Pyrimidine compounds, compositions and methods of use

Abstract

Disclosed are compounds of Formula I, including steroisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, that are useful in modulating PIKK related kinase signaling, e.g., mTOR, and for the treatment of diseases (e.g., cancer) that are mediated at least in part by the dysregulation of the PIKK signaling pathway (e.g., mTOR).

1 . A compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein in Formula I, 
         A is a 5- to 8-membered heterocyclic ring having from 1 to 3 heteroatoms independently selected from N, O and S as ring vertices, and having from 0 to 2 double bonds; optionally fused to the heterocyclic ring of A is a 6-membered aryl ring or a 5- to 6-membered heteroaryl ring having from 1 to 3 heteroatoms selected from N, O and S; and wherein the A ring, and if present, the 6-membered aryl ring or the 5- or 6-membered heteroaryl ring fused thereto, is further substituted with from 0 to 5 R A  substituents selected from the group consisting of —C(O)OR a , —C(O)NR a R b , —NR a R b , —OC(O)R c , —OR a , —SR a , —S(O) 2 R c , —S(O)R c , —R c , —(CH 2 ) 1-4 —NR a R b , —(CH 2 ) 1-4 —NR a C(O)R c , —(CH 2 ) 1-4 —OR a , —(CH 2 ) 1-4 —SR a , —(CH 2 ) 1-4 —S(O) 2 R c , —(CH 2 ) 1-4 —S(O)R c , halogen, F, Cl, Br, I, —NO 2 , —CN and —N 3 , wherein R a  and R b  are each independently selected from hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3s-6  cycloalkyl, phenyl and —(CH 2 ) 1-4 (phenyl), and optionally R a  and R b , together with the nitrogen atom to which each is attached, are combined to form a 3- to 7-membered heterocyclic ring comprising 1 to 2 heteroatoms selected from N, O and S; R c  is selected from C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-6  cycloalkyl, phenyl and —(CH 2 ) 1-4  (phenyl), and any two substituents attached to the same atom in the 5- to 8-membered heterocyclic ring are optionally combined to form a 3- to 5-membered carbocyclic or a 3 to 5-membered heterocyclic ring substituted with 0-3 R A  substituents; 
         R 1  and R 2  are combined with the atoms to which they are attached to form a 5- to 8-membered saturated heterocyclic ring comprising —N(W)— as one of the ring vertices, wherein W is represented by Formula i 
       
       
         
           
           
               
               
           
         
         wherein E is a member selected from the group consisting of hydrogen, C 6-10  aryl, C 5-10  heteroaryl, C 3-10  cycloalkyl, C 3-10  heterocycloalkyl, C 1-6  alkyl and C 1-6  heteroalkyl; and wherein E is independently substituted with from 0 to 5 R E  substituents selected from the group consisting of halogen, F, Cl, Br, I, —NR d R e , —SR d , —OR d , —C(O)OR d , —C(O)NR d R e , —C(O)R d , —NR d C(O)R e , —OC(O)R f , —NR d C(O)NR d R e , —OC(O)NR d R e , —C(═NOR d )NR d R e , —NR d C(═N—CN)NR d R e , —NR d S(O) 2 NR d R e , —S(O) 2 R d , —S(O) 2 NR d R e , —R f , —NO 2 , —N 3 , ═O, —CN, —(CH 2 ) 1-4 —NR d R e , —(CH 2 ) 1-4 —SR d , —(CH 2 ) 1-4 —OR d , —(CH 2 ) 1-4 —C(O)OR d , —(CH 2 ) 1-4 —C(O)NR d R e , —(CH 2 ) 1-4 —C(O)R d , —(CH 2 ) 1-4 —NR d C(O)R e , —(CH 2 ) 1-4 —OC(O)R f , —(CH 2 ) 1-4 —NR d C(O)NR d R e , —(CH 2 ) 1-4 —OC(O)NR d R e , —(CH 2 ) 1-4 —C(═NOR d )NR d R e , —(CH 2 ) 1-4 —NR d C(═N—CN)NR d R e , —(CH 2 ) 1-4 —NR d S(O) 2 NR d R e , —(CH 2 ) 1-4 —S(O) 2 R d , —(CH 2 ) 1-4 —S(O) 2 NR d R e , —(CH 2 ) 1-4 —NO 2 , —(CH 2 ) 1-4 N 3  and —(CH 2 ) 1-4 —CN; wherein R d  and R e  are each independently selected from hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  heterocycloalkyl, phenyl and —(CH 2 ) 1-4 -phenyl, and optionally R d  and R e , when attached to the same nitrogen atom are combined to form a 3- to 6-membered heterocyclic ring comprising 1 to 2 heteroatoms selected from N, O and S; R f  is selected from C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  heterocycloalkyl, phenyl and —(CH 2 ) 1-4 -phenyl; and wherein any two substituents located on adjacent atoms, or located on the same atom of E are optionally combined to form a 5- to 6-membered carbocyclic or heterocyclic ring;
 F is a member selected from the group consisting of C 1-6  alkylene, C 2-6  alkenylene, C 2-6  alkynylene and C 1-6  heteroalkylene; wherein F is independently substituted with from 0 to 3 R F  substituents selected from the group consisting of halogen, F, Cl, Br, I, —NR g R h , —SR g , —OR g , —C(O)OR g , —C(O)NR g R h , —NR g C(O)R i , —OC(O)R i , —NR g C(O)NR g R h , —OC(O)NR g R h , NR g S(O) 2 NR g R h , —S(O) 2 R g , —S(O) 2 NR g R h , —R i , —NO 2 , N 3 , ═O, —CN, —(CH 2 ) 1-4 —NR g R h , —(CH 2 ) 1-4 —SR g , —(CH 2 ) 1-4 —OR g , —(CH 2 ) 1-4 —C(O)OR g , —(CH 2 ) 1-4 —C(O)NR g R h , —(CH 2 ) 1-4 —C(O)R g , —(CH 2 ) 1-4 —NR g C(O)R h , —(CH 2 ) 1-4 —OC(O)R i , —(CH 2 ) 1-4 —NR g C(O)NR g R h , —(CH 2 ) 1-4 —OC(O)NR g R h , —(CH 2 ) 1-4 —NR g S(O) 2 NR g R h , —(CH 2 ) 1-4 —S(O) 2 R g , —(CH 2 ) 1-4 —S(O) 2 NR g R h , —(CH 2 ) 1-4 —NO 2 , —(CH 2 ) 1-4 —N 3  and —(CH 2 ) 1-4 —CN; wherein R g  and R h  are each independently selected from hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 3-7  cycloalkyl, C 3-7  heterocycloalkyl, phenyl and —(CH 2 ) 1-4 -phenyl, and optionally R g  and R h , when attached to the same nitrogen atom are combined to form a 3- to 6-membered heterocyclic ring comprising 1 to 2 heteroatoms selected from N, O and S; R i  is selected from C 1-6  alkyl, C 1-6  haloalkyl, C 3-7  cycloalkyl, C 3-7  heterocycloalkyl, phenyl and —(CH 2 ) 1-4 -phenyl; 
 
         G is a member selected from the group consisting of —C(O)—, —OC(O)—, —NHC(O)—, —NHC(═NOH)—, —S(O) 0-2 — and —NHS(O) 2 —; 
         the subscripts m and p are each independently an integer from 0 to 1; 
         wherein the 5- to 8-membered heterocyclic ring formed by combining R 1  and R 2  further optionally comprises 1 additional heteroatom selected from the group consisting of N, O and S, and is substituted with from 0 to 5 R R  substituents selected from the group consisting of halogen, F, Cl, Br, I, —NR j R k , —SR j , —OR j , —C(O)OR j , —C(O)NR j R k , —NHC(O)R j , —OC(O)R j , —R m , —CN, —(CH 2 ) 1-4 —CN, —(CH 2 ) 1-4 OR j , —(CH 2 ) 1-4 NR j R k , —(CH 2 ) 1-4 —CO 2 R j , —(CH 2 ) 1-4 C(O)NR j R k , C 2-4  alkenylene-CO 2 R j , C 2-4  alkenylene-C(O)NR j R k , ═O, ═S, and ═N—CN, wherein R j  and R k  are each independently selected from hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  heterocycloalkyl, phenyl and —(CH 2 ) 1-4 -(Ph), and R j  and R k , when attached to the same nitrogen atom, are optionally combined to form a 3- to 6-membered heterocyclic ring comprising 1 to 2 heteroatoms selected from N, O and S; and R m  is selected from C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  heterocycloalkyl and —(CH 2 ) 1-4 -(Ph), and wherein when R 1  and R 2  are combined to form a monocyclic 5- to 8-membered heterocyclic ring then any two substitutents attached to the same or adjacent atoms in the monocyclic 5- to 8-membered heterocyclic ring are optionally combined to form a 3- to 7-membered cycloalkyl ring, a 3- to 7-membered heterocycloalkyl ring or a 5- to 6-membered heteroaryl ring comprising 1 to 2 heteroatoms selected from N, O and S and is substituted with 0 to 3 R R  substitutents; 
         B is a member selected from the group consisting of phenylene and 5- to 6-membered heteroarylene, and is substituted with from 0 to 4 R B  substituents selected from halogen, F, Cl, Br, I, —CN, —N 3 , —NO 2 , —C(O)OR n , —C(O)NR n R o , —NR n C(O)R o , —NR n C(O)NR n R o , —OR n , —NR n R o , —(CH 2 ) 1-4 —C(O)OR n , —(CH 2 ) 1-4 —C(O)NR n R o , —(CH 2 ) 1-4 —OR n , —(CH 2 ) 1-4 —NR n R o , —(CH 2 ) 1-4 —SR p  and R p ; wherein R n  and R o  are independently selected from hydrogen and C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  heterocycloalkyl, phenyl and —(CH 2 ) 1-4 -(phenyl) or when attached to the same nitrogen atom, R n  and R o  are optionally are combined to form a 3- to 6-membered heterocyclic ring comprising 1 to 2 heteroatoms selected from N, O and S; R p  is C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  heterocycloalkyl, phenyl and —(CH 2 ) 1-4 -(phenyl), wherein any two substituents, not including the D group, located on adjacent atoms of B are optionally combined to form a 5- to 6-membered carbocyclic, heterocyclic, aryl or heteroaryl ring substituted with 0-2 R B  substituents; 
         D is a member selected from the group consisting of —NR 3 C(O)NR 4 R 5 , —NR 4 R 5 , —C(O)NR 4 R 5 , —OC(O)OR 4 , —OC(O)NR 4 R 5 , —NR 3 C(═N—CN)NR 4 R 5 , —NR 3 C(═N—OR 4 )NR 4 R 5 , —NR 3 C(═N—NR 4 )NR 4 R 5 , —NR 3 C(O)R 4 , —NR 3 C(O)OR 4 , —NR 3 S(O) 2 NR 4 R 5  and —NR 3 S(O) 2 R 4 , wherein R 3  is selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl and C 2-6  alkenyl; R 4  and R 5  are each independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, C 3-10  heterocycloalkyl, C 6-10  aryl and C 5-10  heteroaryl, and R 4  and R 5 , when attached to the same nitrogen atom, are optionally combined to form a 5- to 7-membered heterocyclic or heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O and S as ring vertices and substituted with 0-3 R D  substituents; and wherein R 3 , R 4  and R 5  are further substituted with from 0 to 3 R D  substituents independently selected from the group consisting of halogen, F, Cl, Br, I, —NO 2 , —CN, —NR q R r , —OR q , —SR q , —C(O)OR q , —C(O)NR q R r , —NR q C(O)R r , —NR q C(O)OR s , —(CH 2 ) 1-4 —NR q R r , —(CH 2 ) 1-4 —OR q , —(CH 2 ) 1-4 —SR q , —(CH 2 ) 1-4 —C(O)OR q , —(CH 2 ) 1-4 —C(O)NR q R r , —(CH 2 ) 1-4 —NR q C(O)R r , —(CH 2 ) 1-4 —NR q C(O)OR r , (CH 2 ) 1-4 —CN, —(CH 2 ) 1-4 NO 2 , —S(O)R r , —S(O) 2 R r , ═O, and —R s ; wherein R q  and R r  is selected from hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  heteroalkyl, C 3-7  cycloalkyl, C 3-7  heterocycloalkyl, C 6-10  aryl, C 5-10  heteroaryl; and R s , at each occurrence, is independently selected from C 1-6  alkyl, C 1-6  haloalkyl, C 3-7  cycloalkyl, C 3-7  heterocycloalkyl, C 6-10  aryl and C 5-10  heteroaryl; and wherein the D group and a substituent located on an adjacent atom of the B ring are optionally combined to form a 5- to 6-membered heterocyclic or heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O and S as ring vertices and substituted with 0-3 R D  substituents. 
       
     
     
         2 . The compound of  claim 1 , wherein A is a 5- to 8-membered ring and is further substituted with from 0 to 3 R A  substituents selected from the group consisting of —C(O)OR a , —C(O)NR a R b , —NR a R b , —OC(O)R c , —OR a , —SR a , —S(O) 2 R c , —S(O)R c , R c , —(CH 2 ) 1-4 —NR a R b , —(CH 2 ) 1-4 —OR a , halogen, F, Cl, Br, I, —NO 2 , —CN and —N 3 , wherein R a  and R b  are each independently selected from hydrogen, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  heteroalkyl and C 3-6  cycloalkyl, and optionally R a  and R b , together with the nitrogen atom to which each is attached, are combined to form a 3- to 6-membered heterocyclic ring; R c  is selected from C 1-4  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-6  cycloalkyl, phenyl and —(CH 2 ) 1-4  (phenyl);
 B is selected from the group consisting of phenylene, pyridylene, pyrimidylene, pyridazinylene and pyrazinyline and is substituted with from 0 to 4 R B  substituents selected from halogen, F, Cl, Br, I, —CN, —N 3 , —NO 2 , —C(O)OR n , —C(O)NR n R o , —NR n C(O)R o , —NR n C(O)NR n R o , —OR n , —NR n R o  and R p ; wherein R n  and R o  are independently selected from hydrogen and C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  heteroalkyl, C 3-7  cycloalkyl and C 3-7  heterocycloalkyl, or when attached to the same nitrogen atom, R n  and R o  are optionally are combined to form a 3- to 6-membered ring; R p  is C 1-4  alkyl, C 1-4  haloalkyl, C 3-7  cycloalkyl and C 3-7  heterocycloalkyl; 
 D is a member selected from the group consisting of —NR 3 C(O)NR 4 R 5 , —NR 4 R 5 , —C(O)NR 4 R 5 , —OC(O)NR 4 R 5 , —NR 3 C(═N—CN)NR 4 R 5 , —NR 3 C(O)R 4 , —NR 3 C(O)OR 4 , —NR 3 S(O) 2 NR 4 R 5  and —NR 3 S(O) 2 R 4 , wherein R 3  is selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl and C 2-6  alkenyl; R 4  and R 5  are each independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  heterocycloalkyl, C 6-10  aryl and C 5-10  heteroaryl, and R 4  and R 5 , when attached to the same nitrogen atom, are optionally combined to form an optionally substituted 5- to 7-membered heterocyclic or heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O and S as ring vertices; and wherein R 3 , R 4  and R 5  are further substituted with from 0 to 3 R D  substituents independently selected from the group consisting of halogen, F, Cl, Br, I, —NO 2 , —CN, —NR q R r , —OR q , —SR q , —C(O)OR q , —C(O)NR q R r , —NR q C(O)R r , —NR q C(O)OR s , —(CH 2 ) 1-4 —NR q R r , —(CH 2 ) 1-4 —OR q , —(CH 2 ) 1-4 —SR q , —(CH 2 ) 1-4 —C(O)OR q , —(CH 2 ) 1-4 —C(O)NR q R r , —(CH 2 ) 1-4 —NR q C(O)R r , —(CH 2 ) 1-4 —NR q C(O)OR r , —(CH 2 ) 1-4 —CN, —(CH 2 ) 1-4 —NO 2 , —S(O)R r , —S(O) 2 R r , ═O, and —R s ; wherein R q  and R r  is selected from hydrogen, C 1-4  alkyl, C 1-4  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-4  heteroalkyl, C 3-7  cycloalkyl, C 3-7  heterocycloalkyl, C 6-10  aryl, C 5-10  heteroaryl; and R s , at each occurrence, is independently selected from C 1-4  alkyl, C 1-4  haloalkyl, C 3-7  cycloalkyl, C 3-7  heterocycloalkyl, C 6  aryl and C 5-6  heteroaryl; and wherein the D group and a substituent located on an adjacent atom of the B ring are optionally combined to form an optionally substituted 5- to 6-membered heterocyclic or heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O and S as ring vertices. 
 
     
     
         3 . The compound of  claim 2 , wherein the A ring is a ring selected from the group consisting of morpholin-4-yl, 3-methyl-morpholin-4-yl, 3-ethyl-morpholin-4-yl, 3-iso-propyl-morpholin-4-yl, 3,3-dimethyl-morpholin-4-yl, 3,4-dihydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, tetrahydro-2H-pyran-4-yl, 1,4-oxazepan-4-yl, piperidin-1-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 3-isopropyl-morpholin-4-yl, 4-methoxy-piperidin-1-yl and is optionally substituted with from 1 to 2 R A  substituents selected from the group consisting of —C(O)OR a , —C(O)NR a R b , —NR a R b , —OR a , —SR a , —S(O) 2 R c , —S(O)R c , —R c , halogen, F, Cl, Br, I, —NO 2 , —CN and —N 3 , wherein R a  and R b  are each independently selected from hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 2-6  alkenyl and C 3-6  cycloalkyl, wherein optionally R a  and R b , together with the nitrogen atom to which each is attached, are combined to form a 3- to 6-membered ring, and R c  is selected from C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 3-6  cycloalkyl; and B is an optionally substituted group selected from optionally substituted phenylene, pyrimidinylene and pyridylene. 
     
     
         4 . The compound of  claim 3 , wherein the A ring is optionally substituted with 1 to 2 R A  substituents selected from NR a R b , —OR a  and —R c . 
     
     
         5 . The compound of  claim 1 , wherein B is an optionally substituted ring selected from the group consisting of 1,4-phenylene, 2,5-pyridylene and 2,4-pyridylene. 
     
     
         6 . The compound of  claim 1 , wherein the compound of Formula I is of a sub-formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R R  is selected from the group consisting of halogen, F, Cl, Br, I, —R m , —(CH 2 ) 1-4 —CN, —(CH 2 ) 1-4 —CO 2 R j , —(CH 2 ) 1-4 C(O)NR j R k , —(CH 2 ) 1-4 OR j , —(CH 2 ) 1-4 NR j R k , C 2-4  alkenylene-CO 2 R j , C 2-4  alkenylene-C(O)NR j R k  and ═O; and R B  is selected from the group consisting of F, Cl, Br, I, CN, NO 2  and R p , wherein R p  is selected form C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl and C 2-6  alkyny. 
       
     
     
         7 . The compound of  claim 1 , wherein the compound of Formula I is of a sub-formula selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R R  is selected from the group consisting of halogen, F, Cl, Br, I and —R m ; and R B  is selected from the group consisting of F, Cl, Br, I, CN, NO 2  and R p , wherein R p  is selected form C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl and C 2-6  alkynyl. 
       
     
     
         8 . The compound of  claim 6  or  7 , wherein D is selected from the group consisting of —NR 3 C(O)NR 4 R 5 , —NR 4 R 5 , —C(O)NR 4 R 5 , —NR 3 C(═N—CN)NR 4 R 5 , —NR 3 C(O)R 4 , —NR 3 C(O)OR 4 , and —NR 3 S(O)R 4 . 
     
     
         9 . The compound of  claim 6  or  7 , wherein D is an optionally substituted group selected from —NR 3 C(O)NR 4 R 5  and —NR 4 R 5- , wherein R 3  is hydrogen; R 4  and R 5  are each independently an optionally substituted group selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  heteroalkyl, C 1-6  haloalkyl, C 3-7  cycloalkyl, C 3-7  heterocycloalkyl, C 6-10  aryl and C 5-10  heteroaryl, and R 4  and R 5 , when attached to the same nitrogen atom, are optionally combined to form an optionally substituted 5- to 7-membered heterocyclic or heteroaryl ring. 
     
     
         10 . The compound of  claim 9 , wherein D is —NR 4 R 5 , wherein R 4  is hydrogen or C 1-3  alkyl, and R 5  is an optionally substituted group selected from optionally substituted C 6-10  aryl, C 5-10  heteroaryl and C 3-7  heterocyclylalkyl. 
     
     
         11 . The compound of  claim 10 , wherein D is —NR 4 R 5 , wherein R 4  is hydrogen or C 1-3  alkyl, and R 5  is an optionally substituted C 3-7  heterocyclylalkyl selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein the hydrogen atom attached to one or more nitrogen or carbon ring vertices in the C 3-7  heterocycloalkyl ring is optionally replace with a R D  substituent selected from the group consisting of F, Cl, Br, I, —NR q R r , —OR q , and R s . 
       
     
     
         12 . The compound of  claim 11 , wherein R 5  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 9 , wherein D is —NR 4 R 5 , wherein R 4  and R 5  are combined to form an optionally substituted 5-membered heteroaryl ring selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl and triazolyl. 
     
     
         14 . The compound of  claim 9 , wherein D is —NR 3 C(O)NR 4 R 5 , wherein R 3  is hydrogen; R 4  and R 5  are each independently an optionally substituted group selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 3-7  cycloalkyl, C 3-7  heterocycloalkyl, a 5- to 6-membered heteroaryl, and optionally substituted phenyl. 
     
     
         15 . The compound of  claim 14 , wherein one of R 4  and R 5  is hydrogen. 
     
     
         16 . The compound of  claim 15 , wherein R 3  and R 4  are each hydrogen and R 5  is an optionally substituted group selected from C 1-6  alkyl and C 1-6  haloalkyl. 
     
     
         17 . The compound of  claim 16 , wherein R 5  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound of  claim 17 , wherein R 5  is ethyl. 
     
     
         19 . The compound of  claim 14 , wherein R 3  and R 4  are each hydrogen or C 1-4  alkyl and R 5  is an optionally substituted group selected from the group consisting of optionally substituted isoxazol-3-yl, isoxazol-4-yl isoxazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-oxadiazol-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-oxepanyl, 3-oxepanyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl and phenyl. 
     
     
         20 . The compound of  claim 19 , wherein R 5  is independently substituted with from 0 to 3 substituents selected from F, Cl, Br, I, —CN, —NR q R r  and —OR q . 
     
     
         21 . The compound of  claim 20 , wherein R 5  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound of  claim 1 ,  6  or  7 , wherein in Formula i, E is an optionally substituted group selected from the group consisting of C 6-10  aryl, C 5-10  heteroaryl, C 3-8  heterocycloalkyl, and C 3-8  cycloalkyl; F is an optionally substituted group selected from the group consisting of C 1-4  alkylene, C 2-4  alkenylene, C 1-4  heteroalkylene, G is selected from the group consisting of —C(O)—, —OC(O)—, —NHC(O)—, —S(O) 2 —, —NHS(O) 2 —; and the subscripts m and p are each independently an integer from 0 to 1. 
     
     
         23 . The compound of  claim 22 , wherein in Formula i, E is an optionally substituted group selected from the group consisting of optionally substituted pyridyl, pyrimidinyl, quinolinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, piperidinyl, pyrrolidinyl, morpholinyl, furanyl, triazinyl, thiadiazolyl, imidazolyl, cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, pyridonyl, tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, tetrahydropyrimidinyl and tetrahydropyranyl; F is an optionally substituted group selected from the group consisting of C 1-4  alkylene, C 2-4  alkenylene, C 1-4  heteroalkylene, G is selected from the group consisting of —C(O)—, —OC(O)—, —NHC(O)—, —S(O) 2 —, —NHS(O) 2 —; and the subscripts m and p are each independently an integer from 0 to 1. 
     
     
         24 . The compound of  claim 23 , wherein E is an C 6-10  aryl, C 5-10  heteroaryl, C 3-8  heterocycloalkyl, and C 3-8  cycloalkyl selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein the hydrogen atom attached to one or more nitrogen or carbon ring vertices in the C 6-10  aryl, C 5-10  heteroaryl, C 3-8  heterocycloalkyl, and C 3-8  cycloalkyl ring is optionally replaced with a R E  substituent. 
       
     
     
         25 . The compound of  claim 22 , wherein the subscripts m and p are each 1. 
     
     
         26 . The compound of  claim 22 , wherein the subscript m is 0 and the subscript p is 1. 
     
     
         27 . The compound of  claim 1 ,  6  or  7 , wherein W is selected from the group set forth in  FIG. 1A ,  FIG. 1B ,  FIG. 1C ,  FIG. 1D ,  FIG. 1E  and  FIG. 1F . 
     
     
         28 . The compound of  claim 1 ,  6  or  7 , wherein D is selected from the group set forth in  FIG. 2A  and  FIG. 2B . 
     
     
         29 . The compound of  claim 1 , wherein said compound has the structure selected from the group compounds set forth in Table 1, Table 2,  FIG. 3A ,  FIG. 3B ,  FIG. 3C ,  FIG. 3D  and  FIG. 3E . 
     
     
         30 . A pharmaceutical composition comprising a compound of Formula I, or a sub-formula thereof, and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         31 . A method for the treatment of cancer in a mammal comprising administering to a patient in need thereof a therapeutically acceptable amount of a compound of  claim 1  wherein said cancer is selected from the group consisting of breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin's and leukemia. 
     
     
         32 . The method of  claim 31 , wherein said cancer is selected from breast, NSCLC, small cell carcinoma, liver carcinoma, lymphoid disorders, sarcoma, colon-rectum, rectum, ovary, kidney and leukemia. 
     
     
         33 . The method of  claim 32 , wherein a compound of  claim 1  is administered in combination with another chemotherapeutic agent. 
     
     
         34 . The method of  claim 33 , wherein said mammal is a human. 
     
     
         35 . A method of inhibiting the activity of mTOR kinase in a mammal comprising administering to the mammal a therapeutically acceptable amount of a compound of  claims 1 . 
     
     
         36 . The method of  claim 35 , wherein said compound of  claim 1  selectively inhibits mTORC1 over mTORC2. 
     
     
         37 . The method of  claim 28 , wherein said compound of  claim 1  selectively inhibits mTORC2 over mTORC1. 
     
     
         38 . The use of a compound of  claim 1 , in the preparation of a medicament for the treatment of cancer.