Azaindoles useful as inhibitors of jak and other protein kinases

Abstract

The present invention relates to inhibitors of protein kinases. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof, wherein:
 R 1  is T-R′ or is —Si(R′) 3 ; 
 R 2 , R 3 , and R 4  are each independently halogen, CN, NO 2 , or V—R′; 
 X 1 , X 2  and X 3  are each independently N, or CH, wherein the hydrogen atom of CH is optionally replaced by R 5 ; 
 x is 1, 2, 3, or 4; 
 each occurrence of R 5  is independently halogen, CN, NO 2 , or U—R′, wherein at least one R 5  is other than H; 
 T, V, and U are each independently a bond or an optionally substituted C 1 -C 6  alkylidene chain, wherein up to two methylene units of the chain are optionally and independently replaced by —NR′—, —S—, —O—, —CS—, —CO 2 —, —OCO—, —CO—, —COCO—, —CONR′—, —NR′CO—, —NR′CO 2 —, —SO 2 NR′—, —NR'SO 2 —, —CONR′NR′—, —NR′CONR′—, —OCONR′—, —NR′NR′—, —NR′SO 2 NR′—, —SO—, —SO 2 —, —PO—, —PO 2 —, or —POR′—; and 
 each occurrence of R′ is independently hydrogen or an optionally substituted group selected from a C 1 -C 6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R′, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, provided that:
 a) if R 1  is substituted cyclopentyl, x is 1, X 1  and X 3  are CH, then X 2  is not C—R 5 , where R 5  is fluoro or OMe; 
 b) if R 2  and R 3  are simultaneously H and R 1  and R 4  are independently selected from H or Me, x is 1, X 1  and X 3  are CH, then X 2  is not C—R 5 , where R 5  is OMe, NO 2 , or fluoro; 
 c) if R 1 , R 2 , R 3  and R 4  are simultaneously H, x is 1, R 5  is -SMe, NH 2  or an optionally substituted NH-piperidine, and X 1  and X 2  are N, then X 3  is not CH; 
 d) if R 2 , R 3  and R 4  are simultaneously H, X 1 , X 2  and X 3  are CH, and two R 5  form a fused optionally substituted bicyclic ring with the ring to which they are attached, then R 1  is not CH 2 CH 2 N(Me) 2 ; 
 e) if R 2  and R 3  are simultaneously H, R 4  is NH 2 , and X 1 , X 2  and X 3  are CH, then R 1  is not substituted phenyl; 
 f) if R 2 , R 3  and R 4  are simultaneously H, then R 1  is not Si(R′) 3 ; and 
 g) if R 1 , R 2  and R 4  are simultaneously H and (i) X 2  and X 3  are CH or CR 5  or (ii) any one of X 1 , X 2  or X 3  are N, then R 3  is not phenyl or phenyl substituted with O-phenyl or N(Me) 2 . 
 
 
     
     
         2 . The compound of  claim 1 , wherein:
 a) R 1  is T-R′, wherein T is a bond or is an optionally substituted C 1 -C 6 alkylidene chain wherein up to two methylene units are optionally and independently replaced with —O—, —S—, —NR′—, —OCO—, —COO—, —SO 2 — or —CO—, and R′ is hydrogen, C 1 -C 4 -alkyl, or an optionally substituted 5- or 6-membered aryl or heteroaryl group; or   R 1  is —Si(R′) 3 , R′ is hydrogen, C 3 -C 4 -alkyl, or an optionally substituted 5- or 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.   
     
     
         3 . The compound of  claim 1 , wherein R 1  is hydrogen, C 1 -C 4 alkyl, —COR′, —SO 2 R′, or —Si(R′) 3 . 
     
     
         4 . The compound of  claim 1 , wherein R 1  is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, p-toluenesulfonyl (Ts), t-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS), or triethylsilyl (TES). 
     
     
         5 . The compound of  claim 1 , wherein R 2 , R 3 , and R 4  are each independently hydrogen, R′, halogen; CN, NO 2 , —N(R′) 2 , —CH 2 N(R′) 2 , —OR′, —CH 2 OR′, —SR′, —CH 2 SR′, —COOR′, —NR′COR′, —NR′COCH2R′, or —NR′CO(CH2)2R′, —CON(R′) 2 , —SO 2 N(R′) 2 , —CONR′(CH 2 ) 2 N(R′) 2 , —CONR′(CH 2 ) 3 N(R′) 2 , —CONR′(CH 2 ) 4 N(R′) 2 , —O(CH 2 ) 2 OR′, O(CH 2 ) 3 OR′, O(CH 2 ) 4 OR′, —O(CH 2 ) 2 N(R′) 2 , —O(CH 2 ) 3 N(R′) 2 , or —O(CH 2 ) 4 N(R′) 2 . 
     
     
         6 . The compound of  claim 1 , wherein R 2 , R 3 , and R 4  are each independently Cl, Br, F, —CN, —COOH, —COOMe, —NH 2 , —N(CH 3 ) 2 , —N(Et) 2 , —N(iPr) 2 , —O(CH 2 ) 2 OCH 3 , —CONH 2 , —COOCH 3 , —OH, —CH 2 OH, —NHCOCH 3 , —SO 2 NH 2 , —SO 2 N(Me) 2 , or an optionally substituted group selected from C 1 -C 4 alkyl, C 1 -C 4 alkyloxy, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         7 . The compound of  claim 1  wherein:
 a) R 2 , R 3 , and R 4  are each hydrogen; 
 b) one of R 2 , R 3 , or R 4  is hydrogen; 
 c) two of R 2 , R 3 , or R 4  is hydrogen; 
 d) R 2  and R 4  are both hydrogen, and R 3  is halogen, CN, NO 2 , or V—R′; 
 e) R 2  and R 4  are both hydrogen, and R 3  is an optionally substituted group selected from a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 f) R 2  and R 4  are both hydrogen, and R 3  is an optionally substituted 5- or 6-membered saturated, partially unsaturated, or fully unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or 
 g) R 2  and R 4  are both hydrogen, and R 3  is an optionally substituted ring selected from phenyl, pyridyl, pyrimidinyl, thiazolyl, oxazolyl, thienyl, furyl, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, thiadiazolyl, or oxadiazolyl. 
 
     
     
         8 . The compound of  claim 1 , wherein R 2 , R 3 , and R 4  are each optionally substituted with z occurrences of R 6 , wherein z is 0-5 and R 6  is ═O, ═NR″, ═S, halogen, —CN, —NO 2 , or Z—R″, wherein Z is a bond or an optionally substituted C 1 -C 6  alkylidene chain, wherein up to two methylene units of the chain are optionally and independently replaced by —NR″—, —S—, —O—, —CS—, —CO 2 —, —OCO—, —CO—, —COCO—, —CONR″—, —NR″CO—, —NR″CO 2 —, —SO 2 NR″—, —NR″SO 2 —, —CONR″NR″—, —NR″CONR″—, —OCONR″—, —NR″NR″—, —NR″SO 2 NR″—, —SO—, —SO 2 —, —PO—, —PO 2 —, or —POR″—, and and each occurrence of R″ is independently hydrogen or an optionally substituted C 1 -C 6  aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R″ are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         9 . The compound of  claim 8 , wherein z is 0, 1, 2, or 3, and each occurrence of R 6  is independently hydrogen, R″, —CH 2 R″, halogen, CN, NO 2 , —N(R″) 2 , —CH 2 N(R″) 2 , —OR″, —CH 2 OR″, —SR″, —CH 2 SR″, —COOR″, —NR″COR″, —NR″COOR″, —CON(R″) 2 , —SO 2 N(R″) 2 , —CONR″(CH 2 ) 2 N(R″) 2 , —CONR(CH 2 ) 3 N(R″) 2 , —CONR″(CH 2 ) 4 N(R″) 2 , —O(CH 2 ) 2 OR″, O(CH 2 ) 3 OR″, O(CH 2 ) 4 OR″, —O(CH 2 ) 2 N(R″) 2 , —O(CH 2 ) 3 N(R″) 2 , O(CH 2 ) 4 N(R″) 2 , —NR″CH(CH 2 OH)R″, —NR″CH(CH 2 CH 2 OH)R″, —NR″(CH 2 )R″, —NR″(CH 2 ) 2 R″, —NR″(CH 2 ) 3 R″, —NR″(CH 2 ) 4 R″, —NR″(CH 2 )N(R″) 2 , —NR″(CH 2 ) 2 N(R″) 2 , —NR″(CH 2 ) 3 N(R″) 2 , —NR″(CH 2 ) 4 N(R″) 2 , —NR″(CH 2 )OR″, —NR″(CH 2 ) 2 OR″, —NR″(CH 2 ) 3 OR″, or —NR″(CH 2 ) 4 OR″. 
     
     
         10 . The compound of  claim 8 , wherein z is 1, 2, or 3 and each occurrence of R 6  is independently F, Cl, Br, CN, OH, NH 2 , —CH 2 OH, C 1 -C 6 alkyl, —O(C 1 -C 6 alkyl), —CH 2 O(C 1 -C 6 alkyl), —CO(C 1 -C 6 alkyl), —COO(C 1 -C 6 alkyl), —NHSO 2 (C 1 -C 6 alkyl), —SO 2 NH 2 , —CONH 2 , —CON(C 1 -C 6 alkyl), —SO 2 (C 1 -C 6 alkyl), —SO 2 phenyl, phenyl, benzyl, —N(C 1 -C 6 alkyl) 2 , or —S(C 1 -C 6 alkyl), wherein each of the foregoing phenyl, benzyl, and C 1 -C 6 alkyl groups is independently and optionally substituted, and wherein each of the foregoing C 1 -C 6 alkyl groups is linear, branched, or cyclic. 
     
     
         11 . The compound of  claim 1 , wherein two of X 1 , X 2 , or X 3  is N, and the remaining one of X 1 , X 2 , or X 3  is CH, wherein the hydrogen atom of CH is optionally replaced by R 5 . 
     
     
         12 . The compound of  claim 1 , wherein one of X 1 , X 2 , or X 3  is N, and the remaining two of X 1 , X 2 , or X 3  is CH, wherein the hydrogen atom of CH is optionally replaced by R 5 . 
     
     
         13 . The compound of  claim 1 , wherein each of X 1 , X 2  and X 3  is CH, wherein the hydrogen atom of CH is optionally replaced by R 5 . 
     
     
         14 . The compound of  claim 1 , wherein compounds have one of formulae I-A, I-B, I-C or I-D: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 1 , wherein each occurrence of R 5  is independently hydrogen, R′, —CH 2 R′, halogen, CN, NO 2 , —N(R′) 2 , —CH 2 N(R′) 2 , —OR′, —CH 2 OR′, —SR′, —CH 2 SR′, —COOR′, —NR′COR′, —NR′COCH 2 R′, —NR′CO(CH 2 ) 2 R′, —NR′COOR′, —CON(R′) 2 , —SO 2 N(R′) 2 , —CONR′(CH 2 ) 2 N(R′) 2 , —CONR(CH 2 ) 3 N(R′) 2 , —CONR′(CH 2 ) 4 N(R′) 2 , —O(CH 2 ) 2 OR′, O(CH 2 ) 3 OR′, O(CH 2 ) 4 OR′, —O(CH 2 ) 2 N(R′) 2 , —O(CH 2 ) 3 N(R′) 2 , —O(CH 2 ) 4 N(R′) 2 , —NR′CH(CH 2 OH)R′, —NR′CH(CH 2 CH 2 OH)R′, —NR′(CH 2 )R′, —NR′(CH 2 ) 2 R′, —NR′(CH 2 ) 3 R′, —NR′(CH 2 ) 4 R′, —NR′(CH 2 )N(R′) 2 , —NR′(CH 2 ) 2 N(R′) 2 , —NR′(CH 2 ) 3 N(R′) 2 , —NR′(CH 2 ) 4 N(R′) 2 , —NR′(CH 2 )OR′, —NR′(CH 2 ) 2 OR′, —NR′(CH 2 ) 3 OR′, or —NR′(CH 2 ) 4 OR′. 
     
     
         16 . The compound of  claim 1 , wherein x is 1, 2, or 3, and at least one occurrence of R 5  is —N(R′) 2 , —NR′CH(CH 2 OH)R′, —NR′CH(CH 2 CH 2 OH)R′, —NR′(CH 2 )R′, —NR′(CH 2 ) 2 R′, NR′(CH 2 )N(R′) 2 , or —NR′(CH 2 ) 2 N(R′) 2 . 
     
     
         17 . The compound of  claim 1 , wherein x is 1, 2, or 3, and at least one occurrence of R 5  is —OR′. 
     
     
         18 . The compound of  claim 1 , wherein x is 1, 2, or 3, and at least one occurrence of R 5  is —NR′COR′, —NR′COCH 2 R′, or —NR′CO(CH 2 ) 2 R′. 
     
     
         19 . The compound of  claim 1 , wherein x is 1, 2, or 3, and at least one occurrence of R 5  is an optionally substituted C 1 -C 6  aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         20 . The compound of  claim 1 , wherein x is 1 or 2, and each occurrence of R 5  is independently halogen, R′, CN, —CH 2 CN, —(CH 2 ) 2 CN, NO 2 , —CH 2 NO 2 , —(CH 2 ) 2 NO 2 , CON(R′) 2 , —CH 2 CON(R′) 2 , —(CH 2 ) 2 CON(R′) 2 , COOR′, —CH 2 COOR′, —(CH 2 ) 2 COOR′, —SO 2 N(R′) 2 , —CH 2 SO 2 N(R 2 ) 2 , —(CH 2 ) 2 SO 2 N(R′) 2 , —NR′SO 2 R′, —CH 2 NR′SO 2 R′, —(CH 2 ) 2 NR′SO 2 R′, NR′CON(R′) 2 , —CH 2 NR′CON(R′) 2 , —(CH 2 ) 2 NR′CON(R′) 2 , —NR′SO 2 N(R′) 2 , —CH 2 NR′SO 2 N(R′) 2 , —(CH 2 ) 2 NR′SO 2 N(R′) 2 , —COCOR′, —CH 2 COCOR′, —(CH 2 ) 2 COCOR′, —N(R′) 2 , —CH 2 N(R′) 2 , —(CH 2 ) 2 N(R′) 2 , —OR′, —CH 2 OR′, —(CH 2 ) 2 OR′, —NR′COR′ 9 —NR′COCH 2 R′, —NR′CO(CH 2 ) 2 R′, —CH 2 NR′COR′, or —(CH 2 ) 2 NR′COR′. 
     
     
         21 . The compound of  claim 20 , wherein R 5  is CN, —CH 2 CN, —(CH 2 ) 2 CN, —NO 2 , —CH 2 NO 2 , —(CH 2 ) 2 NO 2 , OR′, —CH 2 OR′, —CON(R′) 2 , —SO 2 N(R′) 2 , —N(R′) 2 , or R′. 
     
     
         22 . The compound of  claim 20 , wherein each occurrence of R 5  is independently hydrogen, halogen, CN, —CH 2 CN, —(CH 2 ) 2 CN, NO 2 , —CH 2 NO 2 , —(CH 2 ) 2 NO 2 , —CONH 2 , —CON(C 1 -C 4 alkyl), —SO 2 NH 2 , —SO 2 N(C 1 -C 4 alkyl), NH 2 , —N(C 1 -C 4 alkyl), —OH, —O(C 1 -C 4 alkyl), —CH 2 OH, —CH 2 O(C 1 -C 4 alkyl), or an optionally substituted 5- or 6-membered unsaturated ring wherein 0-3 ring carbon atoms is optionally replaced by oxygen, sulfur, or nitrogen. 
     
     
         23 . The compound of  claim 1 , wherein R 5  is optionally substituted with y occurrences of R 7 , wherein y is 0-5 and R 7  is ═O, ═NR″, ═S, halogen, —CN, —NO 2 , or W—R″, wherein W is a bond or an optionally substituted C 1 -C 6  alkylidene chain, wherein up to two methylene units of the chain are optionally and independently replaced by —NR″—, —S—, —O—, —CS—, —CO 2 —, —OCO—, —CO—, —COCO—, —CONR″—, —NR″CO—, —NR″CO 2 —, —SO 2 NR″—, —NR″SO 2 —, —CONR″NR″—, —NR″CONR″—, —OCONR″—, —NR″NR″—, —NR″SO 2 NR″—, —SO—, —SO 2 —, —PO—, —PO 2 —, or —POR″—, and and each occurrence of R″ is independently hydrogen or an optionally substituted C 1 -C 6  aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R″, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         24 . The compound of  claim 23 , wherein y is 0, 1, 2, or 3, and each occurrence of R 7  is independently hydrogen, R″, —CH 2 R″, halogen, CN, NO 2 , —N(R″) 2 , —CH 2 N(R″) 2 , —OR″, —CH 2 OR″, —SR″, —CH 2 SR″, —COOR″, —NR″COR″, —NR″COOR″, —CON(R″) 2 , —SO 2 N(R″) 2 , —CONR″(CH 2 ) 2 N(R″) 2 , —CONR(CH 2 ) 3 N(R″) 2 , —CONR″(CH 2 ) 4 N(R″) 2 , O(CH 2 ) 2 OR″, O(CH 2 ) 3 OR″, O(CH 2 ) 4 OR″, —O(CH 2 ) 2 N(R″) 2 , —O(CH 2 ) 3 N(R″) 2 , —O(CH 2 ) 4 N(R″) 2 , —NR″CH(CH 2 OH)R″, —NR″CH(CH 2 CH 2 OH)R″, —NR″(CH 2 )R″, —NR″(CH 2 ) 2 R″, —NR″(CH 2 ) 3 R″, —NR″(CH 2 ) 4 R″, —NR″(CH 2 )N(R″) 2 , —NR″(CH 2 ) 2 N(R″) 2 , —NR″(CH 2 ) 3 N(R″) 2 , —NR″(CH 2 ) 4 N(R″) 2 , —NR″(CH 2 )OR″, —NR″(CH 2 ) 2 OR″, —NR″(CH 2 ) 3 OR″, or —NR″(CH 2 ) 4 OR″. 
     
     
         25 . The compound of  claim 23 , wherein y is 1, 2, or 3 and each occurrence of R 7  is independently F, Cl, Br, CN, OH, NH 2 , —CH 2 OH, C 1 -C 6 alkyl, —O(C 1 -C 6 alkyl), —CH 2 O(C 1 -C 6 alkyl), —CO(C 1 -C 6 alkyl), —COO(C 1 -C 6 alkyl), —NHSO 2 (C 1 -C 6 alkyl), —SO 2 NH 2 , —CONH 2 , —CON(C 1 -C 6 alkyl), —SO 2 (C 1 -C 6 alkyl), —SO 2 phenyl, phenyl, benzyl, —N(C 1 -C 6 alkyl) 2 , or —S(C 1 -C 6 alkyl), wherein each of the foregoing phenyl, benzyl, and C 1 -C 6 alkyl groups is independently and optionally substituted, and wherein each of the foregoing C 1 -C 6 alkyl groups is linear, branched, or cyclic. 
     
     
         26 . The compound of  claim 1 , wherein x is 1, 2, or 3; at least one occurrence of R 5  is —N(R′) 2 , —NR′CH(CH 2 OH)R′, —NR′CH(CH 2 CH 2 OH)R′, —NR′(CH 2 )R′, —NR′(CH 2 ) 2 R′, NR′(CH 2 )N(R′) 2 , —NR′(CH 2 ) 2 N(R′) 2 , —OR′, —NR′COR′, —NR′COCH 2 R′, or —NR′CO(CH 2 ) 2 R′; and R′ is a C 1 -C 6 aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R′ are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each occurrence of R′ is optionally substituted with y occurrences of R 7 . 
     
     
         27 . The compound of  claim 26 , wherein R′ is hydrogen, C 1 -C 6 alkyl optionally substituted with 1-3 occurrences of R 7 , or is a 5-10-membered monocyclic or bicyclic saturated, partially unsaturated or fully unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is optionally substituted with 1-3 occurrences of R 7 . 
     
     
         28 . The compound of  claim 26 , wherein R′ is hydrogen, C 1 -C 4 alkyl optionally substituted with 1-3 occurrences of R 7 , or is a ring selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein y is 0-5 and R 7  is ═O, ═NR″, ═S, halogen, —CN, —NO 2 , or W—R″, wherein W is a bond or an optionally substituted C 1 -C 6  alkylidene chain, wherein up to two methylene units of the chain are optionally and independently replaced by —NR″—, —S—, —O—, —CS—, —CO 2 —, —OCO—, —CO—, —COCO—, —CONR″—, —NR″CO—, —NR″CO 2 —, —SO 2 NR″—, —NR″SO 2 —, —CONR″NR″—, —NR″CONR″—, —OCONR″—, —NR″NR″—, —NR″SO 2 NR″—, —SO—, —SO 2 —, —PO—, —PO 2 —, or —POR″—, and and each occurrence of R″ is independently hydrogen or an optionally substituted C 1 -C 6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R″, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         29 . The compound of  claim 1 , wherein R 5  is —N(R′) 2  and the two occurrences of R′ are taken together with the nitrogen atom to which they are bound to form an optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In certain embodiments, the ring is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein y is 0-5 and R 7  is ═O, ═NR″, ═S, halogen, —CN, —NO 2 , or W—R″, wherein W is a bond or an optionally substituted C 1 -C 6  alkylidene chain, wherein up to two methylene units of the chain are optionally and independently replaced by —NR″—, —S—, —O—, —CS—, —CO 2 —, —OCO—, —CO—, —COCO—, —CONR″—, —NR″CO—, —NR″CO 2 —, —SO 2 NR″—, —NR″SO 2 —, —CONR″NR″—, —NR″CONR″—, —OCONR″—, —NR″NR″—, —NR″SO 2 NR″—, —SO—, —SO 2 —, —PO—, —PO 2 —, or —POR″—, and and each occurrence of R″ is independently hydrogen or an optionally substituted C 1 -C 6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R″, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         30 . A compound selected from Table 1. 
     
     
         31 . The compound according to  claim 1 , wherein the compound has one of formulae I-A, I-B or I-E: 
       
         
           
           
               
               
           
         
       
     
     
         32 . The compound according to any one of  claim 1 ,  14  or  31 , wherein R 2  and R 4  are each independently selected from H, Cl, Br, F, —CN, —COOH, —COOR′, —NH 2 , —N(CH 3 ) 2 , —N(Et) 2 , —N(iPr) 2 , —NHR′, —OR′, —SR′, —O(CH 2 ) 2 OCH 3 , —CONH 2 , —CONHR′, CON(R′) 2 , —OH, —CH 2 OH, CH 2 NH 2 , —CH 2 NHR′, —CH2N(R′) 2 , —C(R′) 2 N(R′) 2 , —NHCOCH 3 , —N(R′)COR′, —SO 2 NH 2 , —SO 2 N(Me) 2 , or an optionally substituted group selected from C 1 -C 6  aliphatic, C 1 -C 6  alkyloxy, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         33 . The compound according to  claim 32 , wherein R 2  and R 4  are each hydrogen. 
     
     
         34 . The compound according to  claim 31 , wherein R 1  is selected from hydrogen, C 1 -C 4 alkyl, —COR′, —SO 2 R′, or —Si(R′) 3 . 
     
     
         35 . The compound according to  claim 34 , wherein R′ is hydrogen. 
     
     
         36 . The compound according to  claim 31 , wherein R 3  is selected from H, Cl, Br, F, —CN, —COOH, —COOMe, —NH 2 , —N(R′) 2 , —NO 2 , —OR′, —CON(R′) 2 , —COOR′, —OH, —SR′, —C(R′) 2 OR′, —N(R′)COR′, —N(R′)C(O)OR, —SO 2 NH 2 , —SO 2 N(R′) 2 , or an optionally substituted group selected from C 1 -C 4  aliphatic, C 1 -C 4  alkyloxy or —C≡C—C 1 -C 4  aliphatic. 
     
     
         37 . The compound according to  claim 36 , wherein R 3  is selected from H, Cl, —Br, —CN, —COOH, —COOMe, —CONHR′, —CON(Me) 2 , —CH 2 OH, —NO 2 , —NH 2  or an optionally substituted C 1 -C 4  aliphatic. 
     
     
         38 . The compound according to  claim 37 , wherein R 3  is selected from Cl, —Br, —CN or an optionally substituted C 1 -C 4  aliphatic. 
     
     
         39 . The compound according to  claim 37 , wherein R 3  is Cl. 
     
     
         40 . The compound according to any one of  claim 1 ,  14  or  31 , wherein R 1 , R 2  and R 4  are hydrogen and R 3  is selected from Cl, —Br, —CN or an optionally substituted C 1 -C 4  aliphatic. 
     
     
         41 . The compound according to  claim 37 , wherein R 3  is H, OR′, NR′C(O)R′, NR′C(O)OR′, CON(R′) 2  or COOMe. 
     
     
         42 . The compound according to  claim 37 , wherein R 3  is OR′, NR′C(O)R′ or NR′C(O)OR′. 
     
     
         43 . The compound according to any one of  claim 1 ,  14  or  31 , wherein R 1 , R 2  and R 4  are hydrogen and R 3  is selected from H, OR′, NR′C(O)R′, NR′C(O)OR′, CON(R′) 2  or COOMe. 
     
     
         44 . The compound according to  claim 31 , wherein x is 1, 2, or 3; wherein each occurrence of R 5  is independently selected from R′, —CH 2 R′, halogen, CN, NO 2 , —N(R′) 2 , —CH 2 N(R′) 2 , —OR′, —CH 2 OR′, —SR′, —CH 2 SR′, —COOR′, —NR′COR′, —NR′COR 8 R′, —NR′COOR′, —CON(R′) 2 , —SO 2 N(R′) 2 , —CONR′R 8 N(R′) 2 , —OR 8 OR′, —OR 8 N(R′) 2 , —NR′CH(R 9 )R′, —NR′CH(R 9 )C(O)OR′, —N(R′)R 8 R′, —N(R′)R 8 R′, —N(R′)R 8 N(R′) 2 , —N(R′) R 8 OR′, —NR′CH(R 9 )R′, —NR′CH 2 C(O)N(R′) 2 , or —NR′CH(R 9 )C(O)N(R′) 2 , wherein R 8  is an optionally substituted C 1 -C 4  alkyl and R 9  is an optionally substituted C 1 -C 6  aliphatic. 
     
     
         45 . The compound according to  claim 44 , wherein each occurrence of R 5  is independently selected from R′, —CH 2 R′, halogen, —CN, —NO 2 , —N(R′) 2 , —CH 2 N(R′) 2 , —OR′, —CH 2 OR′, —SR′, —CH 2 SR′, —COOR′, —NR′COR′, —NR′COCH 2 R′, —NR′CO(CH 2 ) 2 R′, —NR′COOR′, —CON(R′) 2 , —SO 2 N(R′) 2 , —CONR′(CH 2 ) 2 N(R′) 2 , —CONR(CH 2 ) 3 (R′) 2 , —CONR′(CH 2 ) 4 N(R′) 2 , —O(CH 2 ) 2 OR′, O(CH 2 ) 3 OR′, O(CH 2 ) 4 OR′, —O(CH 2 ) 2 N(R′) 2 , —O(CH 2 ) 3 N(R′) 2 , —O(CH 2 ) 4 N(R′) 2 , —NR′CH(CH 2 OR 9 )R′, —NR′CH(CH 2 CH 2 OR 9 )R′, —NR′CH(CH 3 )R′, NR′CH(CF 3 )R′, —NR′CH(CH 3 )C(O)OR′, —NW CH(CF 3 )C(O)OR′, —NR′(CH 2 )R′, —NR′(CH 2 ) 2 R′, —NR′(CH 2 ) 3 R′, —NR′(CH 2 ) 4 R′, —NR′(CH 2 )N(R′) 2 , —NR′(CH 2 ) 2 N(R′) 2 , —NR′(CH 2 ) 3 (R′) 2 , —NR′(CH 2 ) 4 N(R′) 2 , —NR′(CH 2 )OR′, —NR′(CH 2 ) 2 OR′, —NR′(CH 2 ) 3 OR′, (CH 2 ) 4 OR, —NR′CH(CH 2 CH 3 )R′, —NR′CH 2 C(O)N(R′) 2 , —NR′CH(CH 3 )C(O)N(R′) 2 , NR′CH(CF 3 )C(O)N(R′) 2 , —NR′CH(CH 2 CH 3 )C(O)N(R′) 2 , —NR′CH(CH(CH 3 ) 2 )C(O)N(R′) 2 , —NR′CH(C(CH 3 ) 3 )C(O)N(R′) 2 , —NR′CH(CH 2 CH(CH 3 ) 2 )C(O)N(R′) 2 , —NR′CH(CH 2 OR 9 )C(O)N(R′) 2  or —NR′CH(CH 2 CH 2 N(Me) 2 )C(O)N(R′) 2 . 
     
     
         46 . The compound according to  claim 44 , wherein at least one occurrence of R 5  is independently selected from —NR′CH(CH 2 OH)R′, —NR′CH(CH 2 OMe)R′, —NR′CH(CH 2 OEt)R′, —NR′CH(CH 2 OCF 3 )R′, —NR′CH(CH 2 CH 2 OH)R′, —NR′CH(CH 2 CH 2 OMe)R′, —NW CH(CH 2 CH 2 OEt)R′, —NR′CH(CH 2 CH 2 OCF 3 )R′, —CH(CH 3 )C(O)OR′, —NR′CH(CF 3 )C(O)OR′, —NR′CH(CH 3 )C(O)N(R′) 2 , —NR′CH(CF 3 )C(O)N(R′) 2 , —NR′CH(CH 2 CH 3 )C(O)N(R′) 2 , —NR′CH(CH 2 OH)C(O)N(R′) 2 , —NR′CH(CH 2 OMe)C(O)N(R′) 2 , —NR′CH(CH 2 OEt)C(O)N(R′) 2  or —NR′CH(CH 2 OCF 3 )C(O)N(R′) 2 , wherein R′ is an optionally substituted C 1 -C 4  aliphatic. 
     
     
         47 . The compound according to  claim 44 , wherein said at least one occurrence of R 5  is selected from NHCH 2 C(O)NHR′, —NHCH(CH 3 )C(O)NHR′, —NHCH(CH 2 CH 3 )C(O)NHR′, —NHCH(CH(CH 3 ) 2 )C(O)NHR′, —NHCH(C(CH 3 ) 3 )C(O)NHR′, —NHCH(CH 2 CH(CH 3 ) 2 )C(O)NHR′, —NHCH(CH 2 OH)C(O)NHR′, —NHCH(CH 2 OMe)C(O)NHR′ or —NHCH(CH 2 CH 2 N(Me) 2 )C(O)NHR′, wherein R′ is an optionally substituted C 1 -C 4  aliphatic. 
     
     
         48 . The compound according to  claim 44 , wherein at least one occurrence of R 5  is independently selected from —NHR′, —NH(CH 2 )R′, —NH(CH 2 ) 2 R′, —NHCH(CH 3 )R′, —NHCH 2 C(O)NHR′, —NHCH(CH 3 )C(O)NHR′, —NHCH(CH 2 CH 3 )C(O)NHR′, —NHCH(CH(CH 3 ) 2 )C(O)NHR′, —NHCH(C(CH 3 ) 3 )C(O)NHR′, —NHCH(CH 2 CH(CH 3 ) 2 )C(O)NHR′, —NHCH(CH 2 OH)C(O)NHR′, —NHCH(CH 2 OMe)C(O)NHR′ or —NHCH(CH 2 CH 2 N(Me) 2 )C(O)NHR′, wherein R′ is an optionally substituted phenyl. 
     
     
         49 . The compound according to  claim 44 , wherein said at least one occurrence of R 5  is —NHCH(CH 3 )R′, wherein R′ is optionally substituted phenyl. 
     
     
         50 . The compound according to  claim 44 , wherein at least one occurrence of R 5  is H, halogen, CH 3 , CF 3 , COOH, COOMe or OR′, wherein R′ is C 1 -C 4  aliphatic. 
     
     
         51 . The compound according to  claim 44 , wherein x is 2 or 3 and at least one occurrence of R 5  is F. 
     
     
         52 . The compound according to  claim 44 , wherein R 1 , R 2  and R 4  are hydrogen and R 5  is selected from —NHR′, —NH(CH 2 )R′, —NH(CH 2 ) 2 R′, —NHCH(CH 3 )R′, —NHCH 2 C(O)NHR′, —NHCH(CH 3 )C(O)NHR′, —NHCH(CH 2 CH 3 )C(O)NHR′, —NHCH(CH(CH 3 ) 2 )C(O)NHR′, —NHCH(C(CH 3 ) 3 )C(O)NHR′, —NHCH(CH 2 CH(CH 3 ) 2 )C(O)NHR′, —NHCH(CH 2 OH)C(O)NHR′, —NHCH(CH 2 OMe)C(O)NHR′ or —NHCH(CH 2 CH 2 N(Me) 2 )C(O)NHR′, wherein R′ is an optionally substituted phenyl. 
     
     
         53 . The compound according to  claim 44 , wherein R 1 , R 2  and R 4  are hydrogen and R 5  is selected from —NR′CH(CH 2 OH)R′, —NR′CH(CH 2 OMe)R′, —NR′CH(CH 2 OEt)R′, —NR′CH(CH 2 OCF 3 )R′, —NR′CH(CH 2 CH 2 OH)R′, —NR′CH(CH 2 CH 2 OMe)R′, —NR′CH(CH 2 CH 2 OEt)R′, —NR′CH(CH 2 CH 2 OCF 3 )R′, —NR′CH(CH 3 )C(O)OR′, —NR′CH(CF 3 )C(O)OR′, —NR′CH(CH 3 )C(O)N(R′) 2 , —NR′CH(CF 3 )C(O)(R′) 2 , —NR′CH(CH 2 CH 3 )C(O)N(R′) 2 , —NR′CH(CH 2 OH)C(O)N(R′) 2 , —NR′CH(CH 2 OMe)C(O)N(R′) 2 , —NR′CH(CH 2 OEt)C(O)N(R′) 2  or —NR′CH(CH 2 OCF 3 )C(O)N(R′) 2 , wherein R′ is an optionally substituted C 1 -C 4  aliphatic. 
     
     
         54 . The compound according to  claim 31 , wherein R′ is selected from hydrogen, a C 1 -C 6 aliphatic group optionally substituted with y occurrences of R 7 , or R′ is a ring selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or two occurrences of R′ are taken together with the nitrogen atom to which they are bound to form an optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein y is 0, 1, 2, or 3, and each occurrence of R 7  is independently hydrogen, R″, —CH 2 R″, halogen, CN, NO 2 , —N(R″) 2 , —CH 2 N(R″) 2 , —OR″, —CH 2 OR″, —SR″, —CH 2 SR″, —COOR″, —NR″COR″, —NR″COOR″, —CON(R″) 2 , —SO 2 N(R″) 2 , —CONR″(CH 2 ) 2 N(R″) 2 , —CONR(CH 2 ) 3 N(R″) 2 , —CONR″(CH 2 ) 4 N(R″) 2 , —O(CH 2 ) 2 OR″, O(CH 2 ) 3 OR″, O(CH 2 ) 4 OR″, —O(CH 2 ) 2 N(R″) 2 , —O(CH 2 ) 3 N(R″) 2 , —O(CH 2 ) 4 N(R″) 2 , —NR″CH(CH 2 OH)R″, —NR″CH(CH 2 CH 2 OH)R″, —NR″(CH 2 )R″, —NR″(CH 2 ) 2 R″, —NR″(CH 2 ) 3 R″, —NR″(CH 2 ) 4 R″, —NR″(CH 2 )N(R″) 2 , —NR″(CH 2 ) 2 N(R″) 2 , —NR″(CH 2 ) 3 N(R″) 2 , —NR″(CH 2 ) 4 N(R″) 2 , —NR″(CH 2 )OR″, —NR″(CH 2 ) 2 OR″, —NR″(CH 2 ) 3 OR″, or —NR″(CH 2 ) 4 OR″, and each occurrence of R″ is independently hydrogen or an optionally substituted C 1 -C 6  aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R″, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         55 . The compound according to  claim 31 , wherein x is 2, 3 or 4 and at least two R 5  on adjacent ring members are R′, and wherein said two R 5  are taken together with the atoms to which they are bound to form an optionally substituted 3-12 membered saturated, partially saturated or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. 
     
     
         56 . The compound according to  claim 55 , wherein said compound has formula I-B-vii or I-B-viii: 
       
         
           
           
               
               
           
         
         wherein y is 0, 1, 2, or 3, and each occurrence of R 7  is independently hydrogen, R″, —CH 2 R″, halogen, CN, NO 2 , —N(R″) 2 , —CH 2 N(R″) 2 , —OR″, —CH 2 OR″, —SR″, —CH 2 SR″, —COOR″, —NR″COR″, —NR″COOR″, —CON(R″) 2 , —SO 2 N(R″) 2 , —CONR″(CH 2 ) 2 N(R″) 2 , —CONR(CH 2 ) 3 N(R″) 2 , —CONR″(CH 2 ) 4 N(R″) 2 , —O(CH 2 ) 2 OR″, O(CH 2 ) 3 OR″, O(CH 2 ) 4 OR″, —O(CH 2 ) 2 N(R″) 2 , —O(CH 2 ) 3 N(R″) 2 , —O(CH 2 ) 4 N(R″) 2 , —NR″CH(CH 2 OH)R″, —NR″CH(CH 2 CH 2 OH)R″, —NR″(CH 2 )R″, —NR″(CH 2 ) 2 R″, —NR″(CH 2 ) 3 R″, —NR″(CH 2 ) 4 R″, —NR″(CH 2 )N(R″) 2 , —NR″(CH 2 ) 2 N(R″) 2 , —NR″(CH 2 ) 3 N(R″) 2 , —NR″(CH 2 ) 4 N(R″) 2 , —NR″(CH 2 )OR″, —NR″(CH 2 ) 2 OR″, —NR″(CH 2 ) 3 OR″, or —NR″(CH 2 ) 4 OR″, and each occurrence of R″ is independently hydrogen or an optionally substituted C 1 -C 6  aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R″, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         57 . A compound selected from Table 2. 
     
     
         58 . A pharmaceutical composition comprising a compound according to any one of  claim 1 ,  30 ,  31  or  57  and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         59 . The composition of  claim 58 , further comprising an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, a treatment for Alzheimer's Disease, a treatment for Parkinson's Disease, an agent for treating Multiple Sclerosis (MS), a treatment for asthma, an agent for treating schizophrenia, 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 agent for treating a blood disorder, or an agent for treating an immunodeficiency disorder. 
     
     
         60 . A method of inhibiting JAK-3, ROCK or Aurora kinase activity in a biological sample, comprising the step of contacting said biological sample with:
 a) a composition according to  claim 58 ; or   b) a compound according to  claim 1  or  claim 31 .   
     
     
         61 . A method of treating or alleviating a disease or disorder selected from immune responses such as allergic or type I hypersensitivity reactions or asthma; autoimmune diseases such as transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, or multiple sclerosis; neurodegenerative disorders; or solid and hematologic malignancies, comprising administering to a patient in need thereof a composition according to  claim 58  or a compound according to  claim 1  or  claim 31 . 
     
     
         62 . The method of  claim 61 , comprising the further step of administering to said patient an additional therapeutic agent 
     
     
         63 . The method of  claim 61 , wherein the disease is an autoimmune disease and is transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, or multiple sclerosis. 
     
     
         64 . The method of  claim 61 , wherein the disease is hypertension, angina pectoris, cerebrovascular contraction, asthma, peripheral circulation disorder, premature birth, cancer, erectile dysfunction, arteriosclerosis, spasm (cerebral vasospasm and coronary vasospasm), retinopathy (e.g., glaucoma), inflammatory disorders, autoimmune disorders, AIDS, osteoporosis, myocardial hypertrophy, ischemia/reperfusion-induced injury, or endothelial dysfunction. 
     
     
         65 . A method of treating, preventing or lessening the severity of a disease or disorder selected from heart disease, diabetes, Alzheimer's disease, immunodeficiency disorders, inflammatory diseases, hypertension, allergic diseases, autoimmune diseases, destructive bone disorders, osteoporosis, proliferative disorders, infectious diseases, immunologically-mediated diseases, viral diseases, hyperplasia, reperfusion/ischemia in stroke, heart attacks, organ hypoxia, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer, hepatic ischemia, myocardial infarction, congestive heart failure, pathologic immune conditions involving T cell activation, and neurodegenerative disorders comprising administering to a patient in need thereof a composition according to  claim 58  or a compound according to  claim 1  or  claim 31 . 
     
     
         66 . The method according to  claim 65 , wherein said cancer is selected from melanoma, lymphoma, neuroblastoma, leukemia, or a cancer selected from colon, breast, lung, kidney, ovary, endometrial, pancreatic, renal, central nervous system, cervical, prostate, or cancer of the gastric tract, CML, AML, APL, acute lymphocytic leukemia (ALL), mastocytosis or gastrointestinal stromal tumor (GIST).