Heterocyclic compound as syk inhibitor and/or syk-hdac dual inhibitor

Abstract

A heterocyclic compound as a Syk inhibitor and/or a Syk-HDAC dual inhibitor, or pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, and solvates thereof are provided. Specifically, a compound of formula (I) is provided, which has dual inhibitory activity for Syk and/or Syk-HDAC.

1 . A compound of the following formula (I), or the optical isomers, pharmaceutically acceptable salts thereof: 
       
         
           
           
               
               
           
         
         wherein in the formula (I), 
         R 1  is aryl, heteroaryl or 6-membered monocyclic heterocyclyl (including saturated and unsaturated); aryl, heteroaryl or monocyclic heterocyclyl herein may be optionally and independently substituted by 1-3 substituents each independently selected from the group consisting of: halogen, C 1-4  alkyl, C 1-4  halogenated alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 3-8  cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO 2 , OR 8 , SR 8 , NR 8 R 9 , C(O)R 8 , C(O)OR 8 , C(O)NR 8 R 9 , S(O) 2 R 8  and R 7 ; 
         R 2 , R 3  and R 4  are hydrogen; 
         U is NR 5 ; where R 5  is hydrogen; 
         A is the group of formula (III): 
       
       
         
           
           
               
               
           
         
         wherein: 
         “ ” refers to the connection point of formula (III) to U of the formula (I); 
         “*” indicates a chiral center; 
         each X is independently hydrogen, halogen, C 1-4  alkyl, C 3-6  cycloalkyl, 3- to 6-membered heterocyclyl, CN, OR 8 , SR 8 , NR 8 R 9 , C(O)R 8 , C(O)OR 8 , C(O)NR 8 R 9 , or S(O) 2 R 8 ; 
         R 7  is hydrogen, —(CH 2 ) p —V—(CH 2 ) q C(O)NH(OH), —V 1 —(CH 2 ) p —V 2 —V—(CH 2 ) q C(O)NH(OH), C(O)NH(OCH 3 ), 
       
       
         
           
           
               
               
           
         
         J is O; 
         G is NR 10 ; 
         n is 0, 1, 2, or 3; 
         each R 6  is hydrogen, or two R 6  connecting to the same carbon atom form carbonyl group (═O); 
         R 8  and R 9  are each independently hydrogen, C 1-4  alkyl, C 1-4  halogenated alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 3-8  cycloalkyl, 3- to 8-membered heterocyclyl, aryl, or heteroaryl; or R 8  and R 9  together with the nitrogen atom to which they are attached form a 3- to 9-metacyclic ring comprising 1-2 N atom and 0, 1 or 2 heteroatoms selected from O or S; 
         R 10  is C 2-8  alkyl, C 1-8  haloalkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-8  cycloalkyl, 3- to 12-membered heterocyclyl (optionally comprising 1-2 heteroatoms selected from O, N, or S), aryl, heteroaryl, C(O)R 8 , C(O)OR 8 , C(O)NR 8 R 9 , S(O) 2 R 8  or (CH 2 ) p —V—(CH 2 ) q C(O)NH(OH), wherein R 8  is not hydrogen, and the R 8  in C(O)R 8  is not methyl; 
         V is a divalent group, each of p and q is independently an integer from 0 to 10, and the V is selected from the group consisting of bond, O, S, NR 11 , OC(O), OC(O)O, NHC(O), NHC(O)NH, NHC(O)O, OC(O)NH, NHS(O) 2 , C(O), C(O)O, C(O)NH, S(O), S(O) 2 , S(O) 2 NH, or NHS(O) 2 NH, CH═CH, C≡C, CR 12 R 13 , C 3-8  cycloalkyl, 3- to 12-member heterocyclyl, aryl or heteroaryl, 
       
       
         
           
           
               
               
           
         
       
       with the prerequisite that V, p and q together form a chemically stable group;
 V 1  and V 2  are divalent groups selected from the group consisting of bond, O, S, NR 11 , and C(O)NH, with the prerequisite that the group formed by V, V 1 , V 2 , p and q is chemically stable group; 
 R 11  is hydrogen, C 1-4  alkyl, C 3-8  cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, C(O)R 8  or S(O) 2 R 8 ; 
 R 12  and R 13  are each independently hydrogen, halogen, C 1-4  alkyl, C 3-6  cycloalkyl, C 2-4  alkenyl, C 2-4  alkynyl, 3- to 8-membered heterocyclic, OR 8 , SR 8 , NR 8 R 9 , CN, C(O)R 8 , C(O)OR 8 , C(O)NR 8 R 9 , OC(O)R 8 , NR 8 C(O)R 9 , or S(O) 2 R 8 , or R 12  and R 13  together with the carbon atoms to which they are attached form 3-8 membered cyclic structure containing 0, 1 or 2 heteroatoms selected from N, O, or S; 
 with the proviso that when R 1  does not comprise structural unit 
 
       
         
           
           
               
               
           
         
       
       then A is of formula (IIIa), 
       
         
           
           
               
               
           
         
         wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally and independently substituted by 1-3 substituents each independently selected from the group consisting of halogen, C 1-4  alkyl, C 1-4  halogenated alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 3-8  cycloalkyl, 3- to 8-heterocyclyl, aryl, heteroaryl, CN, NO 2 , OR 8 , SR 8 , NR 8 R 9 , C(O)R 8 , C(O)OR 8 , C(O)NR 8 R 9  or S(O) 2 R 8 ; 
         unless otherwise specified, the above aryl group is an aryl group having 6 to 12 carbon atoms; and the heteroaryl group is a 5- to 15-membered heteroaryl group. 
       
     
     
         2 . The compound of  claim 1 , or the optical isomers, pharmaceutically acceptable salts thereof, wherein R 1  is 
       
         
           
           
               
               
           
         
       
       wherein R 7  is as described in  claim 1 . 
     
     
         3 . The compound of  claim 1 , or the optical isomers, pharmaceutically acceptable salts thereof, wherein the formula (III) is a structure selected from group consisting of: 
       
         
           
           
               
               
           
         
         wherein R 10  is C 2-8  alkyl, C 1-8  halogenated alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-8  cycloalkyl, 6-membered heterocyclyl (optionally comprising 1-2 heteroatoms selected from O, N, S), aryl, heteroaryl, C(O)R 8 , C(O)OR 8 , C(O)NR 8 R 9 , S(O) 2 R 8 , wherein R 8  is selected from the group consisting of C 1-4  alkyl, C 1-4  haloalkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 3-8  cycloalkyl, 3- to 8-membered heterocyclyl, aryl, and heteroaryl; wherein R 8  in C(O)R 8  is other than methyl; or R 8  and R 9  together with the nitrogen atom to which they are attached form a 3- to 9-membered ring comprising 1-2 N atom and 0, 1 or 2 hetero atoms selected from O or S. 
       
     
     
         4 . The compound of  claim 1 , or the optical isomers, pharmaceutically acceptable salts thereof, wherein the formula (I) is selected from group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein R 10  is C 2-8  alkyl, C 1-8  haloalkyl, C 3-8  cycloalkyl, unsubstituted or C 1-4  alkyl substituted 6-membered heterocyclyl (optionally containing 1-2 heteroatoms selected from O, or N), C(O)R 8 , or S(O) 2 R 8 ; R 8  is C 1-4  alkyl or C 1-4  haloalkyl; wherein the R 8  in C(O)R 8  is other than methyl. 
     
     
         5 . The compound according to  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 . A method for treating a disease associated with Syk and/or HDAC kinase activity or expression amount, comprising the step: administrating the compound (I) of  claim 1 , or the optical isomers, pharmaceutically acceptable salts thereof to a subject in need thereof, wherein the disease is selected from the group consisting of lymphoma, lymphocytic leukemia, cutaneous T-cell lymphoma, rectal cancer, breast cancer, stomach cancer, pancreatic cancer, liver cancer, lung cancer, head and neck cancer, kidney cancer, colon cancer, ovarian cancer, prostate cancer, multiple sclerosis, immunity diseases, allergic diseases, atherosclerosis, gastrointestinal disorders, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, Alzheimer's disease, stroke and coronary artery disease, Wiskott-Aldrich syndrome, myelofibrosis, and AIDS. 
     
     
         7 . A pharmaceutical composition, comprising: (i) an effective amount of a compound of formula (I) according to  claim 1 , or the optical isomers, pharmaceutically acceptable salts thereof; and (ii) pharmaceutically acceptable carriers. 
     
     
         8 . A method for preparing the compound of  claim 1 , comprising the following steps: 
       
         
           
           
               
               
           
         
         (1) in an inert solvent, compound Ia reacts with A-NH 2  to provide compound Ib; 
         (2) in an inert solvent, compound Ib reacts with compound R 1 B(OH) 2  to obtain compounds of formula I; 
       
       
         
           
           
               
               
           
         
         
           wherein each group is defined as in  claim 1 .