Sulfonyl substituted 1H-indoles as ligands for the 5-hydroxytryptamine receptors
The present invention is directed to compounds of Formula I: which are modulators of the 5-hydroxtryptamine-6 and 5-hydroxytryptamine-2A receptors and which are inhibitors of norepinephrine reuptake. The compounds of the invention, and pharmaceutical composition thereof, are useful in the treatment of disorders related to or associated with the 5-hydroxytryptamine-6 and 5-hydroxtryptamine-2A receptors or with norepinephrine reuptake inhibition.
1. A compound of Formula I:
or pharmaceutically acceptable salt thereof, wherein:
A is C 2-5 alkylene, C 2-5 alkenylene, or C 2-5 alkynylene, wherein each is optionally substituted with 1, 2, 3, or 4 independently selected R A groups;
R 1 is aryl optionally substituted by 1, 2, 3, or 4 independently selected R 1a groups;
each R 2 is, independently, a bond, O, S, C(O), C(O)O, C(O)N(R 2a ), OC(O)N(R 2a ), S(O), S(O) 2 , S(O)N(R 2a ), S(O) 2 N(R 2a ), or N(R 2a );
R 3 is H, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl, wherein said C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 3a groups;
R 4 is H, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl, wherein said C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl are each optionally substituted by 1, 2, 3, or 4 independently R 4a groups;
R 5 is H, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl, wherein said C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 5a groups;
R 6 is H, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl, wherein said C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 6a groups;
or R 5 and R 6 , together with the N atom to which they are attached, form a 3-, 4-, 5-, 6- 7- or 8-membered heterocycloalkyl ring or 5-, 6-, 7- or 8-membered heteroaryl ring, wherein said heterocycloalkyl ring and said heteroaryl ring are each optionally substituted with 1, 2, 3, or 4 independently selected R 8 groups;
each R 7 is, independently, H, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 7a groups;
each R 8 is, independently, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, OR 8b , SR 8b , C(O)R 8b , C(O)NR 8e R 8f , C(O)OR 8c , OC(O)R 8b , OC(O)NR 8e R 8f , NR 8e R 8f , NR 8b C(O)R 8c , NR 8b C(O)OR 8c , S(O)R 8d , S(O)NR 8e R 8f , S(O) 2 R 8c , NR 8b S(O) 2 R 8c , or S(O) 2 NR 8e R 8f , wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 8a groups;
each R A is, independently, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, OR Ab , SR Ab , C(O)R Ab , C(O)NR Ae R Af , C(O)OR Ac , OC(O)R Ab , OC(O)NR Ae R Af , NR Ae R Af , NR Ab C(O)R Ac , NR Ab C(O)OR Ac , S(O)R Ad , S(O)NR Ae R Af , S(O) 2 R Ac , NR Ab S(O) 2 R Ac , or S(O) 2 NR Ae R Af ;
each R Ab , R Ac , R Ae , and R Af is, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl;
each R Ad is, independently, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cyofoalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl;
or any R Ae and R Af , together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
each R 1a is, independently, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, OR 1b , SR 1b , C(O)R 1b , C(O)NR 1e R 1f , C(O)OR 1c , OC(O)R 1b , OC(O)NR 1e R 1f , NR 1e R 1f , NR 1b C(O)R 1c , NR 1b C(O)OR 1c , S(O)R 1d , S(O)NR 1e R 1f , S(O) 2 R 1c , NR 1b S(O) 2 R 1c , or S(O) 2 NR 1e R 1f ;
each R 1b , R 1c , R 1e and R 1f is, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl;
each R 1d is, independently, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl;
or any R 1e and R 1f, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
each R 2a is, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 2b groups;
each R 2b is, independently, halogen, CN, NO 2 , OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl;
each R 3a is, independently, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, OR 3b , SR 3b , C(O)R 3b , C(O)NR 3e R 3f , C(O)OR 3c , OC(O)R 3b , OC(O)NR 3e R 3f , NR 3e R 3f , NR 3b C(O)R 3c , NR 3b C(O)OR 3c , S(O)R 3d , S(O)N R 3e R 3f , S(O) 2 R 3c , NR 3b S(O) 2 R 3c , or S(O) 2 NR 3e R 3f ;
each R 3b , R 3c , R 3e , and R 3f is, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl;
each R 3d is, independently, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl;
or any R 3e and R 3f , together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
each R 4a is, independently, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, OR 4b , SR 4b , C(O)R 4b , C(O)NR 4e R 4f , C(O)O 4c , OC(O)R 4b , OC(O)NR 4e R 4f , NR 4e R 4f , NR 4b C(O)R 4c , NR 4b C(O)OR 4c , S(O)R 4d , S(O)NR 4e R 4f , S(O) 2 R 4c , NR 4b S(O) 2 R 4c , or S(O) 2 NR 4e R 4f ;
each R 4b , R 4c , R 4e , and R 4f is, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl;
each R 4d is, independently, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl;
or any R 4e and R 4f , together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
each R 5a is, independently, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, OR 5b , SR 5b , C(O)R 5b , C(O)NR 5e R 5f , C(O)OR 5c , OC(O)R 5b , OC(O)NR 5e R 5f , NR 5e R 5f , NR 5b C(O)R 5c , NR 5b C(O)OR 5c , S(O)R 5d , S(O)NR 5e R 5f , S(O) 2 R 5c , NR 5b S(O) 2 R 5c , or S(O) 2 NR 5e R 5f ;
each R 5b , R 5c , R 5e , and R 5f is, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyt, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl is optionally substituted with 1, 2, 3, or 4 independently selected R 5′ groups;
each R 5d is, independently, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl, wherein each is optionally substituted with 1, 2, 3, or 4 independently selected R 5′ groups;
or any R 5e and R 5f , together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
each R 6a is, independently, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, OR 6b , SR 6b , C(O)R 6b , C(O)NR 6e R 6f , C(O)OR 6c , OC(O)R 6b , OC(O)NR 6e R 6f , NR 6e R 6f , NR 6b C(O)R 6c , NR 6b C(O)OR 6c , S(O)R 6d , S(O)NR 6e R 6f , S(O) 2 R 6c , NR 6b S(O) 2 R 6c , or S(O) 2 NR 6e R 6f ,
each R 6b , R 6c , R 6e , and R 6f is, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl is optionally substituted with 1, 2, 3, or 4 independently selected R 6′ groups;
each R 6d is, independently, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl, wherein each is optionally substituted with 1, 2, 3, or 4 independently selected R 6′ groups;
or any R 6e and R 6f , together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group;
each R 5′ and R 6′ is, independently, halogen, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl;
each R 7a is, independently, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, OR 7b , SR 7b , C(O)R 7b , C(O)NR 7e R 7f , C(O)OR 7c , OC(O)R 7b , OC(O)NR 7e R 7f , NR 7e R 7f , NR 7b C(O)R 7c , NR 7b C(O)OR 7c , S(O)R 7d , S(O)NR 7e R 7f , S(O) 2 R 7c , NR 7b S(O) 2 R 7c , or S(O) 2 NR 7e R 7f ;
each R 7b , R 7c , R 7e , and R 7f is, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl;
each R 7d is, independently, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl;
or any R 7e and R 7f , together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
each R 8a is, independently, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, OR 8b′ , SR 8b′ , C(O)R 8b′ , CO(O)NR 8e′ R 8f′ , C(O)OR 8c′ , OC(O)R 8b′ , OC(O)NR 8e′ R 8f′ , NR 8e′ R 8f′ , NR 8b′ C(O)R 8c′ , NR 8b′ C(O)OR 8c′ , S(O)R 8d′ , S(O)NR 8e′ R 8f′ , S(O) 2 R 8c′ , NR 8b′ S(O) 2 R 8c′ , or S(O) 2 NR 8e′ R 8f′ ;
each R 8b , R 8c , R 8e , and R 8f is, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl;
each R 8d is, independently, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl;
or any R 8e and R 8f , together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
each R 8b′ , R 8c′ , R 8e′ , and R 8f′ is, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl;
each R 8d′ is, independently, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl;
or any R 8e′ and R 8f′ , together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; and
p is 0, 1, 2, or 3;
with the proviso that if R 7 is halogen, CN, or NO 2 , then R 2 is a bond.
2. The compound of claim 1 wherein A is C 2-5 alkylene.
3. The compound of claim 1 wherein A is ethan-1,2-diyl or propan-1,3-diyl.
4. The compound of claim 1 wherein R 1 is aryl substituted with 1, 2, 3, or 4 independently selected R 1a groups.
5. The compound of claim 1 wherein R 1 is phenyl substituted with 1, 2, 3, or 4 independently selected R 1a groups.
6. The compound of claim 1 wherein R 1 is phenyl or 3-fluorophenyl.
7. The compound of claim 1 wherein R 1 is phenyl.
8. The compound of claim 1 wherein each R 2 is, independently, a bond.
9. The compound of claim 1 wherein R 3 is H, C 1-6 alkyl, or aryl.
10. The compound of claim 1 wherein R 3 is H, methyl, ethyl, or phenyl.
11. The compound of claim 1 wherein R 4 is H.
12. The compound of claim 1 wherein:
R 5 is H, C 1-10 alkyl, cycloalkyl, heterocycloalkylalkyl, or arylalkyl, wherein said C 1-10 alkyl is substituted with 1, 2, 3, or 4 independently selected R 5a groups; and
R 6 is H, C 1-10 alkyl, cycloalkyl, heterocycloalkylalkyl, or arylalkyl, wherein said C 1-10 alkyl is substituted with 1, 2, 3, or 4 independently selected R 6a groups.
13. The compound of claim 1 wherein R 5 and R 6 are each, independently, H, methyl, ethyl, propyl, isopropyl, isobutyl, pentan-3-yl, 1,2,2-trimethylpropyl, 2,2-dimethylpropyl, 2-methyl-1-butyl, 2-hydroxyethyl, dimethylaminopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or (tetrahydrofur-2-yl)methyl.
14. The compound of claim 1 wherein R 5 and R 6 , together with the N atom to which they are attached, form a 3-, 4-, 5-, 6-, 7- or 8-membered heterocycloalkyl ring or 5-, 6-, 7- or 8-membered heteroaryl ring, wherein said heterocycloalkyl ring and said heteroaryl ring are each optionally substituted with 1, 2, 3, or 4 independently selected R 8 groups.
15. The compound of claim 1 wherein R 5 and R 6 , together with the N atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is optionally substituted with 1, 2, 3, or 4 independently selected R 8 groups.
16. The compound of claim 1 wherein R 5 and R 6 , together with the N atom to which they are attached, form a pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 2-methylpiperidin-1-yl, 3-methylpiperidin-1-yl, 2,6-dimethylpiperidin-1-yl, 2-methylpyrrolidin-1-yl, azepan-1-yl, 4-methylpiperazin-1-yl, or azetidin-1-yl ring.
17. The compound of claim 1 wherein each R 7 is H.
18. The compound of claim 1 wherein:
A is C 2-5 alkylene which is optionally substituted with 1, 2, 3, or 4 independently selected R A groups;
each R 2 is, independently, a bond;
R 3 is H, C 1-6 alkyl, cycloalkyl, aryl, or heteroaryl, wherein said C 1-6 alkyl, cycloalkyl, aryl, and heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R 3a groups;
R 4 is H, C 1-6 alkyl, cycloalkyl, aryl, or heteroaryl, wherein said C 1-6 alkyl, cycloalkyl, aryl, and heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R 4a groups;
R 5 is H, C 1-10 alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, or arylalkyl, wherein said C 1-10 alkyl, cycloalkyl, heterocycloalkylalkyl, and arylalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 5a groups;
R 6 is H, C 1-10 alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, or arylalkyl, wherein said C 1-10 alkyl, cycloalkyl, heterocycloalkylalkyl, and arylalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 6a groups;
or R 5 and R 6 , together with the N atom to which they are attached, form a 3-, 4-, 5-, 6- 7- or 8-membered heterocycloalkyl ring or 5-, 6-, 7- or 8-membered heteroaryl ring, wherein said heterocycloalkyl ring and said heteroaryl ring are each optionally substituted with 1, 2, 3, or 4 independently selected R 8 groups; and
each R 7 is, independently, H, halogen, C 1-6 alkyl, cycloalkyl, aryl, or heteroaryl, wherein said C 1-6 alkyl, cycloalkyl, aryl, and heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R 7a groups.
19. The compound of claim 1 wherein:
A is C 2-5 alkylene;
R 1 is aryl, which is optionally substituted by 1, 2, 3, or 4 independently selected R 1a groups;
each R 2 is, independently, a bond;
R 3 is H, C 1-6 alkyl, or aryl, wherein said C 1-6 alkyl and aryl are each optionally substituted by 1, 2, 3, or 4 independently selected R 3a groups;
R 4 is H;
R 5 is H, C 1-10 alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, or arylalkyl, wherein said C 1-10 alkyl, cycloalkyl, heterocycloalkylalkyl, and arylalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 5a groups;
R 6 is H, C 1-10 alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, or arylalkyl, wherein said C 1-10 alkyl, cycloalkyl, heterocycloalkylalkyl, and arylalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 6a groups;
or R 5 and R 6 , together with the N atom to which they are attached, form a 3-, 4-, 5-, 6- 7- or 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is optionally substituted with 1, 2, 3, or 4 independently selected R 8 groups; and
each R 7 is, independently, H.
20. The compound of claim 1 wherein:
A is ethan-1,2-diyl or propan-1,3-diyl;
R 1 is phenyl, which is optionally substituted by 1, 2, 3, or 4 independently selected R 1a groups;
each R 2 is, independently, a bond;
R 3 is H, C 1-6 alkyl, or phenyl;
R 4 is H;
R 5 is H, C 1-10 alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, or arylalkyl, wherein said C 1-10 alkyl, cycloalkyl, heterocycloalkylalkyl, and arylalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 5a groups;
R 6 is H, C 1-10 alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, or arylalkyl, wherein said C 1-10 alkyl, cycloalkyl, heterocycloalkylalkyl, and arylalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 6a groups;
or R 5 and R 6 , together with the N atom to which they are attached, form a 3-, 4-, 5-, 6- 7- or 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is optionally substituted with 1, 2, 3, or 4 independently selected R 8 groups;
each R 7 is, independently, H;
each R 1a is, independently, halogen;
each R 5a is, independently, OR 5b or NR 5e R 5f ;
each R 6a is, independently, OR 6b or NR 6e R 6f ;
each R 8 is, independently, C 1-6 alkyl.
21. The compound of claim 1 wherein:
A is ethan-1,2-diyl or propan-1,3-diyl;
R 1 is phenyl, which is optionally substituted by 1, 2, 3, or 4 independently selected R 1a groups;
each R 2 is, independently, a bond;
R 3 is H, methyl, ethyl, or phenyl;
R 4 is H;
R 5 is H, C 1-10 alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, or arylalkyl, wherein said C 1-10 alkyl, cycloalkyl, heterocycloalkylalkyl, and arylalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 5a groups;
R 6 is H, C 1-10 alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, or arylalkyl, wherein said C 1-10 alkyl, cycloalkyl, heterocycloalkylalkyl, and arylalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 6a groups;
or R 5 and R 6 , together with the N atom to which they are attached, form a 3-, 4-, 5-, 6- 7- or 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is optionally substituted with 1, 2, 3, or 4 independently selected R 8 groups;
each R 7 is, independently, H;
each R 1a is, independently, F;
each R 5a is, independently, OH or N(CH 3 ) 2 ;
each R 6a is, independently, OH or N(CH 3 ) 2 ;
each R 8 is, independently, methyl; and
p is 0 or 1.
22. The compound of claim 1 wherein:
A is ethan-1,2-diyl or propan-1,3-diyl;
R 1 is phenyl or 3-fluorophenyl;
R 3 is H, methyl, ethyl or phenyl;
R 4 is H
R 5 is H, methyl, ethyl, propyl, isopropyl, isobutyl, pentan-3-yl, 1,2,2-trimethylpropyl, 2,2-dimethylpropyl, 2-methyl-1-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or (tetrahydrofur-2-yl)methyl, wherein said ethyl is optionally substituted with 1 R 5a ;
R 6 is H, methyl, ethyl, propyl, isopropyl, isobutyl, pentan-3-yl, 1,2,2-trimethylpropyl, 2,2-dimethylpropyl, 2-methyl-1-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or (tetrahydrofur-2-yl)methyl, wherein said propyl is optionally substituted with 1 R 6a ;
or R 5 and R 6 , together with the N atom to which they are attached, form a pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 2-methylpiperidin-1-yl, 3-methylpiperidin-1-yl, 2,6-dimethyipiperidin-1-yl, 2-methylpyrrolidin-1-yl, azepan-1-yl, 4-methylpiperazin-1-yl, or azetidin-1-yl ring;
each R 5a is, independently, OH;
each R 6a is, independently, N(CH 3 ) 2 ; and
p is 0.
23. The compound of claim 1 wherein:
A is ethan-1,2-diyl or propan-1,3-diyl;
R 1 is phenyl or 3-fluorophenyl;
R 3 is H, methyl, ethyl or phenyl;
R 4 is H
R 5 is H, methyl, ethyl, propyl, isopropyl, isobutyl, pentan-3-yl, 1,2,2-trimethylpropyl, 2,2-dimethylpropyl, 2-methyl-1-butyl, 2-hydroxyethyl, dimethylaminopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or (tetrahydrofur-2-yl) methyl,
R 6 is H, methyl, ethyl, propyl, isopropyl, isobutyl, pentan-3-yl, 1,2,2-trimethylpropyl, 2,2-dimethylpropyl, 2-methyl-1-butyl, 2-hydroxyethyl, dimethylaminopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or (tetrahydrofur-2-yl)methyl.
or R 5 and R 6 , together with the N atom to which they are attached, form a pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 2-methylpiperidin-1-yl, 3-methylpiperidin-1-yl, 2,6-dimethylpiperidin-1-yl, 2-methylpyrrolidin-1-yl, azepan-1-yl, 4-methylpiperazin-1-yl or azetidin-1-yl ring; and
p is 0.
24. The compound of claim 1 having Formula I-A:
or pharmaceutically acceptable salt thereof.
25. The compound of claim 1 having Formula I-B:
or pharmaceutically acceptable salt thereof.
26. The compound of claim 1 having Formula I-C:
or pharmaceutically acceptable salt thereof.
27. The compound of claim 1 having Formula I-D:
or pharmaceutically acceptable salt thereof.
28. The compound of claim 1 which is:
N,N-dimethyl-N-{2-[3-(phenylsulfonyl)-1H-indol-5-yl]ethyl}amine;
N{2-[3-(phenylsulfonyl)-1H-indol-5-yl]ethyl}-N-propylamine;
N{2-[3-(phenylsulfonyl)-1H-indol-5-yl]ethyl}propan-2-amine;
N{2-[3-(phenylsulfonyl)-1H-indol-5-yl]ethyl}cyclopropanamine;
N{2-[3-(phenylsulfonyl)-1H-indol-5-yl]ethyl}cyclopentanamine;
N-benzyl-N-{2[3-(phenlylsulfonyl)-1H-indol-5-yl]ethyl}amine;
N-ethyl-N-methyl-N-{2-[3-(phenylsulfonyl)-1H-indol-5-yl]ethyl}amine;
N,N-diethyl-N-{2-[3-(phenylsulfonyl)-1H-indol-5-yl]ethyl}amine;
3-(phenylsulfonyl)-5-(2-pyrrolidin-1-ylethyl)-1H-indole;
3-(phenylsulfonyl)-5-(2-piperidin-1-ylethyl)-1H-indole;
5-(2-morpholin-4-ylethyl)-3-(phenylsulfonyl)-1H-indole;
{2-[3-(phenylsulfonyl)-1H-indol-5-yl]ethyl}amine;
3-(phenylsulfonyl)-5-(2-piperazin-1-ylethyl)-1H-indole;
N-methyl-N-{2[3-(phenylsulfonyl)-1H-indol-5-yl]ethyl}amine;
N-methyl-N-{2[2-methyl-3-phenysulfonyl-1H-indol-5-yl]ethyl}amine;
N-{2-[2-ethyl-3-(phenylsulfonyl)-1-H-indol-5-yl]ethyl}-N-methylamine;
N-methyl-N-{2-[2-phenyl-3-(phenylsulfonyl)-1H-indol-5-yl]ethyl}amine;
N,N-dimethyl-N-{2-[3-(phenylsulfonyl)-1H-indol-7-yl]ethyl}amine;
N-methyl-N-{2-[3-(phenylsulfonyl)-1H-indol-7-yl]ethyl}amine;
N-{2-[3-(phenylsulfonyl)-1H-indol-7-yl]ethyl}-N-propylamine;
N-{2-[3-(phenylsulfonyl)-1H-indol-7-yl]ethyl}propan-2-amine;
N-{2-[3-(phenylsulfonyl)-1H-indol-7-yl]ethyl}cyclopropanamine;
N-{2-[3-(phenylsulfonyl)-1H-indol-7-yl]ethyl}cyclopentanamine;
N-ethyl-N-methyl-N-{2-[3-(phenylsulfonyl)-1H-indol-7-yl]ethyl}amine;
N,N-diethyl-N-{2-[3-(phenylsulfonyl)-1H-indol-7-yl]ethyl}amine;
3-(phenylsulfonyl)-7-(2-pyrrolidin-1-ylethyl)-1H-indole;
3-(phenylsulfonyl)-7-(2-piperidin-1-ylethyl)-1H-indole;
7-(2-morpholin-4-ylethyl)-3-(phenylsulfonyl)-1H-indole;
{2-[3-(phenylsulfonyl)-1H-indol-7-yl]ethyl}amine;
3-(phenylsulfonyl)-7-(2-piperazin-1-ylethyl)-1H-indole;
N,N-dimethyl-N-{2-[3-(phenylsulfonyl)-1H-indol-4-yl]ethyl}amine;
N-methyl-N-{2-[3-(phenylsulfonyl)-1H-indol-4-yl]ethyl}amine;
N-ethyl-N-{2-[3-(phenylsulfonyl)-1H-indol-4-yl]ethyl}amine;
N-{2-[3-(phenylsulfonyl)-1H-indol-4-yl]ethyl}-N-propylamine;
N-{2-[3-(phenylsulfonyl)-1H-indol-4-yl]ethyl}propan-2-amine;
N-{2-[3-(phenylsulfonyl)-1H-indol-4-yl]ethyl}cyclopropanamine;
N-{2-[3-(phenylsulfonyl)-1H-indol-4-yl]ethyl}cyclobutanamine;
N-{2-[3-(phenylsulfonyl)-1H-indol-4-yl]ethyl}cyclopentanamine;
N-{2-[3-(phenylsulfonyl)-1H-indol-4-yl]ethyl}cyclohexanamine;
N-ethyl-N-methyl-N-{2-[3-(phenylsulfonylyl)-1H-indol-4-yl]ethyl}amine;
N-cyclohexyl-N-methyl-N-{2-[3-(phenylsulfonyl)-1H-indol-4-yl]ethyl}amine;
N,N-diethyl-N-{2-[3-(phenylsulfonyl)-1H-indol-4-yl]ethyl}amine;
3-(phenylsulfonyl)-4-(2-pyrrolidin1-ylethyl)-1H-indole;
3-(phenylsulfonyl)-4-(2-piperidin-1-ylethyl)-1H-indole;
4-(2-morpholin-4-ylethyl)-3-(phenylsulfonyl)-1H-indole;
N-{2-[3-(phenylsulfonyl)-1H-indol-4-yl]ethyl}-N-(1,2,2-trimethylpropyl)amine;
N-benzyl-N-{2-[3-(phenylsulfonyl)1H-indol-4-yl]ethyl}amine;
N-isobutyl-N-{2-[3-(phenylsulfonyl)1H-indo-4-yl]ethyl}amine;
N-(2,2-dimethylpropyl)-N-{2-[3-(phenylsulfonyl)1H-indo-4-yl]ethyl}amine;
N,N-dimethyl-N′-{2-[3-(phenylsulfonyl)1H-indol-4-yl]ethyl}propane-1 ,3-diamine;
N-{2-[3-(phenylsulfonyl)-1H-indol-4-yl]ethyl}-N-((tetrahydrofur-2-yl)methyl)amine;
4-{2-[(2R*,6S*)-2,6-dimethylpiperidin-1-yl]ethyl}-3-(phenylsulfonyl)-1H-indole;
N-methyl-N-{2-[3-(phenylsulfonyl)-1H-indole-4-yl]ethyl}propan-2-amine;
N-ethyl-N-{2-[3-(phenylsulfonyl)-1H-indole-4-yl]ethyl}propan-2-amine;
4-[2-(2-methylpyrrolidin-1-yl)ethyl]-3-(phenylsulfonyl)-1H-indole;
4-[2-(2-methylpiperidin-1-yl)ethyl]-3-(phenylsulfonyl)-1H-indole;
4-[2-(3-methylpiperidin-1-yl)ethyl]-3-(phenylsulfonyl)-1H-indole;
4-(2-azepan-1-ylethyl)-3-(phenylsulfonyl)-1H-indole;
4-[2(4-methylpiperazin-1-yl]ethyl-3-(phenylsulfonyl)-1H-indole;
3-(phenylsulfonyl)-4-(2-piperazin-1-ylethyl)-1H-indole;
{2-[3-(phenylsulfonyl)-1H-indol-4-yl]ethyl}amine;
N-methyl-N-{2-[3-(3-fluorophenylsulfonyl)-1H-indol-4-yl]ethyl}amine;
N-ethyl-N-{2-[3-(3-fluorophenylsulfonyl)-1H-indol-4-yl]ethyl}amine;
N,N-dimethyl-N-{2-[3-(3-fluorophenylsulfonyl)-1H-indol-4-yl]ethyl}amine;
N-{2-[3-(3-fluorophenylsulfonyl)-1H-indol-4-yl]ethyl}-N-propylamine;
N-{2-[3-(3-fluorophenylsulfonyl)-1H-indol-4-yl]ethyl}propan-2-amine;
N-{2-[3-(3-fluorophenylsulfonyl)-1H-indol-4-yl]ethyl}cyclopropanamine;
N-{2-[3-(3-fluorophenylsulfonyl)-1H-indol-4-yl]ethyl}cyclobutanamine;
N-{2-[3-(3-fluorophenylsulfonyl)-1H-indol-4-yl]ethyl}cyclopentanamine;
N-{2-[3-(3-fluorophenylsulfonyl)-1H-indol-4-yl]ethyl}cyclohexanamine;
N-ethyl-N-methyl-N-{2-[3-(3-fluorophenylsulfonyl)-1H-indol-4-yl]ethyl}amine;
N-cyclohexyl-N-methyl-N-{2-[3-(3-fluorophenylsulfonyl)-1H-indol-4-yl]ethyl}amine;
N,N-diethyl-N-{2-[3-(3-fluorophenylsulfonyl)-1H-indol-4-yl]ethyl}amine;
3-(3-fluorophenylsulfonyl)-4-(2-pyrrolidin-1-ylethyl)-1H-indole;
3-(3-fluorophenylsulfonyl)-4-(2-piperidin-1-ylethyl)-1H-indole;
4-(2-morpholin-4-ylethyl)-3-(3-fluorophenylsulfonyl)-1H-indole;
N-isobutyl-N-{2-[3-(3-fluorophenylsulfonyl)-1H-indol-4-yl]ethyl}amine;
(1-Ethyl-propyl)-{2-[3-(3-fluorophenylsulfonyl)-1H-indol-4-yl]-ethyl}-amine;
{2-[3-(3-Fluorophenylsulfonyl)-1-indol-4-yl]-ethyl}-(2-methyl-butyl)-amine;
N-{2-[3-(3-fluorophenylsulfonyl)-1H-indol-4-yl]-ethyl}-N-(1,2,2-trimethylpropyl)amine;
N-(2,2-dimethylpropyl)-N-{2-[3-(3-fluorophenylsulfonyl)-1H-indol-4-yl]ethyl}amine;
N-{2-[3-(3fluorophenylsulfonyl)-1H-indol-4-yl]ethyl}-N-((tetrahydrofur-2-yl)methyl)amine;
N′-{2-[3-(3-Fluorophenylsulfonyl)-1H-indol-4-yl]-ethyl}-N,N-dimethyl-propane-1,3-diamine;
2-({2-[3-(3-Fluorophenylsulfonyl)-1H-indol-4-yl]1-ethyl}-methyl-amino)-ethanol;
{2-[3-(3-fluorophenylsulfonyl)-1H-indol-6-yl]ethyl}amine;
N,N-dimethyl-N-{2-[3-(phenylsulfonyl)-1H-indol-6-yl]ethyl}amine;
N-methyl-N-{2-[3-(phenylsulfonyl)-1H-indol-6-yl]ethyl}amine;
N-ethyl-N-{2-[3-(phenylsulfonyl)-1H-indol-6-yl]ethyl}amine;
N-{2-[3-(phenylsulfonyl)-1H-indol-6-yl]ethyl}-N-propylamine;
N-{2-[3-(phenylsulfonyl)-1H-indol-6-yl]ethyl}propan-2-amine;
N-{2-[3-(phenylsulfonyl)-1H-indol-6-yl]ethyl}cyclopropanamine;
N-{2-[3-(phenylsulfonyl)-1H-indol-6-yl]ethyl}cyclobutanamine;
N-{2-[3-(phenylsulfonyl)-1H-indol-6-yl]ethyl}cyclopentanamine;
N-{2-[3-(phenylsulfonyl)-1H-indol-6-yl]ethyl)}cyclohexanamine;
N-ethyl-N-methyl-N-{2-[3-(phenylsulfonyl)-1H-indol-6-yl]ethyl}amine;
N-cyclohexyl-N-methyl-N-{2-[3-(phenylsulfonyl)-1H-indol-6-yl]ethyl}amine;
N,N-diethyl-N-{2-[3-(phenylsulfonyl)-1H-indol-6-yl]ethyl}amine;
3-(phenylsulfonyl)-6-(2-pyrrolidin-1-ylethyl)-1H-indole;
3-(phenylsulfonyl)-6-(2-piperidin-1-ylethyl)-1H-indole;
4-(2-morpholin-6-ylethyl)-3-(phenylsulfonyl)-1H-indole;
3-phenylsulfonyl-6-(2-piperazin-1-yl-ethyl)-1H-indole;
N-isobutyl-N-{2-[3-(phenylsulfonyl)-1H-indol-6-yl]ethyl}amine;
(1-Ethyl-propyl)-{2-[3-(phenylsulfonyl)-1H-indol-6-yl]-ethyl}-amine;
{2-[3-(phenylsulfonyl)-1H-indol-6-yl]-ethyl}-(2-methyl-butyl)-amine;
N-{2-[3-(phenylsulfonyl)-1H-indol-6-yl]ethyl}-N-(1,2,2-trimethylpropyl)amine;
N-(2,2-dimethylpropyl)-N-{2-[3-(phenylsulfonyl)-1H-indol-6-yl]ethyl}amine;
N-{2-[3-(phenylsulfonyl)-1H-indol-6-yl]ethyl}-N-((tetrahydrofur-2-yl)methyl)amine;
6-(2-Azetidin-1-yl-ethyl)-3-phenylsulfonyl-1H-indole;
{2-[3-(phenylsulfonyl)-1H-indol-6-yl]ethyl}amine;
N-isopropyl-3-[3-(phenylsulfonyl)-1H-indol-4-yl]propan-1-amine;
3-(phenylsulfonyl)-4-(3-piperidin-1-ylpropyl)-1H-indole; or
N-ethyl-N-methyl-3-[3-(phenylsulfonyl)-1H-indol-4-yl]propan-1-amine;
or pharmaceutically acceptable salt thereof.
29. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or pharmaceutically acceptable salt thereof.