Methods and compositions for raf kinase mediated diseases

Abstract

The invention features compounds, pharmaceutical compositions and methods for treating patients who have an EGFR-driven cancer of Formula (I), wherein the variables are as defined herein.

1 . A compound of the Formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 U 1  and U 2  are both N and U 3  is C—R e ; or U 3  is N, one of U 1  and U 2  is N, and the other is C—R d ; or U 3  is C—R e , one of U 1  and U 2  is N, and the other is C—R d ; 
 V 1  is O, S, NR V , CO, CH 2 , or CF 2 ; 
 R V  is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, or aryl; 
 R d  is H, halo, CN, alkyl, cycloalkyl, alkoxy, haloalkyl, alkenyl, haloalkenyl or halocycloalkyl; 
 R e  is H or NH 2 ; or, 
 R d  and R e , together with the ring atom to which each is attached, form a 5- or 6-membered ring containing one, two or three heteroatoms, independently selected from N, S and O, wherein the 5- or 6-membered ring so formed is independently substituted by R h ; 
 R h  is H, C 1-4  alkyl, or halo; 
 R g  is H, F, —P(O)(R 3A )(R 3B ), —S(O)N(R 3C )(R 3D ), —S(O) 2 R 3E , —C(O)N(R 3F )(R 3G ), —OC(O)N(R 3F )(R 3G ), —NR 3H C(O)OR 3I , a 5- or 6-membered heterocyclic ring comprising 1, 2, 3 or 4 N atoms; 
 each R 3A , R 3B , R 3C , R 3D , R 3E , R 3F , R 3G , R 3H , and R 3I  is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heteroalkyl, or R 3A  and R 3B , or R 3C  and R 3D , or R 3F  and R 3G , together with the atom to which each is attached, form an optionally substituted 5- or 6-membered heterocyclic ring; 
 R g2  is H, F, W 1 , —P(O)(R 3A )(R 3B ), —S(O)N(R 3C )(R 3D ), —S(O) 2 R 3E , —C(O)N(R 3F )(R 3G ), —OC(O)N(R 3F )(R 3G ), —NR 3H C(O)OR 3I , C 1-6  alkoxy, C 1-4  alkyl, 
 or, R g2  and R g  together with the atom to which each is attached form an optionally substituted 5- to 7-membered heterocyclic ring comprising 1-3 heteroatoms independently selected from P, N, O and S; 
 R g1  is H, F, —OR 2 , —P(O)(R 3A )(R 3B ), —S(O)N(R 3C )(R 3D ), —S(O) 2 R 3E , —C(O)N(R 3F )(R 3G ), —OC(O)N(R 3F )(R 3G ), —NR 3H C(O)OR 3I , or an optionally substituted 5- or 6-membered heterocyclic ring; 
 Ring A is: 
 
       
         
           
           
               
               
           
         
         R b2  is H, F, or an optionally substituted 5- or 6-membered heterocyclic ring containing 1, 2 or 3 N or O atoms; 
         R b4  is H, F, W 1 , C 1-6  alkoxy, C 3-6  alkenyloxy, C 3-6  cycloalkoxy, —OC(O)N(R 5A )(R 5B ), —NR 5C C(O)OR 5D , or an optionally substituted 5- or 6-membered heterocyclic ring comprising 1, 2 or 3 N or O atoms; 
         each R 5A , R 5B , R 5C , and R 5D  is independently selected from H, alkyl, alkenyl, alkynyl, and heteroalkyl, or R 5A  and R 5B , together with the atom to which each is attached, form an optionally substituted 5- or 6-membered heterocyclic ring; 
         R a1  is H, halo, W 1 , —CN, —NO 2 , —R 1 , —OR 2 , —O—NR 1 R 2 , —NR 1 R 2 , —NR 1 —NR 1 R 2 , —NR 1 —OR 2 , —C(O)YR 2 , —OC(O)YR 2 , —NR 1 C(O)YR 2 , —SC(O)YR 2 , —NR 1 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 1 )YR 2 , —YC(═N—OR 1 )YR 2 , —YC(═N—NR 1 R 2 )YR 2 , —YP(═O)(YR 1 )(YR 2 ), —S(O) r R 2 , —SO 2 NR 1 R 2 , —NR 1 SO 2 NR 1 R 2 , or 
       
       
         
           
           
               
               
           
         
         X 1  and X 2  are each independently CH or N; 
         or R a1  and R b4 , together with the atom to which each is attached, form an optionally substituted 5- or 6-membered heterocyclic ring comprising 1, 2 or 3 heteroatoms independently selected from N and O; 
         R a2  is H, halo, C 1-6  alkyl, C 2-6  alkenyl, C 3-6  cycloalkyl, C 1-6  alkoxy, C 2 -6 alkenyloxy, C 3-6  cycloalkyloxy or 4- to 7-membered heterocyclyl, wherein the alkyl, alkenyl, cycloalkyl, alkoxy, C 2 -6 alkenyloxy, cycloalkyloxy and heterocyclyl are optionally substituted with one or more halo, amino, C 1-6  alkylamino, or di-C 1-6  alkylamino groups; 
         Y is independently a bond, —O—, —S— or —NR 1 —; 
         R 1  and R 2  are independently H or R 15 ; 
         R 4  is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl; 
         W 1  is —NR 7 C(O)C(R 11 )═CR 9 R 10 , —C(O)C(R 11 )═CR 9 R 10 , —CH 2 P(O)C(R 11 )═CR 9 R 10 , —OP(O)C(R8)=CR9R10, —NR 7 S(O) 2 C(R 9 )(R 10 )(R X ), —NR 7 S(O) 2 C(R 11 )═CR 9 R 10 , —NR 7 C(O)C≡C—R 14 , —NR 7 C(O)C(R 9 )(R 10 )(R X ), 
       
       
         
           
           
               
               
           
         
         R X  is halo; 
         R 7  is H, alkyl or heteroalkyl, wherein the alkyl and heteroalkyl groups are independently optionally substituted with an amino, alkylamino or dialkylamino group; 
         R 8  is C 1-6  alkyl; 
         R 9  and R 10  are independently H, halo, —C(O)R 16 , alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclyl or heteroaryl, wherein R 9  and R 10 , if not H, are optionally substituted with one or more halo, amino, alkylamino, dialkylamino, alkoxy, cycloalkyl, heterocyclyl or heteroaryl groups, wherein said group, if not halo, is optionally substituted with one or more halo, C 1-4  alkyl, alkoxyl, halo(C 1-4 )alkyl or C 3-7  cycloalkyl groups; 
         R 11  is H, halo, —C(O)—OR 12 , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic, or heteroaryl, wherein R 11 , if not H, is optionally substituted with one or more halo, amino, alkoxyl, cycloalkyl, heterocyclic or heteroaryl groups, wherein said group, if not halo, is optionally substituted with one or more halo or alkyl, alkoxyl, cycloalkyl or heterocyclyl groups, wherein the alkyl, alkoxyl, cycloalkyl and heterocyclyl group is optionally substituted with one or more alkyl, halo or hydroxyl substituents; 
         or R 9  and R 11 , taken together with the atom to which each is attached, form a cycloalkenyl or heterocyclic ring; 
         R 12  is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic, or heteroaryl; 
         R 13  is H or C 1-4  alkyl; 
         R 14  is R T  or R W ; 
         R 15  is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, 4- to 7-membered heterocyclyl, or heteroaryl, wherein each R 15  is optionally substituted with one or more halo, cycloalkyl, heterocyclic or heteroaryl groups, wherein said cycloalkyl, heterocyclic or heteroaryl groups(s) are independently optionally substituted with one or more halo, alkyl, haloalkyl, hydroxyalkyl, amino, dialkylamino or cycloalkyl groups; 
         R 16  is OH, —O-alkyl, cycloalkyl, heterocyclyl, —NH 2 , —NH-alkyl, or —N-dialkyl wherein the alkyl, cycloalkyl or heterocyclyl moiety is optionally substituted with halo, amino, alkylamino, dialkylamino, alkyl or hydroxyl; 
         R T  is H or —CH 3 ; 
         R W  is halo; substituted methyl; or an optionally substituted group selected from (C 2-6 )alkyl, (C 1-6 )heteroalkyl, heterocyclyl, aryl and heteroaryl; wherein the substituents on the optionally substituted (C 2-6 )alkyl, (C 1-6 )heteroalkyl, heterocyclyl, aryl and heteroaryl groups are selected from halo, haloalkyl, alkoxy, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino, and in the case of an optionally substituted heterocyclyl, the optional substituents may further be selected from hydroxyl, alkyl, haloalkyl, hyroxyalkyl, alkoxyalkyl, amino, alkylamino and dialkylamino; 
         wherein 
         (a) the compound is not one of the following two compounds: 
       
       
         
           
           
               
               
           
         
         (b) at least one of R a1 , R g2 , and R b4  is W 1 ; 
         (c) the compound comprises at least one —P(O)(R 3A )(R 3B ); and 
         (d) the compound further has one or more of the following features: 
         R d  is halo(C 3-5 )cycloalkyl; 
         R a2  is halo; substituted alkyl, substituted alkoxy, or optionally substituted cycloalkyl, wherein substituents on the alkyl, alkoxy or cycloalkyl groups are selected from halo, amino and dialkylamino groups; 
         R a1  is an optionally substituted 4-membered heterocycle; 
         R a1  is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or heteroalkyl, and is substituted with one or more groups selected from halo, OH, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteroaryl; 
         R a1  is heterocyclyl or heterocyclyl-O—, wherein R a1  is substituted with one or more groups selected from —OH, halo, 4-membered heterocyclyl, substituted 4-membered heterocyclyl and R 18 , wherein R 18  is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or heteroalkyl, and R 18  is optionally substituted; 
         R a1  and R b4 , together with the atom to which each is attached, form an optionally substituted 5-membered heterocyclic ring; 
         R a2  is an optionally substituted 4- to 7-membered membered heterocycle; 
         R b4  is —NR 7 C(O)C(R 11 )═CR 9 R 10  or —NR 7 C(O)C C≡C—R W ; 
         R g1  is —OR 2 ; 
         R 9 or R 10  is cycloalkyl, —CO 2 H, —CO 2 -alkyl, —C(O)-heterocyclyl, —C(O)NH 2 , —C(O)NH-alkyl or —C(O)N-dialkyl wherein an alkyl, cycloalkyl or heterocyclyl substituent or portion of a substituent is optionally substituted with amino, alkylamino, dialkylamino, alkyl or hydroxyl; 
         one or more of R 9 , R 10  and R 11  is halo, haloalkyl, alkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl or arylalkyl wherein alkyl, heterocylic, heteroaryl or aryl substituent, or an alkyl, heterocylic, heteroaryl or aryl portion of a substituent, is optionally substituted with one or more groups selected from halo, haloalkyl, hydroxyl, hydroxyalkyl, amino, alkylamino, dialkylamino, alkyl, alkenyl, SO 2 alkyl, oxo, heterocyclyl and heterocycle substituted with one or more alkyl, amino alkylamino, dialkylamino, hydroxyl, hydroxyalkyl, SO 2 alkyl substituents; and, 
         R 9  and R 11 , taken together with the atom to which each is attached, form a cycloalkenyl or heterocyclic ring. 
       
     
     
         2 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein:
 R d  is H, halo, CN, alkyl, alkoxy, haloalkyl, alkenyl, haloalkenyl or halocycloalkyl; 
 W 1  is —NR 7 C(O)C(R 11 )═CR 9 R 10 , —C(O)C(R 11 )═CR 9 R 10 , —CH 2 P(O)C(R 11 )═CR 9 R 10 , —OP(O)(R 8 )═CR 9 R 10 , —NR 7 S(O) 2 C(R 11 )═CR 9 R 10 , —NR 7 C(O)C C≡C—R 14 , 
 
       
         
           
           
               
               
           
         
         R g  is H, —P(O)(R 3A )(R 3B ), —S(O)N(R 3C )(R 3D ), —S(O) 2 R 3E , —C(O)N(R 3F )(R 3G ), —OC(O)N(R 3F )(R 3G ), —NR 3H C(O)OR 3I , a 5- or 6-membered heterocyclic ring comprising 1, 2, 3 or 4 N atoms, wherein each of R 3A , R 3B , R 3C , R 3D , R 3E , R 3F , R 3G , R 3H , and R 3I  is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heteroalkyl, or R 3A  and R 3B , or R 3C  and R 3D , or R 3F  and R 3G , together with the atoms to which each is attached, form an optionally substituted 5- or 6-membered heterocyclic ring; and, 
         R g1  is H, F, —P(O)(R 3A )(R 3B ), —S(O)N(R 3C )(R 3D ), —S(O) 2 R 3E , —C(O)N(R 3F )(R 3G ), —OC(O)N(R 3F )(R 3G ), —NR 3H C(O)OR 3I , or an optionally substituted 5- or 6-membered heterocyclic ring; wherein the variable terms are as defined in  claim 1 . 
       
     
     
         3 . The compound of  claim 1 ,  2  or  3 , wherein said compound is described by any of Formulas (IIIa)-(IIIe), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein R a1 ; R a2 ; R b2 ; R b4 ; R g ; R g1 ; R g2 ; R d ; and R h  are as defined in  claim 1 . 
     
     
         4 . The compound of  claim 1 ,  2  or  3 , wherein said compound is described by any of Formulas (IVa)-(IVe), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein R a2 ; R b2 ; R b4 ; R g ; R g1 ; R g2 ; R d ; and R h  are as defined in  claim 1 . 
     
     
         5 . The compound of  claim 1 ,  2  or  3 , wherein said compound is described by any of Formulas (Va)-(Ve), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein R a1 ; R a2 ; R b2 ; R b4 ; R g ; R g1 ; R g2 ; R d ; and R h  are as defined in  claim 1 . 
     
     
         6 . The compound of  claim 1 ,  2  or  3 , wherein said compound is described by any of Formulas (VIa)-(VIe), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein R a2 ; R b2 ; R b4 ; R g ; R g1 ; R g2 ; R d ; and R h  are as defined in  claim 1 , and R a1  is selected from W 1 , —R 1 , —C(O)YR 2 , —C(═S)YR 2 , —C(═NR 1 )YR 2 , —C(═N—OR 1 )YR 2 , —C(═N—NR 1 R 2 )YR 2 , —S(O) r R 2 , and 
       
         
           
           
               
               
           
         
         each Y is, independently, a bond, —O—, —S— or —NR 1 —; 
         each occurrence of R 1  and R 2  is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl; 
         each of X 1  and X 2  is, independently, selected from CH and N; 
         W 1  is as defined in  claim 1 ; and 
         R 4  is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl. 
       
     
     
         7 . The compound of  claim 1 ,  2  or  3 , wherein said compound is described by any of Formulas (VIIa)-(VIIe), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein R a1 ; R a2 ; R b4 ; R g ; R g1 ; R g2 ; R d ; and R h  are as defined in  claim 1 . 
     
     
         8 . The compound of  claim 1 ,  2  or  3 , wherein said compound is described by any of Formulas (VIIIa)-(VIIIe), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein R a2 ; R b2 ; R g ; R g1 ; R g2 ; R d ; and R h  are as defined in  claim 1 , R a1  is selected from W 1 , —R 1 , —C(O)YR 2 , —C(═S)YR 2 , —C(═NR 1 )YR 2 , —C(═N—OR 1 )YR 2 , —C(═N—NR 1 R 2 )YR 2 , —S(O) r R 2 , and 
       
         
           
           
               
               
           
         
         each Y is, independently, a bond, —O—, —S— or —NR 1 —; 
         W 1  is as defined in  claim 1 ; 
         each occurrence of R 1  and R 2  is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl; 
         each of X 1  and X 2  is, independently, selected from CH and N; and 
       
       R 4  is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl. 
     
     
         9 . The compound of  claim 1 ,  2  or  3 , wherein said compound is described by any of Formulas (IXa)-(IXe), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein R a1  is W 1 , —R 1 , —C(O)YR 2 , —C(═S)YR 2 , —C(═NR 1 )YR 2 , —C(═N—OR 1 )YR 2 , —C(═N—NR 1 R 2 )YR 2 , —S(O) r R 2 , or 
       
         
           
           
               
               
           
         
         each Y is, independently, a bond, —O—, —S— or —NR 1 —; 
         R b2 ; R b4 ; R g ; R g1 ; R g2 ; R d ; R h  and W 1  are as defined in  claim 1 ; 
         each occurrence of R 1  and R 2  is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl; 
         each of X 1  and X 2  is, independently, CH or N; and 
       
       R 4  is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl. 
     
     
         10 . The compound of  claim 1 ,  2  or  3 , wherein said compound is described by any of Formulas (Xa)-(Xe), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein R b2 ; R b4 ; R g ; R g1 ; R g2 ; R d ; and R h  are as defined in  claim 1 , R a1  is selected from W 1 , —R 1 , —C(O)YR 2 , —C(═S)YR 2 , —C(═NR 1 )YR 2 , —C(═N—OR 1 )YR 2 , —C(═N—NR 1 R 2 )YR 2 , —S(O) r R 2 , and 
       
         
           
           
               
               
           
         
         each Y is, independently, a bond, —O—, —S— or —NR 1 —; 
         W 1  is as defined in  claim 1 ; 
         each occurrence of R 1  and R 2  is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl; 
         each of X 1  and X 2  is, independently, selected from CH and N; and 
       
       R 4  is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl. 
     
     
         11 . The compound of any of  claims 1 - 10 , or a pharmaceutically acceptable salt thereof, wherein R a2  is H, halo, —CH 3 , —CF 3 , —CH 2 CH 3 , —OCH 3 , —OCF 3 , —OCH 2 CH 3 , —OCH 2 CH 2 N(CH 3 ) 2  or —O-heterocyclyl. 
     
     
         12 . The compound of any of  claims 1 - 10 , or a pharmaceutically acceptable salt thereof, wherein R d  is H, Cl, F, Br, I, CN, CH 3 , CF 3 , —CH 2 CH═CH 2 , or cyclopropyl. 
     
     
         13 . The compound of any of  claims 1 - 6  or  8 - 10 , or a pharmaceutically acceptable salt thereof, wherein R b2  is H. 
     
     
         14 . The compound of any of  claims 1 - 10 , or a pharmaceutically acceptable salt thereof, wherein R g1  is H, —P(O)(R 3A )(R 3B ) or —OR 2  and R g2  is H, F, C 1-6  alkyl, or C 1-6  alkoxy, wherein R 3A , R 3B , and R 2  are as defined in  claim 1 . 
     
     
         15 . The compound of any of  claims 1 - 10 , or a pharmaceutically acceptable salt thereof, wherein R g  is —P(O)(R 3A )(R 3B ), wherein R 3A  and R 3B , are as defined in  claim 1 . 
     
     
         16 . The compound of  claim 15 , or a pharmaceutically acceptable salt thereof, wherein R g  is —P(O)(CH 3 ) 2  or —P(O)(CH 2 CH 3 ) 2 . 
     
     
         17 . The compound of any of  claims 1 - 10 , or a pharmaceutically acceptable salt thereof, wherein R g  is —S(O) 2 R 3E ), wherein R 3E  is as defined in  claim 1 . 
     
     
         18 . The compound of  claim 17 , or a pharmaceutically acceptable salt thereof, wherein R g  is —S(O) 2 CH(CH 3 ) 2 . 
     
     
         19 . The compound of any of  claims 1 - 4  or  6 - 10 , or a pharmaceutically acceptable salt thereof, wherein R a1  is a 4-, 5-, 6- or 7-membered heterocycle which is optionally substituted with one or more groups selected from halo and R 17 , wherein R 17  is an alkyl, cycloalkyl, heteroalkyl, 4- to 7-membered heterocyclyl or heteroaryl group, wherein R 17  is optionally substituted with one or more halo, alkyl, cycloalkyl, heterocyclic or heteroaryl groups, of which, said cycloalkyl, heterocyclic or heteroaryl substituent is optionally substituted with one or more halo, alkyl, haloalkyl, hydroxyalkyl, amino, dialkylamino or cycloalkyl groups. 
     
     
         20 . The compound of  claim 19 , or a pharmaceutically acceptable salt thereof, wherein R a1  is selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         21 . The compound of any of  claims 1 - 3  or  5 - 10 , or a pharmaceutically acceptable salt thereof, wherein R a1  is —OR 2 , as defined in  claim 1 . 
     
     
         22 . The compound of  claim 21 , or a pharmaceutically acceptable salt thereof, wherein R a1  is selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         23 . The compound of any of  claims 1 - 3  or  5 - 10 , or a pharmaceutically acceptable salt thereof, wherein R a1  is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, or heteroalkyl group, wherein optional substituents are selected from halo, cycloalkyl, heterocyclic or heteroaryl groups, wherein said cycloalkyl, heterocyclic and heteroaryl substituent(s) are independently optionally substituted with one or more halo, alkyl, haloalkyl, hydroxyalkyl, amino, dialkylamino or cycloalkyl groups. 
     
     
         24 . The compound of  claim 23 , or a pharmaceutically acceptable salt thereof wherein R a1  is selected from the following: 
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound of  claim 23 , or a pharmaceutically acceptable salt thereof wherein R a1  is of the Formula: 
       
         
           
           
               
               
           
         
         wherein: 
         J 1  and J 2  are independently H, halo or R J ; or J 1  and J 2  together with the atom to which each is attached form an optionally substituted ring which is C 3-8  cycloalkyl, 3- to 7-membered heterocyclic, or heteroaryl; 
         J 3  and J 4  are independently H or R J ; or J 3  and J 4  together with the atom to which each is attached form an optionally substituted ring which is 3- to 7-membered heterocyclic or heteroaryl ring; 
         R J  is C 1-6  alkyl, C 3-8  cycloalkyl, C 1-8  heteroalkyl, or 3- to 7-membered heterocyclyl, wherein each R J  is independently selected from halo, haloalkyl, hydroxyl, hydroxyalkyl, amino, alkylamino, dialkylamino, cycloalkyl, alkoxy, cycloalkoxy and heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups on R J  are optionally substituted with one or more halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, amino, alkylamino, dialkylamino or cycloalkyl groups; and, 
         z is 1-3. 
       
     
     
         26 . The compound of  claim 25 , or a pharmaceutically acceptable salt thereof, wherein R a1  is selected from the following: 
       
         
           
           
               
               
           
         
       
     
     
         27 . The compound of any of  claims 1 - 3  or  5 - 10 , or a pharmaceutically acceptable salt thereof, wherein R b4  is —NR 7 C(O)C(R 11 )═CR 9 R 10 , —NR 7 S(O) 2 C(R 9 )(R 10 )(R X ), —NR 7 C(O)C≡C—R 14 , or —NR 7 C(O)C(R 9 )(R 10 )(R X ), wherein R 7 , R 9 , R 10 , R 11 , R 14 , and R X  are as defined in  claim 1 . 
     
     
         28 . The compound of  claim 27 , or a pharmaceutically acceptable salt thereof, wherein R b4  is —NHC(O)CH═CH 2  or is selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         29 . The compound of  claim 27 , or a pharmaceutically acceptable salt thereof, wherein R b4  is —NHC(O)C≡CH or is selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         30 . The compound of any of  claims 19 - 24 , or a pharmaceutically acceptable salt thereof, wherein R b4  is W 1  as defined in  claim 1 . 
     
     
         31 . The compound of  claim 30 , wherein R a2  is R a2  is H, halo, —CH 3 , —CF 3 , —CH 2 CH 3 , —OCH 3 , —OCF 3 , —OCH 2 CH 3 , —OCH 2 CH 2 N(CH 3 ) 2  or —O-heterocyclyl. 
     
     
         32 . The compound of  claim 30  or  31 , or a pharmaceutically acceptable salt thereof, wherein R g  is —P(O)(R 3A )(R 3B ), wherein R 3A  and R 3B , are as defined in  claim 1 . 
     
     
         33 . The compound of  claim 32 , or a pharmaceutically acceptable salt thereof, wherein R g  is —P(O)(CH 3 ) 2  or —P(O)(CH 2 CH 3 ) 2 . 
     
     
         34 . The compound of  claim 30  or  31 , or a pharmaceutically acceptable salt thereof, wherein R g  is —S(O) 2 R 3E ), wherein R 3E  is as defined in  claim 1 . 
     
     
         35 . The compound of  claim 34 , or a pharmaceutically acceptable salt thereof, wherein R g  is —S(O) 2 CH(CH 3 ) 2 . 
     
     
         36 . The compound of any of  claims 32 - 35  wherein R d  is Cl, F, Br, I, or CH 3 . 
     
     
         37 . The compound of  claim 1  or  2 , wherein U 1  is N, U 2  is C—R d , and U 3  is C—R e . 
     
     
         38 . The compound of  claim 1  or  2 , wherein U 1  is C—R d , U 2  is N, and U 3  is C—R e . 
     
     
         33 . The compound of  claim 1  or  2 , wherein U 1  is N, U 2  is N, and U 3  is C—R e . 
     
     
         39 . The compound of  claim 1  or  2 , wherein U 1  is N; U 2  is C—R d ; U 3  is C—R e ; R a2  is OCH 3 ; R g  or R g1  is —P(O)(R 3A )(R 3B ); each of R 3A  and R 3B  is, independently, selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heteroalkyl, or R 3A  and R 3B , together with the atom to which each is attached, form a 5- or 6-membered heterocyclic ring which is unsubstituted or substituted; R b4  is W 1  as defined in  claim 1 . 
     
     
         40 . The compound of any of  claims 30 - 39 , wherein R d  is Cl. 
     
     
         41 . The compound of  claim 1  or  2 , wherein U 3  is N, one of U 1  and U 2  is N, and the other is C—R d . 
     
     
         42 . A method for treating an EGFR-driven cancer in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of any of  claims 1 - 41 , or a pharmaceutically acceptable salt thereof. 
     
     
         43 . A method for treating an EGFR-driven cancer in a subject, said method comprising (a) providing a subject having an EGFR-driven cancer characterized by the presence of a mutation in epidermal growth factor receptor kinase (EGFR), and (b) administering to said subject a therapeutically effective amount of a compound of any of  claims 1 - 41 , or a pharmaceutically acceptable salt thereof. 
     
     
         44 . The method of  claim 43 , wherein said EGFR-driven cancer is characterized by the presence of one or more mutations selected from: (i) L858R, (ii) T790M, (iii) both L858R and T790M, (iv) delE746_A750, and (v) both delE746_A750 and T790M. 
     
     
         45 . The method of any of  claims 42 - 44 , wherein said EGFR-driven cancer is a non-small cell lung cancer (NSCLS); glioblastoma; pancreatic cancer; head and neck cancer (e.g., squamous cell carcinoma); breast cancer; colorectal cancer; epithelial cancer; ovarian cancer; prostate cancer; or an adenocarcinoma. 
     
     
         46 . The method of any of  claims 42 - 45 , further comprising administering to said subject a first kinase inhibitor selected from erlotinib, gefitinib, and pharmaceutically acceptable salts thereof, within 6 days of administering said compound of any of  claims 1 - 31 , wherein each of said compound of any of  claims 1 - 31  and said first kinase inhibitor are administered in an amount that together is sufficient to treat said EGFR-driven cancer. 
     
     
         47 . A method of inhibiting the proliferation of a cell expressing an EGFR mutant, said method comprising contacting said cell with a compound of any of  claims 1 - 31 , or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit said proliferation. 
     
     
         48 . The method of  claim 47 , wherein said EGFR mutant is characterized by the presence of one or more mutations in epidermal growth factor receptor kinase (EGFR) selected from: (i) L858R, (ii) T790M, (iii) both L858R and T790M, (iv) delE746_A750, and (v) both delE746_A750 and T790M. 
     
     
         49 . The method of  claims 47  or  48 , wherein said cell is a cancer cell. 
     
     
         50 . The method of  claim 49 , wherein said cancer cell is a cell from a non-small cell lung cancer (NSCLS); glioblastoma; pancreatic cancer; head and neck cancer (e.g., squamous cell carcinoma); breast cancer; colorectal cancer; epithelial cancer; ovarian cancer; prostate cancer; or an adenocarcinoma. 
     
     
         51 . A method of treating an EGFR-driven cancer refractory to a first kinase inhibitor selected from erlotinib, gefitinib, and pharmaceutically acceptable salts thereof, in a subject, said method comprising administering to said subject a compound of any of  claims 1 - 41 , or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat said cancer. 
     
     
         52 . A pharmaceutical composition comprising a compound of  claim 1 .