture was quenched with water (10 mL). The resulting slurry was diluted with EtOAc (40 mL) and stirred vigorously for 15 min. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse preparative HPLC to give N-(4-chlorophenyl)-4-hydroxy-3-6-[4-(trifluoromethoxy)phenyl]-2,6-diazaspiro[3.4]octan-2-ylbutanamide (150.0 mg, 95.0% purity, 294.48 μmol, 13.1% yield). LC-MS (ESI-pos): [M+H] +=484.2 / 486.2

[0129] Synthesis of N-(4-chlorophenyl)-4-hydroxy-3-{1-[4-(trifluoromethoxy)phenyl]-octahydro-1H-pyrrolo[3,2-b]pyridin-4-yl}butanamide Example 8 Step 1: Synthesis of 4-{1-[4-(trifluoromethoxy)phenyl]-octahydro-1H-pyrrolo[3,2-b]pyridin-4-yl}oxolan-2-one [ka] A mixture of 1-[4-(trifluoromethoxy)phenyl]-octahydro-1H-pyrrolo[3,2-b]pyridine (500.44 mg, 1.75 mmol) and 2,5-dihydrofuran-2-one (367.38 mg, 4.37 mmol, 310.0 μL) in 10 mL of EtOH was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was dissolved in 80 mL of MTBE, washed with water (3 × 50 mL), brine (50 mL), and dried over sodium sulfate. The filtrate was concentrated under reduced pressure to give 4-1-[4-(trifluoromethoxy)phenyl]-octahydro-1H-pyrrolo[3,2-b]pyridin-4-yloxolan-2-one (400.0 mg, 64.0% purity, 691.21 μmol, 39.5% yield) as a diastereomeric mixture, which was used in the next step without purification.

[0130] Step 2: Synthesis of N-(4-chlorophenyl)-4-hydroxy-3-{1-[4-(trifluoromethoxy)phenyl]-octahydro-1H-pyrrolo[3,2-b]pyridin-4-yl}butanamide [ka] Trimethylaluminum (311.54 mg, 4.32 mmol, 2.16 mL) was added dropwise to a stirred solution of 4-chloroaniline (275.67 mg, 2.16 mmol) in 4 mL of benzene under argon. After stirring for 10 min, 4-1-[4-(trifluoromethoxy)phenyl]-octahydro-1H-pyrrolo[3,2-b]pyridin-4-yloxolan-2-one (400.0 mg, 1.08 mmol) in 1 mL of benzene was added dropwise, and the mixture was stirred at 50 °C for 2 h. The mixture was quenched with water (10 mL). The resulting slurry was diluted with EtOAc (40 mL) and stirred vigorously for 15 min. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse preparative HPLC to give N-(4-chlorophenyl)-4-hydroxy-3-1-[4-(trifluoromethoxy)phenyl]-octahydro-1H-pyrrolo[3,2-b]pyridin-4-ylbutanamide (77.0 mg, 154.64 μmol, 14.3% yield). LC-MS (ESI-pos): [M+H] + =498.2 / 500.2

[0131] Synthesis of N-(4-chlorophenyl)-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-octahydropyrrolo[3,4-c]pyrrol-2-yl}butanamide Example 9 Step 1: Synthesis of tert-butyl 5-[4-(trifluoromethoxy)phenyl]-octahydropyrrolo[3,4-c]pyrrole-2-carboxylate [ka] tert-Butyl octahydropyrrolo[3,4-c]pyrrole-2-carboxylate (2.0 g, 9.42 mmol), tris(1,5-diphenylpenta-1,4-dien-3-one)dipalladium (239.64 mg, 261.69 μmol), 1-[2-(diphenylphosphanyl)naphthalen-1-yl]naphthalen-2-yldiphenylphosphane (325.9 mg, 523.39 μmol), and sodium tert-butoxide (2.01 g, 20.94 mmol) were subsequently added to a solution of 1-bromo-4-(trifluoromethoxy)benzene (2.52 g, 10.47 mmol) in toluene (50 mL). The mixture was refluxed overnight under argon. Evaporation of the solvent gave crude tert-butyl 5-[4-(trifluoromethoxy)phenyl]-octahydropyrrolo[3,4-c]pyrrole-2-carboxylate (3.9 g), which was used in the next step without purification.

[0132] Step 2: Synthesis of 2-[4-(trifluoromethoxy)phenyl]-octahydropyrrolo[3,4-c]pyrrole [ka] Crude tert-butyl 5-[4-(trifluoromethoxy)phenyl]-octahydropyrrolo[3,4-c]pyrrole-2-carboxylate (3.9 g, 10.47 mmol) was dissolved in DCM (50 mL) and 50 mL of concentrated hydrochloric acid was slowly added. The mixture was stirred at rt for 2 h. The layers were separated and the aqueous layer was washed with DCM (2 × 50 mL) and concentrated under reduced pressure. The residue was dissolved in 30 mL of water and basified with NaHCO3. The resulting slurry was extracted with DCM (2 × 50 mL), and the organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give 2-[4-(trifluoromethoxy)phenyl]-octahydropyrrolo[3,4-c]pyrrole (1.1 g, 3.84 mmol, 36.7% yield).

[0133] Step 3: Synthesis of 4-{5-[4-(trifluoromethoxy)phenyl]-octahydropyrrolo[3,4-c]pyrrol-2-yl}oxolan-2-one [ka] A mixture of 2-[4-(trifluoromethoxy)phenyl]-octahydropyrrolo[3,4-c]pyrrole (1.1 g, 4.04 mmol) and 2,5-dihydrofuran-2-one (1.02 g, 12.12 mmol) in 10 mL of EtOH was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was dissolved in 80 mL of MTBE, washed with water (3 × 50 mL), brine (50 mL), and dried over sodium sulfate. The filtrate was concentrated under reduced pressure to give 4-5-[4-(trifluoromethoxy)phenyl]-octahydropyrrolo[3,4-c]pyrrol-2-yloxolan-2-one (750.0 mg, 87.0% purity, 1.83 mmol, 45.3% yield) as a brown oil, which was used without further purification.

[0134] Step 4: Synthesis of N-(4-chlorophenyl)-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-octahydropyrrolo[3,4-c]pyrrol-2-yl}butanamide [ka] Under argon, trimethylaluminum (510.0 mg, 7.07 mmol, 3.54 mL) was added dropwise to a stirred solution of 4-chloroaniline (452.65 mg, 3.55 mmol) in 8 mL of benzene. After stirring for 10 minutes, 4-5-[4-(trifluoromethoxy)phenyl]-octahydropyrrolo[3,4-c]pyrrol-2-yloxolan-2-one (754.78 mg, 2.12 mmol) in 2 mL of benzene was added dropwise to the reaction, and the mixture was stirred at 50 °C for 2 hours. The mixture was quenched with water (10 mL). The resulting slurry was diluted with EtOAc (40 mL) and stirred vigorously for 15 minutes. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse preparative HPLC to give N-(4-chlorophenyl)-4-hydroxy-3-5-[4-(trifluoromethoxy)phenyl]-octahydropyrrolo[3,4-c]pyrrol-2-ylbutanamide (330.0 mg, 99.0% purity, 675.12 μmol, 31.9% yield). LC-MS (ESI-pos): [M+H] + =484.2 / 486.2

[0135] Synthesis of N-(4-chlorophenyl)-4-hydroxy-3-{8-[4-(trifluoromethoxy)phenyl]-2,8-diazaspiro[5.5]undecan-2-yl}butanamide Example 10 Step 1: Synthesis of 2-[4-(trifluoromethoxy)phenyl]-2,8-diazaspiro[5.5]undecane [ka] 2,8-Diazaspiro[5.5]undecane (2.0 g, 12.97 mmol), tris(1,5-diphenylpenta-1,4-dien-3-one)dipalladium (296.84 mg, 324.17 μmol), 1-[2-(diphenylphosphanyl)naphthalen-1-yl]naphthalen-2-yldiphenylphosphane (403.7 mg, 648.33 μmol), and sodium tert-butoxide (2.49 g, 25.93 mmol) were subsequently added to a solution of 1-bromo-4-(trifluoromethoxy)benzene (2.5 g, 10.37 mmol) in toluene (60 mL). The mixture was refluxed overnight under an Ar atmosphere. The solvent was evaporated, and the residue was treated with 45 mL of concentrated hydrochloric acid and 30 mL of DCM and stirred at room temperature for 1.5 h. After phase separation, the DCM phase was discarded, and the aqueous phase was evaporated to dryness in vacuo. The residue was dissolved in 20 mL of 2.0 M NaOH. DCM (50 mL) was then added, and the mixture was stirred for an additional 0.5 h. The DCM phase was collected, dried over NaSO, and concentrated in vacuo to give 2-[4-(trifluoromethoxy)phenyl]-2,8-diazaspiro[5,5]undecane (2.2 g, 7.0 mmol, 54% yield) as a yellow oil, which was used in the next step without purification.

[0136] Step 2: Synthesis of 4-{8-[4-(trifluoromethoxy)phenyl]-2,8-diazaspiro[5.5]undecan-2-yl}oxolan-2-one [ka] A mixture of 2-[4-(trifluoromethoxy)phenyl]-2,8-diazaspiro[5.5]undecane (1.1 g, 3.5 mmol) and 2,5-dihydrofuran-2-one (588.32 mg, 7.0 mmol) in MeOH (2.2 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo, and the residue was dissolved in MTBE (50 mL), washed with water (2 × 50 mL) and brine (30 mL), and concentrated under reduced pressure to give 4-8-[4-(trifluoromethoxy)phenyl]-2,8-diazaspiro[5.5]undecan-2-yloxolan-2-one (950.0 mg, 2.38 mmol, 68.1% yield, 78% purity) as a brown oil.

[0137] Step 3: Synthesis of N-(4-chlorophenyl)-4-hydroxy-3-{8-[4-(trifluoromethoxy)phenyl]-2,8-diazaspiro[5.5]undecan-2-yl}butanamide [ka] Trimethylaluminum (287.8 mg, 3.99 mmol) was added to a solution of 4-chloroaniline (254.66 mg, 2.0 mmol) in benzene (8 mL). After stirring for 10 minutes, 4-8-[4-(trifluoromethoxy)phenyl]-2,8-diazaspiro[5.5]undecan-2-yloxolan-2-one (398.0 mg, 998.95 μmol) was added to the solution, and the resulting mixture was heated at 50°C for 2.5 hours. After cooling to room temperature, water (3 mL) and EtOAc (15 mL) were added, filtered, and the solvent was evaporated in vacuo. The residue was purified by reverse preparative HPLC to give N-(4-chlorophenyl)-4-hydroxy-3-8-[4-(trifluoromethoxy)phenyl]-2,8-diazaspiro[5.5]undecan-2-ylbutanamide (172 mg, 328.1 μmol, 17% yield). LC-MS (ESI-pos): [M+H] + =526.1 / 528.2.

Claims

1. Compounds of general formula I 【Chemical 1】 where R １ ~R ５ are hydrogen, halogens, CN, NO ２ , C.F. ３ , quaternary ammonium, COOH, COO-C １‐６ Alkyl, OCF ３ , SCF ３ , S.O. ３ -C １‐６ alkyl, with the proviso that R １ ~R ５ At least one of the is not hydrogen, R ６ is C １‐３ Alkyl-R ８ where R ８ are H, OH, SH, and NH ２ Selected from: R ７ a) hydrogen, halogen, CN, C １‐３ Alkyl, NO ２ , C.O.N.H. ２ , NHCO‐C １‐３ Alkyl, CF ３ , tertiary ammonium, COOH, COO-C １‐６ Alkyl, OC １‐３ Alkyl, OCF ３ , SCF ３ , S.O. ２ -C １‐３ Alkyl, SO ３ -C １‐３ a) aryl substituted with one or more groups selected from alkyl, provided that at least one of said groups is not hydrogen; b) halogen, CN, C １‐３ Alkyl, NO ２ , C.O.N.H. ２ , NHCO‐C １‐３ Alkyl, CF ３ , tertiary ammonium, COOH, COO-C １‐６ Alkyl, OC １‐３ Alkyl, OCF ３ , SCF ３ , S.O. ２ -C １‐３ Alkyl, SO ３ -C １‐３ c) pyridyl optionally substituted with one or more groups selected from halogen, CN, C １‐３ Alkyl, NO ２ , C.O.N.H. ２ , NHCO‐C １‐３ Alkyl, CF ３ , tertiary ammonium, COOH, COO-C １‐６ Alkyl, OC １‐３ Alkyl, OCF ３ , SCF ３ , S.O. ２ -C １‐３ Alkyl, SO ３ -C １‐３ d) pyrrolidinyl optionally substituted with one or more groups selected from halogen, CN, C １‐３ Alkyl, NO ２ , C.O.N.H. ２ , NHCO‐C １‐３ Alkyl, CF ３ , tertiary ammonium, COOH, COO-C １‐６ Alkyl, OC １‐３ Alkyl, OCF ３ , SCF ３ , S.O. ２ -C １‐３ Alkyl, SO ３ -C １‐３ e) pyrazolyl optionally substituted with one or more groups selected from halogen, CN, C １‐３ Alkyl, NO ２ , C.O.N.H. ２ , NHCO‐C １‐３ Alkyl, CF ３ , tertiary ammonium, COOH, COO-C １‐６ Alkyl, OC １‐３ Alkyl, OCF ３ , SCF ３ , S.O. ２ -C １‐３ Alkyl, SO ３ -C １‐３ f) thiazolyl optionally substituted with one or more groups selected from halogen, CN, C １‐３ Alkyl, NO ２ , C.O.N.H. ２ , NHCO‐C １‐３ Alkyl, CF ３ , tertiary ammonium, COOH, COO-C １‐６ Alkyl, OC １‐３ Alkyl, OCF ３ , SCF ３ , S.O. ２ -C １‐３ Alkyl, SO ３ -C １‐３ C optionally substituted with one or more groups selected from alkyl ５‐７ cycloalkyl; g) NHCONH ２ ; h) CONH ２ , CON(CH ３ ) ２ , C.F. ３ , and C ２‐４ C optionally substituted with a group selected from alkenes １‐３ is selected from the group consisting of alkyl, X is -CONH- or -NHCO-, or X-R ７ together form CONR'R'', where R' and R'' together with the nitrogen form a) a monoheterocyclic ring having 4-7 ring atoms, 1-2 of which are selected from nitrogen and 0-2 of which are oxygen, the remaining ring atoms being carbon, optionally selected from oxo, OH, C １‐３ a) a monoheterocyclic group substituted with a group selected from alkyl-CN; or b) a biheterocyclic group having 7 to 10 ring atoms, of which 1 to 4 are selected from nitrogen and the remaining ring atoms are carbon, optionally oxo, OH, C １‐３ forming a mono- or biheterocyclic group selected from biheterocyclic groups substituted with a group selected from alkyl-CN, Hy is a biheterocyclic group having fused first and second heterocycles, the biheterocyclic group having 6 to 12 ring atoms, 2 to 4 ring atoms being N, 0 to 2 ring atoms being O, 0 to 2 ring atoms being S, and the remaining ring atoms being carbon, wherein the first heterocycle is a substituent R １ ~R ５ and the second heterocycle is attached to a phenyl ring having the R ６ and CH ２ -X-R ７ and c) a spiroheterocyclic group having first and second heterocycles connected and sharing one carbon atom, the spiroheterocyclic group having 6 to 12 ring atoms, 2 to 4 ring atoms being N, 0 to 2 ring atoms being O, 0 to 2 ring atoms being S, and the remaining ring atoms being carbon, wherein the first heterocycle is a substituent R of formula I. １ ~R ５ and a second heterocycle is attached to a phenyl ring having R ６ and CH ２ -X-R ７ or d) first and second single heterocycles connected by a bond, wherein each single heterocycle is independently selected from single heterocycles having 4 to 7 ring atoms, wherein 1 to 3 ring atoms are N, 0 to 1 ring atoms are O, 0 to 1 ring atoms are S, and the remaining ring atoms are carbon, and the first single heterocycle is bonded to a carbon atom linked to a substituent R １ ~R ５ and the second single heterocycle is attached to a phenyl ring having R ６ and CH ２ -X-R ７ is attached to a carbon atom linked to a pharmaceutically acceptable salt or solvate thereof; However, 3-(4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamido)pyrrolidine-1-carboxamide is excluded.

2. R １ are halogens, CN, NO ２ , C.F. ３ , quaternary ammonium, COOH, COO-C １‐６ Alkyl, OCF ３ , SCF ３ , S.O. ３ -C １‐６ alkyl; R ２ ~R ５ The compound of claim 1 , wherein is hydrogen.

3. R ２ are halogens, CN, NO ２ , C.F. ３ , quaternary ammonium, COOH, COO-C １‐６ Alkyl, OCF ３ , SCF ３ , S.O. ３ -C １‐６ alkyl; R １ , R ３ ~R ５ 3. The compound of claim 1 or 2, wherein is hydrogen.

4. R ３ But halogen, CN, NO ２ , C.F. ３ , quaternary ammonium, COOH, COO-C １‐６ Alkyl, OCF ３ , SCF ３ , S.O. ３ -C １‐６ alkyl; R １ , R ２ , R ４ ~R ５ The compound according to any one of claims 1 to 3, wherein is hydrogen.

5. R ４ are halogens, CN, NO ２ , C.F. ３ , quaternary ammonium, COOH, COO-C １‐６ Alkyl, OCF ３ , SCF ３ , S.O. ３ -C １‐６ alkyl; R １ ~R ３ , R ５ The compound according to any one of claims 1 to 4, wherein is hydrogen.

6. R ５ But halogen, CN, NO ２ , C.F. ３ , quaternary ammonium, COOH, COO-C １‐６ Alkyl, OCF ３ , SCF ３ , S.O. ３ -C １‐６ alkyl; R １ ~R ４ The compound according to any one of claims 1 to 5, wherein is hydrogen.

7. R ６ is C １‐３ Alkyl-R ８ where R ８ The compound according to any one of claims 1 to 6, wherein is OH.

8. R ７ a) hydrogen, halogen, CN, C １‐３ Alkyl, NO ２ , C.O.N.H. ２ , NHCO‐C １‐３ Alkyl, CF ３ , tertiary ammonium, COOH, COO-C １‐６ Alkyl, OC １‐３ Alkyl, OCF ３ , SCF ３ , S.O. ２ -C １‐３ Alkyl, SO ３ -C １‐３ a) phenyl substituted with one or more groups selected from alkyl, provided that at least one of said groups is not hydrogen; b) pyridyl optionally substituted with one or more halogens; c) one or more CONH ２ d) pyrrolidinyl substituted with one or more CONH ２ e) thiazolyl; f) cyclohexyl substituted with one or more CN alkyl; g) NHCONH ２ , and h) CON(CH ３ ) ２ , C.F. ３ and C ２ C substituted with a group selected from alkenes １～２ The compound of any one of claims 1 to 7, wherein the compound is selected from the group consisting of alkyl.

9. The compound of claim 8, wherein the substituted phenyl in a) is a phenyl substituted with a group selected from halogen, CF 3 , OCH 3 , NHCOCH 3 , CN, CH 3 , and SO 2 CH 3 .

10. X-R ７ together form CONR'R'', where R' and R'' together with the nitrogen form a) a monoheterocyclic group having 5 ring atoms, 1-2 of which are selected from nitrogen and the remaining ring atoms are carbon, optionally oxo, OH, CH ２ a) a monoheterocyclic group substituted with a group selected from —CN; or b) a biheterocyclic group having 9 to 10 ring atoms, of which 1 to 3 are selected from nitrogen and the remaining ring atoms are carbon.

11. 11. The compound according to any one of claims 1 to 10, wherein Hy is a non-aromatic ring system selected from b) wherein the biheterocyclic group has 8 to 11 ring atoms, 1 to 2 of which are N, 0 to 1 of which are O, and the remaining ring atoms are carbon.

12. 11. The compound of any one of claims 1 to 10, wherein Hy is a non-aromatic ring system selected from c) wherein the spiroheterocyclic group has 8 to 11 ring atoms, 2 to 3 ring atoms are N, 0 to 1 ring atom is O, and the remaining ring atoms are carbon.

13. 11. The compound of any one of claims 1 to 10, wherein Hy is a non-aromatic ring system selected from d) wherein a first and a second single heterocyclic ring are joined by a bond, the first single heterocyclic ring having 4 to 6 ring atoms, 1 to 2 of which are N, 0 to 1 of which are O, and the remaining ring atoms are carbon, and the second single heterocyclic ring having 4 to 6 ring atoms, 1 to 2 of which are N, 0 to 1 of which are O, and the remaining ring atoms are carbon.

14. The compound of claim 1 selected from the following: N-(4-chlorophenyl)-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, N-(4-chlorophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(4-chlorophenyl)-4-hydroxy-3-(3-{1-[4-(trifluoromethoxy)phenyl]azetidin-3-yl}piperidin-1-yl)butanamide, N-(4-chlorophenyl)-4-hydroxy-3-{6-[4-(trifluoromethoxy)phenyl]-2,6-diazaspiro[3.4]octan-2-yl}butanamide, N-(4-chlorophenyl)-4-hydroxy-3-{1-[4-(trifluoromethoxy)phenyl]-octahydro-1H-pyrrolo[3,2-b]pyridin-4-yl}butanamide, N-(4-chlorophenyl)-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-octahydropyrrolo[3,4-c]pyrrol-2-yl}butanamide, N-(4-chlorophenyl)-4-hydroxy-3-{8-[4-(trifluoromethoxy)phenyl]-2,8-diazaspiro[5.5]undecan-2-yl}butanamide, N-[(dimethylcarbamoyl)methyl]-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-[2-(dimethylcarbamoyl)ethyl]-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 5-(4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamido)-1H-pyrazole-3-carboxamide, 4-hydroxy-N-(2,2,2-trifluoroethyl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}-N-[4-(trifluoromethyl)phenyl]butanamide, N-(5-chloropyridin-2-yl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-N-(3-methoxyphenyl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(4-acetamidophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(3-acetamidophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(4-cyanophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(2-chlorophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(3-chlorophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(4-fluorophenyl)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 1-(4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanoyl)imidazolidin-4-one, 4-hydroxy-N-(prop-2-en-1-yl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-1-(pyrazolidin-1-yl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butan-1-one, 4-hydroxy-1-(3-hydroxypyrrolidin-1-yl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butan-1-one, 2-[1-(4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanoyl)pyrrolidin-3-yl]acetonitrile, N-(3-chlorophenyl)-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, 4-hydroxy-N-(pyridin-3-yl)-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, 4-hydroxy-N-(1,2-thiazol-5-yl)-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, N-[(dimethylcarbamoyl)methyl]-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, N-(2-chlorophenyl)-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, 4-hydroxy-N-(1H-pyrazol-1-yl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(4-cyanophenyl)-4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butanamide, 4-hydroxy-1-{1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butan-1-one, 4-hydroxy-N-[(1r,4r)-4-cyanocyclohexyl]-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, N-(carbamoylamino)-4-hydroxy-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-N-(pyridin-2-yl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-N-(pyridin-3-yl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}-N-(2,4,6-trimethylphenyl)butanamide, 4-hydroxy-N-(4-methanesulfonylphenyl)-3-{2-[4-(trifluoromethoxy)phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-9-yl}butanamide, 4-hydroxy-1-{1H,4H,5H,6H,7H-pyrrolo[3,2-c]pyridin-5-yl}-3-{5-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}butan-1-one; or A pharmaceutically acceptable salt or solvate thereof.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 for treating diabetes, such as type 2 diabetes, or pre-diabetes in a subject in need thereof.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, and optionally a pharmaceutically acceptable excipient.

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