Piperidines as covalent menin inhibitors
The present disclosure provides compounds represented by Formula (I): and the pharmaceutically acceptable salts and solvates thereof, wherein A, R 1a , R 1b , R 1c , R 1d , R 2 , R 3 , R 8a , R 8b , R 10 , X, Z 2 , m, and n are as defined as set forth in the specification. The present disclosure also provides compounds of Formula (I) for use to treat a condition or disorder responsive to menin inhibition such as cancer.
1. A compound having Formula I:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A is selected from the group consisting of:
R 1a , R 1b , and R 1c are each independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, amino, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxy;
R 1d and R 1e are independently selected from the group consisting of hydrogen and C 1-4 alkyl;
R 2 is selected from the group consisting of hydroxy, amino, cyano, and —CH 2 R 4 ;
R 3 is selected from the group consisting of hydrogen, —OC(═O)NR 11a R 11b , —NHC(═O)R 5 , and —NHZ 1 ;
R 4 is selected from the group consisting of amino, optionally substituted aryl, and optionally substituted heteroaryl;
R 5 is selected from the group consisting of —NR 12a R 12b , C 1-4 alkoxy, and C 1-4 alkyl;
X is selected from the group consisting of:
wherein Y is attached to Z 2 ; or
X is absent;
Y is selected from the group consisting of —C(═O)— and —S(═O) 2 —;
R 6a and R 6b are independently selected from the group consisting of hydrogen and C 1-4 alkyl;
m, n, o, p, q, and r are each independently 0, 1, 2, or 3;
Z 1 is selected from the group consisting of —C(═O)R 7 and —S(═O) 2 R 7 ;
Z 2 is selected from the group consisting of —CH═CHR 13 , —C≡CR 13 , —CH 2 Cl, —CH 2 Br, —CH 2 I, alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted cycloalkyl,
with proviso that Z 2 is —CH═CHR 13 , —C≡CR 13 , —CH 2 Cl, —CH 2 Br, or —CH 2 I, when R 3 is hydrogen, —OC(═O)NR 11a R 11b , or —NHC(═O)R 5 ,
R 7 is selected from the group consisting of —CH═CHR 13 , —C≡CR 13 , —CH 2 Cl, —CH 2 Br, and —CH 2 I;
R 8a and R 8b are independently selected from the group consisting of hydrogen, hydrogen, halo, cyano, hydroxy, amino, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxy;
R 9a is selected from the group consisting of hydrogen, hydrogen, halo, cyano, hydroxy, amino, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxy;
R 10 is selected from the group consisting of hydrogen, halo, C 1-4 alkyl, and hydroxy;
R 11a and R 11b are independently selected from the group consisting of hydrogen and C 1-4 alkyl; or
R 11a and R 11b taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclo; and
R 12a and R 12b are independently selected from the group consisting of hydrogen and C 1-4 alkyl; or
R 12a and R 12b taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclo;
R 13 is selected from the group consisting of hydrogen, C 1-4 alkyl, and (amino)alkyl;
R 14 is selected from the group consisting of hydrogen and C 1-4 alkyl; and
B, B 1 , B 2 , and B 3 are each independently selected from the group consisting of ═CR 9a — and ═N—,
with proviso that at least one of B, B 1 , B 2 , and B 3 is ═CR 9a —.
2. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having Formula I-A-I:
3. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having Formula X:
wherein:
X is selected from the group consisting of X-1, X-2, X-3, X-4, X-5, and X-6; or
X is absent;
Z 2 is selected from the group consisting of —CH═CHR 13 and —C≡CR 13 ; and
R 3 is selected from the group consisting of —OC(═O)NR 11a R 11b , and —NHC(═O)R 5 .
4. The compound of claim 3 , or a pharmaceutically acceptable salt or solvate thereof, having Formula XI:
5. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is X-1.
6. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is X-2.
7. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is X-3 and B, B 1 , B 2 , and B 3 are ═CR 9a —.
8. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is X-4 and B, B 1 , B 2 , and B 3 are ═CR 9a —.
9. The compound of claim 2 , or a pharmaceutically acceptable salt or solvate thereof, having Formula XII:
wherein Z 2 is selected from the group consisting of alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted cycloalkyl.
10. The compound of claim 2 , or a pharmaceutically acceptable salt or solvate thereof, having Formula XIV:
11. A compound having Formula XV or Formula XVII:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
R 1a and R 1b are each independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, amino, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxy;
R 2 is selected from the group consisting of hydroxy, amino, cyano, and —CH 2 R 4 ;
R 3 is selected from the group consisting of hydrogen, —OC(═O)NR 11a R 11b , —NHC(═O)R 5 , and —NHZ 1 ;
R 4 is selected from the group consisting of amino, optionally substituted aryl, and optionally substituted heteroaryl;
R 5 is selected from the group consisting of —NR 12a R 12b , C 1-4 alkoxy, and C 1-4 alkyl;
Z 1 is selected from the group consisting of —C(═O)R 7 and —S(═O) 2 R 7 ;
Z 2 is selected from the group consisting of —CH═CHR 13 , —C≡CR 13 , —CH 2 Cl, —CH 2 Br, —CH 2 I, alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted cycloalkyl,
with proviso that Z 2 is —CH═CHR 13 , —C≡CR 13 , —CH 2 Cl, —CH 2 Br, or —CH 2 I, when R 3 is hydrogen, —OC(═O)NR 11a R 11b , or —NHC(═O)R 5 ,
R 7 is selected from the group consisting of —CH═CHR 13 , —C≡CR 13 , —CH 2 Cl, —CH 2 Br, and —CH 2 I;
R 11a and R 11b are independently selected from the group consisting of hydrogen and C 1-4 alkyl; or
R 11a and R 11b taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclo; and
R 12a and R 12b are independently selected from the group consisting of hydrogen and C 1-4 alkyl; or
R 12a and R 12b taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclo;
R 13 is selected from the group consisting of hydrogen, C 1-4 alkyl, and (amino)alkyl; and
s or t is 2, 3, 4, or 5.
12. A compound having Formula XX:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
R 1a and R 1b are each independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, amino, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxy;
R 2 is selected from the group consisting of hydroxy, amino, cyano, and —CH 2 R 4 ;
R 4 is selected from the group consisting of amino, optionally substituted aryl, and optionally substituted heteroaryl;
Z 1 is selected from the group consisting of —C(═O)R 7 and —S(═O) 2 R 7 ;
R 7 is selected from the group consisting of —CH═CHR 13 , —C≡CR 13 , —CH 2 Cl, —CH 2 Br, and —CH 2 I;
R 10 is selected from the group consisting of hydrogen, halo, C 1-4 alkyl, and hydroxy; and
R 8c is selected from the group consisting of hydrogen, halo, cyano, hydroxy, amino, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxy.
13. The compound of claim 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is cyano.
14. The compound of claim 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is CH 2 R 4 and R 4 is:
15. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 10 is hydrogen or fluoro.
16. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a and R 1b are independently selected from the group consisting of hydrogen and halogen.
17. The compound of claim 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
Z 2 is —CH═CHR 13 ;
R 13 is —CH 2 —NR 22c R 22d ; and
R 22c and R 22d are each independently selected from the group consisting of hydrogen and C 1-4 alkyl, or
R 22c and R 22d are taken together to form a 4- to 8-membered optionally substituted heterocyclo.
18. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is any one or more of:
19. The compound of claim 11 , wherein the compound is selected from the group consisting of:
methyl ((1S,2R)-2-((S)-cyano(1-(3-(4-((1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl)sulfonyl) phenoxy)propyl)piperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl) carbamate;
methyl ((1S,2R)-2-((R)-(4-(2-(4-((1-acryloylazetidin-3-yl)sulfonyl)phenoxy)ethoxy)phenyl)(cyano)(3-fluorophenyl)methyl)cyclopentyl) carbamate; and
methyl ((1S,2R)-2-((S)-(4-(2-(4-((1-acryloylazetidin-3-yl)sulfonyl)phenoxy)ethoxy)phenyl)(cyano)(3-fluorophenyl)methyl)cyclopentyl) carbamate, or a pharmaceutically acceptable salt or solvate thereof.
20. The compound of claim 12 , wherein the compound is selected from the group consisting of:
N-((1S,2R)-2-((S)-cyano(1-((1-(4-cyanophenyl)azetidin-3-yl)methyl)piperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)ethenesulfonamide;
N-((1S,2R)-2-((S)-cyano(1-((1-(4-cyanophenyl)azetidin-3-yl)methyl)piperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)acrylamide;
2-chloro-N-((1S,2R)-2-((S)-cyano(1-((1-(4-cyanophenyl)azetidin-3-yl)methyl)piperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)acetamide; and
N-((1S,2R)-2-((S)-cyano(1-((1-(4-cyanophenyl)azetidin-3-yl)methyl)piperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)propiolamide, or a pharmaceutically acceptable salt or solvate thereof.
21. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.