Fused pyrimidine-based hydroxamate derivatives

Abstract

The present invention relates to fused pyrimidine-based hydroxamate compounds of formula (I), comprising a hydroxamate group, that are inhibitors of hiStone deacetylase (HDAC) and kinases. More particularly, the present invention relates to hydroxamate substituted purine or 5H-pyrrolo[3,2-d]pyrimidine derivatives, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of disorders/conditions/diseases involving, relating to or associated with enzymes having histone deacetylase, non-histone deacetylase and kinase activities/functions and/or via unspecified/multi-targeted mechanisms.

1 .- 45 . (canceled) 
     
     
         46 . A method of inhibiting HDAC and/or PI3K in a cell comprising administering to a cell a compound of Formula (I), 
       
         
           
           
               
               
           
         
         wherein X, Y and Z are independently selected from N, CHR 3  or CR 3 , wherein at least one of X, Y or Z is N; 
            is a single or double bond, as valency allows; 
         R 1  and R 2  are independently selected from the group consisting of a bond, halogen, optionally substituted alkyl, optionally substituted amino, optionally substituted alkyloxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; 
         R 3  and R 4  are independently selected from the group consisting of a bond, hydrogen, halogen, optionally substituted alkyl, optionally substituted amino, optionally substituted alkyloxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; 
         at least one of R 1 , R 2 , R 3  or R 4  is further independently substituted by an hydroxamate group -L 1 -R 5 -L 2 -R 6 -L 3 -CON(R a )OR b , wherein;
 R a  and R b  are independently selected from the group consisting of a bond, hydrogen, optionally substituted alkyl, optionally substituted acyl and optionally substituted amino acid residue; 
 L 1 , L 2  and L 3  are independently selected from the group consisting of a bond, optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl; 
 R 5  and R 6  are independently selected from the group consisting of a bond, O, S, NR c , S(O) n , optionally substituted amide, optionally substituted urea, optionally substituted carbonylurea, optionally substituted thiourea, optionally substituted sulfonamide, optionally substituted aminosulfonamide, optionally substituted sulfonylurea, optionally substituted oxime, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; wherein; 
 R c  is independently selected from the group consisting of a bond, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted acyl; and 
 n is an integer from 0 to 2; 
 
         or a pharmaceutically acceptable form or prodrug thereof. 
       
     
     
         47 . The method according to  claim 46 , wherein the inhibition of HDAC and/or PI3K further comprises the inhibition of cell proliferation or reprogramming cells to induce pluripotent stem cells (iPS cells), wherein the cell is in vitro or the cell is from tissue of a subject or the cell is in a subject. 
     
     
         48 . (canceled) 
     
     
         49 . (canceled) 
     
     
         50 . The method according to  claim 47 , wherein the cell is from a cell line, wherein the cell line is an immortalized cell line, a genetically modified cell line or a primary cell line, or is selected from the group consisting of MV4-11, MOLT-4, PC-3, MCF-7, SUP-B15, HL-60, K-562, RPMI-8226, Daudi, Raji, Ramos, Pfeiffer, A431, ACHN, A549, COLO 205, HCT116, HEL92.1.7, NCI-H522, A375, NCI-H460, BxPC-3, PANC-1, SK-OV-3, U87MG, U138MG, HpeG2, SK-HEP1, HuH-7, HCCLM3, PLC/PRF/5, HeLa, BT 474, MDA-MB-231, MDA-MB-436 and MDA-MB-468. 
     
     
         51 .- 54 . (canceled) 
     
     
         55 . A method of treating a HDAC- and/or PI3K-related disorder comprising administering to a subject in need of treatment a compound of Formula (I), 
       
         
           
           
               
               
           
         
         wherein X, Y and Z are independently selected from N, CHR 3  or CR 3 , wherein at least one of X, Y or Z is N; 
            is a single or double bond, as valency allows; 
         R 1  and R 2  are independently selected from the group consisting of a bond, halogen, optionally substituted alkyl, optionally substituted amino, optionally substituted alkyloxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; 
         R 3  and R 4  are independently selected from the group consisting of a bond, hydrogen, halogen, optionally substituted alkyl, optionally substituted amino, optionally substituted alkyloxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; 
         at least one of R 1 , R 2 , R 3  or R 4  is further independently substituted by an hydroxamate group -L 1 -R 5 -L 2 -R 6 -L 3 -CON(R a )OR b , wherein;
 R a  and R b  are independently selected from the group consisting of a bond, hydrogen, optionally substituted alkyl, optionally substituted acyl and optionally substituted amino acid residue; 
 L 1 , L 2  and L 3  are independently selected from the group consisting of a bond, optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl; 
 R 5  and R 6  are independently selected from the group consisting of a bond, O, S, NR c , S(O) n , optionally substituted amide, optionally substituted urea, optionally substituted carbonylurea, optionally substituted thiourea, optionally substituted sulfonamide, optionally substituted aminosulfonamide, optionally substituted sulfonylurea, optionally substituted oxime, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; wherein; 
 R c  is independently selected from the group consisting of a bond, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted acyl; and 
 n is an integer from 0 to 2, 
 
         or a pharmaceutically acceptable form or prodrug thereof, or a composition comprising a compound of Formula (I), or a pharmaceutically acceptable form or prodrug thereof, and a pharmaceutically acceptable excipient. 
       
     
     
         56 . (canceled) 
     
     
         57 . The method according to  claim 55 , wherein the disorder is cancer, angiogenic disorder or pathological angiogenesis, fibrosis, inflammatory conditions, asthma, neurological disorders, neurodegenerative disorders, muscle degenerative disorders, autoimmune disorders, disorders of the blood or disorders of the bone marrow, or is lymphoma, cutaneous T-cell lymphoma, follicular lymphoma, or Hodgkin lymphoma, cervical cancer, ovarian cancer, breast cancer, lung cancer, prostate cancer, colorectal cancer, sarcoma, hepatocellular carcinoma, leukemia or myeloma, retinal angiogenic disease, liver fibrosis, kidney fibrosis, Alzheimer's disease or Huntington's disease, spinal muscular atrophy, HIV/AIDS, polycythemia vera or essential thrombocythemia or myelofibrosis. 
     
     
         58 . (canceled) 
     
     
         59 . (canceled) 
     
     
         60 . A method of modulating the self-renewal or differentiation of stem-cells comprising administering to a subject in need of treatment a compound of Formula (I), 
       
         
           
           
               
               
           
         
         wherein X, Y and Z are independently selected from N, CHR 3  or CR 3 , wherein at least one of X, Y or Z is N; 
            is a single or double bond, as valency allows; 
         R 1  and R 2  are independently selected from the group consisting of a bond, halogen, optionally substituted alkyl, optionally substituted amino, optionally substituted alkyloxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; 
         R 3  and R 4  are independently selected from the group consisting of a bond, hydrogen, halogen, optionally substituted alkyl, optionally substituted amino, optionally substituted alkyloxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; 
         at least one of R 1 , R 2 , R 3  or R 4  is further independently substituted by an hydroxamate group -L 1 -R 5 -L 2 -R 6 -L 3 -CON(R a )OR b , wherein;
 R a  and R b  are independently selected from the group consisting of a bond, hydrogen, optionally substituted alkyl, optionally substituted acyl and optionally substituted amino acid residue; 
 L 1 , L 2  and L 3  are independently selected from the group consisting of a bond, optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl; 
 R 5  and R 6  are independently selected from the group consisting of a bond, O, S, NR c , S(O) n , optionally substituted amide, optionally substituted urea, optionally substituted carbonylurea, optionally substituted thiourea, optionally substituted sulfonamide, optionally substituted aminosulfonamide, optionally substituted sulfonylurea, optionally substituted oxime, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; wherein; 
 R c  is independently selected from the group consisting of a bond, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted acyl; and 
 n is an integer from 0 to 2; 
 
         or a pharmaceutically acceptable form or prodrug thereof, or a composition comprising a compound of Formula (I), or a pharmaceutically acceptable form or prodrug thereof, and a pharmaceutically acceptable excipient. 
       
     
     
         61 .- 71 . (canceled)