Novel compounds

Abstract

The present invention relates to compounds, compositions, combinations and medicaments containing said compounds and processes for their preparation. The invention also relates to the use of said compounds, combinations, compositions and medicaments, for example as inhibitors of the activity of RIP2 kinase, including degrading RIP2 kinase, the treatment of diseases and conditions mediated by the RIP2 kinase, in particular for the treatment of inflammatory diseases or conditions.

1 . A method of treating diseases and conditions mediated by the RIP2 Kinase in a subject comprising administering a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         X represents N or CH; 
         L is a linking group comprising a length of 4-16 atoms in shortest length, 
         R 1  is H, —SO 2 (C 1 -C 4 )alkyl, —CO(C 1 -C 4 )alkyl, or (C 1 -C 4 )alkyl; 
         R 2  is —SR a , —SOR a , —SO 2 R a , —SO 2 NH 2 , or —SO 2 NR b R c , 
         wherein R a  is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 2 )cycloalkyl, 4-7 membered heterocycloalkyl, aryl, or heteroaryl, wherein:
 said (C 1 -C 6 )alkyl is optionally substituted by one or two groups each independently selected from the group consisting of cyano, hydroxyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 2 -C 6 )alkoxy, —CO 2 H, —CO 2 (C 1 -C 4 )alkyl, —SO 2 (C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl, phenyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl, 4-7 membered heterocycloalkyl and (phenyl)(C 1 -C 4  alkyl)amino-, wherein said (C 3 -C 7 )cycloalkyl, phenyl, (phenyl)(C 1 -C 4  alkyl)amino-, 5-6 membered heteroaryl, 9-10 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1-3 groups each independently selected from the group consisting of halogen, —CF 3 , hydroxyl, amino, ((C 1 -C 4 )alkyl)amino-, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)amino-, (C 1 -C 4 )alkyl, phenyl(C 1 -C 4 )alkyl-, hydroxy(C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy, 
 said (C 3 -C 7 )cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted by 1-3 groups each independently selected from the group consisting of halogen, —CF 3 , hydroxyl, amino, ((C 1 -C 4 )alkyl)amino-, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)amino-, (C 1 -C 4 )alkyl, phenyl(C 1 -C 4 )alkyl-, hydroxy(C 1 -C 4 )alkyl-, oxo and (C 1 -C 4 )alkoxy, and 
 said aryl or heteroaryl is optionally substituted by 1-3 groups each independently selected from the group consisting of halogen, —CF 3 , hydroxyl, amino, ((C 1 -C 4 )alkyl)amino-, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)amino-, (C 1 -C 4 )alkyl, phenyl(C 1 -C 4 )alkyl-, hydroxy(C 1 -C 4 )alkyl- and (C 1 -C 4 )alkoxy; 
 R b  is (C 1 -C 6 )alkyl or 4-7 membered heterocycloalkyl, wherein: 
 said (C 1 -C 6 )alkyl is optionally substituted by one or two groups each independently selected from the group consisting of hydroxyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 2 -C 6 )alkoxy, —CO 2 H, —CO 2 (C 1 -C 4 )alkyl, (C 1 -C 4  alkyl)amino-, (C 1 -C 4  alkyl)(C 1 -C 4  alkyl)amino-, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1-3 groups each independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy, 
 said 4-7 membered heterocycloalkyl is optionally substituted by 1-3 groups each independently selected from the group consisting of hydroxyl, amino, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxycarbonyl-, hydroxy(C 1 -C 4 )alkyl-, oxo and (C 1 -C 4 )alkoxy, and 
 R c  is H, (C 1 -C 4 )alkoxy or (C 1 -C 6 )alkyl; 
 or R b  and R c  taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocycloalkyl group, optionally containing one or two additional ring heteroatoms each independently selected from nitrogen and oxygen, wherein said 3-7 membered heterocycloalkyl is optionally substituted by 1-3 groups each independently selected from the group consisting of (C 1 -C 4 )alkyl, hydroxy, —CO 2 H and —CO(C 1 -C 4 )alkyl; 
 
         Z is phenyl or aryl(C 1 -C 4 )alkyl-, wherein in the phenyl group or the aryl moiety of the aryl(C 1 -C 4 )alkyl- group is substituted by R 4 , R 5 , R 6  and R 7 , wherein:
 R 4  is H, halogen, cyano, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, phenoxy, phenyl(C 1 -C 4 )alkoxy, hydroxyl, hydroxy(C 1 -C 4 )alkyl-, or aminocarbonyl, wherein the phenyl moiety of said phenoxy or phenyl(C 1 -C 4 )alkoxy- is optionally substituted by 1-3 substituents each independently selected from the group consisting of halogen, —CF 3 , (C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy; and 
 each of R 5 , R 6  and R 7  is independently selected from the group consisting of H, hydroxyl, halogen, —CF 3 , hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy; or 
 Z is phenyl or pyridyl, substituted by R 8 , R 9  and R 10 , wherein: 
 R 8  and R 9  are located on adjacent atoms and taken together with the atoms to which they are attached form a 5-membered ring containing 1, 2 or 3 heteroatoms each independently selected from N, O and S, which 5-membered ring is substituted by R 11 ; 
 wherein one of R 10  or R 11  is H, halogen, cyano, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, phenoxy, phenyl(C 1 -C 4 )alkoxy, hydroxyl, hydroxy(C 1 -C 4 )alkyl-, or aminocarbonyl, where the phenyl moiety of said phenoxy or phenyl(C 1 -C 4 )alkoxy is optionally substituted by 1-3 substituents each independently selected from the group consisting of halogen, —CF 3 , (C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy; and 
 the other of R 10  or R 11  is H, hydroxyl, halogen, —CF 3 , hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy; or 
 
         Z is pyrazolyl, having the formula: 
       
       
         
           
           
               
               
           
         
         wherein:
 R 12  is H, methyl or hydroxymethyl; 
 R 13  is methyl, trifluoromethyl or hydroxymethyl; 
 R 14  is H, OH, or (C 1 -C 3 )alkyl; or 
 R 12  and R 13 , taken together with the atoms to which they are attached, form a 6-membered ring substituted by R 15  and R 16 , wherein the 6-membered ring optionally contains 1 nitrogen atom; 
 wherein R 15  and R 16  are each independently selected from the group consisting of H, halogen, cyano, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, phenoxy, phenyl(C 1 -C 4 )alkoxy, hydroxyl, hydroxy(C 1 -C 4 )alkyl-, and aminocarbonyl, wherein the phenyl moiety of said phenoxy or phenyl(C 1 -C 4 )alkoxy is optionally substituted by 1-3 substituents each independently selected from the group consisting of halogen, —CF 3 , (C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy; 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A method of treating diseases and conditions mediated by the RIP2 Kinase comprising administering to a human in need thereof a therapeutically effective amount of a combination comprising compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         X represents N or CH; 
         L is a linking group comprising a length of 4-16 atoms in shortest length, R 1  is H, —SO 2 (C 1 -C 4 )alkyl, —CO(C 1 -C 4 )alkyl, or (C 1 -C 4 )alkyl; 
         R 2  is —SR a , —SOR a , —SO 2 R a , —SO 2 NH 2 , or —SO 2 NR b R c , 
         wherein R a  is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, 4-7 membered heterocycloalkyl, aryl, or heteroaryl, wherein:
 said (C 1 -C 6 )alkyl is optionally substituted by one or two groups each independently selected from the group consisting of cyano, hydroxyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 2 -C 6 )alkoxy, —CO 2 H, —CO 2 (C 1 -C 4 )alkyl, —SO 2 (C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl, phenyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl, 4-7 membered heterocycloalkyl and (phenyl)(C 1 -C 4  alkyl)amino-, wherein said (C 3 -C 7 )cycloalkyl, phenyl, (phenyl)(C 1 -C 4  alkyl)amino-, 5-6 membered heteroaryl, 9-10 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1-3 groups each independently selected from the group consisting of halogen, —CF 3 , hydroxyl, amino, ((C 1 -C 4 )alkyl)amino-, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)amino-, (C 1 -C 4 )alkyl, phenyl(C 1 -C 4 )alkyl-, hydroxy(C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy, 
 said (C 3 -C 7 )cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted by 1-3 groups each independently selected from the group consisting of halogen, —CF 3 , hydroxyl, amino, ((C 1 -C 4 )alkyl)amino-, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)amino-, (C 1 -C 4 )alkyl, phenyl(C 1 -C 4 )alkyl-, hydroxy(C 1 -C 4 )alkyl-, oxo and (C 1 -C 4 )alkoxy, and 
 said aryl or heteroaryl is optionally substituted by 1-3 groups each independently selected from the group consisting of halogen, —CF 3 , hydroxyl, amino, ((C 1 -C 4 )alkyl)amino-, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)amino-, (C 1 -C 4 )alkyl, phenyl(C 1 -C 4 )alkyl-, hydroxy(C 1 -C 4 )alkyl- and (C 1 -C 4 )alkoxy; 
 R b  is (C 1 -C 6 )alkyl or 4-7 membered heterocycloalkyl, wherein: 
 said (C 1 -C 6 )alkyl is optionally substituted by one or two groups each independently selected from the group consisting of hydroxyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 2 -C 6 )alkoxy, —CO 2 H, —CO 2 (C 1 -C 4 )alkyl, (C 1 -C 4  alkyl)amino-, (C 1 -C 4  alkyl)(C 1 -C 4  alkyl)amino-, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1-3 groups each independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy, 
 said 4-7 membered heterocycloalkyl is optionally substituted by 1-3 groups each independently selected from the group consisting of hydroxyl, amino, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxycarbonyl-, hydroxy(C 1 -C 4 )alkyl-, oxo and (C 1 -C 4 )alkoxy, and 
 R c  is H, (C 1 -C 4 )alkoxy or (C 1 -C 6 )alkyl; 
 or R b  and R c  taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocycloalkyl group, optionally containing one or two additional ring heteroatoms each independently selected from nitrogen and oxygen, wherein said 3-7 membered heterocycloalkyl is optionally substituted by 1-3 groups each independently selected from the group consisting of (C 1 -C 4 )alkyl, hydroxy, —CO 2 H and —CO(C 1 -C 4 )alkyl; 
 
         Z is phenyl or aryl(C 1 -C 4 )alkyl-, wherein in the phenyl group or the aryl moiety of the aryl(C 1 -C 4 )alkyl- group is substituted by R 4 , R 5 , R 6  and R 7 , wherein:
 R 4  is H, halogen, cyano, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, phenoxy, phenyl(C 1 -C 4 )alkoxy, hydroxyl, hydroxy(C 1 -C 4 )alkyl-, or aminocarbonyl, wherein the phenyl moiety of said phenoxy or phenyl(C 1 -C 4 )alkoxy- is optionally substituted by 1-3 substituents each independently selected from the group consisting of halogen, —CF 3 , (C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy; and 
 each of R 5 , R 6  and R 7  is independently selected from the group consisting of H, hydroxyl, halogen, —CF 3 , hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy; or 
 Z is phenyl or pyridyl, substituted by R 8 , R 9  and R 10 , wherein: 
 R 8  and R 9  are located on adjacent atoms and taken together with the atoms to which they are attached form a 5-membered ring containing 1, 2 or 3 heteroatoms each independently selected from N, O and S, which 5-membered ring is substituted by R 11 ; 
 wherein one of R 10  or R 11  is H, halogen, cyano, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, phenoxy, phenyl(C 1 -C 4 )alkoxy, hydroxyl, hydroxy(C 1 -C 4 )alkyl-, or aminocarbonyl, where the phenyl moiety of said phenoxy or phenyl(C 1 -C 4 )alkoxy is optionally substituted by 1-3 substituents each independently selected from the group consisting of halogen, —CF 3 , (C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy; and 
 the other of R 10  or R 11  is H, hydroxyl, halogen, —CF 3 , hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy; or 
 Z is pyrazolyl, having the formula: 
 
       
       
         
           
           
               
               
           
         
         
            wherein: 
           R 12  is H, methyl or hydroxymethyl; 
           R 13  is methyl, trifluoromethyl or hydroxymethyl; 
           R 14  is H, OH, or (C 1 -C 3 )alkyl; or 
           R 12  and R 13 , taken together with the atoms to which they are attached, form a 6-membered ring substituted by R 15  and R 16 , wherein the 6-membered ring optionally contains 1 nitrogen atom; 
           wherein R 15  and R 16  are each independently selected from the group consisting of H, halogen, cyano, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, phenoxy, phenyl(C 1 -C 4 )alkoxy, hydroxyl, hydroxy(C 1 -C 4 )alkyl-, and aminocarbonyl, wherein the phenyl moiety of said phenoxy or phenyl(C 1 -C 4 )alkoxy is optionally substituted by 1-3 substituents each independently selected from the group consisting of halogen, —CF 3 , (C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy; 
         
         or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent. 
       
     
     
         3 . The method of  claim 1  wherein the compound is a compound of Formula (II), (III), or (IV): 
       
         
           
           
               
               
           
         
         In particular, the definitions of R 1 , Z, X and R 2  in the RIP2 inhibitor moiety in the compounds of formula (II) and (III) are as defined in  claim 1  above. 
         The linker is as defined for  claim 1   
         For the IAP binding moiety, in formula (II) and (III) 
         R 1  and R 2  are independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, optionally substituted aryl, or
 R 1  and R 2  are independently optionally substituted thioalkyl wherein the substituents attached to the S atom of the thioalkyl are optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, —(CH2)vCOR 20 , —CH2CHR 21 COR 22  or —CH 2 R 23 . 
 
         Wherein
 v-1-3, 
 R 20  and R 22  are independently selected from OH, NR 24  R 25  or OR 26 , 
 R 21  is NR 24 R 25 , 
 R23 is optionally substituted aryl or optionally substituted heterocyclyl, where the optional substituents include alkyl and halogen, 
 R 24  is hydrogen or optionally substituted alkyl, 
 R 25  is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, —CH2(OCH 2 CH 2 O) m CH 3 , or a polyamine chain, 
 R 26  is optionally substituted alkyl, 
 w=1-8, 
 
         Where the optional substituents are OH, halogen or NH 2 ; 
         R 3  and R 4  are independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl or optionally substituted hetercycloalkyl, wherein the substitutents are alkyl, halogen or OH;
 R 5 , R 6 , R 7  and R 8  are independently hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; 
 R 9  is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl or CO alkyl; 
 
       
       
         
           
           
               
               
           
         
         In particular, the definitions of R 1 , Z, X and R 2  in the RIP2 inhibitor moiety in the compounds of formula (IV) are as defined in  claim 1   
         The linker is as defined in  claim 1   
         For the IAP binding moiety, in formula (IV) 
         R is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
       
       wherein ring A is C 4-8  aliphatic ring, 
       
         
           
           
               
               
           
         
       
       wherein the B ring is aryl or nitrogen atom-containing heteroaryl and the B rings are optionally substituted;
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         4 . The method according to  claim 3  wherein in formula IV ring B is phenyl, napthyl, pyridinyl, pyrazonyl or pyrimidinyl 
     
     
         5 . The method according to  claim 1  wherein the linker is a straight chain alkyline group of 4-20 carbon atoms wherein one or more carbo atoms is replaced by a group each independently selected from —O—, —NH—, —N(CH 3 ), —CO—, piperidine, piperazine, pyrimidine, pyridine and phenyl. 
     
     
         6 . The method according to  claim 1  wherein the linker is (in the direction RIP2 Kinase inhibitor—IAP inhibitor—
 O(CH 2 CH 2 O) 3-4    
 O(ch 2 ch 2 ) 4  OCH 2 CONH 
 
       
         
           
           
               
               
           
         
         wherein X is O(CH 2 CH 2 ) 0-4    
         and Y is CONH, O or CO 
       
     
     
         7 . The method according to  claim 1  wherein the linker is (in the one linker RIP2 Kinase inhibitor—IAP inhibitor
 (OCH 2 CH 2 ) 4 O— 
 (OCH 2 CH 2 ) 3 O— 
 (OCH 2 CH 2 ) 4 OCH 2 CONH 
 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method according to  claim 1  wherein the compound of Formula (I) is:
 S)-7-(2-(2-(2-(2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-3,3-dimethyl-2-((S)-2-methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, 
 (S)-7-(2-(2-(2-(2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((S)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, 
 (S)-7-(2-(2-(2-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, 
 (2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-t ((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-3-methylbutan-2-yl)pyri 
 (2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide, 
 (2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-N—((R)-2,3-dihydro-1H-inden-1-yl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide, 
 (2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1-phenyl propyl)pyrrolidine-2-carboxamide, 
 (2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-N-(2,6-difluorophenyl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide, 
 (2S,4S)-4-(2-(2-(2-(2-((6-(Tert-butylsulfonyl)-4-((5-fluoro-1H-indazol-3-yl)amino)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide; 
 (2S,4S)-4-(2-(2-(2-((6-(Tert-butylsulfonyl)-4-((5-fluoro-1H-indazol-3-yl)amino)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide, 
 5-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide, 
 2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide 
 5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide; 
 6-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)nicotinamide; 
 2-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide; 
 6-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)nicotinamide; 
 5-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide; 
 2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide; 
 5-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide; 
 (2S,4S)-4-((2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7 yl)oxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide, 
 2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-5-((2,6-difluorophenyl)carbamoyl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide; 
 2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-((3-methyl-1-phenyl-1H-pyrazol-5-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide; 
 2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-((3-methyl-1-phenyl-1H-pyrazol-5-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide; 
 (S)-7-((6-(4-((6-(Tert-butylsulfonyl)-4-((4,5-di methyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)piperidin-1-yl)pyrimidin-4-yl)oxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; 
 (S)-7-((6-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrimidin-4-yl)oxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; 
 (2S,4S)-4-((2-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide, 
 (2S,4S)-4-((2-(4-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)piperidin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide, 
 (2S,4S)-4-((2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide, 
 (2S,4S)-4-((2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide, 
 (2S,4S)-4-((2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide, 
 (2S,4S)-4-((2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide 
 (2S,4S)-4-((2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-N-(2,6-difluorophenyl)-1-((S)-3,3-dimethyl-2-((S)-2 (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide 
 2-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)-N-((3S,5S)-5-((2,6-difluorophenyl)carbamoyl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide; 
 5-(4-(3-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-5-((2,6-difluorophenyl)carbamoyl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide 
 (S)-1-((S)-2-(1-(2-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-di methyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidine-5-carbonyl)piperidin-4-yl)-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide; 
 (S)-1-((S)-2-(1-(2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin yl)oxy)propyl)piperazin-1-yl)pyrimidine-5-carbonyl)piperidin-4-yl)-2-((S)-2-(methylamino)propanamido 1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide; 
 (5S,8S,10aR)—N-Benzhydryl-3-(5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carbonyl)-5-((S)-2-(methylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][ 1 , 5 ]diazocine-8-carboxamide; 
 (5S,8S,10aR)-3-(5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carbonyl)-5-((S)-2-(methylamino)propanamido)-6-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide; 
 (5S,8S,10aR)-3-(5-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)pyrazine-2-carbonyl)-5-((S)-2-(methylamino)propanamido)-6-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide; 
 (5S,8S,10aR)-3-(2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)pyrimidine-5-carbonyl)-5-((S)-2-(methylamino)propanamido)-6-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide; 
 and pharmaceutically acceptable salts thereof