Sulfonamide derivatives and use thereof in the treatment of cryptosporidium infections

Abstract

The invention relates to compounds of formula (I), and pharmaceutically acceptable salts thereof, which are highly potent inhibitors of parasitic infections. The invention also relates to pharmaceutical compositions comprising these compounds, and to the use of these compounds in the treatment or prevention of microbial infections and diseases in animal and in human, such as infections and diseases caused by apicomplexan parasites (e.g., Cryptosporidium infections) or other microbes.

Description

[0001] SULFONAMIDE DERIVATIVES AND USE THEREOF IN THE TREATMENT OF CRYPTOSPORIDIUM INFECTIONS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Swedish patent application No.2330543-6, filed December 7, 2023, the disclosure of which is incorporated herein by reference in its entirety. TECHNICAL FIELD The invention relates to compounds of formula (I), and pharmaceutically acceptable salts thereof, which are highly potent inhibitors of parasitic infections. The invention also relates to pharmaceutical compositions comprising these compounds, and to the use of these compounds in the treatment or prevention of microbial infections and diseases in animal and in human, such as infections and diseases caused by apicomplexan parasites (e.g., Cryptosporidium infections) or other microbes. BACKGROUND Cryptosporidiosis is a mammalian diarrheal disease caused by microscopic parasites of the genus Cryptosporidium, which are protozoa of the phylum Apicomplexa. Many species of Cryptosporidium exist that infect humans, as well as a wide range of commodity animals. Cryptosporidium hominis infects humans and Cryptosporidium parvum infects commodity animals and humans alike. It affects the intestines of mammals and is typically an acute short-term infection, which might become chronic in immunocompromised animals. Especially neonatal ruminants are sensitive to Cryptosporidium parvum infections, which may result in life-long reduced animal health. The parasite is protected by an outer shell that allows it to survive outside the host for long periods of time and makes it highly resistant to chlorine disinfection. Cryptosporidiosis is a waterborne disease, with contaminated water being a major source of contamination. In addition, direct contact between individuals (animals and humans) and living in a contaminated environment greatly increases the risk of infection. Susceptibility to the disease is closely linked to the immune status. Young individuals (in particular neonatal animals and infants <5 years old) with immature immune system or immunodeficiency due to immunosuppressive agents (chemotherapy, viruses) or malnutrition are therefore the most susceptible to the disease (Gilbert et al., BMJ Glob Health 2023, vol.8, e012540). No vaccines are currently available for the prevention of the cryptosporidiosis. In Europe, two drugs are registered for the prevention or treatment of bovine cryptosporidiosis (halofuginone and paromomycin), but both have limitations. Halofuginone (sold under the brand name Halocur™) has a narrow therapeutic index and requires, to reach some level of efficacy, preventive administration during the first 7 days of life to all neonatal animals in the herd, which complicates management for farmers. Halofuginone has been shown to modify TH17 lymphocyte differentiation which also raises questions concerning its specificity of action on the parasite itself. Paromomycin (sold under the band name Gabbrovet™) is an antibiotic of the aminoglycoside family which is considered a critical antibiotic in many countries, and which has the potential to pass the intestinal barrier on young animals, thus causing risk of permanent kidney damage. In addition, paromomycin has very low oral uptake and a large quantity of antibiotics is released in the environment. Treatment with paromomycin is authorized only if administered within 24 hours of the onset of diarrhea and after prior confirmation of the presence of Cryptosporidium. Thus, new options for the prevention and treatment of cryptosporidiosis in small and large ruminants are necessary. In the United States, nitazoxanide (sold under the brand name Alinia™) is the only FDA approved therapeutic for treating Cryptosporidium infection in human. However, it has been shown to be ineffective in immunocompromised individuals, and less than 50% effective in malnourished children of less than 5 years old. As for animals, safe and effective treatment is urgently needed for human cryptosporidiosis, a truly neglected tropical disease. The extracellular gastric / pancreatic lipase inhibitor Orlistat (Xenecal™), an anti-obesity drug that also targets other intracellular proteins in lipid metabolism, like fatty acid synthase type 1 (FAS I), has previously been identified as an inhibitor of Cryptosporidium parvum infection both in vitro and in vivo (WO 2011 / 151088). Several FAS inhibitors have been disclosed during the past two decades, see e.g., WO 2008 / 059214, WO 2008 / 075064, WO 2008 / 075070, WO 2008 / 075077, WO 2012 / 122391, WO 2014 / 008197, WO 2015 / 105860 and WO 2016 / 149271. However, none of these compounds have emerged as suitable for treating Cryptosporidium infections. There is therefore a continued need for potent compounds that specifically target Cryptosporidium infections in both animal and human. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 shows the results for preventive treatment of infected neonatal mice. FIG.1A: Parasite load per gram of intestine for infected mice that were untreated or treated from day 0 to day 3 with Example 59 or Example 63. FIG.1B: Nluc activity per gram of intestine for infected mice that were untreated or treated from day 0 to day 3 with Example 59 or Example 63. (Statistics: Kruskal-Wallis test followed by Dunn’s multiple comparison **** P<0.0001, *** P<0.001). FIG.2 shows the results for curative treatment of infected neonatal mice. Parasite load per gram of intestine for infected mice that were treated at day 4 with various concentrations of Example 59. (Statistics: Kruskal-Wallis test followed by Dunn’s multiple comparison **** P<0.0001, ** P<0.005). FIG.3 shows the results for preventive treatment of infected GKO mice. Nluc activity per gram of feces for infected mice that were untreated or treated with Example 59 or Example 63. (Statistics: data were Log-transformed before statistical analysis using 2-way ANOVA followed by Bonferroni’s multiple comparisons test **** P<0.0001). FIG.4 shows the results for curative treatment of infected GKO mice. Nluc activity per gram of feces for infected mice that were untreated or treated with Example 59 at a total amount of 20, 4, 0.8 or 0.16 mg / kg / day. (Statistics: data were Log-transformed before statistical analysis using 2-way ANOVA followed by Bonferroni’s multiple comparisons test **** P<0.0001, ** P<0.005, * P<0.05). FIG.5 shows the results for curative treatment of infected IL12p40- / - mice. Nluc activity per gram of feces for infected mice that were untreated or treated with Example 59 at a total amount of 20 mg / kg / day. (Statistics: data were Log-transformed before statistical analysis using 2-way ANOVA followed by Bonferroni’s multiple comparisons test **** P<0.0001, *** P<0.001, * P<0.05). FIG.6 shows the results for preventive treatment of infected lambs. FIG 6A: Nluc activity per gram of feces for infected lambs that were untreated or treated with Example 59. (Statistics: data were Log- transformed before statistical analysis using 2-way ANOVA followed by Bonferroni’s multiple comparisons test **** P<0.0001, *** P<0.001, ** P<0.005, * P<0.05). FIG.6B: Fecal index for infected lambs that were untreated or treated with example 59. Score 0 = normal or pasty feces; score 1 = semi-liquid feces; score 2 = liquid feces. (Statistics: two-way ANOVA followed by Bonferroni's multiple comparisons test. *** P<0.001, ** P<0.01). FIG.7 shows the results for curative treatment of infected lambs. Nluc activity per gram of feces for infected lambs that were untreated, treated with Example 59 or treated with Halocur™ (Statistics: data were Log-transformed before statistical analysis using 2-way ANOVA followed by Bonferroni’s multiple comparison test. **** P<0.0001, *** P<0.001, ** P<0.01, * P<0.05). FIG.8 shows the results for curative treatment of infected neonatal mice. Parasite load per gram of intestine for infected mice that were untreated or treated from day 3 to day 5 with various concentrations of Example 104. (Statistics: Kruskal-Wallis test followed by Dunn’s multiple comparison. **** P<0.0001). FIG. 9 shows the results for curative treatment of infected GKO mice. FIG. 9A: Nluc activity per milligram of feces for infected GKO mice that were untreated or treated from day 0 to day 11 with different concentrations of Example 59. FIG.9B: Nluc activity per milligram of feces for GKO mice that were inoculated with oocysts purified from infected mice treated with a suboptimal dosage (0.016 mg / kg / day) of Example 59, and then were treated with that suboptimal dose for 18 days. FIG.10 shows the microbiota composition of mice following treatment. FIG 10A: Relative abundances of the different phyla before treatment, after 4 days of treatment, and one week after the end of treatment with paromomycin. FIG 10B: Relative abundances of the different phyla before treatment, after 4 days of treatment, and one week after the end of treatment with Example 59. FIG.10C: Relative abundance of different classes of bacteria before treatment, after 4 days of treatment, and one week after the end of treatment with paromomycin. (Statistics 2-way ANOVA test followed by Tukey’s multiple comparisons test. **** p<0.0001; *** p<0.0005; ** p<0.005; * p<0.05). DETAILED DESCRIPTION OF THE INVENTION In their search for compounds that specifically target Cryptosporidium, the inventors have tried to find potent compounds starting out from known modulators of fatty acid metabolism based on the 4-aryl piperidine scaffold. It was then discovered that certain sulfonamide derivatives have high efficacy against Cryptosporidium infections. In a first aspect, therefore, the invention relates to a compound of formula (I)

[0002] wherein Ring A is a heteroaromatic ring selected from the group consisting of pyridine, pyrazine, pyrimidine, pyridazine and 1,3,4-thiadiazole; Ring B is para-substituted benzene or a para-substituted heteroaromatic ring selected from the group consisting of pyridine, pyrazine, pyrimidine and pyridazine; R1is selected from the group consisting of hydrogen, cyano, carboxyl, C1-4 alkyl and C1-4 haloalkyl; M is -CR4- or -N-; X is -C(=O)-, -C(=O)-NH-, -S(=O)2- or -S(=O)2-NH-: Y is a bond or -(CR5AR5B)m-, wherein m is an integer 1 or 2; R2is independently selected from the group consisting of halogen, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; n is an integer 0, 1 or 2, R3is selected from the group consisting of C1-4alkyl, -O-R6, -NR6R7and heterocyclyl, wherein heterocyclyl is optionally substituted with R8; Each R4is independently selected from the group consisting of hydrogen, halogen, C1-4 alkyl and C1-4 alkoxy; R5Aand R5Bare each independently selected from the group consisting of hydrogen, hydroxy, halogen and C1-4 alkyl, or R5Aand R5Btogether form =O; R6is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl, C3-6 cycloalkyl-C2-4alkenyl, heterocyclyl, heterocyclyl-C1-4alkyl, heterocyclyl-C2-4alkenyl, amino-C1-4alkyl, N-(C1-4alkyl)amino-C1-4alkyl and N,N-di(C1-4alkyl)amino)-C1-4alkyl, and wherein heterocyclyl is optionally substituted with C1-4 alkyl; R7is C1-4 alkyl; R8is selected from the group consisting of C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, carboxy-C1-3 alkyl and hydroxy-(C1-4 alkoxy)p-C1-4 alkyl; p is an integer 0, 1, 2, 3 or 4; and or a pharmaceutically acceptable salt thereof. In some embodiments, ring A is selected from the group consisting of pyridine, pyridazine, pyrazine and 1,3,4-thiadiazole. In some embodiments, ring A is pyridine, pyridazine or pyrazine. In some embodiments, ring B is benzene. In some embodiments, R1is hydrogen, cyano, carboxyl, methyl, n-propyl, tert-butyl or trifluoromethyl. In some embodiments, R1is methyl, n-propyl, tert-butyl or trifluoromethyl. In a preferred embodiment, R1is trifluoromethyl. In some embodiments, X is -C(=O)- or -S(=O)2-. In some embodiments, X is -S(=O)2-. In some embodiments, Y is -CH2-. In some embodiments, R2is independently selected from the group consisting of chloro, fluoro, bromo, cyano, methyl, trifluoromethyl and trifluoromethoxy. In some embodiments, R2is independently selected from the group consisting of chloro and fluoro. In some embodiments, n is 1 or 0. In a preferred embodiment, n is 0. In some embodiments, R3is OR6or heterocyclyl, wherein heterocyclyl is optionally substituted with R8. In some embodiments, R3is OR6wherein R6is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, heterocyclyl, heterocyclyl-C1-4alkyl, amino-C1-4alkyl, N-(C1-4alkyl)amino-C1-4alkyl and N,N- di(C1-4alkyl)amino)-C1-4alkyl, and wherein heterocyclyl is optionally substituted with C1-4alkyl. In some embodiments, R3is heterocyclyl which is optionally substituted with R8. In some embodiments, R3is heterocyclyl which is substituted with C1-4 alkyl or carboxy-C1-3 alkyl. In some embodiments, R3is piperazinyl which is substituted with C1-4 alkyl. In a preferred embodiment, R3is 4-(1-ethylpiperazinyl). In some embodiments, R3is piperazinyl which is substituted with carboxy-C1-3 alkyl. In a preferred embodiment, R3is 4-(1-(carboxymethyl)piperazinyl) or 4-(1-(2-carboxyethyl)piperazinyl). In some embodiments, each R4is independently selected from the group consisting of hydrogen, fluoro, methyl and methoxy. In some embodiments, each R4is hydrogen. In some embodiments, M is -N-. In some embodiments, M is -CH- or -C(CH3)-. In a preferred embodiment, M is -CH-. In a preferred embodiment, the compound of formula (I) is a compound of formula (I’) wherein Ring A is pyridine, pyridazine, pyrazine or 1,3,4-thiadiazole; R1is hydrogen, cyano, carboxyl, tert-butyl or trifluoromethyl; R2is independently selected from the group consisting of chloro, fluoro, bromo, cyano, methyl, trifluoromethyl and trifluoromethoxy; n is an integer 0, 1 or 2; R3is OR6or heterocyclyl, wherein heterocyclyl is optionally substituted with R8; R6is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, heterocyclyl, heterocyclyl- C1-4 alkyl, amino-C1-4 alkyl, N-(C1-4 alkyl)amino-C1-4 alkyl and N,N-di(C1-4 alkyl)amino)-C1-4 alkyl, and wherein heterocyclyl is optionally substituted with C1-4 alkyl; and R8is selected from the group consisting of C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, carboxy-C1-3 alkyl and hydroxy-(C1-4 alkoxy)p-C1-4 alkyl; or a pharmaceutically acceptable salt thereof. In another preferred embodiment, the compound of formula (I) is a compound of formula (I’’)

[0003] wherein Ring A is para-substituted pyridine, pyridazine or pyrazine; R2is independently selected from the group consisting of chloro, fluoro, bromo, cyano, methyl, trifluoromethyl and trifluoromethoxy; n is an integer 0, 1 or 2; and R8is C1-4 alkyl or carboxy-C1-3 alkyl; or a pharmaceutically acceptable salt thereof. In a particular embodiment, the compound of formula (I) is selected from the group consisting of: N-(2-methyl-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1-carbonyl)- phenyl)-1-phenylmethanesulfonamide; N-(2-methoxy-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1-carbonyl)- phenyl)-1-phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-((5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-methoxy-5-(4-(4-((5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(5-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2-methyl- phenyl)-1-phenylmethanesulfonamide; N-(5-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2-methoxy- phenyl)-1-phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-((5-propyl-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)- 1-phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-(4-(trifluoromethyl)phenoxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-(pyridin-2-yloxy)phenyl)piperidine-1-carbonyl)phenyl)-1-phenylmethane- sulfonamide; N-(2-methyl-5-(4-(4-(pyridin-3-yloxy)phenyl)piperidine-1-carbonyl)phenyl)-1-phenylmethane- sulfonamide; N-(2-methyl-5-(4-(4-phenoxyphenyl)piperidine-1-carbonyl)phenyl)-1-phenylmethane- sulfonamide; N-(2-methyl-5-(4-(4-((5-methylpyridin-2-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)piperidine-1-carbonyl)- phenyl)-1-phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-(pyrazin-2-yloxy)phenyl)piperidine-1-carbonyl)phenyl)-1-phenylmethane- sulfonamide; N-(2-methyl-5-(4-(4-(pyrimidin-2-yloxy)phenyl)piperidine-1-carbonyl)phenyl)-1-phenyl- methanesulfonamide; N-(2-methyl-5-(4-(4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)piperidine-1-carbonyl)- phenyl)-1-phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-((5-methylpyrimidin-2-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)phenyl)piperidine-1-carbonyl)- phenyl)-1-phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)piperidine-1-carbonyl)- phenyl)-1-phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-(pyrimidin-5-yloxy)phenyl)piperidine-1-carbonyl)phenyl)-1-phenyl- methanesulfonamide; N-(2-methyl-5-(4-(4-((5-methylpyrazin-2-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-((3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-((5-(trifluoromethyl)pyrazin-2-yl)oxy)phenyl)piperidine-1-carbonyl)- phenyl)-1-phenylmethanesulfonamide; N-(2-cyclopropoxy-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-isopropoxy-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1-carbonyl)- phenyl)-1-phenylmethanesulfonamide; 3-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenoxy)azetidin-1-ium 2,2,2-trifluoroacetate; 3-(3-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenoxy)propyl)azetidin-1-ium 2,2,2-trifluoroacetate; (E)-3-(3-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenoxy)prop-1-en-1-yl)azetidin-1-ium 2,2,2-trifluoroacetate; N-(2-(2-(dimethylamino)ethoxy)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; N,N-dimethyl-2-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenoxy)ethan-1-aminium chloride; N-(2-methoxy-4-methyl-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(5-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2-methoxy- 4-methylphenyl)-1-phenylmethanesulfonamide; N-(2-cyclopropoxy-4-methyl-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine- 1-carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(5-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2- cyclopropoxy-4-methylphenyl)-1-phenylmethanesulfonamide; N-(5-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2- cyclopropoxyphenyl)-1-phenylmethanesulfonamide; N-(2-(tert-butoxy)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-(tert-butoxy)-5-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; 1-phenyl-N-(2,3,4-trimethyl-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine- 1-carbonyl)phenyl)methanesulfonamide; N-(2,4-dimethyl-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1-carbonyl)- phenyl)-1-phenylmethanesulfonamide; N-(2,4-dimethoxy-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2,3-dimethoxy-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1-carbonyl)- pyridin-3-yl)-1-phenylmethanesulfonamide; N-(2-methoxy-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1-carbonyl)- pyridin-3-yl)-1-phenylmethanesulfonamide; 3-methyl-3-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenoxy)azetidin-1-ium 2,2,2-trifluoroacetate; 4-(2-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenoxy)ethyl)morpholin-4-ium chloride; 1-(2-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenoxy)ethyl)pyrrolidin-1-ium chloride; 4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)piperazin-1-ium chloride; (R)-3-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenoxy)pyrrolidin-1-ium 2,2,2-trifluoroacetate; (S)-2-((2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenoxy)methyl)pyrrolidin-1-ium 2,2,2-trifluoroacetate; N-(2-((1-methylazetidin-3-yl)oxy)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; (R)-N-(2-((1-methylpyrrolidin-3-yl)oxy)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-(4-methylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-(4-isopropylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-((1,3-dimethylazetidin-3-yl)oxy)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; 3-(4-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2- ((phenylmethyl)sulfonamido)phenoxy)azetidin-1-ium 2,2,2-trifluoroacetate; N-(5-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2-(2- (dimethylamino)ethoxy)phenyl)-1-phenylmethanesulfonamide; N-isopropyl-N-(2-((3-((phenylmethyl)sulfonamido)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)pyridin-2-yl)oxy)ethyl)propan-2-aminium chloride; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine- 1-carbonyl)phenyl)-1-phenylmethanesulfonamide; 1-ethyl-4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-ium (S)-2-hydroxypropanoate; (S)-N-(2-((1-methylpyrrolidin-2-yl)methoxy)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; 4-(3-((phenylmethyl)sulfonamido)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)pyridin-2-yl)piperazin-1-ium 2,2,2-trifluoroacetate; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine- 1-carbonyl)pyridin-3-yl)-1-phenylmethanesulfonamide; 1-ethyl-4-(3-((phenylmethyl)sulfonamido)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)pyridin-2-yl)piperazin-1-ium chloride; N,N-dimethyl-2-((3-((phenylmethyl)sulfonamido)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)pyridin-2-yl)oxy)ethan-1-aminium chloride; 1-(4-chlorophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)methanesulfonamide; 1-(3-chlorophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)methanesulfonamide; 4-(2-(((3-chlorophenyl)methyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)-1-ethylpiperazin-1-ium (S)-2-hydroxypropanoate; 1-(2-chlorophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)methanesulfonamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine- 1-carbonyl)phenyl)-1-(p-tolyl)methanesulfonamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine- 1-carbonyl)phenyl)-1-(4-(trifluoromethyl)phenyl)methanesulfonamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine- 1-carbonyl)phenyl)-1-(2-fluorophenyl)methanesulfonamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine- 1-carbonyl)phenyl)benzenesulfonamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine- 1-carbonyl)phenyl)-2-phenylethane-1-sulfonamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine- 1-carbonyl)phenyl)-1-(3-(trifluoromethoxy)phenyl)methanesulfonamide; 1-(3-cyanophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)methanesulfonamide; 1-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-3-phenylurea; 1-benzyl-3-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)urea; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine- 1-carbonyl)phenyl)-2-phenylacetamide; 1-(4-chlorophenyl)-3-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)urea; 1-(3-chlorophenyl)-3-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)urea; 2-(4-chlorophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)acetamide; 2-(3-chlorophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)acetamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine- 1-carbonyl)phenyl)-2,2-difluoro-2-phenylacetamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine- 1-carbonyl)phenyl)-2-oxo-2-phenylacetamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine- 1-carbonyl)phenyl)-2-hydroxy-2-phenylacetamide; 1-(3,5-dichlorophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)methanesulfonamide; 1-(3,4-dichlorophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)methanesulfonamide; 1-(3-bromophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)methanesulfonamide; 1-(3,4-dichlorophenyl)-3-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)urea; 1-(3,5-dichlorophenyl)-3-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)urea; N-(2-(4-ethylpiperazin-1-yl)-3-fluoro-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-(4-ethylpiperazin-1-yl)-3-methyl-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-(4-ethyl-1,4-diazepan-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; 4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)piperidin-1-ium 2,2,2-trifluoroacetate; N-(2-(1-ethylpiperidin-4-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((5-(trifluoromethyl)pyrazin-2-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; 1-ethyl-4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-ium (S)-2-hydroxypropanoate; 1-ethyl-4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-ium (S)-2-hydroxypropanoate; 1-(3-chlorophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)methanesulfonamide; 1-(3-chlorophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)methanesulfonamide; 4-(2-(((3-chlorophenyl)methyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)-1-ethylpiperazin-1-ium (S)-2-hydroxypropanoate; 4-(2-(((3-chlorophenyl)methyl)sulfonamido)-4-(4-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)-1-ethylpiperazin-1-ium (S)-2-hydroxypropanoate; N-(5-(4-(4-((6-cyanopyridazin-3-yl)oxy)phenyl)piperidine-1-carbonyl)-2-(4-ethylpiperazin-1- yl)phenyl)-1-phenylmethanesulfonamide; N-(5-(4-(4-((5-cyanopyridin-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2-(4-ethylpiperazin-1- yl)phenyl)-1-phenylmethanesulfonamide; N-(5-(4-(4-((6-cyanopyridin-3-yl)oxy)phenyl)piperidine-1-carbonyl)-2-(4-ethylpiperazin-1- yl)phenyl)-1-phenylmethanesulfonamide; 1-(carboxymethyl)-4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((5-(trifluoromethyl)pyridin-2- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-ium chloride; 1-(2-carboxyethyl)-4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((5-(trifluoromethyl)pyridin-2- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-ium chloride; 4-(4-(4-(4-((5-carboxypyridin-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2-((phenylmethyl)- sulfonamido)phenyl)-1-ethylpiperazin-1-ium chloride; 4-(4-(4-(4-((6-carboxypyridin-3-yl)oxy)phenyl)piperidine-1-carbonyl)-2-((phenylmethyl)- sulfonamido)phenyl)-1-ethylpiperazin-1-ium chloride; 1-(carboxymethyl)-4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-ium chloride; 1-(2-carboxyethyl)-4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-ium chloride; 1-(carboxymethyl)-4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-ium chloride; and 1-(2-carboxyethyl)-4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-ium chloride; or a pharmaceutically acceptable salt thereof. Definitions As used herein, the term “halo” refers to fluoro, chloro, bromo and iodo. As used herein, the term “C1-6alkyl” refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, and the term “C1-4alkyl” refers to a straight or branched alkyl group having from 1 to 4 carbon atoms. Examples of C1-4 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl and tert-butyl. As used herein, the term “C2-4 alkenyl” refers to a straight or branched alkyl group having from 2 to 4 carbon atoms and one carbon-carbon double bond. Examples of C2-4 alkenyl include vinyl, allyl and crotyl. As used herein, the term “C1-4 alkoxy” refers to a straight or branched C1-4 alkyl group, as defined herein, attached to the remainder of the molecule through an oxygen atom. Examples of C1-4 alkoxy include methoxy, ethoxy, isopropoxy and tert-butoxy. As used herein, the terms “C1-4 haloalkyl” and “C1-4 haloalkoxy” refer to a straight or branched C1-4 alkyl or C1-4alkoxy group, as defined herein, wherein one or more hydrogen atoms have been replaced with halogen. Examples of C1-4 haloalkyl include chloromethyl, fluoroethyl and trifluoromethyl, and examples of C1-4 haloalkoxy include fluoromethoxy and trifluoromethoxy. As used herein, the term “C3-6cycloalkyl” refers to a monocyclic saturated hydrocarbon ring having from 3 to 6 carbon atoms. Examples of C3-6cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. As used herein, the term “heterocyclyl” refers to a monocyclic saturated ring having from 3 to 7 atoms, of which at least one is a heteroatom selected from nitrogen, oxygen or sulfur. Examples of heterocyclyl include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and 1,4- diazacycloheptyl (homopiperazinyl). As used herein, the terms “C3-6cycloalkyl-C1-4alkyl” and “C3-6cycloalkyl-C2-4alkenyl” refer to a C3-6cycloalkyl group, as defined herein, attached to the remainder of the molecule through an C1-4 alkyl or C2-4 alkenyl group, respectively. The terms “heterocyclyl-C1-4 alkyl” and “heterocyclyl-C2-4 alkenyl” should be construed similarly. The term “amino” refers to an -NH2 group. As used herein, the term “amino-C1-4 alkyl” refers to a straight or branched C1-4alkyl group, as defined herein, wherein one of the hydrogen atoms has been replaced with an -NH2group. As used herein, the terms N-(C1-4alkyl)amino-C1-4alkyl and N,N-di(C1-4alkyl)amino)-C1-4 alkyl refer to an amino-C1-4 alkyl group, as defined above, wherein one or both of the hydrogen atoms on the amino group , respectively, have been replaced with a straight or branched C1- 4 alkyl group. Examples of N-(C1-4 alkyl)amino-C1-4 alkyl include methylaminomethyl and ethylaminoethyl, and examples of N,N-di(C1-4 alkyl)amino)-C1-4 alkyl include (dimethylamino)ethyl and (diisopropylamino)ethyl. A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, a base- addition salt of a compound of the invention which is sufficiently acidic, or an acid-addition salt of a compound of the invention which is sufficiently basic. Examples of base-addition salts include an alkali metal salt (e.g., a sodium or potassium salt), an alkaline earth metal salt (e.g., a calcium or magnesium salt), an ammonium salt, or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. Examples of acid-addition salt include a halide salt (e.g., a bromide or chloride salt), or a salt with an organic acid which affords a physiologically acceptable anion, for example a salt with acetic acid, trifluoroacetic acid, lactic acid, succinic acid, tartaric acid, glutaric acid, maleic acid, fumaric acid or citric acid. Some compounds of formula (I), or pharmaceutically acceptable salts thereof, may have chiral centres and / or geometric isomeric centres (E- and Z-isomers). It is to be understood that the invention encompasses all such optical isomers, diastereoisomers and geometric of formula (I). The invention also encompasses any and all tautomeric forms of compounds of formula (I), or pharmaceutically acceptable salts thereof. Certain compounds of formula (I), or pharmaceutically acceptable salts thereof, may exist in unsolvated as well as solvated forms, such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms. As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions and / or dosage forms that are suitable for human or veterinary pharmaceutical use and that are generally safe, non-toxic and neither biologically nor otherwise undesirable. As used herein, the terms "treatment", "treat" and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. As used herein, the term "about" refers to a value or parameter herein that includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to "about 20" includes description of "20." Numeric ranges are inclusive of the numbers defining the range. Generally speaking, the term "about" refers to the indicated value of the variable and to all values of the variable that are within the experimental error of the indicated value (e.g., within the 95% confidence interval for the mean) or within 10 percent of the indicated value, whichever is greater. Pharmaceutical use In another aspect, the invention relates to a compound of formula (I), as defined herein, for use as a medicament. It has been discovered that the compounds of formula (I), or pharmaceutically acceptable salts thereof, are highly potent anti-cryptosporidium compounds. In a further aspect, therefore, the invention relates to a compound of formula (I), as defined herein, for use in the treatment or prevention of microbial infections and diseases in an animal or a human, in particular infections and diseases caused by apicomplexan parasites or other microbes, including, but not limited to, species from the genera Toxoplasma, Sarcocystis, Plasmodium, Neospora, Eimeria, Cryptosporidium, Theileria and Babesia. In a preferred embodiment, the infection or disease is caused by a Cryptosporidium species. In a more preferred embodiment, the infection or disease is caused by Cryptosporidium parvum, Cryptosporidium hominis, Cryptosporidium canis, Cryptosporidium felis, Cryptosporidium meleagridis, Cryptosporidium bovis or Cryptosporidium muris. In some embodiments, the invention relates to a compound of formula (I), as defined herein, for use in the treatment or prevention of Cryptosporidium parvum or Cryptosporidium hominis infections in a human. In some embodiments, the invention relates to a compound of formula (I), as defined herein, for use in the treatment or prevention of parasitic infections and diseases in an animal, such as a mammal, a bird, a fish, a reptile, an amphibian or a crustacean. In a preferred embodiment, the mammal is a ruminant, such as a bovine (including cattle), a goat, a sheep, a giraffe, a deer, a gazelle or an antelope. In a preferred embodiment, the invention relates to a compound of formula (I), as defined herein, for use in the treatment or prevention of Cryptosporidium parvum infections in a ruminant. The invention also relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of any of the conditions, disorders and diseases recited herein. The invention also relates to a method of treating or preventing any of the conditions, disorders and diseases recited herein, in a subject in need thereof, such as man, comprising administering to the subject in need of such treatment or prevention a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions In another aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The excipients may e.g. include fillers, binders, disintegrants, glidants, lubricants, salts (e.g., saline), buffers, surfactants, cosolvents, antioxidants and preservatives. In general, pharmaceutical compositions may be prepared in a conventional manner using conventional excipients. The pharmaceutical composition may be in a form that is suitable for e.g. oral administration, for parenteral injection (including intravenous, subcutaneous, intramuscular and intravascular injection), or for topical administration. In a preferred embodiment, the pharmaceutical composition is in a form that is suitable for oral administration, such as powder for reconstitution as suspension or solution, tablets, coated tablets, dragées, capsules, solutions and syrups, as well as multiparticulate formulations, i.e., formulations comprising a plurality of small pellets, mini tablets, microspheres, granules, microparticles or nanoparticles. In some embodiments, the pharmaceutical composition is a solid composition, comprising one or more excipients such as fillers, binders, disintegrants, glidants, lubricants. Examples of suitable fillers include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose (such as lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, dry starch, hydrolyzed starches and pregelatinized starch. Examples of suitable binders include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (such as sucrose, glucose, dextrose, lactose, sorbitol and maltodextrin), polyethylene glycol, waxes, natural and synthetic gums (such as acacia gum and tragacanth gum), sodium alginate, cellulose derivatives (such as hydroxypropylmethylcellulose (or hypromellose), hydroxypropylcellulose and ethylcellulose) and synthetic polymers (such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid copolymers and polyvinylpyrrolidone (povidone)). Examples of suitable glidants and lubricants include, but are not limited to, talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, colloidal anhydrous silica, aqueous silicon dioxide, synthetic magnesium silicate, fine granulated silicon oxide, starch, sodium lauryl sulfate, boric acid, magnesium oxide, waxes (such as carnauba wax), hydrogenated oil, polyethylene glycol, sodium benzoate, polyethylene glycol, and mineral oil. Examples of suitable disintegrants include, but are not limited to, dry starch, modified starch (such as (partially) pregelatinized starch, sodium starch glycolate and sodium carboxymethyl starch), alginic acid, cellulose derivatives (such as sodium carboxymethylcellulose, hydroxypropyl cellulose, and low substituted hydroxypropyl cellulose (L-HPC)) and cross-linked polymers (such as carmellose, croscarmellose sodium, carmellose calcium and cross-linked PVP (crospovidone)). A solid composition may be conventionally coated with one or more coating layers. Enteric coating layers or coating layers for delayed or targeted release of the compound of formula (I), or pharmaceutically acceptable salts thereof, are also contemplated. The coating layer(s) may comprise one or more coating agents, and may optionally comprise plasticizers and / or pigments (or colorants). Example of suitable coating agents include, but are not limited to, cellulose-based polymers (such as ethylcellulose, hydroxypropylmethylcellulose (or hypromellose), hydroxypropylcellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate), vinyl-based polymers (such as polyvinyl alcohol) and polymers based on acrylic acid and derivatives thereof (such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid copolymers). Examples of suitable plasticizers include, but are not limited to, triethyl citrate, glyceryl triacetate, tributyl citrate, diethyl phthalate, acetyl tributyl citrate, dibutyl phthalate, dibutyl sebacate and polyethylene glycol. Examples of suitable pigments include, but are not limited to, titanium dioxide, iron oxides (such as yellow, brown, red or black iron oxides) and barium sulfate. In some embodiments, the pharmaceutical composition is a liquid composition, comprising one or more excipients such as salts (e.g., saline), buffers, surfactants, cosolvents, antioxidants and preservatives. Examples of suitable buffers include, but are not limited to, salts such as phosphate, citrate, acetate, gluconate, lactate, tartrate, aspartate, glutamate and phthalate, or the corresponding acid forms thereof, as well as histidine or Tris (tris(hydroxymethyl)aminomethane). The pH of a liquid composition is preferably within the range of about 4 to about 9, more preferably within the range of about 5 to about 8, and even more preferably within the range of about 6 to 7. Examples of suitable surfactant include, but are not limited to, cationic surfactants, anionic surfactants and nonionic surfactants. Examples of cationic surfactants include, but are not limited to, cetyltrimethylammonium bromide (cetrimonium bromide) and cetylpyridinium chloride. Examples of anionic surfactants include, but are not limited to, sodium dodecyl sulfate (sodium lauryl sulfate) and ammonium dodecyl sulfate (ammonium lauryl sulfate). Examples of nonionic surfactants include, but are not limited to, glycerol monooleate, glycerol monostearate, polyoxyl castor oil (Cremophor EL), poloxamers (e.g., poloxamer 407 or 188), polysorbate 80 and sorbitan esters (Tween). Examples of suitable cosolvents include, but are not limited to, water ethanol, propylene glycol, polyethylene glycol 400 (PEG 400), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), and N,N- dimethylacetamide (DMA). Examples of suitable antioxidants include, but are not limited to, butylhydroxytoluene (BHT), ascorbyl palmitate, propyl gallate and ascorbic acid, and combinations thereof. Examples of suitable preservatives include, but are not limited to, phenol, benzyl alcohol, methyl paraben, ethyl paraben, propyl paraben, ethylenediaminetetraacetic acid (EDTA), potassium sorbate and sodium benzoate, and combinations thereof. The dosage required for the therapeutic or prophylactic treatment will depend on the route of administration, the severity of the disease, the immune status, the age and weight of the patient and other factors normally considered by the attending physician or veterinarian, when determining the appropriate regimen and dosage level for a particular patient. The amount of the compound to be administered will vary for the animal species being treated and may vary from about 1 µg / kg of body weight to about 50 mg / kg of body weight per day. A unit dose form, such as a tablet or capsule, will usually contain about 0.1 to about 250 mg of active ingredient, such as about 1 to about 250 mg, or such as about 1 to about 100 mg, or such as about 1 to about 50 mg, or such as about 1 to about 20 mg, e.g. about 2.5 mg, or about 5 mg, or about 10 mg, or about 15 mg. The daily dose can be administered as a single dose or divided into one, two, three or more unit doses. The daily dose can also be administered as an appropriate amount of e.g., a solution or a powder for reconstition. An orally administered daily dose of compound of formula (I) is preferably within about 0.1 to about 250 mg, more preferably within about 1 to about 100 mg, such as within about 1 to about 5 mg, such as within about 1 to about 10 mg, such as within about 1 to about 15 mg, or such as within about 1 to about 20 mg. For the treatment of animals, as described herein, a pharmaceutical composition of a compound of formula (I) may also be added to milk replacement, or to the animals’ drinking water or food, e.g., as a solution or a powder for reconstitution. EXAMPLES The invention will now be described by the following examples which do not limit the invention in any respect. All cited documents and references are incorporated by reference. Preparation of compounds The compounds of the invention can be prepared as a free acid or a free base, or a pharmaceutically acceptable salt thereof, by the processes described below. Throughout the following description of such processes it is understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are for example described in Greene’s Protective Groups in Organic Synthesis by P.G.M Wutz and T.W. Greene, 4th Edition, John Wiley & Sons, Hoboken, 2006. Abbreviations AcOH acetic acid BOC tert-butoxycarbonyl DCM dichloromethane DCE 1,2-dichloroethane DIPEA N,N-diisopropylethylamine DMF dimethylformamide DMSO dimethylsulfoxide dppf 1,1′-bis(diphenylphosphino)ferrocene EtOAc ethyl acetate EtOH ethanol equiv. equivalent(s) HBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate IPA isopropyl alcohol MeCN acetonitrile MeOH methanol MTBE methyl tert-butyl ether TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran General methods All solvents used were of analytical grade. Commercially available anhydrous solvents were routinely used for reactions. Starting materials were available from commercial sources or prepared according to literature procedures. Room temperature refers to 20 - 25 °C. Solvent mixture compositions are given as volume percentages or volume ratios. NMR spectra were measured on Bruker Avance 400 MHz and Bruker Avance 600 MHz spectrometers at 295 K. The reported values for the chemical shifts δ (ppm) were calibrated to the residual proton or carbon resonance signal of the deuterated solvent used (CDCl3, MeOD or DMSO-d6). Mass Spectrometer readings were recorded using an Agilent Technologies 1290 Infinity system connected to an Agilent Technologies 6150 Quadrupole LC / MS system (MS) or using an Agilent Technologies 6230 TOF LC / MS spectrometer (HRMS). General procedure A (for the synthesis of aryl-heteroaryl or diaryl ethers): Non-catalyzed method: 1-Boc-4-hydroxyphenylpiperidine or 4-(piperidin-4-yl)phenol hydrobromide was dissolved in anhydrous DMF or MeCN and Cs2CO3 or K2CO3 was added, followed by the addition of the corresponding heteroaryl halide portionwise. The mixture was stirred at room temperature overnight. Workup procedure A: The reaction mixture was partitioned between water and EtOAc, the aqueous layer was separated and re-extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified with column chromatography on silica gel or trituration to afford the product as a white solid. Workup procedure B: The reaction mixture was poured into chilled water and the resulting precipitate was filtered, washed with a small amount of water and dried. The given solid was dissolved in DCM and washed with water. The separated organic phase was washed with brine, dried over anhydrous Na2SO4, filtered through a pad of Celite, and the filtrate was evaporated to dryness in vacuo to give a white crystalline product. The product was sufficiently pure, further purification was not necessary. Cu-catalyzed method: 1-Boc-4-hydroxyphenylpiperidine was dissolved in anhydrous DMSO and K3PO4, CuI, picolinic acid, and the aryl or heteroaryl halide was successively added. The reaction mixture was then stirred at 82 °C overnight. The resulting mixture was cooled to room temperature, partitioned between water and EtOAc, and washed with 5% aqueous LiCl solution. The separated organic phase was washed with brine, dried over anhydrous Na2SO4, then the solution was concentrated in vacuo, and the obtained crude product was purified with column chromatography on silica gel. General procedure B (for the deprotection of N-Boc-piperidines and N-Boc-piperazine with HCl): N-Boc-piperidine or N-Boc-piperazine was dissolved in 1,4-dioxane, 4M HCl solution in dioxane was added and the reaction mixture was stirred overnight. The resulting white suspension was concentrated and the residue was co-evaporated to dryness twice with 1,4-dioxane in vacuo. The solid was triturated with diethyl-ether, collected by filtration and dried to afford white crystals. General procedure C (for the synthesis of acyl chlorides): To a solution of the corresponding carboxylic acid in toluene under N2 atmosphere, SOCl2 and DMF were added and the reaction mixture was stirred at 80 °C. After 6 hours of reaction time the mixture was evaporated to dryness in vacuo, subsequently co-evaporated with toluene two times, and dried under high vacuum to afford the product. General procedure D (for the synthesis of tertiary amides from acyl chlorides and piperidine building blocks): Intermediate 21 was dissolved in DCM, TEA was added under N2 atmosphere, and the mixture was cooled down to -10 °C with salt ice bath. Acyl chloride was dissolved in DCM and added fast to the reaction mixture. After 16 hours of reaction time the mixture was washed with 0.5M aqueous HCl, followed by saturated aqueous NaHCO3, and brine. The organic phase was dried over anhydrous Na2SO4and concentrated in vacuo to give the product as white solid. The product was sufficiently pure, further purification was not necessary. General procedure E (for the substitution of aryl or heteroaryl halides to afford ethers): To a mixture of NaH (60% dispersion in mineral oil) and the appropriate alcohol (alternatively a readily available KOtBu solution) in anhydrous THF or DMF at 0 °C under N2 atmosphere, the corresponding aryl or heteroaryl halide derivative was added slowly. The mixture was allowed to warm up to room temperature and stirred for 4 hours. Workup procedure A: The reaction mixture was partitioned between water and EtOAc, the aqueous phase was re-extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. If the crude solid was sufficiently pure, further purification was not necessary, or if it was required, column chromatography was performed to afford the product as a white solid. Workup procedure B: The product was isolated by precipitation upon slow addition of the reaction mixture into a saturated aqueous KH2PO4solution. The resulting solid was filtered, washed with water, and dried under reduced pressure to afford the product as a white solid. General procedure F (for the substitution of aryl or heteroaryl halides to afford tertiary amines): To a solution of the corresponding aryl or heteroaryl halide derivative in DMSO, 1-Boc-ethylpiperazine, 1-ethylpiperazine or 1-ethyl-1,4-diazepane and TEA were added and the reaction mixture was stirred at 60 °C for 30 minutes. After completion of the reaction, the mixture was added slowly to water, the resulting precipitate was filtered, washed with water, and dried. The obtained yellow product was sufficiently pure and further purification was not necessary. General procedure G (for the synthesis of methyl esters): To a solution of the corresponding benzoic acid in DMF, Cs2CO3and MeI were added and the reaction mixture was stirred at room temperature. After 2 hours of reaction time, the mixture was partitioned between water and EtOAc and the aqueous layer was re-extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified with column chromatography on silica gel to afford the product as a white solid. General procedure H (for the synthesis of tert-butyl esters): To a solution of the corresponding acyl chloride in DCM under N2atmosphere, pyridine andtBuOH were added and the reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was evaporated to dryness, the residue was dissolved in EtOAc and washed with 5% aqueous KHSO4, saturated aqueous NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified with column chromatography on silica gel to afford the product as a white solid. General procedure I (for the synthesis of aryl or heteroaryl primary amines): The corresponding aryl or heteroaryl nitro compound was dissolved in 70% EtOH / H2O, AcOH was added at 80 °C, followed by the addition of Fe powder under vigorous stirring. After 40 minutes the reaction mixture was allowed to cool down to room temperature, saturated aqueous NaHCO3 and EtOAc were added and the reaction mixture for 15 minutes. The organic phase was then decanted and filtered through Celite. To the aqueous phase EtOAc was added again and the mixture was stirred for 15 minutes, decanted, and filtered through Celite. Subsequently the aqueous phase was also filtered and then washed with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, water and brine, dried over anhydrous Na2SO4, filtered, and evaporated to dryness in vacuo to afford the product as a white solid. General procedure J (for the synthesis of sulfonamides): The corresponding amine was dissolved in pyridine, the appropriate sulfonyl-chloride was added and the reaction mixture was stirred at room temperature overnight. The volatiles were then removed, and the residue was co-evaporated with toluene in vacuo twice. The crude product was dissolved in DCM and washed with 5% citric acid. In the presence of a basic side chain, acidic wash was not performed. Subsequently the solution of the crude was washed with saturated aqueous NaHCO3, then with brine, dried over anhydrous Na2SO4, and evaporated to dryness in vacuo. The crude solid was purified with column chromatography on silica gel to afford the product as a white solid. General procedure K (for the synthesis of L-lactate salts of ethyl-piperazines): Ethyl-piperazine was dissolved in IPA or in a mixture of EtOAc / MTBE, a solution of L-lactic acid in IPA or in a mixture of EtOAc / MTBE was added and the reaction mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration, washed with IPA and Et2O or with a mixture of EtOAc / MTBE, and dried under reduced pressure to afford the product as a white solid. General procedure L (for the hydrolysis of ethyl and methyl esters): The corresponding methyl ester was suspended in an 8:1:1 ratio of 1,4-dioxane / MeOH / H2O, followed by the addition of NaOH. The reaction mixture was then stirred at 40 °C overnight. The reaction mixture was then concentrated in vacuo, diluted with water and the pH was lowered to 3 using 10% aqueous KHSO4. The resulting precipitate was collected by filtration, washed with water, and dried to afford the product as a white solid. General procedure M (for the hydrolysis of tert-butyl esters): The corresponding tert-butyl ester was dissolved in a minimum amount of 1,4-dioxane and added to a sealed tube charged with a solution of 4M HCl in dioxane, and the reaction mixture was stirred at 40 °C overnight. The reaction mixture was then evaporated to dryness in vacuo. The crude solid was triturated with 1,4-dioxane and dried under reduced pressure to give the product as a white solid. General procedure N (for the amide coupling between carboxylic acids and piperidines): The carboxylic acid derivative was dissolved in DMF, then DIPEA and HBTU were added and the reaction mixture was stirred at 0 °C. After 5 minutes, the solution of the piperidine HCl salt derivative and DIPEA in DMF was added and the mixture was allowed to warm up to room temperature and stirred overnight. Workup procedure A: The reaction mixture was diluted with EtOAc and washed with water, the aqueous layer was separated and re-extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude was purified with column chromatography on silica gel to afford the product as a white solid. Workup procedure B: The product was isolated by precipitation upon slow addition of the reaction mixture into a 1:1 mixture of saturated aqueous NaHCO3 and saturated aqueous Na2CO3 solutions. The resulting pale pink solid was filtered and washed with saturated aqueous NaHCO3. The residue was dissolved in DCM and washed with water, then with brine, the separated organic phase was dried over anhydrous Na2SO4, and concentrated in vacuo. The crude was purified with column chromatography on silica gel to afford the product as a white solid. Workup procedure C: The product was isolated by precipitation upon slow addition of the reaction mixture into a saturated aqueous KH2PO4 solution. The resulting solid was filtered and washed with saturated aqueous KH2PO4 solution and water. The residue was dissolved in EtOAc and washed with water, then with brine. The separated organic phase was then dried over anhydrous Na2SO4 and concentrated in vacuo. The crude was purified with column chromatography on silica gel to afford the product as a white solid. General procedure O (for the deprotection of N-Boc-azetidines, N-Boc-pyrrolidines and N-Boc- piperazines with TFA): The corresponding N-Boc amine was dissolved in DCE, TFA was added and the reaction mixture was stirred at 0 °C for 30 minutes. The mixture was then evaporated to dryness in vacuo, subsequently co- evaporated with DCE twice and dried to afford the product as a white solid. General procedure P (for the reductive amination of azetidines, pyrrolidines and piperazines): The corresponding amine was dissolved in MeOH, followed by the addition of AcOH and the appropriate carbonyl reagent at 0 °C. After 5 minutes of stirring NaBH3CN was added portionwise to the mixture and the reaction mixture was stirred at 0 °C for 3 hours. The reaction mixture was then diluted with saturated aqueous NaHCO3 and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified with column chromatography on silica gel to afford the product as a white solid. General procedure Q (for the synthesis of HCl salts of aryloxy- and heteroaryloxy-ethylamines): The corresponding amine was dissolved in a minimum amount of DCM and added to a mixture of 4M HCl in dioxane solution in Et2O. The mixture was stirred for 10 minutes, the resulting precipitate was collected by filtration, washed with Et2O, and dried to afford the product as a white solid. General procedure R (for the synthesis of amides): To a solution of Intermediate 86 in DCM at 0 °C under N2 atmosphere, TEA and the appropriate acyl chloride were added and the reaction mixture was stirred overnight. The reaction mixture was then diluted with DCM and washed with water, saturated aqueous NaHCO3and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified with column chromatography on silica gel to afford the product as a white solid. General procedure S (for the synthesis of ureas): The corresponding aniline was dissolved in DCM, the appropriate isocyanate was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with MeOH and evaporated to dryness under reduced pressure. The residue was partitioned between DCM and water, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified with column chromatography on silica gel to afford the product as a white solid. General procedure T (for the alkylation of piperazines): To a solution of the corresponding piperazine trifluoroacetate derivative in THF were added TEA and tert-butyl bromoacetate or tert-butyl acrylate and the reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was evaporated to dryness, the residue was dissolved in DCM and washed with water and brine. The organic layer was dried over anhydrous Na2SO4and concentrated in vacuo. The crude product was purified with column chromatography on silica gel to afford the product as a white solid. Intermediate 1 tert-butyl 4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure A (Non-catalyzed method with Workup procedure B), using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 10.52 g, 37.9290 mmol), K2CO3(2.5 equiv., 13.11 g, 94.8226 mmol) and 3- chloro-6-(trifluoromethyl)pyridazine (1.1 equiv., 7.616 g, 41.7219 mmol). The reaction was performed in 230 mL of MeCN at 45 °C, yield: 15.74 g, 98%; Rf = 0.48 (30% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 7.79 (d, J = 9.2 Hz, 1H), 7.30 (d, J = 9.2 Hz, 1H), 7.27 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 4.26 (m, 2H), 2.81 (td, J = 13.0, 2.6 Hz, 2H), 2.68 (tt, J = 12.2, 3.6 Hz, 1H), 1.84 (m, 2H), 1.62 (qd, J = 12.7, 4.3 Hz, 2H), 1.49 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 167.2, 155.0, 151.2, 148.4 (q, J = 35.3 Hz), 143.8, 128.4, 127.3 (q, J = 1.8 Hz), 121.5 (q, J = 273.9 Hz), 121.3, 117.8, 79.6, 44.5, 42.4, 33.4, 28.6;19F NMR (CDCl3, 376 MHz) δ -66.39. MS (ESI) Found: [M+H]+= 424.2, calcd: [M+H]+= 424.2. Intermediate 2 tert-butyl 4-(4-((5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure A (Non-catalyzed method with Workup procedure A), using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 156 mg, 0.5624 mmol) in 1 mL of DMF, Cs2CO3 (3.0 equiv., 549.8 mg, 1.6873 mmol) and 2-chloro-5-trifluoromethyl-1,3,4-thiadiazole (1.5 equiv., 159.1 mg, 0.843 mmol). The crude was purified with column chromatography using 10% EtOAc / Petroleum Ether to afford the product (178 mg, 74%); Rf = 0.57 (20% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 7.31 – 7.25 (m, 4H), 4.26 (m, 2H), 2.81 (td, J = 13.1, 2.3 Hz, 2H), 2.69 (tt, J = 12.2, 3.6 Hz, 1H), 1.83 (m, 2H), 1.61 (qd, J = 12.7, 4.3 Hz, 2H), 1.48 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 177.8, 154.9, 153.9, 152.0 (q, J = 39.7 Hz), 145.2, 128.8, 119.9, 118.8 (q, J = 273.0 Hz), 79.7, 44.4, 42.3, 33.3, 28.6;19F NMR (CDCl3, 565 MHz) δ -60.29. HRMS (ESI) Found: [M-H]- = 428.1263, calcd: [M-H]- = 428.1261. Intermediate 3 tert-butyl 4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure A (Non-catalyzed method with Workup procedure A), using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 1.0 g, 3.605 mmol) in 12 mL of DMF, Cs2CO3 (2.0 equiv., 2.349 g, 7.211 mmol) and 2-(tert- butyl)-5-chloro-1,3,4-thiadiazole (1.2 equiv., 0.764 g, 4.326 mmol). The crude was purified by trituration with petroleum ether to afford the product (1.45 g, 96%); Rf = 0.52 (30% EtOAc / Petroleum Ether).1H NMR (CDCl3, 600 MHz) δ 7.25 – 7.17 (m, 4H), 4.23 (m, 2H), 2.78 (m, 2H), 2.65 (tt, J = 12.2, 3.5 Hz, 1H), 1.81 (m, 2H), 1.59 (qd, J = 12.6, 4.2 Hz, 2H), 1.47 (s, 9H), 1.41 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 175.6, 174.7, 154.9, 154.3, 143.9, 128.3, 119.8, 79.6, 44.4, 42.2, 36.9, 33.3, 30.7, 28.6. HRMS (ESI) Found: [M+Na]+= 440.1996, calcd: [M+Na]+= 440.1978. Intermediate 4 tert-butyl 4-(4-((5-propyl-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure A (Non-catalyzed method with Workup procedure A), using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 45 mg, 0.1622 mmol) in 1 mL of DMF, Cs2CO3(3.0 equiv., 158.6 mg, 0.4867 mmol) and 2-chloro-5-propyl-1,3,4-thiadiazole (1.5 equiv., 39.6 mg, 0.2434 mmol). The crude was purified with column chromatography using 10% EtOAc / Petroleum Ether to afford the product (60 mg, 92%); Rf1 = 0.14 (20% EtOAc / Petroleum Ether). H NMR (CDCl3, 400 MHz) δ 7.26 – 7.18 (m, 4H), 4.24 (m, 2H), 2.92 (t, J = 7.5 Hz, 2H), 2.79 (t, J = 12.6 Hz, 2H), 2.65 (tt, J = 12.1, 3.5 Hz, 1H), 1.86 – 1.70 (m, 4H), 1.58 (qd, J = 12.6, 4.2 Hz, 2H), 1.47 (s, 9H), 1.01 (t, J = 7.3 Hz, 3H);13C NMR (CDCl3, 100 MHz) δ 174.6, 166.1, 154.9, 154.2, 143.9, 128.3, 119.8, 79.6, 44.4, 42.2, 33.3, 33.1, 28.6, 23.1, 13.6. HRMS (ESI) Found: [M+H]+= 404.2017, calcd: [M+H]+= 404.2002. Intermediate 5 tert-butyl 4-(4-(4-(trifluoromethyl)phenoxy)phenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure A (Cu-catalyzed method), using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 200 mg, 0.7211 mmol) in 2 mL of DMSO, K3PO4(2.0 equiv., 306.1 mg, 1.4422 mmol), picolinic acid (0.2 equiv., 17.8 mg, 0.1442 mmol), CuI (0.1 equiv., 13.7 mg, 0.07211 mmol) and 1-iodo-4- trifluoromethylbenzene (1.5 equiv., 294.2 mg, 1.0816 mmol). The crude was purified with column chromatography using 10% EtOAc / Petroleum Ether to afford the product (194.7 mg, 64%); Rf = 0.60 (15% EtOAc / Petroleum Ether).1H NMR (CDCl3, 600 MHz) δ 7.56 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 4.26 (m, 2H), 2.81 (td, J = 13.0, 2.5 Hz, 2H), 2.66 (tt, J = 12.2, 3.6 Hz, 1H), 1.84 (m, 2H), 1.61 (qd, J = 12.7, 4.3 Hz, 2H), 1.49 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 160.8, 155.0, 154.1, 142.2, 128.4, 127.2 (q, J = 3.7 Hz), 124.9 (q, J = 32.6 Hz), 124.4 (q, J = 271.5 Hz), 120.1, 117.8, 79.7, 44.5, 42.3, 33.5, 28.6;19F NMR (CDCl3, 565 MHz) δ -61.73. MS (ESI) Found: [M+H]+= 422.2, calcd: [M+H]+= 422.2. Intermediate 6 tert-butyl 4-(4-(pyridin-2-yloxy)phenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure A (Cu-catalyzed method) using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 150 mg, 0.5408 mmol) in 1.5 mL of DMSO, K3PO4 (2.0 equiv., 229.6 mg, 1.0816 mmol), picolinic acid (0.2 equiv., 13.3 mg, 0.1082 mmol), CuI (0.1 equiv., 10.3 mg, 0.05408 mmol) and 3-iodopyridine (1.5 equiv., 166.3 mg, 0.8112 mmol). The crude was purified with column chromatography using 35% EtOAc / Petroleum Ether to afford the product (147.5 mg, 77%); Rf= 0.16 (25% EtOAc / Petroleum Ether).1H NMR (CDCl3, 600 MHz) δ 8.38 – 8.34 (m, 2H), 7.43 (m, 1H), 7.38 (m, 1H), 7.22 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 8.2 Hz, 2H), 4.25 (m, 2H), 2.81 (m, 2H), 2.66 (tt, J = 12.2, 3.6 Hz, 1H), 1.83 (m, 2H), 1.61 (qd, J = 10.5, 8.5, 4.9 Hz, 2H), 1.48 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 155.0, 154.0, 142.5, 138.9, 136.0, 132.8, 128.6, 127.0, 124.9, 119.5, 79.7, 44.4, 42.2, 33.4, 28.6. MS (ESI) Found: [M+H]+= 355.2, calcd: [M+H]+= 355.2. Intermediate 7 tert-butyl 4-(4-(pyridin-3-yloxy)phenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure A (Cu-catalyzed method), using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 150 mg, 0.5408 mmol) in 1.5 mL of DMSO, K3PO4 (2.0 equiv., 229.6 mg, 1.0816 mmol), picolinic acid (0.2 equiv., 13.3 mg, 0.1082 mmol), CuI (0.1 equiv., 10.3 mg, 0.05408 mmol) and 2-bromopyridine (1.5 equiv., 128.2 mg, 0.8112 mmol). The crude was purified with column chromatography using 25% EtOAc / Petroleum Ether to afford the product (154.9 mg, 81%); Rf = 0.36 (25% EtOAc / Petroleum Ether).1H NMR (CDCl3, 600 MHz) δ 8.20 (m, 1H), 7.68 (m, 1H), 7.22 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 8.3 Hz, 2H), 6.98 (m, 1H), 6.90 (m, 1H), 4.24 (m, 2H), 2.80 (m, 2H), 2.65 (tt, J = 12.2, 3.6 Hz, 1H), 1.84 (m, 2H), 1.61 (qd, J = 12.4, 4.6 Hz, 2H), 1.48 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 163.9, 155.0, 152.6, 147.8, 142.2, 139.6, 128.1, 121.2, 118.5, 111.7, 79.6, 44.5, 42.3, 33.4, 28.6. MS (ESI) Found: [M+H]+= 355.2, calcd: [M+H]+= 355.2. Intermediate 8 tert-butyl 4-(4-phenoxyphenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure A (Cu-catalyzed method), using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 150 mg, 0.5408 mmol) in 1.5 mL of DMSO, K3PO4 (2.0 equiv., 229.6 mg, 1.0816 mmol), picolinic acid (0.2 equiv., 13.3 mg, 0.1082 mmol), CuI (0.1 equiv., 10.3 mg, 0.05408 mmol) and iodobenzene (1.5 equiv., 165.5 mg, 0.8112 mmol). The crude was purified with column chromatography using 10% EtOAc / Petroleum Ether to afford the product (183.8 mg, 96%); Rf= 0.65 (15% EtOAc / Petroleum Ether).1H NMR (CDCl3, 600 MHz) δ 7.32 (t, J = 7.9 Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H), 7.09 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 8.1 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 4.24 (m, 2H), 2.80 (td, J = 13.4, 2.6 Hz, 2H), 2.63 (tt, J = 12.2, 3.7 Hz, 1H), 1.88 – 1.79 (m, 2H), 1.60 (qd, J = 12.8, 4.4 Hz, 2H), 1.48 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 157.6, 155.7, 155.0, 140.9, 129.8, 128.1, 123.2, 119.1, 118.9, 79.6, 44.5, 42.2, 33.5, 28.6. MS (ESI) Found: [M+H]+= 354.2, calcd: [M+H]+= 354.2. Intermediate 9 tert-butyl 4-(4-((5-methylpyridin-2-yl)oxy)phenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure A (Cu-catalyzed method), using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 150 mg, 0.5408 mmol) in 1.5 mL of DMSO, K3PO4 (2.0 equiv., 229.6 mg, 1.0816 mmol), picolinic acid (0.2 equiv., 13.3 mg, 0.1082 mmol), CuI (0.1 equiv., 10.3 mg, 0.05408 mmol) and 2-bromo-5- methylpyridine (1.5 equiv., 139.6 mg, 0.8112 mmol). The crude was purified with column chromatography using 15% EtOAc / Petroleum Ether to afford the product (114.3 mg, 57%); Rf = 0.50 (15% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 8.02 (m, 1H), 7.49 (dd, J = 8.4, 2.5 Hz, 1H), 7.20 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.4 Hz, 1H), 4.24 (m, 2H), 2.79 (m, 2H), 2.64 (tt, J = 12.2, 3.6 Hz, 1H), 2.28 (s, 3H), 1.83 (d, J = 13.1 Hz, 2H), 1.60 (qd, J = 12.5, 4.2 Hz, 2H), 1.48 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 162.0, 155.0, 153.0, 147.3, 141.9, 140.6, 128.1, 127.9, 120.9, 111.3, 79.6, 44.6, 42.3, 33.4, 28.6, 17.6. MS (ESI) Found: [M+H]+= 369.2, calcd: [M+H]+= 369.2. Intermediate 10 tert-butyl 4-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure A (Non-catalyzed method with Workup procedure A), using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 100 mg, 0.3605 mmol) in 0.8 mL of DMF, Cs2CO3 (2.5 equiv., 293.7 mg, 0.9014 mmol) and 2-chloro-5-(trifluoromethyl)pyridine (1.1 equiv., 72.0 mg, 0.3966 mmol). The crude was purified with column chromatography using 1% EtOAc / DCM to afford the product (145 mg, 98%); Rf = 0.27 (1% EtOAc / DCM).1H NMR (CDCl3, 400 MHz) δ 8.45 (m, 1H), 7.89 (dd, J = 8.7, 2.5 Hz, 1H), 7.26 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 7.00 (d, J = 8.7 Hz, 1H), 4.25 (m, 2H), 2.81 (td, J = 13.0, 2.6 Hz, 2H), 2.68 (tt, J = 12.3, 3.6 Hz, 1H), 1.86 (m, 2H), 1.62 (qd, J = 12.7, 4.3 Hz, 2H), 1.49 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 166.0, 155.0, 151.6, 145.7 (q, J = 4.4 Hz), 143.1, 136.8 (q, J = 3.3 Hz), 128.3, 123.8 (q, J = 271.5 Hz), 121.6 (q, J = 33.2 Hz), 121.5, 111.5, 79.6, 44.3, 42.3, 33.4, 28.6;19F NMR (CDCl3, 376 MHz) δ -61.66. MS (ESI) Found: [M+H]+= 423.2, calcd: [M+H]+= 423.2. Intermediate 11 tert-butyl 4-(4-(pyrazin-2-yloxy)phenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure A (Cu-catalyzed method), using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 150 mg, 0.5408 mmol) in 1.5 mL of DMSO, K3PO4(2.0 equiv., 229.6 mg, 1.0816 mmol), picolinic acid (0.2 equiv., 13.3 mg, 0.1082 mmol), CuI (0.1 equiv., 10.3 mg, 0.05408 mmol) and 2-bromopyrazine (1.5 equiv., 129.0 mg, 0.8112 mmol). The crude was purified with column chromatography using 32% EtOAc / Petroleum Ether to afford the product (140.4 mg, 73%); Rf = 0.17 (25% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 8.42 (s, 1H), 8.25 (d, J = 2.6 Hz, 1H), 8.11 (dd, J = 2.6, 1.4 Hz, 1H), 7.26 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.5 Hz, 2H), 4.25 (d, J = 13.2 Hz, 2H), 2.80 (td, J = 12.9, 2.6 Hz, 2H), 2.67 (tt, J = 12.2, 3.7 Hz, 1H), 1.84 (m, 2H), 1.62 (qd, J = 12.7, 4.4 Hz, 2H), 1.48 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 160.4, 155.0, 151.4, 143.1, 141.3, 138.5, 136.0, 128.3, 121.3, 79.6, 44.5, 42.3, 33.4, 28.6. MS (ESI) Found: [M+H]+= 356.2, calcd: [M+H]+= 356.2. Intermediate 12 tert-butyl 4-(4-(pyrimidin-2-yloxy)phenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure A (Cu-catalyzed method), using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 150 mg, 0.5408 mmol) in 1.5 mL of DMSO, K3PO4(2.0 equiv., 229.6 mg, 1.0816 mmol), picolinic acid (0.2 equiv., 13.3 mg, 0.1082 mmol), CuI (0.1 equiv., 10.3 mg, 0.05408 mmol) and 2-bromopyrimidine (1.5 equiv., 129.0 mg, 0.8112 mmol). The crude was purified with column chromatography using 48% EtOAc / Petroleum Ether to afford the product (159.8 mg, 83%); Rf = 0.12 (25% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 8.57 (d, J = 4.8 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 7.03 (t, J = 4.8 Hz, 1H), 4.24 (m, 2H), 2.80 (td, J = 12.9, 2.6 Hz, 2H), 2.67 (tt, J = 12.3, 3.7 Hz, 1H), 1.86 (m, 2H), 1.62 (qd, J = 12.7, 4.3 Hz, 2H), 1.48 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 165.6, 159.9, 155.0, 151.3, 143.0, 128.1, 121.7, 116.2, 79.6, 44.5, 42.3, 33.4, 28.6. MS (ESI) Found: [M+H]+= 356.2, calcd: [M+H]+= 356.2. Intermediate 13 tert-butyl 4-(4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure A (Cu-catalyzed method), using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 150 mg, 0.5408 mmol) in 1.5 mL of DMSO, K3PO4(2.0 equiv., 229.6 mg, 1.0816 mmol), picolinic acid (0.2 equiv., 13.3 mg, 0.1082 mmol), CuI (0.1 equiv., 10.3 mg, 0.05408 mmol) and 5-bromo- 2-(trifluoromethyl)pyrimidine (1.5 equiv., 184.1 mg, 0.8112 mmol). The crude was purified with column chromatography using 20% EtOAc / Petroleum Ether to afford the product (194.7 mg, 85%); Rf = 0.70 (25% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 8.53 (s, 2H), 7.28 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 4.27 (m, 2H), 2.82 (td, J = 12.8, 2.6 Hz, 2H), 2.69 (tt, J = 12.2, 3.6 Hz, 1H), 1.84 (m, 2H), 1.62 (qd, J = 12.7, 4.3 Hz, 2H), 1.49 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 155.0, 154.1, 152.5, 150.5 (q, J = 37.5 Hz), 146.6, 144.0, 129.0, 120.0, 119.7 (q, J = 273.9 Hz), 79.7, 44.4, 42.3, 33.4, 28.6;19F NMR (CDCl3, 376 MHz) δ -69.29. MS (ESI) Found: [M+H]+= 424.2, calcd: [M+H]+= 424.2. Intermediate 14 tert-butyl 4-(4-((5-methylpyrimidin-2-yl)oxy)phenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure A (Cu-catalyzed method), using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 150 mg, 0.5408 mmol) in 1.5 mL of DMSO, K3PO4(2.0 equiv., 229.6 mg, 1.0816 mmol), picolinic acid (0.2 equiv., 13.3 mg, 0.1082 mmol), CuI (0.1 equiv., 10.3 mg, 0.05408 mmol) and 2-chloro-5- methylpyrimidine (1.5 equiv., 104.3 mg, 0.8112 mmol). The crude was purified with column chromatography using 40% EtOAc / Petroleum Ether to afford the product (164.4 mg, 82%); Rf = 0.17 (25% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 8.37 (s, 2H), 7.24 (d, J = 8.6 Hz, 2H), 7.12 (d, J = 8.6 Hz, 2H), 4.25 (m, 2H), 2.80 (td, J = 13.1, 2.5 Hz, 2H), 2.66 (tt, J = 12.2, 3.6 Hz, 1H), 2.26 (s, 3H), 1.85 (m, 2H), 1.62 (qd, J = 12.7, 4.3 Hz, 2H), 1.48 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 164.0, 159.7, 155.0, 151.6, 142.8, 128.1, 125.3, 121.5, 79.6, 44.5, 42.3, 33.4, 28.6, 14.8. MS (ESI) Found: [M+H]+= 370.2, calcd: [M+H]+= 370.2. Intermediate 15 tert-butyl 4-(4-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)phenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure A (Cu-catalyzed method), using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 150 mg, 0.5408 mmol) in 1.5 mL of DMSO, K3PO4(2.0 equiv., 229.6 mg, 1.0816 mmol), picolinic acid (0.2 equiv., 13.3 mg, 0.1082 mmol), CuI (0.1 equiv., 10.3 mg, 0.05408 mmol) and 2-chloro- 5-(trifluoromethyl)pyrimidine (1.5 equiv., 148.1 mg, 0.8112 mmol). The crude was purified with column chromatography using 15% EtOAc / Petroleum Ether to afford the product (196.1 mg, 86%); Rf = 0.61 (25% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 8.80 (s, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 4.26 (m, 2H), 2.81 (m, 2H), 2.70 (m, 1H), 1.87 (m, 2H), 1.62 (m, 2H), 1.49 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 167.1, 157.7 (q, J = 3.3 Hz), 155.0, 150.8, 143.8, 128.3, 123.6 (q, J = 276.6 Hz), 121.5, 120.4 (q, J = 34.2 Hz), 79.7, 44.5, 42.3, 33.4, 28.6;19F NMR (CDCl3, 376 MHz) δ -61.54. MS (ESI) Found: [M+H]+= 424.2, calcd: [M+H]+= 424.2. Intermediate 16 tert-butyl 4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure A (Cu-catalyzed method), using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 150 mg, 0.5408 mmol) in 1.5 mL of DMSO, K3PO4(2.0 equiv., 229.6 mg, 1.0816 mmol), picolinic acid (0.2 equiv., 13.3 mg, 0.1082 mmol), CuI (0.1 equiv., 10.3 mg, 0.05408 mmol) and 5-iodo-2- (trifluoromethyl)pyridine (1.5 equiv., 221.5 mg, 0.8112 mmol). The crude was purified with column chromatography using 17% EtOAc / Petroleum Ether to afford the product (181.5 mg, 79%); Rf = 0.68 (25% EtOAc / Petroleum Ether).1H NMR (CDCl3, 600 MHz) δ 8.45 (d, J = 2.7 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.32 (dd, J = 8.7, 2.7 Hz, 1H), 7.25 (d, J = 8.6 Hz, 2H), 7.02 (d, J = 8.6 Hz, 2H), 4.26 (m, 2H), 2.81 (td, J = 13.0, 2.5 Hz, 2H), 2.67 (tt, J = 12.3, 3.6 Hz, 1H), 1.84 (m, 2H), 1.61 (qd, J = 12.7, 4.3 Hz, 2H), 1.49 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 156.7, 155.0, 153.3, 143.2, 142.0 (q, J = 35.1 Hz), 140.8, 128.7, 124.4, 121.7 (q, J = 273.3 Hz), 121.6 (q, J = 2.8 Hz), 120.1, 79.7, 44.5, 42.3, 33.4, 28.6;19F NMR (CDCl3, 565 MHz) δ -67.00. MS (ESI) Found: [M+H]+= 423.2, calcd: [M+H]+= 423.2. Intermediate 17 tert-butyl 4-(4-(pyrimidin-5-yloxy)phenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure A (Cu-catalyzed method), using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 150 mg, 0.5408 mmol) in 1.5 mL of DMSO, K3PO4 (2.0 equiv., 229.6 mg, 1.0816 mmol), picolinic acid (0.2 equiv., 13.3 mg, 0.1082 mmol), CuI (0.1 equiv., 10.3 mg, 0.05408 mmol) and 5-iodopyrimidine (1.5 equiv., 167.1 mg, 0.8112 mmol). The crude was purified with column chromatography using 55% EtOAc / Petroleum Ether to afford the product (120.9 mg, 63%); Rf = 0.14 (25% EtOAc / Petroleum Ether).1H NMR (CDCl3, 600 MHz) δ 8.96 (s, 1H), 8.47 (s, 2H), 7.24 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 4.26 (m, 2H), 2.81 (m, 2H), 2.67 (tt, J = 12.3, 3.6 Hz, 1H), 1.83 (m, 2H), 1.61 (qd, J = 12.7, 4.3 Hz, 2H), 1.48 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 155.0, 153.5, 152.8, 152.7, 146.8, 143.1, 128.8, 119.5, 79.7, 44.5, 42.3, 33.4, 28.6. MS (ESI) Found: [M+H]+= 356.2, calcd: [M+H]+= 356.2. Intermediate 18 tert-butyl 4-(4-((5-methylpyrazin-2-yl)oxy)phenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure A (Cu-catalyzed method), using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 150 mg, 0.5408 mmol) in 1.5 mL of DMSO, K3PO4 (2.0 equiv., 229.6 mg, 1.0816 mmol), picolinic acid (0.2 equiv., 13.3 mg, 0.1082 mmol), CuI (0.1 equiv., 10.3 mg, 0.05408 mmol) and 2-bromo-5- methylpyrazine (1.5 equiv., 140.4 mg, 0.8112 mmol). The crude was purified with column chromatography using 34% EtOAc / Petroleum Ether to afford the product (161.8 mg, 81%); Rf = 0.27 (25% EtOAc / Petroleum Ether).1H NMR (CDCl3, 600 MHz) δ 8.30 (s, 1H), 7.98 (s, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.07 (d, J = 8.5 Hz, 2H), 4.25 (m, 2H), 2.80 (m, 2H), 2.66 (tt, J = 12.2, 3.6 Hz, 1H), 2.51 (s, 3H), 1.84 (m, 2H), 1.61 (qd, J = 12.7, 4.7 Hz, 2H), 1.48 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 158.715 151.9, 147.1, 142.8, 140.7, 134.1, 128.2, 121.0, 79.6, 44.5, 42.3, 33.4, 28.6, 20.3. MS (ESI) Found: [M+H]+= 370.2, calcd: [M+H]+= 370.2. Intermediate 19 tert-butyl 4-(4-((3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl)oxy)phenyl)piperidine-1-carboxylate 3 The title compound was prepared according to General procedure A (Non-catalyzed method with Workup procedure A), using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 150 mg, 0.5408 mmol) in 2 mL of DMF, Cs2CO3 (2.0 equiv., 352.4 mg, 1.0816 mmol) and 5-chloro-3-(trifluoromethyl)-1,2,4-thiadiazole (1.5 equiv., 153.0 mg, 0.8112 mmol). The crude was purified with column chromatography using 19% EtOAc / Petroleum Ether to afford the product (144.7 mg, 62%); Rf = 0.64 (25% EtOAc / Petroleum Ether). 1H NMR (CDCl3, 600 MHz) δ 7.33 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 4.27 (m, 2H), 2.82 (td, J = 13.0, 2.5 Hz, 2H), 2.71 (tt, J = 12.2, 3.6 Hz, 1H), 1.85 (m, 2H), 1.62 (qd, J = 12.3, 3.9 Hz, 2H), 1.49 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 194.0, 159.2 (q, J = 39.1 Hz), 154.9, 153.4, 145.9, 129.1, 120.0, 117.7 (q, J = 273.9 Hz), 79.8, 44.4, 42.4, 33.3, 28.6;19F NMR (CDCl3, 565 MHz) δ -67.38. MS (ESI) Found: [M+H]+= 430.1, calcd: [M+H]+= 430.1. Intermediate 20 tert-butyl 4-(4-((5-(trifluoromethyl)pyrazin-2-yl)oxy)phenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure A (Cu-catalyzed method), using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 150 mg, 0.5408 mmol) in 1.5 mL of DMSO, K3PO4 (2.0 equiv., 229.6 mg, 1.0816 mmol), picolinic acid (0.2 equiv., 13.3 mg, 0.1082 mmol), CuI (0.1 equiv., 10.3 mg, 0.05408 mmol) and 5-bromo- 2-(trifluoromethyl)pyrazine (1.5 equiv., 184.1 mg, 0.8112 mmol). The crude was purified with column chromatography using 16% EtOAc / Petroleum Ether to afford the product (207.6 mg, 91%); Rf = 0.71 (25% EtOAc / Petroleum Ether).1H NMR (CDCl3, 600 MHz) δ 8.48 (s, 1H), 8.44 (s, 1H), 7.29 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H), 4.26 (m, 2H), 2.81 (td, J = 13.0, 2.5 Hz, 2H), 2.69 (tt, J = 12.2, 3.6 Hz, 1H), 1.86 (m, 2H), 1.63 (qd, J = 12.9, 4.5 Hz, 2H), 1.49 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 161.6, 155.0, 150.6, 143.9, 139.1 (q, J = 3.4 Hz), 137.7 (q, J = 35.7 Hz), 135.9, 128.4, 121.6 (q, J = 272.9 Hz), 121.4, 79.7, 44.5, 42.3, 33.4, 28.6;19F NMR (CDCl3, 565 MHz) δ -66.80. MS (ESI) Found: [M+H]+= 424.2, calcd: [M+H]+= 424.2. Intermediate 21 4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 1 (1.0 equiv., 16.301 g, 38.4966 mmol), 240 mL 1,4-dioxane and 140 mL 4M HCl in dioxane. Yield: 13.741 g, 99%; Rf= 0.21 (20:3:3:2 = EtOAc / MeOH / AcOH / H2O).1H NMR (D2O, 400 MHz) δ 8.16 (d, J = 9.3 Hz, 1H), 7.62 (d, J = 9.3 Hz, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H), 3.57 (m, 2H), 3.18 (td, J = 13.1, 3.0 Hz, 2H), 3.01 (tt, J = 12.2, 3.6 Hz, 1H), 2.15 (m, 2H), 1.93 (qd, J = 13.9, 4.0 Hz, 2H);13C NMR (D2O, 100 MHz) δ 167.7, 151.1, 148.0 (q, J = 35.5 Hz), 142.5, 129.4 (q, J = 2.2 Hz), 128.6, 121.3, 121.1 (q, J = 273.4 Hz), 120.1, 44.3, 38.7, 29.4;19F NMR (D2O, 376 MHz) δ -66.46. MS (ESI) Found: [M-HCl+H]+= 324.1, calcd: [M-HCl+H]+= 324.1. Intermediate 22 4-(4-((5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 2 (1.0 equiv., 64 mg, 0.1490 mmol), 1 mL 1,4-dioxane and 500 µL 4M HCl in dioxane. Yield: 54 mg, 99%. Rf= 0.12 (10% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 7.46 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 3.52 (m, 2H), 3.17 (td, J = 13.0, 3.1 Hz, 2H), 3.01 (tt, J = 12.2, 3.6 Hz, 1H), 2.11 (m, 2H), 1.94 (qd, J = 13.1, 4.0 Hz, 2H);13C NMR (MeOD, 100 MHz) δ 179.8, 155.8, 153.1 (q, J = 39.4 Hz), 145.0, 129.9, 121.4, 120.3 (q, J = 271.8 Hz), 45.6, 40.5, 31.1;19F NMR (MeOD, 376 MHz) δ -62.15. MS (ESI) Found: [M-HCl+H]+= 330.1, calcd: [M- HCl+H]+= 330.1. Intermediate 23 4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 3 (1.0 equiv., 1.45 g, 3.472 mmol), 20 mL 1,4-dioxane and 15 mL 4M HCl in dioxane. Yield: 0.934 g, 76%; Rf = 0.22 (20:3:3:2 = EtOAc / MeOH / AcOH / H2O).1H NMR (MeOD, 400 MHz) δ 7.41 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H), 3.52 (m, 2H), 3.16 (td, J = 13.0, 2.8 Hz, 2H), 2.98 (tt, J = 12.2, 3.5 Hz, 1H), 2.11 (m, 2H), 1.93 (qd, J = 14.2, 13.6, 4.0 Hz, 2H), 1.42 (s, 9H);13C NMR (MeOD, 100 MHz) δ 177.8, 176.6, 156.1, 144.0, 129.6, 121.2, 45.6, 40.5, 37.9, 31.1, 30.8. MS (ESI) Found: [M-HCl+H]+= 318.2, calcd: [M-HCl+H]+= 318.2. Intermediate 24 4-(4-((5-propyl-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 4 (1.0 equiv., 29 mg, 0.07186 mmol), 1 mL 1,4-dioxane and 500 µL 4M HCl in dioxane. Yield: 24 mg, 99%. Rf= 0.21 (20:3:3:2 = EtOAc / MeOH / AcOH / H2O).1H NMR (MeOD, 400 MHz) δ 7.40 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H), 3.51 (m, 2H), 3.16 (m, 2H), 2.98 (tt, J = 12.1, 3.6 Hz, 1H), 2.96 (t, J = 7.5 Hz, 2H), 2.11 (m, 2H), 1.92 (qd, J = 13.2, 4.0 Hz, 2H), 1.78 (h, J = 7.4 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H). MS (ESI) Found: [M-HCl+H]+= 304.1, calcd: [M-HCl+H]+= 304.1. Intermediate 25 4-(4-(4-(trifluoromethyl)phenoxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 5 (1.0 equiv., 100 mg, 0.2373 mmol), 1.5 mL 1,4-dioxane and 2 mL 4M HCl in dioxane. Yield: 84.0 mg, 99%. Rf= 0.20 (10% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 7.62 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 6.3 Hz, 2H), 7.04 (d, J = 6.3 Hz, 2H), 3.52 (dq, J = 12.8, 2.3, 1.8 Hz, 2H), 3.17 (td, J = 13.0, 3.2 Hz, 2H), 2.96 (tt, J = 12.2, 3.8 Hz, 1H), 2.13 – 2.04 (m, 2H), 1.97 (qd, J = 13.5, 13.1, 3.9 Hz, 2H);13C NMR (MeOD, 100 MHz) δ 162.3, 155.8, 142.0, 129.5, 128.2 (q, J = 3.8 Hz), 125.7 (q, J = 270.6 Hz), 125.7 (q, J = 32.6 Hz), 121.3, 118.8, 45.6, 40.4, 31.2;19F NMR (MeOD, 376 MHz) δ -63.27. MS (ESI) Found: [M-HCl+H]+= 322.1, calcd: [M-HCl+H]+= 322.1. Intermediate 26 4-(4-(pyridin-2-yloxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 6 (1.0 equiv., 100 mg, 0.2821 mmol), 1.5 mL 1,4-dioxane and 2 mL 4M HCl in dioxane. Yield: 81.3 mg, 99%. Rf = 0.09 (10% MeOH / DCM).1H NMR (MeOD, 600 MHz) δ 8.64 (d, J = 2.8 Hz, 1H), 8.60 (m, 1H), 8.19 (m, 1H), 8.05 (m, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H), 3.53 (m, 2H), 3.18 (m, 2H), 3.01 (tt, J = 12.3, 3.8 Hz, 1H), 2.11 (m, 2H), 1.99 (m, 2H);13C NMR (MeOD, 151 MHz) δ 158.9, 154.1, 144.0, 137.0, 135.4, 133.1, 130.3, 129.8, 121.6, 45.6, 40.5, 31.1. MS (ESI) Found: [M-HCl+H]+= 255.1, calcd: [M-HCl+H]+= 255.1. Intermediate 27 4-(4-(pyridin-3-yloxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 7 (1.0 equiv., 100 mg, 0.2821 mmol), 1.5 mL 1,4-dioxane and 2 mL 4M HCl in dioxane. Yield: 80.8 mg, 99%. Rf= 0.08 (10% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.58 (m, 1H), 8.50 (ddd, J = 9.1, 7.4, 1.8 Hz, 1H), 7.68 (ddd, J = 7.2, 6.0, 1.0 Hz, 1H), 7.56 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.9 Hz, 1H), 3.55 (m, 2H), 3.22 (td, J = 12.4, 4.2 Hz, 2H), 3.12 – 3.03 (m, 1H), 2.15 – 1.97 (m, 4H);13C NMR (MeOD, 100 MHz) δ 161.4, 151.6, 150.7, 145.6, 140.8, 130.6, 122.1, 121.3, 113.7, 45.4, 40.4, 30.9. MS (ESI) Found: [M-HCl+H]+= 255.1, calcd: [M-HCl+H]+= 255.1. Intermediate 28 4-(4-phenoxyphenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 8 (1.0 equiv., 100 mg, 0.2829 mmol), 1.5 mL 1,4-dioxane and 2 mL 4M HCl in dioxane. Yield: 81.0 mg, 99%. Rf= 0.13 (10% MeOH / DCM).1H NMR (MeOD, 600 MHz) δ 7.34 (m, 2H), 7.27 (d, J = 8.6 Hz, 2H), 7.10 (tt, J = 7.4, 1.1 Hz, 1H), 6.98 – 6.93 (m, 4H), 3.50 (m, 2H), 3.14 (td, J = 13.1, 3.0 Hz, 2H), 2.91 (tt, J = 12.3, 3.6 Hz, 1H), 2.08 (m, 2H), 1.90 (qd, J = 13.7, 4.0 Hz, 2H);13C NMR (MeOD, 151 MHz) δ 158.8, 157.6, 140.4, 130.9, 129.1, 124.4, 120.1, 119.7, 45.7, 40.4, 31.3. MS (ESI) Found: [M-HCl+H]+= 254.2, calcd: [M-HCl+H]+= 254.2. Intermediate 29 4-(4-((5-methylpyridin-2-yl)oxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 9 (1.0 equiv., 100 mg, 0.2714 mmol), 1.5 mL 1,4-dioxane and 2 mL 4M HCl in dioxane. Yield: 82.4 mg, 99%. Rf = 0.09 (10% MeOH / DCM).1H NMR (MeOD, 600 MHz) δ 8.30 (s, 1H), 8.19 (m, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 9.0 Hz, 1H), 3.53 (m, 2H), 3.18 (td, J = 13.0, 2.9 Hz, 2H), 3.02 (tt, J = 12.2, 3.7 Hz, 1H), 2.44 (s, 3H), 2.12 (m, 2H), 1.97 (qd, J = 13.4, 3.9 Hz, 2H);13C NMR (MeOD, 151 MHz) δ 160.3, 152.5, 150.2, 144.8, 140.7, 132.2, 130.3, 122.1, 113.1, 45.6, 40.5, 31.1, 17.2. MS (ESI) Found: [MHCl+H]+= 269.2, calcd: [M-HCl+H]+= 269.2. Intermediate 30 4-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 10 (1.0 equiv., 100 mg, 0.2367 mmol), 1.5 mL 1,4-dioxane and 2 mL 4M HCl in dioxane. Yield: 84.8 mg, 99%. Rf= 0.12 (10% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.41 (m, 1H), 8.09 (dd, J = 8.7, 2.6 Hz, 1H), 7.37 (d, J = 8.6 Hz, 2H), 7.17 – 7.10 (m, 3H), 3.52 (m, 2H), 3.17 (td, J = 13.0, 3.1 Hz, 2H), 2.97 (tt, J = 12.2, 3.7 Hz, 1H), 2.11 (m, 2H), 1.95 (m, 2H);13C NMR (MeOD, 100 MHz) δ 167.4, 153.5, 146.2 (q, J = 4.4 Hz), 142.7, 138.5 (q, J = 3.2 Hz), 129.1, 125.3 (q, J = 270.5 Hz), 122.9, 122.8 (q, J = 33.1 Hz), 112.8, 45.6, 40.5, 31.2;19F NMR (MeOD, 376 MHz) δ -63.20. MS (ESI) Found: [M-HCl+H]+= 323.1, calcd: [M-HCl+H]+= 323.1. Intermediate 31 4-(4-(pyrazin-2-yloxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 11 (1.0 equiv., 100 mg, 0.2813 mmol), 1.5 mL 1,4-dioxane and 2 mL 4M HCl in dioxane. Yield: 81.4 mg, 99%. Rf= 0.11 (10% MeOH / DCM).1H NMR (MeOD, 600 MHz) δ 8.46 (d, J = 1.0 Hz, 1H), 8.31 (d, J = 2.8 Hz, 1H), 8.21 (q, J = 2.8, 1.0 Hz, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 3.52 (m, 2H), 3.17 (m, 2H), 2.97 (tt, J = 12.3, 3.7 Hz, 1H), 2.11 (m, 2H), 1.95 (qd, J = 13.6, 4.0 Hz, 2H);13C NMR (MeOD, 151 MHz) δ 162.1, 153.3, 143.2, 142.8, 138.5, 135.9, 129.1, 122.6, 45.6, 40.5, 31.2. MS (ESI) Found: [M-HCl+H]+= 256.1, calcd: [M-HCl+H]+= 256.1. Intermediate 32 4-(4-(pyrimidin-2-yloxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 12 (1.0 equiv., 100 mg, 0.2813 mmol), 1.5 mL 1,4-dioxane and 2 mL 4M HCl in dioxane. Yield: 81.5 mg, 99%. Rf = 0.16 (10% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.66 (d, J = 4.9 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 7.30 (t, J = 4.9 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 3.51 (m, 2H), 3.17 (td, J = 13.1, 3.0 Hz, 2H), 2.98 (tt, J = 12.2, 3.7 Hz, 1H), 2.11 (m, 2H), 1.96 (m, 2H); 13C NMR (MeOD, 100 MHz) δ 165.4, 161.1, 152.9, 143.1, 129.1, 122.9, 117.9, 45.6, 40.5, 31.2. MS (ESI) Found: [M-HCl+H]+= 256.1, calcd: [M-HCl+H]+= 256.1. Intermediate 33 4-(4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 13 (1.0 equiv., 100 mg, 0.2362 mmol), 1.5 mL 1,4-dioxane and 2 mL 4M HCl in dioxane. Yield: 84.5 mg, 99%. Rf= 0.16 (10% MeOH / DCM).1H NMR (MeOD, 600 MHz) δ 8.60 (s, 1H), 7.43 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H), 3.52 (m, 2H), 3.17 (td, J = 13.2, 2.9 Hz, 2H), 2.99 (tt, J = 12.3, 3.7 Hz, 1H), 2.12 (m, 2H), 1.94 (qd, J = 13.2, 3.9 Hz, 2H);13C NMR (MeOD, 151 MHz) δ 155.7, 154.5, 151.2 (q, J = 37.3 Hz), 147.9, 143.4, 130.0, 121.3, 121.1 (q, J = 273.6 Hz), 45.6, 40.5, 31.1;19F NMR (MeOD, 376 MHz) δ -70.84. MS (ESI) Found: [M-HCl+H]+= 324.1, calcd: [M-HCl+H]+= 324.1. Intermediate 34 4-(4-((5-methylpyrimidin-2-yl)oxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 14 (1.0 equiv., 100 mg, 0.2707 mmol), 1.5 mL 1,4-dioxane and 2 mL 4M HCl in dioxane. Yield: 82.1 mg, 99%. Rf= 0.12 (10% MeOH / DCM).1H NMR (MeOD, 600 MHz) δ 8.56 (s, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 3.52 (dt, J = 12.3, 2.8 Hz, 2H), 3.17 (td, J = 13.2, 2.9 Hz, 2H), 2.98 (tt, J = 12.2, 3.6 Hz, 1H), 2.33 (s, 3H), 2.14 – 2.08 (m, 2H), 1.96 (qd, J = 13.5, 4.1 Hz, 2H);13C NMR (MeOD, 151 MHz) δ 163.3, 160.7, 152.9, 143.1, 129.1, 128.0, 122.7, 45.6, 40.5, 31.2, 14.5. MS (ESI) Found: [M-HCl+H]+= 270.2, calcd: [M-HCl+H]+= 270.2. Intermediate 35 4-(4-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 15 (1.0 equiv., 100 mg, 0.2362 mmol), 1.5 mL 1,4-dioxane and 2 mL 4M HCl in dioxane. Yield: 84.5 mg, 99%. Rf = 0.10 (10% MeOH / DCM).1H NMR (MeOD, 600 MHz) δ 8.91 (m, 1H), 7.37 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 3.52 (m, 2H), 3.17 (td, J = 13.3, 3.3 Hz, 2H), 2.98 (tt, J = 12.3, 3.7 Hz, 1H), 2.12 (m, 2H), 1.94 (qd, J = 13.5, 3.8 Hz, 2H);13C NMR (MeOD, 151 MHz) δ 168.3, 159.0 (q, J = 3.6 Hz), 152.8, 143.2, 129.0, 124.6 (q, J = 270.7 Hz), 122.9, 121.4 (q, J = 34.5 Hz), 45.6, 40.5, 31.2;19F NMR (MeOD, 376 MHz) δ -63.10. MS (ESI) Found: [M-HCl+H]+= 324.1, calcd: [M-HCl+H]+= 324.1. Intermediate 36 4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 16 (1.0 equiv., 100 mg, 0.2367 mmol), 1.5 mL 1,4-dioxane and 2 mL 4M HCl in dioxane. Yield: 84.3 mg, 99%. Rf= 0.12 (10% MeOH / DCM).1H NMR (MeOD, 600 MHz) δ 8.39 (d, J = 2.8 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.49 (dd, J = 8.7, 2.8 Hz, 1H), 7.40 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 3.51 (m, 2H), 3.16 (td, J = 13.1, 3.0 Hz, 2H), 2.97 (tt, J = 12.3, 3.6 Hz, 1H), 2.12 (m, 2H), 1.92 (qd, J = 13.5, 4.0 Hz, 2H);13C NMR (MeOD, 151 MHz) δ 158.3, 155.1, 142.8, 142.6 (q, J = 36.6 Hz), 141.4, 129.8, 126.2, 123.2 (q, J = 2.9 Hz), 123.1 (q, J = 272.2 Hz), 121.4, 45.6, 40.4, 31.2;19F NMR (MeOD, 376 MHz) δ -68.46. MS (ESI) Found: [M-HCl+H]+= 323.1, calcd: [M-HCl+H]+= 323.1. Intermediate 37 4-(4-(pyrimidin-5-yloxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 17 (1.0 equiv., 100 mg, 0.2813 mmol), 1.5 mL 1,4-dioxane and 2 mL 4M HCl in dioxane. Yield: 81.2 mg, 99%. Rf= 0.06 (10% MeOH / DCM).1H NMR (MeOD, 600 MHz) δ 8.97 (s, 1H), 8.58 (s, 2H), 7.40 (d, J = 7.5 Hz, 2H), 7.17 (d, J = 7.4 Hz, 2H), 3.52 (m, 2H), 3.17 (m, 2H), 2.98 (m, 1H), 2.10 (m, 2H), 1.94 (m, 2H);13C NMR (MeOD, 151 MHz) δ 154.8, 151.5, 147.9, 146.5, 143.1, 130.0, 120.9, 45.6, 40.4, 31.1. MS (ESI) Found: [M-HCl+H]+= 256.1, calcd: [M+H]+= 256.1. Intermediate 38 4-(4-((5-methylpyrazin-2-yl)oxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 18 (1.0 equiv., 100 mg, 0.2707 mmol), 1.5 mL 1,4-dioxane and 2 mL 4M HCl in dioxane. Yield: 82.1 mg, 99%. Rf = 0.13 (10% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.40 (d, J = 1.3 Hz, 1H), 8.24 (dd, J = 1.4, 0.7 Hz, 1H), 7.36 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.6 Hz, 2H), 3.51 (m, 2H), 3.16 (td, J = 12.9, 2.6 Hz, 2H), 2.97 (tt, J = 12.2, 3.6 Hz, 1H), 2.11 (m, 2H), 1.9413 (qd, J = 13.3, 4.0 Hz, 2H); C NMR (MeOD, 100 MHz) δ 160.8, 153.5, 146.8, 143.9, 142.8, 132.6, 129.2, 122.4, 45.6, 40.5, 31.2, 18.9. MS (ESI) Found: [M-HCl+H]+= 270.2, calcd: [M-HCl+H]+= 270.2. Intermediate 39 4-(4-((3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl)oxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 19 (1.0 equiv., 100 mg, 0.2329 mmol), 1.5 mL 1,4-dioxane and 2 mL 4M HCl in dioxane. Yield: 84.7 mg, 99%. Rf= 0.13 (10% MeOH / DCM).1H NMR (MeOD, 600 MHz) δ 7.47 (d, J = 8.7 Hz, 2H), 7.44 (d, J = 8.7 Hz, 2H), 3.52 (m, 2H), 3.17 (m, 2H), 3.00 (m, 1H), 2.13 (m, 2H), 1.92 (m, 2H);13C NMR (MeOD, 151 MHz) δ 195.6, 159.7 (q, J = 39.3 Hz), 155.2, 145.5, 130.1, 121.5, 119.1 (q,19 J = 272.0 Hz), 45.6, 40.5, 31.0; F NMR (MeOD, 376 MHz) δ - 69.14. MS (ESI) Found: [M-HCl+H]+= 330.1, calcd: [M-HCl+H]+= 330.1. Intermediate 40 4-(4-((5-(trifluoromethyl)pyrazin-2-yl)oxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 20 (1.0 equiv., 100 mg, 0.2362 mmol), 1.5 mL 1,4-dioxane and 2 mL 4M HCl in dioxane. Yield: 84.6 mg, 99%. Rf= 0.15 (10% MeOH / DCM).1H NMR (MeOD, 600 MHz) δ 8.54 (s, 1H), 8.49 (s, 1H), 7.38 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H), 3.52 (m, 2H), 3.16 (td, J = 13.0, 3.0 Hz, 2H), 2.98 (tt, J = 12.2, 3.7 Hz, 1H), 2.12 (m, 2H), 1.93 (qd, J = 13.4, 4.0 Hz, 2H);13C NMR (MeOD, 151 MHz) δ 163.2, 152.7, 143.2, 140.1 (q, J = 3.5 Hz), 138.5 (q, J = 35.4 Hz), 137.2, 129.1, 123.1 (q, J = 272.2 Hz), 122.9, 45.6, 40.5, 31.2;19F NMR (MeOD, 376 MHz) δ -68.38. MS (ESI) Found: [M-HCl+H]+= 324.1, calcd: [M-HCl+H]+= 324.1. Intermediate 41 4-fluoro-3-nitrobenzoyl chloride The title compound was prepared according to General procedure C, using 4-fluoro-3- nitrobenzoic acid (4.497 g, 24.2939 mmol) in 80 mL toluene, SOCl2 (3.0 equiv., 8.67 mL, 72.8816 mmol), and DMF (1 mol%, 18.7 µL, 0.2429 mmol). The product (4.92 g, 99%) was obtained as a pale brown oil.1H NMR (CDCl3, 400 MHz) δ 8.84 (dd, J = 6.9, 2.4 Hz, 1H), 8.41 (ddd, J = 8.8, 4.0, 2.4 Hz, 1H), 7.50 (dd, J = 9.8, 8.8 Hz, 1H);13C NMR (CDCl3, 100 MHz) δ 165.7, 159.5 (d, J = 276.2 Hz), 137.7 (d, J = 10.6 Hz), 130.3 (d, J = 3.8 Hz), 129.7, 119.8 (d, J = 21.9 Hz);19F NMR (CDCl3, 376 MHz) δ -105.81. Intermediate 42 6-chloro-5-nitronicotinoyl chloride The title compound was prepared according to General procedure C, using 6-chloro-5- nitronicotinic acid (1.0 g, 4.9371 mmol) in 20 mL toluene, SOCl2 (10.0 equiv., 3.60 mL, 49.3705 mmol) and DMF (1 drop). The product (1.07 g, 98%) was obtained as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 9.24 (d, J = 2.2 Hz, 1H), 8.82 (d, J = 2.2 Hz, 1H). Intermediate 43 3,4-difluoro-5-nitrobenzoyl chloride The title compound was prepared according to General procedure C, using 3,4- difluoro-5-nitrobenzoic acid (390 mg, 1.9202 mmol) in 12 mL toluene, SOCl2 (3.0 equiv., 0.42 mL, 5.7607 mmol) and DMF (1 drop). The product (420 mg, 99%) was obtained as a pale-yellow solid.1H NMR (CDCl3, 400 MHz) δ 8.00 (dd, J = 8.9, 6.9 Hz, 1H), 7.58 (dd, J = 8.9, 7.0 Hz, 1H);13C NMR (CDCl3, 100 MHz) δ 163.8, 153.1 (dd, J = 263.9, 12.9 Hz), 151.5 (dd, J = 262.0, 13.4 Hz), 141.6 (dd, J = 11.5, 7.9 Hz), 129.8 (dd, J = 6.2, 4.5 Hz), 118.0 (dd, J = 21.9, 1.5 Hz), 115.5 (dd, J = 22.5, 2.1 Hz);19F NMR (CDCl3, 376 MHz) δ -123.54 (d, J = 20.5 Hz), -125.16 (d, J = 20.5 Hz). Intermediate 44 4-fluoro-3-methyl-5-nitrobenzoyl chloride The title compound was prepared according to General procedure C, using 4-fluoro-3- methyl-5-nitrobenzoic acid (310 mg, 1.5567 mmol) in 12 mL toluene, SOCl2 (3.0 equiv., 0.34 mL, 4.6701 mmol), and DMF (1 drop). The product (321 mg, 95%) was obtained as a pale-yellow solid.1H NMR (CDCl3, 400 MHz) δ 8.64 (m, 1H), 8.23 (m, 1H), 2.49 (d, J = 2.6 Hz, 3H);13C NMR (CDCl3, 100 MHz) δ 166.0, 157.9 (d, J = 273.7 Hz), 138.5 (d, J = 7.7 Hz), 137.9 (d, J = 6.7 Hz), 130.2 (d, J = 17.6 Hz), 129.3 (d, J = 4.3 Hz), 127.2 (d, J = 1.3 Hz);19F NMR (CDCl3, 376 MHz) δ -109.83. Intermediate 45 (4-fluoro-3-nitrophenyl)(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidin-1-yl)- methanone The title compound was prepared according to General procedure D, using Intermediate 21 (1.0 equiv., 7.63 g, 21.2074 mmol) in 400 mL of DCM, and TEA (3.0 equiv., 8.87 mL, 63.6222 mmol). A solution of Intermediate 41 (1.14 equiv., 4.919 g, 24.1661 mmol) in 25 mL of DCM was added. Yield: 10.33 g, 99%. Rf = 0.32 (2.5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.18 (dd, J = 7.0, 2.2 Hz, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.76 (ddd, J = 8.6, 4.2, 2.2 Hz, 1H), 7.38 (dd, J = 10.4, 8.5 Hz, 1H), 7.33 J = 9.2 Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.6 Hz, 2H), 4.86 (br s, 1H), 3.83 (br s, 1H), 3.24 (br s, 1H), 2.93 (br s, 1H), 2.86 (tt, J = 12.1, 3.6 Hz, 1H), 1.97 (br s, 2H) 1.71 (br s, 2H);13C NMR (CDCl, 100 MHz) δ 167.1, 166.9, 156.1 (d, J = 268.5 Hz), 151.4, 148.5 (q, J = 3 35.4 Hz), 142.5, 137.3 (d, J = 7.5 Hz), 134.5 (d, J = 9.1 Hz), 133.1 (d, J = 4.5 Hz), 128.3, 127.4 (q, J = 2.1 Hz), 125.4 (d, J = 2.4 Hz), 121.6, 121.4 (q, J = 274.0 Hz), 119.1 (d, J = 21.3 Hz), 118.0, 48.5, 43.4, 42.2, 34.1, 33.0;19F NMR (CDCl3, 376 MHz) δ -66.39, -114.86. MS (ESI) Found: [M+H]+= 491.1, calcd: [M+H]+= 491.1. Intermediate 46 (3,4-difluoro-5-nitrophenyl)(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidin-1-yl)- methanone The title compound was prepared according to General procedure D, using Intermediate 21 (1.0 equiv., 180 mg, 0.5003 mmol) in 10 mL of DCM, and TEA (3.0 e quiv., 209 µL, 1.5009 mmol). A solution of Intermediate 43 (1.15 equiv., 127.5 mg, 0.5754 mmol) in 3 mL of DCM was added. Yield: 252 mg, 99%. Rf = 0.22 (2.5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.11 (dd, J = 9.5, 6.7 Hz, 1H), 7.80 (d, J = 9.1 Hz, 1H), 7.34 – 7.27 (m, 4H), 7.17 (d, J = 8.2 Hz, 2H), 4.89 (m, 1H), 3.49 (m, 1H), 3.21 (m, 1H), 3.03 – 2.76 (m, 2H), 2.15 – 1.51 (m, 4H);13C NMR (CDCl3, 100 MHz) δ 167.1, 164.3, 154.1 (dd, J = 267.8, 15.5 Hz), 151.4, 149.8 (dd, J = 256.9, 13.2 Hz), 148.5 q, J = 3 z), 142 .7, 141.1 (dd, J = 23.0, 13.1 Hz), 131.1 (dd, J = 6.1, 4.7 Hz), 128.3, 127.4 (q, J = 1.8 Hz), 121 1 (q, J = 274.0 Hz), 117.9, 117.1 (d, J = 20.3 Hz), 115.5 (t, J = 22.3 Hz), 47.7, 42.8, 42.2, 33.3, 32.5;19F NMR (CDCl3, 376 MHz) δ -66.39, -124.40 (d, J = 20.8 Hz), -130.97 (d, J = 20.7 Hz). MS (ESI) Found: [M+H]+= 509.1, calcd: [M+H]+= 509.1. Intermediate 47 (4-fluoro-3-methyl-5-nitrophenyl)(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidin-1- yl)meth The title compound was prepared according to General procedure D, using Intermediate 21 (1.0 equiv., 254.9 mg, 0.7086 mmol) in 15 mL of DCM, and TEA (3.0 equiv ., 296 µL, 2.1257 mmol). A solution of Intermediate 44 (1.2 equiv., 185 mg, 0.8503 mmol) in 3 mL of DCM was added. Yield: 352 mg, 99%. Rf = 0.32 (2.5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 7.94 (dd, J = 6.5, 2.2 Hz, 1H), 7.80 (d, J = 9.1 Hz, 1H), 7.64 – 7.57 (m, 1H), 7.33 (d, J = 9.1 Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.6 Hz, 2H), 4.85 (br s, 1H), 3.85 (br s, 1H), 3.23 (br s, 1H), 2.91 (br s, 1H), 2.86 (tt, J = 12.2, 3.6 Hz, 1H), 2.42 (d, J = 2.4 Hz, 3H), 1.96 (br s, 2H), 1.71 (br s, 2H);13C NMR 3100 MHz) δ 167.2, 167.1, 154.5 (d, J = 266.0 Hz), 151.4, 148.5 (q, J = 35.3 Hz), 142.5, 137.4 (d, J = 8.9 Hz), 135.6 (d, J = 6.2 Hz), 132.2 (d, J = 5.1 Hz), 129.4 (d, J = 17.2 Hz), 128.3, 127.4 (q, J = 2.3 Hz), 122.5 (d, J = 2.3 Hz), 121.6, 121.4 (q, J = 274.0 Hz), 117.9, 48.6, 43.5, 42.2, 34.1, 32.9, 14.9 (d, J = 4.2 Hz);19F NMR (CDCl3, 376 MHz) δ -66.39, -119.22. MS (ESI) Found: [M+H]+= 505.1, calcd: [M+H]+= 505.1. Intermediate 48 4-cyclopropoxy-3-nitrophenyl)(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidin-1-yl)- methanone The title compound was prepared according to General procedure E (Workup procedure A), using NaH (60% dispersion in mineral oil) (1.5 equiv., 18.4 mg, 0.4588 mmol), cyclopropanol (5.0 equiv., 99 µL, 1.5293 mmol) in 1.6 mL of THF, and Intermediate 45 (1.0 equiv., 150 mg, 0.3059 mmol). The crude was purified with column chromatography using 5% EtOAc / DCM to afford the product (149 mg, 92%). Rf = 0.38 (10% EtOAc / DCM).1H NMR (CDCl3, 400 MHz) δ 7.95 (d, J = 2.2 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.69 (dd, J = 8.6, 2.2 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 9.2 Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.6 Hz, 2H), 4.81 (br s, 1H), 3.99 (br s, 1H), 3.93 (m, 1H), 3.15 (br s, 1H), 3.00 (br s, 1H), 2.85 (tt, J = 12.1, 3.7 Hz, 1H), 1.95 (br s, 2H), 1.71 (br s, 2H), 0.93 – 0.88 (m, 4H);13C NMR (CDCl3, 100 MHz) δ 168.0, 167.1, 153.7, 151.4, 148.5 (q, J = 35.5 Hz), 142.7, 139.1, 133.3, 128.6, 128.3, 127.4 (q, J = 2.2 Hz), 125.0, 121.5, 121.5 (q, J = 273.8 Hz), 117.9, 115.8, 52.9, 48.8, 43.4, 42.3, 33.9, 33.1, 6.7;19F NMR (CDCl3, 376 MHz) δ - 66.39. MS (ESI) Found: [M+H]+= 529.2, calcd: [M+H]+= 529.2. Intermediate 49 (4-isopropoxy-3-nitrophenyl)(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidin-1-yl)- methanone The title compound was prepared according to General procedure E (Workup procedure A), using NaH (60% dispersion in mineral oil) (1.5 equiv., 8.6 mg, 0.2141 mmol), acetone (8.0 equiv., 87.3 µL, 1.1419 mmol) in 1 mL of THF, and Intermediate 45 (1.0 equiv., 70 mg, 0.1427 mmol). The crude was purified with column chromatography using 5% EtOAc / DCM to afford the product (72.0 mg, 95%). Rf = 0.43 (10% EtOAc / DCM).1H NMR (CDCl3, 400 MHz) δ 7.90 (d, J = 2.2 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.64 (dd, J = 8.7, 2.2 Hz, 1H), 7.32 (d, J = 9.2 Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.6 Hz, 2H), 7.12 (d, J = 8.7 Hz, 1H), 4.80 (br s, 1H), 4.73 (hept, J = 6.1 Hz, 1H), 3.06 (br s, 2H), 2.85 (tt, J = 12.2, 3.7 Hz, 1H), 2.05 – 1.85 (m, 2H), 1.71 (br s, 2H), 1.43 (s, 3H), 1.41 (s, 3H);13C NMR (CDCl3, 100 MHz) δ 168.1, 167.1, 152.5, 151.4, 148.5 (q, J = 35.3 Hz), 142.8, 140.4, 133.0, 128.3, 127.8, 127.3, 125.0, 121.5, 121.5 (q, J = 273.9 Hz), 117.9, 115.8, 73.1, 48.6, 42.8, 42.4, 33.6, 33.3, 21.9;19F NMR (CDCl3, 376 MHz) δ -66.39. MS (ESI) Found: [M+H]+= 531.2, calcd: [M+H]+= 531.2. Intermediate 50 tert-butyl 3-(3-(2-nitro-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenoxy)propyl)azetidine-1-carboxylate (d, J = 2.1 Hz, 1H), 7.80 (d, J = 9.1 Hz, 1H), 7.66 (dd, J = 8.6, 2.1 Hz, 1H), 7.32 (d, J = 9.2 Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.6 Hz, 1H), 4.81 (br s, 1H), 4.14 (m, 2H), 4.02 (t, J = 8.3 Hz, 2H), 3.95 (br s, 1H), 3.56 (dd, J = 8.5, 5.5 Hz, 2H), 3.15 (br s, 1H), 3.00 (br s, 1H), 2.85 (tt, J = 12.1, 3.4 Hz, 1H), 2.56 (m, 1H), 1.95 (br s, 2H), 1.85 – 1.76 (m, 4H), 1.71 (br s, 2H), 1.43 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 167.9, 167.1, 156.5, 153.3, 151.4, 148.5 (q, J = 35.2 Hz), 142.7, 139.3, 133.4, 128.3, 128.2, 127.4, 125.1, 121.5, 121.4 (q, J = 273.9 Hz), 117.9, 114.4, 79.4, 69.6, 54.5, 48.6, 43.1, 42.3, 34.0, 33.3, 30.9, 28.6, 28.5, 26.6;19F NMR (CDCl3, 376 MHz) δ -66.39. MS (ESI) Found: [M+H]+= 686.3, calcd: [M+H]+= 686.3. Intermediate 51 tert-butyl (E)-3-(3-(2-nitro-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenoxy)prop-1-en-1-yl)azetidine-1-carboxylate (d, J = 9.2 Hz, 1H), 7.66 (dd, J = 8.6, 2.2 Hz, 1H), 7.32 (d, J = 9.2 Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.6 Hz, 2H), 7.12 (d, J = 8.6 Hz, 1H), 6.10 (ddt, J = 15.5, 8.0, 1.5 Hz, 1H), 5.76 (dtd, J = 15.5, 5.5, 1.1 Hz, 1H), 4.81 (s, 1H), 4.70 (m, 2H), 4.11 (t, J = 8.5 Hz, 2H), 3.96 (br s, 1H), 3.75 (dd, J = 8.6, 5.9 Hz, 2H), 3.26 (m, 1H), 3.06 (br s, 2H), 2.85 (tt, J = 12.2, 3.6 Hz, 1H), 1.98 – 1.93 (m, 2H), 1.71 (br s, 2H), 1.44 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 167.9, 167.1, 156.4, 152.9, 151.4, 148.5 (q, J = 35.6 Hz), 142.7, 139.6, 135.8, 133.4, 128.5, 128.3, 127.4, 125.2, 124.7, 121.5, 121.4 (q, J = 273.1 Hz), 117.9, 115.0, 79.7, 69.8, 54.5, 48.8, 43.6, 42.3, 33.9, 33.1, 31.1, 28.5;19F NMR (CDCl3, 376 MHz) δ -66.39. MS (ESI) Found: [M+H]+= 684.3, calcd: [M+H]+= 684.3. Intermediate 52 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)-3-nitrobenzoic acid The title compound was prepared according to General procedure E (Workup procedure B), using NaH (60% dispersion in mineral oil) (2.5 equiv., 540 mg, 13.5055 mmol), 1-Boc-3-hydroxyazetidine (1.5 equiv., 1.40 g, 8.1032 mmol) in 10 mL of DMF, and 4-fluoro-3-nitrobenzoic acid (1.0 equiv., 1.0 g, 5.4022 mmol). Yield: 1.80 g, 99%. Rf = 0.35 (5% MeOH / DCM).1H NMR (DMSO, 400 MHz) δ 13.37 (br s, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.13 (dd, J = 8.8, 2.2 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 5.26 (tt, J = 6.4, 3.8 Hz, 1H), 4.35 (m, 2H), 3.85 (m, 2H), 1.39 (s, 9H);13C NMR (DMSO, 100 MHz) δ 165.3, 155.4, 139.0, 135.3, 126.6, 123.9, 79.1, 67.8, 55.6, 28.0. MS (ESI) Found: [M+H]+= 339.1, calcd: [M+H]+= 339.1. Intermediate 53 4-cyclopropoxy-2-methyl-5-nitrobenzoic acid The title compound was prepared according to General procedure E (Workup procedure B), using NaH (60% dispersion in mineral oil) (2.5 equiv., 251 mg, 6.2770 mmol), cyclopropanol (1.5 equiv., 243 µL, 3.7662 mmol) in 4 mL of DMF, and 4-fluoro- 2-methyl-5-nitrobenzoic acid (1.0 equiv., 500 mg, 2.5108 mmol). Yield: 595 mg, 99%. Rf = 0.42 (10% MeOH / DCM).1H NMR (DMSO, 400 MHz) δ 13.14 (br s, 1H), 8.35 (s, 1H), 7.55 (s, 1H), 4.16 (tt, J = 6.0, 2.9 Hz, 1H), 2.65 (s, 3H), 0.90 (m, 2H), 0.77 (m, 2H);13C NMR (DMSO, 100 MHz) δ 166.4, 153.9, 147.9, 136.2, 128.0, 122.5, 118.6, 52.9, 22.0, 6.2. MS (ESI) Found: [M+H]+= 238.1, calcd: [M+H]+= 238.1. Intermediate 54 4-cyclopropoxy-3-nitrobenzoic acid The title compound was prepared according to General procedure E (Workup procedure B), using NaH (60% dispersion in mineral oil) (2.5 equiv., 162.0 mg, 4.0516 mmol), cyclopropanol (1.5 equiv., 156.9 µL, 2.4310 mmol) in 4 mL of DMF, and 4-fluoro-3- nitrobenzoic acid (1.0 equiv., 300 mg, 1.6206 mmol). Yield: 241 mg, 67%. Rf= 0.47 (5% MeOH / DCM).1H NMR (Acetone, 400 MHz) δ 8.41 (d, J = 2.2 Hz, 1H), 8.27 (dd, J = 8.8, 2.2 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 4.18 (tt, J = 6.1, 2.9 Hz, 1H), 0.94 (m, 2H), 0.84 (m, 2H);13C NMR (Acetone, 100 MHz) δ 165.7, 156.3, 140.5, 135.9, 127.2, 124.1, 116.8, 53.8, 6.7. MS (ESI) Found: [M+H]+= 224.1, calcd: [M+H]+= 224.1. Intermediate 55 4-(tert-butoxy)-3-nitrobenzoic acid The title compound was prepared according to General procedure E (Workup procedure B), using KOtBu (3.0 equiv., 545.6 mg, 4.8620 mmol) in 10 mL of THF, and 4-fluoro-3- nitrobenzoic acid (1.0 equiv., 300 mg, 1.6207 mmol). Yield: 312.7 mg, 80%. Rf = 0.40 (10% MeOH / DCM).1H NMR (DMSO, 400 MHz) δ 8.23 (d, J = 2.2 Hz, 1H), 8.07 (dd, J = 8.7, 2.2 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 1.42 (s, 9H);13C NMR (DMSO, 100 MHz) δ 165.7, 151.2, 143.7, 133.8, 126.5, 125.3, 122.3, 83.1, 28.4. MS (ESI) Found: [M+H]+= 240.1, calcd: [M+H]+= 240.1. Intermediate 56 4-((1-(tert-butoxycarbonyl)-3-methylazetidin-3-yl)oxy)-3-nitrobenzoic acid The title compound was prepared according to General procedure E (Workup procedure B), using NaH (60% dispersion in mineral oil) (2.5 equiv., 540 mg, 13.5055 mmol), 1-Boc-3-hydroxy-3-methylazetidine (1.5 equiv., 1.012 g, 8.1032 mmol) in 10 mL of DMF, and 4-fluoro-3-nitrobenzoic acid (1.0 equiv., 1.0 g, 5.4022 mmol). Yield: 1.895 g, 99%. Rf = 0.37 (10% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.55 (d, J = 2.2 Hz, 1H), 8.20 (dd, J = 8.8, 2.2 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 4.29 (d, J = 9.4 Hz, 2H), 4.05 (d, J = 9.4 Hz, 2H), 1.79 (s, 3H), 1.46 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 168.8, 156.4, 152.3, 141.0, 135.1, 128.4, 122.5, 115.9, 80.8, 76.2, 61.0, 28.5, 22.2. MS (ESI) Found: [M+H]+= 353.1, calcd: [M+H]+= 353.1. Intermediate 57 (R)-4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)-3-nitrobenzoic acid The title compound was prepared according to General procedure E (Workup procedure B), using NaH (60% dispersion in mineral oil) (2.5 equiv., 540 mg, 13.5055 mmol), (R)-1-N-Boc-3-hydroxypyrrolidine (1.5 equiv., 1.52 g, 8.1032 mmol) in 9 mL of DMF, and 4-fluoro-3-nitrobenzoic acid (1.0 equiv., 1.0 g, 5.4022 mmol). Yield: 1.88 g, 99%. Rf = 0.31 (10% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.52 (m, 1H), 8.22 (m, 1H), 7.08 (m, 1H), 5.12 (m, 1H), 3.81 – 3.51 (m, 4H), 2.37 – 2.15 (m, 2H), 1.48 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 168.3, 155.1, 154.3, 140.5, 135.5, 128.2, 122.5, 114.9, 80.5, 78.1, 51.3, 44.3, 31.9, 28.6. MS (ESI) Found: [M+H]+= 353.1, calcd: [M+H]+= 353.1. Intermediate 58 (S)-4-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-3-nitrobenzoic acid The title compound was prepared according to General procedure E (Workup procedure B), using NaH (60% dispersion in mineral oil) (2.5 equiv., 540 mg, 13.5055 mmol), N-Boc- L-prolinol (1.5 equiv., 1.63 g, 8.1032 mmol) in 9 mL of DMF, and 4-fluoro-3-nitrobenzoic acid (1.0 equiv., 1.0 g, 5.4022 mmol). Yield: 1.96 g, 99%. Rf = 0.34 (10% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 10.04 (br s, 1H), 8.52 (m, 1H), 8.20 (m, 1H), 7.28 (m, 1H), 4.42 – 4.02 (m, 3H), 3.39 (m, 2H), 2.21 – 1.94 (m, 3H), 1.88 (m, 1H), 1.47 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 169.1, 156.1, 155.1, 139.7, 135.9, 127.9, 121.8, 114.4, 80.3, 69.9, 55.8, 47.2, 28.7, 28.2, 23.7. MS (ESI) Found: [M+H]+= 367.2, calcd: [M+H]+= 367.2. Intermediate 59 tert-butyl 4-(2-(dimethylamino)ethoxy)-3-nitrobenzoate The title compound was prepared according to General procedure E (Workup procedure A), using NaH (60% dispersion in mineral oil) (1.2 equiv., 2.4 g, 59.6965 mmol), dimethylaminoethanol (1.1 equiv., 5.5 mL, 54.7218 mmol) in 100 mL of THF, and Intermediate 79 (1.0 equiv., 12.0 g, 49.7471 mmol). The crude was purified with column chromatography using 5% MeOH / DCM to afford the product (15.3 g, 99%). Rf = 0.41 (10% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.42 (d, J = 2.1 Hz, 1H), 8.15 (dd, J = 8.8, 2.1 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 4.37 (t, J = 5.2 Hz, 2H), 2.95 (t, J = 5.2, 3H), 2.48 (s, 6H), 1.59 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 163.6, 154.8, 139.5, 135.3, 127.2, 125.0, 113.9, 82.3, 68.1, 57.6, 45.9, 28.3. MS (ESI) Found: [M+H]+= 311.2, calcd: [M+H]+= 311.2 Intermediate 60 tert-butyl 4-(2-morpholinoethoxy)-3-nitrobenzoate The title compound was prepared according to General procedure E (Workup procedure A), using NaH (60% dispersion in mineral oil) (1.5 equiv., 126.4 mg, 3.1595 mmol), 4-(2-hydroxyethyl)morpholine (1.5 equiv., 414.4 mg, 3.1595 mmol) in 7 mL of THF, and Intermediate 79 (1.0 equiv., 508.1 mg, 2.1064 mmol). The crude was purified with column chromatography using 10% MeOH / DCM to afford the product (720 mg, 97%). Rf= 0.32 (5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.41 (d, J = 2.2 Hz, 1H), 8.15 (dd, J = 8.8, 2.2 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 4.36 (s, 2H), 3.76 (m, 4H), 2.94 (s, 2H), 2.68 (m, 4H), 1.59 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 163.6, 154.9, 139.6, 135.2, 127.1, 124.9, 113.9, 82.3, 67.3, 66.8, 57.1, 54.2, 28.3. MS (ESI) Found: [M+H]+= 353.2, calcd: [M+H]+= 353.2 Intermediate 61 tert-butyl 3-nitro-4-(2-(pyrrolidin-1-yl)ethoxy)benzoate The title compound was prepared according to General procedure E (Workup procedure A), using NaH (60% dispersion in mineral oil) (1.5 equiv., 126.9 mg, 3.1719 mmol), 1-(2-hydroxyethyl)pyrrolidine (1.5 equiv., 365.3 mg, 3.1719 mmol) in 7 mL of THF, and Intermediate 79 (1.0 equiv., 510 mg, 2.1146 mmol). The crude was purified with column chromatography using 10% MeOH / DCM to afford the product (690 mg, 97%). Rf= 0.30 (5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.41 (d, J = 2.2 Hz, 1H), 8.14 (dd, J = 8.8, 2.2 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 4.35 (t, J = 5.3 Hz, 1H), 3.04 (t, J = 5.4 Hz, 1H), 2.74 (m, 4H), 1.85 (m, 4H), 1.59 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 163.5, 154.8, 139.4, 135.1, 127.0, 124.6, 113.8, 82.0, 69.2, 55.0, 54.2, 28.2, 23.6. MS (ESI) Found: [M+H]+= 337.2, calcd: [M+H]+= 337.2. Intermediate 62 tert-butyl 6-(2-(diisopropylamino)ethoxy)-5-nitronicotinate The title compound was prepared according to General procedure E (Workup procedure A), using NaH (60% dispersion in mineral oil) (2.0 equiv., 31 mg, 0.7732 mmol), diisopropylethanolamine (2.0 equiv., 136 µL, 0.7732 mmol) in 1 mL of THF, and Intermediate 80 (1.0 equiv., 100 mg, 0.3866 mmol). The crude was purified with column chromatography using 5% MeOH / DCM to afford the product (123 mg, 86%). Rf = 0.61 (10% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.92 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 4.49 (t, J = 7.0 Hz, 2H), 3.04 (hept, J = 6.3 Hz, 2H), 2.84 (t, J = 7.0 Hz, 2H), 1.60 (s, 9H), 1.02 (d, J = 6.3 Hz, 12H);13C NMR (CDCl3, 100 MHz) δ 162.7, 158.5, 153.3, 135.9, 133.4, 121.4, 82.9, 69.3, 49.6, 43.7, 28.3, 21.0. MS (ESI) Found: [M+H]+= 368.2, calcd: [M+H]+= 368.2. Intermediate 63 tert-butyl 6-(2-(dimethylamino)ethoxy)-5-nitronicotinate The title compound was prepared according to General procedure E (Workup procedure A), using NaH (60% dispersion in mineral oil) (1.5 equiv., 46.4 mg, 1.1598 mmol), dimethylaminoethanol (1.5 equiv., 117 µL, 1.1598 mmol) in 2 mL of THF, and Intermediate 80 (1.0 equiv., 200 mg, 0.7732 mmol). The crude was purified with column chromatography using 2% MeOH / DCM to afford the product (227 mg, 94%). Rf = 0.45 (10% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.92 (d, J = 2.1 Hz, 1H), 8.72 (d, J = 2.1 Hz, 1H), 4.68 (t, J = 5.7 Hz, 2H), 2.82 (t, J = 5.7 Hz, 2H), 2.37 (s, 6H), 1.60 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 162.6, 158.2, 153.3, 136.0, 133.4, 121.7, 83.0, 66.9, 57.6, 46.1, 28.3. MS (ESI) Found: [M+H]+= 312.2, calcd: [M+H]+= 312.2. Intermediate 64 tert-butyl 4-(2-nitro-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)piperazine-1-carboxylate The title compound was prepared according to General procedure F, using Intermediate 45 (1.0 equiv., 400 mg, 0.8156 mmol) in 2 mL of DMSO, TEA (2.5 equiv., 284.2 µL, 2.0391 mmol) and 1-Boc-piperazine (1.05 equiv., 159.5 mg, 0.8564 mmol). Yield: 495 mg, 92%. Rf= 0.41 (20% EtOAc / DCM).1H NMR (CDCl3, 400 MHz) δ 7.93 (d, J = 2.1 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.60 (dd, J = 8.5, 2.1 Hz, 1H), 7.32 (d, J = 9.2 Hz, 1H), 7.28 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 8.5 Hz, 1H), 4.74 (br s, 1H), 4.02 (br s, 1H), 3.63 – 3.54 (m, 4H), 3.12 (br s, 1H), 3.12 – 3.05 (m, 4H), 2.97 (br s, 1H), 2.84 (tt, J = 12.1, 3.6 Hz, 1H), 2.00 – 1.88 (m, 2H), 1.70 (m, 2H), 1.47 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 168.1, 167.1, 154.8, 151.4, 148.4 (q, J = 35.3 Hz), 146.9, 142.7, 141.9, 132.8, 129.1, 128.3, 127.4 (q, J = 2.2 Hz), 125.8, 121.5, 121.4 (q, J = 273.8 Hz), 120.9, 117.9, 80.3, 51.4, 48.0, 43.6, 43.3, 42.3, 33.6, 28.5;19F NMR (CDCl3, 376 MHz) δ - 66.38. MS (ESI) Found: [M+H]+= 657.3, calcd: [M+H]+= 657.3. Intermediate 65 (4-(4-ethylpiperazin-1-yl)-3-nitrophenyl)(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidin-1-yl)methanone The title compound was prepared according to General procedure F, using Intermediate 45 (1.0 equiv., 10.62 g, 21.6553 mmol) in 45 mL of DMSO, TEA (2.0 equiv., 6.04 mL, 43.3107 mmol) and 1-ethylpiperazine (1.05 equiv., 2.888 mL, 22.7381 mmol). Yield: 12.642 g, 99%. Rf = 0.53 (10% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.09 (d, J = 9.2 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8.6, 2.0 Hz, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 8.6 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 4.75 (br s, 1H), 3.92 (br s, 1H), 3.28 (br s, 1H), 3.17 (m, 4H), 3.00 (br s, 1H), 2.94 (tt, J = 12.1, 3.7 Hz, 1H), 2.63 (m, 4H), 2.51 (q, J = 7.3 Hz, 2H), 1.94 (s, 2H), 1.76 (m, 2H), 1.14 (t, J = 7.3 Hz, 3H);13C NMR (MeOD, 100 MHz) δ 170.1, 169.0, 152.9, 149.4 (q, J = 35.0 Hz), 147.8, 144.6, 143.4, 133.4, 129.6, 129.5, 129.4 (q, J = 2.3 Hz), 126.4, 122.9 (q, J = 273.1 Hz), 122.3, 122.1, 119.9, 53.6, 53.3, 51.8, 44.3, 43.2, 34.6, 11.8;19F NMR (MeOD, 376 MHz) δ -67.92. MS (ESI) Found: [M+H]+= 585.2, calcd: [M+H]+= 585.2. Intermediate 66 4-(4-ethylpiperazin-1-yl)-3-fluoro-5-nitrophenyl)(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidin-1-yl)methanone The title compound was prepared according to General procedure F, using Intermediate 46 (1.0 equiv., 223 mg, 0.4386 mmol) in 2 mL of DMSO, TEA (2.0 equiv., 122.3 µL, 0.8772 mmol) and 1-ethylpiperazine (1.02 equiv., 56.8 µL, 0.4474 mmol). Yield: 255.1 mg, 97%. Rf = 0.49 (10% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.09 (d, J = 9.2 Hz, 1H), 8.00 (d, J = 13.5 Hz, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.39 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 7.00 (d, J = 8.4 Hz, 1H), 4.80 (m, 1H), 3.55 (m, 1H), 3.47 – 3.36 (m, 4H), 3.23 (m, 1H), 3.04 – 2.88 (m, 2H), 2.71 – 2.60 (m, 4H), 2.51 (d, J = 7.2 Hz, 2H), 2.07 – 1.62 (m, 4H), 1.15 (t, J = 7.2 Hz, 3H);13C NMR (MeOD, 100 MHz) δ 169.0, 168.4, 153.9 (d, J = 249.9 Hz), 152.9, 149.4 (q, J = 35.0 Hz), 146.6 (d, J = 11.6 Hz), 144.7, 137.8 (d, J = 9.0 Hz), 131.9 (d, J = 3.1 Hz), 129.5, 129.4, 122.9 (q, J = 272.9 Hz), 122.4, 119.9, 117.2 (d, J = 3.9 Hz), 114.7 (d, J = 20.5 Hz), 53.5, 53.3, 50.2 (d, J = 3.6 Hz), 49.3, 43.6, 43.2, 34.3, 33.5, 11.8;19F NMR (MeOD, 376 MHz) δ -67.9, -119.6. MS (ESI) Found: [M+H]+= 603.2, calcd: [M+H]+= 603.2. Intermediate 67 (4-(4-ethylpiperazin-1-yl)-3-methyl-5-nitrophenyl)(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidin-1-yl)methanone The title compound was prepared according to General procedure F, using Intermediate 47 (1.0 equiv., 300 mg, 0.5947 mmol) in 2 mL of DMSO, TEA (2.0 equiv., 165.8 µL, 1.1894 mmol) and 1-ethylpiperazine (1.22 equiv., 92.2 µL, 0.7256 mmol). The crude was purified with column chromatography using 5% MeOH / DCM. Yield: 138 mg, 39%. Rf = 0.60 (10% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.09 (d, J = 9.3 Hz, 1H), 7.59 (m, 1H), 7.58 – 7.51 (m, 2H), 7.39 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 4.76 (br s, 1H), 3.85 (br s, 1H), 3.28 (br s, 1H), 3.11 (m, 4H), 2.99 (br s, 1H), 2.93 (tt, J = 12.2, 3.6 Hz, 1H), 2.62 (m, 4H), 2.50 (q, J = 7.3 Hz, 2H), 2.44 (s, 3H), 1.98 (br s, 1H), 1.85 (br s, 1H), 1.75 (br s, 2H), 1.13 (t, J = 7.3 Hz, 3H);13C NMR (MeOD, 100 MHz) δ 170.0, 169.0, 152.9, 149.4 (q, J = 35.1 Hz), 149.2, 145.0, 144.6, 140.9, 133.9, 133.1, 129.5, 129.4, 122.9 (q, J = 272.9 Hz), 122.3, 122.3, 119.9, 54.4, 53.5, 50.2, 49.8, 44.1, 43.2, 34.9, 34.0, 18.8, 11.7;19F NMR (MeOD, 376 MHz) δ -67.91. MS (ESI) Found: [M+H]+= 599.3, calcd: [M+H]+= 599.3. Intermediate 68 (4-(4-ethyl-1,4-diazepan-1-yl)-3-nitrophenyl)(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidin-1-yl)methanone The title compound was prepared according to General procedure F, using Intermediate 45 (1.0 equiv., 75 mg, 0.1529 mmol) in 0.5 mL of DMSO, TEA (2.5 equiv., 53.29 µL, 0.3823 mmol) and 1-ethyl-1,4-diazepane (1.05 equiv., 22.78 µL, 0.1606 mmol). Yield: 90.2 mg, 99%. Rf = 0.31 (10% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.09 (d, J = 9.3 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.62 – 7.47 (m, 2H), 7.39 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.9 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 4.68 (br s, 1H), 4.07 (br s, 1H), 3.51 – 3.36 (m, 4H), 3.13 (br s, 2H), 2.94 (tt, J = 12.1, 3.6 Hz, 1H), 2.84 (m, 2H), 2.70 (m, 2H), 2.56 (q, J = 7.2 Hz, 2H), 2.09 – 1.84 (m, 4H), 1.75 (m, 2H), 1.09 (t, J = 7.2 Hz, 3H);13C NMR (MeOD, 100 MHz) δ 170.6, 169.0, 152.9, 149.4 (q, J = 35.1 Hz), 147.7, 144.7, 139.0, 132.9, 129.5, 129.4 (q, J = 2.3 Hz), 127.6, 124.8, 122.9 (q, J = 272.9 Hz), 122.3, 119.9, 119.2, 56.7, 54.8, 52.7, 52.4, 52.1, 49.9, 44.0, 43.3, 34.6, 28.2, 12.2;19F NMR (MeOD, 376 MHz) δ -67.91. MS (ESI) Found: [M+H]+= 599.3, calcd: [M+H]+= 599.3. Intermediate 69 tert-butyl 4-(5-(methoxycarbonyl)-3-nitropyridin-2-yl)piperazine-1-carboxylate The title compound was prepared according to General procedure F, using methyl 6- chloro-5-nitronicotinate (1.0 equiv., 1.28 g, 5.9101 mmol) in 35 mL of DMSO, TEA (4.0 equiv., 3.29 mL, 23.6402 mmol) and 1-Boc-piperazine (1.05 equiv., 1.156 g, 6.2056 mmol). Yield: 2.15 g, 99%. Rf= 0.53 (2.5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.86 (d, J = 2.1 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 3.91 (s, 3H), 3.60 – 3.53 (m, 8H), 1.47 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 164.5, 154.7, 153.9, 153.0, 137.3, 131.3, 115.9, 80.6, 52.4, 47.8, 43.1, 28.5. MS (ESI) Found: [M+H]+= 367.2, calcd: [M+H]+= 367.2. Intermediate 70 tert-butyl 4-(4-ethylpiperazin-1-yl)-3-nitrobenzoate The title compound was prepared according to General procedure F, using Intermediate 79 (1.0 equiv., 2.56 g, 10.6127 mmol) in 10 mL of DMSO, TEA (4.0 equiv., 5.917 mL, 42.4509 mmol) and 1-ethylpiperazine (1.1 equiv., 1.483 mL, 11.6740 mmol). Yield: 3.41 g, 96%. Rf= 0.40 (5% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.27 (d, J = 2.1 Hz, 1H), 8.03 (dd, J = 8.8, 2.1 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 3.21 (m, 4H), 2.62 (m, 4H), 2.51 (q, J = 7.2 Hz, 2H), 1.59 (s, 9H), 1.14 (t, J = 7.2 Hz, 3H);13C NMR (MeOD, 100 MHz) δ 165.4, 149.5, 142.1, 135.1, 128.6, 124.8, 121.2, 82.8, 53.5, 53.3, 51.4, 28.4, 11.8. MS (ESI) Found: [M+H]+= 336.2, calcd: [M+H]+= 336.2. Intermediate 71 tert-butyl 4-(4-(methoxycarbonyl)-2-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate Methyl 4-bromo-3-nitrobenzoate (1.0 equiv., 1.5 g, 5.7683 mmol), N-Boc-1,2,3,6- tetrahydropyridine-4-boronic acid pinacol ester (1.2 equiv., 2.14 g, 6.9220 mmol), K2CO3 (2.5 equiv., 1.99 g, 14.4209 mmol) and Pd(dppf)Cl2·DCM (0.05 equiv., 235.5 mg, 0.2884 mmol) were dissolved in 3:1 ratio of 1,4-dioxane / H2O (35 mL) under N2 atmosphere and stirred at 80 °C for 3 hours. The reaction mixture was then partitioned between water and EtOAc, the aqueous phase was re-extracted twice with EtOAc, the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude was purified with column chromatography using 20% EtOAc / Petroleum Ether to afford the product as an oil (1.65 g, 79%); Rf = 0.53 (DCM).1H NMR (CDCl3, 400 MHz) δ 8.52 (d, J = 1.8 Hz, 1H), 8.20 (dd, J = 8.0, 1.8 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 5.66 (m, 1H), 4.04 (m, 2H), 3.96 (s, 3H), 3.64 (m, 2H), 2.34 (m, 2H), 1.49 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 164.9, 154.9, 148.2, 141.8, 134.3, 133.5, 131.2, 130.5, 125.6, 124.3, 80.0, 52.8, 43.2, 39.7, 29.2, 28.5. MS (ESI) Found: [M+H]+= 363.2, calcd: [M+H]+= 363.2. Intermediate 72 tert-butyl 3-(4-(methoxycarbonyl)-2-nitrophenoxy)azetidine-1-carboxylate The title compound was prepared according to General procedure G, using Intermediate 52 (1.0 equiv., 1.80 g, 5.3204 mmol) in 8 mL of DMF, Cs2CO3 (1.2 equiv., 2.08 g, 6.3845 mmol) and MeI (1.2 equiv., 397 µL, 6.3845 mmol). The crude was purified with column chromatography using 2% MeOH / DCM to afford the product (1.78 g, 95%). Rf= 0.36 (2% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.54 (d, J = 2.1 Hz, 1H), 8.19 (dd, J = 8.7, 2.1 Hz, 1H), 6.75 (d, J = 8.7 Hz, 1H), 5.05 (tt, J = 6.4, 4.0 Hz, 1H), 4.36 (ddd, J = 9.9, 6.4, 1.1 Hz, 2H), 4.10 (dd, J = 10.0, 4.0 Hz, 2H), 3.93 (s, 3H), 1.45 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 164.8, 156.0, 153.3, 139.8, 135.4, 127.8, 123.8, 113.9, 80.5, 67.9, 56.1, 52.8, 28.5. MS (ESI) Found: [M+H]+= 353.1, calcd: [M+H]+= 353.1. Intermediate 73 methyl 4-cyclopropoxy-2-methyl-5-nitrobenzoate The title compound was prepared according to General procedure G, using Intermediate 53 (1.0 equiv., 576.4 mg, 2.4299 mmol) in 3 mL of DMF, Cs2CO3 (1.5 equiv., 1.188 g, 3.6449 mmol) and MeI (1.5 equiv., 226.9 µL, 3.6449 mmol). The crude was purified with column chromatography using 10% EtOAc / Petroleum Ether to afford the product (577 mg, 95%). Rf = 0.25 (10% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 8.53 (s, 1H), 7.29 (s, 1H), 3.93 (m, 1H), 3.89 (s, 3H), 2.71 (s, 3H), 0.93 – 0.89 (m, 4H);13C NMR (CDCl3, 100 MHz) δ 165.8, 155.0, 148.6, 137.0, 129.2, 121.8, 118.3, 52.9, 52.3, 22.7, 6.7. MS (ESI) Found: [M+H]+= 252.1, calcd: [M+H]+= 252.1. Intermediate 74 methyl 4-cyclopropoxy-3-nitrobenzoate The title compound was prepared according to General procedure G, using Intermediate 54 (1.0 equiv., 236 mg, 1.0574 mmol) in 3 mL of DMF, Cs2CO3(1.5 equiv., 516.8 mg, 1.5862 mmol) and MeI (1.5 equiv., 98.7 µL, 1.5862 mmol). The crude was purified with column chromatography using 50% EtOAc / Petroleum Ether to afford the product (233 mg, 93%). Rf = 0.31 (50% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 8.48 (d, J = 2.2 Hz, 1H), 8.21 (dd, J = 8.8, 2.2 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 3.95 (m, 1H), 3.93 (s, 3H), 0.93 – 0.90 (m, 4H);13C NMR (CDCl3, 100 MHz) δ 165.1, 156.0, 139.4, 135.2, 127.2, 123.0, 115.4, 53.2, 52.6, 6.6. MS (ESI) Found: [M+H]+= 238.1, calcd: [M+H]+= 238.1. Intermediate 75 methyl 4-(tert-butoxy)-3-nitrobenzoate The title compound was prepared according to General procedure G, using Intermediate 55 (1.0 equiv., 286.4 mg, 1.1972 mmol) in 8 mL of DMF, Cs2CO3 (1.5 equiv., 585 mg, 1.7958 mmol) and MeI (1.5 equiv., 111.8 µL, 1.7956 mmol). The crude was purified with column chromatography using 40% DCM / Petroleum Ether to afford the product (293 mg, 97%). Rf= 0.59 (50% DCM / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 8.36 (d, J = 2.2 Hz, 1H), 8.11 (dd, J = 8.8, 2.2 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 3.92 (s, 3H), 1.49 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 165.1, 153.3, 144.4, 133.8, 126.6, 124.0, 122.3, 84.0, 52.6, 29.0. MS (ESI) Found: [M+H]+= 254.1, calcd: [M+H]+= 254.1. Intermediate 76 tert-butyl 3-(4-(methoxycarbonyl)-2-nitrophenoxy)-3-methylazetidine-1-carboxylate The title compound was prepared according to General procedure G, using Intermediate 56 (1.0 equiv., 1.876 g, 5.3159 mmol) in 8 mL of DMF, Cs2CO3 (1.2 equiv., 2.08 g, 6.3791 mmol) and MeI (1.2 equiv., 397 µL, 6.3791 mmol). The crude was purified with column chromatography using DCM to afford the product (1.84 g, 94%). Rf = 0.24 (DCM).1H NMR (CDCl3, 400 MHz) δ 8.48 (d, J = 2.2 Hz, 1H), 8.15 (dd, J = 8.8, 2.2 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 4.26 (d, J = 9.4 Hz, 2H), 4.02 (d, J = 9.4 Hz, 2H), 3.93 (s, 3H), 1.77 (s, 3H), 1.44 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 164.9, 156.3, 151.7, 140.9, 134.6, 127.8, 123.4, 115.9, 80.5, 76.0, 60.9, 52.7, 28.4, 22.2. MS (ESI) Found: [M+H]+= 367.2, calcd: [M+H]+= 367.2. Intermediate 77 tert-butyl (R)-3-(4-(methoxycarbonyl)-2-nitrophenoxy)pyrrolidine-1-carboxylate The title compound was prepared according to General procedure G, using Intermediate 57 (1.0 equiv., 1.928 g, 5.4720 mmol) in 8 mL of DMF, Cs2CO3 (1.2 equiv., 2.14 g, 6.5664 mmol) and MeI (1.2 equiv., 409 µL, 6.5664 mmol). The crude was purified with column chromatography using 2% MeOH / DCM to afford the product (1.74 g, 87%). Rf = 0.38 (2% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.48 (d, J = 2.2 Hz, 1H), 8.18 (m, 1H), 7.06 (d, J = 8.8 Hz, 1H), 5.09 (m, 1H), 3.93 (s, 3H), 3.73 – 3.50 (m, 4H), 2.32 – 2.11 (m, 2H), 1.46 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 165.0, 154.5, 153.8, 140.4, 135.1, 127.6, 123.1, 114.7, 80.0, 78.7, 52.7, 51.3, 44.0, 31.5, 28.6. MS (ESI) Found: [M+H]+= 367.2, calcd: [M+H]+= 367.2. Intermediate 78 tert-butyl (S)-2-((4-(methoxycarbonyl)-2-nitrophenoxy)methyl)pyrrolidine-1-carboxylate The title compound was prepared according to General procedure G, using Intermediate 58 (1.0 equiv., 1.962 g, 5.3552 mmol) in 8 mL of DMF, Cs2CO3 (1.2 equiv., 2.09 g, 6.4263 mmol) and MeI (1.2 equiv., 400 µL, 6.4263 mmol). The crude was purified with column chromatography using 2% MeOH / DCM to afford the product (1.99 g, 98%). Rf = 0.31 (2% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.48 (m, 1H), 8.18 (dd, J = 8.9, 2.2 Hz, 1H), 7.23 (m, 1H), 4.36 – 4.01 (m, 3H), 3.92 (s, 3H), 3.39 (m, 2H), 2.15 – 1.94 (m, 3H), 1.85 (m, 1H), 1.45 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 165.1, 155.5, 154.9, 139.6, 135.4, 127.3, 122.7, 114.4, 79.9, 69.9, 55.8, 52.6, 47.2, 28.7, 28.2, 24.0. MS (ESI) Found: [M+H]+= 381.2, calcd: [M+H]+= 381.2. Intermediate 79 tert-butyl 4-fluoro-3-nitrobenzoate The title compound was prepared according to General procedure H, using Intermediate 41 (1.0 equiv., 15.1 g, 74.1832 mmol) in 100 mL of DCM,tBuOH (2.0 equiv., 14.19 mL, 148.3665 mmol) and pyridine (2.0 equiv., 11.95 mL, 148.3665 mmol). The crude was purified with column chromatography using 10% EtOAc / Petroleum Ether to afford the product (14.1 g, 79%). Rf = 0.45 (10% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 8.64 (dd, J = 7.2, 2.2 Hz, 1H), 8.25 (ddd, J = 8.7, 4.3, 2.2 Hz, 1H), 7.34 (dd, J = 10.2, 8.7 Hz, 1H), 1.61 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 162.8, 157.9 (q, J = 270.6 Hz), 137.3 (q, J = 7.6 Hz), 136.5 (q, J = 9.7 Hz), 129.2 (q, J = 4.0 Hz), 127.7 (q, J = 1.9 Hz), 118.6 (q, J = 21.3 Hz), 83.0, 28.2;19F NMR (CDCl3, 376 MHz) δ - 111.71. MS (ESI) Found: [M+H]+= 242.1, calcd: [M+H]+= 242.1. Intermediate 80 tert-butyl 6-chloro-5-nitronicotinate The title compound was prepared according to General procedure H, using Intermediate 42 (1.0 equiv., 2.40 g, 10.8631 mmol) in 20 mL of DCM,tBuOH (2.0 equiv., 2.08 mL, 21.7262 mmol) and pyridine (2.0 equiv., 1.75 mL, 21.7262 mmol). The crude was purified with column chromatography using 50% DCM / Petroleum Ether to afford the product (1.60 g, 57%). Rf = 0.32 (50% DCM / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 9.10 (d, J = 2.1 Hz, 1H), 8.66 (d, J = 2.1 Hz, 1H), 1.62 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 161.5, 153.0, 146.7, 144.6, 134.9, 127.9, 84.3, 28.2. MS (ESI) Found: [M+H]+= 259.0, calcd: [M+H]+= 259.0.

[0004] Intermediate 81 (3-amino-4-cyclopropoxyphenyl)(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidin-1- yl)methanone The title compound was prepared according to General procedure I, using Intermediate 48 (1.0 equiv., 53.2 mg, 0.1007 mmol) in 1.2 mL 70% EtOH / H2O, AcOH (5.2 equiv., 29.9 µL, 0.5235 mmol) and Fe powder (10.0 equiv., 56.2 mg, 1.0066 mmol). Yield: 49.9 mg, 99%. Rf = 0.10 (2.5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 7.80 (d, J = 9.2 Hz, 1H), 7.34 – 7.25 (m, 3H), 7.19 – 7.12 (m, 3H), 6.93 – 6.83 (m, 2H), 4.82 (br s, 1H), 4.10 (br s, 1H), 3.79 (m, 1H), 2.97 (br s, 2H), 2.81 (tt, J = 12.1, 3.7 Hz, 1H), 1.90 (br s, 2H), 1.69 (br s, 2H), 0.85 – 0.76 (m, 4H);13C NMR (CDCl3, 100 MHz) δ 170.7, 167.2, 151.3, 148.4 (q, J = 37.8 Hz), 146.5, 143.2, 134.7, 129.2, 128.4, 127.3, 121.5 (q, J = 276.9 Hz), 121.4, 118.7, 117.9, 114.9, 112.2, 51.4, 48.6, 43.1, 42.5, 34.1, 33.3, 6.4;19F NMR (CDCl3, 376 MHz) δ -66.38. MS (ESI) Found: [M+H]+= 499.2, calcd: [M+H]+= 499.2. Intermediate 82 (3-amino-4-isopropoxyphenyl)(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidin-1- yl)methanone The title compound was prepared according to General procedure I, using Intermediate 49 (1.0 equiv., 48.9 mg, 0.09218 mmol) in 1.2 mL 70% EtOH / H2O, AcOH (5.2 equiv., 27.4 µL, 0.4793 mmol) and Fe powder (10.0 equiv., 51.5 mg, 0.9218 mmol). Yield: 45.9 mg, 99%. Rf = 0.25 (2.5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 7.79 (d, J = 9.2 Hz, 1H), 7.31 (d, J = 9.2 Hz, 1H), 7.28 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.6 Hz, 2H), 6.87 – 6.76 (m, 3H), 4.74 (br s, 1H), 4.58 (hept, J = 6.1 Hz, 1H), 4.10 (br s, 1H), 2.97 (br s, 2H), 2.81 (tt, J = 12.2, 3.6 Hz, 1H), 1.90 (br s, 2H), 1.69 (br s, 2H), 1.37 (s, 3H), 1.36 (s, 3H);13C NMR (CDCl3, 100 MHz) δ 170.9, 167.2, 151.3, 148.4 (q, J = 35.5 Hz), 146.7, 143.3, 136.9, 128.7, 128.3, 127.3 (q, J = 2.2 Hz), 121.5 (q, J = 273.6 Hz), 121.4, 117.8, 117.8, 114.4, 112.6, 70.8, 47.3, 43.8, 42.5, 33.9, 33.5, 22.3;19F NMR (CDCl3, 376 MHz) δ -66.38. MS (ESI) Found: [M+H]+= 501.2, calcd: [M+H]+= 501.2. Intermediate 83 tert-butyl 3-(3-(2-amino-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenoxy)propyl)azetidine-1-carboxylate (m, 4H), 1.69 (br s, 2H), 1.43 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 170.8, 167.2, 156.6, 151.3, 148.4 (q, J = 35.5 Hz), 147.7, 143.2, 135.8, 129.0, 128.4, 127.3, 121.5 (q, J = 272.5 Hz), 121.4, 118.1, 117.9, 114.4, 110.8, 79.4, 68.0, 54.4, 48.5, 43.5, 42.5, 34.1, 33.5, 31.1, 28.8, 28.6, 27.0;19F NMR (CDCl3, 376 MHz) δ -66.38. MS (ESI) Found: [M+H]+= 656.3, calcd: [M+H]+= 656.3. Intermediate 84 tert-butyl (E)-3-(3-(2-amino-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenoxy)prop-1-en-1-yl)azetidine-1-carboxylate 1.0 Hz, 1H), 4.78 (br s, 1H), 4.57 (m, 2H), 4.10 (t, J = 8.5 Hz, 2H), 4.04 (br s, 1H), 3.74 (dd, J = 8.5, 5.9 Hz, 2H), 3.24 (m, 1H), 2.97 (br s, 2H), 2.81 (tt, J = 12.1, 3.6 Hz, 1H), 1.89 (br s, 2H), 1.68 (br s, 2H), 1.43 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 170.6, 167.2, 156.4, 151.3, 148.4 (q, J = 35.2 Hz), 147.9, 147.1, 143.2, 134.9, 129.1, 128.3, 127.3, 126.3, 121.5 (q, J = 273.7 Hz), 121.4, 118.8, 117.9, 115.3, 111.5, 79.7, 68.7, 54.6, 48.6, 43.2, 42.5, 33.8, 33.3, 31.1, 28.5;19F NMR (CDCl3, 376 MHz) δ -66.38. MS (ESI) Found: [M+H]+= 654.3, calcd: [M+H]+= 654.3. Intermediate 85 tert-butyl 4-(2-amino-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)piperazine-1-carboxylate The title compound was prepared according to General procedure I, using Intermediate 64 (1.0 equiv., 479 mg, 0.7294 mmol) in 12.5 mL 70% EtOH / H2O, AcOH (5.2 equiv., 216.9 µL, 3.7931 mmol) and Fe powder (10.0 equiv., 407.4 mg, 7.2945 mmol). Yield: 457 mg, 99%. Rf = 0.48 (10% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.09 (d, J = 9.3 Hz, 1H), 7.54 (d, J = 9.3 Hz, 1H), 7.38 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 7.02 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.74 (dd, J = 8.1, 2.0 Hz, 1H), 4.75 (br s, 1H), 3.98 (br s, 1H), 3.71 – 3.47 (m, 4H), 3.21 (br s, 1H), 3.04 – 2.78 (m, 6H), 1.98 (br s, 1H), 1.84 (br s, 1H), 1.71 (br s, 2H), 1.48 (s, 9H);13C NMR (MeOD, 100 MHz) δ 173.1, 169.0, 156.5, 152.9, 149.4 (q, J = 35.2 Hz), 144.7, 143.7, 141.5, 133.3, 129.5, 129.4 (q, J = 2.6 Hz), 122.9 (q, J = 272.9 Hz), 122.3, 120.7, 119.9, 117.5, 114.6, 81.3, 51.9, 49.8, 45.3, 44.0, 43.3, 35.2, 34.2, 28.7;19F NMR (MeOD, 376 MHz) δ -67.90. MS (ESI) Found: [M+H]+= 627.3, calcd: [M+H]+= 627.3. Intermediate 86 (3-amino-4-(4-ethylpiperazin-1-yl)phenyl)(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidin-1-yl)methanone The title compound was prepared according to General procedure I, using Intermediate 65 (1.0 equiv., 13.32 g, 22.7848 mmol) in 230 mL 70% EtOH / H2O, AcOH (5.2 equiv., 6.776 mL, 118.481 mmol) and Fe powder (10.0 equiv., 12.73 g, 227.8481 mmol). Yield: 12.233 g, 97%. Rf = 0.32 (10% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.09 (d, J = 9.2 Hz, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.39 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.76 (dd, J = 8.0, 2.0 Hz, 1H), 4.76 (br s, 1H), 3.99 (br s, 1H), 3.22 (br s, 1H), 3.09 – 2.87 (m, 6H), 2.68 (m, 4H), 2.53 (q, J = 7.2 Hz, 2H), 1.98 (br s, 1H), 1.85 (br s, 1H), 1.72 (br s, 2H), 1.16 (t, J = 7.2 Hz, 3H);13C NMR (MeOD, 100 MHz) δ 173.1, 169.0, 152.9, 149.4 (q, J = 35.1 Hz), 144.8, 143.6, 141.6, 133.0, 129.5, 129.4 (q, J = 2.1 Hz), 122.9 (q, J = 272.9 Hz), 122.3, 120.4, 119.9, 117.6, 114.6, 54.3, 53.4, 51.4, 49.7, 44.0, 43.3, 35.2, 34.2, 11.8;19F NMR (MeOD, 376 MHz) δ -67.90. MS (ESI) Found: [M+H]+= 555.3, calcd: [M+H]+= 555.3. Intermediate 87 (3-amino-4-(4-ethylpiperazin-1-yl)-5-fluorophenyl)(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidin-1-yl)methanone The title compound was prepared according to General procedure I, using Intermediate 66 (1.0 equiv., 267 mg, 0.4431 mmol) in 7 mL 70% EtOH / H2O, AcOH (5.0 equiv., 126.7 µL, 2.2154 mmol) and Fe powder (10.0 equiv., 247.5 mg, 4.4309 mmol). Yield: 252 mg, 99%. Rf = 0.26 (10% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.09 (d, J = 9.3 Hz, 1H), 7.54 (d, J = 9.3 Hz, 1H), 7.39 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 9.2 Hz, 1H), 6.56 (d, J = 13.9 Hz, 1H), 4.31 (br s, 2H), 3.25 – 2.96 (m, 6H), 2.92 (tt, J = 12.0, 3.6 Hz, 1H), 2.64 (m, 4H), 2.49 (q, J = 7.2 Hz, 2H), 2.01 – 1.85 (m, 2H), 1.77 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H);13C NMR (MeOD, 100 MHz) δ 171.1, 169.0, 159.1 (d, J = 247.4 Hz), 152.9, 149.4 (q, J = 35.4 Hz), 144.8, 144.0 (d, J = 11.1 Hz), 131.7 (d, J = 10.6 Hz), 129.5, 129.4 (q, J = 2.4 Hz), 122.9 (q, J = 272.9 Hz), 122.3, 120.5 (d, J = 4.8 Hz), 119.9, 117.2 (d, J = 2.8 Hz), 105.2 (d, J = 24.2 Hz), 53.9, 53.3, 52.1 (d, J = 2.4 Hz), 49.8, 43.9, 43.3, 34.8, 34.6, 11.8;19F NMR (MeOD, 376 MHz) δ -67.92, -122.10. MS (ESI) Found: [M+H]+= 573.3, calcd: [M+H]+= 573.3. Intermediate 88 (3-amino-4-(4-ethylpiperazin-1-yl)-5-methylphenyl)(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidin-1-yl)methanone The title compound was prepared according to General procedure I, using Intermediate 67 (1.0 equiv., 91 mg, 0.1520 mmol) in 5 mL 70% EtOH / H2O, AcOH (5.0 equiv., 43.5 µL, 0.7601 mmol) and Fe powder (10.0 equiv., 84.9 mg, 1.5201 mmol). Yield: 66 mg, 76%. Rf = 0.18 (10% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.09 (d, J = 9.2 Hz, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.39 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 6.68 (d, J = 2.1 Hz, 1H), 6.49 (m, 1H), 4.74 (m, 1H), 3.97 (m, 1H), 3.39 (m, 2H), 3.21 (m, 1H), 3.02 – 2.84 (m, 6H), 2.56 (q, J = 7.2 Hz, 2H), 2.40 (m, 2H), 2.36 (s, 3H), 1.98 (m, 1H), 1.86 (m, 1H), 1.72 (m, 2H), 1.17 (t, J = 7.2 Hz, 3H);13C NMR (MeOD, 100 MHz) δ 172.9, 169.0, 152.9, 149.4 (q, J = 35.1 Hz), 147.0, 144.7, 138.4, 137.5, 135.0, 129.5, 129.4, 122.9 (q, J = 272.9 Hz), 122.3, 119.9, 119.8, 112.4, 55.2, 53.6, 49.7, 49.6, 43.9, 43.3, 35.2, 34.2, 20.0, 11.7;19F NMR (MeOD, 376 MHz) δ -67.92. MS (ESI) Found: [M+H]+= 569.3, calcd: [M+H]+= 569.3. Intermediate 89 (3-amino-4-(4-ethyl-1,4-diazepan-1-yl)phenyl)(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidin-1-yl)methanone The title compound was prepared according to General procedure I, using Intermediate 68 (1.0 equiv., 80 mg, 0.1336 mmol) in 2.5 mL 70% EtOH / H2O, AcOH (5.2 equiv., 39.7 µL, 0.6949 mmol) and Fe powder (10.0 equiv., 74.6 mg, 1.3364 mmol). Yield: 51.7 mg, 68%. Rf = 0.07 (10% MeOH / DCM).1H NMR (MeOD, 600 MHz) δ 8.09 (d, J = 9.2 Hz, 1H), 7.55 (d, J = 9.2 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.73 (dd, J = 8.0, 2.0 Hz, 1H), 4.76 (br s, 1H), 3.99 (br s, 1H), 3.23 (br s, 1H), 3.18 (m, 2H), 3.13 (m, 2H), 2.98 – 2.87 (m, 6H), 2.71 (q, J = 7.3 Hz, 2H), 2.03 – 1.94 (m, 3H), 1.86 (br s, 1H), 1.72 (br s, 2H), 1.17 (d, J = 7.3 Hz, 3H);13C NMR (MeOD, 151 MHz) δ 173.2, 169.0, 152.9, 149.4 (q, J = 35.1 Hz), 144.8, 144.2, 143.9, 132.9, 129.5, 129.4 (q, J = 2.5 Hz), 122.9 (q, J = 272.9 Hz), 122.3, 122.3, 119.9, 117.7, 114.7, 57.0, 55.0, 54.7, 54.4, 53.4, 49.7, 44.0, 43.3, 35.2, 34.2, 29.1, 12.0;19F NMR (MeOD, 376 MHz) δ -67.95. MS (ESI) Found: [M+H]+= 569.3, calcd: [M+H]+= 569.3. Intermediate 90 tert-butyl 3-(2-amino-4-(methoxycarbonyl)phenoxy)azetidine-1-carboxylate The title compound was prepared according to General procedure I, using Intermediate 72 (1.0 equiv., 1.368 g, 3.8826 mmol) in 30 mL 70% EtOH / H2O, AcOH (5.2 equiv., 1.154 mL, 20.1896 mmol) and Fe powder (10.0 equiv., 2.17 g, 38.8261 mmol). Yield: 1.237 g, 99%. Rf = 0.30 (2.5% MeOH / DCM).1H NMR (DMSO, 400 MHz) δ 7.28 (d, J = 2.1 Hz, 1H), 7.13 (dd, J = 8.4, 2.1 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 5.15 (br s, 2H), 5.00 (tt, J = 6.4, 3.8 Hz, 1H), 4.29 (m, 2H), 3.86 (m, 2H), 3.77 (s, 3H), 1.39 (s, 9H);13C NMR (DMSO, 100 MHz) δ 166.4, 155.5, 146.9, 138.0, 122.8, 117.9, 114.2, 110.9, 78.9, 65.8, 56.4, 55.5, 51.6, 28.0. MS (ESI) Found: [M+H]+= 323.2, calcd: [M+H]+= 323.2. Intermediate 91 methyl 5-amino-4-cyclopropoxy-2-methylbenzoate The title compound was prepared according to General procedure I, using Intermediate 73 (1.0 equiv., 351.2 mg, 1.3979 mmol) in 15 mL 70% EtOH / H2O, AcOH (5.2 equiv., 415.7 µL, 7.2689 mmol) and Fe powder (10.0 equiv., 780.7 mg, 13.9787 mmol). Yield: 307 mg, 99%. Rf= 0.47 (DCM).1H NMR (DMSO, 400 MHz) δ 7.20 (s, 1H), 6.98 (s, 1H), 4.67 (br s, 2H), 3.88 (tt, J = 6.0, 2.9 Hz, 1H), 3.74 (s, 3H), 2.42 (s, 3H), 0.79 (m, 2H), 0.68 (m, 2H);13C NMR (DMSO, 100 MHz) δ 167.2, 148.7, 135.2, 128.5, 121.0, 115.7, 115.2, 51.3, 51.0, 21.2, 6.1. MS (ESI) Found: [M+H]+= 222.1, calcd: [M+H]+= 222.1. Intermediate 92 methyl 3-amino-4-cyclopropoxybenzoate The title compound was prepared according to General procedure I, using Intermediate 74 (1.0 equiv., 188.3 mg, 0.7938 mmol) in 3.5 mL 70% EtOH / H2O, AcOH (5.2 equiv., 236.0 µL, 4.1278 mmol) and Fe powder (10.0 equiv., 443 mg, 7.9381 mmol). Yield: 163.3 mg, 99%. Rf = 0.31 (DCM).1H NMR (DMSO, 400 MHz) δ 7.26 (d, J = 2.1 Hz, 1H), 7.21 (dd, J = 8.4, 2.1 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 4.91 (br s, 2H), 3.89 (tt, J = 6.0, 2.9 Hz, 1H), 3.77 (s, 3H), 0.80 (m, 2H), 0.69 (m, 2H);13C NMR (DMSO, 100 MHz) δ 166.5, 149.4, 137.6, 122.3, 118.1, 114.0, 111.7, 51.6, 51.0, 6.0. MS (ESI) Found: [M+H]+= 208.1, calcd: [M+H]+= 208.1. Intermediate 93 methyl 3-amino-4-(tert-butoxy)benzoate The title compound was prepared according to General procedure I, using Intermediate 75 (1.0 equiv., 230.5 mg, 0.9102 mmol) in 7.5 mL 70% EtOH / H2O, AcOH (5.2 equiv., 270.7 µL, 4.7329 mmol) and Fe powder (10.0 equiv., 508.3 mg, 9.1017 mmol). Yield: 202 mg, 99%. Rf= 0.40 (DCM).1H NMR (DMSO, 400 MHz) δ 7.31 (d, J = 2.2 Hz, 1H), 7.10 (dd, J = 8.3, 2.2 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 4.97 (br s, 2H), 3.77 (s, 3H), 1.36 (s, 9H);13C NMR (DMSO, 100 MHz) δ 166.5, 145.9, 142.4, 124.1, 121.2, 117.2, 115.0, 79.8, 51.7, 28.5. MS (ESI) Found: [M+H]+= 224.1, calcd: [M+H]+= 224.1. Intermediate 94 methyl 5-amino-2,3,4-trimethylbenzoate The title compound was prepared according to General procedure I, using methyl 2,3,4- trimethyl-5-nitrobenzoate (1.0 equiv., 3.4 g, 15.23 mmol) in 120 mL 70% EtOH / H2O, AcOH (5.2 equiv., 4.53 mL, 79.20 mmol) and Fe powder (10.0 equiv., 8.51 g, 152.31 mmol). Yield: 2.92 g, 99%. Rf = 0.40 (5% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 7.02 (s, 1H), 3.86 (s, 3H), 3.74 (br s, 2H), 2.38 (s, 3H), 2.22 (s, 3H), 2.14 (s, 3H);13C NMR (CDCl3, 100 MHz) δ 169.6, 142.0, 137.1, 129.0, 127.7, 125.5, 114.3, 51.9, 16.9, 16.5, 14.0. MS (ESI) Found: [M+H]+= 194.1, calcd: [M+H]+= 194.1. Intermediate 95 tert-butyl 3-(2-amino-4-(methoxycarbonyl)phenoxy)-3-methylazetidine-1-carboxylate The title compound was prepared according to General procedure I, using Intermediate 76 (1.0 equiv., 1.546 g, 4.2198 mmol) in 30 mL 70% EtOH / H2O, AcOH (5.2 equiv., 1.255 mL, 20.1896 mmol) and Fe powder (10.0 equiv., 2.36 g, 42.1978 mmol). Yield: 1.40 g, 99%. Rf= 0.27 (2.5% MeOH / DCM).1H NMR (DMSO, 400 MHz) δ 7.29 (d, J = 2.2 Hz, 1H), 7.12 (dd, J = 8.3, 2.2 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 5.10 (s, 2H), 4.08 (d, J = 9.1 Hz, 2H), 3.98 (d, J = 9.1 Hz, 2H), 3.77 (s, 3H), 1.61 (s, 3H), 1.38 (s, 9H);13C NMR (DMSO, 100 MHz) δ 166.4, 155.7, 144.8, 139.2, 122.7, 117.6, 114.6, 113.5, 79.0, 73.7, 60.7, 51.6, 28.0, 21.7. MS (ESI) Found: [M+H]+= 337.2, calcd: [M+H]+= 337.2. Intermediate 96 tert-butyl (R)-3-(2-amino-4-(methoxycarbonyl)phenoxy)pyrrolidine-1-carboxylate The title compound was prepared according to General procedure I, using Intermediate 77 (1.0 equiv., 1.73 g, 4.7220 mmol) in 36 mL 70% EtOH / H2O, AcOH (5.2 equiv., 1.40 mL, 24.5544 mmol) and Fe powder (10.0 equiv., 2.64 g, 47.2200 mmol). Yield: 1.57 g, 99%. Rf = 0.26 (2.5% MeOH / DCM).1H NMR (DMSO, 400 MHz) δ 7.28 (d, J = 2.2 Hz, 1H), 7.18 (dd, J = 8.4, 2.2 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.01 (br s, 2H), 5.00 (m, 1H), 3.77 (s, 3H), 3.56 (m, 1H), 3.47 – 3.35 (m, 3H), 2.08 (m, 2H), 1.39 (s, 9H);13C NMR (DMSO, 100 MHz) δ 166.5, 153.5, 147.5, 138.4, 122.3, 118.1, 114.3, 111.8, 78.8, 76.2, 51.6, 51.2, 43.9, 30.7, 28.2. MS (ESI) Found: [M+H]+= 337.2, calcd: [M+H]+= 337.2. Intermediate 97 tert-butyl (S)-2-((2-amino-4-(methoxycarbonyl)phenoxy)methyl)pyrrolidine-1-carboxylate The title compound was prepared according to General procedure I, using Intermediate 78 (1.0 equiv., 1.566 g, 4.1167 mmol) in 30 mL 70% EtOH / H2O, AcOH (5.2 equiv., 1.224 mL, 21.4069 mmol) and Fe powder (10.0 equiv., 2.3 g, 41.1672 mmol). Yield: 1.407 g, 98%. Rf = 0.49 (5% MeOH / DCM).1H NMR (DMSO, 400 MHz) δ 7.27 (m, 1H), 7.17 (dd, J = 8.3, 2.1 Hz, 1H), 6.90 (m, 1H), 4.96 (m, 2H), 4.15 – 3.99 (m, 2H), 3.94 (m, 1H), 3.77 (s, 3H), 2.01 – 1.85 (m, 3H), 1.81 (m, 1H), 1.40 (s, 9H);13C NMR (DMSO, 100 MHz) δ 166.5, 153.7, 149.2, 137.7, 122.1, 118.2, 113.9, 110.5, 78.8, 68.2, 55.4, 51.6, 46.4, 28.1, 27.8, 22.8. MS (ESI) Found: [M+H]+= 351.2, calcd: [M+H]+= 351.2. Intermediate 98 tert-butyl 3-amino-4-(2-(dimethylamino)ethoxy)benzoate The title compound was prepared according to General procedure I, using Intermediate 59 (1.0 equiv., 15.3 g, 49.2992 mmol) in 275 mL 70% EtOH / H2O, AcOH (5.2 equiv., 14.7 mL, 256.36 mmol) and Fe powder (10.0 equiv., 27.5 g, 492.99 mmol). Yield: 13.3 mg, 96%. Rf= 0.25 (10% MeOH / DCM).1H NMR (DMSO, 400 MHz) δ 7.21 (d, J = 2.1 Hz, 1H), 7.13 (dd, J = 8.4, 2.1 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.90 (br s, 2H), 4.07 (t, J = 5.8 Hz, 2H), 2.65 (t, J = 5.8 Hz, 2H), 2.22 (s, 6H), 1.50 (s, 9H);13C NMR (DMSO, 100 MHz) δ 165.3, 149.0, 137.7, 123.9, 118.2, 114.0, 110.9, 79.5, 66.4, 57.6, 45.5, 27.9. MS (ESI) Found: [M+H]+= 281.2, calcd: [M+H]+= 281.2. Intermediate 99 tert-butyl 3-amino-4-(2-morpholinoethoxy)benzoate The title compound was prepared according to General procedure I, using Intermediate 60 (1.0 equiv., 721.2 mg, 2.0465 mmol) in 10 mL 70% EtOH / H2O, AcOH (5.2 equiv., 609 µL, 10.6418 mmol) and Fe powder (10.0 equiv., 1.14 g, 20.4651 mmol). Yield: 640 mg, 97%. Rf = 0.10 (10% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 7.38 (dd, J = 8.4, 2.1 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 4.21 (t, J = 5.7 Hz, 2H), 3.77 (m, 4H), 2.89 (m, 2H), 2.64 (m, 4H), 1.56 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 166.0, 149.6, 136.4, 125.5, 120.7, 116.0, 111.2, 80.6, 66.7, 66.1, 57.6, 54.0, 28.4. MS (ESI) Found: [M+H]+= 323.2, calcd: [M+H]+= 323.2. Intermediate 100 tert-butyl 3-amino-4-(2-(pyrrolidin-1-yl)ethoxy)benzoate The title compound was prepared according to General procedure I, using Intermediate 61 (1.0 equiv., 692.3 mg, 2.0583 mmol) in 10 mL 70% EtOH / H2O, AcOH (5.2 equiv., 612 µL, 10.7031 mmol) and Fe powder (10.0 equiv., 1.15 g, 20.5829 mmol). Yield: 555 mg, 88%. Rf = 0.12 (10% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 7.38 (dd, J = 8.4, 2.1 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 4.23 (t, J = 5.8 Hz, 2H), 4.02 (br s, 2H), 3.05 (t, J = 5.8 Hz, 2H), 2.79 (m, 4H), 1.89 (m, 4H), 1.56 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 166.0, 149.6, 136.4, 125.3, 120.7, 115.9, 110.9, 80.5, 67.3, 54.8, 54.8, 28.4, 23.6. MS (ESI) Found: [M+H]+= 307.2, calcd: [M+H]+= 307.2. Intermediate 101 tert-butyl 5-amino-6-(2-(diisopropylamino)ethoxy)nicotinate The title compound was prepared according to General procedure I, using Intermediate 62 (1.0 equiv., 110 mg, 0.2994 mmol) in 1.2 mL 70% EtOH / H2O, AcOH (5.2 equiv., 89 µL, 1.5567 mmol) and Fe powder (10.0 equiv., 167.2 mg, 2.9936 mmol). Yield: 96 mg, 95%. Rf= 0.22 (10% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.18 (m, 1H), 7.37 (d, J = 2.1 Hz, 1H), 4.34 (m, 2H), 3.84 (br s, 2H), 3.04 (m, 2H), 2.82 (m, 2H), 1.56 (s, 9H), 1.04 (d, J = 6.5 Hz, 12H);13C NMR (CDCl3, 100 MHz) δ 165.4, 164.1, 138.3, 130.3, 121.9, 120.1, 81.4, 81.0, 67.4, 49.6, 44.2, 28.4, 21.0. MS (ESI) Found: [M+H]+= 338.2, calcd: [M+H]+= 338.2. Intermediate 102 tert-butyl 5-amino-6-(2-(dimethylamino)ethoxy)nicotinate The title compound was prepared according to General procedure I, using Intermediate 63 (1.0 equiv., 105 mg, 0.3373 mmol) in 1.2 mL 70% EtOH / H2O, AcOH (5.2 equiv., 100 µL, 1.7537 mmol) and Fe powder (10.0 equiv., 188 mg, 3.3725 mmol). Yield: 92 mg, 97%. Rf = 0.15 (10% MeOH / DCM).1H NMR (DMSO, 400 MHz) δ 7.90 (d, J = 2.1 Hz, 1H), 7.30 (d, J = 2.1 Hz, 1H), 5.14 (br s, 2H), 4.40 (t, J = 6.0 Hz, 2H), 2.64 (t, J = 6.0 Hz, 2H), 2.20 (s, 6H), 1.51 (s, 9H);13C NMR (DMSO, 100 MHz) δ 164.6, 154.0, 134.8, 132.2, 121.4, 117.8, 80.3, 63.8, 57.5, 45.5, 27.8. MS (ESI) Found: [M+H]+= 282.2, calcd: [M+H]+= 282.2. Intermediate 103 tert-butyl 4-(3-amino-5-(methoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate The title compound was prepared according to General procedure I, using Intermediate 69 (1.0 equiv., 2.256 g, 6.1577 mmol) in 48 mL 70% EtOH / H2O, AcOH (5.2 equiv., 1.83 mL, 32.0201 mmol) and Fe powder (10.0 equiv., 3.4 g, 61.5771 mmol). Yield: 1.88 g, 91%. Rf= 0.19 (2.5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.40 (d, J = 2.0 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 3.88 (s, 3H), 3.79 (br s, 2H), 3.57 (m, 4H), 3.18 (m, 4H), 1.47 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 166.5, 155.0, 153.7, 139.8, 134.4, 122.3, 121.8, 80.1, 52.2, 48.2, 44.1, 28.5. MS (ESI) Found: [M+H]+= 337.2, calcd: [M+H]+= 337.2. Intermediate 104 tert-butyl 3-amino-4-(4-ethylpiperazin-1-yl)benzoate The title compound was prepared according to General procedure I, using Intermediate 70 (1.0 equiv., 2.944 g, 8.7776 mmol) in 39 mL 70% EtOH / H2O, AcOH (5.0 equiv., 2.51 mL, 43.8879 mmol) and Fe powder (10.0 equiv., 4.90 g, 87.f 7758 mmol). Yield: 2.55 g, 95%. R = 0.35 (10% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 7.35 (d, J = 2.0 Hz, 1H), 7.29 (dd, J = 8.2, 2.0 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 2.99 (m, 4H), 2.67 (m, 4H), 2.52 (q, J = 7.2 Hz, 2H), 1.56 (s, 9H), 1.15 (t, J = 7.2 Hz, 3H);13C NMR (MeOD, 100 MHz) δ 168.0, 144.3, 142.9, 128.7, 120.9, 119.7, 117.0, 81.6, 54.2, 53.4, 51.0, 28.5, 11.8. MS (ESI) Found: [M+H]+= 306.2, calcd: [M+H]+= 306.2. Intermediate 105 tert-butyl 4-(2-amino-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate A solution of Intermediate 71 (1.0 g, 2.7595 mmol) and 1 drop of AcOH in 30 mL of MeOH was stirred under hydrogen atmosphere using palladium on carbon catalyst (100 mg of 10% Pd / C) at 50 °C overnight. The reaction mixture was then allowed to cool down to room temperature and quenched by addition of chloroform (20 mL). The catalyst was filtered off on a pad of Celite, and the filtrate was evaporated to dryness in vacuo. The oily product was sufficiently pure, further purification was not necessary. Yield: 0.91 g, 99%. Rf= 0.74 (10% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 7.43 (dd, J = 8.0, 1.8 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 4.28 (m, 2H), 3.87 (s, 3H), 2.82 (m, 2H), 2.63 (tt, J = 11.9, 3.3 Hz, 1H), 1.84 (m, 2H), 1.60 (qd, J = 12.8, 4.3 Hz, 2H), 1.48 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 167.3, 154.9, 143.6, 134.8, 128.9, 126.2, 120.5, 117.0, 79.8, 52.1, 44.5, 37.1, 31.4, 28.6. MS (ESI) Found: [M+H]+= 335.2, calcd: [M+H]+= 335.2. Intermediate 106 tert-butyl 3-(3-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenoxy)propyl)azetidine-1-carboxylate Th titl d d di t G l d Hz, 2H), 3.97 (m, 2H), 3.94 (br s, 1H), 3.52 (dd, J = 8.5, 5.5 Hz, 2H), 3.13 (br s, 1H), 2.91 (br s, 1H), 2.83 (tt, J = 12.1, 3.6 Hz, 1H), 2.49 (m, 1H), 1.93 (br s, 2H), 1.73 (br s, 2H), 1.65 – 1.60 (m, 4H), 1.44 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 169.7, 167.2, 156.5, 151.3, 148.4 (q, J = 35.2 Hz), 148.3, 143.1, 130.9, 129.3, 129.1, 128.9, 128.5, 128.4, 127.3, 126.4, 124.3, 121.5 (q, J = 274.1 Hz), 121.5, 117.8, 117.1, 111.4, 79.5, 68.6, 67.3, 57.7, 48.8, 43.9, 42.5, 34.1, 33.7, 30.8, 28.7, 28.6, 26.6;19F NMR (CDCl3, 376 MHz) δ -66.38. MS (ESI) Found: [M+H]+= 810.3, calcd: [M+H]+= 810.3. Intermediate 107 tert-butyl (E)-3-(3-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenoxy)prop-1-en-1-yl)azetidine-1-carboxylate 1H), 5.61 (dtd, J = 15.4, 6.1, 1.1 Hz, 1H), 4.85 (br s, 1H), 4.50 (m, 2H), 4.36 (s, 2H), 4.12 (t, J = 8.5 Hz, 2H), 3.91 (br s, 1H), 3.73 (dd, J = 8.6, 5.8 Hz, 2H), 3.23 (m, 1H), 3.13 (br s, 1H), 2.90 (br s, 1H), 2.83 (tt, J = 12.2, 3.7 Hz, 1H), 1.93 (br s, 2H), 1.74 (br s, 2H), 1.45 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 169.6, 167.2, 156.4, 151.3, 148.2 (q, J = 14.8 Hz), 148.1, 143.1, 136.4, 130.9, 129.5, 129.1, 128.9, 128.5, 128.4, 127.3, 126.6, 125.3, 124.3, 121.5 (q, J = 259.1 Hz), 121.5, 117.8, 117.4, 111.8, 79.7, 69.2, 57.8, 54.4, 48.6, 43.4, 42.5, 33.4, 33.1, 31.1, 28.5;19F NMR (CDCl3, 376 MHz) δ -66.38. MS (ESI) Found: [M+H]+= 808.3, calcd: [M+H]+= 808.3. Intermediate 108 tert-butyl 4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)piperazine-1-carboxylate The title compound was prepared according to General procedure J, using Intermediate 85 (1.0 equiv., 155 mg, 0.2473 mmol) in 2 mL of pyridine and benzylsulfonyl chloride (2.0 equiv., 94.3 mg, 0.4946 mmol). The crude was purified with column chromatography using 20% EtOAc / DCM to afford the product (173 mg, 90%). Rf = 0.37 (20% EtOAc / DCM).1H NMR (CDCl3, 400 MHz) δ 7.80 (d, J = 9.2 Hz, 1H), 7.66 (br s, 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.38 – 7.27 (m, 6H), 7.23 – 7.15 (m, 6H), 4.87 (br s, 1H), 4.45 (s, 2H), 3.88 (br s, 1H), 3.39 (m, 4H), 3.16 (br s, 1H), 2.89 (br s, 1H), 2.84 (tt, J = 12.0, 3.6 Hz, 1H), 2.65 (m, 4H), 2.01 (br s, 1H), 1.86 (br s, 1H), 1.77 (br s, 1H), 1.68 (br s, 1H), 1.46 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 169.4, 167.1, 154.6, 151.3, 148.4 (q, J = 35.2 Hz), 142.9, 141.0, 134.5, 133.2, 130.7, 129.2, 129.0, 128.7, 128.3, 127.3, 123.0, 122.0, 121.5, 121.5 (q, J = 274.6 Hz), 117.9, 115.2, 80.4, 57.9, 52.2, 48.6, 43.8, 43.1, 42.4, 34.0, 33.1, 28.5;19F NMR (CDCl3, 376 MHz) δ -66.38. MS (ESI) Found: [M+H]+= 781.3, calcd: [M+H]+= 781.3. Intermediate 109 methyl 4-methyl-3-((phenylmethyl)sulfonamido)benzoate The title compound was prepared according to General procedure J, using methyl-3- amino-4-methyl benzoate (1.0 equiv., 1.037 g, 6.2776 mmol) in 10 mL of pyridine and benzylsulfonyl chloride (1.2 equiv., 1.436 g, 7.5325 mmol). The crude was purified with column chromatography using 2.5% MeOH / DCM to afford the product (1.241 g, 62%).1H NMR (CDCl3, 600 MHz) δ 8.13 (d, J = 1.6 Hz, 1H), 7.78 (dd, J = 7.9, 1.6 Hz, 1H), 7.39 – 7.32 (m, 3H), 7.26 – 7.20 (m, 3H), 5.97 (s, 1H), 4.43 (s, 2H), 3.93 (s, 3H), 2.07 (s, 3H);13C NMR (CDCl3, 151 MHz) δ 166.6, 135.6, 133.8, 131.3, 130.8, 129.8, 129.2, 129.1, 128.5, 126.4, 120.8, 58.1, 52.4, 18.0. HRMS (ESI) Found: [M-H]- = 318.0807, calcd: [M-H]- = 318.0806. Intermediate 110 methyl 4-methoxy-3-((phenylmethyl)sulfonamido)benzoate The title compound was prepared according to General procedure J, using methyl-3- amino-4-methoxy benzoate (1.0 equiv., 272 mg, 1.5012 mmol) in 4 mL of pyridine and benzylsulfonyl chloride (1.2 equiv., 343.4 mg, 1.8014 mmol). The crude was purified with column chromatography using 2.5% MeOH / DCM to afford the product (474 mg, 94%). Rf = 0.07 (25% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 8.15 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 8.6, 2.0 Hz, 1H), 7.36 – 7.27 (m, 3H), 7.23 – 7.14 (m, 2H), 6.90 (d, J = 8.6 Hz, 1H), 6.75 (br s, 1H), 4.35 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H);13C NMR (CDCl3, 100 MHz) δ 166.4, 151.8, 130.8, 129.0, 128.8, 128.4, 127.1, 126.7, 123.6, 119.7, 110.1, 57.8, 56.1, 52.2. HRMS (ESI) Found: [M-H]- = 334.0752, calcd: [M-H]- = 334.0755. Intermediate 111 tert-butyl 3-(4-(methoxycarbonyl)-2-((phenylmethyl)sulfonamido)phenoxy)azetidine-1-carboxylate The title compound was prepared according to General procedure J, using Intermediate 90 (1.0 equiv., 1.213 g, 3.7629 mmol) in 8 mL of pyridine and benzylsulfonyl chloride (1.2 equiv., 861 mg, 4.5154 mmol). The crude was purified with column chromatography using 5% EtOAc / DCM to afford the product (1.648 g, 92%). Rf= 0.28 (5% EtOAc / DCM).1H NMR (CDCl3, 400 MHz) δ 8.21 (d, J = 2.1 Hz, 1H), 7.79 (dd, J = 8.5, 2.1 Hz, 1H), 7.37 – 7.28 (m, 3H), 7.25 – 7.18 (m, 2H), 6.66 (s, 1H), 6.52 (d, J = 8.5 Hz, 1H), 4.85 (tt, J = 6.4, 4.0 Hz, 1H), 4.38 (s, 2H), 4.29 (ddd, J = 10.0, 6.4, 1.1 Hz, 2H), 3.91 (s, 3H), 3.86 (dd, J = 10.0, 4.0 Hz, 2H), 1.47 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 166.2, 155.9, 148.7, 130.7, 129.2, 128.9, 128.5, 127.0, 126.9, 124.6, 120.2, 110.8, 80.5, 67.0, 57.9, 56.1, 52.4, 28.5. MS (ESI) Found: [M+H]+= 477.2, calcd: [M+H]+= 477.2. Intermediate 112 methyl 4-methoxy-2-methyl-5-((phenylmethyl)sulfonamido)benzoate The title compound was prepared according to General procedure J, using methyl 5-amino-4-methoxy-2-methylbenzoate (1.0 equiv., 187 mg, 0.9579 mmol) in 2 mL of pyridine and benzylsulfonyl chloride (1.3 equiv., 237.4 mg, 1.2453 mmol). The crude was purified with column chromatography using 30% EtOAc / Petroleum Ether to afford the product (263 mg, 79%). Rf= 0.28 (30% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.35 – 7.28 (m, 3H), 7.20 (m, 2H), 6.71 (s, 1H), 6.61 (br s, 1H), 4.32 (s, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 2.62 (s, 3H);13C NMR (CDCl3, 100 MHz) δ 167.1, 151.1, 139.1, 130.9, 128.9, 128.8, 128.6, 124.1, 122.2, 121.9, 113.6, 57.5, 55.9, 52.0, 22.1. MS (ESI) Found: [M+H]+= 350.1, calcd: [M+H]+= 350.1. Intermediate 113 methyl 4-cyclopropoxy-2-methyl-5-((phenylmethyl)sulfonamido)benzoate The title compound was prepared according to General procedure J, using Intermediate 91 (1.0 equiv., 315 mg, 1.4237 mmol) in 3 mL of pyridine and benzylsulfonyl chloride (1.2 equiv., 325.7 mg, 1.7084 mmol. The crude was purified with column chromatography using 20% EtOAc / Petroleum Ether to afford the product (500 mg, 94%). Rf= 0.29 (20% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 8.11 (s, 1H), 7.38 – 7.29 (m, 3H), 7.23 – 7.16 (m, 2H), 7.08 (s, 1H), 4.31 (s, 2H), 3.88 (s, 3H), 3.75 (tt, J = 6.1, 2.9 Hz, 1H), 2.63 (s, 3H), 0.84 (m, 2H), 0.70 (m, 2H);13C NMR (CDCl3, 100 MHz) δ 167.2, 150.5, 138.8, 130.8, 129.0, 128.8, 128.6, 123.9, 122.6, 121.6, 115.6, 57.3, 52.0, 51.9, 22.1, 6.4. MS (ESI) Found: [M+H]+= 376.1, calcd: [M+H]+= 376.1. Intermediate 114 methyl 4-cyclopropoxy-3-((phenylmethyl)sulfonamido)benzoate The title compound was prepared according to General procedure J, using Intermediate 92 (1.0 equiv., 157.8 mg, 0.7615 mmol) in 2 mL of pyridine and benzylsulfonyl chloride (1.2 equiv., 174.2 mg, 0.9134 mmol). The crude was purified with column chromatography using 20% EtOAc / Petroleum Ether to afford the product (265 mg, 96%). Rf = 0.21 (20% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 8.17 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 8.6, 2.0 Hz, 1H), 7.38 – 7.26 (m, 4H), 7.20 – 7.16 (m, 2H), 6.62 (br s, 1H), 4.35 (s, 2H), 3.91 (s, 3H), 3.76 (tt, J = 6.1, 2.9 Hz, 1H), 0.83 (m, 2H), 0.71 (m, 2H);13C NMR (CDCl3, 100 MHz) δ 166.5, 151.3, 130.8, 129.1, 128.9, 128.5, 126.9, 126.5, 123.9, 119.5, 112.3, 57.6, 52.3, 52.1, 6.4. MS (ESI) Found: [M+H]+= 362.1, calcd: [M+H]+= 362.1. Intermediate 115 methyl 4-(tert-butoxy)-3-((phenylmethyl)sulfonamido)benzoate The title compound was prepared according to General procedure J, using Intermediate 93 (1.0 equiv., 195.1 mg, 0.8738 mmol) in 2.5 mL of pyridine and benzylsulfonyl chloride (1.2 equiv., 199.9 mg, 1.0486 mmol). The crude was purified with column chromatography using 20% EtOAc / Petroleum Ether to afford the product (312 mg, 95%). Rf = 0.34 (20% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 8.11 (d, J = 2.1 Hz, 1H), 7.73 (dd, J = 8.6, 2.1 Hz, 1H), 7.38 – 7.29 (m, 2H), 7.26 – 7.22 (m, 2H), 7.09 (d, J = 8.6 Hz, 1H), 6.77 (br s, 1H), 4.38 (s, 2H), 3.90 (s, 3H), 1.41 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 166.5, 148.6, 130.8, 130.1, 129.0, 129.0, 128.5, 125.8, 124.4, 118.9, 118.3, 82.0, 57.9, 52.3, 29.0. MS (ESI) Found: [M+H]+= 378.1, calcd: [M+H]+= 378.1. Intermediate 116 methyl 2,3,4-trimethyl-5-((phenylmethyl)sulfonamido)benzoate The title compound was prepared according to General procedure J, using Intermediate 94 (1.0 equiv., 1.0 g, 5.1746 mmol) in 10 mL of pyridine and benzylsulfonyl chloride (1.6 equiv., 1.58 g, 8.2794 mmol). The crude was purified with column chromatography using 5% EtOAc / DCM to afford the product (1.19 g, 66%). Rf = 0.70 (5% EtOAc / DCM).1H NMR (CDCl3, 400 MHz) δ 7.66 (s, 1H), 7.41 – 7.29 (m, 5H), 5.90 (s, 1H), 4.37 (s, 2H), 3.90 (s, 3H), 2.47 (s, 3H), 2.26 (s, 3H), 2.12 (s, 3H);13C NMR (CDCl3, 100 MHz) δ 168.6, 138.4, 135.8, 134.9, 132.1, 130.9, 129.5, 129.0, 128.9, 128.7, 122.7, 58.1, 52.3, 17.3, 16.9, 15.4. MS (ESI) Found: [M+H]+= 348.1, calcd: [M+H]+= 348.1. Intermediate 117 methyl 2,4-dimethyl-5-((phenylmethyl)sulfonamido)benzoate The title compound was prepared according to General procedure J, using methyl 5-amino-2,4-dimethylbenzoate (1.0 equiv., 330 mg, 1.8413 mmol) in 3 mL of pyridine and benzylsulfonyl chloride (1.2 equiv., 421 mg, 2.2096 mmol). The crude was purified with column chromatography using 50% EtOAc / Petroleum Ether to afford the product (601 mg, 98%). Rf = 0.20 (30% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 8.00 (s, 1H), 7.39 – 7.32 (m, 3H), 7.29 – 7.24 (m, 2H), 7.07 (s, 1H), 5.97 (s, 1H), 4.39 (s, 2H), 3.90 (s, 3H), 2.55 (s, 3H), 2.07 (s, 3H). MS (ESI) Found: [M+H]+= 334.1, calcd: [M+H]+= 334.1. Intermediate 118 methyl 2,4-dimethoxy-5-((phenylmethyl)sulfonamido)benzoate The title compound was prepared according to General procedure J, using methyl 5-amino-2,4-dimethoxybenzoate (1.0 equiv., 184 mg, 0.8711 mmol) in 2 mL of pyridine and benzylsulfonyl chloride (1.3 equiv., 215.9 mg, 1.1325 mmol). The crude was purified with column chromatography using 30% EtOAc / Petroleum Ether to afford the product (292 mg, 92%). Rf = 0.27 (30% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 7.99 (s, 1H), 7.37 – 7.29 (m, 3H), 7.26 – 7.22 (m, 2H), 6.48 (s, 1H), 6.41 (br s, 1H), 4.30 (s, 2H), 3.94 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H). MS (ESI) Found: [M+H]+= 366.1, calcd: [M+H]+= 366.1. Intermediate 119 methyl 3,4-dimethoxy-5-((phenylmethyl)sulfonamido)benzoate The title compound was prepared according to General procedure J, using methyl 3-amino-4,5-dimethoxybenzoate (1.0 equiv., 320 mg, 1.5150 mmol) in 2 mL of pyridine and benzylsulfonyl chloride (1.2 equiv., 346.6 mg, 1.8180 mmol). The crude was purified with column chromatography using 10% EtOAc / Toluene to afford the product (352 mg, 64%). Rf = 0.54 (20% EtOAc / Toluene).1H NMR (CDCl3, 400 MHz) δ 7.79 (d, J = 1.8 Hz, 1H), 7.40 (d, J = 1.8 Hz, 1H), 7.34 – 7.30 (m, 3H), 7.24 – 7.21 (m, 2H), 6.92 (br s, 1H), 4.41 (s, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 3.81 (s, 3H). MS (ESI) Found: [M+H]+= 366.1, calcd: [M+H]+= 366.1. Intermediate 120 ethyl 6-methyl-5-((phenylmethyl)sulfonamido)nicotinate The title compound was prepared according to General procedure J, using ethyl 5- amino-6-methylnicotinate (1.0 equiv., 112 mg, 0.6215 mmol) in 1.5 mL of pyridine and benzylsulfonyl chloride (1.3 equiv., 154.0 mg, 0.8079 mmol). The crude was purified with column chromatography using 50% EtOAc / Petroleum Ether to afford the product (130 mg, 63%). Rf = 0.20 (40% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 8.87 (d, J = 1.9 Hz, 1H), 8.23 (d, J = 1.9 Hz, 1H), 7.39 – 7.29 (m, 3H), 7.27 – 7.21 (m, 2H), 6.41 (br s, 1H), 4.41 (s, 2H), 4.41 (q, J = 7.1 Hz, 2H), 2.35 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H). MS (ESI) Found: [M+H]+= 335.1, calcd: [M+H]+= 335.1. Intermediate 121 methyl 6-methoxy-5-((phenylmethyl)sulfonamido)nicotinate The title compound was prepared according to General procedure J, using methyl 5- amino-6-methoxynicotinate (1.0 equiv., 218 mg, 1.1966 mmol) in 4 mL of pyridine and benzylsulfonyl chloride (1.2 equiv., 273.7 mg, 1.4359 mmol). The crude was purified with column chromatography using 10% EtOAc / Toluene to afford the product (279 mg, 69%). Rf = 0.25 (10% EtOAc / Toluene).1H NMR (CDCl3, 400 MHz) δ 8.55 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 7.36 – 7.28 (m, 3H), 7.22 (dd, J = 7.7, 1.7 Hz, 2H), 6.63 (br s, 1H), 4.38 (s, 2H), 3.99 (s, 3H), 3.91 (s, 3H). MS (ESI) Found: [M+H]+= 337.1, calcd: [M+H]+= 337.1. Intermediate 122 tert-butyl 3-(4-(methoxycarbonyl)-2-((phenylmethyl)sulfonamido)phenoxy)-3-methylazetidine-1- carboxylate The title compound was prepared according to General procedure J, using Intermediate 95 (1.0 equiv., 1.474 g, 4.3818 mmol) in 8 mL of pyridine and benzylsulfonyl chloride (1.3 equiv., 1.086 g, 5.6964 mmol). The crude was purified with column chromatography using 10% EtOAc / DCM to afford the product (2.099 g, 98%). Rf= 0.43 (10% EtOAc / DCM).1H NMR (CDCl3, 400 MHz) δ 8.23 (d, J = 2.0 Hz, 1H), 7.76 (dd, J = 8.6, 2.0 Hz, 1H), 7.37 – 7.28 (m, 3H), 7.23 – 7.17 (m, 2H), 6.64 (br s, 1H), 6.46 (d, J = 8.6 Hz, 1H), 4.39 (s, 2H), 4.03 (d, J = 9.3 Hz, 2H), 3.94 (d, J = 9.3 Hz, 2H), 3.91 (s, 3H), 1.65 (s, 3H), 1.48 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 166.2, 156.1, 146.7, 130.7, 129.3, 129.0, 128.5, 127.7, 126.3, 124.1, 119.8, 112.7, 80.5, 74.9, 61.0, 57.6, 52.4, 28.5, 22.1. MS (ESI) Found: [M+H]+= 491.2, calcd: [M+H]+= 491.2. Intermediate 123 tert-butyl (R)-3-(4-(methoxycarbonyl)-2-((phenylmethyl)sulfonamido)phenoxy)pyrrolidine-1- carboxylate The title compound was prepared according to General procedure J, using Intermediate 96 (1.0 equiv., 1.646 g, 4.8931 mmol) in 10 mL of pyridine and benzylsulfonyl chloride (1.2 equiv., 1.12 g, 5.8718 mmol). The crude was purified with column chromatography using 10% EtOAc / DCM to afford the product (2.16 g, 90%). Rf= 0.43 (10% EtOAc / DCM).1H NMR (CDCl3, 400 MHz) δ 8.18 (d, J = 2.1 Hz, 1H), 7.81 (dd, J = 8.6, 2.1 Hz, 1H), 7.36 – 7.26 (m, 3H), 7.21 – 7.14 (m, 2H), 6.83 (d, J = 8.6 Hz, 1H), 6.64 (s, 1H), 4.91 (m, 1H), 4.37 (s, 2H), 3.91 (s, 3H), 3.67 (dd, J = 12.7, 4.9 Hz, 1H), 3.55 (m, 1H), 3.44 (m, 1H), 3.28 (td, J = 10.4, 7.0 Hz, 1H), 2.20 – 1.99 (m, 2H), 1.47 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 166.3, 154.3, 149.3, 130.7, 129.1, 128.9, 128.4, 127.2, 126.8, 124.0, 119.8, 111.5, 80.1, 77.4, 57.7, 52.3, 51.4, 43.9, 31.3, 28.6. MS (ESI) Found: [M+H]+= 491.2, calcd: [M+H]+= 491.2. Intermediate 124 tert-butyl (S)-2-((4-(methoxycarbonyl)-2-((phenylmethyl)sulfonamido)phenoxy)methyl)pyrrolidine- 1-carboxylate The title compound was prepared according to General procedure J, using Intermediate 97 (1.0 equiv., 1.212 g, 3.4587 mmol) in 10 mL of pyridine and benzylsulfonyl chloride (1.3 equiv., 857.2 mg, 4.4963 mmol). The crude was purified with column chromatography using 5% EtOAc / DCM to afford the product (1.664 g, 95%)f13 . R = 0.40 (5% EtOAc / DCM). H NMR (CDCl, 400 MHz) δ 8.12 (d, J = 2.1 Hz, 1H), 7.80 (dd, J = 8.5, 2.1 Hz, 1H), 7.34 – 7.26 (m, 3H), 7.25 – 7.18 (m, 2H), 6.98 (d, J = 8.6 Hz, 1H), 4.38 (s, 2H), 4.21 – 4.07 (m, 2H), 3.89 (s, 3H), 3.87 (m, 1H), 3.34 (m, 2H), 1.99 – 1.70 (m, 4H), 1.48 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 166.5, 155.2, 151.2, 130.8, 128.9, 128.8, 128.5, 127.0, 127.0, 123.6, 119.8, 111.1, 80.2, 69.9, 57.9, 55.6, 52.2, 47.0, 28.7, 28.0, 23.9. MS (ESI) Found: [M+H]+= 505.2, calcd: [M+H]+= 505.2. Intermediate 125 tert-butyl 4-(2-(dimethylamino)ethoxy)-3-((phenylmethyl)sulfonamido)benzoate The title compound was prepared according to General procedure J, using Intermediate 98 (1.0 equiv., 13.312 g, 47.4801 mmol) in 100 mL of pyridine and benzylsulfonyl chloride (1.3 equiv., 11.77 g, 61.7242 mmol). The crude was purified with column chromatography using 5% MeOH / DCM to afford the product (20.1 g, 97%). Rf= 0.35 (5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.24 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.4, 2.1 Hz, 1H), 7.33 – 7.26 (m, 5H), 7.01 (d, J = 8.4 Hz, 1H), 4.30 (s, 2H), 4.02 (t, J = 5.3 Hz, 2H), 2.47 (t, J = 5.4 Hz, 2H), 2.13 (s, 6H), 1.59 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 165.2, 152.0, 131.2, 130.8, 129.3, 128.6, 128.6, 127.9, 126.3, 121.9, 118.1, 81.2, 70.1, 57.8, 57.6, 44.6, 28.3. MS (ESI) Found: [M+H]+= 435.2, calcd: [M+H]+= 435.2. Intermediate 126 tert-butyl 4-(2-morpholinoethoxy)-3-((phenylmethyl)sulfonamido)benzoate The title compound was prepared according to General procedure J, using Intermediate 99 (1.0 equiv., 641.7 mg, 1.9903 mmol) in 9 mL of pyridine and benzylsulfonyl chloride (1.3 equiv., 493.2 mg, 2.5873 mmol). The crude was purified with column chromatography using 10% MeOH / DCM to afford the product (940 mg, 99%). Rf = 0.30 (10% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.24 (d, J = 2.1 Hz, 1H), 7.79 (dd, J = 8.5, 2.1 Hz, 1H), 7.33 – 7.29 (m, 5H), 7.02 (d, J = 8.5 Hz, 1H), 4.28 (s, 2H), 4.14 (t, J = 5.5 Hz, 2H), 3.60 (m, 4H), 2.45 (t, J = 5.5 Hz, 2H), 2.35 (m, 4H), 1.60 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 165.0, 152.0, 131.3, 129.8, 129.0, 128.7, 128.6, 127.7, 127.2, 123.0, 117.0, 81.4, 68.1, 66.2, 58.0, 56.8, 53.4, 28.3. MS (ESI) Found: [M+H]+= 477.2, calcd: [M+H]+= 477.2. Intermediate 127 tert-butyl 3-((phenylmethyl)sulfonamido)-4-(2-(pyrrolidin-1-yl)ethoxy)benzoate The title compound was prepared according to General procedure J, using Intermediate 100 (1.0 equiv., 551.8 mg, 1.8010 mmol) in 8 mL of pyridine and benzylsulfonyl chloride (1.3 equiv., 446.3 mg, 2.3413 mmol). The crude was purified with column chromatography using 10% MeOH / DCM to afford the product (730 mg, 88%). Rf= 0.32 (10% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.23 (d, J = 2.1 Hz, 1H), 7.76 (dd, J = 8.5, 2.1 Hz, 1H), 7.33 – 7.29 (m, 5H), 7.01 (d, J = 8.5 Hz, 1H), 4.27 (s, 2H), 4.12 (t, J = 5.5 Hz, 2H), 2.59 (t, J = 5.5 Hz, 2H), 2.45 (m, 5H), 1.73 (m, 4H), 1.59 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 165.2, 152.4, 138.2, 131.2, 130.7, 129.3, 128.6, 127.7, 126.9, 123.2, 117.6, 81.3, 58.0, 54.1, 53.6, 28.3, 23.3. MS (ESI) Found: [M+H]+= 461.2, calcd: [M+H]+= 461.2. Intermediate 128 tert-butyl 6-(2-(diisopropylamino)ethoxy)-5-((phenylmethyl)sulfonamido)nicotinate The title compound was prepared according to General procedure J, using Intermediate 101 (1.0 equiv., 99 mg, 0.2934 mmol) in 1.0 mL of pyridine and benzylsulfonyl chloride (1.3 equiv., 72.7 mg, 0.3814 mmol). The crude was purified with column chromatography using 5% MeOH / DCM to afford the product (139.2 mg, 97%). Rf = 0.36 (5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.41 (m, 1H), 8.06 (m, 1H), 7.36 – 7.27 (m, 5H), 4.61 – 4.27 (m, 4H), 3.07 (m, 2H), 2.77 (m, 2H), 1.58 (s, 9H), 1.08 (br s, 12H);13C NMR (CDCl3, 100 MHz) δ 164.2, 155.2, 143.6, 131.0, 129.0, 128.9, 128.9, 128.4, 122.5, 121.8, 81.7, 67.8, 59.8, 55.5, 49.7, 28.3, 20.8. MS (ESI) Found: [M+H]+= 492.3, calcd: [M+H]+= 492.3. Intermediate 129 tert-butyl 6-(2-(dimethylamino)ethoxy)-5-((phenylmethyl)sulfonamido)nicotinate The title compound was prepared according to General procedure J, using Intermediate 102 (1.0 equiv., 177 mg, 0.6291 mmol) in 1.5 mL of pyridine and benzylsulfonyl chloride (1.3 equiv., 156 mg, 0.8178 mmol). The crude was purified with column chromatography using 5% MeOH / DCM to afford the product (244 mg, 89%). Rf = 0.34 (5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.31 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.48 – 7.42 (m, 2H), 7.27 – 7.22 (m, 3H), 4.63 (s, 2H), 4.60 (m, 2H), 3.40 (m, 2H), 2.81 (s, 6H), 1.56 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 164.0, 154.7, 142.9, 131.3, 128.7, 128.7, 128.7, 128.4, 123.2, 122.7, 81.7, 59.9, 59.9, 56.1, 43.2, 28.3. MS (ESI) Found: [M+H]+= 436.2, calcd: [M+H]+= 436.2. Intermediate 130 tert-butyl 4-(5-(methoxycarbonyl)-3-((phenylmethyl)sulfonamido)pyridin-2-yl)piperazine-1- carboxylate The title compound was prepared according to General procedure J, using Intermediate 103 (1.0 equiv., 1.072 g, 3.1868 mmol) in 10 mL of pyridine and benzylsulfonyl chloride (1.3 equiv., 790 mg, 4.1428 mmol). The crude was purified with column chromatography using 10% EtOAc / DCM to afford the product (1.21 g, 77%). Rf = 0.58 (2.5% MeOH / DCM).1H NMR (CDCl3 , 400 MHz) δ 8.68 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.39 – 7.30 (m, 3H), 7.20 (m, 2H), 4.45 (s, 2H), 3.92 (s, 3H), 3.43 (m, 4H), 2.92 (m, 4H), 1.46 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 165.4, 155.4, 154.7, 144.7, 130.6, 129.4, 129.2, 128.2, 126.8, 125.1, 125.1, 122.8, 80.3, 58.7, 52.5, 49.7, 43.4, 28.5. MS (ESI) Found: [M+H]+= 491.2, calcd: [M+H]+= 491.2. Intermediate 131 tert-butyl 4-(4-(methoxycarbonyl)-2-((phenylmethyl)sulfonamido)phenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure J, using Intermediate 105 (1.0 equiv., 800 mg, 2.3922 mmol) in 10 mL of pyridine and benzylsulfonyl chloride (1.3 equiv., 593 mg, 3.1099 mmol). The crude was purified with column chromatography using 30% EtOAc / Petroleum Ether to afford the product (1.12 g, 96%). Rf= 0.78 (50% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 8.01 (d, J = 1.7 Hz, 1H), 7.89 (dd, J = 8.2, 1.7 Hz, 1H), 7.38 – 7.31 (m, 6H), 6.51 (s, 1H), 4.41 (s, 2H), 4.18 (m, 2H), 3.92 (s, 3H), 2.84 (tt, J = 12.0, 3.6 Hz, 1H), 2.70 (m, 2H), 1.66 (m, 2H), 1.54 (m, 2H), 1.46 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 166.3, 154.8, 145.3, 133.8, 130.8, 129.3, 129.2, 129.1, 128.5, 128.1, 127.7, 125.2, 79.8, 58.4, 52.4, 44.2, 36.8, 32.3, 28.6. MS (ESI) Found: [M+H]+= 489.2, calcd: [M+H]+= 489.2. Intermediate 132 tert-butyl 4-(4-ethylpiperazin-1-yl)-3-((phenylmethyl)sulfonamido)benzoate The title compound was prepared according to General procedure J, using Intermediate 104 (1.0 equiv., 450 mg, 1.4734 mmol) in 8 mL of pyridine and benzylsulfonyl chloride (1.3 equiv., 365 mg, 1.9154 mmol). The crude was purified with column chromatography using 5% MeOH / DCM to afford the product (628 mg, 93%). Rf= 0.33 (5% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 7.98 (d, J = 1.9 Hz, 1H), 7.69 (dd, J = 8.3, 1.9 Hz, 1H), 7.36 – 7.28 (m, 3H), 7.27 – 7.21 (m, 3H), 4.56 (s, 2H), 2.86 (m, 4H), 2.54 (m, 4H), 2.47 (q, J = 7.2 Hz, 2H), 1.60 (s, 9H), 1.12 (t, J = 7.2 Hz, 3H);13C NMR (MeOD, 100 MHz) δ 166.7, 146.9, 134.2, 131.9, 130.5, 129.9, 129.8, 129.8, 126.5, 121.9, 119.4, 82.4, 58.7, 53.9, 53.2, 52.2, 28.4, 11.8. MS (ESI) Found: [M+H]+= 460.2, calcd: [M+H]+= 460.2. Intermediate 133 4-methyl-3-((phenylmethyl)sulfonamido)benzoic acid The title compound was prepared according to General procedure L, using Intermediate 109 (1.0 equiv., 1.214 g, 3.8011 mmol) in 20 mL of 8:1:1 ratio of 1,4- dioxane / MeOH / H2O, and NaOH (5.0 equiv., 760 mg, 19.00 mmol). Yield: 1.020 g, 88%. Rf = 0.20 (50% EtOAc / Petroleum Ether).1H NMR (DMSO, 600 MHz) δ 12.91 (br s, 1H), 9.27 (s, 1H), 7.86 (d, J = 1.7 Hz, 1H), 7.68 (dd, J = 7.9, 1.7 Hz, 1H), 7.38 – 7.27 (m, 6H), 4.45 (s, 2H), 2.29 (s, 3H);13C NMR (DMSO, 151 MHz) δ 166.85, 138.46, 135.77, 131.02, 130.84, 129.47, 129.30, 128.33, 128.20, 126.54, 125.75, 58.00, 18.40. HRMS (ESI) Found: [M-H]- = 304.0647, calcd: [M-H]- = 304.0469. Intermediate 134 4-methoxy-3-((phenylmethyl)sulfonamido)benzoic acid The title compound was prepared according to General procedure L, using Intermediate 110 (1.0 equiv., 474 mg, 1.4134 mmol) in 12 mL of 8:1:1 ratio of 1,4- dioxane / MeOH / H2O, and NaOH (5.0 equiv., 282 mg, 7.0668 mmol). Yield: 334 mg, 74%. Rf = 0.11 (50% EtOAc / Petroleum Ether).1H NMR (DMSO, 600 MHz) δ 12.71 (br s, 1H), 9.04 (s, 1H), 7.81 (d, J = 2.1 Hz, 1H), 7.76 (dd, J = 8.6, 2.1 Hz, 1H), 7.38 – 7.28 (m, 5H), 7.14 (d, J = 8.6 Hz, 1H), 4.42 (s, 2H), 3.91 (s, 3H);13C NMR (DMSO, 151 MHz) δ 166.7, 155.3, 130.9, 129.5, 128.2, 128.1, 127.9, 126.0, 125.3, 123.0, 111.4, 58.0, 56.0. HRMS (ESI) Found: [M-H]- = 320.0603, calcd: [M- H]- = 320.0598. Intermediate 135 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)-3-((phenylmethyl)sulfonamido)benzoic acid The title compound was prepared according to General procedure L, using Intermediate 111 (1.0 equiv., 600 mg, 1.2591 mmol) in 12 mL of 8:1:1 ratio of 1,4- dioxane / MeOH / H2O, and NaOH (5.0 equiv., 251.8 mg, 6.2954 mmol). Yield: 554 mg, 95%. Rf = 0.15 (EtOAc).1H NMR (DMSO, 400 MHz) δ 12.78 (br s, 1H), 9.22 (br s, 1H), 7.94 (d, J = 2.1 Hz, 1H), 7.69 (dd, J = 8.6, 2.1 Hz, 1H), 7.43 – 7.18 (m, 5H), 6.85 (d, J = 8.6 Hz, 1H), 5.09 (tt, J = 6.4, 3.7 Hz, 1H), 4.44 (s, 2H), 4.31 (m, 2H), 3.95 (m, 2H), 1.38 (s, 9H);13C NMR (DMSO, 100 MHz) δ 166.7, 155.4, 151.5, 130.9, 129.4, 128.2, 128.1, 127.4, 126.5, 124.5, 123.8, 112.0, 78.9, 66.4, 57.7, 56.2, 28.0. MS (ESI) Found: [M+H]+= 463.2, calcd: [M+H]+= 463.2. Intermediate 136 4-methoxy-2-methyl-5-((phenylmethyl)sulfonamido)benzoic acid The title compound was prepared according to General procedure L, using Intermediate 112 (1.0 equiv., 263 mg, 0.7527 mmol) in 5 mL of 8:1:1 ratio of 1,4- dioxane / MeOH / H2O, and NaOH (5.0 equiv., 150.5 mg, 3.763 mmol). Yield: 207 mg, 82%. Rf = 0.28 (30% EtOAc / Petroleum Ether).1H NMR (MeOD, 400 MHz) δ 8.02 (s, 1H), 7.30 (s, 5H), 6.90 (s, 1H), 4.36 (s, 2H), 3.91 (s, 3H), 2.59 (s, 3H);13C NMR (MeOD, 100 MHz) δ 170.3, 154.9, 140.9, 132.0, 130.6, 129.5, 129.4, 126.9, 125.2, 123.2, 115.0, 58.8, 56.5, 22.1. MS (ESI) Found: [M+H]+= 336.1, calcd: [M+H]+= 336.1. Intermediate 137 4-cyclopropoxy-2-methyl-5-((phenylmethyl)sulfonamido)benzoic acid The title compound was prepared according to General procedure L, using Intermediate 113 (1.0 equiv., 487 mg, 1.2971 mmol) in 10 mL of 8:1:1 ratio of 1,4- dioxane / MeOH / H2O, and NaOH (5.0 equiv., 259.4 mg, 6.4857 mmol). Yield: 328 mg, 70%. Rf= 0.51 (30% EtOAc / Petroleum Ether).1H NMR (DMSO, 400 MHz) δ 12.59 (br s, 1H), 8.93 (br s, 1H), 7.77 (s, 1H), 7.38 – 7.29 (m, 5H), 7.24 (s, 1H), 4.33 (s, 2H), 4.02 (tt, J = 6.1, 2.9 Hz, 1H), 2.55 (s, 3H), 0.84 (m, 2H), 0.77 (m, 2H);13C NMR (DMSO, 100 MHz) δ 167.7, 154.3, 139.1, 130.9, 129.7, 128.3, 128.1, 128.1, 123.2, 122.2, 116.2, 57.8, 51.6, 21.7, 6.0. MS (ESI) Found: [M+H]+= 362.1, calcd: [M+H]+= 362.1. Intermediate 138 4-cyclopropoxy-3-((phenylmethyl)sulfonamido)benzoic acid The title compound was prepared according to General procedure L, using Intermediate 114 (1.0 equiv., 218 mg, 0.6032 mmol) in 6 mL of 8:1:1 ratio of 1,4- dioxane / MeOH / H2O, and NaOH (5.0 equiv., 120.6 mg, 3.0160 mmol). Yield: 162 mg, 77%. Rf = 0.62 (EtOAc).1H NMR (DMSO, 400 MHz) δ 12.75 (br s, 1H), 9.00 (br s, 1H), 7.82 (d, J = 2.1 Hz, 1H), 7.78 (dd, J = 8.5, 2.1 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.38 – 7.26 (m, 5H), 4.39 (s, 2H), 4.03 (tt, J = 6.2, 3.0 Hz, 1H), 0.84 (m, 2H), 0.78 (m, 2H);13C NMR (DMSO, 100 MHz) δ 166.7, 154.8, 130.9, 129.5, 128.3, 128.2, 127.7, 125.9, 125.4, 123.4, 113.1, 57.9, 51.7, 5.9. MS (ESI) Found: [M+H]+= 348.1, calcd: [M+H]+= 348.1. Intermediate 139 4-(tert-butoxy)-3-((phenylmethyl)sulfonamido)benzoic acid The title compound was prepared according to General procedure L, using Intermediate 115 (1.0 equiv., 303 mg, 0.8027 mmol) in 6 mL of 8:1:1 ratio of 1,4- dioxane / MeOH / H2O, and NaOH (5.0 equiv., 160.5 mg, 4.0137 mmol). Yield: 244 mg, 84%. Rf = 0.56 (EtOAc).1H NMR (DMSO, 400 MHz) δ 12.72 (br s, 1H), 8.55 (s, 1H), 7.81 (d, J = 2.2 Hz, 1H), 7.66 (dd, J = 8.6, 2.2 Hz, 1H), 7.38 – 7.30 (m, 5H), 7.27 (d, J = 8.6 Hz, 1H), 4.46 (s, 2H), 1.46 (s, 9H);13C NMR (DMSO, 100 MHz) δ 166.7, 151.5, 129.3, 129.2, 128.4, 128.2, 126.7, 124.3, 123.7, 118.5, 81.0, 58.2, 28.4. MS (ESI) Found: [M+H]+= 364.1, calcd: [M+H]+= 364.1. Intermediate 140 2,3,4-trimethyl-5-((phenylmethyl)sulfonamido)benzoic acid The title compound was prepared according to General procedure L, using Intermediate 116 (1.0 equiv., 1.30 g, 3.7418 mmol) in 30 mL of 8:1:1 ratio of 1,4- dioxane / MeOH / H2O, and NaOH (5.0 equiv., 748.4 mg, 18.7088 mmol). Yield: 950 mg, 76%. Rf = 0.13 (2.5% MeOH / DCM).1H NMR (DMSO, 400 MHz) δ 12.81 (br s, 1H), 9.20 (br s, 1H), 7.46 (s, 1H), 7.38 – 7.32 (m, 5H), 4.37 (s, 2H), 2.40 (s, 3H), 2.23 (s, 3H), 2.20 (s, 3H);13C NMR (DMSO, 100 MHz) δ 169.3, 137.7, 137.3, 134.6, 132.5, 130.9, 129.9, 129.6, 128.3, 128.1, 125.6, 5 16.9, 16.4, 15.8. MS (ESI) Found: [M+H]+= 334.1, calcd: [M+H]+= 334.1. Intermediate 141 2,4-dimethyl-5-((phenylmethyl)sulfonamido)benzoic acid The title compound was prepared according to General procedure L, using Intermediate 117 (1.0 equiv., 601 mg, 1.8026 mmol) in 6 mL of 8:1:1 ratio of 1,4- dioxane / MeOH / H2O, and NaOH (5.0 equiv., 360.5 mg, 9.0132 mmol). Yield: 492 mg, 85%. Rf= 0.20 (2.5% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 7.87 (s, 1H), 7.39 – 7.32 (m, 5H), 7 .14 (s, 1H), 4.41 (s, 2H), 2.53 (s, 3H), 2.26 (s, 3H);13C NMR (MeOD, 100 MHz) δ 170.4, 13 , 139.2, 135.3, 134.5, 132.0, 130.7, 129.6, 129.6, 128.6, 115.2, 59.2, 21.3, 18.5. MS (ESI) Found: [M+H]+= 320.1, calcd: [M+H]+= 320.1. Intermediate 142 2,4-dimethoxy-5-((phenylmethyl)sulfonamido)benzoic acid The title compound was prepared according to General procedure L, using Intermediate 118 (1.0 equiv., 292 mg, 0.7991 mmol) in 3 mL of 8:1:1 ratio of 1,4-dioxane / MeOH / H2O, and NaOH (5.0 equiv., 159.8 mg, 3.9956 mmol). Yield: 201 mg, 72%. Rf= 0.29 (30% EtOAc / Petroleum Ether).1H NMR (DMSO, 400 MHz) δ 12.29 (br s, 1H), 8.91 (br s, 1H), 7.59 (s, 1H), 7.38 – 7.31 (m, 5H), 6.75 (s, 1H), 4.32 (s, 2H), 3.95 (s, 3H), 3.88 (s, 3H);13C NMR (DMSO, 100 MHz) δ 166.0, 159.0, 157.7, 130.9, 130.5, 129.8, 128.2, 128.0, 117.6, 111.7, 97.2, 58.0, 56.3, 56.1. MS (ESI) Found: [M+H]+= 352.1, calcd: [M+H]+= 352.1. Intermediate 143 3,4-dimethoxy-5-((phenylmethyl)sulfonamido)benzoic acid The title compound was prepared according to General procedure L, using Intermediate 119 (1.0 equiv., 352 mg, 0.9633 mmol) in 6 mL of 8:1:1 ratio of 1,4- dioxane / MeOH / H2O, and NaOH (5.0 equiv., 192.7 mg, 4.8166 mmol). Yield: 213 mg, 63%. Rf = 0.13 (2.5% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 7.75 (d, J = 1.9 Hz, 1H), 7.42 (d, J = 1.9 Hz, 1H), 7.32 – 7.28 (m, 5H), 4.46 (s, 2H), 3.91 (s, 3H), 3.86 (s, 3H);13C NMR (MeOD, 100 MHz) δ 169.1, 153.7, 144.2, 132.7, 132.1, 130.5, 129.6, 129.6, 127.3, 115.6, 110.5, 61.3, 59.1, 56.5. MS (ESI) Found: [M+H]+= 352.1, calcd: [M+H]+= 352.1. Intermediate 144 6-methyl-5-((phenylmethyl)sulfonamido)nicotinic acid The title compound was prepared according to General procedure L, using Intermediate 120 (1.0 equiv., 130 mg, 0.3888 mmol) in 2 mL of 8:1:1 ratio of 1,4- dioxane / MeOH / H2O, and NaOH (5.0 equiv., 77.8 mg, 1.9438 mmol). Yield: 89 mg, 75%. Rf = 0.33 (5% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.72 (d, J = 1.9 Hz, 1H), 8.12 (d, J = 1.9 Hz, 1H), 7.39 – 7.35 (m, 2H), 7.34 – 7.30 (m, 3H), 4.52 (s, 2H), 2.49 (s, 3H);13C NMR (MeOD, 100 MHz) δ 167.5, 157.3, 146.8, 134.4, 132.7, 132.0, 130.3, 129.8, 129.7, 126.8, 60.3, 21.3. MS (ESI) Found: [M+H]+= 307.1, calcd: [M+H]+= 307.1. Intermediate 145 6-methoxy-5-((phenylmethyl)sulfonamido)nicotinic acid The title compound was prepared according to General procedure L, using Intermediate 121 (1.0 equiv., 292 mg, 0.8681 mmol) in 6 mL of 8:1:1 ratio of 1,4- dioxane / MeOH / H2O, and NaOH (5.0 equiv., 173.6 mg, 4.3406 mmol). Yield: 162 mg, 58%. Rf= 0.31 (5% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.44 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.33 – 7.29 (m, 2H), 7.27 – 7.23 (m, 3H), 4.47 (s, 2H), 4.04 (s, 3H);13C NMR (MeOD, 100 MHz) δ 168.1, 158.6, 145.2, 132.0, 130.2, 129.7, 129.5, 129.5, 123.6, 121.8, 59.9, 54.9. MS (ESI) Found: [M+H]+= 323.1, calcd: [M+H]+= 323.1. Intermediate 146 4-((1-(tert-butoxycarbonyl)-3-methylazetidin-3-yl)oxy)-3-((phenylmethyl)sulfonamido)benzoic acid The title compound was prepared according to General procedure L, using Intermediate 122 (1.0 equiv., 200 mg, 0.4077 mmol) in 6 mL of 8:1:1 ratio of 1,4- dioxane / MeOH / H2O, and NaOH (5.0 equiv., 81.5 mg, 2.0384 mmol). Yield: 193 mg, 99%. Rf = 0.16 (EtOAc).1H NMR (DMSO, 400 MHz) δ 7.95 (d, J = 2.2 Hz, 1H), 7.66 (dd, J = 8.6, 2.2 Hz, 1H), 7.35 – 7.26 (m, 5H), 6.75 (d, J = 8.6 Hz, 1H), 4.41 (s, 2H), 4.16 (d, J = 9.0 Hz, 2H), 4.01 (d, J = 9.0 Hz, 2H), 1.63 (s, 3H), 1.39 (s, 9H);13C NMR (DMSO, 100 MHz) δ 166.7, 155.6, 149.5, 130.9, 129.4, 128.2, 128.1, 127.4, 126.8, 124.4, 123.8, 113.8, 79.0, 74.3, 60.5, 57.6, 28.0, 21.3. MS (ESI) Found: [M+H]+= 477.2, calcd: [M+H]+= 477.2. Intermediate 147 (R)-4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)-3-((phenylmethyl)sulfonamido)benzoic acid The title compound was prepared according to General procedure L, using Intermediate 123 (1.0 equiv., 200 mg, 0.4077 mmol) in 6 mL of 8:1:1 ratio of 1,4- dioxane / MeOH / H2O, and NaOH (5.0 equiv., 81.5 mg, 2.0384 mmol). Yield: 192 mg, 99%. Rf = 0.20 (EtOAc).1H NMR (DMSO, 400 MHz) δ 12.74 (br s, 1H), 9.17 (m, 1H), 7.87 (d, J = 2.1 Hz, 1H), 7.75 (dd, J = 8.7, 2.1 Hz, 1H), 7.37 – 7.24 (m, 5H), 7.14 (d, J = 8.7 Hz, 1H), 5.14 (m, 1H), 4.36 (s, 2H), 3.66 – 3.48 (m, 2H), 3.43 (m, 2H), 2.16 (m, 2H), 1.32 (s, 9H);13C NMR (DMSO, 100 MHz) δ 166.7, 153.4, 153.0, 130.8, 129.4, 128.3, 128.1, 127.8, 126.4, 125.9, 123.0, 112.4, 78.4, 77.0, 57.9, 51.1, 43.9, 30.2, 28.1. MS (ESI) Found: [M+H]+= 477.2, calcd: [M+H]+= 477.2. Intermediate 148 (S)-4-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-3-((phenylmethyl)sulfonamido)benzoic acid The title compound was prepared according to General procedure L, using Intermediate 124 (1.0 equiv., 1.366 g, 2.7071 mmol) in 40 mL of 8:1:1 ratio of 1,4- dioxane / MeOH / H2O, and NaOH (5.0 equiv., 541 mg, 13.5354 mmol). Yield: 1.2 g, 90%. Rf= 0.47 (10% MeOH / DCM).1H NMR (DMSO, 400 MHz) δ 12.79 (br s, 1H), 8.97 (br s, 1H), 7.85 (m, 1H), 7.73 (dd, J = 8.6, 2.1 Hz, 1H), 7.37 – 7.27 (m, 5H), 7.18 (m, 1H), 4.40 (s, 2H), 4.13 (m, 2H), 4.02 (m, 1H), 3.28 (m, 2H), 2.10 – 1.85 (m, 3H), 1.79 (m, 1H), 1.38 (s, 9H);13C NMR (DMSO, 100 MHz) δ 166.7, 154.1, 153.9, 130.8, 129.4, 128.3, 128.2, 127.7, 126.0, 125.2, 123.3, 111.8, 78.8, 68.6, 57.9, 55.3, 46.5, 28.1, 27.8, 22.7. MS (ESI) Found: [M+H]+= 491.2, calcd: [M+H]+= 491.2. Intermediate 149 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-((phenylmethyl)sulfonamido)nicotinic acid The title compound was prepared according to General procedure L, using Intermediate 130 (1.0 equiv., 1.175 g, 2.3951 mmol) in 38 mL of 8:1:1 ratio of 1,4- dioxane / MeOH / H2O, and NaOH (5.0 equiv., 479 mg, 11.9756 mmol). Yield: 1.09 g, 96%. Rf = 0.11 (5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.76 (m, 1H), 8.11 (m, 1H), 7.43 – 7.28 (m, 3H), 7.27 – 7.19 (m, 2H), 6.78 (br s, 1H), 4.48 (s, 2H), 3.46 (m, 4H), 2.99 (m, 4H), 1.47 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 169.4, 156.0, 154.8, 145.3, 130.7, 129.5, 129.3, 128.1, 126.6, 126.1, 121.6, 80.5, 58.9, 49.6, 43.2, 28.5. MS (ESI) Found: [M+H]+= 477.2, calcd: [M+H]+= 477.2. Intermediate 150 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-((phenylmethyl)sulfonamido)benzoic acid The title compound was prepared according to General procedure L, using Intermediate 131 (1.0 equiv., 1.0 g, 2.0467 mmol) in 38 mL of 8:1:1 ratio of 1,4- dioxane / MeOH / H2O, and NaOH (5.0 equiv., 409 mg, 10.2333 mmol). The reaction was worked up alternatively, the reaction mixture was partitioned between water and EtOAc, the aqueous phase was re-extracted twice with EtOAc, the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude was purified with column chromatography using 5% MeOH / DCM to afford the product as an oil. Yield: 885 mg, 91%. Rf= 0.46 (10% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.09 (d, J = 1.7 Hz, 1H), 7.95 (dd, J = 8.2, 1.7 Hz, 1H), 7.42 – 7.32 (m, 6H), 6.60 (s, 1H), 4.44 (s, 2H), 4.20 (m, 2H), 2.87 (tt, J = 11.8, 3.5 Hz, 1H), 2.73 (m, 2H), 1.69 (m, 2H), 1.57 (m, 2H), 1.47 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 170.3, 155.0, 146.2, 134.0, 130.9, 129.3, 129.1, 128.6, 128.6, 128.4, 127.9, 125.8, 80.0, 58.6, 44.1, 36.9, 32.3, 28.6. MS (ESI) Found: [M+H]+= 475.2, calcd: [M+H]+= 475.2. Intermediate 151 2-(4-carboxy-2-((phenylmethyl)sulfonamido)phenoxy)-N,N-dimethylethan-1-aminium chloride The title compound was prepared according to General procedure M, using Intermediate 125 (1.0 equiv., 20 g, 46.0246 mmol) and 200 mL of 4M HCl in dioxane. Yield: 18.9 g, 99%. Rf = 0.14 (10% MeOH / DCM).1H NMR (DMSO, 400 MHz) δ 12.79 (br s, 1H), 10.48 (br s, 1H), 9.26 (s, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.74 (dd, J = 8.6, 2.1 Hz, 1H), 7.37 – 7.26 (m, 5H), 7.16 (d, J = 8.7 Hz, 1H), 4.49 (s, 2H), 4.43 (t, J = 4.9 Hz, 2H), 3.54 (t, J = 4.9 Hz, 3H), 2.85 (s, 3H), 2.84 (s, 3H);13C NMR (DMSO, 100 MHz) δ 166.7, 152.4, 130.9, 129.3, 128.3, 128.2, 127.1, 126.3, 124.0, 123.7, 111.9, 62.2, 57.8, 54.9, 42.1. MS (ESI) Found: [M- HCl+H]+= 379.1, calcd: [M-HCl+H]+= 379.1. Intermediate 152 4-(2-(4-carboxy-2-((phenylmethyl)sulfonamido)phenoxy)ethyl)morpholin-4-ium chloride The title compound was prepared according to General procedure M, using Intermediate 126 (1.0 equiv., 945.8 mg, 1.9845 mmol) and 20 mL of 4M HCl in dioxane. Yield: 720 mg, 79%. Rf = 0.39 (10% MeOH / DCM).1H NMR (DMSO, 400 MHz) δ 11.41 (br s, 1H), 9.35 (s, 1H), 7.86 (d, J = 2.1 Hz, 1H), 7.74 (dd, J = 8.6, 2.1 Hz, 1H), 7.35 – 7.28 (m, 5H), 7.16 (d, J = 8.7 Hz, 1H), 4.51 (s, 2H), 4.49 (t, J = 4.9 Hz, 2H), 3.95 (m, 4H), 3.60 (m, 2H), 3.52 (m, 2H), 3.19 (m, 2H);13C NMR (DMSO, 100 MHz) δ 166.7, 152.9, 130.9, 129.4, 128.3, 128.2, 127.3, 126.2, 124.7, 123.6, 112.0, 63.0, 61.8, 58.0, 54.4, 51.0. MS (ESI) Found: [M- HCl+H]+= 421.1, calcd: [M-HCl+H]+= 421.1. Intermediate 153 1-(2-(4-carboxy-2-((phenylmethyl)sulfonamido)phenoxy)ethyl)pyrrolidin-1-ium chloride The title compound was prepared according to General procedure M, using Intermediate 127 (1.0 equiv., 735 mg, 1.5972 mmol) and 15 mL of 4M HCl in dioxane. Yield: 500 mg, 71%. Rf = 0.08 (10% MeOH / DCM).1H NMR (DMSO, 400 MHz) δ 10.55 (br s, 1H), 9.24 (s, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.75 (dd, J = 8.6, 2.1 Hz, 1H), 7.36 – 7.29 (m, 5H), 7.15 (d, J = 8.6 Hz, 1H), 4.50 (s, 2H), 4.41 (m, 2H), 3.60 (m, 4H), 3.13 (m, 2H), 2.04 (m, 2H), 1.93 (m, 2H);13C NMR (DMSO, 100 MHz) δ 166.7, 152.7, 133.1, 130.9, 129.3, 128.3, 128.2, 127.3, 126.2, 124.4, 111.9, 63.6, 57.8, 53.1, 52.5, 22.6. MS (ESI) Found: [M-HCl+H]+= 405.1, calcd: [M-HCl+H]+= 405.1. Intermediate 154 N-(2-((5-carboxy-3-((phenylmethyl)sulfonamido)pyridin-2-yl)oxy)ethyl)-N-isopropylpropan-2- aminium chloride title compound was prepared according to General procedure M, using Intermediate 128 (1.0 equiv., 75 mg, 0.1525 mmol) and 2.5 mL of 4M HCl in dioxane. Yield: 42 mg, 58%. Rf= 0.25 (10% MeOH / DCM).1H NMR (DMSO, 400 MHz) δ 13.13 (br s, 1H), 9.94 (br s, 1H), 9.49 (s, 1H), 8.41 (d, J = 2.1 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.37 – 7.27 (m, 5H), 4.71 (t, J = 5.7 Hz, 2H), 4.61 (s, 2H), 3.74 (m, 2H), 3.55 (m, 2H), 1.38 (d, J = 6.4 Hz, 6H), 1.34 (d, J = 6.4 Hz, 6H);13C NMR (DMSO, 100 MHz) δ 165.7, 156.0, 143.2, 130.9, 129.0, 128.9, 128.3, 128.3, 122.1, 121.2, 62.5, 58.5, 54.7, 45.0, 18.2, 16.6. MS (ESI) Found: [M-HCl+H]+= 436.2, calcd: [M-HCl+H]+= 436.2. Intermediate 155 2-((5-carboxy-3-((phenylmethyl)sulfonamido)pyridin-2-yl)oxy)-N,N-dimethylethan-1-aminium chloride The title compound was prepared according to General procedure M, using Intermediate 129 (1.0 equiv., 225 mg, 0.5166 mmol) and 8 mL of 4M HCl in dioxane. Yield: 189 mg, 88%. Rf = 0.18 (20:3:3:2 = EtOAc / MeOH / AcOH / H2O).1H NMR (DMSO, 400 MHz) δ 13.09 (s, 1H), 10.69 (m, 1H), 9.58 (s, 1H), 8.39 (d, J = 2.1 Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.36 – 7.32 (m, 2H), 7.30 – 7.26 (m, 3H), 4.65 (m, 2H), 4.64 (s, 2H), 3.55 (m, 2H), 2.85 (s, 3H), 2.84 (s, 3H);13C NMR (DMSO, 100 MHz) δ 165.8, 155.6, 143.1, 130.9, 129.0, 128.9, 128.3, 128.2, 122.1, 121.2, 60.6, 58.4, 54.8, 42.1. MS (ESI) Found: [M-HCl+H]+= 380.1, calcd: [M-HCl+H]+= 380.1. Intermediate 156 4-(4-carboxy-2-((phenylmethyl)sulfonamido)phenyl)-1-ethylpiperazin-1-ium chloride The title compound was prepared according to General procedure M, using Intermediate 132 (1.0 equiv., 596 mg, 1.2968 mmol) and 20 mL of 4M HCl in dioxane. Yield: 567 mg, 99%. Rf = 0.23 (20:3:3:2 = EtOAc / MeOH / AcOH / H2O).1H NMR (DMSO, 400 MHz) δ 12.89 (br s, 1H), 10.80 (br s, 1H), 8.86 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 8.3, 2.0 Hz, 1H), 7.40 – 7.30 (m, 5H), 7.26 (d, J = 8.3 Hz, 1H), 4.60 (s, 2H), 3.54 – 3.44 (m, 2H), 3.27 – 3.09 (m, 8H), 1.29 (t, J = 7.3 Hz, 3H);13C NMR (DMSO, 100 MHz) δ 166.7, 146.5, 132.1, 130.9, 129.2, 128.4, 128.4, 127.1, 126.2, 122.5, 121.0, 58.2, 50.6, 50.2, 47.8, 8.9. MS (ESI) Found: [M-HCl+H]+= 404.2, calcd: [M-HCl+H]+= 404.2. Intermediate 157 tert-butyl 3-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenoxy)azetidine-1-carboxylate The title compound was prepared according to General procedure N (Workup procedure C), using Intermediate 135 (1.0 equiv., 259 mg, 0.5600 mmol), DIPEA (1.5 equiv., 146.3 µL, 0.8400 mmol), HBTU (1.05 equiv., 223 mg, 0.5880 mmol) in 2 mL DMF, and Intermediate 21 (1.0 equiv., 201.5 mg, 0.5246 mmol), DIPEA (1.5 equiv., 146.3 µL, 0.8400 mmol) in 3 mL DMF. The crude was purified with column chromatography using 90% EtOAc / Petroleum Ether to afford the product (426.6 mg, 99%). Rf = 0.34 (80% EtOAc / Petroleum Ether).1H NMR (CDCl3, 400 MHz) δ 7.80 (d, J = 9.2 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.37 – 7.27 (m, 6H), 7.26 – 7.19 (m, 3H), 7.17 (d, J = 8.6 Hz, 2H), 6.73 (s, 1H), 6.54 (d, J = 8.4 Hz, 1H), 4.85 (tt, J = 6.4, 4.0 Hz, 1H), 4.37 (s, 2H), 4.29 (dd, J = 9.9, 6.4 Hz, 2H), 3.87 (dd, J = 10.1, 3.9 Hz, 2H), 3.14 (br s, 1H), 2.88 (br s, 1H), 2.83 (tt, J = 12.2, 3.7 Hz, 1H), 2.06 – 1.83 (m, 2H), 1.72 (br s, 2H), 1.47 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 169.3, 167.2, 156.0, 151.3, 148.4 (q, J = 35.4 Hz), 146.1, 143.0, 130.8, 130.3, 129.2, 128.9, 128.4, 128.4, 127.3, 126.6, 124.3, 121.5, 121.5 (q, J = 273.9 Hz), 118.0, 117.9, 111.4, 80.4, 66.8, 58.0, 56.1, 48.7, 43.2, 42.4, 34.0, 33.2, 28.5;19F NMR (CDCl3, 376 MHz) δ -66.37. MS (ESI) Found: [M+H]+= 768.3, calcd: [M+H]+= 768.3. Intermediate 158 tert-butyl (R)-3-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenoxy)pyrrolidine-1-carboxylate The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 147 (1.0 equiv., 250 mg, 0.5246 mmol), DIPEA (1.5 equiv., 137 µL, 0.7869 mmol), HBTU (1.05 equiv., 208.9 mg, 0.5508 mmol) in 2.5 mL DMF, and Intermediate 21 (1.0 equiv., 188.7 mg, 0.5246 mmol), DIPEA (1.5 equiv., 137 µL, 0.7869 mmol) in 3.3 mL DMF. The crude was purified with column chromatography using 90% EtOAc / Petroleum Ether to afford the product (407 mg, 99%). Rf = 0.37 (EtOAc).1H NMR (CDCl3 , 400 MHz) δ 7.80 (d, J = 9.2 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.36 – 7.27 (m, 6H), 7.24 (m, 1H), 7.23 – 7.14 (m, 4H), 6.86 (d, J = 8.4 Hz, 1H), 6.69 (s, 1H), 4.91 (m, 1H), 4.84 (br s, 1H), 4.36 (s, 2H), 3.90 (br s, 1H), 3.66 (dd, J = 12.7, 4.7 Hz, 1H), 3.61 – 3.37 (m, 2H), 3.30 (td, J = 10.4, 7.0 Hz, 1H), 3.13 (br s, 1H), 2.90 (br s, 1H), 2.84 (tt, J = 12.1, 3.6 Hz, 1H), 2.17 – 2.03 (m, 2H), 2.02 – 1.83 (m, 2H), 1.73 (br s, 2H), 1.47 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 169.6, 167.2, 154.3, 151.3, 148.4 (q, J = 35.3 Hz), 146.7, 143.0, 130.8, 129.4, 129.2, 128.9, 128.4, 127.3, 126.9, 124.2, 121.5, 121.5 (q, J = 273.9 Hz), 117.8, 117.6, 112.2, 80.1, 77.4, 57.9, 51.4, 48.6, 43.9, 43.3, 42.4, 33.7, 33.4, 31.3, 28.6;19F NMR (CDCl3, 376 MHz) δ -66.37. MS (ESI) Found: [M+H]+= 782.3, calcd: [M+H]+= 782.3. Intermediate 159 tert-butyl (S)-2-((2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenoxy)methyl)pyrrolidine-1-carboxylate The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 148 (1.0 equiv., 150 mg, 0.3057 mmol), DIPEA (1.5 equiv., 79.9 µL, 0.4586 mmol), HBTU (1.05 equiv., 121.7 mg, 0.3210 mmol) in 2 mL DMF, and Intermediate 21 (1.0 equiv., 110 mg, 0.3057 mmol), DIPEA (1.5 equiv., 79.9 µL, 0.4586 mmol) in 2.5 mL DMF. The crude was purified with column chromatography using 20% EtOAc / DCM to afford the product (241 mg, 99%). Rf = 0.32 (20% EtOAc / DCM).1H NMR (CDCl3, 400 MHz) δ 7.79 (d, J = 9.2 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.33 – 7.27 (m, 6H), 7.26 – 7.19 (m, 3H), 7.17 (d, J = 8.6 Hz, 2H), 6.99 (m, 1H), 4.83 (br s, 1H), 4.38 (s, 2H), 4.25 – 4.07 (m, 2H), 4.05 – 3.68 (m, 2H), 3.36 (m, 2H), 3.06 (br s, 1H), 2.92 (br s, 1H), 2.82 (tt, J = 12.1, 3.6 Hz, 1H), 2.00 – 1.68 (m, 8H), 1.48 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 169.8, 167.2, 151.3, 151.3, 148.4 (q, J = 35.3 Hz), 143.1, 130.9, 129.1, 128.9, 128.8, 128.5, 128.4, 127.3 (q, J = 2.4 Hz), 126.8, 124.3, 121.5 (q, J = 273.8 Hz), 121.4, 117.8, 117.4, 111.7, 80.1, 70.0, 58.1, 55.8, 48.7, 47.1, 43.4, 42.5, 33.6, 28.7, 27.9, 23.9;19F NMR (CDCl3, 376 MHz) δ -66.37. MS (ESI) Found: [M+H]+= 796.3, calcd: [M+H]+= 796.3. Intermediate 160 tert-butyl 3-methyl-3-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)- oxy)phenyl)piperidine-1-carbonyl)phenoxy)azetidine-1-carboxylate The title compound was prepared according to General procedure N (Workup procedure C), using Intermediate 146 (1.0 equiv., 200 mg, 0.4197 mmol), DIPEA (1.5 equiv., 109.6 µL, 0.6295 mmol), HBTU (1.05 equiv., 167.1 mg, 0.4407 mmol) in 1.5 mL DMF, and Intermediate 21 (1.0 equiv., 151 mg, 0.4197 mmol), DIPEA (1.5 equiv., 109.6 µL, 0.6295 mmol) in 2 mL DMF. The crude was purified with column chromatography using 80% EtOAc / Petroleum Ether to afford the product (323.5 mg, 99%). Rf= 0.50 (10% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 7.80 (d, J = 9.2 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.38 – 7.27 (m, 6H), 7.25 – 7.19 (m, 3H), 7.18 (d, J = 8.6 Hz, 2H), 6.69 (s, 1H), 6.50 (d, J = 8.4 Hz, 1H), 4.84 (br s, 1H), 4.38 (s, 2H), 4.05 (d, J = 9.2 Hz, 2H), 3.94 (d, J = 9.2 Hz, 2H), 3.91 (br s, 1H), 3.15 (br s, 1H), 2.90 (br s, 1H), 2.84 (tt, J = 12.0, 3.6 Hz, 1H), 2.03 – 1.84 (m, 2H), 1.73 (m, 2H), 1.66 (s, 3H), 1.48 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 169.5, 167.2, 156.2, 151.3, 148.4 (q, J = 35.6 Hz), 144.1, 142.9, 130.8, 129.6, 129.3, 129.0, 128.5, 128.4, 127.4, 127.3, 123.7, 121.5, 121.5 (q, J = 272.8 Hz), 117.9, 117.7, 113.4, 80.5, 74.7, 61.0, 57.8, 48.8, 43.0, 42.4, 33.7, 33.4, 28.5, 22.1;19F NMR (CDCl3, 376 MHz) δ -66.38. MS (ESI) Found: [M+H]+= 782.3, calcd: [M+H]+= 782.3. Intermediate 161 N-(2-(2-morpholinoethoxy)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure B), using Intermediate 152 (1.0 equiv., 88.9 mg, 0.1946 mmol), DIPEA (2.0 equiv., 68 µL, 0.3891 mmol), HBTU (1.05 equiv., 77.5 mg, 0.2043 mmol) in 1 mL DMF, and Intermediate 21 (1.0 equiv., 70 mg, 0.1946 mmol), DIPEA (2.0 equiv., 68 µL, 0.3891 mmol) in 1.2 mL DMF. The crude was purified with column chromatography using 5% MeOH / DCM to afford the product (124 mg, 88%). Rf= 0.31 (5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 9.39 (br s, 1H) 7.80 (d, J = 9.2 Hz, 1H), 7.69 (br s, 1H), 7.35 – 7.27 (m, 9H), 7.17 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 8.2 Hz, 1H), 4.85 (br s, 1H), 4.27 (s, 2H), 4.16 (m, 2H), 3.89 (br s, 1H), 3.60 (m, 4H), 3.14 (br s, 1H), 2.88 (br s, 1H), 2.83 (tt, J = 12.2, 3.4 Hz, 1H), 2.58 – 2.20 (m, 6H), 1.97 (br s, 1H), 1.89 (br s, 1H), 1.74 (br s, 2H);13C NMR (CDCl3, 100 MHz) δ 169.5, 167.2, 151.3, 149.7, 148.4 (q, J = 35.6 Hz), 143.1, 131.8, 131.3, 130.4, 129.0, 128.7, 128.6, 128.4, 127.3, 125.2, 121.5 (q, J = 274.0 Hz), 121.5, 121.3, 119.2, 117.8, 68.7, 66.0, 58.4, 56.7, 53.2, 43.2, 42.5, 33.9, 33.2;19F NMR (CDCl3, 376 MHz) δ -66.37. MS (ESI) Found: [M+H]+= 726.3, calcd: [M+H]+= 726.3. Intermediate 162 1-phenyl-N-(2-(2-(pyrrolidin-1-yl)ethoxy)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)methanesulfonamide The title compound was prepared according to General procedure N (Workup procedure B), using Intermediate 153 (1.0 equiv., 85.8 mg, 0.1946 mmol), DIPEA (2.0 equiv., 68 µL, 0.3891 mmol), HBTU (1.05 equiv., 77.5 mg, 0.2043 mmol) in 1 mL DMF, and Intermediate 21 (1.0 equiv., 70 mg, 0.1946 mmol), DIPEA (2.0 equiv., 68 µL, 0.3891 mmol) in 1.2 mL DMF. The crude was purified with column chromatography using 5% MeOH / DCM to afford the product (137 mg, 99%). Rf = 0.30 (5% MeOH / DCM).1H NMR (CDCl3 , 400 MHz) δ 7.80 (d, J = 9.1 Hz, 1H), 7.62 (s, 1H), 7.36 – 7.26 (m, 8H), 7.24 (dd, J = 8.3, 2.0 Hz, 1H), 7.17 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 8.3 Hz, 1H), 4.85 (br s, 1H), 4.29 (s, 2H), 4.14 (m, 1H), 3.87 (br s, 1H), 3.12 (br s, 1H), 2.94 – 2.78 (m, 2H), 2.77 – 2.21 (m, 6H), 1.96 (br s, 1H), 1.88 (br s, 1H), 1.82 – 1.56 (m, 6H);13C NMR (CDCl3, 100 MHz) δ 169.7, 167.2, 151.3, 150.1, 148.4 (q, J = 35.3 Hz), 143.1, 131.7, 129.4, 128.5, 128.5, 128.4, 127.3, 124.7, 121.5 (q, J = 272.3 Hz), 121.4, 121.3, 117.8, 58.5,54.0, 53.5, 48.6, 43.2, 42.5, 34.0, 33.1, 23.3;19F NMR (CDCl3, 376 MHz) δ -66.37. MS (ESI) Found: [M+H]+= 710.3, calcd: [M+H]+= 710.3. Intermediate 163 tert-butyl 3-(4-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2- ((phenylmethyl)sulfonamido)phenoxy)azetidine-1-carboxylate The title compound was prepared according to General procedure N (Workup procedure C), using Intermediate 135 (1.0 equiv., 58.8 mg, 0.1272 mmol), DIPEA (1.5 equiv., 33.2 µL, 0.1907 mmol), HBTU (1.05 equiv., 50.6 mg, 0.1335 mmol) in 0.5 mL DMF, and Intermediate 23 (1.0 equiv., 45.0 mg, 0.1272 mmol), DIPEA (1.5 equiv., 33.2 µL, 0.1907 mmol) in 0.5 mL DMF. The crude was purified with column chromatography using 5% MeOH / DCM to afford the product (91 mg, 94%). Rf = 0.24 (2.5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 7.67 (d, J = 1.9 Hz, 1H), 7.37 – 7.19 (m, 10H), 6.71 (s, 1H), 6.55 (d, J = 8.4 Hz, 1H), 4.85 (tt, J = 6.4, 4.0 Hz, 1H), 4.81 (br s, 1H), 4.37 (s, 2H), 4.29 (ddd, J = 9.9, 6.3, 1.0 Hz, 2H), 3.87 (dd, J = 10.1, 4.0 Hz, 2H), 3.84 (s, 1H), 3.12 (br s, 1H), 2.89 (br s, 1H), 2.82 (tt, J = 12.1, 3.6 Hz, 1H), 2.02 – 1.81 (m, 2H), 1.71 (br s, 2H), 1.47 (s, 9H), 1.43 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 175.8, 174.7, 169.4, 156.0, 154.5, 146.2, 143.1, 130.8, 130.0, 129.2, 128.9, 128.4, 128.4, 126.6, 124.3, 120.0, 118.0, 111.4, 80.4, 66.9, 58.0, 56.2, 48.6, 43.2, 42.3, 37.0, 33.6, 30.8, 28.5. MS (ESI) Found: [M+H]+= 762.3, calcd: [M+H]+= 762.3. Intermediate 164 N-(2-(2-(diisopropylamino)ethoxy)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)pyridin-3-yl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure B), using Intermediate 154 (1.0 equiv., 36.7 mg, 0.07775 mmol), DIPEA (2.0 equiv., 27.1 µL, 0.1555 mmol), HBTU (1.05 equiv., 31 mg, 0.08164 mmol) in 0.5 mL DMF, and Intermediate 21 (1.0 equiv., 28 mg, 0.07775 mmol), DIPEA (2.0 equiv., 27.1 µL, 0.1555 mmol) in 0.5 mL DMF. The crude was purified with column chromatography using 5% MeOH / DCM to afford the product (38.1 mg, 66%). Rf = 0.34 (5% MeOH / DCM).1H NMR (CDCl3 , 600 MHz) δ 8.00 (d, J = 2.1 Hz, 1H), 7.80 (d, J 9.2 Hz, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.36 – 7.27 (m, 6H), 7.24 (m, 2H), 7.18 (d, J = 8.5 Hz, 2H), 4.84 (br s, 1H), 4.38 (s, 2H), 4.29 (t, J = 6.9 Hz, 2H), 3.84 (br s, 1H), 3.16 (br s, 1H), 3.04 (hept, J = 6.6 Hz, 2H), 2.88 (br s, 1H), 2.84 (tt, J = 12.2, 3.6 Hz, 1H), 2.73 (t, J = 6.9 Hz, 2H), 2.03 – 1.85 (m, 2H), 1.71 (br s, 2H), 1.02 (d, J = 6.6 Hz, 12H);13C NMR (CDCl3, 151 MHz) δ 167.7, 167.2, 153.7, 151.4, 148.4 (q, J = 35.4 Hz), 142.9, 140.4, 130.9, 129.2, 128.9, 128.4, 128.3, 127.3 (q, J = 2.3 Hz), 125.7, 124.4, 122.0, 121.5, 121.5 (q, J = 273.9 Hz), 117.9, 67.5, 58.6, 49.7, 48.7, 44.0, 43.2, 42.4, 34.0, 33.1, 20.8;19F NMR (CDCl3, 565 MHz) δ -66.37. MS (ESI) Found: [M+H]+= 741.3, calcd: [M+H]+= 741.3. Intermediate 165 tert-butyl 4-(3-((phenylmethyl)sulfonamido)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)pyridin-2-yl)piperazine-1-carboxylate The title compound was prepared according to General procedure N (Workup procedure B), using Intermediate 149 (1.0 equiv., 331 mg, 0.6948 mmol), DIPEA (2.0 equiv., 242 µL, 1.3897 mmol), HBTU (1.05 equiv., 276.7 mg, 0.7296 mmol) in 4 mL DMF, and Intermediate 21 (1.0 equiv., 250 mg, 0.6948 mmol), DIPEA (2.0 equiv., 242 µL, 1.3897 mmol) in 5 mL DMF. The crude was purified with column chromatography using 50% EtOAc / DCM to afford the product (539 mg, 99%). Rf = 0.27 (50% EtOAc / DCM).1H NMR (CDCl3, 400 MHz) δ 8.19 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.40 – 7.27 (m, 6H), 7.25 – 7.20 (m, 2H), 7.18 (d, J = 8.6 Hz, 2H), 7.09 (br s, 1H), 4.86 (br s, 1H), 4.45 (s, 2H), 3.84 (br s, 1H), 3.44 (m, 4H), 3.19 (br s, 1H), 3.02 – 2.76 (m, 6H), 2.01 (br s, 1H), 1.91 (br s, 1H), 1.72 (br s, 2H), 1.46 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 167.2, 167.1, 154.7, 152.7, 151.4, 148.4 (q, J = 35.3 Hz), 142.7, 141.2, 130.7, 129.5, 129.2, 129.1, 128.3, 128.2, 127.4, 127.4 (q, J = 2.2 Hz), 123.4, 121.5, 121.4 (q, J = 274.1 Hz), 117.9, 80.3, 58.8, 50.0, 48.6, 43.2, 42.3, 34.0, 33.0, 28.5;19F NMR (CDCl3, 376 MHz) δ -66.38. MS (ESI) Found: [M+H]+= 782.3, calcd: [M+H]+= 782.3. Intermediate 166 N-(2-(2-(dimethylamino)ethoxy)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine- 1-carbonyl)pyridin-3-yl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure B), using Intermediate 155 (1.0 equiv., 84.4 mg, 0.2029 mmol), DIPEA (2.0 equiv., 70.7 µL, 0.4058 mmol), HBTU (1.05 equiv., 36 mg, 0.09465 mmol) in 2 mL DMF, and Intermediate 21 (1.0 equiv., 73.0 mg, 0.2029 mmol), DIPEA (2.0 equiv., 70.7 µL, 0.4058 mmol) in 2 mL DMF. The crude was purified with column chromatography using 5% MeOH / DCM to afford the product (126 mg, 91%). Rf= 0.32 (5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 7.98 (d, J = 2.1 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.68 (d, J = 2.1 Hz, 1H), 7.34 – 7.26 (m, 8H), 7.18 (d, J = 8.6 Hz, 2H), 4.80 (br s, 1H), 4.45 (m, 2H), 4.42 (s, 2H), 3.77 (br s, 1H), 3.12 (br s, 1H), 2.97 – 2.70 (m, 4H), 2.35 (s, 6H), 1.94 (br s, 2H), 1.70 (br s, 2H);13C NMR (CDCl3, 100 MHz) δ 167.6, 167.2, 153.9, 151.4, 148.4 (q, J = 35.2 Hz), 142.9, 140.3, 131.0, 128.9, 128.7, 128.6, 128.4, 127.4, 126.3, 125.8, 122.8, 121.5, 121.5 (q, J = 272.1 Hz), 117.9, 63.6, 59.2, 57.5, 48.6, 44.8, 43.0, 42.4, 34.0, 33.1;19F NMR (CDCl3, 376 MHz) δ -66.37. MS (ESI) Found: [M+H]+= 685.2, calcd: [M+H]+= 685.2. Intermediate 167 tert-butyl 4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)piperidine-1-carboxylate The title compound was prepared according to General procedure N (Workup procedure B), using Intermediate 150 (1.0 equiv., 300 mg, 0.6322 mmol), DIPEA (1.5 equiv., 165.2 µL, 0.9482 mmol), HBTU (1.05 equiv., 251.7 mg, 0.6638 mmol) in 2 mL DMF, and Intermediate 21 (1.0 equiv., 227.4 mg, 0.6322 mmol), DIPEA (1.5 equiv., 165.2 µL, 0.9482 mmol) in 3 mL DMF. The crude was purified with column chromatography using 2% MeOH / DCM to afford the product (395 mg, 80%). Rf = 0.61 (10% MeOH / DCM).1H NMR (CDCl3, 600 MHz) δ 7.80 (d, J = 9.2 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.40 – 7.27 (m, 10H), 7.18 (d, J = 8.6 Hz, 2H), 6.34 (s, 1H), 4.88 (br s, 1H), 4.42 (s, 2H), 4.19 (m, 2H), 3.91 (br s, 1H), 3.16 (br s, 1H), 2.88 (br s, 1H), 2.84 (tt, J = 12.2, 3.6 Hz, 1H), 2.68 (m, 2H), 2.60 (tt, J = 11.9, 3.5 Hz, 1H), 2.02 (br s, 1H), 1.87 (br s, 1H), 1.78 (br s, 1H), 1.67 (br s, 1H), 1.64 (m, 2H), 1.55 (m, 2H), 1.47 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 169.4, 167.1, 154.8, 151.4, 148.4 (q, J = 35.4 Hz), 142.9, 139.7, 135.3, 133.9, 130.9, 129.2, 129.1, 128.6, 128.4, 127.6, 127.4, 125.1, 121.5, 121.5 (q, J = 273.9 Hz), 121.5, 117.9, 79.8, 58.5, 48.6, 43.1, 42.4, 36.5, 34.1, 33.1, 32.4, 29.8, 28.6;19F NMR (CDCl3, 565 MHz) δ -66.38. MS (ESI) Found: [M+H]+= 780.3, calcd: [M+H]+= 780.3. Intermediate 168 4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)piperazin-1-ium 2,2,2-trifluoroacetate The title compound was prepared according to General procedure O, using Intermediate 108 (1.0 equiv., 163 mg, 0.2087 mmol) in 3 mL of DCE, and 3 mL of TFA. Yield: 165 mg, 99%. Rf = 0.27 (20:3:3:2 = EtOAc / MeOH / AcOH / H2O).1H NMR (MeOD, 400 MHz) δ 8.10 (d, J = 9.2 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.41 (d, J = 8.6 Hz, 2H), 7.40 – 7.32 (m, 5H), 7.29 (d, J = 8.2 Hz, 1H), 7.25 – 7.18 (m, 3H), 7.03 (d, J = 1.8 Hz, 1H), 4.75 (m, 1H), 4.64 (s, 2H), 3.79 (m, 1H), 3.36 (m, 4H), 3.21 (m, 1H), 3.08 (m, 4H), 3.02 – 2.90 (m, 2H), 2.02 (m, 1H), 1.90 – 1.63 (m, 3H);13C NMR (MeOD, 100 MHz) δ 171.4, 169.0, 152.9, 149.4 (q, J = 34.9 Hz), 144.6, 144.2, 134.4, 134.3, 132.3, 130.7, 130.0, 129.9, 129.5, 129.4, 124.4, 122.9 (q, J = 272.6 Hz), 122.6, 122.4, 120.0, 119.7, 59.9, 49.9, 49.7, 44.9, 44.1, 43.2, 35.0, 34.1;19F NMR (MeOD, 376 MHz) δ -67.92, -77.08. MS (ESI) Found: [M-TFA+H]+= 681.2, calcd: [M-TFA+H]+= 681.2. Intermediate 179 tert-butyl 4-(4-((6-cyanopyridazin-3-yl)oxy)phenyl)piperidine-1-carboxylate The title compound was prepared using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 200 mg, 0.7211 mmol) in 1 mL of DMF, Cs2CO3 (2.0 equiv., 469.9 mg, 1.4422 mmol) and 6-chloropyridazine-3-carbonitrile (1.2 equiv., 120.7 mg, 0.8653 mmol) according to General procedure A (Non-catalyzed method with Workup procedure A), except that the reaction mixture was stirred at 90 °C. The crude was purified with column chromatography using 5% EtOAc / DCM to afford the product (166 mg, 61%); Rf = 0.41 (20% EtOAc / Toluene).1H NMR (CDCl3, 400 MHz) δ 7.79 (d, J = 9.2 Hz, 1H), 7.30 – 7.25 (m, 3H), 7.14 (d, J = 8.6 Hz, 2H), 4.25 (m, 2H), 2.81 (m, 2H), 2.69 (tt, J = 12.2, 3.6 Hz, 1H), 1.84 (m, 2H), 1.62 (m, 2H), 1.48 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 166.1, 155.0, 150.8, 144.1, 135.9, 133.3, 128.5, 121.2, 116.9, 115.4, 79.7, 44.6, 42.4, 33.4, 28.6. MS (ESI) Found: [M+H]+= 381.2, calcd: [M+H]+= 381.2. Intermediate 170 tert-butyl 4-(4-((5-cyanopyridin-2-yl)oxy)phenyl)piperidine-1-carboxylate The title compound was prepared using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 200 mg, 0.7211 mmol) in 1 mL of DMF, Cs2CO3(2.0 equiv., 469.9 mg, 1.4422 mmol) and 6-chloronicotinonitrile (1.2 equiv., 119.9 mg, 0.8653 mmol) according to General procedure A (Non-catalyzed method with Workup procedure A), except that the reaction mixture was stirred at 90 °C. The crude was purified with column chromatography using 5% EtOAc / DCM to afford the product (253 mg, 92%); Rf = 0.53 (20% EtOAc / Toluene).1H NMR (CDCl3, 400 MHz) δ 8.46 (d, J = 2.3 Hz, 1H), 7.90 (dd, J = 8.7, 2.3 Hz, 1H), 7.26 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.7 Hz, 1H), 4.25 (m, 2H), 2.81 (m, 2H), 2.68 (tt, J = 12.4, 3.5 Hz, 1H), 1.85 (m, 2H), 1.62 (qd, J = 12.8, 4.2 Hz, 2H), 1.48 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 165.8, 155.0, 152.3, 151.1, 143.4, 142.2, 128.3, 121.5, 116.9, 112.0, 104.1, 79.6, 44.4, 42.3, 33.3, 28.6. MS (ESI) Found: [M+H]+= 380.2, calcd: [M+H]+= 380.2. Intermediate 171 tert-butyl 4-(4-((6-cyanopyridin-3-yl)oxy)phenyl)piperidine-1-carboxylate The title compound was prepared using 1-Boc-4-hydroxyphenylpiperidine (1.0 equiv., 200 mg, 0.7211 mmol) in 1 mL of DMF, Cs2CO3 (2.0 equiv., 469.9 mg, 1.4422 mmol) and 5-bromopicolinonitrile (1.2 equiv., 158.4 mg, 0.8653 mmol) according to General procedure A (Non-catalyzed method with Workup procedure A), except that the reaction mixture was stirred at 90 °C. The crude was purified with column chromatography using 5% EtOAc / DCM to afford the product (258 mg, 94%); Rf = 0.51 (20% EtOAc / Toluene).1H NMR (CDCl3, 400 MHz) δ 8.43 (d, J = 2.9 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.27 (d, J = 8.5 Hz, 2H), 7.24 (m, 1H), 7.03 (d, J = 8.5 Hz, 2H), 4.26 (m, 2H), 2.81 (m, 2H), 2.68 (tt, J = 12.3, 3.6 Hz, 1H), 1.84 (m, 2H), 1.63 (m, 2H), 1.49 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 157.3, 155.0, 152.5, 143.7, 142.0, 129.6, 128.9, 126.9, 123.5, 120.4, 117.4, 79.7, 44.4, 42.3, 33.4, 28.6. MS (ESI) Found: [M+H]+= 380.2, calcd: [M+H]+= 380.2. Intermediate 172 tert-butyl 6-(4-(piperidin-4-yl)phenoxy)nicotinate The title compound was prepared using 4-(piperidin-4-yl)phenol hydrobromide (1.0 equiv., 100 mg, 0.3874 mmol) in 0.8 mL of DMF, Cs2CO3 (3.0 equiv., 378.6 mg, 1.1621 mmol) and 6-chloronicotinic acid tert-butyl ester (1.1 equiv., 91.0 mg, 0.4261 mmol) according to General procedure A (Non-catalyzed method with Workup procedure A), except that the reaction mixture was stirred at 90 °C for 2.5 hours. The crude was purified with column chromatography using 1:9:90 = (25% NH4OH) / MeOH / DCM to afford the product (73.2 mg, 53%); Rf = 0.25 (20:3:3:2 = EtOAc / MeOH / AcOH / H2O).1H NMR (CDCl3, 600 MHz) δ 8.78 (m, 1H), 8.21 (dd, J = 8.6, 2.1 Hz, 1H), 7.26 (d, J = 7.8 Hz, 2H), 7.07 (d, J = 7.8 Hz, 2H), 6.89 (d, J = 8.6 Hz, 1H), 3.20 (m, 2H), 2.75 (m, 2H), 2.64 (tt, J = 12.2, 3.8 Hz, 1H), 1.86 (m, 2H), 1.65 (qd, J = 12.1, 3.5 Hz, 2H), 1.57 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 166.4, 164.3, 151.7, 150.4, 143.8, 140.6, 128.2, 122.9, 121.3, 110.7, 81.7, 47.3, 42.7, 34.7, 28.3. MS (ESI) Found: [M-HCl+H]+= 355.2, calcd: [M- HCl+H]+= 355.2. Intermediate 173 tert-butyl 5-(4-(piperidin-4-yl)phenoxy)picolinate The title compound was prepared using 4-(piperidin-4-yl)phenol hydrobromide (1.0 equiv., 100 mg, 0.3874 mmol) in 0.8 mL of DMF, Cs2CO3 (3.0 equiv., 378.6 mg, 1.1621 mmol) and tert-butyl 5-bromopicolinate (1.1 equiv., 110.0 mg, 0.4261 mmol) according to General procedure A (Non-catalyzed method with Workup procedure A) except that the reaction mixture was stirred at 90 °C. The crude was purified with column chromatography using 1:9:90 = (25% NH4OH) / MeOH / DCM to afford the product (70.6 mg, 51%); Rf = 0.22 (20:3:3:2 = EtOAc / MeOH / AcOH / H2O).1H NMR (CDCl3, 600 MHz) δ 8.46 (m, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.26 (m, 1H), 7.24 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 8.1 Hz, 2H), 3.20 (m, 2H), 2.75 (m, 2H), 2.63 (tt, J = 12.1, 3.8 Hz, 1H), 1.84 (m, 2H), 1.64 (m, 2H), 1.63 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 164.0, 156.9, 153.4, 143.8, 143.6, 140.7, 128.6, 126.1, 124.0, 119.9, 82.2, 47.3, 42.6, 34.8, 28.3. MS (ESI) Found: [M-HCl+H]+= 355.2, calcd: [M-HCl+H]+= 355.2. Intermediate 174 4-(4-((6-cyanopyridazin-3-yl)oxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 169 (1.0 equiv., 20 mg, 0.05257 mmol), 0.8 mL 1,4-dioxane and 0.2 mL 4M HCl in dioxane. Yield: 16.1 mg, 96%; Rf = 0.26 (20:3:3:2 = EtOAc / MeOH / AcOH / H2O). 1H NMR (DMSO, 400 MHz) δ 9.08 (m, 2H), 8.38 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 3.34 (m, 2H), 2.99 (m, 2H), 2.91 (m, 1H), 2.00 – 1.84 (m, 4H);13C NMR (DMSO, 100 MHz) δ 166.0, 151.0, 142.4, 135.8, 135.0, 128.1, 121.4, 117.9, 116.0, 43.4, 38.4, 29.3. MS (ESI) Found: [M-HCl+H]+= 281.1, calcd: [M-HCl+H]+= 281.1. Intermediate 175 4-(4-((5-cyanopyridin-2-yl)oxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 170 (1.0 equiv., 20 mg, 0.05271 mmol), 0.4 mL 1,4-dioxane and 0.4 mL 4M HCl in dioxane. Yield: 16.4 mg, 98%; Rf = 0.27 (20:3:3:2 = EtOAc / MeOH / AcOH / H2O). 1H NMR (DMSO, 400 MHz) δ 9.16 (m, 2H), 8.64 (d, J = 2.3 Hz, 1H), 8.31 (dd, J = 8.7, 2.3 Hz, 1H), 7.30 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.7 Hz, 1H), 7.16 (d, J = 8.6 Hz, 2H), 3.34 (m, 2H), 2.97 (m, 2H), 2.88 (m, 1H), 1.98 – 1.84 (m, 4H);13C NMR (DMSO, 100 MHz) δ 165.2, 152.3, 151.1, 143.4, 142.0, 127.9, 121.8, 117.1, 112.0, 103.5, 43.4, 38.4, 29.3. MS (ESI) Found: [M- HCl+H]+= 280.1, calcd: [M-HCl+H]+= 280.1. Intermediate 176 4-(4-((6-cyanopyridin-3-yl)oxy)phenyl)piperidin-1-ium chloride The title compound was prepared according to General procedure B, using Intermediate 171 (1.0 equiv., 20 mg, 0.05271 mmol), 0.4 mL 1,4-dioxane and 0.4 mL 4M HCl in dioxane. Yield: 16.5 mg, 99%; Rf= 0.28 (20:3:3:2 = EtOAc / MeOH / AcOH / H2O). 1H NMR (DMSO, 400 MHz) δ 9.20 (br s, 2H), 8.52 (d, J = 2.8 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.46 (dd, J = 8.7, 2.8 Hz, 1H), 7.34 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.6 Hz, 2H), 3.33 (m, 2H), 2.97 (m, 2H), 2.89 (m, 1H), 1.97 – 1.86 (m, 4H);13C NMR (DMSO, 100 MHz) δ 156.7, 152.5, 142.1, 142.0, 130.7, 128.6, 125.9, 124.5, 120.2, 117.5, 43.4, 38.3, 29.3. MS (ESI) Found: [M-HCl+H]+= 280.1, calcd: [M-HCl+H]+= 280.1. Intermediate 177 tert-butyl 4-(4-(methoxycarbonyl)-2-nitrophenyl)piperazine-1-carboxylate The title compound was prepared according to General procedure F, using methyl 4- fluoro-3-nitrobenzoate (1.0 equiv., 3.0 g, 15.0648 mmol) in 20 mL of DMSO, TEA (2.0 equiv., 4.20 mL, 30.1296 mmol) and 1-Boc-piperazine (1.05 equiv., 2.95 g, 15.8180 mmol). Yield: 5.47 g, 99%. Rf = 0.25 (30% EtOAc / Heptane).1H NMR (CDCl3, 400 MHz) δ 8.46 (d, J = 2.1 Hz, 1H), 8.09 (dd, J = 8.7, 2.1 Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H), 3.91 (s, 3H), 3.60 (m, 4H), 3.15 (m, 4H), 1.47 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 165.3, 154.8, 148.8, 140.8, 134.6, 128.6, 122.3, 119.7, 80.4, 52.5, 50.8, 43.1, 28.5. MS (ESI) Found: [M+H]+= 366.2, calcd: [M+H]+= 366.2. Intermediate 178 tert-butyl 4-(2-amino-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate The title compound was prepared according to General procedure I, using Intermediate 177 (1.0 equiv., 5.5 g, 15.0524 mmol) in 160 mL 70% EtOH / H2O, AcOH (5.0 equiv., 4.30 mL, 75.2620 mmol) and Fe powder (10.0 equiv., 8.41 g, 150.5241 mmol). Yield: 5.02 g, 99%. Rf= 0.48 (20% EtOA1 c / Petroleum Ether). H NMR (CDCl3, 400 MHz) δ 7.44 (dd, J = 8.2, 2.0 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 3.97 (br s, 2H), 3.87 (s, 3H), 3.57 (m, 4H), 2.90 (m, 4H), 1.49 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 167.3, 154.9, 143.3, 141.0, 126.3, 120.7, 119.2, 116.3, 80.1, 52.1, 50.5, 44.5, 28.6. MS (ESI) Found: [M+H]+= 336.2, calcd: [M+H]+= 336.2. Intermediate 179 tert-butyl 3-(((3-chlorophenyl)methyl)sulfonamido)-4-(4-ethylpiperazin-1-yl)benzoate The title compound was prepared according to General procedure J, using Intermediate 104 (1.0 equiv., 1.0 g, 3.2742 mmol) in 12 mL of pyridine and (3- chlorophenyl)methanesulfonyl chloride (1.3 equiv., 958.0 mg, 4.2564 mmol) The crude was purified with column chromatography using 5% MeOH / DCM to afford the product (999 mg, 91%). Rf = 0.31 (5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.16 (d, J = 1.9 Hz, 1H), 7.74 (dd, J = 8.3, 1.9 Hz, 1H), 7.54 (br s, 1H), 7.31 (m, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.14 (dt, J = 7.5, 1.5 Hz, 1H), 7.05 (t, J = 1.9 Hz, 1H), 4.41 (s, 2H), 2.80 (m, 4H), 2.45 (m, 4H), 2.43 (q, J = 7.2 Hz, 2H), 1.60 (s, 9H), 1.09 (t, J = 7.2 Hz, 3H);13C NMR (CDCl3, 100 MHz) δ 165.1, 144.5, 134.7, 132.9, 130.8, 130.5, 130.2, 129.7, 129.2, 129.0, 125.5, 121.1, 116.5, 81.5, 56.8, 53.1, 52.3, 52.1, 28.3, 12.1. MS (ESI) Found: [M+H]+= 494.2, calcd: [M+H]+= 494.2. Intermediate 180 tert-butyl 4-(4-(methoxycarbonyl)-2-((phenylmethyl)sulfonamido)phenyl)piperazine-1-carboxylate The title compound was prepared according to General procedure J, using Intermediate 178 (1.0 equiv., 3.0 g, 8.9445 mmol) in 50 mL of pyridine and benzylsulfonyl chloride (2.0 equiv., 3.41 g, 17.8891 mmol). The crude was purified with column chromatography using 10% EtOAc / Toluene to afford the product (4.35 g, 99%). Rf = 0.44 (20% EtOAc / Toluene).1H NMR (CDCl3, 400 MHz) δ 8.06 (d, J = 1.9 Hz, 1H), 7.79 (dd, J = 8.3, 1.9 Hz, 1H), 7.54 (br s, 1H), 7.37 – 7.27 (m, 3H), 7.18 (m, 2H), 7.15 (d, J = 8.3 Hz, 1H), 4.47 (s, 2H), 3.92 (s, 3H), 3.40 (m, 4H), 2.67 (m, 4H), 1.46 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 166.3, 154.6, 144.3, 133.2, 130.7, 129.1, 129.0, 128.7, 128.3, 125.7, 121.2, 117.5, 80.4, 57.8, 52.5, 52.0, 43.8, 28.5. MS (ESI) Found: [M+H]+= 490.2, calcd: [M+H]+= 490.2. Intermediate 181 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-((phenylmethyl)sulfonamido)benzoic acid The title compound was prepared according to General procedure L, using Intermediate 178 (1.0 equiv., 4.50 g, 9.1914 mmol) in 100 mL of 8:1:1 ratio of 1,4- dioxane / MeOH / H2O, and NaOH (5.0 equiv., 1.84 g, 45.9568 mmol). Yield: 3.88 g, 89%. Rf = 0.51 (10% MeOH / DCM).1H NMR (DMSO, 400 MHz) δ 12.87 (br s, 1H), 8.51 (br s, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.66 (dd, J = 8.3, 2.0 Hz, 1H), 7.37 – 7.29 (m, 5H), 7.24 (d, J = 8.3 Hz, 1H), 4.61 (s, 2H), 3.44 (m, 4H), 2.80 (m, 4H), 1.42 (s, 9H);13C NMR (DMSO, 100 MHz) δ 166.8, 153.9, 147.5, 131.9, 130.8, 129.3, 128.4, 128.3, 126.8, 126.0, 121.8, 121.0, 79.0, 58.1, 50.9, 43.4, 28.1. MS (ESI) Found: [M+H]+= 476.2, calcd: [M+H]+= 476.2. Intermediate 182 4-(4-carboxy-2-(((3-chlorophenyl)methyl)sulfonamido)phenyl)-1-ethylpiperazin-1-ium chloride The title compound was prepared according to General procedure M, using Intermediate 179 (1.0 equiv., 650 mg, 1.3157 mmol) and 20 mL of 4M HCl in dioxane. Yield: 605 mg, 97%. Rf= 0.23 (20:3:3:2 = EtOAc / MeOH / AcOH / H2O).1H NMR (DMSO, 400 MHz) δ 12.89 (br s, 1H), 10.92 (br s, 1H), 8.98 (s, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.71 (dd, J = 8.3, 2.0 Hz, 1H), 7.47 – 7.34 (m, 3H), 7.31 (dt, J = 6.6, 1.9 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 4.66 (s, 2H), 3.50 (m, 2H), 3.32 – 3.08 (m, 8H), 1.30 (t, J = 7.2 Hz, 3H);13C NMR (DMSO, 100 MHz) δ 166.6, 146.8, 132.9, 131.8, 131.7, 130.6, 130.2, 129.6, 128.3, 127.1, 126.5, 123.1, 121.0, 57.6, 50.6, 50.2, 47.8, 8.8. MS (ESI) Found: [M-HCl+H]+= 438.1, calcd: [M-HCl+H]+= 438.1. Intermediate 183 tert-butyl 6-(4-(1-(4-(4-ethylpiperazin-1-yl)-3-((phenylmethyl)sulfonamido)benzoyl)piperidin-4-yl)- phenoxy)nicotinate The title compound was prepared according to General procedure N (Workup procedure B), using Intermediate 156 (1.0 equiv., 100.0 mg, 0.2273 mmol), DIPEA (2.0 equiv., 79.2 µL, 0.4546 mmol), HBTU (1.05 equiv., 90.5 mg, 0.2387 mmol) in 1.0 mL DMF, and Intermediate 172 (1.0 equiv., 80.6 mg, 0.2273 mmol), DIPEA (1.0 equiv., 39.6µL, 0.2273 mmol) in 1.0 mL DMF. The crude was purified with column chromatography using 5% MeOH / DCM to afford the product (126 mg, 75%). Rf = 0.45 (10% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.65 (dd, J = 2.4, 0.7 Hz, 1H), 8.27 (dd, J = 8.7, 2.4 Hz, 1H), 7.38 (d, J = 8.6 Hz, 2H), 7.38 – 7.25 (m, 6H), 7.25 (d, J = 1.9 Hz, 1H), 7.19 (dd, J = 8.1, 1.9 Hz, 1H), 7.11 (d, J = 8.6 Hz, 2H), 6.98 (dd, J = 8.7, 0.7 Hz, 1H), 4.77 (m, 1H), 4.61 (s, 2H), 3.85 (m, 1H), 3.23 (m, 1H), 2.98 (m, 1H), 2.93 (tt, J = 12.1, 3.6 Hz, 1H), 2.85 (m, 4H), 2.56 (m, 4H), 2.48 (q, J = 7.2 Hz, 2H), 2.02 (m, 1H), 1.86 (m, 1H), 1.75 (m, 2H), 1.59 (s, 9H), 1.12 (t, J = 7.2 Hz, 3H);13C NMR (MeOD, 100 MHz) δ 171.7, 167.8, 165.4, 153.3, 150.6, 144.3, 144.0, 142.1, 134.5, 133.9, 132.1, 130.6, 129.9, 129.8, 129.4, 124.3, 123.9, 122.6, 122.5, 117.4, 111.9, 83.0, 59.0, 54.0, 53.2, 52.5, 49.8, 44.2, 43.2, 35.0, 34.2, 28.4, 11.8. MS (ESI) Found: [M+H]+= 740.3, calcd: [M+H]+= 740.3. Intermediate 184 tert-butyl 5-(4-(1-(4-(4-ethylpiperazin-1-yl)-3-((phenylmethyl)sulfonamido)benzoyl)piperidin-4-yl)- phenoxy)picolinate The title compound was prepared according to General procedure N (Workup procedure B), using Intermediate 156 (1.0 equiv., 100.0 mg, 0.2273 mmol), DIPEA (2.0 equiv., 79.2 µL, 0.4546 mmol), HBTU (1.05 equiv., 90.5 mg, 0.2387 mmol) in 1.0 mL DMF, and Intermediate 173 (1.0 equiv., 80.6 mg, 0.2273 mmol), DIPEA (1.0 equiv., 39.6µL, 0.2273 mmol) in 1.0 mL DMF. The crude was purified with column chromatography using 5% MeOH / DCM to afford the product (136 mg, 81%). Rf= 0.36 (10% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.34 (d, J = 2.7 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.45 – 7.37 (m, 3H), 7.38 – 7.25 (m, 6H), 7.25 (d, J = 1.8 Hz, 1H), 7.19 (dd, J = 8.1, 1.9 Hz, 1H), 7.11 (d, J = 8.6 Hz, 2H), 4.77 (m, 1H), 4.61 (s, 2H), 3.85 (m, 1H), 3.23 (m, 1H), 2.99 (m, 1H), 2.94 (tt, J = 12.1, 3.6 Hz, 1H), 2.85 (m, 4H), 2.56 (m, 4H), 2.49 (q, J = 7.2 Hz, 2H), 2.02 (m, 1H), 1.86 (m, 1H), 1.75 (m, 2H), 1.61 (s, 9H), 1.13 (t, J = 7.2 Hz, 3H);13C NMR (MeOD, 100 MHz) δ 171.7, 164.8, 158.9, 154.7, 144.3, 144.1, 143.9, 140.7, 134.5, 133.8, 132.1, 130.7, 129.9, 129.9, 129.8, 127.6, 125.5, 123.9, 122.6, 121.3, 117.5, 83.4, 58.9, 53.9, 53.2, 52.5, 49.7, 44.1, 43.2, 35.0, 34.2, 28.3, 11.8. MS (ESI) Found: [M+H]+= 740.3, calcd: [M+H]+= 740.3. Intermediate 185 tert-butyl 4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)piperazine-1-carboxylate The title compound was prepared according to General procedure N (Workup procedure B), using Intermediate 181 (1.0 equiv., 596 mg, 1.2542 mmol), DIPEA (2.0 equiv., 437 µL, 2.5084 mmol), HBTU (1.05 equiv., 499 mg, 1.3169 mmol) in 3.0 mL DMF, and Intermediate 30 (1.0 equiv., 450 mg, 1.2542 mmol), DIPEA (1.5 equiv., 328 µL, 1.8813 mmol) in 5.0 mL DMF. The crude was purified with column chromatography using 5% MeOH / DCM to afford the product (966 mg, 99%). Rf = 0.32 (60% EtOAc / Heptane).1H NMR (CDCl3, 600 MHz) δ 8.45 (d, J = 2.6 Hz, 1H), 7.90 (m, 1H), 7.61 (br s, 1H), 7.55 (m, 1H), 7.35 (m, 1H), 7.33 – 7.27 (m, 4H), 7.22 – 7.17 (m, 3H), 7.17 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 4.88 (m, 1H), 4.44 (s, 2H), 3.88 (m, 1H), 3.37 (m, 4H), 3.16 (m, 1H), 2.88 (m, 1H), 2.83 (tt, J = 12.2, 3.7 Hz, 1H), 2.64 (m, 4H), 2.03 (m, 1H), 1.88 (m, 1H), 1.78 (m, 1H), 1.68 (m, 1H), 1.47 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 169.5, 166.0, 154.7, 151.8, 145.6 (q, J = 4.3 Hz), 142.2, 141.3, 136.8 (q, J = 3.3 Hz), 134.4, 133.3, 130.7, 129.2, 129.0, 128.7, 128.2, 123.8 (q, J = 271.5 Hz), 122.8, 122.1, 121.6 (q, J = 33.2 Hz), 121.6, 114.6, 111.5, 80.3, 57.7, 52.1, 48.6, 44.5, 43.5, 43.1, 42.3, 34.0, 33.1, 28.5;19F NMR (CDCl3, 565 MHz) δ -61.65. MS (ESI) Found: [M+H]+= 780.3, calcd: [M+H]+= 780.3. Intermediate 186 tert-butyl 4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)piperazine-1-carboxylate The title compound was prepared according to General procedure N (Workup procedure B), using Intermediate 181 (1.0 equiv., 596 mg, 1.2542 mmol), DIPEA (2.0 equiv., 437 µL, 2.5084 mmol), HBTU (1.05 equiv., 499 mg, 1.3169 mmol) in 3.0 mL DMF, and Intermediate 36 (1.0 equiv., 450 mg, 1.2542 mmol), DIPEA (1.5 equiv., 328 µL, 1.8813 mmol) in 5.0 mL DMF. The crude was purified with column chromatography using 5% MeOH / DCM to afford the product (964 mg, 99%). Rf = 0.26 (60% EtOAc / Heptane).1H NMR (CDCl3, 600 MHz) δ 8.46 (m, 1H), 7.64 – 7.59 (m, 2H), 7.55 (m, 1H), 7.38 – 7.25 (m, 6H), 7.23 – 7.15 (m, 3H), 7.17 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 7.9 Hz, 2H), 4.88 (m, 1H), 4.45 (s, 2H), 3.89 (m, 1H), 3.37 (m, 4H), 3.17 (m, 1H), 2.89 (m, 1H), 2.83 (tt, J = 12.2, 3.6 Hz, 1H), 2.64 (m, 4H), 2.02 (m, 1H), 1.86 (m, 1H), 1.77 (m, 1H), 1.69 (m, 1H), 1.46 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 169.6, 156.6, 154.7, 153.5, 142.3, 142.1 (q, J = 35.1 Hz), 141.4, 140.9, 134.3, 133.3, 130.7, 129.2, 129.0, 128.7, 128.7, 124.5, 122.9, 122.1, 121.7 (q, J = 273.3 Hz), 121.6 (q, J = 2.7 Hz), 120.2, 114.6, 80.3, 57.8, 52.1, 48.5, 44.4, 43.5, 43.0, 42.3, 34.0, 33.2, 28.5;19F NMR (CDCl3, 565 MHz) δ -66.99. MS (ESI) Found: [M+H]+= 780.3, calcd: [M+H]+= 780.3. Intermediate 187 4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)piperidine- 1-carbonyl)phenyl)piperazin-1-ium 2,2,2-trifluoroacetate The title compound was prepared according to General procedure O, using Intermediate 185 (1.0 equiv., 313 mg, 0.4013 mmol) in 8 mL of DCE, and 3 mL of TFA. Yield: 317 mg, 99%. Rf = 0.37 (10% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.41 (m, 1H), 8.08 (dd, J = 8.6, 2.5 Hz, 1H), 7.43 – 7.30 (m, 7H), 7.29 (d, J = 8.2 Hz, 1H), 7.20 (dd, J = 8.2, 1.9 Hz, 1H), 7.13 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 1.9 Hz, 1H), 4.76 (m, 1H), 4.64 (s, 2H), 3.78 (m, 1H), 3.36 (m, 4H), 3.21 (m, 1H), 3.09 (m, 4H), 2.98 (m, 1H), 2.94 (tt, J = 11.9, 3.5 Hz, 1H), 2.03 (m, 1H), 1.90 – 1.59 (m, 3H);13C NMR (MeOD, 100 MHz) δ 171.4, 167.6, 153.2, 146.2 (q, J = 4.4 Hz), 144.2, 144.0, 138.5 (q, J = 3.3 Hz), 134.4, 134.3, 132.3, 130.7, 129.9, 129.9, 129.3, 125.3 (q, J = 270.9 Hz), 124.4, 122.7 (q, J = 33.1 Hz), 122.7, 122.5, 119.8, 112.7, 60.0, 49.9, 49.7, 44.9, 44.1, 43.2, 35.1, 34.2;19F NMR (MeOD, 376 MHz) δ -63.19, -77.08. MS (ESI) Found: [M-TFA+H]+= 680.3, calcd: [M-TFA+H]+= 680.3. Intermediate 188 4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)piperidine- 1-carbonyl)phenyl)piperazin-1-ium 2,2,2-trifluoroacetate The title compound was prepared according to General procedure O, using Intermediate 186 (1.0 equiv., 329 mg, 0.4219 mmol) in 8 mL of DCE, and 3 mL of TFA. Yield: 332 mg, 99%. Rf = 0.33 (10% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.40 (d, J = 2.8 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.47 (dd, J = 8.7, 2.8 Hz, 1H), 7.41 (d, J = 8.6 Hz, 2H), 7.41 – 7.30 (m, 5H), 7.29 (d, J = 8.2 Hz, 1H), 7.20 (dd, J = 8.2, 1.9 Hz, 1H), 7.13 (d, J = 8.6 Hz, 2H), 7.02 (d, J = 1.9 Hz, 1H), 4.76 (m, 1H), 4.64 (s, 2H), 3.78 (m, 1H), 3.36 (m, 4H), 3.21 (m, 1H), 3.09 (m, 4H), 2.99 (m, 1H), 2.94 (tt, J = 12.0, 3.6 Hz, 1H), 2.02 (m, 1H), 1.89 – 1.60 (m, 3H);13C NMR (MeOD, 100 MHz) δ 171.4, 158.5, 154.7, 144.2, 144.1, 142.6 (q, J = 34.9 Hz), 141.3, 134.4, 134.3, 132.3, 130.7, 130.0, 129.9, 129.9, 126.0, 124.4, 123.2 (q, J = 2.9 Hz), 123.1 (q, J = 272.2 Hz), 122.5, 121.3, 119.8, 59.9, 49.9, 49.7, 44.9, 44.1, 43.1, 35.0, 34.1;19F NMR (MeOD, 376 MHz) δ -69.15, -77.79. MS (ESI) Found: [M-TFA+H]+= 680.3, calcd: [M-TFA+H]+= 680.3. Intermediate 189 tert-butyl 2-(4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-yl)acetate The title compound was prepared according to General procedure T, using Intermediate 168 (1.0 equiv., 80 mg, 0.1007 mmol) in 0.8 mL of THF, TEA (2.5 equiv., 35.1 µL, 0.2516 mmol) and tert-butyl bromoacetate (1.05 equiv., 15.6 µL, 0.1057 mmol). The crude was purified with column chromatography using 2.5% MeOH / DCM to afford the product (69.0 mg, 86%). Rf = 0.55 (10% MeOH / DCM).1H NMR (CDCl3, 600 MHz) δ 7.80 (d, J = 9.2 Hz, 1H), 7.64 (br s, 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.36 – 7.26 (m, 6H), 7.22 (d, J = 8.1 Hz, 1H), 7.21 – 7.15 (m, 5H), 4.88 (m, 1H), 4.43 (s, 2H), 3.89 (m, 1H), 3.15 (m, 1H), 3.11 (s, 2H), 2.88 (m, 1H), 2.84 (tt, J = 12.3, 3.6 Hz, 1H), 2.79 (m, 4H), 2.57 (m, 4H), 2.02 (m, 1H), 1.86 (m, 1H), 1.78 (m, 1H), 1.67 (m, 1H), 1.47 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 169.7, 169.5, 167.2, 151.3, 148.4 (q, J = 35.4 Hz), 143.0, 141.6, 134.1, 133.3, 130.7, 129.1, 129.0, 128.7, 128.4, 127.3 (q, J = 2.1 Hz), 122.8, 122.1, 121.5, 121.5 (q, J = 274.0 Hz), 117.8, 114.4, 81.5, 59.8, 57.7, 53.3, 52.0, 48.6, 43.1, 42.4, 34.0, 33.2, 28.3;19F NMR (CDCl3, 565 MHz) δ -66.38. MS (ESI) Found: [M+H]+= 795.3, calcd: [M+H]+= 795.3. Intermediate 190 tert-butyl 3-(4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-yl)propanoate The title compound was prepared using Intermediate 168 (1.0 equiv., 85 mg, 0.1069 mmol) in 1.0 mL of THF, TEA (2.5 equiv., 37.3 µL, 0.2674 mmol) and tert-butyl acrylate (2.0 equiv., 31.3 µL, 0.2139 mmol) according to General procedure T, except that the reaction mixture was stirred at 60 °C. The crude was purified with column chromatography using 2.5% MeOH / DCM to afford the product (68.1 mg, 79%). Rf = 0.55 (10% MeOH / DCM).1H NMR (CDCl3 , 600 MHz) δ 7.80 (d, J = 9.1 Hz, 1H), 7.62 (br s, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.36 – 7.28 (m, 6H), 7.23 – 7.17 (m, 6H), 4.88 (m, 1H), 4.43 (s, 2H), 3.89 (m, 1H), 3.16 (m, 1H), 2.88 (m, 1H), 2.84 (tt, J = 12.2, 3.6 Hz, 1H), 2.72 (m, 4H), 2.66 (m, 2H), 2.45 (m, 4H), 2.40 (m, 2H), 2.02 (m, 1H), 1.86 (m, 1H), 1.78 (m, 1H), 1.67 (m, 1H), 1.46 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 171.8, 169.7, 167.2, 151.3, 148.4 (q, J = 35.5 Hz), 143.0, 141.7, 134.0, 133.3, 130.7, 129.1, 129.0, 128.7, 128.4, 127.3 (q, J = 2.3 Hz), 122.8, 122.0, 121.5, 121.5 (q, J = 273.9 Hz), 117.9, 114.4, 80.7, 57.7, 53.7, 53.2, 52.2, 48.6, 43.1, 42.4, 34.0, 33.7, 33.2, 28.3;19F NMR (CDCl3, 565 MHz) δ -66.38. MS (ESI) Found: [M+H]+= 809.3, calcd: [M+H]+= 809.3. Intermediate 191 tert-butyl 2-(4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-yl)acetate The title compound was prepared according to General procedure T, using Intermediate 187 (1.0 equiv., 80 mg, 0.1008 mmol) in 0.8 mL of THF, TEA (2.5 equiv., 35.1 µL, 0.2520 mmol) and tert-butyl bromoacetate (1.05 equiv., 15.6 µL, 0.1058 mmol). The crude was purified with column chromatography using 2.5% MeOH / DCM to afford the product (75.3 mg, 94%). Rf= 0.55 (10% MeOH / DCM).1H NMR (CDCl3, 600 MHz) δ 8.45 (m, 1H), 7.89 (dd, J = 8.7, 2.5 Hz, 1H), 7.64 (br s, 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.33 (m, 1H), 7.32 – 7.26 (m, 4H), 7.22 (d, J = 8.1 Hz, 1H), 7.21 – 7.16 (m, 3H), 7.11 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 8.7 Hz, 1H), 4.88 (m, 1H), 4.43 (s, 2H), 3.89 (m, 1H), 3.15 (m, 1H), 3.11 (s, 2H), 2.88 (m, 1H), 2.83 (tt, J = 12.3, 3.6 Hz, 1H), 2.79 (m, 4H), 2.56 (m, 4H), 2.03 (m, 1H), 1.87 (m, 1H), 1.78 (m, 1H), 1.68 (m, 1H), 1.47 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 169.7, 169.5, 166.0, 151.8, 145.6 (q, J = 4.4 Hz), 142.3, 141.6, 136.8 (q, J = 3.2 Hz), 134.1, 133.3, 130.7, 129.1, 129.0, 128.7, 128.2, 123.8 (q, J = 271.5 Hz), 122.8, 122.1, 121.6 (q, J = 33.2 Hz), 121.6, 114.4, 111.5, 81.5, 59.8, 57.7, 53.3, 52.0, 48.6, 43.1, 42.4, 34.0, 33.2, 28.3;19F NMR (CDCl3, 565 MHz) δ -61.65. MS (ESI) Found: [M+H]+= 794.3, calcd: [M+H]+= 794.3. Intermediate 192 tert-butyl 3-(4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-yl)propanoate The title compound was prepared using Intermediate 187 (1.0 equiv., 85 mg, 0.1071 mmol) in 1.0 mL of THF, TEA (2.5 equiv., 37.3 µL, 0.2677 mmol) and tert-butyl acrylate (2.0 equiv., 31.4 µL, 0.2142 mmol) according to General procedure T, except that the reaction mixture was stirred at 60 °C. The crude was purified with column chromatography using 2.5% MeOH / DCM to afford the product (69.6 mg, 80%). Rf = 0.55 (10% MeOH / DCM).1H NMR (CDCl3 , 600 MHz) δ 7.90 (dd, J = 8.7, 2.5 Hz, 1H), 7.62 (br s, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.34 (m, 1H), 7.31 – 7.28 (m, 4H), 7.22 – 7.18 (m, 4H), 7.11 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 8.7 Hz, 1H), 4.88 (m, 1H), 4.43 (s, 2H), 3.89 (m, 1H), 3.15 (m, 1H), 2.88 (m, 1H), 2.83 (tt, J = 12.0, 3.5 Hz, 1H), 2.72 (m, 4H), 2.66 (m, 2H), 2.44 (m, 4H), 2.40 (m, 2H), 2.03 (m, 1H), 1.87 (m, 1H), 1.78 (m, 1H), 1.67 (m, 1H), 1.46 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 171.8, 169.7, 166.0, 151.8, 145.6 (q, J = 4.3 Hz), 142.3, 141.7, 136.8 (q, J = 3.3 Hz), 134.0, 133.3, 130.7, 129.1, 129.0, 128.7, 128.3, 123.8 (q, J = 271.4 Hz), 122.8, 122.0, 121.6 (q, J = 33.4 Hz), 121.6, 114.4, 111.5, 80.6, 57.7, 53.7, 53.2, 52.2, 48.6, 43.1, 42.4, 34.0, 33.8, 33.2, 28.3;19F NMR (CDCl3, 565 MHz) δ -61.65. MS (ESI) Found: [M+H]+= 808.3, calcd: [M+H]+= 808.3. Intermediate 193 tert-butyl 2-(4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-yl)acetate The title compound was prepared according to General procedure T, using Intermediate 188 (1.0 equiv., 80 mg, 0.1008 mmol) in 0.8 mL of THF, TEA (2.5 equiv., 35.1 µL, 0.2520 mmol) and tert-butyl bromoacetate (1.05 equiv., 15.6 µL, 0.1058 mmol). The crude was purified with column chromatography using 2.5% MeOH / DCM to afford the product (76.0 mg, 95%). Rf = 0.55 (10% MeOH / DCM).1H NMR (CDCl3, 600 MHz) δ 8.46 (d, J = 2.7 Hz, 1H), 7.63 (br s, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.35 – 7.31 (m, 2H), 7.31 – 7.27 (m, 4H), 7.22 (d, J = 8.1 Hz, 1H), 7.20 – 7.17 (m, 3H), 7.04 (d, J = 8.6 Hz, 2H), 4.88 (m, 1H), 4.43 (s, 2H), 3.90 (m, 1H), 3.15 (m, 1H), 3.12 (s, 2H), 2.88 (m, 1H), 2.83 (tt, J = 12.4, 3.6 Hz, 1H), 2.79 (m, 4H), 2.57 (m, 4H), 2.01 (m, 1H), 1.85 (m, 1H), 1.77 (m, 1H), 1.67 (m, 1H), 1.47 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 169.7, 169.5, 156.6, 153.5, 142.4, 142.1 (q, J = 35.1 Hz), 141.7, 140.9, 134.0, 133.3, 130.7, 129.1, 129.0, 128.7, 128.7, 124.5, 122.8, 122.2, 121.7 (q, J = 273.1 Hz), 121.6 (q, J = 2.7 Hz), 120.2, 114.4, 81.6, 59.7, 57.7, 53.3, 52.0, 48.5, 43.0, 42.3, 34.0, 33.2, 28.3;19F NMR (CDCl3, 565 MHz) δ -66.99. MS (ESI) Found: [M+H]+= 794.3, calcd: [M+H]+= 794.3. Intermediate 194 tert-butyl 3-(4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-yl)propanoate The title compound was prepared using Intermediate 188 (1.0 equiv., 85 mg, 0.1071 mmol) in 1.0 mL of THF, TEA (2.5 equiv., 37.3 µL, 0.2677 mmol) and tert-butyl acrylate (2.0 equiv., 31.4 µL, 0.2142 mmol) according to General procedure T, except that the reaction mixture was stirred at 60 °C. The crude was purified with column chromatography using 2.5% MeOH / DCM to afford the product (64.2 mg, 74%). Rf= 0.55 (10% MeOH / DCM).1H NMR (CDCl3, 600 MHz) δ 8.46 (d, J = 2.7 Hz, 1H), 7.62 (br s, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.54 (m, 1H), 7.36 – 7.32 (m, 2H), 7.31 – 7.27 (m, 4H), 7.22 – 7.18 (m, 4H), 7.04 (d, J = 8.6 Hz, 2H), 4.88 (m, 1H), 4.43 (s, 2H), 3.90 (m, 1H), 3.16 (m, 1H), 2.88 (m, 1H), 2.83 (tt, J = 12.1, 3.6 Hz, 1H), 2.72 (m, 4H), 2.66 (m, 2H), 2.44 (m, 4H), 2.40 (m, 2H), 2.01 (m, 1H), 1.85 (m, 1H), 1.77 (m, 1H), 1.67 (m, 1H), 1.46 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 171.8, 169.7, 156.6, 153.5, 142.4, 142.1 (q, J = 35.2 Hz), 141.7, 140.9, 134.0, 133.3, 130.7, 129.1, 129.0, 128.7, 128.7, 124.5, 122.8, 122.1, 121.7 (q, J = 273.1 Hz), 121.6 (q, J = 2.7 Hz), 120.2, 114.4, 80.6, 57.7, 53.7, 53.2, 52.2, 48.6, 43.0, 42.3, 34.0, 33.7, 33.2, 28.3;19F NMR (CDCl3, 565 MHz) δ -67.00. MS (ESI) Found: [M+H]+= 808.3, calcd: [M+H]+= 808.3. Example 1 N-(2-methyl-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)- 1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 133 (1.0 equiv., 30 mg, 0.1637 mmol), DIPEA (2.0 equiv., 57.0 µL, 0.3275 mmol), HBTU (1.1 equiv., 68.3 mg, 0.1801 mmol) in 0.2 mL DMF, and Intermediate 21 (1.0 equiv., 58.9 mg, 0.1637 mmol), DIPEA (2.0 equiv., 57.0 µL, 0.3275 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 30% EtOAc / Petroleum Ether to afford the product (81 mg, 81%). Rf= 0.77 (80% EtOAc / Petroleum Ether).1H NMR (MeOD, 600 MHz) δ 8.09 (d, J = 9.3 Hz, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.41 (d, J = 8.6 Hz, 2H), 7.38 – 7.31 (m, 5H), 7.31 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 1.7 Hz, 1H), 7.21 (d, J = 8.6 Hz, 2H), 7.18 (dd, J = 7.8, 1.7 Hz, 1H), 4.78 (m, 1H), 4.48 (s, 2H), 3.84 (m, 1H), 3.22 (m, 1H), 2.99 – 2.90 (m, 2H), 2.27 (s, 3H), 2.02 (m, 1H), 1.86 (m, 1H), 1.81 – 1.64 (m, 3H);13C NMR (MeOD, 151 MHz) δ 171.8, 169.0, 152.9, 149.4 (q, J = 35.0 Hz), 144.7, 137.2, 135.4, 135.2, 132.3, 132.1, 130.7, 129.6, 129.6, 129.5, 129.4 (q, J = 2.2 Hz), 125.1, 123.2, 122.9 (q, J = 272.9 Hz), 122.3, 119.9, 59.8, 49.7, 44.1, 43.2, 35.0, 34.2, 18.4;19F NMR (MeOD, 565 MHz) δ -67.91. HRMS (ESI) Found: [M-H]- = 609.1781, calcd: [M-H]- = 609.1789. Example 2 N-(2-methoxy-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 134 (1.0 equiv., 30 mg, 0.1556 mmol), DIPEA (2.0 equiv., 54.2 µL, 0.3112 mmol), HBTU (1.1 equiv., 64.9 mg, 0.1712 mmol) in 0.2 mL DMF, and Intermediate 21 (1.0 equiv., 56.0 mg, 0.1556 mmol), DIPEA (2.0 equiv., 54.2 µL, 0.3112 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 50% EtOAc / Petroleum Ether to afford the product (84 mg, 86%). R = 0.55 (80% EtOA1 f c / Petroleum Ether). H NMR (CDCl3, 600 MHz) δ 7.79 (d, J = 9.2 Hz, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.34 – 7.26 (m, 7H), 7.19 (m, 2H), 7.16 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.3 Hz, 1H), 6.83 (s, 1H), 4.83 (br s, 1H), 4.34 (s, 2H), 3.89 (br s, 1H), 3.82 (s, 3H), 3.13 (br s, 1H), 2.94 – 2.75 (m, 2H), 1.96 (br s, 1H), 1.87 (br s, 1H), 1.71 (br s, 2H);13C NMR (CDCl3, 151 MHz) δ 171.8, 169.0, 152.9, 149.4 (q, J = 35.0 Hz), 144.7, 137.2, 135.4, 135.2, 132.3, 132.1, 130.7, 129.6, 129.6, 129.5, 129.4 (q, J = 2.2 Hz), 125.1, 123.2, 122.9 (q, J = 272.9 Hz), 122.3, 119.9, 59.8, 49.7, 44.1, 43.2, 35.0, 34.2, 18.4;19F NMR (CDCl3, 565 MHz) δ -67.91. HRMS (ESI) Found: [M+H]+= 627.1892, calcd: [M+H]+= 627.1884. Example 3 N-(2-methyl-5-(4-(4-((5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 133 (1.0 equiv., 30 mg, 0.1637 mmol), DIPEA (2.0 equiv., 57.0 µL, 0.3275 mmol), HBTU (1.1 equiv., 68.3 mg, 0.1801 mmol) in 0.2 mL DMF, and Intermediate 22 (1.0 equiv., 59.9 mg, 0.1637 mmol), DIPEA (2.0 equiv., 57.0 µL, 0.3275 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 80% EtOAc / Petroleum Ether to afford the product (83 mg, 82%). Rf = 0.75 (80% EtOAc / Petroleum Ether).1H NMR (MeOD, 600 MHz) δ 7.46 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 8.7 Hz, 2H), 7.38 – 7.28 (m, 6H), 7.27 (d, J = 1.7 Hz, 1H), 7.18 (dd, J = 7.7, 1.7 Hz, 1H), 4.77 (m, 1H), 4.48 (s, 2H), 3.84 (m, 1H), 3.22 (m, 1H), 3.03 – 2.89 (m, 2H), 2.27 (s, 3H), 2.00 (m, 1H), 1.84 (m, 1H), 1.80 – 1.63 (m, 2H);13C NMR (MeOD, 151 MHz) δ 180.0, 171.8, 155.7, 153.0 (q, J = 39.5 Hz), 146.4, 137.2, 135.3, 135.2, 132.3, 132.1, 130.8, 130.1, 129.6, 129.6, 125.1, 123.2, 121.1, 120.3 (q, J = 271.8 Hz), 59.8, 49.6, 44.0, 43.2, 34.9, 34.1, 18.4;19F NMR (MeOD, 565 MHz) δ -62.12. HRMS (ESI) Found: [M-H]- = 615.1349, calcd: [M-H]- = 615.1353. Example 4 N-(2-methoxy-5-(4-(4-((5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 134 (1.0 equiv., 30 mg, 0.1556 mmol), DIPEA (2.0 equiv., 54.2 µL, 0.3112 mmol), HBTU (1.1 equiv., 64.9 mg, 0.1712 mmol) in 0.2 mL DMF, and Intermediate 22 (1.0 equiv., 56.9 mg, 0.1556 mmol), DIPEA (2.0 equiv., 54.2 µL, 0.3112 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 50% EtOAc / Petroleum Ether to afford the product (88 mg, 89%). Rf = 0.54 (80% EtOAc / Petroleum Ether).1H NMR (CDCl3 , 600 MHz) δ 7.62 (d, J = 1.4 Hz, 1H), 7.35 – 7.27 (m, 8H), 7.20 (m, 2H), 6.93 (d, J = 8.0 Hz, 1H), 6.81 (s, 1H), 4.84 (br s, 1H), 4.34 (s, 2H), 3.92 (br s, 1H), 3.82 (s, 3H), 3.10 (br s, 1H), 2.99 – 2.79 (m, 2H), 2.07 – 1.81 (m, 2H), 1.72 (m, 2H);13C NMR (CDCl3, 151 MHz) δ 177.7, 169.8, 154.0, 152.0 (q, J = 39.7 Hz), 149.4, 144.5, 130.8, 129.0, 128.9, 128.8, 128.8, 128.4, 126.4, 124.6, 120.0, 118.8 (q, J = 272.9 Hz), 117.7, 110.7, 57.9, 56.0, 48.6, 43.2, 42.4, 33.7, 33.2;19F NMR (CDCl3, 565 MHz) δ -60.25. HRMS (ESI) Found: [M+H]+= 633.1455, calcd: [M+H]+= 633.1448. Example 5 N-(5-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2-methylphenyl)- 1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 133 (1.0 equiv., 43.1 mg, 0.1412 mmol), DIPEA (2.0 equiv., 36.9 µL, 0.2119 mmol), HBTU (1.05 equiv., 56.3 mg, 0.1483 mmol) in 0.2 mL DMF, and Intermediate 23 (1.0 equiv., 50 mg, 0.1412 mmol), DIPEA (1.5 equiv., 36.9 µL, 0.2119 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 1% MeOH / DCM to afford the product (80 mg, 94%). Rf = 0.51 (5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 7.54 (d, J = 1.3 Hz, 1H), 7.37 – 7.26 (m, 3H), 7.27 – 7.16 (m, 8H), 6.46 (s, 1H), 4.85 (br s, 1H), 4.40 (s, 2H), 3.86 (br s, 1 H), 3.12 (b r s, 1H), 2.90 – 2.76 (m, 2H), 2.07 (s, 3H), 1.97 (br s, 1H), 1.85 – 1.59 (m, 3H), 1.43 (s 9H);13C NMR (CDCl3, 100 MHz) δ 175.7, 174.7, 169.7, 154.4, 143.1, 135.4, 135.3, 131.4, 130.8, 129.8, 129.1, 129.0, 128.5, 128.3, 123.7, 120.0, 118.4, 58.1, 48.5, 43.0, 42.3, 36.9, 33.9, 33.1, 30.7, 17.7. HRMS (ESI) Found: [M+H]+= 605.2242, calcd: [M+H]+= 605.2251. Example 6 N-(5-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2- methoxyphenyl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 134 (1.0 equiv., 30 mg, 0.1556 mmol), DIPEA (2.0 equiv., 54.2 µL, 0.3112 mmol), HBTU (1.1 equiv., 64.9 mg, 0.1712 mmol) in 0.2 mL DMF, and Intermediate 23 (1.0 equiv., 55.1 mg, 0.1556 mmol), DIPEA (2.0 equiv., 54.2 µL, 0.3112 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 60% EtOAc / Petroleum Ether to afford the product (76 mg, 79%). Rf = 0.46 (80% EtOAc / Petroleum Ether).1H NMR (CDCl3, 600 MHz) δ 7.61 (d, J = 1.7 Hz, 1H), 7.34 – 7.26 (m, 4H), 7.26 – 7.23 (m, 4H), 7.19 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 6.82 (s, 1H), 4.82 (br s, 1H), 4.34 (s, 2H), 3.89 (br s, 1H), 3.81 (s, 3H), 3.11 (br s, 1H), 2.89 (br s, 1H), 2.81 (tt, J = 12.3, 3.5 Hz, 1H), 2.07 – 1.79 (m, 2H), 1.70 (m, 2H), 1.41 (s, 9H);13C NMR (CDCl3, 151 MHz) δ 175.7, 174.7, 169.7, 154.4, 149.3, 143.2, 130.8, 129.0, 128.9, 128.7, 128.4, 128.3, 126.3, 124.5, 119.9, 117.7, 110.7, 57.9, 55.9, 48.6, 43.2, 42.3, 36.9, 33.7, 33.2, 30.7. HRMS (ESI) Found: [M+H]+= 621.2205, calcd: [M+H]+= 621.2200. Example 7 N-(2-methyl-5-(4-(4-((5-propyl-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 133 (1.0 equiv., 30 mg, 0.1637 mmol), DIPEA (2.0 equiv., 57.0 µL, 0.3275 mmol), HBTU (1.1 equiv., 68.3 mg, 0.1801 mmol) in 0.2 mL DMF, and Intermediate 24 (1.0 equiv., 55.7 mg, 0.1637 mmol), DIPEA (2.0 equiv., 57.0 µL, 0.3275 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 40% EtOAc / Petroleum Ether to afford the product (77 mg, 80%). Rf= 0.59 (80% EtOAc / Petroleum Ether).1H NMR (CDCl3, 600 MHz) δ 7.50 (d, J = 1.5 Hz, 1H), 7.34 – 7.27 (m, 3H), 7.26 – 7.14 (m, 8H), 6.66 (s, 1H), 4.84 (br s, 1H), 4.37 (s, 2H), 3.85 (br s, 1H), 3.11 (br s, 1H), 2.92 (t, J = 7.4 Hz, 1H), 2.85 (br s, 1H), 2.80 (tt, J = 12.1, 3.6 Hz, 1H), 2.08 (s, 3H), 1.97 (br s, 1H), 1.81 (br s, 2H), 1.77 (h, J = 7.4 Hz, 2H), 1.64 (br s, 1H), 1.01 (t, J = 7.4 Hz, 3H);13C NMR (CDCl3, 151 MHz) δ 174.5, 169.7, 166.2, 154.3, 143.2, 135.4, 135.1, 131.4, 130.7, 130.2, 129.0, 128.9, 128.5, 128.3, 123.8, 119.9, 118.9, 58.2, 48.4, 42.9, 42.2, 33.8, 33.1, 33.0, 23.0, 17.8, 13.6. MS (ESI) Found: [M+H]+= 591.2101, calcd: [M+H]+= 591.2094. Example 8 N-(2-methyl-5-(4-(4-(4-(trifluoromethyl)phenoxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 133 (1.1 equiv., 50 mg, 0.1637 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol), HBTU (1.1 equiv., 62.1 mg, 0.1637 mmol) in 0.2 mL DMF, and Intermediate 25 (1.0 equiv., 53.3 mg, 0.1489 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 1% MeOH / DCM to afford the product (19.9 mg, 22%). Rf = 0.45 (3% MeOH / DCM).1H NMR (CDCl3, 600 MHz) δ 7.61 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.38 – 7.30 (m, 3H), 7.26 – 7.17 (m, 6H), 7.04 (d, J = 8 .5 Hz, 2H), 7.01 (d, J = 8.5 Hz, 2H), 6.02 (s, 1H), 4.89 (br s, 1H), 4.41 (s, 2H), 3.88 (br s, 1H), 3.15 (br s, 1H), 2.88 (br s, 1H), 2.81 (tt, J = 12.2, 3.6 Hz, 1H), 2.03 (s, 3H), 2.00 (m, 1H), 1.92 – 1.60 (m, 3H);13C NMR (CDCl3, 151 MHz) δ 169.7, 160.7, 154.3, 141.5, 135.6, 135.4, 131.5, 130.8, 129.3, 129.1, 128.9, 128.5, 128.4, 127.2 (q, J = 3.9 Hz), 124.9 (q, J = 32.4 Hz), 124.3 (q, J = 271.8 Hz), 123.7, 120.2, 117.9, 117.6, 58.0, 48.6, 43.1, 42.3, 34.0, 33.2, 17.6;19F NMR (CDCl3, 565 MHz) δ -61.73. HRMS (ESI) Found: [M+H]+= 609.2020, calcd: [M+H]+= 609.2029. Example 9 N-(2-methyl-5-(4-(4-(pyridin-2-yloxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide title compound was prepared according to General procedure N (Workup A), using Intermediate 133 (1.1 equiv., 50 mg, 0.1637 mmol), DIPEA equiv., 51.9 µL, 0.2977 mmol), HBTU (1.1 equiv., 62.1 mg, 0.1637 mmol) in mL DMF, and Intermediate 26 (1.0 equiv., 43.3 mg, 0.1489 mmol), DIPEA equiv., 51.9 µL, 0.2977 mmol) in 0.3 mL DMF. The crude was purified with chromatography using 3% MeOH / DCM to afford the product (30.6 mg, . Rf = 0.26 (3% MeOH / DCM).1H NMR (CDCl3 , 600 MHz) δ 8.38 (d, J = 2.8 Hz, , 8.34 (d d, J = 4.6, 1.6 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.36 – 7.25 (m, 5H), 7.2 – 7.21 , 5H), 7.18 (dd, J = 7.7, 1.6 Hz, 1H), 6.98 (d, J = 8.6 Hz, 2H), 6.35 (s, 1H), 4.87 (br s, 1H), 4.40 (s, 2H), 3.87 (br s, 1H), 3.14 (br s, 1H), 2.87 (br s, 1H), 2.80 (tt, J = 12.1, 3.6 Hz, 1H), 2.05 (s, 3H), 2.01 (br s, 1H), 1.72 (m, 3H);13C NMR (CDCl3, 151 MHz) δ 169.7, 154.9, 154.2, 144.2, 141.2, 141.2, 135.5, 135.5, 131.5, 130.8, 129.5, 129.2, 129.0, 128.6, 128.4, 125.6, 124.3, 123.7, 119.3, 118.1, 58.1, 48.6, 43.0, 42.2, 34.0, 33.2, 17.7. HRMS (ESI) Found: [M+H]+= 542.2111, calcd: [M+H]+= 542.2108. Example 10 N-(2-methyl-5-(4-(4-(pyridin-3-yloxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 133 (1.1 equiv., 50 mg, 0.1637 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol), HBTU (1.1 equiv., 62.1 mg, 0.1637 mmol) in 0.2 mL DMF, and Intermediate 27 (1.0 equiv., 43.3 mg, 0.1489 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 80% EtOAc / Petroleum Ether to afford the product (27.4 mg, 34%). R = 0.14 (50% EtOAc / Petroleum E1 f ther). H NMR (CDCl3, 600 MHz) δ 8.20 (d d, J = 5.0, 1. 9 Hz, 1H), 7.68 (m, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.38 – 7.29 (m, 3H), 7.27 – 7.18 (m, 5H), 7.18 (dd, J = 7.7, 1.6 Hz, 1H), 7.09 (d, J = 8.5 Hz, 2H), 6.99 (dd, J = 7.2, 5.0 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.23 (s, 1H), 4.87 (br s, 1H), 4.40 (s, 2H), 3.86 (br s, 1H), 3.14 (br s, 1H), 2.87 (br s, 1H), 2.80 (tt, J = 12.1, 3.6 Hz, 1H), 2.05 (s, 3H), 2.01 (br s, 1H), 1.87 – 1.64 (m, 3H);13C NMR (CDCl3, 151 MHz) δ 169.7, 163.8, 152.7, 147.8, 141.4, 139.6, 135.6, 135.4, 131.5, 130.8, 129.4, 129.2, 129.0, 128.6, 128.1, 123.7, 121.3, 118.6, 118.0, 111.7, 58.1, 48.6, 43.1, 42.3, 34.0, 33.2, 17.7. HRMS (ESI) Found: [M+H]+= 542.2111, calcd: [M+H]+= 542.2108. Example 11 N-(2-methyl-5-(4-(4-phenoxyphenyl)piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 133 (1.1 equiv., 50 mg, 0.1637 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol), HBTU (1.1 equiv., 62.1 mg, 0.1637 mmol) in 0.2 mL DMF, and Intermediate 28 (1.0 equiv., 43.1 mg, 0.1489 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 30% EtOAc / Petroleum Ether to afford the product (70.0 mg, 81 7%). Rf = 0.40 (50% EtOAc / Petroleum Ether). H NMR (CDCl3, 600 MHz) δ 7.53 (d, J = 1.6 Hz, 1H), 7.37 – 7.28 (m, 5H), 7.25 – 7.15 (m, 6H), 7.09 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 7.5 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 6.47 (s, 1H), 4.86 (br s, 1H), 4.39 (s, 2H), 3.86 (br s, 1H), 3.12 (br s, 1H), 2.86 (br s, 1H), 2.78 (tt, J = 12.1, 3.5 Hz, 1H), 2.07 (s, 3H), 1.98 (m, 1H), 1.87 – 1.61 (m, 3H);13C NMR (CDCl3, 151 MHz) δ 169.7, 157.4, 155.8, 140.1, 135.4, 135.3, 131.4, 130.8, 129.9, 129.8, 129.1, 129.0, 128.6, 128.0, 123.7, 123.2, 119.1, 118.8, 118.5, 58.1, 48.6, 43.1, 42.2, 34.0, 33.2, 17.7. HRMS (ESI) Found: [M+H]+= 541.2152, calcd: [M+H]+= 541.2156. Example 12 N-(2-methyl-5-(4-(4-((5-methylpyridin-2-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 133 (1.1 equiv., 50 mg, 0.1637 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol), HBTU (1.1 equiv., 62.1 mg, 0.1637 mmol) in 0.2 mL DMF, and Intermediate 29 (1.0 equiv., 45.4 mg, 0.1489 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 80% EtOAc / Petroleum Ether to afford the product (62.0 mg, 75%). Rf = 0.15 (50% EtOAc / Petroleum Ether).1H NMR (CDCl3 , 600 MHz) δ 8.01 (d , J = 2.5 Hz, 1H), 7.54 (s, 1H), 7.49 (dd, J = 8.4, 2.5 Hz, 1H), 7.37 – 7.28 (m, 3H), 7.24 – 7.19 (m, 5H), 7.17 (dd, J = 7.7, 1.6 Hz, 1H), 7.06 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.3 Hz, 1H), 6.39 (s, 1H), 4.86 (br s, 1H), 4.39 (s, 2H), 3.85 (br s, 1H), 3.13 (br s, 1H), 2.86 (br s, 1H), 2.79 (tt, J = 12.2, 3.6 Hz,1H), 2.27 (s, 3H), 2.06 (s, 3H), 1.99 (br s, 2H), 1.86 – 1.62 (m, 3H);13C NMR (CDCl3, 151 MHz) δ 169.7, 161.9, 153.2, 147.4, 141.0, 140.5, 135.4, 135.4, 131.4, 130.8, 129.7, 129.1, 129.0, 128.6, 128.0, 127.9, 123.7, 120.9, 118.4, 111.3, 58.1, 48.6, 43.1, 42.3, 34.0, 33.1, 17.7, 17.6. HRMS (ESI) Found: [M+H]+= 556.2267, calcd: [M+H]+= 556.2265. Example 13 N-(2-methyl-5-(4-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide title compound was prepared according to General procedure N (Workup A), using Intermediate 133 (1.1 equiv., 50 mg, 0.1637 mmol), DIPEA equiv., 51.9 µL, 0.2977 mmol), HBTU (1.1 equiv., 62.1 mg, 0.1637 mmol) in mL DMF, and Intermediate 30 (1.0 equiv., 53.4 mg, 0.1489 mmol), DIPEA equiv., 51.9 µL, 0.2977 mmol) in 0.3 mL DMF. The crude was purified with chromatography using 30% EtOAc / Petroleum Ether to afford the (50.8 mg, 56%). R = 0.45 (50% EtOAc1 f / Petroleum Ether). H NMR (CDCl3, 600 MHz) δ 8.44 (m, J = 2.3, 1.2 Hz, 1H), 7.89 (dd, J = 8.7, 2.5 Hz, 1H), 7.59 (s, 1H), 7.38 – 7.31 (m, 3H), 7.29 (d, J = 8.5 Hz, 2H), 7.26 – 7.21 (m, 3H), 7.19 (dd, J = 7.7, 1.6 Hz, 1H), 7.11 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 8.7 Hz, 1H), 6.14 (s, 1H), 4.88 (br s, 1H), 4.41 (s, 2H), 3.88 (br s, 1H), 3.15 (br s, 1H), 2.88 (br s,1H), 2.83 (tt, J = 12.2, 3.6 Hz, 1H), 2.04 (s, 3H), 2.02 (br s, 1H), 1.89 – 1.64 (m, 3H);13C NMR (CDCl3, 151 MHz) δ 169.7, 166.0, 151.8, 145.6 (q, J = 4.3 Hz), 142.3, 136.8 (q, J = 3.2 Hz), 135.6, 135.5, 131.5, 130.8, 129.2, 129.2, 129.1, 128.5, 128.3, 123.8 (q, J = 271.5 Hz), 123.7, 121.6 (q, J = 33.2 Hz), 121.6, 117.8, 111.5, 58.1, 48.6, 43.1, 42.4, 34.0, 33.1, 17.6;19F NMR (CDCl3, 565 MHz) δ -61.65. HRMS (ESI) Found: [M+H]+= 610.2003, calcd: [M+H]+= 610.1982. Example 14 N-(2-methyl-5-(4-(4-(pyrazin-2-yloxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide title compound was prepared according to General procedure N (Workup A), using Intermediate 133 (1.1 equiv., 50 mg, 0.1637 mmol), DIPEA equiv., 51.9 µL, 0.2977 mmol), HBTU (1.1 equiv., 62.1 mg, 0.1637 mmol) in mL DMF, and Intermediate 31 (1.0 equiv., 43.4 mg, 0.1489 mmol), DIPEA equiv., 51.9 µL, 0.2977 mmol) in 0.3 mL DMF. The crude was purified with chromatography using 80% EtOAc / Petroleum Ether to afford the (56.5 mg, 70%). Rf = 0.11 (50% EtOAc / Petroleum Ether).1H NMR (CDCl3, MHz) δ 8.42 (m, 1H), 8.25 (m, 1H), 8.10 (d, J = 2.6 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.38 – 7.29 (m, 3H), 7.28 (d, J = 8.5 Hz, 2H), 7.24 – 7.20 (m, 3H), 7.18 (dd, J = 7.7, 1.6 Hz, 1H), 7.12 (d, J = 8.6 Hz, 2H), 6.29 (s, 1H), 4.87 (br s, 1H), 4.40 (s, 2H), 3.87 (br s, 1H), 3.14 (br s, 1H), 2.87 (br s, 1H), 2.82 (tt, J = 12.1, 3.5 Hz, 1H), 2.05 (s, 3H), 2.01 (br s, 1H), 1.87 – 1.64 (m, 3H);13C NMR (CDCl3, 151 MHz) δ 169.7, 160.3, 151.6, 142.3, 141.2, 138.5, 136.1, 135.5, 135.5, 131.5, 130.8, 129.4, 129.2, 129.0, 128.6, 128.2, 123.7, 121.4, 118.1, 58.1, 48.6, 43.1, 42.4, 34.0, 33.1, 17.7. HRMS (ESI) Found: [M+H]+= 543.2060, calcd: [M+H]+= 543.2061. Example 15 N-(2-methyl-5-(4-(4-(pyrimidin-2-yloxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 133 (1.1 equiv., 50 mg, 0.1637 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol), HBTU (1.1 equiv., 62.1 mg, 0.1637 mmol) in 0.2 mL DMF, and Intermediate 32 (1.0 equiv., 43.4 mg, 0.1489 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 60% EtOAc / Petroleum Ether to afford the product (53.3 mg, 66%). Rf = 0.53 (EtOAc).1H NMR (CDCl3, 600 MHz) δ 8.55 (d, J = 4.8 Hz, 2H), 7.56 (d, J = 1.6 Hz, 1H), 7.37 – 7.28 (m, 3H), 7.27 (d, J = 8.5 Hz, 2H), 7.24 – 7.19 (m, 3H), 7.18 (dd, J = 7.7, 1.6 Hz, 1H), 7.15 (d, J = 8.5 Hz, 2H), 7.03 (t, J = 4.8 Hz, 1H), 6.31 (s, 1H), 4.86 (br s, 1H), 4.39 (s, 2H), 3.86 (br s, 1H), 3.13 (br s, 1H), 2.86 (br s, 1H), 2.82 (tt, J = 12.2, 3.4 Hz, 1H), 2.05 (s, 3H), 2.01 (br s, 1H), 1.87 – 1.65 (m, 3H);13C NMR (CDCl3, 151 MHz) δ 169.7, 165.5, 159.9, 151.5, 142.2, 135.5, 135.4, 131.5, 130.8, 129.5, 129.1, 129.0, 128.6, 128.1, 123.7, 121.8, 118.2, 116.3, 58.1, 48.6, 43.0, 42.4, 34.0, 33.1, 17.7. HRMS (ESI) Found: [M+H]+= 543.2063, calcd: [M+H]+= 543.2061. Example 16 N-(2-methyl-5-(4-(4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)- 1-phenylmethanesulfonamide title compound was prepared according to General procedure N (Workup A), using Intermediate 133 (1.1 equiv., 50 mg, 0.1637 mmol), DIPEA equiv., 51.9 µL, 0.2977 mmol), HBTU (1.1 equiv., 62.1 mg, 0.1637 mmol) in mL DMF, and Intermediate 33 (1.0 equiv., 53.6 mg, 0.1489 mmol), DIPEA equiv., 51.9 µL, 0.2977 mmol) in 0.3 mL DMF. The crude was purified with chromatography using 60% EtOAc / Petroleum Ether to afford the (72.7 mg, 80%). Rf = 0.19 (50% EtOAc / Petroleum Ether).1H NMR (CDCl3, MHz) δ 8.53 (s, 2H), 7.58 (d, J = 1.6 Hz, 1H), 7.37 – 7.29 (m, 5H), 7.25 – 7.19 (m, 3H), 7.19 (dd, J = 7.7, 1.6 Hz, 1H), 7.07 (d, J = 8.5 Hz, 2H), 6.25 (s, 1H), 4.88 (br s, 1H), 4.40 (s, 2H), 3.89 (br s, 1H), 3.15 (br s, 1H), 2.88 (br s, 1H), 2.84 (tt, J = 12.0, 3.6 Hz, 1H), 2.05 (s, 3H), 2.01 (br s, 1H), 1.88 – 1.63 (m, 3H);13C NMR (CDCl3, 151 MHz) δ 169.7, 160.2, 154.0, 152.6, 150.5 (q, J = 37.2 Hz), 146.7, 143.2, 135.5, 135.4, 131.5, 130.8, 129.4, 129.2, 129.0, 128.5, 123.7, 120.0, 119.7 (q, J = 274.5 Hz), 118.0, 58.1, 48.5, 43.0, 42.3, 33.9, 33.1, 17.6;19F NMR (CDCl3, 565 MHz) δ -69.29. HRMS (ESI) Found: [M+H]+= 611.1937, calcd: [M+H]+= 611.1934. Example 17 N-(2-m l-5-(4-(4-((5-methylpyrimidin-2-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 133 (1.1 equiv., 50 mg, 0.1637 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol), HBTU (1.1 equiv., 62.1 mg, 0.1637 mmol) in 0.2 mL DMF, and Intermediate 34 (1.0 equiv., 45.5 mg, 0.1489 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 70% EtOAc / Petroleum Ether to afford the f13 product (42.3 mg, 51%). R = 0.48 (EtOAc). H NMR (CDCl, 600 MHz) δ 8.37 (s, 2H), 7.56 (d, J = 1.6 Hz, 1H), 7.38 – 7.29 (m, 3H), 7.26 (d, J = 8.4 Hz, 2H), 7.24 – 7.20 (m, 3H), 7.18 (dd, J = 7.7, 1.6 Hz, 1H), 7.13 (d, J = 8.5 Hz, 2H), 6.27 (s, 1H), 4.87 (br s, 1H), 4.40 (s, 2H), 3.86 (br s, 1H), 3.13 (br s, 1H), 2.86 (br s, 1H), 2.81 (tt, J = 12.1, 3.6 Hz, 1H), 2.25 (s, 3H), 2.05 (s, 3H), 2.01 (s, 1H), 1.88 – 1.63 (m, 3H);13C NMR (CDCl3, 151 MHz) δ 169.7, 164.0, 159.7, 151.8, 142.0, 135.5, 135.4, 131.5, 130.8, 129.4, 129.1, 129.0, 128.6, 128.0, 125.3, 123.7, 121.7, 118.1, 58.1, 48.6, 43.1, 42.4, 34.0, 33.1, 17.7, 14.8. HRMS (ESI) Found: [M+H]+= 557.2220, calcd: [M+H]+= 557.2217. Example 18 N-(2-methyl-5-(4-(4-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)- 1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 133 (1.1 equiv., 50 mg, 0.1637 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol), HBTU (1.1 equiv., 62.1 mg, 0.1637 mmol) in 0.2 mL DMF, and Intermediate 35 (1.0 equiv., 53.6 mg, 0.1489 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 1% MeOH / DCM to afford the product (9.1 mg, 10%). Rf = 0.23 (1% MeOH / DCM).1H NMR (CDCl3, 600 MHz) δ 8.79 (s, 2H), 7.57 (d, J = 1.6 Hz, 1H), 7.38 – 7.28 (m, 5H), 7.24 – 7.19 (m, 3H), 7.18 (dd, J = 7.8, 1.6 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 6.31 (s, 1H), 4.88 (br s, 1H), 4.40 (s, 2H), 3.88 (br s, 1H), 3.14 (br s, 1H), 2.88 (br s, 1H), 2.84 (m, 1H), 2.05 (s, 3H), 2.01 (br s, 1H), 1.89 – 1.65 (m, 3H);13C NMR (CDCl3, 151 MHz) δ 169.7, 167.0, 157.7 (q, J = 3.4 Hz), 150.9, 143.0, 135.5, 135.4, 131.5, 130.8, 129.5, 129.1, 129.0, 128.5, 128.2, 123.7, 123.1 (q, J = 271.6 Hz), 121.6, 120.4 (q, J = 34.6 Hz), 118.1, 58.1, 48.6, 43.1, 42.4, 33.9, 33.1, 17.7;19F NMR (CDCl3, 565 MHz) δ -61.54. HRMS (ESI) Found: [M+H]+= 611.1942, calcd: [M+H]+= 611.1934. Example 19 N-(2-methyl-5-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 133 (1.1 equiv., 50 mg, 0.1637 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol), HBTU (1.1 equiv., 62.1 mg, 0.1637 mmol) in 0.2 mL DMF, and Intermediate 36 (1.0 equiv., 53.4 mg, 0.1489 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 40% EtOAc / Petroleum Ether to afford the product (67.2 mg, 74%). Rf = 0.40 (50% EtOAc / Petroleum Ether).1H NMR (CDCl3, 600 MHz) δ 8.45 (d, J = 2.8 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.38 – 7.29 (m, 4H), 7.27 (d, J = 8.5 Hz, 2H), 7.25 – 7.19 (m, 3H), 7.19 (dd, J = 7.7, 1.6 Hz, 1H), 7.03 (d, J = 8.5 Hz, 2H), 6.30 (s, 1H), 4.88 (br s, 1H), 4.40 (s, 2H), 3.88 (br s, 1H), 3.14 (br s, 1H), 2.89 (br s, 1H), 2.82 (tt, J = 12.1, 3.6 Hz, 1H), 2.05 (s, 3H), 2.00 (br s, 1H), 1.87 – 1.62 (m, 3H);13C NMR (CDCl3, 151 MHz) δ 169.7, 156.6, 153.5, 142.4, 142.1 (q, J = 35.2 Hz), 140.9, 135.4, 135.4, 131.5, 130.8, 129.5, 129.2, 129.0, 128.7, 128.5, 124.5, 123.7, 121.7 (q, J = 273.3 Hz), 121.6 (q, J = 2.8 Hz), 120.2, 118.1, 58.1, 48.5, 43.0, 42.3, 34.0, 33.1, 17.7;19F NMR (CDCl3, 565 MHz) δ -67.00. HRMS (ESI) Found: [M+H]+= 610.1989, calcd: [M+H]+= 610.1982. Example 20 N-(2-methyl-5-(4-(4-(pyrimidin-5-yloxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 133 (1.1 equiv., 50 mg, 0.1637 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol), HBTU (1.1 equiv., 62.1 mg, 0.1637 mmol) in 0.2 mL DMF, and Intermediate 37 (1.0 equiv., 43.4 mg, 0.1489 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 1% MeOH / DCM to afford the product (12.1 mg, 15%). Rf= 0.50 (3% MeOH / DCM).1H NMR (CDCl3, 600 MHz) δ 8.97 (s, 1H), 8.49 (s, 2H), 7.60 (s, 1H), 7.39 – 7.31 (m, 3H), 7.28 – 7.26 (m, 2H), 7.25 – 7.18 (m, 4H), 7.03 (d, J = 7.8 Hz, 2H), 6.09 (s, 1H), 4.89 (br s, 1H), 4.41 (s, 2H), 3.89 (br s, 1H), 3.16 (br s, 1H), 2.88 (br s, 1H), 2.82 (m, 1H), 2.04 (s, 3H), 2.00 (br s, 1H), 1.86 – 1.63 (m, 3H);13C NMR (CDCl3, 151 MHz) δ 169.7, 153.9, 153.2, 152.7, 147.0, 142.2, 135.6, 135.5, 131.6, 130.8, 129.2, 129.1, 129.0, 128.8, 128.5, 123.7, 119.5, 117.7, 58.1, 48.5, 43.0, 42.3, 34.0, 33.2, 17.6. HRMS (ESI) Found: [M+H]+= 543.2059, calcd: [M+H]+= 543.2061. Example 21 N-(2-methyl-5-(4-(4-((5-methylpyrazin-2-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 133 (1.1 equiv., 50 mg, 0.1637 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol), HBTU (1.1 equiv., 62.1 mg, 0.1637 mmol) in 0.2 mL DMF, and Intermediate 38 (1.0 equiv., 45.5 mg, 0.1489 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 2% MeOH / DCM to afford the product (43.1 mg, 52%). Rf = 0.15 (1% MeOH / DCM).1H NMR (CDCl3, 600 MHz) δ 8.30 (s, 1H), 7.97 (s, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.37 – 7.30 (m, 3H), 7.26 (d, J = 8.5 Hz, 2H), 7.24 – 7.21 (m, 3H), 7.18 (dd, J = 7.7, 1.6 Hz, 1H), 7.09 (d, J = 8.5 Hz, 2H), 6.23 (s, 1H), 4.87 (br s, 1H), 4.40 (s, 2H), 3.87 (br s, 1H), 3.14 (br s, 1H), 2.87 (br s, 1H), 2.81 (tt, J = 12.1, 3.6 Hz, 1H), 2.51 (s, 3H), 2.05 (s, 3H), 2.01 (br s, 1H), 1.89 – 1.63 (m, 3H);13C NMR (CDCl3, 151 MHz) δ 169.7, 158.5, 152.2, 147.5, 141.9, 140.4, 135.5, 135.4, 134.5, 131.5, 130.8, 129.3, 129.2, 129.0, 128.6, 128.2, 123.7, 121.1, 118.0, 58.1, 48.6, 43.1, 42.3, 34.0, 33.1, 20.5, 17.7. HRMS (ESI) Found: [M+H]+= 557.2215, calcd: [M+H]+= 557.2217. Example 22 N-(2-methyl-5-(4-(4-((3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 133 (1.1 equiv., 50 mg, 0.1637 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol), HBTU (1.1 equiv., 62.1 mg, 0.1637 mmol) in 0.2 mL DMF, and Intermediate 39 (1.0 equiv., 54.5 mg, 0.1489 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 50% EtOAc / Petroleum Ether to afford the product (69.8 mg, 76%). Rf = 0.25 (50% EtOAc / Petroleum Ether).1H NMR (CDCl3, 600 MHz) δ 7.58 (d, J = 1.6 Hz, 1H), 7.38 – 7.28 (m, 7H), 7.25 – 7.19 (m, 3H), 7.18 (dd, J = 7.7, 1.5 Hz, 1H), 6.30 (s, 1H), 4.88 (br s, 1H), 4.40 (s, 2H), 3.89 (br s, 1H), 3.15 (br s, 1H), 2.90 (br s, 1H), 2.86 (tt, J = 12.0, 3.3 Hz, 1H), 2.05 (s, 3H), 2.02 (br s, 1H), 1.88 – 1.66 (m, 3H);13C NMR (CDCl3, 151 MHz) δ 193.8, 169.8, 159.1 (q, J = 39.4 Hz), 153.5, 145.1, 135.5, 135.3, 131.5, 130.8, 129.5, 129.2, 129.1, 129.0, 128.5, 123.7, 120.1, 118.0, 117.7 (q, J = 273.7 Hz), 58.1, 48.5, 42.9, 42.4, 33.8, 33.0, 17.7;19F NMR (CDCl3, 565 MHz) δ -67.36. HRMS (ESI) Found: [M+H]+= 617.1502, calcd: [M+H]+= 617.1499. Example 23 N-(2-methyl-5-(4-(4-((5-(trifluoromethyl)pyrazin-2-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 133 (1.1 equiv., 50 mg, 0.1637 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol), HBTU (1.1 equiv., 62.1 mg, 0.1637 mmol) in 0.2 mL DMF, and Intermediate 40 (1.0 equiv., 53.6 mg, 0.1489 mmol), DIPEA (2.0 equiv., 51.9 µL, 0.2977 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 85% EtOAc / Petroleum Ether to afford the product (65.4 mg, 72%). Rf= 0.40 (EtOAc).13 H NMR (CDCl, 600 MHz) δ 8.49 (d, J = 1.4 Hz, 1H), 8.43 (d, J = 1.4 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.38 – 7.29 (m, 5H), 7.25 – 7.20 (m, 3H), 7.19 (dd, J = 7.7, 1.6 Hz, 1H), 7.13 (d, J = 8.6 Hz, 2H), 6.28 (s, 1H), 4.88 (br s, 1H), 4.40 (s, 2H), 3.88 (br s, 1H), 3.15 (br s, 1H), 2.88 (br s, 1H), 2.84 (tt, J = 12.6, 3.8 Hz, 1H), 2.05 (s, 3H), 2.03 (br s, 1H), 1.89 – 1.65 (m, 3H);13C NMR (CDCl3, 151 MHz) δ 169.7, 161.6, 150.8, 143.1, 139.1 (q, J = 3.4 Hz), 137.7 (q, J = 35.8 Hz), 135.9, 135.5, 135.4, 131.5, 130.8, 129.4, 129.2, 129.0, 128.5, 128.4, 123.7, 121.6 (q, J = 273.0 Hz), 121.5, 118.1, 58.1, 48.6, 43.0, 42.4, 33.9, 33.1, 17.7;19F NMR (CDCl3, 565 MHz) δ -66.79. HRMS (ESI) Found: [M+H]+= 611.1932, calcd: [M+H]+= 610.1934. Example 24 N-(2-cyclopropoxy-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure J, using Intermediate 81 (1.0 equiv., 42 mg, 0.08425 mmol) in 0.8 mL of pyridine and benzylsulfonyl chloride (1.2 equiv., 19.3 mg, 0.1011 mmol). The crude was purified with column chromatography using 10% EtOAc / DCM to afford the product (53.9 mg, 99%). Rf = 0.24 (10% EtOAc / DCM).1H NMR (CDCl3, 600 MHz) δ 7.80 (d, J = 9.2 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.38 – 7.25 (m, 8H), 7.22 – 7.15 (m, 4H), 6.68 (s, 1H), 4.86 (br s, 1H), 4.34 (s, 2H), 3.92 (s, 1H), 3.75 (tt, J = 6.0, 2.9 Hz, 1H), 3.15 (br s, 1H), 2.88 (br s, 1H), 2.83 (tt, J = 12.1, 3.6 Hz, 1H), 1.99 (br s, 1H), 1.87 (br s, 1H), 1.73 (br s, 2H), 0.83 (m, 2H), 0.71 (m, 2H);13C NMR (CDCl3, 151 MHz) δ 169.8, 167.2, 151.3, 148.6, 148.4 (q, J = 35.4 Hz), 143.1, 130.8, 129.5, 129.1, 128.9, 128.5, 128.4, 127.3 (q, J = 2.3 Hz), 126.2, 124.3, 121.5 (q, J = 273.9 Hz), 121.5, 117.8, 117.3, 112.9, 57.7, 51.9, 48.7, 43.2, 42.5, 34.0, 33.2, 6.4;19F NMR (CDCl3, 565 MHz) δ -66.37. HRMS (ESI) Found: [M+H]+= 653.2035, calcd: [M+H]+= 653.2040. Example 25 N-(2-isopropoxy-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure J, using Intermediate 82 (1.0 equiv., 34 mg, 0.06793 mmol) in 0.8 mL of pyridine and benzylsulfonyl chloride (1.2 equiv., 15.5 mg, 0.08152 mmol). The crude was purified with column chromatography using 10% EtOAc / DCM to afford the product (44 mg, 99%). Rf= 0.26 (10% EtOAc / DCM).1H NMR (CDCl3, 600 MHz) δ 7.80 (d, J = 9.2 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.35 – 7.29 (m, 6H), 7.25 (m, 2H), 7.22 (m, 2H), 7.18 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.5 Hz, 1H), 6.83 (s, 1H), 4.85 (br s, 1H), 4.62 (hept, J = 6.1 Hz, 1H), 4.36 (s, 2H), 3.94 (br s, 1H), 3.15 (br s, 1H), 2.88 (br s, 1H), 2.83 (tt, J = 12.1, 3.6 Hz, 1H), 1.98 (br s, 1H), 1.88 (br s, 1H), 1.73 (br s, 2H), 1.31 (d, J = 6.1 Hz, 6H);13C NMR (CDCl3, 151 MHz) δ 169.8, 167.2, 151.3, 148.4 (q, J = 35.4 Hz), 147.4, 143.1, 130.8, 129.0, 128.9, 128.7, 128.5, 128.4, 127.3 (q, J = 2.2 Hz), 126.9, 124.2, 121.5 (q, J = 273.9 Hz), 121.5, 117.8, 117.3, 112.5, 71.5, 57.7, 48.7, 43.2, 42.5, 34.0, 33.2, 22.1;19F NMR (CDCl3, 565 MHz) δ -66.37. HRMS (ESI) Found: [M+H]+= 655.2201, calcd: [M+H]+= 655.2197. Example 26 3-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenoxy)azetidin-1-ium 2,2,2-trifluoroacetate The title compound was prepared according to General procedure O, using Intermediate 157 (1.0 equiv., 198 mg, 0.2579 mmol) in 3 mL of DCE, and 3 mL of TFA. Yield: 199 mg, 99%. Rf= 0.10 (5% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.09 (d, J = 9.3 Hz, 1H), 7.56 (d, J = 9.3 Hz, 1H), 7.41 (d, J = 8.6 Hz, 2H), 7.38 – 7.28 (m, 6H), 7.24 – 7.16 (m, 3H), 6.80 (d, J = 8.4 Hz, 1H), 5.21 (tt, J = 6.6, 5.0 Hz, 1H), 4.74 (br s, 1H), 4.56 (dd, J = 12.6, 6.5 Hz, 2H), 4.52 (s, 2H), 4.25 (dd, J = 12.4, 5.0 Hz, 2H), 3.80 (br s, 1H), 3.21 (br s, 1H), 3.06 – 2.90 (m, 2H), 2.00 (br s, 1H), 1.87 (br s, 1H), 1.74 (br s, 2H);13C NMR (MeOD, 100 MHz) δ 171.3, 169.0, 152.9, 149.4 (q, J = 34.9 Hz), 149.2, 144.7, 132.2, 130.9, 130.5, 129.7, 129.6, 129.5, 129.4 (q, J = 2.2 Hz), 128.6, 125.6, 122.9 (q, J = 272.7 Hz), 122.4, 122.2, 120.0, 113.7, 69.7, 59.9, 54.3, 49.7, 44.2, 43.2, 35.0, 34.2;19F NMR (MeOD, 376 MHz) δ -67.91, -77.11. HRMS (ESI) Found: [M-TFA+H]+= 668.2158, calcd: [M-TFA+H]+= 668.2149. Example 27 3-(3-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenoxy)propyl)azetidin-1-ium 2,2,2-trifluoroacetate The title compound was prepared according to General procedure O, using Intermediate 106 (1.0 equiv., 20 mg, 0.02469 mmol) in 0.5 mL of DCE, and 0.5 mL of TFA. Yield: 20.1 mg, 99%. Rf = 0.21 (10% MeOH / DCM). 1H NMR (MeOD, 400 MHz) δ 8.1 (d, J = 9.2 Hz, 1H), 7.6 (d, J = 9.2 Hz, 1H), 7.4 (d, J = 8.6 Hz, 2H), 7.4 – 7.3 (m, 6H), 7.3 – 7.2 (m, 3H), 7.1 (d, J = 8.5 Hz, 1H), 4.8 (br s, 1H), 4.5 (s, 2H), 4.2 – 4.1 (m, 4H), 3.9 (br s, 1H), 3.8 (m, 2H), 3.2 (br s, 1H), 3.1 – 2.9 (m, 3H), 2.0 (br s, 2H), 1.9 – 1.7 (m, 6H);13C NMR (MeOD, 100 MHz) δ 171.8, 169.0, 152.9, 152.4, 149.4 (q, J = 35.4 Hz), 144.7, 132.2, 130.6, 129.7, 129.6, 129.5, 129.4, 129.2, 127.8, 125.9, 122.9 (q, J = 271.6 Hz), 122.4, 122.0, 120.0, 113.0, 69.4, 59.7, 52.8, 49.9, 44.2, 43.3, 35.1, 34.2, 33.4, 31.0, 27.0;19F NMR (MeOD, 376 MHz) δ -67.90, -77.12. HRMS (ESI) Found: [M-TFA+H]+= 710.2609, calcd: [M-TFA+H]+= 710.2619. Example 28 (E)-3-(3-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenoxy)prop-1-en-1-yl)azetidin-1-ium 2,2,2-trifluoroacetate The title compound was prepared according to General procedure O, using Intermediate 107 (1.0 equiv., 20 mg, 0.02476 mmol) in 0.5 mL of DCE, and 0.5 mL of TFA. Yield: 20.2 mg, 99%. Rf = 0.13 (5% MeOH / DCM). 1H NMR (MeOD, 600 MHz) δ 8.11 (d, J = 9.2 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.43 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 2.1 Hz, 1H), 7.37 – 7.27 (m, 5H), 7.26 – 7.21 (m, 3H), 7.10 (d, J = 8.5 Hz, 1H), 6.09 (ddt, J = 15.5, 7.7, 1.4 Hz, 1H), 5.94 (dtd, J = 15.6, 5.4, 1.1 Hz, 1H), 4.77 (br s, 1H), 4.73 (m, 2H), 4.50 (s, 2H), 4.18 (m, 2H), 3.99 (m, 2H), 3.88 (br s, 1H), 3.71 (h, J = 8.4 Hz, 1H), 3.24 (br s, 1H), 3.01 (br s, 1H), 2.97 (tt, J = 12.1, 3.4 Hz, 1H), 2.03 (br s, 1H), 1.90 (br s, 1H), 1.77 (br s, 2H);13C NMR (MeOD, 151 MHz) δ 171.8, 169.0, 152.9, 151.8, 149.4 (q, J = 35.1 Hz), 144.7, 132.8, 132.1, 130.6, 129.7, 129.6, 129.5, 129.5, 129.4, 129.3, 128.2, 125.7, 122.9 (q, J = 272.8 Hz), 122.4, 122.0, 120.0, 113.7, 69.6, 59.6, 52.6, 49.9, 44.3, 43.3, 35.5, 35.1, 34.2;19F NMR (MeOD, 565 MHz) δ - 67.94, -77.04. HRMS (ESI) Found: [M-TFA+H]+= 708.2446, calcd: [M-TFA+H]+= 708.2462. Example 29 N-(2-(2-(dimethylamino)ethoxy)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine- 1-carbonyl)phenyl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure B), using Intermediate 151 (1.0 equiv., 5.8 g, 14.0 mmol), DIPEA (2.0 equiv., 4.87 mL, 28.0 mmol), HBTU (1.05 equiv., 5.57 g, 14.7 mmol) in 50 mL DMF, and Intermediate 21 (1.0 equiv., 5.037 g, 14.0 mmol), DIPEA (2.0 equiv., 4.87 mL, 28.0 mmol) in 75 mL DMF. The crude was purified with column chromatography using 10% MeOH / DCM to afford the product (9.54 g, 99%). Rf = 0.50 (20% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 7.80 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.35 – 7.24 (m, 8H), 7.20 (dd, J = 8.2, 2.0 Hz, 1H), 7.17 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.2 Hz, 1H), 4.86 (br s, 1H), 4.28 (s, 2H), 4.01 (t, J = 5.1 Hz, 2H), 3.88 (br s, 1H), 3.13 (br s, 1H), 2.88 (br s, 1H), 2.83 (tt, J = 12.2, 3.6 Hz, 1H), 2.44 (t, J = 5.1 Hz, 2H), 2.12 (s, 6H), 1.98 (br s, 1H), 1.87 (br s, 1H), 1.74 (br s, 2H);13C NMR (CDCl3, 100 MHz) δ 169.6, 167.1, 151.2, 149.6, 148.3 (q, J = 35.4 Hz), 143.0, 132.1, 131.5, 131.1, 129.3, 128.4, 128.4, 128.3, 127.2, 124.1 (q, J = 274.0 Hz), 123.8, 121.3, 120.2, 119.5, 117.7, 70.8, 58.0, 57.6, 48.5, 44.3, 43.0, 42.4, 33.9, 33.1;19F NMR (CDCl3, 376 MHz) δ -66.37. HRMS (ESI) Found: [M+H]+= 684.2447, calcd: [M+H]+= 684.2462. Example 30 N,N-dimethyl-2-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenoxy)ethan-1-aminium chloride The title compound was prepared according to General procedure Q, using Example 29 (1.0 equiv., 8.31 g, 12.1536 mmol) in 80 mL of DCM, and 4M HCl in dioxane (5.0 equiv., 15.2 mL, 60.7678 mmol) in 415 mL of Et2O. Yield: 8.674 g, 99%.1H NMR (MeOD, 400 MHz) δ 8.10 (d, J = 9.3 Hz, 1H), 7.56 (d, J = 9.3 Hz, 1H), 7.41 (d, J = 8.6 Hz, 2H), 7.39 – 7.28 (m, 6H), 7.25 (dd, J = 8.5, 2.0 Hz, 1H), 7.21 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 8.5 Hz, 1H), 4.74 (br s, 1H), 4.57 (s, 2H), 4.44 (m, 2H), 3.82 (m, 1H), 3.63 (m, 2H), 3.22 (s, 1H), 3.04 – 2.90 (m, 8H), 2.00 (br s, 1H), 1.87 (br s, 1H), 1.74 (br s, 2H);13C NMR (MeOD, 100 MHz) δ 171.5, 169.0, 152.9, 150.9, 149.4 (q, J = 34.8 Hz), 144.7, 132.2, 130.6, 130.2, 129.8, 129.6, 129.5, 129.5, 128.1, 125.6, 122.9 (q, J = 273.6 Hz), 122.4, 121.7, 120.0, 113.3, 63.6, 59.7, 57.3, 49.9, 44.3, 43.7, 43.2, 35.1, 34.1;19F NMR (MeOD, 376 MHz) δ -67.90. HRMS (ESI) Found: [M-HCl+H]+= 684.2467, calcd: [M-HCl+H]+= 684.2462. Example 31 N-(2-methoxy-4-methyl-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 136 (1.0 equiv., 28.0 mg, 0.08338 mmol), DIPEA (1.5 equiv., 21.8 µL, 0.1251 mmol), HBTU (1.05 equiv., 33.2 mg, 0.08755 mmol) in 0.2 mL DMF, and Intermediate 21 (1.0 equiv., 30 mg, 0.08338 mmol), DIPEA (1.5 equiv., 21.8 µL, 0.1251 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 15% EtOAc / DCM to afford the product (48.7 mg, 92%). Rf = 0.48 (20% EtOAc / DCM).1H NMR (CDCl3 , 400 MHz) δ 7.79 (d, J = 9.2 Hz, 1H), 7.44 (m, 1H), 7.35 – 7.26 (m, 6H), 7.23 – 7.13 (m, 4H), 6.78 – 6.65 (m, 2H), 4.94 (br s, 1H), 4.31 (s, 2H), 3.80 (s, 3H), 3.62 (m, 1H), 3.10 (m, 1H), 2.91 – 2.77 (m, 2H), 2.35 (s, 3H), 2.03 (m, 1H), 1.87 – 1.42 (m, 3H);13C NMR (CDCl3, 100 MHz) δ 169.3, 167.2, 151.3, 148.6, 148.4 (q, J = 33.6 Hz), 143.0, 131.9, 130.9, 129.2, 128.9, 128.8, 128.5, 128.4, 127.3 (q, J = 2.4 Hz), 124.4, 121.5 (q, J = 273.8 Hz), 121.5, 117.8, 116.8, 112.8, 57.3, 55.8, 47.8, 42.4, 42.2, 34.8, 33.4, 19.3;19F NMR (CDCl3, 376 MHz) δ -66.37. HRMS (ESI) Found: [M+H]+= 641.2034, calcd: [M+H]+= 641.2040. Example 32 N-(5-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2-methoxy-4- methylphenyl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 136 (1.0 equiv., 47.4 mg, 0.1412 mmol), DIPEA (1.5 equiv., 36.9 µL, 0.2119 mmol), HBTU (1.05 equiv., 56.3 mg, 0.1483 mmol) in 0.2 mL DMF, and Intermediate 23 (1.0 equiv., 50 mg, 0.1412 mmol), DIPEA (1.5 equiv., 36.9 µL, 0.2119 mmol) in 0.3 mL DMF. The crude was purified with column chromatography using 1% MeOH / DCM to afford the product (86 mg, 96%). Rf= 0.46 (5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 7.52 – 7.26 (m, 5H), 7.26 – 7.22 (m, 3H), 7.21 – 7.16 (m, 2H), 6.72 (m, 2H), 4.92 (m, 1H), 4.29 (s, 2H), 3.79 (s, 3H), 3.61 (m, 1H), 3.09 (m, 1H), 2.89 – 2.75 (m, 2H), 2.34 (s, 3H), 2.00 (m, 1H), 1.84 – 1.62 (m, 3H), 1.41 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 175.7, 174.7, 169.2, 154.5, 148.5, 143.1, 131.8, 130.9, 129.1, 128.9, 128.7, 128.5, 128.3, 124.4, 120.0, 116.8, 112.7, 57.3, 55.8, 47.8, 42.3, 42.1, 36.9, 33.3, 33.1, 30.7, 19.2. HRMS (ESI) Found: [M+H]+= 635.2366, calcd: [M+H]+= 635.2356. Example 33 N-(2-cyclopropoxy-4-methyl-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 137 (1.0 equiv., 60 mg, 0.1660 mmol), DIPEA (1.5 equiv., 43.4 µL, 0.2490 mmol), HBTU (1.05 equiv., 66.1 mg, 0.1743 mmol) in 1 mL DMF, and Intermediate 21 (1.05 equiv., 62.7 mg, 0.1743 mmol), DIPEA (1.5 equiv., 43.4 µL, 0.2490 mmol) in 1 mL DMF. The crude was purified with column chromatography using 70% MTBE / Toluene to afford the product (100.6 mg, 91%). Rf = 0.34 (70% MTBE / Toluene).1H NMR (CDCl3, 400 MHz) δ 7.80 (d, J = 9.2 Hz, 1H), 7.45 (m, 1H), 7.35 – 7.26 (m, 6H), 7.23 – 7.14 (m, 4H), 7.10 (s, 1H), 6.59 (s, 1H), 4.95 (br s, 1H), 4.30 (m, 2H), 3.71 (tt, J = 6.1, 2.9 Hz, 1H), 3.64 (m, 1H), 3.12 (m, 1H), 2.92 – 2.76 (m, 2H), 2.36 (m, 3H), 2.03 (m, 1H), 1.87 – 1.70 (m, 2H), 1.50 (m, 1H), 0.82 (m, 2H), 0.69 (m, 2H);13C NMR (CDCl3, 100 MHz) δ 169.3, 167.2, 151.3, 148.4 (q, J = 35.6 Hz), 147.9, 143.0, 131.6, 130.8, 129.6, 129.0, 128.8, 128.6, 128.4, 127.3, 124.2, 121.5, 121.5 (q, J = 274.1 Hz), 117.8, 116.5, 114.8, 57.2, 51.7, 48.1, 47.7, 42.6, 42.4, 34.8, 33.4, 19.3, 6.3;19F NMR (CDCl3, 376 MHz) δ -66.37. HRMS (ESI) Found: [M+H]+= 667.2182, calcd: [M+H]+= 667.2197. Example 34 N-(5-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2-cyclopropoxy- 4-methylphenyl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 137 (1.0 equiv., 60 mg, 0.1660 mmol), DIPEA (1.5 equiv., 43.4 µL, 0.2490 mmol), HBTU (1.05 equiv., 66.1 mg, 0.1743 mmol) in 1 mL DMF, and Intermediate 23 (1.05 equiv., 61.7 mg, 0.1743 mmol), DIPEA (1.5 equiv., 43.4 µL, 0.2490 mmol) in 1 mL DMF. The crude was purified with column chromatography using 70% MTBE / Toluene to afford the product (107 mg, 98%). Rf = 0.34 (70% MTBE / Toluene).1H NMR (CDCl3, 400 MHz) δ 7.43 (m, 1H), 7.37 – 7.27 (m, 4H), 7.26 – 7.22 (m, 3H), 7.22 – 7.15 (m, 2H), 7.09 (s, 1H), 6.58 (s, 1H), 4.94 (br s, 1H), 4.29 (m, 2H), 3.71 (tt, J = 6.0, 2.9 Hz, 1H), 3.64 (m, 1H), 3.10 (m, 1H), 2.91 – 2.75 (m, 2H), 2.35 (m, 3H), 2.01 (m, 1H), 1.85 – 1.68 (m, 2H), 1.46 (br s, 1H), 1.42 (s, 9H), 0.82 (m, 2H), 0.69 (m, 2H);13C NMR (CDCl3, 100 MHz) δ 175.7, 174.7, 169.3, 154.5, 147.8, 143.1, 131.6, 130.8, 129.5, 129.0, 128.8, 128.6, 128.3, 124.2, 120.0, 116.4, 114.8, 57.2, 51.7, 48.0, 47.6, 42.5, 42.3, 36.9, 34.7, 33.3, 30.8, 19.3, 6.4. HRMS (ESI) Found: [M+H]+= 661.2504, calcd: [M+H]+= 661.2513. Example 35 N-(5-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2- cyclopropoxyphenyl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 138 (1.0 equiv., 44.2 mg, 0.1272 mmol), DIPEA (1.5 equiv., 33.2 µL, 0.1907 mmol), HBTU (1.05 equiv., 50.6 mg, 0.1335 mmol) in 0.7 mL DMF, and Intermediate 23 (1.0 equiv., 45 mg, 0.1272 mmol), DIPEA (1.5 equiv., 33.2 µL, 0.1907 mmol) in 1 mL DMF. The crude was purified with column chromatography using 70% MTBE / Toluene to afford the product (81.7 mg, 99%). Rf = 0.28 (70% MTBE / Toluene).1H NMR (CDCl3, 400 MHz) δ 7.62 (m, 1H), 7.37 – 7.26 (m, 9H), 7.21 – 7.16 (m, 2H), 6.68 (s, 1H), 4.84 (br s, 1H), 4.33 (s, 2H), 3.92 (br s, 1H), 3.74 (tt, J = 6.0, 2.9 Hz, 1H), 3.11 (br s, 1H), 2.89 (br s, 1H), 2.81 (tt, J = 12.1, 3.6 Hz, 1H), 1.91 (br s, 2H), 1.71 (br s, 2H), 1.42 (s, 9H), 0.83 (m, 2H), 0.71 (m, 2H);13C NMR (CDCl3, 100 MHz) δ 175.7, 174.7, 169.8, 154.5, 148.6, 143.2, 130.8, 129.5, 129.1, 128.9, 128.5, 128.4, 126.1, 124.3, 120.0, 117.3, 112.9, 57.7, 51.9, 48.7, 43.2, 42.4, 36.9, 33.6, 30.8, 6.4. HRMS (ESI) Found: [M+H]+= 647.2376, calcd: [M+H]+= 647.2356. Example 36 N-(2-(tert-butoxy)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 139 (1.0 equiv., 45.5 mg, 0.1251 mmol), DIPEA (1.5 equiv., 32.7 µL, 0.1876 mmol), HBTU (1.05 equiv., 49.8 mg, 0.1313 mmol) in 0.7 mL DMF, and Intermediate 21 (1.0 equiv., 45 mg, 0.1251 mmol), DIPEA (1.5 equiv., 32.7 µL, 0.1876 mmol) in 1 mL DMF. The crude was purified with column chromatography using 1% MeOH / DCM to afford the product (82.6 mg, 99%). Rf= 0.48 (2% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 7.80 (d, J = 9.2 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.38 – 7.27 (m, 6H), 7.29 – 7.22 (m, 2H), 7.21 – 7.14 (m, 3H), 7.12 (d, J = 8.4 Hz, 1H), 6.82 (br s, 1H), 4.85 (br s, 1H), 4.36 (s, 2H), 3.93 (br s, 1H), 3.13 (br s, 1H), 2.89 (br s, 1H), 2.84 (tt, J = 12.1, 3.6 Hz, 1H), 2.05 – 1.85 (m, 2H), 1.74 (br s, 2H), 1.40 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 169.8, 167.2, 151.3, 148.5 (q, J = 37.9 Hz), 145.7, 143.1, 130.9, 130.4, 130.1, 129.1, 129.0, 128.4, 128.4, 127.3, 123.3, 121.5 (q, J = 273.5 Hz), 121.5, 119.8, 117.8, 116.8, 81.6, 58.1, 48.8, 43.2, 42.5, 33.9, 33.1, 29.1;19F NMR (CDCl3, 376 MHz) δ -66.38. HRMS (ESI) Found: [M+H]+= 669.2360, calcd: [M+H]+= 669.2353. Example 37 N-(2-(tert-butoxy)-5-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 139 (1.0 equiv., 60 mg, 0.1651 mmol), DIPEA (1.5 equiv., 43.1 µL, 0.2476 mmol), HBTU (1.05 equiv., 65.7 mg, 0.1733 mmol) in 0.7 mL DMF, and Intermediate 23 (1.0 equiv., 61.3 mg, 0.1733 mmol), DIPEA (1.5 equiv., 43.1 µL, 0.2476 mmol) in 1 mL DMF. The crude was purified with column chromatography using 2% MeOH / DCM to afford the product (108 mg, 99%). Rf= 0.49 (5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 7.55 (d, J = 2.0 Hz, 1H), 7.37 – 7.29 (m, 3 H), 7.27 – 7.22 (m, 6H), 7.17 (dd, J = 8.4, 2.0 Hz, 1H), 7.11 (d, J = 8.4 Hz , 1H), 6.82 (br s, 1H), 4.84 (br s, 1H), 4.35 (s, 2H), 3.92 (br s, 1H), 3.12 (br s, 1H), 2.87 (br s, 1H), 2. 81 (tt, J = 12.1, 3.6 Hz, 1H), 2.06 – 1.81 (m, 2H), 1.71 (br s, 2H), 1.42 (s, 9H), 1.39 (s, 9H);13C NMR (CDCl3, 100 MHz) δ 175.72, 174.71, 169.74, 154.47, 145.69, 143.21, 130.88, 130.32, 130.07, 129.05, 128.99, 128.42, 128.36, 123.29, 120.00, 119.76, 116.76, 81.61, 58.11, 48.59, 43.08, 42.37, 36.94, 33.81, 33.24, 30.76, 29.06. HRMS (ESI) Found: [M+H]+= 663.2666, calcd: [M+H]+= 663.2669. Example 38 1-phenyl-N-(2,3,4-trimethyl-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)methanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 140 (1.0 equiv., 27.8 mg, 0.08338 mmol), DIPEA (1.5 equiv., 21.8 µL, 0.1251 mmol), HBTU (1.05 equiv., 33.2 mg, 0.08755 mmol) in 0.5 mL DMF, and Intermediate 21 (1.0 equiv., 30 mg, 0.08338 mmol), DIPEA (1.5 equiv., 21.8 µL, 0.1251 mmol) in 0.5 mL DMF. The crude was purified with column chromatography using 2% MeOH / DCM to afford the product (52.7 mg, 99%). Rf = 0.37 (2.5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 7.80 (d, J = 9.2 Hz, 1H), 7.37 – 7.25 (m, 8H), 7.17 (d, J = 8.7 Hz, 2H), 7.11 (s, 1H), 6.40 (s, 1H), 4.97 (m, 1H), 4.33 (s, 2H), 3.59 (m, 1H), 3.08 (m, 1H), 2.91 – 2.76 (m, 2H), 2.25 (s, 3H), 2.22 (s, 3H), 2.04 (s, 3H), 1.87 – 1.43 (m, 4H);13C NMR (CDCl3, 100 MHz) δ 169.9, 167.2, 151.3, 148.4 (q, J = 35.6 Hz), 142.9, 137.9, 135.1, 132.9, 130.9, 130.3, 130.0, 129.0, 128.9, 128.8, 128.3, 127.3, 121.5, 121.5 (q, J = 275.4 Hz), 117.9, 117.4, 58.1, 47.8, 42.3, 42.3, 33.8, 33.4, 17.3, 16.7, 14.6;19F NMR (CDCl3, 376 MHz) δ -66.37. HRMS (ESI) Found: [M+H]+= 639.2236, calcd: [M+H]+= 639.2247. Example 39 N-(2,4-dimethyl-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 141 (1.0 equiv., 26.6 mg, 0.08338 mmol), DIPEA (1.5 equiv., 21.8 µL, 0.1251 mmol), HBTU (1.05 equiv., 33.2 mg, 0.08755 mmol) in 0.5 mL DMF, and Intermediate 21 (1.0 equiv., 30 mg, 0.08338 mmol), DIPEA (1.5 equiv., 21.8 µL, 0.1251 mmol) in 0.5 mL DMF. The crude was purified with column chromatography using 1% MeOH / DCM to afford the product (50 mg, 96%). Rf = 0.44 (2.5% MeOH / DCM).1H NMR (CDCl3 , 400 MHz) δ 7.80 (d, J = 9.2 Hz, 1H), 7.45 – 7.21 (m, 9H), 7.17 (d, J = 8.6 Hz, 2H), 7.04 (s, 1H), 6.20 (s, 1H), 4.95 (m, 1H), 4.36 (s, 2H), 3.60 (m, 1H), 3.11 (m, 1H), 2.92 – 2.77 (m, 2H), 2.30 (s, 1H), 2.05 (m, 1H), 2.01 (s, 3H), 1.87 – 1.42 (m, 3H);13C NMR (CDCl3, 100 MHz) δ 169.2, 167.2, 151.3, 148.4 (q, J = 35.3 Hz), 142.9, 135.4, 133.3, 133.3, 131.2, 130.8, 129.1, 129.1, 129.0, 128.7, 128.4, 127.3, 121.5, 121.5 (q, J = 273.8 Hz), 117.9, 117.6, 57.8, 47.7, 42.3, 42.2, 34.7, 33.4, 18.6, 17.5;19F NMR (CDCl3, 376 MHz) δ - 66.37. HRMS (ESI) Found: [M+H]+= 625.2095, calcd: [M+H]+= 625.2091. Example 40 N-(2,4-dimethoxy-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 142 (1.0 equiv., 29.3 mg, 0.08338 mmol), DIPEA (1.5 equiv., 21.8 µL, 0.1251 mmol), HBTU (1.05 equiv., 33.2 mg, 0.08755 mmol) in 0.5 mL DMF, and Intermediate 21 (1.0 equiv., 30 mg, 0.08338 mmol), DIPEA (1.5 equiv., 21.8 µL, 0.1251 mmol) in 0.5 mL DMF. The crude was purified with column chromatography using 20% EtOAc / DCM to afford the product (54.1 mg, 99%). Rf = 0.34 (20% EtOAc / DCM).1H NMR (CDCl3, 400 MHz) δ 7.80 (m, 1H), 7.54 – 7.26 (m, 7H), 7.26 – 7.21 (m, 2H), 7.17 (d, J = 8.6 Hz, 2H), 6.54 – 6.45 (m, 2H), 4.93 (m, 1H), 4.30 (s, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.62 (m, 1H), 3.12 (m, 1H), 2.90 – 2.75 (m, 2H), 1.99 (m, 1H), 1.87 – 1.58 (m, 3H);13C NMR (CDCl3, 100 MHz) δ 167.2, 166.9, 153.7, 151.3, 150.6, 148.4 (q, J = 33.4 Hz), 143.3, 130.9, 128.9, 128.7, 128.7, 128.4, 127.3, 121.5 (q, J = 272.0 Hz), 121.4, 120.1, 119.6, 118.6, 117.9, 95.7, 57.5, 56.3, 56.0, 47.9, 42.5, 42.4, 34.1, 33.0;19F NMR (CDCl3, 376 MHz) δ -66.38. HRMS (ESI) Found: [M+H]+= 657.1995, calcd: [M+H]+= 657.1989. Example 41 N-(2,3-dimethoxy-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 143 (1.0 equiv., 29.3 mg, 0.08338 mmol), DIPEA (1.5 equiv., 21.8 µL, 0.1251 mmol), HBTU (1.05 equiv., 33.2 mg, 0.08755 mmol) in 0.5 mL DMF, and Intermediate 21 (1.0 equiv., 30 mg, 0.08338 mmol), DIPEA (1.5 equiv., 21.8 µL, 0.1251 mmol) in 0.5 mL DMF. The crude was purified with column chromatography using 1% MeOH / DCM to afford the product (53.6 mg, 98%). Rf = 0.62 (2.5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 7.80 (d, J = 9.2 Hz, 1H), 7.36 – 7.27 (m, 6H), 7.27 – 7.20 (m, 2H), 7.20 (d, J = 1.8 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.96 (s, 1H), 6.86 (d, J = 1.8 Hz, 1H), 4.86 (br s, 1H), 4.39 (s, 2H), 3.93 (br s, 1H), 3.92 (s, 3H), 3.79 (s, 3H), 3.15 (br s, 1H), 2.96 – 2.79 (m, 2H), 2.00 (br s, 1H), 1.88 (br s, 1H), 1.72 (br s, 2H);13C NMR (CDCl3, 100 MHz) δ 169.6, 167.2, 152.7, 151.3, 148.4 (q, J = 35.6 Hz), 146.8, 143.0, 138.1, 132.2, 130.9, 130.9, 129.2, 129.0, 128.4, 127.4, 121.5, 121.5 (q, J = 275.6 Hz), 117.9, 108.4, 107.4, 61.0, 58.0, 56.2, 48.6, 43.0, 42.4, 34.0, 33.0;19F NMR (CDCl3, 376 MHz) δ -66.38. HRMS (ESI) Found: [M+H]+= 657.1983, calcd: [M+H]+= 657.1989. Example 42 N-(2-methyl-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1-carbonyl)pyridin- 3-yl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 144 (1.0 equiv., 25.5 mg, 0.08338 mmol), DIPEA (1.5 equiv., 21.8 µL, 0.1251 mmol), HBTU (1.05 equiv., 33.2 mg, 0.08755 mmol) in 0.5 mL DMF, and Intermediate 21 (1.0 equiv., 30 mg, 0.08338 mmol), DIPEA (1.5 equiv., 21.8 µL, 0.1251 mmol) in 0.5 mL DMF. The crude was purified with column chromatography using 2.5% MeOH / DCM to afford the product (41.2 mg, 81%). Rf = 0.63 (5% MeOH / DCM).1H NMR (CDCl3 , 400 MHz) δ 8.38 (d, J = 1.9 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.78 (d, J = 1.9 Hz, 1H), 7.41 – 7.31 (m, 4H), 7.30 (d, J = 8.7 Hz, 2H), 7.28 – 7.21 (m, 2H), 7.19 (d, J = 8.7 Hz, 2H), 6.33 (s, 1H), 4.87 (m, 1H), 4.42 (s, 2H), 3.79 (m, 1H), 3.19 (m, 1H), 2.89 (m, 1H), 2.84 (tt, J = 12.2, 3.7 Hz, 1H), 2.32 (s, 3H), 2.02 (m, 1H), 1.86 (m, 1H), 1.77 (m, 1H), 1.66 (m, 1H);13C NMR (CDCl3, 100 MHz) δ 167.2, 151.4, 151.3, 149.6, 148.5 (q, J = 35.4 Hz), 143.3, 142.7, 131.9, 130.7, 130.6, 129.5, 129.2, 128.3, 128.1, 127.4, 125.2, 121.5, 121.5 (q, J = 274.5 Hz), 117.9, 59.0, 48.6, 43.2, 42.3, 34.0, 33.1, 20.8;19F NMR (CDCl3, 376 MHz) δ - 66.38. HRMS (ESI) Found: [M+H]+= 612.1896, calcd: [M+H]+= 612.1887. Example 43 N-(2-methoxy-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1-carbonyl)pyridin- 3-yl)-1-phenylmethanesulfonamide The title compound was prepared according to General procedure N (Workup procedure A), using Intermediate 145 (1.0 equiv., 26.9 mg, 0.08338 mmol), DIPEA (1.5 equiv., 21.8 µL, 0.1251 mmol), HBTU (1.05 equiv., 33.2 mg, 0.08755 mmol) in 0.5 mL DMF, and Intermediate 21 (1.0 equiv., 30 mg, 0.08338 mmol), DIPEA (1.5 equiv., 21.8 µL, 0.1251 mmol) in 0.5 mL DMF. The crude was purified with column chromatography using 2% MeOH / DCM to afford the product (51.7 mg, 99%). Rf = 0.34 (2.5% MeOH / DCM).1H NMR (CDCl3, 400 MHz) δ 8.04 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.37 – 7.26 (m, 6H), 7.26 – 7.19 (m, 2H), 7.18 (d, J = 8.6 Hz, 2H), 6.69 (s, 1H), 4.83 (br s, 1H), 4.38 (s, 2H), 3.97 (s, 3H), 3.84 (br s, 1H), 3.14 (br s, 1H), 2.89 (br s, 1H), 2.84 (tt, J = 12.2, 3.7 Hz, 1H), 2.09 – 1.83 (m, 2H), 1.71 (br s, 2H);13C NMR (CDCl3, 100 MHz) δ 167.5, 167.1, 153.9, 151.4, 148.4 (q, J = 35.4 Hz), 142.9, 140.6, 130.8, 129.3, 129.0, 128.4, 128.1, 127.3 (q, J = 2.3 Hz), 125.9, 124.6, 121.6, 121.5, 121.5 (q, J = 273.8 Hz), 117.9, 58.8, 54.4, 48.6, 43.2, 42.4, 34.0, 33.1;19F NMR (CDCl3, 376 MHz) δ -66.38. HRMS (ESI) Found: [M+H]+= 628.1826, calcd: [M+H]+= 628.1836. Example 44 3-methyl-3-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenoxy)azetidin-1-ium 2,2,2-trifluoroacetate The title compound was prepared according to General procedure O, using Intermediate 160 (1.0 equiv., 200 mg, 0.2558 mmol) in 4 mL of DCE, and 4 mL of TFA. Yield: 184 mg, 90%. Rf = 0.23 (10% MeOH / DCM).1H NMR (MeOD, 400 MHz) δ 8.09 (d, J = 9.3 Hz, 1H), 7.56 (d, J = 9.3 Hz, 1H), 7.41 (d, J = 8.6 Hz, 2H), 7.38 – 7.29 (m, 6H), 7.21 (d, J = 8.6 Hz, 2H), 7.17 (dd, J = 8.4, 2.1 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 4.73 (br s, 1H), 4.52 (s, 2H), 4.50 (d, J = 12.0 Hz, 2H), 4.27 (d, J = 12.0 Hz, 2H), 3.81 (br s, 1H), 3.20 (br s, 1H), 3.05 – 2.89 (m, 2H), 2.00 (br s, 1H), 1.89 (br s, 1H), 1.77 (s, 3H), 1.74 (br s, 2H);13C NMR (MeOD, 100 MHz) δ 171.3, 169.0, 152.9, 149.4 (q, J = 35.2 Hz), 147.0, 144.7, 132.2, 130.9, 130.5, 130.0, 129.8, 129.7, 129.5, 129.4 (q, J = 1.9 Hz), 124.9, 122.9 (q, J = 272.9 Hz), 122.4, 122.2, 120.0, 116.4, 77.6, 60.0, 58.7, 49.8, 44.3, 43.2, 35.1, 34.2, 21.3;19F NMR (MeOD, 376 MHz) δ -67.91, -77.02. HRMS (ESI) Found: [M-TFA+H]+= 682.2295, calcd: [M-TFA+H]+= 682.2306. Example 45 4-(2-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenoxy)ethyl)morpholin-4-ium chloride The title compound was prepared according to General procedure Q, using Intermediate 161 (1.0 equiv., 30 mg, 0.04133 mmol) in 0.5 mL of DCM, and 4M HCl in dioxane (5.0 equiv., 52 µL, 0.2067 mmol) in 1 mL of Et2O. Yield: 28.1 mg, 89%.1H NMR (MeOD, 400 MHz) δ 8.10 (d, J = 9.3 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.41 (d, J = 8.6 Hz, 2H), 7.41 – 7.34 (m, 2H), 7.36 – 7.29 (m, 3H), 7.27 (dd, J = 8.4, 2.1 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 8.4 Hz, 1H), 4.73 (m, 1H), 4.58 (s, 2H), 4.49 (t, J = 4.9 Hz, 2H), 4.04 (m, 2H), 3.87 (m, 2H), 3.67 (m, 4H), 3.57 (m, 2H), 2.99 (br s, 1H), 2.95 (tt, J = 11.9, 3.4 Hz, 1H), 2.00 (br s, 1H), 1.84 (br s, 1H), 1.73 (br s, 2H);13C NMR (MeOD, 100 MHz) δ 171.4, 169.0, 152.9, 151.7, 149.4 (q, J = 35.0 Hz), 144.7, 132.3, 130.6, 130.4, 129.8, 129.7, 129.5, 129.4, 127.9, 126.0, 122.9 (q, J = 273.2 Hz), 122.8, 122.4, 120.0, 113.4, 67.4, 67.4, 64.9, 63.1, 59.9, 57.1, 53.4, 49.9, 44.2, 43.2, 35.0, 34.1;19F NMR (MeOD, 376 MHz) δ -67.89. HRMS (ESI) Found: [M-HCl+H]+= 726.2570, calcd: [M-HCl+H]+= 726.2568. Example 46 1-(2-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenoxy)ethyl)pyrrolidin-1-ium chloride The title compound was prepared according to General procedure Q, using Intermediate 162 (1.0 equiv., 30 mg, 0.04227 mmol) in 0.5 mL of DCM, and 4M H...

Claims

CLAIMS 1. A compound of formula (I)wherein Ring A is a heteroaromatic ring selected from the group consisting of pyridine, pyrazine, pyrimidine, pyridazine and 1,3,4-thiadiazole; Ring B is para-substituted benzene or a para-substituted heteroaromatic ring selected from the group consisting of pyridine, pyrazine, pyrimidine and pyridazine; R1is selected from the group consisting of hydrogen, cyano, carboxyl, C1-4 alkyl and C1-4 haloalkyl; M is -CR4- or -N-; X is -C(=O)-, -C(=O)-NH-, -S(=O)2- or -S(=O)2-NH-; Y is a bond or -(CR5AR5B)m-, wherein m is an integer 1 or 2; R2is independently selected from the group consisting of halogen, cyano, C1-4alkyl, C1-4haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; n is an integer 0, 1 or 2, R3is selected from the group consisting of C1-4 alkyl, -O-R6, -NR6R7and heterocyclyl, wherein heterocyclyl is optionally substituted with R8; Each R4is independently selected from the group consisting of hydrogen, halogen, C1-4 alkyl and C1-4alkoxy; R5Aand R5Bare each independently selected from the group consisting of hydrogen, hydroxy, halogen and C1-4 alkyl, or R5Aand R5Btogether form =O; R6is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl, C3-6 cycloalkyl-C2-4 alkenyl, heterocyclyl, heterocyclyl-C1-4 alkyl, heterocyclyl-C2-4 alkenyl,amino-C1-4 alkyl, N-(C1-4 alkyl)amino-C1-4 alkyl and N,N-di(C1-4 alkyl)amino)-C1-4 alkyl, and wherein heterocyclyl is optionally substituted with C1-4 alkyl; R7is C1-4 alkyl; R8is selected from the group consisting of C1-4alkyl, C1-4alkoxy-C1-4alkyl, carboxy-C1-3alkyl and hydroxy-(C1-4alkoxy)p-C1-4alkyl; p is an integer 0, 1, 2, 3 or 4; and q is an integer 1 or 2; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein ring A is pyridine, pyridazine or pyrazine.

3. A compound according to claim 1 or 2, wherein ring B is benzene.

4. A compound according to any one of claims 1 to 3, wherein R1is trifluoromethyl.

5. A compound according to any one of claims 1 to 4, wherein X is -C(=O)- or -S(=O)2-.

6. A compound according to any one of claims 1 to 5, wherein Y is -CH2-.

7. A compound according to any one of claims 1 to 6, wherein R2is independently selected from the group consisting of chloro and fluoro.

8. A compound according to any one of claims 1 to 7, wherein R3is OR6and wherein R6is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, amino- C1-4 alkyl, N-(C1-4 alkyl)amino-C1-4 alkyl and N,N-di(C1-4 alkyl)amino)-C1-4 alkyl, and wherein heterocyclyl is optionally substituted with C1-4alkyl 9. A compound according to any one of claims 1 to 7, wherein R3is heterocyclyl which is optionally substituted with R8.

10. A compound according to any one of claims 1 to 7 and 9, wherein R3is 4-(1-ethylpiperazinyl), 4- (1-(carboxymethyl)piperazinyl) or 4-(1-(2-carboxyethyl)piperazinyl).

11. A compound according to any one of claims 1 to 10, wherein each R4is hydrogen.

12. A compound according to any one of claims 1 to 11, wherein M is -CH-.

13. A compound according to any one of claims 1 to 12, selected from the group consisting of: N-(2-methyl-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-methoxy-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-((5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-methoxy-5-(4-(4-((5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine- 1-carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(5-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2- methylphenyl)-1-phenylmethanesulfonamide; N-(5-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2- methoxyphenyl)-1-phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-((5-propyl-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)- phenyl)-1-phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-(4-(trifluoromethyl)phenoxy)phenyl)piperidine-1-carbonyl)phenyl)- 1-phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-(pyridin-2-yloxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-(pyridin-3-yloxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-phenoxyphenyl)piperidine-1-carbonyl)phenyl)-1-phenylmethane- sulfonamide; N-(2-methyl-5-(4-(4-((5-methylpyridin-2-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)piperidine-1-carbonyl)- phenyl)-1-phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-(pyrazin-2-yloxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-(pyrimidin-2-yloxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide;N-(2-methyl-5-(4-(4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-((5-methylpyrimidin-2-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)- 1-phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)piperidine-1-carbonyl)- phenyl)-1-phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-(pyrimidin-5-yloxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-((5-methylpyrazin-2-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)-1- phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-((3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-((5-(trifluoromethyl)pyrazin-2-yl)oxy)phenyl)piperidine-1-carbonyl)- phenyl)-1-phenylmethanesulfonamide; N-(2-cyclopropoxy-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-isopropoxy-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; 3-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenoxy)azetidin-1-ium 2,2,2-trifluoroacetate; 3-(3-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenoxy)propyl)azetidin-1-ium 2,2,2-trifluoroacetate; (E)-3-(3-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenoxy)prop-1-en-1-yl)azetidin-1-ium 2,2,2-trifluoroacetate; N-(2-(2-(dimethylamino)ethoxy)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; N,N-dimethyl-2-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin- 3-yl)oxy)phenyl)piperidine-1-carbonyl)phenoxy)ethan-1-aminium chloride; N-(2-methoxy-4-methyl-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(5-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2- methoxy-4-methylphenyl)-1-phenylmethanesulfonamide;N-(2-cyclopropoxy-4-methyl-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(5-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2- cyclopropoxy-4-methylphenyl)-1-phenylmethanesulfonamide; N-(5-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2- cyclopropoxyphenyl)-1-phenylmethanesulfonamide; N-(2-(tert-butoxy)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-(tert-butoxy)-5-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; 1-phenyl-N-(2,3,4-trimethyl-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)methanesulfonamide; N-(2,4-dimethyl-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2,4-dimethoxy-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2,3-dimethoxy-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-methyl-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)pyridin-3-yl)-1-phenylmethanesulfonamide; N-(2-methoxy-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)piperidine-1- carbonyl)pyridin-3-yl)-1-phenylmethanesulfonamide; 3-methyl-3-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenoxy)azetidin-1-ium 2,2,2-trifluoroacetate; 4-(2-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenoxy)ethyl)morpholin-4-ium chloride; 1-(2-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenoxy)ethyl)pyrrolidin-1-ium chloride; 4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-ium chloride; (R)-3-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenoxy)pyrrolidin-1-ium 2,2,2-trifluoroacetate; (S)-2-((2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenoxy)methyl)pyrrolidin-1-ium 2,2,2-trifluoroacetate;N-(2-((1-methylazetidin-3-yl)oxy)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; (R)-N-(2-((1-methylpyrrolidin-3-yl)oxy)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-(4-methylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-(4-isopropylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-((1,3-dimethylazetidin-3-yl)oxy)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; 3-(4-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2- ((phenylmethyl)sulfonamido)phenoxy)azetidin-1-ium 2,2,2-trifluoroacetate; N-(5-(4-(4-((5-(tert-butyl)-1,3,4-thiadiazol-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2-(2- (dimethylamino)ethoxy)phenyl)-1-phenylmethanesulfonamide; N-isopropyl-N-(2-((3-((phenylmethyl)sulfonamido)-5-(4-(4-((6-(trifluoromethyl)- pyridazin-3-yl)oxy)phenyl)piperidine-1-carbonyl)pyridin-2-yl)oxy)ethyl)propan-2-aminium chloride; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; 1-ethyl-4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-ium (S)-2-hydroxypropanoate; (S)-N-(2-((1-methylpyrrolidin-2-yl)methoxy)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; 4-(3-((phenylmethyl)sulfonamido)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)pyridin-2-yl)piperazin-1-ium 2,2,2-trifluoroacetate; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)pyridin-3-yl)-1-phenylmethanesulfonamide; 1-ethyl-4-(3-((phenylmethyl)sulfonamido)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)pyridin-2-yl)piperazin-1-ium chloride; N,N-dimethyl-2-((3-((phenylmethyl)sulfonamido)-5-(4-(4-((6-(trifluoromethyl)pyridazin- 3-yl)oxy)phenyl)piperidine-1-carbonyl)pyridin-2-yl)oxy)ethan-1-aminium chloride; 1-(4-chlorophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)methanesulfonamide;1-(3-chlorophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)methanesulfonamide; 4-(2-(((3-chlorophenyl)methyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)-1-ethylpiperazin-1-ium (S)-2-hydroxypropanoate; 1-(2-chlorophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)methanesulfonamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-(p-tolyl)methanesulfonamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-(4-(trifluoromethyl)phenyl)methanesulfonamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-(2-fluorophenyl)methanesulfonamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)benzenesulfonamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-2-phenylethane-1-sulfonamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-(3-(trifluoromethoxy)phenyl)methanesulfonamide; 1-(3-cyanophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)methanesulfonamide; 1-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-3-phenylurea; 1-benzyl-3-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)urea; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-2-phenylacetamide; 1-(4-chlorophenyl)-3-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)urea; 1-(3-chlorophenyl)-3-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)urea; 2-(4-chlorophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)acetamide; 2-(3-chlorophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)acetamide;N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-2,2-difluoro-2-phenylacetamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-2-oxo-2-phenylacetamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-2-hydroxy-2-phenylacetamide; 1-(3,5-dichlorophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)- pyridazin-3-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)methanesulfonamide; 1-(3,4-dichlorophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)- pyridazin-3-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)methanesulfonamide; 1-(3-bromophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)methanesulfonamide; 1-(3,4-dichlorophenyl)-3-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)- pyridazin-3-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)urea; 1-(3,5-dichlorophenyl)-3-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)- pyridazin-3-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)urea; N-(2-(4-ethylpiperazin-1-yl)-3-fluoro-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-(4-ethylpiperazin-1-yl)-3-methyl-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-(4-ethyl-1,4-diazepan-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; 4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)piperidin-1-ium 2,2,2-trifluoroacetate; N-(2-(1-ethylpiperidin-4-yl)-5-(4-(4-((6-(trifluoromethyl)pyridazin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((5-(trifluoromethyl)pyrazin-2-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)- piperidine-1-carbonyl)phenyl)-1-phenylmethanesulfonamide; 1-ethyl-4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-ium (S)-2-hydroxypropanoate;1-ethyl-4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)- phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-ium (S)-2-hydroxypropanoate; 1-(3-chlorophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((6-(trifluoromethyl)pyridin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)methanesulfonamide; 1-(3-chlorophenyl)-N-(2-(4-ethylpiperazin-1-yl)-5-(4-(4-((5-(trifluoromethyl)pyridin-2- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)methanesulfonamide; 4-(2-(((3-chlorophenyl)methyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)pyridin-3- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)-1-ethylpiperazin-1-ium (S)-2-hydroxypropanoate; 4-(2-(((3-chlorophenyl)methyl)sulfonamido)-4-(4-(4-((5-(trifluoromethyl)pyridin-2- yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)-1-ethylpiperazin-1-ium (S)-2-hydroxypropanoate; N-(5-(4-(4-((6-cyanopyridazin-3-yl)oxy)phenyl)piperidine-1-carbonyl)-2-(4- ethylpiperazin-1-yl)phenyl)-1-phenylmethanesulfonamide; N-(5-(4-(4-((5-cyanopyridin-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2-(4-ethylpiperazin- 1-yl)phenyl)-1-phenylmethanesulfonamide; N-(5-(4-(4-((6-cyanopyridin-3-yl)oxy)phenyl)piperidine-1-carbonyl)-2-(4-ethylpiperazin- 1-yl)phenyl)-1-phenylmethanesulfonamide; 1-(carboxymethyl)-4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((5-(trifluoromethyl)- pyridin-2-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-ium chloride; 1-(2-carboxyethyl)-4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((5-(trifluoromethyl)- pyridin-2-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-ium chloride; 4-(4-(4-(4-((5-carboxypyridin-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2-((phenylmethyl)- sulfonamido)phenyl)-1-ethylpiperazin-1-ium chloride; 4-(4-(4-(4-((6-carboxypyridin-3-yl)oxy)phenyl)piperidine-1-carbonyl)-2-((phenylmethyl)- sulfonamido)phenyl)-1-ethylpiperazin-1-ium chloride; 1-(carboxymethyl)-4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)- pyridin-3-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-ium chloride; 1-(2-carboxyethyl)-4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)- pyridin-3-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-ium chloride; 1-(carboxymethyl)-4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)- pyridazin-3-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-ium chloride; and 1-(2-carboxyethyl)-4-(2-((phenylmethyl)sulfonamido)-4-(4-(4-((6-(trifluoromethyl)- pyridazin-3-yl)oxy)phenyl)piperidine-1-carbonyl)phenyl)piperazin-1-ium chloride; or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 13, and one or more pharmaceutically acceptable excipients.

15. The compound according to any one of claims 1 to 13, for use as a medicament.

16. The compound according to any one of claims 1 to 13, for use in the treatment or prevention of microbial infections and diseases in an animal or a human, such as infections and diseases caused by apicomplexan parasites or other microbes.

17. The compound for use according to claim 16, wherein the infection or disease is caused by species from the genera Toxoplasma, Sarcocystis, Plasmodium, Neospora, Eimeria, Cryptosporidium, Theileria or Babesia.

18. The compound for use according to claim 16 or 17, for use in the treatment or prevention of Cryptosporidium parvum infections.

19. The compound for use according to any one of claims 16 to 18, wherein the subject is an animal, such as a ruminant.

20. The compound for use according to claim 16 or 17, for use in the treatment or prevention of Cryptosporidium hominis infections.

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