Substituted piperidine compounds
View Patent ↗The present disclosure provides substituted piperidine compounds having Formula (I), and the pharmaceutically acceptable salts and solvates thereof, wherein R 1 , B, X, and Z are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I to treat a disorder responsive to the blockade of SMYD proteins such as SMYD3 or SMYD2. Compounds of the present disclosure are especially useful for treating cancer.
1. A compound having Formula I:
or a pharmaceutically acceptable salt or hydrate thereof,
wherein:
B is:
X is selected from the group consisting of —S(═O) 2 —, S(═O) 2 N(R 7 )—, —S(═O) 2 C(R 8 )(H)—, —C(═O)—, —C(═O)N(R 7 )—, —C(═O)O—, —C(═O)C(R 8 )(H)—, and —S(═O) 2 N(R 7 )C(═O)N(R 11 )—; or X is absent;
wherein the sulfur atom of —S(═O) 2 N(R 7 )—, —S(O) 2 C(R 8 )(H)—, or —S(═O) 2 N(R 7 )C(═O)N(R 11 )— is attached to the nitrogen atom of B, the carbon atom of —C(═O)N(R 7 )— or —C(═O)O— is attached to the nitrogen atom of B, and the carbonyl carbon atom of —C(═O)C(R 8 )(H)— is attached the nitrogen atom of B;
Z is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, fluoroalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, [(cycloalkyl)alkylamino]alkyl, [(heterocyclo)alkylamino]alkyl, alkoxyalkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C 3-12 cycloalkyl, aralkyl, and heteroaralkyl;
R 1 is cyclopropyl;
R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, C 1-6 alkyl, C 3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C 6-14 aryl, aralkyl, and alkoxycarbonyl; or
R 2a and R 2b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
R 3a and R 3b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
R 4a and R 4b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 3a , R 3b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
R 5a and R 5b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
R 2a and R 5a taken together form a C 1-4 bridge; and R 2b , R 3a , R 3b , R 4a , R 4b , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
R 3a and R 4a taken together form a C 1-4 bridge; and R 2a , R 2b , R 3b , R 4a , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
R 2a and R 4a taken together form a C 1-4 bridge; and R 2b , R 3a , R 3b , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
R 3a and R 5a taken form a C 1-4 bridge; and R 2a , R 2b , R 3b , R 4a , R 4b , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl;
R 6 is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 7 is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 8 is selected from the group consisting of hydrogen, C 1-4 alkyl, amino, alkylamino, dialkylamino, cycloalkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, and —N(R 9 )C(═O)R 10 ;
R 9 is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 10 is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl; and
R 11 is selected from the group consisting of hydrogen and C 1-4 alkyl;
with the proviso that said compound having Formula I is not:
5-cyclopropyl-N-(piperidin-4-yl)isoxazole-3-carboxamide;
N-(8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide;
N-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide;
5-cyclopropyl-N-(1-(methylsulfonyl)piperidin-4-yl)isoxazole-3-carboxamide;
N-(1-benzylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide;
5-cyclopropyl-N-(1-isobutyrylpiperidin-4-yl)isoxazole-3-carboxamide;
N-(1-benzoylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide;
ethyl 4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylate;
5-cyclopropyl-N-(1-(furan-3-carbonyl)piperidin-4-yl)isoxazole-3-carboxamide;
5-cyclopropyl-N-(1-((4-methoxyphenyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide;
5-cyclopropyl-N-(1-tosylpiperidin-4-yl)isoxazole-3-carboxamide;
5-cyclopropyl-N-(1-(2,6-dimethylpyrimidin-4-yl)piperidin-4-yl)isoxazole-3-carboxamide;
N-(1-((4-acetamidophenyl)sulfonyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide; or
5-cyclopropyl-N-(1-(4-isopropyl-5-(pyridin-4-yl)pyrimidin-2-yl)piperidin-4-yl)isoxazole-3-carboxamide; or.
2. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:
3. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:
and R 2a s selected from the group consisting of halo, C 1-6 alkyl, C 3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C 6-14 aryl, aralkyl, and alkoxycarbonyl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:
and R 3a is selected from the group consisting of halo, C 1-6 alkyl, C 3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C 6-14 aryl, aralkyl, and alkoxycarbonyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:
and R 2a and R 2b are each independently selected from the group consisting of halo and C 1-6 alkyl; or
R 2a and R 2b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:
and R 3a and R 3b are each independently selected from the group consisting of halo and C 1-6 alkyl; or
R 3a and R 3b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:
and R 3a and R 5a are each independently C 1-6 alkyl; or
R 3a and R 5a taken together form a C 1-4 bridge.
8. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:
and R 2a and R 3a are each independently C 1-6 alkyl.
9. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:
and R 3a and R 4a are each independently C 1-6 alkyl; or
R 3a and R 4a taken together form a C 1-4 bridge.
10. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:
and R 2a and R 5a are each independently selected from the group consisting of C 1-6 alkyl and alkoxycarbonyl; or
R 2a and R 5a taken together form a C 1-6 bridge.
11. The compound of claim 1 having Formula III:
or a pharmaceutically acceptable salt or hydrate thereof.
12. The compound of claim 1 having Formula IV:
or a pharmaceutically acceptable salt or hydrate thereof.
13. The compound of claim 1 having Formula V:
or a pharmaceutically acceptable salt or hydrate thereof.
14. The compound of claim 1 having Formula VI:
or a pharmaceutically acceptable salt or hydrate thereof.
15. The compound of claim 1 having Formula VII:
or a pharmaceutically acceptable salt or hydrate thereof.
16. The compound of claim 1 having Formula VIII:
or a pharmaceutically acceptable salt or hydrate thereof.
17. The compound of claim 1 having Formula IX:
or a pharmaceutically acceptable salt or hydrate thereof.
18. The compound of claim 1 having Formula X:
or a pharmaceutically acceptable salt or hydrate thereof.
19. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt or hydrate thereof.