Novel aromatic compounds

Abstract

To provide novel aromatic molecules which can be used in treatment of pathological conditions, such as cancer, skin diseases, muscle disorders, and immune system-related disorders such as disorders of the hematopoietic system including the hematologic system.SOLUTION: The invention provides compounds represented by the formula, where: X is CH or N; R1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, or tricycloalkyl; and R2 is H, alkyl, or cycloalkyl.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to novel aromatic compounds and their use as therapeutic agents that can be used in human and veterinary medicine in the treatment of conditions such as cancer, skin disorders, muscle disorders, and immune system-related disorders such as disorders of the hematopoietic system, including the blood system. [Background technology]

[0002] Notch signaling is a fundamental intercellular communication pathway that regulates the central processes in embryonic development and the maintenance of adult tissues. The effect of Notch signaling is highly dependent on signal strength, duration, and most importantly, cellular context. In this regard, Notch activity leads to numerous cell type-specific responses, such as those involved in determining cell fate, inducing or inhibiting differentiation, and regulating cell proliferation.

[0003] When signaling events are not properly controlled, the resulting loss of balance in corresponding cellular processes can drive aberrant cellular changes, ultimately resulting in various disease states such as cancer.

[0004] Notch signaling was first discovered as a carcinogenic pathway. Corresponding pathologies are associated with abnormally elevated signaling levels. In these specific cases, the use of Notch inhibitors represents a promising therapeutic intervention strategy, and numerous corresponding drugs are currently under development.

[0005] Conversely, there is growing evidence for the tumor suppressor function of the Notch pathway in other cellular contexts (Lobry et al., J. Exp. Med. 2011, 208, 1931-1935; South et al., Semin. Cell Dev. Biol. 2012, 23, 458-464), most notably in involved organs, where Notch negatively influences proliferation or triggers differentiation, for example, in the skin or neuroendocrine system (Dotto, Oncogene 2008, 27, 5115-5123; Kunnimalaiyaan et al., The Oncologist 2007, 12, 535-542). This finding is not only based on the observation that certain tumors exhibit dysfunction in Notch activity. In addition, various successful studies have confirmed that artificial activation of Notch signaling has beneficial effects on various malignant diseases (Jaskula-Sztul et al., J. Surg. Res. 2011, 171, 23-27; Yu et al., Cancer 2013, 119, 774-781; Ye et al., Sci. Rep. 2016, 6, 26510). Notable examples include non-melanoma skin cancer, neuroendocrine tumors, and certain cancers of the hematopoietic system.

[0006] In a broader sense, due to the central role of this pathway, the potential use of Notch enhancers is not only restricted to the treatment of cancer, but is equally expected to be beneficial in other pathological conditions shown to be responsive to Notch induction, such as diseases of the skin, muscle or immune system.

[0007] To achieve this goal, it is highly desirable to develop therapeutic agents that enhance Notch signaling.

[0008] [State of the art of Notch enhancers] Current methods for enhancing Notch signaling for potential therapeutic use involve the application of small molecules or receptor-activating peptides that exhibit Notch-enhancing properties. However, approved Notch enhancers are not yet available in the clinic. In addition, only a few comparable drugs are known to date, and even fewer have entered drug development programs to date. Reported small molecule Notch enhancers include resveratrol (Pinchot et al., Cancer 2011, 117, 1386-1398; Truong et al., Ann. Surg. Oncol. 2011, 18, 1506-1511; Yu et al., Mol. Cancer Ther. 2013, 12, 1276-1287), valproic acid (Greenblatt et al., Oncologist 2007, 12, 942-951; Platta et al., J. Surg. Res. 2008, 148, 31-37; Mohammed et al., Oncologist 2011, 16, 835-843), hesperetin (Patel et al., Ann. Surg. Oncol. 2014, 21, 497-504), and chrysin (Yu et al., Mol. Cancer Ther. 2013, 12, 1276-1287). al., Cancer 2013, 119, 774-778), phenethyl isothiocyanate (Kim et al., PLoSOne 2011, 6, 10), thiocoraline (Wyche et al., Cancer Gene Ther. 2014, 21, 518-525), and N-methylhemeanthidine chloride (Ye et al., Sci. Rep. 2016, 6, 26510).

[0009] A common drawback associated with most of the compounds mentioned is a lack of efficacy.

[0010] It is therefore of absolute importance to provide novel Notch enhancers with high therapeutic efficacy.

[0011] Screening of a small library of chemical molecules in a Notch-dependent luciferase reporter assay revealed a novel family of compounds with Notch-enhancing properties (Reinmuller et al., 2015, EPFL Thesis 6887, published March 2016), the contents of which are incorporated herein by reference. Summary of the Invention [Problem to be solved by the invention]

[0012] The present invention covers refined structures relative to the initially discovered limited set of Notch enhancer molecules. These second-generation compounds are designed to exhibit increased potency and greater metabolic stability. Alternatively, they offer specific modifications of chemical residues that do not impair Notch-enhancing activity but may provide novel molecular properties that may prove to favorably affect pharmacological and physicochemical parameters addressed in the general drug development process. [Means for solving the problem]

[0013] Thus, the present invention relates to compounds as defined herein which are characterized by Notch-enhancing activity and may be used in the treatment of conditions responsive to Notch modulation, such as cancer, skin diseases, muscle disorders, and immune system-related disorders such as disorders of the hematopoietic system, including the blood system, in human and veterinary medicine.

[0014] Biological activity, for example, the antiproliferative activity of the claimed compounds, can be attributed to, but not limited to, Notch signaling enhancing activity.Therefore, the present invention also relates to compounds defined herein that feature antiproliferative activity, and can be used in the treatment of benign and malignant hyperproliferative disorders in human and veterinary medicine.In particular, the present invention relates to compounds defined herein for the treatment of immune system-related disorders, such as disorders of the hematopoietic system, including the blood system, such as malignant tumors of the myeloid lineage, malignant and non-malignant disorders of the skin and mucous membranes, for example, squamous cell carcinoma and basal cell carcinoma, actinic keratosis, and hyperproliferative disorders of the skin and mucous membranes, such as keratinization disorders, malignant and non-malignant disorders of muscle, including muscle hyperproliferative disorders such as muscle hyperplasia and muscle hypertrophy, disorders of the neuroendocrine system, such as medullary thyroid carcinoma, and hyperproliferative disorders of the urogenital tract, for example, cervical cancer, in human and veterinary medicine. DETAILED DESCRIPTION OF THE INVENTION

[0015] A first aspect of the present invention relates to compounds of formula I and their salts and solvates: JPEG0007807487000001.jpg3483(I) where X is CH or N; R 1 is C1-C 12 , preferably C1-C6 alkyl, C2-C 12 Preferably C2-C6 alkenyl, C2-C 12 Preferably, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C4-C 12 Bicycloalkyl, C6-C 12 Bicycloalkenyl, C5-C 14 is tricycloalkyl, wherein all alkyl, alkenyl and alkynyl residues may be linear or branched and may be unsubstituted or substituted by one or more substituents independently selected from, in particular: -F, -Cl, -Br, -I, -CN, -NCO, -NCS; and O-C-C alkyl, which may optionally be halogenated or perhalogenated, in particular perfluorinated; wherein all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues may be unsubstituted or substituted by one or more substituents independently selected from, in particular: -F, -Cl, -Br, -I, -CN, -NCO, -NCS; and C1-C3 alkyl, such as -CH3, which may optionally be halogenated or perhalogenated, in particular perfluorinated, such as -CF3; and O-C1-C3 alkyl, which may optionally be halogenated or perhalogenated, in particular perfluorinated; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues may be perhalogenated, in particular perfluorinated; and where R 1 is preferably selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, iso-propyl, tert-butyl, tert-pentyl, 3-pentyl, -CF3, -CF2CF3, -(CF2)2CF3, -(CF2)3CF3, -CH(CF3)2, -CF(CF3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, bicyclo[2.2.2]octyl, adamantyl, and 9-methylbicyclo[3.3.1]nonyl; R 2 is H, C1-C6 alkyl, C3-C6 cycloalkyl, wherein all alkyl residues may be linear or branched and may be unsubstituted or substituted by one or more substituents independently selected from, in particular: -F, -Cl, -Br, -I; and O-C-C alkyl, which may optionally be halogenated or perhalogenated, in particular perfluorinated; wherein all cycloalkyl residues may be unsubstituted or substituted by one or more substituents independently selected from, among others: -F, -Cl, -Br, -I; and C1-C3 alkyl, such as -CH3, which may optionally be halogenated or perhalogenated, in particular perfluorinated, such as -CF3; and O-C1-C3 alkyl, which may optionally be halogenated or perhalogenated, in particular perfluorinated; wherein all alkyl and cycloalkyl residues may be perhalogenated, in particular perfluorinated; and where R 2 is preferably selected from H, methyl and ethyl.

[0016] In some embodiments, the following compounds shown in Table Ia are expressly excluded from the scope of the present invention: JPEG0007807487000002.jpg218166

[0017] Compounds IA-IT of Table Ia are known in the art for specific applications in the field of medicine, while, to the best of the inventors' knowledge, compounds IU-I-AA are not known for any use in medicine. Thus, the present invention encompasses any medical use for compounds IU-I-AA.

[0018] Specific examples of compounds falling within the scope of Formula I are shown in Table Ib. The compounds in Table Ib are defined by their chemical structure and the nomenclature shown is for illustrative purposes only. Table Ib: JPEG0007807487000003.jpg222166JPEG0007807487000004.jpg216166JPEG0007807487000005.jpg217166JPEG0007807487000006.jpg254131 001 4-(p-Tolyloxy)benzoic acid 002 4-(4-ethylphenoxy)benzoic acid 003 4-(4-propylphenoxy)benzoic acid 004 4-(4-butylphenoxy)benzoic acid 005 4-(4-pentylphenoxy)benzoic acid 006 4-(4-hexylphenoxy)benzoic acid 007 4-(4-isopropylphenoxy)benzoic acid 008 4-(4-(pentan-3-yl)phenoxy)benzoic acid 009 4-(4-(trifluoromethyl)phenoxy)benzoic acid 010 4-(4-(perfluoroethyl)phenoxy)benzoic acid 011 4-(4-(perfluoropropyl)phenoxy)benzoic acid 012 4-(4-(perfluorobutyl)phenoxy)benzoic acid 013 4-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)benzoic acid 014 4-(4-(perfluoropropan-2-yl)phenoxy)benzoic acid 015 4-(4-cyclopropylphenoxy)benzoic acid 016 4-(4-cyclobutylphenoxy)benzoic acid 017 4-(4-cyclopentylphenoxy)benzoic acid 018 4-(4-cycloheptylphenoxy)benzoic acid 019 4-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)benzoic acid 020 4-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)benzoic acid 021 4-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)benzoic acid 022 4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)benzoic acid 023 Methyl 4-(p-tolyloxy)benzoate 024 Methyl 4-(4-ethylphenoxy)benzoate 025 Methyl 4-(4-propylphenoxy)benzoate 026 Methyl 4-(4-butylphenoxy)benzoate 027 Methyl 4-(4-pentylphenoxy)benzoate 028 Methyl 4-(4-hexylphenoxy)benzoate 029 Methyl 4-(4-isopropylphenoxy)benzoate 030 Methyl 4-(4-(tert-pentyl)phenoxy)benzoate 031 Methyl 4-(4-(pentan-3-yl)phenoxy)benzoate 032 Methyl 4-(4-(trifluoromethyl)phenoxy)benzoate 033 Methyl 4-(4-(perfluoroethyl)phenoxy)benzoate 034 Methyl 4-(4-(perfluoropropyl)phenoxy)benzoate 035 Methyl 4-(4-(perfluorobutyl)phenoxy)benzoate 036 Methyl 4-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)benzoate 037 Methyl 4-(4-(perfluoropropan-2-yl)phenoxy)benzoate 038 Methyl 4-(4-cyclopropylphenoxy)benzoate 039 Methyl 4-(4-cyclobutylphenoxy)benzoate 040 Methyl 4-(4-cyclopentylphenoxy)benzoate 041 Methyl 4-(4-cyclohexylphenoxy)benzoate 042 Methyl 4-(4-cycloheptylphenoxy)benzoate 043 Methyl 4-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)benzoate 044 Methyl 4-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)benzoate 045 Methyl 4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)benzoate 046 Methyl 4-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)benzoate 047 Methyl 4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)benzoate 048 Ethyl 4-(p-tolyloxy)benzoate 049 Ethyl 4-(4-ethylphenoxy)benzoate 050 Ethyl 4-(4-propylphenoxy)benzoate 051 Ethyl 4-(4-butylphenoxy)benzoate 052 Ethyl 4-(4-pentylphenoxy)benzoate 053 Ethyl 4-(4-hexylphenoxy)benzoate 054 Ethyl 4-(4-isopropylphenoxy)benzoate 055 Ethyl 4-(4-(pentan-3-yl)phenoxy)benzoate 056 Ethyl 4-(4-(trifluoromethyl)phenoxy)benzoate 057 Ethyl 4-(4-(perfluoroethyl)phenoxy)benzoate 058 Ethyl 4-(4-(perfluoropropyl)phenoxy)benzoate 059 Ethyl 4-(4-(perfluorobutyl)phenoxy)benzoate 060 Ethyl 4-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)benzoate 061 Ethyl 4-(4-(perfluoropropan-2-yl)phenoxy)benzoate 062 Ethyl 4-(4-cyclopropylphenoxy)benzoate 063 Ethyl 4-(4-cyclobutylphenoxy)benzoate 064 Ethyl 4-(4-cyclopentylphenoxy)benzoate 065 Ethyl 4-(4-cycloheptylphenoxy)benzoate 066 Ethyl 4-(4-((1S,4S)-bicyclo[2.2.1]heptan-2-yl)phenoxy)benzoate 067 Ethyl 4-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)benzoate 068 Ethyl 4-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)benzoate 069 Ethyl 4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)benzoate 070 6-(4-ethylphenoxy)nicotinic acid 071 6-(4-propylphenoxy)nicotinic acid 072 6-(4-butylphenoxy)nicotinic acid 073 6-(4-pentylphenoxy)nicotinic acid 074 6-(4-hexylphenoxy)nicotinic acid 075 6-(4-Isopropylphenoxy)nicotinic acid 076 6-(4-(pentan-3-yl)phenoxy)nicotinic acid 077 6-(4-(perfluoroethyl)phenoxy)nicotinic acid 078 6-(4-(perfluoropropyl)phenoxy)nicotinic acid 079 6-(4-(perfluorobutyl)phenoxy)nicotinic acid 080 6-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)nicotinic acid 081 6-(4-(perfluoropropan-2-yl)phenoxy)nicotinic acid 082 6-(4-cyclopropylphenoxy)nicotinic acid 083 6-(4-Cyclobutylphenoxy)nicotinic acid 084 6-(4-Cyclopentylphenoxy)nicotinic acid 085 6-(4-cycloheptylphenoxy)nicotinic acid 086 6-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)nicotinic acid 087 6-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)nicotinic acid 088 6-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)nicotinic acid 089 6-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)nicotinic acid 090 6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)nicotinic acid 091 Methyl 6-(p-tolyloxy)nicotinate 092 Methyl 6-(4-ethylphenoxy)nicotinate 093 Methyl 6-(4-propylphenoxy)nicotinate 094 Methyl 6-(4-butylphenoxy)nicotinate 095 Methyl 6-(4-pentylphenoxy)nicotinate 096 Methyl 6-(4-hexylphenoxy)nicotinate 097 Methyl 6-(4-isopropylphenoxy)nicotinate 099 Methyl 6-(4-(tert-pentyl)phenoxy)nicotinate 100 Methyl 6-(4-(pentan-3-yl)phenoxy)nicotinate 101 Methyl 6-(4-(trifluoromethyl)phenoxy)nicotinate 102 Methyl 6-(4-(perfluoroethyl)phenoxy)nicotinate 103 Methyl 6-(4-(perfluoropropyl)phenoxy)nicotinate 104 Methyl 6-(4-(perfluorobutyl)phenoxy)nicotinate 105 Methyl 6-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)nicotinate 106 Methyl 6-(4-(perfluoropropan-2-yl)phenoxy)nicotinate 107 Methyl 6-(4-cyclopropylphenoxy)nicotinate 108 Methyl 6-(4-cyclobutylphenoxy)nicotinate 109 Methyl 6-(4-cyclopentylphenoxy)nicotinate 110 Methyl 6-(4-cyclohexylphenoxy)nicotinate 111 Methyl 6-(4-cycloheptylphenoxy)nicotinate 112 Methyl 6-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)nicotinate 113 Methyl 6-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)nicotinate 114 Methyl 6-(4-((3r,5r,7r)-adamantan-1-yl)phenoxynicotinate 115 Methyl 6-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)nicotinate 116 Methyl 6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)nicotinate 117 Ethyl 6-(4-ethylphenoxy)nicotinate 118 Ethyl 6-(4-propylphenoxy)nicotinate 119 Ethyl 6-(4-butylphenoxy)nicotinate 120 Ethyl 6-(4-pentylphenoxy)nicotinate 121 Ethyl 6-(4-hexylphenoxy)nicotinate 122 Ethyl 6-(4-isopropylphenoxy)nicotinate 123 Ethyl 6-(4-(pentan-3-yl)phenoxy)nicotinate 124 Ethyl 6-(4-(perfluoroethylphenoxy))nicotinate 125 Ethyl 6-(4-(perfluoropropyl)phenoxy)nicotinate 126 Ethyl 6-(4-(perfluorobutyl)phenoxy)nicotinate 127 Ethyl 6-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)nicotinate 128 Ethyl 6-(4-(perfluoropropan-2-yl)phenoxy)nicotinate 129 Ethyl 6-(4-cyclopropylphenoxy)nicotinate 130 Ethyl 6-(4-cyclobutylphenoxy)nicotinate 131 Ethyl 6-(4-cyclopentylphenoxy)nicotinate 132 Ethyl 6-(4-cycloheptylphenoxy)nicotinate 133 Ethyl 6-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)nicotinate 134 Ethyl 6-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)nicotinate 135 Ethyl 6-(4-((3r,5r,7t)-adamantan-1-yl)phenoxy)nicotinate 136 Ethyl 6-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)nicotinate 137 Ethyl 6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)nicotinate

[0019] Also included are isomers, for example enantiomers or diastereomers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds named above.

[0020] A second aspect of the present invention relates to compounds of formula II and salts and solvates thereof: JPEG0007807487000007.jpg3183(II) where X and R 1 is as defined in formula I, and R 1 including the preferred definition of R 3 is H, C1-C6 alkyl, or C3-C6 cycloalkyl; wherein all alkyl residues may be linear or branched and may be unsubstituted or substituted by one or more substituents independently selected from, among others: -F, -Cl, -Br, -I; and C1-C3 alkyl, such as -CH3, which may optionally be halogenated or perhalogenated, in particular perfluorinated, such as -CF3; and O-C1-C3 alkyl, which may optionally be halogenated or perhalogenated, in particular perfluorinated; wherein all cycloalkyl residues may be unsubstituted or substituted by one or more substituents independently selected from, among others: -F, -Cl, -Br, -I; and C1-C3 alkyl, such as -CH3, which may optionally be halogenated or perhalogenated, in particular perfluorinated, such as -CF3; and O-C1-C3 alkyl, which may optionally be halogenated or perhalogenated, in particular perfluorinated; wherein all alkyl and cycloalkyl residues may be perhalogenated, in particular perfluorinated; and where R 3 is preferably H or methyl; R 4 is H, C1-C6 alkyl, C3-C6 cycloalkyl, OH or OC1-C6 alkyl; wherein all alkyl residues may be linear or branched and may be unsubstituted or substituted by one or more substituents independently selected from, among others: -F, -Cl, -Br, -I; and C1-C3 alkyl, such as -CH3, which may optionally be halogenated or perhalogenated, in particular perfluorinated, such as -CF3; and O-C1-C3 alkyl, which may optionally be halogenated or perhalogenated, in particular perfluorinated; wherein all cycloalkyl residues may be unsubstituted or substituted by one or more substituents independently selected from, among others: -F, -Cl, -Br, -I; and C1-C3 alkyl, such as -CH3, which may optionally be halogenated or perhalogenated, in particular perfluorinated, such as -CF3; and O-C1-C3 alkyl, which may optionally be halogenated or perhalogenated, in particular perfluorinated; wherein all alkyl and cycloalkyl residues may be perhalogenated, in particular perfluorinated; and where R 4 is preferably H, OH or methyl.

[0021] In a particularly preferred embodiment, R 3 and R 4 is in each case H; H and OH; H and -CH3; or in each case -CH3.

[0022] In some embodiments, the following compounds shown in Table IIa are explicitly excluded from the scope of the present invention: JPEG0007807487000008.jpg49166

[0023] Compounds II-A and II-B of Table IIa are known in the art for specific applications in the field of medicine, while, to the best of the inventors' knowledge, compound II-C is not known for any use in medicine. Thus, the present invention encompasses any medical use for compound II-C.

[0024] Specific examples of compounds falling within the scope of Formula II are shown in Table IIb. The compounds in Table IIb are defined by their chemical structure and the nomenclature shown is for illustrative purposes only. Table IIb: JPEG0007807487000009.jpg239166JPEG0007807487000010.jpg224166JPEG0007807487000011.jpg243166JPEG0007807487000012.jpg218166JPEG0007807487000013.jpg232166JPEG0007807487000014.jpg25471138 4-(p-Tolyloxy)benzamide 139 4-(4-ethylphenoxy)benzamide 140 4-(4-propylphenoxy)benzamide 141 4-(4-butylphenoxy)benzamide 142 4-(4-pentylphenoxy)benzamide 143 4-(4-hexylphenoxy)benzamide 144 4-(4-Isopropylphenoxy)benzamide 145 4-(4-(tert-butyl)phenoxy)benzamide 146 4-(4-(tert-pentyl)phenoxy)benzamide 147 4-(4-(pentan-3-yl)phenoxy)benzamide 148 4-(4-(trifluoromethyl)phenoxy)benzamide 149 4-(4-(perfluoroethyl)phenoxy)benzamide 150 4-(4-(perfluoropropyl)phenoxy)benzamide 151 4-(4-(perfluorobutyl)phenoxy)benzamide 152 4-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)benzamide 153 4-(4-(perfluoropropan-2-yl)phenoxy)benzamide 154 4-(4-cyclopropylphenoxy)benzamide 155 4-(4-cyclobutylphenoxy)benzamide 156 4-(4-Cyclopentylphenoxy)benzamide 157 4-(4-cyclohexylphenoxy)benzamide 158 4-(4-cycloheptylphenoxy)benzamide 159 4-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)benzamide 160 4-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)benzamide 161 4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)benzamide 162 4-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)benzamide 163 4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)benzamide 164 N-Hydroxy-4-(p-tolyloxy)benzamide 165 4-(4-ethylphenoxy)-N-hydroxybenzamide 166 N-Hydroxy-4-(4-propylphenoxy)benzamide 167 4-(4-butylphenoxy)-N-hydroxybenzamide 168 N-Hydroxy-4-(4-pentylphenoxy)benzamide 169 4-(4-Hexylphenoxy)-N-hydroxybenzamide 170 N-Hydroxy-4-(4-isopropylphenoxy)benzamide 171 N-Hydroxy-4-(4-(tert-pentyl)phenoxy)benzamide 172 N-Hydroxy-4-(4-(pentan-3-yl)phenoxy)benzamide 173 N-Hydroxy-4-(4-(trifluoromethyl)phenoxy)benzamide 174 N-Hydroxy-4-(4-(perfluoroethyl)phenoxy)benzamide 175 N-Hydroxy-4-(4-(perfluoropropyl)phenoxy)benzamide 176 N-Hydroxy-4-(4-(perfluorobutyl)phenoxy)benzamide 177 4-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy-N-hydroxybenzamide 178 N-Hydroxy-4-(4-(perfluoropropan-2-yl)phenoxy)benzamide 179 4-(4-cyclopropylphenoxy)-N-hydroxybenzamide 180 4-(4-cyclobutylphenoxy)-N-hydroxybenzamide 181 4-(4-cyclopentylphenoxy)-N-hydroxybenzamide 182 4-(4-cyclohexylphenoxy)-N-hydroxybenzamide 183 4-(4-cycloheptylphenoxy)-N-hydroxybenzamide 184 4-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)-N-hydroxybenzamide 185 4-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)-N-hydroxybenzamide 186 4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-N-hydroxybenzamide 187 4-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)-N-hydroxybenzamide 188 N-Hydroxy-4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)benzamide 189 N-Methyl-4-(p-tolyloxy)benzamide 190 4-(4-ethylphenoxy)-N-methylbenzamide 191 N-methyl-4-(4-propylphenoxy)benzamide 192 4-(4-butylphenoxy)-N-methylbenzamide 193 N-methyl-4-(4-pentylphenoxy)benzamide 194 4-(4-hexylphenoxy)-N-methylbenzamide 195 4-(4-Isopropylphenoxy)-N-methylbenzamide 196 4-(4-(tert-butyl)phenoxy)-N-methylbenzamide 197 N-methyl-4-(4-(tert-pentyl)phenoxy)benzamide 198 N-methyl-4-(4-(pentan-3-yl)phenoxy)benzamide 199 N-Methyl-4-(4-(trifluoromethyl)phenoxy)benzamide 200 N-methyl-4-(4-(perfluoroethyl)phenoxy)benzamide 201 N-methyl-4-(4-(perfluoropropyl)phenoxy)benzamide 202 N-methyl-4-(4-(perfluorobutyl)phenoxy)benzamide 203 4-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)-N-methylbenzamide 204 N-methyl-4-(4-(perfluoropropan-2-yl)phenoxy)benzamide 205 4-(4-cyclopropylphenoxy)-N-methylbenzamide 206 4-(4-cyclobutylphenoxy)-N-methylbenzamide 207 4-(4-cyclopentylphenoxy)-N-methylbenzamide 208 4-(4-cyclohexylphenoxy)-N-methylbenzamide 209 4-(4-cycloheptylphenoxy)-N-methylbenzamide 210 4-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)-N-methylbenzamide 211 4-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)-N-methylbenzamide 212 4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-N-methylbenzamide 213 4-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)-N-methylbenzamide 214 N-methyl-4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)benzamide 215 N,N-Dimethyl-4-(p-tolyloxy)benzamide 216 4-(4-ethylphenoxy)-N,N-dimethylbenzamide 217 N,N-Dimethyl-4-(4-propylphenoxy)benzamide 218 4-(4-butylphenoxy)-N,N-dimethylbenzamide 219 N,N-Dimethyl-4-(4-pentylphenoxy)benzamide 220 4-(4-hexylphenoxy)-N,N-dimethylbenzamide 221 4-(4-Isopropylphenoxy)-N,N-dimethylbenzamide 222 4-(4-(tert-butyl)phenoxy)-N,N-dimethylbenzamide 223 N,N-Dimethyl-4-(4-(tert-pentyl)phenoxy)benzamide 224 N,N-Dimethyl-4-(4-(pentan-3-yl)phenoxy)benzamide 225 N,N-Dimethyl-4-(4-(trifluoromethyl)phenoxy)benzamide 226 N,N-Dimethyl-4-(4-(perfluoroethyl)phenoxy)benzamide 227 N,N-Dimethyl-4-(4-(perfluoropropyl)phenoxy)benzamide 228 N,N-Dimethyl-4-(4-(perfluorobutyl)phenoxy)benzamide 229 4-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)-N,N-dimethylbenzamide 230 N,N-Dimethyl-4-(4-(perfluoropropan-2-yl)phenoxy)benzamide 231 4-(4-cyclopropylphenoxy)-N,N-dimethylbenzamide 232 4-(4-cyclobutylphenoxy)-N,N-dimethylbenzamide 233 4-(4-Cyclopentylphenoxy)-N,N-dimethylbenzamide 234 4-(4-cyclohexylphenoxy)-N,N-dimethylbenzamide 235 4-(4-cycloheptylphenoxy)-N,N-dimethylbenzamide 236 4-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)-N,N-dimethylbenzamide 237 4-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)-N,N-dimethylbenzamide 238 4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-N,N-dimethylbenzamide 239 4-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)-N,N-dimethylbenzamide 240 N,N-Dimethyl-4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)benzamide 241 6-(p-Tolyloxy)nicotinamide 242 6-(4-ethylphenoxy)nicotinamide 243 6-(4-propylphenoxy)nicotinamide 244 6-(4-butylphenoxy)nicotinamide 245 6-(4-pentylphenoxy)nicotinamide 246 6-(4-hexylphenoxy)nicotinamide 247 6-(4-Isopropylphenoxy)nicotinamide 248 6-(4-(tert-pentyl)phenoxy)nicotinamide 249 6-(4-(pentan-3-yl)phenoxy)nicotinamide 250 6-(4-(trifluoromethyl)phenoxy)nicotinamide 251 6-(4-(perfluoroethyl)phenoxy)nicotinamide 252 6-(4-(perfluoropropyl)phenoxy)nicotinamide 253 6-(4-(perfluorobutyl)phenoxy)nicotinamide 254 6-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)nicotinamide 255 6-(4-(perfluoropropan-2-yl)phenoxy)nicotinamide 256 6-(4-Cyclopropylphenoxy)nicotinamide 257 6-(4-cyclobutylphenoxy)nicotinamide 258 6-(4-Cyclopentylphenoxy)nicotinamide 259 6-(4-cyclohexylphenoxy)nicotinamide 260 6-(4-cycloheptylphenoxy)nicotinamide 261 6-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)nicotinamide 262 6-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)nicotinamide 263 6-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)nicotinamide 264 6-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)nicotinamide 265 6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)nicotinamide 266 N-Hydroxy-6-(p-tolyloxy)nicotinamide 267 6-(4-ethylphenoxy)-N-hydroxynicotinamide 268 N-Hydroxy 6-(4-propylphenoxy)nicotinamide 269 ​​6-(4-butylphenoxy)-N-hydroxynicotinamide 270 N-Hydroxy-6-(4-pentylphenoxy)nicotinamide 271 6-(4-hexylphenoxy)-N-hydroxynicotinamide 272 N-Hydroxy-6-(4-isopropylphenoxy)nicotinamide 273 N-Hydroxy-6-(4-(tert-pentyl)phenoxy)nicotinamide 274 N-Hydroxy-6-(4-(pentan-3-yl)phenoxy)nicotinamide 275 N-Hydroxy-6-(4-(trifluoromethyl)phenoxy)nicotinamide 276 N-Hydroxy-6-(4-(perfluoroethyl)phenoxy)nicotinamide 277 N-Hydroxy-6-(4-(perfluoropropyl)phenoxy)nicotinamide 278 (There is no Japanese translation because the compound name is not included in the original text) 279 6-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)-N-hydroxynicotinamide 280 N-hydroxy-6-(4-(perfluoropropan-2-yl)phenoxy)nicotinamide 281 6-(4-cyclopropylphenoxy)-N-hydroxynicotinamide 282 6-(4-cyclobutylphenoxy)-N-hydroxynicotinamide 283 6-(4-Cyclopentylphenoxy)-N-hydroxynicotinamide 284 6-(4-cyclohexylphenoxy)-N-hydroxynicotinamide 285 6-(4-cycloheptylphenoxy)-N-hydroxynicotinamide 286 6-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)-N-hydroxynicotinamide 287 6-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)-N-hydroxynicotinamide 288 6-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-N-hydroxynicotinamide 289 6-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)-N-hydroxynicotinamide 290 N-Hydroxy-6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)nicotinamide 291 N-methyl-6-(p-tolyloxy)nicotinamide 292 6-(4-ethylphenoxy)-N-methylnicotinamide 293 N-methyl-6-(4-propylphenoxy)nicotinamide 294 6-(4-butylphenoxy)-N-methylnicotinamide 295 N-methyl-6-(4-pentylphenoxy)nicotinamide 296 6-(4-Hexylphenoxy)-N-methylnicotinamide 297 6-(4-Isopropylphenoxy)-N-methylnicotinamide 298 N-methyl-6-(4-(tert-pentyl)phenoxy)nicotinamide 299 N-methyl-6-(4-(pentan-3-yl)phenoxy)nicotinamide 300 N-methyl-6-(4-(trifluoromethyl)phenoxy)nicotinamide 301 N-methyl-6-(4-(perfluoroethyl)phenoxy)nicotinamide 302 N-methyl-6-(4-(perfluoropropyl)phenoxy)nicotinamide 303 N-methyl-6-(4-(perfluorobutyl)phenoxy)nicotinamide 304 6-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)-N-methylnicotinamide 305 N-methyl-6-(4-(perfluoropropan-2-yl)phenoxy)nicotinamide 306 6-(4-Cyclopropylphenoxy)-N-methylnicotinamide 307 6-(4-Cyclobutylphenoxy)-N-methylnicotinamide 308 6-(4-Cyclopentylphenoxy)-N-methylnicotinamide 309 6-(4-Cyclohexylphenoxy)-N-methylnicotinamide 310 6-(4-cycloheptylphenoxy)-N-methylnicotinamide 311 6-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)-N-methylnicotinamide 312 6-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)-N-methylnicotinamide 313 6-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-N-methylnicotinamide 314 6-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)-N-methylnicotinamide 315 N-methyl-6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)nicotinamide 316 N,N-Dimethyl-6-(p-tolyloxy)nicotinamide 317 6-(4-Ethylphenoxy)-N,N-dimethylnicotinate 318 N,N-Dimethyl-6-(4-propylphenoxy)nicotinamide 319 6-(4-butylphenoxy)-N,N-dimethylnicotinate 320 N,N-Dimethyl-6-(4-pentylphenoxy)nicotinamide 321 6-(4-hexylphenoxy)-N,N-dimethylnicotinate 322 6-(4-Isopropylphenoxy)-N,N-dimethylnicotinate 323 N,N-Dimethyl-6-(4-(tert-pentyl)phenoxy)nicotinamide 324 N,N-Dimethyl-6-(4-(pentan-3-yl)phenoxy)nicotinamide 325 N,N-Dimethyl-6-(4-(trifluoromethyl)phenoxy)nicotinamide 326 N,N-Dimethyl-6-(4-(perfluoroethyl)phenoxy)nicotinamide 327 N,N-Dimethyl-6-(4-(perfluoropropyl)phenoxy)nicotinamide 328 N,N-Dimethyl-6-(4-(perfluorobutyl)phenoxy)nicotinamide 329 6-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)-N,N-dimethylnicotinamide 330 N,N-Dimethyl-6-(4-(perfluoropropan-2-yl)phenoxy)nicotinamide 331 6-(4-Cyclopropylphenoxy)-N,N-dimethylnicotinamide 332 6-(4-Cyclobutylphenoxy)-N,N-dimethylnicotinamide 333 6-(4-Cyclopentylphenoxy)-N,N-dimethylnicotinamide 334 6-(4-Cyclohexylphenoxy)-N,N-dimethylnicotinamide 335 6-(4-Cycloheptylphenoxy)-N,N-dimethylnicotinamide 336 6-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)-N,N-dimethylnicotinamide 337 6-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)-N,N-dimethylnicotinamide 338 6-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-N,N-dimethylnicotinamide 339 6-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)-N,N-dimethylnicotinamide 340 N,N-Dimethyl-6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)nicotinamide

[0025] Also included are isomers, for example enantiomers or diastereomers or rotamers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds named above.

[0026] A third aspect of the present invention relates to compounds of formula III and salts and solvates thereof: JPEG0007807487000015.jpg4383(III) where X and R 1 and R 2 is as defined in formula I, and R 1 and R 2 This includes the preferred definition of

[0027] In some embodiments, the following compounds shown in Table IIIa are explicitly excluded from the scope of the present invention: JPEG0007807487000016.jpg47166

[0028] Specific examples of compounds falling within the scope of Formula III are shown in Table IIIb. The compounds in Table IIIb are defined by their chemical structure and the nomenclature shown is for illustrative purposes only. Table IIIb: JPEG0007807487000017.jpg241166JPEG0007807487000018.jpg225166JPEG0007807487000019.jpg216166JPEG0007807487000020.jpg239166JPEG0007807487000021.jpg254130341 3-Fluoro-4-(p-tolyloxy)benzoic acid 342 4-(4-Ethylphenoxy)-3-fluorobenzoic acid 343 3-Fluoro-4-(4-propylphenoxy)benzoic acid 344 4-(4-butylphenoxy)-3-fluorobenzoic acid 345 3-Fluoro-4-(4-pentylphenoxy)benzoic acid 346 3-Fluoro-4-(4-hexylphenoxy)benzoic acid 347 3-Fluoro-4-(4-isopropylphenoxy)benzoic acid 348 3-Fluoro-4-(4-(tert-pentyl)phenoxy)benzoic acid 349 3-Fluoro-4-(4-(pentan-3-yl)phenoxy)benzoic acid 350 3-Fluoro-4-(4-(trifluoromethyl)phenoxy)benzoic acid 351 3-Fluoro-4-(4-(perfluoroethyl)phenoxy)benzoic acid 352 3-Fluoro-4-(4-(perfluoropropyl)phenoxy)benzoic acid 353 3-Fluoro-4-(4-(perfluorobutyl)phenoxy)benzoic acid 354 3-Fluoro-4-(4-(1,1,1,3,3,3-hexafluoropentan-2-yl)phenoxy)benzoic acid 355 3-Fluoro-4-(4-(perfluoropropan-2-yl)phenoxy)benzoic acid 356 4-(4-Cyclopropylphenoxy)-3-fluorobenzoic acid 357 4-(4-Cyclobutylphenoxy)-3-fluorobenzoic acid 358 4-(4-Cyclopentylphenoxy)-3-fluorobenzoic acid 359 4-(4-Cyclohexylphenoxy)-3-fluorobenzoic acid 360 4-(4-Cycloheptylphenoxy)-3-fluorobenzoic acid 361 4-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)-3-fluorobenzoic acid 362 4-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)-3-fluorobenzoic acid 363 4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-3-fluorobenzoic acid 364 4-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)-3-fluorobenzoic acid 365 3-Fluoro-4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)benzoic acid 366 Methyl 3-fluoro-4-(p-tolyloxy)benzoate 367 Methyl 4-(4-ethylphenoxy)-3-fluorobenzoate 368 Methyl 3-fluoro-4-(4-propylphenoxy)benzoate 369 Methyl 4-(4-butylphenoxy)-3-fluorobenzoate 370 Methyl 3-fluoro-4-(4-pentylphenoxy)benzoate 371 Methyl 3-fluoro-4-(4-hexylphenoxy)benzoate 372 Methyl 3-fluoro-4-(4-isopropylphenoxy)benzoate 373 Methyl 4-(4-(tert-butyl)phenoxy)-3-fluorobenzoate 374 Methyl 3-fluoro-4-(4-(tert-pentyl)phenoxy)benzoate 375 Methyl 3-fluoro-4-(4-(pentan-3-yl)phenoxy)benzoate 376 Methyl 3-fluoro-4-(4-(trifluoromethyl)phenoxy)benzoate 377 Methyl 3-fluoro-4-(4-(perfluoroethyl)phenoxy)benzoate 378 Methyl 3-fluoro-4-(4-(perfluoropropyl)phenoxy)benzoate 379 Methyl 3-fluoro-4-(4-(perfluorobutyl)phenoxy)benzoate 380 Methyl 3-fluoro-4-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)benzoate 381 Methyl 3-fluoro-4-(4-(perfluoropropan-2-yl)phenoxy)benzoate 382 Methyl 4-(4-cyclopropylphenoxy)-3-fluorobenzoate 383 Methyl 4-(4-cyclobutylphenoxy)-3-fluorobenzoate 384 Methyl 4-(4-cyclopentylphenoxy)-3-fluorobenzoate 385 Methyl 4-(4-cyclohexylphenoxy)-3-fluorobenzoate 386 Methyl 4-(4-cycloheptylphenoxy)-3-fluorobenzoate 387 Methyl 4-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)-3-fluorobenzoate 388 Methyl 4-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)-3-fluorobenzoate 389 Methyl 4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-3-fluorobenzoate 390 Methyl 4-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)-3-fluorobenzoate 391 Methyl 3-fluoro-4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)benzoate 392 Ethyl 3-fluoro-4-(p-tolyloxy)benzoate 393 Ethyl 4-(4-ethylphenoxy)-3-fluorobenzoate 394 Ethyl 3-fluoro-4-(4-propylphenoxy)benzoate 395 Ethyl 4-(4-butylphenoxy)-3-fluorobenzoate 396 Ethyl 3-fluoro-4-(4-pentylphenoxy)benzoate 397 Ethyl 3-fluoro-4-(4-hexylphenoxy)benzoate 398 Ethyl 3-fluoro-4-(4-isopropylphenoxy)benzoate 399 Ethyl 3-fluoro-4-(4-(tert-pentyl)phenoxy)benzoate 400 Ethyl 3-fluoro-4-(4-(pentan-3-yl)phenoxy)benzoate 401 Ethyl 3-fluoro-4-(4-(trifluoromethyl)phenoxy)benzoate 402 Ethyl 3-fluoro-4-(4-(perfluoroethyl)phenoxy)benzoate 403 Ethyl 3-fluoro-4-(4-(perfluoropropyl)phenoxy)benzoate 404 Ethyl 3-fluoro-4-(4-(perfluorobutyl)phenoxy)benzoate 405 Ethyl 3-fluoro-4-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)benzoate 406 Ethyl 3-fluoro-4-(4-(perfluoropropan-2-yl)phenoxy)benzoate 407 Ethyl 4-(4-cyclopropylphenoxy)-3-fluorobenzoate 408 Ethyl 4-(4-cyclobutylphenoxy)-3-fluorobenzoate 409 Ethyl 4-(4-cyclopentylphenoxy)-3-fluorobenzoate 410 Ethyl 4-(4-cyclohexylphenoxy)-3-fluorobenzoate 411 Ethyl 4-(4-cycloheptylphenoxy)-3-fluorobenzoate 412 Ethyl 4-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)-3-fluorobenzoate 413 Ethyl 4-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)-3-fluorobenzoate 414 Ethyl 4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-3-fluorobenzoate 415 Ethyl 4-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)-3-fluorobenzoate 416 Ethyl 3-fluoro-4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)benzoate 417 5-Fluoro-6-(p-tolyloxy)nicotinic acid 418 6-(4-Ethylphenoxy)-5-fluoronicotinic acid 419 5-Fluoro-6-(4-propylphenoxy)nicotinic acid 420 6-(4-butylphenoxy)-5-fluoronicotinic acid 421 5-Fluoro-6-(4-pentylphenoxy)nicotinic acid 422 5-Fluoro-6-(4-hexylphenoxy)nicotinic acid 423 5-Fluoro-6-(4-isopropylphenoxy)nicotinic acid 424 6-(4-(tert-butyl)phenoxy)-5-fluoronicotinic acid 425 5-Fluoro-6-(4-(tert-pentyl)phenoxy)nicotinic acid 426 5-Fluoro-6-(4-(pentan-3-yl)phenoxy)nicotinic acid 427 5-Fluoro-6-(4-(trifluoromethyl)phenoxy)nicotinic acid 428 5-Fluoro-6-(4-(perfluoroethyl)phenoxy)nicotinic acid 429 5-Fluoro-6-(4-(perfluoropropyl)phenoxy)nicotinic acid 430 5-Fluoro-6-(4-(perfluorobutyl)phenoxy)nicotinic acid 431 5-Fluoro-6-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)nicotinic acid 432 5-Fluoro-6-(4-(perfluoropropan-2-yl)phenoxy)nicotinic acid 433 6-(4-Cyclopropylphenoxy)-5-fluoronicotinic acid 434 6-(4-Cyclobutylphenoxy)-5-fluoronicotinic acid 435 6-(4-Cyclopentylphenoxy)-5-fluoronicotinic acid 436 6-(4-Cyclohexylphenoxy)-5-fluoronicotinic acid 437 6-(4-Cycloheptylphenoxy)-5-fluoronicotinic acid 438 6-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)-5-fluoronicotinic acid 439 6-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)-5-fluoronicotinic acid 440 6-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-5-fluoronicotinic acid 441 6-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)-5-fluoronicotinic acid 442 5-Fluoro-6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)nicotinic acid 443 Methyl 5-fluoro-6-(p-tolyloxy)nicotinate 444 Methyl 6-(4-ethylphenoxy)-5-fluoronicotinate 445 Methyl 5-fluoro-6-(4-propylphenoxy)nicotinate 446 Methyl 6-(4-butylphenoxy)-5-fluoronicotinate 447 Methyl 5-fluoro-6-(4-pentylphenoxy)nicotinate 448 Methyl 5-fluoro-6-(4-hexylphenoxy)nicotinate 449 Methyl 5-fluoro-6-(4-isopropylphenoxy)nicotinate 450 Methyl 6-(4-(tert-butyl)phenoxy)-5-fluoronicotinate 451 Methyl 5-fluoro-6-(4-(tert-pentyl)phenoxy)nicotinate 452 Methyl 5-fluoro-6-(4-(pentan-3-yl)phenoxy)nicotinate 453 Methyl 5-fluoro-6-(4-(trifluoromethyl)phenoxy)nicotinate 454 Methyl 5-fluoro-6-(4-(perfluoroethyl)phenoxy)nicotinate 455 Methyl 5-fluoro-6-(4-(perfluoropropyl)phenoxy)nicotinate 456 Methyl 5-fluoro-6-(4-(perfluorobutyl)phenoxy)nicotinate 457 Methyl 5-fluoro-6-(4-(1,1,1,3,3,3-hexafluoropentan-2-yl)phenoxy)nicotinate 458 Methyl 5-fluoro-6-(4-(perfluoropropan-2-yl)phenoxy)nicotinate 459 Methyl 6-(4-cyclopropylphenoxy)-5-fluoronicotinate 460 Methyl 6-(4-cyclobutylphenoxy)-5-fluoronicotinate 461 Methyl 6-(4-cyclopentylphenoxy)-5-fluoronicotinate 462 Methyl 6-(4-cyclohexylphenoxy)-5-fluoronicotinate 463 Methyl 6-(4-cycloheptylphenoxy)-5-fluoronicotinate 464 Methyl 6-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)-5-fluoronicotinate 465 Methyl 6-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)-5-fluoronicotinate 466 Methyl 6-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-5-fluoronicotinate 467 Methyl 6-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)-5-fluoronicotinate 468 Methyl 5-fluoro-6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)nicotinate 469 Ethyl 5-fluoro-6-(p-tolyloxy)nicotinate 470 Ethyl 6-(4-ethylphenoxy)-5-fluoronicotinate 471 Ethyl 5-fluoro-6-(4-propylphenoxy)nicotinate 472 Ethyl 6-(4-butylphenoxy)-5-fluoronicotinate 473 Ethyl 5-fluoro-6-(4-pentylphenoxy)nicotinate 474 Ethyl 5-fluoro-6-(4-hexylphenoxy)nicotinate 475 Ethyl 5-fluoro-6-(4-isopropylphenoxy)nicotinate 476 Ethyl 6-(4-(tert-butyl)phenoxy)-5-fluoronicotinate 477 Ethyl 5-fluoro-6-(4-(tert-pentyl)phenoxy)nicotinate 478 Ethyl 5-fluoro-6-(4-(pentan-3-yl)phenoxy)nicotinate 479 Ethyl 5-fluoro-6-(4-(trifluoromethyl)phenoxy)nicotinate 480 Ethyl 5-fluoro-6-(4-(perfluoroethyl)phenoxy)nicotinate 481 Ethyl 5-fluoro-6-(4-(perfluoropropyl)phenoxy)nicotinate 482 Ethyl 5-fluoro-6-(4-(perfluorobutyl)phenoxy)nicotinate 483 Ethyl 5-fluoro-6-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)nicotinate 484 Ethyl 5-fluoro-6-(4-(perfluoropropan-2-yl)phenoxy)nicotinate 485 Ethyl 6-(4-cyclopropylphenoxy)-5-fluoronicotinate 486 Ethyl 6-(4-cyclobutylphenoxy)-5-fluoronicotinate 487 Ethyl 6-(4-cyclopentylphenoxy)-5-fluoronicotinate 488 Ethyl 6-(4-cyclohexylphenoxy)-5-fluoronicotinate 489 Ethyl 6-(4-cycloheptylphenoxy)-5-fluoronicotinate 490 Ethyl 6-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)-5-fluoronicotinate 491 Ethyl 6-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)-5-fluoronicotinate 492 Ethyl 6-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-5-fluoronicotinate 493 Ethyl 6-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)-5-fluoronicotinate 494 Ethyl 5-fluoro-6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)nicotinate

[0029] Also included are isomers, such as enantiomers or diastereomers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds named above.

[0030] A fourth aspect of the present invention relates to compounds of formula IV and salts and solvates thereof: JPEG0007807487000022.jpg4083(IV) where X and R 1 is as defined in formula I, and R 1 including the preferred definition of and R 3 and R 4 is as defined in formula II, and R 3 and R 4 This includes the preferred definition of

[0031] Specific examples of compounds falling within the scope of Formula IV are shown in Table IV. The compounds in Table IV are defined by their chemical structure and the nomenclature shown is for illustrative purposes only. Table IV: JPEG0007807487000023.jpg233166JPEG0007807487000024.jpg218166JPEG0007807487000025.jpg221166 JPEG0007807487000026.jpg232166JPEG0007807487000027.jpg216166JPEG0007807487000028.jpg222166 495 3-Fluoro-4-(p-tolyloxy)benzamide 496 4-(4-ethylphenoxy)-3-fluorobenzamide 497 3-Fluoro-4-(4-propylphenoxy)benzamide 498 4-(4-butylphenoxy)-3-fluorobenzamide 499 3-Fluoro-4-(4-pentylphenoxy)benzamide 500 3-fluoro-4-(4-hexylphenoxy)benzamide 501 3-Fluoro-4-(4-isopropylphenoxy)benzamide 502 4-(4-(tert-butyl)phenoxy)-3-fluorobenzamide 503 3-Fluoro-4-(4-(tert-pentyl)phenoxy)benzamide 504 3-Fluoro-4-(4-(pentan-3-yl)phenoxy)benzamide 505 3-Fluoro-4-(4-(trifluoromethyl)phenoxy)benzamide 506 3-Fluoro-4-(4-(perfluoroethyl)phenoxy)benzamide 507 3-Fluoro-4-(4-(perfluoropropyl)phenoxy)benzamide 508 3-Fluoro-4-(4-(perfluorobutyl)phenoxy)benzamide 509 3-Fluoro-4-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)benzamide 510 3-Fluoro-4-(4-(perfluoropropan-2-yl)phenoxy)benzamide 511 4-(4-cyclopropylphenoxy)-3-fluorobenzamide 512 4-(4-cyclobutylphenoxy)-3-fluorobenzamide 513 4-(4-Cyclopentylphenoxy)-3-fluorobenzamide 514 4-(4-Cyclohexylphenoxy)-3-fluorobenzamide 515 4-(4-cycloheptylphenoxy)-3-fluorobenzamide 516 4-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)-3-fluorobenzamide 517 4-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)-3-fluorobenzamide 518 4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-3-fluorobenzamide 519 4-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)-3-fluorobenzamide 520 3-Fluoro-4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)benzamide 521 3-Fluoro-N-hydroxy-4-(p-tolyloxy)benzamide 522 4-(4-ethylphenoxy)-3-fluoro-N-hydroxybenzamide 523 3-Fluoro-N-hydroxy-4-(4-propylphenoxy)benzamide 524 4-(4-butylphenoxy)-3-fluoro-N-hydroxybenzamide 525 3-Fluoro-N-hydroxy-4-(4-pentylphenoxy)benzamide 526 3-Fluoro-4-(4-hexylphenoxy)-N-hydroxybenzamide 527 3-Fluoro-N-hydroxy-4-(4-isopropylphenoxy)benzamide 528 4-(4-(tert-butyl)phenoxy)-3-fluoro-N-hydroxybenzamide 529 3-Fluoro-N-hydroxy-4-(4-(tert-pentyl)phenoxy)benzamide 530 3-Fluoro-N-hydroxy-4-(4-(pentan-3-yl)phenoxy)benzamide 531 3-Fluoro-N-hydroxy-4-(4-(trifluoromethyl)phenoxy)benzamide 532 3-Fluoro-N-hydroxy-4-(4-(perfluoroethyl)phenoxy)benzamide 533 3-Fluoro-N-hydroxy-4-(4-(perfluoropropyl)phenoxy)benzamide 534 3-Fluoro-N-hydroxy-4-(4-(perfluorobutyl)phenoxy)benzamide 535 3-Fluoro-4-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)-N-hydroxybenzamide 536 3-Fluoro-N-hydroxy-4-(4-(perfluoropropan-2-yl)phenoxy)benzamide 537 4-(4-cyclopropylphenoxy)-3-fluoro-N-hydroxybenzamide 538 4-(4-Cyclobutylphenoxy)-3-fluoro-N-hydroxybenzamide 539 4-(4-Cyclopentylphenoxy)-3-fluoro-N-hydroxybenzamide 540 4-(4-cyclohexylphenoxy)-3-fluoro-N-hydroxybenzamide 541 4-(4-cycloheptylphenoxy)-3-fluoro-N-hydroxybenzamide 542 4-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)-3-fluoro-N-hydroxybenzamide 543 4-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)-3-fluoro-N-hydroxybenzamide 544 4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-3-fluoro-N-hydroxybenzamide 545 4-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)-3-fluoro-N-hydroxybenzamide 546 3-Fluoro-N-hydroxy-4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)benzamide 547 3-Fluoro-N-methyl-4-(p-tolyloxy)benzamide 548 4-(4-ethylphenoxy)-3-fluoro-N-methylbenzamide 549 3-Fluoro-N-methyl-4-(4-propylphenoxy)benzamide 550 4-(4-butylphenoxy)-3-fluoro-N-methylbenzamide 551 3-Fluoro-N-methyl-4-(4-pentylphenoxy)benzamide 552 3-Fluoro-4-(4-hexylphenoxy)-N-methylbenzamide 553 3-Fluoro-4-(4-isopropylphenoxy)-N-methylbenzamide 554 4-(4-(tert-butyl)phenoxy)-3-fluoro-N-methylbenzamide 555 3-Fluoro-N-methyl-4-(4-(tert-pentyl)phenoxy)benzamide 556 3-Fluoro-N-methyl-4-(4-(pentan-3-yl)phenoxy)benzamide 557 3-Fluoro-N-methyl-4-(4-(trifluoromethyl)phenoxy)benzamide 558 3-Fluoro-N-methyl-4-(4-(perfluoroethyl)phenoxy)benzamide 559 3-Fluoro-N-methyl-4-(4-(perfluoropropyl)phenoxy)benzamide 560 3-Fluoro-N-methyl-4-(4-(perfluorobutyl)phenoxy)benzamide 561 3-Fluoro-4-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)-N-methylbenzamide 562 3-Fluoro-N-methyl-4-(4-(perfluoropropan-2-yl)phenoxy)benzamide 563 4-(4-cyclopropylphenoxy)-3-fluoro-N-methylbenzamide 564 4-(4-cyclobutylphenoxy)-3-fluoro-N-methylbenzamide 565 4-(4-Cyclopentylphenoxy)-3-fluoro-N-methylbenzamide 566 4-(4-cyclohexylphenoxy)-3-fluoro-N-methylbenzamide 567 4-(4-cycloheptylphenoxy)-3-fluoro-N-methylbenzamide 568 4-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)-3-fluoro-N-methylbenzamide 569 4-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)-3-fluoro-N-methylbenzamide 570 4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-3-fluoro-N-methylbenzamide 571 4-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)-3-fluoro-N-methylbenzamide 572 3-Fluoro-N-methyl-4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)benzamide 573 3-Fluoro-N,N-dimethyl-4-(p-tolyloxy)benzamide 574 4-(4-ethylphenoxy)-3-fluoro-N,N-dimethylbenzamide 575 3-Fluoro-N,N-dimethyl-4-(4-propylphenoxy)benzamide 576 4-(4-butylphenoxy)-3-fluoro-N,N-dimethylbenzamide 577 3-Fluoro-N,N-dimethyl-4-(4-pentylphenoxy)benzamide 578 3-Fluoro-4-(4-hexylphenoxy)-N,N-dimethylbenzamide 579 3-Fluoro-4-(4-isopropylphenoxy)-N,N-dimethylbenzamide 580 4-(4-(tert-butyl)phenoxy)-3-fluoro-N,N-dimethylbenzamide 581 3-Fluoro-N,N-dimethyl-4-(4-(tert-pentyl)phenoxy)benzamide 582 3-Fluoro-N,N-dimethyl-4-(4-(pentan-3-yl)phenoxy)benzamide 583 3-Fluoro-N,N-dimethyl-4-(4-(trifluoromethyl)phenoxy)benzamide 584 3-Fluoro-N,N-dimethyl-4-(4-(perfluoroethyl)phenoxy)benzamide 585 3-Fluoro-N,N-dimethyl-4-(4-(perfluoropropyl)phenoxy)benzamide 586 3-Fluoro-N,N-dimethyl-4-(4-(perfluorobutyl)phenoxy)benzamide 587 3-Fluoro-4-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)-N,N-dimethylbenzamide 588 3-Fluoro-N,N-dimethyl-4-(4-(perfluoropropan-2-yl)phenoxy)benzamide 589 4-(4-cyclopropylphenoxy)-3-fluoro-N,N-dimethylbenzamide 590 4-(4-cyclobutylphenoxy)-3-fluoro-N,N-dimethylbenzamide 591 4-(4-cyclopentylphenoxy)-3-fluoro-N,N-dimethylbenzamide 592 4-(4-cyclohexylphenoxy)-3-fluoro-N,N-dimethylbenzamide 593 4-(4-cycloheptylphenoxy)-3-fluoro-N,N-dimethylbenzamide 594 4-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)-3-fluoro-N,N-dimethylbenzamide 595 4-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)-3-fluoro-N,N-dimethylbenzamide 596 4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-3-fluoro-N,N-dimethylbenzamide 597 4-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)-3-fluoro-N,N-dimethylbenzamide 598 3-Fluoro-N,N-dimethyl-4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)benzamide 599 5-Fluoro-6-(p-tolyloxy)nicotinamide 600 6-(4-ethylphenoxy)-5-fluoronicotinamide 601 5-Fluoro-6-(4-propylphenoxy)nicotinamide 602 6-(4-butylphenoxy)-5-fluoronicotinamide 603 5-Fluoro-6-(4-pentylphenoxy)nicotinamide 604 5-Fluoro-6-(4-hexylphenoxy)nicotinamide 605 5-Fluoro-6-(4-isopropylphenoxy)nicotinamide 606 6-(4-(tert-butyl)phenoxy)-5-fluoronicotinamide 607 5-Fluoro-6-(4-(tert-pentyl)phenoxy)nicotinamide 608 5-Fluoro-6-(4-(pentan-3-yl)phenoxy)nicotinamide 609 5-Fluoro-6-(4-(trifluoromethyl)phenoxy)nicotinamide 610 5-Fluoro-6-(4-(perfluoroethyl)phenoxy)nicotinamide 611 5-Fluoro-6-(4-(perfluoropropyl)phenoxy)nicotinamide 612 5-Fluoro-6-(4-(perfluorobutyl)phenoxy)nicotinamide 613 5-Fluoro-6-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)nicotinamide 614 5-Fluoro-6-(4-(perfluoropropan-2-yl)phenoxy)nicotinamide 615 6-(4-cyclopropylphenoxy)-5-fluoronicotinamide 616 6-(4-Cyclobutylphenoxy)-5-fluoronicotinamide 617 6-(4-Cyclopentylphenoxy)-5-fluoronicotinamide 618 6-(4-Cyclohexylphenoxy)-5-fluoronicotinamide 619 6-(4-Cycloheptylphenoxy)-5-fluoronicotinamide 620 6-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)-5-fluoronicotinamide 621 6-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)-5-fluoronicotinamide 622 6-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-5-fluoronicotinamide 623 6-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)-5-fluoronicotinamide 624 5-Fluoro-6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)nicotinamide 625 5-Fluoro-N-hydroxy-6-(p-tolyloxy)nicotinamide 626 6-(4-ethylphenoxy)-5-fluoro-N-hydroxynicotinamide 627 5-Fluoro-N-hydroxy-6-(4-propylphenoxy)nicotinamide 628 6-(4-butylphenoxy)-5-fluoro-N-hydroxynicotinamide 629 5-Fluoro-N-hydroxy-6-(4-pentylphenoxy)nicotinamide 630 5-Fluoro-6-(4-hexylphenoxy)-N-hydroxynicotinamide 631 5-Fluoro-N-hydroxy-6-(4-isopropylphenoxy)nicotinamide 632 6-(4-(tert-butyl)phenoxy)-5-fluoro-N-hydroxynicotinamide 633 634 5-Fluoro-N-hydroxy-6-(4-(pentan-3-yl)phenoxy)nicotinamide 635 5-Fluoro-N-hydroxy-6-(4-(trifluoromethyl)phenoxy)nicotinamide 636 5-Fluoro-N-hydroxy-6-(4-(perfluoroethyl)phenoxy)nicotinamide 637 5-Fluoro-N-hydroxy-6-(4-(perfluoropropyl)phenoxy)nicotinamide 638 5-Fluoro-N-hydroxy-6-(4-(perfluorobutyl)phenoxy)nicotinamide 639 5-Fluoro-6-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)-N-hydroxynicotinamide 640 5-Fluoro-N-hydroxy-6-(4-(perfluoropropan-2-yl)phenoxy)nicotinamide 641 6-(4-cyclopropylphenoxy)-5-fluoro-N-hydroxynicotinamide 642 6-(4-cyclobutylphenoxy)-5-fluoro-N-hydroxynicotinamide 643 6-(4-Cyclopentylphenoxy)-5-fluoro-N-hydroxynicotinamide 644 6-(4-cyclohexylphenoxy)-5-fluoro-N-hydroxynicotinamide 645 6-(4-cycloheptylphenoxy)-5-fluoro-N-hydroxynicotinamide 646 6-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)-5-fluoro-N-hydroxynicotinamide 647 6-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)-5-fluoro-N-hydroxynicotinamide 648 6-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-5-fluoro-N-hydroxynicotinamide 649 6-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)-5-fluoro-N-hydroxynicotinamide 650 5-Fluoro-N-hydroxy-6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)nicotinamide 651 5-Fluoro-N-methyl-6-(p-tolyloxy)nicotinamide 652 6-(4-ethylphenoxy)-5-fluoro-N-methylnicotinamide 653 5-Fluoro-N-methyl-6-(4-propylphenoxy)nicotinamide 654 6-(4-butylphenoxy)-5-fluoro-N-methylnicotinamide 655 5-Fluoro-N-methyl-6-(4-pentylphenoxy)nicotinamide 656 5-Fluoro-6-(4-hexylphenoxy)-N-methylnicotinamide 657 5-Fluoro-6-(4-isopropylphenoxy)-N-methylnicotinamide 658 6-(4-(tert-butyl)phenoxy)-5-fluoro-N-methylnicotinamide 659 5-Fluoro-N-methyl-6-(4-(tert-pentyl)phenoxy)nicotinamide 660 5-Fluoro-N-methyl-6-(4-(pentan-3-yl)phenoxy)nicotinamide 661 5-Fluoro-N-methyl-6-(4-(trifluoromethyl)phenoxy)nicotinamide 662 5-Fluoro-N-methyl-6-(4-(perfluoroethyl)phenoxy)nicotinamide 663 5-Fluoro-N-methyl-6-(4-(perfluoropropyl)phenoxy)nicotinamide 664 5-Fluoro-N-methyl-6-(4-(perfluorobutyl)phenoxy)nicotinamide 665 5-Fluoro-6-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)-N-methylnicotinamide 666 5-Fluoro-N-methyl-6-(4-(perfluoropropan-2-yl)phenoxy)nicotinamide 667 6-(4-cyclopropylphenoxy)-5-fluoro-N-methylnicotinamide 668 6-(4-cyclobutylphenoxy)-5-fluoro-N-methylnicotinamide 669 6-(4-Cyclopentylphenoxy)-5-fluoro-N-methylnicotinamide 670 6-(4-cyclohexylphenoxy)-5-fluoro-N-methylnicotinamide 671 6-(4-cycloheptylphenoxy)-5-fluoro-N-methylnicotinamide 672 6-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)-5-fluoro-N-methylnicotinamide 673 6-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)-5-fluoro-N-methylnicotinamide 674 6-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-5-fluoro-N-methylnicotinamide 675 6-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)-5-fluoro-N-methylnicotinamide 676 5-Fluoro-N-methyl-6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)nicotinamide 677 5-Fluoro-N,N-dimethyl-6-(p-tolyloxy)nicotinamide 678 6-(4-ethylphenoxy)-5-fluoro-N,N-dimethylnicotinamide 679 5-Fluoro-N,N-dimethyl-6-(4-propylphenoxy)nicotinamide 680 6-(4-butylphenoxy)-5-fluoro-N,N-dimethylnicotinamide 681 5-Fluoro-N,N-dimethyl-6-(4-pentylphenoxy)nicotinamide 682 5-Fluoro-6-(4-hexylphenoxy)-N,N-dimethylnicotinamide 683 5-Fluoro-6-(4-isopropylphenoxy)-N,N-dimethylnicotinamide 684 6-(4-(tert-butyl)phenoxy)-5-fluoro-N,N-dimethylnicotinamide 685 5-Fluoro-N,N-dimethyl-6-(4-(tert-pentyl)phenoxy)nicotinamide 686 5-Fluoro-N,N-dimethyl-6-(4-(pentan-3-yl)phenoxy)nicotinamide 687 5-Fluoro-N,N-dimethyl-6-(4-(trifluoromethyl)phenoxy)nicotinamide 688 5-Fluoro-N,N-dimethyl-6-(4-(perfluoroethyl)phenoxy)nicotinamide 689 5-Fluoro-N,N-dimethyl-6-(4-(perfluoropropyl)phenoxy)nicotinamide 690 5-Fluoro-N,N-dimethyl-6-(4-(perfluorobutyl)phenoxy)nicotinamide 691 5-Fluoro-6-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy)-N,N-dimethylnicotinamide 692 5-Fluoro-N,N-dimethyl-6-(4-(perfluoropropan-2-yl)phenoxy)nicotinamide 693 6-(4-cyclopropylphenoxy)-5-fluoro-N,N-dimethylnicotinamide 694 6-(4-cyclobutylphenoxy)-5-fluoro-N,N-dimethylnicotinamide 695 6-(4-Cyclopentylphenoxy)-5-fluoro-N,N-dimethylnicotinamide 696 6-(4-cyclohexylphenoxy)-5-fluoro-N,N-dimethylnicotinamide 697 6-(4-cycloheptylphenoxy)-5-fluoro-N,N-dimethylnicotinamide 698 6-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)phenoxy)-5-fluoro-N,N-dimethylnicotinamide 699 6-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl)phenoxy)-5-fluoro-N,N-dimethylnicotinamide 700 6-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-5-fluoro-N,N-dimethylnicotinamide 701 6-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)-5-fluoro-N,N-dimethylnicotinamide 702 5-Fluoro-N,N-dimethyl-6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl)phenoxy)nicotinamide

[0032] Also included are isomers, for example enantiomers or diastereomers or rotamers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds named above.

[0033] A fifth aspect of the present invention relates to compounds of formula V and salts and solvates thereof: JPEG0007807487000029.jpg4983(V) where n=0 to 5, including cyclopropyl (n=0), cyclobutyl (n=1), cyclopentyl (n=2), cyclohexyl (n=3), cycloheptyl (n=4), and cyclooctyl (n=5); wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups may be unsubstituted or substituted by one or more substituents independently selected from, among others: -F, -Cl, -Br, -I, -CN, -NCO, -NCS; and C1-C3 alkyl, such as -CH3, which may optionally be halogenated or perhalogenated, in particular perfluorinated, such as -CF3; and O-C1-C3 alkyl, which may optionally be halogenated or perhalogenated, in particular perfluorinated; wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups may be perhalogenated, in particular perfluorinated; and wherein n is preferably 0 so as to constitute cyclopropyl, in particular unsubstituted cyclopropyl; R 5 is C1-C 12 , preferably C1-C6 alkyl, C2-C 12 Preferably C2-C6 alkenyl, C2-C 12 Preferably, it is C2-C6 alkynyl, C3-C8 cycloalkyl, or C3-C8 cycloalkenyl; wherein all alkyl, alkenyl and alkynyl residues may be linear or branched and may be perhalogenated, in particular perfluorinated. and wherein all cycloalkyl and cycloalkenyl residues are perhalogenated, in particular perfluorinated; or where all alkyl, alkenyl and alkynyl residues may be linear or branched and may be unsubstituted or substituted by one or more substituents independently selected from, in particular: -F, -Cl, -Br, -I, -CN, -NCO, -NCS; and O-C-C alkyl, which may optionally be halogenated or perhalogenated, in particular perfluorinated; and wherein all cycloalkyl and cycloalkenyl residues may be unsubstituted or substituted by one or more substituents independently selected from, among others: -F, -Cl, -Br, -I, -CN, -NCO, -NCS; and C1-C3 alkyl, such as -CH3, which may optionally be halogenated or perhalogenated, in particular perfluorinated, such as -CF3; and O-C1-C3 alkyl, which may optionally be halogenated or perhalogenated, in particular perfluorinated; where R 5 is preferably -CF3 or -CF2CF3; R 6 -R 9are selected independently from one another from H, -F, -Cl, -Br, -I, linear or branched C1-C4 alkyl, linear or branched C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 cycloalkyl, and in which all alkyl, alkenyl, alkynyl and cycloalkyl residues may be unsubstituted or substituted by one or more substituents independently selected from, in particular: -F, -Cl, -Br, -I; and C1-C3 alkyl, such as -CH3, which may optionally be halogenated or perhalogenated, in particular perfluorinated, such as -CF3; and O-C1-C3 alkyl, which may optionally be halogenated or perhalogenated, in particular perfluorinated; where R 6 -R 8 are each preferably H, and R 9 is preferably —H, —F, —Cl, or —CH; Y is a six-membered aromatic ring selected from benzene, pyridine, pyrimidine, pyridazine, or pyrazine; where the benzene ring is unsubstituted or R 10 -R 13 substituted by 1 to 4 substituents independently selected from and wherein the pyridine ring is unsubstituted or R 10 -R 12 and wherein preferably the N atom of the pyridine ring is ortho to the ether bond; and wherein the pyrimidine ring is unsubstituted or R 10 -R 11 and wherein preferably the N atom of the pyrimidine ring is ortho to the ether bond, and wherein the pyridazine ring is unsubstituted or R 10 -R 11and wherein preferably the N atom of the pyridazine ring is ortho to the ether bond, and wherein the pyrazine ring is unsubstituted or R 10 -R 11 and wherein preferably the N atom of the pyrazine ring is ortho to the ether bond, Preferably, Y is benzene or pyridine, and R 10 -R 13 or R 10 -R 13 and wherein F at the carbon atom is ortho to the ether bond; R 10 -R 13 are selected independently from one another from -F, -Cl, -Br, -I, linear or branched C1-C4 alkyl, linear or branched C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 cycloalkyl, and in which all alkyl, alkenyl, alkynyl and cycloalkyl residues may be unsubstituted or substituted by one or more substituents independently selected from, in particular, -F, -Cl, -Br, -I; and C1-C3 alkyl, such as -CH3, which may optionally be halogenated or perhalogenated, in particular perfluorinated, such as -CF3; and O-C1-C3 alkyl, which may optionally be halogenated or perhalogenated, in particular perfluorinated; Z is O or S, preferably Z is O; R 14 is OR 2 or NR 3 R 4 and where R 2 is as defined in formula I, with R as H, methyl or ethyl 2 Contains the preferred definition of; where R 3 and R 4is as defined in formula II, with R as H or -CH 3 and R as H, OH or -CH 4 Contains the preferred definition of; In a particularly preferred embodiment of compounds of formula V, the present invention relates to compounds of formula Va and salts and solvates thereof: JPEG0007807487000030.jpg4583(Va) wherein n is as defined in formula V, including the preferred definition of n where n=0, so as to constitute cyclopropyl, particularly unsubstituted cyclopropyl. wherein Z is as defined in formula V, including the preferred definition of Z such that Z=O. where R 5 is as defined in formula V, and R 5 including all preferred definitions of R 6 -R 9 is as defined in formula V, and R 6 -R 9 including all preferred definitions of where R 14 is as defined in formula V, where X is N or CR 13 and and where R 10 -R 13are selected independently from one another from H, -F, -Cl, -Br, -I, linear or branched C-C alkyl, linear or branched C-C alkenyl, C-C alkynyl, C-C cycloalkyl, and in which all alkyl, alkenyl, alkynyl and cycloalkyl residues may be unsubstituted or substituted by one or more substituents independently selected from, in particular, -F, -Cl, -Br, -I; and C-C alkyl, such as -CH, which may optionally be halogenated or perhalogenated, in particular perfluorinated, such as -CF; and O-C alkyl, which may optionally be halogenated or perhalogenated, in particular perfluorinated.

[0034] Specific examples of compounds falling within the scope of Formula V are shown in Table V. The compounds in Table V are defined by their chemical structure and the nomenclature shown is for illustrative purposes only. Table V: JPEG0007807487000031.jpg174166JPEG0007807487000032.jpg172166JPEG0007807487000033.jpg176166JPEG0007807487000034.jpg169166JPEG0007807487000035.jpg254162703 4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoic acid 704 4-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzoic acid 705 3-Fluoro-4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoic acid 706 3-Fluoro-4-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzoic acid 707 4-(2-methyl-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoic acid 708 4-(2-methyl-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzoic acid 709 4-(2-fluoro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoic acid 710 4-(2-fluoro-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzoic acid 711 4-(2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoic acid 712 Methyl 4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoate 713 Methyl 4-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzoate 714 Methyl 3-fluoro-4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoate 715 Methyl 3-fluoro-4-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzoate 716 Methyl 4-(2-methyl-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoate 717 Methyl 4-(2-methyl-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzoate 718 Methyl 4-(2-fluoro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoate 719 Methyl 4-(2-fluoro-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzoate 720 Methyl 4-(2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoate 721 Ethyl 4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoate 722 Ethyl 4-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzoate 723 Ethyl 3-fluoro-4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoate 724 Ethyl 3-fluoro-4-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzoate 725 Ethyl 4-(2-methyl-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoate 726 Ethyl 4-(2-methyl-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzoate 727 Ethyl 4-(2-fluoro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoate 728 Ethyl 4-(2-fluoro-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzoate 729 Ethyl 4-(2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoate 730 6-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinic acid 731 6-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinic acid 732 5-Fluoro-6-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinic acid 733 5-Fluoro-6-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinic acid 734 6-(2-methyl-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinic acid 735 6-(2-methyl-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinic acid 736 6-(2-fluoro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinic acid 737 6-(2-fluoro-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinic acid 738 6-(2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinic acid 739 Methyl 6-(4-(1-trifluoromethyl)cyclopropyl)phenoxy)nicotinate 740 Methyl 6-(4-(1-perfluoroethyl)cyclopropyl)phenoxy)nicotinate 741 Methyl 5-fluoro-6-(4-(1-(trifluoromethyl)cyclopropyl)phenoxynicotinate 742 Methyl 5-fluoro-6-(4-(1-(perfluoroethyl)cyclopropyl)phenoxynicotinate 743 Methyl 6-(2-methyl-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinate 744 Methyl 6-(2-methyl-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinate 745 Methyl 6-(2-fluoro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinate 746 Methyl 6-(2-fluoro-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinate 747 Methyl 6-(2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinate 748 Ethyl 6-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinate 749 Ethyl 6-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinate 750 Ethyl 5-fluoro-6-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinate 751 Ethyl 5-fluoro-6-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinate 752 Ethyl 6-(2-methyl-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinate 753 Ethyl 6-(2-methyl-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinate 754 Ethyl 6-(2-fluoro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinate 755 Ethyl 6-(2-fluoro-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinate 756 Ethyl 6-(2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinate 757 4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzamide 758 4-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzamide 759 3-Fluoro-4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzamide 760 3-Fluoro-4-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzamide 761 4-(2-methyl-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzamide 762 4-(2-methyl-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzamide 763 4-(2-fluoro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzamide 764 4-(2-fluoro-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzamide 765 4-(2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzamide 766 N-Hydroxy-4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzamide 767 N-Hydroxy-4-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzamide 768 3-Fluoro-N-hydroxy-4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzamide 769 3-Fluoro-N-hydroxy-4-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzamide 770 N-Hydroxy-4-(2-methyl-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzamide 771 N-Hydroxy-4-(2-methyl-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzamide 772 4-(2-fluoro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-N-hydroxybenzamide 773 4-(2-fluoro-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)-N-hydroxybenzamide 774 4-(2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-N-hydroxybenzamide 775 N-methyl-4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzamide 776 N-methyl-4-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzamide 777 3-Fluoro-N-methyl-4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzamide 778 3-Fluoro-N-methyl-4-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzamide 779 N-methyl-4-(2-methyl-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzamide 780 N-methyl-4-(2-methyl-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzamide 781 4-(2-fluoro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-N-methylbenzamide 782 4-(2-fluoro-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)-N-methylbenzamide 783 4-(2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-N-methylbenzamide 784 N,N-Dimethyl-4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzamide 785 N,N-Dimethyl-4-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzamide 786 3-Fluoro-N,N-dimethyl-4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzamide 787 3-Fluoro-N,N-dimethyl-4-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzamide 788 N,N-Dimethyl-4-(2-methyl-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzamide 789 N,N-Dimethyl-4-(2-methyl-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzamide 790 4-(2-fluoro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-N,N-dimethylbenzamide 791 4-(2-fluoro-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)-N,N-dimethylbenzamide 792 4-(2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-N,N-dimethylbenzamide 793 6-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinamide 794 6-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinamide 795 5-Fluoro-6-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinamide 796 5-Fluoro-6-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinamide 797 6-(2-methyl-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinamide 798 6-(2-methyl-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinamide 799 6-(2-fluoro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinamide 800 6-(2-fluoro-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinamide 801 6-(2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinamide 802 N-Hydroxy-6-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinamide 803 N-Hydroxy-6-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinamide 804 5-Fluoro-N-hydroxy-6-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinamide 805 5-Fluoro-N-hydroxy-6-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinamide 806 N-Hydroxy-6-(2-methyl-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinamide 807 N-Hydroxy-6-(2-methyl-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinamide 808 6-(2-fluoro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-N-hydroxynicotinamide 809 6-(2-fluoro-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)-N-hydroxynicotinamide 810 6-(2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-N-hydroxynicotinamide 811 N-methyl-4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzamide 812 N-methyl-4-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzamide 813 3-Fluoro-N-methyl-4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzamide 814 3-Fluoro-N-methyl-4-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzamide 815 N-methyl-4-(2-methyl-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzamide 816 N-methyl-4-(2-methyl-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)benzamide 817 4-(2-fluoro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-N-methylbenzamide 818 4-(2-fluoro-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)-N-methylbenzamide 819 4-(2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-N-methylbenzamide 820 N,N-Dimethyl-6-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinamide 821 N,N-Dimethyl-6-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinamide 822 5-Fluoro-N,N-dimethyl-6-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinamide 823 5-Fluoro-N,N-dimethyl-6-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinamide 824 N,N-Dimethyl-6-(2-methyl-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinamide 825 N,N-Dimethyl-6-(2-methyl-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinamide 826 6-(2-fluoro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-N,N-dimethylnicotinamide 827 6-(2-fluoro-4-(1-(perfluoroethyl)cyclopropyl)phenoxy)-N,N-dimethylnicotinamide 828 6-(2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-N,N-dimethylnicotinamide

[0035] Also included are isomers, for example enantiomers or diastereomers or rotamers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds named above.

[0036] [Further definitions:] The term “C1-C 12 "Alkyl" includes all isomers of the corresponding saturated aliphatic hydrocarbon groups containing 1 to 12 carbon atoms; this includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, sec-pentyl, 3-pentyl, 2-methylbutyl, iso-pentyl, 2-methylbut-2-yl, 3-methylbut-2-yl, all hexyl isomers, all heptyl isomers, all octyl isomers, all nonyl isomers, all decyl isomers, all undecyl isomers, and all dodecyl isomers.

[0037] The term “C2-C 12 "Alkenyl" includes all isomers of the corresponding unsaturated olefinic hydrocarbon groups containing 2 to 12 carbon atoms linked by one or more double bonds; this includes vinyl, all propenyl isomers, all butenyl isomers, all pentenyl isomers, all hexenyl isomers, all heptenyl isomers, all octenyl isomers, all nonenyl isomers, all decenyl isomers, all undecenyl isomers, and all dodecenyl isomers.

[0038] The term “C2-C 12"Alkynyl" includes all isomers of the corresponding unsaturated olefinic hydrocarbon groups containing 2 to 12 carbon atoms connected by one or more triple bonds; this includes ethynyl, all propynyl isomers, all butynyl isomers, all pentynyl isomers, all hexynyl isomers, all heptynyl isomers, all octynyl isomers, all nonynyl isomers, all decynyl isomers, all undecynyl isomers, and all dodecynyl isomers. The term "alkynyl" also includes compounds with one or more triple bonds and one or more double bonds.

[0039] The term "C3-C8 cycloalkyl" includes the corresponding saturated hydrocarbon groups containing from 3 to 8 carbon atoms arranged in a monocyclic ring structure; this includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

[0040] The term "C3-C8 cycloalkenyl" includes the corresponding unsaturated non-aromatic, anti-aromatic, or aromatic hydrocarbon groups containing from 3 to 8 carbon atoms arranged in a monocyclic ring structure and connected by one or more double bonds; this includes cyclopropenyl, all cyclobutenyl isomers, all cyclopentenyl isomers, all cyclohexenyl isomers, all cycloheptenyl isomers, and all cyclooctenyl isomers.

[0041] The term “C4-C 12 "Bicycloalkyl" includes the corresponding saturated hydrocarbon groups containing 4 to 12 carbon atoms arranged in a bicyclic ring structure;

[0042] The term “C6-C 12 "Bicycloalkenyl" includes the corresponding unsaturated hydrocarbon groups containing 6 to 12 carbon atoms arranged in a bicyclic ring structure and joined by one or more double bonds;

[0043] The term “C5-C 14 "Tricycloalkyl" includes the corresponding saturated hydrocarbon groups containing 5 to 14 carbon atoms arranged in a tricyclic ring structure;

[0044] The term "perhalogenated" refers to the exhaustive halogenation of the carbon scaffold; equivalent residues include the corresponding perfluorinated, perchlorinated, perbrominated, and periodinated groups. Preferably, the term "perhalogenated" refers to a perfluorinated or perchlorinated group, more preferably a perfluorinated group.

[0045] The following contains definitions of terms used herein: The first definition provided for a group or term herein applies to that group or term throughout the specification, unless otherwise indicated, either individually or as part of another group.

[0046] The compounds of the present invention may form salts, which are also within the scope of the present invention. Reference to the compounds of the present invention herein is understood to include reference to their salts unless otherwise specified. As used herein, the term "salt(s)" refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. Zwitterions (internal or internal salts) are included within the term "salt(s)" as used herein (and may be formed, for example, when a substituent contains an acid moiety such as a carboxyl group). Quaternary ammonium salts, such as alkylammonium salts, are also included herein. Salts of compounds can be formed, for example, by reacting the compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium, followed by lyophilization.

[0047] Exemplary acid addition salts include acetates (e.g., those formed with acetic acid or trihaloacetic acids, e.g., trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, bromides, and the like. salts such as chlorate, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., formed with sulfuric acid), sulfonate (e.g., those mentioned herein), tartrate, thiocyanate, toluenesulfonate, e.g., tosylate, undecanoate, and the like.

[0048] Exemplary base salts (e.g., formed when a substituent contains an acidic moiety such as a carboxyl group) include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g., organic amines) such as benzathine, dicyclohexylamine, hydrabamine, N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfate), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.

[0049] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science 1977, 66(2), each of which is incorporated herein by reference in its entirety.

[0050] As used herein, the phrase "pharmaceutically acceptable" is used to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0051] Furthermore, in the case of compounds of the present invention containing asymmetric carbon atoms, the present invention relates to D-, L- and D,L-mixtures, and also to diastereomeric forms when more than one asymmetric carbon atom is present. Compounds of the present invention containing asymmetric carbon atoms and generally occurring as racemates can be separated into optically active isomers in a known manner, for example, using an optically active acid. However, it is also possible to use optically active starting materials from the beginning, so that the corresponding optically active or diastereomeric compounds are obtained as the final products.

[0052] The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the swapping of adjacent double and single bonds with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which a proton can occupy more than one position in a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or sterically locked into one form by appropriate substitution.

[0053] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are contemplated unless otherwise specified. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolution of racemic mixtures or stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separate isomers.

[0054] Compounds of the present invention may also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0055] Also included are solvates and hydrates of the compounds of the invention and of their pharmaceutically acceptable salts.

[0056] As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, tautomers, rotamers, and isotopes of the structures depicted, unless otherwise indicated.

[0057] In some embodiments, the compounds may be provided as prodrugs. As used herein, the term "prodrug" refers to a compound that, when administered to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the invention or a salt and / or solvate thereof.

[0058] In some embodiments, the compounds of the present invention and salts thereof are substantially isolated. By "substantially isolated," it is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation may include, for example, enrichment of the composition in the compound of the present invention. Substantial separation may include a composition comprising at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% (by weight) of the compound of the present invention or a salt thereof.

[0059] [Dispensing method] The compounds according to the invention have been found to have important pharmacological properties which can be used therapeutically. The compounds of the invention can be used alone, in combination with each other, or in combination with other active compounds.

[0060] In certain embodiments, the compounds of the present invention may be enhancers of Notch signaling.

[0061] Intercellular communication via Notch signaling (reviewed in Kopan et al., Cell 2009, 137, 216-233; Bray, Nat. Rev. Mol. Cell Biol. 2016, 17, 722-735) is mediated in an initial step by two types of transmembrane proteins: Notch receptors, which are distributed within the plasma membrane of receiving cells, and Notch ligands, which coat the membrane of sending cells. Mechanistically, Notch signaling is activated by receptor-ligand interaction, leading to the proteolytic release of the membrane-bound Notch receptor intracellular domain (NICD) inside the receiving cell. Subsequent translocation of NICD to the nucleus, in turn, leads to the transcriptional activation of specific and cell-type-specific genes. Notch-mediated alterations of a cell's previous gene expression program are manifested in corresponding cellular changes, which represent the cell's response to the Notch signal.

[0062] The activation level of Notch signaling can be most reliably quantified in vitro by measuring the expression level of Notch-specific target genes.This can be achieved by quantifying the corresponding mRNA or protein of specific Notch target genes.Alternatively, cells can be genetically modified to carry luciferase gene as an artificial Notch target gene, which is expressed depending on Notch activity.In this situation, the level of Notch signaling can be quantified by measuring the value of bioluminescence derived from luciferase.

[0063] A similar Notch-reporter assay, i.e., a luciferase-based luminescence readout, was used herein to quantify the ability of the claimed small molecules to increase Notch signaling in cell lines. To this end, HeLa cells, obtainable from the American Type Culture Collection (ATCC) under accession number ATCC-CCL-2, were transfected using FuGENE® HD (Promega, #E2311) as transfection reagent with an expression vector for a membrane-tethered form of the constitutively active intracellular domain of the human Notch1 receptor (hNotch1ΔE) (BPS Bioscience, Notch Pathway Reporter Kit #60509, human analog of component C) to activate the signaling cascade, and firefly luciferase expressed under the control of a Notch-responsive promoter (BPS Bioscience, Notch Pathway Reporter Kit #60509) to monitor Notch signaling. To include measurements of cell number per sample, cells were transiently transfected for 24 hours with a CSL luciferase reporter vector (derived from component A, not premixed with the Renilla luciferase vector, #60509) and Renilla luciferase (Promega, pRL-SV40, #E2231), which constitutively expresses Renilla luciferase in a Notch signaling-independent manner. HeLa cells were cultured in DMEM medium (Fisher Scientific, #11584456) containing 10% fetal bovine serum (Fisher Scientific, #15517589) according to the supplier's protocol. Transfections were performed in 100 mm culture dishes (StarLab, #CC7682-3394) with cells properly attached to the plate at 80-90% confluency in a total volume of 7 mL culture medium.For each dish to be transfected, 238 μL of Opti-MEM (Fisher Scientific, #10149832) was added to prepare a transfection mix: 40 μL of hNotch1ΔE expression vector (100 ng / μL), 80 μL of CSL luciferase reporter vector (40 ng / μL), 4 μL of pRL-SV40-Renilla luciferase vector (10 ng / μL), and, in the final step, 18.1 μL of FuGENE® HD. After adding FuGENE® HD, the transfection mix was left at room temperature for 15 minutes and then distributed equally among the culture dishes. Subsequently, 24 hours after transfection, transfected cells (10,000 cells per well) were incubated with test compounds (diluted from a 10 mM stock solution in DMSO to a final DMSO concentration of 0.1% v / v) at a final concentration of 10 μM or with empty carrier DMSO at 0.1% v / v as a control in a 96-well plate (CORNING, #3610) suitable for luminescence readout for 20 hours. Cells were then lysed using 30 μL per well of Passive Lysis Buffer (Promega, #E194A, a component of the Dual-Luciferase® Reporter Assay System, #E1910), and firefly and Renilla luciferase levels were measured using a luminescence reader by adding 15 μL per well of the corresponding enzyme substrate required to generate the respective luminescent signal (Promega, #E1910).

[0064] The suitability of the assay for monitoring Notch signaling was controlled by further including a commonly accepted commercially available Notch inhibitor, i.e., DAPT, as a negative control and the reported Notch enhancer resveratrol (RES) as a positive control (Pinchot et al., Cancer 2011, 117, 1386-1398; Truong et al., Ann. Surg. Oncol. 2011, 18, 1506-1511; Yu et al., Mol. Cancer Ther. 2013, 12, 1276-1287). Both control compounds were tested at 10 μM.

[0065] Measurements were performed with six replicates per compound per single experiment. For all compounds, the experiment was repeated with three or more independent replicates. Notch-reporter luciferase values ​​were normalized by division through the corresponding individual Notch-independent Renilla values ​​to remove the effect of variations in absolute cell number between samples. For all individual plates, a second normalization was performed to the equally weighted arithmetic mean (abbreviated here as AVE) of the six relevant Renilla-normalized DMSO-control values ​​within a single experiment to obtain values ​​relative to a baseline level of 1.0. Two independent outlier analyses were performed according to the method by Peirce and Chauvenet (Ross, Journal of Engineering Technology 2003, 1-12). Outliers identified by at least one method were excluded from the calculation, but at most one value out of six per compound within a single experiment. The weighted arithmetic mean (abbreviated here as AVE) for each compound was calculated. w The corresponding standard deviations for the weighted arithmetic means were calculated as in Bronstein et al. (Bronstein, Semendjajew, Musiol, Muhlig, Taschenbuch der Mathematik, 5 thThe standard deviation was calculated according to the method described by Harri, "Combined Standard Deviation" (Germany, ed. 2001, Published by Verlag Harri Deutsch, Frankfurt am Main and Thun) and combined with a Gaussian error propagation associated with the calculations performed for normalization. The resulting standard deviation is referred to herein as the "combined standard deviation."

[0066] A compound is considered a Notch-upper molecule, i.e., an enhancer of Notch signaling, if the weighted arithmetic mean of the luminescence values, after subtracting the corresponding combined standard deviation, is 1.1 or greater, specifically 1.2 or greater, 1.3 or greater, 1.4 or greater, 1.5 or greater, 1.7 or greater, and 2.0 or greater, compared to an overall basal level of 1.0. The overall basal level was calculated as the weighted arithmetic mean of all double-normalized values ​​from the DMSO control measurements, similar to the calculation performed for the test compound. The corresponding combined standard deviation for the DMSO values ​​was 1·10 -2 It will be less than.

[0067] According to the above-described method, several molecules falling within the five compound families defined herein as Formula I, Formula II, Formula III, Formula IV, and Formula V have been identified as enhancers of Notch signaling. The Notch enhancers identified to date relate to the compounds listed in Table VI. The entries in Table VI are sorted by the corresponding weighted arithmetic mean of the compounds falling within the indicated activity range. JPEG0007807487000036.jpg254161JPEG0007807487000037.jpg254158

[0068] Several other molecules have not been identified as enhancers of Notch signaling according to the above methods.

[0069] In the course of evaluating molecules falling within Formula I, Formula II, Formula III, Formula IV, and Formula V in further cellular assays, results indicate that compounds of said molecular families exhibit growth inhibitory properties in hyperproliferative processes. In some cases, the growth inhibitory properties correlate with Notch-enhancing properties, and in other cases, the growth inhibitory properties do not correlate with Notch-enhancing properties.

[0070] The biological activity of the claimed compounds may be attributable to, but is not limited to, Notch signaling enhancing activity. The secondary mechanisms of the claimed compounds that lead to antiproliferative effects may be used alternatively or in combination with Notch enhancing properties in medical therapy, preferably in the treatment of hyperproliferative disorders, including cancer and non-malignant hyperproliferative disorders.

[0071] The antiproliferative activity of compounds falling within Formula I, Formula II, Formula III, Formula IV, and Formula V was investigated against cells or cell lines derived from myeloid cell compartments, neuroendocrine system, cervical, and mucosal epithelial lesions, and skin epithelium. To this end, HL-60 cells, TT cells, HeLa cells, CAL-27 cells, and human primary epithelial keratinocytes (HPEK) were seeded in 96-well plates (CORNING #3598) suitable for fluorescence assays at the following initial cell numbers: 1,000 cells per well for HL-60; 9,000 cells per well for TT; 2,000 cells per well for HeLa, 2,000 cells per well for CAL-27, and 2,000 cells per well for HPEK. Cells were treated for 5 days with the indicated final concentrations of compounds (diluted from a 1,000x stock solution in DMSO to a final DMSO concentration of 0.1% v / v) or with the empty carrier DMSO (0.1% v / v). Five days after the start of treatment, cells were subjected to the alamarBlue® Proliferation Assay (Bio-Rad Serotec GmbH, BUF012B) according to the manufacturer's protocol. Readouts were obtained using a multiwell plate reader in fluorescence mode, applying filters at 560 nm for excitation (bandwidth 10 nm) and 590 nm for emission (bandwidth 10 nm). Resveratrol (RES) treatment was included as a control for growth inhibition.

[0072] Assays were performed in duplicate or more replicates of an independent single experiment, each containing six replicates for all conditions. For every individual plate, the measured fluorescence intensity values ​​of the compound-treated conditions were normalized to the corresponding equally weighted arithmetic mean of the fluorescence intensity values ​​of the six DMSO-treated control wells to obtain a relative value to a baseline level of 1.0. Statistical calculations were performed similarly to the luciferase assay described above. To achieve this, two independent outlier analyses were performed according to the method by Peirce and Chauvenet (Ross, Journal of Engineering Technology 2003, 1-12). Outliers identified by at least one method were excluded from the calculation, but at most one value out of six per compound within a single experiment. The weighted arithmetic mean AVE for each compound was calculated. w was calculated from the normalized values ​​for all independent replicates of a single experiment containing six replicates each. The corresponding standard deviations for the weighted arithmetic means were calculated as in Bronstein et al. (Bronstein, Semendjajew, Musiol, Muhlig, Taschenbuch der Mathematik, 5 th The standard deviation was calculated according to the method described by Harri, ed., 2001 (Germany, Publisher: Verlag Harri Deutsch, Frankfurt am Main and Thun) and combined with a Gaussian error propagation associated with the calculations performed for normalization. The resulting standard deviation is referred to herein as the "combined standard deviation."

[0073] In certain embodiments, the compounds of the present invention may be growth inhibitors in hyperproliferative processes, including malignant and non-malignant hyperproliferative processes.

[0074] In one embodiment, some compounds of the present invention were found to inhibit the proliferation of HL-60 cells (human acute myeloid leukemia cells), which can be obtained from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 3. HL-60 cells were cultured in RPMI 1640 medium (Fisher Scientific, #11554526) containing 10% fetal bovine serum (Fisher Scientific, #15517589) according to the supplier's protocol.

[0075] A compound is considered to be an inhibitor of HL-60 cell proliferation if the weighted arithmetic mean of the normalized fluorescence intensity values, after adding the corresponding combined standard deviation at a reference concentration of -20 μM, is ≤0.9, specifically ≤0.8, ≤0.7, ≤0.6, ≤0.4, and ≤0.2, compared to an overall basal level of 1.0. The overall basal level was calculated as the weighted arithmetic mean of all normalized values ​​from the DMSO control measurements, similar to the calculation performed for the test compound. The corresponding combined standard deviation for the DMSO values ​​was 1·10 -2 It will be less than.

[0076] Following the above-described methods, several molecules falling within the five compound families defined herein as Formula I, Formula II, Formula III, Formula IV, and Formula V have been identified as HL-60 cell proliferation inhibitors. The HL-60 proliferation inhibitors identified to date relate to the compounds listed in Table VII. The entries in Table VII are sorted by the corresponding weighted arithmetic mean of the compounds falling within the indicated activity range. JPEG0007807487000038.jpg243166JPEG0007807487000039.jpg242166JPEG0007807487000040.jpg159166

[0077] In one embodiment, some compounds of the present invention were found to inhibit the growth of CAL-27 cells (human tongue squamous cell carcinoma cells), which can be obtained from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 446. CAL-27 cells were cultured in DMEM medium (Fisher Scientific, #11584456) containing 10% fetal bovine serum (Fisher Scientific, #15517589) according to the supplier's protocol (but at 5% instead of 10% CO).

[0078] A compound is considered to be a proliferation inhibitor of CAL-27 cells if the weighted arithmetic mean of the normalized fluorescence intensity values, after adding the corresponding combined standard deviation at a reference concentration of -20 μM, is ≤0.9, specifically ≤0.8, ≤0.7, ≤0.6, ≤0.4, and ≤0.2, compared to an overall basal level of 1.0. The overall basal level was calculated as the weighted arithmetic mean of all normalized values ​​from the DMSO control measurements, similar to the calculation performed for the test compound. The corresponding combined standard deviation for the DMSO values ​​was 1·10 -2 It will be less than.

[0079] According to the above-described method, several molecules that fall within the three compound families defined herein as Formula II, Formula IV, and Formula V have been identified as inhibitors of CAL-27 cell proliferation. The CAL-27 proliferation inhibitors identified to date relate to the compounds listed in Tables VIIIa and VIIIb. The entries in Tables VIIIa and VIIIb are sorted by the corresponding weighted arithmetic mean of the compounds that fall within the indicated activity ranges. JPEG0007807487000041.jpg237166JPEG0007807487000042.jpg114166 JPEG0007807487000043.jpg127166

[0080] In one embodiment, some compounds of the present invention were found to inhibit the proliferation of TT cells (human medullary thyroid carcinoma cells), which can be obtained from the American Type Culture Collection (ATCC) under accession number ATCC-CRL- 1803. TT cells were cultured in F12K medium (Fisher Scientific, #11580556, or ATCC, #ATCC-30-2004) containing 10% fetal bovine serum (Fisher Scientific, #15517589) according to the supplier's protocol.

[0081] A compound is considered an inhibitor of TT cell proliferation if, at a reference concentration of -40 μM, the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding combined standard deviation is 0.9 or less, specifically 0.8 or less, 0.7 or less, 0.6 or less, 0.4 or less, and 0.2 or less, compared to an overall basal level of 1.0. The overall basal level was calculated as the weighted arithmetic mean of all normalized values ​​from the DMSO control measurements, similar to the calculation performed for the test compound. The corresponding combined standard deviation for the DMSO values ​​is 1·10 -2 It will be less than.

[0082] According to the above-described method, several molecules that fall within the three compound families defined herein as Formula II, Formula IV, and Formula V have been identified as TT cell proliferation inhibitors. The TT proliferation inhibitors defined thus far relate to the compounds listed in Table IX. The entries in Table IX are sorted by the corresponding weighted arithmetic mean of the compounds that fall within the indicated activity range. JPEG0007807487000044.jpg179166

[0083] In one embodiment, some compounds of the present invention were found to inhibit the growth of HeLa cells (human cervical adenocarcinoma cells), which can be obtained from the American Type Culture Collection (ATCC) under accession number ATCC-CCL-2. HeLa cells were cultured in DMEM medium (Fisher Scientific, #11584456) containing 10% fetal bovine serum (Fisher Scientific, #15517589) according to the supplier's protocol.

[0084] A compound is considered a HeLa cell proliferation inhibitor if, at a reference concentration of -40 μM, the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding combined standard deviation is ≤0.9, specifically ≤0.8, ≤0.7, ≤0.6, ≤0.4, and ≤0.2, compared to an overall baseline level of 1.0. The overall baseline level was calculated as the weighted arithmetic mean of all normalized values ​​from the DMSO control measurements, similar to the calculation performed for the test compound. The corresponding combined standard deviation for the DMSO values ​​is 1·10 -2 It will be less than.

[0085] Following the above-described method, several molecules that fall within the family of compounds defined herein by Formula II have been identified as inhibitors of HeLa cell proliferation. The HeLa proliferation inhibitors identified to date relate to the compounds listed in Table X. The entries in Table X are sorted by the corresponding weighted arithmetic mean of the compounds that fall within the indicated activity range. JPEG0007807487000045.jpg66166

[0086] In one embodiment, certain compounds of the present invention were found to inhibit the proliferation of human epidermal keratinocyte progenitor cells (HPEKp, pool), obtainable from CELLnTEC Advanced Cell Systems AG under accession number HPEKp. HPEKp cells were cultured in CnT-Prime epithelial culture medium (CELLnTEC, #CnT-PR, a fully defined, low-calcium formulation completely free of animal- or human-derived components) according to the supplier's protocol without the addition of additional components.

[0087] A compound is considered to be a proliferation inhibitor of HPEKp cells if, at a reference concentration of -10 μM, the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding combined standard deviation is ≤0.9, specifically ≤0.8, ≤0.7, ≤0.6, ≤0.4, and ≤0.2, compared to an overall basal level of 1.0. The overall basal level was calculated as the weighted arithmetic mean of all normalized values ​​from the DMSO control measurements, similar to the calculation performed for the test compound. The corresponding combined standard deviation for the DMSO values ​​is 1·10 -2 It will be less than.

[0088] Following the methods described above, several molecules that previously fall within the four compound families defined herein as Formula II, Formula III, Formula IV, and Formula V have been identified as inhibitors of HPEKp cell proliferation. The HPEKp proliferation inhibitors identified thus far relate to the compounds listed in Table XI. The entries in Table XI are sorted by the corresponding weighted arithmetic mean of the compounds that fall within the indicated activity range. JPEG0007807487000046.jpg212166

[0089] Preliminary results from a single proliferation assay with six replicates per condition using cells derived from murine muscle tissue indicated that compounds of the present invention may exhibit antiproliferative activity against muscle cells. Compounds were tested against C2C12 cells using the alamarBlue® proliferation assay, similar to the method described above, with cells seeded at an initial number of 2000 cells per 96-well, and compound treatment lasting 3 days.

[0090] In one embodiment, two compounds of the present invention have been found to inhibit the proliferation of C2C12 cells (murine myoblasts), which can be obtained from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 565. C2C12 cells were cultured in RPMI 1640 medium (Fisher Scientific, #11554526) containing 10% fetal bovine serum (Fisher Scientific, #15517589) according to the supplier's protocol.

[0091] A compound is considered to be a C2C12 cell proliferation inhibitor if the equally weighted arithmetic mean (AVE) of the six normalized fluorescence intensity values, after adding the corresponding standard deviation at a reference concentration of -40 μM, is ≤0.9, specifically ≤0.8, ≤0.7, ≤0.6, ≤0.4, and ≤0.2, compared to an overall reference level of 1.0. The overall reference level was calculated as the equally weighted arithmetic mean (AVE) of the six normalized values ​​from the DMSO control measurement, similar to the calculation performed for the test compound. The corresponding standard deviation for the tested compound was calculated including the Gaussian error propagation associated with the calculation performed for normalization, and is 3·10 for the DMSO value. -2 Outlier analysis was performed as described above.

[0092] According to the above-described method, molecules falling within the two compound families defined herein as Formula II and Formula V have been identified as inhibitors of C2C12 cell proliferation. The C2C12 proliferation inhibitors identified to date relate to the compounds listed in Table XII. The entries in Table XII are sorted by the corresponding equally weighted arithmetic mean of the compounds falling within the indicated activity range. JPEG0007807487000047.jpg46166

[0093] Preliminary results from a single proliferation assay with six replicates per condition using squamous cell carcinoma (SCC) cells derived from human oral mucosa confirm that compounds of the present invention exhibit antiproliferative activity against SCC of the mucosal epithelium. Compounds were tested on BHY cells using the alamarBlue® proliferation assay, similar to the method described above, with cells plated at an initial number of 4000 cells per 96-well plate and compound treatment lasting 3 days.

[0094] In one embodiment, some compounds of the present invention were found to inhibit the proliferation of BHY cells (human oral squamous cell carcinoma cells), which can be obtained from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 404. BHY cells were cultured in DMEM medium (Fisher Scientific, #11584456) containing 10% fetal bovine serum (Fisher Scientific, #15517589) according to the supplier's protocol (but at 5% instead of 10% CO).

[0095] A compound is considered to be a proliferation inhibitor of BHY cells if, at a reference concentration of -40 μM, the equally weighted arithmetic mean (AVE) of the six normalized fluorescence intensity values ​​after adding the corresponding standard deviation is 0.9 or less, specifically 0.8 or less, 0.7 or less, 0.6 or less, 0.4 or less, and 0.2 or less, compared to an overall reference level of 1.0. The overall reference level is the weighted arithmetic mean (AVE) of all normalized values ​​from the DMSO control measurement. w ) The corresponding combined standard deviation for DMSO values ​​was 1 10 -2 The corresponding standard deviations for the tested compounds were calculated including the Gaussian error propagation associated with the calculations performed for normalization. The weighted arithmetic mean (AVE) for RES w ) and combined standard deviations were calculated in the same way as for DMSO. Outlier analysis was performed as described above.

[0096] According to the above-described method, molecules falling within the two compound families defined herein as Formula II and Formula IV have been identified as inhibitors of BHY cell proliferation. The BHY proliferation inhibitors identified to date relate to the compounds listed in Table XIII. The entries in Table XIII are sorted by the corresponding equally weighted arithmetic mean of the compounds falling within the indicated activity range. JPEG0007807487000048.jpg100166

[0097] In one aspect, the present invention relates to the treatment of skin, skin appendages, mucous membranes, mucosal appendages, cornea, and all types of epithelial tissue. The term "skin" relates to tissues comprising the epidermis and dermis. The term "mucosa" relates to mucosal and submucosal tissues, including oral, nasal, ocular, aural, respiratory, genital, urothelial, anal, and rectal mucosa. The term "appendages" relates to tissues comprising hair follicles, hair, fingernails, toenails, and glands, including sebaceous glands, sweat glands, e.g., apocrine or eccrine sweat glands, and mammary glands.

[0098] In one embodiment, the invention relates to the treatment of non-melanoma skin cancers and pre-cancerous lesions, such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), e.g., cutaneous SCC, lung SCC, head and neck SCC, oral SCC, esophageal SCC, cervical SCC, periocular SCC, thyroid SCC, penile SCC, vaginal SCC, prostate SCC, bladder SCC, sebaceous gland carcinoma, Merkel cell carcinoma, angiosarcoma, cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, dermatofibrosarcoma, actinic keratosis (AK) or Bowen's disease (BD).

[0099] In a further embodiment, the present invention relates to the treatment of skin and mucous membrane disorders with defective keratinization (keratosis) and / or abnormal keratinocyte proliferation, such as psoriasis, Darier's disease, lichen planus, lupus erythematosus, ichthyosis or common warts (senile).

[0100] In a further embodiment, the present invention relates to the treatment of skin and mucosal diseases associated with and resulting from viral infections, such as warts, HPV-associated warts, papillomas, HPV-associated papillomas, papillomatosis and HPV-associated papillomatosis, including verruca (plantar warts), flat warts (flat warts), filiform warts (filiform warts), mosaic warts, periungual warts, subungual warts. , oral warts, genital warts, fibroepithelial papillomas, intracanalicular papillomas, intraductal papillomas, inverted papillomas, basal cell papillomas, squamous cell papillomas, cutaneous papillomas, fibrovasular papillomas, choroid plexus papillomas, nasal papillomas, pharyngeal papillomas, papillomatosis dermal carcinoid, papillomatosis dermal lymphostasis, papillomatosis confluens et reticularis or laryngeal papillomatosis (respiratory papillomatosis), herpes-related diseases such as herpes labialis, herpes genitalis, shingles, herpes cornea or Kaposi's sarcoma.

[0101] In a further embodiment, the present invention relates to the treatment of atopic dermatitis.

[0102] In a further embodiment, the present invention relates to the treatment of acne.

[0103] In a further embodiment, the present invention relates to the treatment of skin wounds, wherein the wound healing process is accelerated.

[0104] A further aspect of the present invention relates to the treatment of immune system-related disorders. As used herein, the term "immune system-related" refers to pathologies of the hematopoietic system, including the blood system, and intervention in the proliferation, differentiation and / or activation of cell lineages of the hematopoietic system, including the blood system, in order to modulate the immune response (immunomodulation).

[0105] Examples are diseases of the hematopoietic system, including the blood system, such as malignancies of the myeloid lineage, such as chronic myelomonocytic leukemia (CMML) or acute myeloid leukemia (AML) (including acute promyelocytic leukemia (APL)); malignancies of the lymphoid system, such as B-cell acute lymphoblastic leukemia (BALL), pre-B-cell acute lymphoblastic leukemia (pre-B-ALL), Hodgkin's lymphoma or myeloma; or acute lymphoblastic leukemia and acute myeloid mixed lineage leukemia (with MLL gene translocations).

[0106] Furthermore, the compounds of the present invention can be used in immunotherapy, either alone or together with other immunotherapeutic methods or compounds, or as adjuvants for immunotherapy. As used herein, the term "immunotherapy" refers to activating immunotherapy in patients without immunodeficiency or with acquired or congenital immunodeficiency, enhancing the function of the immune system in response to pathogens or pathologically transformed endogenous cells, such as cancer cells, as immune restoration.

[0107] As used herein, the term "other immunotherapeutic methods" refers to vaccination, antibody therapy, cytokine therapy, the use of immune checkpoint inhibitors and immune response stimulators, as well as autologous transplantation of genetically modified or unmodified immune cells, which may be stimulated by intercellular signals, or signaling molecules, or antigens, or antibodies, i.e., adoptive immune-cell transfer.

[0108] Specific examples are activation of peripheral T lymphocytes to amplify the immune response, in particular stimulation of proliferation and / or cytokine production and / or secretion upon antigen recognition to amplify the immune response, for example activation of B lymphocytes to amplify the immune response, in particular stimulation of proliferation and / or antibody production and / or secretion, for example enhancement of the immune response through increasing the numbers of specific immune cell subtypes, for example by modulating differentiation and / or cell fate decisions during immune cell development to increase the numbers of marginal zone B cells, or T helper (Th) subsets (in particular Th1, Th2) and regulatory T cells; or use as a vaccine adjuvant.

[0109] A further aspect of the invention relates to the treatment of muscle disorders, including disorders of skeletal, cardiac and smooth muscle.

[0110] In one embodiment, the present invention relates to the treatment of muscular dystrophy (MD).

[0111] Specific examples are Duchenne MD, Becker MD, congenital MD, limb-girdle MD, facioscapulohumeral MD, Emery-Dreifuss MD, distal MD, myotonic MD or oculopharyngeal MD.

[0112] In a further embodiment, the invention relates to the treatment of hyperproliferative disorders of muscle, including myoblastoma, rhabdomyoma, and rhabdomyosarcoma, as well as muscle hyperplasia and hypertrophy.

[0113] In a further embodiment, the compounds of the invention may be used for muscle regeneration after pathological muscle degeneration or atrophy, for example, due to trauma, due to muscle ischemia, or due to inflammation in age-related muscle atrophy or disease-related muscle atrophy, such as myositis and fibromyositis or poliovirus.

[0114] Further embodiments relate to the treatment of disorders of the neuroendocrine system, e.g., cancers of the neuroendocrine system (including neuroendocrine small cell carcinoma, neuroendocrine large cell carcinoma, and carcinoid tumors), e.g., cancers of the brain, thyroid, pancreas, gastrointestinal tract, liver, esophagus, and lung, e.g., neuroendocrine tumors of the pituitary gland, neuroendocrine tumors of the adrenal gland, medullary thyroid carcinoma (MTC), C-cell hyperplasia, anaplastic thyroid carcinoma (ATC), parathyroid adenoma, intrathyroid nodule, insular thyroid carcinoma, hyalinizing tract neoplasm, paraganglioma, small cell lung cancer (SCLC), pulmonary carcinoid tumor, neuroblastoma, gastrointestinal carcinoid, goblet cell carcinoid, pancreatic carcinoid, gastrinoma, glucagonoma, somatostatinoma, vipoma, islet cell adenoma, non-competent islet cell tumor, multiple endocrine neoplasia type 1, or pulmonary carcinoid.

[0115] Further aspects relate to the treatment of cancers or precancerous lesions of the brain, pancreas, liver, thyroid, genitourinary tract, and endothelial tissues, including glioma, mixed glioma, glioblastoma, glioblastoma multiforme, astrocytoma, anaplastic astrocytoma, glioblastoma, oligodendroglioma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, ependymoma, anaplastic ependymoma, myxopapillary ependymoma, subependymoma, brain stem glioma, optic nerve glioma, and forebrain tumors, adenocarcinoma of the pancreas, ductal adenocarcinoma of the pancreas, acinar cell carcinoma of the pancreas, pseudopapillary neoplasm of the pancreas, intraductal papillary-mucinous tumor of the pancreas, mucinous cystadenocarcinoma of the pancreas, pancreatoblastoma and pancreatic intraepithelial neoplasia, hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, papillary and follicular thyroid carcinoma, cervical carcinoma, and angiosarcoma.

[0116] As used herein, the term "treating" or "treatment" refers to one or more of: (1) inhibiting a disease; for example, inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder (i.e., preventing further progression of the pathology and / or symptomology); and (2) ameliorating a disease; for example, ameliorating a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder (i.e., reversing the pathology and / or symptomology), e.g., reducing the severity of the disease. The term "treating" also encompasses pre-treatment care.

[0117] In some embodiments, administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, is effective in preventing a disease; for example, preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but who has not yet experienced or exhibited the pathology or symptomology of the disease.

[0118] The compounds of the invention may be used in human and veterinary medicine, including the treatment of companion animals such as horses, dogs, cats, rabbits, guinea pigs, birds, fish; and livestock such as cattle, poultry, pigs, sheep, goats, donkeys, yaks, and camels.

[0119] [Pharmaceutical composition] The present invention further provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, for use in medicine, e.g., human or veterinary medicine. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0120] An effective dosage of the compound according to the present invention, or a salt thereof, solvate thereof, or prodrug thereof, is used in addition to a physiologically acceptable carrier, diluent, and / or adjuvant to produce a pharmaceutical composition. The dosage of the active compound may vary depending on the route of administration, the age and weight of the patient, the nature and severity of the disease being treated, and similar factors. The daily dosage may be given as a single dose administered once, or may be divided into two or more daily dosages, typically 0.001 to 2000 mg. A particular preference is given to administering a daily dosage of 0.1 to 500 mg, for example 0.1 to 100 mg.

[0121] Suitable modes of administration may be local or systemic, and include enteral, oral, rectal, and parenteral, as infusions and infusions, intravenous, intraarterial, intraperitoneal, intramuscular, intracardiac, epidural, intracerebral, intraventricular, intraosseous, intraarticular, intraocular, intravitreal, intrathecal, intravaginal, intracavity, intravesical, subcutaneous, intradermal, transdermal, transmucosal, inhalative, intranasal, buccal, sublingual, and intralesional formulations. Particular preference is given to using oral, parenteral, e.g., intravenous or intramuscular, intranasal formulations, e.g., dry powder or sublingual, of the compounds of the present invention. Conventional galenical formulation forms may be used, such as tablets, sugar-coated tablets, capsules, dispersible powders, granules, aqueous solutions, alcohol-containing aqueous solutions, aqueous or oily suspensions, gels, hydrogels, ointments, creams, lotions, shampoos, lip balms, mouthwashes, foams, pastes, tinctures, skin patches and tapes, time-release drug transport systems, electrophoretic skin delivery systems including implants and devices, and occlusion or combined forms with jet injectors, liposomes and transfersome vesicles, vapors, sprays, syrups, juices or drops and eye drops.

[0122] Solid pharmaceutical forms may contain inert ingredients and carrier materials such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginic acid, gelatin, guar gum, magnesium stearate, aluminum stearate, methylcellulose, talc, highly dispersed silicic acid, silicone oil, higher molecular weight fatty acids (e.g., stearic acid), gelatin, agar, or vegetable or animal fats and oils, or solid high molecular weight polymers (e.g., polyethylene glycol); formulations suitable for oral administration may contain additional flavorings and / or sweeteners, as desired.

[0123] Liquid pharmaceutical forms may be sterilized and / or, where appropriate, may contain auxiliary substances, such as preservatives, stabilizers, wetting agents, osmotic agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols, and / or viscosity-regulating agents, for adjusting osmotic pressure or buffering. Examples of such additives are tartaric acid and citrate buffers, ethanol, and sequestering agents (e.g., ethylenediaminetetraacetic acid and its non-toxic salts). High molecular weight polymers, such as liquid polyethylene oxide, microcrystalline cellulose, carboxymethylcellulose, polyvinylpyrrolidone, dextran, or gelatin, are suitable for adjusting viscosity. Examples of solid carrier materials are starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acid, high molecular weight fatty acids (e.g., stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats, and solid high molecular weight polymers, such as polyethylene glycol.

[0124] Oily suspensions for parenteral or topical application may be vegetable, synthetic or semi-synthetic oils, for example liquid fatty acid esters having in each case 8 to 22 carbon atoms in the fatty acid chain, for example palmitic acid, lauric acid, tridecanoic acid, margaric acid, stearic acid, arachidic acid, myristic acid, behenic acid, pentadecanoic acid, linoleic acid, elaidic acid, brassidic acid, erucic acid or oleic acid, esterified with mono- to trihydric alcohols having 1 to 6 carbon atoms, for example methanol, ethanol, propanol, butanol, pentanol or their isomers, glycol or glycerol. Examples of such fatty acid esters are commercially available Miglyol, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG-6-caprate, caprylic / capric acid esters of saturated fatty alcohols, polyoxyethylene glycerol trioleate, ethyl oleate, waxy fatty acid esters, such as artificial ducktail gland fat, coconut fatty acid isopropyl esters, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, and polyol fatty acid esters, among others. Silicone oils of different viscosities, or fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, or oleyl alcohol, or fatty acids such as oleic acid, are also suitable. It is also possible to use vegetable oils such as castor oil, almond oil, olive oil, sesame oil, cottonseed oil, peanut oil, or soybean oil.

[0125] Suitable solvents, gelatinizing agents and solubilizing agents are water or water-miscible solvents. Examples of suitable substances are alcohols such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycol, phthalic acid, adipic acid, propylene glycol, glycerol, di- or tripropylene glycol, wax, methyl cellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc.

[0126] Cellulose ethers, such as hydroxypropylmethylcellulose, methylcellulose or ethylcellulose, or soluble starch, which can dissolve or swell in both water or organic solvents, can be used as film-forming agents.

[0127] Mixtures of gelatinizing agents and film-forming agents are also entirely possible. In this case, use is made, in particular, of ionic polymers, such as sodium carboxymethylcellulose, polyacrylic acid, polymethacrylic acid and their salts, sodium amylopectin semiglycolate, alginic acid or propylene glycol alginate as the sodium salt, gum arabic, xanthan gum, guar gum or carrageenan. The following can be used as further formulation aids: glycerol, paraffins of different viscosities, triethanolamine, collagen, allantoin and novantisolic acid. The use of surfactants, emulsifiers, or wetting agents, such as sodium lauryl sulfate, fatty alcohol ether sulfate, di-Na-N-lauryl-β-iminodipropionate, polyethoxylated castor oil, or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g., Tween), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ether, cetyltrimethylammonium chloride, or mono / dialkyl polyglycol ether orthophosphate monoethanolamine salt, may also be necessary for formulation. Stabilizers, such as montmorillonite or colloidal silicic acid, such as tocopherol or butylhydroxyanisole, or preservatives, such as p-hydroxybenzoic acid esters, to stabilize emulsions or prevent the destruction of active substances (e.g., antioxidants), may also be used to prepare the desired formulation.

[0128] The preparation for parenteral administration can be in the form of separate dosage units, such as ampoules or vials.Preferably, the solution of active compound is used, preferably aqueous solution and particularly isotonic solution and also suspension.These injection forms can be made available as ready-to-use preparations, or can be prepared directly before use by mixing active compound (for example, lyophilized), and if appropriate, contain other solid carrier materials together with desired solvent or suspension agent.

[0129] Intranasal formulations may be in the form of aqueous or oily solutions or suspensions, or may be in the form of lyophilisates prepared before use with appropriate solvents or suspending agents.

[0130] The inhalable formulation may be present as a powder, a solution or a suspension. Preferably, the inhalable formulation is in the form of a powder, for example as a mixture of the active ingredient with suitable formulation aids such as lactose.

[0131] The formulations are produced, aliquoted and sealed under customary antimicrobial and aseptic conditions.

[0132] As explained above, the compounds of the present invention can be administered as combination therapy, sequential therapy, or simultaneous therapy with additional active agents, such as therapeutically active compounds useful in the treatment of the disorders listed above. These therapeutically active compounds include, but are not limited to, chemotherapeutic agents, such as nucleoside analogs, such as cytarabine, gemcitabine, azathioprine, mercaptopurine, fluorouracil, thioguanine, hydroxyurea, azacitidine, capecitabine, doxifluridine, and methotrexate; platinum-based drugs, such as cisplatin, oxaliplatin, carboplatin, and nedaplatin; anthracyclines, such as doxorubicin, epirubicin, valrubicin, idarubicin, daunorubicin, sabarubicin, pixa ntrone and mitoxantrone; for example, peptide antibiotics such as actinomycin and bleomycin; for example, alkylating agents such as mechlorethamine, chlorambucil, melphalan, nitrosoureas, dacarbazine, temozolomide and cyclophosphamide; for example, mitotic inhibitors including taxanes and vinca alkaloids such as docetaxel, paclitaxel, abraxane, cabazitaxel, vinblastine, vindesine, vinorelbine and vincristine; for example, topoisomerase inhibitors such as irinotecan, topotecan, teniposide and etoposide;and targeted therapeutic agents, such as kinase inhibitors, regulators, i.e., inhibitors and activators of signal transduction pathways including growth factor signaling, cytokine signaling, NF-κB signaling, AP1 signaling, JAK / STAT signaling, EGFR signaling, TGF-β signaling, Notch signaling, Wnt signaling, Hedgehog signaling, hormone and nuclear receptor signaling, e.g., erlotinib, lapatinib, dasatinib, imatinib, alpha-2, alpha-1, alpha-2, alpha-3, alpha-4, alpha-5, alpha-6, alpha-7, alpha-8, alpha-9, alpha-10, alpha-11, alpha-12, alpha-13, alpha-14, alpha-15, alpha-16, alpha-17, alpha-18, alpha-19, alpha-20, alpha-21, alpha-22, alpha-23, alpha-24, alpha-25, alpha-26, alpha-27, alpha-28, alpha-29 ... Fatinib, vemurafenib, dabrafenib, nilotinib, cetuximab, trametinib, palbociclib, cobimetinib, cabozantinib, pegaptanib, crizotinib, olaparib, panitumumab, cabozantinib, ponatinib, regorafenib, entrectinib, ranibizumab, ibrutinib, trastuzumab, rituximab, alemtuzumab, gefitinib, bevacizumab, lenvatinib, bosutinib, axitinib, pazopanib, everolimus, temsirolimus, ruxolitinib, tofacitinib, and sorafenib. benzophenone, sunitinib, aflibercept, bortezomib, vandetanib; vismodegib and sonidegib; retinoids, such as retinol, tretinoin, isotretinoin, alitretinoin, bexarotene, tazarotene, acitretin, adapalene and etretinate; hormone signaling modulators, including estrogen receptor modulators, androgen receptor modulators and aromatase inhibitors, such as raloxifene, tamoxifen, fulvestrant, lasofoxifene, toremifequin histone deacetylase inhibitors, such as vorinostat, romidepsin, panobinostat, belinstat, and chidamide; and ingenol mebutate; and other Notch enhancers not included in the compounds of the present invention, such as valproic acid, resveratrol, hesperetin, chrysin, phenethyl isothiocyanate, thiocoraline, N-methylhemeanthidine chloride, and Notch signaling activating peptides or antibodies;and immune response modifiers, such as imiquimod, ipilimumab, atezolizumab, ofatumumab, rituximab, nivolumab, and pembrolizumab; and anti-inflammatory agents, including glucocorticoids and nonsteroidal anti-inflammatory drugs, such as cortisol-based preparations, dexamethasone, betamethasone, prednisone, prednisolone, methylprednisolone, triamcinolone hexacetonide, mometasone furoate, clobetasol propionate, acetylsalicylic acid, salicylic acid and other salicylates, diflunisal, ibuprofen, dexibuprofen, These may include phen, naproxen, fenoprofen, ketoprofen, dexketoprofen, loxoprofen, flurbiprofen, oxaprozin, indomethacin, ketorolac, tolmetin, diclofenac, etodolac, aceclofenac, nabumetone, sulindac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, parecoxib, etoricoxib, and firocoxib; ACE inhibitors; beta-blockers; myostatin inhibitors; PDE-5 inhibitors; and antihistamines. For combination therapy, the active ingredients may be formulated as a composition containing several active ingredients in a single dosage form and / or as a kit containing individual active ingredients in separate dosage forms. The active ingredients used in combination therapy may be co-administered or administered separately.

[0133] The compounds of the invention may be administered as antibody-drug conjugates.

[0134] The compounds of the invention may be administered in combination with surgery, cryotherapy, electrodesis, radiation therapy, photodynamic therapy, laser therapy, chemotherapy, targeted therapy, immunotherapy, gene therapy, antisense therapy, cell line transplant therapy, stem cell therapy, physical therapy, and occupational therapy.

[0135] The compounds of the present invention falling within the scope of Formula I, Formula II, Formula III, Formula IV and Formula V can be synthesized by a coupling step to establish a diaryl ether scaffold, similar to the method described in Reinmuller et al., 2015, EPFL Thesis 6887, which can be prepared by the following method: reacting a phenol and an electron-deficient aryl halide in the presence of a base such as potassium carbonate or cesium carbonate in an aprotic organic solvent such as DMSO or DMF at room temperature or elevated temperature or reflux, preferably at 80°C or 100°C, optionally with the aid of microwave irradiation (Li et al., Org. Lett. 2003, 5, 2169-2171);

[0136] Alternatively, a method of reacting phenols and nitroarenes in an aprotic organic solvent such as DMSO or DMF at elevated temperature or reflux with the aid of microwave irradiation in the presence of a base such as potassium carbonate or cesium carbonate (Sarkate et al., Synlett 2013, 24, 1513-1516);

[0137] Alternatively, an electron-deficient aryl halide is reacted with an aryl silyl ether in an aprotic organic solvent such as DMSO or DMF in the presence of a base such as DBU and a trace amount of water at elevated temperature or reflux (Yeom et al., Synlett 2007, 146-150);

[0138] Alternatively, the reaction of phenols with diaryliodonium triflates or tosylates in the presence of a base such as potassium carbonate or cesium carbonate in an aprotic organic solvent such as acetonitrile at ambient or elevated temperature (Kakinuma et al., Synthesis 2013, 45, 183-184);

[0139] Alternatively, an aryl halide and a phenol can be reacted under Buchwald-Hartwig conditions in an organic solvent such as toluene at elevated temperature or reflux in the presence of a transition metal-based catalyst such as palladium(II) acetate, an organophosphorus ligand such as dppf, and a base such as potassium phosphate (Burgos et al., Angew. Chem. Int. Ed. 2006, 45, 4321-4326);

[0140] Alternatively, the reaction of arylboronic acids or esters with phenols under Chan-Lam conditions in an aprotic organic solvent such as DCM or chloroform at ambient temperature in the presence of air, a copper-based catalyst system such as copper(II) acetate, and a base such as pyridine or triethylamine (Evans et al., Tetrahedron Letters 1998, 39, 2937-2940);

[0141] Here, all said methods of preparation may require a subsequent derivatization step by standard chemical procedures known to those skilled in the art, such as saponification, hydrolysis, esterification or amidation, to give the corresponding carboxylic acids, esters, primary amides, secondary amides, tertiary amides, hydroxamic acids and hydroxamates.

[0142] For example, the corresponding carboxylic acids are synthesized by saponification of the corresponding benzoate esters, fluorobenzoate esters, nicotinate esters, or fluoronicotinate esters in the presence of potassium hydroxide or sodium hydroxide in a binary solvent mixture of water and alcohol, preferably ethanol, or water and tetrahydrofuran, at ambient or elevated temperature (Becker et al., Organikum, 22nd edition 2004 (Germany), pp. 488, Publisher: Wiley-VCH Weinheim);

[0143] Esters, primary amides, secondary amides, tertiary amides, and hydroxamic acids are synthesized by in situ transformation of the corresponding benzoic acid, fluorobenzoic acid, nicotinic acid, or fluoronicotinic acid to the corresponding acid chloride in the presence of thionyl chloride and a catalytic amount of DMF (in toluene) at ambient or elevated temperature, preferably 80°C, and under an inert gas atmosphere, followed by addition of the respective nucleophile, i.e., alcohol, ammonia, secondary amine, tertiary amine, or hydroxylamine, in the presence or absence of a non-nucleophilic base, such as triethylamine, at ambient temperature under an inert gas atmosphere (Becker et al., Organikum, 22nd edition 2004 (Germany), pp. 459, Publisher: Wiley-VCH Weinheim).

[0144] The perfluoroalkylcyclopropyl moiety associated with the compounds of the present invention falling within the scope of Formula V is synthesized in three steps according to the procedure described by Barnes-Seeman et al., ACS Med. Chem. Lett. 2013, 4, 514-516; first, a bromoperfluoroalkenylbenzene such as 1-bromo-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene or 1-bromo-4-(3,3,4,4,4-pentafluorobut-1-en-2-yl)benzene is reacted with 1-(4-bromophenyl)-2,2,2-trifluoroethan-1-one or 1-(4-bromophenyl)-2,2,3,3,3-pentafluoropropan-1-one, respectively, in an aprotic organic solvent such as DMF, in a crown ether such as 18-crown-6, and in the presence of a base such as methanesulfonyl chloride and potassium fluoride at elevated temperature, preferably 80°C;

[0145] Second, bromophenylperfluoroalkyldihydropyrazoles such as 3-(4-bromophenyl)-3-(trifluoromethyl)-4,5-dihydro-3H-pyrazole or 3-(4-bromophenyl)-3-(perfluoroethyl)-4,5-dihydro-3H-pyrazole can be obtained by reacting a bromoperfluoroalkenylbenzene such as 1-bromo-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene or 1-bromo-4-(3,3,4,4,4-pentafluorobut-1-en-2-yl)benzene, respectively, in the presence of diazomethane in an ether such as diethyl ether or methyl tert-butyl ether at ambient temperature;

[0146] Third, perfluoroalkylcyclopropylaryl bromides such as 1-bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene or 1-bromo-4-(1-(perfluoroethyl)cyclopropyl)benzene can be obtained by reacting 3-(4-bromophenyl)-3-(trifluoromethyl)-4,5-dihydro-3H-pyrazole or 3-(4-bromophenyl)-3-(perfluoroethyl)-4,5-dihydro-3H-pyrazole, respectively, in an organic solvent such as toluene or xylene or a mixture thereof.

[0147] The resulting perfluoroalkylcyclopropylaryl bromides can then be converted to the corresponding phenols by one of the above-mentioned coupling reactions with electron-deficient aryl halides, nitroarenes, diaryliodonium triflates or tosylates by the following methods: reaction at elevated temperature or reflux, preferably 100°C, under an inert gas atmosphere, in a biphasic solvent system such as water / dioxane or water / toluene, in the presence of a transition metal-based catalyst system such as Pd2dba3, an organophosphorus-based ligand such as 2-di-tert-butylphosphino-2',4',6'-triisopropyldiphenyl (t-BuXphos), and a base such as potassium hydroxide or sodium hydroxide (Anderson et al., J. Am. Chem. Soc. 2006, 128, 10694-10695);

[0148] Alternatively, a method of reaction at elevated temperature or reflux, preferably 110°C, under an inert gas atmosphere in an aprotic organic solvent such as DMSO or DMF, in the presence of a copper-based catalyst system such as CuI, 2-methylquinolin-8-ol or preferably 8-hydroxyquinoline-N-oxide, and a pyridyl-based ligand such as tetrabutylammonium hydroxide or preferably cesium hydroxide monohydrate (Paul et al., Synthesis 2010, 4268-4272; Yang et al., Org. Lett. 2011, 13, 4340-4343).

[0149] Compounds of the present invention falling within the scope of Formula I, Formula II, Formula III, Formula IV and Formula V, as well as intermediates, can be purified by column chromatography using silica gel as the stationary phase and common organic solvents such as petroleum ether, ethyl acetate, dichloromethane, methanol, or acetic acid as the eluent, preferably as binary or ternary solvent mixtures thereof;

[0150] Alternatively, it can be isolated by crystallization from common organic solvents such as petroleum ether, ethyl acetate, dichloromethane, chloroform, methanol, ethanol, toluene, or tert-butyl methyl ether, and mixtures thereof.

[0151] The compounds of the present invention falling within the scope of Formula I, Formula II, Formula III, Formula IV and Formula V, as well as the starting materials and intermediates, can be identified by conventional methods such as nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), or thin layer chromatography (TLC).

[0152] [Chemical synthesis] The compounds of the present invention falling within the scope of Formula I, Formula II, Formula III, Formula IV and Formula V can be synthesized and purified by one skilled in the art, preferably according to General Procedure A, or General Procedure B, or General Procedure C, or General Procedure D, respectively, and according to the detailed synthetic procedures described herein;

[0153] [Abbreviation] Ac Acetyl BRSM based on recovered starting material (yield) Bu butyl δ chemical shift parts per million (ppm) dba Dibenzylideneacetone DCE 1,2-dichloroethane DCM dichloromethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide Et Ethyl ESI electrospray ionization M mol / L Me methyl Ms methanesulfonyl PE Petroleum Ether TBAF Tetrabutylammonium fluoride THF tetrahydrofuran TMS trimethylsilyl

[0154] General Procedure A: Synthesis of Diaryl Ether Esters The diaryl ether esters according to Formula I, Formula III, and Formula V can be prepared by nucleophilic aromatic substitution, for example, by reaction of a phenol derivative (nucleophile, see Table XIV) with an alkyl 4-fluorobenzoate, or alkyl 3,4-difluorobenzoate, or alkyl 6-chloronicotinate, or alkyl 6-chloro-5-fluoronicotinate, in the presence of a base such as potassium carbonate in a solvent such as dimethyl sulfoxide in an inert atmosphere such as argon at a temperature between 80°C and 150°C.

[0155] General Procedure B: Synthesis of Diaryl Ether Acids The diaryl ether acids according to Formula I, Formula III, and Formula V can be prepared by saponification, for example, by reaction of the corresponding diaryl ether ester with an aqueous base such as sodium hydroxide (nucleophile, see Table XIV) in a solvent such as ethanol, methanol, tetrahydrofuran, or mixtures thereof, at temperatures between room temperature and reflux.

[0156] General Procedure C: Synthesis of Diaryl Ether Esters The diaryl ether esters according to Formula I, Formula III, and Formula V can be prepared by esterification via the corresponding acid chloride, for example, by reaction of thionyl chloride with a diaryl ether acid in the presence of a catalytic amount of DMF in a solvent such as toluene under an inert atmosphere such as argon at a temperature between 50° C. and 100° C. After removal of volatiles, the resulting acid chloride intermediate is reacted with an alcohol corresponding to the desired ester (nucleophile, see Table XIV) in the presence of an organic base such as triethylamine under an inert atmosphere such as argon at a temperature between 0° C. and room temperature.

[0157] Alternatively, the diaryl ether esters according to Formula I, Formula III, and Formula V can be prepared by esterification via the corresponding acid chloride, for example by reaction of a diaryl ether acid with thionyl chloride in the presence of an alcohol corresponding to the desired ester (nucleophile, see Table XIV), preferably as solvent, at a temperature between 50° C. and reflux.

[0158] General Procedure D: Synthesis of Diaryl Ether Amides The diaryl ether amides of Formula II, Formula IV, and Formula V can be prepared by amidation via the corresponding acid chloride, for example, by reaction of thionyl chloride with a diaryl ether acid in the presence of a catalytic amount of DMF in a solvent such as toluene at temperatures between 50°C and 100°C under an inert atmosphere such as argon. After removal of volatiles, the resulting acid chloride intermediate is reacted with an amine corresponding to the desired amide (nucleophile, see Table XIV) in a solvent such as methanol, ethanol, or tetrahydrofuran under an inert atmosphere such as argon at temperatures between 0°C and room temperature. The presence of an organic base such as triethylamine is necessary if the hydrochloride salt of the amine is used. JPEG0007807487000049.jpg243166JPEG0007807487000050.jpg246166JPEG000 7807487000051.jpg243166JPEG0007807487000052.jpg243166JPEG00078074870 00053.jpg247166JPEG0007807487000054.jpg247166JPEG0007807487000055.j pg247166JPEG0007807487000056.jpg249166JPEG0007807487000057.jpg103166

[0159] Synthesis of representative compounds Compound 005: 4-(4-pentylphenoxy)benzoic acid JPEG0007807487000058.jpg2783 According to general procedure B, to a solution of ethyl 4-(4-pentylphenoxy)benzoate (1.69 g, 5.4 mmol) in THF (25 mL) and MeOH (3 mL) was added 2 M aqueous NaOH (10 mL, 20 mmol), and the reaction was stirred at room temperature for 48 h. The organic solvent was evaporated, and the residue was acidified with 5 M aqueous HCl to adjust the pH to 1-2. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by recrystallization from warm EtOAc to give the title compound (1.21 g, 79%) as a colorless solid. 1 H NMR (300MHz, CDCl3) δ8.12-8.01(m, 2H), 7.25-7.15(m, 2H), 7.05-6.94(m, 4H), 2.68-2. 57(m, 2H), 1.72-1.56(m, 2H), 1.46-1.33(m, 2H), 1.38-1.23(m, 2H), 0.97-0.86(m, 3H). 13 C NMR (75MHz, CDCl3) δ171.9, 163.3, 153.2, 139.7, 132.5, 130.0, 123.3, 120.4, 117.0, 35.4, 31.6, 31.4, 22.7, 14.2. HRMS(C 18 H 19 O3 - ): Predicted value: 283.1339; Found value: 283.1326.

[0160] Compound 030: Methyl 4-(4-(tert-pentyl)phenoxy)benzoate JPEG0007807487000059.jpg3183 According to general procedure C, to a solution of 4-(4-(tert-pentyl)phenoxy)benzoic acid (122 mg, 0.43 mmol) in MeOH (2 mL) was added SOCl (0.1 mL, 1.4 mmol) at 0 °C, and the reaction was then stirred at 80 °C in a sealed vessel under an argon atmosphere for 3 h. The reaction was cooled to room temperature and quenched by the addition of saturated aqueous NaHCO. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 90% PE-EtOAc gradient to give the title compound (120 mg, 94%) as a colorless oil. 1 H NMR (300MHz, CDCl3) δ8.05-7.94(m, 2H), 7.39-7.28(m, 2H), 7.04-6.92(m, 4 H), 3.89(s, 3H), 1.65(q, J=7.4Hz, 2H), 1.30(s, 6H), 0.71(t, J=7.4Hz, 3H). 13 C NMR (75MHz, CDCl3) δ166.8, 162.3, 153.1, 146.0, 131.8, 127.6, 124.3, 119.7, 117.2, 52.1, 37.8, 37.1, 28.7, 9.3. HRMS(C 19 H 23 O3 + ): Predicted value: 299.1642; Found value: 299.1640.

[0161] Compound 044: (±)-Methyl 4-(4-(bicyclo[2.2.2]octan-2-yl)phenoxy)benzoate JPEG0007807487000060.jpg2883 According to general procedure C, to a solution of (±)-4-(4-(bicyclo[2.2.2]octan-2-yl)phenoxy)benzoic acid (30.3 mg, 0.1 mmol) in toluene (1 mL) was added 1 drop of DMF followed by SOCl (0.02 mL, 0.3 mmol) at room temperature, and the reaction was then stirred at 80 °C for 3.5 h under an argon atmosphere. The reaction was cooled to room temperature, and the volatiles were evaporated on a rotary evaporator. A solution of NEt (0.2 mL, 1.4 mmol) in MeOH (1 mL) was added, and the reaction was stirred overnight at room temperature under an argon atmosphere. The reaction was quenched by the addition of 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 85% PE-EtOAc gradient to afford the title compound as a colorless oil (29.3 mg, 93%). 1 H NMR (300MHz, CDCl3) δ8.05-7.94(m, 2H), 7.35-7.21(m, 2H), 7.06-6.91(m, 4H), 3.89(s, 3H), 3.11 -2.94(m, 1H), 2.01(dddd, J=12.9, 10.6, 3.9, 1.9Hz, 1H), 1.85-1.45(m, 10H), 1.43-1.23(m, 1H). 13 C NMR (75MHz, CDCl3) δ166.8, 162.3, 153.3, 143.1, 131.8, 129.3, 124.3, 120.0, 117.1, 52.1, 41.4, 32.6, 31.2, 27.6, 26.1, 25.4, 24.9, 20.6. HRMS(C 22 H 25 O3 + ): Predicted value: 337.1798; Found value: 337.1778.

[0162] Compound 051: Ethyl 4-(4-butylphenoxy)benzoate JPEG0007807487000061.jpg2683 According to general procedure A, to 4-butylphenol (1.75 mL, 11.4 mmol) and K2CO3 (1.89 g, 13.7 mmol) in DMSO (18 mL) was added ethyl 4-fluorobenzoate (1.35 mL, 9.2 mmol), and the reaction was then stirred at 120 °C for 3 days under an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of water. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed first with 1 M aqueous NaOH (1x), then with brine (1x), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 70% PE-DCM gradient to give the title compound (1.72 g, 63%) as a colorless oil. 1 H NMR (300MHz, CDCl3) δ8.05-7.94(m, 2H), 7.24-7.13(m, 2H), 7.02-6.91(m, 4H), 4.36(q, J=7 .1Hz, 2H), 2.67-2.56(m, 2H), 1.69-1.53(m, 2H), 1.47-1.23(m, 5H), 0.95(t, J=7.3Hz, 3H). 13 C NMR (75MHz, CDCl3) δ166.3, 162.3, 153.5, 139.4, 131.7, 130.0, 124.7, 120.1, 117.1, 60.9, 35.1, 33.8, 22.5, 14.5, 14.1. HRMS(C 19 H 23 O3 + ): Predicted value: 299.1642; Found value: 299.1642.

[0163] Compound 071: 6-(4-propylphenoxy)nicotinic acid JPEG0007807487000062.jpg3183 Following general procedure B, to a solution of ethyl 6-(4-propylphenoxy)nicotinate (2.11 g, 7.4 mmol) in EtOH (15 mL) was added 2 M aqueous NaOH (10 mL, 20 mmol) and the reaction was stirred at room temperature for 48 h. The reaction was acidified with 5 M aqueous HCl to adjust the pH to 1-2. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by recrystallization from warm EtOAc to give the title compound (1.26 g, 66%) as a colorless solid. 1 H NMR (300MHz, CDCl3) δ11.01 (br, s, 1H), 8.92 (dd, J=2.4, 0.7Hz, 1H), 8.31 (dd, J=8.7, 2.4Hz, 1H), 7.28-7.18 (m, 2H), 7 .12-7.02(m, 2H), 6.94(dd, J=8.7, 0.7Hz, 1H), 2.61(dd, J=8.7, 6.7Hz, 2H), 1.76-1.58(m, 2H), 0.97(t, J=7.3Hz, 3H). 13 C NMR (75MHz, CDCl3) δ170.5, 167.4, 151.4, 151.2, 141.2, 140.2, 129.9, 121.3, 120.3, 110.9, 37.6, 24.6, 14.0. HRMS(C 15 H 14 No. 3 - ): Predicted value: 256.0979; Found value: 256.0979.

[0164] Compound 114: Methyl 6-(4-(adamantan-1-yl)phenoxy)nicotinate JPEG0007807487000063.jpg2883 According to general procedure C, to a solution of 6-(4-(adamantan-1-yl)phenoxy)nicotinic acid (170 mg, 0.49 mmol) in MeOH (2 mL) was added SOCl (0.1 mL, 1.37 mmol) at room temperature, and the reaction was then stirred at 80 °C in a sealed vessel under an argon atmosphere for 3.5 h. The reaction was cooled to room temperature and quenched by the addition of saturated aqueous NaHCO. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 90% PE-EtOAc gradient to give the title compound (47 mg, 27%) as a colorless solid. 1 H NMR (300MHz, CDCl3) δ8.84(dd, J=2.4, 0.7Hz, 1H), 8.25(dd, J=8.6, 2.4Hz, 1H), 7.46-7.35(m, 2H), 7.15-7.04(m , 2H), 6.90(dd, J=8.6, 0.7Hz, 1H), 3.91(s, 3H), 2.11(p, J=3.0Hz, 4H), 1.93(d, J=2.9Hz, 6H), 1.87-1.68(m, 6H). 13 C NMR (75MHz, CDCl3) δ166.7, 165.6, 150.9, 150.5, 148.4, 140.5, 126.3, 121.0, 120.7, 110.7, 52.2, 43.3, 36.8, 36.0, 29.0. HRMS(C 23 H 26 No. 3 + ): Predicted value: 364.1907; Found value: 364.1900.

[0165] Compound 117: Ethyl 6-(4-ethylphenoxy)nicotinate JPEG0007807487000064.jpg3083 According to general procedure A, to 4-ethylphenol (1.36 g, 11.1 mmol) and K2CO3 (1.89 g, 13.7 mmol) in DMSO (18 mL) was added ethyl 6-chloronicotinate (1.65 mL, 10.9 mmol), and the reaction was then stirred at 80 °C for 48 h under an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of water. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed first with 1 M aqueous NaOH (1x), then with brine (1x), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 60% PE-MeOH gradient to give the title compound (1.78 g, 60%) as a colorless oil. 1 H NMR (300MHz, CDCl3) δ8.83(dd, J=2.4, 0.7Hz, 1H), 8.25(dd, J=8.6, 2.4Hz, 1H), 7.28-7.20(m, 2H), 7.11-7.00(m, 2H), 6 .90(dd, J=8.7, 0.8Hz, 1H), 4.37(q, J=7.1Hz, 2H), 2.68(q, J=7.6Hz, 2H), 1.38(t, J=7.1Hz, 3H), 1.26(t, J=7.6Hz, 3H). 13 C NMR (75MHz, CDCl3) δ166.8, 165.2, 151.3, 150.5, 141.4, 140.6, 129.3, 121.4, 121.3, 110.7, 61.2, 28.4, 15.6, 14.4. HRMS(C 16 H 18 No. 3 + ): Predicted value: 272.1281; Found value: 272.1271.

[0166] Compound 159: (±)-4-(4-(bicyclo[2.2.1]heptan-2-yl)phenoxy)benzamide, a mixture of endo and exo JPEG0007807487000065.jpg2883 According to general procedure D, to a solution of (±)-4-(4-(bicyclo[2.2.1]heptan-2-yl)phenoxy)benzoic acid (50.2 mg, 0.16 mmol) in toluene (0.8 mL) was added 1 drop of DMF followed by SOCl (0.04 mL, 0.55 mmol) at room temperature, and the reaction was then stirred at 80 °C for 3 h under an argon atmosphere. The reaction was cooled to room temperature, and the volatiles were evaporated on a rotary evaporator. 2 M ammonia in MeOH (0.6 mL, 1.3 mmol) was added, and the reaction was stirred overnight at room temperature under an argon atmosphere. The reaction was quenched by the addition of 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 10% PE-EtOAc gradient to give the title compound as a colorless solid (46.6 mg, 93%, 6:1 mixture endo:exo). 1 H NMR (300 MHz, CDCl, 0.3:1 mixture of rotamers and 6:1 diastereomers) δ 7.82-7.72 (m, 2H), 7.26-7.13 (m, 2H), 7.08-6.91 (m, 4H), 6.05 (s, 2H), 3.20 (major diastereomer, tt, J = 14.0, 4.8 Hz, 0.85H), 2.79-2.70 (minor diastereomer, m, 0.15H), 2.46-2.29 (major diastereomer, m, 1.7H), 2.28-2.14 (minor diastereomer, m, 0.3H), 2.12-1.10 (m, 8H). 13C NMR (75 MHz, CDCl3, 0.3:1 mixture of rotamers and 6:1 diastereomers) δ 169.0, 161.5, 161.4, 153.5, 153.3, 144.1, 140.1, 139.9, 129.8, 129.7, 129.5, 128.6, 127.5, 127.4, 119.9, 119.7, 119.6, 11 7.6, 117.5, 117.4, 50.3, 46.9, 46.6, 45.6, 43.6, 43.1, 42.7, 42.4, 42.2, 42.1, 41.6, 41.1 , 40.7, 39.4, 37.7, 37.7, 37.0, 36.7, 36.4, 36.2, 34.6, 30.7, 30.3, 29.0, 24.7, 24.6, 23.0. HRMS(C 20 H 22 NO2 + ): Predicted value: 308.1645; Found value: 308.1624.

[0167] Compound 186: 4-(4-(adamantan-1-yl)phenoxy)-N-hydroxybenzamide JPEG0007807487000066.jpg2783 According to general procedure D, to a solution of 4-(4-(adamantan-1-yl)phenoxy)benzoic acid (200 mg, 0.57 mmol) in toluene (2 mL) was added 2 drops of DMF followed by SOCl (0.1 mL, 1.37 mmol) at room temperature, and the reaction was then stirred at 80 °C for 3.5 h under an argon atmosphere. The reaction was cooled to room temperature, and the volatiles were evaporated on a rotary evaporator. Hydroxylamine hydrochloride (208 mg, 3 mmol) in a solution of NEt (1.0 mL, 7.2 mmol) and MeOH (2 mL) was added, and the reaction was stirred overnight at room temperature under an argon atmosphere. The reaction was quenched by the addition of 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed first with 1 M aqueous HCl (1×), then with brine (1×), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 30% PE-EtOAc gradient to give the title compound (176 mg, 84%) as a colorless solid. 1 H NMR (300MHz, CDCl3 / DMSO-d6) δ11.10(s, 1H), 8.87(s, 1H), 7.80-7.69(m, 2H), 7.37-7.26 (m, 2H), 6.98-6.86(m, 4H), 2.09-2.01(m, 4H), 1.85(d, J=2.8Hz, 6H), 1.81-1.63(m, 6H). 13 C NMR (75MHz, CDCl3 / DMSO-d6) δ163.8, 159.7, 152.9, 146.7, 128.6, 126.7, 126.0, 118.9, 116.7, 42.6, 36.1, 35.3, 28.2. HRMS(C 23 H 24 No. 3 - ): Predicted value: 362.1761; Found value: 362.1672.

[0168] Compound 195: 4-(4-isopropylphenoxy)-N-methylbenzamide JPEG0007807487000067.jpg3383 According to general procedure D, to a solution of 4-(4-isopropylphenoxy)benzoic acid (177 mg, 0.7 mmol) in toluene (2.5 mL) was added 2 drops of DMF followed by SOCl (0.15 mL, 2.1 mmol) at room temperature, and the reaction was then stirred at 80 °C for 3 h under an argon atmosphere. The reaction was cooled to room temperature, and the volatiles were evaporated on a rotary evaporator. 33 wt% methylamine in EtOH (2 mL, 16 mmol) was added, and the reaction was stirred overnight at room temperature under an argon atmosphere. The reaction was quenched by the addition of 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 40% PE-EtOAc gradient to give the title compound as a colorless solid (178 mg, 94%). 1 H NMR (300MHz, CDCl3) δ7.78-7.67(m, 2H), 7.27-7.16(m, 2H), 7.01-6.90(m, 4H), 6. 31(s, 1H), 2.98(d, J=4.6Hz, 3H), 2.90(hept, J=6.9Hz, 1H), 1.26(d, J=6.9Hz, 6H). 13 C NMR (75MHz, CDCl3) δ167.8, 160.8, 153.8, 145.1, 128.8, 128.8, 127.9, 119.8, 117.5, 33.6, 26.9, 24.2. HRMS(C 17 H 18 NO2 - ): Predicted value: 268.1343; Found value: 268.1384.

[0169] Compound 222: 4-(4-(tert-butyl)phenoxy)-N,N-dimethylbenzamide JPEG0007807487000068.jpg3383 According to general procedure D, to a solution of 4-(4-(tert-butyl)phenoxy)benzoic acid (154 mg, 0.57 mmol) in toluene (2.5 mL) was added 2 drops of DMF followed by SOCl (0.1 mL, 1.4 mmol) at room temperature, and the reaction was then stirred at 80 °C for 3 h under an argon atmosphere. The reaction was cooled to room temperature, and the volatiles were evaporated on a rotary evaporator. 2 M dimethylamine in THF (2.5 mL, 5 mmol) was added, and the reaction was stirred at room temperature overnight under an argon atmosphere. The reaction was quenched by the addition of 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 40% PE-EtOAc gradient to give the title compound as a colorless oil (166 mg, 98%). 1 H NMR (300MHz, CDCl3) δ7.44-7.31(m, 4H), 7.03-6.91(m, 4H), 3.06(s, 6H), 1.33(s, 9H). 13 C NMR (75MHz, CDCl3) δ171.4, 159.1, 153.9, 147.0, 130.6, 129.2, 126.8, 119.2, 117.8, 39.9(br), 35.6(br), 34.5, 31.6. HRMS(C 19 H 24 NO2 + ): Predicted value: 298.1802; Found value: 298.1820.

[0170] Compound 241: 6-(p-Tolyloxy)nicotinamide JPEG0007807487000069.jpg3683 According to general procedure D, to a solution of 6-(p-tolyloxy)nicotinic acid (148 mg, 0.66 mmol) in toluene (2.5 mL) was added 2 drops of DMF followed by SOCl (0.12 mL, 1.6 mmol) at room temperature, and the reaction was then stirred at 80 °C for 3.5 h under an argon atmosphere. The reaction was cooled to room temperature, and the volatiles were evaporated on a rotary evaporator. 2 M ammonia in MeOH (3 mL, 1.3 mmol) was added, and the reaction was stirred overnight at room temperature under an argon atmosphere. The reaction was quenched by the addition of 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3 ×). The combined organics were washed with brine (1 ×), dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 20% PE-EtOAc gradient to give the title compound (104 mg, 70%) as a colorless solid. 1 H NMR (300 MHz, CDCl / DMSO-d, 0.3:1 mix of rotamers): δ 8.89 (d, J = 2.5 Hz, 0.25 H, minor rotamer), 8.65 (d, J = 2.4 Hz, 0.75 H, major rotamer), 8.25 (dt, J = 8.6, 2.9 Hz, 1 H), 7.96 (br, s, 1 H), 7.49 (d, J = 8.4 Hz, 0.25 H, minor rotamer), 7.27 (br, s, 1 H), 7.21 (d, J = 8.2 Hz, 2 H), 7.06-6.97 (m, 2 H), 6.93 (d, J = 8.6 Hz, 0.75 H, major rotamer), 2.35 (s, 3 H). 13 C NMR (75 MHz, CDCl3 / DMSO-d6, 0.3:1 mix of rotamers) δ 166.6, 165.9 (minor rotamer), 165.4 (major rotamer), 153.3 (minor rotamer), 151.5 (major rotamer), 149.7 (minor rotamer), 148.0 (major rotamer), 139.5 (major rotamer), 138.9 (minor rotamer), 134.4, 130.3, 129.3 (minor rotamer), 125.2 (major rotamer), 124.1 (minor rotamer), 121.4, 110.5 (major rotamer), 20.9. HRMS (C 13 H 13 N2O2 +): Predicted value: 229.0972; Found value: 229.0978.

[0171] Compound 275: N-hydroxy-6-(4-(trifluoromethyl)phenoxy)nicotinamide JPEG0007807487000070.jpg3083 According to general procedure D, to a solution of 6-(4-(trifluoromethyl)phenoxy)nicotinic acid (62.9 mg, 0.22 mmol) in toluene (1.5 mL) was added 2 drops of DMF followed by SOCl (0.06 mL, 0.82 mmol) at room temperature, and the reaction was then stirred at 80 °C for 3 h under an argon atmosphere. The reaction was cooled to room temperature, and the volatiles were evaporated on a rotary evaporator. Hydroxylamine hydrochloride (94 mg, 1.35 mmol) in a solution of NEt (0.5 mL, 3.6 mmol) and MeOH (1 mL) was added, and the reaction was stirred overnight at room temperature under an argon atmosphere. The reaction was quenched by the addition of 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a gradient of 90% to 40% PE-EtOAc (+0.2% AcOH) to afford the title compound as a colorless solid (42.7 mg, 65%). 1 H NMR (300MHz, CDCl3 / DMSO-d6) δ11.29(s, 1H), 9.07(s, 1H), 8.52(d, J=2.4Hz, 1H), 8.19(d d, J=8.6, 2.4Hz, 1H), 7.69(d, J=8.4Hz, 2H), 7.29(d, J=8.4Hz, 2H), 7.06(d, J=8.5Hz, 1H). 13 C NMR (75MHz, CDCl3 / DMSO-d6) δ163.6, 161.9, 156.2 (d, J=1.5Hz), 146.4, 138.8, 126.6 ( q, J=3.8Hz), 125.6(q, J=32.4Hz), 124.2, 123.8(q, J=273.0Hz), 121.5, 111.1.HRMS(C 13 H8F3N2O3- ): Predicted value: 297.0492; Found value: 297.0597.

[0172] Compound 284: 6-(4-cyclohexylphenoxy)-N-hydroxynicotinamide JPEG0007807487000071.jpg2783 According to general procedure D, to a solution of 6-(4-cyclohexylphenoxy)nicotinic acid (150 mg, 0.5 mmol) in toluene (2 mL) was added 2 drops of DMF followed by SOCl (0.1 mL, 1.4 mmol) at room temperature, and the reaction was then stirred at 80 °C for 3 h under an argon atmosphere. The reaction was cooled to room temperature, and the volatiles were evaporated on a rotary evaporator. Hydroxylamine hydrochloride (208 mg, 3 mmol) in a solution of NEt (1.0 mL, 7.2 mmol) and MeOH (2 mL) was added, and the reaction was stirred overnight at room temperature under an argon atmosphere. The reaction was quenched by the addition of 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 95% PE-EtOAc gradient to give the title compound as a colorless solid (150 mg, 95%). 1 H NMR (300MHz, CDCl3 / DMSO-d6) δ11.27(s, 1H), 9.05(s, 1H), 8.54(s, 1H), 8.20-8.06(m, 1H), 7.23(d, J=8.0Hz, 2H), 7.02(d, J=8. 0Hz, 2H), 6.95(d, J=8.6Hz, 1H), 1.86(d, J=8.3Hz, 4H), 1.74(d, J=12.6Hz, 1H), 1.43(q, J=11.3, 10.1Hz, 4H), 1.35-1.16(m, 2H). 13 C NMR (75MHz, CDCl3 / DMSO-d6) δ163.4, 160.9, 149.8, 145.2, 142.8, 137.1, 126.2, 122.0, 119.5, 109.0, 41.9, 32.7, 25.0, 24.2. HRMS(C 18H 21 N2O3 + ): Predicted value: 313.1547; Found value: 313.1622.

[0173] Compound 297: 6-(4-isopropylphenoxy)-N-methylnicotinamide JPEG0007807487000072.jpg3383 According to general procedure D, to a solution of 6-(4-isopropylphenoxy)nicotinic acid (151 mg, 0.6 mmol) in toluene (2.5 mL) was added 2 drops of DMF followed by SOCl (0.1 mL, 1.5 mmol) at room temperature, and the reaction was then stirred at 80 °C for 3 h under an argon atmosphere. 33 wt% methylamine in EtOH (2.5 mL, 20 mmol) was added, and the reaction was stirred overnight at room temperature under an argon atmosphere. The reaction was quenched by the addition of 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 20% PE-EtOAc gradient to give the title compound (150 mg, 96%) as a colorless solid. 1 H NMR (300MHz, CDCl3) δ8.55(dd, J=2.5, 0.7Hz, 1H), 8.11(dd, J=8.6, 2.5Hz, 1H), 7.32-7.21(m, 2H), 7.11-7.00(m, 2H), 6. 90(dd, J=8.6, 0.7Hz, 1H), 6.47(d, J=5.3Hz, 1H), 2.98(d, J=4.7Hz, 3H), 2.94(hept, J=7.0Hz, 1H), 1.27(d, J=6.9Hz, 6H). 13 C NMR (75MHz, CDCl3) δ166.1, 165.8, 151.4, 146.6, 145.9, 139.0, 127.8, 125.3, 121.1, 111.0, 33.7, 26.9, 24.1. HRMS(C 16 H 19 N2O2 + ): Predicted value: 271.1441; Found value: 271.1491.

[0174] Compound 322: 6-(4-isopropylphenoxy)-N,N-dimethylnicotinamide JPEG0007807487000073.jpg3383 According to general procedure D, to a solution of 6-(4-isopropylphenoxy)nicotinic acid (156 mg, 0.6 mmol) in toluene (2.5 mL) was added 2 drops of DMF followed by SOCl (0.1 mL, 1.5 mmol) at room temperature, and the reaction was then stirred at 80 °C for 3 h under an argon atmosphere. The reaction was cooled to room temperature, and the volatiles were evaporated on a rotary evaporator. 2 M dimethylamine in THF (2.5 mL, 5.4 mmol) was added, and the reaction was stirred overnight at room temperature under an argon atmosphere. The reaction was quenched by the addition of 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 30% PE-EtOAc gradient to give the title compound (169 mg, 98%) as a colorless oil. 1 H NMR (300MHz, CDCl3) δ8.28(dd, J=2.4, 0.8Hz, 1H), 7.79(dd, J=8.5, 2.4Hz, 1H), 7.31-7.20(m, 2H), 7.11- 7.00(m, 2H), 6.91(dd, J=8.5, 0.7Hz, 1H), 3.07(s, 6H), 2.92(hept, J=7.0Hz, 1H), 1.26(d, J=6.9Hz, 6H). 13 C NMR (75MHz, CDCl3) δ168.9, 164.5, 151.4, 146.8, 145.6, 139.2, 127.7, 126.6, 121.0, 111.0, 39.7(br), 35.6(br), 33.6, 24.1. HRMS(C 17 H 21 N2O2 + ): Predicted value: 285.1598; Found value: 285.1643.

[0175] Compound 344: 4-(4-(butylphenoxy)-3-fluorobenzoic acid JPEG0007807487000074.jpg3583 According to general procedure B, to a solution of ethyl 4-(4-butylphenoxy)-3-fluorobenzoate (1.42 g, 4.5 mmol) in EtOH (9 mL) was added 2 M aqueous NaOH (5 mL, 10 mmol) and the reaction was stirred at room temperature overnight. 1 M aqueous HCl was added to adjust the pH to 1-2. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (2x), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by recrystallization from warm EtOAc to give the title compound as a colorless solid (0.56 g, 43%). 1 H NMR (300MHz, CDCl3) δ11.18 (br, s, 1H), 7.91 (dd, J=11.0, 2.0Hz, 1H), 7.82 (ddd, J=8.6, 2.0, 1.1Hz, 1H), 7.26-7 .15(m, 2H), 7.04-6.88(m, 3H), 2.68-2.57(m, 2H), 1.70-1.54(m, 2H), 1.47-1.23(m, 2H), 0.95(t, J=7.3Hz, 3H). 13 C NMR (75MHz, CDCl3) δ171.0(d, J=2.5Hz), 153.3, 152.9(d, J=249.5Hz), 150.8(d, J=11.0Hz), 139.7, 130.1, 127 .3(d, J=3.5Hz), 124.3(d, J=6.5Hz), 119.4, 118.9(d, J=19.9Hz), 118.6(d, J=1.4Hz), 35.1, 33.8, 22.5, 14.1. HRMS(C 17 H 16 FO3 - ): Predicted value: 287.1089; Found value: 287.1062.

[0176] Compound 395: Ethyl 4-(4-butylphenoxy)-3-fluorobenzoate JPEG0007807487000075.jpg3383 According to general procedure A, to 4-butylphenol (1.75 mL, 11.4 mmol) and K2CO3 (1.90 g, 13.8 mmol) in DMSO (18 mL) was added ethyl 3,4-difluorobenzoate (1.37 mL, 9 mmol), and the reaction was then stirred at 80 °C for 24 h under an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of water. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed first with 1 M aqueous NaOH (1x), then with brine (1x), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 80% PE-DCM gradient to give the title compound (1.80 g, 63%) as a colorless oil. 1 H NMR (300MHz, CDCl3) δ7.84(dd, J=11.2, 2.0Hz, 1H), 7.75(ddd, J=8.5, 2.0, 1.2Hz, 1H), 7.23-7.12(m, 2H), 7.01-6. 88(m, 3H), 4.37(q, J=7.1Hz, 2H), 2.67-2.55(m, 2H), 1.68-1.52(m, 2H), 1.46-1.23(m, 5H), 0.94(t, J=7.3Hz, 3H). 13 C NMR (75MHz, CDCl3) δ165.4(d, J=2.6Hz), 153.7, 153.0(d, J=249.0Hz), 149.5(d, J=11.2Hz), 139.3, 129.9, 126.4(d, J=3.5Hz), 126.0(d, J=6.3Hz), 119.0, 119.0(d, J=1.4Hz), 118.3(d, J=19.9Hz), 61.3, 35.1, 33.8, 22.5, 14.4, 14.1. HRMS(C 19 H 22 FO3 + ): Predicted value: 317.1548; Found value: 317.1549.

[0177] Compound 451: Methyl 5-fluoro-6-(4-(tert-pentyl)phenoxy)nicotinate JPEG0007807487000076.jpg3883 According to general procedure C, to a solution of 5-fluoro-6-(4-(tert-pentyl)phenoxy)nicotinic acid (100 mg, 0.33 mmol) in MeOH (2 mL) was added SOCl (0.1 mL, 1.4 mmol) at 0 °C, and the reaction was then stirred at 80 °C for 3 h under an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of saturated aqueous NaHCO. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 90% PE-EtOAc gradient to give the title compound (30 mg, 29%) as a colorless solid. 1 H NMR (300MHz, CDCl3) δ8.56 (d, J=1.9Hz, 1H), 8.02 (dd, J=10.0, 1.9Hz, 1H), 7.43-7.31 (m, 2H) , 7.17-7.04(m, 2H), 3.92(s, 3H), 1.66(q, J=7.4Hz, 2H), 1.31(s, 6H), 0.72(t, J=7.4Hz, 3H). 13 C NMR (75MHz, CDCl3) δ164.8(d, J=1.6Hz), 155.7(d, J=11.1Hz), 150.4, 147.1(d, J=261.8Hz), 146.9, 14 4.4(d, J=6.1Hz), 127.4, 125.0(d, J=17.0Hz), 122.1(d, J=1.7Hz), 120.7, 52.6, 37.9, 37.1, 28.6, 9.3. HRMS(C 18 H 21 FNO3 + ): Predicted value: 318.1500; Found value: 318.1555.

[0178] Compound 544: 4-(4-(adamantan-1-yl)phenoxy)-3-fluoro-N-hydroxybenzamide JPEG0007807487000077.jpg3383 According to general procedure D, to a solution of 4-(4-(adamantan-1-yl)phenoxy)-3-fluorobenzoic acid (110 mg, 0.3 mmol) in toluene (2 mL) was added 2 drops of DMF followed by SOCl (0.1 mL, 1.4 mmol) at room temperature, and the reaction was then stirred at 80 °C for 3.5 h under an argon atmosphere. The reaction was cooled to room temperature, and the volatiles were evaporated on a rotary evaporator. NEt (0.7 mL, 5.1 mmol) and hydroxylamine hydrochloride (148 mg, 2.1 mmol) in MeOH (1.5 mL) were added, and the reaction was stirred overnight at room temperature under an argon atmosphere. The reaction was quenched by the addition of 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified twice by silica gel flash chromatography, eluting first with a 100% to 40% PE-EtOAc gradient and then with a 100% to 97% DCM-MeOH gradient, to give the title compound as a colorless solid (60 mg, 52%). 1 H NMR (300MHz, CDCl3 / DMSO-d6) δ11.23(s, 1H), 9.00(s, 1H), 7.68(dd, J=11.6, 2.0Hz, 1H), 7.57(ddd, J=8.5, 2.1, 1.1Hz, 1H) , 7.37-7.25(m, 2H), 6.97(t, J=8.4Hz, 1H), 6.96-6.86(m, 2H), 2.12-1.97(m, 4H), 1.84(d, J=2.9Hz, 6H), 1.80-1.63(m, 6H). 13 C NMR (75MHz, CDCl3 / DMSO-d6) δ162.4, 153.2, 152.4 (d, J=247.5Hz), 146.6, 146.3 (d, J=11.1Hz) , 128.4(d, J=5.7Hz), 126.0, 123.5, 119.5, 117.4, 115.5(d, J=19.6Hz), 42.6, 36.1, 35.3, 28.2. HRMS(C 23 H 23 FNO3 - ): Predicted value: 380.1667; Found value: 380.1541.

[0179] Compound 644: 6-(4-cyclohexylphenoxy)-5-fluoro-N-hydroxynicotinamide JPEG0007807487000078.jpg3383 According to general procedure D, to a solution of 6-(4-cyclohexylphenoxy)-5-fluoronicotinic acid (120 mg, 0.4 mmol) in toluene (2.5 mL) was added 2 drops of DMF followed by SOCl (0.1 mL, 1.4 mmol) at room temperature, and the reaction was then stirred at 80 °C for 3.5 h under an argon atmosphere. The reaction was cooled to room temperature, and the volatiles were evaporated on a rotary evaporator. Hydroxylamine hydrochloride (208 mg, 3 mmol) in a solution of NEt (1.0 mL, 7.2 mmol) and MeOH (2 mL) was added, and the reaction was stirred overnight at room temperature under an argon atmosphere. The reaction was quenched by the addition of 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 30% PE-EtOAc gradient to give the title compound as a colorless solid (110 mg, 88%). 1 H NMR (300MHz, CDCl3 / DMSO-d6) δ11.32(s, 1H), 9.12(s, 1H), 8.28(d, J=1.9Hz, 1H), 8.06-7.94(m, 1H), 7.26-7 .15(m, 2H), 7.08-6.97(m, 2H), 1.88-1.75(m, 4H), 1.75-1.64(m, 1H), 1.48-1.31(m, 4H), 1.31-1.13(m, 2H). 13 C NMR (75MHz, CDCl3 / DMSO-d6) δ161.0, 153.2 (d, J=11.3Hz), 150.4, 146.3 (d, J=259.6H z), 144.4, 140.6, 127.4, 124.5, 123.1 (d, J=16.7Hz), 120.7, 43.2, 34.0, 26.2, 25.5. HRMS(C 18 H 18 FN2O3 - ): Predicted value: 329.1307; Found value: 329.1279.

[0180] Compound 703: 4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoic acid JPEG0007807487000079.jpg3183 According to general procedure B, to a solution of ethyl 4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoate (0.86 g, 2.5 mmol) in EtOH (20 mL) was added 2 M aqueous NaOH (10 mL, 20 mmol) and the reaction was stirred at room temperature overnight. 1 M aqueous HCl was added to adjust the pH to 1-2. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (2×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 75% PE-EtOAc (+0.2% AcOH) gradient to give the title compound (0.75 g, 95%) as a slightly yellow solid. 1 H NMR (300MHz, CDCl3) δ11.15 (br, s, 1H), 8.15-8.04 (m, 2H), 7.54-7.43 (m, 2H), 7.09-6.98 (m, 4H), 1.38 (dd, J=6.7, 5.1Hz, 2H), 1.07-1.01 (m, 2H). 13 C NMR (75MHz, CDCl3) δ171.8, 162.3, 155.7, 133.2, 132.6, 132.5, 126.5 (q, J=273.4Hz), 124.0, 119.9, 117.8, 27.8 (q, J=33.7Hz), 10.0 (q, J=2.4Hz). HRMS(C 17 H 12 F3O3 - ): Predicted value: 321.0744; Found value: 321.0712.

[0181] Compound 712: Methyl 4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoate JPEG0007807487000080.jpg3083 According to general procedure C, to a solution of 4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoic acid (112 mg, 0.35 mmol) in toluene (2 mL) was added 2 drops of DMF followed by SOCl (0.1 mL, 1.4 mmol) at room temperature, and the reaction was then stirred at 80 °C for 3.5 h under an argon atmosphere. The reaction was cooled to room temperature, and the volatiles were evaporated on a rotary evaporator. A solution of NEt (0.6 mL, 4.4 mmol) in MeOH (1.2 mL) was added, and the reaction was stirred at room temperature overnight under an argon atmosphere. The reaction was quenched by the addition of 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 85% PE-EtOAc gradient to afford the title compound as a colorless oil (176 mg, 93%). 1 H NMR (300MHz, CDCl3) δ8.07-7.96(m, 2H), 7.52-7.41(m, 2H), 7.07-6.95(m, 4H), 3.90(s, 3H), 1.41-1.31(m, 2H), 1.09-0.97(m, 2H). 13 C NMR (75MHz, CDCl3) δ166.7, 161.4, 156.0, 133.1, 132.2, 131.9, 126.4 (q, J=2 73.0Hz), 125.0, 119.7, 117.9, 52.2, 27.8(q, J=33.6Hz), 10.0(q, J=2.5Hz). HRMS(C 18 H 16 F3O3 + ): Predicted value: 337.1046; Found value: 337.1036.

[0182] Compound 729: Ethyl 4-(2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-benzoate JPEG0007807487000081.jpg3683 According to general procedure A, to 2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenol (245 mg, 1.5 mmol) and K2CO3 (220 mg, 1.6 mmol) in DMSO (2 mL) was added ethyl 4-fluorobenzoate (0.15 mL, 1.1 mmol), and the reaction was then stirred at 120 °C for 2 days under an argon atmosphere. K2CO3 (220 mg, 1.6 mmol) was added, and the reaction was then stirred at 150 °C for 9 hours under an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of water. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 70% PE-DCM gradient to give the title compound (100 mg, 18%) as a yellow oil. 1 H NMR (300MHz, CDCl3) δ8.08-7.97(m, 2H), 7.58(d, J=2.1Hz, 1H), 7.41-7.27(m, 1H), 7.03(d, J =8.4Hz, 1H), 7.03-6.88(m, 2H), 4.36(q, J=7.1Hz, 2H), 1.44-1.33(m, 5H), 1.11-1.00(m, 2H). 13 C NMR (75MHz, CDCl3) δ166.0, 160.7, 151.3, 133.9, 133.8, 131.7, 131.1, 126.2, 126.0(q , J=273.4Hz), 125.5, 121.6, 116.8, 60.9, 27.6(q, J=33.1Hz), 14.4, 10.0(q, J=2.3Hz). HRMS(C 19 H 17 ClF3O3 + ): Predicted value: 385.0813; Found value: 385.0796.

[0183] Compound 730: 6-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinic acid JPEG0007807487000082.jpg3183 According to general procedure B, to a solution of ethyl 6-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinate (1.47 g, 4.2 mmol) in EtOH (20 mL) was added 2 M aqueous NaOH (10 mL, 20 mmol) and the reaction was stirred overnight at room temperature. 1 M aqueous HCl was added to adjust the pH to 1-2. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (2×), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 75% PE-EtOAc (+0.2% AcOH) gradient to give the title compound (1.21 g, 90%) as a colorless solid. 1 H NMR (300MHz, CDCl3 / DMSO-d6) δ12.16(s, 1H), 8.80(d, J=2.4Hz, 1H), 8.30(dd, J=8.6, 2.3Hz, 1H), 7.51( dd, J=8.1, 1.6Hz, 2H), 7.19-7.08(m, 2H), 6.97(d, J=8.6Hz, 1H), 1.41-1.30(m, 2H), 1.18-1.02(m, 2H). 13 C NMR (75MHz, CDCl3 / DMSO-d6) δ166.1, 165.3, 152.9, 149.8, 140.5, 132.2, 132.2, 1 25.9(q, J=273.1Hz), 121.8, 120.7, 110.5, 27.1(q, J=33.5Hz), 9.3(q, J=2.4Hz). HRMS(C 16 H 13 F3NO3 + ): Predicted value: 324.0842; Found value: 324.0847.

[0184] Compound 749: Ethyl 6-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinate JPEG0007807487000083.jpg2683 According to general procedure A, to 4-(1-(perfluoroethyl)cyclopropyl)phenol (330 mg, 1.3 mmol) and K2CO3 (305 mg, 2.2 mmol) in DMSO (2.7 mL) was added ethyl 6-chloronicotinate (0.2 mL, 1.3 mmol), and the reaction was then stirred at 80 °C for 3 days under an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of water. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed first with 1 M aqueous NaOH (1x), then with brine (1x), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 90% PE-EtOAc gradient to give the title compound as a yellow oil (445 mg, 88%). 1 H NMR (300MHz, CDCl3) δ8.83(dd, J=2.4, 0.7Hz, 1H), 8.28(dd, J=8.6, 2.4Hz, 1H), 7.48(d, J=8.6Hz, 2H), 7.1 4-7.07(m, 2H), 6.93(dd, J=8.6, 0.7Hz, 1H), 4.38(q, J=7.1Hz, 2H), 1.43-1.34(m, 5H), 1.12-1.04(m, 2H). 13 C NMR (75 MHz, CDCl3) δ 166.14, 165.10, 153.39, 150.44, 140.84, 133.21, 133.12, 121.86, 121.20, 111.12, 61.31, 25.88 (t, J = 23.9 Hz), 14.42, 10.02 (t, J = 4.0 Hz). The two multiplets of CF2(tq) and CF3(qt) are too weak to resolve. HRMS (C 19 H 17 F5NO3+): Predicted value: 402.1123; Detected value: 402.1124.

[0185] Compound 784: N,N-dimethyl-4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-benzamide JPEG0007807487000084.jpg3083 According to general procedure D, to a solution of 4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoic acid (101 mg, 0.3 mmol) in toluene (2 mL) was added 2 drops of DMF followed by SOCl (0.1 mL, 1.4 mmol) at room temperature, and the reaction was then stirred at 80 °C for 3 h under an argon atmosphere. The reaction was cooled to room temperature, and the volatiles were evaporated on a rotary evaporator. 2 M dimethylamine in THF (1.2 mL, 2.5 mmol) was added, and the reaction was stirred at room temperature overnight under an argon atmosphere. The reaction was quenched by the addition of 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 15% PE-EtOAc gradient to give the title compound as a colorless oil (110 mg, 100%). 1 H NMR (300MHz, CDCl3) δ7.48-7.37(m, 4H), 7.06-6.92(m, 4H), 3.06(d, J=9.8Hz, 6H), 1.39-1.28(m, 2H), 1.07-0.95(m, 2H). 13 C NMR (75MHz, CDCl3) δ171.2, 158.2, 156.7, 133.0, 131.6, 131.4, 129.3, 126.5 (q, J=2 72.1Hz), 119.0, 118.6, 39.8(br), 35.6(br), 27.7(q, J=33.7Hz), 10.0(q, J=2.5Hz). HRMS(C 19 H 19 F3NO2 + ): Predicted value: 350.1363; Found value: 350.1351.

[0186] Compound 820: N,N-dimethyl-6-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-nicotinamide JPEG0007807487000085.jpg3083 According to general procedure D, to a solution of 6-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)nicotinic acid (162 mg, 0.5 mmol) in toluene (2 mL) was added 2 drops of DMF followed by SOCl (0.1 mL, 1.4 mmol) at room temperature, and the reaction was then stirred at 80 °C for 3 h under an argon atmosphere. The reaction was cooled to room temperature, and the volatiles were evaporated on a rotary evaporator. 2 M dimethylamine in THF (2.5 mL, 5 mmol) was added, and the reaction was stirred at room temperature overnight under an argon atmosphere. The reaction was quenched by the addition of 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 30% PE-EtOAc gradient to give the title compound as a colorless solid (172 mg, 100%). 1 H NMR (300MHz, CDCl3) δ8.28 (dd, J=2.4, 0.8Hz, 1H), 7.82 (dd, J=8.5, 2.4Hz, 1H), 7.54-7.44 (m, 2H), 7.1 6-7.06(m, 2H), 6.96(dd, J=8.5, 0.8Hz, 1H), 3.18-2.96(m, 6H), 1.40-1.29(m, 2H), 1.10-0.98(m, 2H). 13 C NMR (75MHz, CDCl3) δ168.8, 163.9, 153.5, 146.7, 139.3, 132.7, 132.7, 127.1, 126.3(q, J=274.0Hz), 121.0, 111.4, 39.7(br), 35.63(br), 27.7(q, J=33.6Hz), 9.8(q, J=2.5Hz). HRMS(C 18 H 18 F3N2O2 + ): Predicted value: 351.1315; Found value: 351.1293.

[0187] Synthesis of intermediates (±)-4-(bicyclo[2.2.1]heptan-2-yl)phenol, a mixture of endo and exo JPEG0007807487000086.jpg4183 To a solution of 4-acetoxystyrene (3 mL, 20 mmol) in dicyclopentadiene (3 mL, 22 mmol) was added hydroquinone (10 mg, 0.1 mmol). The reaction vessel was purged with argon and sealed. The reaction mixture was stirred at 160 °C for 24 h. The reaction mixture was filtered through silica and washed with DCM. The solution was concentrated in vacuo and used in the next step without further purification.

[0188] The resulting oil was dissolved in EtOAc (40 mL). Under an argon atmosphere, palladium on charcoal (5% Pd, 0.2 g, 0.1 mmol) was added and the reaction vessel was flushed with H. The reaction was stirred vigorously at room temperature for 22 h. The reaction mixture was then purged again with argon, filtered through Celite, washed with EtOAc, and concentrated in vacuo. The crude mixture was then filtered onto silica (PE / EtOAc), concentrated in vacuo, and used in the next step without further purification.

[0189] The resulting oil was dissolved in EtOH (40 mL) and 2 M aqueous NaOH (20 mL, 40 mmol) was added. The reaction mixture was stirred at room temperature for 17 h. The reaction was quenched with 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 0% PE-DCM gradient. Recrystallization in warm PE gave the title compound as white needles (1.5 g, 40%, 7:1 mixture endo:exo over 3 steps).

[0190] (±)-4-(bicyclo[2.2.2]octan-2-yl)phenol JPEG0007807487000087.jpg4183 To a solution of 4-acetoxystyrene (3 mL, 20 mmol) in cyclohexadiene (2.1 mL, 22 mmol) was added hydroquinone (10 mg, 0.1 mmol). The reaction vessel was purged with argon and sealed. The reaction mixture was stirred at 160° C. for 24 hours. The reaction mixture was filtered through silica and washed with DCM. The solution was concentrated in vacuo and used in the next step without further purification.

[0191] The resulting oil was dissolved in EtOAc (40 mL). Under an argon atmosphere, palladium on charcoal (5% Pd, 0.2 g, 0.1 mmol) was added and the reaction vessel was flushed with H. The reaction was stirred vigorously for 22 h. The reaction mixture was then purged again with argon, filtered through Celite, washed with EtOAc, and concentrated in vacuo. The crude mixture was then filtered onto silica (PE / DCM), concentrated in vacuo, and used in the next step without further purification.

[0192] The resulting oil was dissolved in EtOH (40 mL) and 2 M aqueous NaOH (20 mL, 40 mmol) was added. The reaction mixture was stirred at room temperature for 17 h. The reaction was quenched with 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 0% PE-DCM gradient. Recrystallization in warm PE gave the title compound as white needles (0.6 g, 15% over 3 steps).

[0193] 4-(1-(trifluoromethyl)cyclopropyl)phenol JPEG0007807487000088.jpg4683 According to the procedure by Anderson, K. et al., J. Am. Chem. Soc., 2006, 128(33), 10694-10695, 1-bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene (3.98 g, 15.0 mmol) was added to a solution of KOH (2.6 g, 46.3 mmol), Pd2dba3 (278 mg, 0.30 mmol), and di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphate (510 mg, 1.20 mmol) in degassed 1,4-dioxane (7.5 mL) and water (7.5 mL) under argon. The reaction vessel was then sealed and submerged in a preheated oil bath at 100 °C. The reaction was stirred for 4-10 h. The reaction was quenched with 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 90% PE-EtOAc gradient to give the title compound (3.0 g, 99%) as a yellow oil.

[0194] 2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenol JPEG0007807487000089.jpg5983 To a solution of 4-(1-(trifluoromethyl)cyclopropyl)phenol (1.03 g, 5.1 mmol) in DCE (25 mL) at 0° C. under argon was added N-chlorosuccinimide (737 mg, 5.52 mmol) and aluminum trichloride (740 mg, 5.55 mmol). The reaction mixture was stirred at 0° C. for 3 h before being quenched with water. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 80% PE-EtOAc gradient to give the title compound as a yellow oil (380 mg, 31%).

[0195] 6-chloro-5-fluoronicotinic acid JPEG0007807487000090.jpg5683 To a solution of 2-chloro-3-fluoro-5-methylpyridine (512 mg, 3.52 mmol) in pyridine (2.5 mL) and water (2.5 mL) was added a portion of potassium permanganate (1.1 g, 6.9 mmol). The reaction mixture was heated to 100 °C. Two more equal portions of potassium permanganate (for a total of 3.3 g, 20.7 mmol) were added after 1 h and 2 h, respectively, of stirring at 100 °C. If necessary, solids that had accumulated in the condenser were washed off with water and pyridine. After stirring at 100 °C for an additional 1 h, the reaction mixture was cooled to room temperature. The reaction mixture was quenched with saturated aqueous NaSO and stirred for 30 min. The mixture was filtered and then acidified to pH 2 with 5 M HCl. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 70% PE-EtOAc gradient to give the title compound as a white solid (300 mg, 49%).

[0196] 6-Chloro-5-fluoronicotinic acid ethyl ester JPEG0007807487000091.jpg5483 To a solution of 6-chloro-5-fluoronicotinic acid (5.1 g, 29.1 mmol) in EtOH (150 mL) at 0 °C was added SOCl (4.5 mL, 61.7 mmol). The mixture was heated at reflux for 4 h. The reaction mixture was allowed to cool to room temperature, and the reaction was quenched with saturated aqueous NaHCO. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 80% PE-EtOAc gradient to give the title compound as a white solid (5.28 mg, 89%).

[0197] 1-(4-Bromophenyl)-N-cyclohexylethane-1-imine JPEG0007807487000092.jpg9083 According to the procedure by Mercadante, MA, et al., Chemical Science, 2014, 5, 3983-3994, to a solution of 4'-bromoacetophenone (10.0 g, 50.2 mmol) and p-toluenesulfonic acid monohydrate (100 mg, 0.53 mmol) in toluene (70 mL), cyclohexylamine (6.1 mL, 53.5 mmol) was added, and the mixture was stirred at reflux with a Dean-Stark for 21 hours. The reaction mixture was allowed to cool to room temperature, and PE was added (100 mL). p-Toluenesulfonic acid precipitated and could be removed by filtration. The solid was washed with PE (2x). The filtrate was concentrated in vacuo to give the crude product, which was recrystallized from warm PE to give the title compound as slightly yellow flakes (12.4 g, 88%).

[0198] (Iodomethyl)dimethylphenylsilane JPEG0007807487000093.jpg5583 According to the procedure by Mercadante, MA, et al., Chemical Science, 2014, 5, 3983-3994, sodium iodide (7.1 g, 47.3 mmol) was added to a solution of (chloromethyl)dimethylphenylsilane (4.9 mL, 27 mmol) in acetone (30 mL). The reaction mixture was then stirred at reflux for 19 hours. The mixture was concentrated in vacuo, filtered over Celite, and the solid was washed with PE (60 mL). The solution was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 70% PE-DCM gradient to give the title compound as a yellow oil (7.1 g, 95%).

[0199] 1-(4-Bromophenyl)-3-(dimethyl(phenyl)silyl)propan-1-one JPEG0007807487000094.jpg3883 Following the procedure by Mercadante, MA, et al., Chemical Science, 2014, 5, 3983-3994, freshly prepared LDA in THF (approximately 1.5 M, 15 mL, 22 mmol) was slowly added dropwise to a solution of 1-(4-bromophenyl)-N-cyclohexylethan-1-imine (5.6 g, 20 mmol) in THF (10 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h before adding (iodomethyl)dimethylphenylsilane (6.1 g, 22 mmol). The reaction was stirred for an additional 1 h at 0 °C before being quenched with a buffered aqueous solution of sodium acetate (29.5 g, 360 mmol), acetic acid (10.3 mL, 180 mmol) in water (11 mL). The mixture was stirred for 15 min before being diluted with water. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 95% PE-EtOAc gradient to give the title compound as a yellow solid (5.24 g, 75%).

[0200] Trimethyl(perfluoroethyl)silane JPEG0007807487000095.jpg5783 A solution of n-BuLi (2.3 M in cyclohexane, 9 mL, 20.7 mmol) in THF (40 mL) was stirred at -90 °C (acetone / N). The system was purged with an atmosphere of pentafluoroethane and maintained at -78 °C to -90 °C for 1 h, then slowly warmed to -65 °C and stirred for an additional 0.5 h. A solution of TMSCl (2.55 mL, 20 mmol) in THF (5 mL) was added, and the mixture was slowly warmed in an acetone bath and stirred at room temperature for 15 h. The solution was then distilled to give the title compound as a solution in THF (65 mL).

[0201] 4-(1-(perfluoroethyl)cyclopropyl)phenol JPEG0007807487000096.jpg4383 According to the procedure by Mercadante, MA, et al., Chemical Science, 2014, 5, 3983-3994, to a solution of trimethyl(perfluoroethyl)silane in THF (60 mL) obtained previously at 0 °C was added 1-(4-bromophenyl)-3-(dimethyl(phenyl)silyl)propan-1-one (4.9 g, 14.2 mmol). The mixture was stirred for 10 minutes, TBAF (1 M solution in THF, 0.14 mL, 0.14 mmol) was added, and the reaction mixture was stirred at room temperature for 7.5 hours. The reaction mixture was cooled to 0 °C, and water (1.4 mL) and TBAF (1 M solution in THF, 1.4 mL, 1.4 mmol) were added, and the reaction mixture was stirred at room temperature for 14 hours. The reaction was quenched with water. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 95% PE-EtOAc gradient to give 3-(4-bromophenyl)-5-(dimethyl(phenyl)silyl)-1,1,1,2,2-pentafluoropentan-3-ol as a mixture with the starting 1-(4-bromophenyl)-3-(dimethyl(phenyl)silyl)propan-1-one due to similar polarity (4.9 g, 1:1 ratio by NMR).

[0202] To a solution of the previous alcohol / ketone mixture (4.5 g, containing approximately 5.5 mmol of 3-(4-bromophenyl)-5-(dimethyl(phenyl)silyl)-1,1,1,2,2-pentafluoropentan-3-ol) in THF (25 mL) at 0 °C was added NaH (60 wt% in oil, 565 mg, 14.1 mmol). The mixture was stirred at room temperature for 45 min. The reaction was cooled to 0 °C, and MsCl (0.9 mL, 11.6 mmol) was added dropwise. After stirring at room temperature for 2 h, the reaction mixture was cooled to 0 °C and quenched with water. The aqueous layer was extracted with EtOAc (3 ×). The combined organics were washed with water, saturated aqueous NaHCO 3 , brine (1 ×), dried over Na 2 SO 4 , filtered, and concentrated in vacuo.

[0203] At 0°C, a mixture of pyridine (0.9 mL, 11.2 mmol) and 1,1,1,3,3,3-hexafluoropropan-2-ol (8 mL) was added to the resulting oil. The flask was sealed, and the reaction mixture was stirred for 12.5 hours. The reaction was quenched with water. The aqueous layer was extracted with PE (3x). The combined organics were washed with aqueous HCl (1 M), water, saturated aqueous NaHCO3, and brine (1x), dried over Na2SO4, filtered, and concentrated in vacuo (25°C water bath, >200 mbar; the desired product is volatile). The residue was purified by silica gel flash chromatography eluting with 100% PE to give 1-bromo-4-(1-(perfluoroethyl)cyclopropyl)benzene. Due to the very volatile product, PE was not completely removed, and the product was taken directly to the next step. Further elution of the column with 9:1 PE / EtOAc recovered 1.7 g of starting 1-(4-bromophenyl)-3-(dimethyl(phenyl)silyl)propan-1-one.

[0204] Following the procedure by Anderson, K. et al., J. Am. Chem. Soc., 2006, 128(33), 10694-10695, under argon, to a solution of KOH (900 mg, 6.0 mmol), Pd2dba3 (93 mg, 0.10 mmol), and di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphate (170 mg, 0.40 mmol) in degassed 1,4-dioxane (2 mL) and water (2 mL) was added 1-bromo-4-(1-(perfluoroethyl)cyclopropyl)benzene (obtained in the previous step) in 1,4-dioxane (0.5 mL) and water (0.5 mL). The reaction vessel was then sealed and submerged in a preheated oil bath at 100 °C. The reaction was stirred for 4-10 h. The reaction was quenched with 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (1x), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 90% PE-EtOAc gradient to give the title compound as a yellow oil (1.04 g, 29% over 4 steps, 44% BRSM).

[0205] The compounds listed in Table XIV have been identified by TLC using precoated silica TLC sheets and common organic solvents such as petroleum ether, ethyl acetate, dichloromethane, methanol, or acetic acid as eluents, preferably binary or ternary solvent mixtures thereof, UV light at wavelengths of 254 or 366 nm, and / or common staining solutions such as phosphomolybdic acid, potassium permanganate, or ninhydrin.

[0206] The compounds listed in Table XIV were further identified by mass spectrometry using formic acid in the mobile phase for detection of positive ions, while no additive was used for negative ions. Ammonium carbonate was used when molecules were difficult to ionize. Representative compounds were also identified by nuclear magnetic resonance spectroscopy. Chemical shifts (δ) were reported in parts per million (ppm) relative to the residual solvent peak, rounded to 0.01 ppm for protons and 0.1 ppm for carbons (reference: CHCl3[ 1 H: 7.26 ppm, 13 C: 77.2 ppm], DMSO [ 1 H: 2.50 ppm, 13 C: 39.5 ppm]. Coupling constants (J) were reported in Hz rounded to the nearest 0.1 Hz. Peak multiplicities were designated as follows: s (singlet), d (doublet), t (triplet), q (quartet), hept (septet), m (multiplet), and br (broad).

Claims

1. 1. A pharmaceutical composition for the treatment of hyperproliferative disorders, including malignant and non-malignant hyperproliferative disorders, comprising: The pharmaceutical composition comprises: (i) a compound of formula I, where X is CH or N; R １ is C １ -C １２ Alkyl, C ２ -C １２ Alkenyl, C ２ -C １２ Alkynyl, C ３ -C ８ Cycloalkyl, C ３ -C ８ Cycloalkenyl, C ４ -C １２ Bicycloalkyl, C ６ -C １２ bicycloalkenyl, or C ５ -C １４ is tricycloalkyl, wherein all alkyl, alkenyl and alkynyl residues may be linear or branched and may be unsubstituted or include the following: -F, -Cl, -Br, -I, -CN, -NCO, -NCS; and -OC １ -C ３ Alkyl, halogenated OC １ -C ３ Alkyl and perhalogenated OC １ -C ３ may be substituted by one or more substituents independently selected from alkyl; wherein all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues may be unsubstituted or may be selected from the group consisting of -F, -Cl, -Br, -I, -CN, -NCO, -NCS; and -C １ -C ３ Alkyl, halogenated C １ -C ３ Alkyl and perhalogenated C １ -C ３ alkyl; and OC １ -C ３ Alkyl, halogenated OC １ -C ３ Alkyl and perhalogenated OC １ -C ３ may be substituted by one or more substituents independently selected from alkyl; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues may be perhalogenated; R ２ is H, C １ -C ６ Alkyl, or C ３ -C ６ is cycloalkyl, wherein all alkyl residues may be linear or branched and may be unsubstituted or may be selected from the group consisting of -F, -Cl, -Br, -I; and -OC １ -C ３ Alkyl, halogenated OC １ -C ３ Alkyl and perhalogenated OC １ -C ３ may be substituted by one or more substituents independently selected from alkyl; wherein all cycloalkyl residues may be unsubstituted or may be selected from the group consisting of -F, -Cl, -Br, -I; and -C １ -C ３ Alkyl, halogenated C １ -C ３ Alkyl and perhalogenated C １ -C ３ alkyl; and OC １ -C ３ Alkyl, halogenated OC １ -C ３ Alkyl and perhalogenated OC １ -C ３ may be substituted by one or more substituents independently selected from alkyl; wherein all alkyl and cycloalkyl residues may be perhalogenated; or a salt or solvate thereof, However, compounds selected from the following are excluded (Table Ia): (ii) a compound of formula III, where X and R ２ is as defined in formula I, R 1 is C 2 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, C 4 -C 12 bicycloalkyl, C 6 -C 12 bicycloalkenyl, or C 5 -C 14 tricycloalkyl; wherein all alkyl, alkenyl, and alkynyl residues may be linear or branched, and may be unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS; and OC 1 -C 3 alkyl, halogenated OC 1 -C 3 alkyl, and perhalogenated OC 1 -C 3 alkyl; wherein all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues may be unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS; and C1-C3 alkyl, halogenated C1-C3 alkyl, and perhalogenated C1-C3 alkyl; and OC1-C3 alkyl, halogenated OC1-C3 alkyl, and perhalogenated OC1-C3 alkyl; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues may be perhalogenated; or a salt or solvate thereof, However, compounds selected from the following are excluded (Table IIIa): comprising a compound selected from Pharmaceutical compositions.

2. 2. The pharmaceutical composition of claim 1, R １ is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, tert-pentyl, 3-pentyl, -CF ３ , -CF ２ CF ３ , -(CF ２ ) ２ CF ３ , -(CF ２ ) ３ CF ３ , -CH(CF ３ ) ２ , -CF(CF ３ ) ２ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, bicyclo[2.2.2]octyl, adamantyl, and 9-methylbicyclo[3.3.1]nonyl; Pharmaceutical compositions.

3. The pharmaceutical composition according to any one of claims 1 to 2, R ２ is H, methyl, or ethyl; Pharmaceutical compositions.

4. 1. A pharmaceutical composition for the treatment of hyperproliferative disorders, including malignant and non-malignant hyperproliferative disorders, comprising: (i) The pharmaceutical composition comprises the following compounds 1 to 6, 8 to 137: or a stereoisomer, salt, or solvate thereof; and (ii) The pharmaceutical composition comprises the following compounds 342 to 494: or a stereoisomer, salt, or solvate thereof, Pharmaceutical compositions.

5. The pharmaceutical composition of any one of claims 1 to 4 for the treatment of tumors.

6. 5. The pharmaceutical composition of any one of claims 1 to 4 for the treatment of hyperproliferative disorders of the skin, mucous membranes, skin and mucosal appendages, cornea, and epithelial tissues, including non-melanoma skin cancers and precancerous lesions, including squamous cell carcinoma and basal cell carcinoma.

7. 5. The pharmaceutical composition of any one of claims 1 to 4 for the treatment of diseases of the hematopoietic system, including the blood system, including malignancies of the myeloid or lymphoid lineages, including chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), B-cell acute lymphoblastic leukemia (B-ALL), pre-B-cell acute lymphoblastic leukemia (pre-B-ALL), Hodgkin's lymphoma, myeloma, and acute myeloid mixed lineage leukemia with MLL gene translocations.

8. 5. The pharmaceutical composition of any one of claims 1 to 4 for the treatment of hyperproliferative disorders of muscle, including rhabdomyomas and rhabdomyosarcomas.

9. A pharmaceutical composition according to any one of claims 1 to 4 for the treatment of hyperproliferative disorders, including cancers of the neuroendocrine system, including small cell carcinoma, large cell carcinoma and carcinoid tumors.

10. 5. The pharmaceutical composition of any one of claims 1 to 4 for the treatment of cancer or precancerous lesions of the brain, pancreas, liver, thyroid, urogenital tract and endothelial tissues, including medullary thyroid carcinoma and cervical cancer.

11. 7. The pharmaceutical composition of claim 6, wherein the hyperproliferative disorder of the skin and mucous membranes is associated with, accompanied by, and / or caused by a viral infection.

12. 5. A pharmaceutical composition according to any one of claims 1 to 4 for use in human or veterinary medicine for the treatment of hyperproliferative disorders, including malignant and non-malignant hyperproliferative disorders and tumours.

13. 5. The pharmaceutical composition of any one of claims 1 to 4, wherein said hyperproliferative disorder, including tumors, is associated with, accompanied by and / or caused by aberrant Notch signaling.

14. The pharmaceutical composition of any one of claims 1 to 4 as an enhancer of Notch signalling for the treatment of hyperproliferative disorders, including tumors.

15. A compound according to any one of claims 1 to 4, or a salt thereof, or a solvate thereof, R １ But C ５ -C １２ Alkyl, C ２ -C １２ Alkenyl, C ３ -C １２ Alkynyl, C ３ -C ８ Cycloalkyl, C ３ -C ８ Cycloalkenyl, C ４ -C １２ Bicycloalkyl, C ６ -C １２ Bicycloalkenyl, C ５ -C １４ tricycloalkyl; wherein all alkyl, alkenyl and alkynyl residues may be linear or branched and may be unsubstituted or include the following: -F, -Cl, -Br, -I, -CN, -NCO, -NCS; and -OC １ -C ３ Alkyl, halogenated OC １ -C ３ Alkyl and perhalogenated OC １ -C ３ may be substituted by one or more substituents independently selected from alkyl; wherein all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues may be unsubstituted or may be selected from the group consisting of -F, -Cl, -Br, -I, -CN, -NCO, -NCS; and -C １ -C ３ Alkyl, halogenated C １ -C ３ Alkyl and perhalogenated C １ -C ３ alkyl; and OC １ -C ３ Alkyl, halogenated OC １ -C ３ Alkyl and perhalogenated OC １ -C ３ may be substituted by one or more substituents independently selected from alkyl; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues may be perhalogenated; The compound, or a salt thereof, or a solvate thereof.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or a salt thereof, or a solvate thereof, for the treatment of a disease.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or a salt thereof, or a solvate thereof, for use in human or veterinary medicine.

18. 18. A pharmaceutical composition according to any one of claims 16 or 17, comprising for use in immune system related therapeutic applications, including the treatment of disorders of the hematopoietic system, including the blood system, for use in immunotherapy, or for use as a vaccine adjuvant; Pharmaceutical compositions.

Images