Deazapurines useful as inhibitors of janus kinases

Abstract

The present invention relates to compounds useful as inhibitors of protein kinases, particularly of JAK family kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Ring A is a 5-membered monocyclic heteroaryl having 1-4 heteroatoms selected from nitrogen, oxygen, or sulfur linked via a carbon atom to the deazapurine, provided that there is no more than one oxygen or sulfur heteroatom in Ring A, and if there is an oxygen or sulfur heteroatom, then there are no more than two nitrogen heteroatoms in Ring A, wherein Ring A is optionally substituted with up to 1-3 occurrences of R 8 ; 
         R 1  is —(C 1-2  aliphatic) p -R 4 , wherein R 1  is optionally substituted with 1-3 occurrences of J R1 . 
         R 2  is —(C 1-2  aliphatic) d -R 5 , wherein R 2  is optionally substituted with 1-3 occurrences of J R2 ; 
         p and d are each independently 0 or 1; 
         R 4  is H, halogen, CN, NH 2 , NO 2 , CF 3 , C 1-4  aliphatic, cyclopropyl, NCH 3 , OCH 3 , —C(═O)NH 2 , —C(═O)CH 3 , —NC(═O)CH 3 , or OH; 
         R 5  is H, halogen, CN, NH 2 , NO 2 , CF 3 , C 1-4  aliphatic, cyclopropyl, NCH 3 , OCH 3 , —C(═O)NH 2 , —C(═O)CH 3 , —NC(═O)CH 3 , or OH; 
         each J R1  is independently selected from halogen, OCH 3 , OH, NO 2 , NH 2 , SCH 3 , NCH 3 , CN, or unsubstituted C 1-2 aliphatic; or two J R1 , together with the carbon to which they are attached, form a cyclopropyl ring or C═O; 
         each J R2  is independently selected from halogen, OCH 3 , OH, NO 2 , NH 2 , SCH 3 , NCH 3 , CN, or unsubstituted C 1-2 aliphatic; or two J R2 , together with the carbon to which they are attached, form a cyclopropyl ring or C═O; 
         R 3  is —(U) m —X; 
         U is a C 1-6  aliphatic, wherein up to two methylene units are optionally and independently replaced by G U  and wherein U is optionally substituted with 1-4 J U ; 
         G U  is —NH—, —NR 6 , —O—, —S—, CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NH—, —C(O)NR 6 —, —NC(═N—CN)N—, —NHCO—, —NR 6 CO—, —NHC(O)O—, —NR 6 C(O)O—, —SO 2 NH—, —SO 2 NR 6 —, —NHSO 2 —, —NR 6 SO 2 —, —NHC(O)NH—, —NR 6 C(O)NH—, —NHC(O)NR 6 —, —NR 6 C(O)NR 6 , —OC(O)NH—, —OC(O)NR 6 —, —NHSO 2 NH—, —NR 6 SO 2 NH—, —NHSO 2 NR 6 —, —NR 6 SO 2 NR 6 —, —SO—, or —SO 2 —; 
         R 6  is C 1-6  aliphatic or a C 3-10  cycloaliphatic; or two R 6  groups, together with the atom to which they are attached, optionally form a 3-7 membered cycloaliphatic or heterocyclyl, wherein said aliphatic, cycloaliphatic or heterocyclyl is optionally substituted with R″, —OR″, —SR″, —NO 2 , —CF 3 , —CN, —CO 2 R″, —COR″, OCOR″, CONHR″, or NHCOR″, wherein R″ is H or an unsubstituted C 1-6  aliphatic; 
         m is 0 or 1; 
         X is H, halogen, CN, NO 2 , S(O)R, SO 2 R, or a group selected from a C 1-6  aliphatic, a C 3-10  cycloaliphatic, a C 6-10  aryl, a 5-10 membered heteroaryl, or a 5-10 membered heterocyclyl, wherein said group is optionally substituted with 1-4 J X ; 
         R is an optionally substituted group selected from a C 1-6  aliphatic, a C 3-10  cycloaliphatic, a C 6-10  aryl, a 5-10 membered heteroaryl, or a 5-10 membered heterocyclyl, wherein R is independently and optionally substituted with 1-6 occurrences of J R ; 
         each J R  is independently selected from halogen, L, -(L n )—R′, -(L n )-N(R′) 2 , -(L n )-SR′, -(L n )-OR′, -(L n )-(C 3-10  cycloaliphatic), -(L n )-(C 6-10  aryl), -(L n )-(5-10 membered heteroaryl), -(L n )-(5-10 membered heterocyclyl), oxo, C 1-4 haloalkoxy, C 1-4 haloalkyl, -(L n )-NO 2 , -(L n )-CN, -(L n )-OH, -(L n )-CF 3 , —CO 2 R′, —CO 2 H, —COR′, —COH, —OC(O)R′, —C(O)NHR′, C(O)N(R′) 2 , —NHC(O)R′, or NR′C(O)R′; or two J R  groups, on the same substituent or different substituents, together with the atom(s) to which each J R  group is bound, form a 5-7 membered saturated, unsaturated, or partially saturated ring; 
         each J U  is independently selected from halogen, L, -(L n )-R′, -(L n )—N(R′) 2 , -(L n )—SR′, -(L n )—OR′, -(L n )-(C 3-10  cycloaliphatic), -(L n )-(C 6-10  aryl), -(L n )-(5-10 membered heteroaryl), -(L n )-(5-10 membered heterocyclyl), oxo, C 1-4 haloalkoxy, C 1-4 haloalkyl, -(L n )-NO 2 , -(L n )-CN, -(L n )-OH, -(L n )-CF 3 , —CO 2 R′, —CO 2 H, —COR′, —COH, —OC(O)R′, —C(O)NHR′, C(O)N(R′) 2 , —NHC(O)R′, or NR′C(O)R′; or two J U  groups, on the same substituent or different substituents, together with the atom(s) to which each J U  group is bound, form a 5-7 membered saturated, unsaturated, or partially saturated ring; 
         each J X  is independently selected from halogen, L, -(L n )-R′, -(L n )—N(R′) 2 , -(L n )—SR′, -(L n )—OR′, -(L n )-(C 3-10  cycloaliphatic), -(L n )-(C 6-10  aryl), -(L n )-(5-10 membered heteroaryl), -(L n )-(5-10 membered heterocyclyl), oxo, C 1-4 haloalkoxy, C 1-4 haloalkyl, -(L n )-NO 2 , -(L n )-CN, -(L n )-OH, -(L n )-CF 3 , —CO 2 R′, —CO 2 H, —COR′, —COH, —OC(O)R′, —C(O)NHR', C(O)N(R′) 2 , —NHC(O)R′; 
         each L is independently a C 1-6  aliphatic wherein up to three methylene units are replaced by —NH—, —NR 7 —, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NH—, —C(O)NR 7 —, —NC(═N—CN)N, —NHCO—, —NR 7 CO—, —NHC(O)O—, —NR 7 C(O)O—, —SO 2 NH—, —SO 2 NR 7 —, —NHSO 2 —, —NR 7 SO 2 —, —NHC(O)NH—, —NR 7 C(O)NH—, —NHC(O)NR 7 —, —NR 7 C(O)NR 7 , —OC(O)NH—, —OC(O)NR 7 —, —NHSO 2 NH—, —NR 7 SO 2 NH—, —NHSO 2 NR 7 —, —NR 7 SO 2 NR 7 —, —SO—, or —SO 2 —; 
         each n is independently 0 or 1; 
         each R′ is independently H or C 1-6  aliphatic; or two R′ groups, together with the atom to which they are attached, optionally form a 3-6 membered cycloaliphatic or heterocyclyl, wherein said aliphatic, cycloaliphatic or heterocyclyl is optionally substituted with R*, —OR*, —SR*, —NO 2 , —CF 3 , —CN, —CO 2 R*, —COR*, OCOR*, NHCOR*, wherein R* is H or C 1-6  aliphatic; 
         R 7  is selected from C 1-6  aliphatic, C 3-10  cycloaliphatic, C 6-10  aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl; or two R 7  groups, on the same substituent or different substituents, together with the atom(s) to which each R 6  group is bound, form a 3-8 membered heterocyclyl; 
         each R 8  is independently —(C 1-3  aliphatic) y —R 9 , wherein R 8  is optionally substituted with 1-5 occurrences of J R8 ; 
         each y is independently 0 or 1; 
         R 9  is halogen, CN, NH 2 , NO 2 , CF 3 , C 1-4  aliphatic, cyclopropyl, NHR 10 , N(R 10 ) 2 , OR 10 , C(O)OR 10 , —C(O)NH 2 , —C(O)R 10 , —NC(O)R 10 , or OH; 
         R 10  is C 1-4  aliphatic; 
         each J R8  is independently selected from halogen, OCH 3 , OH, NO 2 , NH 2 , SCH 3 , NCH 3 , CN, or unsubstituted C 1-2 aliphatic; or two J R8 , together with the carbon to which they are attached, form a cyclopropyl ring or C═O; provided that said compound is not 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound according to  claim 1 , wherein R 1  is H, halogen or C 1-4  aliphatic. 
     
     
         3 . The compound according to  claim 2 , wherein R 1  is H or halogen. 
     
     
         4 . The compound according to  claim 3 , wherein R 1  is H. 
     
     
         5 . The compound according to any one of  claims 1 - 4 , wherein R 2  is H, halogen or C 1-4  aliphatic. 
     
     
         6 . The compound according to  claim 5 , wherein R 2  is H, Cl, F or CH 3 . 
     
     
         7 . The compound according to  claim 6 , wherein R 2  is H. 
     
     
         8 . The compound according to any one of  claims 1 - 7 , wherein Ring A is selected from the following: 
       
         
           
           
               
               
           
         
       
       wherein Ring A is optionally substituted with 1-3 occurrences of R 8 . 
     
     
         9 . The compound according to  claim 8 , wherein Ring A is selected from the following: 
       
         
           
           
               
               
           
         
       
       wherein Ring A is optionally substituted with 1-3 occurrences of R 8 . 
     
     
         10 . The compound according to  claim 9 , wherein Ring A is selected from 
       
         
           
           
               
               
           
         
       
       wherein Ring A is optionally substituted with 1-3 occurrences of R 8 . 
     
     
         11 . The compound according to  claim 10 , wherein Ring A is selected from 
       
         
           
           
               
               
           
         
       
       wherein Ring A is optionally substituted with 1-3 occurrences of R 8 . 
     
     
         12 . The compound according to  claim 8 , wherein Ring A is selected from 
       
         
           
           
               
               
           
         
       
       wherein Ring A is optionally substituted with 1-3 occurrences of R 8 . 
     
     
         13 . The compound according to  claim 12 , wherein Ring A is selected from 
       
         
           
           
               
               
           
         
       
       wherein Ring A is optionally substituted with 1-3 occurrences of R 8 , and R 1  and R 2  are both H. 
     
     
         14 . The compound according to  claim 8 , wherein Ring A is selected from 
       
         
           
           
               
               
           
         
       
       wherein Ring A is optionally substituted with 1-3 occurrences of R 8 . 
     
     
         15 . The compound according to any one of  claims 1 - 14 , wherein Ring A is unsubstituted by R 8 . 
     
     
         16 . The compound according to any one of  claims 1 - 14 , wherein Ring A is substituted by one occurrence of R 8  and R 8  is halogen. 
     
     
         17 . The compound according to any one of  claims 1 - 16 , wherein R 3  is not H. 
     
     
         18 . The compound according to  claim 17 , wherein m is 1 and U is selected from C(O)NH, C(O)NR 6 , NHC(O), NR 6 C(O), C(O), C(O)O, C(O)NH(CH 2 ) 1-3 , C(O)NR 6 (CH 2 ) 1-3 , NHC(O)(CH 2 ) 1-3 , NR 6 C(O)(CH 2 ) 1-3 , C(O)(CH 2 ) 1-3 , C(O)O(CH 2 ) 1-3 , (CH 2 ) 1-3 C(O)NH, (CH 2 ) 1-3 C(O)NR 6 , (CH 2 ) 1-3 NHC(O), (CH 2 ) 1-3 NR 6 C(O), (CH 2 ) 1-3 C(O) or (CH 2 ) 1-3 C(O)O. 
     
     
         19 . The compound according to  claim 18 , wherein U is selected from C(O)NH, C(O)NR 6 , NHC(O), NR 6 C(O), C(O), C(O)O, C(O)NHCH 2 , C(O)NR 6 CH 2 , NHC(O)CH 2 , NR 6 C(O)CH 2 , C(O)CH 2 , C(O)OCH 2 , CH 2 C(O)NH, CH 2 C(O)NR 6 , CH 2 NHC(O), CH 2 NR 6 C(O), CH 2 C(O) or CH 2 C(O)O. 
     
     
         20 . The compound according to  claim 19 , wherein U is selected from C(O)NH, C(O)NR 6 , NHC(O), NR 6 C(O), C(O), C(O)NHCH 2 , C(O)NR 6 CH 2 , NHC(O)CH 2  or NR 6 C(O)CH 2 . 
     
     
         21 . The compound according to any one of  claims 1 - 20 , wherein R 6  is C 1-4  aliphatic optionally substituted with —OH, —OCH 3 , —SH, —SCH 3 , —CF 3 , —CN, —CO 2 H, —CO 2 CH 3 , NHCOH, NHCOCH 3 , CONH 2  or CONHCH 3 . 
     
     
         22 . The compound according to  claim 21 , wherein R 6  is C 1-3  aliphatic optionally substituted with —OH, —CF 3  or —CN. 
     
     
         23 . The compound according to  claim 17 , wherein m is 0. 
     
     
         24 . The compound according to any one of  claims 1 - 23 , wherein X is a group selected from a C 1-6  aliphatic, a C 3-7  cycloaliphatic, a C 6-10  aryl, a 5-8 membered heteroaryl, or a 5-8 membered heterocyclyl, wherein said group is optionally substituted with 1-4 J X . 
     
     
         25 . The compound according to  claim 24 , wherein X is a group selected from a C 1-6  aliphatic, a C 3-6  cycloaliphatic, phenyl, a 5-6 membered heteroaryl, or a 5-7 membered heterocyclyl, wherein said group is optionally substituted with 1-4 J X . 
     
     
         26 . The compound according to  claim 25 , wherein X is C 1-4  straight or branched alkyl, C 2-4  straight or branched alkenyl, C 2-4  straight or branched alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, pyrrolyl, piperindinyl, pyrrolidinyl, dihydro-1H-pyrrolyl, tetrohydro-1H-pyranyl, tetrohydrofuranyl, wherein said group is optionally substituted with 1-4 J X . 
     
     
         27 . The compound according to any one of  claims 1 - 26 , wherein each J X  is independently selected from halogen, R′, -(L n )-N(R′) 2 , -(L n )-SR′, -(L n )-OR′, -(L n )—(C 3-6  cycloaliphatic), oxo, C 1-4 haloalkyl, -(L n )—CN, -(L n )-OH, -(L n )-CF 3 , —CO 2 R′, —CO 2 H, —COR′, —COH, —OC(O)R′, —C(O)NHR′, or —NC(O)R′. 
     
     
         28 . The compound according to  claim 27 , wherein each J X  is independently selected from C 1-4  aliphatic, C 3-7  cycloaliphatic, halogen, (CH 2 ) 0-3 OH, (CH 2 ) 0-3 OCH 3 , (CH 2 )(O) 3 OCH 2 CH 3 , OXO, (CH 2 ) 0-3 NH 2 , (CH 2 ) 0-3 NHCH 3 , (CH 2 ) 0-3 N(CH 3 ) 2 , (CH 2 ) 0-3 SH, (CH 2 ) 0-3 SCH 3 , (CH 2 ) 0-3 SCH 2 CH 3 , (CH 2 ) 0-3 CN, (CH 2 ) 0-3 CF 3 , CO 2 H, —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —COCH 3 , —COCH 2 CH 3 , —COH, —OC(O)CH 3 , —C(O)NHCH 3 , or —NC(O)CH 3 . 
     
     
         29 . The compound according to  claim 28 , wherein each J X  is independently selected from C 1-4  straight or branched alkyl, C 2-4  straight or branched alkenyl, C 2-4  straight or branched alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, chloro, fluoro, —OH, —OCH 3 , —CH 2 OCH 3 , —CH 2 OH, oxo, —CH 2 CN, —CH 2 CF 3 , —CN, or —CF 3 , CO 2 H, —CO 2 CH 3 , or —COCH 3 . 
     
     
         30 . The compound according to  claim 1 , having formula II 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         31 . The compound according to  claim 30 , wherein Ring A is selected from the following: 
       
         
           
           
               
               
           
         
       
       wherein Ring A is optionally substituted with 1-3 occurrences of R 8 . 
     
     
         32 . The compound according to  claim 31 , wherein Ring A is selected from 
       
         
           
           
               
               
           
         
       
       wherein Ring A is optionally substituted with 1-3 occurrences of R 8 . 
     
     
         33 . The compound according to  claim 32 , wherein Ring A is selected from 
       
         
           
           
               
               
           
         
       
       wherein Ring A is optionally substituted with 1-3 occurrences of R 8 . 
     
     
         34 . The compound according to  claim 30 , wherein Ring A is selected from 
       
         
           
           
               
               
           
         
       
       wherein Ring A is optionally substituted with 1-3 occurrences of R 8 . 
     
     
         35 . The compound according to  claim 34 , wherein Ring A is selected from 
       
         
           
           
               
               
           
         
       
       wherein Ring A is optionally substituted with 1-3 occurrences of R 8 , and R 1  and R 2  are both H. 
     
     
         36 . The compound according to  claim 30 , wherein Ring A is selected from 
       
         
           
           
               
               
           
         
       
       wherein Ring A is optionally substituted with 1-3 occurrences of R 8 . 
     
     
         37 . The compound according to any one of  claims 30 - 36 , wherein Ring A is unsubstituted by R 8 . 
     
     
         38 . The compound according to any one of  claims 30 - 37 , wherein R 3  is not H. 
     
     
         39 . The compound according to  claim 38 , wherein m is 1 and U is selected from C(O)NH, C(O)NR 6 , NHC(O), NR 6 C(O), C(O), C(O)O, C(O)NH(CH 2 ) 1-3 , C(O)NR 6 (CH 2 ) 1-3 , NHC(O)(CH 2 ) 1-3 , NR 6 C(O)(CH 2 ) 1-3 , C(O)(CH 2 ) 1-3 , C(O)O(CH 2 ) 1-3 , (CH 2 ) 1-3 C(O)NH, (CH 2 ) 1-3 C(O)NR 6 , (CH 2 ) 1-3 NHC(O), (CH 2 ) 1-3 NR 6 C(O), (CH 2 ) 1-3 C(O) or (CH 2 ) 1-3 C(O)O. 
     
     
         40 . The compound according to  claim 39 , wherein U is selected from C(O)NH, C(O)NR 6 , NHC(O), NR 6 C(O), C(O), C(O)O, C(O)NHCH 2 , C(O)NR 6 CH 2 , NHC(O)CH 2 , NR 6 C(O)CH 2 , C(O)CH 2 , C(O)OCH 2 , CH 2 C(O)NH, CH 2 C(O)NR 6 , CH 2 NHC(O), CH 2 NR 6 C(O), CH 2 C(O) or CH 2 C(O)O. 
     
     
         41 . The compound according to  claim 40 , wherein U is selected from C(O)NH, C(O)NR 6 , NHC(O), NR 6 C(O), C(O), C(O)NHCH 2 , C(O)NR 6 CH 2 , NHC(O)CH 2  or NR 6 C(O)CH 2 . 
     
     
         42 . The compound according to any one of  claims 30 - 41 , wherein R 6  is C 1-4  aliphatic optionally substituted with —OH, —OCH 3 , —SH, —SCH 3 , —CF 3 , —CN, —CO 2 H, —CO 2 CH 3 , NHCOH, NHCOCH 3 , CONH 2  or CONHCH 3 . 
     
     
         43 . The compound according to  claim 42 , wherein R 6  is C 1-3  aliphatic optionally substituted with —OH, —CF 3  or —CN. 
     
     
         44 . The compound according to  claim 38 , wherein m is 0. 
     
     
         45 . The compound according to any one of  claims 30 - 44 , wherein X is a group selected from a C 1-6  aliphatic, a C 3-7  cycloaliphatic, a C 6-10  aryl, a 5-8 membered heteroaryl, or a 5-8 membered heterocyclyl, wherein said group is optionally substituted with 1-4 J X . 
     
     
         46 . The compound according to  claim 45 , wherein X is a group selected from a C 1-6  aliphatic, a C 3-6  cycloaliphatic, phenyl, a 5-6 membered heteroaryl, or a 5-7 membered heterocyclyl, wherein said group is optionally substituted with 1-4 J X . 
     
     
         47 . The compound according to  claim 46 , wherein X is C 1-4  straight or branched alkyl, C 2-4  straight or branched alkenyl, C 2-4  straight or branched alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, pyrrolyl, piperindinyl, pyrrolidinyl, dihydro-1H-pyrrolyl, tetrohydro-1H-pyranyl, tetrohydrofuranyl, wherein said group is optionally substituted with 1-4 J X . 
     
     
         48 . The compound according to any one of  claims 30 - 47 , wherein each J X  is independently selected from halogen, R′, -(L n )-N(R′) 2 , -(L n )-SR′, -(L n )-OR′, -(L n )-(C 3-6  cycloaliphatic), oxo, C 1-4 haloalkyl, -(L n )-CN, -(L n )-OH, -(L n )-CF 3 , —CO 2 R′, —CO 2 H, —COR′, —COH, —OC(O)R′, —C(O)NHR', or —NC(O)R′; or two J X  groups, on the same substituent or different substituents, together with the atom(s) to which each J X  group is bound, form a 5-7 membered saturated, unsaturated, or partially saturated ring. 
     
     
         49 . The compound according to  claim 48 , wherein each J X  is independently selected from C 1-4  aliphatic, C 3-2  cycloaliphatic, halogen, (CH 2 ) 0-3 OH, (CH 2 ) 0-3 OCH 3 , (CH 2 )(O) 3 OCH 2 CH 3 , oxo, (CH 2 ) 0-3 NH 2 , (CH 2 ) 0-3 NHCH 3 , (CH 2 ) 0-3 N(CH 3 ) 2 , (CH 2 ) 0-3 SH, (CH 2 ) 0-3 SCH 3 , (CH 2 ) 0-3 SCH 2 CH 3 , (CH 2 ) 0-3 CN, (CH 2 ) 0-3 CF 3 , CO 2 H, —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —COCH 3 , —COCH 2 CH 3 , —COH, —OC(O)CH 3 , —C(O)NHCH 3 , or —NC(O)CH 3 . 
     
     
         50 . The compound according to  claim 49 , wherein each J X  is independently selected from C 1-4  straight or branched alkyl, C 2-4  straight or branched alkenyl, C 2-4  straight or branched alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, chloro, fluoro, —OH, —OCH 3 , —CH 2 OCH 3 , —CH 2 OH, oxo, —CH 2 CN, —CH 2 CF 3 , —CN, or —CF 3 , CO 2 H, —CO 2 CH 3 , or —COCH 3 . 
     
     
         51 . A compound according to  claim 1 , selected from Table 1. 
     
     
         52 . A compound according to  claim 1 , selected from Table 2. 
     
     
         53 . A pharmaceutical composition comprising a compound according to any one of  claims 1 - 52  and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         54 . The composition according to  claim 53 , additionally comprising a therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders. 
     
     
         55 . A method of inhibiting JAK kinase activity in a biological sample, comprising contacting said biological sample with a compound according to any one of  claims 1 - 52  or with a composition according to either of  claim 53  or  54 . 
     
     
         56 . A method of inhibiting JAK kinase activity in a patient, comprising administering to said patient a compound according to any one of  claims 1 - 52  or with a composition according to either of  claim 53  or  54 . 
     
     
         57 . A method of treating or lessening the severity of a disease of condition selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, or an immunologically mediated disorder in a patient, comprising the step of administering to said patient a compound according to any one of  claims 1 - 53  or with a composition comprising said compound. 
     
     
         58 . The method of  claim 57 , comprising the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein said additional therapeutic agent is appropriate for the disease being treated. 
     
     
         59 . The method according to  claim 58 , wherein the disease or disorder is allergic or type I hypersensitivity reactions, asthma, diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-associated dementia, amyotrophic lateral sclerosis (AML, Lou Gehrig's disease), multiple sclerosis (MS), schizophrenia, cardiomyocyte hypertrophy, reperfusion/ischemia, stroke, baldness, transplant rejection, graft versus host disease, rheumatoid arthritis, a solid malignancy, a hematologic malignancy, a leukemia, a lymphoma and a myeloproliferative disorder. 
     
     
         60 . The method according to  claim 59 , wherein said disease or disorder is asthma. 
     
     
         61 . The method according  claim 59 , wherein said disease or disorder is transplant rejection. 
     
     
         62 . The method according to  claim 59 , wherein said disease or disorder is rheumatoid arthritis. 
     
     
         63 . The method according to  claim 59 , wherein said disease or disorder is psoriasis. 
     
     
         64 . The method according to  claim 59 , wherein said disease is a myeloproliferative disorder selected from polycythemia vera, essential thrombocythemia, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome or systematic mast cell disease.