N-[4-(1H-PYRAZOLO[3,4-b]PYRAZIN-6-YL)-PHENYL]-SULFONAMIDES AND THEIR USE AS PHARMACEUTICALS

Abstract

The present invention relates to N-[4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-sulfonamides of the formula I, wherein Ar, R1, R2 and n have the meanings indicated in the claims. The compounds of the formula I are valuable pharmacologically active compounds which modulate protein kinase activity, specifically the activity of serum and glucocorticoid regulated kinase (SGK), in particular of serum and glucocorticoid regulated kinase isoform 1 (SGK-1, SGK1), and are suitable for the treatment of diseases in which SGK activity is inappropriate, for example degenerative joint disorders or inflammatory processes such as osteoarthritis or rheumatism. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use as pharmaceuticals, and pharmaceutical compositions comprising them.

1 . A method of treating a disease selected from the group consisting of a degenerative joint disorder, diabetes, a cardiovascular disease, fibrosis, an inflammatory process, a pain, a tumor, and a cerebral infarction in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein 
         Ar is selected from the series consisting of phenyl and a 5-membered or 6-membered monocyclic aromatic heterocycle comprising 1, 2 or 3 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur and bonded via a ring carbon atom, which are all unsubstituted or substituted by one or more identical or different substituents R10; 
         n is selected from the series consisting of 0, 1 and 2; 
         R1 is selected from the series consisting of hydrogen, —N(R11)-R12, —N(R13)-C(O)—R14, —N(R13)-S(O) 2 —R15, —N(R13)-C(O)—NH—R14, —C(O)—N(R16)-R17, —CN, (C 1 -C 4 )-alkyl and —(C 1 -C 4 )-alkyl-O—R18; 
         R2 is selected from the series consisting of halogen, (C 1 -C 4 )-alkyl, —O—(C 1 -C 4 )-alkyl and —CN; 
         R10 is selected from the series consisting of halogen, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, —(C 1 -C 4 )-alkyl-(C 3 -C 7 )-cycloalkyl, —O—(C 1 -C 4 )-alkyl, —O—(C 3 -C 7 )-cycloalkyl, —O—(C 1 -C 4 )-alkyl-(C 3 -C 7 )-cycloalkyl, —N(R19)-R20, —N(R21)-N(R19)-R20, —N(R21)-C(O)—R22, —NO 2 , —C(O)—N(R23)-R24 and —CN, 
         and two groups R10 bonded to adjacent ring carbon atoms in Ar, together with the carbon atoms carrying them, can form a 5-membered to 8-membered unsaturated ring which comprises 0, 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (C 1 -C 4 )-alkyl, —O—(C 1 -C 4 )-alkyl and —CN; 
         R11 and R12 are independently of one another selected from the series consisting of hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl and —(C 1 -C 4 )-alkyl-(C 3 -C 7 )-cycloalkyl, 
         or R11 and R12, together with the nitrogen atom carrying them, form a monocyclic, 4-membered to 7-membered, saturated heterocycle which, in addition to the nitrogen atom carrying R11 and R12, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl; 
         R13 is selected from the series consisting of hydrogen, (C 1 -C 4 )-alkyl and (C 3 -C 7 )-cycloalkyl; 
         R14 and R15 are independently of one another selected from the series consisting of (C 1 -C 8 )-alkyl, (C 3 -C 7 )-cycloalkyl, —(C 1 -C 4 )-alkyl-(C 3 -C 7 )-cycloalkyl, phenyl, —(C 1 -C 4 )-alkyl-phenyl, Het and —(C 1 -C 4 )-alkyl-Het, wherein phenyl and Het all are unsubstituted or substituted by one or more identical or different substituents R30; 
         R16 is selected from the series consisting of hydrogen, (C 1 -C 4 )-alkyl and (C 3 -C 7 )-cycloalkyl; 
         R17 is selected from the series consisting of hydrogen, (C 1 -C 8 )-alkyl, (C 3 -C 7 )-cycloalkyl, —(C 1 -C 4 )-alkyl-(C 3 -C 7 )-cycloalkyl, phenyl, —(C 1 -C 4 )-alkyl-phenyl, Het and —(C 1 -C 4 )-alkyl-Het, wherein phenyl and Het all are unsubstituted or substituted by one or more identical or different substituents R30, 
         or R16 and R17, together with the nitrogen atom carrying them, form a monocyclic, 4-membered to 7-membered, saturated heterocycle which, in addition to the nitrogen atom carrying R16 and R17, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl; 
         R18 is selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl; 
         R19 is selected from the series consisting of hydrogen, (C 1 -C 4 )-alkyl and (C 3 -C 7 )-cycloalkyl; 
         R20 is selected from the series consisting of hydrogen, (C 1 -C 8 )-alkyl, (C 3 -C 7 )-cycloalkyl, —(C 1 -C 4 )-alkyl-(C 3 -C 7 )-cycloalkyl, phenyl, —(C 1 -C 4 )-alkyl-phenyl, Het and —(C 1 -C 4 )-alkyl-Het, wherein phenyl and Het all are unsubstituted or substituted by one or more identical or different substituents R30, 
         or R19 and R20, together with the nitrogen atom carrying them, form a monocyclic, 4-membered to 7-membered, saturated heterocycle which, in addition to the nitrogen atom carrying R19 and R20, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl; 
         R21 is selected from the series consisting of hydrogen, (C 1 -C 4 )-alkyl and (C 3 -C 7 )-cycloalkyl; 
         R22 is selected from the series consisting of (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl and —(C 1 -C 4 )-alkyl-(C 3 -C 7 )-cycloalkyl; 
         R23 and R24 are independently of one another selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl; 
         R30 is selected from the series consisting of halogen, (C 1 -C 4 )-alkyl, —O—(C 1 -C 4 )-alkyl and —CN; and 
         Het is a monocyclic, 4-membered to 7-membered, saturated, partially unsaturated or aromatic heterocycle which comprises 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is bonded via a ring carbon atom; 
         wherein all cycloalkyl groups can be substituted by one or more identical substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl; 
         wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one or more fluorine substituents. 
       
     
     
         2 . The method of  claim 1 , wherein
 Ar is selected from the series consisting of phenyl and a 5-membered or 6-membered monocyclic aromatic heterocycle comprising 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur and bonded via a ring carbon atom, which are all unsubstituted or substituted by one or more identical or different substituents R10;   n is selected from the series consisting of 0, 1 and 2;   R1 is selected from the series consisting of hydrogen, —N(R11)-R12, —N(R13)-C(O)—R14, —N(R13)-S(O) 2 —R15, —N(R13)-C(O)—NH—R14, (C 1 -C 4 )-alkyl and —(C 1 -C 4 )-alkyl-O—R18;   R2 is selected from the series consisting of halogen, (C 1 -C 4 )-alkyl and —CN;   R10 is selected from the series consisting of halogen, (C 1 -C 4 )-alkyl, —O—(C 1 -C 4 )-alkyl, —N(R19)-R20, —N(R21)-N(R19)-R20, —N(R21)-C(O)—R22, —NO 2 , —C(O)—N(R23)-R24 and —CN,   and two groups R10 bonded to adjacent ring carbon atoms in Ar, together with the carbon atoms carrying them, can form a 5-membered to 7-membered unsaturated ring which comprises 0, 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (C 1 -C 4 )-alkyl and —CN;   R11 and R12 are independently of one another selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl,   or R11 and R12, together with the nitrogen atom carrying them, form a monocyclic, 4-membered to 6-membered, saturated heterocycle which, in addition to the nitrogen atom carrying R11 and R12, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl;   R13 is selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;   R14 and R15 are independently of one another selected from the series consisting of (C3-C7)-cycloalkyl, phenyl, —(C 1 -C 4 )-alkyl-phenyl, Het and —(C 1 -C 4 )-alkyl-Het, wherein phenyl and Het all are unsubstituted or substituted by one or more identical or different substituents R30;   R18 is selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;   R19 is selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;   R20 is selected from the series consisting of hydrogen, (C 1 -C 8 )-alkyl, (C 3 -C 7 )-cycloalkyl and —(C 1 -C 4 )-alkyl-(C 3 -C 7 )-cycloalkyl;   or R19 and R20, together with the nitrogen atom carrying them, form a monocyclic, 4-membered to 6-membered, saturated heterocycle which, in addition to the nitrogen atom carrying R19 and R20, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl;   R21 is selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;   R22 is selected from the series consisting of (C 1 -C 4 )-alkyl and (C 3 -C 7 )-cycloalkyl;   R23 and R24 are independently of one another selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;   R30 is selected from the series consisting of halogen, (C 1 -C 4 )-alkyl and —CN; and   Het is a monocyclic, 4-membered to 7-membered, saturated, partially unsaturated or aromatic heterocycle which comprises 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is bonded via a ring carbon atom;   wherein all cycloalkyl groups can be substituted by one or more identical substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl;   wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one or more fluorine substituents.   
     
     
         3 . The method of  claim 1 , wherein
 Ar is selected from the series consisting of phenyl and a 5-membered or 6-membered monocyclic aromatic heterocycle comprising 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur and bonded via a ring carbon atom, which are all unsubstituted or substituted by one or more identical or different substituents R10;   n is selected from the series consisting of 0 and 1;   R1 is selected from the series consisting of hydrogen, —N(R11)-R12, —N(R13)-C(O)—R14, —N(R13)-S(O) 2 —R15, —N(R13)-C(O)—NH—R14 and (C 1 -C 4 )-alkyl;   R2 is selected from the series consisting of halogen and (C 1 -C 4 )-alkyl;   R10 is selected from the series consisting of halogen, (C 1 -C 4 )-alkyl, —O—(C 1 -C 4 )-alkyl, —N(R19)-R20, —N(R21)-N(R19)-R20, —N(R21)-C(O)—R22, —NO 2  and —CN,   and two groups R10 bonded to adjacent ring carbon atoms in Ar, together with the carbon atoms carrying them, can form a 5-membered to 7-membered unsaturated ring which comprises 0, 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen and (C 1 -C 4 )-alkyl;   R11 and R12 are independently of one another selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl,   or R11 and R12, together with the nitrogen atom carrying them, form a monocyclic, 5-membered or 6-membered, saturated heterocycle which, in addition to the nitrogen atom carrying R11 and R12, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl;   R13 is selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;   R14 and R15 are independently of one another selected from the series consisting of (C 3 -C 7 )-cycloalkyl, phenyl, —(C 1 -C 4 )-alkyl-phenyl, Het and —(C 1 -C 4 )-alkyl-Het, wherein phenyl and Het all are unsubstituted or substituted by one or more identical or different substituents R30;   R19 is selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;   R20 is selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;   or R19 and R20, together with the nitrogen atom carrying them, form a monocyclic, 4-membered to 6-membered, saturated heterocycle which, in addition to the nitrogen atom carrying R19 and R20, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl;   R21 is selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;   R22 is selected from the series consisting of (C 1 -C 4 )-alkyl;   R30 is selected from the series consisting of halogen, (C 1 -C 4 )-alkyl and —CN; and   Het is a monocyclic, 5-membered or 6-membered, saturated, partially unsaturated or aromatic heterocycle which comprises 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is bonded via a ring carbon atom;   wherein all cycloalkyl groups can be substituted by one or more identical substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl;   wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one or more fluorine substituents.   
     
     
         4 . The method of  claim 1 , wherein
 Ar is phenyl which is unsubstituted or substituted by one or more identical or different substituents R10;   n is selected from the series consisting of 0 and 1;   R1 is selected from the series consisting of hydrogen, —N(R11)-R12, —N(R13)-C(O)—R14, —N(R13)-S(O) 2 —R15, —N(R13)-C(O)—NH—R14 and (C 1 -C 4 )-alkyl;   R2 is selected from the series consisting of halogen and (C 1 -C 4 )-alkyl;   R10 is selected from the series consisting of halogen, (C 1 -C 4 )-alkyl, —O—(C 1 -C 4 )-alkyl, —N(R19)-R20, —N(R21)-N(R19)-R20, —N(R21)-C(O)—R22, —NO 2  and —CN,   and two groups R10 bonded to adjacent ring carbon atoms in Ar, together with the carbon atoms carrying them, can form a 5-membered to 7-membered unsaturated ring which comprises 0, 1 or 2 oxygen atoms as ring heteroatoms, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen and (C 1 -C 4 )-alkyl;   R11 and R12 are independently of one another selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;   R13 is selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;   R14 and R15 are independently of one another selected from the series consisting of (C 3 -C 7 )-cycloalkyl, phenyl, —(C 1 -C 4 )-alkyl-phenyl, Het and —(C 1 -C 4 )-alkyl-Het, wherein phenyl and Het all are unsubstituted or substituted by one or more identical or different substituents R30;   R19 is selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;   R20 is selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;   R21 is selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;   R22 is (C 1 -C 4 )-alkyl;   R30 is selected from the series consisting of halogen and (C 1 -C 4 )-alkyl; and   Het is a monocyclic, 5-membered or 6-membered, saturated, partially unsaturated or aromatic heterocycle which comprises 1 ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is bonded via a ring carbon atom;   wherein all cycloalkyl groups can be substituted by one or more identical substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl;   wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one or more fluorine substituents.   
     
     
         5 . The method of  claim 1 , wherein
 Ar is selected from the series consisting of 2,3-dichloro-phenyl, 2,5-dichloro-phenyl, 5-chloro-2-hydrazino-phenyl, 5-chloro-2-cyano-phenyl, 2-cyano-5-methyl-phenyl, 2-fluoro-5-methyl-phenyl, 2-chloro-5-methoxy-phenyl, 2,5-dichloro-thiophen-3-yl, 8-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, 5-chloro-1,3-dimethyl-pyrazol-4-yl, naphthalen-1-yl, 2,4,6-trichloro-phenyl, 5-chloro-2-fluoro-phenyl, 2,4,5-trifluoro-phenyl, 2,4,5-trichloro-phenyl, 5-chloro-2,4-difluoro-phenyl, 2,3,4-trichloro-phenyl, 2,3,4-trifluoro-phenyl, 2-chloro-4-trifluoromethyl-phenyl, 5-cyano-2-fluoro-phenyl, 2-cyano-5-methoxy-phenyl, 2-cyano-5-fluoro-phenyl, 2-fluoro-5-methoxy-phenyl, 4-acetylamino-2-methyl-phenyl, 2-methyl-5-nitro-phenyl, and 2-nitro-4-trifluoromethyl-phenyl;   n is selected from the series consisting of 0 and 1;   R1 is selected from the series consisting of hydrogen, —N(R11)-R12, —N(R13)-C(O)—R14, —N(R13)-S(O) 2 —R15, —N(R13)-C(O)—NH—R14 and (C 1 -C 4 )-alkyl;   R2 is selected from the series consisting of halogen and (C 1 -C 4 )-alkyl;   R11 and R12 are independently of one another selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;   R13 is selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;   R14 and R15 are independently of one another selected from the series consisting of (C 3 -C 7 )-cycloalkyl, phenyl, —(C 1 -C 4 )-alkyl-phenyl, Het and —(C 1 -C 4 )-alkyl-Het, wherein phenyl and Het all are unsubstituted or substituted by one or more identical or different substituents R30;   R30 is selected from the series consisting of halogen and (C 1 -C 4 )-alkyl; and   Het is a monocyclic, 5-membered or 6-membered, saturated, partially unsaturated or aromatic heterocycle which comprises 1 ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is bonded via a ring carbon atom;   wherein all cycloalkyl groups can be substituted by one or more identical substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl;   wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one or more fluorine substituents.   
     
     
         6 . The method of  claim 1 , wherein
 Ar is selected from the series consisting of 2,3-dichloro-phenyl, 2,5-dichloro-phenyl, 5-chloro-2-hydrazino-phenyl, 5-chloro-2-cyano-phenyl, 2-cyano-5-methyl-phenyl, 2-fluoro-5-methyl-phenyl, 2-chloro-5-methoxy-phenyl, 2,5-dichloro-thiophen-3-yl, 8-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, 5-chloro-1,3-dimethyl-pyrazol-4-yl, naphthalen-1-yl, 5-cyano-2-fluoro-phenyl, 2-cyano-5-methoxy-phenyl, 2-cyano-5-fluoro-phenyl, 2-fluoro-5-methoxy-phenyl, 4-acetylamino-2-methyl-phenyl, 2-methyl-5-nitro-phenyl, and 2-nitro-4-trifluoromethyl-phenyl;   n is selected from the series consisting of 0 and 1;   R1 is selected from the series consisting of hydrogen, —N(R11)-R12, —N(R13)-C(O)—R14, —N(R13)-S(O) 2 —R15, —N(R13)-C(O)—NH—R14 and (C 1 -C 4 )-alkyl;   R2 is selected from the series consisting of halogen and (C 1 -C 4 )-alkyl;   R11 and R12 are independently of one another selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;   R13 is selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;   R14 and R15 are independently of one another selected from the series consisting of (C 3 -C 7 )-cycloalkyl, phenyl, —(C 1 -C 4 )-alkyl-phenyl, Het and —(C 1 -C 4 )-alkyl-Het, wherein phenyl and Het all are unsubstituted or substituted by one or more identical or different substituents R30;   R30 is selected from the series consisting of halogen and (C 1 -C 4 )-alkyl; and   Het is a monocyclic, 5-membered or 6-membered, saturated, partially unsaturated or aromatic heterocycle which comprises 1 ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is bonded via a ring carbon atom;   wherein all cycloalkyl groups can be substituted by one or more identical substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl;   wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one or more fluorine substituents.   
     
     
         7 . The method of  claim 1 , wherein R1 is selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl. 
     
     
         8 . The method of  claim 1 , wherein R1 is selected from the series consisting of —N(R11)-R12, —N(R13)-C(O)—R14, —N(R13)-S(O) 2 —R15 and —N(R13)-C(O)—NH—R14. 
     
     
         9 . The method of  claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, is selected from the series consisting of:
 N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,3-dichloro-benzenesulfonamide,   2,5-dichloro-N-[4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,   2,5-dichloro-N-[2-fluoro-4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,   2,3-dichloro-N-[2-fluoro-4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,5-dichloro-benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-2-hydrazino-benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-fluoro-phenyl]-5-chloro-2-fluoro-benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-fluoro-phenyl]-2,5-dichloro-benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-fluoro-phenyl]-2,3-dichloro-benzenesulfonamide,   2,5-dichloro-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,   2,3-dichloro-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,   5-chloro-2-fluoro-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,   5-chloro-2-cyano-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,   2-cyano-5-methyl-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,   2-fluoro-5-methyl-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,   2-chloro-5-methoxy-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-cyano-5-methyl-benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-chloro-5-methoxy-benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-fluoro-5-methyl-benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-5-chloro-2-cyano-benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,5-dichloro-thiophene-3-sulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-8-chloro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-7-sulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-1,3-dimethyl-pyrazole-4-sulfonamide,   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]cyclopropanecarboxamide,   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]tetrahydropyran-4-carboxamide,   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]piperidine-4-carboxamide,   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]cyclopentanecarboxamide,   2,3-dichloro-N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]benzamide,   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]cyclohexanecarboxamide,   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]-2-phenyl-acetamide,   N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]thiophene-3-carboxamide,   4-chloro-N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]benzamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]naphthalene-1-sulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,4,6-trichloro-benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-2-fluoro-benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,4,5-trifluoro-benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,4,5-trichloro-benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-2,4-difluoro-benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,3,4-trichloro-benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2,3,4-trifluoro-benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide,   5-chloro-N-[4-[3-[(5-chloro-2,4-difluoro-phenyl)sulfonylamino]-1H-pyrazolo[3,4-b]pyrazin-6-yl]phenyl]-2,4-difluoro-benzenesulfonamide,   5-chloro-N-[4-[3-[(5-chloro-1,3-dimethyl-pyrazol-4-yl)sulfonylamino]-1H-pyrazolo[3,4-b]pyrazin-6-yl]phenyl]-1,3-dimethyl-pyrazole-4-sulfonamide,   2,4,5-trifluoro-N-[4-[3-[(2,4,5-trifluorophenyl)sulfonylamino]-1H-pyrazolo[3,4-b]pyrazin-6-yl]phenyl]benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-5-cyano-2-fluoro-benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-cyano-5-methoxy-benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-cyano-5-fluoro-benzenesulfonamide,   N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-2-fluoro-5-methoxy-benzenesulfonamide,   1-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]-3-(3-pyridyl)urea,   1-(4-chlorophenyl)-3-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]urea,   2-chloro-N-[4-[3-[[2-chloro-4-trifluoromethyl-phenyl]sulfonylamino]-1H-pyrazolo[3,4-b]pyrazin-6-yl]phenyl]-4-trifluoromethyl-benzenesulfonamide,   N-[6-[4-(1-naphthylsulfonylamino)phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]naphthalene-1-sulfonamide,   2,4,6-trichloro-N-[4-[3-[(2,4,6-trichlorophenyl)sulfonylamino]-1H-pyrazolo[3,4-b]pyrazin-6-yl]phenyl]benzenesulfonamide,   N-[3-methyl-4-[[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]sulfamoyl]phenyl]acetamide,   2-methyl-N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-nitro-benzenesulfonamide, and   N-[4-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-nitro-4-trifluoromethyl-benzenesulfonamide.   
     
     
         10 - 14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein R1 is —N(R11)-R12, where R11 and R12 are hydrogen. 
     
     
         16 . The method of  claim 1 , wherein the disease is a cardiovascular disease. 
     
     
         17 . The method of  claim 1 , wherein the disease is a tumor. 
     
     
         18 . The method of  claim 17 , wherein the treatment of tumor comprises inhibiting tumor growth or tumor metastases.