Therapeutic methods for type I diabetes

Abstract

The invention relates to the treatment and prevention of type I diabetes. More specifically, the invention relates to compounds that treat or prevent the body's immune system from destroying β-cells (i.e., insulin-producing cells in the pancreatic islets of Langerhans) by inhibition of JNK2, selective inhibition of JNK2, or inhibition of the expression of the MAPK9 gene or gene product. In one embodiment, the present invention contemplates the diagnosis, identification, production, and use of compounds which modulate MAPK9 gene expression or the activity of the MAPK9 gene product including but not limited to, JNK2, the nucleic acid encoding MAPK9 and homologues, analogues, and deletions thereof, as well as antisense, ribozyme, triple helix, antibody, and polypeptide molecules as well as small inorganic molecules. The present invention contemplates a variety of pharmaceutical formulations and routes of administration for such compounds.

1 . A method for treating type I diabetes in a subject, comprising administering a compound that inhibits activity of JNK2 in the subject.  
     
     
         2 . The method of  claim 1 , wherein the compound inhibits enzymatic activity of JNK2, and has minimal effect on inhibiting enzymatic activity of JNK1.  
     
     
         3 . The method of  claim 1  in which the activity of JNK1 is not inhibited.  
     
     
         4 . The method in  claim 1 , wherein the activity of the compound does not result in an adverse drug reaction to the subject.  
     
     
         5 . The method of  claim 1 , wherein the JNK2 inhibitor is an amino acid sequence of greater than 10 amino acids within JIP-1 or JIP-2.  
     
     
         6 . The method of  claim 5 , wherein the amino acid sequence has a minimal effect on the enzymatic activity of JNK1.  
     
     
         7 . The method of  claim 1 , wherein the compound has the following formula:  
       
         
           
           
               
               
           
         
       
       wherein: Ar 1  is a substituted or unsubstituted aryl or heteroaryl group; X is O or S; Ar 2  a substituted or unsubstituted aryl or heteroaryl group; R 1  and R 2  are independently selected from the group consisting of hydrogen and a C 1 -C 6 -alkyl group; R a , R a ′, R b , R b′  are independently selected from the group consisting of hydrogen and C 1 -C 6 -alkyl; or R a′  and R a  or R b′  together with the carbon atoms they are linked, form a substituted or unsubstituted 5-8-membered saturated, partially unsaturated or aromatic ring containing optionally one or more heteroatoms selected from O, N, S; R 3  is selected from the group consisting of H, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, aryl, heteroaryl, 3-8 membered cycloalkyl optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S; aryl C 1 -C 10 -alkyl and heteroaryl C 1 -C 10 -alkyl; or R 3  and R a  or R a ′ form, together with the N atom linked to R 3 , a 5-8-membered saturated ring, containing optionally at least one further heteroatom selected from O, N, S; R 4  is selected from the group consisting of H and —C(H)R 5 R 6 ; R 5  and R 6  are independently selected from the group consisting of H, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, aryl, heteroaryl, 3-8 membered cycloalkyl optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S; aryl C 1 -C 10 -alkyl and heteroaryl C 1 -C 10 -alkyl; 
 m is an integer from 1 to 5;  
 n is an integer from 0 to 2; and  
 p is an integer from 1 to 10.  
 
     
     
         8 . A method of  claim 1 , wherein the compound has the following formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 Ar 1  and Ar 2  are independently from each other substituted or unsubstituted aryl or heteroaryl groups;  
 X is O or S;  
 R 1  is hydrogen or a C 1 -C 6  alkyl group, or R 1  forms a substituted or unsubstituted 5-6 membered saturated or unsaturated ring with Ar 1 ;  
 n is an integer from 0 to 5, preferably between 1-3 and most preferred 1;  
 Y is an unsubstituted or a substituted 4-12 membered saturated cyclic or bicyclic alkyl containing at least one nitrogen atom, whereby one nitrogen atom within said ring is forming a bond with the sulfonyl group thus providing a sulfamide.  
 
     
     
         9 . The method of  claim 1 , wherein the compounds has the following formula:  
       
         
           
           
               
               
           
         
       
       wherein Ar 1  and Ar 2  are independently from each other substituted or unsubstituted aryl or heteroaryl; X is O or S; R 1  is hydrogen or an unsubstituted or substituted C 1 -C 6 -alkyl group, or R 1  could form a substituted or unsubstituted 5-6-membered saturated or unsaturated fused ring with Ar 1 , or R 2  and R 4  form a substituted or unsubstituted 5-6-membered saturated or non-saturated ring; R 2  is hydrogen or a substituted or unsubstituted C 1 -C 6 -alkyl group; n is an integer from 0 to 5; R 3  and R 4  are independently from each other selected from the group comprising or consisting of natural amino acid residues or synthetic amino acid residues, hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, like trihalomethyl, substituted or unsubstituted C 1 -C 6 -alkoxy, NH 2 , SH, thioalkyl, aminoacyl, aminocarbonyl, substituted or unsubstituted C 1 -C 6 -alkoxycarbonyl, aryl, heteroaryl, substituted or unsubstituted 4-8-membered cyclic alkyl, optionally containing 1-3 heteroatoms, carboxyl, cyano, halogen, hydroxy, nitro, acetoxy, aminoacyl, sulfoxy, sulfonyl, C 1 -C 6 -thioalkoxy, whereby at least one of R 3  and/or R 4  must be an amino acid residue; R 5  is H or substituted or unsubstituted C 1 -C 6 -alkyl; R 6  is selected from the group comprising or consisting of H, substituted or unsubstituted C 1 -C 6 -aliphatic alkyl, substituted or unsubstituted saturated cyclic C 4 -C 8 -alkyl optionally containing 1-3 heteroatoms and optionally fused with an aryl or an heteroaryl; or R 6  is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, whereby said aryl or heteroaryl groups are optionally substituted with substituted or unsubstituted C 1 -C 6 -alkyl, like trihalomethyl, substituted or unsubstituted C 1 -C 6 -alkoxy, substituted or unsubstituted C 2 -C 6 -alkenyl, substituted or unsubstituted C 2 -C 6 -alkynyl, amino, aminoacyl, aminocarbonyl, substituted or unsubstituted C 1 -C 6 -alkoxycarbonyl, aryl, carboxyl, cyano, halogen, hydroxy, nitro, acetoxy, aminoacyl, sulfoxy, sulfonyl, C 1 -C 6 -thioalkoxy; or R 5  and R 6  taken together could form a substituted or unsubstituted 4-8-membered saturated cyclic alkyl or heteroalkyl group.  
     
     
         10 . The method of  claim 1 , wherein the compound has the following formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 Ar 1  and Ar 2  are independently from each other substituted or unsubstituted aryl or heteroaryl groups;  
 X 1  and X 2  are independently from each other O or S;  
 R 1 , R 2 , and R 3  are independently from each other hydrogen or a C 1 -C 6  alkyl substituent or R 1  forms a substituted or unsubstituted 5-6-membered saturated or unsaturated ring with Ar 1 ; or R 2  and R 3  form a substituted or unsubstituted 5-6-membered saturated or unsaturated ring; n is an integer from 0 to 5;  
 G is selected from a group comprising or consisting of an unsubstituted or substituted 4-8-membered heterocycle containing at least one heteroatom, or G is a substituted or unsubstituted C 1 -C 6  alkyl group.  
 
     
     
         11 . The method of  claim 1 , wherein the compound has the following formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 Z 11  and Z 12  each independently represent a carbonyl group, an oxygen atom, a sulfur atom, a methine group which may be substituted, a methylene group which may be substituted or a nitrogen atom which may be substituted;  
    represents a double bond or a single bond;  
 R 1a  represents a hydrogen atom, a C 1 -C 6  alkyl group, a phenyl group or a benzyl group;  
 R 2a , R 2b  and R 2c  each independently represent a group selected from the following Substituent Group (a); the ring A represents a benzene ring which may have one to three groups selected from the following Substituent Group (a), a naphthalene ring which may have one to three groups selected from the following Substituent Group (a) or a 5- to 10-membered aromatic heterocyclic ring which may have one to three groups selected from the following Substituent Group (a); Substituent Group (a) (1) a hydrogen atom, (2) halogen atoms, (3) a nitro group, (4) a hydroxyl group, (5) a cyano group, (6) a carboxyl group, (7) an amino group, (8) a formyl group or (9) a group represented by the formula:  
                     
 wherein 
 X 1  and X 2  each independently represent a single bond, —CO—, —SO 2 — or C 1 -C 6 -methylene group; X 3  represents a single bond, —CO—, —SO 2 , —O—, —CO—O— or —O—CO—;  
 R 3b  represents a C 1 -C 6  alkylene group or a single bond;  
 R 3a  and R 3c  represent a hydrogen atom, a C 1 -C 6  alkyl group which may be substituted, a C 2 -C 6  alkenyl group which may be substituted, a C 2 -C 6  alkynyl group which may be substituted, a C 3 -C 8  cycloalkyl group which may be substituted, a C 6 -C 14  aromatic cyclic hydrocarbon group which may be substituted, a 5- to 14-membered aromatic heterocyclic group which may be substituted or a hydrogen atom.  
 
 
     
     
         12 . The method of  claim 1 , wherein the compound has the following formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 A is a direct bond, —(CH 2 ) a —, —(CH 2 ) b CH═CH(CH 2 ) c —, or —(CH 2 ) b C≡C(CH 2 ) c —;  
 R 1  is aryl, heteroaryl or heterocycle fused to phenyl, each being optionally substituted with one to four substituents independently selected from R 3 ;  
 R 2  is —R 3 , —R 4 , —(CH 2 ) b C(═O)R 5 , —(CH 2 ) b C(═O)OR 5 , —(CH 2 ) b C(═O)NR 5 R 6 , —(CH 2 ) b C(═O)NR 5 (CH 2 )CC(═O)R 6 , —(CH 2 ) b NR 5 C(═O)R 6 , —(CH 2 ) b NR 5 C(═O)NR 6 R 7 , —(CH 2 ) b NR 5 R 6 , —(CH 2 ) b OR 5 , —(CH 2 ) b SO d R 5  or —(CH 2 ) b SO 2 NR 5 R 6 ; a is 1, 2, 3, 4, 5 or 6; b and c are the same or different and at each occurrence independently selected from 0, 1, 2, 3 or 4; d is at each occurrence 0, 1 or 2;  
 R 3  is at each occurrence independently halogen, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, —C(═O)OR 8 , —OC(═O)R 8 , —C(═O)NR 8 R 9 , —C(═O)NR 8 OR 9 , —SO 2 NR 8 R 9 , —NR 8 SO 2 R 9 , —CN, —NO 2 , —NR 8 R 9 , —NR 8 C(═O)R 9 , —NR 8 C(═O)(CH 2 ) b OR 9 , —NR 8 C(═O)(CH 2 ) b R 9 , —O(CH 2 ) b NR 8 R 9 , or heterocycle fused to phenyl;  
 R 4  is alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, each being optionally substituted with one to four substituents independently selected from R 3 , or R 4  is halogen or hydroxy;  
 R 5 , R 6  and R 7  are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, wherein each of R 5 , R 6  and R 7  are optionally substituted with one to four substituents independently selected from R 3 ; and  
 R 8  and R 9  are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle, or heterocycloalkyl, or R 8  and R 9  taken together with the atom or atoms to which they are bonded form a heterocycle, wherein each of R 8 , R 9 , and R 8  and R 9  taken together to form a heterocycle are optionally substituted with one to four substituents independently selected from R 3 .  
 
     
     
         13 . The method of  claim 1 , wherein the compound has the following formula:  
       
         
           
           
               
               
           
         
         wherein R 1  is aryl or heteroaryl optionally substituted with one to four substituents independently selected from R 7 ; R 2  is hydrogen; R 3  is hydrogen or lower alkyl; R 4  represents one to four optional substituents, wherein each substituent is the same or different and independently selected from halogen, hydroxy, lower alkyl and lower alkoxy; R 5  and R 6  are the same or different and independently —R 8 , —(CH 2 ) a C(═O)R 9 , —(CH2) a C(═O)OR 9 , —(CH2) a C(═O)NR 9 R 10 , —(CH2) a C(═O)NR 9 (CH2) b C(═O)R 10 , —(CH2) a NR 9 C(═O)R 10 , (CH2) a NR 11 C(═O)NR 9 R 10 , —(CH2) a NR 9 R 10 , —(CH2) a OR 9 , —(CH2) a SO c R 9  or —(CH2) n SO2NR 9 R 10 ; or R 5  and R 6  taken together with the nitrogen atom to which they are attached to form a heterocycle or substituted heterocycle; R 7  is at each occurrence independently halogen, hydroxy, cyano, nitro, carboxyl, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, substituted heterocycle, heterocycloalkyl, —C(═O)OR 8 , —OC(═O)R 8 , —C(═O)NR 8 R 9 , —C(═O)NR 8 OR 9 , —SO c R 8 , —SO c NR 8 R 9 , NR 8 SOR 9 , —NR 8 R 9 , —NR 8 C(═O)R 9 , —NR 8 C(═O)(CH 2 )bOR 9 , —NR 8 C(═O)(CH2) b R 9 , —O(CH2) b NR 8 R 9 , or heterocycle fused to phenyl; R 8 , R 9 , R 10  and R 11  are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl; or R 8  and R 9  taken together with the atom or atoms to which they are attached to form a heterocycle; a and b are the same or different and at each occurrence independently selected from 0, 1, 2, 3 or 4; and c is at each occurrence 0, 1 or 2.  
       
     
     
         14 . A method of  claim 1 , wherein the compound has the following formula:  
       
         
           
           
               
               
           
         
       
       wherein R 0  is —O—, —S—, —S(O)—, —S(O) 2 —, NH or —CH 2 —; being: (i) unsubstituted, (ii) monosubstituted and having a first substituent, or (iii) disubstituted and having a first substituent and a second substituent; the first or second substituent, when present, is at the 3, 4, 5, 7, 8, 9, or 10 position, wherein the first and second substituent, when present, are independently alkyl, hydroxy, halogen, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, —NHR 3 R 4 , —NH(CH 2 ) n NR 3 R 4 , —NH(═O)R 5 , —NHSO 2 R 5 , —C(═O)NR 3 R 4 , or —SO 2 NR 3 R 4 ; wherein n is 0-6, R 3  and R 4  are taken together and represent alkylidene or a heteroatom-containing cyclic alkylidene or R 3  and R 4  are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, or di-alkylaminoalkyl; and R 5  is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl, mono-alkylaminoalkyl, or di-alkylaminoalkyl.  
     
     
         15 . The method of  claim 1 , wherein the compound has the following formula:  
       
         
           
           
               
               
           
         
         wherein N 1  is a nitrogen atom optionally having a substituent or a hydrogen atom, X 1  is (i) a carbon atom optionally having substituent(s) or hydrogen atom(s), (ii) an oxygen atom, (iii) a sulfur atom or (iv) a nitrogen atom optionally having a substituent or a hydrogen atom, X 2  is (i) a carbon atom optionally having substituent(s) or hydrogen atom(s), (ii) an oxygen atom, (iii) a sulfur atom or (iv) a nitrogen atom optionally having a substituent or a hydrogen atom, X 3  is (i) a carbon atom or (ii) a nitrogen atom, wherein (1) when X 1  is an oxygen atom or a sulfur atom, X 2  is a carbon atom optionally having substituent(s) or hydrogen atom(s), X 3  is a carbon atom and N 1  is a nitrogen atom, (2) when X 1  is a nitrogen atom having a substituent or a hydrogen atom and X 3  is a carbon atom, X2 is a carbon atom optionally having substituent(s) or hydrogen atom(s) and N 1  is a nitrogen atom, (3) when X 1  and X 3  are each a nitrogen atom, X 2  is a carbon atom optionally having substituent(s) or hydrogen atom(s), and N 1  is a nitrogen atom, (4) when X 1  is a carbon atom optionally having substituent(s) or hydrogen atom(s) and X 2  is an oxygen atom or a sulfur atom, X 3  is a carbon atom and N 1  is a nitrogen atom, (5) when X 1  is a carbon atom optionally having substituent(s) or hydrogen atom(s) and X 3  is a carbon atom, one of N 1  and X 2  is a nitrogen atom, and the other is a nitrogen atom having a substituent or a hydrogen atom, (6) when X 1  and X 2  are each a carbon atom optionally having substituent(s) or hydrogen atom(s) and X 3  is a carbon atom, N 1  is a nitrogen atom having a substituent or a hydrogen atom, and (7) when X 1  and X 2  are each a carbon atom optionally having substituent(s) or hydrogen atom(s) and X 3  is a nitrogen atom, N 1  is a nitrogen atom, ring A optionally further has substituent(s), ring B is an aromatic ring, Y is (i) a carbon atom optionally having substituent(s) or hydrogen atom(s) or (ii) a nitrogen atom, Z is a bond, —NR 4 —(R 4  is a hydrogen atom or a hydrocarbon group optionally having substituent(s)), an oxygen atom or an optionally oxidized sulfur atom, W is a bond or a divalent hydrocarbon group optionally having substituent(s), R 2  is an aromatic group optionally having substituent(s), and R 3  is a hydrocarbon group optionally having substituent(s) or a heterocyclic group optionally having substituent(s).  
       
     
     
         16 . The method of  claim 1 , wherein the compound has the following formula:  
       
         
           
           
               
               
           
         
       
       wherein: W is nitrogen or CH; G is hydrogen or C 1-3  aliphatic wherein one methylene unit of G is optionally replaced by —C(O)—, —C(O)O—, —C(O)NH—, —SO 2 —, or —SO 2 NH—; A is —N-T (n) -R, oxygen, or sulfur; R 1  is selected from -T (n) -R or -T (n) -Ar 1 ; each n is independently 0 or 1; T is a C 1-4  alkylidene chain wherein one methylene unit of T is optionally replaced by —C(O)—, —C(O)O—, —C(O)NH—, —SO 2 —, or —SO 2 NH—; Ar 1  is a 3-7 membered monocyclic saturated, partially saturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 8-10 membered bicyclic saturated, partially saturated or aromatic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each member of Ar 1  is optionally substituted with one -Z-R 3  and one to three additional groups independently selected from —R, halogen, oxo, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRCO 2 R, —C(O)R, —CO 2 R, —OC(O)R, —C(O)N(R) 2 , —OC(O)N(R) 2 , —S(O)R, —SO 2 R, —SO 2 N(R) 2 , —NRSO 2 R, —NRSO 2 N(R) 2 , —C(O)C(O)R, or —C(O)CH 2 C(O)R; each R is independently selected from hydrogen or a C 1-6  aliphatic, wherein said aliphatic is optionally substituted with one to three groups independently selected from oxo, —CO 2 R′, —OR′, —N(R′) 2 , —SR′, —NO 2 , —NR′C(O)R′, —NR′C(O)N(R′) 2 , —NR′CO 2 R′, —C(O)R′, —OC(O)R′, —C(O)N(R′) 2 , —OC(O)N(R′) 2 , —S(O)R′, —SO 2 R′, —SO 2 N(R′) 2 , —NR′SO 2 R′, —NR′SO 2 N(R′) 2 , —C(O)C(O)R′, —C(O)CH 2 C(O)R′, halogen, or —CN, or two R bound to the same nitrogen atom are taken together with that nitrogen atom to form a five or six membered heterocyclic or heteroaryl ring having one to two additional heteroatoms independently selected from oxygen, nitrogen, or sulfur; each R′ is independently selected from hydrogen or C 1-6  aliphatic, wherein said aliphatic is optionally substituted with one to three groups independently selected from oxo, —CO 2 H, —OH, —NH 2 , —SH, —NO 2 , —NHC(O)H, —NHC(O)NH 2 , —NHCO 2 H, —C(O)H, —OC(O)H, —C(O)NH 2 , —OC(O)NH 2 , —S(O)H, —SO 2 H, —SO 2 NH 2 , —NHSO 2 H, —NHSO 2 NH 2 , —C(O)C(O)H, —C(O)CH 2 C(O)H, halogen, or —CN, or two R′ bound to the same nitrogen atom are taken together with that nitrogen atom to form a five or six membered heterocyclic or heteroaryl ring optionally having one or two additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; Z is a C 1 -C 6  alkylidene chain wherein up to two nonadjacent methylene units of Z are optionally replaced by —C(O)—, —C(O)O—, —C(O)C(O)—, —C(O)N(R)—, —OC(O)N(R)—, —N(R)N(R)—, —N(R)N(R)C(O)—, —N(R)C(O)—, —N(R)C(O)O—, —N(R)C(O)N(R)—, —S(O)—, —SO 2 —, —N(R)SO 2 —, —SO 2 N(R)—, —N(R)SO 2 N(R)—, —O—, —S—, or —N(R)—; R 2  is -Q (n) -Ar 2 ; Ar 2  is selected from a 3-7 membered monocyclic saturated, saturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 8-10 membered bicyclic saturated, saturated or aromatic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each member of Ar 2  is optionally substituted with 1-5 groups independently selected from -Z-R 3 , —R, halogen, oxo, —NO2, —CN, —OR, —SR, —N(R) 2 , NRC(O)R, —NRC(O)N(R) 2 , —NRCO 2 R, —C(O)R, —CO 2 R, OC(O)R, —C(O)N(R) 2 , —OC(O)N(R) 2 , —S(O)R, —SO 2 R, SO 2 N(R) 2 , —N(R)SO 2 R, —N(R)SO 2 N(R) 2 , —C(O)C(O)R, or —C(O)CH 2 C(O)R; Q is a C 1-3  alkylidene chain wherein up to two nonadjacent methylene units of Q are optionally replaced by —C(O)—, —C(O)O—, —C(O)C(O)—, —C(O)N(R)—, —OC(O)N(R)—, —N(R)N(R)—, —N(R)N(R)C(O)—, —N(R)C(O)—, —N(R)C(O)O—, —N(R)C(O)N(R)—, —S(O)—, —SO 2 —, —N(R)SO 2 —, —SO 2 N(R)—, —N(R)SO 2 N(R)—, —O—, —S—, or —N(R)—; R 3  is selected from —Ar 3 , —R, halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRCO 2 R, —C(O)R, —CO 2 R, —OC(O)R, —C(O)N(R) 2 , —OC(O)N(R) 2 , —SOR, —SO 2 R, —SO 2 N(R) 2 , —NRSO 2 R, —NRSO 2 N(R) 2 , —C(O)C(O)R, or —C(O)CH2C(O)R; and Ar 3  is a 5-6 membered saturated, partially saturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each member of Ar 3  is optionally substituted with halogen, oxo, —CN, —NO 2 , —R′, —OR′, —N(R′) 2 , —N(R′)C(O)R′, N(R′)C(O)N(R′) 2 , —N(R′)CO 2 R′, —C(O)R′, —CO 2 R′, OC(O)R′, —C(O)N(R′) 2 , —OC(O)N(R′) 2 , or —SO 2 R′; provided that when W is nitrogen and: (i) A is —N-T (n) -R and R2 is a saturated ring or (ii) A is sulfur, then R 1  is other than an optionally substituted phenyl.  
     
     
         17 . The method of  claim 1 , wherein the compound has the following formula:  
       
         
           
           
               
               
           
         
         wherein R 1  is optionally substituted carbocyclyl or heterocyclyl group, R 2  is an optionally substituted five or six membered heterocyclyl group or an optionally substituted six membered carbocyclyl group, E is hydrogen, halogen cyano, C 1-6  alkoxyl or C 1-6  alkyl, G is hydrogen, halogen, cyano, C 1-6  alkoxy or C 1-6  alkyl, and L is hydrogen, halogen, cyano, C 1-6  alkoxy or C 1-6  alkyl.  
       
     
     
         18 . The method of  claim 1 , wherein the compound has the following formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1  is an optionally substituted C 3-16  carbocyclyl or C 3-12  heterocyclyl group, Y is N or C and Z is lone electron pair, hydrogen, C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 1-12  haloalkyl, C 3-12  carbocyclyl, C 3-12  heterocyclyl, —(CH 2 ) n OR 2 , —(CH 2 ) n NR 2   2 , —CO 2 R 2 , —COR 2 , —CONR 2   2 , wherein the C 1-12  alkyl group optionally contains one or more insertions selected from —O—, —N(R 2 )—, —S—, —SO—, —SO 2 —; and each substitutable nitrogen atom in Z is optionally substituted by —R 3 , —COR 3 , —SO 2 R 3  or —CO 2 R 3 ; wherein n is 1 to 6, preferably n is 1, 2, or 3; wherein R 2  is hydrogen, C 1-12  alkyl, C 3-16  carbocyclyl or C 3-12  heterocyclyl, C 1-2  alkylC 3-16  carbocyclyl, or C 1-12  alkylC 3-12  heterocyclyl optionally substituted by one or more of C 1-6  alkyl, halogen, C 1-6  haloalkyl, —OR 4 , —SR 4 , —NO 2 , CN, —NR 4 R 4 , —NR 4 COR 4 , —NR 4 CONR 4 R 4 , —NR 4 CO 2 R 4 , —CO 2 R 4 , —COR 4 , —CONR 4   2 , —SO 2 R 4 , —SONR 4   2 , —SOR 4 , —SO 2 NR 4 R 4 , —NR 4 SO 2 R 4 , wherein the C 1-2  alkyl group optionally incorporates on or two insertions selected for the group consisting of —O—, —N(R 4 )—, —S—, —SO—, —52—, wherein each R 4  may be the same or different and is defined below; wherein two R 2  and NR 2   2  may form a partially saturated, unsaturated or fully saturated five to seven membered ring containing one to three heteroatoms, optionally and independently substituted with one or more halogen, C 1-2  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 1-12  haloalkyl, C 3-12  carbocyclyl, C 3-12  heterocyclyl, —OR 5 , —SR 5 , —NO 2 , CN, —NR 5 R 5 , —NR 5 COR 5 , —NR 5 CONR 5 R 5 , —NR 5 CO 2 R 5 , —CO 2 R 5 , —COR 5 , —CONR 5   2 , —SO 2 R 5 , —SONR 5   2 , —SOR 5 , —SO 2 NR 5 R 5 , —NR 5 SO 2 R 5 ; and each saturated carbon in the optional ring is further optionally and independently substituted by ═O, ═S, NNR 6   2 , ═N—OR 6 , ═NNR 6 COR 6 , ═NNR 6 CO 2 R 6 , ═NNSO 2 R 6 , or ═NR 6 ; wherein R 3  is hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, or C 6-12  aryl; wherein R 4  is hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, or C 6-12  aryl; wherein R 5  is hydrogen, C 1-12  alkyl, C 3-16  carbocyclyl or C 3-12  heterocyclyl, optionally substituted by one or more of C 1-6  alkyl, halogen, C 1-6  haloalkyl, —OR 7 , —SR 7 , —NO 2 , CN, —NR 7 R 7 , —NR 7 COR 7 , —NR 7 CONR 7 R 7 , —NR 7 CO 2 R 7 , —CO 2 R 7 , —COR 7 , —CONR 7   2 , —SO 2 R 7 , —SONR 7   2 , —SOR 7 , —SO 2 NR 7 R 7 , —NR 7 SO 2 R 7 ; wherein the C 1-12  alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 7 )—, —S—, —SO—, —SO 2 —, wherein each R 7  may be the same or different and is defined below; wherein R 6  is hydrogen, C 1-12  alkyl, C 3-16  carbocyclyl or C 3-12  heterocyclyl, optionally substituted by one or more of C 1-6  alkyl, halogen, C 1-6  haloalkyl, —OR 7 —SR 7 , —NO 2 , CN, —NR 7 R 7 , —NR 7 COR 7 , —NR 7 CONR 7 R 7 , —NR 7 CO 2 R 7 , —CO 2 R 7 , —COR 7 , —CONR 7   2 , —SO 2 R 7 , —SONR 7   2 , —SOR 7 , —SO 2 NR 7 R 7 , —NR 7 SO 2 R 7 ; wherein the C 1-12  alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 7 )—, —S—, —SO—, —SO 2 —, wherein each R 7  may be the same or different and is defined below; wherein R 7  is hydrogen, C 1-6  alkyl, or C 1-6  haloalkyl; wherein the optionally substituted carbocyclyl or heterocyclyl group in R 1  and Z is optionally and independently fused to a partially saturated, unsaturated or fully saturated five to seven membered ring containing zero to three heteroatoms, and each substitutable carbon atom in R 1  or Z, including the optional fused ring, is optionally and independently substituted by one or more of halogen, C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 1-12  haloalkyl, C 3-12  carbocyclyl, C 3-12  heterocyclyl, —(CH 2 ) n OR 12 , —(CH 2 ) n NR 12   2 , —OR 12 , —SR 12 , —NO 2 , CN, —NR 12 R 12 , —NR 12 COR 12 , —NR 12 CONR 12 R 12 , —NR 12 CO 2 R 12 , —CO 2 R 12 , —COR 12 , —CONR 12   2 , —SO 2 R 12 , —SONR 12   2 , —SOR 12 , —SO 2 NR 12 R 12 , —NR 12 S 2 R 12 ; wherein the C 1-12  alkyl group optionally contains one or more insertions selected from —O—, —N(R 12 )—, —S—, —SO—, —SO 2 —, and each saturated carbon in the optionally fused ring is further optionally and independently substituted by ═O, ═S, NNR 13   2 , ═N—OR 13 , ═NNR 13 COR 13 , ═NNR 13 CO 2 R 13 , ═NNSO 2 R 13 , or ═NR 13 ; and each substitutable nitrogen atom in R 1  is optionally substituted by —R 14 , —COR 14 , —SO 2 R 14 , or —CO 2 R 14 ; wherein n is 1 to 6, preferably n is 1, 2, or 3; wherein R 12  is hydrogen, C 1-12  alkyl, C 3-16  carbocyclyl or C 3-12  heterocyclyl, optionally substituted by one or more of C 1-6  alkyl, halogen, C 1-6  haloalkyl, —OR 15 , —SR 15 , —NO 2 , CN, —NR 15 R 15 , —NR 15 COR 15 , —NR 15 CONR 15 R 15 , —NR 15 CO 2 R 15 , —CO 2 R 15 , —COR 15 , —CONR 15   2 , —SO 2 R 15 , SONR 15   2 , —SOR 15 , —SO 2 NR 15 R 15 , —NR 15 SO 2 R 15 ; wherein the C 1-12  alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 15 )—, —S—, —SO—, —SO 2 —, wherein each R 7  may be the same or different and is defined below; wherein two R 12  and NR 12   2  may form a partially saturated, unsaturated or fully saturated five to seven membered ring containing one to three heteroatoms, optionally and independently substituted with one or more halogen, C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 1-12  haloalkyl, C 3-12  carbocyclyl, C 3-12  heterocyclyl, —OR 16 , —SR 16 , —NO 2 , CN, —NR 16 R 16 , —NR 16 COR 16 , —NR 16 CONR 16 R 16 , —NR 16 CO 2 R 16 , —CO 2 R 16 , —COR 16 , —CONR 16   2 , —SO 2 R 16 , —SONR 16   2 , —SOR 16 , —SO 2 NR 16 R 16 , —NR 16 SO 2 R 16 ; and each saturated carbon in the optional ring is further optionally and independently substituted by ═O, ═S, NNR 17   2 , ═N—OR 17 , ═NNR 17 COR 17 , ═NNR 17 CO 2 R 17 , ═NNSO 2 R 17 , or ═NR 17 ; wherein R 13  is hydrogen, C 1-12  alkyl, C 3-16  carbocyclyl or C 3-12  heterocyclyl, optionally substituted by one or more of C 1-6  alkyl, halogen, C 1-6  haloalkyl, —OR 15 , —SR 15 —NO 2 , CN, —NR 15 R 15 , —NR 15 COR 15 , —NR 15 CONR 15 R 15 , —NR 15 CO 2 R 15 , —CO 2 R 15 , —COR 15 , —CONR 15   2 , —SO 2 R 15 , —SONR 15   2 , —SOR 15 , —SO 2 NR 15 R 15 , —NR 15 SO 2 R 15 ; wherein the C 1-12  alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 15 )—, —S—, —SO—, —SO 2 —, wherein each R 15  may be the same or different and is defined below; wherein R 14  is hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, or C 6-12  aryl; wherein R 15  is hydrogen, C 1-6  alkyl, C 1-6  haloalkyl; wherein R 16  is hydrogen, C 1-12  alkyl, C 3-16  carbocyclyl or C 3-12  heterocyclyl, optionally substituted by one or more of C 1-6  alkyl, halogen, C 1-6  haloalkyl, —OR 18 , —SR 18 , —NO 2 , CN, —NR 18 R 18 , —NR 18 COR 18 , —NR 18 CONR 18 R 18 , —NR 18 CO 2 R 18 , —CO 2 R 18 , —COR 18 , —CONR 18   2 —SO 2 R 18 , —SONR 18   2 , —SOR 18 , —SO 2 NR 18 R 18 , —NR 18 SO 2 R 18 ; wherein the C 1-12  alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 18 )—, —S—, —SO—, —SO 2 —, wherein each R 18  may be the same or different and is defined below; wherein R 17  is hydrogen, C 1-12  alkyl, C 3-16  carbocyclyl or C 3-12  heterocyclyl, optionally substituted by one or more of C 1-6  alkyl, halogen, C 1-6  haloalkyl, —OR 18 , —SR 18 —NO 2 , CN, —NR 18 R 18 , —NR 18 COR 18 , —NR 18 CONR 18 R 18 , —NRCO 2 R 18 , —CO 2 R 18 , —COR 18 , —CONR 18   2 , —SO 2 R 18 , —SONR 18   2 , —SOR 18 , —SO 2 NR 18 R 18 , —NR 18 SO 2 R 18 ; wherein the C 1-12  alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 18 )—, —S—, —SO—, —SO 2 —, wherein each R 18  may be the same or different and is defined below; wherein R 18  is hydrogen, C 1-6  alkyl, C 1-6  haloalkyl.  
     
     
         19 . A method of  claim 1 , wherein the compound has the following formula:  
       
         
           
           
               
               
           
         
         wherein ring A is an optionally substituted benzene ring, X is —O—, —N═, —NR 3 — or —CHR 3 —, R 2  is an acyl group, an optionally esterified or thioesterified carboxyl group, and optionally substituted carbamoyl group or an optionally substituted amino group and the line, a broken line shows a single bond or a double bond, and R 1  is a hydrogen atom, optionally substituted hydrocarbon group, and optionally substituted heterocyclic group and the like.  
       
     
     
         20 . A method of  claim 1 , wherein the compound has the following formula:  
       
         
           
           
               
               
           
         
         wherein each of Ar a  and Ar b  is an aromatic group optionally having substituents, Ar a  and Ar b  optionally form a condensed cyclic group together with the adjacent carbon atom; ring B a  is a nitrogen-containing heterocycle optionally having substituents; X a  and Y a  are the same or different and each is (1) a bond, (2) an oxygen atom, (3) S(O) p  (wherein p is an integer of 0 to 2), (4) NR d  (wherein R d  is a hydrogen atom or a lower alkyl group) or (5) a divalent linear lower hydrocarbon group optionally having substituents and containing 1 to 3 hetero atom(s); ring A a  is a 5-membered ring optionally having substituents; R a  and R b  are the same or different and each is (1) a hydrogen atom, (2) a halogen atom, (3) a hydrocarbon group optionally having substituents, (4) an acyl group or (5) a hydroxy group optionally having a substituent; R c  is (1) a hydrogen atom, (2) a hydroxy group optionally substituted by a lower alkyl group or (3) a carboxyl group.