Patent Publication Number: US-7902373-B2

Title: Nicotinamide derivatives

Description:
The present invention relates to pharmaceutically active compounds which are useful in the treatment of allergic and respiratory conditions and diseases. More particularly, the present invention relates to nicotinamide derivatives, and pharmaceutically acceptable salts and solvates thereof, and their use for treating prostaglandin D 2  mediated diseases including, but not limited to, allergic rhinitis, nasal congestion, rhinorrhea, perennial rhinitis, nasal inflammation, asthma of all types, chronic obstructive pulmonary diseases, allergic conjunctivitis, atopic dermatitis and other forms of lung inflammation. The invention also relates to pharmaceutical compositions comprising the nicotinamide derivatives. 
     Prostaglandin D 2  (PGD 2 ) is a metabolite of arachidonic acid. PGD 2  promotes sleep, inhibits platelet aggregation, relaxes smooth muscle contraction, induces bronchoconstriction and attracts inflammatory cells including Th2 cells, eosinophils and basophils. Both lipocalin-type PGD synthase (L-PGDS) and hematopoietic PGDS (H-PGDS) convert PGH 2  to PGD 2 . 
     
       
         
         
             
             
         
       
     
     L-PGDS, also known as glutathione-independent PGDS or brain PGDS, is a 26 kDa secretory protein that is expressed by meningeal cells, epithelial cells of the choroid plexus and oligodendrocytes in the brain. L-PGDS secreted into cerebrospinal fluid is thought to be the source of PGD 2  in the central nervous system. In addition, epithelial cells in the epididymis and Leydig cells in the testis express L-PGDS and are thought to be the source of PGD 2  found in the seminal fluid. L-PGDS belongs to the lipocalin superfamily that consists of lipophilic ligand carrier proteins such as retinol- and retinoic acid-binding proteins. 
     In contrast, H-PGDS is a 26 kDa cytosolic protein that is responsible for the synthesis of PGD 2  in immune and inflammatory cells including mast cells, antigen-presenting cells and Th2 cells. H-PGDS is the only vertebrate member of the sigma class of glutathione S-transferases (GSTs). While both H- and L-PGDS convert PGH 2  to PGD 2 , the mechanism of catalysis and specific activity of the enzymes are quite different. 
     The production of PGD 2  by H-PGDS is thought to play a pivotal role in airway allergic and inflammatory processes and induces vasodilatation, bronchoconstriction, pulmonary eosinophil and lymphocyte infiltration, and cytokine release in asthmatics. PGD 2  levels increase dramatically in bronchoalveolar lavage fluid following allergen challenge and the observation that patients with asthma exhibit bronchoconstriction upon inhalation of PGD 2  underscores the pathologic consequences of high levels of PGD 2  in the lung. Treatment with PGD 2  produces significant nasal congestion and fluid secretion in man and dogs, and PGD 2  is 10 times more potent than histamine and 100 times more potent than bradykinin in producing nasal blockage in humans, demonstrating a role for PGD 2  in allergic rhinitis. 
     Several lines of evidence suggest that PGDS is an excellent target for allergic and respiratory diseases or conditions. H-PGDS overexpressing transgenic mice show increased allergic reactivity accompanied by elevated levels of Th2 cytokines and chemokines as well as enhanced accumulation of eosinophils and lymphocytes in the lung. In addition, PGD 2  binds to two GPCR receptors, DP1 and CRTH2. Antigen-induced airway and inflammatory responses are strongly decreased in DP1-receptor null mice and recent evidence shows that PGD 2  binding to CRTH2 mediates cell migration and the activation of Th2 cells, eosinophils, and basophils in vitro and likely promotes allergic disease in vivo. Finally, several published reports link H-PGDS gene polymorphisms with atopic asthma. For example, Aritake et al., Structural and Functional Characterization of HQL-79, and Orally Selective inhibitor of Human Hematopoietic Prostaglandin D Synthase,  Journal of Biological Chemistry  2006, 281(22), pp. 15277-15286, provides a rational basis for believing that inhibition of H-PGDS is an effective way of treating several allergic and non-allergic diseases. 
     Compounds have now been found that are effective for treating allergic and respiratory diseases. The compounds are inhibitors of H-PGDS, and at expected efficacious doses, do not significantly inhibit L-PGDS or kinases. 
     The invention therefore provides a compound of formula (I): 
                         
or a pharmaceutically acceptable salt or solvate thereof, wherein:
 
     R 1 , R 3  and R 4  are independently H, F, Cl, —CHF 2 , —CF 3 , —OH, —CH 2 OH, —CH 2 CH 2 OH, —C≡N, —CH 2 C≡N, —CH 2 CH 2 C≡N, C 1 -C 5  alkyl, —C(O)OR 16 , —NC(O)R 16 , —NSO 2 R 16 , —C(O)R 16 , or —OCH 3 ; 
     R 2  is H or F; 
     R 5  is H, —NH 2 , —OH or —CH 3 ; 
     R 15  is H, F, Cl, —CH 3  or —OCH 3 ; 
     R 16  is C 1 -C 5  alkyl; 
     L is —C(O)NH—, —NHC(O)— or —CH 2 NHC(O)—; 
     A is: 
                         
wherein: n is 0 or 1;
         m is 0 or 1;   R 6  is H or OH and R 17  is H, or R 6  and R 17  form a bridge across the ring;   R 7  is absent when m is 0 and is (—H,—H), ═O, (—H,—F) or (—H,—OCH 3 ) when m is 1; or   R 6  and R 7 , where both are present, together with the bonds with which they are attached, form a carbocyclic or heterocyclic ring system such that a bicyclic nitrogen-containing heterocyclic system is formed;       

     Q is C 1 -C 6  alkyl, —CH 2 CF 3 , —C(O)CH 2 CH 3 , —C(O)CH 2 CH 2 CH 3 , —C(O)CH(CH 3 ) 2 , —OCH 3 , —CH 2 OCH 3  or —CO 2 CH 2 CH 3 , or Q is represented by the formula: 
                         
wherein: R 8  is a bond, —CH 2 —, —CH 2 CH 2 —, or —CO 2 CH 2 CH 2 —;
         Y is a bond, H, C 3 -C 7  cycloalkyl, phenyl, 5-7 membered heterocyclyl or 5-6 membered heteroaryl;   R 9  is not present, or R 9  is H, F, Cl, ═O, ≡N, —C≡N, —CH 2 C≡N, —CH 2 CH 2 C≡N or C 1 -C 6  alkyl;   R 10  is not present, or R 10  is H, F, Cl, Br, —NH 2 , —CH 3 , —CH 2 CH 3 , —CF 3 , —OH, —OCH 3 , —OCH(CH 3 ) 2 , —CH 2 OCH 3 , —C(O)NH 2 , ═O, —CO 2 CH 2 CH 3 , —NHCH 2 CH 2 OH, —NHCO 2 CH 3 , —NHCO 2 CH 2 CH 3 , —NHCO 2 C(CH 3 ) 2 CH 3 , —N(CH 3 ) 2 , or heteroaryl substituted with methyl;   R 11  is not present or R 11  is a bond, H, —CH 2 —, —NH—, —CH 2 CH 2 —. —OCH 2 —. —CO—, —CO 2 CH 2 CH 2 —, —C(O)NH—, —C(O)NHCH 2 —, —C(O)NHCH 2 CH 2 —, —NHCO 2 —, —NHCO 2 CH 2 —, —NHCO 2 CH 2 CH 2 — or —NHCO 2 C(CH 3 ) 2 CH 2 —;   Z is not present, or Z is a bond, H, C 1 -C 3  alkyl, C 3 -C 7  cycloalkyl, phenyl, 5-7 membered heterocyclyl or 5-6 membered heteroaryl;   R 12  is not present, or R 12  is H, F, Cl, —CH 3 , —CH 2 CH 3 , —OCH 3 , —CO 2 CH 2 CH 3 , —NHCO 2 CH 3 , —NHCO 2 CH 2 CH 3  or —NHCO 2 C(CH 3 ) 2 CH 3 ;   R 13  is not present, or R 13  is H, F, Cl, —CH 3 , —CH 2 CH 3 , —OCH 3 , —CO 2 CH 2 CH 3 —NHCO 2 CH 3 , —NHCO 2 CH 2 CH 3  or NHCO 2 C(CH 3 ) 2 CH 3 ;   R 14  is not present, or R 14  is H, ═O, —OH, C 1 -C 6 alkyl, —CH 3 , —CF 3 , —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —O(CH 2 ) 2 OH, —CO 2 CH 2 CH 3 , F, Cl, Br, ≡N, —C≡N, —N(CH 3 ) 2 , —C(O)CH 3 , —C(O)NH 2 , —CH 2 CH 2 OH, —C(O)NHCH 3 , —C(O)N(CH 2 CH 3 ) 2 , (C 1 -C 3 )alkylsulfonyl, aminosulfonyl, (C 1 -C 3 )alkylaminosulfonyl, 2-methylbutanolyl, 1-methoxy-2-methyl butanyl, 2-methylhex-5-ene-2-yl, —N(CH 3 ) 2 , N-ethyl-N-methylethanaminyl, 5-6 membered cycloalkyl, 5-7 membered heterocyclyl, 5-6 membered heteroaryl or phenyl, wherein each cyclic system is optionally substituted with H, —CH 3 , or —C≡N, and wherein when R 14  is cycloalkyl, heterocyclyl, phenyl or heteroaryl, and when Z is a cycloalkyl, heterocyclyl, phenyl or heteroaryl, R 14  and Z may form a bicyclic ring system,   and wherein when Y is a cyclic system and R 11  and is not present, Y and Z may form a saturated, partially unsaturated or aromatic bicyclic carbocyclic or heterocyclic ring system or a saturated, partially unsaturated or aromatic spiro-fused carbocyclic or heterocyclic ring system;
 
with the proviso that the compound is not ethyl 4-{[(2-methyl-6-phenylpyridin-3-yl)carbonyl]amino}piperidine-1-carboxylate.
       

     A preferred compound of formula (I) is a compound of formula (Ia): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein: 
     R 3a  is H or F; and 
     Q is —CH 2 CF 3  or 5-(morpholin-4-ylcarbonyl)pyridin-2-yl. 
     In an embodiment of the present invention, a compound of formula (Ia) is provided wherein R 3a  is H and Q is —CH 2 CF 3 . 
     In another embodiment of the present invention, a compound of formula (Ia) is provided wherein R 3a  is F and Q is —CH 2 CF 3 . 
     In another embodiment of the present invention, a compound of formula (Ia) is provided wherein R 3a  is F and Q is 5-(morpholin-4-ylcarbonyl)pyridin-2-yl. 
     In another embodiment of the present invention, a compound of formula (Ia) is provided wherein R 3a  is H and Q is 2-(5-morpholine-4-carbonyl)pyridinyl-2-yl. 
     Referring to a compound of formula (I), Q is preferably C 1 -C 6  alkyl, —CH 2 CF 3 , —C(O)CH 2 CH 3 , —C(O)CH 2 CH 2 CH 3 , —C(O)CH(CH 3 ) 2 , —OCH 3 , —CH 2 OCH 3 , —CO 2 CH 2 CH 3 , —(CH 2 ) r -A 1 , —(CH 2 ) r -A 1 -—B, —(CH 2 ) r -A 1 —B-A 2  or —(CH 2 ) r —CO-A 1 , wherein: 
     A 1  is (a) phenyl; (b) naphthyl; (c) a five-membered aromatic heterocyclic group containing either (i) 1-4 nitrogen atoms or (ii) 0-3 nitrogen atoms and 1 oxygen or 1 sulphur atom; (d) a six-membered aromatic heterocyclic group containing 1-3 nitrogen atoms; (e) a nine-membered bicyclic aromatic heterocyclic group containing either (i) 1-5 nitrogen atoms or (ii) 0-4 nitrogen atoms and 1 oxygen or 1 sulphur atom; (f) a ten-membered bicyclic aromatic heterocyclic group containing 1-6 nitrogen atoms; (g) a five- or six-membered saturated or partially unsaturated heterocyclic group containing one or two nitrogen or oxygen groups; (h) a C 3 -C 6  cycloalkyl or cycloalkenyl group, optionally benzo-fused; each of said groups (a)-(h) being optionally substituted by one or more of C 1 -C 6  alkyl, C 1 -C 6  fluoroalkyl, C 3 -C 6  cycloalkyl, hydroxy(C 3 -C 6  cycloalkyl), C 1 -C 6  alkenyl, —(CH 2 ) p OH, —(CH 2 ) p CN, halo, oxo, —(CH 2 ) p NR 18 R 19 , —(CH 2 ) p CONR 18 R 19 , —(CH 2 ) p OR 18 , —(CH 2 ) p COR 18  and —(CH 2 ) p COOR 18 , wherein p is 0-3 and R 18  and R 19  are each H or C 1 -C 6  alkyl optionally substituted with —OH or C 1 -C 6  alkoxy; 
     r is 0 or 1; 
     B is C 1 -C 6  alkylene or C 1 -C 6  cycloalkylene, wherein one or two —CH 2 — groups of said C 1 -C 6  alkylene or C 1 -C 6  cycloalkylene may each be replaced with a group independently selected from —NH—, —CO— and —O—; 
     A 2  is (a) phenyl; (b) naphthyl; (c) a five-membered aromatic heterocyclic group containing either (i) 1-4 nitrogen atoms or (ii) 0-3 nitrogen atoms and 1 oxygen or 1 sulphur atom; (d) a six-membered aromatic heterocyclic group containing 1-3 nitrogen atoms; (e) a nine-membered bicyclic aromatic heterocyclic group containing either (i) 1-5 nitrogen atoms or (ii) 0-4 nitrogen atoms and 1 oxygen or 1 sulphur atom; (f) a ten-membered bicyclic aromatic heterocyclic group containing 1-6 nitrogen atoms; (g) a five- or six-membered saturated or partially unsaturated heterocyclic group containing one or two nitrogen or oxygen groups; (h) a C 3 -C 6  cycloalkyl or cycloalkenyl group, optionally benzo-fused; each of said groups (a)-(h) being optionally substituted by one or more of C 1 -C 6  alkyl, C 1 -C 6  fluoroalkyl, C 3 -C 6  cycloalkyl, hydroxy(C 3 -C 6  cycloalkyl), C 1 -C 6  alkenyl, —(CH 2 ) p OH, —(CH 2 ) p CN, halo, —(CH 2 ) p NR 18 R 19 , —(CH 2 ) p CONR 18 R 19 , —(CH 2 ) p OR 18 , —(CH 2 ) p COR 18  and —(CH 2 ) p COOR 18 , wherein p is 0-3 and R 18  and R 19  are each H or C 1 -C 6  alkyl optionally substituted with —OH or C 1 -C 6  alkoxy; 
     Compounds in which Q is —(CH 2 ) r -A 1 , optionally substituted as described above, are particularly preferred, especially where r is 0. For example, Q may be optionally substituted tetrazolyl, such as (C 1 -C 6  alkyl)tetrazolyl. More specifically Q may be methyltetrazolyl such as 1-methyltetrazol-5-yl. 
     In general, suitable choices for Q include isopropyl, (trifluoromethyl)methyl, 1-oxo-butan-1-yl, ethoxycarbonyl and the following (Me=methyl, Et=ethyl): 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Referring to a compound of formula (I), A is preferably: 
                         
wherein: R 6  is H or OH and R 17  is H, or R 6  and R 17  form a zero, one or two carbon bridge (preferably a zero carbon bridge) across the ring; and
         R 7  is H; or   R 6  and R 7 , where both are present, together with the bonds with which they are attached, form a carbocyclic or heterocyclic ring system such that a bicyclic nitrogen-containing heterocyclic system is formed.       

     Most preferably, A is: 
                         
wherein: R 6  is H and R 7  is H, or R 6  and R 17  form a zero, one or two carbon bridge (preferably a zero carbon bridge) across the ring; and
         R 7  is H.       

     In one embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in which Q is represented by the formula: 
                         
wherein R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , Y and Z are as defined above.
 
     In another embodiment, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in which A, L, R 2 , R 5  and R 15  are as defined above and R 1 , R 3  and R 4  are independently H, F, Cl, CHF 2 , CF 3 , or OH. In a preferred aspect of this embodiment, Q is represented by the formula: 
                         
wherein R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , Y and Z are as defined above.
 
     In another embodiment, the invention provides a compound of Formula (III): 
                         
or a pharmaceutically acceptable salt or solvate thereof, wherein Q is as defined above for a compound of formula (I).
 
     In a preferred group of compounds of formula (III), Q is: 
     
       
         
         
             
             
         
       
     
     In another embodiment, the invention provides a compound of Formula (IV): 
                         
or a pharmaceutically acceptable salt or solvate thereof, wherein Q is as defined above for a compound of formula (I).
 
     In a preferred group of compounds of formula (IV), Q is: 
     
       
         
         
             
             
         
       
     
     In another embodiment, the invention provides a compound of Formula (V): 
                         
or a pharmaceutically acceptable salt or solvate thereof, wherein Q is as defined above for a compound of formula (I).
 
     In a preferred group of compounds of formula (V), Q is: 
     
       
         
         
             
             
         
       
     
     In another embodiment, the invention provides a compound of Formula (VI): 
                         
or a pharmaceutically acceptable salt or solvate thereof, wherein Q is as defined above for a compound of formula (I).
 
     In a preferred group of compounds of formula (VI), Q is: 
     
       
         
         
             
             
         
       
     
     In another embodiment, the invention provides a compound of Formula (VII): 
                         
or a pharmaceutically acceptable salt or solvate thereof, wherein Q is as defined above for a compound of formula (I).
 
     In another embodiment, the invention provides a compound of Formula (VIII): 
                         
or a pharmaceutically acceptable salt or solvate thereof, wherein Q is as defined above for a compound of formula (I).
 
     In a preferred group of compounds of formula (VIII), Q is carboxylate or (trifluoromethyl)methyl. 
     In another embodiment, the invention provides a compound of Formula (IX): 
                         
or a pharmaceutically acceptable salt or solvate thereof, wherein Q is as defined above for a compound of formula (I).
 
     In another embodiment, the invention provides a compound of Formula (X): 
                         
or a pharmaceutically acceptable salt or solvate thereof, wherein A is as defined above for a compound of formula (I).
 
     In another embodiment, the invention provides a compound of Formula (XII): 
                         
or a pharmaceutically acceptable salt or solvate thereof, wherein Q is as defined above for a compound of formula (I).
 
     In another embodiment, the invention provides a compound of Formula (XIII): 
                         
or a pharmaceutically acceptable salt or solvate thereof, wherein A is as defined above for a compound of formula (I).
 
     In another embodiment, the present invention provides a compound of Formula (Ib): 
                         
or a pharmaceutically acceptable salt or solvate thereof, wherein:
 
     R 1 , R 3  and R 4  are independently H, F, Cl, —CHF 2 , —CF 3 , —OH, —CH 2 OH, —CH 2 CH 2 OH, —C≡H, —CH 2 C≡N, —CH 2 CH 2 C≡N, C 1 -C 5  alkyl, C(O)OR 16 , —NC(O)R 16 , —NS(O) 2 R 16 , —C(O)R 16 , or —OCH 3 ; 
     R 2  is H or F; 
     R 5  is H, —NH 2 , —OH or —CH 3 ; 
     R 15  is H, F, Cl, —CH 3  or —OCH 3 ; 
     L is —C(O)NH—, —NHC(O)— or —CH 2 NHC(O)—; and 
     A is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
     In another embodiment, the invention provides a compound selected from the group consisting of:
     6-(3-fluorophenyl)-N-(1-{9-[1-(hydroxymethyl)propyl]-9H-purin-6-yl}piperidin-4-yl)nicotinamide; fluorophenyl)-N-[1-(1-methyl-1H-tetrazol-5-yl)piperidin-4-yl]nicotinamide; and   6-(3-fluorophenyl)-N-{1-[5-(morpholin-4-ylcarbonyl)pyridin-2-yl]piperidin-4-yl}nicotinamide;
 
and the pharmaceutically acceptable salts and solvates thereof.
   

     In another embodiment, the invention provides 6-(3-fluoro-phenyl)-N-[1-(1-methyl-1H-tetrazol-5-yl)-piperidin-4-yl]-nicotinamide, and pharmaceutically acceptable salts and solvates thereof. 
     The present invention also provides: a method of treating a disease or condition mediated at least in part by prostaglandin D 2  produced by H-PGDS, in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof; the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for treating a disease or condition mediated at least in part by prostaglandin D 2  produced by H-PGDS; a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament; a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a disease or condition mediated at least in part by prostaglandin D 2  produced by H-PGDS; a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient; a pharmaceutical composition for the treatment of a disease or condition mediated at least in part by prostaglandin D 2  produced by H-PGDS comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. 
     The diseases and conditions mediated at least in part by prostaglandin D 2  produced by H-PGDS include allergy and allergic inflammation. Important diseases and conditions of this kind are allergic respiratory conditions such as allergic rhinitis, nasal congestion, rhinorrhea, perennial rhinitis, nasal inflammation, asthma of all types, chronic obstructive pulmonary disease (COPD), chronic or acute bronchoconstriction, chronic bronchitis, small airways obstruction, emphysema, chronic eosinophilic pneumonia, adult respiratory distress syndrome, exacerbation of airways hyper-reactivity consequent to other drug therapy, airways disease that is associated with pulmonary hypertension, acute lung injury, bronchiectasis, sinusitis, allergic conjunctivitis or atopic dermatitis, particularly asthma or chronic obstructive pulmonary disease. 
     Types of asthma include atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or inapparent cause, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen induced asthma, cold air induced asthma, occupational asthma, infective asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma, incipient asthma, wheezy infant syndrome and bronchiolytis. 
     Included in the use of the compounds of formula (I) for the treatment of asthma, is palliative treatment for the symptoms and conditions of asthma such as wheezing, coughing, shortness of breath, tightness in the chest, shallow or fast breathing, nasal flaring (nostril size increases with breathing), retractions (neck area and between or below the ribs moves inward with breathing), cyanosis (gray or bluish tint to skin, beginning around the mouth), runny or stuffy nose, and headache. 
     Other important diseases and conditions mediated at least in part by prostaglandin D 2  produced by H-PGDS are arthritis (especially rheumatoid arthritis), irritable bowel diseases (such as Crohns disease and ulcerative colitis), irritable bowel syndrome, inflammatory pain, skin inflammation and irritiation (such as eczema), niacin-induced skin flushing and cealic type disease (e.g. as a result of lactose intolerance). 
     The present invention also provides any of the uses, methods or compositions as defined above wherein the compound of formula (I), or pharmaceutically acceptable salt or solvate thereof, is used in combination with another pharmacologically active compound, particularly one of the compounds listed in Table 1 below. Specific combinations useful according to the present invention include combinations comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and (i) a glucocorticosteroid or DAGR (dissociated agonist of the corticoid receptor); (ii) a β 2  agonist, an example of which is a long-acting β 2  agonist; (iii) a muscarinic M3 receptor antagonist or an anticholinergic agent; (iv) a histamine receptor antagonist, which may be an H1 or an H3 antagonist; (v) a 5-lypoxygenase inhibitor; (vi) a thromboxane inhibitor; or (vii) an LTD 4  inhibitor. Generally, the compounds of the combination will be administered together as a formulation in association with one or more pharmaceutically acceptable excipients. 
     
       
         
           
               
               
             
               
                 TABLE I 
               
               
                   
               
             
            
               
                 (a) 
                 5-Lipoxygenase activating protein (FLAP) antagonists 
               
               
                 (b) 
                 Leukotriene antagonists (LTRAs) including antagonists of 
               
               
                   
                 LTB 4 , LTC 4 , LTD 4 , and LTE 4   
               
               
                 (c) 
                 Histamine receptor antagonists including H1 and H3 antagonists 
               
               
                 (d) 
                 α 1 - and α 2 -Adrenoceptor agonist vasoconstrictor sympathomimetic 
               
               
                   
                 agents for decongestant use 
               
               
                 (e) 
                 Muscarinic M3 receptor antagonists or anticholinergic agents 
               
               
                 (f) 
                 PDE inhibitors, e.g. PDE3, PDE4 and PDE5 inhibitors, such as 
               
               
                   
                 theophylline 
               
               
                 (g) 
                 Sodium cromoglycate 
               
               
                 (h) 
                 COX inhibitors, including both non-selective and selective 
               
               
                   
                 COX-1 or COX-2 inhibitors (such as NSAIDs) 
               
               
                 (i) 
                 Glucocorticosteroids or DAGR (dissociated agonists of the 
               
               
                   
                 corticoid receptor) 
               
               
                 (j) 
                 Monoclonal antibodies active against endogenous inflammatory 
               
               
                   
                 entities 
               
               
                 (k) 
                 β2 agonists, including long-acting β2 agonists 
               
               
                 (l) 
                 Integrin antagonists 
               
               
                 (m) 
                 Adhesion molecule inhibitors, including VLA-4 antagonists 
               
               
                 (n) 
                 Kinin-B 1 - and B 2 -receptor antagonists 
               
               
                 (o) 
                 Immunosuppressive agents, including inhibitors of the IgE 
               
               
                   
                 pathway, and cyclosporin; 
               
               
                 (p) 
                 Inhibitors of matrix metalloproteases (MMPs), such as., 
               
               
                   
                 MMP9, and MMP12 
               
               
                 (q) 
                 Tachykinin NK 1 , NK 2  and NK 3  receptor antagonists 
               
               
                 (r) 
                 Protease inhibitors, such as elastase inhibitors, chymase and 
               
               
                   
                 cathepsin G; 
               
               
                 (s) 
                 Adenosine A2a receptor agonists and A2b antagonists 
               
               
                 (t) 
                 Inhibitors of urokinase 
               
               
                 (u) 
                 Compounds that act on dopamine receptors, such as D2 agonists 
               
               
                 (v) 
                 Modulators of the NFκB pathway, such as IKK inhibitors 
               
               
                 (w) 
                 Modulators of cytokine signaling pathways such as syk kinase, 
               
               
                   
                 JAK kinase inhibitors, p38 kinase, SPHK-1 kinase, Rho kinase, 
               
               
                   
                 EGF-R or MK-2 
               
               
                 (x) 
                 Agents that can be classed as mucolytics or anti-tussive, and 
               
               
                   
                 mucokinetics; 
               
               
                 (y) 
                 Antibiotics; 
               
               
                 (z) 
                 Antivirals; 
               
               
                 (aa) 
                 Vaccines 
               
               
                 (bb) 
                 Chemokines 
               
               
                 (cc) 
                 Epithelial sodium channel (ENaC) blockers or Epithelial sodium 
               
               
                   
                 channel (ENaC) inhibitors 
               
               
                 (dd) 
                 P2Y2 Agonists and other Nucleotide receptor agonists 
               
               
                 (ee) 
                 Inhibitors of thromboxane 
               
               
                 (ff) 
                 Niacin 
               
               
                 (gg) 
                 Inhibitors of 5-lypoxygenase (5-LO) 
               
               
                 (hh) 
                 Adhesion factors including VLAM, ICAM, and ELAM 
               
               
                   
               
            
           
         
       
     
     Besides being useful for human treatment, compounds of formula (I) are also useful for veterinary treatment of companion animals, exotic animals and farm animals. 
     When used in the present application, the following abbreviations have the meanings set out below: 
     HATU is N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate; 
     HOBt is 1-hydroxybenzotriazole; 
     BOP is (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; 
     HBTU is N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate; 
     TBTU is O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate; 
     DIPEA is N,N-diisopropylethylamine; 
     TEA is triethylamine; 
     TFA is trifluoroacetic acid; 
     DCM is dichloromethane; 
     DMA is N,N-dimethylacetamide; 
     EDC/EDAC is N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; 
     NMM is 4-methylmorpholine; 
     DCC is N,N′-dicyclohexylcarbodiimide; 
     HOAt is 1-hydroxy-7-azabenzotriazole; 
     Me is methyl; 
     Et is ethyl; 
     EtOAc is ethyl acetate; 
     CDCl 3  is deuterochloroform; 
     CH 2 Cl 2  is dichloromethane; 
     iPr is isopropyl; and 
     CO 2 Et is ethyl carboxylate. 
     Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. 
     Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Generally, nomenclature used in connection with, and techniques of chemistry and molecular biology described herein are those well known and commonly used in the art. 
     The phrase “therapeutically effective” is intended to qualify the amount of compound or pharmaceutical composition, or the combined amount of active ingredients in the case of combination therapy. This amount or combined amount will achieve the goal of treating the relevant condition. 
     The term “treatment,” as used herein to describe the present invention and unless otherwise qualified, means administration of the compound, pharmaceutical composition or combination to effect preventative, palliative, supportive, restorative or curative treatment. The term treatment encompasses any objective or subjective improvement in a subject with respect to a relevant condition or disease. 
     The term “preventive treatment,” as used herein to describe the present invention, means that the compound, pharmaceutical composition or combination is administered to a subject to inhibit or stop the relevant condition from occurring in a subject, particularly in a subject or member of a population that is significantly predisposed to the relevant condition. 
     The term “palliative treatment,” as used herein to describe the present invention, means that the compound, pharmaceutical composition or combination is administered to a subject to remedy signs and/or symptoms of a condition, without necessarily modifying the progression of, or underlying etiology of, the relevant condition. 
     The term “supportive treatment,” as used herein to describe the present invention, means that the compound, pharmaceutical composition or combination is administered to a subject as a part of a regimen of therapy, but that such therapy is not limited to administration of the compound, pharmaceutical composition or combination. Unless otherwise expressly stated, supportive treatment may embrace preventive, palliative, restorative or curative treatment, particularly when the compounds or pharmaceutical compositions are combined with another component of supportive therapy. 
     The term “restorative treatment,” as used herein to describe the present invention, means that the compound, pharmaceutical composition or combination is administered to a subject to modify the underlying progression or etiology of a condition. Non-limiting examples include an increase in forced expiratory volume in one second (FEV 1) for lung disorders, inhibition of progressive nerve destruction, reduction of biomarkers associated and correlated with diseases or disorders, a reduction in relapses, improvement in quality of life and the like. 
     The term “curative treatment,” as used herein to describe the present invention, means that compound, pharmaceutical composition or combination is administered to a subject for the purpose of bringing the disease or disorder into complete remission, or that the disease or disorder is undetectable after such treatment. 
     The term “alkyl”, alone or in combination, means an acyclic alkyl radical, linear or branched, preferably containing from 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. Where no specific substitution is specified, alkyl radicals can be optionally substituted with groups consisting of hydroxy, methoxy, amino, cyano, chloro, and fluoro. Examples of such substituted alkyl radicals include chloroethyl, hydroxyethyl, cyanobutyl, aminopentyl and the like. 
     The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating a lower and upper number of carbon atoms in the moiety, that is, the prefix C i-j  indicates a moiety of the integer “i” to the integer “j” carbon atoms, inclusive. Thus, for example, ‘C 1-6  alkyl’ or ‘C 1 -C 6  alkyl’ refers alkyl of one to six carbon atoms, inclusive. 
     The term “hydroxyl,” as used herein, means an OH radical. 
     The terms ‘heterocycle’, ‘heterocylic ring system’ and ‘heterocyclyl’ refer to a saturated or unsaturated mono- or multi-ring cycloalkyl wherein one or more carbon atoms is replaced by N, S or O. This includes, for example, the following structures: 
                         
wherein Z, Z 1 , Z 2  and Z 3  are C, S, O, or N, with the proviso that one of Z, Z 1 , Z 2  or Z 3  is other than carbon, but is not O or S when attached to another Z atom by a double bond or when attached to another O or S atom. Wherein Z, Z 1 , Z 2  or Z 3  is S or N, the atom may be substituted by oxygen to form a sulfinyl (S═O), sulfonyl (S(═O) 2 ), or N-oxide (N + —O − ) radical. The term “heterocycle” also includes fully saturated ring structures such as piperazinyl, dioxanyl, tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, and others. The term “heterocycle” or also includes partially unsaturated ring structures such as dihydrofuranyl, pyrazolinyl, imidazolinyl, pyrrolinyl, chromanyl, dihydrothiophenyl, and others.
 
     The term ‘heteroaryl’ refers to an aromatic heterocyclic group. Heteroaryl is preferably: (a) a five-membered aromatic heterocyclic group containing either (i) 1-4 nitrogen atoms or (ii) 0-3 nitrogen atoms and 1 oxygen or 1 sulphur atom; (b) a six-membered aromatic heterocyclic group containing 1-3 nitrogen atoms; (c) a nine-membered bicyclic aromatic heterocyclic group containing either (i) 1-5 nitrogen atoms or (ii) 0-4 nitrogen atoms and 1 oxygen or 1 sulphur atom; or (d) a ten-membered bicyclic aromatic heterocyclic group containing 1-6 nitrogen atoms; each of said groups (a)-(d) being optionally substituted by one or more of C 1 -C 6  alkyl, C 1 -C 6  fluoroalkyl, C 3 -C 6  cycloalkyl, hydroxy(C 3 -C 6  cycloalkyl), C 1 -C 6  alkenyl, —(CH 2 ) p OH, —(CH 2 ) p CN, halo, oxo, —(CH 2 ) p NR 18 R 19 , —(CH 2 ) p CONR 18 R 19 , —(CH 2 ) p OR 18 , —(CH 2 ) p COR 18  and —(CH 2 ) p COOR 18 , wherein p is 0-3 and R 18  and R 19  are each H or C 1 -C 6  alkyl optionally substituted with —OH or C 1 -C 6  alkoxy. Examples of “heteroaryl” include pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl (optionally substituted as specified above). 
     A preferred non-aromatic heterocyclic group is a five- or six-membered saturated or partially unsaturated heterocyclic group containing one or two nitrogen or oxygen groups, optionally substituted by one or more of C 1 -C 6  alkyl, C 1 -C 6  fluoroalkyl, C 3 -C 6  cycloalkyl, hydroxy(C 3 -C 6  cycloalkyl), C 1 -C 6 cycloalkyl), C 1 -C 6  alkenyl, —(CH 2 ) p OH, —(CH 2 ) p CN, halo, oxo, —(CH 2 ) p NR 18 R 19 , —(CH 2 ) p CONR 18 R 19 , —(CH 2 ) p OR 18 , —(CH 2 ) p COR 18  and —(CH 2 ) p COOR 18 , wherein p is 0-3 and R 18  and R 19  are each H or C 1 -C 6  alkyl optionally substituted with —OH or C 1 -C 6  alkoxy. Preferred examples of non-aromatic heterocyclic groups include azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperdininyl, piperazinyl and morpholinyl (optionally substituted as specified above). 
     In either “heterocyle” or “heteroaryl,” the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring. 
     The term “nitrogen-containing heterocycle,” or “nitrogen containing heteroaryl,” as used herein to describe the present invention, means a heterocyclic or heteroaryl group, respectively, that comprises at least one nitrogen atom. Such substitutents may also be referred to herein as “heterocycle containing at least one nitrogen,” and “heteroaryl containing at least one nitrogen.” 
     The term “cycloalkyl” or “carbocyclyl” means a mono- or multi-ringed cycloalkyl wherein each ring contains three to seven carbon atoms, preferably three to six carbon atoms. ‘Cycloalkyl’ is preferably a monocyclic cycloalkyl containing from three to seven carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. 
     The term “oxo” means a doubly bonded oxygen. 
     The term “alkoxy” means a radical comprising an alkyl radical that is bonded to an oxygen atom, such as a methoxy radical. More preferred alkoxy radicals are “lower alkoxy” radicals having one to about ten carbon atoms. Still more preferred alkoxy radicals have one to about six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy. 
     The term “aryl” means a fully unsaturated mono- or multi-ring cycloalkyl having a cyclic array of p-orbitals containing 4n+2 electrons, including, but not limited to, substituted or unsubstituted phenyl, naphthyl, or anthracenyl optionally fused to a carbocyclic radical wherein aryl is optionally substituted with one or more substituents selected from the group consisting of: (a) halo; (b) C 1-6 alkoxy optionally substituted by halo and phenyl; (c) C 1-6 alkyl optionally substituted by halo; (d) phenyl; (e) O-phenyl; (f) cyano; (g) nitro; (h) hydroxyl, or any two adjacent substituents taken together constitute a group of the formula —O(CH 2 ) m O— where m is 1-3. 
     The symbols 
                         
denote the point of attachment of a substituent.
 
     As used herein, the terms “co-administration”, “co-administered” and “in combination with”, referring to a combination of a compound of formula (I) and one or more other therapeutic agents, is intended to mean, and does refer to and include the following:
         simultaneous administration of such a combination of a compound of formula (I) and a further therapeutic agent to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components at substantially the same time to said patient,   substantially simultaneous administration of such a combination of a compound of formula (I) and a further therapeutic agent to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at substantially the same time by said patient, whereupon said components are released at substantially the same time to said patient,   sequential administration of such a combination of a compound of formula (I) and a further therapeutic agent to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at consecutive times by said patient with a significant time interval between each administration, whereupon said components are released at substantially different times to said patient; and   sequential administration of such a combination of a compound of formula (I) and a further therapeutic agent to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components in a controlled manner whereupon they are concurrently, consecutively, and/or overlappingly administered at the same and/or different times by said patient, where each part may be administered by either the same or different route.       

     The term ‘excipient’ is used herein to describe any ingredient other than a compound of formula (I). The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. The term “excipient” encompasses diluent, carrier or adjuvant. 
     Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof. 
     Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, naphatlene-1,5-disulfonic acid and xinofoate salts. 
     Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. 
     Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). 
     Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods:
     (i) by reacting the compound of formula (I) with the desired acid or base;   (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or   (iii) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.   

     All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised. 
     The compounds of formula (I) may also exist in unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular complex comprising the compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term ‘hydrate’ is employed when said solvent is water. 
     A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates—see  Polymorphism in Pharmaceutical Solids  by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion. 
     When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm. 
     Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together—see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004). For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975). 
     The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term ‘amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order (‘glass transition’). The term ‘crystalline’ refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order (‘melting point’). 
     The compounds of formula (I) may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as ‘thermotropic’ and that resulting from the addition of a second component, such as water or another solvent, is described as ‘lyotropic’. Compounds that have the potential to form lyotropic mesophases are described as ‘amphiphilic’ and consist of molecules which possess an ionic (such as —COO − Na + , —COO − K + , or —SO 3   − Na + ) or non-ionic (such as —N − N + (CH 3 ) 3 ) polar head group. For more information, see  Crystals and the Polarizing Microscope  by N. H. Hartshorne and A. Stuart, 4 th  Edition (Edward Arnold, 1970). 
     Hereinafter all references to compounds of formula (I) (also referred to as compounds of the invention) include references to salts, solvates, multi-component complexes and liquid crystals thereof and to solvates, multi-component complexes and liquid crystals of salts thereof. 
     Also included within the scope of the invention are all polymorphs and crystal habits of compounds of formula (I), prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled forms thereof. 
     As indicated, so-called ‘prodrugs’ of the compounds of formula (I) are also within the scope of the invention. Thus certain derivatives of a compound of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into a compound of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as ‘prodrugs’. Further information on the use of prodrugs may be found in  Pro - drugs as Novel Delivery Systems , Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and  Bioreversible Carriers in Drug Design , Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association). 
     Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in  Design of Prodrugs  by H. Bundgaard (Elsevier, 1985). 
     Some examples of prodrugs in accordance with the invention include:
     (i) where the compound of formula (I) contains a carboxylic acid functionality (—COOH), an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of formula (I) is replaced by (C 1 -C 8 )alkyl;   (ii) where the compound of formula (I) contains an alcohol functionality (—OH), an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of formula (I) is replaced by (C 1 -C 6 )alkanoyloxymethyl; and   (iii) where the compound of formula (I) contains a primary or secondary amino functionality (—NH 2  or —NHR where R≠H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of formula (I) is/are replaced by (C 1 -C 10 )alkanoyl.   

     Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references. 
     Moreover, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I). 
     Also included within the scope of the invention are metabolites of compounds of formula (I), that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include
     (i) where the compound of formula (I) contains a methyl group, an hydroxymethyl derivative thereof (—CH 3 —&gt;—CH 2 OH):   (ii) where the compound of formula (I) contains an alkoxy group, an hydroxy derivative thereof (—OR—&gt;—OH);   (iii) where the compound of formula (I) contains a tertiary amino group, a secondary amino derivative thereof (—NR 1 R 2 —&gt;—NHR 1  or —NHR 2 );   (iv) where the compound of formula (I) contains a secondary amino group, a primary derivative thereof (—NHR 1 —&gt;—NH 2 );   (v) where the compound of formula (I) contains a phenyl moiety, a phenol derivative thereof (-Ph-&gt;-PhOH); and   

     (vi) where the compound of formula (I) contains an amide group, a carboxylic acid derivative thereof (—CONH 2 —&gt;COOH). 
     Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula (I) contains an alkenyl or alkenylene group, geometric cis/trans (or ZIE) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (‘tautomerism’) can occur. This can take the form of proton tautomerism in compounds of formula (I) containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. 
     Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, d-lactate or I-lysine, or racemic, for example, dl-tartrate or dl-arginine. 
     Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation. 
     Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds of formula (I) (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. Chiral chromatography using sub- and supercritical fluids may be employed. Methods for chiral chromatography useful in some embodiments of the present invention are known in the art. (See, for example, Smith, Roger M. Loughborough University, Loughborough, UK. Chromatographic Science Series (1998), 75(Supercritical Fluid Chromatography with Packed Columns), pp. 223-249 and references cited therein.) In the relevant examples herein, columns were obtained from Chiral Technologies, Inc, West Chester, Pa., USA, a subsidiary of Daicel® Chemical Industries, Ltd., Tokyo, Japan. 
     When any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer. While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art—see, for example,  Stereochemistry of Organic Compounds  by E. L. Eliel and S. H. Wilen (Wiley, 1994). 
     The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed. 
     For administration to human patients, the total daily dose of a compound of formula (I) is typically in the range of 0.01 mg to 500 mg depending, of course, on the mode of administration. In another embodiment of the present invention, the total daily dose of a compound of formula (I) is typically in the range of 0.1 mg to 300 mg. In yet another embodiment of the present invention, the total daily dose of a compound of formula (I) is typically in the range of 1 mg to 30 mg. The total daily dose may be administered in single or divided doses and may, at the physician&#39;s discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 65 kg to 70 kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly. In the case of aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or “puff” containing from 0.001 mg to 10 mg of a compound of the invention. The overall daily dose will typically be in the range 0.001 mg to 40 mg which may be administered in a single dose or, more usually, as divided doses throughout the day. 
     A compound of formula (I) can be administered per se, or in the form of a pharmaceutical composition, which, as active constituent contains an efficacious dose of at least one compound of the invention, in addition to customary pharmaceutically innocuous excipients and/or additives. 
     Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in  Remington&#39;s Pharmaceutical Sciences,  19th Edition (Mack Publishing Company, 1995). 
     Compounds of formula (I) may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations. 
     Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. 
     Compounds of formula (I) may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001). 
     For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %. In one embodiment of the present invention, the disintegrant will comprise from 5 weight % to 20 weight % of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet. Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %. In one embodiment of the present invention, lubricants comprise from 0.5 weight % to 3 weight % of the tablet. Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents. 
     Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant. 
     Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. Formulations of tablets are discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, N.Y., 1980). 
     Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (I), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function. The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %. Other possible ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents. Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming. 
     Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release includes delayed, sustained, pulsed, controlled, targeted and programmed release. Suitable modified release formulations for the purposes of the invention are described in U.S. Pat. No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. 
     Compounds of formula (I) may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques. 
     Compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. 
     The compounds of formula (I) can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. 
     The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound of formula (I) comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the compound, a propellant as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. 
     Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying. 
     Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as I-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. 
     A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 μg to 20 mg of the compound of the invention per actuation and the actuation volume may vary from 1 μl to 100 μl. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol. 
     Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for intranasal administration. Formulations for intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA. Modified release includes delayed, sustained, pulsed, controlled, targeted and programmed release. 
     Compounds of formula (I) may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. 
     Compounds of formula (I) may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration. Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in international patent publications WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148. 
     Inasmuch as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound of formula (I), may conveniently be combined in the form of a kit suitable for coadministration of the compositions. Thus, a kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I), and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like. Such a kit is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid. 
     All the compound of formula (I) can be made by the specific and general experimental procedures described below in combination with the common general knowledge of one skilled in the art (see, for example, Comprehensive Organic Chemistry, Ed. Barton and Ollis, Elsevier; Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Larock, John Wiley and Sons). 
     Methods for Preparing Aryl Pyridyl Linked Compounds 
     Those skilled in the art will appreciate that there are many known ways of preparing aryl pyridyl linked compounds. Such methods are disclosed in patent textbooks and laboratory handbooks which constitute the common general knowledge of the skilled person, including the textbooks referenced above and references cited therein. Typically, an aryl halide (Cl, Br, I) or trifluoromethanesulphonate is stirred with an organometallic species such as a stannane, organomagnesium derivative or a boronate ester or boronic acid in the presence of a catalyst, usually a palladium derivative between 0° C. and 120° C. in solvents including tetrahydrofuran, toluene, DMF and water for 1 to 24 hours. For example, an aryl bromide may be heated to 100° C. in a mixture of water/toluene with a base such as sodium carbonate or sodium hydroxide, a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0), a phase transfer catalyst such as tetra-n-butyl ammonium bromide and an aryl boronic acid or ester. As a second example, an aryl boronic ester an aryl halide (Cl, Br, I) or aryl trifluoromethanesulphonate and a fluoride source such as KF or CsF in a non-aqueous reaction medium such as 1,4-dioxane may be employed. 
     General Scheme for the Preparation of Amides 
     Those skilled in the art will appreciate that there are many known ways of preparing amides. For example, see Montalbetti, C. A. G. N and Falque, V.,  Amide bond formation and peptide coupling , Tetrahedron, (2005) 61: (46), pp. 10827-10852 and references cited therein. The examples provided herein are thus not intended to be exhaustive, but merely illustrative. The general scheme for amide formation is as follows: 
     
       
         
         
             
             
         
       
     
     As an example: 
     
       
         
         
             
             
         
       
     
     In the following Examples, unless otherwise stated, the following general method was used: To the carboxylic acid (0.15 mmol) and 1-hydroxybenzotriazole (0.3 mmol) in DMF (1.0 mL) was added 0.3.mmol of PS-Carbodiimide resin (Argonaut, 1.3 mmol/g). The mixture was shaken for 10 min and then the amine (0.1 mmol) in DMF (1 mL) was added. The mixture was allowed to agitate overnight at rt and subsequently treated with 0.60 mmole of PS-trisamine (Argonaut, 3.8 mmol/g). Reaction mixture was filtered, concentrated in vacuo and purified by reverse phase chromatography. 
     Where it is stated that compounds were prepared in the manner described for an earlier Example, the skilled person will appreciate that reaction times, number of equivalents of reagents and reaction temperatures may be modified for each specific reaction, and that it may nevertheless be necessary or desirable to employ different work-up or purification conditions. 
    
    
     EXAMPLE 1 
     6-Phenyl-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)nicotinamide 
     
       
         
         
             
             
         
       
     
     Step A: 8-(Trifluoroacetyl)-1,4-dioxa-8-azaspiro[4.5]decane 
     4-Piperidone ethylene ketal (127.0 g, 0.887 mol), Et 3 N (145 mL, 1.044 mol), and 4-dimethylaminopyrid (DMAP, 10.5 g, 0.086 mol) were mixed in dichloromethane (1 L). A solution of trifluoroacetic anhydride (192.0 g, 0.91 mol) in dichloromethane (500 mL) was added dropwise at 0-5° C. for 1 h. The mixture was allowed to warm up to room temperature and stirred overnight. The reaction mixture was washed with 1 N aqueous HCl (2×1.2 L), water (1.2 L), 10% aqueous NaHCO 3  (1.2 L), brine (600 mL), dried over anhydrous Na 2 SO 4 , and evaporated under vacuum to afford 8-(trifluoroacetyl)-1,4-dioxa-8-azaspiro[4.5]decane (194.5 g). 
     Step B: 1-(2,2,2-Trifluoroethyl)piperidin-4-one 
     A solution of 8-(trifluoroacetyl)-1,4-dioxa-8-azaspiro[4.5]decane (87.0 g, 0.364 mol) in THF (375 added dropwise under argon to 1 M BH 3  in THF (800 mL, 0.8 mol) at 0-5° C. for 10 min. The cool was removed. The reaction mixture was refluxed for 5 h, cooled to 0-5° C., and quenched by adding carefully 6 N aqueous HCl (130 mL) for ˜1 h under stirring. The organic solvents were removed under vacuum. The aqueous residue was alkalized with a 50% solution of NaOH (150 mL), diluted with water (500 mL), and extracted with ether (3×400 mL). The combined extracts were dried over anhydrous Na 2 SO 4  and evaporated to give a mixture (98.8 g) of the intermediate 8-(2,2,2-trifluoroethyl)-1,4-dioxa-8-azaspiro[4.5]decane and butanol in 79:21 weight ratio. Water (1.1 L) and concentrated HCl (100 mL) were added, and the obtained mixture was refluxed for 3 h. After cooling to room temperature, the reaction mixture was alkalized to pH 9 by adding a 40% solution of NaOH (˜150 mL) and extracted with ether (3×350 mL). The combined extracts were dried over anhydrous Na 2 SO 4  and evaporated to afford a mixture (72.8 g) of 1-(2,2,2-trifluoroethyl)piperidin-4-one and butanol in 86:14 weight ratio. 
     Step C: 1-(2,2,2-Trifluoroethyl)piperidin-4-amine 
     A 25% aqueous solution of ammonia (170 mL), 10% Pd/C (7.4 g), and a solution of the above 1-(2,2,2-trifluoroethyl)piperidin-4-one /butanol mixture (72.5 g, 0.344 mol, 86:14 weight ratio) in methanol (420 mL) were placed into a 2 L glass autoclave purged with argon. The reaction mixture was hydrogenated in a Parr apparatus at a hydrogen pressure of 40 psi for 18 h. The catalyst was removed by filtration. The filtrate was concentrated in vacuo to 150 mL. Potash (46 g) and ether (200 mL) were added, and the mixture was vigorously stirred for 20 min. The organic layer was separated, and the aqueous one was extracted with ether (100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4  and evaporated to afford a mixture (74.4 g) of 1-(2,2,2-trifluoroethyl)piperidin-4-amine and 1-(2,2,2-trifluoroethyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]piperidin-4-amine in 72:28 weight ratio (contain butanol). This mixture was fractionated at 7-8 mmHg on a 15 cm Vigreaux column (a fraction with bp 75-95° C. was collected) to afford 1-(2,2,2-trifluoroethyl)piperidin-4-amine (38.5 g) as a colorless liquid. 
     Step D: 6-Phenyl-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]nicotinamide 
     To a 250 mL 3-necked flask containing 2-phenyl-5-pyridinecarboxylic acid (2.75 g, 13.8 mmol) in N,N-dimethylacetamide (DMA, 35 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC/EDC*HCl, 2.95 g, 15.2 mmol), 1-hydroxybenzotriazole (HOBt. 1.89 g, 13.8 mmol), 1-(2,2,2-trifluoroethyl)piperidin-4-amine (3.36 g, 15.2 mmol) and 4-methylmorpholine (NMM, 3.8 mL, 34.5 mmol). After stirring at room temperature for 1 hour, the reaction was diluted with water (˜200 mL) and the resulting solid collected by filtration. The solid was washed with H 2 O (3×100 mL), collected and dried in a vacuum oven (45° C.) overnight to give the desired product (4.24 g). LCMS (ES+) 4.30 min (TIC, 75%;  1 H NMR purity &gt;95%);  1 H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.46-1.65 (m, 2H) 1.77 (d, J=10.80 Hz, 2 H) 2.31-2.54 (m, 4H) 2.90 (d, J=11.53 Hz, 2H) 3.65-3.86 (m, 1H) 7.36-7.56 (m, 3H) 8.01 (d, J=8.24 Hz, 1H) 8.09 (d, J=6.95 Hz, 2H) 8.22 (d, J=8.42 Hz, 1H) 8.38 (d, J=7.32 Hz, 1H) 9.02 (s, 1 H); MS(ES+) 364 (M+1); HRMS (TOF, ES+) calculated for C 19 H 20 F 3 N 3 O+H + : 364.1637; observed 364.1611. 
     EXAMPLE 2 
     6-(3-Fluorophenyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1-(2,2,2-Trifluoroethyl)piperidin-4-amine was synthesized as in steps a-c of Example 1. To a 250 mL round bottom flask containing 6-(3-fluorophenyl)pyridine-3-carboxylic acid (see Example 3, Step A)(2.01 g, 9.25 mmol ) in DMA (35 mL) was added EDAC/EDC*HCl(1.95 g, 10.2 mmol), HOBt (1.38 g, 10.2 mmol), 1-(2,2,2-trifluoroethyl)piperidin-4-amine (1.85 g, 10.2 mmol) and NMM (2.23 mL, 20.4). After stirring at room temperature for 2 hours the reaction mixture was diluted with water (100 mL) and the resulting solid filtered and dried to give the desired product (2.96 g). LCMS (ES+) 4.55 min (TIC, 90%; 1H NMR purity &gt;95%); 1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.60 (dq, J=11.84, 3.48 Hz, 2 H) 1.81 (d, J=10.62 Hz, 2H) 2.44 (t, J=11.16 Hz, 2H) 2.50 (br. s., 2H) 2.94 (d, J=11.53 Hz, 2H) 3.74-3.87 (m, 1H) 7.32 (dt, J=8.37, 2.29 Hz, 1H) 7.57 (q, 1H) 7.96 (d, J=10.43 Hz, 1H) 8.01 (d, J=7.69 Hz, 1H) 8.14 (d, J=8.24 Hz, 1H) 8.28 (dd, J=8.24, 2.20 Hz, 1H) 8.49 (d, J=7.50 Hz, 1H) 9.07 (d, J=1.83 Hz, 1H); MS(ES+) 382 (M+1); HRMS (TOF, ES+) calculated for C 19 H 19 F 4 N 3 O+H + : 382.1542; observed 382.1548. 
     EXAMPLE 3 
     6-(3-Fluorophenyl)-N-{1-[5-(morpholin-4-ylcarbonyl)pyridin-2-yl]piperidin-4-yl}nicotinamide 
     
       
         
         
             
             
         
       
     
     Step A: 6-(3-fluorophenyl)nicotinic acid 
     3-Fluorophenylboronic acid (39.5 g, 0.282 mol), a solution of K 2 CO 3  (150 g) in water (700 mL), [Bu 4 N]Br (3.5 g, 0.0107 mol), and Pd(PPh 3 ) 4  (12.4 g, 0.0107 mol) were added to a solution of 6-chloronicotinic acid (37.0 g, 0.235 mol) in toluene. The reaction mixture was stirred under reflux for 20 h. After cooling, the reaction mixture was filtered and acidified with 2 M HCl to pH 3. The formed precipitate was separated by filtration and dried to give 6-(3-fluorophenyl)nicotinic acid (49.9 g).  1 H NMR (400 MHz, DMSO-d 6 ) δppm 7.29 (td, J=8.46, 2.42 Hz, 1H) 7.50-7.56 (m, 1H) 7.93 (dd, J=10.47, 2.15 Hz, 1 H) 7.97 (d, J=7.79 Hz, 1 H) 8.11 (d, J=8.06 Hz, 1H) 8.30 (dd, J=8.32, 2.15 Hz, 1H) 9.11 (d, J=1.88 Hz, 1 H), 13.48 (bs, 1H). 
     Step B: tert-Butyl 4-(2-(3-fluorophenyl)nicotinamido)piperidine-1-carboxylate 
     1-Boc-4-aminopiperidine hydrochloride (55.9 g, 0.230 mol, 1.18 HCl), (benzotriaxol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 112 g, 0.253 mol), and N, N-diisopropylethylamine (DIPEA, 140 mL, 0.805 mol) were added to a solution of 6-(3-fluorophenyl)nicotinic acid (49.9 g, 0.230 mol) in dichloromethane (1 L). The reaction mixture was stirred at room temperature for 18 h, evaporated, and chromatographed (silica gel, ethyl acetate-hexane, 2:1). The appropriate fractions were collected and evaporated to give tert-butyl 4-(2-(3-fluorophenyl)nicotinamido)piperidine-1-carboxylate (56.4 g). MS(ES+)=400 (M+1). 
     Step C: 6-(3-Fluorophenyl)-N-(piperidin-4-yl)nicotinamide 
     4 M HCl in dioxane (400 mL) was added to a solution of tert-butyl 4-(2-(3-fluorophenyl)nicotinamido)piperidine-1-carboxylate (56.4 g, 0.14 mol) in dioxane (100 mL). The reaction mixture was stirred at room temperature for 4 h. The formed precipitate was separated by filtration, washed with ether, and dried to give 6-(3-fluorophenyl)-N-(piperidin-4-yl)nicotinamide (52 g as the HCl salt).  1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 1.77-1.93 (m, 2H) 1.93-2.06 (m, 2H) 2.91-3.12 (m, 2H) 3.31 (d, J=12.89 Hz, 2H) 4.02-4.18 (m, 1H) 7.26-7.40 (m, 1H) 7.50-7.64 (m, 1H) 7.91-8.09 (m, 2 H) 8.17 (d, J=8.59 Hz, 1H) 8.40 (dd, J=8.32, 2.15 Hz, 1H) 8.87 (d, J=7.52 Hz, 1 H) 9.13 (d, J=1.61 Hz, 2 H); HRMS (TOF, ES+) calculated for C 17 H 19 FN 3 O+H + : 300.1507; observed 300.1538. 
     Step D: 6-(3-Fluorophenyl)-N-{1-[5-(morpholin-4-ylcarbonyl)pyridin-2-yl]piperidin-4-yl}nicotinamide 
     To a vial containing CsF (684 mg, 4.50 mmol) and 1-methyl-2-pyrrolidinone (NMP, 2 mL) was added 6-(3-fluorophenyl)-N-(piperidin-4-yl)nicotinamide hydrochloride (247 mg) and (6-chloropyridin-3-yl)(morpholino)methanone (170 mg, 0.750 mmol). The reaction mixture was heated to 96° C. for 24 hrs. After allowing the reaction to cool to room temperature the reaction was diluted with H 2 O (3 mL) and the mixture extracted with ethyl acetate (3×10 mL). The organics were combined, dried (MgSO 4 ) and the solvent removed to give an oil, which after chromatography (silica, 5% MeOH: DCM) gave 6-(3-fluorophenyl)-N-{1-[5-(morpholin-4-ylcarbonyl)pyridin-2-yl]piperidin-4-yl}nicotinamide (55 mg).  1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.09 (1H, s), 8.53 (1H, d, J=7.7 Hz), 8.30 (1H, dd, J=8.4, 1.6 Hz), 8.23 (2 H, d, J=11.9 Hz), 8.15 (1H, d, J=8.4 Hz), 8.02 (1H, d, J=7.9 Hz), 7.98 (1H, br. s.), 7.53-7.61 (1H, m), 7.26-7.37 (1H, m), 5.02 (1H, br. s.), 4.45 (1H, br. s.), 4.24 (1H, br. s.), 3.86 (1H, br. s.) 3.73 (1H, br. s.), 3.30 (3H, br. s.), 1.87-2.05 (5H, m), 1.61 (2H, br. s.), 0.75 (3H, t, J=7.3 Hz) 
     EXAMPLE 3a 
     N-(1-Methylpiperidin-4-yl)-6-phenylnicotinamide 
     
       
         
         
             
             
         
       
     
     A total of 25.3 mg (86%) was obtained after chromatography: LCMS (ES+) 2.84 min (TIC, 100%); 1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.49-1.71 (m, 2H) 1.81 (d, J=10.62 Hz, 2H) 2.21 (t, J=11.35 Hz, 2H) 2.27 (s, 3H) 2.89 (d, J=11.16 Hz, 2H) 3.79 (br. s., 1H) 7.38-7.56 (m, 3H) 8.02 (d, J=8.24 Hz, 1H) 8.10 (d, J=6.77 Hz, 2H) 8.22 (d, J=6.04 Hz, 1H) 8.42 (d, J=6.77 Hz, 1H) 9.03 (s, 1H); MS(ES+) 296 (M+1); HRMS (TOF, ES+) calculated for C 18 H 21 N 3 O+H + : 296.1763; observed 296.1758. 
     The following table lists compounds of Formula (III) that have been prepared. 
     
       
         
           
               
               
            
               
                   
               
               
                   
                 (III) 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 MS 
                 MS 
               
               
                   
                   
                   
                 Calc 
                 Obs 
               
               
                 Ex 
                 Q 
                 Name 
                 (M + H) 
                 (M + H) 
               
               
                   
               
               
                 3b 
                 CO 2 Et 
                 Ethyl 4-{[(6-phenylpyridin-3- 
                 354.1818 
                 354.1830 
               
               
                   
                   
                 yl)carbonyl]amino}piperidine-1-carboxylate 
               
               
                 4 
                 iPr 
                 N-(1-Isopropylpiperidin-4-yl)-6- 
                 324.2076 
                 324.2108 
               
               
                   
                   
                 phenylnicotinamide 
               
               
                   
               
               
                 5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-Phenyl-N-[1-(pyridin-2-ylmethyl)piperidin-4- yl]nicotinamide 
                 373.2028 
                 373.1919 
               
               
                   
               
               
                 6 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-Phenyl-N-[1-(tetrahydro-2H-pyran-4- ylmethyl)piperidin-4-yl]nicotinamide 
                 380.2338 
                 380.2363 
               
               
                   
               
               
                 7 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2,2-Dimethylpropanoyl)piperidin-4-yl]-6- phenylnicotinamide 
                 366.2181 
                 366.2227 
               
               
                   
               
               
                 8 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-Benzylpiperidin-4-yl)-6-phenylnicotinamide 
                 372.2076 
                 372.2028 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 9 
     6-(4-Fluorophenyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)nicotinamide 
     
       
         
         
             
             
         
       
     
     A total of 14.7 mg (39%) was obtained after chromatography: LCMS (ES+) 4.47 min (TIC, 100%); 1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.52-1.70 (m, 2H) 1.81 (d, J=11.71 Hz, 2H) 2.33-2.61 (m, 4H) 2.94 (d, J=11.35 Hz, 2H) 3.80 (br. s., 1H) 7.34 (t, J=8.69 Hz, 2H) 8.06 (d, J=8.24 Hz, 1H) 8.14-8.33 (m, 3H) 8.42 (d, J=7.14 Hz, 1H) 9.05 (br. s., 1H); MS(ES+) 382 (M+1); HRMS (TOF, ES+) calculated for C 19 H 19 F 4 N 3 O+H + : 382.1542; observed 382.1529. 
     The following table lists compounds of formula (IV) that have been prepared. 
     
       
         
           
               
               
            
               
                   
               
               
                   
                 (IV) 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 MS 
                 MS 
               
               
                   
                   
                   
                 calc 
                 obs 
               
               
                 Ex 
                 Q 
                 Name 
                 (M + H) 
                 (M + H) 
               
               
                   
               
               
                 10 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-Butyrylpiperidin-4-yl)-6-(4- fluorophenyl)nicotinamide 
                 370.1931 
                 370.1918 
               
               
                   
               
               
                 11 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(4-Fluorophenyl)-N-[1-(pyridin-2- ylmethyl)piperidin-4-yl]nicotinamide 
                 391.1934 
                 391.1955 
               
               
                   
               
               
                 12 
                 Me 
                 6-(4-Fluorophenyl)-N-(1-methylpiperidin-4- yl)nicotinamide 
                 314.1668 
                 314.1661 
               
               
                   
               
               
                 13 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-Benzylpiperidin-4-yl)-6-(4- fluorophenyl)nicotinamide 
                 390.1982 
                 390.1944 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 14 
     6-(3-Methoxyphenyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)nicotinamide 
     
       
         
         
             
             
         
       
     
     A total of 20.6 mg (52%) was obtained after chromatography: LCMS (ES+) 4.41 min (TIC, 100%); 1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.50-1.72 (m, 2H) 1.82 (d, J=11.35 Hz, 2H) 2.34-2.58 (m, 4H) 2.95 (d, J=10.98 Hz, 2H) 3.85 (br. s., 4H) 7.05 (d, J=6.77 Hz, 1H) 7.43 (t, J=7.87 Hz, 1H) 7.62-7.80 (m, 2H) 8.07 (d, J=8.24 Hz, 1H) 8.25 (d, J=8.42 Hz, 1H) 8.42 (d, J=7.32 Hz, 1H) 9.06 (d, J=1.28 Hz, 1 H); MS(ES+) 394 (M+1); HRMS (TOF, ES+) calculated for C 20 H 22 F 3 N 3 O 2 +H + : 394.1742 observed 394.1742. 
     The following table lists compounds of formula (V) that have been prepared. 
     
       
         
           
               
               
            
               
                   
               
               
                   
                 (V) 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 MS 
                 MS 
               
               
                   
                   
                   
                 Calc 
                 Obs 
               
               
                 Ex 
                 Q 
                 Name 
                 (M + H) 
                 (M + H) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 15 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Methoxyphenyl)-N-[1-(pyridin-2- ylmethyl)piperidin-4-yl]nicotinamide 
                 403.2134 
                 403.2203 
               
               
                   
               
               
                 16 
                 methyl 
                 6-(3-Methoxyphenyl)-N-(1-methylpiperidin-4- 
                 326.1869 
                 326.5 
               
               
                   
                   
                 yl)nicotinamide 
                   
                   
               
               
                 17 
                 benzyl 
                 N-(1-Benzylpiperidin-4-yl)-6-(3- 
                 402.2181 
                 402.2181 
               
               
                   
                   
                 methoxyphenyl)nicotinamide 
                   
                   
               
               
                 18 
                 —CO 2 Et 
                 Ethyl 4-({[6-(3-methoxyphenyl)pyridin-3- 
                 384.1923 
                 384.1911 
               
               
                   
                   
                 yl]carbonyl}amino)piperidine-1-carboxylate 
                   
                   
               
               
                   
               
               
                 19 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-Butyrylpiperidin-4-yl)-6-(3- methoxyphenyl)nicotinamide 
                 382.2130 
                 382.2142 
               
               
                   
               
               
                 20 
                 isopropyl 
                 N-(1-Isopropylpiperidin-4-yl)-6-(3- 
                 354.2181 
                 354.2247 
               
               
                   
                   
                 methoxyphenyl)nicotinamide 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 21 
     6-m-Tolyl-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)nicotinamide 
     
       
         
         
             
             
         
       
     
     A total of 10.1 mg (27%) was obtained after chromatography: LCMS (ES+) 4.64 min (TIC, 100%); 1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.61 (q, J=10.01 Hz, 2H) 1.81 (d, J=10.07 Hz, 2H) 2.41 (s, 3H) 2.43-2.59 (m, 4H) 2.95 (d, J=12.45 Hz, 2H) 3.80 (br. s., 1H) 7.29 (d, J=7.14 Hz, 1 H) 7.40 (t, J=7.50 Hz, 1 H) 7.92 (d, J=8.24 Hz, 1H) 7.97 (br. s., 1H) 8.04 (d, J=8.42 Hz, 1H) 8.25 (d, J=8.05 Hz, 1H) 8.42 (d, J=7.69 Hz, 1H) 9.05 (br. s., 1H); MS(ES+) 378 (M+1); HRMS (TOF, ES+) calculated for C 20 H 22 F 3 N 3 O+H + : 378.1793; observed 378.1783. 
     Using methods similar to the method set out in Example 21, the following compounds of formula (VI) were prepared. 
     
       
         
           
               
               
            
               
                   
               
               
                   
                 (VI) 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 MS 
                 MS 
               
               
                   
                   
                   
                 Calc 
                 Obs 
               
               
                 Ex 
                 Q 
                 Name 
                 (M + H) 
                 (M + H) 
               
               
                   
               
               
                 22 
                 methyl 
                 6-(3-Methylphenyl)-N-(1-methylpiperidin-4- 
                 310.1919 
                 310.1935 
               
               
                   
                   
                 yl)nicotinamide 
                   
                   
               
               
                 23 
                 benzyl 
                 N-(1-Benzylpiperidin-4-yl)-6-(3- 
                 386.2232 
                 386.2117 
               
               
                   
                   
                 methylphenyl)nicotinamide 
                   
                   
               
               
                   
               
               
                 24 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-Butyrylpiperidin-4-yl)-6-(3- methylphenyl)nicotinamide 
                 366.2181 
                 366.2144 
               
               
                   
               
               
                 25 
                 isopropyl 
                 N-(1-Isopropylpiperidin-4-yl)-6-(3- 
                 338.2232 
                 338.2118 
               
               
                   
                   
                 methylphenyl)nicotinamide 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 27 
     6-(3-Fluorophenyl)-N-(1-methylpiperidin-4-yl)nicotinamide 
     
       
         
         
             
             
         
       
     
     A total of 33.2 mg (quant.) was obtained after chromatography: LCMS (ES+) 2.79 min (TIC, 100%); 1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.57-1.72 (m, 2H) 1.85 (d, J=10.62 Hz, 2H) 2.21 (t, J=11.35 Hz, 2 H) 2.30 (s, 3H) 2.92 (d, J=11.71 Hz, 2H) 3.83 (dd, J=11.16, 3.84 Hz, 1H) 7.30-7.37 (m, 1H) 7.54-7.62 (m, 1H) 7.96 (d, J=10.62 Hz, 1H) 8.02 (d, J=8.05 Hz, 1H) 8.14 (d, J=8.24 Hz, 1H) 8.29 (dd, J=8.33, 2.10 Hz, 1H) 8.55 (d, J=7.50 Hz, 1H) 9.08 (d, J=1.83 Hz, 1H); MS(ES+) 314 (M+1); HRMS (TOF, ES+) calculated for C 18 H 20 FN 3 O+H + : 314.1668; observed 314.1696. 
     The following table lists compounds of formula (VII) that have been prepared. 
     
       
         
           
               
               
            
               
                   
               
               
                   
                 (VII) 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 MS 
                 MS 
               
               
                   
                   
                   
                 Calc 
                 Obs 
               
               
                 Ex 
                 Q 
                 Name 
                 (M + H) 
                 (M + H) 
               
               
                   
               
               
                 28 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(pyridin-2- ylmethyl)piperidin-4-yl]nicotinamide 
                 391.1934 
                 391.1889 
               
               
                   
               
               
                 29 
                 benzyl 
                 N-(1-Benzylpiperidin-4-yl)-6-(3- 
                 390.1982 
                 390.1946 
               
               
                   
                   
                 fluorophenyl)nicotinamide 
                   
                   
               
               
                 30 
                 isopropyl 
                 6-(3-Fluorophenyl)-N-(1-isopropylpiperidin-4- 
                 342.1982 
                 342.1932 
               
               
                   
                   
                 yl)nicotinamide 
                   
                   
               
               
                   
               
               
                 31 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-Butyrylpiperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 370.1911 
                 370.1911 
               
               
                   
               
               
                 32 
                 —CO 2 Et 
                 Ethyl 4-({[6-(3-fluorophenyl)pyridin-3- 
                 372.1723 
                 372.1729 
               
               
                   
                   
                 yl]carbonyl}amino)piperidine-1-carboxylate 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 33 
     Ethyl 4-({[6-(3,5-difluorophenyl)pyridin-3-yl]carbonyl}amino)piperidine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of tert-butyl 6-bromonicotinate 
     To a round bottom flask containing 2-bromo-5-pyridinecarboxylic acid (10.0 g, 49 mmol) in DCM (500 mL) was added oxalyl bromide (7.4 mL) and 5 drops of DMF. After some gas evolution, the reaction mixture was stirred at reflux ca 6 h, then cooled to rt and heptane 100 mL was added, followed by concentration of the mixture. The mixture was then suspended in THF 400 mL, cooled to 0° C. t-BuOK (5.8 g, 52 mmol) was then added and the r×n allowed to warm to rt and stirred for 2 h. The mixture poured into EtOAc, washed with 1 N NaOH, water, brine, dried MgSO 4  filtered and concentrated. The residue was purified by silica gel chromatography Biotage 40S Heptane EtOAc 0-80% 3 L to afford the title compound 4.2 g (36%) of as a white solid.  1 H NMR (400 MHz, DMSO-d 6 ) □ ppm 8.78-8.86 (1H, m), 8.14 (1H, dd, J=8.4, 2.4 Hz), 7.81 (1H d, J=8.4 Hz), 1.56 (9H, s). 
     Step B: Preparation of tert-butyl 6-(3,5-difluorophenyl)nicotinate 
     To round-bottom flask was added 3,5-difluoro phenylboronic acid (1.84 g, 11.6 mmol), palladium tetrakis(triphenylphosphine) (89.5 mg, 0.08 mmol) and tert-butyl 6-bromonicotinate (2.0 g, 7.75 mmol) and the mixture was evacuated 3× with N 2 . The solids were dissolved in 50 mL of DMF, followed by addition of 11 mL of 2 M cesium carbonate. The resulting mixture was heated to ˜90° C. until no starting bromide material was apparent by HPLC. The mixture was cooled to rt and then poured into a separatory funnel, followed by addition of EtOAc and water (1×200 mL). The layers were separated and the organic extract washed with brine (1×200 mL), dried MgSO 4 , filtered and concentrated to afford an orange oil. The crude mixture was purified by silica gel column chromatography on Biotage (silica, 2-10% EtOAc in Heptane)-ca 2.5 L to afford the title compound 2.1 g (93%) as white solid.  1 H NMR (400 MHz, DMSO-d6) □ ppm 9.10-9.14 (1H, m), 8.29-8.35 (1H, m), 8.20-8.25 (1H, m), 7.90 (2H, dd, J=9.0, 1.5 Hz), 7.42 (1H, s), 1.59 (9H, s). 
     Step C: Preparation of 6-(3,5-difluoro-phenyl)-nicotinic acid 
     To tert-butyl 6-(3,5-difluorophenyl)nicotinate in DCM (80 mL) was added trifluroacetic acid (20 mL). After stirring at rt overnight, toluene was added (100 mL) and the solvent removed to give the crude product as a white powder. The solid was re-crystallized from MeOH to afford the title compound 1.269 g (74%) as a white solid.  1 H NMR (400 MHz, DMSO-d6) □ ppm 9.16 (1H, d, J=1.7 Hz), 8.37 (1 H, dd, J=8.2, 2.0 Hz), 8.23 (1 H, d, J=8.2 Hz), 7.86-7.95 (2H, m), 7.36-7.47 (1H, m). 
     Step D: Preparation of Ethyl 4-({[6-(3,5-difluorophenyl)pyridin-3-yl]carbonyl}amino)piperidine-1-carboxylate 
     6-(3,5-difluoro-phenyl)-nicotinic acid (55 mg, 0.23 mmol), HOBt (40 mg, 0.29 mmol), ethyl 4-aminopiperidine-1-carboxylate (23 mg, 0.13 mmol), and PS-carbodimide (350 mg) in DCM (5 ml) was shaken 12 h. After shaking, PS-trisamine (3 mg) was added and the reaction shaken for 4 h, then filtered and washed with 15% MeOH/DCM. The organic was concentrated and purified by reversed phase automatic chromatography to provide 8.3 mg (9%) of the title compound.  1 H NMR (400 MHz, DMSO-d6) □ ppm 9.08 (1H, d, J=1.5 Hz), 8.51 (1H, d, J=7.3 Hz), 8.31 (1H, dd, J=8.2, 2.4 Hz), 8.19 (1 h, d, J=8.8 Hz), 7.89 (2H, br. s.), 4.03 (2H, br. s.), 4.05 (4H, d, J=7.3 Hz), 2.94 (2H, br. s.), 1.85 (2H, d, J=13.5 Hz), 1.48 (2H, br. s.), 1.20 (3H, t, J=7.1 Hz). 
     EXAMPLE 34 
     6-(3,5-Difluorophenyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     6-(3,5-Difluoro-phenyl)-nicotinic acid (50 mg, 0.21 mmol), 1-(2,2,2-trifluoroethyl)piperidin-4-amine hydrochloride (48 mg, 0.22 mmol) N,N-diisopropylethylamine (0.296 mL, 1.69 mmol), HATU (101 mg, 0.26 mmol) in acetonitrile (5 mL) was shaken at room temperature for 12 h. The reaction mixture was concentrated and the crude reaction mixture purified by automated reversed phase chromatography to provide 6 mg (7%) of the title compound.  1 H NMR (400 MHz, DMSO-d6) □ ppm 9.08 (1H, s), 8.47 (1H, d, J=7.0 Hz), 8.30 (1H, dd, J=8.4, 2.2 Hz), 8.19 (1H, d, J=8.1 Hz), 7.88 (2H, d, J=7.0 Hz), 7.36 (1H, t, J=10.1 Hz), 3.82 (1H, br. s.), 3.11-3.23 (2H, m), 2.95 (2H, d, J=11.0 Hz), 2.42-2.48 (2H, m), 1.76-1.87 (2H, m), 1.56-1.66 (2H, m). 
     EXAMPLE 35 
     6-(3-Fluorophenyl)-N-(1-(5-methoxy-2-(pyridin-2-yl)pyrimidin-4-yl)piperidin-4-yl)nicotinamide 
     
       
         
         
             
             
         
       
     
     Step A: 6-(3-Fluorophenyl)nicotinic acid 
     3-Fluorophenylboronic acid (39.5 g, 0.282 mol), a solution of K 2 CO 3  (150 g) in water (700 mL), [Bu 4 N]Br (3.5 g, 0.0107 mol), and Pd(PPh 3 ) 4  (12.4 g, 0.0107 mol) were added to a solution of 6-chloronicotinic acid (37.0 g, 0.235 mol) in toluene. The reaction mixture was stirred under reflux for 20 h. After cooling, the reaction mixture was filtered and acidified with 2 M HCl to pH 3. The formed precipitate was separated by filtration and dried to give 6-(3-fluorophenyl)nicotinic acid (yield 97%, 49.9 g).  1 H NMR (400 MHz, DMSO-d 6 ) □ ppm 7.29 (td, J=8.46, 2.42 Hz, 1H) 7.50-7.56 (m, 1H) 7.93 (dd, J=10.47, 2.15 Hz, 1H) 7.97 (d, J=7.79 Hz, 1H) 8.11 (d, J=8.06 Hz, 1H) 8.30 (dd, J=8.32, 2.15 Hz, 1H) 9.11 (d, J=1.88 Hz, 1H), 13.48 (bs, 1H). 
     Step B: tert-Butyl 4-(2-(3-fluorophenyl)nicotinamido)piperidine-1-carboxylate 
     1-Boc-4-aminopiperidine hydrochloride (55.9 g, 0.230 mol, 1.18 HCl), BOP (112 g, 0.253 mol), and DIPEA (140 mL, 0.805 mol) were added to a solution of the compound from Step 1 (49.9 g, 0.230 mol) in dichloromethane (1 L). The reaction mixture was stirred at room temperature for 18 h, evaporated, and chromatographed (silica gel, ethyl acetate-hexane, 2:1). The product was evaporated to give tert-butyl 4-(2-(3-fluorophenyl)nicotinamido)piperidine-1-carboxylate (yield 61%, 56.4 g). MS(ES+)=400 (M+H) observed, 400.20 expected. 
     Step C: 6-(3-Fluorophenyl)-N-(piperidin-4-yl)nicotinamide 
     4 M HCl in dioxane (400 mL) was added to a solution of the compound of Step 2 (56.4 g, 0.14 mol) in dioxane (100 mL). The reaction mixture was stirred at room temperature for 4 h. The formed precipitate was separated by filtration, washed with ether, and dried to give 6-(3-fluorophenyl)-N-(piperidin-4-yl)nicotinamide as an HCl salt (quantitative yield, 52 g).  1 H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.77-1.93 (m, 2H) 1.93-2.06 (m, 2H) 2.91-3.12 (m, 2H) 3.31 (d, J=12.89 Hz, 2H) 4.02-4.18 (m, 1H) 7.26-7.40 (m, 1H) 7.50-7.64 (m, 1H) 7.91-8.09 (m, 2H) 8.17 (d, J=8.59 Hz, 1H) 8.40 (dd, J=8.32, 2.15 Hz, 1H) 8.87 (d, J=7.52 Hz, 1H) 9.13 (d, J=1.61 Hz, 2H); HRMS (TOF, ES+) calculated for C17H19FN30+H + : 300.1507; observed 300.1538. 
     Step D: 6-(3-Fluorophenyl)-N-(1-(5-methoxy-2-(pyridin-2-yl)pyrimidin-4-yl)piperidin-4-yl)nicotinamide 
     To a vial containing CsF (60-85 mgs, 5-7 eqs) was added (0.2 mL, 0.08 mmol) of a solution of 4-chloro-5-methoxy-2-phenylpyrimidine in DMF followed by addition of (0.22 mL, 0.088 mmol) of 6-(3-fluorophenyl)-N-(piperidin-4-yl)nicotinamide-HCl salt in DMF and triethylamine (2-3 eq). The reaction mixture was heated to 85-90° C. for 24 hrs and then allowed to cool to room temperature. The crude reaction mixture was then filtered and purified by RP-HPLC to give the desired product.  1 H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.63-1.73 (m, 2H) 1.96 (d, J=10.25 Hz, 2H) 3.11-3.19 (m, 2H) 3.94 (s, 3 H) 4.18 (d, J=7.69 Hz, 1H) 4.64 (d, J=12.81 Hz, 2H) 7.31 (td, J=8.33, 2.38 Hz, 1H) 7.43 (d, J=5.12 Hz, 1 H) 7.53-7.59 (m, 1H) 7.87-7.97 (m, 2H) 8.00 (d, J=7.69 Hz, 1H) 8.12 (d, J=8.42 Hz, 1H) 8.20 (s, 1H) 8.26 (d, J=8.05 Hz, 1H) 8.29 (dd, J=8.42, 1.83 Hz, 1H) 8.50 (d, J=7.69 Hz, 1H) 8.68 (d, J=4.39 Hz, 1H) 9.08 (s, 1H); LC/MS(ES+)=485.5 observed, 485.21 expected. 
     EXAMPLE 36 
     6-(3-Fluorophenyl)-N-(piperidin-4-yl)nicotinamide 
     See under Example 35, step 3. 
     Using techniques analogous to Example 35 the following compounds of Formula (VII) may be prepared. 
     
       
         
         
             
             
         
       
     
     EXAMPLE 37 
     N-(1-(6-(1H-Pyrazol-3-ylamino)pyrimidin-4-yl)piperidin-4-yl)-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     NMR: 1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.49-1.59 (m, 2H) 1.90 (br. s., 2H) 3.01 (d, J=15.37 Hz, 2 H) 4.15 (br. s., 1H) 4.26 (d, J=12.45 Hz, 3H) 6.16 (br. s., 1H) 6.78 (br. s., 1H) 7.31 (d, J=2.20 Hz, 1H) 7.53-7.60 (m, 2H) 7.95 (d, J=10.98 Hz, 1H) 8.00 (d, J=8.05 Hz, 1H) 8.14 (d, J=4.39 Hz, 1H) 8.11 (s, 1 H) 8.29 (dd, J=8.24, 2.01 Hz, 1H) 8.49 (d, J=7.32 Hz, 1H) 9.08 (d, J=1.46 Hz, 1H) 9.17 (br. s., 1H). 
     MS calc (M+H) 459.2; MS obs (M+H) 459.5. 
     EXAMPLE 38 
     N-(1-(6-Chloroquinazolin-4-yl)piperidin-4-yl)-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.68-1.87 (m, 2H) 2.01 (d, J=2.93 Hz, 2H) 3.41 (t, 2H) 4.22 (br. s., 1H) 4.32 (d, J=13.18 Hz, 2H) 7.24-7.37 (m, 1H) 7.50-7.64 (m, 1H) 7.84 (s, 2H) 7.92-7.99 (m, 2 H) 8.01 (d, J=7.32 Hz, 1H) 8.14 (d, J=8.42 Hz, 1H) 8.31 (dd, J=8.24, 2.01 Hz, 1H) 8.57 (d, J=7.32 Hz, 1 H) 8.65 (s, 1H) 9.10 (s, 1H). 
     MS calc (M+H) 462.14; MS obs (M+H) 462.5. 
     EXAMPLE 39 
     6-(3-Fluorophenyl)-N-(1-(1-phenyl-1H-tetrazol-5-yl)piperidin-4-yl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.57-1.73 (m, 2H) 1.83 (d, J=10.62 Hz, 2H) 3.06 (t, J=11.35 Hz, 2H) 3.50 (d, J=13.18 Hz, 2H) 4.04 (d, J=6.95 Hz, 1H) 7.52-7.59 (m, 2H) 7.59-7.72 (m, 5H) 7.95 (d, J=10.62 Hz, 1H) 8.00 (d, J=7.69 Hz, 1H) 8.12 (d, J=8.42 Hz, 1H) 8.28 (dd, J=8.60, 2.01 Hz, 1H) 8.51 (d, J=7.32 Hz, 1H) 9.07 (s, 1H). 
     MS calc (M+H) 444.19; MS obs (M+H) 444.8. 
     EXAMPLE 40 
     6-(3-Fluorophenyl)-N-(1-(9-(2-hydroxycyclopentyl)-9H-purin-6-yl)piperidin-4-yl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.50-1.68 (m, 4H) 1.75-1.90 (m, 2H) 1.93-2.11 (m, 5H) 2.31-2.26 (m, 1H) 4.17-4.29 (m, 1H) 4.43-4.52 (m, 1H) 4.55 (d, J=7.69 Hz, 1H) 5.13 (d, J=5.12 Hz, 1H) 5.33 (br. s., 2H) 7.23-7.37 (m, 1H) 7.49-7.64 (m, 1H) 7.93 (d, 1H) 8.00 (d, J=7.69 Hz, 1H) 8.12 (d, J=8.42 Hz, 1H) 8.18-8.26 (m, 2H) 8.29 (dd, J=8.42, 2.20 Hz, 1H) 8.49 (d, J=7.32 Hz, 1H) 9.08 (d, J=1.83 Hz, 1H). 
     MS calc (M+H) 502.23; MS obs (M+H) 502.6. 
     EXAMPLE 40 
     N-[1-(3-Cyano-6-methylpyridin-2-yl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.62-1.78 (m, 2H) 1.96 (br. s., 2H) 2.41 (s, 3H) 3.09-3.21 (m, 2 H) 4.15 (br. s., 1H) 4.28 (d, J=13.54 Hz, 2H) 6.78 (d, J=7.69 Hz, 1H) 7.24-7.37 (m, 1H) 7.50-7.65 (m, 1H) 7.87-7.98 (m, 2H) 8.01 (d, J=7.69 Hz, 1H) 8.13 (d, J=8.42 Hz, 1H) 8.31 (dd, J=8.24, 2.01 Hz, 1H) 8.54 (d, J=7.69 Hz, 1H) 9.10 (s, 1H). 
     MS calc (M+H) 416.18; MS obs (M+H) 416.5. 
     EXAMPLE 42 
     6-(3-Fluorophenyl)-N-[1-(3-phenylpyrazin-2-yl)piperidin-4-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.53-1.69 (m, 2H) 1.78 (br. s., 2H) 2.81 (t, J=11.53 Hz, 2H) 3.62 (d, J=12.81 Hz, 2H) 3.98 (br. s., 1H) 7.24-7.36 (m, 1H) 7.39-7.47 (m, 1H) 7.50 (t, J=7.32 Hz, 2H) 7.53-7.61 (m, 1H) 7.84-7.98 (m, 3H) 8.01 (d, J=7.69 Hz, 1H) 8.12 (d, J=8.42 Hz, 1H) 8.15-8.21 (m, 2H) 8.29 (dd, J=8.42, 2.20 Hz, 1H) 8.52 (d, J=7.69 Hz, 1H) 9.08 (d, J=1.83 Hz, 1H). 
     MS calc (M+H) 454.2; MS obs (M+H) 454.5. 
     EXAMPLE 43 
     6-(3-Fluorophenyl)-N-(1-{3-[(2-hydroxyethyl)amino]quinoxalin-2-yl}piperidin-4-yl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.79-1.95 (m, 2H) 2.02 (d, J=10.98 Hz, 2H) 2.91-3.04 (m, 2H) 3.56 (q, J=5.73 Hz, 2H) 3.66 (t, J=5.49 Hz, 2H) 3.69-3.78 (m, 2H) 4.08 (d, J=7.32 Hz, 1H) 4.78-4.89 (m, 1H) 6.38 (t, J=5.49 Hz, 1H) 7.22-7.35 (m, 2H) 7.38 (t, J=6.95 Hz, 1H) 7.49-7.55 (m, 1H) 7.59 (dd, J=12.99, 6.77 Hz, 2H) 7.96 (d, J=10.62 Hz, 1H) 8.01 (d, J=8.05 Hz, 1H) 8.13 (d, J=8.42 Hz, 1H) 8.32 (dd, J=8.42, 2.20 Hz, 1H) 8.61 (d, J=7.32 Hz, 1H) 9.11 (d, J=1.83 Hz, 1 H). 
     MS calc (M+H) 487.22; MS obs (M+H) 487.5. 
     EXAMPLE 44 
     N-{1-[5-(3,4-Dimethoxyphenyl)-2-methylpyrimidin-4-yl]piperidin-4-yl}-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.46-1.63 (m, 2H) 1.79 (br. s., 2H) 2.58 (s, 3H) 2.87 (t, J=11.71 Hz, 2H) 3.84 (d, J=8.79 Hz, 6H) 3.90 (d, J=12.81 Hz, 2H) 4.06 (br. s., 1H) 6.98-7.12 (m, 3H) 7.30-7.41 (m, 1H) 7.53-7.66 (m, 1H) 7.97 (br. s., 1H) 8.04 (d, J=7.69 Hz, 1H) 8.10 (s, 1H) 8.15 (d, J=8.42 Hz, 1H) 8.31 (dd, J=8.24, 2.01 Hz, 1H) 8.51 (d, J=7.69 Hz, 1H) 9.10 (d, J=1.46 Hz, 1H). 
     MS calc (M+H) 528.23; MS obs (M+H) 528.5. 
     EXAMPLE 45 
     N-[1-(2-Amino-6-methylpyrimidin-4-yl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.48 (d, J=12.08 Hz, 2H) 1.86 (d, J=10.62 Hz, 2H) 2.08 (s, 3H) 2.87-3.01 (m, 2H) 4.10 (br. s., 1H) 4.29 (br. s., 2H) 5.83 (s, 2H) 5.97 (s, 1H) 7.24-7.38 (m, 1H) 7.50-7.64 (m, 1H) 7.95 (d, J=10.62 Hz, 1H) 8.00 (d, J=7.69 Hz, 1H) 8.12 (d, J=8.42 Hz, 1H) 8.29 (dd, J=8.24, 2.01 Hz, 1H) 8.47 (d, J=7.69 Hz, 1H) 9.08 (d, J=1.83 Hz, 1H). 
     MS calc (M+H) 407.19; MS obs (M+H) 407.5. 
     EXAMPLE 46 
     N-{1-[5,6-Dimethyl-2-(trifluoromethyl)pyrimidin-4-yl]piperidin-4-yl}-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.60-1.77 (m, 2H) 1.96 (d, J=9.88 Hz, 2H) 2.21 (s, 3H) 2.42 (s, 3H) 3.10 (t, J=12.08 Hz, 2H) 3.89 (d, J=13.18 Hz, 2H) 4.05-4.21 (m, 1H) 7.24-7.37 (m, 1H) 7.50-7.61 (m, 1H) 7.95 (d, J=10.98 Hz, 1H) 8.01 (d, J=7.69 Hz, 1H) 8.13 (d, J=8.42 Hz, 1H) 8.31 (dd, J=8.42, 1.83 Hz, 1H) 8.54 (d, J=7.69 Hz, 1H) 9.09 (s, 1H). 
     MS calc (M+H) 474.18; MS obs (M+H) 474.6. 
     EXAMPLE 47 
     6-(3-Fluorophenyl)-N-(1-{4-[2-(5-methylisoxazol-3-yl)pyrrolidin-1-yl]pyrimidin-2-yl}piperidin-4-yl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.44 (br. s., 1H) 1.78 (br. s., 2H) 1.97 (d, J=5.86 s., 2H) 2.32 (s, 4H) 2.89 (br. s., 2H) 3.47 (br. s., 1H) 3.61 (br. s., 1H) 4.08 (br. s., 1H) 4.52 (br. s., 2H) 5.14 (br. s., 1H) 5.78 (br. s., 1H) 6.07 (br. s., 1H) 7.23-7.39 (m, 1H) 7.49-7.64 (m, 1H) 7.84 (d, J=6.22 Hz, 1H) 7.95 (d, J=10.62 Hz, 1H) 8.00 (d, J=8.05 Hz, 1H) 8.12 (d, J=8.42 Hz, 1H) 8.28 (dd, J=8.05, 1.83 Hz, 1H) 8.42 (d, J=7.69 Hz, 1H) 9.07 (s, 1H). 
     MS calc (M+H) 528.24; MS obs (M+H) 528.8. 
     EXAMPLE 48 
     N-[1-(5-Chloro-6-methyl-2-pyridin-2-ylpyrimidin-4-yl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.77 (br. s., 2H) 1.99 (br. s., 2H) 2.57 (s, 3H) 3.15-3.23 (m, 2H) 4.17 (br. s., 1H) 4.35 (d, J=13.18 Hz, 2H) 7.26-7.37 (m, 1H) 7.49 (dd, J=7.14, 4.94 Hz, 1H) 7.53-7.63 (m, 1H) 7.89-7.98 (m, 2H) 8.01 (d, J=7.69 Hz, 1H) 8.13 (d, J=8.05 Hz, 1H) 8.25-8.37 (m, 2H) 8.55 (d, J=7.69 Hz, 1H) 8.72 (d, J=4.39 Hz, 1H) 9.10 (s, 1H). 
     MS calc (M+H) 503.17; MS obs (M+H) 503.5. 
     EXAMPLE 49 
     6-(3-Fluorophenyl)-N-[1-(6-methoxypyrimidin-4-yl)piperidin-4-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.41-1.59 (m, 2H) 1.89 (br. s., 2H) 3.00-3.11 (m, 2H) 3.83 (s, 3 H) 4.15 (br. s., 1H) 4.34 (d, J=13.18 Hz, 2H) 6.12 (s, 1H) 7.25-7.37 (m, 1H) 7.51-7.63 (m, 1H) 7.95 (d, J=10.62 Hz, 1H) 8.01 (d, J=7.69 Hz, 1H) 8.12 (d, J=8.05 Hz, 1H) 8.23-8.33 (m, 2H) 8.47 (d, J=7.69 Hz, 1H) 9.08 (d, J=1.83 Hz, 1H). 
     MS calc (M+H) 408.18; MS obs (M+H) 408.5. 
     EXAMPLE 50 
     6-(3-Fluorophenyl)-N-{1-[5-(morpholin-4-ylcarbonyl)pyridin-2-yl]piperidin-4-yl}nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 9.08 (1H, d, J=2.4 Hz), 8.53 (1H, d, J=7.9 Hz), 8.29 (1H, dd, J=8.4, 2.2 Hz), 8.22 (1H, d, J=2.4 Hz), 8.14 (1H, d, J=8.5 Hz), 7.90-8.07 (2H, m) 7.50-7.65 (2H, m), 7.25-7.39 (1H, m), 6.91 (1H, d, J=8.9 Hz), 4.30-4.47 (2H, m), 4.04-4.26 (1H, m) 3.44-3.67 (8H, m), 2.97-3.14 (2H, m), 1.90 (2H, dd, J=13.1, 2.6 Hz), 1.45-1.62 (2H, m). 
     MS calc (M+H) 490.22; MS obs (M+H) 490.5. 
     EXAMPLE 51 
     6-(3-Fluorophenyl)-N-[1-(1-methyl-1H-tetrazol-5-yl)piperidin-4-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) F ppm 9.10 (1H, d, J=1.6 Hz), 8.61 (1H, d, J=7.4 Hz), 8.27-8.36 (1H, m), 8.15 (1H, d, J=8.2 Hz), 7.91-8.08 (2H, m), 7.51-7.64 (1H, m), 7.24-7.38 (1H, m), 4.02-4.20 (1 H, m), 3.85-3.92 (3H, m), 3.60-3.74 (2H, m), 3.07-3.22 (2H, m), 1.87-2.01 (2H, m), 1.67-1.85 (2 H, m). 
     MS calc (M+H) 382.17; MS obs (M+H) 382.4. 
     
       
         
           
               
               
               
               
               
             
               
                   
               
               
                   
                   
                   
                 MS 
                 MS 
               
               
                   
                   
                   
                 Calc 
                 Obs 
               
               
                 Ex 
                 Q 
                 Name 
                 (M + H) 
                 (M + H) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 52 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(7-methoxyquinazolin- 4-yl)piperidin-4-yl]nicotinamide 
                 458.2 
                 458.5 
               
               
                   
               
               
                 53 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[6-(pyridin-2- ylmethoxy)pyrimidin-4-yl]piperidin-4- yl}nicotinamide 
                 485.2 
                 485.5 
               
               
                   
               
               
                 54 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{6-[(1-methyl-1H- imidazol-2-yl)methoxy]pyrimidin-4-yl}piperidin-4- yl)nicotinamide 
                 488.2 
                 488.6 
               
               
                   
               
               
                 55 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[6-(3,4-Dimethoxyphenyl)pyrimidin-4- yl]piperidin-4-yl}-6-(3-fluorophenyl)nicotinamide 
                 514.2 
                 514.7 
               
               
                   
               
               
                 56 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[4-(1-methyl-1H- pyrazol-5-yl)quinazolin-2-yl]piperidin-4- yl}nicotinamide 
                 508.2 
                 508.1 
               
               
                   
               
               
                 57 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(9-Ethyl-9H-purin-6-yl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 446.2 
                 446.6 
               
               
                   
               
               
                 58 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[2-(3,4-Dihydroisoquinolin-2(1H)- yl)pyrimidin-4-yl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 509.2 
                 509.6 
               
               
                   
               
               
                 59 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{4-[(pyridin-2- ylmethyl)amino]pyrimidin-2-yl}piperidin-4- yl)nicotinamide 
                 484.2 
                 484.5 
               
               
                   
               
               
                 60 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-pyrazin-2-ylpiperidin-4- yl)nicotinamide 
                 378.2 
                 378.3 
               
               
                   
               
               
                 61 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-phthalazin-1- ylpiperidin-4-yl)nicotinamide 
                 428.2 
                 428.4 
               
               
                   
               
               
                 62 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[4-(1-methyl-1H- imidazol-2-yl)quinazolin-2-yl]piperidin-4- yl}nicotinamide 
                 508.2 
                 508.5 
               
               
                   
               
               
                 63 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-pyrido[2,3-d]pyrimidin- 4-ylpiperidin-4-yl)nicotinamide 
                 429.2 
                 429.4 
               
               
                   
               
               
                 64 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[3-(Aminocarbonyl)pyridin-2-yl]piperidin-4- yl}-6-(3-fluorophenyl)nicotinamide 
                 420.2 
                 420.5 
               
               
                   
               
               
                 65 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3-Ahloropyridin-2-yl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 411.1 
                 411.5 
               
               
                   
               
               
                 66 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Ethyl 2-[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]nicotinate 
                 449.2 
                 449.5 
               
               
                   
               
               
                 67 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3-Cyano-4-methoxypyridin-2-yl)piperidin- 4-yl]-6-(3-fluorophenyl)nicotinamide 
                 432.2 
                 432.5 
               
               
                   
               
               
                 68 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[5-(Aminocarbonyl)pyridin-2-yl]piperidin-4- yl}-6-(3-fluorophenyl)nicotinamide 
                 420.2 
                 420.5 
               
               
                   
               
               
                 69 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3-Cyano-46-dimethylpyridin-2-yl)piperidin- 4-yl]-6-(3-fluorophenyl)nicotinamide 
                 430.2 
                 430.5 
               
               
                   
               
               
                 70 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[3-Cyano-6-(trifluoromethyl)pyridin-2- yl]piperidin-4-yl}-6-(3-fluorophenyl)nicotinamide 
                 470.2 
                 470.6 
               
               
                   
               
               
                 71 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(7-methylthieno[3,2- d]pyrimidin-4-yl)piperidin-4-yl]nicotinamide 
                 448.2 
                 448.5 
               
               
                   
               
               
                 72 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(2,3-Dihydro-1H-inden-2-yl)-2-[4-({[6-(3- fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]nicotinamide 
                 536.2 
                 536.5 
               
               
                   
               
               
                 73 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[6-(methoxymethyl)-2- (2-methyl-13-thiazol-4-yl)pyrimidin-4- yl]piperidin-4-yl}nicotinamide 
                 519.2 
                 519.5 
               
               
                   
               
               
                 74 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[3-(pyridin-2- ylcarbonyl)pyridin-2-yl]piperidin-4- yl}nicotinamide 
                 482.2 
                 482.5 
               
               
                   
               
               
                 75 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[3-(1,3-thiazol-2- ylcarbonyl)pyridin-2-yl]piperidin-4- yl}nicotinamide 
                 488.2 
                 488.5 
               
               
                   
               
               
                 76 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(5-Acetyl-3-cyano-6-methylpyridin-2- yl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide 
                 458.2 
                 458.4 
               
               
                   
               
               
                 77 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[3-(2-Cyanobenzoyl)pyridin-2-yl]piperidin- 4-yl}-6-(3-fluorophenyl)nicotinamide 
                 506.2 
                 506.5 
               
               
                   
               
               
                 78 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Methyl 2-amino-4-[4-({[6-(3-fluorophenyl) pyridin-3-yl]carbonyl}amino)piperidin-1- yl]pyrimidine-5-carboxylate 
                 451.2 
                 451.5 
               
               
                   
               
               
                 79 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3-Benzylpyrazin-2-yl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 468.2 
                 468.6 
               
               
                   
               
               
                 80 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-[4-({[6-(3-Fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-N- methylpyridazine-3-carboxamide 
                 435.2 
                 435.5 
               
               
                   
               
               
                 81 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[(1-Ethylpyrrolidin-2-yl)methyl]-6-[4-({[6-(3- fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]pyridazine-3- carboxamide 
                 532.3 
                 532.5 
               
               
                   
               
               
                 82 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-[4-({[6-(3-Fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-N-methyl-N- propylpyridazine-3-carboxamide 
                 477.2 
                 477.5 
               
               
                   
               
               
                 83 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-Ethyl-6-[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]pyridazine-3- carboxamide 
                 449.2 
                 449.5 
               
               
                   
               
               
                 84 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-[4-({[6-(3-Fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-N-(2- morpholin-4-ylethyl)pyridazine-3-carboxamide 
                 534.3 
                 534.7 
               
               
                   
               
               
                 85 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-[4-({[6-(3-Fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-N-isoxazol-3- ylpyridazine-3-carboxamide 
                 488.2 
                 488.5 
               
               
                   
               
               
                 86 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(3,4-Dimethylisoxazol-5-yl)-6-[4-({[6-(3- fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]pyridazine-3- carboxamide 
                 516.2 
                 516.5 
               
               
                   
               
               
                 87 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{6-[(4-Ethylpiperazin-1- yl)carbonyl]pyridazin-3-yl}piperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 518.3 
                 518.7 
               
               
                   
               
               
                 88 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(2-Ethoxyethyl)-6-[4-({[6-(3- fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]pyridazine-3- carboxamide 
                 493.2 
                 493.6 
               
               
                   
               
               
                 89 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-[4-({[6-(3-Fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-N-(1,3,5- trimethyl-1H-pyrazol-4-yl)pyridazine-3- carboxamide 
                 529.2 
                 529.7 
               
               
                   
               
               
                 90 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{9-[1- (hydroxymethyl)propyl]-9H-purin-6-yl}piperidin- 4-yl)nicotinamide 
                 490.2 
                 490.6 
               
               
                   
               
               
                 91 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(5-methoxy-13- benzoxazol-2-yl)piperidin-4-yl]nicotinamide 
                 447.2 
                 447.5 
               
               
                   
               
               
                 92 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[1-(2,3-Dihydro-1H-inden-5-yl)-1H-tetrazol  5-yl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 484.2 
                 484.5 
               
               
                   
               
               
                 93 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[8-(1,1-Dimethylbut-3-en-1-yl)-9-methyl- 9H-purin-6-yl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 514.3 
                 514.8 
               
               
                   
               
               
                 94 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[1-(2-fluorophenyl)-1H- tetrazol-5-yl]piperidin-4-yl}nicotinamide 
                 462.2 
                 461.5 
               
               
                   
               
               
                 95 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[1-(4-methylphenyl)-1H- tetrazol-5-yl]piperidin-4-yl}nicotinamide 
                 458.2 
                 458.4 
               
               
                   
               
               
                 96 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[1-(2-methoxybenzyl)- 1H-tetrazol-5-yl]piperidin-4-yl}nicotinamide 
                 488.2 
                 488.6 
               
               
                   
               
               
                 97 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(1-isopropyl-1H- tetrazol-5-yl)piperidin-4-yl]nicotinamide 
                 410.2 
                 410.5 
               
               
                   
               
               
                 98 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Ethyl 3-{5-[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-1H-tetrazol-1- yl}benzoate 
                 516.2 
                 516.8 
               
               
                   
               
               
                 99 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[1-(Cyclopropylmethyl)-1H-tetrazol-5- yl]piperidin-4-yl}-6-(3-fluorophenyl)nicotinamide 
                 422.2 
                 422.5 
               
               
                   
               
               
                 100 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Isopropyl {5-[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-1H-tetrazol-1- yl}acetate 
                 468.2 
                 468.6 
               
               
                   
               
               
                 101 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-fluorophenyl)-N-{1-[1-(2-methoxy-1- methylethyl)-1H-tetrazol-5-yl]piperidin-4- yl}nicotinamide 
                 440.2 
                 440.4 
               
               
                   
               
               
                 102 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[1-(4-Cyanobenzyl)-1H-tetrazol-5- yl]piperidin-4-yl}-6-(3-fluorophenyl)nicotinamide 
                 483.2 
                 483.5 
               
               
                   
               
               
                 103 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[1-(3-Ethoxyphenyl)-1H-tetrazol-5- yl]piperidin-4-yl}-6-(3-fluorophenyl)nicotinamide 
                 488.2 
                 488.5 
               
               
                   
               
               
                 104 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{1-[(1R)-1-phenylethyl]- 1H-tetrazol-5-yl}piperidin-4-yl)nicotinamide 
                 472.2 
                 472.9 
               
               
                   
               
               
                 105 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[1-(2-Ethoxyphenyl)-1H-tetrazol-5- yl]piperidin-4-yl}-6-(3-fluorophenyl)nicotinamide 
                 440.2 
                 440.4 
               
               
                   
               
               
                 106 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[9-(2,2,2-trifluoroethyl- 9H-purin-6-yl]piperidin-4-yl}nicotinamide 
                 500.2 
                 500.8 
               
               
                   
               
               
                 107 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[9-(2-piperidin-1- ylethyl)-9H-purin-6-yl]piperidin-4-yl}nicotinamide 
                 529.3 
                 529.7 
               
               
                   
               
               
                 108 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[1-(3-methoxybenzyl)- 1H-tetrazol-5-yl}piperidin-4-yl)nicotinamide 
                 488.2 
                 488.5 
               
               
                   
               
               
                 109 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[8-(3-hydroxyphenyl)-9- methyl-9H-purin-6-yl]piperidin-4-yl}nicotinamide 
                 524.2 
                 524.8 
               
               
                   
               
               
                 110 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{9-[1- (methoxymethyl)propyl]-9H-purin-6-yl}piperidin- 4-yl)nicotinamide 
                 504.2 
                 504.5 
               
               
                   
               
               
                 111 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[3-(4-Cyanobenzoyl)pyridin-2-yl]piperidin- 4-yl}-6-(3-fluorophenyl)nicotinamide 
                 506.2 
                 506.5 
               
               
                   
               
               
                 112 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(9-Cyclopentyl-9H-purin-6-yl)piperidin-4-yl]- 6-(3-fluorophenyl)nicotinamide 
                 486.2 
                 486.6 
               
               
                   
               
               
                 113 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(5-{[(2- methoxyethyl)amino]carbonyl}pyridin-2- yl)piperidin-4-yl]nicotinamide 
                 478.2 
                 478.5 
               
               
                   
               
               
                 114 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[5-(pyrrolidin-1- ylcarbonyl)pyridin-2-yl]piperidin-4- yl}nicotinamide 
                 474.2 
                 474.6 
               
               
                   
               
               
                 115 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(9-Cyclopropyl-9H-purin-6-yl)piperidin-4- yl]-6-(3-fluorophenyl)nicotinamide 
                 458.2 
                 458.5 
               
               
                   
               
               
                 116 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(6-methyl-2-piperidin-1- ylpyrimidin-4-yl)piperidin-4-yl]nicotinamide 
                 475.3 
                 475.5 
               
               
                   
               
               
                 117 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(7-fluoroquinazolin-4- yl)piperidin-4-yl]nicotinamide 
                 446.3 
                 446.5 
               
               
                   
               
               
                 118 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(9-isopropyl-9H-purin-6- yl)piperidin-4-yl]nicotinamide 
                 460.2 
                 460.5 
               
               
                   
               
               
                 119 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{4-[2-(2- hydroxyethyl)phenyl]pyrimidin-2-yl}piperidin-4- yl)nicotinamide 
                 498.2 
                 498.8 
               
               
                   
               
               
                 120 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Ethyl 6-[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-4-morpholin-4- ylnicotinate 
                 534.2 
                 534.5 
               
               
                   
               
               
                 121 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3-Cyano-5-fluoro-6-methylpyridin-2- yl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide 
                 434.2 
                 434.5 
               
               
                   
               
               
                 122 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(7,8-Dimethoxyquinazolin-4-yl)piperidin-4- yl]-6-(3-fluorophenyl)nicotinamide 
                 488.2 
                 488.5 
               
               
                   
               
               
                 123 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(678- trimethoxyquinazolin-4-yl)piperidin-4- yl]nicotinamide 
                 518.2 
                 518.5 
               
               
                   
               
               
                 124 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-fluorophenyl)-N-[1-(7H-pyrrolo[23- d]pyrimidin-4-yl)piperidin-4-yl]nicotinamide 
                 417.2 
                 417.5 
               
               
                   
               
               
                 125 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(9-methyl-9H-purin-6- yl)piperidin-4-yl]nicotinamide 
                 432.2 
                 432.5 
               
               
                   
               
               
                 126 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(4-Amino-5-cyanopyrimidin-2-yl)piperidin- 4-yl]-6-(3-fluorophenyl)nicotinamide 
                 418.2 
                 418.6 
               
               
                   
               
               
                 127 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(5-Bromopyrimidin-2-yl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 456.1 
                 456.1 
               
               
                   
               
               
                 128 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[4-(1H-pyrazol-3- ylamino)pyrimidin-2-yl]piperidin-4- yl}nicotinamide 
                 459.2 
                 459.5 
               
               
                   
               
               
                 129 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(1H-pyrazolo[3,4- d]pyrimidin-4-yl)piperidin-4-yl]nicotinamide 
                 418.2 
                 418.8 
               
               
                   
               
               
                 130 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(4-Amino-6,7-dimethoxyquinazolin-2- yl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide 
                 503.2 
                 503.5 
               
               
                   
               
               
                 131 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(4-methylphthalazin-1- yl)piperidin-4-yl]nicotinamide 
                 442.2 
                 442.5 
               
               
                   
               
               
                 132 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2-Amino-9H-purin-6-yl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 433.2 
                 433.5 
               
               
                   
               
               
                 133 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(6-Amino-2-methylpyrimidin-4-yl)piperidin- 4-yl]-6-(3-fluorophenyl)nicotinamide 
                 407.2 
                 407.5 
               
               
                   
               
               
                 134 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3,6-Dimethylpyrazin-2-yl)piperidin-4-yl]-6- (3-fluorophenyl)nicotinamide 
                 406.2 
                 406.5 
               
               
                   
               
               
                 135 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[3- (trifluoromethyl)pyridin-2-yl]piperidin-4- yl}nicotinamide 
                 445.2 
                 445.8 
               
               
                   
               
               
                 136 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[4- (trifluoromethyl)pyrimidin-2-yl]piperidin-4- yl}nicotinamide 
                 446.2 
                 446.6 
               
               
                   
               
               
                 137 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(5-Chloropyridin-2-yl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 411.2 
                 411.5 
               
               
                   
               
               
                 138 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-quinoxalin-2-ylpiperidin- 4-yl)nicotinamide 
                 428.2 
                 428.4 
               
               
                   
               
               
                 139 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-pyrimidin-2-ylpiperidin- 4-yl)nicotinamide 
                 378.2 
                 378.3 
               
               
                   
               
               
                 140 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3-Cyanopyridin-2-yl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 402.2 
                 402.5 
               
               
                   
               
               
                 141 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(4-Cyano-3-methylisoxazol-5-yl)-2-[4-({[6-(3- fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]nicotinamide 
                 526.2 
                 526.8 
               
               
                   
               
               
                 142 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3-Cyanopyrazin-2-yl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 403.2 
                 403.4 
               
               
                   
               
               
                 143 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[4-(Dimethylamino)-6-methylpyrimidin-2- yl]piperidin-4-yl}-6-(3-fluorophenyl)nicotinamide 
                 435.2 
                 435.5 
               
               
                   
               
               
                 144 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[6-(methoxymethyl)-2- phenylpyrimidin-4-yl]piperidin-4-yl}nicotinamide 
                 498.2 
                 498.8 
               
               
                   
               
               
                 145 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Ethyl 4-[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-2- (trifluoromethyl)pyrimidine-5-carboxylate 
                 518.2 
                 518.7 
               
               
                   
               
               
                 146 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[3-(morpholin-4- ylcarbonyl)pyridin-2-yl]piperidin-4- yl}nicotinamide 
                 490.2 
                 490.5 
               
               
                   
               
               
                 147 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[9-(tetrahydro-2H- pyran-2-yl)-9H-purin-6-yl]piperidin-4- yl}nicotinamide 
                 502.2 
                 502.8 
               
               
                   
               
               
                 148 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[4-({[6-(3-Fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-6- (trifluoromethyl)nicotinamide 
                 488.2 
                 488.4 
               
               
                   
               
               
                 149 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[5-(pyridin-2- ylcarbonyl)pyridin-2-yl]piperidin-4- yl}nicotinamide 
                 482.2 
                 482.5 
               
               
                   
               
               
                 150 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Methyl 2-[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-6- methylpyrimidine-4-carboxylate 
                 450.2 
                 450.5 
               
               
                   
               
               
                 151 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(6-Aminopyrmidin-4-yl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 393.2 
                 393.4 
               
               
                   
               
               
                 152 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-Benzyl-2-[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]nicotinamide 
                 510.2 
                 510.5 
               
               
                   
               
               
                 153 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(1,3-Benzothiazol-2-yl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 433.1 
                 433.5 
               
               
                   
               
               
                 154 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2-Ethylimidazo[1,2-b]pyridazin-6- yl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide 
                 445.2 
                 445.8 
               
               
                   
               
               
                 155 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(3-isopropylpyrazin-2- yl)piperidin-4-yl]nicotinamide 
                 420.2 
                 420.5 
               
               
                   
               
               
                 156 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{3-[(1R)-1- methylpropyl]pyrazin-2-yl}piperidin-4- yl)nicotinamide 
                 434.2 
                 434.5 
               
               
                   
               
               
                 157 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-[4-({[6-(3-Fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-N- isopropylpyridazine-3-carboxamide 
                 463.2 
                 463.6 
               
               
                   
               
               
                 158 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(1,3-Benzoxazol-2-yl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 417.2 
                 417.5 
               
               
                   
               
               
                 159 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-[4-({[6-(3-Fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-N-isobutyl-N- methylpyridazine-3-carboxamide 
                 491.3 
                 491.5 
               
               
                   
               
               
                 160 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1,3-Dimethyl-1H-pyrazol-5-yl)-6-[4-({[6-(3- fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]pyridazine-3- carboxamide 
                 515.2 
                 515.5 
               
               
                   
               
               
                 161 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[8-(3-Cyanophenyl)-9-methyl-9H-purin-6- yl]piperidin-4-yl}-6-(3-fluorophenyl)nicotinamide 
                 533.2 
                 533.5 
               
               
                   
               
               
                 162 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{9-[(5-methyl pyrazin-2- yl)methyl]-9H-purin-6-yl}piperidin-4- yl)nicotinamide 
                 524.2 
                 524.5 
               
               
                   
               
               
                 163 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(Cyclohexylmethyl)-6-[4-({[6-(3- fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]pyridazine-3- carboxamide 
                 517.3 
                 517.7 
               
               
                   
               
               
                 164 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-[4-({[6-(3-Fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-N-[2-(2- oxoimidazolidin-1-yl)ethyl]pyridazine-3- carboxamide 
                 533.2 
                 533.5 
               
               
                   
               
               
                 165 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[3-(pyrrolidin-1- ylcarbonyl)pyridin-2-yl]piperidin-4- yl}nicotinamide 
                 474.2 
                 474.5 
               
               
                   
               
               
                 166 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-quinazolin-2-ylpiperidin- 4-yl)nicotinamide 
                 428.2 
                 428.3 
               
               
                   
               
               
                 167 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Methyl 5-[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]pyrazine-2- carboxylate 
                 436.2 
                 436.6 
               
               
                   
               
               
                 168 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[4-({[6-(3-Fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-N-(5- methylisoxazol-3-yl)nicotinamide 
                 501.2 
                 501.6 
               
               
                   
               
               
                 169 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3,6-Diethylpyrazin-2-yl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 434.2 
                 434.5 
               
               
                   
               
               
                 170 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[4-({[6-(3-Fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-6,7-dihydro- 5H-cyclopenta[b]pyridine-3-carboxamide 
                 460.2 
                 460.5 
               
               
                   
               
               
                 171 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)- N-(1-pyrido[2,3-d]pyrimidin- 2-ylpiperidin-4-yl)nicotinamide 
                 429.2 
                 429.5 
               
               
                   
               
               
                 172 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[4-(3- fluorophenyl)pyrimidin-2-yl]piperidin-4- yl}nicotinamide 
                 472.2 
                 472.8 
               
               
                   
               
               
                 173 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(6,7-Dimethoxyquinoxalin-2-yl)piperidin-4- yl]-6-(3-fluorophenyl)nicotinamide 
                 488.2 
                 488.6 
               
               
                   
               
               
                 174 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(7-fluoroquinazolin-2- yl)piperidin-4-yl]nicotinamide 
                 446.2 
                 446.8 
               
               
                   
               
               
                 175 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(5-Cyano-6-methylpyridin-2-yl)piperidin-4- yl]-6-(3-fluorophenyl)nicotinamide 
                 416.2 
                 416.5 
               
               
                   
               
               
                 176 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(4-Amino-2-methylpteridin-6-yl)piperidin-4- yl]-6-(3-fluorophenyl)nicotinamide 
                 459.2 
                 459.5 
               
               
                   
               
               
                 177 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[4-(3- methoxyphenyl)pyrimidin-2-yl]piperidin-4- yl}nicotinamide 
                 484.2 
                 484.5 
               
               
                   
               
               
                 178 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(6-methoxyquinazolin- 4-yl)piperidin-4-yl]nicotinamide 
                 458.2 
                 458.5 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 179 
     N-(1-(3-Ethoxy-4-hydroxybenzyl)piperidin-4-yl)-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     To a solution of (0.2 mL, 0.08 mmol in 1:1 THF:DMSO) aldehyde was added the amine (in 1:1 THF:DMSO, 0.2 mL, 0.08 mmol), sodium triacetoxyborohydride dispersion (0.33 mL, 2.5 eq, in 1:1 THF:DMSO) and glacial acetic acid (0.01 mL). The reaction mixture was stirred at room temperature for 16-24 h and then aqueous K 2 CO 3  (3 M, 0.2 mL) and ethanol (0.55 mL) was added. The reaction was shaken for 30 min and then the mixture was filtered and the filtrate concentrated and the residue purified by RP-HPLC to give the desired product.  1 H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.33 (t, J=6.95 Hz, 3H) 1.60 (d, J=10.98 Hz, 2H) 1.80 (br. s., 2H) 2.01 (br. s., 2H) 2.82 (br. s., 2H) 3.37 (br. s., 2H) 3.81 (br. s., 1H) 4.01 (q, J=6.95 Hz, 2H) 6.63-6.77 (m, 2H) 6.84 (s, 1H) 7.26-7.37 (m, 1H) 7.51-7.62 (m, 1H) 7.95 (d, J=10.62 Hz, 1H) 8.00 (d, J=8.05 Hz, 1H) 8.12 (d, J=8.42 Hz, 1H) 8.28 (dd, J=8.24, 201 Hz, 1 H) 8.44 (d, J=7.69 Hz, 1H) 8.65 (br. s., 1H) 9.07 (s, 1H). MS(ES+)=450.3 observed. 
     The following compounds of formula (VII) were prepared using methods analogous to that of Example 179. 
     
       
         
         
             
             
         
       
     
     EXAMPLE 180 
     6-(3-Fluorophenyl)-N-{1-[2-(5-methyl-2,4-dioxo-34-dihydropyrimidin-1(2H)-yl)ethyl]piperidin-4-yl}nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.46-1.65 (m, 2H) 1.77 (s, 5H) 2.10 (br. s., 2H) 2.90 (br. s., 2H) 3.39 (s, 3H) 3.74 (t, J=6.22 Hz, 2H) 7.25-7.39 (m, 1H) 7.48 (s, 1H) 7.52-7.63 (m, 1H) 7.94 (d, J=10.25 Hz, 1H) 8.00 (d, J=8.05 Hz, 1H) 8.11 (d, J=8.42 Hz, 1H) 8.28 (dd, J=8.24, 2.01 Hz, 1H) 8.45 (d, J=7.69 Hz, 1H) 9.07 (d, J=1.46 Hz, 1H). 
     MS calc (M+H) 452.2; MS obs (M+H) 452.0. 
     EXAMPLE 181 
     6-(3-Fluorophenyl)-N-[1-(3-pyrimidin-2-ylbenzyl)piperidin-4-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.65 (br. s., 2H) 1.83 (br. s., 2H) 2.11 (br. s., 2H) 2.89 (br. s., 2 H) 3.59 (br. s., 2H) 3.84 (br. s., 1H) 7.32 (s, 1H) 7.41-7.52 (m, 4H) 7.57 (d, J=6.22 Hz, 1H) 7.97 (br. s., 1H) 8.01 (d, J=8.05 Hz, 1H) 8.12 (d, J=8.05 Hz, 1H) 8.24-8.33 (m, 2H) 8.39 (s, 1H) 8.46 (d, J=7.69 Hz, 1H) 8.91 (d, J=5.12 Hz, 1H) 9.08 (s, 1H). 
     MS calc (M+H) 468.21; MS obs (M+H) 468.6. 
     EXAMPLE 182 
     6-(3-Fluorophenyl)-N-{1-[(3-phenyl-1H-pyrazol-4-yl)methyl]piperidin-4-yl}nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.60 (d, J=9.88 Hz, 2H) 1.82 (br. s., 2H) 1.97-2.15 (m, 2H) 2.91 (br. s., 2H) 3.39 (s, 2H) 3.83 (d, J=6.95 Hz, 1H) 7.23-7.61 (m, 6H) 7.61-8.04 (m, 5H) 8.11 (d, J=8.05 Hz, 1H) 8.29 (dd, J=8.05, 2.20 Hz, 1H) 8.46 (d, J=7.69 Hz, 1H) 9.07 (s, 1H). 
     MS calc (M+H) 456.21; MS obs (M+H) 456.6. 
     EXAMPLE 183 
     N-{1-[(6-Fluoro-1H-indol-3-yl)methyl]piperidin-4-yl}-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.58 (d, J=12.08 Hz, 2H) 1.79 (br. s., 2H) 1.94-2.10 (m, 2H) 2.90 (d, J=11.35 Hz, 2H) 3.62 (s, 2H) 3.79 (br. s., 1H) 6.77-6.91 (m, 1H) 7.11 (dd, J=10.07, 2.01 Hz, 1 H) 7.21 (d, J=1.83 Hz, 1H) 7.26-7.35 (m, 1H) 7.50-7.61 (m, 1H) 7.64 (dd, J=8.42, 5.86 Hz, 1H) 7.94 (d, J=10.62 Hz, 1H) 8.00 (d, J=7.69 Hz, 1H) 8.11 (d, J=8.42 Hz, 1H) 8.28 (dd, J=8.42, 2.20 Hz, 1H) 8.43 (d, J=7.32 Hz, 1H) 9.06 (s, 1H) 10.93 (br. s., 1H). 
     MS calc (M+H) 447.19; MS obs (M+H) 447.4. 
     EXAMPLE 184 
     6-(3-Fluorophenyl)-N-[1-(4-isopropoxy-3-methoxybenzyl)piperidin-4-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.24 (d, J=6.22 Hz, 6H) 1.62 (d, J=3.66 Hz, 2H) 1.80 (br. s., 2H) 2.03 (br. s., 2H) 2.82 (br. s., 2H) 3.40 (s, 1H) 3.75 (s, 3H) 3.81 (br. s., 1H) 4.46 (d, J=5.86 Hz, 1H) 6.78 (d, J=8.05 Hz, 1H) 6.83-6.96 (m, 3H) 7.31 (s, 1H) 7.50-7.62 (m, 1H) 7.95 (br. s., 1H) 7.99 (s. 1 H) 8.12 (d, J=8.05 Hz, 1H) 8.27 (d, J=1.83 Hz, 1H) 8.46 (s, 1H) 9.07 (d, J=1.46 Hz, 1H). 
     MS calc (M+H) 478.24; MS obs (M+H) 478.3. 
     EXAMPLE 185 
     N-{1-[(1-Ethyl-1H-pyrazol-4-yl)methyl]piperidin-4-yl}-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.35 (t, J=7.14 Hz, 3H) 1.49-1.65 (m, 2H) 1.79 (br. s., 2H) 1.97 (t, J=10.98 Hz, 2H) 2.84 (d, J=11.35 Hz, 2H) 3.34 (s, 2H) 3.76 (d, J=7.32 Hz, 1H) 4.08 (q, J=7.08 Hz, 2 H) 7.26-7.36 (m, 2H) 7.52-7.62 (m, 2H) 7.95 (d, J=10.62 Hz, 1H) 8.00 (d, J=7.69 Hz, 1H) 8.12 (d, J=8.42 Hz, 1H) 8.28 (dd, J=8.05, 1.83 Hz, 1H) 8.43 (d, J=7.69 Hz, 1H) 9.07 (s, 1H). 
     MS calc (M+H) 408.21; MS obs (M+H) 408.5. 
     EXAMPLE 186 
     N-[1-(3,4-Dihydro-2H-pyran-2-ylmethyl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.46-1.67 (m, 3H) 1.75-1.94 (m, 4H) 1.97-2.21 (m, 4H) 2.33-2.45 (m, 1H) 2.83-2.96 (m, 2H) 3.67-3.86 (m, 1H) 3.87-4.00 (m, 1H) 4.65 (br. s., 1H) 6.35 (br. s., 1 H) 7.25-7.37 (m, 1H) 7.50-7.64 (m, 1H) 7.95 (d, J=10.62 Hz, 1H) 8.01 (d, J=7.69 Hz, 1H) 8.12 (d, J=8.05 Hz, 1H) 8.28 (dd, J=8.42, 1.83 Hz, 1H) 8.43 (d, J=7.32 Hz, 1H) 9.07 (s, 1H). 
     MS calc (M+H) 396.2; MS obs (M+H) 396.4. 
     EXAMPLE 187 
     6-(3-Fluorophenyl)-N-(1-{[3-(4-fluorophenyl)-1H-pyrazol-4-yl]methyl}piperidin-4-yl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.50-1.70 (m, 2H) 1.83 (br. s., 2H) 1.98-2.13 (m, 2H) 2.91 (br. s., 2H) 3.37 (s, 2H) 3.84 (br. s., 1H) 7.16-7.39 (m, 3H) 7.41-7.52 (m, 1H) 7.51-7.62 (m, 1H) 7.70 (br. s., 1H) 7.84 (br. s., 1H) 7.95 (d, J=10.62 Hz, 2H) 8.00 (d, J=7.32 Hz, 1H) 8.11 (d, J=8.05 Hz, 1H) 8.29 (dd, J=8.24, 2.01 Hz, 1H) 8.46 (d, J=7.69 Hz, 1H) 9.08 (s, 1H). 
     MS calc (M+H) 474.2; MS obs (M+H) 474.5. 
     EXAMPLE 188 
     6-(3-Fluorophenyl)-N-[1-(3-pyridin-2-ylbenzyl)piperidin-4-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.63 (dd, J=11.71, 2.56 Hz, 2H) 1.83 (d, J=11.71 Hz, 2H) 2.03-2.21 (m, 2H) 2.88 (d, J=11.35 Hz, 2H) 3.35 (s, 3H) 3.58 (s, 2H) 3.84 (d, J=4.76 Hz, 1H) 7.25-7.41 (m, 2H) 7.45 (t, J=7.50 Hz, 1H) 7.52-7.63 (m, 1H) 7.83-7.91 (m, 1H) 7.94 (d, J=8.42 Hz, 1H) 8.00 (d, J=7.69 Hz, 1H) 8.04 (s, 1H) 8.11 (d, J=8.42 Hz, 1H) 8.28 (dd, J=8.42, 2.20 Hz, 1H) 8.46 (d, J=7.69 Hz, 1H) 8.67 (d, J=4.03 Hz, 1H) 9.07 (d, J=1.46 Hz, 1H). 
     MS calc (M+H) 467.22; MS obs (M+H) 467.5. 
     EXAMPLE 189 
     6-(3-Fluorophenyl)-N-[1-(quinolin-4-ylmethyl)piperidin-4-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.63 (dd, J=12.08, 2.93 Hz, 2H) 1.84 (d, J=10.25 Hz, 2H) 2.22 (t, J=10.80 Hz, 2H) 2.92 (d, J=11.35 Hz, 2H) 3.87 (br. s., 1H) 3.97 (s, 2H) 7.24-7.38 (m, 1H) 7.50 (d, J=4.03 Hz, 1H) 7.52-7.68 (m, 2H) 7.76 (t, J=7.69 Hz, 1H) 7.95 (d, J=10.98 Hz, 1H) 8.02 (dd, J=12.26, 8.24 Hz, 2H) 8.12 (d, J=8.42 Hz, 1H) 8.28 (dd, J=8.24, 2.01 Hz, 1H) 8.34 (d, J=8.42 Hz, 1H) 8.45 (d, J=7.69 Hz, 1H) 8.85 (d, J=4.03 Hz, 1H) 9.07 (s, 1H). 
     MS calc (M+H) 441.2; MS obs (M+H) 441.5. 
     EXAMPLE 190 
     6-(3-Fluorophenyl)-N-[1-(1H-imidazol-5-ylmethyl)piperidin-4-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.57 (d, J=10.25 Hz, 2H) 1.79 (br. s., 2H) 2.02 (t, J=10.98 Hz, 2 H) 2.87 (br. s., 2H) 3.40 (br. s., 2H) 3.76 (br. s., 1H) 6.75 (br. s., 1H) 6.93 (br. s., 1H) 7.26-7.37 (m, 1 H) 7.47-7.62 (m, 2H) 7.95 (d, J=10.62 Hz, 1H) 8.00 (d, J=8.05 Hz, 1H) 8.12 (d, J=8.42 Hz, 1H) 8.28 (dd, J=8.24, 2.01 Hz, 1H) 8.44 (d, J=7.32 Hz, 1H) 9.07 (d, J=1.83 Hz, 1H). 
     MS calc (M+H) 380.18; MS obs (M+H) 380.1. 
     EXAMPLE 191 
     N-{1-[(4-Chloro-1-methyl-1H-pyrazol-3-yl)methyl]piperidin-4-yl}-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.48-1.64 (m, 2H) 1.79 (br. s., 2H) 2.09 (t, J=10.98 Hz, 2H) 2.86 (d, J=12.08 Hz, 2H) 3.42 (s, 2H) 3.74 (s, 4H) 6.31-7.43 (m, 1H) 7.49-7.64 (m, 1H) 7.85 (s, 1H) 7.95 (d, J=10.62 Hz, 1H) 8.00 (d, J=8.05 Hz, 1H) 8.11 (d, J=8.42 Hz, 1H) 8.28 (dd, J=8.42, 1.83 Hz, 1H) 8.43 (d, J=7.69 Hz, 1H) 9.06 (s, 1H). 
     MS calc (M+H) 428.16; MS obs (M+H) 428.3. 
     EXAMPLE 194 
     N-[1-(4-Fluoro-3-methoxybenzyl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.50-1.69 (m, 2H) 1.81 (br. s., 2H) 2.06 (t, J=10.98 Hz, 2H) 2.83 (d, J=11.35 Hz, 2H) 3.45 (s, 2H) 3.84 (s, 4H) 6.87 (d, J=1.83 Hz, 1H) 7.04-7.18 (m, 2H) 7.26-7.37 (m, 1H) 7.50-7.64 (m, 1H) 7.95 (d, J=10.98 Hz, 1H) 8.01 (d, J=7.69 Hz, 1H) 8.12 (d, J=8.42 HZ, 1H) 8.28 (dd, J=8.42, 2.20 Hz, 1H) 8.45 (d, J=7.69 Hz, 1H) 9.07 (s, 1H). 
     MS calc (M+H) 438.19; MS obs (M+H) 438.5. 
     EXAMPLE 193 
     N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.62 (t, J=11.71 Hz, 2H) 1.82 (d, J=1.46 Hz, 2H) 2.08 (t, J=10.98 Hz, 2H) 2.80 (br. s., 2H) 3.48 (s, 2H) 3.80 (br. s., 1H) 7.16 (br. s., 1H) 7.24-7.45 (m, 3H) 7.51-7.63 (m, 1H) 7.96 (s, 1H) 8.01 (d, J=7.69 Hz, 1H) 8.12 (d, J=8.42 Hz, 1H) 8.28 (dd, J=8.24, 2.01 Hz, 1H) 8.45 (d, J=7.32 Hz, 1H) 9.07 (s, 1H). 
     MS calc (M+H) 426.17; MS obs (M+H) 425.9. 
     EXAMPLE 194 
     6-(3-Fluorophenyl)-N-[1-(2-oxo-2-phenylethyl)piperidin-4-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     MS calc (M+H) 418.19; MS obs (M+H) 418.3. 
     EXAMPLE 195 
     N-{1-[(5-Chloro-1-methyl-3-phenyl-1H-pyrazol-4-yl)methyl]piperidin-4-yl}-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.61 (br. s., 2H) 1.83 (br. s., 2H) 2.13 (br. s., 2H) 2.90 (d, J=11.35 Hz, 2H) 3.34 (s, 1H) 3.87 (s, 4H) 7.26-7.40 (m, 3H) 7.44 (t, J=7.32 Hz, 2H) 7.51-7.62 (m, 1 H) 7.95 (d, J=8.05 Hz, 3H) 8.00 (d, J=7.69 Hz, 1H) 8.11 (d, J=8.42 Hz, 1H) 8.29 (dd, J=8.05, 1.83 Hz, 1 H) 8.46 (d, J=7.69 Hz, 1H) 9.08 (s, 1H). 
     MS calc (M+H) 504.19; MS obs (M+H) 504.5. 
     EXAMPLE 196 
     6-(3-Fluorophenyl)-N-{1-[(1-methyl-1H-pyrazol-4-yl)methyl]piperidin-4-yl}nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.48-1.64 (m, 2H) 1.80 (d, J=9.52 Hz, 2H) 1.90-2.04 (m, 2H) 2.84 (d, J=11.35 Hz, 2H) 3.35 (br. s., 1H) 3.75 (br. s., 1H) 3.79 (s, 3H) 7.26-7.37 (m, 2H) 7.51-7.62 (m, 3H) 7.95 (d, J=10.25 Hz, 1H) 8.00 (d, J=8.05 Hz, 1H) 8.11 (d, J=8.42 Hz, 1H) 8.28 (dd, J=8.24, 2.01 Hz, 1H) 8.44 (d, J=7.69 Hz, 1H) 9.07 (d, J=1.83 Hz, 1H). 
     MS calc (M+H) 394.2; MS obs (M+H) 394.1. 
     EXAMPLE 197 
     6-(3-Fluorophenyl)-N-[1-(quinolin-8-ylmethyl)piperidin-4-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.60-1.76 (m, 2H) 1.84 (br. s., 2H) 2.13-2.29 (m, 2H) 2.89-3.03 (m, 2H) 3.84 (br. s., 1H) 4.20 (s, 2H) 7.24-7.37 (m, 1H) 7.50-7.68 (m, 3H) 7.86 (dd, J=13.54, 7.69 Hz, 2H) 7.95 (d, J=10.25 Hz, 1H) 8.01 (d, J=7.69 Hz, 1H) 8.12 (d, J=8.05 Hz, 1H) 8.29 (dd, J=8.42, 1.83 Hz, 1H) 8.36 (d, J=7.69 Hz, 1H) 8.47 (d, J=7.32 Hz, 1H) 8.93 (d, J=2.93 Hz, 1H) 9.08 (s, 1 H). 
     MS calc (M+H) 441.2; MS obs (M+H) 441.5. 
     EXAMPLE 198 
     6-(3-Fluorophenyl)-N-[1-(3-pyrazin-2-ylbenzyl)piperidin-4-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.55-1.72 (m, 2H) 1.84 (d, J=9.52 Hz, 2H) 2.11 (t, J=11.16 Hz, 2 H) 2.89 (d, J=10.98 Hz, 2H) 3.59 (s, 2H) 3.84 (br. s., 1H) 7.25-7.38 (m, 1H) 7.48-7.62 (m, 2H) 7.95 (d, J=10.98 Hz, 1H) 8.01 (t, J=7.50 Hz, 2H) 8.10 (d, J=4.76 Hz, 1H) 8.13 (s, 1H) 8.28 (dd, J=8.42, 1.83 Hz, 1H) 8.46 (d, J=7.32 Hz, 1H) 8.62 (d, J=2.20 Hz, 1H) 8.73 (s, 1H) 9.07 (s, 1 H) 9.24 (s, 1H). 
     MS calc (M+H) 468.21; MS obs (M+H) 468.3. 
     EXAMPLE 199 
     N-{1-[(2-Butyl-1H-imidazol-4-yl)methyl]piperidin-4-yl}-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 0.88 (t, J=7.32 Hz, 3H) 1.21-1.36 (m, 3H) 1.49-1.66 (m , 5H) 1.79 (br. s., 2H) 2.01 (t, J=10.80 Hz, 2H) 2.57 (s, 1H) 2.85 (br. s., 2H) 3.34 (br. s., 1H) 3.77 (br. s., 1H) 7.23-7.38 (m, 1H) 7.50-7.64 (m, 1H) 7.95 (d, J=10.62 Hz, 1H) 8.00 (d, J=8.05 Hz, 1H) 8.12 (d, J=8.42 Hz, 1H) 8.28 (dd, J=8.24, 2.01 Hz, 1H) 8.43 (d, J=7.69 Hz, 1H) 9.07 (d, J=1.46 Hz, 1H) 11.39 (br. s., 1H). 
     MS calc (M+H) 436.24; MS obs (M+H) 436.3. 
     EXAMPLE 200 
     N-[1-(3,4-Dihydro-2H-15-benzodioxepin-7-ylmethyl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.59 (dd, J=11.71, 2.93 Hz, 2H) 1.97-2.07 (m, 2H) 2.05-2.14 (m, 2H) 2.81 (d, J=11.35 Hz, 2H) 3.38 (s, 2H) 3.81 (br. s., 1H) 4.11 (q, J=5.73 Hz, 4H) 6.82-6.95 (m, 2H) 7.31 (d, J=2.20 Hz, 1H) 7.51-7.64 (m, 1H) 7.95 (d, J=10.25 Hz, 1H) 8.00 (d, J=8.05 Hz, 1H) 8.12 (d, J=8.42 Hz, 1H) 8.28 (dd, J=8.42, 1.83 Hz, 1H) 8.44 (d, J=7.69 Hz, 1H) 9.07 (s, 1H. 
     MS calc (M+H) 462.21; MS obs (M+H) 462.5. 
     EXAMPLE 201 
     6-(3-Fluorophenyl)-N-[1-(4-pyridin-2-ylbenzyl)piperidin-4-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.57-1.71 (m, 2H) 1.84 (d, J=10.25 Hz, 2H) 2.02-2.16 (m, 2H) 2.87 (d, J=11.35 Hz, 2H) 3.55 (s, 2H) 3.83 (d, J=11.35 Hz, 1H) 7.26-7.39 (m, 2H) 7.43 (d, J=8.05 Hz, 2H) 7.51-7.62 (m, 1H) 7.87 (t, J=6.95 Hz, 1H) 7.91-7.98 (m, 2H) 7.99-8.09 (m, 3H) 8.12 (d, J=8.42 Hz, 1H) 8.29 (dd, J=8.42, 1.83 Hz, 1H) 8.46 (d, J=7.32 Hz, 1H) 8.66 (d, J=4.03 Hz, 1H) 9.08 (d, J=1.83 Hz, 1H). 
     MS calc (M+H) 467.22; MS obs (M+H) 467.5. 
     EXAMPLE 202 
     N-[1-(3-Fluoro-4-methylbenzyl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.51-1.69 (m, 2H) 1.81 (br. s., 2H) 2.05 (br. s., 2H) 2.21 (s, 3H) 2.82 (d, J=11.35 Hz, 2H) 3.45 (s, 2H) 3.81 (br. s., 1H) 7.00-7.11 (m, 2H) 7.22 (t, J=7.87 Hz, 1H) 7.27-7.36 (m, 1H) 7.51-7.63 (m, 1H) 7.95 (d, J=10.98 Hz, 1H) 8.00 (d, J=7.69 Hz, 1H) 8.12 (d, J=8.42 Hz, 1H) 8.28 (dd, J=8.42, 1.83 Hz, 1H) 8.44 (d, J=7.32 Hz, 1H) 9.07 (s, 1H). 
     MS calc (M+H) 422.2; MS obs (M+H) 422.0. 
     EXAMPLE 203 
     tert-Butyl(1-{[4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidin-1-yl]methyl}cyclopropyl)carbamate 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 0.52 (br. s., 1H) 0.64 (br. s., 1H) 1.32-1.45 (m, 10H) 1.58 (br. s., 3H) 1.78 (br. s., 3H) 1.91 (br. s., 1H) 2.07 (br. s., 1H) 2.39 (br. s., 1H) 2.99 (s, 2H) 3.77 (br. s., 2H) 7.26-7.37 (m, 1H) 7.51-7.65 (m, 1H) 7.95 (d, J=10.62 Hz, 1H) 8.01 (d, J=7.69 Hz, 1H) 8.12 (d, J=8.05 Hz, 1H) 8.24-8.34 (m, 1H) 8.43 (d, J=7.69 Hz, 1H) 9.07 (br. s., 1H). 
     MS calc (M+H) 469.25; MS obs (M+H) 469.5. 
     EXAMPLE 204 
     N-[1-(3-Chloro-4-methoxybenzyl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.51-1.66 (m, 2H) 1.80 (br. s., 2H) 2.04 (t, J=11.16 Hz, 2H) 2.81 (d, J=10.98 Hz, 2H) 3.42 (s, 2H) 3.74 (d, J=5.12 Hz, 1H) 3.84 (s, 3H) 7.09 (d, J=8.42 Hz, 1H) 7.18-7.26 (m, 1H) 7.27-7.39 (m, 2H) 7.52-7.64 (m, 1H) 7.96 (br. s., 1H) 8.00 (d, J=7.32 Hz, 1H) 8.12 (d, J=8.05 Hz, 1H) 8.28 (dd, J=8.24, 2.01 Hz, 1H) 8.44 (d, J=7.69 Hz, 1H) 9.07 (d, J=1.46 Hz, 1H). 
     MS calc (M+H) 454.16; MS obs (M+H) 454.4. 
     EXAMPLE 205 
     N-[1-(2,5-Dimethoxybenzyl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.55-1.70 (m, 2H) 1.81 (br. s., 2H) 2.10 (t, J=11.16 Hz, 2H) 2.85 (d, J=12.08 Hz, 2H) 3.46 (s, 2H) 3.71 (s, 3H) 3.73 (s, 3H) 3.81 (br. s., 1H) 6.78 (dd, J=8.79, 2.93 Hz, 1 H) 6.86-6.96 (m, 2H) 7.26-7.37 (m, 1H) 7.51-7.63 (m, 1H) 7.95 (d, J=10.25 Hz, 1H) 8.01 (d, J=8.05 Hz, 1H) 8.12 (d, J=8.05 Hz, 1H) 8.29 (dd, J=8.42, 1.83 Hz, 1H) 8.45 (d, J=7.69 Hz, 1H) 9.08 (s, 1H). 
     MS calc (M+H) 450.21; MS obs (M+H) 450.5. 
     EXAMPLE 206 
     6-(3-Fluorophenyl)-N-[1-(3-isopropoxybenzyl)piperidin-4-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.19-1.31 (m, 6H) 1.53-1.70 (m, 2H) 1.81 (br. s., 2H) 1.98-2.14 (m, 2H) 2.83 (d, J=11.35 Hz, 2H) 3.44 (s, 2H) 3.79 (d, J=4.03 Hz, 1H) 4.49-4.66 (m, 1H) 6.78 (d, J=7.32 Hz, 1H) 6.81-6.88 (m, 2H) 7.21 (t, J=7.87 Hz, 1H) 7.27-7.37 (m, 1H) 7.51-7.62 (m, 1H) 7.95 (d, J=10.98 Hz, 1H) 8.01 (d, J=8.05 Hz, 1H) 8.12 (d, J=8.42 Hz, 1H) 8.28 (dd, J=8.24, 2.01 Hz, 1H) 8.45 (d, J=7.32 Hz, 1H) 9.07 (s, 1H). 
     MS calc (M+H) 448.23; MS obs (M+H) 448.5. 
     EXAMPLE 207 
     6-(3-Fluorophenyl)-N-{1-[(1-methyl-1H-indol-2-yl)methyl]piperidin-4-yl}nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.51-1.68 (m, 2H) 1.83 (d, J=10.98 Hz, 2H) 2.11 (t, J=10.98 Hz, 2H) 2.91 (d, J=11.35 Hz, 2H) 3.65 (s, 2H) 3.78 (s, 3H) 3.83 (br. s., 1H) 6.34 (s, 1H) 6.99 (t, J=7.50 Hz, 1H) 7.11 (t, J=7.69 Hz, 1H) 7.26-7.35 (m, 1H) 7.40 (d, J=8.42 Hz, 1H) 7.48 (d, J=7.69 Hz, 1H) 7.51-7.63 (m, 1H) 7.95 (d, J=10.62 Hz, 1H) 8.00 (d, J=7.69 Hz, 1H) 8.11 (d, J=8.05 Hz, 1H) 8.23-8.34 (m, 1 H) 8.45 (d, J=7.69 Hz, 1H) 9.07 (s, 1H). 
     MS calc (M+H) 443.22; MS obs (M+H) 443.4. 
     EXAMPLE 208 
     N-{1-[(2-Ethyl-1H-imidazol-5-yl)methyl]piperidin-4-yl}-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.18 (t, J=7.69 Hz, 3H) 1.48-1.66 (m, 2H) 1.81 (d, J=11.71 Hz, 2 H) 2.01 (t, J=10.98 Hz, 2H) 2.55-2.63 (m, 2H) 2.86 (d, J=10.25 Hz, 2H) 3.34 (br. s., 2H) 3.65-3.86 (m, 1H) 6.68 (br. s., 1H) 7.25-7.38 (m, 1H) 7.51-7.64 (m, 1H) 7.95 (d, J=10.98 Hz, 1H) 8.00 (d, J=7.69 Hz, 1H) 8.12 (d, J=8.05 Hz, 1H) 8.28 (dd, J=8.24, 2.01 Hz, 1H) 8.44 (d, J=7.69 Hz, 1H) 9.07 (d, J=1.83 Hz, 1H). 
     MS calc (M+H) 408.21; MS obs (M+H) 408.5. 
     EXAMPLE 209 
     N-{1-[(1-tert-Butyl-3,5-dimethyl-1H-pyrazol-4-yl)methyl]piperidin-4-yl}-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.53 (s, 9H) 1.79 (d, J=9.88 Hz, 2H) 1.97 (t, J=10.98 Hz, 2H) 2.06 (s, 3H) 2.32 (s, 3H) 2.78 (d, J=10.98 Hz, 2H) 3.17 (s, 2H) 3.37-3.40 (m, 2H) 3.73-3.88 (m, 1H) 7.23-7.37 (m, 1H) 7.49-7.61 (m, 1H) 7.94 (d, J=10.25 Hz, 1H) 8.00 (d, J=7.69 Hz, 1H) 8.11 (d, J=8.42 Hz, 1H) 8.27 (dd, J=8.24, 2.01 Hz, 1H) 8.42 (d, J=7.32 Hz, 1H) 9.06 (d, J=1.83 Hz, 1H). 
     MS calc (M+H) 464.27; MS obs (M+H) 464.6. 
     EXAMPLE 210 
     6-(3-Fluorophenyl)-N-{1-[4-(1H-pyrazol-1-yl)benzyl]piperidin-4-yl}nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.54-1.71 (m, 2H) 1.84 (d, J=10.98 Hz, 2H) 2.09 (t, J=10.98 Hz, 2H) 2.86 (d, J=10.98 Hz, 2H) 3.52 (s, 2H) 3.83 (br. s., 1H) 6.53 (s, 1H) 7.26-7.36 (m, 1H) 7.42 (d, J=8.42 Hz, 2H) 7.52-7.63 (m, 1H) 7.73 (s, 1H) 7.79 (d, J=8.42 Hz, 2H) 7.95 (d, J=10.25 Hz, 1H) 8.01 (d, J=7.32 Hz, 1H) 8.12 (d, J=8.05 Hz, 1H) 8.28 (dd, J=8.05, 1.83 Hz, 1H) 8.41-8.53 (m, 2H) 9.08 (d, J=1.83 Hz, 1H). 
     MS calc (M+H) 456.21; MS obs (M+H) 456.5. 
     EXAMPLE 211 
     N-[1-(2-Fluoro-6-methoxybenzyl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.44-1.63 (m, 2H) 1.78 (d, J=10.25 Hz, 2H) 2.10 (t, J=1.35 Hz, 2H) 2.82 (d, J=111.71 Hz, 2H) 3.53 (s, 2H) 3.73 (br. s., 1H) 3.82 (s, 3H) 6.78 (t, J=8.60 Hz, 1H) 6.87 (d, J=8.42 Hz, 1H) 7.24-7.37 (m, 2H) 7.49-7.63 (m, 1H) 7.94 (d, J=10.62 Hz, 1H) 8.00 (d, J=7.69 Hz, 1 H) 8.11 (d, J=8.42 Hz, 1H) 8.27 (dd, J=8.42, 1.83 Hz, 1H) 8.40 (d, J=7.69 Hz, 1H) 9.06 (d, J=1.83 Hz, 1 H). 
     MS calc (M+H) 438.19; MS obs (M+H) 438.5. 
     EXAMPLE 212 
     N-[2-(3,4-Dimethoxybenzyl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.51-1.69 (m, 2H) 1.77-1.88 (m, 2H) 2.03 (t, J=10.98 Hz, 2H) 2.83 (d, J=11.35 Hz, 2H) 3.41 (s, 2H) 3.74 (d, J=5.12 Hz, 6H) 3.81 (br. s., 1H) 6.77-6.84 (m, 1H) 6.85-6.96 (m, 2H) 7.24-7.37 (m, 1H) 7.51-7.63 (m, 1H) 7.95 (d, J=10.98 Hz, 1H) 8.00 (d, J=7.69 Hz, 1H) 8.11 (d, J=8.42 Hz, 1H) 8.28 (dd, J=8.24, 2.01 Hz, 1H) 8.45 (d, J=7.32 Hz, 1H) 9.07 (d, J=1.83 Hz, 1H). 
     MS calc (M+H) 450.21; MS obs (M+H) 450.4. 
     
       
         
           
               
               
               
               
               
             
               
                   
               
               
                   
                   
                   
                 MS 
                 MS 
               
               
                   
                   
                   
                 Calc 
                 Obs 
               
               
                 Ex 
                 Q 
                 Name 
                 (M + H) 
                 (M + H) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 213 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2-Cyanobenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 415.2 
                 415.4 
               
               
                   
               
               
                 214 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{4-[3-(Dimethylamino)propoxy]benzyl}piperidin- 4-yl)-6-(3-fluorophenyl)nicotinamide 
                 491.3 
                 491.5 
               
               
                   
               
               
                 215 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(1-methyl-1H-imidazol-2- yl)methyl]piperidin-4-yl}nicotinamide 
                 394.2 
                 394.5 
               
               
                   
               
               
                 216 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(1,3-thiazol-2- ylmethyl)piperidin-4-yl]nicotinamide 
                 397.1 
                 397.3 
               
               
                   
               
               
                 217 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(4- isopropoxybenzyl)piperidin-4-yl]nicotinamide 
                 448.2 
                 448.5 
               
               
                   
               
               
                 218 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(245- trifluorobenzyl)piperidin-4-yl]nicotinamide 
                 444.2 
                 444.5 
               
               
                   
               
               
                 219 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(1-methyl-1H-benzimidazol- 2-yl)methyl]piperidin-4-yl}nicotinamide 
                 444.2 
                 444.5 
               
               
                   
               
               
                 220 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2,4-Dimethoxybenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 450.2 
                 450.5 
               
               
                   
               
               
                 221 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(Cyclohex-3-en-1-ylmethyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 394.2 
                 394.4 
               
               
                   
               
               
                 222 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(4-methoxybenzyl)piperidin- 4-yl]nicotinamide 
                 420.2 
                 420.5 
               
               
                   
               
               
                 223 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(5-Bromo-2-hydroxybenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 484.1 
                 486.4 (Br iso) 
               
               
                   
               
               
                 224 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(3-methoxybenzyl)piperidin- 4-yl]nicotinamide 
                 420.2 
                 420.3 
               
               
                   
               
               
                 225 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(4-Chlorobenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 424.2 
                 424.1 
               
               
                   
               
               
                 226 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(5-methoxy-1H-indol-3- yl)methyl]piperidin-4-yl}nicotinamide 
                 459.2 
                 459.5 
               
               
                   
               
               
                 227 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(4-Cyanobenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 415.2 
                 415.4 
               
               
                   
               
               
                 228 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3,4-Diethoxybenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 478.2 
                 478.3 
               
               
                   
               
               
                 229 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2-Ethoxybenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 434.2 
                 434.4 
               
               
                   
               
               
                 230 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2,3-Dimethoxybenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 450.2 
                 450.4 
               
               
                   
               
               
                 231 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(2-methoxybenzyl)piperidin- 4-yl]nicotinamide 
                 420.2 
                 420.3 
               
               
                   
               
               
                 232 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H- pyrazol-4-yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 500.2 
                 500.5 
               
               
                   
               
               
                 233 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3-Chlorobenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 424.2 
                 424.3 
               
               
                   
               
               
                 234 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(4-Ethoxybenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 434.2 
                 434.5 
               
               
                   
               
               
                 235 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(4-methoxy-3- methylbenzyl)piperidin-4-yl]nicotinamide 
                 434.2 
                 434.5 
               
               
                   
               
               
                 236 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(2,3,4- trifluorobenzyl)piperidin-4-yl]nicotinamide 
                 444.2 
                 444.5 
               
               
                   
               
               
                 237 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2,4-Difluorobenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 426.2 
                 426.1 
               
               
                   
               
               
                 238 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3-Cyanobenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 415.2 
                 415.1 
               
               
                   
               
               
                 239 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2,5-Difluorobenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 426.2 
                 426.0 
               
               
                   
               
               
                 240 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2,3-Difluorobenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 426.2 
                 425.9 
               
               
                   
               
               
                 241 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2,3-Dihydro-14-benzodioxin-6- ylmethyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 448.2 
                 448.5 
               
               
                   
               
               
                 242 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(1-methyl-1H-indol-3- yl)methyl]piperidin-4-yl}nicotinamide 
                 443.2 
                 443.6 
               
               
                   
               
               
                 243 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(1-Acetyl-1H-indol-3-yl)methyl]piperidin-4-yl}-6- (3-fluorophenyl)nicotinamide 
                 471.2 
                 471.3 
               
               
                   
               
               
                 244 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2,6-Difluorobenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 426.2 
                 425.9 
               
               
                   
               
               
                 245 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3-Bromo-4-methoxybenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 498.1 
                 500.1 
               
               
                   
               
               
                 246 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(quinolin-3- ylmethyl)piperidin-4-yl]nicotinamide 
                 441.2 
                 441.3 
               
               
                   
               
               
                 247 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3-Fluoro-4-methoxybenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 438.2 
                 438.3 
               
               
                   
               
               
                 248 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3,5-Difluorobenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 426.2 
                 426.0 
               
               
                   
               
               
                 249 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3-Ethoxy-4-methoxybenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 464.2 
                 464.4 
               
               
                   
               
               
                 250 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(1,3-trimethyl-1H-pyrazol-4- yl)methyl]piperidin-4-yl}nicotinamide 
                 422.2 
                 422.0 
               
               
                   
               
               
                 251 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2,2-Dimethylpropyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 370.2 
                 370.4 
               
               
                   
               
               
                 252 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(5-Fluoro-1H-indol-3-yl)methyl]piperidin-4-yl}-6- (3-fluorophenyl)nicotinamide 
                 447.2 
                 447.3 
               
               
                   
               
               
                 253 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(4-Ethoxy-3-methoxybenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 464.2 
                 464.5 
               
               
                   
               
               
                 254 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(2,4-Dioxo-1234-tetrahydropyrimidin-5- yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 424.2 
                 424.3 
               
               
                   
               
               
                 255 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[2-(2- hydroxyethoxy)benzyl]piperidin-4-yl}nicotinamide 
                 450.2 
                 450.4 
               
               
                   
               
               
                 256 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[3-(2- hydroxyethoxy)benzyl]piperidin-4-yl}nicotinamide 
                 450.2 
                 450.0 
               
               
                   
               
               
                 257 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3-Chloro-4-hydroxy-5-methoxybenzyl)piperidin- 4-yl]-6-(3-fluorophenyl)nicotinamide 
                 470.2 
                 470.5 
               
               
                   
               
               
                 258 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[4-(2- hydroxyethoxy)benzyl]piperidin-4-yl}nicotinamide 
                 450.2 
                 450.4 
               
               
                   
               
               
                 259 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[4- (methylsulfonyl)benzyl]piperidin-4-yl}nicotinamide 
                 468.2 
                 468.1 
               
               
                   
               
               
                 260 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2-Chloro-3,4-dimethoxybenzyl)piperidin-4-yl]-6- (3-fluorophenyl)nicotinamide 
                 484.2 
                 484.1 
               
               
                   
               
               
                 261 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(Cinnolin-3-ylmethyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 442.2 
                 442.4 
               
               
                   
               
               
                 262 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(3-methylquinoxalin-2- yl)methyl]piperidin-4-yl}nicotinamide 
                 456.2 
                 456.5 
               
               
                   
               
               
                 263 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(quinoxalin-2- ylmethyl)piperidin-4-yl]nicotinamide 
                 442.2 
                 442.5 
               
               
                   
               
               
                 264 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(1,3-Dimethyl-2,4-dioxo-1,2,3,4- tetrahydropyrimidin-5-yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 452.2 
                 452.3 
               
               
                   
               
               
                 265 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Methyl 3-{[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]methyl}-1H-indole-6- carboxylate 
                 487.2 
                 487.4 
               
               
                   
               
               
                 266 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(2-methyl-1H-imidazol-4- yl)methyl]piperidin-4-yl}nicotinamide 
                 394.2 
                 394.3 
               
               
                   
               
               
                 267 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3,5-Dichloro-4-hydroxybenzyl)piperidin-4-yl]-6- (3-fluorophenyl)nicotinamide 
                 474.1 
                 474.1 
               
               
                   
               
               
                 268 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl {2-[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-1,1- dimethylethyl}carbamate 
                 471.2 
                 471.5 
               
               
                   
               
               
                 269 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl {3-[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1- yl]propyl}methylcarbamate 
                 471.3 
                 471.5 
               
               
                   
               
               
                 270 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(1,3,6-trimethyl-2,4-dioxo- 1,2,3,4-tetrahydropyrimidin-5-yl)methyl]piperidin-4- yl}nicotinamide 
                 466.2 
                 466.5 
               
               
                   
               
               
                 271 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{4-[(Diethylamino)carbonyl]benzyl}piperidin-4- yl)-6-(3-fluorophenyl)nicotinamide 
                 489.3 
                 489.3 
               
               
                   
               
               
                 272 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(2-oxo-1,2-dihydropyridin-3- yl)methyl]piperidin-4-yl}nicotinamide 
                 407.2 
                 407.1 
               
               
                   
               
               
                 273 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{2-[3-(Dimethylamino)propoxy]benzyl}piperidin-4- yl)-6-(3-fluorophenyl)nicotinamide 
                 491.3 
                 491.6 
               
               
                   
               
               
                 274 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(1-Ethyl-3,5-dimethyl-1H-pyrazol-4- yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 436.2 
                 436.1 
               
               
                   
               
               
                 275 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[1-(4-fluorophenyl)-1H- pyrazol-4-yl]methyl}piperidin-4-yl)nicotinamide 
                 474.2 
                 474.5 
               
               
                   
               
               
                 276 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(1-Ethyl-3-methyl-1H-pyrazol-4- yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 422.2 
                 422.4 
               
               
                   
               
               
                 277 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-({1-[(Dimethylamino)methyl] cyclopentyl}methyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 439.3 
                 439.4 
               
               
                   
               
               
                 278 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2-tert-Butoxyethyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 400.2 
                 400.5 
               
               
                   
               
               
                 279 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl 4-[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]butanoate 
                 442.2 
                 442.5 
               
               
                   
               
               
                 280 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{4-[(methylsulfonyl) amino]benzyl}piperidin-4-yl)nicotinamide 
                 483.2 
                 483.4 
               
               
                   
               
               
                 281 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl {3-[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]propyl}carbamate 
                 457.3 
                 457.6 
               
               
                   
               
               
                 282 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{4- [(methylamino)sulfonyl]benzyl}piperidin-4- yl)nicotinamide 
                 483.2 
                 483.1 
               
               
                   
               
               
                 283 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(6-methylpyridin-2- yl)methyl]piperidin-4-yl}nicotinamide 
                 405.2 
                 405.0 
               
               
                   
               
               
                 284 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Ethyl (5-{[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]methyl}-1H-indol-1- yl)acetate 
                 515.2 
                 515.3 
               
               
                   
               
               
                 285 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[4-(2- methoxyphenyl)tetrahydro-2H-pyran-4- yl]methyl}piperidin-4-yl)nicotinamide 
                 504.3 
                 504.4 
               
               
                   
               
               
                 286 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[4-(3- methoxyphenyl)tetrahydro-2H-pyran-4- yl]methyl}piperidin-4-yl)nicotinamide 
                 504.3 
                 504.5 
               
               
                   
               
               
                 287 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]piperidin-4- yl}-6-(3-fluorophenyl)nicotinamide 
                 408.2 
                 408.5 
               
               
                   
               
               
                 288 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2,1,3-Benzothiadiazol-5-ylmethyl)piperidin-4-yl]- 6-(3-fluorophenyl)nicotinamide 
                 448.2 
                 448.0 
               
               
                   
               
               
                 289 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(2-phenyl-1,3-thiazol-5- yl)methyl]piperidin-4-yl}nicotinamide 
                 473.2 
                 473.1 
               
               
                   
               
               
                 290 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(quinolin-6- ylmethyl)piperidin-4-yl]nicotinamide 
                 441.2 
                 441.4 
               
               
                   
               
               
                 291 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3-Ethoxybenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 434.2 
                 434.5 
               
               
                   
               
               
                 292 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[2-(Difluoromethoxy)benzyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 456.2 
                 456.5 
               
               
                   
               
               
                 293 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(4-Cyano-2-methyl-2-phenylbutyl)piperidin-4-yl]- 6-(3-fluorophenyl)nicotinamide 
                 471.3 
                 471.4 
               
               
                   
               
               
                 294 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(1H-imidazol-4- ylmethyl)piperidin-4-yl]nicotinamide 
                 380.2 
                 380.5 
               
               
                   
               
               
                 295 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(5-Fluoro-2-methoxybenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 438.2 
                 438.5 
               
               
                   
               
               
                 296 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(4-methyl-1H-imidazol-5- yl)methyl]piperidin-4-yl}nicotinamide 
                 394.2 
                 394.5 
               
               
                   
               
               
                 297 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3,5-Dimethoxybenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 450.2 
                 450.1 
               
               
                   
               
               
                 298 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3,3-Dimethylbutyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 384.2 
                 384.5 
               
               
                   
               
               
                 299 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2-Chlorobenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 424.2 
                 424.0 
               
               
                   
               
               
                 300 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(1H-imidazol-2- ylmethyl)piperidin-4-yl]nicotinamide 
                 380.2 
                 380.4 
               
               
                   
               
               
                 301 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(3-phenylpropyl)piperidin-4- yl]nicotinamide 
                 418.2 
                 418.3 
               
               
                   
               
               
                 302 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(4-Fluoro-3-methylbenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 422.2 
                 422.4 
               
               
                   
               
               
                 303 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3-Cyano-4-fluorobenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 433.2 
                 433.1 
               
               
                   
               
               
                 304 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(1H-indol-5- ylmethyl)piperidin-4-yl]nicotinamide 
                 429.2 
                 429.6 
               
               
                   
               
               
                 305 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2,6-Dimethoxy-4-methylbenzyl)piperidin-4-yl]-6- (3-fluorophenyl)nicotinamide 
                 464.2 
                 464.5 
               
               
                   
               
               
                 306 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2-Ethoxy-4-methoxybenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 464.2 
                 464.5 
               
               
                   
               
               
                 307 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[3-(4-methylphenyl)-1H- pyrazol-4-yl]methyl}piperidin-4-yl)nicotinamide 
                 470.2 
                 470.5 
               
               
                   
               
               
                 308 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{[6-(4-Cyanophenoxy)pyridin-3- yl]methyl}piperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 508.2 
                 508.1 
               
               
                   
               
               
                 309 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-[(4-Chloro-6-fluoro-2H-chromen-3- yl)methyl]piperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 496.2 
                 496.6 
               
               
                   
               
               
                 310 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(2,6-Dioxo-1,2,3,6-tetrahydropyrimidin-4- yl)methyl]piperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 424.2 
                 424.1 
               
               
                   
               
               
                 311 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Methyl 3-{[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]methyl}-1H-indole-5- carboxylate 
                 487.2 
                 487.6 
               
               
                   
               
               
                 312 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(4,4,4-trifluorobutyl)piperidin- 4-yl]nicotinamide 
                 410.2 
                 410.0 
               
               
                   
               
               
                 313 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2,3-Dihydro-1-benzofuran-5-ylmethyl)piperidin- 4-yl]-6-(3-fluorophenyl)nicotinamide 
                 432.2 
                 432.5 
               
               
                   
               
               
                 314 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{[5-Chloro-1-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl]methyl}piperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 496.2 
                 496.3 
               
               
                   
               
               
                 315 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[3-(Difluoromethoxy)benzyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 456.2 
                 456.5 
               
               
                   
               
               
                 316 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2-Ethoxy-3-methoxybenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 464.2 
                 464.4 
               
               
                   
               
               
                 317 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[6-(trifluoromethyl)pyridin-3- yl]methyl}piperidin-4-yl)nicotinamide 
                 459.2 
                 459.4 
               
               
                   
               
               
                 318 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2,3-Difluoro-4-methylbenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 440.2 
                 440.4 
               
               
                   
               
               
                 319 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4- yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 442.2 
                 442.5 
               
               
                   
               
               
                 320 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(2-phenyl-1H-imidazol-4- yl)methyl]piperidin-4-yl}nicotinamide 
                 456.2 
                 456.1 
               
               
                   
               
               
                 321 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(4-Bromo-1-methyl-1H-pyrazol-3- yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 472.1 
                 472.0 
               
               
                   
               
               
                 322 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[3-(4- methoxyphenyl)propyl]piperidin-4-yl}nicotinamide 
                 448.2 
                 448.0 
               
               
                   
               
               
                 323 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2-Fluoro-5-methoxybenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 438.2 
                 438.1 
               
               
                   
               
               
                 324 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2-Fluoro-4-methoxybenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 438.2 
                 438.1 
               
               
                   
               
               
                 325 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-pentylpiperidin-4- yl)nicotinamide 
                 370.2 
                 370.5 
               
               
                   
               
               
                 326 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(2- isopropoxybenzyl)piperidin-4-yl]nicotinamide 
                 448.2 
                 448.5 
               
               
                   
               
               
                 327 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[4-methoxy-3- (methoxymethyl)benzyl]piperidin-4-yl}nicotinamide 
                 464.2 
                 464.4 
               
               
                   
               
               
                 328 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(1,3-Dimethyl-1H-pyrazol-4-yl)methyl]piperidin- 4-yl}-6-(3-fluorophenyl)nicotinamide 
                 408.2 
                 408.5 
               
               
                   
               
               
                 329 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(1-Ethyl-5-methyl-1H-pyrazol-4- yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 422.2 
                 422.5 
               
               
                   
               
               
                 330 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(4-pyrimidin-2- ylbenzyl)piperidin-4-yl]nicotinamide 
                 468.2 
                 468.8 
               
               
                   
               
               
                 331 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(2,3,5- trifluorobenzyl)piperidin-4-yl]nicotinamide 
                 444.2 
                 444.3 
               
               
                   
               
               
                 332 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-fluorophenyl)-N-[1-(345-trifluorobenzyl)piperidin- 4-yl]nicotinamide 
                 444.2 
                 444.3 
               
               
                   
               
               
                 333 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl 3-{[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]methyl}piperidine-1- carboxylate 
                 497.3 
                 497.5 
               
               
                   
               
               
                 334 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (1-{[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1- yl]methyl}cyclobutyl)carbamate 
                 483.3 
                 483.6 
               
               
                   
               
               
                 335 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(3,5-Dimethyl-1-phenyl-1H-pyrazol-4- yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 484.2 
                 484.5 
               
               
                   
               
               
                 336 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(7-hydroxy-3,7- dimethyloctyl)piperidin-4-yl]nicotinamide 
                 456.3 
                 456.5 
               
               
                   
               
               
                 337 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(1H-Benzimidazol-2-ylmethyl)piperidin-4-yl]-6- (3-fluorophenyl)nicotinamide 
                 430.2 
                 430.3 
               
               
                   
               
               
                 338 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[(6-Ethoxyquinolin-2-yl)methyl]piperidin-4-yl}-6- (3-fluorophenyl)nicotinamide 
                 485.2 
                 485.5 
               
               
                   
               
               
                 339 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Methyl (3-{[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]methyl}-1H-indol-1- yl)acetate 
                 501.2 
                 501.5 
               
               
                   
               
               
                 340 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(4,5,6,7-tetrahydro-1,3- benzothiazol-2-ylmethyl)piperidin-4-yl]nicotinamide 
                 451.2 
                 451.3 
               
               
                   
               
               
                 341 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2H-Chromen-3-ylmethyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 444.2 
                 444.5 
               
               
                   
               
               
                 342 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(2-pyrimidin-5- ylbenzyl)piperidin-4-yl]nicotinamide 
                 468.2 
                 468.1 
               
               
                   
               
               
                 343 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(2-Bromoimidazo[1,2-a]pyridin-8- yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 508.1 
                 508.5 
               
               
                   
               
               
                 344 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(5-methyl-3-phenylisoxazol- 4-yl)methyl]piperidin-4-yl}nicotinamide 
                 471.2 
                 471.5 
               
               
                   
               
               
                 345 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl 3-{[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]methyl}pyrrolidine-1- carboxylate 
                 483.3 
                 483.6 
               
               
                   
               
               
                 346 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-({2-[(2,2-Dimethylpropanoyl)amino]pyridin-3- yl}methyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 490.3 
                 490.5 
               
               
                   
               
               
                 347 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl {3-[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-2,2- dimethylpropyl}carbamate 
                 485.3 
                 485.6 
               
               
                   
               
               
                 348 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(2,3,5,6- tetrafluorobenzyl)piperidin-4-yl]nicotinamide 
                 462.2 
                 462.3 
               
               
                   
               
               
                 349 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(4,5,6,7-tetrafluoro-1H-indol- 3-yl)methyl]piperidin-4-yl}nicotinamide 
                 501.2 
                 501.1 
               
               
                   
               
               
                 350 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(tetrahydrofuran-3- ylmethyl)piperidin-4-yl]nicotinamide 
                 384.2 
                 384.6 
               
               
                   
               
               
                 351 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(5-methylisoxazol-3- yl)methyl]piperidin-4-yl}nicotinamide 
                 395.2 
                 394.9 
               
               
                   
               
               
                 352 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(1-methyl-1H-pyrazol-5- yl)methyl]piperidin-4-yl}nicotinamide 
                 394.2 
                 394.3 
               
               
                   
               
               
                 353 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(6-methoxypyridin-3- yl)methyl]piperidin-4-yl}nicotinamide 
                 421.2 
                 421.4 
               
               
                   
               
               
                 354 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(6-methylpyridin-3- yl)methyl]piperidin-4-yl}nicotinamide 
                 405.2 
                 405.4 
               
               
                   
               
               
                 355 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(2-methylpyridin-4- yl)methyl]piperidin-4-yl}nicotinamide 
                 405.2 
                 405.1 
               
               
                   
               
               
                 356 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(5-methyl-1-phenyl-1H- pyrazol-4-yl)methyl]piperidin-4-yl}nicotinamide 
                 470.2 
                 470.5 
               
               
                   
               
               
                 357 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(4-methyl-2- phenylpyrimidin-5-yl)methyl]piperidin-4- yl}nicotinamide 
                 482.2 
                 482.5 
               
               
                   
               
               
                 358 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(6-phenoxypyridin-3- yl)methyl]piperidin-4-yl}nicotinamide 
                 483.2 
                 483.6 
               
               
                   
               
               
                 359 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(isoxazol-5- ylmethyl)piperidin-4-yl]nicotinamide 
                 381.2 
                 381.4 
               
               
                   
               
               
                 360 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(3-methylpentyl)piperidin-4- yl]nicotinamide 
                 384.2 
                 384.4 
               
               
                   
               
               
                 361 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(1-isopropyl-3,5-dimethyl- 1H-pyrazol-4-yl)methyl]piperidin-4-yl}nicotinamide 
                 450.3 
                 450.3 
               
               
                   
               
               
                 362 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[1-(4-fluorophenyl)-3,5- dimethyl-1H-pyrazol-4-yl]methyl}piperidin-4- yl)nicotinamide 
                 502.2 
                 502.5 
               
               
                   
               
               
                 363 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(isoxazol-3- ylmethyl)piperidin-4-yl]nicotinamide 
                 381.2 
                 381.4 
               
               
                   
               
               
                 364 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{3-[(Dimethylamino)methyl]-4- methoxybenzyl}piperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 477.3 
                 477.4 
               
               
                   
               
               
                 365 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[1-(4-methoxyphenyl)-1H- imidazol-2-yl]methyl}piperidin-4-yl)nicotinamide 
                 486.2 
                 486.5 
               
               
                   
               
               
                 366 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{5-[(1-isopropyl-1H-pyrazol-3- yl)methyl]piperidin-4-yl}nicotinamide 
                 422.2 
                 422.5 
               
               
                   
               
               
                 367 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[3-(1H-pyrazol-1- yl)benzyl]piperidin-4-yl}nicotinamide 
                 456.2 
                 456.5 
               
               
                   
               
               
                 368 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(2-Aminopyrimidin-5-yl)methyl]piperidin-4-yl}-6- (3-fluorophenyl)nicotinamide 
                 407.2 
                 407.5 
               
               
                   
               
               
                 369 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[3-(3,5-Dimethyl-1H-pyrazol-1- yl)benzyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 484.2 
                 484.4 
               
               
                   
               
               
                 370 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(6-Fluoro-4H-1,3-benzodioxin-8- yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 466.2 
                 466.1 
               
               
                   
               
               
                 371 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2,1,3-Benzothiadiazol-4-ylmethyl)piperidin-4-yl]- 6-(3-fluorophenyl)nicotinamide 
                 448.2 
                 448.1 
               
               
                   
               
               
                 372 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(1,3-Dimethyl-1H-pyrazol-5-yl)methyl]piperidin- 4-yl}-6-(3-fluorophenyl)nicotinamide 
                 408.2 
                 408.5 
               
               
                   
               
               
                 373 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(2-phenyl-1,3-thiazol-4- yl)methyl]piperidin-4-yl}nicotinamide 
                 473.2 
                 473.0 
               
               
                   
               
               
                 374 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(1-methyl-1H-imidazol-4- yl)methyl]piperidin-4-yl}nicotinamide 
                 394.2 
                 394.0 
               
               
                   
               
               
                 375 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[6-(1H-pyrazol-1-yl)pyridin- 2-yl]methyl}piperidin-4-yl)nicotinamide 
                 457.2 
                 457.6 
               
               
                   
               
               
                 376 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[4-(1-methyl-1H-imidazol-2- yl)benzyl]piperidin-4-yl}nicotinamide 
                 470.2 
                 470.4 
               
               
                   
               
               
                 377 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(3-Bromoimidazo[1,2-a]pyridin-8- yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 508.1 
                 508.4 
               
               
                   
               
               
                 378 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(6-oxo-16-dihydropyridin-3- yl)methyl]piperidin-4-yl}nicotinamide 
                 407.2 
                 407.0 
               
               
                   
               
               
                 379 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Ethyl 5-{[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]methyl}imidazo[1,2- a]pyridine-2-carboxylate 
                 502.2 
                 502.4 
               
               
                   
               
               
                 380 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[3-(2-Amino-6-methylpyridin-3- yl)benzyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 496.2 
                 496.5 
               
               
                   
               
               
                 381 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(3-pyrimidin-5- ylbenzyl)piperidin-4-yl]nicotinamide 
                 468.2 
                 468.1 
               
               
                   
               
               
                 382 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{[5-(2-Chlorophenyl)-1H-pyrazol-4- yl]methyl}piperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 490.2 
                 490.4 
               
               
                   
               
               
                 383 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(2,7-Dimethylimidazo[1,2,a]pyridin-3- yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 458.2 
                 458.5 
               
               
                   
               
               
                 384 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(1H-pyrazol-5- ylmethyl)piperidin-4-yl]nicotinamide 
                 380.2 
                 380.0 
               
               
                   
               
               
                 385 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[4-(1-Cyanocyclopent-3-en-1-yl)benzyl]piperidin- 4-yl}-6-(3-fluorophenyl)nicotinamide 
                 481.2 
                 481.6 
               
               
                   
               
               
                 386 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-3-ylmethyl)piperidin- 4-yl]nicotinamide 
                 434.2 
                 434.1 
               
               
                   
               
               
                 387 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a]azepin-3-ylmethyl)piperidin-4- yl]nicotinamide 
                 448.2 
                 448.5 
               
               
                   
               
               
                 388 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{3-[(3-Ethyl-1,2,4-oxadiazol-5- yl)methoxy]benzyl}piperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 516.2 
                 516.5 
               
               
                   
               
               
                 389 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(2-methylpyrmidin-4- yl)methyl]piperidin-4-yl}nicotinamide 
                 406.2 
                 406.1 
               
               
                   
               
               
                 390 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-({2-[Cyclohexyl(methyl)amino]pyrimidin-4- yl}methyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 503.3 
                 503.4 
               
               
                   
               
               
                 391 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-({2-[(3- methoxypropyl)amino]pyrimidin-4-yl}methyl)piperidin- 4-yl]nicotinamide 
                 479.3 
                 479.5 
               
               
                   
               
               
                 392 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{[2-(Dimethylamino)pyrimidin-4- yl]methyl}piperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 435.2 
                 435.3 
               
               
                   
               
               
                 393 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{[2-(Cyclopropylamino)pyrimidin-4- yl]methyl}piperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 447.2 
                 447.1 
               
               
                   
               
               
                 394 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[1-(2-phenylethyl)-1H- pyrazol-3-yl]methyl}piperidin-4-yl)nicotinamide 
                 484.2 
                 484.6 
               
               
                   
               
               
                 395 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[1-(2-phenylethyl)-1H- pyrazol-5-yl]methyl}piperidin-4-yl)nicotinamide 
                 484.2 
                 484.5 
               
               
                   
               
               
                 396 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(1-methyl-1H-pyrazol-3- yl)methyl]piperidin-4-yl}nicotinamide 
                 394.2 
                 394.3 
               
               
                   
               
               
                 397 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(2-morpholin-4-ylpyrimidin- 4-yl)methyl]piperidin-4-yl}nicotinamide 
                 477.2 
                 477.5 
               
               
                   
               
               
                 398 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-({2-[Ethyl(methyl)amino]-5,6,7,8- tetrahydroquinazolin-6-yl}methyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 503.3 
                 503.6 
               
               
                   
               
               
                 399 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{[2-(cyclopropylmethyl)-5,6,7,8- tetrahydroquinazolin-6-yl]methyl}piperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 500.3 
                 500.5 
               
               
                   
               
               
                 400 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(2-isopropyl-5,6,7,8- tetrahydroquinazolin-6-yl)methyl]piperidin-4- yl}nicotinamide 
                 488.3 
                 488.5 
               
               
                   
               
               
                 401 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(2-methyl-5,6,7,8- tetrahydroquinazolin-6-yl)methyl]piperidin-4- yl}nicotinamide 
                 460.2 
                 460.5 
               
               
                   
               
               
                 402 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(2-tert-Butyl-5,6,7,8-tetrahydroquinazolin-6- yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 502.3 
                 502.4 
               
               
                   
               
               
                 403 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(2-propyl-5,6,7,8- tetrahydroquinazolin-6-yl)methyl]piperidin-4- yl}nicotinamide 
                 488.3 
                 488.5 
               
               
                   
               
               
                 404 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[3-methoxy-2-(2- methoxyethoxy)benzyl]piperidin-4-yl}nicotinamide 
                 494.2 
                 494.1 
               
               
                   
               
               
                 405 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(2,2-Difluoroethoxy)-3- methoxybenzyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 500.2 
                 500.5 
               
               
                   
               
               
                 406 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(imidazo[1,2-a]pyridin-2- ylmethyl)piperidin-4-yl]nicotinamide 
                 430.2 
                 430.4 
               
               
                   
               
               
                 407 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[4-(4-fluorophenyl)-1,3- thiazol-2-yl]methyl}piperidin-4-yl)nicotinamide 
                 491.2 
                 491.6 
               
               
                   
               
               
                 408 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[4-(3-fluorophenyl)-1,3- thiazol-2-yl]methyl}piperidin-4-yl)nicotinamide 
                 491.2 
                 491.5 
               
               
                   
               
               
                 409 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[4-(3-methoxyphenyl)-1,3- thiazol-2-yl]methyl}piperidin-4-yl)nicotinamide 
                 503.2 
                 503.4 
               
               
                   
               
               
                 410 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{[4-(3-Cyanophenyl)-1,3-thiazol-2- yl]methyl}piperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 498.2 
                 498.3 
               
               
                   
               
               
                 411 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(4-Ethyl-1,3-thiazol-2-yl)methyl]piperidin-4-yl}-6- (3-fluorophenyl)nicotinamide 
                 425.2 
                 425.0 
               
               
                   
               
               
                 412 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(5-methyl-4-phenyl-13- thiazol-2-yl)methyl]piperidin-4-yl}nicotinamide 
                 487.2 
                 487.5 
               
               
                   
               
               
                 413 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{[4-(3,4)-1,3-Thiazol-2-yl]methyl}piperidin-4-yl)- 6-(3-fluorophenyl)nicotinamide 
                 509.2 
                 509.4 
               
               
                   
               
               
                 414 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(3-Bromoimidazo[1,2-a]pyridin-2- yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 508.1 
                 508.5 
               
               
                   
               
               
                 415 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(3-methyl-3H-imidazo[4,5- b]pyridin-2-yl)methyl]piperidin-4-yl}nicotinamide 
                 445.2 
                 445.5 
               
               
                   
               
               
                 416 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (4-{[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1- yl]methyl}cyclohexyl)carbamate 
                 511.3 
                 511.5 
               
               
                   
               
               
                 417 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{3-[3-(Dimethylamino)propoxy]benzyl}piperidin- 4-yl)-6-(3-fluorophenyl)nicotinamide 
                 491.3 
                 491.9 
               
               
                   
               
               
                 418 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2,3-Dihydro-1,4-benzodioxin-5- ylmethyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 448.2 
                 448.5 
               
               
                   
               
               
                 419 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2-Fluoro-4-(1-hydroxy-1- methylethyl)benzyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 466.2 
                 466.5 
               
               
                   
               
               
                 420 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[1-(2-methoxyethyl)-1H- benzimidazol-2-yl]methyl}piperidin-4-yl)nicotinamide 
                 488.2 
                 488.6 
               
               
                   
               
               
                 421 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(1-methyl-1H-imidazo[4,5- b]pyridin-2-yl)methyl]piperidin-4-yl}nicotinamide 
                 445.2 
                 445.8 
               
               
                   
               
               
                 422 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(1-Cyclopropyl-1H-benzimidazol-2- yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 470.2 
                 470.6 
               
               
                   
               
               
                 423 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{[(1-(2-Fluoroethyl)-1H-benzimidazol-2- yl]methyl}piperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 476.2 
                 476.5 
               
               
                   
               
               
                 424 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{[(1-(Fluoromethyl)-1H-benzimidazol-2- yl]methyl}piperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 462.2 
                 462.5 
               
               
                   
               
               
                 425 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[3-(2,2-Difluoroethyoxy)-4- methoxybenzyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 500.2 
                 500.8 
               
               
                   
               
               
                 426 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(2-phenyl-1,3-oxazol-4- yl)methyl]piperidin-4-yl}nicotinamide 
                 457.2 
                 457.5 
               
               
                   
               
               
                 427 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(3-methyl-1-propyl-1H- pyrazol-4-yl)methyl]piperidin-4-yl}nicotinamide 
                 436.2 
                 436.6 
               
               
                   
               
               
                 428 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[3-(hydroxymethyl)-4- isopropoxybenzyl]piperidin-4-yl}nicotinamide 
                 478.2 
                 478.5 
               
               
                   
               
               
                 429 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(5-isobutyl-1H-pyrazol-3- yl)methyl]piperidin-4-yl}nicotinamide 
                 436.2 
                 436.6 
               
               
                   
               
               
                 430 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(8-fluoroquinolin-2- yl)methyl]piperidin-4-yl}nicotinamide 
                 459.2 
                 459.5 
               
               
                   
               
               
                 431 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(1-Ethyl-1H-imidazol-2-yl)methyl]piperidin-4- yl}-6-(3-fluorophenyl)nicotinamide 
                 408.2 
                 408.5 
               
               
                   
               
               
                 432 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(3-methylimidazo[1,2- a]pyridin-2-yl)methyl]piperidin-4-yl}nicotinamide 
                 444.2 
                 444.9 
               
               
                   
               
               
                 433 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(4-isopropyl-1,3-thiazol-2- yl)methyl]piperidin-4-yl}nicotinamide 
                 439.2 
                 439.5 
               
               
                   
               
               
                 434 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[2-(2- methylphenyl)pyrimidin-5-yl]methyl}piperidin-4- yl)nicotinamide 
                 482.2 
                 482.5 
               
               
                   
               
               
                 435 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[1-(3-methylphenyl)-1H- imidazol-2-yl]methyl}piperidin-4-yl)nicotinamide 
                 470.2 
                 470.6 
               
               
                   
               
               
                 436 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[2-(1H-pyrazol-1- ylmethyl)benzyl]piperidin-4-yl}nicotinamide 
                 470.2 
                 470.8 
               
               
                   
               
               
                 437 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[2-(2- methoxyphenyl)pyrimidin-5-yl]methyl}piperidin-4- yl)nicotinamide 
                 498.2 
                 498.8 
               
               
                   
               
               
                 438 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[5-methyl-2-(1H-pyrazol-1- yl)benzyl]piperidin-4-yl}nicotinamide 
                 470.2 
                 470.6 
               
               
                   
               
               
                 439 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[3-(3-fluorophenyl)-1H- pyrazol-4-yl]methyl}piperidin-4-yl)nicotinamide 
                 474.2 
                 474.6 
               
               
                   
               
               
                 440 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[2-(2- methoxyethyl)pyrimidin-5-yl]methyl}piperidin-4- yl)nicotinamide 
                 450.2 
                 450.3 
               
               
                   
               
               
                 441 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(2-propylpyrimidin-5- yl)methyl]piperidin-4-yl}nicotinamide 
                 434.2 
                 434.5 
               
               
                   
               
               
                 442 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(2-Ethylpyrimidin-5-yl)methyl]piperidin-4-yl}-6- (3-fluorophenyl)nicotinamide 
                 420.2 
                 420.5 
               
               
                   
               
               
                 443 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(2-methylpyrimidin-5- yl)methyl]piperidin-4-yl}nicotinamide 
                 406.2 
                 406.5 
               
               
                   
               
               
                 444 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(3,5,6-trimethylpyrazin-2- yl)methyl]piperidin-4-yl}nicotinamide 
                 434.2 
                 434.6 
               
               
                   
               
               
                 445 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(6-Chloro-2-methylimidazo[1,2-a]pyridin-3- yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 478.2 
                 478.4 
               
               
                   
               
               
                 446 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(2-methyl-1,3-thiazol-5- yl)methyl]piperidin-4-yl}nicotinamide 
                 411.2 
                 411.5 
               
               
                   
               
               
                 447 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[1-(methoxymethyl)-1H- benzimidazol-2-yl]methyl}piperidin-4-yl)nicotinamide 
                 474.2 
                 474.6 
               
               
                   
               
               
                 448 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(5,6-Dihydro-4H-imidazo[4,51-ij]quinolin-2- ylmethyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 470.2 
                 470.5 
               
               
                   
               
               
                 449 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(5,6-Difluoro-1-methyl-1H-benzimidazol-2- yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 480.2 
                 480.5 
               
               
                   
               
               
                 450 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(1,5-naphthyridin-4- ylmethyl)piperidin-4-yl]nicotinamide 
                 442.2 
                 442.5 
               
               
                   
               
               
                 451 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(pyrido[2,3-b]pyrazin-8- ylmethyl)piperidin-4-yl]nicotinamide 
                 443.2 
                 443.8 
               
               
                   
               
               
                 452 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(1,8-naphthyridin-4- ylmethyl)piperidin-4-yl]nicotinamide 
                 442.2 
                 442.6 
               
               
                   
               
               
                 453 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[4-(morpholin-4- ylmethyl)benzyl]piperidin-4-yl}nicotinamide 
                 489.3 
                 489.5 
               
               
                   
               
               
                 454 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[4-(5-methyl-1,3,4-oxadiazol- 2-yl)benzyl]piperidin-4-yl}nicotinamide 
                 472.2 
                 472.9 
               
               
                   
               
               
                 455 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(5-methylpyrazin-2- yl)methyl]piperidin-4-yl}nicotinamide 
                 406.2 
                 406.5 
               
               
                   
               
               
                 456 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(4H-imidazo[4,51-ij]quinolin- 2-ylmethyl)piperidin-4-yl]nicotinamide 
                 468.2 
                 468.6 
               
               
                   
               
               
                 457 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Ethyl 2-{[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]methyl}-1,3-thiazole- 4-carboxylate 
                 469.2 
                 469.6 
               
               
                   
               
               
                 458 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (2S,3R)-5-{[4-({[6-(3-Fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]methyl}-2-methyl-2,3- dihydro-1-benzofuran-3-carboxylic acid 
                 490.2 
                 490.5 
               
               
                   
               
               
                 459 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(2-Ethoxypyridin-3-yl)methyl]piperidin-4-yl}-6- (3-fluorophenyl)nicotinamide 
                 435.2 
                 435.6 
               
               
                   
               
               
                 460 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(2-methoxypyridin-3- yl)methyl]piperidin-4-yl}nicotinamide 
                 421.2 
                 421.5 
               
               
                   
               
               
                 461 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(2-isopropoxypyridin-3- yl)methyl]piperidin-4-yl}nicotinamide 
                 449.2 
                 449.5 
               
               
                   
               
               
                 462 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{[2-(Cyclopropylmethoxy)pyridin-3- yl]methyl}piperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 461.2 
                 461.6 
               
               
                   
               
               
                 463 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{[6-(Fluoromethyl)pyridin-2-yl]methyl}piperidin-4- yl)-6-(3-fluorophenyl)nicotinamide 
                 423.2 
                 423.4 
               
               
                   
               
               
                 464 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[2-(1-hydroxy-1- methylethyl)pyridin-4-yl]methyl}piperidin-4- yl)nicotinamide 
                 449.2 
                 449.6 
               
               
                   
               
               
                 465 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(5,6,7,8-tetrahydro-18- naphthyridin-2-ylmethyl)piperidin-4-yl]nicotinamide 
                 446.2 
                 446.8 
               
               
                   
               
               
                 466 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Ethyl (4-{[4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]methyl}-1H-pyrazol- 1-yl)acetate 
                 466.2 
                 466.3 
               
               
                   
               
               
                 467 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(4-Chloro-2-fluoro-5-methoxybenzyl)piperidin-4- yl]-6-(3-fluorophenyl)nicotinamide 
                 472.2 
                 472.6 
               
               
                   
               
               
                 468 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2-Chloro-2-fluoro-5-methoxybenzyl)piperidin-4- yl]-6-(3-fluorophenyl)nicotinamide 
                 472.2 
                 472.8 
               
               
                   
               
               
                 469 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(6-oxo-1,6-dihydropyridazin- 3-yl)methyl]piperidin-4-yl}nicotinamide 
                 408.2 
                 408.5 
               
               
                   
               
               
                 470 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(3- isopropyl[1,2,4]triazolo[4,3-a]pyridin-6- yl)methyl]piperidin-4-yl}nicotinamide 
                 473.2 
                 473.6 
               
               
                   
               
               
                 471 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(6-methoxyquinolin-4- yl)methyl]piperidin-4-yl}nicotinamide 
                 471.2 
                 471.6 
               
               
                   
               
               
                 472 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[6-(1-hydroxy-1- methylethyl)pyridin-3-yl]methyl}piperidin-4- yl)nicotinamide 
                 449.2 
                 449.5 
               
               
                   
               
               
                 473 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[4-(1-methyl-1H-pyrazol-3- yl)benzyl]piperidin-4-yl}nicotinamide 
                 470.2 
                 470.6 
               
               
                   
               
               
                 474 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[4-(1-methyl-1H-pyrazol-5- yl)benzyl]piperidin-4-yl}nicotinamide 
                 470.2 
                 470.6 
               
               
                   
               
               
                 475 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(5-Bromopyridin-2-yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 469.1 
                 471.5 (Br iso) 
               
               
                   
               
               
                 476 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{[6-(Fluoromethyl)pyridin-3-yl]methyl}piperidin-4- yl)-6-(3-fluorophenyl)nicotinamide 
                 423.2 
                 423.4 
               
               
                   
               
               
                 477 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[1-methyl-3-(6- methylpyridazin-3-yl)-1H-1,2,4-triazol-5- yl]methyl}piperidin-4-yl)nicotinamide 
                 487.2 
                 487.5 
               
               
                   
               
               
                 478 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(1-methyl-3-pyridin-2-yl-1H- 1,2,4-triazol-5-yl)methyl]piperidin-4-yl}nicotinamide 
                 472.2 
                 472.9 
               
               
                   
               
               
                 479 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{[1,3-Dimethyl-5-(1,4-oxazepan-4-yl)-1H- pyrazol-4-yl]methyl}piperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 507.3 
                 507.5 
               
               
                   
               
               
                 480 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[1-methyl-5-(1-methyl-1H- pyrazol-5-yl)-1H-1,2,4-triazol-3-yl]methyl}piperidin-4- yl)nicotinamide 
                 475.2 
                 475.5 
               
               
                   
               
               
                 481 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(1-methyl-3-pyrimidin-2-yl- 1H-1,2,4-triazol-5-yl)methyl]piperidin-4- yl}nicotinamide 
                 473.2 
                 473.6 
               
               
                   
               
               
                 482 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[5-(2-fluorophenyl)-1- methyl-1H-1,2,4-triazol-3-yl]methyl}piperidin-4- yl)nicotinamide 
                 489.2 
                 489.6 
               
               
                   
               
               
                 483 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[3-(3-fluorophenyl)-1- methyl-1H-1,2,4-triazol-5-yl]methyl}piperidin-4- yl)nicotinamide 
                 489.2 
                 489.5 
               
               
                   
               
               
                 484 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[5-(4-fluorophenyl)-1- methyl-1H-1,2,4-triazol-3-yl]methyl}piperidin-4- yl)nicotinamide 
                 489.2 
                 489.5 
               
               
                   
               
               
                 485 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(1-methyl-5-pyridin-2-yl-1H- 1,2,4-triazol-3-yl)methyl]piperidin-4-yl}nicotinamide 
                 472.2 
                 472.9 
               
               
                   
               
               
                 486 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[3-(Cyclopropyloxy)-4- (difluoromethoxy)benzyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 512.2 
                 512.7 
               
               
                   
               
               
                 487 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[5-(4-methoxy-3,5- dimethylpyridin-2-yl)methyl]piperidin-4- yl)nicotinamide 
                 449.2 
                 449.5 
               
               
                   
               
               
                 488 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[4-(1H-pyrazol-5- yl)benzyl]piperidin-4-yl}nicotinamide 
                 456.2 
                 456.5 
               
               
                   
               
               
                 489 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(4-Aminopyrimidin-5-yl)methyl]piperidin-4-yl}-6- (3-fluorophenyl)nicotinamide 
                 407.2 
                 407.5 
               
               
                   
               
               
                 490 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2,3-Dihydro-1-benzofuran-7-ylmethyl)piperidin- 4-yl]-6-(3-fluorophenyl)nicotinamide 
                 432.2 
                 432.5 
               
               
                   
               
               
                 491 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(6-methoxy-1,5- naphthyridin-4-yl)methyl]piperidin-4-yl}nicotinamide 
                 472.2 
                 472.9 
               
               
                   
               
               
                 492 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[4-(1H-1,2,3-triazol-1- yl)benzyl]piperidin-4-yl}nicotinamide 
                 457.2 
                 457.5 
               
               
                   
               
               
                 493 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[4-(2H-1,2,3-triazol-2- yl)benzyl]piperidin-4-yl}nicotinamide 
                 457.2 
                 457.5 
               
               
                   
               
               
                 494 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(8-methoxy-2,3-dihydro-1,4- benzodioxin-6-yl)methyl]piperidin-4-yl}nicotinamide 
                 478.2 
                 478.6 
               
               
                   
               
               
                 495 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(1-methyl-1H-1,2,3-triazol-5- yl)methyl]piperidin-4-yl}nicotinamide 
                 395.2 
                 395.4 
               
               
                   
               
               
                 496 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(3-methoxy-4- methylbenzyl)piperidin-4-yl]nicotinamide 
                 434.2 
                 434.5 
               
               
                   
               
               
                 497 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(3-oxo-3,4-dihydro-2H-14- benzoxazin-6-yl)methyl]piperidin-4-yl}nicotinamide 
                 461.2 
                 461.5 
               
               
                   
               
               
                 498 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(1-methyl-5-phenyl-1H- pyrazol-4-yl)methyl]piperidin-4-yl}nicotinamide 
                 470.2 
                 470.6 
               
               
                   
               
               
                 499 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[5-(4-methoxyphenyl)-1- methyl-1H-pyrazol-4-yl]methyl}piperidin-4- yl)nicotinamide 
                 500.2 
                 500.8 
               
               
                   
               
               
                 500 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[5-(4-fluorophenyl)-1- methyl-1H-pyrazol-4-yl]methyl}piperidin-4- yl)nicotinamide 
                 488.2 
                 488.5 
               
               
                   
               
               
                 501 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{3- [(methylsulfonyl)amino]benzyl}piperidin-4- yl)nicotinamide 
                 483.2 
                 483.6 
               
               
                   
               
               
                 502 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(1H-indol-6- ylmethyl)piperidin-4-yl]nicotinamide 
                 429.2 
                 429.5 
               
               
                   
               
               
                 503 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2-Fluoro-4-methylbenzyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 422.2 
                 422.0 
               
               
                   
               
               
                 504 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(5,7-Dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2- yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 460.2 
                 460.6 
               
               
                   
               
               
                 505 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(1- methylcyclopropyl)methyl]piperidin-4-yl}nicotinamide 
                 368.2 
                 368.1 
               
               
                   
               
               
                 506 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[5-(3-methoxyphenyl)-1- methyl-1H-pyrazol-4-yl]methyl}piperidin-4- yl)nicotinamide 
                 500.2 
                 500.5 
               
               
                   
               
               
                 507 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[5-(3-fluorophenyl)-1- methyl-1H-pyrazol-4-yl]methyl}piperidin-4- yl)nicotinamide 
                 488.2 
                 488.3 
               
               
                   
               
               
                 508 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[5-(2-methoxyphenyl)-1- methyl-1H-pyrazol-4-yl]methyl}piperidin-4- yl)nicotinamide 
                 500.2 
                 500.5 
               
               
                   
               
               
                 509 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[1-methyl-5-(2- methylphenyl)-1H-pyrazol-4-yl]methyl}piperidin-4- yl)nicotinamide 
                 484.2 
                 484.6 
               
               
                   
               
               
                 510 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{[1-methyl-5-(4- methylphenyl)-1H-pyrazol-4-yl]methyl}piperidin-4- yl)nicotinamide 
                 484.2 
                 484.3 
               
               
                   
               
               
                 511 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(1- methylcyclobutyl)methyl]piperidin-4-yl}nicotinamide 
                 382.2 
                 382.5 
               
               
                   
               
               
                 512 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(5-Chloro-1H-indazol-3-yl)methyl]piperidin-4-yl}- 6-(3-fluorophenyl)nicotinamide 
                 464.2 
                 464.0 
               
               
                   
               
               
                 513 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(1H-indazol-3- ylmethyl)piperidin-4-yl]nicotinamide 
                 430.2 
                 430.5 
               
               
                   
               
               
                 514 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(2-oxo-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7-yl)methyl]piperidin-4- yl}nicotinamide 
                 462.2 
                 462.5 
               
               
                   
               
               
                 515 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(2-methoxy-5- methylbenzyl)piperidin-4-yl]nicotinamide 
                 434.2 
                 434.5 
               
               
                   
               
               
                 516 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(1-propyl-1H-pyrazol-4- yl)methyl]piperidin-4-yl}nicotinamide 
                 422.2 
                 422.5 
               
               
                   
               
               
                 517 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[(1-propyl-1H-pyrazol-5- yl)methyl]piperidin-4-yl}nicotinamide 
                 422.2 
                 422.5 
               
               
                   
               
               
                 518 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(1-Benzofuran-3-ylmethyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 430.2 
                 430.5 
               
               
                   
               
               
                 519 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[(4-Chloro-1-methyl-1H-pyrazol-5- yl)methyl]piperidin-4-yl}-6-(3- fluorophenyl)nicotinamide 
                 428.2 
                 428.4 
               
               
                   
               
               
                 520 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(1-Benzofuran-5-ylmethyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 430.2 
                 430.0 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 521 
     Benzyl 4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Benzyl 4-aminopiperidine-1-carboxylate (11 g, 46.9 mmol), EDAC (9.94 g, 51.9 mmol), NMM (20.7 mL, 189 mmol) and HOBt*H2O (7.22 g, 47 mmol) were added to a solution of 6-(3-fluorophenyl)nicotinic acid (10.2 g, 47 mmol) in dichloromethane:DMF (200 mL:2 mL). The reaction mixture was stirred at room temperature for 18 h, evaporated, and chromatographed (silica gel, ethyl acetate-hexane, 2:1). The solvent was evaporated to give tert-butyl 4-(2-(3-fluorophenyl)nicotinamido)piperidine-1-carboxylate (yield 61%, 12.7 g). LC/MS=434 observed, 434.19 expected 
     The following compounds of formula (VII) were prepared in a manner analogous to Example 521. 
     
       
         
           
               
               
            
               
                   
               
               
                   
                 (VII) 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 MS calc 
                 MS obs 
               
               
                 Ex 
                 Q 
                 Name 
                 (M) 
                 (M + H) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 522 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (1R,5S)-3-({[6-(3- fluorophenyl)pyridin-3- yl]carbonyl}amino)-8- azabicyclo[3.2.1]octane-8-carboxylate 
                 425.2115 
                 426.2305 
               
               
                   
               
               
                 523 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl 3-(4-fluorophenyl)-4-({[6-(3- fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidine-1- carboxylate 
                 493.2 
                 494.0 
               
               
                   
               
               
                 524 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1- formylpiperidin-4-yl)nicotinamide 
                 327.1 
                 327.1 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 525 
     6-(3-Fluorophenyl)-N-[3-(4-fluorophenyl)piperidin-4-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl 3-(4-fluorophenyl)-4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidine-1-carboxylate (348 mg, 0.71 mmol) in CH 2 Cl 2  (5 mL) at 0° C. was added TFA (1.2 mL). After stirring overnight at rt the the reaction was diluted with toluene (5 mL) and then the solvent removed and the residue purified by chromatography (silica, 10% MeOH/DCM) to give the desired product, 6-(3-fluorophenyl)-N-[3-(4-fluorophenyl)piperidin-4-yl]nicotinamide. (168 mg, 61% yield). 1H NMR (400 MHz, DMSO-d6) □ ppm 8.87 (1H, d, J=2.0 Hz), 8.52 (1H, s), 8.04-8.15 (2H, m), 8.00 (2H, d, J=7.9 Hz), 7.58 (1H, d, J=6.1 Hz), 7.35 (4H, dd, J=9.0, 3.5 Hz), 7.08-7.22 (2H, m), 4.60-4.72 (1H, m), 3.81 (1H, t), 3.05-3.27 (4H, m), 1.91 (1H, s). LC/MS=(M+H)=394.1 observed, 394.17 expected. 
     EXAMPLE 526 
     N-Acetyl-3-(4-fluorophenyl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     To a solution of 6-(3-fluorophenyl)-N-[3-(4-fluorophenyl)piperidin-4-yl]nicotinamide (250 mg, 0.64 mmol) in DCM (5 mL) at 0° C. was added TEA (0.11 mL, 0.76 mmol ), DMAP (7.76 mg, 0.064 mmol ) and acetic anhydride (97.3 mg, 0.95 mmol ). After stirring at rt for 1 hr the reaction was diluted with water and then extracted with dcm. The organic extracts were combined, dried (Na 2 SO 4 ) and solvent removed to give an oil, which after chromatography gave the desired product, N-[1-acetyl-3-(4-fluorophenyl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide (235 mg, 85% yield). 1H NMR (400 MHz, DMSO-d6) □ ppm 8.76-8.89 (1 H, m), 8.27-8.51 (1H, m), 8.03-8.17 (2H, m), 7.87-8.02 (2H, m), 7.50-7.62 (1H, m), 7.22-7.46 (3 H, m), 7.03-7.17 (2H, m), 4.33-4.62 (1H, m), 3.89-4.12 (1H, m), 3.54-3.86 (2H, m), 3.34-3.44 (1 H, m), 2.63-2.92 (1H, m), 2.05-2.14 (3H, m), 1.94-2.04 (1H, m), 1.71-1.92 (1H, m). LC/MS (M+H)=436.0 observed, 436.18 expected. 
     EXAMPLE 527 
     N-[1-(2-Cyclopropyl-1-methylethyl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     To a solution of 1-cyclopropylpropan-2-one (0.2 mL, 0.08 mmol in 1:1 THF:DMSO) was added 6-(3-fluorophenyl)-N-(piperidin-4-yl)nicotinamide (in 1:1 THF:DMSO, 0.2 mL, 0.08 mmol), sodium triacetoxyborohydride dispersion (0.33 mL, 2.5 eq, in 1:1 THF:DMSO) and glacial acetic acid (0.01 mL). The reaction mixture was stirred at room temperature for 16-24 h and then aqueous K 2 CO 3  (3 M, 0.2 mL) and ethanol (0.55 mL) was added. The reaction was shaken for 30 min and then the mixture was filtered and the filtrate concentrated and the residue purified by RP-HPLC to give the desired product. LC/MS=382.4 (M+H) observed, 382.23 expected. 
     The following compounds of formula (VII) were prepared by methods analogous to the method described for Example 527. 
     
       
         
           
               
               
            
               
                   
               
               
                   
                 (VII) 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 MS 
                   
               
               
                   
                   
                   
                 calc 
                 MS obs 
               
               
                 Ex 
                 Q 
                 Name 
                 (M) 
                 (M + H) 
               
               
                   
               
               
                 528 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(5-methoxy-2,3- dihydro-1H-inden-1-yl)piperidin-4- yl]nicotinamide 
                 445.2 
                 446.4 
               
               
                   
               
               
                 529 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[1-methyl-2-(1- methylcyclopropyl)ethyl]piperidin-4- yl}nicotinamide 
                 395.2 
                 396.5 
               
               
                   
               
               
                 530 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[1-(2- methoxyphenyl)ethyl]piperidin-4-yl}nicotinamide 
                 433.2 
                 434.4 
               
               
                   
               
               
                 531 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(1- phenylethyl)piperidin-4-yl]nicotinamide 
                 403.2 
                 404.4 
               
               
                   
               
               
                 532 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[1-(3- methoxyphenyl)ethyl]piperidin-4-yl}nicotinamide 
                 433.2 
                 434.1 
               
               
                   
               
               
                 533 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[1-(2,6-Dimethoxyphenyl)ethyl]piperidin- 4-yl}-6-(3-fluorophenyl)nicotinamide 
                 463.2 
                 464.5 
               
               
                   
               
               
                 534 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[2-(4-methoxyphenyl)- 1-methylethyl]piperidin-4-yl}nicotinamide 
                 447.2 
                 448.1 
               
               
                   
               
               
                 535 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[1-(4- methoxyphenyl)ethyl]piperidin-4-yl}nicotinamide 
                 433.2 
                 434.5 
               
               
                   
               
               
                 536 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[1-(3,4-Dimethoxyphenyl)ethyl]piperidin-4- yl}-6-(3-fluorophenyl)nicotinamide 
                 463.2 
                 464.4 
               
               
                   
               
               
                 537 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[1-(Cyclopropylmethyl)-7-oxoazepan-4- yl]piperidin-4-yl}-6-(3-fluorophenyl)nicotinamide 
                 464.2 
                 465.5 
               
               
                   
               
               
                 538 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(1-isobutyl-7- oxoazepan-4-yl)piperidin-4-yl]nicotinamide 
                 466.2 
                 467.5 
               
               
                   
               
               
                 539 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[1-(2-methoxyethyl)-7- oxoazepan-4-yl]piperidin-4-yl}nicotinamide 
                 468.3 
                 469.6 
               
               
                   
               
               
                 540 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[1-(1-phenyl-1H- pyrazol-4-yl)ethyl]piperidin-4-yl}nicotinamide 
                 469.2 
                 470.6 
               
               
                   
               
               
                 541 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[1-(3,4-Dimethoxyphenyl)propyl]piperidin- 4-yl}-6-(3-fluorophenyl)nicotinamide 
                 477.2 
                 478.4 
               
               
                   
               
               
                 542 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[1-(Cyclobutylmethyl)-7-oxoazepan-4- yl]piperidin-4-yl}-6-(3-fluorophenyl)nicotinamide 
                 478.3 
                 479.5 
               
               
                   
               
               
                 543 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[1-(2,4-Dimethoxyphenyl)ethyl]piperidin-4- yl}-6-(3-fluorophenyl)nicotinamide 
                 463.2 
                 464.0 
               
               
                   
               
               
                 544 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[1-(3,5-Dimethoxyphenyl)ethyl]piperidin-4- yl}-6-(3-fluorophenyl)nicotinamide 
                 463.2 
                 464.5 
               
               
                   
               
               
                 545 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-sec-Butylpiperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 355.2 
                 356.1 
               
               
                   
               
               
                 546 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[4-(Acetylamino)cyclohexyl]piperidin-4-yl}- 6-(3-fluorophenyl)nicotinamide 
                 438.2 
                 439.4 
               
               
                   
               
               
                 547 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(tetrahydro-2H-pyran- 4-yl)piperidin-4-yl]nicotinamide 
                 383.2 
                 384.5 
               
               
                   
               
               
                 548 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[1-methyl-3-(1H- pyrazol-1-yl)propyl]piperidin-4-yl}nicotinamide 
                 421.2 
                 422.3 
               
               
                   
               
               
                 549 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(3- methoxycyclohexyl)piperidin-4-yl]nicotinamide 
                 411.2 
                 412.1 
               
               
                   
               
               
                 550 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(3-hydroxy-1- methylpropyl)piperidin-4-yl]nicotinamide 
                 371.2 
                 372.4 
               
               
                   
               
               
                 551 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-Cyclopentylpiperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 367.2 
                 368.4 
               
               
                   
               
               
                 552 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-Azetidin-3-ylpiperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 354.2 
                 355.0 
               
               
                   
               
               
                 553 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[2-(2- methoxyphenoxy)-1-methylethyl]piperidin-4- yl}nicotinamide 
                 463.2 
                 464.4 
               
               
                   
               
               
                 554 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(4-hydroxy-4-pyrimidin- 5-ylcyclohexyl)piperidin-4-yl]nicotinamide 
                 475.2 
                 476.3 
               
               
                   
               
               
                 555 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[4-hydroxy-4-(1,3- thiazol-2-yl)cyclohexyl]piperidin-4- yl}nicotinamide 
                 480.2 
                 481.1 
               
               
                   
               
               
                 556 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(4- phenoxycyclohexyl)piperidin-4-yl]nicotinamide 
                 473.2 
                 474.5 
               
               
                   
               
               
                 557 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[1-(3-Amino-3-oxopropyl)-7-oxoazepan-4- yl]piperidin-4-yl}-6-(3-fluorophenyl)nicotinamide 
                 481.2 
                 482.5 
               
               
                   
               
               
                 558 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(4-hydroxy-4- phenylcyclohexyl)piperidin-4-yl]nicotinamide 
                 473.2 
                 474.4 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 579 
     tert-Butyl 6-[4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidin-1-yl]nicotinate 
     
       
         
         
             
             
         
       
     
     To a microwave tube was added 6-(3-fluorophenyl)-N-(piperidin-4-yl)nicotinamide (2.2 g, 7.35 mmol, tert-butyl 6-bromonicotinate (2.85 g, 11 mmol), DMA (5 mL), CsF(6.70 g, 44.1 mmol) and TEA (5 drops). After heating the reaction mixture on CEM microwave at fullpower (100° C. for 45 min), the solution was extracted with ethyl acetate and washed with water. The solvent was removed and the residue purified by chromatography (silica, 50% EtOAc: Hep) to give the desired product, tert-butyl 6-[4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidin-1-yl]nicotinate (3.39 g, 97%). 1H NMR (400 MHz, DMSO-d6) □ ppm 9.06 (1H, d, J=1.1 Hz), 8.58 (1H, d, J=1.6 Hz), 8.47 (1H, d, J=7.9 Hz), 8.27 (1H, d, J=8.4 Hz), 8.10 (1H, d, J=8.2 Hz), 7.98 (1H, d, J=8.4 Hz), 7.93 (1H, d, J=10.8 Hz), 7.86 (1H, d, J=9.1 Hz), 7.54 (1H, q), 7.29 (1H, t, J=8.6 Hz), 6.88 (1H, d, J=9.1 Hz), 4.41 (2H, d, J=13.5 Hz, 4.15 (1H, d, J=4.8 Hz), 3.10 (2H, t, J=12.3 Hz), 2.48 (2H, br. s.), 1.91 (2H, d, J=13.4 Hz), 1.50 (9H, s), HRMS (TOF, ES+) calculated 477.2302; observed 477.2515. 
     EXAMPLE 560 
     6-[4-({[6-(3-Fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidin-1-yl]nicotinic acid 
     
       
         
         
             
             
         
       
     
     To a round-bottom flask containing tert-butyl 6-[4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidin-1-yl]nicotinate was added DCM (50 mL) and TFA (18 mL). After stirring at rt overnight the reaction was diluted with toluene (10 mL) and the solvent removed to give 6-[4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidin-1-yl]nicotinic acid, as a white solid (30 mg, 78%). 1H NMR (400 MHz, DMSO-d6) □ ppm 9.06 (1H, s), 8.62 (1H, s), 8.47 (1H, d, J=7.9 Hz), 8.22-8.32 (1H, m), 8.10 (1H, d, J=8.1 Hz), 7.85-8.01 (3H, m), 7.47-7.60 (1H, m), 7.29 (1H, t, J=7.8 Hz), 6.89 (1H, d, J=9.3 Hz), 4.42 (2H, d, J=13.2 Hz), 3.10 (2H, t, J=12.7 Hz), 2.33-2.54 (2H, m), 1.91 (2 h, d, J=13.2 Hz), 1.41-1.63 (2H, m). HRMS (TOF, ES+) calculated: 421.1676; observed 421.1722. 
     EXAMPLE 561 
     N-Ethyl-6-[4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidin-1-yl]-N-(2-hydroxyethyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     To a vial containing 6-[4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidin-1-yl]nicotinic acid (63.07 mg, 0.15 mmol) was added 0.375 mL of DMA, EDC (31.6 mg, 0.16 mmol), HOBt (20.3 mg, 0.15 mmol), NMM (0.04 mL, 0.37 mmol) and 2-(ethylamino)ethanol (13.4 mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 12 hours and then diluted with water and ethyl acetate. The layers were separated and the organic layer collected and concentrated to give an oil, which was purified by RP-HPLC to give N-ethyl-6-[4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidin-1-yl]-N-(2-hydroxyethyl)nicotinamide 
     (32 mg, 43%). HRMS (TOF, ES+) calculated for C27H30FN5O+H: 492.2333; observed 492.2611. 
     The following compounds of formula (VII) were prepared using a method analogous to Example 561. 
     
       
         
           
               
               
            
               
                   
               
               
                   
                 (VII) 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 MS calc 
                 MS obs 
               
               
                 Ex 
                 Q 
                 Name 
                 (M + H) 
                 (M + H) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 562 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-[4-({[6-(3-Fluorophenyl)pyridin- 3-yl]carbonyl}amino)piperidin-1- yl]-N-methyl-N-(2-methylprop-2-en- 1-yl)nicotinamide 
                 488.2462 
                 488.2553 
               
               
                   
               
               
                 563 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-Allyl-6-[4-({[6-(3- fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-N- methylnicotinamide 
                 474.2305 
                 474.2396 
               
               
                   
               
               
                 564 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[5-(Azetidin-1- ylcarbonyl)pyridin-2-yl]piperidin-4- yl}-6-(3-fluorophenyl)nicotinamide 
                 460.2149 
                 460.2224 
               
               
                   
               
               
                 565 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-[4-({[6-(3-Fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-N- methyl-N-prop-2-yn-1- ylnicotinamide 
                 472.2149 
                 472.2223 
               
               
                   
               
               
                 566 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-Ethyl-6-[4-({[6-(3- fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-N- methylnicotinamide 
                 462.2305 
                 462.2389 
               
               
                   
               
               
                 567 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-[4-({[6-(3-Fluorophenyl)pyridin- 3-yl]carbonyl}amino)piperidin-1- yl]-N-(2-hydroxy-1-methylethyl)-N- methylnicotinamide 
                 492.2411 
                 492.2495 
               
               
                   
               
               
                 568 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-{5-[(3- fluoropyrrolidin-1- yl)carbonyl]pyridin-2-yl}piperidin-4- yl)nicotinamide 
                 492.2211 
                 492.2303 
               
               
                   
               
               
                 569 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-Cyclobutyl-6-[4-({[6-(3- fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-N- methylnicotinamide 
                 488.2462 
                 488.2545 
               
               
                   
               
               
                 570 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N,N-Diethyl-6-[4-({[6-(3- fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1- yl]nicotinamide 
                 476.2462 
                 476.2496 
               
               
                   
               
               
                 571 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{1-[5-(2,5-Dihydro-1H-pyrrol-1- ylcarbonyl)pyridin-2-yl]piperidin-4- yl)-6-(3-fluorophenyl)nicotinamide 
                 472.2149 
                 472.2187 
               
               
                   
               
               
                 572 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-[4-({[6-(3-Fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-N- methyl-N-propylnicotinamide 
                 476.2462 
                 476.2497 
               
               
                   
               
               
                 573 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[5-(1,3- thiazolidin-3-ylcarbonyl)pyridin-2- yl]piperidin-4-yl}nicotinamide 
                 492.1870 
                 492.1910 
               
               
                   
               
               
                 574 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(Cyclopropylmethyl)-6-[4-({[6-(3- fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-N- methylnicotinamide 
                 488.2462 
                 488.2582 
               
               
                   
               
               
                 575 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-[4-({[6-(3-Fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-N- isobutyl-N-methylnicotinamide 
                 490.2618 
                 490.2657 
               
               
                   
               
               
                 576 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(2-Cyanoethyl)-6-[4-({[6-(3- fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidin-1-yl]-N- methylnicotinamide 
                 487.2258 
                 487.2419 
               
               
                   
               
               
                 577 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[5-({[1- (2,2,2-trifluoroethyl)piperidin-4- yl]amino}carbonyl)pyridin-2- yl]piperidin-4-yl}nicotinamide 
                 585.2601 
                 585.2723 
               
               
                   
               
               
                 578 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1-{5-[(2,5-Dimethyl-2,5-dihydro- 1H-pyrrol-1-yl)carbonyl]pyridin-2- yl}piperidin-4-yl)-6-(3- fluorophenyl)nicotinamide 
                 500.1 
                 500.1 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 579 
     N-[1-(7,8-Dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     To a vial was added, 6-(3-fluorophenyl)nicotinic acid (46.4 mg, 0.213 mmol), 1-(7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)piperidin-4-amine (50 mg, 0.21 mmol), EDAC (45.0 mg, 0.235 mmol), HOBT (28.8 mg, 0.213 mmol), and DMA (1 mL) followed by NMM (0.058 mL, 0.534 mmol). The reaction was stirred overnight at room temperature and then diluted with H 2 O and the resulting solid filtered and collected to give the desired product, N-(1-{5-[(2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]pyridin-2-yl}piperidin-4-yl)-6-(3-fluorophenyl)nicotinamide (81 mg, 88%). 1H NMR (400 MHz, DMSO-d6) □ ppm 9.06 (1H, s), 8.45 (1H, d, J=7.5 Hz), 8.21-8.30 (1H, m), 8.04-8.14 (2H, m), 7.89-8.02 (2H, m) 7.49-7.59 (1H, m), 7.29 (1H, t), 4.49-4.64 (5H, m), 4.11 (1H, br. s.), 3.89 (2H, t, J=5.9 Hz), 2.94-3.07 (2 H, m), 1.88 (2H, d, J=10.1 Hz), 1.42-1.56 (3H, m). HRMS (TOF, ES+) calculated for M+H: 434.1992; observed 434.2165. 
     EXAMPLE 580 
     6-(3-Fluorophenyl)-N-(1-pyridazin-3-ylpiperidin-4-yl)nicotinamide 
     
       
         
         
             
             
         
       
     
     6-(3-fluorophenyl)-N-(1-pyridazin-3-ylpiperidin-4-yl)nicotinamide was prepared analogous to N-(1-{5-[(2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]pyridin-2-yl}piperidin-4-yl)-6-(3-fluorophenyl)nicotinamide, except 1-(pyridazin-3-yl)piperidin-4-amine was used as R—NH2. M+H=378.3 observed, 378.17 expected. 
     EXAMPLE 88 
     EXAMPLE 581 
     EXAMPLE 582 
     6-(3-Fluorophenyl)-N-(1-{9-[1-(hydroxymethyl)propyl]-9H-purin-6-yl}piperidin-4-yl)nicotinamide 
     
       
         
         
             
             
         
       
     
     6-(3-fluorophenyl)-N-(piperidin-4-yl)nicotinamide (2.0 g, 5.37 mmol) and 2-(6-chloro-9H-purin-9-yl)butan-1-ol (1.58 g, 6.98 mmol) were placed in a flask along with 10 mL of butanol, 10 mL of water and 10 mL of triethylamine. The mixture was heated to 85° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate and brine. The ethyl acetate was washed 3× with brine and then dried over MgSO 4 , filtered and concentrated. The residue was purified by chromatography (silica, 1.5% EtOH/EtOAc) to give the desired racemic product (Example 88, 1.34 g, 57%). The material was purified by chiral chromatography-SFC (50% iPrOH in CO 2 , AD-H 30×250 mm col) to give the two peaks (enantiomeric pair) 
     Example 581. Peak 1: 1H NMR (400 MHz, DMSO-d 6 ) □ ppm 9.08 (1H, d, J=2.0 Hz), 8.52 (1H, d, J=7.9 Hz), 8.29 (1H, dd, J=8.4, 2.2 Hz), 8.24 (1H, s), 8.21 (1H, s), 8.14 (1H, d, J=8.5 Hz), 7.91-8.04 (2 H, m), 7.52-7.62 (1H, m), 7.27-7.38 (1H, m), 5.36 (1H, s), 5.02 (1H, t, J=5.5 Hz), 4.38-3.50 (1H, m), 4.16-4.29 (1H, m), 3.80-3.90 (1H, m), 3.66-3.76 (1H, m), 3.21-3.37 (2H, m) 1.84-2.04 (4H, m), 1.51-1.67 (2H, m), 0.74 (3H, t, J=7.3 Hz). wt=0.66 g; M+H=490.2368 expected, 490.2406 observed; [□] 25   D =+10 (ethanol, 0.01) where c=g/00 mL 
     Example 582. Peak 2: 1H NMR (400 MHz, DMSO-d 6 ) □ ppm 9.08 (1H, d, J=2.4 Hz), 8.53 (1H, d, J=7.9 Hz), 8.29 (1H, dd, J=8.4, 2.2 Hz), 8.23-8.26 (1H, m), 8.21 (1H, s), 8.14 (1H, d, J=8.5 Hz), 7.90-8.07 (2H, m), 7.48-7.64 (1H, m), 7.24-7.40 (1H, m), 5.35 (1H, d, J=12.6 Hz), 5.02 (1H, t, J=5.5 Hz), 4.35-4.53 (1H, m), 4.10-4.33 (1H, m), 3.79-3.93 (1H, m), 3.62-3.78 (1H, m), 3.19-3.39 (2H, m), 1.82-2.11 (4H, m), 1.48-1.70 (2H, m), 0.74 (3H, t, J=7.3 Hz). wt=0.64 g; M+H=490.2367 expected, 490.2361 observed; [□] 25   D =−10 (ethanol, 0.01) where c=g/100 mL 
     EXAMPLE 583 
     6-(2,5-Difluorophenyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of tert-butyl 6-(2,5-difluorophenyl)nicotinate 
     To round-bottom flask was added 2,5-difluoro phenylboronic acid (306 mg, 1.94 mmol), palladium tetrakis(triphenylphosphine) (22.4 mg, 0.0194 mmol)) and tert-butyl 6-bromonicotinate (500 mg, 1.94 mmol) and the mixture was evacuated 3× with N 2 . The solids were dissolved in 25 mL of DMF, followed by addition of 2.9 mL of 2 M cesium carbonate. The resulting mixture was heated to ˜90° C. The mixture was cooled to rt and then poured into a sep. funnel, followed by addition of EtOAc and water (1×200 mL). The layers were separated and the organic extract washed with brine (1×200 mL), dried MgSO 4 , filtered and concentrated to afford an orange oil. The crude mixture was purified by chromatography (silica, 10% EtOAc:Heptane) to afford the desired product (224 mg, 40%). 1H NMR (400 MHz, DMSO-d6) □ ppm 9.07-9.19 (1H, m), 8.36 (1H, dd, J=8.2, 2.2 Hz), 7.99 (1H, dd, J=8.3, 1.8 Hz), 7.75-7.86 (1H, m), 7.36-7.52 (1H, m), 7.36-7.52 (2H, m), 1.59 (9H, s). LC/MS (M+H)=292.1 observed, 292.11 expected. 
     Step B: 6-(2,5-difluorophenyl)nicotinic acid 
     To tert-butyl 6-(2,5-difluorophenyl)nicotinate in DCM (12 mL) at 0° C. was added TFA (5 mL). After stirring at room temperature overnight, toluene was added (10 mL) and the solvent removed to give a white solid (176 mg, 97%), 6-(2,5-difluorophenyl)nicotinic acid. LC/MS (M+H)=236.0 observed, 236.05 expected 
     Step C: Preparation of 6-(2,5-difluorophenyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]nicotinamide 
     To a 50 mL flask was added 6-(2,5-difluorophenyl)nicotinic acid (100 mg, 0.46 mmol), 1-(2,2,2-trifluoroethyl)piperidin-4-amine (77.5 mg, 0.46 mmol), EDAC (89.7 mg, 0.468 mmol), HOBT (57.5 mg, 0.46 mmol), and DMA (2 mL) followed by NMM (0.117 mL, 1.06 mmol). The reaction was stirred for 1 hour at room temperature and then diluted with EtOAc (0.2 mL) followed by H 2 O (4 mL). The resulting solids were washed in H 2 O and collected by filtration. 1H NMR (400 MHz, DMSO-d6) □ ppm 9.12 (1H, d, J=2.2 Hz), 8.55 (1H, d, J=7.5 Hz), 8.31 (1H, dd, J=8.3, 2.3 Hz), 7.95 (1 H, dd, J=8.2, 1.5 Hz), 7.73-7.84 (1H, m), 7.35-7.51 (2H, m), 3.73-3.90 (1H, m), 3.19 (2H, q, J=10.3 Hz), 2.95 (2H, d, J=11.9 Hz), 2.39-2.50 (2H, m), 1.82 (2H, dd, J=14.0, 3.2 Hz), 1.53-1.68 (2H, m). LC/MS (M+H)=400.36 expected, 400.0 observed. 
     EXAMPLE 584 
     Ethyl 4-({[6-(2,5-Difluorophenyl)pyridine-3-yl]carbonyl}amino)piperidine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Ethyl 4-({[6-(2,5-difluorophenyl)pyridin-3-yl]carbonyl}amino)piperidine-1-carboxylate was prepared analogously to 6-(2,5-difluorophenyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]nicotinamide. 1H NMR (400 MHz, DMSO-d6) □ ppm 9.12 (1H, d, J=1.7 Hz), 8.58 (1H, d, J=7.5 Hz), 8.31 (1H, dd, J=8.3, 2.3 Hz), 7.95 (1H, dd, J=8.2, 1.4 Hz), 7.74-7.85 (1H, m), 7.36-7.52 (2H, m), 3.93-4.09 (6H, m) 2.97 (2H, br. s.), 1.86 (2H, dd, J=12.4, 2.5 Hz), 1.37-1.54 (2H, m), 1.20 (4H, t, J=7.1 Hz). LC/MS (M+H)=390.16 expected, 390.1 observed. 
     EXAMPLE 585 
     6-(2-Fluorophenyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of tert-butyl 6-(2-fluorophenyl)nicotinate 
     To a round-bottom flask was added 2-fluoro phenylboronic acid (271 mg, 1.94 mmol), palladium tetrakis(triphenylphosphine) (22.4 mg, 0.0194 mmol)) and tert-butyl 6-bromonicotinate (500 mg, 1.94 mmol) and the mixture was evacuated 3× with N 2 . The solids were dissolved in 25 mL of DMF, followed by addition of 2.9 mL of 2 M cesium carbonate. The resulting mixture was heated to ˜90° C. The mixture was cooled to room temperature and then poured into a seperatory funnel, followed by addition of EtOAc and water (1×200 mL). The layers were separated and the organic extract washed with brine (1×200 mL), dried MgSO 4 , filtered and concentrated to afford an orange oil. The crude mixture was purified by chromatography (silica, 10% EtOAc:Heptane) to afford the desired product (224 mg, 40%). 1H NMR (400 MHz, DMSO-d6) □ ppm 9.16 (1H, d, J=2.2 Hz), 8.34 (1H, dd, J=8.3, 2.3 Hz), 7.90-8.05 (2H, m), 7.50-7.62 (1H, m), 7.33-7.44 (2H, m) 1.59 (9 H, s). 
     Step B: 6-(2-Fluorophenyl)nicotinic acid 
     To tert-butyl 6-(2-fluorophenyl)nicotinate (479 mg, 1.75 mmol) in DCM (12 mL) at 0° C. was added TFA (2.5 mL). After stirring at rt overnight, toluene was added (10 mL) and the solvent removed to give a white solid (375 mg, 98%), 6-(2-fluorophenyl)nicotinic acid. LC/MS (M+H)=218.0 observed, 218.06 expected. 
     Step C: 6-(2-Fluorophenyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]nicotinamide 
     To a vial was added 6-(2-fluorophenyl)nicotinic acid (100 mg, 0.46 mmol), 1-(2,2,2-trifluoroethyl)piperidin-4-amine (83.8 mg, 0.46 mmol), EDAC (97.1 mg, 0.51 mmol), HOBT (62.2 mg, 0.46 mmol), DMA (2 mL) and NMM (0.127 mL, 1.15 mmol). The reaction was stirred for 1 hour at room temperature and then diluted with EtOAc (0.2 mL) followed by H 2 O (4 mL). The resulting solids were washed in H 2 O and collected by filtration. 1H NMR (400 MHz, DMSO-d6) □ ppm 9.11 (1H, d, J=1.9 Hz), 8.52 (1H, d, J=7.5 Hz), 8.28 (1H, dd, J=8.3, 2.3 Hz), 7.94-8.05 (1H, m), 7.90 (1H, dd, J=8.4, 1.5 Hz), 7.50-7.58 (1H, m), 3.72-3.89 (1H, m), 3.19 (2H, q, J=10.3 Hz), 2.95 (2H, d, J=11.9 Hz), 2.40-2.48 (2H, m) 1.82 (2H, d, J=13.1 Hz), 1.52-1.67 (2H, m). 
     The following compounds of formula (X) were prepared using methods analogous to the method of Example 585. 
     
       
         
           
               
               
            
               
                   
               
               
                   
                 (X) 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 MS 
                 MS 
               
               
                   
                   
                   
                 calc 
                 obs 
               
               
                 Ex 
                 A 
                 Name 
                 (M + H) 
                 (M + H) 
               
               
                   
               
               
                 586 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Ethyl 4-({[6-(2-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidine-1- carboxylate 
                 372.2 
                 372.0 
               
               
                   
               
               
                 587 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(2-Fluorophenyl)-N-[1-(pyridin-2- ylmethyl)piperidin-4-yl]nicotinamide 
                 391.2 
                 391.0 
               
               
                   
               
               
                 588 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3-Fluorobenzyl)piperidin-4-yl]-6-(2- fluorophenyl)nicotinamide 
                 407.2 
                 408.0 
               
               
                   
               
            
           
         
       
     
     The compounds of the following formula were also prepared using methods analogous to the method of Example 585. 
     
       
         
           
               
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 MS 
                   
               
               
                   
                   
                   
                 calc 
                 MS obs 
               
               
                 Ex 
                 A 
                 Name 
                 (M) 
                 (M + H) 
               
               
                   
               
               
                 589 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-isopropylpyrrolidin- 3-yl)nicotinamide 
                 327.2 
                 328.1 
               
               
                   
               
               
                 590 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(7,8-Dihydro-5H-pyrano[43-d]pyrimidin- 2-yl)pyrrolidin-3-yl]-6-(3- fluorophenyl)nicotinamide 
                 419.2 
                 420.3 
               
               
                   
               
               
                 591 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-propylpiperidin-4- yl)nicotinamide 
                 341.2 
                 342.1 
               
               
                   
               
               
                 592 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1- [(methylamino)carbonyl]piperidin-4- yl}nicotinamide 
                 356.2 
                 357.3 
               
               
                   
               
               
                 593 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(tetrahydro-2H- pyran-4-ylmethyl)piperidin-4-yl]nicotinamide 
                 397.2 
                 398.0 
               
               
                   
               
               
                 594 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Ethyl 3-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)pyrrolidine-1-carboxylate 
                 357.1 
                 358.1 
               
               
                   
               
               
                 595 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(6,7-Dihydro-5H- cyclopenta[d]pyrimidin-2-yl)pyrrolidin-3-yl]- 6-(3-fluorophenyl)nicotinamide 
                 403.2 
                 404.3 
               
               
                   
               
               
                 596 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(Cyclopropylmethyl)piperidin-4-yl]-6-(3- fluorophenyl)nicotinamide 
                 353.2 
                 354.3 
               
               
                   
               
               
                 597 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(6-methyl-5,6,7,8- tetrahydropyrido[4.3-d]pyrimidin-2- yl)pyrrolidin-3-yl]nicotinamide 
                 432.2 
                 433.4 
               
               
                   
               
               
                 598 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl 4-({[6-(3-fluorophenyl)pyridin-3- yl]carbonyl}amino)piperidine-1-carboxylate 
                 399.2 
                 400.3 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 599 
     tert-Butyl 3-(2-(3-fluorophenyl)nicotinamido)azetidine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     To a solution of 6-(3-fluorophenyl)nicotinic acid (0.50 g, 2.30 mmol) in DMF (10 mL) was added HBTU (0.96 g, 2.53 mmol) and DIPEA (0.52 mL, 2.99 mmol). After 1 hr at room temperature, tert-butyl 3-aminoazetidine-1-carboxylate was added and the reaction stirred overnight. The solvent was removed and the residue was partitioned between ethyl acetate and sodium bicarbonate (aqueous saturated). The organic layer was washed with brine (2×), dried (MgSO 4 ), filtered and concentrated to give the desired product, tert-butyl 3-(2-(3-fluorophenyl)nicotinamido)azetidine-1-carboxylate (630 mg, 74%). LC/MS (M+H)=372.2 observed, 372.17 expected 
     EXAMPLE 600 
     N-Azetidin-3-yl-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl 3-(2-(3-fluorophenyl)nicotinamido)azetidine-1-carboxylate (570 mg, 1.53 mmol) in methanol (1 mL) was added 4N HCl/dioxane (3 mL). The reaction mixture was stirred at room temperature overnight and then diluted with ether to give a solid, which was filtered and collected to give the desired product as the hydrochloride salt, N-azetidin-3-yl-6-(3-fluorophenyl)nicotinamide (480 mg, 92%). LC/MS (M+H)=272.9 observed, 272.12 expected. 
     EXAMPLE 601 
     N-[1-(2,2-Dimethylpropanoyl)azetidin-3-yl]-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     To a solution of N-azetidin-3-yl-6-(3-fluorophenyl)nicotinamide (50 mg, 0.12 mmol) in DMF (1 mL) was added DIPEA (0.06 mL, 0.32 mmol) and pivaloyl chloride (29.4 mg, 0.24 mmol). The reaction mixture was stirred at room temperature overnight and then diluted with ethyl acetate and water. The layers were separated and the organic layer washed with brine, dried (MgSO 4 ) and the solvent removed to give a solid, which was purified by chromatography (silica, 80% etoac:hex) to give the desired product, N-[1-(2,2-dimethylpropanoyl)azetidin-3-yl]-6-(3-fluorophenyl)nicotinamide (50 mg, 86%). HRMS (M+H)=356.1856 observed, 356.1774 expected. 
     EXAMPLE 602 
     N-[1-(3-Cyano-4,6-dimethylpyridin-2-yl)azetidin-3-yl-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     To a vial containing N-azetidin-3-yl-6-(3-fluorophenyl)nicotinamide (40 mg, 0.13 mmol) was added 2-chloro-4,6-dimethyinicotinonitrile (32 mg, 0.19), n-butanol (0.3 mL) and TEA (4 drops). The mixture was heated to 90° C. overnight and then cooled to room temperature. The mixture was diluted with water and CH 2 Cl 2  and the layers separated. The organic layer was collected and the solvent removed to give an oil, which was purified by RP-HPLC to give the desired product, N-[1-(3-cyano-4,6-dimethylpyridin-2-yl)azetidin-3-yl]-6-(3-fluorophenyl) nicotinamide (40 mg, 77%). HRMS (M+H) expected 402.1730, (M+H) observed 402.1832. 
     The following compounds of formula were prepared using methods analogous to the method of Example 602. 
     
       
         
           
               
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 MS calc 
                 MS obs 
               
               
                 Ex 
                 R 
                 Name 
                 (M + H) 
                 (M + H) 
               
               
                   
               
               
                 603 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(2-Ethylimidazo[1,2- b]pyridazin-6-yl)azetidin-3-yl]-6-(3- fluorophenyl)nicotinamide 
                 417.1839 
                 417.1864 
               
               
                   
               
               
                 604 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-{1-[3- (trifluoromethyl)pyridin-2-yl]azetidin- 3-yl}nicotinamide 
                 417.1339 
                 417.1357 
               
               
                   
               
               
                 605 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-(1-quinoxalin- 2-ylazetidin-3-yl)nicotinamide 
                 400.1573 
                 400.1758 
               
               
                   
               
               
                 606 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(1,3-Benzoxazol-2-yl)azetidin- 3-yl]-6-(3-fluorophenyl)nicotinamide 
                 389.1414 
                 389.1473 
               
               
                   
               
               
                 607 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-[1-(3-Cyano-6-methylpyridin-2- yl)azetidin-3-yl]-6-(3- fluorophenyl)nicotinamide 
                 388.1573 
                 388.1648 
               
               
                   
               
               
                 608 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-(3-Fluorophenyl)-N-[1-(1-phenyl- 1H-tetrazol-5-yl)azetidin-3- yl]nicotinamide 
                 416.1635 
                 416.1653 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 609 
     cis-tert-Butyl 3-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)-4-hydroxypyrrolidine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     To a solution of 6-(3-fluorophenyl)nicotinic acid (391 mg, 1.8 mmol ) in DMF (10 mL) at 0° C. was added HATU (753 mg, 1.98 mmol) and DIPEA (0.47 mL, 2.07 mmol ). After 15 min, cis-tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate was added and the reaction stirred at room temperature for 5 hrs. The solvent was removed in vacuo and the residue diluted with ethyl acetate and water. The layers were separated and the organic layer washed with brine, dried (MgSO 4 ) and the solvent removed to give an oil, which after chromatography (silica, 65% ethyl acetate:hex) to give the desired product, cis-tert-butyl-3-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)-4-hydroxypyrrolidine-1-carboxylate (420 mg, 58%). LC/MS (M+H)=401.9 observed, 402.18 expected. 
     EXAMPLE 610 
     Trans-tert-Butyl 3-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)-4-hydroxypyrrolidine-1-carboxylate was synthesized analogous to the above, except using the trans-derivative of tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate. LC/MS (M+H)=401.9 observed, 402.18 expected. 
     EXAMPLE 611 
     trans-6-(3-Fluorophenyl)-N-[4-hydroxypyrrolidin-3-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     To a solution of trans-tert-butyl 3-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)-4-hydroxypyrrolidine-1-carboxylate (500 mg, 1.24 mmol) in dioxane was added 4N HCl in dioxane (10 mL). The reaction was stirred at room temperature for ˜4 hrs and then diluted with ether to give a white solid, which was filtered and collected to give the desired product as the hydrochloride salt, trans-6-(3-fluorophenyl)-N-[4-hydroxypyrrolidin-3-yl]nicotinamide (390 mg, 92% ). LC/MS (M+H)=301.9 observed, 302.13 expected. 
     EXAMPLE 612 
     Trans-N-[1-(2,2-dimethylpropanoyl)-4-hydroxypyrrolidin-3-yl]-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     To a solution of trans-6-(3-fluorophenyl)-N-[4-hydroxypyrrolidin-3-yl]nicotinamide (50 mg, 0.15 mmol) in DMF (1.0 mL) was added DIPEA (95 mg, 0.32 mmol) and pivaloyl chloride (66 mg, 0.24 mmol). After stirring at rt overnight the mixture was partitioned between ethyl acetate and brine. The organic layer was dried (MgSO 4 ), filtered and the solvent removed to give an oil, which after chromatography (silica, 1% MeOH/EtOAc) gave the product (36 mg, 63%). HRMS (M+H)=386.1880 expected, 386.1914 observed. 
     EXAMPLE 613 
     trans-6-(3-Fluorophenyl)-N-[4-hydroxy-1-quinoxalin-2-ylpyrrolidin-3-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     To a vial was added trans-6-(3-fluorophenyl)-N-[4-hydroxypyrrolidin-3-yl]nicotinamide (40 mg, 0.12 mmol 2-chloroquinoxaline (29.2 mg, 0.18 mmol), n-butanol, water and triethylamine (0.3 mL of each). The reaction mixture was heated to 90° C. overnight and then cooled to room temperature and the solvent removed. The residue was taken up in DMSO and purified by RP-HPLC to give the desired product, trans-6-(3-fluorophenyl)-N-[4-hydroxy-1-quinoxalin-2-ylpyrrolidin-3-yl]nicotinamide (40 mg, 79%). HRMS (M+H) expected 430.1679, observed 430.1793 
     The following compounds of Formula (XII) were prepared using methods analogous to the method of Example 613. 
     
       
         
           
               
               
            
               
                   
               
               
                   
                 (XII) 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 MS calc 
                 MS obs 
               
               
                 Ex 
                 Q 
                 Name 
                 (M + H) 
                 (M + H) 
               
               
                   
               
               
                 614 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Trans-N-[1-(2-ethylimidazo[12-b]pyridazin- 6-yl)-4-hydroxypyrrolidin-3-yl]-6-(3- fluorophenyl)nicotinamide 
                 447.1945 
                 447.2054 
               
               
                   
               
               
                 615 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Trans-N-[1-(3-cyano-4,6-dimethylpyridin-2- yl)-4-hydroxypyrrolidin-3-yl]-6-(3- fluorophenyl)nicotinamide 
                 432.1836 
                 432.1868 
               
               
                   
               
               
                 616 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Trans-N-[1-(1,3-benzoxazol-2-yl)-4- hydroxypyrrolidin-3-yl]-6-(3- fluorophenyl)nicotinamide 
                 419.1519 
                 419.1589 
               
               
                   
               
               
                 617 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Trans-N-[(1-(3-cyano-6-methylpyridin-2-yl)- 4-hydroxypyrrolidin-3-yl]-6-(3- fluorophenyl)nicotinamide 
                 418.1679 
                 418.1645 
               
               
                   
               
               
                 618 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Trans-6-(3-fluorophenyl)-N-[1-(7- fluoroquinazolin-2-yl)-4-hydroxypyrrolidin- 3-yl]nicotinamide 
                 448.1585 
                 448.1792 
               
               
                   
               
               
                 619 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Trans-6-(3-fluorophenyl)-N-[4-hydroxy-1- (1-phenyl-1H-tetrazol-5-yl)pyrrolidin-3- yl]nicotinamide 
                 446.1741 
                 446.1854 
               
               
                   
               
            
           
         
       
     
     Preparation of 5-chloro-6-(3-fluorophenyl)nicotinic acid 
     
       
         
         
             
             
         
       
     
     To a round bottom flask was added 5,6-dichloronicotinic acid (500 mg, 2.60 mmol), 3-fluorophenylboronic acid (364 mg, 2.60 mmol), DMF (25 mL), 2 M Cs 2 CO 3  (6 mL) and Pd(Ph 3 ) 4  (30.1 mg, 0.0026 mmol). The reaction mixture was heated to 90° C. for 3 hrs and then allowed to cool to rt. The mixture was diluted with ethyl acetate/water and the layers separated. The organic layer was washed with brine, dried (MgSO 4 ) and the solvent removed to give a solid, which was purified by chromatography (silica, DCM/MeOH) to give the desired product, 5-chloro-6-(3-fluorophenyl)nicotinic acid (623 mg, 95%). LC/MS (M+H)=252 observed, 252.02 expected. 
     The following compounds of formula (XIII) were synthesized using methods analogous to the method of Example 585 (preparation of 6-(2-fluorophenyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]nicotinamide). 
     
       
         
           
               
               
            
               
                   
               
               
                   
                 (XIII) 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 MS calc 
                 MS obs 
               
               
                 Ex 
                 A 
                 Name 
                 (M + H) 
                 (M + H) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 620 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 5-Chloro-6-(3-fluorophenyl)-N-[1-(2,2,2- trifluoroethyl)piperidin-4-yl]nicotinamide 
                 416.1153 
                 416.0 
               
               
                   
               
               
                 621 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 5-Chloro-6-(3-fluorophenyl)-N-(1- pyridazin-3-ylpiperidin-4-yl)nicotinamide 
                 411.1262 
                 411.1 
               
               
                   
               
               
                 622 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 5-Chloro-6-(3-fluorophenyl)-N-(1- pivaloylpiperidin-4-yl)nicotinamide 
                 418.1697 
                 418.1801 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 51 
     Alternative Preparation 
     
       
         
         
             
             
         
       
     
     Step A: Tert-butyl[1-(1-Methyl-1H-tetrazol-5-yl)-piperidin-4-yl]-carbamate 
     Piperidin-4-yl-carbamic acid tert-butyl ester (30.0 g, 0.189 mol), 5-chloro-1-methyl-1H-tetrazole (28.8 g, 0.242 mol) and triethylamine (80 mL, 0.573 mol) were added to a mixture of n-butanol (80 mL) and water (80 mL) and the reaction mixture heated to 80° C. for 5 hours. The reaction was cooled to room temperature and stirred at this temperature overnight. The resulting precipitate was filtered off and washed with water (2×25 mL) and then dried to give tert-butyl[1-(1-methyl-1H-tetrazol-5-yl)-piperidin-4-yl]-carbamate as a white powder (41.8 g).  1 H NMR (300 MHz, DMSO-d 6 ) ppm 1.39 (s, 9H) 1.44-1.65 (qd, J=12, 4 Hz, 2H) 1.75-1.92)dd, J=13, 3 Hz, 2H) 2.95-3.16 (td, J=13, 3 Hz, 2H) 3.34-3.50 (broad s, 1H) 3.50-3.65 (dt, J=13, 3 Hz, 2H) 3.85 (s, 3H) 6.83-7.04 (m, 1H). 
     Step B: 1-(1-Methyl-1H-tetrazol-5-yl)-piperidin-4-amine methanesulphonic acid salt 
     A mixture of tert-butyl[1-(1-methyl-1H-tetrazol-5-yl)-piperidin-4-yl]-carbamate (39.0 g, 0.138 mol) and methanesulphonic acid (23 mL, 0.354 mol) in isopropanol (290 mL) was stirred at 44° C. over night. The reaction mixture was cooled slowly to 0° C. and stirred for 2 hours. The precipitate was washed with cold isopropanol (2×25 mL) and dried to give 1-(1-methyl-1H-tetrazol-5-yl)-piperidin-4-amine methanesulphonic acid salt as a white powder (35.0 g).  1 H NMR (300 MHz, MeOH-d 4 ) ppm 1.75-1.94 (qd, J=12, 3 Hz, 2H) 2.03-2.19 (d, J=12 Hz, 2H) 2.71 (s, 3H), 3.08-3.26 (t, J=13 Hz, 2H) 3.37-3.50 (m, 1H) 3.63-3.87 (d, J=13 Hz, 2H) 3.94 (s, 3H) 4.74-4.90 (d, J=1 Hz, 3H). 
     Step C: 6-(3-Fluorophenyl)nicotinicacid 
     6-Chloronicotinic acid (25.4 g, 161 mmol) and 3-fluorophenylboronic acid (33.9 g, 242 mmol) were dissolved in dimethylformamide (300 mL) and the mixture degassed with nitrogen. Tetrakis(triphenylphosphine)palladium (0) (1.0 g, 0.87 mmol) was added followed by a solution of sodium carbonate (34.0 g in 160 mL of water) drop wise. The reaction was heated overnight at 90° C. The reaction was cooled to room temperature and then water (200 mL) was added. The reaction mixture was filtered over celite and then the filtrate was washed with a mixture of ethyl acetate (50 mL) and heptane (50 mL). The phases were separated and the aqueous layer was acidified to pH 2 with 6M HCl. The yellow precipitate was filtered off and dried to give 6-(3-fluorophenyinicotinic acid) 27.9 g.  1 H NMR (400 MHz, DMSO-d 6 ) ppm 7.36 (dt, J=2.3, 8.3 Hz, 1H) 7.79 (m, 1H) 8.01 (m, 2H) 8.18 (d, J=8.3 Hz, 1H) 8.36 (dd, J=2.3, 8.3 Hz, 1H) 9.16 (d, J=1.8 Hz, 1H). 
     Step D: 6-(3-Fluoro-phenyl)-N-[1-(1-methyl-1H-tetrazol-5-yl)-piperidin-4-yl]-nicotinamide 
     To a slurry of 6-(3-fluorophenyl)nicotinic acid (20.4 g, 94.0 mmol) and 1-methylimidazole (30 mL, 376 mmol) in acetonitrile (140 mL) was added a solution of p-toluenesulphonyl chloride (27.3 g, 143 mmol) in acetonitrile (40 mL) over a period of 40 minutes keeping the internal temperature below 34° C. The reaction was stirred at room temperature for 2.5 hours and then 1-(1-methyl-1H-tetrazol-5-yl)-piperidin-4-amine methane sulphonic acid salt (26.1 g, 94 mmol) was added drop wise over 40 minutes keeping the temperature below 33° C. At the end of the addition the reaction mixture was heated to 42° C. for 2 hours and then cooled to room temperature overnight. The reaction was then cooled to 0-5° C. for approximately 1 hour and then the precipitate was filtered off, washed with cold acetonitrile (2×40 mL) to give the product as a white solid. This solid was refluxed in ethanol (530 mL) for 2 hours and then stirred at room temperature for approximately 2 hours. The precipitate was filtered, washed with ethanol (3×100 mL) and dried to give 6-(3-fluoro-phenyl)-N-[1-(1-methyl-1H-tetrazol-5-yl)-piperidin-4-yl]-nicotinamide as a white powder (43.3 g).  1 H NMR (300 MHz, DMSO-d 6 ) ppm 1.66-1.86 (qd, J=12, 4 Hz, 2H), 1.86-2.01 (dd, J=13, 3 Hz, 2H) 3.06-3.22 (td, J=12, 2 Hz, 2H) 3.59-3.74 (d, J=13 Hz, 2H) 3.90 (s, 3H) 4.03-4.18 (m, 1H) 7.27-7.37 (tdd, J=6, 3, 1 Hz, 1H) 7.51-7.63 (m, 1H) 7.91-8.00 (dt, J=10, 2 Hz, 1H) 8.00-8.06 (d, J=8 Hz, 1H) 8.10-8.19 (dd, J=8, 1 Hz, 1H) 8.26-8.35 (dd, J=8, 2 Hz, 1H) 8.53-8.65 (d, J=8 Hz, 1H) 9.07-9.13 (d, J=2 Hz, 1H). 
     EXAMPLE 623 
     6-(3-Cyanophenyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     Step A: Methyl 6-(3-cyanophenyl)nicotinate 
     Methyl 6-chloronicotinate (467 mg, 2.72 mmol) and (3-cyanophenyl)boronic acid (400 mg, 2.72 mmol) were added to 1,4-dioxane (25 mL). To this was added 6.80 mL of a 2 M solution of aqueous potassium carbonate and tetrakis(triphenylphosphine)palladium(0) (157 mg, 0.136 mmol). The above reagents were heated at reflux for 5 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate (50 mL) and water (20 mL), the phases were separated and the organic layer was dried over anhydrous MgSO 4 , filtered and evaporated to a pale yellow solid. The solid was purified using chromatography on silica eluting with a mixture of heptane: ethyl acetate 90:10, 80:20, 70:30. The product fractions were combined and evaporated to give methyl 6-(3-cyanophenyl)nicotinate as a white solid (278 mg). LCMS (ES+) 239 (M+1)  1 H NMR (400 MHz CDCl 3 ) ppm 4.00 (s, 3H) 7.62 (t, J=8.2 Hz, 1H) 7.76 (m, 1H) 7.83 (d, J=10.6 Hz, 1H) 8.31 (m, 1H) 8.40 (m, 2H) 9.30 (s, 1H). 
     Step B: 6-(3-Cyanophenyl)nicotinic acid 
     A mixture of methyl 6-(3-cyanophenyl)nicotinate (300 mg, 1.26 mmol) and 2 M lithium hydroxide solution (1.89 mL) in tetrahydrofuran (30 mL) was heated at 40° C. overnight. The tetrahydrofuran was evaporated off, water (5 mL) was added and the reaction mixture was acidified to pH 6 with 2N aqueous HCl. The precipitated solid was filtered off and dried under vacuum to give 6-(3-cyanophenyl)nicotinic acid (208 mg).  1 H NMR (400 MHz, DMSO-d6) ppm 7.74 (t, J=7.8 Hz, 1H), 7.96 (m, 1H), 8.23 (m, 1H), 8.36 (m, 1H), 8.49 (m, 1H), 8.55 (m, 1H), 9.15 (m, 1H), 13.5 (broad s, 1H) LCMS 225 (M+1) ELSD 1.33 minutes. 
     Step C: 6-(3-Cyanophenyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]nicotinamide 
     To a solution of 6-(3-cyanophenyl)nicotinic acid (50 mg, 0.222 mmol) in dimethylformamide (1 mL) was added 1,1 1 -carbonylbis(1H-imidazole) (36.3 mg, 0.224 mmol) and the reaction mixture stirred at room temperature for 1 hour. A solution of 1-(2,2,2-trifluoroethyl)piperidin-4-amine (49 mg, 0.269 mmol) in dimethylformamide (0.5 mL) was then added and the reaction stirred overnight at room temperature. Further 1,1 1 -carbonylbis(1H-imidazole) (18 mg, 0.132 mmol) was added and the reaction stirred for 30 minutes and then further 1-(2,2,2-trifluoroethyl)piperidin-4-amine (25 mg, 0.134 mmol) in dimethylformamide (0.5 mL) was added and the solution stirred for one hour. The dimethylformamide was evaporated off and the residue partitioned between ethyl acetate (10 mL) and water (3 mL). The organic layer was separated, dried over anhydrous MgSO 4 , filtered and evaporated to a white solid. This was triturated with t-butyl methyl ether and the white solid was filtered off and dried to give 6-(3-cyanophenyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]nicotinamide 53 mg 1H NMR (400 MHz, DMSO-d6) ppm 1.57-1.67 (m, 2H) 1.80-1.87 (m, 2H) 2.43-2.54 (m, 2H) 2.93-2.99 (m, 2H) 3.20 (q, J=10.1 Hz, 2H) 3.83 (m , 1H) 7.76 (t, J=8.2 Hz, 1H) 7.97 (m, 1H) 8.24 (m, 1H) 8.34 (dd, J=6.2, 2.4 Hz, 1H) 8.52 (m, 2H) 8.61*m, 1H) 9.12 (m, 1H) LCMS 389 (M+1) ELSD 1.27 minutes. 
     EXAMPLE 624 
     6-(2-Cyanophenyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     Step A: Methyl 6-(2-cyanophenyl)nicotinate 
     Methyl 6-chloronicotinate (1.00 g, 5.83 mmol) and (2-cyanophenyl)boronic acid (856 mg, 5.83 mmol) were added to 1,4-dioxane (50 mL). To this was added 14.6 mL of a 2 M solution of aqueous potassium carbonate and tetrakis(triphenylphosphine)palladium(0) (337 mg, 0.291 mmol). The above reagents were heated at reflux for 5 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate (50 mL) and water (20 mL), the phases were separated and the organic layer was dried over anhydrous MgSO 4 , filtered and evaporated to a gum. The solid was purified using chromatography on silica eluting with a mixture of heptane: ethyl acetate 80:20, 70:30, 30:70. The product fractions were combined and evaporated to give methyl 6-(2-cyanophenyl)nicotinate as a white solid (195 mg). LCMS (ES+) 239 (M+1), 1.37 minutes;  1 H NMR (400 MHz CDCl 3 ) ppm 4.00 (s, 3H) 7.58 (t, J=7.4 Hz, 1H) 7.74 (d, J=6.2 Hz, 1H) 7.85 (d, J=7.8 Hz, 1H) 7.90 (m, 2H) 8.45 (dd, J=5.8, 2.4 Hz, 1H) 9.37 (d, J=2.0, Hz, 1H). 
     Step B: 6-(2-Cyanophenyl)nicotinic acid 
     A mixture of methyl 6-(2-cyanophenyl)nicotinate (195 mg, 0.818 mmol) and 2 M lithium hydroxide solution (1.23 mL) in tetrahydrofuran (15 mL) was heated at 40° C. overnight. The tetrahydrofuran was evaporated off, water (5 mL) was added and the reaction mixture was acidified to pH 6 with 2N HCl. The precipitated solid was filtered off and dried under vacuum to give 6-(3-cyanophenyl)nicotinic acid (55 mg) ppm  1 H NMR (400 MHz, DMSO-d6) 7.71 (td, J=6.3, 1.5 Hz, 1H), 7.87 (td, J=7.8, 1.6 Hz, 1H) 7.96 (d, J=7.8 Hz, 1H) 8.02 (m, 2H) 8.45 (dd, J=5.8, 2.4 Hz, 1H) 9.20 (d, J=2.3 Hz, 1H), 13.55 (broad s, 1H) LCMS 225 (M+1) ELSD 1.20 minutes. 
     Step C: 6-(2-Cyanophenyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]nicotinamide 
     To a solution of 6-(2-cyanophenyl)nicotinic acid (50.2 mg, 0.224 mmol) in dimethylformamide (1 mL) was added 1,1 1 -carbonylbis(1H-imidazole) (36.3 mg, 0.224 mmol) and the reaction mixture stirred at room temperature for 1 hour. A solution of 1-(2,2,2-trifluoroethyl)piperidin-4-amine (49 mg, 0.269 mmol) in dimethylformamide (0.5 mL) was then added and the reaction stirred overnight at room temperature. Further 1-(2,2,2-trifluoroethyl)piperidin-4-amine (25 mg, 0.134 mmol) in dimethylformamide (0.5 mL) was added and stirred for a further 48 hours. The dimethylformamide was evaporated off and the residue partitioned between ethyl acetate (10 mL) and water (3 mL). The organic layer was separated, dried over anhydrous MgSO 4 , filtered and evaporated to a buff coloured solid. This was triturated with a mixture of heptane and t-butyl methyl ether and the white solid was filtered off and dried to give 6-(2-cyanophenyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]nicotinamide (44 mg) 1H NMR (400 MHz, DMSO-d6) ppm 1.58-1.68 (m, 2H) 1.82-1.86 (m, 2H) 2.47-2.54 (m, 2H) 2.97 (m, 2H) 3.20 (q, J=10.25 Hz, 2H) 3.84 (m, 1H) 7.71 (td, J=6.2, 1.6 Hz, 1H) 7.87 (td, J=6.2, 1.6 Hz, 1H) 7.99 (m, 3H) 8.37 (dd, J=13.0, 2.4 Hz, 1H) 8.59 (d, J=7.4 Hz, 1H) 9.15 (dd, J=1.3, 0.8 Hz, 1H) LCMS 389 (M+1) ELSD 1.19 minutes. 
     EXAMPLE 625 
     6-(2-Hydroxyphenyl)-N-(1-pyrimidin-2-ylpiperidin-4-yl)nicotinamide 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of methyl 6-(2-hydroxyphenyl)nicotinate 
     To a round bottom flask containing (2-hydroxyphenyl)boronic acid (1.37 g, 9.9 mmol) in 1,4-dioxane:water (8:1, 40 ml) was added methyl 6-chloronicotinate (1.71 g, 10.0 mmol), potassium carbonate (4.14 g, 30.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.3 g, 0.26 mmol) and the resulting mixture stirred at 80° C. for 10 h, then stood at r.t. for 72 h. The solution was acidified to pH 1 with aqueous 2 N HCl and concentrated in vacuo to a volume of approximately 5 ml. This solution was then partitioned between saturated sodium hydrogen carbonate (30 ml) and dichloromethane:methanol (95:5, 150 ml). The layers were separated and the aqueous layer extracted with dichloromethane (50 ml). The organic layers were combined and dried with anhydrous MgSO 4 , filtered and concentrated to afford a yellow solid. The solid was recrystallised from ethyl acetate/methanol to give the title compound as a yellow solid (1.14 g) (50%).  1 H NMR (400 MHz, CDCl 3 ) □ ppm 9.16 (1H, s), 8.46-8.40 (1H, m), 8.02-7.96 (1H, m ), 7.86-7.80 (1H, m), 7.39-7.33 (1H, m), 7.10-7.04 (1H, m), 6.96-6.90 (1H, m), 4.00 (3H, s). LRMS: AP m/z 230 [M+H] + . 
     Step B: Preparation of 6-(2-hydroxyphenyl)nicotinic acid 
     Methyl 6-(2-hydroxyphenyl)nicotinate (1.13 g, 4.9 mmol) was dissolved in 1,4-dioxane (10.0 ml) and 1N aqueous NaOH (12.0 ml) added. The resulting solution was stirred at r.t. for 16 h. This solution was then acidified to pH 4-5 with glacial acetic acid and concentrated under reduced pressure to 5 ml volume. This solution was diluted with water (30 ml) and the resulting precipitate filtered, washed with water (10 ml) and dried to give the title compound as a yellow solid (0.77 g) (72%).  1 H NMR (400 MHz, DMSO-d6) □ ppm 9.07 (1H, s), 8.39-8.34 (1H, m), 8.30-8.25 (1H, m), 8.06-7.99 (1H, m), 7.36-7.29 (1H, m), 6.96-6.89 (2H, m). LRMS: ES m/z 216 [M+H] + . 
     Step C: Preparation of 6-(2-hydroxyphenyl)-N-(1-pyrimidin-2-ylpiperidin-4-yl)nicotinamide 
     1-pyrimidin-2-ylpiperidin-4-amine (45 mg, 0.25 mmol) was added to a solution of 6-(2-hydroxyphenyl)nicotinic acid (50 mg, 0.23 mmol) in DMF (0.25 ml) and triethylamine (0.176 ml, 1.26 mmol). O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (125 mgs, 0.33 mmol) in DMF (0.5 ml) was then added and the reaction sealed. The reaction was shaken at 50° C. for 16 hours. The reaction was then evaporated to dryness in vacuo. Dichloromethane (2 ml) and saturated aqueous sodium hydrogen carbonate (0.5 ml) were added, the sealed reaction was shaken vigorously for 2 h. After this time the plates were opened and the biphasic mixture filtered through an Isolute SPE phase separation tube. The organic layer (filtrate) was evaporated to dryness in vacuo. DMSO (1 ml) was then added and the plate sealed and shaken at 50° C. until all the residue had dissolved then purified by reverse phase preparative HPLC using method B as defined below. R.T. 3.06 MS ES m/z 376 [M+H] + . This gave the title compound. 
     Examples 626-634, listed below, were similarly prepared according to the method described above for example 625, starting from 6-(2-hydroxyphenyl)nicotinic acid and the appropriate amine. HPLC purification was conducted according to Method A or Method B as indicated in the Table. 
     Method A: 
                                    HPLC separation conditions:   Preparative                             Analytical (QC)   Acidic conditions               Column   XTerra C18   Sunfire Prep C18 OBD           5 μm 4.6 × 50 mm   5 μm 19 × 100 mm       Temperature   Ambient   Ambient       Detection   UV 225 nm - ELSD-MS   ELSD-MS       System/Data   CTC - MUX1   Fractionlynx 4       file               Injection   5 μL   1000 μL       volume               Flow rate   1.5 mL/min   18 mL/min       Mobile phase   A: H2O + 0.1% ammonia   A: H2O + 0.1% formic acid           B: MeCN + 0.1% ammonia   B: MeCN + 0.1% formic               acid                                         Gradient   Time (min)   % B   Time (min)   % B                   0   5     0-1.0   5             0-3.0    5-95   1.0-7.0    5-98           3.0-4.0   95    7.0-9.0   98            4.0-4.1   95-5    9.0-9.10   98-5           4.1-5.0   5   9.10-10     5                    
Method B:
 
     
       
         
           
               
               
             
               
                   
               
             
            
               
                 HPLC separation conditions: 
                 Preparative 
               
            
           
           
               
               
               
            
               
                   
                 Analytical (QC) 
                 Basic conditions 
               
               
                   
               
               
                 Column 
                 XTerra C18 
                 Xterra Prep MS C18 
               
               
                   
                 5 μm 4.6 × 50 mm 
                 5 μm 19 × 100 mm 
               
               
                 Temperature 
                 Ambient 
                 Ambient 
               
               
                 Detection 
                 UV 225 nm - ELSD-MS 
                 ELSD-MS 
               
               
                 System/Data 
                 CTC - MUX1 
                 Fractionlynx 4 
               
               
                 file 
                   
                   
               
               
                 Injection 
                 5 μL 
                 1000 μL 
               
               
                 volume 
                   
                   
               
               
                 Flow rate 
                 1.5 mL/min 
                 18 mL/min 
               
               
                 Mobile phase 
                 A: H2O + 0.1% ammonia 
                 A: H2O + 0.1% DEA 
               
               
                   
                 B: MeCN + 0.1% ammonia 
                 B: MeCN + 0.1% DEA 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Gradient 
                 Time (min) 
                 % B 
                 Time (min) 
                 % B 
               
               
                   
               
               
                   
                 0 
                 5 
                   0-1.0 
                 5 
               
               
                   
                   0-3.0 
                  5-95 
                 1.0-7.0 
                  5-98 
               
               
                   
                 3.0-4.0 
                 95  
                 7.0-9.0 
                 98  
               
               
                   
                 4.0-4.1 
                 95-5 
                  9.0-9.10 
                 98-5 
               
               
                   
                 4.1-5.0 
                 5 
                 9.10-10   
                 5 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Example 
                 Q 1   
                 HPLC Method 
                 Data 
               
               
                   
               
               
                 626 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 R.T. 3.06 ES m/z 376 [M + H] +   
               
               
                   
               
               
                 627 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 R.T. 3.06 ES m/z 382 [M + H] +   
               
               
                   
               
               
                 628 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 R.T. 3.12 ES m/z 370 [M + H] +   
               
               
                   
               
               
                 629 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 R.T. 3.17 ES m/z 352 [M + H] +   
               
               
                   
               
               
                 630 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 R.T. 2.84 ES m/z 356 [M + H] +   
               
               
                   
               
               
                 631 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 R.T. 3.14 ES m/z 340 [M + H] +   
               
               
                   
               
               
                 632 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 R.T. 2.75 ES m/z 376 [M + H] +   
               
               
                   
               
               
                 633 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 R.T. 3.20 ES m/z 404 [M + H] +   
               
               
                   
               
               
                 634 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 R.T. 2.77 ES m/z 380 [M + H] +   
               
               
                   
               
            
           
         
       
     
     Preparation of 6-(5-fluoro-2-hydroxyphenyl)nicotinic acid 
     
       
         
         
             
             
         
       
     
     Step A: Methyl 6-(5-fluoro-2-hydroxyphenyl)nicotinate 
     To a degassed mixture of 1,4-dioxane:water (4:1, 15 mls) was added (5-fluoro-2-hydroxyphenyl)boronic acid (0.781 g, 5.0 mmol), methyl 6-chloronicotinate (0.86 g, 5.0 mmol), potassium carbonate (2.08 g, 15.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.05 mmol) and the resulting mixture stirred at 80° C. for 2 h. After this time additional tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.05 mmol) was added and then heating continued at 80° C. for 3 h. The mixture was then stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue suspended in ethyl acetate (50 ml). The suspension was filtered through a plug of arbocel and the filtrate concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (100 ml) and washed with saturated aqueous sodium carbonate (3×100 ml). The aqueous washings were combined and extracted with ethyl acetate (3×50 ml). The ethyl acetate layers were combined, dried with anhydrous MgSO 4  and concentrated in vacuo to afford a solid which was recrystallised from dichloromethane/heptane to afford the title compound as a yellow solid (0.71 g) (57%).  1 H NMR (400 MHz, CDCl 3 ) □ ppm 9.14 (1H, s), 8.46-8.40 (1H, m), 7.91-7.86 (1H, m) 7.53-7.46 (1H, m), 7.11-7.03 (1H, m), 7.02-6.96 (1H, m), 3.99 (3H, s). LRMS: AP m/z 248 [M+H] + . 
     Step B: 6-(5-Fluoro-2-hydroxyphenyl)nicotinic acid 
     methyl 6-(5-fluoro-2-hydroxyphenyl)nicotinate (1.47 g, 6.0 mmol) was dissolved in MeOH (35 ml) and cooled to 0° C. Lithium hydroxide (0.71 g, 30.0 mmol) was then added and the mixture stirred at 0° C. for 0.5 h. The mixture was then allowed to warm to room temperature. Additional lithium hydroxide (0.43 g, 18.0 mmol) was added and the allowed to stir at room temperature for 72 h. The mixture was then concentrated in vacuo and the resulting yellow solid dissolved in water (150 ml). Acidified to pH 1 by addition of 1 N aqueous HCl and the resulting precipitate was filtered and washed with 0.5 M aqueous HCl to afford the title compound as a yellow powder (1.15 g) (72%).  1 H NMR (400 MHz, DMSO-d6) □ ppm 9.11 (1H, s), 8.42-8.28 (2H, m) 7.94-7.84 (1H, m), 7.26-7.15 (1H, m), 7.02-6.92 (1H, m). LRMS: ES m/z 234 [M+H] + . 
     Examples 635-644, listed below, were similarly prepared according to the method described above for example 625, starting from 6-(5-fluoro-2-hydroxyphenyl)nicotinic acid and the appropriate amine. HPLC purification was conducted according to Method A or Method B (see above) as indicated in the Table. 
     
       
         
           
               
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Example 
                 Q 
                 HPLC method 
                 Data 
               
               
                   
               
               
                 635 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 R.T. 3.29 ES m/z 398 [M + H] +   
               
               
                   
               
               
                 636 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 R.T. 3.42 ES m/z 400 [M + H] +   
               
               
                   
               
               
                 637 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 R.T. 2.37 ES m/z 374 [M + H] +   
               
               
                   
               
               
                 638 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 R.T. 2.30 ES m/z 358 [M + H] +   
               
               
                   
               
               
                 639 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 R.T. 2.38 ES m/z 394 [M + H] +   
               
               
                   
               
               
                 640 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 R.T. 2.29 ES m/z 344 [M + H] +   
               
               
                   
               
               
                 641 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 R.T. 2.36 ES m/z 370 [M + H] +   
               
               
                   
               
               
                 642 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 R.T. 3.43 ES m/z 422 [M + H] +   
               
               
                   
               
               
                 643 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 R.T. 3.07 ES m/z 398 [M + H] +   
               
               
                   
               
               
                 644 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 R.T. 3.36 ES m/z 394 [M + H] +   
               
               
                   
               
            
           
         
       
     
     The following specific compounds also fall within the scope of formula (I): 
     
       
         
         
             
             
         
       
     
     EXAMPLE 645 
     Q=(CH 3 )NHCO— 
     EXAMPLE 646 
     Q=CH 3 CH 2 OCO— 
     EXAMPLE 647 
     Q=(CH 3 CH 2 ) 2 CH— 
     Further examples of compounds that are useful according to the invention are: 
     EXAMPLE 648 
     ethyl (3R,4S)-4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)-3-methylpiperidine-1-carboxylate; and 
     EXAMPLE 649 
     N-(1-ethyl-7-methyl-1,2,3,4-tetrahydro-1,8-naphthyridin-4-yl)-6-(3-fluorophenyl)nicotinamide. 
     EXAMPLE 650 
     6-(3-Fluorophenyl)-N-(2-oxo-1,2,3,4-tetrahydroquinolin-4-yl)nicotinamide 
     
       
         
         
             
             
         
       
     
     This compound was made using a method analogous to those described above. 1H NMR (400 MHz, DMSO-d6) □ ppm 2.68-2.78 (m, 2H) 5.34-5.42 (m, 1H) 6.89-7.02 (m, 2H) 7.18-7.34 (m, 3H) 7.52-7.60 (m, 1H) 7.90-8.02 (m, 2H) 8.13 (dd, 1H) 8.33 (dd, 1H) 9.11 (d, J=2.01 Hz, 2 H) 10.21 (s, 1H). 
     MS calc (M+H)=362.13, obs (M+H)=362.13. 
     EXAMPLE 651 
     6-(3-Fluorophenyl)-N-((1R,5S,6S)-3-(2,2,2-trifluoroethyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)nicotinamide 
     
       
         
         
             
             
         
       
     
     To a solution of N-((1R,5S,6S)-3-aza-bicyclo[3.1.0]hexan-6-yl)-6-(3-fluorophenyl)nicotinamide (40 mg, 0.13 mmoL) in toluene (2 mL) was added 2,2,2-trifluoroethyltrichloromethane suflonate (45.4 mg, 0.16 mmol) and TEA (0.06 mL, 0.40 mmol). The reaction mixture was heated to reflux for 4 hrs and then cooled to room temperature and the solvent removed. The residue was taken up into DMSO and purified by RP-HPLC to give the product, 6-(3-fluorophenyl)-N-((1R,5S,6S)-3-(2,2,2-trifluoroethyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)nicotinamide (20 mg, 39%). HRMS (M+H) expected 380.1386, 380.1538 observed. 1H NMR (400 MHz, DMSO-d6) □ ppm 1.19 (s, 1H) 1.71 (br. s., 1H) 2.46 (br. s., 1H) 2.59 (br. s., 1H) 2.70 (br. s., 1H) 3.02 (br. s., 1H) 3.17 (br. s., 4H) 3.40 (br. s., 2H) 7.28-7.34 (m, 1H) 7.54 (br. s., 1H) 7.97 (br. s., 1H) 8.13 (br. s., 1H) 8.24 (br. s., 1H). 
     EXAMPLE 652 
     Tert-butyl(1R,5S,6s)-6-({[6-(3-fluorophenylpyridine-3-yl]carbonyl}amino)3-azabicyclo[3.1.0]hexane-3-carboxylate 
     
       
         
         
             
             
         
       
     
     6-(3-Fluorophenyl)nicotinic acid (1.00 g, 4.60 mmol) was dissolved in dimethylformamide (5 mL) and 1,1′-carbonylbis(1H-imidazole) (746 mg, 4.60 mmol) was added and the reaction was stirred at room temperature for 1.5 hours. Tert-butyl(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (913 mg, 4.60 mmol) which can be prepared by the method of de Meijere, Chem. Eur. J. 2002, 8, No. 16, 3789-3801 was then added and the reaction stirred at room temperature overnight. The solvent was evaporated off and the residue partitioned between ethyl acetate (20 mL) and water (5 mL). The organic layer was separated and dried over anhydrous MgSO 4 , filtered and evaporated to orange oil which crystallised on standing. The solid was triturated with tert-butyl methyl ether and the pale buff coloured solid was filtered off and dried to give tert-butyl(1R,5S,6s)-6-({[6-(3-fluorophenylpyridine-3-yl]carbonyl}amino)3-azabicyclo[3.1.0]hexane-3-carboxylate (1.13 g)  1 H NMR (400 MHz, CDCl 3 ) ppm 1.46 (s, 9H) 1.84 (m, 2H) 2.67 (m, 1H) 3.46 (t, J=9.7 Hz, 2H) 3.79 (m, 2H) 6.30 (s, 1H) 7.16 (m, 1H) 7.47 (m, 1H) 7.80 (m, 3H) 8.18 (dd, J=5.8, 2.4 Hz, 1H) 8.99 (dd, J=1.6, 0.7 Hz, 1H). 
     EXAMPLE 653 
     N-[(1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl]-6-(3-fluorophenyl)nicotinamide di-hydrochloride 
     
       
         
         
             
             
         
       
     
     Tert-butyl(1R,5S,6s)-6-({[6-(3-fluorophenylpyridine-3-yl]carbonyl}amino)3-azabicyclo[3.1.0]hexane-3-carboxylate (900 mg, 2.26 mmol) was dissolved in methanol (15 mL) and a 4M solution of HCl in 1,4,dioxane (5.66 mL) was added and the reaction stirred at room temperature for 48 hours. The solvent was evaporated off and the residue triturated with a mixture of tert-butyl methyl ether and methanol in a ratio of approximately 3:1. The buff coloured solid was filtered off and dried to give the product N-[(1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl]-6-(3-fluorophenyl)nicotinamide dihydrochloride as a buff coloured solid (720 mg)  1 H NMR (400 MHz, DMSO-d6) ppm 3.09 (m, 1H) 3.40 (m, 4H) 7.35 (m, 1H) 7.59 (m, 1H) 8.01 (m, 2H), 8.17 (dd, J=1.5, 0.8 Hz, 1H) 8.31 (dd, J=7.7, 1.3 Hz, 1H) 8.91 (d, J=3.9 Hz, 1H) 9.10 (m, 2H) 9.60 (m, 2H). 
     EXAMPLE 654 
     N-[(1R,5S,6s)-3-acetyl-3-azabicyclo[3.1.0]hex-6-yl]-6-(3-fluorophenyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     N-[(1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl]-6-(3-fluorophenyl)nicotinamide hydrochloride(100 mg, 0.270 mmol) was suspended in dichloromethane (5 mL) and N-ethyl-N-isopropylpropan-2-amine (0.165 mL, 0.165 mL) was added. The reaction mixture was cooled in ice and then acetyl chloride (0.023 mL, 0.324 mmol) was added and the reaction stirred with cooling for 15 minutes and then at room temperature overnight. Further acetyl chloride (0.006 mL, 0.084 mmol) was added and stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane (5 mL) and washed with water (5 mL). The organic layer was separated off and dried over anhydrous MgSO 4 , filtered and evaporated to a white solid. This was triturated with tert-butyl methyl ether and the solid filtered off and dried to give N-[(1R,5S,6s)-3-acetyl-3-azabicyclo[3.1.0]hex-6-yl]-6-(3-fluorophenyl)nicotinamide as a white solid (72 mg) LCMS 340 (M+1) ELSD 1.26 minutes  1 H NMR (400 MHz, DMSO-d6) ppm 1.86 (m, 1H) 1.94 (m, 4H) 2.61 (m, 1H) 3.86 (m, 1H) 3.67 (m, 3H) 7.35 (td, J=10.0, 3.5 Hz, 1H) 7.59 (m, 1H) 8.00 (m, 2H) 8.17 (dd, J=9.0, 0.8 Hz, 1H) 8.28 (dd, J=5.8, 2.4 Hz, 1H) 8.01 (d, J=3.8 Hz, 1H) 9.08 (d, J=1.5 Hz, 1H). 
     EXAMPLE 655 
     6-(3-Fluorophenyl)-N-[1R,5S,6S)-3-propyl-3-azabicyclo[3.1.0]hex-6-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     N-[(1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl]-6-(3-fluorophenyl)nicotinamide di-hydrochloride (100 mg, 0.270 mmol), potassium carbonate (130 mg, 0.945 mmol) and 1-iodopropane (0.029 mL, 0.0297 mmol) were added to 2-propanol and the mixture heated at 55° C. overnight in a reactivial™. Further 1-iodopropane (0.029 mL, 0.0297 mmol) was added and heated at 70° C. for 20 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate (10 mL) and water (5 mL). The organic layer was separated, dried over anhydrous MgSO 4 , filtered and evaporated to a white solid. This was triturated with tert-butyl methyl ether and the solid filtered off and dried to give 6-(3-fluorophenyl)-N-[1R,5S,6s)-3-propyl-3-azabicyclo[3.1.0]hex-6-yl]nicotinamide as a white solid (43 mg) LCMS 340 (M+1) ELSD 0.90 minutes  1 H NMR (400 MHz, DMSO-d6) ppm 0.87 (t, J=7.4 Hz, 3H) 1.43 (m, 2H) 1.66 (m, 2H) 2.33 (q, J=7.4 Hz, 4H) 3.09 (m, 3H) 7.34 (m, 1H) 7.59 (m, 1H) 7.97 (m, 1H) 7.99 (m, 1H) 8.14 (dd, J=7.5, 0.7 Hz, 1H) 8.26 (dd, J=6.2, 0.7 Hz, 1H) 8.61 (d, J=4.7 Hz, 1H) 9.06 (d, J=1.1 Hz, 1H). 
     EXAMPLE 656 
     6-(3-Fluorophenyl)-N-[1R,5S,6s)-3-(isopropylsulfonyl)-3-azabicyclo[3.1.0]hex-6-yl]nicotinamide 
     
       
         
         
             
             
         
       
     
     N-[(1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl]-6-(3-fluorophenyl)nicotinamide di-hydrochloride (100 mg, 0.270 mmol) and pyridine (0.076 mL, 0.945 mmol) were added to dichloromethane (5 mL) and the reaction mixture cooled in ice. Propane-2-sulfonyl chloride (0.036 mL, 0.324 mmol) was added and the reaction stirred for 30 minutes with cooling and then at room temperature overnight. After this time the dichloromethane was evaporated off and pyridine (2 mL) was added along with further propane-2-sulfonyl chloride (0.036 mL, 0.324 mmol) and the resulting mixture stirred at room temperature overnight. Further propane-2-sulfonyl chloride (0.036 mL, 0.324 mmol) was added and stirred at room temperature for 24 hours. The pyridine was evaporated off and the residue was partitioned between ethyl acetate (10 mL) and dilute sodium bicarbonate solution (5 mL), some insoluble material was filtered off at the interface and then the organic layer was evaporated to a bright pink solid. This was purified, giving 6-(3-fluorophenyl)-N-[1R,5S,6s)-3-(isopropylsulfonyl)-3-azabicyclo[3.1.0]hex-6-yl]nicotinamide (17.6 mg) LCMS Method A (acidic conditions) RT 2.97 (100% area) min ES m/z 404 [M+H] + . 
     Biological Data 
     Fluorescence Intensity h-PGDSTBA Enzyme Assay 
     Prostaglandin D Synthase (PGDS) converts the substrate prostaglandin H 2  (PGH 2 ) to prostaglandin D 2 . The depletion of PGH 2  was measured via an Fe(II) reduction of the remaining PGH 2  to malondialdehyde (MDA) and 12-HHT. The enzyme assay is based on the quantitative formation of a fluorescent complex from the non-fluorescent compounds MDA and 2-thiobarbituric acid (TBA), substantially as described in U.S. patent application publication US-2004/152148 by Lambalot. 
     The enzyme assay (31 μls) contained 100 mM Tris base pH 8.0, 100 μM MgCl 2 , 0.1 mg/ml IgG Rabbit serum, 5.0 μM PGH2 (Cayman; ethanol solution, #17020), 2.5 mM L-Glutathione (Sigma; reduced form #G4251), 1:175,000 human recombinant H-PGDS (from 1 mg/ml), 0.5% DMSO and inhibitor (varying concentration). Three μls of diluted inhibitor (dissolved in DMSO) was plated into a 384-well assay plate followed by a 25 μl addition of an enzyme solution containing h-PGDS, Tris, MgCl 2 , IgG and L-Glutathione. After preincubation of inhibitor and enzyme solution for 10 minutes at room temperature, the reaction was initiated with a 3 μl addition of substrate solution in 10 mM HCl. The reaction was terminated after 42 second by the addition (3 μl) of stop buffer containing FeCl 2  and citric acid. After addition of 45.5 μls of TBA plates were heated for one hour in a 70° C. oven. Plates were cooled at room temperature overnight and read on a plate reader the next day with excitation @ 530 nm and emission @ 565 nm. IC 50 &#39;s of inhibitors were calculated with a 4-parameter fit using 11 inhibitor concentrations in duplicate with 3-fold serial dilutions. Controls on each plate included no inhibitor (zero % effect) and an inhibitor 10-fold in excess of its&#39; IC 50  (100% effect). The highest inhibitor concentration tested was typically 1 μM. 
     Examples 623 onwards were tested in a slightly modified assay: The enzyme assay (30 μls during biological process) contained 100 mM Trizma pH 8.0, 100 μM MgCl 2 , 0.1 mg/ml IgG Rabbit serum, 5.0 μM PGH2 (Cayman; ethanol solution, #17020), 2.5 mM L-Glutathione (Sigma; reduced form #G4251), 1:40,000 human recombinant H-PGDS (from 1 mg/ml), 0.5% DMSO and inhibitor (varying concentration). 3 μls of diluted inhibitor (dissolved in DMSO) was plated into a 384-well assay plate followed by a 24 μl addition of an enzyme solution containing h-PGDS, Trizma, MgCl 2 , IgG and L-Glutathione. After pre-incubation of inhibitor and enzyme solution for 10 minutes at room temperature, the reaction was initiated with a 3 μl addition of substrate solution in 10 mM HCl. The reaction was terminated after 40 second by the addition of 3 μl stop buffer containing FeCl 2  and citric acid. After addition of 45 μl of TBA plates were heated for one hour in a 70° C. oven. Plates were cooled at room temperature overnight and read on a plate reader the next day with excitation @ 530 nm and emission @ 560 nm. IC 50 &#39;s of inhibitors were calculated with a 4-parameter fit using 11 inhibitor concentrations in duplicate with 1/2 log serial dilutions. Controls on each plate included no inhibitor (zero % effect) and an inhibitor 500-fold in excess of its&#39; IC 50  (100% effect). The highest inhibitor concentration tested was typically 10 μM. 
     Table II shows the IC 50  values thus obtained. 
                             TABLE II                   Example   IC 50  (nM)                                                 1   0.204            2   0.852            3   0.343            4   2.58            5   0.665            6   0.377            7   0.351            8   1.57            9   23.6            10   78.4            11   39.4            12   694            13   58            14   4.29            15   2.91            16   146            17   11.7            18   3.94            19   36.2            20   1000            21   0.898            22   73.3            23   1.72            24   2.64            25   7.66            27   19.1            28   1.72            29   0.946            30   3.79            31   19.9            32   0.387            33   2.41            34   1.85            35   2.95            36   7.11            37   0.478            38   1.04            39   0.924            40   0.556            41   0.893            42   8.58            43   2.18            44   1.36            45   0.773            46   1.73            47   2.92            48   2.9            49   0.619            50   0.681            51   0.266            52   0.332            53   1.03            54   1.31            55   1.67            56   12.8            57   0.285            58   8.25            59   0.822            60   0.593            61   0.365            62   3.33            63   0.183            64   0.246            65   0.354            66   0.627            67   0.955            68   0.361            69   1.21            70   3.26            71   2.18            72   4.97            73   2.89            74   0.293            75   0.314            76   1.35            77   0.425            78   0.148            79   2.28            80   0.408            81   0.947            82   1.05            83   0.37            84   0.635            85   0.72            86   0.876            87   0.538            88   0.694            89   0.365            90   0.305            91   0.603            92   5.15            93   17.9            94   0.426            95   0.764            96   1.19            97   0.319            98   3.7            99   2.08           100   1.53           101   1.4           102   0.943           103   2.15           104   3.18           105   0.655           106   0.873           107   0.804           108   1.29           109   2.74           110   1.61           111   1.62           112   1.87           113   0.263           114   2.3           115   0.241           116   2.56           117   0.429           118   0.89           119   3.74           120   3.49           121   1.21           122   0.168           123   4.66           124   0.345           125   0.176           126   0.656           127   4.01           128   0.687           129   6.24           130   4.57           131   0.463           132   0.365           133   0.395           134   1.81           135   1.47           136   5.12           137   1.41           138   1.23           139   0.222           140   0.628           141   0.721           142   0.33           143   0.688           144   9.56           145   5.94           146   1.55           147   0.737           148   1.75           149   1.82           150   1.8           151   0.519           152   3.35           153   1.89           154   0.96           155   2.3           156   3.15           157   0.678           158   1.58           159   1.59           160   0.483           161   3.85           162   1.1           163   14.5           164   0.422           165   1.16           166   3.44           167   3.13           168   2.53           169   23.2           170   1.77           171   1.41           172   35           173   16           174   8.97           175   5.4           176   0.759           177   68.4           178   0.735           179   2.26           180   0.372           181   3.4           182   0.424           183   1.12           184   3.67           185   11           186   1.79           187   2.59           188   2.25           189   0.502           190   1.83           191   0.171           192   0.701           193   0.768           194   3.5           195   0.194           196   1.35           197   0.578           198   1.04           199   2.7           200   1.61           201   1.93           202   1.17           203   2.17           204   0.067           205   0.238           206   1.84           207   1.59           208   5.98           209   1.37           210   0.46           211   0.453           212   1.4           213   0.469           214   5.55           215   0.38           216   0.36           217   1.51           218   0.448           219   0.749           220   2.42           221   0.446           222   6.64           223   0.928           224   0.342           225   2.48           226   1.42           227   0.815           228   2.5           229   0.509           230   0.53           231   0.552           232   2.71           233   0.352           234   1.65           235   1.98           236   0.577           237   0.698           238   0.135           239   0.245           240   0.181           241   2.19           242   0.781           243   1.03           244   0.288           245   1.2           246   1.97           247   0.653           248   1.05           249   1.17           250   0.409           251   0.623           252   0.865           253   1.45           254   1.68           255   0.738           256   0.397           257   0.58           258   1.24           259   1.68           260   0.578           261   1.48           262   3.86           263   1.16           264   2           265   4.29           266   2.15           267   0.994           268   8.08           269   3.5           270   0.507           271   5.62           272   0.816           273   1.11           274   2.57           275   5.49           276   0.743           277   5.72           278   5.01           279   4.17           280   0.851           281   1.8           282   0.629           283   0.5           284   1.43           285   1.53           286   1.21           287   3           288   1.25           289   2.09           290   0.843           291   1.17           292   0.465           293   0.592           294   1.76           295   0.506           296   1.4           297   1.25           298   0.939           299   0.308           300   0.362           301   1.16           302   0.636           303   0.662           304   2.11           305   2.7           306   2.71           307   0.784           308   2.03           309   4.32           310   4.78           311   1.72           312   1.08           313   2.15           314   0.24           315   0.549           316   1.36           317   2.07           318   1.18           319   0.384           320   2.34           321   0.365           322   0.748           323   0.622           324   0.531           325   4.01           326   2.45           327   1.55           328   0.566           329   1.94           330   1.71           331   2.71           332   1.19           333   1.04           334   2.74           335   0.776           336   1.82           337   1.42           338   62.7           339   1.17           340   1.17           341   0.485           342   0.281           343   1.9           344   0.174           345   0.508           346   4.07           347   0.578           348   0.612           349   2.96           350   0.247           351   0.531           352   0.625           353   0.959           354   2.92           355   0.513           356   2           357   6.66           358   1.72           359   0.443           360   2.76           361   1.35           362   1.05           363   0.299           364   4.03           365   0.13           366   2.42           367   0.707           368   2.03           369   1.36           370   0.456           371   0.438           372   0.981           373   2.36           374   2.99           375   0.667           376   0.876           377   0.491           378   1.41           379   1.43           380   1.25           381   0.0854           382   0.681           383   1.25           384   0.959           385   11.7           386   1.2           387   1.85           388   0.951           389   2.23           390   11.6           391   1.2           392   0.849           393   1.18           394   0.379           395   1.43           396   1.45           397   1.47           398   8.56           399   1.02           400   1.04           401   0.574           402   1.64           403   0.121           404   0.469           405   0.483           406   2.36           407   5.4           408   61.9           409   2.25           410   16.3           411   1.36           412   4.12           413   1000           414   0.35           415   1.96           416   1.68           417   1.1           418   0.427           419   1.03           420   3.4           421   1.34           422   2.53           423   0.931           424   1.3           425   2.81           426   5.53           427   0.656           428   0.926           429   1.12           430   1.2           431   0.822           432   0.962           433   0.401           434   1.51           435   0.908           436   0.885           437   3.52           438   0.417           439   0.762           440   1.96           441   2.58           442   2.78           443   1.59           444   0.135           445   4.24           446   0.891           447   1.1           448   2.45           449   2.8           450   2.05           451   0.88           452   0.724           453   1.42           454   0.82           455   1.34           456   2.05           457   0.76           458   1.78           459   0.721           460   1.28           461   0.239           462   0.264           463   0.385           464   1.02           465   0.881           466   1.49           467   0.257           468   0.375           469   0.855           470   4.14           471   2.68           472   0.491           473   2.36           474   1.44           475   4.07           476   0.935           477   4.04           478   2.01           479   0.421           480   2.69           481   2.45           482   2.39           483   3.58           484   2.68           485   2.77           486   2.32           487   0.372           488   0.489           489   1.18           490   0.601           491   2.4           492   0.285           493   1.1           494   0.817           495   0.409           496   0.569           497   1.06           498   0.3           499   1.64           500   0.633           501   0.432           502   1.99           503   2.7           504   2.84           505   0.418           506   1.25           507   0.551           508   0.551           509   0.665           510   2.74           511   1.09           512   0.391           513   0.363           514   0.348           515   1.1           516   2.2           517   0.41           518   0.96           519   0.445           520   1.93           521   556           522   6.54           523   217           524   1.76           525   14.8           526   76.3           527   2.84           528   2.49           529   2.5           530   2.71           531   1.15           532   1.3           533   2.42           534   0.234           535   2.11           536   1.75           537   2.68           538   1.94           539   2.71           540   1.99           541   0.951           542   1.68           543   3.27           544   1.27           545   2.65           546   2.83           547   1.14           548   2.07           549   2.26           550   2.38           551   1.32           552   2.37           553   1.78           554   1.72           555   0.928           556   0.364           557   6.56           558   0.345           559   10.6           560   0.641           561   1.14           562   1.74           563   0.981           564   1.09           565   1.05           566   1.82           567   0.867           568   0.649           569   2.13           570   1.41           571   1.04           572   5.25           573   1.35           574   1.24           575   2.24           576   0.561           577   1.48           578   3.1           579   1.05           580   0.35           581   0.69           582   1.22           583   1.05           584   1.38           585   0.734           586   0.787           587   1.19           588   0.621           589   33.3           590   0.74           591   5.57           592   2.44           593   2.0           594   2.7           595   1.06           596   1.93           597   0.85           598   3.79           599   2.92           600               601   6.76           602   2.98           603   2.29           604   11.5           605   2.9           606   10.8           607   4.44           608               609   5.43           610   6.92           611               612   12           613   3.57           614   52.5           615   5.1           616   5.12           617   4.1           618   7.33           619   1.19           620   3.66           621   1.59           622   3.48           623   104           624   36           625   4.06           626   11.5           627   6.75           628   6.22           629   22.2           630   32.8           631   82.4           632   5.57           633   16.6           634   6.13           635   10.9           636   17.2           637   62.4           638   83.3           639   10000           640   129           641               642   13.9           643   7.77           644               645               646               647               648               649               650   0.568           651   2.01           652               653   177           654   33.8           655   66.8           656                3a   6.86            3b   0.403                    
In vivo Assay—Anti-Asthmatic Effects in a Sheep Model of Asthma
 
     A validated model of  A. suum  antigen-induced asthmatic response in conscious sheep was used to evaluate the pharmacokinetic properties, inhibition of antigen-induced early and late airway bronchoconstriction in the lung by compound (Abraham, W. M., et al., Am Rev Respir Dis 1991; 143:787-796). 
     Sheep used in these studies exhibit both early and late airway responses to inhalation challenge with  A. suum  antigen as well as antigen-induced airway hyper-responsiveness to inhaled carbachol. An aerosol of  A. suum  extract, generated using a disposable medical nebulizer (Raindrop®, Puritan Bennett) was delivered in at a tidal volume of 500 mL and a rate of 20 breaths/min. 
     A compound of Example 2 was delivered by i.v. infusion over the interval t=0-20 min prior to antigen challenge. A single dose of 1, 0.3 or 0.1 mg//kg was evaluated. Baseline and post-drug measurements of specific lung resistance (R L ) were obtained immediately prior to challenge (t=30 min) with  A. suum  antigen, immediately after challenge and then hourly from 1 to 6 h post challenge and on the half-hour from 6.5, 5-8 h post challenge. Measurements of R L  were obtained 24 h post challenge, followed by the 24 h post-challenge dose-response curve for carbachol. 
     To determine the effect of the compound of Example 2 on antigen-induced airway hyper-responsiveness, measurements of R L  were repeated immediately after inhalation of buffer and after each administration of 10 breaths of increasing concentrations of carbachol solution (0.25%, 0.5%, 1.0%, 2.0%, and 4.0% wt/vol). To assess airway responsiveness, the cumulative carbachol dose in breath units (BU) that increased R L  400% over the post-buffer value (i.e., PC 400 ) were calculated from the dose-response curve. One breath unit is defined as one breath of a 1% wt/vol carbachol solution. Measurements of PC 400  obtained after antigen were compared with those obtained before antigen challenge to determine if antigen challenge induced airway hyper-responsiveness. 
     The early airway response (0-2 h after allergen challenge) was not reduced but the late airway response (4-8 h after antigen challenge) was inhibited by approximately 60%.