Granted Patent B2

US 12,240,846 · App. 18/233,259 · Granted Mar 4, 2025

Inventors: Joseph P. Lyssikatos (Boulder, CO); Samuel Kintz (Boulder, CO); Li Ren (Superior, CO)

Assignee: Enliven Inc.

C07D471/04C07D519/00

Abstract

Claims (70)

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 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 3 -C 6 cycloalkyl, halogen, or —CN;

R 3′ is —H, —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 optionally substituted with 1-5 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 claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) 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 —CH 3 , CD 3 , —CHF 2 , or —CH 2 CH 3 ;

R 3 is —H, C 3 -cycloalkyl, halogen, or —CN;

R 3′ is —H, 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 optionally substituted with 1-5 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.

3. 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.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl optionally substituted with 1-3 R 9 groups.

5. 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; and

R 4 is —H, —F or —CH 3 .

6. 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 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (I-A-i) or formula (I-A-ii):

wherein

m is an integer 0 or 1;

R 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 is —H, —F, —CH 3 , or —CN;

R 3′ is —H;

R 4 is —H, —F or —CH 3 ;

R 5 is phenyl optionally substituted with 1-3 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, —C 1 , —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

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 .

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R 2 is —CH 3 ;

R 3 is —H;

R 3′ is —H; and

R 4 is —H or —CH 3 .

10. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

and pharmaceutically acceptable salt of any of the foregoing.

11. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

12. A method of inhibiting Bcr-Abl enzymatic activity in a cell, comprising exposing the cell to an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

13. 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 an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

14. The method of claim 13 , wherein the leukemia is refractory leukemia.

Assignments (2)

Continuity (5)

References Cited (175)