TYROSINE KINASE INHIBITOR COMPOSITIONS, METHODS OF MAKING AND METHODS OF USE
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.