4,6-disubstituted aminopyrimidine derivatives as inhibitors of protein kinases

Abstract

The present invention relates to inhibitors of cyclin-dependent kinases and therapeutic applications thereof. Furthermore, the invention relates to methods of preventing and/or treating any type of pain, inflammatory disorders, immunological diseases, proliferative diseases, infectious diseases, cardiovascular diseases and neurodegenerative diseases comprising the administration of an effective amount of at least one inhibitor of cyclin-dependent kinases.

1 . A method for the treatment of a disease selected from the group of pain, an inflammatory disorder, an immunological disease, a proliferative disease, an infectious disease, a cardiovascular disease and a neurodegenerative disease, comprising administering a therapeutically effective amount of at least one of the compounds of general Formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 101  is selected from the group consisting of: 
       
       hydrogen, linear or branched C 1 -C 6  substituted or unsubstituted alkyl, linear or branched C 2 -C 6  alkenyl, and linear or branched C 2 -C 6  alkynyl;
 R 102  is selected from the group consisting of: 
 
       hydrogen, linear or branched substituted or unsubstituted C 1 -C 6  alkyl, linear or branched C 2 -C 6  alkenyl, linear or branched C 2 -C 6  alkynyl, —F, —Cl, —Br, —I, —CN, —NH 2 , N(C 1 -C 4 alkyl) 2 , and —NO 2 ;
 R 104  is selected from the group consisting of: 
 
       hydrogen, linear or branched substituted or unsubstituted C 1 -C 6  alkyl, linear or branched C 2 -C 6  alkenyl, linear or branched C 2 -C 6  alkynyl, —F, —Cl, —Br, —I, —CN, —NH 2  and —NO 2 ;
 R 103  is selected from substituted or unsubstituted phenyl or pyridine, wherein each substituent is independently selected from the group consisting of linear or branched C 1 -C 6  substituted or unsubstituted alkyl, linear or branched substituted or unsubstituted C 1 -C 6  alkoxy, linear or branched C 2 -C 6  alkenyl, substituted or unsubstituted C 2-4  alkenyloxy, linear or branched C 2 -C 6  alkynyl, substituted or unsubstituted C 3-7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted —O-heterocycloalkyl, substituted or unsubstituted C 1-4 alkylsulfonyl, substituted or unsubstituted mono- and di-(C 1 -C 4 alkyl)sulfonamido, —F, —Cl, —Br, —I, —COOH, —CN, —NH 2 , —OH, —NO 2 , —NR 20 R 21 , —CO—R 20 , —CO—O—R 20 , and —CO—NR 20 R 21 , wherein R 20  and R 21  are independently of each other selected from the group consisting of hydrogen, linear or branched substituted or unsubstituted C 1 -C 6  alkyl, acetyl, and substituted or unsubstituted amino; 
 R 105  is selected from the group consisting of substituted or unsubstituted phenyl or pyridine, wherein each substituent is independently selected from the group consisting of linear or branched C 1 -C 6  substituted or unsubstituted alkyl, linear or branched substituted or unsubstituted C 1 -C 6  alkoxy, linear or branched C 2 -C 6  alkenyl, linear or branched C 2 -C 6  alkynyl, —F, —Cl, —Br, —CN, —NO 2 , —NR 20 R 21 , —CO—R 20 , and —CO—NR 20 R 21 , wherein R 20  and R 21  are independently of each other selected from the group consisting of hydrogen, linear or branched substituted or unsubstituted C 1 -C 6  alkyl, acetyl, and substituted or unsubstituted amino; 
 R 106  is selected from the group consisting of hydrogen, linear or branched substituted or unsubstituted C 1 -C 8  alkyl, substituted or unsubstituted C 3-4 alkenyl, substituted or unsubstituted C 3-8 -cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, and —(CH 2 ) q -A, wherein q is an integer selected from 0 to 5 and A is selected from the group consisting of hydrogen, —F, —Cl, —Br, —I, —CN, —NH 2 , —NO 2 , linear or branched substituted or unsubstituted C 1 -C 6  alkyl, linear or branched substituted or unsubstituted C 1 -C 6  alkoxy, linear or branched C 2 -C 6  alkenyl, linear or branched C 2 -C 6  alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, and carboxamido substituted with one or two C 1 -C 6  alkyl; or 
 R 106 , when M is —NR 140 —, can form a heterocyclic structure when taken together with the nitrogen of M and R 140 ; 
 L is —CR 150 R 151 —SO 2 -M-, 
 wherein R 150  and R 151  are independently selected from the group consisting of hydrogen, linear C 1 -C 3  alkyl and fluorine, wherein M is a bond or —NR 140 —; 
 R 140  is selected from the group consisting of hydrogen, linear or branched substituted or unsubstituted C 1 -C 8  alkyl, and substituted or unsubstituted C 3 -C 8  cycloalkyl; 
 or, alternatively, -L-R 106 , when taken together, is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         and tautomeric forms, N-oxides, stereoisomers, mixtures of stereoisomers, and pharmaceutically acceptable salts of such compounds to a patient suffering from said disease. 
       
     
     
         2 . The method of  claim 1 , wherein:
 R 101  is selected from the group consisting of:   
       hydrogen, linear or branched C 1 -C 6  substituted or unsubstituted alkyl, linear or branched C 2 -C 6  alkenyl, and linear or branched C 2 -C 6  alkynyl;
 R 102  and R 104  are independently selected from the group consisting of: 
 
       hydrogen, linear or branched substituted or unsubstituted C 1 -C 6  alkyl, linear or branched C 2 -C 6  alkenyl, linear or branched C 2 -C 6  alkynyl, —F, —Cl, —Br, —CN, —NH 2 , and —NO 2 ;
 R 103  and R 105  are independently selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted pyridine, wherein each substituent is independently selected from the group consisting of linear or branched C 1 -C 6  substituted or unsubstituted alkyl, linear or branched substituted or unsubstituted C 1 -C 6  alkoxy, linear or branched C 2 -C 6  alkenyl, linear or branched C 2 -C 6  alkynyl, —F, —Cl, —Br, —I, —CN, —NH 2 , —NO 2 , —NR 20 R 21 , —CO—R 20 , and —CO—NR 20 R 21 , wherein R 20  and R 21  are independently of each other selected from the group consisting of hydrogen, linear or branched substituted or unsubstituted C 1 -C 6  alkyl, acetyl, and substituted or unsubstituted amino; 
 R 106  is selected from the group consisting of hydrogen, linear or branched substituted or unsubstituted C 1 -C 8  alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, and —(CH 2 ) q -A, wherein g is an integer selected from 0 to 5 and A is selected from the group consisting of hydrogen, —F, —Cl, —Br, —I, —CN, —NH 2 , —NO 2 , linear or branched substituted or unsubstituted C 1 -C 6  alkyl, linear or branched substituted or unsubstituted C 1 -C 6  alkoxy, linear or branched C 2 -C 6  alkenyl, linear or branched C 2 -C 6  alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, and carboxamido substituted with one or two C 1 -C 6  alkyl; or 
 R 106 , when M is —NR 140 —, can form a heterocyclic structure when taken together with the nitrogen of M and R 140 ; 
 L is —CR 150 R 151 —SO 2 -M-, 
 
       wherein R 150  and R 151  are independently selected from the group consisting of hydrogen, linear C 1 -C 3  alkyl, and fluorine, wherein M is a bond or —NR 140 —; and
 R 140  is selected from hydrogen, linear or branched substituted or unsubstituted C 1 -C 8  alkyl, and substituted or unsubstituted C 3 -C 8  cycloalkyl; 
 and tautomeric forms and pharmaceutically acceptable salts thereof. 
 
     
     
         3 . The method of  claim 2  wherein the administered compound is represented by general Formula (II) 
       
         
           
           
               
               
           
         
         wherein: 
         R 101  and R 104  are hydrogen; 
         R 102  is hydrogen or —NH 2 ; 
         R 106  is selected from the group consisting of hydrogen, linear or branched substituted or unsubstituted C 1 -C 8  alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, and —(CH 2 ) q -A, wherein q is an integer selected from 0 to 5 and A is selected from the group consisting of hydrogen, —F, —Cl, —Br, —I, —CN, —NH 2 , —NO 2 , linear or branched substituted or unsubstituted C 1 -C 6  alkyl, linear or branched substituted or unsubstituted C 1 -C 6  alkoxy, linear or branched C 2 -C 6  alkenyl, linear or branched C 2 -C 6  alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, and carboxamido substituted with one or two C 1 -C 6  alkyl; or 
         R 106 , when M is —NR 140 —, can form a heterocyclic structure when taken together with the nitrogen of M and R 140 ; 
         L is —CR 150 R 151 —SO 2 -M-, 
         wherein R 150  and R 151  are independently selected from the group consisting of hydrogen, linear C 1 -C 3  alkyl, and fluorine, wherein M is a bond or —NR 140 —; 
         R 140  is selected from the group consisting of hydrogen, linear or branched substituted or unsubstituted C 1 -C 8  alkyl, and substituted or unsubstituted C 3 -C 8  cycloalkyl; 
         o is an integer selected from 0 to 5; 
         p is an integer selected from 0 to 4; 
         each R 141  and R 142  is independently selected from the group consisting of linear or branched C 1 -C 6  substituted or unsubstituted alkyl, linear or branched substituted or unsubstituted C 1 -C 6  alkoxy, linear or branched C 2 -C 6  alkenyl, linear or branched C 2 -C 6  alkynyl, —F, —Cl, —Br, —I, —CN, —NH 2 , and —NO 2 ; 
         and tautomeric forms and pharmaceutically acceptable salts thereof. 
       
     
     
         4 . The method of  claim 3  wherein at least one R 141  is methoxy. 
     
     
         5 . The method of  claim 3 , wherein at least one R 141  is in the ortho position. 
     
     
         6 . The method of  claim 5 , wherein R 141  in the ortho-position is methoxy. 
     
     
         7 . The method of  claim 3  wherein R 150  and R 151  are both hydrogen. 
     
     
         8 . The method of  claim 3  wherein M is —NR 140  and R 140  is selected from the group consisting of hydrogen, methyl, ethyl, and isopropyl. 
     
     
         9 . The method of  claim 8  wherein R 140  is hydrogen. 
     
     
         10 . The method of  claim 8  wherein R 140  is methyl. 
     
     
         11 . The method of  claim 3 , wherein R 106  is selected from the group consisting of hydrogen, linear or branched substituted or unsubstituted C 1 -C 8  alkyl, and —(CH 2 ) q -A, wherein q is an integer selected from 0 to 5 and A is selected from the group consisting of linear or branched substituted or unsubstituted C 1 -C 6  alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and carboxamido substituted with one or two C 1 -C 6  alkyl. 
     
     
         12 . The method of  claim 11 , wherein R 106  is hydrogen. 
     
     
         13 . The method of  claim 11 , wherein R 106  is linear or branched unsubstituted C 1-5  alkyl. 
     
     
         14 . The method of  claim 3  wherein L is linked to the phenyl group of the compound in the meta-position. 
     
     
         15 . The method of  claim 1  wherein the administered compound is represented by general Formula (III) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is —XSO 2 NR 5 R 6  or —XSO 2 R 8 ; 
         X is methylene; 
         R 5  and R 6  independently of each other are selected from the group consisting of hydrogen, C 1-4 alkyl, hydroxy-C 1-4 alkyl or C 3-4 alkenyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-4 alkyl, C 4-7 -heterocycloalkyl-C 0-4 alkyl, C 4-7 -aryl-C 0-4 alkyl, and C 4-7 -heteroaryl-C 0-4 alkyl or 
         wherein R 5  and R 6  together with the N-atom to which they are bound also form a 5- to 8-membered heterocycloalkyl, 
         wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkyl is further optionally substituted by up to 2 radicals selected from the group consisting of halo, hydroxy, aminocarbonyl, C 1-4  alkyl, hydroxy-C 1-4  alkyl, C 1-4  alkyl-O—C 1-4  alkyl, C 1-4  alkyl-O—, and —NR 5 R 6 ; 
         or XSO 2 NR 5 R 6  is: 
       
       
         
           
           
               
               
           
         
         R 8  is C 1-4  alkyl, hydroxy-C 2-4 alkyl or C 3-4 alkenyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-4 alkyl, and C 4-7 -heterocycloalkyl-C 0-4  alkyl; 
         wherein said cycloalkyl, heterocycloalkyl or alkyl is further optionally substituted by up to 2 radicals selected from the group consisting of halo, hydroxy, C 1-4  alkyl, hydroxy-C 1-4  alkyl, C 1-4  alkyl-O—C 1-4  alkyl, C 1-4  alkyl-O, and —NR 5 R 6 ; 
         n is selected from 0, 1 and 2; 
         R 2  is independently selected from halo; 
         m is selected from 0, 1, 2 and 3; 
         R 3  is independently selected from the group consisting of: halo, hydroxy, C 1-4 alkyl, C 3-7 cycloalkyl, C 1-4  alkyl-cycloalkyl, C 1-4  alkyl heterocycloalkyl, —O-heterocycloalkyl, C 1-4  alkoxy, C 2-4  alkenyloxy, —OCF 3 , C 2-4  alkanoyl, C 1-4 alkylsulfonyl, mono- and di-(C 1 -C 4 alkyl)sulfonamido, aminocarbonyl, mono- and di-(C 1 -C 4 alkyl)aminocarbonyl, aryl-C 1-4  alkoxy, heteroaryl-C 1-4  alkoxy, heterocycloalkyl-C 1-4  alkoxy, heterocycloalkyl-C 1-4  alkyl, heteroaryl-C 1-4 -alkyl, C 1-4  alkyloxymethyl, hydroxy-C 1-4 alkyloxymethyl, cyano, —COOH, and C 1 -C 4  alkoxycarbonyl, wherein the above mentioned substituents can be further substituted by radicals selected from the group of C 1-4 -alkyl, hydroxyl-C 0-4 -alkyl, C 1-4 -alkoxy, aminocarbonyl, halo, and NR 5 R 6 ; and 
         R 4  is hydrogen, C 1-4  alkyl or NR′R″, wherein R′ and R″ are each independently selected from the group consisting of hydrogen and C 1-4  alkyl. 
       
     
     
         16 . The method of  claim 15 , wherein R 1  is —XSO 2 NR 5 R 6 , R 6  is hydrogen or methyl and R 5  is selected from the group consisting of ethyl, 2-hydroxyethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, n-propyl, tert-butyl, 3-methoxy-propyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, piperidinyl, pyridinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-furan-2-ylmethyl, 4-chloro-benzyl, and thiophen-2-yl-methyl, or R 5  and R 6  are both hydrogen, methyl or ethyl, or R 5  and R 6  together with the N-atom to which they are bound form morpholine, 4-aminocarbonyl-piperidine or azepane, or
 —XSO 2 NR 5 R 6  is: 
 
       
         
           
           
               
               
           
         
       
     
     
         17 . The method of  claim 15 , wherein R 1  is —XSO 2 R 8  and R 8  is C 1-4  alkyl or hydroxy C 2-4  alkyl. 
     
     
         18 . The method of  claim 15 , wherein m is selected from 1, 2 and 3, R 3  is independently selected from the group consisting of hydrogen, halo, hydroxy, C 1-4 alkyl, C 1-4  alkoxy, C 2-4  alkenyloxy, —OCF 3 , C 2-4  alkanoyl, C 1-4 alkylsulfonyl, mono- and di-(C 1 -C 4 alkyl)sulfonamido, aminocarbonyl, mono- and di-(C 1 -C 4 alkyl)aminocarbonyl, C 1-4  alkyloxymethyl, hydroxy-C 1-4 alkyloxymethyl, cyano, —COOH, and C 1 -C 4 alkoxycarbonyl; or one substituent selected from C 3-7 cycloalkyl, C 1-4  alkyl-cycloalkyl, C 1-4  alkyl-heterocycloalkyl, —O-heterocycloalkyl, aryl-C 1-4  alkoxy, heterocycloalkyl-C 1-4  alkoxy, heterocycloalkyl-C 1-4 -alkyl, heteroaryl-C 1-4  alkoxy, and heteroaryl-C 1-4 -alkyl; wherein said substituents can be further substituted by one or more radicals selected from the group of C 1-4 -alkyl, hydroxyl-C 0-4 -alkyl, C 1-4 -alkoxy, halo, aminocarbonyl, and NR 5 R 6 . 
     
     
         19 . The method of  claim 18  wherein R 3  is selected from the group consisting of methyl, ethyl, hydroxymethyl, hydroxy, methoxy, ethoxy, isopropoxy, benzyloxy, hydrogen, fluoro, chloro, trifluoromethyl, 2-methoxy-ethoxy, methoxymethyl, 2-methoxy-ethyl, tetrahydro-furan-3-yloxy, tetrahydro-furan-2-yl-methoxy, —N(CH 3 )SO 2 CH 3 , piperidin-1-yl-methyl, 2-hydroxymethyl-piperidin-1-yl-methyl, 3-hydroxymethyl-piperidin-1-yl-methyl, 3-(2-hydroxy-ethyl)-piperidin-1-yl-methyl, 3-aminocarbonyl-piperidin-1-yl-methyl, dimethylaminomethyl, diethylaminomethyl, (ethyl-isopropyl-amino)-methyl, morpholin-4-ylmethyl, 4-methyl-piperazin-1-yl-methyl, [1,2,4]triazol-1-yl-methyl, pyridine-3-yl-methoxy, and pyridine-4-yl-methoxy. 
     
     
         20 . The method of  claim 15 , wherein X is methylene. 
     
     
         21 . The method of  claim 15 , wherein the compound has a structure according to Formula (IIIa), 
       
         
           
           
               
               
           
         
       
     
     
         22 . The method of  claim 1 , wherein the administered compound is selected from the group consisting of:
 {3-[6-(2-Ethoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 1);   {3-[6-(2,3-Dimethoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 2);   {3-[6-(4-Fluoro-2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 3);   {3-[6-(2-Ethoxy-5-fluoro-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 4);   {3-[6-(2-Isopropoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 5);   {3-[6-(3-Fluoro-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 6);   {3-[6-(4-Fluoro-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 7);   {3-[6-(3-Ethoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 8);   {3-[6-(3-Benzyloxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 9);   N-Isopropyl-C-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 10);   N-Cyclopropyl-C-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 11);   C-{3-[6-(2-Ethoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-propyl-methanesulfonamide (Compound 12);   N-Cyclopentyl-C-{3-[6-(2-ethoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 13);   C-{3-[6-(2-Methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-propyl-methanesulfonamide (Compound 14);   N-tert-Butyl-C-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 15);   N-Cyclopentyl-C-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 16);   C-{3-[6-(2-Ethoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-isopropyl-methanesulfonamide (Compound 17);   N-Cyclopropyl-C-{3-[6-(2-ethoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 18);   N-tert-Butyl-C-{3-[6-(2-ethoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 19);   C-{3-[6-(2-Methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N,N-dimethyl-methanesulfonamide (Compound 20);   C-{3-[6-(2-Benzyloxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-propyl-methanesulfonamide (Compound 21);   C-{3-[6-(2-Benzyloxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-isopropyl-methanesulfonamide (Compound 22);   C-{3-[6-(2-Benzyloxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-cyclopropyl-methanesulfonamide (Compound 23);   C-{3-[6-(2-Benzyloxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N,N-dimethyl-methanesulfonamide (Compound 24);   C-{3-[6-(3-Benzyloxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N,N-dimethyl-methanesulfonamide (Compound 25);   {3-[6-(2-Ethyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 26);   C-{3-[6-(3-Ethoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N,N-dimethyl-methanesulfonamide (Compound 27);   C-{3-[6-(2-Ethoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N,N-dimethyl-methanesulfonamide (Compound 28);   C-{3-[6-(2-Benzyloxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-cyclopentyl-methanesulfonamide (Compound 29);   C-{3-[6-(2-Benzyloxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-tert-butyl-methanesulfonamide (Compound 30);   C-{3-[6-(3-Benzyloxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-isopropyl-methanesulfonamide (Compound 31);   {3-[6-(2-Benzyloxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 32);   C-{3-[6-(2-Methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-(3-methoxy-propyl)-methanesulfonamide (Compound 33);   N-Cyclohexyl-C-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 34);   C-{3-[6-(2-Methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-(tetrahydro-furan-2-ylmethyl)-methanesulfonamide (Compound 35);   N-(4-Chloro-benzyl)-C-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 36);   C-{3-[6-(2-Methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-thiophen-2-ylmethyl-methanesulfonamide (Compound 37);   N,N-Diethyl-C-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 38);   N-(2-Hydroxy-ethyl)-C-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-methyl-methanesulfonamide (Compound 39);   1-{3-[6-(2-Methoxy-phenyl)-pyrimidin-4-ylamino]-phenylmethanesulfonyl}-piperidine-4-carboxylic acid amide (Compound 40);   [6-(2-Methoxy-phenyl)-pyrimidin-4-yl]-[3-(morpholine-4-sulfonylmethyl)-phenyl]-amine (Compound 41);   [3-(Azepane-1-sulfonylmethyl)-phenyl]-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-amine (Compound 42);   C-{3-[6-(2-Ethoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-methyl-methanesulfonamide (Compound 43);   C-{3-[6-(2-Benzyloxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-methyl-methanesulfonamide (Compound 44);   N-Ethyl-C-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 45);   N-(2-Hydroxy-ethyl)-C-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 46);   C-{3-[6-(2-Benzyloxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N,N-diethyl-methanesulfonamide (Compound 47);   C-{3-[6-(2-Benzyloxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-(2-hydroxy-ethyl)-N-methyl-methanesulfonamide (Compound 48);   C-{3-[6-(2-Methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-methyl-methanesulfonamide (Compound 49);   [3-(6-Phenyl-pyrimidin-4-ylamino)-phenyl]-methanesulfonamide (Compound 50);   {3-[6-(2-Chloro-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 51);   2-[6-(3-Methanesulfonylmethyl-phenylamino)-pyrimidin-4-yl]-phenol (Compound 52);   [6-(2-Benzyloxy-phenyl)-pyrimidin-4-yl]-(3-methanesulfonylmethyl-phenyl)-amine (Compound 53);   {3-[6-(2-Hydroxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 54);   {3-[6-(2-Hydroxymethyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 55);   {2-[6-(3-Methanesulfonylmethyl-phenylamino)-pyrimidin-4-yl]-phenyl}-methanol (Compound 56);   (3-Methanesulfonylmethyl-phenyl)-{6-[2-(2-methoxy-ethoxy)-phenyl]-pyrimidin-4-yl}-amine (Compound 57);   [6-(2-Benzyloxy-phenyl)-pyrimidin-4-yl]-(3-methanesulfonylmethyl-phenyl)-amine (Compound 58);   (3-Methanesulfonylmethyl-phenyl)-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-amine (Compound 59);   (3-Methanesulfonylmethyl-phenyl)-{6-[2-(tetrahydro-furan-3-yloxy)-phenyl]-pyrimidin-4-yl}-amine (Compound 60);   {3-[6-(2-Fluoro-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 61);   {3-[6-(4-Methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 62);   {3-[6-(3-Trifluoromethyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 63);   (3-Methanesulfonylmethyl-phenyl)-{6-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-pyrimidin-4-yl}-amine (Compound 64);   (3-{6-[2-(Tetrahydro-furan-3-yloxy)-phenyl]-pyrimidin-4-ylamino}-phenyl)-methanesulfonamide (Compound 65);   {3-[2-Amino-6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 66);   [3-(1,1-Dioxo-[1,2]thiazinan-6-yl)-phenyl]-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-amine (Compound 67);   [6-(2-Methoxy-phenyl)-pyrimidin-4-yl]-[3-(2-methyl-1,1-dioxo-[1,2]thiazinan-6-yl)-phenyl]-amine (Compound 68);   {3-[6-(3-Hydroxymethyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 69);   (3-{6-[3-(2-Hydroxymethyl-piperidin-1-ylmethyl)-phenyl]-pyrimidin-4-ylamino}-phenyl)-methanesulfonamide (Compound 70);   (3-{6-[3-(3-Hydroxymethyl-piperidin-1-ylmethyl)-phenyl]-pyrimidin-4-ylamino}-phenyl)-methanesulfonamide (Compound 71);   [3-(6-{3-[3-(2-Hydroxy-ethyl)-piperidin-1-ylmethyl]-phenyl}-pyrimidin-4-ylamino)-phenyl]-methanesulfonamide (Compound 72);   1-{3-[6-(3-Sulfamoylmethyl-phenylamino)-pyrimidin-4-yl]-benzyl}-piperidine-3-carboxylic acid amide (Compound 73);   {3-[6-(3-Dimethylaminomethyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 74);   {3-[6-(3-Diethylaminomethyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 75);   [3-(6-{3-[(Ethyl-isopropyl-amino)-methyl]-phenyl}-pyrimidin-4-ylamino)-phenyl]-methanesulfonamide (Compound 76);   {3-[6-(3-Morpholin-ylmethyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 77);   (3-{6-[3-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-4-ylamino}-phenyl)-methanesulfonamide (Compound 78);   {3-[6-(3-[1,2,4]Triazol-1-ylmethyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 79);   C-{3-[6-(2-Methoxymethyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-methyl-methanesulfonamide (Compound 80);   (3-{6-[2-(2-Methoxy-ethoxy)-phenyl]-pyrimidin-4-ylamino}-phenyl)-methanesulfonamide (Compound 81);   (3-{6-[2-(Tetrahydro-furan-2-ylmethoxy)-phenyl]-pyrimidin-4-ylamino}-phenyl)-methanesulfonamide (Compound 82);   (3-{6-[2-(2-Methoxy-ethoxy)-phenyl]-2-methyl-pyrimidin-4-ylamino}-phenyl)-methanesulfonamide (Compound 83);   [3-(3-Dimethylamino-propane-1-sulfonylmethyl)-phenyl]-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-amine (Compound 84);   C-{3-[6-(2-Methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 85); and   N-(2-Methoxy-ethyl)-C-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 86).   
     
     
         23 . The method of  claim 1  wherein the administered compound is C-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide. 
     
     
         24 . The method of  claim 1 , wherein the pain is selected from the group consisting of chronic pain, inflammatory pain, neuropathic pain, and a combination thereof.