Benzotriazine Inhibitors of Kinases

Abstract

The invention provides benzotriazine compounds having formula (I). The benzotriazine compounds of the invention are capable of inhibiting kinases, such members of the Src kinase family, and various other specific receptor and non-receptor kinases.

1 . (canceled) 
   
   
       2 . The method of  claim 21 , wherein the compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       3 . The method of  claim 21 , wherein the compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       4 . The method of  claim 21 , wherein the compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       5 . (canceled) 
   
   
       6 . The method of  claim 21 , wherein the compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       7 . The method of  claim 21 , wherein the compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       8 . The method of  claim 21 , wherein the compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       9 . (canceled) 
   
   
       10 . The method of  claim 21 , wherein the compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       11 . The method of  claim 21 , wherein the compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       12 . (canceled) 
   
   
       13 . The method of  claim 21 , wherein the compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       14 . The method of  claim 21 , wherein the compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       15 . The method of  claim 21 , wherein the compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       16 . The method of  claim 21 , wherein the compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       17 . The method of  claim 21 , wherein the compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       18 . The method of  claim 21 , wherein the compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       19 . The method of  claim 21 , wherein the compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       20 . The method of  claim 21 , wherein the compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       21 . A method for treating a disorder associated with compromised vasculostasis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by: 
     
       
         
         
             
             
         
       
       wherein each of A is independently selected from a group consisting of CH, N, NH, O, S, and a part of a ring fusion to form a second ring, where the second ring is an aromatic, a heteroaromatic, a bicyclic aromatic, a bicyclic aromatic heterocyclic ring, or a bicyclic with only the first ring being aromatic or heteroaromatic; 
       each of B is independently selected from a group consisting of CH, N, NH, O, S, and a part of a ring fusion to form a second ring, where the second ring is an aromatic, a heteroaromatic, a bicyclic aromatic, a bicyclic aromatic heterocyclic ring, or a bicyclic with only the first ring being aromatic or heteroaromatic; 
       R 0  is selected from a group consisting of H and lower alkyl; 
       L is selected from a group consisting of a bond, and a substituted or unsubstituted alkyl, alkenyl, or alkynyl linking moiety; 
       R 1  is selected from a group consisting of C(R′) 3 , OR′, N(R′) 2 , NR′C(O)R′, NR′C(O)O(R′), NR′C(O)N(R′) 2 , SR′, C(O)(O)R′, C(O), C(O)N(R′) 2 , SO 3 R′, OSO 2 R′, SO 2 R′, SOR′, S(O)N(R′) 2 , OS(O)(O)N(R′) 2 , S(O)(O)N(R′) 2 , PO 4 R′, OPO 2 R′, PO 3 R′, PO 2 R′, and a 3-6 membered heterocycle with one or more heterocyclic atoms with each heteroatom independently being capable of carrying any R′ group on it, wherein R′ is selected from a group consisting of hydrogen, lower alkyl, alkyl-hydroxyl, thiol-alkyl, alkyl-thiol, aminoalkyl, alkylamino, branched alkyl, branched alkyl hydroxyl, branched thio-alkyl, branched alkyl-thiol, branched aminoalkyl branched alkylamino, and a closed 3-6 membered carbocycle or heterocycle, with each heteroatom in the 3-6 membered heterocycle being capable of carrying any R′ group on it, and wherein each R′ is independent in case there is more than one R′; 
       R 2  is a substituent situated at position 5, 6 or 8 of the ring, wherein R 2  is selected from a group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, iso-pentyl, phenyl, substituted phenyl, halogen, branched or unbranched alkylamino, branched or unbranched aminoalkyl, branched or unbranched alkyloxo, branched or unbranched oxyalkyl, branched or unbranched thioalkyl, branched or unbranched alkylthiol CF 3 , sulfonamido, substituted sulfonamido, sulfonate, sulfonate ester, phosphate, phosphate ester, phosphonate, phosphonate ester, carboxo, amido, ureido, substituted carboxo, substituted amido, substituted ureido, or a 3-6 membered carbocycle or heterocycle attached to positions 5, 6 or 8 directly or through group L, each heteroatom independently being capable of carrying any group R 2 , with the further proviso that either one, two or three substituents R 2  are present in the ring, each of the substituents R 2  being the same or different; 
       R 3  selected from a group consisting of hydrogen, alkyl, alkoxy, halogen, CF 3 , cyano, substituted alkyl, or hydroxyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, C(R″) 3 , OR″, N(R″) 2 , NR″C(O)R″, NR″C(O)NR″, R″, C(O)(O)R″, OC(O)R″, C(O)N(R″) 2 , C(O), OC(O)N(R″) 2 , SO 3 R″, OSO 2 R″, SO 2 R″, SOR″, PO 4 R″, OPO 2 R″, PO 3 R″, PO 2 R″, wherein R″ is hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, lower alkyl, branched lower alkyl, alkyl-hydroxyl, branched alkyl-hydroxyl, amino-alkyl, branched amino-alkyl, alkyl-amino, branched alkyl-amino, thiol-alkyl, branched thiol-alkyl, alkyl-thiol, branched thiol-alkyl, or may form a closed 3-6 membered heterocycle with one or more heterocyclic atoms, branched alkyl, branched alkyl hydroxyl, where each R″ is independent in case there is more than one R″; 
       n is an integer having the value between 1 and 5, with the further proviso that if n≧2, then each group R 3  is independent of the other groups R 3 , 
       or a pharmaceutically acceptable salt, N-oxide, or an individual diastereomer thereof. 
     
   
   
       22 . The method of  claim 21 , wherein the disorder is myocardial infarction, stroke, congestive heart failure, an ischemia or reperfusion injury, arthritis or other arthropathy, retinopathy or vitreoretinal disease, macular degeneration, vascular leakage syndrome, edema, transplant rejection, burn, or acute or adult respiratory distress syndrome (ARDS). 
   
   
       23 . The method of  claim 21 , wherein the disorder is vascular leakage syndrome (VLS). 
   
   
       24 . (canceled) 
   
   
       25 . The method of  claim 21 , wherein the disorder is a vitreoretinal disease. 
   
   
       26 . The method of  claim 21 , wherein the disorder is ARDS. 
   
   
       27 - 28 . (canceled) 
   
   
       29 . The method of  claim 21 , wherein the disorder is stroke. 
   
   
       30 . The method of  claim 21 , wherein the disorder is myocardial infarction. 
   
   
       31 . The method of  claim 21 , wherein the disorder is ischemia or reperfusion injury. 
   
   
       32 . The method of  claim 21 , wherein the disorder is arthritis. 
   
   
       33 . The method of  claim 21 , wherein the disorder is edema. 
   
   
       34 . The method of  claim 21 , wherein the disorder is transplant rejection. 
   
   
       35 . (canceled) 
   
   
       36 . The method of  claim 21 , wherein the disorder is congestive heart failure. 
   
   
       37 - 58 . (canceled) 
   
   
       59 . The method of  claim 21 , further comprising administering an anti-inflammatory agent, chemotherapeutic agent, immunomodulatory agent, therapeutic antibody, or a protein kinase inhibitor, to the subject in need of such treatment. 
   
   
       60 - 74 . (canceled) 
   
   
       75 . A method for treating a disorder associated with compromised vasculostasis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by: 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts thereof.