Triazolopyrazine compounds useful for the treatment of degenerative and inflammatory diseases

Abstract

Novel [1.2.4]triazolo[1,5-a]pyrazine compounds are disclosed that have a formula represented by the following: The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, inflammation, and others.

1 . A compound according to formula III: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is H, or substituted or unsubstituted alkyl; and each of R 8  and R 9  is independently selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, isotopic variants and tautomers thereof. 
       
     
     
         2 . A compound according to  claim 1 , wherein R 8  is selected from substituted or unsubstituted cyclopentyl, cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidine, and substituted or unsubstituted pyrazine, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole and substituted or unsubstituted imidazole. 
     
     
         3 . A compound according to  claim 1 , wherein R 8  is selected from substituted phenyl, substituted pyridyl, and substituted pyrimidine; and the substitution is
 —L-R 8d ; and wherein   L is selected from bond, alkylene, heteroalkylene, —O—, —N(R 8e )—, —CO—, —CO 2 —, —SO—, —SO 2 —, —CON(R 8e )—, —SO 2 N(R 8e )—, —N(R 8e )—CO—, —N(R 8e )SO 2 —, —N(R 8e )CO N(R 8e )—, —N(R 8e )SO 2  N(R 8e )—; and   R 8d  is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted amino, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl and substituted or unsubstituted aminoalkyl; and   R 8e  is selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl.   
     
     
         4 . A compound according to  claim 1 , wherein R 8  is 
       
         
           
           
               
               
           
         
         wherein L, and R 8d  are as in  claim 3 ; the subscript n is selected from 1-4; and each R 8a  is independently selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, cyano, and halo. 
       
     
     
         5 . (canceled) 
     
     
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         8 . (canceled) 
     
     
         9 . A compound according to  claim 1 , wherein the compound is according to formula IVa, IVb, IVc, or IVd: 
       
         
           
           
               
               
           
         
         wherein L is-a bond, —CO—, —O(CH 2 ) m1 —, —CON(H)(CH 2 ) ml —, or —NHCO—; the subscript m1 is selected from 1-4; and R 8d  is 
       
       
         
           
           
               
               
           
         
         and wherein the ring P is substituted or unsubstituted heterocycloalkyl; 
         the subscript n, is selected from 1-4; each R 8a  is independently selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, cyano, and halo; and R 9  is independently selected from substituted or unsubstituted aryl and heteroaryl; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, isotopic variants and tautomers thereof. 
       
     
     
         10 . (canceled) 
     
     
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         18 . A compound according to  claim 1 , wherein the compound is according to formula Va, Vb, Vc, Vd, Ve, or Vf: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and wherein R 9  is as in  claim 1  and R 8b  is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl. 
       
     
     
         19 . (canceled) 
     
     
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         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
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         33 . (canceled) 
     
     
         34 . A compound according to  claim 1 , wherein the compound is according to formula VIa, VIb, VIc, VId, VIe or VIf: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and R 8b  is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl. 
       
     
     
         35 . A compound according to  claim 1 , wherein the compound is according to formula VIIa, VIIb, VIIc, VIIc, VIId, VIIe or VIIf: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and R 8b  is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl. 
       
     
     
         36 . A compound according to  claim 1 , wherein the compound is according to formula VIIIa, VIIIb, VIIIc, VIIId, VIIIe or VIIIf: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and R 8b  is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl. 
       
     
     
         37 . A compound according to  claim 1 , wherein the compound is according to formula IXa, IXb, IXc, IXd, IXe, or IXf: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and R 8b  is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl 
       
     
     
         38 . A compound according to  claim 1 , wherein the compound is according to formula Xa, Xb, Xc, Xd, Xe, or Xf: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and R 8b  is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl. 
       
     
     
         39 . A compound according to  claim 1 , wherein the compound is according to formula XIa, XIb, XIc, XId, XIe or XIf: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and R 8b  is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; and R 9e  is hydrogen, Me, or CN. 
       
     
     
         40 . (canceled) 
     
     
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         45 . A compound according to  claim 1 , wherein the compound is according to formula XIIa, XIIb, XIIc or XIId: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         46 . A compound according to  claim 1 , wherein the compound is according to formula XIIIa, XIIIb, XIIIc or XIIId: 
       
         
           
           
               
               
           
         
       
     
     
         47 . A compound according to  claim 1 , wherein the compound is according to formula XIVa, XIVb, XIVc or XIVd: 
       
         
           
           
               
               
           
         
       
     
     
         48 . A compound according to  claim 1 , wherein the compound is according to formula XVa, XVb, or XIVc: 
       
         
           
           
               
               
           
         
         and L is a bond, —CO—, or —O—CH 2 —CH 2 —; the ring P is 
       
       
         
           
           
               
               
           
         
         and R 8b  is H, Me, i-Pr, t-Bu, CH 2 CONH 2 , cyclopropylmethyl, or CH 2 CF 3 . 
       
     
     
         49 . (canceled) 
     
     
         50 . A compound according to  claim 1  wherein the compound is selected from
 (4-Morpholin-4-yl-phenyl)-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; 
 [4-(4-Methyl-piperazin-1-yl)-phenyl]-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; 
 4-{8-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-benzamide; 
 4-{8-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-1H-pyridin-2-one; 
 4-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-benzamide; 
 4-{8-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 2-Fluoro-4-{8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-benzamide; 
 3-Fluoro-4-{8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-benzamide; 
 5-{8-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 3-Fluoro-4-[8-(4-morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-benzamide; 
 2-Fluoro-4-[8-(4-morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-benzamide; 
 [5(5-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-(4-morpholin-4-yl-phenyl)-amine; 
 [5(5-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-(4-morpholin-4-yl-phenyl)-amine; 
 5-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-thiophene-2-carboxylic acid amide; 
 2,6-Difluoro-4-[8-(4-morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-benzamide; 
 4-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-thiophene-2-carboxylic acid amide; 
 [4-(4-Methyl-piperazin-1-yl)-phenyl]-[5-(5-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; 
 (3-Fluoro-4-morpholin-4-yl-phenyl)[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; 
 (3-Chloro-4-morpholin-4-yl-phenyl)[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; 
 [4(2-Morpholin-4-yl-ethoxy)-phenyl]-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; 
 4-{8-[4-(2-Morpholin-4-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 5-{8-[4-(2-Morpholin-4-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 (4-Morpholin-4-yl-phenyl)-[5(2H-pyrazol-3-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; 
 4-{8-[4-((2R,6S)-2,6-Dimethyl-morpholin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 (4-Morpholin-4-yl-3-trifluoromethyl-phenyl)-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; 
 2,6-Difluoro-4-{8-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-benzamide; 
 4-[8-(4-Piperazin-1-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-thiophene-2-carboxylic acid amide; 
 4-{8-[4-(4-Isopropyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 5-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-furan-3-carboxylic acid amide; 
 5-{8-[4-(4-Isopropyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-furan-3-carboxylic acid amide; 
 [5-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-[4-((2S,5R)-2,4,5-trimethyl-piperazin-1-yl)-phenyl]-amine; 
 4-{8-[4-((2S,5R)-2,4,5-Trimethyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 5-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-2,3-dihydro-isoindol-1-one; 
 4-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-furan-2-carboxylic acid amide; 
 6-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-3,4-dihydro-2H-isoquinolin-1-one; 
 5-{8-[4-(4-Isopropyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-2,3-dihydro-isoindol-1-one; 
 {2-Morpholin-4-yl-5-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-phenyl}-methanol; 
 [4-(4-Isopropyl-piperazin-1-yl)-phenyl]-(5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; 
 6-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-3,4-dihydro-1H-quinolin-2-one; 
 (4-piperazin-1-yl-phenyl)-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; 
 (6-Morpholin-4-yl-pyridin-3-yl)-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; 
 [6-(4-Cyclopropylmethyl-piperazin-1-yl)-pyridin-3-yl]-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; 
 [6-(4-Isopropyl-piperazin-1-yl)-pyridin-3-yl]-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]amine; 
 [5-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-{6-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-pyridin-3-yl}-amine; 
 [5-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-{-4-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-phenyl}-amine; 
 [4-(4-Cyclopropylmethyl-piperazin-1-yl)-phenyl]-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; 
 4-[8-(6-Morpholin-4-yl-pyridin-3-ylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-thiophene-2-carboxylic acid amide; 
 (5-Benzo[#b!]thiophen-3-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-(4-morpholin-4-yl-phenyl)-amine; 
 (5-Benzo[#b!]thiophen-3-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-amine; 
 (4-Morpholin-4-yl-phenyl)-(5-thiophen-3-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-amine; 
 [4-(4-Isopropyl-piperazin-1-yl)-phenyl]-(5-thiophen-3-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-amine; 
 [5-(5-Ethyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-(4-morpholin-4-yl-phenyl)-amine; 
 6-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-1,1-dioxo-1,2-dihydro-1$1%6&-benzo[#d!]isothiazol-3-one; 
 4-{8-[6-(4-Cyclopropylmethyl-piperazin-1-yl)-pyridin-3-ylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 4-{8-[6-(4-Isopropyl-piperazin-1-yl)-pyridin-3-ylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 4-(8-{6-[4-(2,2,2-Trifluoro-ethyl)-piperazin-1-yl]-pyridin-3-ylamino}-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)-thiophene-2-carboxylic acid amide; 
 4-(8-{4-[4-(2,2,2-Trifluoro-ethyl)-piperazin-1-yl]-phenylamino}-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)-thiophene-2-carboxylic acid amide; 
 4-{8-[4-(4-Cyclopropylmethyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 [4-(4-Cyclopropyl-piperazin-1-yl)-phenyl]-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; 
 [6-(4-Cyclopropyl-piperazin-1-yl)-pyridin-3-yl]-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; 
 4-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-thiazole-2-carboxylic acid amide; 
 4-{8-[4-(4-Isopropyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiazole-2-carboxylic acid amide; 
 4-(8-{4-[1-(2,2,2-Trifluoro-ethyl)-piperidin-4-yl]-phenylamino-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)-thiophene-2-carboxylic acid amide; 
 [5-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-{4-[1-(2,2,2-trifluoro-ethyl)-piperidin-4-yl]-phenyl}-amine; 
 5-{8-[4-(2-Morpholin-4-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-2,3-dihydro-isoindol-1-one; 
 (5-Benzothiazol-6-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-(4-morpholin-4-yl-phenyl)-amine; 
 (2-Fluoro-4-morpholin-4-yl-phenyl)-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; 
 (2-Chloro-4-morpholin-4-yl-phenyl)-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; 
 1-{5-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-thiophen-2-yl}-ethanone; 
 {4-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-2H-pyrazol-3-yl}-methanol; 
 6-{4-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-phenyl}-4,5-dihydro-2H-pyridazin-3-one; 
 (5-Benzo[1,2,5]oxadiazol-5-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-(4-morpholin-4-yl-phenyl)-amine; 
 4-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-thiazole-2-carboxylic acid methylamide; 
 4-{8-[4-(4-Isopropyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiazole-2-carboxylic acid methylamide; 
 5-[8-(2-Fluoro-4-morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-2,3-dihydro-isoindol-1-one; 
 5-[8-(2-Chloro-4-morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-2,3-dihydro-isoindol-1-one; 
 5-{8-[2-Chloro-4-(4-isopropyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-2,3-dihydro-isoindol-1-one; 
 [5-(2-Amino-pyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-(4-morpholin-4-yl-phenyl)-amine; 
 5-{8-[6-(4-Isopropyl-piperazin-1-yl)-pyridin-3-ylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-2,3-dihydro-isoindol-1-one; 
 3-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-benzo[#b!]thiophene-7-carboxylic acid amide; 
 3-{8-[4-(4-Isopropyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-benzo[#b!]thiophene-7-carboxylic acid amide; 
 {4-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-pyridin-2-yl}-methanol; 
 (4-{8-[4-(4-Isopropyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-pyridin-2-yl)-methanol; 
 [4-(1-Isopropyl-piperidin-4-yl)-phenyl]-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; 
 {5-[4-(2-Amino-thiazol-4-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyrazin-8-yl}-(4-morpholin-4-yl-phenyl)-amine; 
 4-{8-[6-(4-Isopropyl-piperazin-1-yl)-pyridin-3-ylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-furan-2-carboxylic acid amide; 
 5-[8-(6-Morpholin-4-yl-pyridin-3-ylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-2,3-dihydro-isoindol-1-one; 
 4-{8-[4-(4-Isopropyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-furan-2-carboxylic acid amide; 
 4-{8-[4-(1-Isopropyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 (4-{8-[6-(4-Isopropyl-piperazin-1-yl)-pyridin-3-ylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-pyridin-2-yl)-methanol; 
 [5-(2-Fluoromethyl-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-amine; 
 5-{8-[4-(1-Isopropyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-2,3-dihydro-isoindol-1-one; 
 [5-(1H-Indazol-6-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-(4-morpholin-4-yl-phenyl)-amine; 
 4-[8-(6-Morpholin-4-yl-pyridin-3-ylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-furan-2-carboxylic acid amide; 
 4-{8-[4-(4-Isopropyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-5-methyl-thiophene-2-carboxylic acid amide; 
 4-{8-[6-(4-Isopropyl-piperazin-1-yl)-pyridin-3-ylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-5-methyl-thiophene-2-carboxylic acid amide; 
 4-{8-[4-(4-Isopropyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-2,3-dihydro-isoindol-1-one; 
 4-{8-[6-(4-Isopropyl-piperazin-1-yl)-pyridin-3-ylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-2,3-dihydro-isoindol-1-one; 
 5-[8-(2-Morpholin-4-yl-pyrimidin-5-ylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-2,3-dihydro-isoindol-1-one; 
 1-{4-[5-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-phenyl}-piperazin-2-one; 
 5-{8-[2-(4-Isopropyl-piperazin-1-yl)-pyrimidin-5-ylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-2,3-dihydro-isoindol-1-one; 
 5-{8-[4-(4-#tert!-Butyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)-2,3-dihydro-isoindol-1-one; 
 [4-(4-#tert!-Butyl-piperazin-1-yl)-phenyl]-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; 
 [5-(1H-Indazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-(4-morpholin-4-yl-phenyl)-amine; 
 5-{8-[4-(2-oxo-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-2,3-dihydro-isoindol-1-one; 
 [5-(1H-Indazol-6-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-amine; 
 [6-(4-Isopropyl-piperazin-1-yl)-pyridin-3-yl]-(5-{(E)-1-[4-methylene-2,4-dihydro-pyrazol-(3E)-ylidenemethyl]-propenyl}-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-amine; 
 7-Fluoro-5-{8-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-2,3-dihydro-isoindol-1-one; 
 6-{8-[4-(4-Isopropyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-2,3-dihydro-isoindol-1-one; 
 (3-Methylaminomethyl-4-morpholin-4-yl-phenyl)-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; 
 2-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-5,6-dihydro-furo[2,3-#c!]pyrrol-4-one; 
 5-{8-[4-(4-Isopropyl-2-oxo-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-2,3-dihydro-isoindol-1-one; 
 2-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-4,5-dihydro-thieno[2,3-#c!]pyrrol-6-one; 
 5-{8-[4-(4-Isopropyl-piperazin-1-yl)-phenylamino]-[1,2,4]thiazolo[1,5-a]pyrazin-5-yl}-3,3-dimethyl-2,3-dihydro-isoindol-1-one; 
 5-(8-Cyclohexylamino-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)-2,3-dihydro-isoindol-1-one; 
 5-[8-(Tetrahydro-pyran-4-ylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-2,3-dihydro-isoindol-1-one; and 
 5-[8-(4-Fluoro-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-2,3-dihydro-isoindol-1-one. 
 
     
     
         51 . A compound according to  claim 1  wherein the compound is selected from:
 4-[5-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-N-pyridin-3-ylmethyl-benzamide; 
 4-[5-(2-oxo-1,2-dihydro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-N-pyridin-3-ylmethyl-benzamide; 
 2-Methoxy-N-(6-methyl-pyridin-3-ylmethyl)-4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 4-(8-{3-Methoxy-4-[(6-methyl-pyridin-3-ylmethyl)-carbamoyl]-phenylamino}-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)-thiophene-2-carboxylic acid amide; 
 N-Benzyl-2-methoxy-4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 N-Benzyl-3-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 3-[5-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-N-pyridin-2-ylmethyl-benzamide; 
 N,N-Diethyl-3-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 {3-[5-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-phenyl}-pyrrolidin-1-yl-methanone; 
 (4-Isopropyl-piperazin-1-yl)-{3-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-phenyl}-methanone; 
 3-[5-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 N-Ethyl-3-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 N-Cyclohexylmethyl-3-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 N-(4-Hydroxy-benzyl)-3-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 4-[8-(4-Benzylcarbamoyl-3-methoxy-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-thiophene-2-carboxylic acid amide; 
 4-[8-(6-Benzoylamino-pyridin-3-ylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-thiophene-2-carboxylic acid amide; 
 N-Benzyl-N-methyl-3-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 N-{5-[5-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-pyridin-2-yl}-benzamide; 
 1-{4-[5-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzoyl}-piperidine-4-carboxylic acid methylamide; 
 4-[5-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-N-(2-pyridin-4-yl-ethyl)-benzamide; 
 (4-Ethyl-piperazin-1-yl)-{4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-phenyl}-methanone; 
 N-(1-Ethyl-pyrrolidin-2-ylmethyl)-4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 (2,5-Dihydro-pyrrol-1-yl)-{4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-phenyl}-methanone; 
 [4-(2-Ethoxy-ethyl)-piperazin-1-yl]-{4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-phenyl}-methanone; 
 N-Cyclopropylmethyl-4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 N-Methyl-N-(1-{4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzoyl}-pyrrolidin-3-yl)-acetamide; 
 [4-(4-Fluoro-benzyl)-piperazin-1-yl]-{4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-phenyl}-methanone; 
 (4-Phenyl-piperazin-1-yl)-{4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-phenyl}-methanone; 
 ((S)-2-Methoxymethyl-pyrrolidin-1-yl)-{4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-phenyl}-methanone; 
 N—((R)-1-Benzyl-pyrrolidin-3-yl)-4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 {4-[5-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-phenyl}-(4-pyridin-2-yl-piperazin-1-yl)-methanone; 
 N-(1-Methoxymethyl-propyl)-4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 [4-(2-Methoxy-ethyl)-piperazin-1-yl]-{4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-phenyl}-methanone; 
 N-[2-(4-Hydroxy-phenyl)-ethyl]-4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 (4-#sec!-Butyl-piperazin-1-yl)-{4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-phenyl}-methanone; 
 N-[4-(4-Methyl-piperazin-1-yl)-phenyl]-4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 (Benzyl-{4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzoyl}-amino)-acetic acid ethyl ester; 
 N-Isopropyl-2-(4-{4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzoyl}-piperazin-1-yl)-acetamide; 
 N-(2-Methoxy-ethyl)-N-methyl-4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 N-Ethyl-N-(2-methoxy-ethyl)-4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 4-[5-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-N-(tetrahydro-furan-2-ylmethyl)-benzamide; 
 (3,6-Dihydro-2H-pyridin-1-yl)-{4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-phenyl}-methanone; 
 N-(2-Methylsulfanyl-ethyl)-4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 N-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 N-(2-Diisopropylamino-ethyl)-4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 N—((S)-1-Ethyl-pyrrolidin-2-ylmethyl)-4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 N-Isobutyl-4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-benzamide; 
 [1,4′]Bipiperidinyl-1 ′-yl-{4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-phenyl}-methanone; 
 N-(2-Hydroxy-ethyl)-4-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl amino]-benzamide; and 
 4-[8-(6-Phenylacetylamino-pyridin-3-ylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-thiophene-2-carboxylic acid amide. 
 
     
     
         52 . A compound according to  claim 1  wherein the compound is selected from
 4-{8-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 5-{8-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 [5-(5-Methyl-1H-pyrazol-4-yl)-[1,2,4]thiazolo[1,5-a]pyrazin-8-yl]-(4-morpholin-4-yl-phenyl)-amine; 
 4-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-thiophene-2-carboxylic acid amide; 
 4-{8-[4-(2-Morpholin-4-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 4-{8-[4-((2R,6S)-2,6-Dimethyl-morpholin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 4-[8-(4-piperazin-1-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-thiophene-2-carboxylic acid amide; 
 4-{8-[4-(4-Isopropyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 4-{8-[4-((2S,5R)-2,4,5-Trimethyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 5-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-2,3-dihydro-isoindol-1-one; 
 4-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-furan-2-carboxylic acid amide; 
 5-{8-[4-(4-Isopropyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-2,3-dihydro-isoindol-1-one; 
 4-[8-(6-Morpholin-4-yl-pyridin-3-ylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-thiophene-2-carboxylic acid amide; 
 4-{8-[6-(4-Cyclopropylmethyl-piperazin-1-yl)-pyridin-3-ylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 4-{8-[6-(4-Isopropyl-piperazin-1-yl)-pyridin-3-ylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 4-(8-{6-[4-(2,2,2-Trifluoro-ethyl)-piperazin-1-yl]-pyridin-3-ylamino}-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)-thiophene-2-carboxylic acid amide; 
 4-(8-{4-[4-(2,2,2-Trifluoro-ethyl)-piperazin-1-yl]-phenylamino}-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)-thiophene-2-carboxylic acid amide; 
 4-{8-[4-(4-Cyclopropylmethyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 5-{8-[4-(2-Morpholin-4-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-2,3-dihydro-isoindol-1-one; 
 5-{8-[6-(4-Isopropyl-piperazin-1-yl)-pyridin-3-ylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-2,3-dihydro-isoindol-1-one; 
 5-[8-(6-Morpholin-4-yl-pyridin-3-ylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-2,3-dihydro-isoindol-1-one; 
 4-{8-[4-(4-Isopropyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-furan-2-carboxylic acid amide; 
 4-{8-[4-(1-Isopropyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-thiophene-2-carboxylic acid amide; 
 5-{8-[4-(1-Isopropyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl}-2,3-dihydro-isoindol-1-one; 
 5-[8-(2-Morpholin-4-yl-pyrimidin-5-ylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-2,3-dihydro-isoindol-1-one; 
 [4-(4-tert-Butyl-piperazin-1-yl)-phenyl]-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amine; and 
 2-[8-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-4,5-dihydro-thieno[2,3-c]pyrrol-6-one. 
 
     
     
         53 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of  claim 1 . 
     
     
         54 . The pharmaceutical composition of  claim 53 , wherein the carrier is selected from a parenteral carrier, an oral carrier and a topical carrier. 
     
     
         55 . (canceled) 
     
     
         56 . (canceled) 
     
     
         57 . (canceled) 
     
     
         58 . (canceled) 
     
     
         59 . (canceled) 
     
     
         60 . (canceled) 
     
     
         61 . A method of treatment of a condition characterised by abnormal matrix metallo proteinase activity, which comprises administering a therapeutically effective amount of a matrix metallo proteinase inhibiting compound according to  claim 1 . 
     
     
         62 . (canceled) 
     
     
         63 . (canceled) 
     
     
         64 . A method of treatment or prevention of inflammatory diseases, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         65 . A method of treatment or prevention of rheumatoid arthritis, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound according to  claim 1 .