Inhibitors of the fibroblast growth factor receptor

Abstract

Described herein are inhibitors of FGFR, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions to inhibit the activity of tyrosine kinases.

We claim: 
     
         1 .- 25 . (canceled) 
     
     
         26 . An inhibited FGFR-4 protein comprising an irreversible inhibitor having a covalent bond to a cysteine (Cys) residue of FGFR-4. 
     
     
         27 . The inhibited protein of  claim 26 , wherein the covalent bond is formed between a portion of a warhead moiety on the inhibitor and a portion of a cysteine residue of FGFR-4. 
     
     
         28 . The inhibited protein of  claim 26 , wherein the warhead moiety comprises an acrylamide. 
     
     
         29 . The inhibited protein of  claim 26 , wherein the inhibitor has a covalent bond to Cys 552 of the FGFR-4. 
     
     
         30 . The inhibited FGFR-4 protein of  claim 26 , wherein the inhibitor does not form a covalent bond with FGFR-1, FGFR-2, and/or FGFR-3. 
     
     
         31 . An irreversible inhibitor of FGFR-4. 
     
     
         32 . The irreversible inhibitor of  claim 31 , wherein the inhibitor forms a covalent bond with an amino acid residue of FGFR-4. 
     
     
         33 . The irreversible inhibitor of  claim 31 , wherein the inhibitor forms a covalent bond with a cysteine (Cys) residue of FGFR-4. 
     
     
         34 . The irreversible inhibitor of  claim 31 , wherein the inhibitor forms a covalent bond with Cys 552 of FGFR-4. 
     
     
         35 . The irreversible inhibitor of  claim 31 , wherein the inhibitor comprises a warhead. 
     
     
         36 . The irreversible inhibitor of  claim 35 , wherein the warhead forms a covalent bond with a portion of an amino acid of FGFR-4. 
     
     
         37 . The irreversible inhibitor of  claim 36 , wherein the amino acid is a cysteine (Cys) residue. 
     
     
         38 . The irreversible inhibitor of  claim 36 , wherein the amino acid is Cys552 of FGFR-4. 
     
     
         39 . The irreversible inhibitor of  claim 35 , wherein the warhead comprises an acrylamide. 
     
     
         40 . A covalent inhibitor of FGFR-4. 
     
     
         41 . The covalent inhibitor of  claim 40 , wherein the covalent inhibitor forms a covalent bond with an amino acid of FGFR-4. 
     
     
         42 . The covalent inhibitor of  claim 40 , wherein the inhibitor forms a covalent bond with a cysteine (Cys) residue of FGFR-4. 
     
     
         43 . The covalent inhibitor of  claim 40 , wherein the inhibitor forms a covalent bond with Cys 552 of FGFR-4. 
     
     
         44 . The covalent inhibitor of  claim 40 , wherein the inhibitor comprises a warhead. 
     
     
         45 . The covalent inhibitor of  claim 44 , wherein the warhead forms a covalent bond with a portion of an amino acid of FGFR-4. 
     
     
         46 . The covalent inhibitor of  claim 45 , wherein the amino acid is a cysteine (Cys). 
     
     
         47 . The covalent inhibitor of  claim 45 , wherein the amino acid is Cys552. 
     
     
         48 . The covalent inhibitor of  claim 44 , wherein the warhead comprises an acrylamide. 
     
     
         49 . The covalent inhibitor of  claim 40 , wherein the inhibitor does not form a covalent bond with FGFR-1, FGFR-2, and/or FGFR-3. 
     
     
         50 . A compound that inhibits FGFR-4 activity more potently, when measured in a biochemical assay, than it inhibits FGFR-1 activity, wherein the compound has a molecular weight of less than 1500 daltons. 
     
     
         51 . The compound of  claim 50 , wherein the compound inhibits FGFR-4 activity at least 2 times more potently, when measured in a biochemical assay, than it inhibits FGFR-1 activity. 
     
     
         52 . The compound of  claim 50 , wherein the compound inhibits FGFR-4 activity at least 5 times more potently, when measured in a biochemical assay, than it inhibits FGFR-1 activity. 
     
     
         53 . The compound of  claim 50 , wherein the compound inhibits FGFR-4 activity at least 10 times more potently, when measured in a biochemical assay, than it inhibits FGFR-1 activity. 
     
     
         54 . The compound of  claim 50 , wherein the compound inhibits FGFR-4 activity at least 25 times more potently, when measured in a biochemical assay, than it inhibits FGFR-1 activity. 
     
     
         55 . The compound of  claim 50 , wherein the compound inhibits FGFR-4 activity at least 50 times more potently, when measured in a biochemical assay, than it inhibits FGFR-1 activity. 
     
     
         56 . The compound of  claim 50 , wherein the compound inhibits FGFR-4 activity at least 100 times more potently, when measured in a biochemical assay, than it inhibits FGFR-1 activity. 
     
     
         57 . The compound of  claim 50 , wherein the compound forms a covalent bond to FGFR-4. 
     
     
         58 . The compound of  claim 50 , wherein the compound forms a covalent bond with Cys 522 of FGFR-4.