Patent Publication Number: US-2023150923-A1

Title: Novel aromatic compounds

Description:
This application is a divisional from Ser. No. 16/488,458 filed Aug. 23, 2019, which is a 35 U.S.C. 371 National Phase Entry Application from PCT/EP2018/054686 filed Feb. 26, 2018, which claims priority to European Application No. 17160326.9 filed Mar. 10, 2017 and European Application No. 17205950.3 filed Dec. 7, 2017, and claims the benefit of U.S. Patent Application No. 62/463,212, filed on Feb. 24, 2017, the disclosures of which are incorporated herein by reference in their entirety. 
    
    
     The present invention relates to novel aromatic compounds and their use as therapeutic agents, which can be used in the treatment of pathological conditions, such as cancer, skin disorders, muscle disorders, and immune system-related disorders such as disorders of the hematopoietic system including the hematologic system in human and veterinary medicine. 
     BACKGROUND 
     Notch signaling is a fundamental cell-to-cell communication pathway that regulates central processes in embryonic development as well as in the maintenance of adult tissues. The effect of a Notch signal is highly dependent on the signal strength, duration, and most importantly on the cellular context. In this regard, Notch activity leads to numerous cell-type specific responses, which implicate for example cell fate decisions, the induction or inhibition of differentiation, and the regulation of cell proliferation. 
     If a signaling event is not correctly controlled, a consequent loss of balance in according cellular processes may drive abnormal cellular changes and finally end in diverse disease situations, such as cancer. 
     Initially, Notch signaling was discovered as an oncogenic pathway. Corresponding pathological conditions are linked to abnormally augmented signaling levels. In these particular cases, the use of Notch inhibiting agents represents a promising strategy for therapeutic intervention and numerous corresponding drugs are currently in development. 
     Conversely, there is increasing evidence for tumor-suppressor functions 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 concerning organs, in which Notch negatively impacts proliferation or triggers differentiation, such as in the skin or in the neuroendocrine system (Dotto,  Oncogene  2008, 27, 5115-5123; Kunnimalaiyaan et al.,  The Oncologist  2007, 12, 535-542). This finding is not only based on observations that certain tumors display impairments in Notch activity. Additionally, various successful demonstrations confirmed that the artificial activation of Notch signaling has a beneficial impact on according malignant degenerations (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). Prominent examples comprise non-melanoma skin cancer, neuroendocrine tumors and certain cancers of the hematopoietic system. 
     In a broader sense, due to the central role of this pathway, the potential use of Notch enhancers is not only limited to the treatment of cancer, but likewise expected to be beneficial in other pathologic conditions that have been shown to be responsive to Notch induction, such as diseases of the skin, muscle or immune system. 
     To this end, it is highly desirable to develop therapeutic agents that enhance Notch signaling. 
     Notch Enhancers State of the Art 
     Current methods to enhance Notch signaling for a potential therapeutic use entail the application of receptor-activating peptides or of small molecules that show Notch-augmenting properties. However, no approved Notch enhancer is available yet in the clinics. Besides, only a small number of according agents is known to date and much less have so far entered a drug development program. Reported small molecule Notch enhancers comprise 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), chrysin (Yu et al.,  Cancer  2013, 119, 774-778), phenethyl isothiocyanate (Kim et al.,  PLoS One  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). 
     A common drawback associated with most of the mentioned compounds is the lack of potency. 
     Hence, it is absolutely crucial to provide novel Notch enhancers with high therapeutic efficacy. 
     The screening of a small library of chemical molecules in a Notch-dependent luciferase reporter assay revealed a novel compound family with Notch-augmenting properties (Reinmüller et al., 2015, EPFL Thesis 6887, published in March 2016), the content of which is herein incorporated by reference. 
    
    
     DESCRIPTION OF THE INVENTION 
     The present invention covers refined structures to the initially discovered limited set of Notch enhancer molecules. These second generation compounds have been designed and are supposed to exhibit increased potency and greater metabolic stability. Alternatively, they present specific modifications of chemical residues, which are supposed to not impair the Notch-augmenting activity, but yet provide novel molecular features that may turn out to beneficially influence pharmacological and physicochemical parameters addressed in the general drug development process. 
     Thus, the present invention relates to compounds as defined herein that feature Notch enhancing activity, which can be used in the treatment of pathological conditions that are responsive for Notch-regulation, such as cancer, skin diseases, muscle disorders, and immune system-related disorders such as disorders of the hematopoietic system including the hematologic system in human and veterinary medicine. 
     The biological activity, e.g. the antiproliferative activity of the claimed compounds can be attributed to but may not be limited to Notch signaling enhancing activity. Thus, the present invention also relates to compounds as defined herein that feature antiproliferative activity, which 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 as defined herein for the treatment of immune system-related disorders such as disorders of the hematopoietic system including the hematologic system, such as malignancies of the myeloid lineage, malignant and non-malignant disorders of the skin and mucosa, such as squamous and basal cell carcinoma, actinic keratosis, and hyperproliferative disorders of the skin and mucosa, e.g. cornification disorders, malignant and non-malignant disorders of the muscle, including hyperproliferative disorders of the muscle, such as muscle hyperplasia and muscle hypertrophy, disorders of the neuroendocrine system, such as medullary thyroid cancer, and hyperproliferative disorders of the genitourinary tract, e.g. cervical cancer in human and veterinary medicine. 
     A first aspect of the present invention relates to compounds of formula I and salts and solvates thereof: 
     
       
         
         
             
             
         
       
     
     wherein X is CH or N, 
     R 1 ═C 1 -C 12  preferably C 1 -C 6  alkyl, C 2 -C 12  preferably C 2 -C 6  alkenyl, C 2 -C 12  preferably C 2 -C 6  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 can be linear or branched, and can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS; and OC 1 -C 3  alkyl optionally halogenated or perhalogenated, particularly perfluorinated; 
     wherein all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS; and C 1 -C 3  alkyl such as —CH 3  optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3  alkyl optionally halogenated or perhalogenated, particularly perfluorinated; 
     wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues can be perhalogenated, particularly perfluorinated; 
     and wherein R 1  is preferably selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, iso-propyl, 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; 
     R 2 ═H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, 
     wherein all alkyl residues can be linear or branched, and can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and OC 1 -C 3  alkyl optionally halogenated or perhalogenated, particularly perfluorinated; 
     wherein all cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: -F, —Cl, -Br, -I; and C 1 -C 3  alkyl such as —CH 3  optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3  alkyl optionally halogenated or perhalogenated, particularly perfluorinated; 
     wherein all alkyl and cycloalkyl residues can be perhalogenated, particularly perfluorinated; 
     and wherein R 2  is preferably selected from H, methyl and ethyl. 
     In some embodiments, the following compounds shown in Table Ia are explicitly excluded from the scope of the invention: 
     
       
         
           
               
               
               
               
               
             
               
                   
                 TABLE Ia 
               
               
                   
                   
               
               
                   
                 Compound 
                 R 1   
                 R 2   
                 X 
               
               
                   
                   
               
             
            
               
                   
                 I-A 
                 tert-butyl 
                 H 
                 CH 
               
               
                   
                 I-B 
                 tert-butyl 
                 ethyl 
                 CH 
               
               
                   
                 I-C 
                 tert-pentyl 
                 H 
                 CH 
               
               
                   
                 I-D 
                 tert-pentyl 
                 ethyl 
                 CH 
               
               
                   
                 I-E 
                 cyclo-hexyl 
                 H 
                 CH 
               
               
                   
                 I-F 
                 cyclo-hexyl 
                 ethyl 
                 CH 
               
               
                   
                 I-G 
                 adamant-1-yl 
                 H 
                 CH 
               
               
                   
                 I-H 
                 adamant-1-yl 
                 ethyl 
                 CH 
               
               
                   
                 I-I 
                 methyl 
                 H 
                 N 
               
               
                   
                 I-J 
                 methyl 
                 ethyl 
                 N 
               
               
                   
                 I-K 
                 tert-butyl 
                 H 
                 N 
               
               
                   
                 I-L 
                 tert-butyl 
                 ethyl 
                 N 
               
               
                   
                 I-M 
                 tert-pentyl 
                 H 
                 N 
               
               
                   
                 I-N 
                 tert-pentyl 
                 ethyl 
                 N 
               
               
                   
                 I-O 
                 cyclo-hexyl 
                 H 
                 N 
               
               
                   
                 I-P 
                 cyclo-hexyl 
                 ethyl 
                 N 
               
               
                   
                 I-Q 
                 isopropyl 
                 H 
                 CH 
               
               
                   
                 I-R 
                 phenyl 
                 H 
                 CH 
               
               
                   
                 I-S 
                 methyl 
                 H 
                 CH 
               
               
                   
                 I-T 
                 tert-butyl 
                 methyl 
                 N 
               
               
                   
                 I-U 
                 methyl 
                 methyl 
                 N 
               
               
                   
                 I-V 
                 methyl 
                 methyl 
                 CH 
               
               
                   
                 I-W 
                 methyl 
                 ethyl 
                 CH 
               
               
                   
                 I-X 
                 n-hexyl 
                 H 
                 CH 
               
               
                   
                 I-Y 
                 n-octyl 
                 H 
                 CH 
               
               
                   
                 I-Z 
                 n-dodecyl 
                 H 
                 CH 
               
               
                   
                 I-AA 
                 iso-propyl 
                 H 
                 N 
               
               
                   
                   
               
            
           
         
       
     
     Compounds I-A to I-T of Table Ia are known in the art for certain applications in the field of medicine whereas to the best of the inventor&#39;s knowledge, compounds I-U to I-AA are not known for any use in medicine. Thus, the invention encompasses any medical use for compounds I-U to I-AA. 
     Specific examples of compounds falling under the scope of formula I are shown in Table Ib. The compounds in Table Ib are defined by their chemical structure, the indicated nomenclature is only for illustrative purposes. 
     
       
         
           
               
               
             
               
                 TABLE Ib 
               
               
                   
               
             
            
               
                 X = CH, R 2  = H 
                   
               
               
                   
               
               
                                   
   4(p-tolyloxy)benzoic acid 
                 001 
               
               
                   
               
               
                                   
   4-(4-ethylphenoxy)benzoic acid 
                 002 
               
               
                   
               
               
                                   
   4-(4-propylphenoxy)benzoic acid 
                 003 
               
               
                   
               
               
                                   
   4-(4-butylphenoxy)benzoic acid 
                 004 
               
               
                   
               
               
                                   
   4-(4-pentylphenoxy)benzoic acid 
                 005 
               
               
                   
               
               
                                   
   4-(4-hexylphenoxy)benzoic acid 
                 006 
               
               
                   
               
               
                                   
   4-(4-isopropylphenoxy)benzoic acid 
                 007 
               
               
                   
               
               
                                   
   4-(4-(pentan-3-yl)phenoxy)benzoic acid 
                 008 
               
               
                   
               
               
                                   
   4-(4-(trifluoromethyl)phenoxy)benzoic acid 
                 009 
               
               
                   
               
               
                                   
   4-(4-(perfluoroethyl)phenoxy)benzoic acid 
                 010 
               
               
                   
               
               
                                   
   4-(4-(perfluoropropyl)phenoxy)benzoic acid 
                 011 
               
               
                   
               
               
                                   
   4-(4-(perfluorobutyl)phenoxy)benzoic acid 
                 012 
               
               
                   
               
               
                                   
   4-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenoxy) benzoic acid 
                 013 
               
               
                   
               
               
                                   
   4-(4-(perfluoropropan-2-yl)phenoxy)benzoic acid 
                 014 
               
               
                   
               
               
                                   
   4-(4-cyclopropylphenoxy)benzoic acid 
                 015 
               
               
                   
               
               
                                   
   4-(4-cyclobutylphenoxy)benzoic acid 
                 016 
               
               
                   
               
               
                                   
   4-(4-cyclopentylphenoxy)benzoic acid 
                 017 
               
               
                   
               
               
                                   
   4-(4-cycloheptylphenoxy)benzoic acid 
                 018 
               
               
                   
               
               
                                   
   4-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl) phenoxy)benzoic acid 
                 019 
               
               
                   
               
               
                                   
   4-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl) phenoxy)benzoic acid 
                 020 
               
               
                   
               
               
                                   
   4-(4-((1r,3r,5r,7r)-adamantan-2-yl) phenoxy)benzoic acid 
                 021 
               
               
                   
               
               
                                   
   4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl) phenoxy)benzoic acid 
                 022 
               
               
                   
               
               
                 X = CH, R 2  = Me 
                   
               
               
                   
               
               
                                   
   methyl 4-(p-tolyloxy)benzoate 
                 023 
               
               
                   
               
               
                                   
   methyl 4-(4-ethylphenoxy)benzoate 
                 024 
               
               
                   
               
               
                                   
   methyl 4-(4-propylphenoxy)benzoate 
                 025 
               
               
                   
               
               
                                   
   methyl 4-(4-butylphenoxy)benzoate 
                 026 
               
               
                   
               
               
                                   
   methyl 4-(4-pentylphenoxy)benzoate 
                 027 
               
               
                   
               
               
                                   
   methyl 4-(4-hexylphenoxy)benzoate 
                 028 
               
               
                   
               
               
                                   
   methyl 4-(4-isopropylphenoxy)benzoate 
                 029 
               
               
                   
               
               
                                   
   methyl 4-(4-(tert-pentyl)phenoxy)benzoate 
                 030 
               
               
                   
               
               
                                   
   methyl 4-(4-(pentan-3-yl)phenoxy)benzoate 
                 031 
               
               
                   
               
               
                                   
   methyl 4-(4-(trifluoromethyl)phenoxy)benzoate 
                 032 
               
               
                   
               
               
                                   
   methyl 4-(4-(perfluoroethyl)phenoxy)benzoate 
                 033 
               
               
                   
               
               
                                   
   methyl 4-(4-(perfluoropropyl)phenoxy)benzoate 
                 034 
               
               
                   
               
               
                                   
   methyl 4-(4-(perfluorobutyl)phenoxy)benzoate 
                 035 
               
               
                   
               
               
                                   
   methyl 4-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl) phenoxy)benzoate 
                 036 
               
               
                   
               
               
                                   
   methyl 4-(4-(perfluoropropan-2-yl)phenoxy)benzoate 
                 037 
               
               
                   
               
               
                                   
   methyl 4-(4-(cyclopropyl)phenoxy)benzoate 
                 038 
               
               
                   
               
               
                                   
   methyl 4-(4-(cyclobutyl)phenoxy)benzoate 
                 039 
               
               
                   
               
               
                                   
   methyl 4-(4-(cyclopentyl)phenoxy)benzoate 
                 040 
               
               
                   
               
               
                                   
   methyl 4-(4-(cyclohexyl)phenoxy)benzoate 
                 041 
               
               
                   
               
               
                                   
   methyl 4-(4-(cycloheptyl)phenoxy)benzoate 
                 042 
               
               
                   
               
               
                                   
   methyl 4-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl) phenoxy)benzoate 
                 043 
               
               
                   
               
               
                                   
   methyl 4-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl) phenoxy)benzoate 
                 044 
               
               
                   
               
               
                                   
   methyl 4-(4-((3r,5r,7r)-adamantan-1-yl) phenoxy)benzoate 
                 045 
               
               
                   
               
               
                                   
   methyl 4-(4-((1r,3r,5r,7r)-adamantan-2-yl) phenoxy)benzoate 
                 046 
               
               
                   
               
               
                                   
   methyl 4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl) phenoxy)benzoate 
                 047 
               
               
                   
               
               
                 X = CH, R 2  = Et 
                   
               
               
                   
               
               
                                   
   ethyl 4-(p-tolyoxy)benzoate 
                 048 
               
               
                   
               
               
                                   
   ethyl 4-(4-ethylphenoxy)benzoate 
                 049 
               
               
                   
               
               
                                   
   ethyl 4-(4-propylphenoxy)benzoate 
                 050 
               
               
                   
               
               
                                   
   ethyl 4-(4-butylphenoxy)benzoate 
                 051 
               
               
                   
               
               
                                   
   ethyl 4-(4-pentylphenoxy)benzoate 
                 052 
               
               
                   
               
               
                                   
   ethyl 4-(4-hexylphenoxy)benzoate 
                 053 
               
               
                   
               
               
                                   
   ethyl 4-(4-isopropylphenoxy)benzoate 
                 054 
               
               
                   
               
               
                                   
   ethyl 4-(4-(pentan-3-yl)phenoxy)benzoate 
                 055 
               
               
                   
               
               
                                   
   ethyl 4-(4-(trifluoromethyl)phenoxy)benzoate 
                 056 
               
               
                   
               
               
                                   
   ethyl 4-(4-(perfluoroethyl)phenoxy)benzoate 
                 057 
               
               
                   
               
               
                                   
   ethyl 4-(4-(perfluoropropyl)phenoxy)benzoate 
                 058 
               
               
                   
               
               
                                   
   ethyl 4-(4-(perfluorobutyl)phenoxy)benzoate 
                 059 
               
               
                   
               
               
                                   
   ethyl 4-(4-(1,1,1,3,3,3-hexafluoropropan- 2-yl)phenoxy)benzoate 
                 060 
               
               
                   
               
               
                                   
   ethyl 4-(4-(perfluoropropan-2-yl)phenoxy)benzoate 
                 061 
               
               
                   
               
               
                                   
   ethyl 4-(4-cyclopropylphenoxy)benzoate 
                 062 
               
               
                   
               
               
                                   
   ethyl 4-(4-cyclobutylphenoxy)benzoate 
                 063 
               
               
                   
               
               
                                   
   ethyl 4-(4-cyclopentylphenoxy)benzoate 
                 064 
               
               
                   
               
               
                                   
   ethyl 4-(4-cycloheptylphenoxy)benzoate 
                 065 
               
               
                   
               
               
                                   
   ethyl 4-(4-((1S,4R)-bicyclo[2.2.1]heptan-2yl) phenoxy)benzoate 
                 066 
               
               
                   
               
               
                                   
   ethyl 4-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl) phenoxy)benzoate 
                 067 
               
               
                   
               
               
                                   
   ethyl 4-(4-((1r,3r,5r,7r)-adamantan-2-yl) phenoxy)benzoate 
                 068 
               
               
                   
               
               
                                   
   ethyl 4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl) phenoxy)benzoate 
                 069 
               
               
                   
               
               
                 X = N, R 2  = H 
                   
               
               
                   
               
               
                                   
   6-(4-ethylphenoxy)nicotinic acid 
                 070 
               
               
                   
               
               
                                   
   6-(4-propylphenoxy)nicotinic acid 
                 071 
               
               
                   
               
               
                                   
   6-(4-butylphenoxy)nicotinic acid 
                 072 
               
               
                   
               
               
                                   
   6-(4-pentylphenoxy)nicotinic acid 
                 073 
               
               
                   
               
               
                                   
   6-(4-hexylphenoxy)nicotinic acid 
                 074 
               
               
                   
               
               
                                   
   6-(4-isopropylphenoxy)nicotinic acid 
                 075 
               
               
                   
               
               
                                   
   6-(4-(pentan-3-ylphenoxy)nicotinic acid 
                 076 
               
               
                   
               
               
                                   
   6-(4-(perfluoroethyl)phenoxy)nicotinic acid 
                 077 
               
               
                   
               
               
                                   
   6-(4-(perfluoropropyl)phenoxy)nicotinic acid 
                 078 
               
               
                   
               
               
                                   
   6-(4-(perfluorobutyl)phenoxy)nicotinic acid 
                 079 
               
               
                   
               
               
                                   
   6-(4-(1,1,1,3,3,3-hexafluoropropan- 2-yl)phenoxy)nicotinic acid 
                 080 
               
               
                   
               
               
                                   
   6-(4-(perfluoropropan-2-yl)phenoxy)nicotinic acid 
                 081 
               
               
                   
               
               
                                   
   6-(4-cyclopropylphenoxy)nicotinic acid 
                 082 
               
               
                   
               
               
                                   
   6-(4-cyclobutylphenoxy)nicotinic acid 
                 083 
               
               
                   
               
               
                                   
   6-(4-cyclopentylphenoxy)nicotinic acid 
                 084 
               
               
                   
               
               
                                   
   6-(4-cycloheptylphenoxy)nicotinic acid 
                 085 
               
               
                   
               
               
                                   
   6-(4-((1S,4R)-bicyclo[2.2.1]heptan-2-yl) phenoxy)nicotinic acid 
                 086 
               
               
                   
               
               
                                   
   6-(4-((1s,4s)-bicyclo[2.2.2]octan-2-yl) phenoxy)nicotinic acid 
                 087 
               
               
                   
               
               
                                   
   6-(4-((3r,5r,7r)-adamantan-1-yl) phenoxy)nicotinic acid 
                 088 
               
               
                   
               
               
                                   
   6-(4-((1r,3r,5r,7r)-adamantan-2-yl) phenoxy)nicotinic acid 
                 089 
               
               
                   
               
               
                                   
   6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9-yl) phenoxy)nicotinic acid 
                 090 
               
               
                   
               
               
                 X = N, R 2  = Me 
                   
               
               
                   
               
               
                                   
   methyl 6-(p-tolyloxy)nicotinate 
                 091 
               
               
                   
               
               
                                   
   methyl 6-(4-ethylphenoxy)nicotinate 
                 092 
               
               
                   
               
               
                                   
   methyl 6-(4-propylphenoxy)nicotinate 
                 093 
               
               
                   
               
               
                                   
   methyl 6-(4-butylphenoxy)nicotinate 
                 094 
               
               
                   
               
               
                                   
   methyl 6-(4-pentylphenoxy)nicotinate 
                 095 
               
               
                   
               
               
                                   
   methyl 6-(4-hexylphenoxy)nicotinate 
                 096 
               
               
                   
               
               
                                   
   methyl 6-(4-isopropylphenoxy)nicotinate 
                 097 
               
               
                   
               
               
                                   
   methyl 6-(4-(tert-pentyl)phenoxy)nicotinate 
                 099 
               
               
                   
               
               
                                   
   methyl 6-(4-(pentan-3-yl)phenoxy)nicotinate 
                 100 
               
               
                   
               
               
                                   
   methyl 6-(4-(trifluoromethyl)phenoxy)nicotinate 
                 101 
               
               
                   
               
               
                                   
   methyl 6-(4-(perfluoroethyl)phenoxy)nicotinate 
                 102 
               
               
                   
               
               
                                   
   methyl 6-(4-(perfluoropropyl)phenoxy)nicotinate 
                 103 
               
               
                   
               
               
                                   
   methyl 6-(4-(perfluorobutyl)phenoxy)nicotinate 
                 104 
               
               
                   
               
               
                                   
   methyl 6-(4-(1,1,1,3,3,3-hexafluoropropan- 2-yl)phenoxy)nicotinate 
                 105 
               
               
                   
               
               
                                   
   methyl 6-(4-(perfluoropropan-2-yl)phenoxy)nicotinate 
                 106 
               
               
                   
               
               
                                   
   methyl 6-(4-cyclopropyl)phenoxy)nicotinate 
                 107 
               
               
                   
               
               
                                   
   methyl 6-(4-cyclobutylphenoxy)nicotinate 
                 108 
               
               
                   
               
               
                                   
   methyl 6-(4-cyclobutylphenoxy)nicotinate 
                 109 
               
               
                   
               
               
                                   
   methyl 6-(4-cyclohexylphenoxy)nicotinate 
                 110 
               
               
                   
               
               
                                   
   methyl 6-(4-cycloheptylphenoxy)nicotinate 
                 111 
               
               
                   
               
               
                                   
   methyl 6-(4-((1S,4R)-bicyclo[2.2.1]heptan- 2-yl)phenoxy)nicotinate 
                 112 
               
               
                   
               
               
                                   
   methyl 6-(4-((1s,4s)-bicyclo[2.2.2]octan- 2-yl)phenoxy)nicotinate 
                 113 
               
               
                   
               
               
                                   
   methyl 6-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)nicotinate 
                 114 
               
               
                   
               
               
                                   
   methyl 6-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)nicotinate 
                 115 
               
               
                   
               
               
                                   
   methyl 6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan- 9-yl)phenoxy)nicotinate 
                 116 
               
               
                   
               
               
                 X = N, R 2  = Et 
                   
               
               
                   
               
               
                                   
   ethyl 6-(4-ethylphenoxy)nicotinate 
                 117 
               
               
                   
               
               
                                   
   ethyl 6-(4-propylphenoxy)nicotinate 
                 118 
               
               
                   
               
               
                                   
   ethyl 6-(4-butylphenoxy)nicotinate 
                 119 
               
               
                   
               
               
                                   
   ethyl 6-(4-pentylphenoxy)nicotinate 
                 120 
               
               
                   
               
               
                                   
   ethyl 6-(4-hexylphenoxy)nicotinate 
                 121 
               
               
                   
               
               
                                   
   ethyl 6-(4-isopropylphenoxy)nicotinate 
                 122 
               
               
                   
               
               
                                   
   ethyl 6-(4-(pentan-3-yl)phenoxy)nicotinate 
                 123 
               
               
                   
               
               
                                   
   ethyl 6-(4-(perfluoroethylphenoxy)nicotinate 
                 124 
               
               
                   
               
               
                                   
   ethyl 6-(4-(perfluoropropyl)phenoxy)nicotinate 
                 125 
               
               
                   
               
               
                                   
   ethyl 6-(4-(perfluorobutyl)phenoxy)nicotinate 
                 126 
               
               
                   
               
               
                                   
   ethyl 6-(4-(1,1,1,3,3,3-hexafluoropropan- 2-yl)phenoxy)nicotinate 
                 127 
               
               
                   
               
               
                                   
   ethyl 6-(4-(perfluoropropan-2-yl)phenoxy)nicotinate 
                 128 
               
               
                   
               
               
                                   
   ethyl 6-(4-cyclopropyl)phenoxy)nicotinate 
                 129 
               
               
                   
               
               
                                   
   ethyl 6-(4-cyclobutyl)phenoxy)nicotinate 
                 130 
               
               
                   
               
               
                                   
   ethyl 6-(4-cyclopentylphenoxy)nicotinate 
                 131 
               
               
                   
               
               
                                   
   ethyl 6-(4-cycloheptylphenoxy)nicotinate 
                 132 
               
               
                   
               
               
                                   
   ethyl 6-(4-((1S,4R)-bicyclo[2.2.1]heptan- 2-yl)phenoxy)nicotinate 
                 133 
               
               
                   
               
               
                                   
   ethyl 6-(4-((1s,4s)-bicyclo[2.2.2]octan- 2-yl)phenoxy)nicotinate 
                 134 
               
               
                   
               
               
                                   
   ethyl 6-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)nicotinate 
                 135 
               
               
                   
               
               
                                   
   ethyl 6-(4-((1r,3r,5r,7r)-adamantan-2-yl)phenoxy)nicotinate 
                 136 
               
               
                   
               
               
                                   
   ethyl 6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan- 9-yl)phenoxy)nicotinate 
                 137 
               
               
                   
               
            
           
         
       
     
     Also included are isomers, e.g. enantiomers or diastereomers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds listed above. 
     A second aspect of the present invention relates to compounds of formula II and salts and solvates thereof: 
     
       
         
         
             
             
         
       
     
     wherein X and R 1  are defined as in formula I, including the preferred definition of R 1 , 
     R 3 ═H, C 1 -C 6  alkyl, or C 3 -C 6  cycloalkyl, wherein all alkyl residues can be linear or branched, and can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C 1 -C 3  alkyl such as —CH 3  optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3  alkyl optionally halogenated or perhalogenated, particularly perfluorinated; 
     wherein all cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C 1 -C 3  alkyl such as —CH 3  optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3  alkyl optionally halogenated or perhalogenated, particularly perfluorinated; 
     wherein all alkyl and cycloalkyl residues can be perhalogenated, particularly perfluorinated; 
     and wherein R 3  is preferably H or methyl; 
     R 4 ═H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, OH or OC 1 -C 6  alkyl, 
     wherein all alkyl residues can be linear or branched, and can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C 1 -C 3  alkyl such as —CH 3  optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3  alkyl optionally halogenated or perhalogenated, particularly perfluorinated; 
     wherein all cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C 1 -C 3  alkyl such as —CH 3  optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3  alkyl optionally halogenated or perhalogenated, particularly perfluorinated; 
     wherein all alkyl and cycloalkyl residues can be perhalogenated, particularly perfluorinated; 
     and wherein R 4  is preferably H, OH or methyl. 
     In especially preferred embodiments, R 3  and R 4  are in each case H; H and OH; H and —CH 3 ; or in each case —CH 3 . 
     In some embodiments, the following compounds shown in Table IIa are explicitly excluded from the scope of the invention: 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE IIa 
               
               
                   
               
               
                 Compound 
                 R 1   
                 R 3   
                 R 4   
                 X 
               
               
                   
               
             
            
               
                 II-A 
                 tert-butyl 
                 H 
                 H 
                 N 
               
               
                 II-B 
                 methyl 
                 H 
                 methyl 
                 CH 
               
               
                 II-C 
                 methyl 
                 methyl 
                 methyl 
                 CH 
               
               
                   
               
            
           
         
       
     
     Compound II-A and II-B of Table IIa are known in the art for certain applications in the field of medicine whereas to the best of the inventor&#39;s knowledge, compound II-C is not known for any use in medicine. Thus, the invention encompasses any medical use for compound II-C. 
     Specific examples of compounds falling under the scope of formula II are shown in Table IIb. The compounds in Table IIb are defined by their chemical structure, the indicated nomenclature is only for illustrative purposes. 
     
       
         
           
               
               
             
               
                 TABLE IIb 
               
               
                   
               
             
            
               
                 X = CH, R 3  = H, R 4  = H 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 138 
               
               
                   
               
               
                 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 
                   
               
               
                   
               
               
                 X = CH, R 3  = H, R 4  = OH 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 164 
               
               
                   
               
               
                 N-hydroxy-4-(p-tolyltoxy)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,7r)-adamantan-2-yl)phenoxy)-N-hydroxybenzamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 188 
               
               
                   
               
               
                 N-hydroxy-4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9- 
                   
               
               
                 yl)phenoxy)benzamide 
                   
               
               
                   
               
               
                 X = CH, R 3  = H, R 4  = Me 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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-4-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 
                   
               
               
                   
               
               
                 X = CH, R 3  = Me, R 4  = Me 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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-cyclopentylpheoxy)-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)pheoxy)-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 
                   
               
               
                   
               
               
                 X = N, R 3  = H, R 4  = H 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 241 
               
               
                   
               
               
                 6-(p-tolyloxy)nicolinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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-(perfluorobutylphenoxy)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)nictinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 262 
               
               
                   
               
               
                 6-(4-((1s,4)-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 
                   
               
               
                   
               
               
                 X = N, R 3  = H, R 4  = OH 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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  
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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-hyeroxynicotinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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 
                   
               
               
                   
               
               
                 X = N, R 3  = H, R 4  = Me 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 291 
               
               
                   
               
               
                 N-methyl-6-(p-tolyloxy)nicotinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 292 
               
               
                   
               
               
                 6-(4-ethylphenoxy)-N-mtehylnicotinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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-mtehyl-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-mtehylnicotinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 307 
               
               
                   
               
               
                 6-(4-cyclobutylphenoxy)-N-methylnicotinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 308 
               
               
                   
               
               
                 6-(4-cyclopentylphenoxy)-N-mtehylnicotinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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 
                   
               
               
                   
               
               
                 X = N, R 3  = Me, R 4  = Me 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 316 
               
               
                   
               
               
                 N,N-dimethyl-6-(p-tolyloxy)nicotinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 317 
               
               
                   
               
               
                 6-(4-ethylphenoxy)-N,N-dimethylnicotinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 318 
               
               
                   
               
               
                 N,N-dimethyl-6-(4-propylphenoxy)nicotinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 319 
               
               
                   
               
               
                 6-(4-butylphenoxy)-N,N-dimethylnicotinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 320 
               
               
                   
               
               
                 N,N-dimethyl-6-(4-pentylphenoxy)nicotinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 321 
               
               
                   
               
               
                 6-(4-hexylphenoxy)-N,N-dimethylnicotinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 322 
               
               
                   
               
               
                 6-(4-isopropylphenoxy)-N,N-dimethylnictinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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 
               
               
                   
               
            
           
         
       
     
     Also included are isomers, e.g. enantiomers or diastereomers or rotamers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds listed above. 
     A third aspect of the present invention relates to compounds of formula III and salts and solvates thereof: 
     
       
         
         
             
             
         
       
     
     wherein X, R 1  and R 2  are defined as in formula I, including the preferred definitions of R 1  and R 2 . 
     In some embodiments, the following compounds shown in Table IIIa are explicitly excluded from the scope of the invention: 
     
       
         
           
               
               
               
               
               
             
               
                   
                 TABLE IIIa 
               
               
                   
                   
               
               
                   
                 Compound 
                 R 1   
                 R 2   
                 X 
               
               
                   
                   
               
             
            
               
                   
                 III-A 
                 tert-butyl 
                 H 
                 CH 
               
               
                   
                 III-B 
                 tert-butyl 
                 ethyl 
                 CH 
               
               
                   
                 III-C 
                 phenyl 
                 H 
                 CH 
               
               
                   
                   
               
            
           
         
       
     
     Specific examples of compounds falling under the scope of formula III are shown in Table IIIb. The compounds in Table IIIb are defined by their chemical structure, the indicated nomenclature is only for illustrative purposes. 
     
       
         
           
               
               
             
               
                 TABLE IIIb 
               
               
                   
               
             
            
               
                 X = CH, R 2  = H 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 341 
               
               
                   
               
               
                 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-hexafluoropropan-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 
                   
               
               
                   
               
               
                 X = CH, R 2  = Me 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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 
                   
               
               
                   
               
               
                 X = CH, R 2  = Et 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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-methylbiccyclo[3.3.1] 
                   
               
               
                 nonan-9-yl)phenoxy)benzoate 
                   
               
               
                   
               
               
                 X = N, R 2  = H 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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-cylcloheptylphenoxy)-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 
                   
               
               
                   
               
               
                 X = N, R 2  = Me 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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-hexafluoropropan-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- 
                   
               
               
                 fluoronictinate 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 468 
               
               
                   
               
               
                 methyl 5-fluoro-6-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan- 
                   
               
               
                 9-yl)phenoxy)nicotinate 
                   
               
               
                   
               
               
                 X = N, R 2  = Et 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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-fluoronictinate 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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 
               
               
                   
               
            
           
         
       
     
     Also included are isomers, e.g. enantiomers or diastereomers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds listed above. 
     A fourth aspect of the present invention relates to compounds of formula IV and salts and solvates thereof: 
     
       
         
         
             
             
         
       
     
     wherein X and R 1  are defined as in formula I, including the preferred definition of R 1 , 
     and R 3  and R 4  are defined as in formula II, including the preferred definitions of R 3  and R 4 . 
     Specific examples of compounds falling under the scope of formula IV are shown in Table IV. The compounds in Table IV are defined by their chemical structure, the indicated nomenclature is only for illustrative purposes. 
     
       
         
           
               
               
             
               
                 TABLE IV 
               
               
                   
               
             
            
               
                 X = CH, R 3  = H, R 4  = H 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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-fluorobenz- 
                   
               
               
                 amide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 520 
               
               
                   
               
               
                 3-fluoro-4-(4-((1R,5S)-9-methylbicyclo[3.3.1]nonan-9- 
                   
               
               
                 yl)phenoxy)benzamide 
                   
               
               
                   
               
               
                 X = CH, R 3  = H, R 4  = OH 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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-fluooro-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 
                   
               
               
                   
               
               
                 X = CH, R 3  = H, R 4  = Me 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 547 
               
               
                   
               
               
                 3-fluoro-N-mtehyl-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)phenxoy)-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 
                   
               
               
                   
               
               
                 X = CH, R 3  = Me, R 4  = Me 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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-dimethyl- 
                   
               
               
                 benzamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 580 
               
               
                   
               
               
                 4-(4-(tert-butyl)phenoxy)-3-fluoro-N,N-dimethyl- 
                   
               
               
                 benzamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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-dimethyl- 
                   
               
               
                 benzamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 590 
               
               
                   
               
               
                 4-(4-cyclobutylphenoxy)-3-fluoro-N,N-dimethyl- 
                   
               
               
                 benzamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 591 
               
               
                   
               
               
                 4-(4-cyclopentylphenoxy)-3-fluoro-N,N-dimethyl- 
                   
               
               
                 benzamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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 
                   
               
               
                   
               
               
                 X = N, R 3  = H, R 4  = H 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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)nictinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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)nicotinamdie 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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-fluoro- 
                   
               
               
                 nicotinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 624 
               
               
                   
               
               
                 5-fluoro-6-(4-((1R,5S)-9-methybicyclo[3.3.1]nonan-9- 
                   
               
               
                 yl)phenoxy)nicotinamide 
                   
               
               
                   
               
               
                 X = N, R 3  = H, R 4  = OH 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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-hydroxy- 
                   
               
               
                 nicotinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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-hydroxynictinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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 
                   
               
               
                   
               
               
                 X = N, R 3  = H, R 4  = Me 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 651 
               
               
                   
               
               
                 5-fluoro-N-methyl-6-(p-tolyloxy)nicotinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 652 
               
               
                   
               
               
                 6-(4-ethylphenoxy)-5-fluoro-N-mtehylnictinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 653 
               
               
                   
               
               
                 5-fluoro-N-methyl-6-(4-propylphenoxy)nicotinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 654 
               
               
                   
               
               
                 6-(4-butylphenoxy)-5-fluoro-N-methylnictinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 655 
               
               
                   
               
               
                 5-fluoro-N-methyl-6-(4-pentylphenoxy)nicotnamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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- 
                   
               
               
                 methylnictinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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 
                   
               
               
                   
               
               
                 X = N, R 3  = Me, R 4  = Me 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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-dimethyl- 
                   
               
               
                 nicotinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 694 
               
               
                   
               
               
                 6-(4-cyclobutylphenoxy)-5-fluoro-N,N-dimethyl- 
                   
               
               
                 nicotinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 695 
               
               
                   
               
               
                 6-(4-cyclopentylphenoxy)-5-fluoro-N,N-dimethyl- 
                   
               
               
                 nicotinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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- 
                   
               
               
                 dimethylnictinamide 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 702 
               
               
                   
               
               
                 5-fluoro-N,N-dimethyl-6-(4-((1R,5S)-9-methylbicyclo[3.3.1] 
                   
               
               
                 nonan-9-yl)phenoxy)nicotinamide 
               
               
                   
               
            
           
         
       
     
     Also included are isomers, e.g. enantiomers or diastereomers or rotamers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds listed above. 
     A fifth aspect of the present invention relates to compounds of formula V and salts and solvates thereof: 
     
       
         
         
             
             
         
       
     
     wherein n=0-5, which comprises cyclopropyl (n=0), cyclobutyl (n=1), cyclopentyl (n=2), cyclohexyl (n=3), cycloheptyl (n=4) and cyclooctyl (n=5), 
     wherein the said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS; and C 1 -C 3  alkyl such as —CH 3  optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3  alkyl optionally halogenated or perhalogenated, particularly perfluorinated; 
     wherein the said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups can be perhalogenated, particularly perfluorinated; 
     and wherein n is preferably 0 as constituting cyclopropyl, particularly as constituting cyclopropyl being unsubstituted; 
     R 5 =C 1 -C 12  preferably C 1 -C  6  alkyl, C 2 -C 12  preferably C 2 -C 6  alkenyl, C 2 -C 12  preferably C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, 
     wherein all alkyl, alkenyl and alkynyl residues can be linear or branched, and are perhalogenated, particularly perfluorinated, 
     and wherein all cycloalkyl and cycloalkenyl residues are perhalogenated, particularly perfluorinated; 
     or wherein all alkyl, alkenyl and alkynyl residues can be linear or branched, and can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS; and OC 1 -C 3  alkyl optionally halogenated or perhalogenated, particularly perfluorinated; 
     and wherein all cycloalkyl and cycloalkenyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS; and C 1 -C 3  alkyl such as —CH 3  optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3  alkyl optionally halogenated or perhalogenated, particularly perfluorinated; 
     wherein R 5  is preferably —CF 3  or —CF 2 CF 3 ; 
     R 6 -R 9  are independently from each other selected from —H, —F, —Cl, —Br, —I, linear or branched C 1 -C 4  alkyl, linear or branched C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 3 -C 5  cycloalkyl, and wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from: —F, —Cl, —Br, —I; and C 1 -C 3  alkyl such as —CH 3  optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3  alkyl optionally halogenated or perhalogenated, particularly perfluorinated; 
     wherein R 6 -R 8  each are preferably H, and R 9  is preferably —H, —F, —Cl, or —CH 3 ; 
     Y=a six-membered aromatic ring selected from benzene, pyridine, pyrimidine, pyridazine or pyrazine; 
     wherein the benzene ring is not substituted, or it is substituted with one to four of the substituents independently selected from R 10 -R 13 , 
     and wherein the pyridine ring is not substituted, or it is substituted at the carbon positions with one to three of the substituents independently selected from R 10 -R 12 , and wherein preferably the N-atom of the pyridine ring is in ortho-position relative to the ether bond, and wherein the pyrimidine ring is not substituted, or it is substituted at the carbon positions with one or two of the substituents independently selected from R 10 -R 11 , and wherein preferably an N-atom of the pyrimidine ring is in ortho-position relative to the ether bond, 
     and wherein the pyridazine ring is not substituted, or it is substituted at the carbon positions with one or two of the substituents independently selected from R 10 -R 11 , and wherein preferably an N-atom of the pyridazine ring is in ortho-position relative to the ether bond, 
     and wherein the pyrazine ring is not substituted, or it is substituted at the carbon positions with one or two of the substituents independently selected from R 10 -R 11 , and wherein preferably an N-atom of the pyrazine ring is in ortho-position relative to the ether bond, 
     wherein preferably Y=benzene or pyridine being not substituted with any of the residues selected from R 10 -R 13 , or being substituted with one of the substituents selected from R 10 -R 13  being F at the carbon atom in ortho-position relative to the ether bond; 
     R 10 -R 13  are independently from each other selected from —F, —Cl, —Br, —I, linear or branched C 1 -C 4  alkyl, linear or branched C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 3 -C 5  cycloalkyl, and wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from —F, —Cl, —Br, —I; and C 1 -C 3  alkyl such as —CH 3  optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3  alkyl optionally halogenated or perhalogenated, particularly perfluorinated; 
     Z═O or S, and preferably Z═O; 
     R 14 ═OR 2  or NR 3 R 4    
     wherein R 2  is defined as in formula I including the preferred definition of R 2  as H, methyl or ethyl; 
     wherein R 3  and R 4  are defined as in formula II, including the preferred definitions of R 3  as H or —CH 3  and R 4  as H, OH or —CH 3 ; 
     In a particularly preferred embodiment of the compounds of formula V, the present invention relates to compounds of formula Va and salts and solvates thereof: 
     
       
         
         
             
             
         
       
     
     wherein n is defined as in formula V, including the preferred definition of n being n=0 as constituting cyclopropyl, particularly as constituting cyclopropyl being unsubstituted, 
     wherein Z is defined as in formula V, including the preferred definition of Z as Z═O, 
     wherein R 5  is defined as in formula V, including all preferred definitions of R 5 , 
     R 6 -R 9  are defined as in formula V, including all preferred definitions of R 6 -R 9 , 
     wherein R 14  is defined as in formula V, 
     wherein X is N or CR 13 , 
     and wherein R 10 -R 13  are independently from each other selected from —H, —F, —Cl, —Br, —I, linear or branched C 1 -C 4  alkyl, linear or branched C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 3 -C 5  cycloalkyl, and wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues can be unsubstituted or substituted with one or more substituents in particular independently selected from —F, —Cl, —Br, —I; and C 1 -C 3  alkyl such as —CH 3  optionally halogenated or perhalogenated, particularly perfluorinated such as —CF 3 ; and OC 1 -C 3  alkyl optionally halogenated or perhalogenated, particularly perfluorinated. 
     Specific examples of compounds falling under the scope of formula V are shown in Table V. The compounds in Table V are defined by their chemical structure, the indicated nomenclature is only for illustrative purposes. 
     
       
         
           
               
               
             
               
                 TABLE V 
               
               
                   
               
             
            
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 703 
               
               
                   
               
               
                 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) 
                   
               
               
                 pheoxy)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)benozate 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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) 
                   
               
               
                 phenoxy)nicotinic acid 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 731 
               
               
                   
               
               
                 6-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy) 
                   
               
               
                 phenoxy)nicotinic acid 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 732 
               
               
                   
               
               
                 5-fluoro-6-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy) 
                   
               
               
                 phenoxy)nicotinic acid 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 733 
               
               
                   
               
               
                 5-fluoro-6-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy) 
                   
               
               
                 phenoxy)nicotinic acid 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 734 
               
               
                   
               
               
                 6-(2-methyl-4-(1-(trifluoromethyl)cyclopropyl)phenoxy) 
                   
               
               
                 phenoxy)nicotinic acid 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 735 
               
               
                   
               
               
                 6-(2-methyl-4-(1-(perfluoroethyl)cyclopropyl)phenoxy) 
                   
               
               
                 phenoxy)nicotinic acid 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 736 
               
               
                   
               
               
                 6-(2-fluoro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy) 
                   
               
               
                 phenoxy)nicotinic acid 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 737 
               
               
                   
               
               
                 6-(2-fluoro-4-(1-(perfluoroethyl)cyclopropyl)phenoxy) 
                   
               
               
                 phenoxy)nicotinic acid 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 738 
               
               
                   
               
               
                 6-(2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy) 
                   
               
               
                 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) 
                   
               
               
                 phenoxy)nicotinate 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 742 
               
               
                   
               
               
                 methyl 5-fluoro-6-(4-(1-(perfluoroethyl)cyclopropyl) 
                   
               
               
                 phenoxy)nicotinate 
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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)cyclo- 
                   
               
               
                 propyl)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-(trifluoroemthyl)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 
               
               
                   
               
            
           
         
       
     
     Also included are isomers, e.g. enantiomers or diastereomers or rotamers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds listed above. 
     Further Definitions: 
     The term “C 1 -C 12  alkyl” comprises all isomers of the corresponding saturated aliphatic hydrocarbon groups containing one to twelve 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. The term “C 2 -C 12  alkenyl” comprises all isomers of the corresponding unsaturated olefinic hydrocarbon groups containing two to twelve 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. 
     The term “C 2 -C 12  alkynyl” comprises all isomers of the corresponding unsaturated olefinic hydrocarbon groups containing two to twelve carbon atoms linked 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 having one or more triple bonds and one or more double bonds. 
     The term “C 3 -C 8  cycloalkyl” comprises the corresponding saturated hydrocarbon groups containing three to eight carbon atoms arranged in a monocyclic ring structure; this includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. 
     The term “C 3 -C 8  cycloalkenyl” comprises the corresponding unsaturated non-aromatic, anti-aromatic or aromatic hydrocarbon groups containing three to eight carbon atoms arranged in a monocyclic ring structure and linked by one or more double bonds; this includes cyclopropenyl, all cyclobutenyl-isomers, all cyclopentenyl-isomers, all cyclohexenyl-isomers, all cycloheptenyl-isomers, all cyclooctenyl-isomers. 
     The term “C 4 -C 12  bicycloalkyl” comprises the corresponding saturated hydrocarbon groups containing four to twelve carbon atoms arranged in a bicyclic ring structure; 
     The term “C 6 -C 12  bicycloalkenyl” comprises the corresponding unsaturated hydrocarbon groups containing six to twelve carbon atoms arranged in a bicyclic ring structure and linked by one or more double bonds; 
     The term “C 5 -C 14  tricycloalkyl” comprises the corresponding saturated hydrocarbon groups containing five to fourteen carbon atoms arranged in a tricyclic ring structure; 
     The term “perhalogenated” relates to the exhaustive halogenation of the carbon scaffold; according residues comprise the corresponding perfluorinated, perchlorinated, perbrominated and periodinated groups. Preferably, the term “perhalogenated” relates to perfluorinated or perchlorinated groups, more preferably to perfluorinated groups. 
     The following contains definitions of terms used in this specification, The initial definition provided for a group or term herein applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated. 
     The compounds of the present invention may form salts, which are also within the scope of this invention. Reference to a compound of the invention herein is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. Zwitterions (internal or inner salts) are included within the term “salt(s)” as used herein (and may be formed, for example, where the substituents comprise an acid moiety such as a carboxyl group). Also included herein are quaternary ammonium salts such as alkylammonium salts. Salts of the compounds may be formed, for example, by reacting a 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. 
     Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like. 
     Exemplary basic salts (formed, for example, where the substituents comprise 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 (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines, N-methyl-D-glucamines, N-methyl-D-glucamides, tert-butyl amines, and salts with amino acids such as arginine, lysine and the like. The 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 sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others. 
     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 wherein the parent compound is modified by converting an existing acid or base moiety to 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 the 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 which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in  Remington&#39;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. 
     The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which 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. 
     Furthermore, in the case of the compounds of the invention which contain an asymmetric carbon atom, the invention relates to the D form, the L form and D,L mixtures and also, where more than one asymmetric carbon atom is present, to the diastereomeric forms. Those compounds of the invention which contain asymmetric carbon atoms, and which as a rule accrue as racemates, can be separated into the optically active isomers in a known manner, for example using an optically active acid. However, it is also possible to use an optically active starting substance from the outset, with a corresponding optically active or diastereomeric compound then being obtained as the end product. 
     Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. 
     The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C═N double bonds, and the like can 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 separated isomeric forms. 
     Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. 
     Also included are solvates and hydrates of the compounds of the invention and solvates and hydrates of their pharmaceutically acceptable salts. 
     The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, rotamers, and isotopes of the structures depicted, unless otherwise indicated. 
     In some embodiments, the compound can be provided as a prodrug. The term “prodrug”, as employed herein, denotes a compound, which, upon administration 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. 
     In some embodiments, the compounds of the invention, and salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the invention. Substantial separation can include compositions containing 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 invention, or salt thereof. 
     Pharmaceutical Methods 
     The compounds according to the invention have been found to have pharmacologically important 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. 
     In certain embodiments, compounds of the present invention may be enhancers of Notch signalling. 
     The communication between cells via Notch signaling (reviewed in Kopan et al.,  Cell  2009, 137, 216-233; Bray,  Nat. Rev. Mol. Cell Biol.  2016, 17, 722-735) is in the first step mediated by two types of transmembrane proteins: The Notch receptors being distributed within the cell membrane of the signal-receiving cell and the Notch ligands covering the membrane of the signal-sending cell. Mechanistically, Notch signaling is activated by receptor-ligand interaction, which leads to the proteolytic release of the intra cellular domain (NICD) of the membrane bound Notch receptor into the inside of the signal receiving cell. Subsequent translocation of NICD into the nucleus in turn leads to the transcriptional activation of certain and cell type specific genes. The Notch-mediated alteration of the previous gene-expression program of a cell is manifested in according cellular changes, which represent the response of the cell to a Notch signal. 
     The activation level of Notch signaling can be quantified in vitro most reliably by measuring the expression levels of Notch specific target genes. This can be accomplished by the quantification of corresponding mRNA or protein of a particular Notch target gene. Alternatively, cells can be genetically modified to carry a luciferase gene as an artificial Notch target gene, which is expressed in dependence of Notch activity. In this setting, Notch signaling levels can be quantified by measuring the luciferase-derived bioluminescence values. 
     An according Notch-reporter assay, i.e. a luciferase-based luminescence readout, was used here to quantify the ability of the claimed small molecules to augment Notch signaling in a cellular system. For this purpose, HeLa cells, obtainable from the American Type Culture Collection (ATCC) under the accession number ATCC-CCL-2, were transiently transfected for 24 hours using FuGENE® HD (Promega, #E2311) as transfection reagent with expression vectors of a membrane-tethered form of the constitutively active intracellular domain of the human Notch1 receptor (hNotch1ΔE) to activate the signaling cascade (BPS Bioscience, human analogue to Notch Pathway Reporter Kit #60509 component C), a Firefly luciferase being expressed under the control of a Notch-responsive promoter to monitor Notch signaling (BPS Bioscience, Notch Pathway Reporter Kit #60509, CSL luciferase reporter vector from component A not premixed with Renilla luciferase vector), and a Renilla luciferase being constitutively expressed in a Notch signaling independent manner to include a measure for the cell number per sample (Promega, pRL-SV40, #E2231). HeLa cells were cultivated according to the protocol of the provider in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589). The transfection was carried out in a 100 mm-culture dish (StarLab, #CC7682-3394) with cells being properly attached to the plate at a cell confluency of 80-90% in a total volume of 7 mL culture medium. Per dish to be transfected, a transfection mix was prepared by adding to 238 μL Opti-MEM (Fisherscientific, #10149832) 40 μL of the hNotch1ΔE expression vector (100 ng/μL), 80 μL of the CSL luciferase reporter vector (40 ng/μL), 4 μL of the pRL-SV40-Renilla luciferase vector (10 ng/μL), and in the last step 18.1 μL of FuGENE® HD. After addition of FuGENE® HD the transfection mix was let stand for 15 min at room temperature and hereafter equally distributed into the culture dish. Subsequently, i.e. after 24 hours of transfection, the transfected cells (10.000 cells per well) were incubated with the test-compounds at a final concentration of 10 μM (diluted from 10 mM stock-solutions in DMSO to a final DMSO concentration of 0.1% v/v) or with the empty carrier DMSO at 0.1% v/v as control for 20 hours in 96-well plates suitable for luminescence readouts (CORNING, #3610). Hereafter, the cells were lysed with 30 μL per well of Passive Lysis Buffer (Promega, #E194A, component of Dual-Luciferase® Reporter Assay System, #E1910) and the Firefly as well as Renilla luciferase values were measured with a luminescence reader with applying 15 μL per well each of the corresponding enzyme substrates needed to create the luminescence signals (Promega, Dual-Luciferase® Reporter Assay System, #E1910). 
     The suitability of the assays for monitoring Notch signaling was controlled by additionally including a generally accepted commercial Notch inhibitor, i.e. DAPT, as negative control, as well as the reported Notch enhancer resveratrol (RES) as 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 likewise tested at 10 μM. 
     Per single experiment the measurement was performed in six replicates per compound. For every compound, this experiment was repeated in three or more independent replicates. The values of the Notch-reporter luciferase were normalized by division through the corresponding individual Notch-independent Renilla values in order to eliminate the impact of variation in the absolute cell-numbers in between the samples. For every individual plate, a second normalization was performed against the equally weighted arithmetic mean (here abbreviated as AVE) of the six associated Renilla-normalized DMSO-control values within a single experiment in order to obtain the relative values to a baseline level of 1.0. Two independent outlier analyses were performed according to the methods by Peirce and Chauvenet (Ross,  Journal of Engineering Technology  2003, 1-12). Outliers confirmed by at least one of the methods were excluded from the calculations but not more than one value out of six per compound within a single experiment. The weighted arithmetic mean (here abbreviated as AVE w ) for each compound was calculated from the double-normalized values over all independent replicates of the single experiments comprising the six replicates each. The corresponding standard deviation for the weighted arithmetic mean was calculated according to the method described by Bronstein et al. (Bronstein, Semendjajew, Musiol, Mühlig, Taschenbuch der Mathematik, 5 th  edition 2001 (German), publisher: Verlag Harri Deutsch, Frankfurt am Main and Thun) and was combined with the Gauβ′ error propagation associated with the performed calculation for the normalization. The resulting standard deviation is herein referred to as “combined standard deviation”. 
     A compound is considered as a Notch augmenting molecule, i.e. an enhancer of Notch signaling, if the weighted arithmetic mean of the luminescence values after subtraction of the corresponding combined standard deviation amounts to 1.1 or higher, in particular to 1.2 or higher, 1.3 or higher, 1.4 or higher, 1.5 or higher, 1.7 or higher, and 2.0 or higher relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all double-normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10 −2 . 
     According to the method described above, several molecules falling under the scope of the five compound families herein defined in formula I, formula II, formula III, formula IV and formula V have been identified as enhancers of Notch signaling. The so far identified Notch enhancers relate to the compounds listed in Table VI. The entries of Table VI are categorized by the corresponding weighted arithmetic mean of the compounds falling into the activity ranges as indicated. 
     
       
         
           
               
             
               
                 TABLE VI 
               
             
            
               
                   
               
               
                 Notch reporter assay 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Activity Range 
                 Entry 
                 Compound 
                 Specification 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 AVE w  ≥ 2.0 
                 1 
                 030 
                   
               
               
                   
                   
                 2 
                 186 
                   
               
               
                   
                   
                 3 
                 322 
                   
               
               
                   
                 1.7 ≤ AVE w  &lt; 2.0 
                 4 
                 003 
                   
               
               
                   
                   
                 5 
                 005 
                   
               
               
                   
                   
                 6 
                 027 
                   
               
               
                   
                   
                 7 
                 043 
                   
               
               
                   
                   
                 8 
                 045 
                   
               
               
                   
                   
                 9 
                 051 
                   
               
               
                   
                   
                 10 
                 114 
                   
               
               
                   
                   
                 11 
                 272 
                   
               
               
                   
                   
                 12 
                 284 
                   
               
               
                   
                   
                 13 
                 288 
                   
               
               
                   
                   
                 14 
                 318 
                   
               
               
                   
                 1.4 ≤ AVE w  &lt; 1.7 
                 15 
                 004 
                   
               
               
                   
                   
                 16 
                 026 
                   
               
               
                   
                   
                 17 
                 041 
                   
               
               
                   
                   
                 18 
                 050 
                   
               
               
                   
                   
                 19 
                 052 
                   
               
               
                   
                   
                 20 
                 067 
                   
               
               
                   
                   
                 21 
                 071 
                   
               
               
                   
                   
                 22 
                 072 
                   
               
               
                   
                   
                 23 
                 073 
                   
               
               
                   
                   
                 24 
                 075 
                   
               
               
                   
                   
                 25 
                 117 
                   
               
               
                   
                   
                 26 
                 120 
                   
               
               
                   
                   
                 27 
                 134 
                   
               
               
                   
                   
                 28 
                 216 
                   
               
               
                   
                   
                 29 
                 266 
                   
               
               
                   
                   
                 30 
                 269 
                   
               
               
                   
                   
                 31 
                 291 
                   
               
               
                   
                   
                 32 
                 297 
                   
               
               
                   
                   
                 33 
                 317 
                   
               
               
                   
                   
                 34 
                 336 
                   
               
               
                   
                   
                 35 
                 337 
                   
               
               
                   
                   
                 36 
                 385 
                   
               
               
                   
                   
                 37 
                 394 
                   
               
               
                   
                   
                 38 
                 395 
                   
               
               
                   
                   
                 39 
                 410 
                   
               
               
                   
                   
                 40 
                 544 
                   
               
               
                   
                   
                 41 
                 820 
                   
               
               
                   
                 1.5 ± 0.0 
                 42 
                 RES 
                 Positive control 
               
               
                   
                 1.3 ≤ AVE w  &lt; 1.4 
                 43 
                 044 
                   
               
               
                   
                   
                 44 
                 066 
                   
               
               
                   
                   
                 45 
                 122 
                   
               
               
                   
                   
                 46 
                 168 
                   
               
               
                   
                   
                 47 
                 182 
                   
               
               
                   
                   
                 48 
                 184 
                   
               
               
                   
                   
                 49 
                 268 
                   
               
               
                   
                   
                 50 
                 286 
                   
               
               
                   
                   
                 51 
                 292 
                   
               
               
                   
                   
                 52 
                 319 
                   
               
               
                   
                   
                 53 
                 334 
                   
               
               
                   
                   
                 54 
                 344 
                   
               
               
                   
                 1.2 ≤ AVE w  &lt; 1.3 
                 55 
                 007 
                   
               
               
                   
                   
                 56 
                 019 
                   
               
               
                   
                   
                 57 
                 025 
                   
               
               
                   
                   
                 58 
                 091 
                   
               
               
                   
                   
                 59 
                 092 
                   
               
               
                   
                   
                 60 
                 133 
                   
               
               
                   
                   
                 61 
                 166 
                   
               
               
                   
                   
                 62 
                 195 
                   
               
               
                   
                   
                 63 
                 217 
                   
               
               
                   
                   
                 64 
                 222 
                   
               
               
                   
                   
                 65 
                 241 
                   
               
               
                   
                   
                 66 
                 242 
                   
               
               
                   
                   
                 67 
                 247 
                   
               
               
                   
                   
                 68 
                 273 
                   
               
               
                   
                   
                 69 
                 275 
                   
               
               
                   
                   
                 70 
                 316 
                   
               
               
                   
                   
                 71 
                 325 
                   
               
               
                   
                   
                 72 
                 363 
                   
               
               
                   
                   
                 73 
                 396 
                   
               
               
                   
                   
                 74 
                 784 
                   
               
               
                   
                 1.1 ≤ AVE w  &lt; 1.2 
                 75 
                 086 
                   
               
               
                   
                   
                 76 
                 118 
                   
               
               
                   
                   
                 77 
                 159 
                   
               
               
                   
                   
                 78 
                 170 
                   
               
               
                   
                   
                 79 
                 171 
                   
               
               
                   
                   
                 80 
                 189 
                   
               
               
                   
                   
                 81 
                 215 
                   
               
               
                   
                   
                 82 
                 221 
                   
               
               
                   
                   
                 83 
                 234 
                   
               
               
                   
                   
                 84 
                 267 
                   
               
               
                   
                   
                 85 
                 287 
                   
               
               
                   
                   
                 86 
                 300 
                   
               
               
                   
                   
                 87 
                 323 
                   
               
               
                   
                   
                 88 
                 343 
                   
               
               
                   
                   
                 89 
                 374 
                   
               
               
                   
                   
                 90 
                 399 
                   
               
               
                   
                   
                 91 
                 451 
                   
               
               
                   
                   
                 92 
                 644 
                   
               
               
                   
                   
                 93 
                 703 
                   
               
               
                   
                   
                 94 
                 712 
                   
               
               
                   
                   
                 95 
                 721 
                   
               
               
                   
                   
                 96 
                 730 
                   
               
               
                   
                 1.0 ± 0.0 
                 97 
                 DMSO 
                 Baseline control 
               
               
                   
                 0.1 ± 0.0 
                 98 
                 DAPT 
                 Negative control 
               
               
                   
                   
               
            
           
         
       
     
     Several other molecules have not been identified as enhancers of Notch signaling according to the above method. 
     In the course of the evaluation of molecules falling under formula I, formula II, formula III, formula IV and formula V in further cellular assays, results indicate that compounds of said molecule families exhibit growth inhibiting properties in hyperproliferative processes. In some cases, the growth inhibiting properties correlate with Notch enhancing properties, in other cases the growth inhibiting properties do not correlate with Notch enhancing properties. 
     The biological activity of the claimed compounds can be attributed to but may not be limited to Notch signaling enhancing activity. The secondary mechanisms of the claimed compounds leading to antiproliferative effects can be used alternatively or in combination with the Notch enhancing properties in medicinal treatments, preferably in the treatment of hyperproliferative disorders including cancer and non-malignant hyperproliferative disorders. 
     The antiproliferative activities of compounds falling under formula I, formula II, formula III, formula IV and formula V were investigated on cells or cell lines originating from a disorder of the myeloid cell compartment, the neuroendocrine system, the cervix, and the mucosal epithelium, as well as from the skin epithelium. To this end, HL-60 cells, TT cells, HeLa cells, CAL-27 cells and human primary epidermal keratinocytes (HPEK) were seeded into 96-well plates suitable for fluorescence assays (CORNING #3598) at following initial cell numbers: 1000 cells per well for HL-60; 9000 cells per well for TT; 2000 cells per well for HeLa, 2000 cells per well for CAL-27, 2000 cells per well for HPEK. The cells were treated with compounds at indicated final concentrations (diluted from the 1000×stock-solutions in DMSO to a final DMSO concentration of 0.1% v/v) or with the empty carrier DMSO at 0.1% v/v as control for 5 days. At day 5 after starting the treatments the cells were subjected to the alamarBlue® Proliferation Assay (Bio-Rad Serotec GmbH, BUF012B) according to the protocol of the manufacturer. The readout was taken with a multi-well plate-reader in the fluorescence mode with applying a filter for excitation at 560 nm (band width 10 nm) and for emission at 590 nm (band width 10 nm). Resveratrol (RES) treatment was included as control for growth inhibition. 
     The assays were performed in duplicate or more replicates of independent single experiments each containing a six-fold replicate for every condition. For every individual plate, the measured fluorescence intensity values of the conditions with compound treatment were normalized against the corresponding equally weighted arithmetic mean of the fluorescence intensity values of the six DMSO treated control wells in order to obtain the relative values to a baseline level of 1.0. The statistical calculations were performed in analogy to the luciferase assay as described above. To this end, two independent outlier analyses were performed according to the methods by Peirce and Chauvenet (Ross,  Journal of Engineering Technology  2003, 1-12). Outliers confirmed by at least one of the methods were excluded from the calculations but not more than one value out of six per compound within a single experiment. The weighted arithmetic mean AVE w  for each compound was calculated from the normalized values over all independent replicates of the single experiments comprising the six replicates each. The corresponding standard deviation for the weighted arithmetic mean was calculated according to the method described by Bronstein et al. (Bronstein, Semendjajew, Musiol, Mühlig, Taschenbuch der Mathematik, 5 th  edition 2001 (German), publisher: Verlag Harri Deutsch, Frankfurt am Main and Thun) and was combined with the Gauβ′ error propagation associated with the performed calculation for the normalization. The resulting standard deviation is herein referred to as “combined standard deviation”. 
     In certain embodiments, the compounds of the present invention may be growth inhibitors in hyperproliferative processes, including malignant and non-malignant hyperproliferative processes. 
     In one embodiment, several compounds of the invention were found to inhibit the growth of HL-60 cells (human acute myeloid leukemia cells) obtainable from the Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH (DSMZ) under the accession number ACC 3. HL-60 cells were cultivated according to the protocol of the provider in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589). 
     A compound is considered as a growth inhibitor of HL-60 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10 −2 . 
     According to the method described above, several molecules falling under the scope of the five compound families herein defined in formula I, formula II, formula III, formula IV and formula V have been identified as growth inhibitors of HL-60 cells. The so far identified HL-60 growth inhibitors relate to the compounds listed in Table VII. The entries of Table VII are categorized by the corresponding weighted arithmetic means of the compounds falling into the activity ranges as indicated. 
     
       
         
           
               
             
               
                 TABLE VII 
               
             
            
               
                   
               
               
                 Proliferation assay with HL-60 cells at 20 μM 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Activity Range 
                 Entry 
                 Compound 
                 Specification 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 1.0 ± 0.0 
                 1 
                 DMSO 
                 Baseline control 
               
               
                   
                 0.8 &lt; AVE w  ≤ 0.9 
                 2 
                 002 
                   
               
               
                   
                   
                 3 
                 030 
                   
               
               
                   
                   
                 4 
                 054 
                   
               
               
                   
                   
                 5 
                 072 
                   
               
               
                   
                   
                 6 
                 073 
                   
               
               
                   
                   
                 7 
                 075 
                   
               
               
                   
                   
                 8 
                 087 
                   
               
               
                   
                   
                 9 
                 092 
                   
               
               
                   
                   
                 10 
                 165 
                   
               
               
                   
                   
                 11 
                 245 
                   
               
               
                   
                   
                 12 
                 248 
                   
               
               
                   
                   
                 13 
                 298 
                   
               
               
                   
                   
                 14 
                 300 
                   
               
               
                   
                   
                 15 
                 316 
                   
               
               
                   
                   
                 16 
                 317 
                   
               
               
                   
                   
                 17 
                 325 
                   
               
               
                   
                   
                 18 
                 337 
                   
               
               
                   
                   
                 19 
                 374 
                   
               
               
                   
                   
                 20 
                 385 
                   
               
               
                   
                   
                 21 
                 395 
                   
               
               
                   
                   
                 22 
                 399 
                   
               
               
                   
                   
                 23 
                 427 
                   
               
               
                   
                   
                 24 
                 477 
                   
               
               
                   
                   
                 25 
                 592 
                   
               
               
                   
                   
                 26 
                 712 
                   
               
               
                   
                   
                 27 
                 723 
                   
               
               
                   
                   
                 28 
                 731 
                   
               
               
                   
                   
                 29 
                 738 
                   
               
               
                   
                   
                 30 
                 739 
                   
               
               
                   
                   
                 31 
                 740 
                   
               
               
                   
                   
                 32 
                 792 
                   
               
               
                   
                   
                 33 
                 793 
                   
               
               
                   
                   
                 34 
                 811 
                   
               
               
                   
                   
                 35 
                 812 
                   
               
               
                   
                   
                 36 
                 819 
                   
               
               
                   
                 0.7 &lt; AVE w  ≤ 0.8 
                 37 
                 041 
                   
               
               
                   
                   
                 38 
                 134 
                   
               
               
                   
                   
                 39 
                 215 
                   
               
               
                   
                   
                 40 
                 223 
                   
               
               
                   
                   
                 41 
                 322 
                   
               
               
                   
                   
                 42 
                 410 
                   
               
               
                   
                   
                 43 
                 440 
                   
               
               
                   
                   
                 44 
                 488 
                   
               
               
                   
                   
                 45 
                 581 
                   
               
               
                   
                   
                 46 
                 674 
                   
               
               
                   
                   
                 47 
                 685 
                   
               
               
                   
                   
                 48 
                 756 
                   
               
               
                   
                   
                 49 
                 785 
                   
               
               
                   
                   
                 50 
                 786 
                   
               
               
                   
                   
                 51 
                 822 
                   
               
               
                   
                 0.6 &lt; AVE w  ≤ 0.7 
                 52 
                 067 
                   
               
               
                   
                   
                 53 
                 217 
                   
               
               
                   
                   
                 54 
                 222 
                   
               
               
                   
                   
                 55 
                 334 
                   
               
               
                   
                   
                 56 
                 336 
                   
               
               
                   
                   
                 57 
                 414 
                   
               
               
                   
                   
                 58 
                 492 
                   
               
               
                   
                   
                 59 
                 700 
                   
               
               
                   
                   
                 60 
                 821 
                   
               
               
                   
                   
                 61 
                 828 
                   
               
               
                   
                 0.4 &lt; AVE w  ≤ 0.6 
                 62 
                 043 
                   
               
               
                   
                   
                 63 
                 044 
                   
               
               
                   
                   
                 64 
                 045 
                   
               
               
                   
                   
                 65 
                 066 
                   
               
               
                   
                   
                 66 
                 133 
                   
               
               
                   
                   
                 67 
                 159 
                   
               
               
                   
                   
                 68 
                 164 
                   
               
               
                   
                   
                 69 
                 167 
                   
               
               
                   
                   
                 70 
                 218 
                   
               
               
                   
                   
                 71 
                 221 
                   
               
               
                   
                   
                 72 
                 236 
                   
               
               
                   
                   
                 73 
                 238 
                   
               
               
                   
                   
                 74 
                 313 
                   
               
               
                   
                   
                 75 
                 318 
                   
               
               
                   
                   
                 76 
                 319 
                   
               
               
                   
                   
                 77 
                 320 
                   
               
               
                   
                   
                 78 
                 323 
                   
               
               
                   
                   
                 79 
                 389 
                   
               
               
                   
                   
                 80 
                 721 
                   
               
               
                   
                   
                 81 
                 722 
                   
               
               
                   
                   
                 82 
                 729 
                   
               
               
                   
                   
                 83 
                 784 
                   
               
               
                   
                   
                 84 
                 820 
                   
               
               
                   
                 0.4 ± 0.0 
                 85 
                 RES 20 μM 
                 Control 
               
               
                   
                 0.2 &lt; AVE w  ≤ 0.4 
                 86 
                 161 
                   
               
               
                   
                   
                 87 
                 210 
                   
               
               
                   
                   
                 88 
                 211 
                   
               
               
                   
                   
                 89 
                 237 
                   
               
               
                   
                   
                 90 
                 596 
                   
               
               
                   
                 0.0 ≤ AVE w  ≤ 0.2 
                 91 
                 166 
                   
               
               
                   
                   
                 92 
                 168 
                   
               
               
                   
                   
                 93 
                 170 
                   
               
               
                   
                   
                 94 
                 171 
                   
               
               
                   
                   
                 95 
                 182 
                   
               
               
                   
                   
                 96 
                 184 
                   
               
               
                   
                   
                 97 
                 185 
                   
               
               
                   
                   
                 98 
                 186 
                   
               
               
                   
                   
                 99 
                 216 
                   
               
               
                   
                   
                 100 
                 266 
                   
               
               
                   
                   
                 101 
                 267 
                   
               
               
                   
                   
                 102 
                 268 
                   
               
               
                   
                   
                 103 
                 269 
                   
               
               
                   
                   
                 104 
                 270 
                   
               
               
                   
                   
                 105 
                 272 
                   
               
               
                   
                   
                 106 
                 273 
                   
               
               
                   
                   
                 107 
                 275 
                   
               
               
                   
                   
                 108 
                 284 
                   
               
               
                   
                   
                 109 
                 286 
                   
               
               
                   
                   
                 110 
                 287 
                   
               
               
                   
                   
                 111 
                 288 
                   
               
               
                   
                   
                 112 
                 529 
                   
               
               
                   
                   
                 113 
                 540 
                   
               
               
                   
                   
                 114 
                 544 
                   
               
               
                   
                   
                 115 
                 633 
                   
               
               
                   
                   
                 116 
                 644 
                   
               
               
                   
                   
                 117 
                 648 
                   
               
               
                   
                   
                 118 
                 766 
                   
               
               
                   
                   
                 119 
                 767 
                   
               
               
                   
                   
                 120 
                 768 
                   
               
               
                   
                   
                 121 
                 774 
                   
               
               
                   
                   
                 122 
                 802 
                   
               
               
                   
                   
                 123 
                 803 
                   
               
               
                   
                   
                 124 
                 804 
                   
               
               
                   
                   
                 125 
                 810 
               
               
                   
                   
               
            
           
         
       
     
     In one embodiment, several compounds of the invention were found to inhibit the growth of CAL-27 cells (human tongue squamous cell carcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH (DSMZ) under the accession number ACC 446. CAL-27 cells were cultivated according to the protocol of the provider (but at 5% instead of 10% CO 2 ) in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589). 
     A compound is considered as a growth inhibitor of CAL-27 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10 −2 . 
     According to the method described above, several molecules falling so far under the scope of the three compound families herein defined in formula II, formula IV and formula V have been identified as growth inhibitors of CAL-27 cells. The so far identified CAL-27 growth inhibitors relate to the compounds listed in Table VIIIa and VIIIb. The entries of Table VIIIa and VIIIb are categorized by the corresponding weighted arithmetic means of the compounds falling into the activity ranges as indicated. 
     
       
         
           
               
             
               
                 TABLE VIIIa 
               
             
            
               
                   
               
               
                 Proliferation assay with CAL-27 cells at 20 μM 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Activity Range 
                 Entry 
                 Compound 
                 Specification 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 1.0 ± 0.0 
                 1 
                 DMSO 
                 Baseline control 
               
               
                   
                 0.9 ± 0.0 
                 2 
                 RES 20 μM 
                 Control 
               
               
                   
                 0.8 &lt; AVE w  ≤ 0.9 
                 3 
                 236 
                   
               
               
                   
                   
                 4 
                 300 
                   
               
               
                   
                   
                 5 
                 596 
                   
               
               
                   
                   
                 6 
                 820 
                   
               
               
                   
                   
                 7 
                 822 
                   
               
               
                   
                 0.7 &lt; AVE w  ≤ 0.8 
                 8 
                 164 
                   
               
               
                   
                   
                 9 
                 210 
                   
               
               
                   
                   
                 10 
                 313 
                   
               
               
                   
                   
                 11 
                 774 
                   
               
               
                   
                 0.6 &lt; AVE w  ≤ 0.7 
                 12 
                 167 
                   
               
               
                   
                   
                 13 
                 238 
                   
               
               
                   
                 0.4 &lt; AVE w  ≤ 0.6 
                 14 
                 211 
                   
               
               
                   
                   
                 15 
                 237 
                   
               
               
                   
                   
                 16 
                 266 
                   
               
               
                   
                 0.4 ± 0.0 
                 17 
                 RES 40 μM 
                 Control 
               
               
                   
                 0.2 &lt; AVE w  ≤ 0.4 
                 18 
                 166 
                   
               
               
                   
                   
                 19 
                 170 
                   
               
               
                   
                   
                 20 
                 182 
                   
               
               
                   
                   
                 21 
                 267 
                   
               
               
                   
                   
                 22 
                 287 
                   
               
               
                   
                   
                 23 
                 288 
                   
               
               
                   
                   
                 24 
                 768 
                   
               
               
                   
                 0.0 ≤ AVE w  ≤ 0.2 
                 25 
                 168 
                   
               
               
                   
                   
                 26 
                 171 
                   
               
               
                   
                   
                 27 
                 184 
                   
               
               
                   
                   
                 28 
                 185 
                   
               
               
                   
                   
                 29 
                 186 
                   
               
               
                   
                   
                 30 
                 268 
                   
               
               
                   
                   
                 31 
                 269 
                   
               
               
                   
                   
                 32 
                 270 
                   
               
               
                   
                   
                 33 
                 272 
                   
               
               
                   
                   
                 34 
                 273 
                   
               
               
                   
                   
                 35 
                 275 
                   
               
               
                   
                   
                 36 
                 284 
                   
               
               
                   
                   
                 37 
                 286 
                   
               
               
                   
                   
                 38 
                 529 
                   
               
               
                   
                   
                 39 
                 540 
                   
               
               
                   
                   
                 40 
                 544 
                   
               
               
                   
                   
                 41 
                 633 
                   
               
               
                   
                   
                 42 
                 644 
                   
               
               
                   
                   
                 43 
                 648 
                   
               
               
                   
                   
                 44 
                 766 
                   
               
               
                   
                   
                 45 
                 767 
                   
               
               
                   
                   
                 46 
                 802 
                   
               
               
                   
                   
                 47 
                 803 
                   
               
               
                   
                   
                 48 
                 804 
                   
               
               
                   
                   
                 49 
                 810 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE VIIIb 
               
             
            
               
                   
               
               
                 Proliferation assay with CAL-27 cells at 40 μM 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Activity Range 
                 Entry 
                 Compound 
                 Specification 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 1.0 ± 0.0 
                 1 
                 DMSO 
                 Baseline control 
               
               
                   
                 0.9 ± 0.0 
                 2 
                 RES 20 μM 
                 Control 
               
               
                   
                 0.8 &lt; AVE w  ≤ 0.9 
                 3 
                 300 
                   
               
               
                   
                   
                 4 
                 334 
                   
               
               
                   
                 0.7 &lt; AVE w  ≤ 0.8 
                 5 
                 722 
                   
               
               
                   
                 0.6 &lt; AVE w  ≤ 0.7 
                 6 
                 159 
                   
               
               
                   
                 0.5 ± 0.0 
                 7 
                 RES 40 μM 
                 Control 
               
               
                   
                 0.2 &lt; AVE w  ≤ 0.4 
                 8 
                 161 
                   
               
               
                   
                   
                 9 
                 237 
                   
               
               
                   
                   
                 10 
                 729 
                   
               
               
                   
                   
                 11 
                 768 
                   
               
               
                   
                 0.0 ≤ AVE w  ≤ 0.2 
                 12 
                 166 
                   
               
               
                   
                   
                 13 
                 167 
                   
               
               
                   
                   
                 14 
                 210 
                   
               
               
                   
                   
                 15 
                 272 
                   
               
               
                   
                   
                 16 
                 287 
               
               
                   
                   
               
            
           
         
       
     
     In one embodiment, several compounds of the invention were found to inhibit the growth of TT cells (human medullary thyroid carcinoma cells) obtainable from the American Type Culture Collection (ATCC) under the accession number ATCC-CRL-1803. TT cells were cultivated according to the protocol of the provider in F-12K medium (Fisherscientific, #11580556, or ATCC, #ATCC-30-2004) containing 10% fetal bovine serum (Fisherscientific, #15517589). 
     A compound is considered as a growth inhibitor of TT cells, if—at a reference concentration of 40 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10 −2 . 
     According to the method described above, several molecules falling so far under the scope of the three compound families herein defined in formula II, formula IV and formula V have been identified as growth inhibitors of TT cells. The so far identified TT growth inhibitors relate to the compounds listed in Table IX. The entries of Table IX are categorized by the corresponding weighted arithmetic means of the compounds falling into the activity ranges as indicated. 
     
       
         
           
               
             
               
                 TABLE IX 
               
             
            
               
                   
               
               
                 Proliferation assay with TT cells at 40 μM 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Activity Range 
                 Entry 
                 Compound 
                 Specification 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 1.0 ± 0.0 
                 1 
                 DMSO 
                 Baseline control 
               
               
                   
                 0.9 ± 0.0 
                 2 
                 RES 20 μM 
                 Control 
               
               
                   
                 0.8 &lt; AVE w  ≤ 0.9 
                 3 
                 159 
                   
               
               
                   
                   
                 4 
                 309 
                   
               
               
                   
                   
                 5 
                 334 
                   
               
               
                   
                 0.8 ± 0.0 
                 6 
                 RES 40 μM 
                 Control 
               
               
                   
                 0.7 &lt; AVE w  ≤ 0.8 
                 7 
                 748 
                   
               
               
                   
                 0.6 &lt; AVE w  ≤ 0.7 
                 8 
                 210 
                   
               
               
                   
                 0.4 &lt; AVE w  ≤ 0.6 
                 9 
                 161 
                   
               
               
                   
                   
                 10 
                 237 
                   
               
               
                   
                 0.2 &lt; AVE w  ≤ 0.4 
                 11 
                 166 
                   
               
               
                   
                   
                 12 
                 167 
                   
               
               
                   
                   
                 13 
                 171 
                   
               
               
                   
                   
                 14 
                 182 
                   
               
               
                   
                   
                 15 
                 186 
                   
               
               
                   
                   
                 16 
                 287 
                   
               
               
                   
                   
                 17 
                 540 
                   
               
               
                   
                   
                 18 
                 544 
                   
               
               
                   
                   
                 19 
                 644 
                   
               
               
                   
                   
                 20 
                 729 
                   
               
               
                   
                 0.0 ≤ AVE w  ≤ 0.2 
                 21 
                 272 
                   
               
               
                   
                   
                 22 
                 284 
                   
               
               
                   
                   
                 23 
                 288 
                   
               
               
                   
                   
                 24 
                 768 
               
               
                   
                   
               
            
           
         
       
     
     In one embodiment, several compounds of the invention were found to inhibit the growth of HeLa cells (human cervical adenocarcinoma cells) obtainable from the American Type Culture Collection (ATCC) under the accession number ATCC-CCL-2. HeLa cells were cultivated according to the protocol of the provider in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589). 
     A compound is considered as a growth inhibitor of HeLa cells, if—at a reference concentration of 40 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10 −2 . 
     According to the method described above, several molecules falling so far under the scope of the compound family herein defined in formula II have been identified as growth inhibitors of HeLa cells. The so far identified HeLa growth inhibitors relate to the compounds listed in Table X. The entries of Table X are categorized by the corresponding weighted arithmetic means of the compounds falling into the activity ranges as indicated. 
     
       
         
           
               
             
               
                 TABLE X 
               
             
            
               
                   
               
               
                 Proliferation assay with HeLa cells at 40 μM 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Activity Range 
                 Entry 
                 Compound 
                 Specification 
               
               
                   
                   
               
               
                   
                 1.0 ± 0.0 
                 1 
                 DMSO 
                 Baseline control 
               
               
                   
                 0.9 ± 0.0 
                 2 
                 RES 20 μM 
                 Control 
               
               
                   
                 0.4 &lt; AVE w  ≤ 0.6 
                 3 
                 166 
                   
               
               
                   
                 0.4 ± 0.0 
                 4 
                 RES 40 μM 
                 Control 
               
               
                   
                 0.2 &lt; AVE w  ≤ 0.4 
                 5 
                 167 
                   
               
               
                   
                   
                 6 
                 287 
                   
               
               
                   
                 0.0 ≤ AVE w  ≤ 0.2 
                 7 
                 272 
               
               
                   
                   
               
            
           
         
       
     
     In one embodiment, several compounds of the invention were found to inhibit the growth of human epidermal keratinocyte progenitors, (HPEKp, pooled), obtainable from CELLnTEC Advanced Cell Systems AG under the accession number HPEKp. HPEKp cells were cultivated according to the protocol of the provider in CnT-Prime epithelial culture medium (CELLnTEC, #CnT-PR, a fully defined, low calcium formulation, completely free of animal or human-derived components) without addition of further components. 
     A compound is considered as a growth inhibitor of HPEKp cells, if—at a reference concentration of 10 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10 −2 . 
     According to the method described above, several molecules falling so far under the scope of the four compound families herein defined in formula II, formula III, formula IV and formula V have been identified as growth inhibitors of HPEKp cells. The so far identified HPEKp growth inhibitors relate to the compounds listed in Table XI. The entries of Table XI are categorized by the corresponding weighted arithmetic means of the compounds falling into the activity ranges as indicated. 
     
       
         
           
               
             
               
                 TABLE XI 
               
             
            
               
                   
               
               
                 Proliferation assay with HPEKp cells at 10 μM 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Activity Range 
                 Entry 
                 Compound 
                 Specification 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 1.0 ± 0.0 
                 1 
                 DMSO 
                 Baseline control 
               
               
                   
                 0.8 &lt; AVE w  ≤ 0.9 
                 3 
                 140 
                   
               
               
                   
                   
                 4 
                 374 
                   
               
               
                   
                   
                 5 
                 731 
                   
               
               
                   
                   
                 6 
                 747 
                   
               
               
                   
                   
                 7 
                 749 
                   
               
               
                   
                   
                 8 
                 801 
                   
               
               
                   
                 0.7 &lt; AVE w  ≤ 0.8 
                 10 
                 312 
                   
               
               
                   
                   
                 11 
                 323 
                   
               
               
                   
                   
                 12 
                 424 
                   
               
               
                   
                   
                 13 
                 721 
                   
               
               
                   
                   
                 14 
                 819 
                   
               
               
                   
                   
                 15 
                 828 
                   
               
               
                   
                 0.6 &lt; AVE w  ≤ 0.7 
                 16 
                 086 
                   
               
               
                   
                   
                 17 
                 190 
                   
               
               
                   
                   
                 18 
                 334 
                   
               
               
                   
                 0.4 &lt; AVE w  ≤ 0.6 
                 19 
                 112 
                   
               
               
                   
                   
                 20 
                 722 
                   
               
               
                   
                 0.4 ± 0.0 
                 21 
                 RES 10 μM 
                 Control 
               
               
                   
                 0.2 &lt; AVE w  ≤ 0.4 
                 22 
                 389 
                   
               
               
                   
                   
                 23 
                 440 
                   
               
               
                   
                   
                 24 
                 540 
                   
               
               
                   
                 0.0 ≤ AVE w  ≤ 0.2 
                 25 
                 159 
                   
               
               
                   
                   
                 26 
                 182 
                   
               
               
                   
                   
                 27 
                 185 
                   
               
               
                   
                   
                 28 
                 273 
                   
               
               
                   
                   
                 29 
                 287 
                   
               
               
                   
                   
                 30 
                 644 
                   
               
               
                   
                   
                 31 
                 810 
               
               
                   
                   
               
            
           
         
       
     
     Preliminary results from a single proliferation assay of six replicates per condition using cells derived from murine muscle tissue show that compounds of the invention may exhibit antiproliferative activity on muscle cells. Compounds were tested on C2C12 cells using the alamarBlue® proliferation assay in analogy to the above described method with seeding the cells at an initial number of 2000 cells per 96-well and a duration of treatment with compounds for 3 days. 
     In one embodiment, two compounds of the invention were found so far to inhibit the growth of C2C12 cells (murine myoblast cells) obtainable from the Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH (DSMZ) under the accession number ACC 565. C2 C12 cells were cultivated according to the protocol of the provider in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589). 
     A compound is considered as a growth inhibitor of C2C12 cells, if—at a reference concentration of 40 μM—the equally weighted arithmetic mean (AVE) of the six normalized fluorescence intensity values after addition of the corresponding standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the equally weighted arithmetic mean (AVE) of the six normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding standard deviations for the tested compounds were calculated including the Gaugβ′ error propagation associated with the performed calculation for the normalization and amounts for the DMSO values to less than 3·10 −2 . Outlier analyses were performed as described above. 
     According to the method described above, molecules falling so far under the scope of the two compound families herein defined in formula II and formula V have been identified as growth inhibitors of C2C12 cells. The so far identified C2C12 growth inhibitors relate to the compounds listed in Table XII. The entries of Table XII are categorized by the corresponding equally weighted arithmetic means of the compounds falling into the activity ranges as indicated. 
     
       
         
           
               
             
               
                 TABLE XII 
               
             
            
               
                   
               
               
                 Proliferation assay with C2C12 cells at 40 μM 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Activity Range 
                 Entry 
                 Compound 
                 Specification 
               
               
                   
                   
               
               
                   
                 1.0 ± 0.0 
                 1 
                 DMSO 
                 Baseline control 
               
               
                   
                 0.8 &lt; AVE ≤ 0.9 
                 2 
                 748 
                   
               
               
                   
                 0.3 ± 0.0 
                 3 
                 RES 40 μM 
                 Control 
               
               
                   
                 0.2 &lt; AVE ≤ 0.4 
                 4 
                 288 
               
               
                   
                   
               
            
           
         
       
     
     Preliminary results from a single proliferation assay of six replicates per condition using squamous cell carcinoma (SC C) cells derived from the human oral mucosa may confirm that compounds of the invention exhibit antiproliferative activity on SCC of the mucosal epithelium. Compounds were tested on BHY cells using the alamarBlue® proliferation assay in analogy to the above described method with seeding the cells at an initial number of 4000 cells per 96-well and a duration of treatment with compounds for 3 days. 
     In one embodiment, several compounds of the invention were found to inhibit the growth of BHY cells (human oral squamous cell carcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH (DSMZ) under the accession number ACC 404. BHY cells were cultivated according to the protocol of the provider (but at 5% instead of 10% CO2) in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589). 
     A compound is considered as a growth 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 addition of the corresponding standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean (AVE w ) of all normalized values from the DMSO control measurements. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10 −2 . The corresponding standard deviations for the tested compounds were calculated including the Gaugβ′ error propagation associated with the performed calculation for the normalization. The weighted arithmetic mean (AVE w ) and the combined standard deviation for RES was calculated in analogy to DMSO. Outlier analyses were performed as described above. 
     According to the method described above, molecules falling so far under the scope of the two compound families herein defined in formula II and formula IV have been identified as growth inhibitors of BHY cells. The so far identified BHY growth inhibitors relate to the compounds listed in Table XIII. The entries of Table XIII are categorized by the corresponding equally weighted arithmetic means of the compounds falling into the activity ranges as indicated. 
     
       
         
           
               
             
               
                 TABLE XIII 
               
             
            
               
                   
               
               
                 Proliferation assay with BHY cells at 40 μM 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Activity Range 
                 Entry 
                 Compound 
                 Specification 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 1.0 ± 0.0 
                 1 
                 DMSO 
                 Baseline control 
               
               
                   
                 0.6 &lt; AVE ≤ 0.7 
                 2 
                 644 
                   
               
               
                   
                 0.6 ± 0.0 
                 3 
                 RES 40 μM 
                 Control 
               
               
                   
                 0.4 &lt; AVE ≤ 0.6 
                 4 
                 171 
                   
               
               
                   
                 0.2 &lt; AVE ≤ 0.4 
                 5 
                 182 
                   
               
               
                   
                   
                 6 
                 186 
                   
               
               
                   
                   
                 7 
                 272 
                   
               
               
                   
                   
                 8 
                 284 
                   
               
               
                   
                   
                 9 
                 288 
                   
               
               
                   
                   
                 10 
                 544 
                   
               
               
                   
                   
                 11 
                 633 
                   
               
               
                   
                 0.0 ≤ AVE ≤ 0.2 
                 12 
                 540 
               
               
                   
                   
               
            
           
         
       
     
     In one aspect, the present invention relates to the treatment of skin, skin appendages, mucosa, mucosal appendages, cornea, and all kinds of epithelial tissue. The term “skin” relates to tissue including epidermis and dermis. The term “mucosa” relates to mucous and submucous tissues including oral mucosa, nasal mucosa, ocular mucosa, mucosa of the ear, respiratory mucosa, genital mucosa, urothelial mucosa, anal mucosa and rectal mucosa. The term “appendages” relates to tissue including hair follicles, hair, fingernails, toenails and glands including sebaceous glands, sweat glands, e.g. apocrine or eccrine sweat glands and mammary glands. 
     In one embodiment, the present invention relates to treatment of non-melanoma skin cancer 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, SCC of the thyroid, SCC of the penis, SCC of the vagina, SCC of the prostate, SCC of the bladder, sebaceous gland carcinoma, Merkel cell carcinoma, angiosarcoma, cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, dermatofibrosarcoma, actinic keratosis (AK) or Bowen&#39;s disease (BD). 
     In a further embodiment, the present invention relates to the treatment of skin and mucosal disorders with cornification defects (keratoses) and/or abnormal keratinocyte proliferation, such as Psoriasis, Darier&#39;s disease, Lichen planus, Lupus erythematosus, Ichthyosis or Verruca vulgaris (senilis). 
     In a further embodiment, the invention relates to the treatment of skin and mucosal diseases related to and caused by viral infections, such as warts, HPV-related warts, papillomas, HPV-related papillomas, papillomatoses and HPV-related papillomatoses, e.g. Verruca (plantar warts), Verruca plana (flat warts/plane warts), Verruca filiformis (filiform warts), mosaic warts, periungual warts, subungual warts, oral warts, genital warts, fibroepithelial papilloma, intracanalicular papilloma, intraductal papilloma, inverted papilloma, basal cell papilloma, squamous papilloma, cutaneous papilloma, fibrovasular papilloma, plexus papilloma, nasal papilloma, pharyngeal papilloma, Papillomatosis cutis carcinoides, Papillomatosis cutis lymphostatica, Papillomatosis confluens et reticularis or laryngeal papillomatosis (respiratory papillomatosis), Herpes-related diseases, e.g. Herpes labialis, Herpes genitalis, Herpes zoster, Herpes corneae or Kaposi&#39;s sarcoma. 
     In a further embodiment, the invention relates to the treatment of atopic dermatitis. 
     In a further embodiment, the invention relates to the treatment of acne. 
     In a further embodiment, the invention relates to the treatment of wounds of the skin, wherein the process of wound healing is accelerated. 
     A further aspect of the present invention relates to the treatment of immune system-related disorders. The term “immune system-related” as used herein applies to a pathological condition of the hematopoietic system including the hematologic system, as well as to the intervention into proliferation, differentiation and/or activation of cell lineages of the hematopoietic system including the hematologic system in order to modulate an immune response (immune modulation). 
     Examples are diseases of the hematopoietic system including the hematologic system, such as malignancies of the myeloid lineage, e.g. chronic myelomonocytic leukemia (CMML) or acute myeloid leukemia (AML), including acute promyelocytic leukemia (APL); malignancies of the lymphoid lineage, e.g. B-cell acute lymphoblastic leukemia (B-ALL), pre-B-cell acute lymphoblastic leukemia (pre-B-ALL), Hodgkin lymphoma or myeloma; or acute lymphoblastic and acute myeloid mixed lineage leukemia with MLL gene translocation. 
     Furthermore, the compounds of the invention may be used in immunotherapy, alone or together with other immunotherapeutic methods or compounds, or as adjuvant for immunotherapy. The term “immunotherapy” as used herein applies to activation-immunotherapy in patients without immune deficiency or with acquired or congenital immune deficiency, and as immune recovery to enhance the functionality of the immune system in the response against pathogens or pathologically transformed endogenous cells, such as cancer cells. 
     The term “other immunotherapy methods” as used herein applies to vaccinations, antibody treatment, cytokine therapy, the use of immune checkpoint inhibitors and immune response-stimulating drugs, as well as to autologous transplantations of genetically modified or non-modified immune cells, which may be stimulated with intercellular signals, or signaling molecules, or antigens, or antibodies, i.e. adoptive immune-cell transfer. 
     Specific examples are activation of peripheral T-lymphocytes in order to amplify an immune response, particularly the stimulation of proliferation and/or cytokine production and/or secretion upon antigen recognition in order to amplify an immune response, such as the activation of B-lymphocytes in order to amplify an immune response, particularly the stimulation of proliferation and/or antibody production and/or secretion, such as the enhancement of an immune response through augmentation of the number of specific immune-cell subtypes, by regulation of differentiation and/or cell fate decision during immune-cell development, as for example to augment the number of marginal zone B-cells, or T-helper (Th) subsets in particular Th1, Th2 and regulatory T-cells; or the use as vaccine adjuvant. 
     A still further aspect of the invention relates to the treatment of muscular diseases including diseases of skeletal muscle, cardiac muscle and smooth muscle. 
     In one embodiment, the invention relates to the treatment of muscular dystrophies (MD). 
     Specific examples are Duchenne MD, Becker MD, congenital MD, Limb-Girdle MD, facioscapulohumeral MD, Emery-Dreifuss MD, distal MD, myotonic MD or oculopharyngeal MD. 
     In a further embodiment, the invention relates to the treatment of hyperproliferative disorders of the muscle, including myoblastoma, rhabdomyoma, and rhabdomyosarcoma, as well as muscle hyperplasia and muscle hypertrophy. 
     In a further embodiment, the compounds of the invention may be used for muscle regeneration after pathologic muscle degeneration or atrophy, e.g. caused by traumata, caused by muscle ischemia or caused by inflammation, in aging-related muscle-atrophy or in disease-related muscle atrophy such as myositis and fibromyositis or poliomyelitis. 
     A still further aspect relates to the treatment of disorders of the neuroendocrine system such as cancer of the neuroendocrine system, comprising neuroendocrine small cell carcinomas, neuroendocrine large cell carcinomas and carcinoid tumors, e.g. of the brain, thyroid, pancreas, gastrointestinal tract, liver, esophagus, and lung, such as neuroendocrine tumor of the pituitary gland, neuroendocrine tumor of the adrenal gland, medullary thyroid cancer (MTC), C-cell hyperplasia, anaplastic thyroid cancer (ATC), parathyroid adenoma, intrathyroidal nodules, insular carcinoma, hyalinizing trabecular neoplasm, paraganglioma, small-cell lung cancer (SCLC), lung carcinoid tumors, neuroblastoma, gastrointestinal carcinoid, Goblet-cell carcinoid, pancreatic carcinoid, gastrinoma, glucagenoma, somatostatinoma, VlPoma, insulinoma, non-functional islet cell tumor, multiple endocrine neoplasia type-1, or pulmonary carcinoid. 
     A still further aspect relates to the treatment of cancers or precancerous lesions of the brain, pancreas, liver, thyroid, genitourinary tract and endothelial tissue, including glioma, mixed glioma, 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, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, pancreatic acinar cell carcinoma, pancreatic pseudopapillary neoplasm, pancreatic intraductal papillary-mucinous neoplasm, pancreatic mucinous cystadenocarcinoma, pancreatoblastoma and pancreatic intraepithelial neoplesia, hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, papillary thyroid cancer and follicular thyroid cancer, cervical cancer and angiosarcoma. 
     As used herein, the term “treating” or “treatment” refers to one or more of (1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease. The term “treating” also encompasses post-treatment care. 
     In some embodiments, administration of a compound of the invention, or pharmaceutically acceptable salt thereof, is effective in preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease. 
     The compounds of the invention may be used in human and veterinary medicine, which includes the treatment of companion animals, e.g. horses, dogs, cats, rabbits, guinea pigs, birds, fishes; and livestock, e.g. cattle, poultry, pig, sheep, goat, donkey, yak and camel. 
     Pharmaceutical Compositions 
     The present invention further provides pharmaceutical compositions comprising a compound as described herein or a pharmaceutically acceptable salt thereof for use in medicine, e.g. in human or veterinary medicine. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. 
     An effective dose of the compounds according to the invention, or their salts, solvates or prodrugs thereof is used, in addition to physiologically acceptable carriers, diluents and/or adjuvants for producing a pharmaceutical composition. The dose of the active compounds can vary depending on the route of administration, the age and weight of the patient, the nature and severity of the diseases to be treated, and similar factors. The daily dose can be given as a single dose, which is to be administered once, or be subdivided into two or more daily doses, and is as a rule 0.001-2000 mg. Particular preference is given to administering daily doses of 0.1-500 mg, e.g. 0.1-100 mg. 
     Suitable administration forms are topical or systemical including enteral, oral, rectal, and parenteral, as infusion and injection, intravenous, intra-arterial, intraperitoneal, intramuscular, intracardial, epidural, intracerebral, intracerebroventricular, intraosseous, intra-articular, intraocular, intravitreal, intrathecal, intravaginal, intracavernous, intravesical, subcutaneous, intradermal, transdermal, transmucosal, inhalative, intranasal, buccal, sublingual and intralesional preparations. Particular preference is given to using oral, parenteral, e.g. intravenous or intramuscular, intranasal preparations, e.g. dry powder or sublingual, of the compounds according to the invention. The customary galenic preparation forms, such as tablets, sugar-coated tablets, capsules, dispersible powders, granulates, aqueous solutions, alcohol-containing aqueous solutions, aqueous or oily suspensions, gels, hydrogels, ointments, creams, lotions, shampoos, lip balms, mouthwashs, foams, pastes, tinctures, dermal patches and tapes, forms in occlusion or in combination with time release drug delivery systems, with electrophoretic dermal delivery systems including implants and devices, and with jet injectors, liposome and transfersome vesicles, vapors, sprays, syrups, juices or drops and eye drops, can be used. 
     Solid medicinal forms can comprise inert components and carrier substances, such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatine, guar gum, magnesium stearate, aluminium stearate, methyl cellulose, talc, highly dispersed silicic acids, silicone oil, higher molecular weight fatty acids, (such as stearic acid), gelatine, agar agar or vegetable or animal fats and oils, or solid high molecular weight polymers (such as polyethylene glycol); preparations which are suitable for oral administration can comprise additional flavourings and/or sweetening agents, if desired. 
     Liquid medicinal forms can be sterilized and/or, where appropriate, comprise auxiliary substances, such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols for regulating the osmotic pressure or for buffering, and/or viscosity regulators. Examples of such additives are tartrate and citrate buffers, ethanol and sequestering agents (such as ethylenediaminetetraacetic acid and its non-toxic salts). High molecular weight polymers, such as liquid polyethylene oxides, microcrystalline celluloses, carboxymethyl celluloses, polyvinylpyrrolidones, dextrans or gelatine, are suitable for regulating the viscosity. Examples of solid carrier substances are starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar agar, calcium phosphate, magnesium stearate, animal and vegetable fats, and solid high molecular weight polymers, such as polyethylene glycol. 
     Oily suspensions for parenteral or topical applications can be vegetable, synthetic or semisynthetic oils, such as liquid fatty acid esters having in each case from 8 to 22 C atoms in the fatty acid chains, for example palmitic acid, lauric acid, tridecanoic acid, margaric acid, stearic acid, arachidic acid, myristic acid, behenic acid, pentadecanoic acid, linoleic acid, elaidic acid, brasidic acid, erucic acid or oleic acid, which are esterified with monohydric to trihydric alcohols having from 1 to 6 C atoms, such as methanol, ethanol, propanol, butanol, pentanol or their isomers, glycol or glycerol. Examples of such fatty acid esters are commercially available miglyols, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-capric acid, caprylic/capric acid esters of saturated fatty alcohols, polyoxyethylene glycerol trioleates, ethyl oleate, waxy fatty acid esters, such as artificial ducktail gland fat, coconut fatty acid isopropyl ester, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters, inter alia. Silicone oils of differing viscosity, 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 furthermore possible to use vegetable oils, such as castor oil, almond oil, olive oil, sesame oil, cotton seed oil, groundnut oil or soybean oil. 
     Suitable solvents, gelatinizing agents and solubilizers are water or water-miscible solvents. Examples of suitable substances are alcohols, such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, methyl cellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulphoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc. 
     Cellulose ethers which can dissolve or swell both in water or in organic solvents, such as hydroxypropylmethyl cellulose, methyl cellulose or ethyl cellulose, or soluble starches, can be used as film-forming agents. 
     Mixtures of gelatinizing agents and film-forming agents are also perfectly possible. In this case, use is made, in particular, of ionic macromolecules such as sodium carboxymethyl cellulose, 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 additional formulation aids: glycerol, paraffin of differing viscosity, triethanolamine, collagen, allantoin and novantisolic acid. Use of surfactants, emulsifiers or wetting agents, for example of Na lauryl sulphate, fatty alcohol ether sulphates, 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 ethers, cetyltrimethylammonium chloride or mono-/dialkylpolyglycol ether orthophosphoric acid monoethanolamine salts can also be required for the formulation. Stabilizers, such as montmorillonites or colloidal silicic acids, for stabilizing emulsions or preventing the breakdown of active substances such as antioxidants, for example tocopherols or butylhydroxyanisole, or preservatives, such as p-hydroxybenzoic acid esters, can likewise be used for preparing the desired formulations. 
     Preparations for parenteral administration can be present in separate dose unit forms, such as ampoules or vials. Use is preferably made of solutions of the active compound, preferably aqueous solution and, in particular, isotonic solutions and also suspensions. These injection forms can be made available as ready-to-use preparations or only be prepared directly before use, by mixing the active compound, for example the lyophilisate, where appropriate containing other solid carrier substances, with the desired solvent or suspending agent. 
     Intranasal preparations can be present as aqueous or oily solutions or as aqueous or oily suspensions. They can also be present as lyophilisates which are prepared before use using the suitable solvent or suspending agent. 
     Inhalable preparations can present as powders, solutions or suspensions. Preferably, inhalable preparations are in the form of powders, e.g. as a mixture of the active ingredient with a suitable formulation aid such as lactose. 
     The preparations are produced, aliquoted and sealed under the customary antimicrobial and aseptic conditions. 
     As indicated above, the compounds of the invention may be administered as a combination therapy, as sequence therapy or as simultaneous combination therapy, with further active agents, e.g. therapeutically active compounds useful in the treatment of the above indicated disorders. These therapeutically active compounds may include but are not limited to chemotherapeutic agents such as nucleoside analogs, e.g. Cytarabin, Gemcitabine, Azathioprine, Mercaptopurine, Fluorouracil, Thioguanine, Hydroxyurea, Azacitidine, Capecitabine, Doxifluridine, and Methotrexate; such as platinum-based drugs, e.g. Cisplatin, Oxaliplatin, Carboplatin and Nedaplatin; such as anthracyclines, e.g. Doxorubicin, Epirubicin, Valrubicin, I darubicin, Daunorubicin, Sabarubicin, Pixantrone and Mitoxantrone; such as peptide antibiotics, e.g. Actinomycin and Bleomycin; such as alkylating agents e.g. Mechlorethamine, Chlorambucil, Melphalan, Nitrosoureas, Dacarbazine, Temozolomide and Cyclophosphamide; such as antimitotic agents including taxanes and vinca alkaloids, e.g. Docetaxel, Paclitaxel, Abraxane, Cabazitaxel, Vinblastine, Vindesine, Vinorelbine and Vincristine; such as topoisomerase inhibitors, e.g. Irinotecan, Topotecan, Teniposide and Etoposide; and targeted therapeutic agents such as kinase inhibitors, regulators i.e. inhibitors and activators of signaling pathways including growth factor signaling, cytokine signaling, NF-kappaB signaling, AP1 signaling, JAK/STAT signaling, EGFR signaling, TGF-beta signaling, Notch signaling, Wnt signaling, Hedgehog signaling, hormone and nuclear receptor signaling, e.g. Erlotinib, Lapatinib, Dasatinib, Imatinib, Afatinib, 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, Sorafenib, 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 e.g. Raloxifene, Tamoxifen, Fulvestrant, Lasofoxifene, Toremifene, Bicalutamide, Flutamide, Anastrozole, Letrozole and Exemestane; histone deacetylase inhibitors, e.g. Vorinostat, Romidepsin, Panobinostat, Belinostat and Chidamide; and Ingenol mebutate; and other Notch enhancers not encompassed by the compounds of the present invention, e.g. Valproic acid, Resveratrol, hesperetin, chrysin, phenethyl isothiocyanate, thiocoraline, N-methylhemeanthidine chloride and Notch Signaling-activating peptides or antibodies; and immune response modulating agents e.g. Imiquimod, Ipilimumab, Atezolizumab, Ofatumumab, Rituximab, Nivolumab and Pembrolizumab; and anti-inflammatory agents including glucocorticoids and non-steroidal anti-inflammatory drugs, e.g. cortisol-based preparations, Dexamethason, Betamethason, Prednisone, Prednisolone, Methylprednisolone, Triamcinolon-hexacetonid, M ometasonfuroat, Clobetasolpropionat, acetylsalicylic acid, salicylic acid and other salicylates, Diflunisal, Ibuprofen, Dexibuprofen, 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; and ACE inhibitors; and beta-blockers; and myostatin inhibitors; and PDE-5 inhibitors; and antihistamines. For a combination therapy, the active ingredients may be formulated as compositions containing several active ingredients in a single dose form and/or as kits containing individual active ingredients in separate dose forms. The active ingredients used in combination therapy may be co-administered or administered separately. 
     The compounds of the invention may be administered as antibody-drug conjugates. 
     The compounds of the invention may be administered in combination with surgery, cryotherapy, electrodessication, radiotherapy, photodynamic therapy, laser therapy, chemotherapy, targeted therapy, immunotherapy, gene therapy, antisense therapy, cell-based transplantation therapy, stem cell therapy, physical therapy and occupational therapy. 
     The compounds of the invention falling under the scope of formula I, formula II, formula III, formula IV and formula V can be synthesized in analogy to the methods described in Reinmüller et al., 2015, EPFL Thesis 6887 by a coupling step to establish the diaryl ether scaffold, which can be prepared by a method of reacting a phenol and an electron-deficient aryl halide in the presence of a base such as potassium carbonate or cesium carbonate in a non-protic organic solvent such as DMSO or DMF at room temperature or at elevated temperature or reflux, preferably at 80° C. or 100° C., with optional assistance of microwave irradiation (Li et al., Org. Lett. 2003, 5, 2169-2171); 
     or by a method of reacting a phenol and a nitroarene in the presence of a base such as potassium carbonate or cesium carbonate in a non-protic organic solvent such as DMSO or DMF at elevated temperature or reflux, with assistance of microwave irradiation (Sarkate et al., Synlett 2013, 24, 1513-1516); 
     or by a method of reacting an aryl silyl ether with an electron-deficient aryl halide in the presence of a base such as DBU and trace water in a non-protic organic solvent such as DMSO or DMF at elevated temperature or reflux (Yeom et al., Synlett 2007, 146-150); 
     or by a method of reacting a phenol with a diaryliodonium triflate or tosylate in the presence of a base such as potassium carbonate or cesium carbonate in a non-protic organic solvent such as acetonitrile at ambient or elevated temperature (Kakinuma et al., Synthesis 2013, 45, 183-184); 
     or by a method of reacting under Buchwald-Hartwig conditions a phenol with an aryl halide in the presence of a transition metal-based catalyst system such as palladium(II) acetate, an organophosphorus-based ligand such as dppf, a base such as potassium phosphate in an organic solvent such as toluene at elevated temperature or reflux (Burgos et al., Angew. Chem. Int. Ed. 2006, 45, 4321-4326); 
     or by a method of reacting under Chan-Lam conditions a phenol with an arylboronic acid or ester in the presence of air, a copper-based catalyst system such as copper(II) acetate, a base such as pyridine or triethylamine in a non-protic organic solvent such as DCM, chloroform at ambient temperature (Evans et al., Tetrahedron Letters 1998, 39, 2937-2940); 
     wherein all said methods of preparation may require a subsequent derivatisation step by standard chemical procedures known to the person skilled in the art, such as saponification, hydrolysis, esterification or amidation to obtain the corresponding carboxylic acids, esters, primary amides, secondary amides, tertiary amides, hydroxamic acids and hydroxamates. 
     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 an alcohol, preferably ethanol, or water and tetrahydrofuran at ambient or elevated temperature (Becker et al., Organikum, 22nd edition 2004 (German), pp. 488, publisher: Wiley-VCH Weinheim); 
     the 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 chlorides in the presence of thionyl chloride and catalytic amounts of DMF in toluene at ambient or elevated temperature, preferably at 80° C., and under inert gas atmosphere, followed by the 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 inert gas atmosphere (Becker et al., Organikum, 22nd edition 2004 (German), pp. 459, publisher: Wiley-VCH Weinheim). 
     The perfluoroalkylcyclopropyl moiety associated with the compounds of the invention falling under the scope of formula V is synthesized in three steps according to the procedure described in 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 obtained by a method of reacting 1-(4-bromophenyl)-2,2,2-trifluoroethan-1-one or 1-(4-bromophenyl)-2,2,3,3,3-pentafluoropropan-1-one, respectively, in the presence of methanesulfonyl chloride and a base such as potassium fluoride in a crown ether such as 18-crown-6 in a non-protic organic solvent such as DMF at elevated temperature, preferably at 80° C.; 
     second, a bromophenylperfluoroalkyldihydropyrazole such as 3-(4-bromophenyl)-3-(trifluoromethyl)-4,5-dihydro-3H-pyrazole or 3-(4-bromophenyl)-3-(perfluoroethyl)-4,5-dihydro-3H -pyrazole is obtained by a method of 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; 
     and third, the perfluoroalkylcyclopropylarylbromide such as 1-bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene or 1-bromo-4-(1-(perfluoroethyl)cyclopropyl)benzene is obtained by a method of 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 xylenes or a mixture thereof. 
     The obtained perfluoroalkylcyclopropylarylbromide can subsequently be converted into the corresponding phenol for one of the above said coupling reactions with an electron-deficient aryl halide, a nitroarene, a diaryliodonium triflate or tosylate by a method of reaction 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′-triisopropylbiphenyl (t-Bu XPhos), a base such as potassium hydroxide or sodium hydroxide in a biphasic solvent system such as water/dioxane or water/toluene at elevated temperature or reflux, preferably at 100° C., and under an inert gas atmosphere (Anderson et al., J. Am. Chem. Soc. 2006, 128, 10694-10695); 
     or by a method of reaction in the presence of a copper-based catalyst system such as Cul, a pyridyl based ligand such as 2-methylquinolin-8-ol or preferably 8-hydroxyquinoline-N-oxide, and tetrabutyl-ammonium hydroxide or preferably cesium hydroxide monohydrate in a non-protic organic solvent such as DMSO or DMF at elevated temperature or reflux, preferably at 110° C., and under an inert gas atmosphere (Paul et al., Synthesis 2010, 4268-4272; Yang et el., Org. Lett. 2011, 13, 4340-4343). 
     The compounds of the invention falling under the scope of formula I, formula II, formula III, formula IV and formula V, as well as intermediates, can be isolated by column chromatography using silica gel as stationary phase and common organic solvents such as petroleum ether, ethyl acetate, dichloromethane, methanol, or acetic acids as eluent, preferably as binary or tertiary solvent mixtures thereof; 
     or 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. 
     The compounds of the invention falling under the scope of formula I, formula II, formula III, formula IV and formula V, as well as 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). 
     Chemical Synthesis 
     The compounds of the invention falling under the scope of formula I, formula II, formula III, formula IV and formula V can be synthesized and purified by those persons skilled in the art and are preferably synthesized according to the general procedure A, or general procedure B, or general procedure C, or general procedure D, respectively, and according to the detailed synthesis procedures described herein; 
     Abbreviations 
     Ac acetyl 
     BRSM based on recovered starting material (yield) 
     Bu butyl 
     δ chemical shift in parts per million (ppm) 
     dba dibenzylideneacetone 
     DCE 1,2-dichloroethane 
     DCM dichloromethane 
     DMF N,N-dimethylformamide 
     DMSO dimethyl sulfoxide 
     Et ethyl 
     ESI electron spray ionization 
     M mol/L 
     Me methyl 
     Ms methanesulfonyl 
     PE petroleum ether 
     TBAF tetrabutylammonium fluoride 
     THF tetrahydrofuran 
     TMS trimethylsilyl 
     General Procedure A: Synthesis of Diaryl Ether Esters 
     Diaryl ether esters according to formula I, formula III, and formula V can be prepared by nucleophilic aromatic substitution, e.g. by reaction of an alkyl 4-fluorobenzoate, or an alkyl 3,4-difluorobenzoate, or an alkyl 6-chloronicotinate, or an alkyl 6-chloro-5-fluoronicotinate, with a phenol derivative (nucleophile, see Table XIV) in the presence of a base like potassium carbonate in a solvent like dimethyl sulfoxide at a temperature between 80° C. and 150° C. and in an inert atmosphere such as argon. 
     General Procedure B: Synthesis of Diaryl Ether Acids 
     Diaryl ether acids according to formula I, formula III, and formula V can be prepared by saponification, e.g. by reaction of the corresponding diaryl ether esters with an aqueous base solution like sodium hydroxide (nucleophile, see Table XIV) in a solvent like ethanol, methanol, tetrahydrofuran or a mixture thereof at a temperature between room temperature and reflux. 
     General Procedure C: Synthesis of Diaryl Ether Esters 
     Diaryl ether esters according to formula I, formula III, and formula V can be prepared by esterification via the corresponding acid chloride, e.g by reaction of a diaryl ether acid with thionyl chloride in the presence of catalytic amounts of DMF in a solvent like toluene ata temperature between 50° C. and 100° C. and in an inert atmosphere such as argon. After removal of the volatiles, the such obtained acid chloride intermediate is reacted with the alcohol corresponding to the desired ester (nucleophile, see Table XIV) in the presence of an organic base like triethylamine at a temperature between 0° C. and room temperature and in an inert atmosphere such as argon. 
     Alternatively, diaryl ether esters according to formula I, formula III, and formula V can be prepared by esterification via the corresponding acid chloride, e.g. by reaction of a diaryl ether acid with thionyl chloride in the presence of the alcohol corresponding to the desired ester (nucleophile, see Table XIV), preferably as the solvent at a temperature between 50° C. and reflux. 
     General Procedure D: Synthesis of Diaryl Ether Amides 
     Diaryl ether amides according to formula II, formula IV, and formula V can be prepared by amidation via the corresponding acid chloride, e.g by reaction of a diaryl ether acid with thionyl chloride in the presence of catalytic amounts of DMF in a solvent like toluene ata temperature between 50° C. and 100° C. and in an inert atmosphere such as argon. After removal of the volatiles, the such obtained acid chloride intermediate is reacted with the amine corresponding to the desired amide (nucleophile, see Table XIV) in a solvent like methanol, ethanol, or tetrahydrofuran at a temperature between 0° C. and room temperature and in an inert atmosphere such as argon. The presence of an organic base like triethylamine is needed if the hydrochloride salt of the amine is used. 
     
       
         
           
               
             
               
                 TABLE XIV 
               
             
            
               
                   
               
               
                 List of Synthesized compounds 
               
            
           
           
               
               
               
               
               
            
               
                 Compound 
                   
                 ESI Ion 
                 General 
                 Nucleophile used  
               
               
                 Number 
                 m/z 
                 Type 
                 Procedure 
                 in the General Procedure 
               
               
                   
               
               
                 002 
                 241.17 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 003 
                 255.18 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 004 
                 269.18 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 005 
                 283.21 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 019 
                 307.28 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 020 
                 321.34 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 023 
                 243.09 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 024 
                 257.10 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 025 
                 271.11 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 026 
                 285.13 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 027 
                 299.20 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 029 
                 271.11 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 030 
                 299.20 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 041 
                 311.21 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 043 
                 323.24 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 044 
                 337.25 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 045 
                 362.32 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 048 
                 257.11 
                 [M + H] +   
                 A 
                 4-methylphenol 
               
               
                 049 
                 271.12 
                 [M + H] +   
                 A 
                 4-ethylphenol 
               
               
                 050 
                 285.15 
                 [M + H] +   
                 A 
                 4-n-propylphenol 
               
               
                 051 
                 299.21 
                 [M + H] +   
                 A 
                 4-n-butylphenol 
               
               
                 052 
                 313.26 
                 [M + H] +   
                 A 
                 4-n-pentylphenol 
               
               
                 054 
                 285.15 
                 [M + H] +   
                 A 
                 4-isopropylphenol 
               
               
                 056 
                 311.17 
                 [M + H] +   
                 A 
                 4-(trifluoromethyl)phenol 
               
               
                 066 
                 337.25 
                 [M + H] +   
                 A 
                 (±)-4-(bicyclo[2.2.1]heptan- 
               
               
                   
                   
                   
                   
                 2-yl)phenol (7:1 endo:exo) 
               
               
                 067 
                 351.26 
                 [M + H] +   
                 A 
                 (±)-4-(bicyclo[2.2.2]octan- 
               
               
                   
                   
                   
                   
                 2-yl)phenol 
               
               
                 070 
                 244.00 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 071 
                 258.09 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 072 
                 272.11 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 073 
                 286.16 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 075 
                 258.10 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 086 
                 308.25 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 087 
                 322.30 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 091 
                 244.07 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 092 
                 258.09 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 093 
                 272.11 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 094 
                 286.15 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 095 
                 300.19 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 097 
                 272.11 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 099 
                 300.19 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 101 
                 298.09 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 110 
                 312.19 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 112 
                 324.22 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 113 
                 338.24 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 114 
                 364.29 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 117 
                 272.12 
                 [M + H] +   
                 A 
                 4-ethylphenol 
               
               
                 118 
                 286.16 
                 [M + H] +   
                 A 
                 4-n-propylphenol 
               
               
                 119 
                 300.20 
                 [M + H] +   
                 A 
                 4-n-butylphenol 
               
               
                 120 
                 314.24 
                 [M + H] +   
                 A 
                 4-n-pentylphenol 
               
               
                 122 
                 286.16 
                 [M + H] +   
                 A 
                 4-isopropylphenol 
               
               
                 133 
                 338.24 
                 [M + H] +   
                 A 
                 (±)-4-(bicyclo[2.2.1]heptan- 
               
               
                   
                   
                   
                   
                 2-yl)phenol (7:1 endo:exo) 
               
               
                 134 
                 352.28 
                 [M + H] +   
                 A 
                 (±)-4-(bicyclo[2.2.2]octan- 
               
               
                   
                   
                   
                   
                 2-yl)phenol 
               
               
                 138 
                 228.10 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 139 
                 242.10 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 140 
                 256.12 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 141 
                 270.11 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 142 
                 284.16 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 144 
                 256.12 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 145 
                 270.12 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 146 
                 284.16 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 157 
                 296.20 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 159 
                 308.22 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 160 
                 322.26 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 161 
                 348.27 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 164 
                 244.07 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 165 
                 258.09 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 166 
                 272.11 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 167 
                 286.15 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 168 
                 300.19 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 170 
                 272.11 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 171 
                 300.19 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 182 
                 312.20 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 184 
                 324.22 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 185 
                 338.25 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 186 
                 364.36 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 190 
                 256.12 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 191 
                 270.12 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 192 
                 284.15 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 193 
                 298.21 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 195 
                 270.12 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 196 
                 284.15 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 197 
                 298.22 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 208 
                 310.23 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 210 
                 322.26 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 211 
                 336.28 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 212 
                 362.30 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 215 
                 256.12 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 216 
                 270.12 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 217 
                 284.16 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 218 
                 298.21 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 219 
                 312.23 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 221 
                 284.15 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 222 
                 298.21 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 223 
                 312.24 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 234 
                 324.27 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 236 
                 336.28 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 237 
                 350.30 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 238 
                 376.33 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 241 
                 229.09 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 242 
                 243.09 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 243 
                 257.11 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 244 
                 271.12 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 245 
                 285.15 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 247 
                 257.11 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 248 
                 285.16 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 250 
                 283.04 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 259 
                 297.17 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 261 
                 309.21 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 262 
                 323.26 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 263 
                 349.29 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 266 
                 245.07 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 267 
                 259.09 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 268 
                 273.11 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 269 
                 287.14 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 270 
                 301.18 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 272 
                 273.12 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 273 
                 301.19 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 275 
                 299.08 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 284, 
                 313.20 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 286 
                 325.21 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 287 
                 339.24 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 288 
                 365.29 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 291 
                 243.10 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 292 
                 257.11 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 293 
                 271.12 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 294 
                 285.15  
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 295 
                 299.21 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 297 
                 271.12 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 298 
                 299.21 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 300 
                 297.08 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 309 
                 311.22 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 311 
                 323.25 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 312 
                 337.26 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 313 
                 363.32 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 316 
                 257.11 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 317 
                 271.12 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 318 
                 285.15 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 319 
                 299.21 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 320 
                 313.24 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 322 
                 285.16 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 323 
                 313.25 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 325 
                 311.13 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 334 
                 325.26 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 336 
                 337.26 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 337 
                 351.28 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 338 
                 377.32 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 341 
                 245.13 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 342 
                 259.15 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 343 
                 273.17 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 344 
                 287.18 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 345 
                 301.21 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 347 
                 273.15 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 348 
                 301.24 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 350 
                 299.12 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 359 
                 313.24 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 363 
                 365.39 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 374 
                 317.22 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 385 
                 329.24 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 389 
                 381.34 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 392 
                 275.09 
                 [M + H] +   
                 A 
                 4-methylphenol 
               
               
                 393 
                 289.13 
                 [M + H] +   
                 A 
                 4-ethylphenol 
               
               
                 394 
                 303.17 
                 [M + H] +   
                 A 
                 4-n-propylphenol 
               
               
                 395 
                 317.23 
                 [M + H] +   
                 A 
                 4-n-butylphenol 
               
               
                 396 
                 331.24 
                 [M + H] +   
                 A 
                 4-n-pentylphenol 
               
               
                 398 
                 303.19 
                 [M + H] +   
                 A 
                 4-isopropylphenol 
               
               
                 399 
                 331.25 
                 [M + H] +   
                 A 
                 4-tert-pentylphenol 
               
               
                 401 
                 329.17 
                 [M + H] +   
                 A 
                 4-(trifluoromethyl)phenol 
               
               
                 410 
                 343.28 
                 [M + H] +   
                 A 
                 4-cyclohexylphenol 
               
               
                 414 
                 395.33 
                 [M + H] +   
                 A 
                 4-(1-adamantyl)phenol 
               
               
                 417 
                 246.12 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 423 
                 274.15 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 424 
                 288.17 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 425 
                 304.16 
                 [M + H] +   
                 B 
                 NaOH 
               
               
                 427 
                 300.10 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 436 
                 314.24 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 440 
                 368.29 
                 [M + H] +   
                 B 
                 NaOH 
               
               
                 451 
                 318.21 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 462 
                 330.23 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 466 
                 382.29 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 469 
                 276.08 
                 [M + H] +   
                 A 
                 4-methylphenol 
               
               
                 475 
                 304.15 
                 [M + H] +   
                 A 
                 4-isopropylphenol 
               
               
                 476 
                 318.20 
                 [M + H] +   
                 A 
                 4-tert-butylphenol 
               
               
                 477 
                 332.24 
                 [M + H] +   
                 A 
                 4-tert-pentylphenol 
               
               
                 479 
                 330.14 
                 [M + H] +   
                 A 
                 4-(trifluoromethyl)phenol 
               
               
                 488 
                 344.24 
                 [M + H] +   
                 A 
                 4-cyclohexylphenol 
               
               
                 492 
                 396.29 
                 [M + H] +   
                 A 
                 4-(1-adamantyl)phenol 
               
               
                 503 
                 302.20 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 514 
                 314.20 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 518 
                 366.29 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 529 
                 318.21 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 540 
                 330.23 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 544 
                 382.30 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 555 
                 316.23 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 566 
                 328.25 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 570 
                 380.31 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 581 
                 330.26 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 592 
                 342.28 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 596 
                 394.33 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 607 
                 303.19 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 618 
                 315.21 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 622 
                 367.36 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 633 
                 319.21 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 644 
                 331.21 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 648 
                 383.27 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 659 
                 317.22 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 670 
                 329.25 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 674 
                 381.31 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 685 
                 331.25 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 696 
                 343.28 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 700 
                 395.31 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 703 
                 321.22 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 704 
                 371.30 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 705 
                 339.22 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 711 
                 355.21 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 712 
                 337.16 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 714 
                 353.31 
                 [M − H] −   
                 C 
                 methanol 
               
               
                 721 
                 351.20 
                 [M + H] +   
                 A 
                 4-(1-(trifluoromethyl) 
               
               
                   
                   
                   
                   
                 cyclopropyl)phenol 
               
               
                 722 
                 401.25 
                 [M + H] +   
                 A 
                 4-(1-(perfluoroethyl) 
               
               
                   
                   
                   
                   
                 cyclopropyl)phenol 
               
               
                 723 
                 369.24 
                 [M + H] +   
                 A 
                 4-(1-(trifluoromethyl) 
               
               
                   
                   
                   
                   
                 cyclopropyl)phenol 
               
               
                 729 
                 385.18 
                 [M + H] +   
                 A 
                 2-chloro-4-(1- 
               
               
                   
                   
                   
                   
                 (trifluoromethyl) 
               
               
                   
                   
                   
                   
                 cyclopropyl)phenol 
               
               
                 730 
                 322.22 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 731 
                 374.19 
                 [M + H] +   
                 B 
                 NaOH 
               
               
                 732 
                 340.21 
                 [M − H] −   
                 B 
                 NaOH 
               
               
                 738 
                 358.13 
                 [M + H] +   
                 B 
                 NaOH 
               
               
                 739 
                 338.17 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 740 
                 388.21 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 741 
                 356.19 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 747 
                 372.15 
                 [M + H] +   
                 C 
                 methanol 
               
               
                 748 
                 352.21 
                 [M + H] +   
                 A 
                 4-(1-(trifluoromethyl) 
               
               
                   
                   
                   
                   
                 cyclopropyl)phenol 
               
               
                 749 
                 402.25 
                 [M + H] +   
                 A 
                 4-(1-(perfluoroethyl) 
               
               
                   
                   
                   
                   
                 cyclopropyl)phenol 
               
               
                 750 
                 370.20 
                 [M + H] +   
                 A 
                 4-(1-(trifluoromethyl) 
               
               
                   
                   
                   
                   
                 cyclopropyl)phenol 
               
               
                 756 
                 386.17 
                 [M + H] +   
                 A 
                 2-chloro-4-(1- 
               
               
                   
                   
                   
                   
                 (trifluoromethyl) 
               
               
                   
                   
                   
                   
                 cyclopropyl)phenol 
               
               
                 757 
                 322.18 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 759 
                 340.18 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 766 
                 338.17 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 767 
                 388.22 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 768 
                 356.19 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 774 
                 372.19 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 775 
                 336.20 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 777 
                 354.19 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 784 
                 350.21 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 785 
                 400.26 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 786 
                 368.22 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 792 
                 384.23 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 793 
                 323.17 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 794 
                 373.21 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 795 
                 341.17 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 801 
                 357.14 
                 [M + H] +   
                 D 
                 ammonia 
               
               
                 802 
                 339.17 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 803 
                 389.22 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 804 
                 357.17 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 810 
                 373.17 
                 [M + H] +   
                 D 
                 hydroxylamine 
               
               
                 811 
                 337.18 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 812 
                 387.23 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 813 
                 355.20 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 819 
                 371.17 
                 [M + H] +   
                 D 
                 methylamine 
               
               
                 820 
                 351.21 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 821 
                 401.26 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 822 
                 369.21 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                 828 
                 385.21 
                 [M + H] +   
                 D 
                 dimethylamine 
               
               
                   
               
            
           
         
       
     
     Synthesis of Representative Compounds 
     Compound 005 
     4-(4-Pentylphenoxy)benzoic acid 
     
       
         
         
             
             
         
       
     
     Following 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 hours. The organic solvents were evaporated and the residue acidified with 5 M aqueous HCl to adjust a pH of 1-2. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by recrystallization from hot EtOAc to give the title compound as colorless solid (1.21 g, 79%).  1 H NMR (300 MHz, CDCl 3 ) δ 8.12-8.01 (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 (75 MHz, CDCl 3 ) δ 171.9, 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 O 3   − ): expected: 283.1339; found: 283.1326. 
     Compound 030 
     Methyl 4-(4-(tert-Pentyl)phenoxy)benzoate 
     
       
         
         
             
             
         
       
     
     Following 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 2  (0.1 mL, 1.4 mmol) at 0° C. and the reaction was then stirred at 80° C. in a sealed vessel for 3 hours in an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of saturated aqueous NaHCO 3 . The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , 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 colorless oil (120 mg, 94%).  1 H NMR (300 MHz, CDCl 3 ) δ 8.05-7.94 (m, 2H), 7.39-7.28 (m, 2H), 7.04-6.92 (m, 4H), 3.89 (s, 3H), 1.65 (q, J=7.4 Hz, 2H), 1.30 (s, 6H), 0.71 (t, J=7.4 Hz, 3H).  13 C NMR (75 MHz, CDCl 3 ) δ 166.8, 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 O 3   + ): expected: 299.1642; found: 299.1640. 
     Compound 044 
     (±) -Methyl 4-(4-(bicyclo[2.2.2]octan-2-yl)phenoxy)benzoate 
     
       
         
         
             
             
         
       
     
     Following 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 one drop of DMF followed by SOCl 2  (0.02 mL, 0.3 mmol) at room temperature and the reaction was then stirred at 80° C. for 3.5 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. A solution of NEt 3  (0.2 mL, 1.4 mmol) in MeOH (1 mL) was added and the reaction was stirred at room temperature overnight in 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 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 85% PE-EtOAc gradient to give the title compound as colorless oil (29.3 mg, 93%).  1 H NMR (300 MHz, CDCl 3 ) 8 8.05-7.94 (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, 1.9 Hz, 1H), 1.85-1.45 (m, 10H), 1.43-1.23 (m, 1H).  13 C NMR (75 MHz, CDCl 3 ) δ 166.8, 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 O 3   + ): expected: 337.1798; found: 337.1778. 
     Compound 051 
     Ethyl 4-(4-butylphenoxy)benzoate 
     
       
         
         
             
             
         
       
     
     Following general procedure A, to 4-butylphenol (1.75 mL, 11.4 mmol) and K 2 CO 3  (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 in an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of water. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed first with 1 M aqueous NaOH (1×) then washed with brine (1×), dried over Na 2 SO 4 , 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 as colorless oil (1.72 g, 63%).  1 H NMR (300 MHz, CDCl 3 ) δ 8.05-7.94 (m, 2H), 7.24-7.13 (m, 2H), 7.02-6.91 (m, 4H), 4.36 (q, J=7.1 Hz, 2H), 2.67-2.56 (m, 2H), 1.69-1.53 (m, 2H), 1.47-1.23 (m, 5H), 0.95 (t, J=7.3 Hz, 3H).  13 C NMR (75 MHz, CDCl 3 ) δ 166.3, 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 O 3   + ): expected: 299.1642; found: 299.1642. 
     Compound 071 
     6-(4-Propylphenoxy)nicotinic acid 
     
       
         
         
             
             
         
       
     
     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 hours. The reaction was acidified with 5 M aqueous HCl to adjust a pH of 1-2. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by recrystallization from hot EtOAc to give the title compound as colorless solid (1.26 g, 66%).  1 H NMR (300 MHz, CDCl 3 ) δ 11.01 (br, s, 1H), 8.92 (dd, J=2.4, 0.7 Hz, 1H), 8.31 (dd, J=8.7, 2.4 Hz, 1H), 7.28-7.18 (m, 2H), 7.12-7.02 (m, 2H), 6.94 (dd, J=8.7, 0.7 Hz, 1H), 2.61 (dd, J=8.7, 6.7 Hz, 2H), 1.76-1.58 (m, 2H), 0.97 (t, J=7.3 Hz, 3H).  13 C NMR (75 MHz, CDCl 3 ) 8 170.5, 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   − ): expected: 256.0979; found: 256.0979. 
     Compound 114 
     Methyl 6-(4-(adamantan-1-yl)phenoxy)nicotinate 
     
       
         
         
             
             
         
       
     
     Following 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 2  (0.1 mL, 1.37 mmol) at room temperature and the reaction was then stirred at 80° C. in a sealed vessel for 3.5 hours in an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of saturated aqueous NaHCO 3 . The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , 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 colorless solid (47 mg, 27%).  1 H NMR (300 MHz, CDCl 3 ) δ 8.84 (dd, J=2.4, 0.7 Hz, 1H), 8.25 (dd, J=8.6, 2.4 Hz, 1H), 7.46-7.35 (m, 2H), 7.15-7.04 (m, 2H), 6.90 (dd, J=8.6, 0.7 Hz, 1H), 3.91 (s, 3H), 2.11 (p, J=3.0 Hz, 4H), 1.93 (d, J=2.9 Hz, 6H), 1.87-1.68 (m, 6H).  13 C NMR (75 MHz, CDCl 3 ) δ 166.7, 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   + ): expected: 364.1907; found: 364.1900. 
     Compound 117 
     Ethyl 6-(4-Ethylphenoxy)nicotinate 
     
       
         
         
             
             
         
       
     
     Following general procedure A, to 4-ethylphenol (1.36 g, 11.1 mmol) and K 2 CO 3  (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 hours in an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of water. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed first with 1 M aqueous NaOH (1×) then washed with brine (1×), dried over Na 2 SO 4 , 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 as colorless oil (1.78 g, 60%).  1 H NMR (300 MHz, CDCl 3 ) δ 8.83 (dd, J=2.4, 0.7 Hz, 1H), 8.25 (dd, J=8.6, 2.4 Hz, 1H), 7.28-7.20 (m, 2H), 7.11-7.00 (m, 2H), 6.90 (dd, J=8.7, 0.8 Hz, 1H), 4.37 (q, J=7.1 Hz, 2H), 2.68 (q, J=7.6 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H), 1.26 (t, J=7.6 Hz, 3H).  13 C NMR (75 MHz, CDCl 3 ) δ 166.8, 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   + ): expected: 272.1281; found: 272.1271. 
     Compound 159 
     (±)-4-(4-(Bicyclo[2.2.1]heptan-2-yl)phenoxy)benzamide, mixture of endo and exo 
     
       
         
         
             
             
         
       
     
     Following general procedure D, to a solution of (±)-4-(4-(bicyclo[2.2.1]heptan yl)phenoxy)benzoic acid (50.2 mg, 0.16 mmol) in toluene (0.8 mL) was added one drop of DMF followed by SOCl 2  (0.04 mL, 0.55 mmol) at room temperature and the reaction was then stirred at 80° C. for 3 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. 2 M ammonia in MeOH (0.6 mL, 1.3 mmol) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , 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 colorless solid (46.6 mg, 93%, 6:1 mixture endo:exo).  1 H NMR (300 MHz, CDCl 3 , mixture of rotamers 0.3:1, and diastereoisomers 6:1) 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).  13 C NMR (75 MHz, CDCl 3 , mixture of rotamers 0.3:1, and diastereoisomers 6:1) 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, 117.6, 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 NO 2   + ): expected: 308.1645; found: 308.1624. 
     Compound 186 
     4-(4-(Adamantan-1-yl)phenoxy)-N-hydroxybenzamide 
     
       
         
         
             
             
         
       
     
     Following general procedure D, to a solution of 4-(4-(adamantan yl)phenoxy)benzoic acid (200 mg, 0.57 mmol) in toluene (2 mL) was added two drops of DMF followed by SOCl 2  (0.1 mL, 1.37 mmol) at room temperature and the reaction was then stirred at 80° C. for 3.5 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. Hydroxylamine hydrochloride (208 mg, 3 mmol) in a solution of NEt 3  (1.0 mL, 7.2 mmol) and MeOH (2 mL) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed first with 1 M aqueous HCl (1×) then washed with brine (1×), dried over Na 2 SO 4 , 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 colorless solid (176 mg, 84%).  1 H NMR (300 MHz, CDCl 3 /DMSO-d 6 ) δ 11.10 (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=2.8 Hz, 6H), 1.81-1.63 (m, 6H).  13 C NMR (75 MHz, CDCl 3 /DMSO-d 6 ) δ 163.8, 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   − ): expected: 362.1761; found: 362.1672. 
     Compound 195 
     4-(4-Isopropylphenoxy)-N-methylbenzamide 
     
       
         
         
             
             
         
       
     
     Following general procedure D, to a solution of 4-(4-isopropylphenoxy)benzoic acid (177 mg, 0.7 mmol) in toluene (2.5 mL) was added two drops of DMF followed by SOCl 2  (0.15 mL, 2.1 mmol) at room temperature and the reaction was then stirred at 80° C. for 3 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. 33 wt % methylamine in EtOH (2 mL, 16 mmol) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , 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 colorless solid (178 mg, 94%).  1 H NMR (300 MHz, CDCl 3 ) δ 7.78-7.67 (m, 2H), 7.27-7.16 (m, 2H), 7.01-6.90 (m, 4H), 6.31 (s, 1H), 2.98 (d, J=4.6 Hz, 3H), 2.90 (hept, J=6.9 Hz, 1H), 1.26 (d, J=6.9 Hz, 6H).  13 C NMR (75 MHz, CDCl 3 ) δ 167.8, 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 NO 2   − ): expected: 268.1343; found: 268.1384. 
     Compound 222 
     4-(4-(tert-Butyl)phenoxy)-N,N-dimethylbenzamide 
     
       
         
         
             
             
         
       
     
     Following 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 two drops of DMF followed by SOCl 2  (0.1 mL, 1.4 mmol) at room temperature and the reaction was then stirred at 80° C. for 3 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles 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 in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , 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 colorless oil (166 mg, 98%).  1 H NMR (300 MHz, CDCl 3 ) δ 7.44-7.31 (m, 4H), 7.03-6.91 (m, 4H), 3.06 (s, 6H), 1.33 (s, 9H).  13 C NMR (75 MHz, CDCl 3 ) δ 171.4, 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 NO 2   + ): expected: 298.1802; found: 298.1820. 
     Compound 241 
     6-(p-Tolyloxy)nicotinamide 
     
       
         
         
             
             
         
       
     
     Following general procedure D, to a solution of 6-(p-tolyloxy)nicotinic acid (148 mg, 0.66 mmol) in toluene (2.5 mL) was added two drops of DMF followed by SOCl 2  (0.12 mL, 1.6 mmol) at room temperature and the reaction was then stirred at 80° C. for 3.5 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. 2 M ammonia in MeOH (3 mL, 1.3 mmol) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , 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 as colorless solid (104 mg, 70%).  1 H NMR (300 MHz, CDCl 3 /DMSO-d 6 , mixture of rotamers 0.3:1) δ 8.89 (d, J=2.5 Hz, 0.25H, minor rotamer), 8.65 (d, J=2.4 Hz, 0.75H, major rotamer), 8.25 (dt, J=8.6, 2.9 Hz, 1H), 7.96 (br, s, 1H), 7.49 (d, J=8.4 Hz, 0.25H, minor rotamer), 7.27 (br, s, 1H), 7.21 (d, J=8.2 Hz, 2H), 7.06-6.97 (m, 2H), 6.93 (d, J=8.6 Hz, 0.75H, major rotamer), 2.35 (s, 3H).  13 C NMR (75 MHz, CDCl 3 /DMSO-d 6 , mixture of rotamers 0.3:1) 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 N 2 O 2   + ): expected: 229.0972; found: 229.0978. 
     Compound 275 
     N-Hydroxy-6-(4-(trifluoromethyl)phenoxy)nicotinamide 
     
       
         
         
             
             
         
       
     
     Following 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 two drops of DMF followed by SOCl 2  (0.06 mL, 0.82 mmol) at room temperature and the reaction was then stirred at 80° C. for 3 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. Hydroxylamine hydrochloride (94 mg, 1.35 mmol) in a solution of NEt 3  (0.5 mL, 3.6 mmol) and MeOH (1 mL) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 40% PE-EtOAc (+0.2% AcOH) gradient to give the title compound as colorless solid (42.7 mg, 65%).  1 H NMR (300 MHz, CDCl 3 /DMSO-d 6 ) δ 11.29 (s, 1H), 9.07 (s, 1H), 8.52 (d, J=2.4 Hz, 1H), 8.19 (dd, J=8.6, 2.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.5 Hz, 1H).  13 C NMR (75 MHz, CDCl 3 /DMSO-d 6 ) δ 163.6, 161.9, 156.2 (d, J=1.5 Hz), 146.4, 138.8, 126.6 (q, J=3.8 Hz), 125.6 (q, J=32.4 Hz), 124.2, 123.8 (q, J=273.0 Hz), 121.5, 111.1. HRMS (C 13 H 8 F 3 N 2 O 3   − ): expected: 297.0492; found: 297.0597. 
     Compound 284 
     6-(4-Cyclohexylphenoxy)-N-hydroxynicotinamide 
     
       
         
         
             
             
         
       
     
     Following general procedure D, to a solution of 6-(4-cyclohexylphenoxy)nicotinic acid (150 mg, 0.5 mmol) in toluene (2 mL) was added two drops of DMF followed by SOCl 2  (0.1 mL, 1.4 mmol) at room temperature and the reaction was then stirred at 80° C. for 3 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. Hydroxylamine hydrochloride (208 mg, 3 mmol) in a solution of NEt 3  (1.0 mL, 7.2 mmol) and MeOH (2 mL) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , 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 colorless solid (150 mg, 95%).  1 H NMR (300 MHz, CDCl 3 /DMSO-d 6 ) δ 11.27 (s, 1H), 9.05 (s, 1H), 8.54 (s, 1H), 8.20-8.06 (m, 1H), 7.23 (d, J=8.0 Hz, 2H), 7.02 (d, J=8.0 Hz, 2H), 6.95 (d, J=8.6 Hz, 1H), 1.86 (d, J=8.3 Hz, 4H), 1.74 (d, J=12.6 Hz, 1H), 1.43 (q, J=11.3, 10.1 Hz, 4H), 1.35-1.16 (m, 2H).  13 C NMR (75 MHz, CDCl 3 /DMSO-d 6 ) δ 163.4, 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 18 H 21 N 2 O 3   + ): expected: 313.1547; found: 313.1622. 
     Compound 297 
     6-(4-Isopropylphenoxy)-N-methylnicotinamide 
     
       
         
         
             
             
         
       
     
     Following general procedure D, to a solution of 6-(4-isopropylphenoxy)nicotinic acid (151 mg, 0.6 mmol) in toluene (2.5 mL) was added two drops of DMF followed by SOCl 2  (0.1 mL, 1.5 mmol) at room temperature and the reaction was then stirred at 80° C. for 3 hours in an argon atmosphere. 33 wt % methylamine in EtOH (2.5 mL, 20 mmol) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , 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 as colorless solid (150 mg, 96%). 1 H NMR (300 MHz, CDCl 3 ) δ 8.55 (dd, J=2.5, 0.7 Hz, 1H), 8.11 (dd, J=8.6, 2.5 Hz, 1H), 7.32-7.21 (m, 2H), 7.11-7.00 (m, 2H), 6.90 (dd, J=8.6, 0.7 Hz, 1H), 6.47 (d, J=5.3 Hz, 1H), 2.98 (d, J=4.7 Hz, 3H), 2.94 (hept, J=7.0 Hz, 1H), 1.27 (d, J=6.9 Hz, 6H).  13 C NMR (75 MHz, CDCl 3 ) δ 166.1,165.8, 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 N 2 O 2   + ): expected: 271.1441; found: 271.1491. 
     Compound 322 
     6-(4-Isopropylphenoxy)-N,N-dimethylnicotinamide 
     
       
         
         
             
             
         
       
     
     Following general procedure D, to a solution of 6-(4-isopropylphenoxy)nicotinic acid (156 mg, 0.6 mmol) in toluene (2.5 mL) was added two drops of DMF followed by SOCl 2  (0.1 mL, 1.5 mmol) at room temperature and the reaction was then stirred at 80° C. for 3 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. 2 M dimethylamine in THF (2.5 mL, 5.4 mmol) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , 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 colorless oil (169 mg, 98%).  1 H NMR (300 MHz, CDCl 3 ) δ 8.28 (dd, J=2.4, 0.8 Hz, 1H), 7.79 (dd, J=8.5, 2.4 Hz, 1H), 7.31-7.20 (m, 2H), 7.11-7.00 (m, 2H), 6.91 (dd, J=8.5, 0.7 Hz, 1H), 3.07 (s, 6H), 2.92 (hept, J=7.0 Hz, 1H), 1.26 (d, J=6.9 Hz, 6H).  13 C NMR (75 MHz, CDCl 3 ) δ 168.9, 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 N 2 O 2   + ): expected: 285.1598; found: 285.1643. 
     Compound 344 
     4-(4-(Butylphenoxy)-3-fluorobenzoic acid 
     
       
         
         
             
             
         
       
     
     Following general procedure B, to a solution of ethyl 4-(4-butylphenoxy) 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 a pH of 1-2. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (2×), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by recrystallization from hot EtOAc to give the title compound as colorless solid (0.56 g, 43%).  1 H NMR (300 MHz, CDCl 3 ) δ 11.18 (br, s, 1H), 7.91 (dd, J=11.0, 2.0 Hz, 1H), 7.82 (ddd, J=8.6, 2.0, 1.1 Hz, 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=7.3 Hz, 3H).  13 C NMR (75 MHz, CDCl 3 ) δ 171.0 (d, J=2.5 Hz), 153.3, 152.9 (d, J=249.5 Hz), 150.8 (d, J=11.0 Hz), 139.7, 130.1, 127.3 (d, J=3.5 Hz), 124.3 (d, J=6.5 Hz), 119.4, 118.9 (d, J=19.9 Hz), 118.6 (d, J=1.4 Hz), 35.1, 33.8, 22.5, 14.1. HRMS (C 17 H 16 FO 3   − ): expected: 287.1089; found: 287.1062. 
     Compound 395 
     Ethyl 4-(4-butylphenoxy)-3-fluorobenzoate 
     
       
         
         
             
             
         
       
     
     Following general procedure A, to 4-butylphenol (1.75 mL, 11.4 mmol) and K 2 CO 3  (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 hours in an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of water. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed first with 1 M aqueous NaOH (1×) then washed with brine (1×), dried over Na 2 SO 4 , 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 as colorless oil (1.80 g, 63%).  1 H NMR (300 MHz, CDCl 3 ) δ 7.84 (dd, J=11.2, 2.0 Hz, 1H), 7.75 (ddd, J=8.5, 2.0, 1.2 Hz, 1H), 7.23-7.12 (m, 2H), 7.01-6.88 (m, 3H), 4.37 (q, J=7.1 Hz, 2H), 2.67-2.55 (m, 2H), 1.68-1.52 (m, 2H), 1.46-1.23 (m, 5H), 0.94 (t, J=7.3 Hz, 3H).  13 C NMR (75 MHz, CDCl 3 ) δ 165.4 (d, J=2.6 Hz), 153.7, 153.0 (d, J=249.0 Hz), 149.5 (d, J=11.2 Hz), 139.3, 129.9, 126.4 (d, J=3.5 Hz), 126.0 (d, J=6.3 Hz), 119.0, 119.0 (d, J=1.4 Hz), 118.3 (d, J=19.9 Hz), 61.3, 35.1, 33.8, 22.5, 14.4, 14.1. HRMS (C 19 H 22 FO 3   + ): expected: 317.1548; found: 317.1549. 
     Compound 451 
     Methyl 5-fluoro-6-(4-(tert-pentyl)phenoxy)nicotinate 
     
       
         
         
             
             
         
       
     
     Following 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 2  (0.1 mL, 1.4 mmol) at 0° C. and the reaction was then stirred at 80° C. for 3 hours in an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of saturated aqueous NaHCO 3 . The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , 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 colorless solid (30 mg, 29%).  1 H NMR (300 MHz, CDCl 3 ) δ 8.56 (d, J=1.9 Hz, 1H), 8.02 (dd, J=10.0, 1.9 Hz, 1H), 7.43-7.31 (m, 2H), 7.17-7.04 (m, 2H), 3.92 (s, 3H), 1.66 (q, J=7.4 Hz, 2H), 1.31 (s, 6H), 0.72 (t, J=7.4 Hz, 3H).  13 C NMR (75 MHz, CDCl 3 ) δ 164.8 (d, J=1.6 Hz), 155.7 (d, J=11.1 Hz), 150.4, 147.1 (d, J=261.8 Hz), 146.9, 144.4 (d, J=6.1 Hz), 127.4, 125.0 (d, J=17.0 Hz), 122.1 (d, J=1.7 Hz), 120.7, 52.6, 37.9, 37.1, 28.6, 9.3. HRMS (C 18 H 21 FNO 3   + ): expected: 318.1500; found: 318.1555. 
     Compound 544 
     4-(4-(Adamantan-1-yl)phenoxy)-3-fluoro-N-hydroxybenzamide 
     
       
         
         
             
             
         
       
     
     Following 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 two drops of DMF followed by SOCl 2  (0.1 mL, 1.4 mmol) at room temperature and the reaction was then stirred at 80° C. for 3.5 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. NEt 3  (0.7 mL, 5.1 mmol) and hydroxylamine hydrochloride (148 mg, 2.1 mmol) in MeOH (1.5 mL) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography twice, 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 colorless solid (60 mg, 52%).  1 H NMR (300 MHz, CDCl 3 /DMSO-d 6 ) δ 11.23 (s, 1H), 9.00 (s, 1H), 7.68 (dd, J=11.6, 2.0 Hz, 1H), 7.57 (ddd, J=8.5, 2.1, 1.1 Hz, 1H), 7.37-7.25 (m, 2H), 6.97 (t, J=8.4 Hz, 1H), 6.96-6.86 (m, 2H), 2.12-1.97 (m, 4H), 1.84 (d, J=2.9 Hz, 6H), 1.80-1.63 (m, 6H).  13 C NMR (75 MHz, CDCl 3 /DMSO-d 6 ) δ 162.4, 153.2, 152.4 (d, J=247.5 Hz), 146.6, 146.3 (d, J=11.1 Hz), 128.4 (d, J=5.7 Hz), 126.0, 123.5, 119.5, 117.4, 115.5 (d, J=19.6 Hz), 42.6, 36.1, 35.3, 28.2. HRMS (C 23 H 23 FNO 3   − ): expected: 380.1667; found: 380.1541. 
     Compound 644 
     6-(4-Cyclohexylphenoxy)-5-fluoro-N-hydroxynicotinamide 
     
       
         
         
             
             
         
       
     
     Following general procedure D, to a solution of 6-(4-cyclohexylphenoxy) fluoronicotinic acid (120 mg, 0.4 mmol) in toluene (2.5 mL) was added two drops of DMF followed by SOCl 2  (0.1 mL, 1.4 mmol) at room temperature and the reaction was then stirred at 80° C. for 3.5 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. Hydroxylamine hydrochloride (208 mg, 3 mmol) in a solution of NEt 3  (1.0 mL, 7.2 mmol) and MeOH (2 mL) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , 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 colorless solid (110 mg, 88%).  1 H NMR (300 MHz, CDCl 3 /DMSO-d 6 ) δ 11.32 (s, 1H), 9.12 (s, 1H), 8.28 (d, J=1.9 Hz, 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 (75 MHz, CDCl 3 /DMSO-d 6 ) δ 161.0, 153.2 (d, J=11.3 Hz), 150.4, 146.3 (d, J=259.6 Hz), 144.4, 140.6, 127.4, 124.5, 123.1 (d, J=16.7 Hz), 120.7, 43.2, 34.0, 26.2, 25.5. HRMS (C 18 H 18 FN 2 O 3   − ): expected: 329.1307; found: 329.1279. 
     Compound 703 
     4-(4-(1-(Trifluoromethyl)cyclopropyl)phenoxy)benzoic acid 
     
       
         
         
             
             
         
       
     
     Following 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 a pH of 1-2. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (2×), dried over Na 2 SO 4 , 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 as slightly yellow solid (0.75 g, 95%).  1 H NMR (300 MHz, CDCl 3 ) δ 11.15 (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, 5.1 Hz, 2H), 1.07-1.01 (m, 2H). 13 C NMR (75 MHz, CDCl 3 ) δ 171.8, 162.3, 155.7, 133.2, 132.6, 132.5, 126.5 (q, J=273.4 Hz), 124.0, 119.9, 117.8, 27.8 (q, J=33.7 Hz), 10.0 (q, J=2.4 Hz). HRMS (C 17 H 12 F 3 O 3   − ): expected: 321.0744; found: 321.0712. 
     Compound 712 
     Methyl 4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)benzoate 
     
       
         
         
             
             
         
       
     
     Following 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 two drops of DMF followed by SOCl 2  (0.1 mL, 1.4 mmol) at room temperature and the reaction was then stirred at 80° C. for 3.5 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles evaporated on a rotary evaporator. A solution of NEt 3  (0.6 mL, 4.4 mmol) in MeOH (1.2 mL) was added and the reaction was stirred at room temperature overnight in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 85% PE-EtOAc gradient to give the title compound as colorless oil (176 mg, 93%).  1 H NMR (300 MHz, CDCl 3 ) δ 8.07-7.96 (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 (75 MHz, CDCl 3 ) δ 166.7, 161.4, 156.0, 133.1, 132.2, 131.9, 126.4 (q, J=273.0 Hz), 125.0, 119.7, 117.9, 52.2, 27.8 (q, J=33.6 Hz), 10.0 (q, J=2.5 Hz). HRMS (C 18 H 16 F 3 O 3+ ): expected: 337.1046; found: 337.1036. 
     Compound 729 
     Ethyl 4-(2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-benzoate 
     
       
         
         
             
             
         
       
     
     Following general procedure A, to 2-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenol (245 mg, 1.5 mmol) and K 2 CO 3  (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 in an argon atmosphere. K 2 CO 3  (220 mg 1.6 mmol) was added and the reaction was then stirred at 150° C. for 9 hours in an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of water. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , 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 as yellow oil (100 mg, 18%).  1 H NMR (300 MHz, CDCl 3 ) δ 8.08-7.97 (m, 2H), 7.58 (d, J=2.1 Hz, 1H), 7.41-7.27 (m, 1H), 7.03 (d, J=8.4 Hz, 1H), 7.03-6.88 (m, 2H), 4.36 (q, J=7.1 Hz, 2H), 1.44-1.33 (m, SH), 1.11-1.00 (m, 2H).  13 C NMR (75 MHz, CDCl 3 ) δ 166.0, 160.7, 151.3, 133.9, 133.8, 131.7, 131.1, 126.2, 126.0 (q, J=273.4 Hz), 125.5, 121.6, 116.8, 60.9, 27.6 (q, J=33.1 Hz), 14.4, 10.0 (q, J=2.3 Hz). HRMS (C 19 H 17 ClF 3 O 3   + ): expected: 385.0813; found: 385.0796. 
     Compound 730 
     6-(4-(1-(Trifluoromethyl)cyclopropyl)phenoxy)nicotinic acid 
     
       
         
         
             
             
         
       
     
     Following 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 at room temperature overnight. 1 M aqueous HCl was added to adjust a pH of 1-2. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (2×), dried over Na 2 SO 4 , 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 as colorless solid (1.21 g, 90%).  1 H NMR (300 MHz, CDCl 3 /DMSO-d 6 ) δ 12.16 (s, 1H), 8.80 (d, J=2.4 Hz, 1H), 8.30 (dd, J=8.6, 2.3 Hz, 1H), 7.51 (dd, J=8.1, 1.6 Hz, 2H), 7.19-7.08 (m, 2H), 6.97 (d, J=8.6 Hz, 1H), 1.41-1.30 (m, 2H), 1.18-1.02 (m, 2H).  13 C NMR (75 MHz, CDCl 3 /DMSO-d 6 ) δ 166.1, 165.3, 152.9, 149.8, 140.5, 132.2, 132.2, 125.9 (q, J=273.1 Hz), 121.8, 120.7, 110.5, 27.1 (q, J=33.5 Hz), 9.3 (q, J=2.4 Hz). HRMS (C 16 H 13 F 3 NO 3   + ): expected: 324.0842; found: 324.0847. 
     Compound 749 
     Ethyl 6-(4-(1-(perfluoroethyl)cyclopropyl)phenoxy)nicotinate 
     
       
         
         
             
             
         
       
     
     Following general procedure A, to 4-(1-(perfluoroethyl)cyclopropyl)phenol (330 mg, 1.3 mmol) and K 2 CO 3  (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 in an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of water. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed first with 1 M aqueous NaOH (1×) then washed with brine (1×), dried over Na 2 SO 4 , 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 yellow oil (445 mg, 88%).  1 H NMR (300 MHz, CDCl 3 ) δ 8.83 (dd, J=2.4, 0.7 Hz, 1H), 8.28 (dd, J=8.6, 2.4 Hz, 1H), 7.48 (d, J=8.6 Hz, 2H), 7.14-7.07 (m, 2H), 6.93 (dd, J=8.6, 0.7 Hz, 1H), 4.38 (q, J=7.1 Hz, 2H), 1.43-1.34 (m, 5H), 1.12-1.04 (m, 2H).  13 C NMR (75 MHz, CDCl 3 ) 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 the CF 2  (tq) and the CF 3  (qt) are too weak to be resolved. HRMS (C 19 H 17 F 5 NO 3   + ): expected: 402.1123; found: 402.1124. 
     Compound 784 
     N,N-Dimethyl-4-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-benzamide 
     
       
         
         
             
             
         
       
     
     Following 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 two drops of DMF followed by SOCl 2  (0.1 mL, 1.4 mmol) at room temperature and the reaction was then stirred at 80° C. for 3 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles 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 in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , 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 colorless oil (110 mg, 100%).  1 H NMR (300 MHz, CDCl 3 ) δ 7.48-7.37 (m, 4H), 7.06-6.92 (m, 4H), 3.06 (d, J=9.8 Hz, 6H), 1.39-1.28 (m, 2H), 1.07-0.95 (m, 2H).  13 C NMR (75 MHz, CDCl 3 ) δ 171.2, 158.2, 156.7, 133.0, 131.6, 131.4, 129.3, 126.5 (q, J=272.1 Hz), 119.0, 118.6, 39.8 (br), 35.6 (br), 27.7 (q, J=33.7 Hz), 10.0 (q, J=2.5 Hz). HRMS (C 19 H 19 F 3 NO 2   + ): expected: 350.1363; found: 350.1351. 
     Compound 820 
     N,N-Dimethyl-6-(4-(1-(trifluoromethyl)cyclopropyl)phenoxy)-nicotinamide 
     
       
         
         
             
             
         
       
     
     Following 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 two drops of DMF followed by SOCl 2  (0.1 mL, 1.4 mmol) at room temperature and the reaction was then stirred at 80° C. for 3 hours in an argon atmosphere. The reaction was cooled to room temperature and the volatiles 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 in an argon atmosphere. The reaction was quenched by the addition 1 M aqueous HCl. 
     The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , 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 colorless solid (172 mg, 100%).  1 H NMR (300 MHz, CDCl 3 ) δ 8.28 (dd, J=2.4, 0.8 Hz, 1H), 7.82 (dd, J=8.5, 2.4 Hz, 1H), 7.54-7.44 (m, 2H), 7.16-7.06 (m, 2H), 6.96 (dd, J=8.5, 0.8 Hz, 1H), 3.18-2.96 (m, 6H), 1.40-1.29 (m, 2H), 1.10-0.98 (m, 2H).  13 C NMR (75 MHz, CDCl 3 ) δ 168.8, 163.9, 153.5, 146.7, 139.3, 132.7, 132.7, 127.1, 126.3 (q, J=274.0 Hz), 121.0, 111.4, 39.7 (br), 35.63 (br), 27.7 (q, J=33.6 Hz), 9.8 (q, J=2.5 Hz). HRMS (C 18 H 18 F 3 N 2 O 2   + ): expected: 351.1315; found: 351.1293. 
     Synthesis of Intermediates 
     (±)-4-(Bicyclo[2.2.1]heptan-2-yl)phenol, mixture of endo and exo 
     
       
         
         
             
             
         
       
     
     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. 
     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 Hz. The reaction was stirred strongly for 22 h at room temperature. The reaction mixture was then purged back with argon, filtered through celite, washed with EtOAc, and concentrated in vacuo. The crude mixture was then filtered on silica (PE/EtOAc), concentrated in vacuo and used in the next step without further purification. 
     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 for 17 h at room temperature. 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 Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 100% to 0% PE-DCM gradient. Recrystallization in hot PE afforded the title compound as white needles (1.5 g, 40% over three steps, 7:1 mixture endo:exo) 
     (±)-4-(Bicyclo[2.2.2]octan-2-yl)phenol 
     
       
         
         
             
             
         
       
     
     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 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. 
     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 Hz. The reaction was stirred strongly for 22 h. The reaction mixture was then purged back with argon, filtered through celite, washed with EtOAc, and concentrated in vacuo. The crude mixture was then filtered on silica (PE/DCM), concentrated in vacuo and used in the next step without further purification. 
     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 for 17 h at room temperature. 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 Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 100% to 0% PE-DCM gradient. Recrystallization in hot PE afforded the title compound as white needles (0.6 g, 15% over three steps) 
     4-(1-(Trifluoromethyl)cyclopropyl)phenol 
     
       
         
         
             
             
         
       
     
     Following a procedure from Anderson, K. W. et al.,  J. Am. Chem. Soc.,  2006, 128 (33), 10694-10695, to a solution of KOH (2.6 g, 46.3 mmol), Pd 2 dba 3  (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 was added 1-bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene (3.98 g, 15.0 mmol). The reaction vessel was then sealed and immerged in a pre-heated 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 (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 100% to 90% PE-EtOAc gradient to give the title compound as a yellow oil (3.0 g, 99%). 
     2-Chloro-4-(1-(trifluoromethyl)cyclopropyl)phenol 
     
       
         
         
             
             
         
       
     
     To a solution of 4-(1-(trifluoromethyl)cyclopropyl)phenol (1.03 g, 5.1 mmol) in DCE (25 mL) under argon at 0° C. were added N-chlorosuccinimide (737 mg, 5.52 mmol) and aluminium 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 Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 100% to 80% PE-EtOAc gradient to give the title compound as a yellow oil (380 mg, 31%). 
     6-Chloro-5-fluoronicotinic acid 
     
       
         
         
             
             
         
       
     
     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 one portion of potassium permanganate (1.1 g, 6.9 mmol). The reaction mixture was heated to 100° C. Two more equal portion of potassium permanganate (for a total of 3.3 g, 20.7 mmol) were added after respectively 1 h and 2 h of stirring at 100° C. When needed, the solid accumulated in the condenser were washed down with water and pyridine. After another 1 h of stirring at 100° C., the reaction mixture was cooled down to room temperature. The reaction mixture was quenched with saturated aqueous Na 2 S 2 O 3  and stirred 30 minutes. The mixture was filtered, then acidified to pH 2 with HCl 5 M. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 90% to 70% PE-EtOAc gradient to give the title compound as a white solid (300 mg, 49%). 
     6-Chloro-5-fluoronicotinic acid ethyl ester 
     
       
         
         
             
             
         
       
     
     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 2  (4.5 mL, 61.7 mmol). The mixture was heated at reflux for 4 h. The reaction mixture was allowed to cool down to room temperature, and the reaction was quenched with saturated aqueous NaHCO 3 . The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 100% to 80% PE-EtOAc gradient to give the title compound as a white solid (5.28 mg, 89%). 
     1-(4-Bromophenyl)-N-cyclohexylethan-1-imine 
     
       
         
         
             
             
         
       
     
     Following a procedure from Mercadante, M. A., 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) was added cyclohexylamine (6.1 mL, 53.5 mmol) and the mixture was stirred at reflux with a Dean-Stark for 21 h. The reaction mixture was allowed to cool down to room temperature and PE was added (100 mL). The p-toluenesulfonic acid precipitated and could be filtered off. The solid was washed with PE (2×). The filtrate was concentrate in vacuo to afford crude product that was recrystallized from hot PE to give the title compound as slightly yellow flakes (12.4 g, 88%). 
     (Iodomethyl)dimethylphenylsilane 
     
       
         
         
             
             
         
       
     
     Following a procedure from Mercadante, M. A., et al.,  Chemical Science,  2014, 5, 3983-3994, to a solution of (chloromethyl)dimethylphenylsilane (4.9 mL, 27 mmol) in acetone (30 mL) was added sodium iodide (7.1 g, 47.3 mmol). The reaction mixture was then stirred at reflux for 19 h. The mixture was concentrated in vacuo, filtered over celite, and the solid washed with PE (60 mL). The solution was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 100% to 70% PE-DCM gradient to give the title compound as a yellow oil (7.1 g, 95%). 
     1-(4-Bromophenyl)-3-(dimethyl(phenyl)silyl)propan-1-one 
     
       
         
         
             
             
         
       
     
     Following a procedure from Mercadante, M. A., et al.,  Chemical Science,  2014, 5, 3983-3994, to a solution of 1-(4-bromophenyl)-N-cyclohexylethan-1-imine (5.6 g, 20 mmol) in THF (10 mL) at 0° C. was slowly added freshly prepared LDA in THF (approximatively 1.5 M, 15 mL, 22 mmol) dropwise. The mixture was stirred 1 h at 0° C. before adding (iodomethyl)dimethylphenylsilane (6.1 g, 22 mmol). The reaction was stirred for another 1 h at 0° C. before quenching with a buffer 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 minutes before being diluted with water. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 100% to 95% PE-EtOAc gradient to give the title compound as a yellow solid (5.24 g, 75%). 
     Trimethyl (perfluoroethyl) silane 
     
       
         
         
             
             
         
       
     
     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 2 ). The system was purged with an atmosphere of pentafluoroethane and the system was kept between −78° C. and −90° C. for 1 h, then slowly warmed to −65° C. and stirred for another 0.5 h. A solution of TMSCl (2.55 mL, 20 mmol) in THF (5 mL) was added and the mixture was allowed to warm-up slowly in the acetone bath and stirred for 15 h at room temperature. The solution was then distilled to obtain the title compound as a solution in THF (65 mL). 
     4-(1-(Perfluoroethyl)cyclopropyl)phenol 
     
       
         
         
             
             
         
       
     
     Following a procedure from Mercadante, M. A., et al.,  Chemical Science,  2014, 5, 3983-3994, to the solution of trimethyl(perfluoroethyl)silane in THF previously obtained (60 mL) 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 and 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 h. The reaction mixture was cooled down to 0° C., 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 h. The reaction was quenched with water. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , 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 (4.9 g, 1:1 ratio by NMR) due to similar polarity. 
     To a solution of the previous alcohol/ketone mixture (4.5 g, containing approximatively 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 minutes. The reaction was cooled down 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 down 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. 
     To the resulting oil at 0° C. was added a mixture of pyridine (0.9 mL, 11.2 mmol) and 1,1,1,3,3,3-Hexafluoropropan-2-ol (8 mL). The flask was sealed and the reaction mixture was stirred for 12.5 h. The reaction was quenched with water. The aqueous layer was extracted with PE (3×). The combined organics were washed with aqueous HCl 1 M, water, saturated aqueous NaHCO 3  and brine (1×), dried over Na 2 SO 4 , filtered and concentrated in vacuo (water bath at 25° C., no lower than 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. As it is a highly volatile product, the PE was not fully removed and the product was directly subjected to the next step. By further eluting the column with 9:1 PE/EtOAc, 1.7 g of the starting 1-(4-bromophenyl)-3-(dimethyl(phenyl)silyl)propan-1-one was recovered. 
     Following a procedure from Anderson, K. W. et al.,  J. Am. Chem. Soc.,  2006, 128 (33), 10694-10695, to a solution of KOH (900 m 16.0 mmol), Pd 2 dba 3  (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) under argon 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 immerged in a pre-heated 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 (3×). The combined organics were washed with brine (1×), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 100% to 90% PE-EtOAc gradient to give the title compound as ayellow oil (1.04 g, 29% over 4 steps, 44% BRSM). 
     The compounds listed in Table XIV have been identified by TLC using pre-coated silica TLC sheets and common organic solvents such as petroleum ether, ethyl acetate, dichloromethane, methanol, or acetic acids as eluent, preferably as binary or tertiary solvent mixtures thereof, UV light at a wavelength of 254 or 366 nm, and/or common staining solutions such as phosphomolybdic acid, potassium permanganate, or ninhydrin. 
     The compounds listed in Table XIV have furthermore been 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 if the molecule was difficult to ionize. Representative compounds have also been identified by nuclear magnetic resonance spectroscopy. Chemical shifts (6) were reported in parts per million (ppm) relative to residual solvent peaks rounded to the nearest 0.01 ppm for proton and 0.1 ppm for carbon (ref.: CHCl 3  [ 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 to the nearest 0.1 Hz. Peak multiplicity was indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), hept (heptet), m (multiplet), and br (broad).