Tyrosine kinase inhibitor compositions, methods of making and methods of use

Abstract

The present disclosure relates to new compounds or pharmaceutically acceptable salts or stereoisomers thereof of formula I as inhibitors of receptor tyrosine kinases (RTK), in particular extracellular mutants of ErbB-receptors. The present disclosure also relates to methods of preparation these compounds, compositions comprising these compounds, and methods of using them in the treatment of cancer in mammals (e.g. humans).

1 . A compound or pharmaceutically acceptable salts or stereoisomers thereof of formula I 
       
         
           
           
               
               
           
         
         wherein 
         L is a covalent bond, straight chain or branched C 1-4  alkyl or 
       
       
         
           
           
               
               
           
         
       
       wherein m1 and m2 are independently of each other 0, 1, 2, 3, or 4
 Y 2  is a covalent bond, —O—, —NH—, —NCH 3 —, or —C≡C—; 
 Z is —(NR 6 R 7 ), —(CHR 6 R 7 ), wherein R 6  and R 7  form together with the atom to which they are attached to 
 
       
         
           
           
               
               
           
         
         R c  is H, C 1-4  alkyl, or oxetane; 
         R d  is H or C 1-4  alkyl; 
         X 6  is H, —CH 3 , —OH, —OCH 3 , —OCF 3 , —N(CH 3 ) 2 , F, or Cl; 
         X 7  is —O—, —NH—, —N(CH 3 )—, or —SO 2 ; 
         R 1  is —CR b ═CHR a , —C≡CH or —C≡C—CH 3 ; wherein R a  and R b  are independently of each other H or —CH 2 —O—CH 3 ; 
         X is a group of formula (i)a 
       
       
         
           
           
               
               
           
         
         wherein 
         X 1  is —O—, —CH 2 —, —NH—, or —S—; 
         Ar 1  is 6 membered aryl or N-heteroaryl, which is unsubstituted or substituted with one or more of a group selected from hal, C 1-6 alkyl, or C 1-6 alkoxy; 
         Ar 2  is 6 membered aryl or N-heteroaryl, which is unsubstituted or substituted with one or more of a group selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, —CF 3 , or —OCF 3 ; and 
         L 1  is a covalent bond or straight or branched C 1-3 alkyl, which is unsubstituted or substituted with hal. 
       
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1  or pharmaceutically acceptable salts or stereoisomers thereof, wherein L 1  is covalent bond, —CH 2 —, —CH(CH 3 )—, CH(hal)-, —CH 2 —CH 2 —, —CH 2 —CH(CH 3 )—, or —CH 2 —CH(hal)-. 
     
     
         4 . The compound of  claim 1  or pharmaceutically acceptable salts or stereoisomers thereof, wherein R a  and R b  are hydrogen. 
     
     
         5 . (canceled) 
     
     
         6 . The compound of  claim 1  or pharmaceutically acceptable salts or stereoisomers thereof, wherein X 1 -L 1  is —O—, —CH 2 —, —O—CH 2 —, —NH—CH 2 —, —S—CH 2 —, —CH 2 —CH 2 —, —O—CH(CH 3 )—, —CH 2 —CH(CH 3 )—, —NH—CH(CH 3 )—, —S—CH(CH 3 )—, —O—CH(hal)-, —CH 2 —CH(hal)-, —NH—CH(hal)-, or —S—CH(hal). 
     
     
         7 . (canceled) 
     
     
         8 . The compound of  claim 1  or pharmaceutically acceptable salts or stereoisomers thereof, wherein X is a group of formula (ii)a, 
       
         
           
           
               
               
           
         
         wherein X 1  is —O—, —CH 2 —, —NH—, or —S—; 
         L 1  is a covalent bond or C 1-3 alkyl, which is unsubstituted or substituted with —CH 3 , or hal; 
         X 2 , X 2′ , X 3 , X 3′ , X 5 , X 5′ , and X 6  are independently of each other —N═ or —CH═; and 
         R 2 , R 2′ , R 3 , and R 3′  are independently of each other H, C 1-6 alkyl, hal, —CF 3 , or —OCF 3 . 
       
     
     
         9 . The compound of  claim 1  or pharmaceutically acceptable salts or stereoisomers thereof wherein X is a group of formula (ii)b, (ii)b-1, (ii)b-2, (ii)c, (ii)c-1, or (ii)c-2 
       
         
           
           
               
               
           
         
         wherein 
         X 2 , X 2′ , X 3 , X 3′ , X 5 , X 5′ , and X 6  are independently of each other —N═ or —CH═; 
         R 2 , R 2′ , R 3 , and R 3′  are independently of each other H, C 1-6  alkyl, hal, —CF 3 , or —OCF 3 ; and 
         n is 0, 1, 2, or 3. 
       
     
     
         10 .- 15 . (canceled) 
     
     
         16 . The compound of  claim 1  or pharmaceutically acceptable salts or stereoisomers thereof, wherein X is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
         R 2  and R 2′  are independently of each other H, C 1-6 alkyl, or hal; 
         R 3  and R 3′  are independently of each other H, C 1-6 alkyl, hal, —CF 3 , or —OCF 3 ; and 
         n is 0 or 1. 
       
     
     
         17 . (canceled) 
     
     
         18 . The compound of  claim 1  or pharmaceutically acceptable salts or stereoisomers thereof, wherein the compound is of formula II or III 
       
         
           
           
               
               
           
         
         wherein 
         L is a covalent bond, straight chain or branched C 1-4  alkyl or 
       
       
         
           
           
               
               
           
         
       
       wherein m1 and m2 are independently of each other 0, 1, 2, 3, or 4;
 Y 2  is a covalent bond, —O—, —NH—, —NCH 3 —, or —C≡C—; 
 Z is 
 
       
         
           
           
               
               
           
         
         R c  is H, C 1-4  alkyl, or oxetane; 
         R d  is H or C 1-4  alkyl; 
         X 6  is H, —CH 3 , —OH, —OCH 3 , —OCF 3 , —N(CH 3 ) 2 , F, or Cl; 
         X 7  is —O—, —NH—, —N(CH 3 )—, or —SO 2 ; 
         R a  and R b  are independently of each other H or —CH 2 —O—CH 3 ; 
         X is a group of formula (ii)a 
       
       
         
           
           
               
               
           
         
         wherein 
         X 1  is —O—, —CH 2 —, or S; 
         L 1  is a covalent bond or C 1-3 alkyl, which is unsubstituted or substituted with —CH 3  or hal; 
         X 2 , X 2′ , X 3 , X 3′ , X 5 , X 5′ , and X 6  are independently of each other —N═ or —CH═; and 
         R 2 , R 2′ , R 3 , and R 3′  are independently of each other H, C 1-6  alkyl, hal, —CF 3 , or —OCF 3 . 
       
     
     
         19 . The compound of  claim 1  or pharmaceutically acceptable salts or stereoisomers thereof, wherein the compound is of formula IV 
       
         
           
           
               
               
           
         
         wherein 
         X 2 , X 2′ , X 3 , X 3′ , X 5 , X 5′ , and X 6  are independently of each other —N═ or —CH═; 
         X 1  is —O—, —CH 2 —, or —NH—; 
         L 1  is a covalent bond or straight chain or branched C 1-3 alkyl, which is unsubstituted or substituted with hal; 
         R 1  is —CR b ═CHR a , —C≡CH or —C≡C—CH 3 ; wherein R a  and R b  are independently of each other H or —CH 2 —O—CH 3 ; 
         R 2 , R 2′ , R 3 , and R 3′  are independently of each other H, C 1-6  alkyl, hal, —CF 3 , or —OCF 3 ; 
         L is a covalent bond, straight chain or branched C 1-4  alkyl or 
       
       
         
           
           
               
               
           
         
       
       wherein m1 and m2 are independently of each other 0, 1, 2, 3, or 4;
 Z is 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R c  is H, C 1-4  alkyl, or oxetane; 
         R d  is H or C 1-4  alkyl; 
         X 6  is H, —CH 3 , —OH, —OCH 3 , —OCF 3 , —N(CH 3 ) 2 , F, or Cl; and 
         X 7  is —O—, —NH—, —N(CH 3 )—, or —SO 2 . 
       
     
     
         20 . The compound of  claim 1  or pharmaceutically acceptable salts or stereoisomers thereof, wherein the compound is of formula VII 
       
         
           
           
               
               
           
         
         wherein 
         X 2 , X 2′ , X 3 , X 3′ , X 5 , X 5′ , and X 6  are independently of each other —N═ or —CH═; 
         X 1  is —O—, —CH 2 —, —NH—, or —S—; 
         L 1  is a covalent bond or straight chain or branched C 1-3 alkyl, which is unsubstituted or substituted with hal; 
         R 1  is —CR b ═CHR a , —C≡CH or —C≡C—CH 3 ; wherein R a  and R b  are independently of each other H or —CH 2 —O—CH 3 ; 
         R 2 , R 2′ , R 3 , and R 3′  are independently of each other H, C 1-6  alkyl, hal, —CF 3 , or —OCF 3 ; 
         L is a covalent bond, straight chain or branched C 1-4  alkyl or 
       
       
         
           
           
               
               
           
         
       
       wherein m1 and m2 are independently of each other 0, 1, 2, 3, or 4;
 Z is 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R c  is H, C 1-4  alkyl, or oxetane; 
         R d  is H or C 1-4  alkyl; 
         X 6  is H, —CH 3 , —OH, —OCH 3 , —OCF 3 , —N(CH 3 ) 2 , F, or Cl; and 
         X 7  is —O—, —NH—, —N(CH 3 )—, or —SO 2 . 
       
     
     
         21 . The compound of  claim 1  or pharmaceutically acceptable salts or stereoisomers thereof, wherein the compound is of formula X 
       
         
           
           
               
               
           
         
         wherein 
         X 2 , X 2′ , X 3 , X 3′ , X 5 , X 5′ , and X 6  are independently of each other —N═ or —CH═; 
         X 1  is —O—, —CH 2 —, —NH—, or —S—; 
         L 1  is a covalent bond or straight chain or branched C 1-3 alkyl, which is unsubstituted or substituted with hal; 
         R 1  is —CR b ═CHR a , —C≡CH or —C≡C—CH 3 ; wherein R a  and R b  are independently of each other H or —CH 2 —O—CH 3 ; 
         R 2 , R 2′ , R 3 , and R 3′  are independently of each other H, C 1-6  alkyl, hal, —CF 3 , —OCF 3 ; 
         L is a covalent bond, straight chain or branched C 1-4  alkyl or 
       
       
         
           
           
               
               
           
         
       
       wherein m1 and m2 are independently of each other 0, 1, 2, 3, or 4;
 R′″ is H or —CH 3 ; and 
 Z is 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R c  is H, C 1-4  alkyl, or oxetane; 
         R d  is H or C 1-4  alkyl; 
         X 6  is H, —CH 3 , —OH, —OCH 3 , —OCF 3 , —N(CH 3 ) 2 , F, or Cl; and 
         X 7  is —O—, —NH—, —N(CH 3 )—, or —SO 2 . 
       
     
     
         22 . The compound of  claim 1  or pharmaceutically acceptable salts or stereoisomers thereof, wherein the compound is of formula XIII 
       
         
           
           
               
               
           
         
         wherein 
         X 2 , X 2′ , X 3 , X 3′ , X 5 , X 5′ , and X 6  are independently of each other —N— or —CH—; 
         X 1  is —O—, —CH 2 —, —NH—, or —S—; 
         L 1  is a covalent bond or straight chain or branched C 1-3 alkyl, which is unsubstituted or substituted with hal; 
         R 1  is —CH═CH 2 , —C≡CH or —C≡C—CH 3 ; 
         R 2 , R 2′ , R 3 , and R 3′  are independently of each other H, C 1-6  alkyl, hal, —CF 3 , or —OCF 3 ; 
         L is a covalent bond, straight chain or branched C 1-4  alkyl or 
       
       
         
           
           
               
               
           
         
       
       wherein m1 and m2 are independently of each other 0, 1, 2, 3, or 4;
 Z is 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R c  is H, C 1-4  alkyl, or oxetane; 
         R d  is H or C 1-4  alkyl; 
         X 6  is H, —CH 3 , —OH, —OCH 3 , —OCF 3 , —N(CH 3 ) 2 , F, or Cl; and 
         X 7  is —O—, —NH—, —N(CH 3 )—, or —SO 2 . 
       
     
     
         23 . (canceled) 
     
     
         24 . A compound selected from the compounds described in Table I and pharmaceutically acceptable salts thereof. 
     
     
         25 . (canceled) 
     
     
         26 . A composition comprising the compound of  claim 1  or pharmaceutically acceptable salts or stereoisomers thereof, and one or more pharmaceutically acceptable carrier. 
     
     
         27 .- 31 . (canceled) 
     
     
         32 . A method of preventing or treating cancer, comprising administering to the subject in need thereof a therapeutically effective amount of the compound of  claim 1 . 
     
     
         33 . A method of preventing or treating cancer, comprising administering to the subject in need thereof the composition of  claim 26 . 
     
     
         34 .- 412 . (canceled) 
     
     
         113 . The method of  claim 32 , wherein the cancer comprises a solid tumor. 
     
     
         114 . The method of  claim 32 , wherein the cancer is a bladder cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a gastric cancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, a non-small cell lung cancer (NSCLC) or any subtype thereof. 
     
     
         115 .- 141 . (canceled) 
     
     
         142 . The method of  claim 33 , wherein the cancer comprises a solid tumor. 
     
     
         143 . The method of  claim 33 , wherein the cancer is a bladder cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a gastric cancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, a non-small cell lung cancer (NSCLC) or any subtype thereof.