5- and 6-azaindole compounds for inhibition of BCR-ABL tyrosine kinases
The present disclosure relates to compounds and compositions for inhibition of Bcr-Abl tyrosine kinases, methods of preparing said compounds and compositions, and their use in the treatment of various cancers, such as chronic myeloid leukemia (CML).
1. A compound of formula (I-A):
or a pharmaceutically acceptable salt thereof, wherein:
X is NR 3′ or CR 3 ,
Y is NR 2 or CR 4 ,
wherein when X is NR 3′ then Y is CR 4 , Y has a double bond to CR 5 , and X has a single bond to CR 5 ; or when X is CR 3 then Y is NR 2 , Y has a single bond to CR 5 , and X has a double bond to CR 5 ;
m is an integer from 0 to 3;
each R 1 is independently -D, -F, C 1 -C 3 alkyl, C 1 -C 3 alkylene-NR 7 R 8 , C 1 -C 3 alkylene-NR 7′ R 8′ , C 1 -C 3 alkylene-OH, C 1 -C 3 alkylene-CN, C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-NR 7 R 8 , C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-NR 7′ R 8′ , C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-OH, C 1 -C 2 alkylene-(4- to 8-membered heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7 R 8 , C 1 -C 2 alkylene-(4- to 8-membered heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7′ R 8′ , C 1 -C 2 alkylene-(C 3 -C 7 heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7 R 8 , or C 1 -C 2 alkylene-(C 3 -C 7 heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7′ R 8′ , wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene moieties in R 1 are optionally substituted with 1-3 fluorine atoms and/or 1-6 deuterium atoms, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkylene-CN, or C 2 -C 3 heteroalkyl;
R 2 is —H, C 1 -C 3 alkyl, or C 3 -C 6 cycloalkyl, wherein said C 1 -C 3 alkyl is optionally substituted with 1-3 fluorine atoms and/or 1-6 deuterium atoms;
R 3 is —H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, halogen, or —CN;
R 3′ is —H, C 1 -C 3 alkyl, —C 3 -C 6 cycloalkyl, or —CN;
R 4 is —H, C 1 -C 3 alkyl, or halogen, wherein said C 1 -C 3 alkyl is optionally substituted with 1-3 fluorine atoms and/or 1-6 deuterium atoms;
R 5 is C 6 -C 14 aryl, wherein said C 6 -C 14 aryl is substituted with —OR 10 and optionally further substituted with 1-4 R 9 groups;
each R 7 is independently —H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylene-CN, or C 1 -C 6 heteroalkyl;
each R 8 is independently —H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylene-CN, or C 1 -C 6 heteroalkyl;
each pair of R 7′ and R 8′ taken together with the nitrogen atom to which they are attached independently form a 3- to 8-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkylene-CN, or C 2 -C 3 heteroalkyl;
each R 9 is independently halogen, —OR 10 , —NR 7 R 8 , C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, —CN, S(O) n C 1 -C 3 alkyl, or S(O) n C 3 -C 6 cycloalkyl,
wherein n is an integer from 0 to 2; and
each R 10 is independently —H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl, wherein said C 1 -C 3 alkyl is optionally substituted with hydroxyl, C 1 -C 3 alkoxy, and/or 1-6 deuterium atoms.
2. The compound of formula (I) of claim 1 ,
or a pharmaceutically acceptable salt thereof, wherein:
X is NR 3′ or CR 3 ,
Y is NR 2 or CR 4 ,
wherein when X is NR 3′ then Y is CR 4 , Y has a double bond to CR 5 , and X has a single bond to CR 5 ; or when X is CR 3 then Y is NR 2 , Y has a single bond to CR 5 , and X has a double bond to CR 5 ;
m is an integer from 0 to 3;
each R 1 is independently -D, —F, C 1 -C 3 alkyl, C 1 -C 3 alkylene-NR 7 R 8 , C 1 -C 3 alkylene-NR 7′ R 8′ , C 1 -C 3 alkylene-OH, C 1 -C 3 alkylene-CN, C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-NR 7 R 8 , C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-NR 7′ R 8′ , C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-OH, C 1 -C 2 alkylene-(C 4 -C 6 heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7 R 8 , or C 1 -C 2 alkylene-(C 4 -C 6 heterocycloalkylene)-(C 0 —C 2 alkylene)-NR 7′ R 8′ , wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene moieties in R 1 are optionally substituted with 1-3 fluorine atoms and/or 1-6 deuterium atoms, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkylene-CN, or C 2 -C 3 heteroalkyl;
R 2 is —H, C 1 -C 3 alkyl, or C 3 -C 6 cycloalkyl, wherein said C 1 -C 3 alkyl is optionally substituted with 1-3 fluorine atoms and/or 1-6 deuterium atoms;
R 3 is —H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, halogen, or —CN;
R 3′ is —H, C 1 -C 3 alkyl, —C 3 -C 6 cycloalkyl, or —CN;
R 4 is —H, C 1 -C 3 alkyl, or halogen, wherein said C 1 -C 3 alkyl is optionally substituted with 1-3 fluorine atoms and/or 1-6 deuterium atoms;
R 5 is C 6 -C 14 aryl, wherein said C 6 -C 14 aryl is substituted with —OR 10 and optionally further substituted with 1-4 R 9 groups;
each R 7 is independently —H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylene-CN, or C 1 -C 6 heteroalkyl;
each R 8 is independently —H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylene-CN, or C 1 -C 6 heteroalkyl;
each pair of R 7′ and R 8′ taken together with the nitrogen atom to which they are attached independently form a 4-to-6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkylene-CN, or C 2 -C 3 heteroalkyl;
each R 9 is independently halogen, —OR 10 , —NR 7 R 8 , C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, —CN, S(O) n C 1 -C 3 alkyl, or S(O) n C 3 -C 6 cycloalkyl,
wherein n is an integer from 0 to 2; and
each R 10 is independently —H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl, wherein said C 1 -C 3 alkyl is optionally substituted with hydroxyl, C 1 -C 3 alkoxy, and/or 1-6 deuterium atoms.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I-A) is a compound of formula (I-A-i) or formula (I-A-ii):
wherein
m is an integer 0 or 2;
each R 1 is independently —F, C 1 -C 3 alkyl, C 1 -C 3 alkylene-NR 7 R 8 , C 1 -C 3 alkylene-NR 7′ R 8′ , C 1 -C 3 alkylene-OH, C 1 -C 3 alkylene-CN, C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-NR 7 R 8 , C 1 -C 3 alkylene-CN, C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-NR 7′ R 8′ , C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-OH, C 1 -C 2 alkylene-(C 4 -C 6 heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7 R 8 , or C 1 -C 2 alkylene-(C 4 -C 6 heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7′ R 8′ , wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene in R 1 are optionally substituted with 1-3 fluorine atoms and/or 1-6 deuterium atoms, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkylene-CN, or C 2 -C 3 heteroalkyl;
R 2 is —H, —CH 3 , CD 3 , —CHF 2 , or —CH 2 CH 3 ;
R 3 is —H, C 1 -C 3 alkyl, C 3 -cycloalkyl, halogen, or —CN;
R 3′ is —H, C 1 -C 3 alkyl, C 3 -cycloalkyl, or —CN;
R 4 is —H, —CH 3 , —CD 3 , —CHF 2 , —CH 2 CH 3 , or halogen;
R 5 is C 6 -C 14 aryl, wherein said C 6 -C 14 aryl is substituted with —OR 10 and optionally further substituted with 1-4 R 9 groups;
each R 7 is independently —H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkyl-CN, or C 2 -C 3 heteroalkyl;
each R 8 is independently —H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkyl-CN, or C 2 -C 3 heteroalkyl;
each pair of R 7′ and R 8′ taken together with the nitrogen atom to which they are attached independently form a 4-to-6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkylene-CN, or C 2 -C 3 heteroalkyl;
each R 9 is independently halogen, —OR 10 , C 1 -C 3 alkyl, —CF 2 H, —CF 3 , C 3 -C 6 cycloalkyl, or —CN, and
each R 10 is independently —H, C 1 -C 3 alkyl, —CD 3 , —CF 2 H, —CF 3 , or C 3 -C 6 cycloalkyl, wherein said C 1 -C 3 alkyl is optionally substituted with hydroxyl and/or C 1 -C 3 alkoxy and/or 1-6 deuterium atoms.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
each R 1 is independently —F, C 1 -C 3 alkylene-NR 7′ R 8′ , or C 1 -C 3 alkylene-OH; and
wherein each pair of R 7′ and R 8′ of R 1 taken together with the nitrogen atom to which they are attached independently form a 4-to-6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N and O, and wherein the nitrogen atom of any primary or secondary amine present in the heterocyclic ring is optionally substituted by —H or C 1 -C 3 alkyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 5 is phenyl, wherein said phenyl is substituted with —OR 10 and optionally further substituted with 1-2 R 9 groups.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 2 is —CH 3 , —CD 3 , or —CH 2 CH 3 ;
R 3 is —H, —F, —CH 3 , or —CN;
R 3′ is —H or —CH 3 ; and
R 4 is —H, —F or —CH 3 .
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
each R 9 is independently —F, —Cl, —OR 10 , —CH 3 , or —CN, and
each R 10 is independently —H, —CH 3 , —CD 3 , or —CH 2 CH 3 , wherein said —CH 3 or said —CH 2 CH 3 is optionally substituted with hydroxyl and/or —OCH 3 .
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I-A) is a compound of formula (I-A-i) or formula (I-A-ii):
wherein
m is an integer 0 or 1;
R 1 is —F, C 1 -C 3 alkylene-NR 7′ R 8′ , or C 1 -C 3 alkylene-OH;
R 2 is —CH 3 , —CD 3 , or —CH 2 CH 3 ;
R 3 is —H, —F, —CH 3 , or —CN;
R 3′ is —H or —CH 3 ;
R 4 is —H, —F or —CH 3 ;
R 5 is phenyl, wherein said phenyl is substituted with —OR 10 and is optionally further substituted with 1-2 R 9 groups;
each pair of R 7′ and R 8′ taken together with the nitrogen atom to which they are attached independently form a 4-to-6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N and O, and wherein the nitrogen atom of any primary or secondary amine present in the heterocyclic ring is optionally substituted by —H or C 1 -C 3 alkyl;
each R 9 is independently —F, —Cl, —OR 10 , —CH 3 , or —CN, and
each R 10 is independently —H, —CH 3 , —CD 3 , or —CH 2 CH 3 , wherein said —CH 3 or said —CH 2 CH 3 is optionally substituted with hydroxyl and/or —OCH 3 .
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 5 is phenyl, wherein said phenyl is substituted with —OR 10 and optionally further substituted with 1-2 R 9 groups.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
each R 9 is independently —F, —OR 10 , or —CH 3 , and
each R 10 is independently —H, —CH 3 , —CD 3 , —CF 2 H, or —CF 3 .
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 2 is —H or —CH 3 ;
R 3 is —H;
R 3′ is —H; and
R 4 is —H or —CH 3 .
12. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
13. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
15. A method of inhibiting Bcr-Abl enzymatic activity in a cell, comprising exposing the cell with an effective amount of the compound claim 1 , or a pharmaceutically acceptable salt thereof.
16. A method of treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia, in a human in need thereof, comprising administering to the human the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising the compound of claim 12 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
18. A compound of formula (I-B):
or a pharmaceutically acceptable salt thereof, wherein:
X is NR 3′ or CR 3 ,
Y is NR 2 or CR 4 ,
wherein when X is NR 3′ then Y is CR 4 , Y has a double bond to CR 5 , and X has a single bond to CR 5 ; or when X is CR 3 then Y is NR 2 , Y has a single bond to CR 5 , and X has a double bond to CR 5 ;
R 2 is —H, C 1 -C 3 alkyl, or C 3 -C 6 cycloalkyl, wherein said C 1 -C 3 alkyl is optionally substituted with 1-3 fluorine atoms and/or 1-6 deuterium atoms;
R 3 is —H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, halogen, or —CN;
R 3′ is —H, C 1 -C 3 alkyl, —C 3 -C 6 cycloalkyl, or —CN;
R 4 is —H, C 1 -C 3 alkyl, or halogen, wherein said C 1 -C 3 alkyl is optionally substituted with 1-3 fluorine atoms and/or 1-6 deuterium atoms;
R 5 is C 6 -C 14 aryl or 5-to-10-membered heteroaryl, wherein said C 6 -C 14 aryl or said 5-to-10-membered heteroaryl is optionally substituted with 1-5 R 9 groups;
R 6 is —H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylene-NR 7 R 8 , C 1 -C 6 alkylene-NR 7′ R 8′ , C 1 -C 6 alkylene-OH, C 1 -C 6 alkylene-CN, C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-NR 7 R 8 , C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-NR 7′ R 8′ , C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-OH, C 1 -C 2 alkylene-(4- to 8-membered heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7 R 8 , C 1 -C 2 alkylene-(4- to 8-membered heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7′ R 8′ , C 1 -C 2 alkylene-(C 3 -C 7 heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7 R 8 , or C 1 -C 2 alkylene-(C 3 -C 7 heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7′ R 8′ , wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene moieties in R 6 are optionally substituted with 1-3 fluorine atoms and/or 1-6 deuterium atoms, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkylene-CN, or C 2 -C 3 heteroalkyl;
each R 7 is independently —H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylene-CN, or C 1 -C 6 heteroalkyl;
each R 8 is independently —H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylene-CN, or C 1 -C 6 heteroalkyl;
each pair of R 7′ and R 8′ taken together with the nitrogen atom to which they are attached independently form a 3- to 8-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkylene-CN, or C 2 -C 3 heteroalkyl;
each R 9 is independently halogen, —OR 10 , —NR 7 R 8 , C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, —CN, S(O) n C 1 -C 3 alkyl, or S(O) n C 3 -C 6 cycloalkyl,
wherein n is an integer from 0 to 2; and
each R 10 is independently —H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl, wherein said C 1 -C 3 alkyl is optionally substituted with hydroxyl, C 1 -C 3 alkoxy, and/or 1-6 deuterium atoms.
19. The compound of formula (I-B) of claim 18 ,
or a pharmaceutically acceptable salt thereof, wherein:
X is NR 3′ or CR 3 ,
Y is NR 2 or CR 4 ,
wherein when X is NR 3′ then Y is CR 4 , Y has a double bond to CR 5 , and X has a single bond to CR 5 ; or when X is CR 3 then Y is NR 2 , Y has a single bond to CR 5 , and X has a double bond to CR 5 ;
R 2 is —H, C 1 -C 3 alkyl, or C 3 -C 6 cycloalkyl, wherein said C 1 -C 3 alkyl is optionally substituted with 1-3 fluorine atoms and/or 1-6 deuterium atoms;
R 3 is —H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, halogen, or —CN;
R 3′ is —H, C 1 -C 3 alkyl, —C 3 -C 6 cycloalkyl, or —CN;
R 4 is —H, C 1 -C 3 alkyl, or halogen, wherein said C 1 -C 3 alkyl is optionally substituted with 1-3 fluorine atoms and/or 1-6 deuterium atoms;
R 5 is C 6 -C 14 aryl or 5-to-10-membered heteroaryl, wherein said C 6 -C 14 aryl or said 5-to-10-membered heteroaryl is optionally substituted with 1-5 R 9 groups;
R 6 is —H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylene-NR 7 R 8 , C 1 -C 6 alkylene-NR 7′ R 8′ , C 1 -C 6 alkylene-OH, C 1 -C 6 alkylene-CN, C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-NR 7 R 8 , C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-NR 7′ R 8′ , C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-OH, C 1 -C 2 alkylene-(C 4 -C 6 heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7 R 8 , or C 1 -C 2 alkylene-(C 4 -C 6 heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7′ R 8′ , wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene moieties in R 6 are optionally substituted with 1-3 fluorine atoms and/or 1-6 deuterium atoms, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkylene-CN, or C 2 -C 3 heteroalkyl;
each R 7 is independently —H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylene-CN, or C 1 -C 6 heteroalkyl;
each R 8 is independently —H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylene-CN, or C 1 -C 6 heteroalkyl;
each pair of R 7′ and R 8′ taken together with the nitrogen atom to which they are attached independently form a 4-to-6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkylene-CN, or C 2 -C 3 heteroalkyl;
each R 9 is independently halogen, —OR 10 , —NR 7 R 8 , C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, —CN, S(O) n C 1 -C 3 alkyl, or S(O) n C 3 -C 6 cycloalkyl,
wherein n is an integer from 0 to 2; and
each R 10 is independently —H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl, wherein said C 1 -C 3 alkyl is optionally substituted with hydroxyl, C 1 -C 3 alkoxy, and/or 1-6 deuterium atoms.
20. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein
R 5 is phenyl or 5-to-10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl is selected from the group consisting of:
wherein indicates a single or double bond, and wherein said phenyl or said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R 9 groups.
21. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein
R 2 is —CH 3 , —CD 3 , or —CH 2 CH 3 ;
R 3 is —H, —F, —CH 3 , or —CN;
R 3′ is —H or —CH 3 ; and
R 4 is —H, —F or —CH 3 .
22. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein
each R 9 is independently —F, —Cl, —OR 10 , —CH 3 , or —CN, and
each R 10 is independently —H, —CH 3 , —CD 3 , or —CH 2 CH 3 , wherein said —CH 3 or said —CH 2 CH 3 is optionally substituted with hydroxyl and/or —OCH 3 .
23. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I-B) is a compound of formula (I-B-i) or formula (I-B-ii):
wherein
R 2 is —H, —CH 3 , CD 3 , —CHF 2 , or —CH 2 CH 3 ;
R 3 is —H, C 1 -C 3 alkyl, C 3 -cycloalkyl, halogen, or —CN;
R 3′ is —H, C 1 -C 3 alkyl, C 3 -cycloalkyl, or —CN;
R 4 is —H, —CH 3 , —CD 3 , —CHF 2 , —CH 2 CH 3 , or halogen;
R 5 is C 6 -C 14 aryl or 5-to-10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl is selected from the group consisting of:
wherein indicates a single or double bond, and wherein said C 6 -C 14 aryl or said 5-to-10-membered heteroaryl is optionally substituted with 1-5 R 9 groups;
R 6 is C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkylene-NR 7 R 8 , C 1 -C 3 alkylene-NR 7′ R 8′ , C 1 - C 3 alkylene-OH, C 1 -C 3 alkylene-CN, C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-NR 7 R 8 , C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-NR 7′ R 8′ , C 1 -C 2 alkylene-(C 3 -C 6 cycloalkylene)-(C 0 -C 2 alkylene)-OH, C 1 -C 2 alkylene-(C 4 -C 6 heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7 R 8 , or C 1 -C 2 alkylene-(C 4 -C 6 heterocycloalkylene)-(C 0 -C 2 alkylene)-NR 7′ R 8′ , wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene moieties in R 6 are optionally substituted with 1-3 fluorine atoms and/or 1-6 deuterium atoms, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkylene-CN, or C 2 -C 3 heteroalkyl;
each R 7 is independently —H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkyl-CN, or C 2 -C 3 heteroalkyl;
each R 8 is independently —H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkyl-CN, or C 2 -C 3 heteroalkyl;
each pair of R 7′ and R 8′ taken together with the nitrogen atom to which they are attached independently form a 4-to-6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkylene-CN, or C 2 -C 3 heteroalkyl;
each R 9 is independently halogen, —OR 10 , C 1 -C 3 alkyl, —CF 2 H, —CF 3 , C 3 -C 6 cycloalkyl, or —CN, and
each R 10 is independently —H, C 1 -C 3 alkyl, —CD 3 , —CF 2 H, —CF 3 , or C 3 -C 6 cycloalkyl, wherein said C 1 -C 3 alkyl is optionally substituted with hydroxyl and/or C 1 -C 3 alkoxy.
24. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein
R 6 is C 1 -C 3 alkyl or C 1 -C 3 alkylene-NR 7′ R 8′ ; and
wherein each pair of R 7′ and R 8′ of R 6 taken together with the nitrogen atom to which they are attached independently form a 4-to-6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkylene-CN, or C 2 -C 3 heteroalkyl.
25. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein
R 5 is phenyl or 5-to-10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl is selected from the group consisting of:
wherein said phenyl or said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R 9 groups.
26. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein
each R 9 is independently —F, —OR 10 , or —CH 3 , and
each R 10 is independently —H, —CH 3 , —CD 3 , —CF 2 H, or —CF 3 .
27. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein
R 2 is —H or —CH 3 ;
R 3 is —H;
R 3′ is —H; and
R 4 is —H or —CH 3 .
28. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I-B) is a compound of formula (I-B-i) or formula (I-B-ii):
wherein
R 2 is —H or —CH 3 ;
R 3 is —H;
R 3′ is —H;
R 4 is —H or —CH 3 ;
R 5 is phenyl or 5-to-10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl is selected from the group consisting of:
wherein said phenyl or said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R 9 groups;
R 6 is C 1 -C 3 alkyl or C 1 -C 3 alkylene-NR 7′ R 8′ ;
each pair of R 7′ and R 8′ taken together with the nitrogen atom to which they are attached independently form a 4-to-6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 haloalkyl, C 2 -C 3 alkylene-CN, or C 2 -C 3 heteroalkyl;
each R 9 is independently —F, —OR 10 , or —CH 3 , and
each R 10 is independently —H, —CH 3 , —CD 3 , —CF 2 H, or —CF 3 .
29. A pharmaceutical composition comprising the compound of claim 18 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
30. A method of inhibiting Bcr-Abl enzymatic activity in a cell, comprising exposing the cell with an effective amount of the compound claim 18 , or a pharmaceutically acceptable salt thereof.
31. A method of treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia, in a human in need thereof, comprising administering to the human the compound of claim 18 , or a pharmaceutically acceptable salt thereof.