Phenylalkynes

Abstract

Substituted phenylalkynes of formula (I), compositions containing them, and methods of making and using them to treat histamine-mediated conditions.

1 . A method of making a compound of formula (I)  
       
         
           
           
               
               
           
         
         wherein n is an integer from 0 to 1;  
         R 1  and R 2  are independently selected from C 1-3  alkyl, allyl, and C 3-8  cycloalkyl, or taken together with the nitrogen to which they are attached, they form a non-aromatic 4-7 membered heterocyclyl optionally including up to two additional heteroatoms independently selected from O, S, and N;  
         one of R 3 , R 4 , and R 5  is G, one of the remaining two is hydrogen, and the other is selected from hydrogen, fluoro, and chloro;  
         G is L 2 Q;  
         L 2  is methylene;  
         Q is NR 8 R 9  wherein R 8  is independently selected from hydrogen, C 1-6  alkyl, C 3-6  alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C 1-6  alkylene, and (phenyl) C 1-6  alkylene; and R 9  is independently selected from C 1-6  alkyl, C 3-6  alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C 1-6  alkylene, and (phenyl) C 1-6  alkylene;  
         or  
         Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms independently selected from O, S, and N;  
         wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, and aryl groups of formula (I) may each be independently and optionally substituted with between 1 and 3 substituents independently selected from methoxy, halo, amino, nitro, hydroxyl, and C 1-3  alkyl;  
         and wherein 1-3 substituents of Q can be further independently selected (in addition to the preceding paragraph) from tert-butyloxycarbonyl, carboxamide, C 1-6  alkyl, 5-9-membered heterocyclyl, N(C 1-6  alkyl)(5-9 membered heterocyclyl), NH(5-9 membered heterocyclyl), O(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)C 1-3  alkylene, phenyl, C 1-2 -hydroxyalkylene, C 2-6  alkoxy, (C 3-6  cycloalkyl)-O—, phenyl, (phenyl)C 1-3  alkylene, and (phenyl)C 1-3  alkylene-O— and where said substituent groups of Q may optionally have between 1 and 3 substituents independently selected from trifluoromethyl, halo, nitro, cyano, and hydroxy; a pharmaceutically acceptable salt, ester, or amide thereof, comprising at least one of the following steps: reacting a compound of formula (VI) with a compound of formula (V)  
         
           
             
             
                 
                 
             
           
         
         performing a nucleophilic substitution of X 1  in compound of formula (VIII) with an organic base R 1 R 2 NH, wherein X 2  is a suitable leaving group in a coupling reaction with an alkyne, and X 1  is a suitable leaving group in a nucleophilic substitution with an amine.  
       
     
     
         2 . A method according to  claim 1 , wherein NR 1 R 2  taken together form piperidinyl, methylpiperidinyl, dimethylamino, pyrrolidinyl, diethylamino, methylethylamino, ethylpropylamino, or dipropylamino.  
     
     
         3 . A method according to  claim 2 , wherein NR 1 R 2  taken together form piperidinyl, pyrrolidinyl, or diethylamino.  
     
     
         4 . A method according to  claim 3 , wherein NR 1 R 2  taken together form piperidinyl or pyrrolidinyl.  
     
     
         5 . A method according to  claim 1 , wherein one of R 4  and R 5  is G.  
     
     
         6 . A method according to  claim 5 , wherein R 4  is G.  
     
     
         7 . A method according to  claim 5 , wherein R 5  is G.  
     
     
         8 . A method according to  claim 1 , wherein n is 1.  
     
     
         9 . A method according to  claim 1 , wherein Q is a saturated N-linked nitrogen-containing heterocyclyl.  
     
     
         10 . A method according to  claim 9 , wherein Q is selected from substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl.  
     
     
         11 . A method according to  claim 10 , wherein substituted Q is selected from N—(C 1-6  alkyl)piperazinyl, N-phenyl-piperazinyl, 1,3,8-triaza-spiro[4.5]decyl, and 1,4-dioxa-8-aza-spiro[4.5]decyl.  
     
     
         12 . A method according to  claim 9 , wherein Q is a monovalent radical of an amine selected from aziridine, 1,4,7-trioxa-10-aza-cyclododecane, thiazolidine, 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, piperidine-3-carboxylic acid diethylamide, 1,2,3,4,5,6-hexahydro-[2,3′]bipyridinyl, 4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazin-1-yl-pyrimidine, piperidine-4-carboxylic acid amide, methyl-(2-pyridin-2-yl-ethyl)-amine, [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine, thiomorpholinyl, allyl-cyclopentyl-amine, [2-(1H-indol-3-yl)-ethyl]-methyl-amine, 1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one, 2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin-2-yl-amine, phenylamine, pyridin-2-ylamine.  
     
     
         13 . A method according to  claim 11 , wherein Q is selected from N-morpholinyl and N-piperidinyl, optionally substituted with between 1 and 3 substituents selected from hydroxyl, carboxamide, C 1-6  alkyl, 5-9 membered heterocyclyl, N(C 1-6  alkyl)(5-9 membered heterocyclyl), NH(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)C 1-3  alkylene, C 1-2 -hydroxyalkylene, O(5-9 membered heterocyclyl), C 1-6  alkoxy, (C 3-6  cycloalkyl)-O—, phenyl, (phenyl)C 1-3  alkylene, and (phenyl)C 1-3  alkylene-O— where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from halo, nitro, cyano, and C 1-3  alkyl.  
     
     
         14 . A method according to  claim 11 , wherein Q is substituted with a substituent comprising a C 1-6  heterocyclyl group selected from: pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C 1-6  alkylene, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl, (tetrazolyl)C 1-6  alkylene, tetrazolyl, (triazolyl)C 1-6  alkylene, triazolyl, (pyrrolyl)C 1-16  alkylene, and pyrrolyl.  
     
     
         15 . A method according to  claim 14 , wherein Q is a substituted or unsubstituted N-morpholinyl.  
     
     
         16 . A method according to  claim 1 , wherein n is 1; 
 R 1  and R 2  are independently selected from C 2  alkyl, or taken together with the nitrogen to which they are attached, they form a non-aromatic 5-6 membered heterocyclyl optionally including an additional heteroatom independently selected from O, S, and N;    one of R 3 , R 4 , and R 5  is G and the two remaining are H;    G is L 2 Q;    L 2  is methylene;    Q is NR 8 R 9  wherein R 3  is independently selected from hydrogen, C 1-2  alkyl, C 3  alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C 2  alkylene, and (phenyl) C 2  alkylene; and R 9  is independently selected from C 1-2  alkyl, C 3  alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C 2  alkylene, and (phenyl) C 2  alkylene;    or    Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms selected from O, S, and N;    wherein each of the above alkyl, alkylene, alkenyl, alkenylene, heterocyclyl, and carbocyclyl groups may each be independently and optionally substituted with between 1 and 3 substituents selected from methoxy, halo, amino, nitro, hydroxyl, and C 1-3  alkyl;    and wherein substituents of Q can be further selected from tert-butyloxycarbonyl, carboxamide, 5-9-membered heterocyclyl, NH(6-membered heterocyclyl), O(6-membered heterocyclyl), phenyl, C 2 -hydroxyalkylene, hydroxy, benzyl and, where each of above heterocyclyl, phenyl, and alkyl substituent groups of Q may be optionally substituted with trifluoromethyl.    
     
     
         17 . A method according to  claim 1 , wherein 
 (a) NR 1 R 2  taken together form piperidinyl, pyrrolidinyl, or diethylamino, and    (b) Q is selected from substituted or unsubstituted piperidinyl, piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl.    
     
     
         18 . A method according to  claim 1 , wherein said organic base R 1 R 2 NH is piperidine and said nucleophilic substitution is performed at room temperature.  
     
     
         19 . A method according to  claim 1 , wherein said nucleophilic substitution is performed at room temperature with 10 equivalents of piperidine in the presence of ethanol.  
     
     
         20 . A method according to  claim 1 , wherein said nucleophilic substitution is performed at room temperature with 10 equivalents of piperidine in the presence of ethanol and X 1  is mesylate, to yield a mixture of a substituted base and an elimination product.  
     
     
         21 . A method according to  claim 20 , further comprising exposing said mixture to HCl to yield a saline solution, selectively precipitating and crystallizing form said saline solution a phenylalkyne dihydrochloride salt.  
     
     
         22 . A method according to  claim 21 , wherein said phenylalkyne dihydrochloride salt is 4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]morpholine dihydrochloride.  
     
     
         23 . A method according to  claim 1 , wherein NR 1 R 2  taken together form piperidinyl or pyrrolidinyl, n is 1, and Q is selected from morpholinyl and piperidinyl.  
     
     
         24 . A method according to  claim 1 , wherein NR 1 R 2  taken together form piperidinyl or pyrrolidinyl, n is 1, and Q is morpholinyl or substituted morpholinyl.  
     
     
         25 . A method according to  claim 1 , wherein n=1, R 3  is H, R 5  is H, R 4  is L 2 Q, with Q being morpholinyl, L 2  as defined in  claim 1 , and NR 1 R 2  taken together form piperidinyl.  
     
     
         26 . A method according to  claim 1 , wherein said organic base R 1 R 2 NH is piperidine.  
     
     
         27 . A method according to  claim 1 , wherein said nucleophilic substitution is performed in the presence of ethanol at room temperature.  
     
     
         28 . A method according to  claim 1 , wherein said nucleophilic substitution is performed in the presence of ethanol at room temperature and said organic base R 1 R 2 NH is piperidine.  
     
     
         29 . A method according to  claim 28 , wherein the amount of said piperidine is 10 equivalents.  
     
     
         30 . A method according to  claim 1 , wherein n=1, R 3  is H, R 5  is H, R 4  is L 2 Q, with Q being morpholinyl, L 2  as defined in  claim 1 , said organic base R 1 R 2 NH is piperidine, and said nucleophilic substitution is performed in the presence of ethanol at room temperature.  
     
     
         31 . A method according to  claim 1 , wherein said nucleophilic substitution yields a mixture of a substitution product and an elimination product and is performed in an alcoholic medium at a temperature such that said substitution product is obtained in at least 80%.  
     
     
         32 . A method according to  claim 1 , wherein said nucleophilic substitution yields a mixture of a substitution product and an elimination product and is performed in the presence of ethanol at room temperature, and said organic base R 1 R 2 NH is piperidine, further comprising treating said mixture with an acid to obtain a saline solution, and selectively precipitating and crystallizing said saline solution to obtain a salt.  
     
     
         33 . A method according to  claim 32 , wherein said acid is HCl.  
     
     
         34 . A method according to  claim 32 , wherein diethyl ether and ethanol are used in said crystallization.  
     
     
         35 . A method according to  claim 34 , wherein n=1, R 3  is H, R 5  is H, R 4  is L 2 Q, with Q being morpholinyl, L 2  as defined in  claim 1 , and NR 1 R 2  taken together form piperidinyl, said substitution product is 4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine and said salt is the dihydrochloride salt of said substitution product.  
     
     
         36 . A method according to  claim 28 , further comprising converting an alcohol of formula (VII) to said compound of formula (VIII).  
     
     
         37 . A method according to  claim 36 , further comprising the reductive amination of a compound of formula (VIIa) with an amine R 8 R 9 NH, wherein one of R 3′ , R 4′ , and R 5′  is C(O)H and the other two are selected from H, chloro and bromo, to give a compound of formula (VII), wherein one of R 3 , R 4 , and R 5  is NR 8 R 9  and the other two are selected from H, chloro and bromo,  
       
         
           
           
               
               
           
         
       
     
     
         38 . A method according to  claim 37 , wherein said amine is morpholine.  
     
     
         39 . A method according to  claim 37 , further comprising the coupling in the presence of a palladium-containing catalyst and a copper salt of a compound of formula (II) with a disubstituted benzene, wherein one of said benzene substitutents is C(O)H and the other of said benzene substitutents is selected from chloro and bromo, to yield a compound of formula (VIIa).  
     
     
         40 . A method of making a compound of formula (I)  
       
         
           
           
               
               
           
         
         wherein n is an integer from 0 to 1;  
         R 1  and R 2  are independently selected from C 1-3  alkyl, allyl, and C 3-8  cycloalkyl, or taken together with the nitrogen to which they are attached, they form a non-aromatic 4-7 membered heterocyclyl optionally including up to two additional heteroatoms independently selected from O, S, and N;  
         one of R 3  and R 5  is G, one of the remaining and R 4  is H, and the other is selected from hydrogen, fluoro, and chloro;  
         G is L 2 Q;  
         L 2  is methylene;  
         Q is NR 8 R 9  wherein R 8  is independently selected from hydrogen, C 1-6  alkyl, C 3-6  alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C 1-6  alkylene, and (phenyl) C 1-6  alkylene; and R 9  is independently selected from C 1-6  alkyl, C 3-6  alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C 1-6  alkylene, and (phenyl) C 1-6  alkylene;  
         or  
         Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms independently selected from O, S, and N;  
         wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, and aryl groups of formula (I) may each be independently and optionally substituted with between 1 and 3 substituents independently selected from methoxy, halo, amino, nitro, hydroxyl, and C 1-3  alkyl;  
         and wherein 1-3 substituents of Q can be further independently selected (in addition to the preceding paragraph) from tert-butyloxycarbonyl, carboxamide, C 1-6  alkyl, 5-9-membered heterocyclyl, N(C 1-6  alkyl)(5-9 membered heterocyclyl), NH(5-9 membered heterocyclyl), O(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)C 1-3  alkylene, phenyl, C 1-2 -hydroxyalkylene, C 2-6  alkoxy, (C 3-6  cycloalkyl)-O—, phenyl, (phenyl)C 1-3  alkylene, and (phenyl)C 1-3  alkylene-O— and where said substituent groups of Q may optionally have between 1 and 3 substituents independently selected from trifluoromethyl, halo, nitro, cyano, and hydroxy; a pharmaceutically acceptable salt, ester, or amide thereof, comprising reacting at least one of the compounds of formulae (XXIIIw) and (XXIIIow) with a compound of formula (V)  
         
           
             
             
                 
                 
             
           
         
         wherein W is C(O)H or G, and X 2  is a suitable leaving group in a coupling reaction with an alkyne.  
       
     
     
         41 . A method according to  claim 40 , wherein said W is C(O)H, further comprising performing a reductive amination of said W with an organic base R 9 R 8 NH.  
     
     
         42 . A method according to  claim 40 , wherein NR 1 R 2  taken together form piperidinyl, methylpiperidinyl, dimethylamino, pyrrolidinyl, diethylamino, methylethylamino, ethylpropylamino, or dipropylamino.  
     
     
         43 . A method according to  claim 42 , wherein NR 1 R 2  taken together form piperidinyl, pyrrolidinyl, or diethylamino.  
     
     
         44 . A method according to  claim 43 , wherein NR 1 R 2  taken together form piperidinyl or pyrrolidinyl.  
     
     
         45 . A method according to  claim 40 , wherein R 5  is G.  
     
     
         46 . A method according to  claim 40 , wherein R 3  is G.  
     
     
         47 . A method according to  claim 40 , wherein n is 1.  
     
     
         48 . A method according to  claim 40 , wherein Q is a saturated N-linked nitrogen-containing heterocyclyl.  
     
     
         49 . A method according to  claim 40 , wherein Q is selected from substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl.  
     
     
         50 . A method according to  claim 49 , wherein substituted Q is selected from N—(C 1-6  alkyl)piperazinyl, N-phenyl-piperazinyl, 1,3,8-triaza-spiro[4.5]decyl, and 1,4-dioxa-8-aza-spiro[4.5]decyl.  
     
     
         51 . A method according to  claim 48 , wherein Q is a monovalent radical of an amine selected from aziridine, 1,4,7-trioxa-10-aza-cyclododecane, thiazolidine, 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, piperidine-3-carboxylic acid diethylamide, 1,2,3,4,5,6-hexahydro-[2,3′]bipyridinyl, 4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazin-1-yl-pyrimidine, piperidine-4-carboxylic acid amide, methyl-(2-pyridin-2-yl-ethyl)-amine, [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine, thiomorpholinyl, allyl-cyclopentyl-amine, [2-(1H-indol-3-yl)-ethyl]-methyl-amine, 1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one, 2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin-2-yl-amine, phenylamine, pyridin-2-ylamine.  
     
     
         52 . A method according to  claim 40 , wherein Q is selected from N-morpholinyl and N-piperidinyl, optionally substituted with between 1 and 3 substituents selected from hydroxyl, carboxamide, C 1-6  alkyl, 5-9 membered heterocyclyl, N(C 1-6  alkyl)(5-9 membered heterocyclyl), NH(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)C 1-3  alkylene, C 1-2 -hydroxyalkylene, O(5-9 membered heterocyclyl), C 1-6  alkoxy, (C 3-6  cycloalkyl)-O—, phenyl, (phenyl)C 1-3  alkylene, and (phenyl)C 1-3  alkylene-O— where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from halo, nitro, cyano, and C 1-3  alkyl.  
     
     
         53 . A method according to  claim 40 , wherein Q is substituted with a substituent comprising a C 1-6  heterocyclyl group selected from: pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C 1-6  alkylene, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl, (tetrazolyl)C 1-6  alkylene, tetrazolyl, (triazolyl)C 1-6  alkylene, triazolyl, (pyrrolyl)C 1-6  alkylene, and pyrrolyl.  
     
     
         54 . A method according to  claim 40 , wherein Q is a substituted or unsubstituted N-morpholinyl.  
     
     
         55 . A method according to  claim 40 , wherein n is 1; 
 R 1  and R 2  are independently selected from C 2  alkyl, or taken together with the nitrogen to which they are attached, they form a non-aromatic 5-6 membered heterocyclyl optionally including an additional heteroatom independently selected from O, S, and N;    one of R 3  and R 5  is G, and the remaining and R 4  are H;    G is L 2 Q;    L 2  is methylene;    Q is NR 8 R 9  wherein R 8  is independently selected from hydrogen, C 1-2  alkyl, C 3  alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C 2  alkylene, and (phenyl) C 2  alkylene; and R 9  is independently selected from C 1-2  alkyl, C 3  alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C 2  alkylene, and (phenyl) C 2  alkylene;    or    Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms selected from O, S, and N;    wherein each of the above alkyl, alkylene, alkenyl, alkenylene, heterocyclyl, and carbocyclyl groups may each be independently and optionally substituted with between 1 and 3 substituents selected from methoxy, halo, amino, nitro, hydroxyl, and C 1-3  alkyl;    and wherein substituents of Q can be further selected from tert-butyloxycarbonyl, carboxamide, 5-9-membered heterocyclyl, NH(6-membered heterocyclyl), O(6-membered heterocyclyl), phenyl, C 2 -hydroxyalkylene, hydroxy, benzyl and, where each of above heterocyclyl, phenyl, and alkyl substituent groups of Q may be optionally substituted with trifluoromethyl.    
     
     
         56 . A method according to  claim 40 , wherein 
 NR 1 R 2  taken together form piperidinyl, pyrrolidinyl, or diethylamino, and    Q is selected from substituted or unsubstituted piperidinyl, piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl.    
     
     
         57 . A method according to  claim 40 , wherein NR 1 R 2  taken together form piperidinyl or pyrrolidinyl, n is 1, and Q is selected from morpholinyl and piperidinyl.  
     
     
         58 . A method according to  claim 40 , wherein NR 1 R 2  taken together form piperidinyl or pyrrolidinyl, n is 1, and Q is morpholinyl or substituted morpholinyl.  
     
     
         59 . A method according to  claim 40 , wherein n is 1, R 4  is H, one of R 3  and R 5  is H, the other one of R 3  and R 5  is L 2 Q, with Q being morpholinyl, and L 2  as defined in  claim 40 , and NR 1 R 2  taken together form piperidinyl.  
     
     
         60 . A method of making a compound of formula (I)  
       
         
           
           
               
               
           
         
         wherein n is an integer from 0 to 1;  
         R 1  and R 2  are independently selected from C 1-3  alkyl, allyl, and C 3-8  cycloalkyl, or taken together with the nitrogen to which they are attached, they form a non-aromatic 4-7 membered heterocyclyl optionally including up to two additional heteroatoms independently selected from O, S, and N;  
         one of R 3 , R 4 , and R 5  is G, one of the remaining two is hydrogen, and the other is selected from hydrogen, fluoro, and chloro;  
         G is L 2 Q;  
         L 2  is methylene;  
         Q is NR 8 R 9  wherein R 8  is independently selected from hydrogen, C 1-6  alkyl, C 3-6  alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C 1-6  alkylene, and (phenyl) C 1-6  alkylene; and R 9  is independently selected from C 1-6  alkyl, C 3-6  alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C 1-6  alkylene, and (phenyl) C 1-6  alkylene;  
         or  
         Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms independently selected from O, S, and N;  
         wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, and aryl groups of formula (I) may each be independently and optionally substituted with between 1 and 3 substituents independently selected from methoxy, halo, amino, nitro, hydroxyl, and C 1-3  alkyl;  
         and wherein 1-3 substituents of Q can be further independently selected (in addition to the preceding paragraph) from tert-butyloxycarbonyl, carboxamide, C 1-6  alkyl, 5-9-membered heterocyclyl, N(C 1-6  alkyl)(5-9 membered heterocyclyl), NH(5-9 membered heterocyclyl), O(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)C 1-3  alkylene, phenyl, C 1-2 -hydroxyalkylene, C 2-6  alkoxy, (C 3-6  cycloalkyl)-O—, phenyl, (phenyl)C 1-3  alkylene, and (phenyl)C 1-3  alkylene-O— and where said substituent groups of Q may optionally have between 1 and 3 substituents independently selected from trifluoromethyl, halo, nitro, cyano, and hydroxy; a pharmaceutically acceptable salt, ester, or amide thereof, comprising reacting a compound of formula (VII)  
         
           
             
             
                 
                 
             
           
         
         with an organic base R 1 R 2 NH in the presence of a trialkylphosphonium halide and a base.  
       
     
     
         61 . A method according to  claim 60 , wherein said trialkylphosphonium halide is (cyanomethyl)trimethylphosphonium iodide, and said base is DIPEA.  
     
     
         62 . A method according to  claim 60 , wherein NR 1 R 2  taken together form piperidinyl, methylpiperidinyl, dimethylamino, pyrrolidinyl, diethylamino, methylethylamino, ethylpropylamino, or dipropylamino.  
     
     
         63 . A method according to  claim 60 , wherein NR 1 R 2  taken together form piperidinyl, pyrrolidinyl, or diethylamino.  
     
     
         64 . A method according to  claim 60 , wherein NR 1 R 2  taken together form piperidinyl or pyrrolidinyl.  
     
     
         65 . A method according to  claim 60 , wherein one of R 4  and R 5  is G.  
     
     
         66 . A method according to  claim 65 , wherein R 4  is G.  
     
     
         67 . A method according to  claim 66 , wherein R 5  is G.  
     
     
         68 . A method according to  claim 60 , wherein n is 1.  
     
     
         69 . A method according to  claim 60 , wherein Q is a saturated N-linked nitrogen-containing heterocyclyl.  
     
     
         70 . A method according to  claim 60 , wherein Q is selected from substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl.  
     
     
         71 . A method according to  claim 60 , wherein 
 NR 1 R 2  taken together form piperidinyl, pyrrolidinyl, or diethylamino, and    Q is selected from substituted or unsubstituted piperidinyl, piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl.    
     
     
         72 . A method according to  claim 60 , wherein NR 1 R 2  taken together form piperidinyl or pyrrolidinyl, n is 1, and Q is selected from morpholinyl and piperidinyl.  
     
     
         73 . A method according to  claim 60 , wherein NR 1 R 2  taken together form piperidinyl or pyrrolidinyl, n is 1, and Q is morpholinyl or substituted morpholinyl.  
     
     
         74 . A method according to  claim 60 , wherein n=1, R 3  is H, R 5  is H, R 4  is L 2 Q, with Q being morpholinyl, L 2  as defined in  claim 60 , and NR 1 R 2  taken together form piperidinyl.  
     
     
         75 . A method of making a compound of formula (I)  
       
         
           
           
               
               
           
         
         wherein n is an integer from 0 to 1;  
         R 1  and R 2  are independently selected from C 1-3  alkyl, allyl, and C 3-8  cycloalkyl, or taken together with the nitrogen to which they are attached, they form a non-aromatic 4-7 membered heterocyclyl optionally including up to two additional heteroatoms independently selected from O, S, and N;  
         R 4  is G, one of the remaining R 3  and R 5  is hydrogen, and the other is selected from hydrogen, fluoro, and chloro;  
         G is L 2 Q;  
         L 2  is methylene;  
         Q is NR 8 R 9  wherein R 8  is independently selected from hydrogen, C 1-6  alkyl, C 3-6  alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C 1-6  alkylene, and (phenyl) C 1-6  alkylene; and R 9  is independently selected from C 1-6  alkyl, C 3-6  alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C 1-6  alkylene, and (phenyl) C 1-6  alkylene;  
         or  
         Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms independently selected from O, S, and N;  
         wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, and aryl groups of formula (I) may each be independently and optionally substituted with between 1 and 3 substituents independently selected from methoxy, halo, amino, nitro, hydroxyl, and C 1-3  alkyl;  
         and wherein 1-3 substituents of Q can be further independently selected (in addition to the preceding paragraph) from tert-butyloxycarbonyl, carboxamide, C 1-6  alkyl, 5-9-membered heterocyclyl, N(C 1-6  alkyl)(5-9 membered heterocyclyl), NH(5-9 membered heterocyclyl), O(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)C 1-3  alkylene, phenyl, C 1-2 -hydroxyalkylene, C 2-6  alkoxy, (C 3-6  cycloalkyl)-O—, phenyl, (phenyl)C 1-3  alkylene, and (phenyl)C 1-3  alkylene-O— and where said substituent groups of Q may optionally have between 1 and 3 substituents independently selected from trifluoromethyl, halo, nitro, cyano, and hydroxy; a pharmaceutically acceptable salt, ester, or amide thereof, comprising: reacting a compound of formula (XXIIImw) with a compound of formula (V).  
         
           
             
             
                 
                 
             
           
         
         wherein W is C(O)H or G, and X 2  is a suitable leaving group in a coupling reaction with an alkyne.  
       
     
     
         76 . A method according to  claim 75 , wherein said W is C(O)H, further comprising performing a reductive amination of said W with an organic base R 9 R 8 NH.  
     
     
         77 . A method according to  claim 75 , wherein NR 1 R 2  taken together form piperidinyl, methylpiperidinyl, dimethylamino, pyrrolidinyl, diethylamino, methylethylamino, ethylpropylamino, or dipropylamino.  
     
     
         78 . A method according to  claim 75 , wherein NR 1 R 2  taken together form piperidinyl, pyrrolidinyl, or diethylamino.  
     
     
         79 . A method according to  claim 75 , wherein NR 1 R 2  taken together form piperidinyl or pyrrolidinyl.  
     
     
         80 . A method according to  claim 75 , wherein n is 1.  
     
     
         81 . A method according to  claim 75 , wherein Q is a saturated N-linked nitrogen-containing heterocyclyl.  
     
     
         82 . A method according to  claim 75 , wherein Q is selected from substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl.  
     
     
         83 . A method according to  claim 75 , wherein substituted Q is selected from N—(C 1-6  alkyl)piperazinyl, N-phenyl-piperazinyl, 1,3,8-triaza-spiro[4.5]decyl, and 1,4-dioxa-8-aza-spiro[4.5]decyl.  
     
     
         84 . A method according to  claim 75 , wherein Q is a monovalent radical of an amine selected from aziridine, 1,4,7-trioxa-10-aza-cyclododecane, thiazolidine, 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, piperidine-3-carboxylic acid diethylamide, 1,2,3,4,5,6-hexahydro-[2,3′]bipyridinyl, 4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazin-1-yl-pyrimidine, piperidine-4-carboxylic acid amide, methyl-(2-pyridin-2-yl-ethyl)-amine, [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine, thiomorpholinyl, allyl-cyclopentyl-amine, [2-(1H-indol-3-yl)-ethyl]-methyl-amine, 1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one, 2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin-2-yl-amine, phenylamine, pyridin-2-ylamine.  
     
     
         85 . A method according to  claim 75 , wherein Q is selected from N-morpholinyl and N-piperidinyl, optionally substituted with between 1 and 3 substituents selected from hydroxyl, carboxamide, C 1-6  alkyl, 5-9 membered heterocyclyl, N(C 1-6  alkyl)(5-9 membered heterocyclyl), NH(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)C 1-3  alkylene, C 1-2 -hydroxyalkylene, O(5-9 membered heterocyclyl), C 1-6  alkoxy, (C 3-6  cycloalkyl)-O—, phenyl, (phenyl)C 1-3  alkylene, and (phenyl)C 1-3  alkylene-O— where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from halo, nitro, cyano, and C 1-3  alkyl.  
     
     
         86 . A method according to  claim 75 , wherein Q is substituted with a substituent comprising a C 1-6  heterocyclyl group selected from: pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C 1-6  alkylene, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl, (tetrazolyl)C 1-6  alkylene, tetrazolyl, (triazolyl)C 1-6  alkylene, triazolyl, (pyrrolyl)C 1-6  alkylene, and pyrrolyl.  
     
     
         87 . A method according to  claim 75 , wherein Q is a substituted or unsubstituted N-morpholinyl.  
     
     
         88 . A method according to  claim 75 , wherein n is 1; 
 R 1  and R 2  are independently selected from C 2  alkyl, or taken together with the nitrogen to which they are attached, they form a non-aromatic 5-6 membered heterocyclyl optionally including an additional heteroatom independently selected from O, S, and N;    R 3  and R 5  are H;    G is L 2 Q;    L 2  is methylene;    Q is NR 8 R 9  wherein R 8  is independently selected from hydrogen, C 1-2  alkyl, C 3  alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C 2  alkylene, and (phenyl) C 2  alkylene; and R 9  is independently selected from C 1-2  alkyl, C 3  alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C 2  alkylene, and (phenyl) C 2  alkylene;    or    Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms selected from O, S, and N;    wherein each of the above alkyl, alkylene, alkenyl, alkenylene, heterocyclyl, and carbocyclyl groups may each be independently and optionally substituted with between 1 and 3 substituents selected from methoxy, halo, amino, nitro, hydroxyl, and C 1-3  alkyl;    and wherein substituents of Q can be further selected from tert-butyloxycarbonyl, carboxamide, 5-9-membered heterocyclyl, NH(6-membered heterocyclyl), O(6-membered heterocyclyl), phenyl, C 2 -hydroxyalkylene, hydroxy, benzyl and, where each of above heterocyclyl, phenyl, and alkyl substituent groups of Q may be optionally substituted with trifluoromethyl.    
     
     
         89 . A method according to  claim 75 , wherein 
 NR 1 R 2  taken together form piperidinyl, pyrrolidinyl, or diethylamino, and    Q is selected from substituted or unsubstituted piperidinyl, piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl.    
     
     
         90 . A method according to  claim 75 , wherein NR 1 R 2  taken together form piperidinyl or pyrrolidinyl, n is 1, and Q is selected from morpholinyl and piperidinyl.  
     
     
         91 . A method according to  claim 90 , wherein NR 1 R 2  taken together form piperidinyl or pyrrolidinyl, n is 1, and Q is morpholinyl or substituted morpholinyl.  
     
     
         92 . A method according to  claim 75 , wherein n is 1, R 5  is H, R 3  is H and R 4  is L 2 Q, with Q being morpholinyl, and L 2  as defined in  claim 75 , and NR 1 R 2  taken together form piperidinyl.  
     
     
         93 . A method according to  claim 75 , wherein n is 1, R 3  is H, R 5  is H, W is C(O)H) and X 2  is chloro or bromo, and compound of formula (V) is 1-but-3-ynyl-piperidine, to form a phenylalkyne.  
     
     
         94 . A method according to  claim 93 , wherein said reacting is performed in the presence of pyrrolidine and at a temperature of about 50° C. to form a phenylalkyne.  
     
     
         95 . A method according to  claim 94 , wherein said reacting is performed in the presence of a palladium-containing catalyst and a copper salt.  
     
     
         96 . A method according to  claim 93 , wherein X 2  is bromo, and said reacting is performed under conditions such that the yield of said phenylalkyne is at least 80%.  
     
     
         97 . A method according to  claim 93 , further comprising a reductive amination with R 8 R 9 NH of said phenylalkyne to yield a base.  
     
     
         98 . A method according to  claim 97 , wherein said R 8 R 9 NH is morpholine and said base is 4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine.  
     
     
         99 . A method according to  claim 97 , further comprising forming a saline solution with HCl.  
     
     
         100 . A method according to  claim 99 , further comprising obtaining a dihydrochloride salt of said base by crystallization.  
     
     
         101 . A method according to  claim 100 , wherein said base is 4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine.  
     
     
         102 . A method according to  claim 40 , wherein n is 1, R 4  is H, R 3  is H, R 5  is C(O)H, NR 1 R 2  taken together form a piperidinyl, wherein said reacting is performed at room temperature.  
     
     
         103 . A method according to  claim 40 , wherein n is 1, R 4  is H, R 3  is H, R 5  is C(O)H, NR 1 R 2  taken together form a piperidinyl, wherein said reacting is performed at room temperature in the presence of a palladium-containing catalyst and a copper salt, and said reacting yields a phenylalkyne.  
     
     
         104 . A method according to  claim 40 , wherein n is 1, R 4  is H, R 3  is H, R 5  is C(O)H, NR 1 R 2  taken together form a piperidinyl, X 2  is bromo, wherein said reacting is performed at room temperature in the presence of a palladium-containing catalyst and a copper salt, and said reacting yields a phenylalkyne.  
     
     
         105 . A method according to  claim 40 , wherein n is 1, R 4  is H, R 3  is H, R 5  is C(O)H, NR 1 R 2  taken together form a piperidinyl, wherein said reacting is performed at room temperature in the presence of a palladium-containing catalyst and a copper salt, and said reacting yields a phenylalkyne, further comprising a reductive amination with R 8 R 9 NH of said phenylalkyne to yield a base.  
     
     
         106 . A method according to  claim 105 , wherein said R 8 R 9 NH is morpholine and said base is 4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine  
     
     
         107 . A method according to  claim 105 , further comprising forming a saline solution with HCl.  
     
     
         108 . A method according to  claim 107 , further comprising obtaining a dihydrochloride salt of said base by crystallization.  
     
     
         109 . A method according to  claim 108 , wherein said base is 4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine.