HDAC inhibitors
Disclosed herein are compounds of formula (I), and methods of inhibiting histone deacetylase (“HDAC”) enzymes (e.g., HDAC1, HDAC2, and HDAC3) using compounds of formula (I).
1. A method of treating a disease or disorder wherein the disease or disorder is a neurological disorder selected from myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, Niemann Pick, Pitt Hopkins, spinal and bulbar muscular atrophy, and Alzheimer's disease; an inflammatory disease; a memory impairment condition; or a drug addiction in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure of formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
R 1 —X is attached to only one of the ring nitrogen atoms;
X is:
(i) —Y—[C(R a ) 2 ] a -A-[C(R b ) 2 ] b —B—;
(ii) direct bond; or
(iii) C═O, C(R j ) 2 —C(═O), C(═O)—C(R j ) 2 , SO 2 —NR k , NR k —SO 2 , C(═O)NR k or NR k —C(═O);
wherein:
Y is bond, CR c ═CR d , O, NR e , or S(O) m ;
each of A and B is, independently, a bond, O, NR e , or S(O) m ;
a is 1, 2, or 3;
b is 0, 1, 2, or 3;
m is 0, 1, or 2;
each occurrence of R a and R b is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH 2 , OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano; or
one or more of the following can apply with respect to R a and R b :
any two R a , together with the carbons to which each is attached, together form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O, S(O) m and NR g ; or
one R e and one R b , together with the carbons to which each is attached, form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O)m and NR g ; or
any two R b , together with the carbons to which each is attached, form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the ring atoms is selected from O; S(O)m and NR g ;
each of R c and R d is independently selected from H, F, OH, C1-C6 alkyl, C3-C5 cycloalkyl, NH 2 , OCO—(C1-C6 alkyl), OCO—(C3-C5 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;
or R c and R d , together with the carbons to which each is attached form a C5-C7 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which from 1-2 of the heterocyclyl ring atoms are independently selected from O, S(O) m and NR g′ ;
each occurrence of R e , R f , R g and R g′ is independently selected from H, C1-C6 alkyl, —C(═O)H, —C(═O)R h , C(═O)O(C1-C6 alkyl), C(═O)N(R j ) 2 , and SO 2 —R h ; wherein R h is selected from C1-C6 alkyl, CH 2 -(heteroaryl including 5-10 ring atoms), CH 2 —(C6-C10 aryl), and C6-C10 aryl; and each occurrence of R i is independently selected from H, C1-C6 alkyl, CH 2 -(heteroaryl including 5-10 ring atoms), CH 2 —(C6-C10 aryl), and C6-C10 aryl;
each occurrence of R j is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH 2 , OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;
or R j —C—R j together form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O)m and NR j′ ;
each occurrence of R j′ and R k is independently selected from H, C1-C6 alkyl, —C(═O)H, —C(═O)R m , C(═O)O(C1-C6 alkyl), C(═O)N(R n ) 2 , and SO 2 —R m , wherein R m is selected from C1-C6 alkyl, CH 2 -(heteroaryl including 5-10 ring atoms), CH 2 —(C6-C10aryl), and C6-C10aryl; and each occurrence of R n is independently selected from H, C1-C6 alkyl, CH 2 -(heteroaryl including 5-10 ring atoms), CH 2 —(C6-C10 aryl), and C6-C10 aryl, and wherein the aryl and heteroaryl portion in R m and R n can be optionally substituted with 1-3 independently selected substituents F, C1-C6 alkyl, fluoro C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, or cyano;
further wherein:
(a) when each of A and B is a bond, and b is 0, then X has the following formula: —Y—[C(R a ) 2 ] a —;
(b) when b is 0 or 1, then A and B cannot both be heteroatoms; and
(c) when A or B serves as the point of connection of X to the nitrogen ring atoms, then A or B cannot be a heteroatom;
R1 is:
(i) monocyclic or bicyclic heteroaryl including from 5-10 ring atoms, which is optionally substituted with from 1-3 R o ; wherein from 1-4 of the ring atoms are a heteroatom independently selected from O, N, N—H, N—R o , and S;
(ii) C6-C10 aryl, which is optionally substituted with from 1-3 R o ;
(iii) C3-C10 cycloalkyl or C3-C10 cycloalkenyl, each of which is optionally substituted with from 1-6 R o ; or
(iv) hydrogen;
R4 is H or R o and each occurrence of R o is independently selected from the group consisting of halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C 1 -C 4 )alkyl; C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6 alkyl) 2 N—; —N*(R o′ ) 2 , wherein R o′ —N*—R o′ together form a saturated ring having 5 or 6 ring atoms, in which 1 or 2 ring atoms are optionally a heteroatom independently selected from NH, N(C1-C6alkyl), O, or S; formyl; formyl(C 1 -C 4 ) alkyl; cyano; cyano(C 1 -C 4 ) alkyl; benzyl; benzyloxy; (heterocyclyl)-(C0-C6) alkyl, wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms are a heteroatom independently selected from NH, N(alkyl), O, or S; phenyl; heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ring atoms are a heteroatom independently selected from O, N, N—H, N—R o″ , and S, each of which is optionally substituted with from 1-3 R o″ ; SO 2 —(C1-C6)alkyl; SO—(C1-C6)alkyl; and nitro;
each occurrence of R o″ is independently selected from the group consisting of halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C 1 -C 4 )alkyl; C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6 alkyl) 2 N—; formyl; formyl(C 1 -C 4 ) alkyl; cyano; cyano(C 1 -C 4 ) alkyl; benzyl; benzyloxy; (heterocyclyl)-(C0-C6) alkyl, wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms are a heteroatom independently selected from NH, N(C1-C6alkyl), 0, or S; phenyl; heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ring atoms are a heteroatom independently selected from O, N, N—H, N—(C1-C6 alkyl), and S; SO 2 —(C1-C6)alkyl; SO—(C1-C6)alkyl; and nitro;
R5 is selected from the group consisting of: hydrogen, halogen; C1-C6 alkyl;
fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C 1 -C 4 )alkyl; (C1-C6 alkyl)C(O)—; formyl; formyl(C 1 -C 4 ) alkyl; cyano; cyano(C 1 -C 4 ) alkyl; benzyl; (heterocyclyl)-(C0-C6)alkyl, wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms are a heteroatom independently selected from NH, N(C1-C6alkyl), O, or S; phenyl; heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ring atoms are a heteroatom independently selected from O, N, N—H, and S; SO 2 —(C1-C6)alkyl; SO—(C1-C6)alkyl; and nitro;
R2 is selected from H, F, Cl, CF 3 , CF 2 CF 3 , CH 2 CF 3 , OCF 3 , OCHF 2 , phenyl; or phenyl substituted with 1-3 R o ; and
R3 is H, F, or Cl.
2. The method of claim 1 , wherein the compound or salt has formula (Ia) or (Ib):
3. The method of claim 1 , wherein X is —Y—[C(R a ) 2 ] a -A-[C(R b ) 2 ] b —B—.
4. The method of claim 1 , wherein X is CH 2 or (CH 2 ) 2-4 .
5. The method of claim 1 , wherein X is bond —CH═CH—C(R a ) 2 — or —CH═CHC(R a ) 2 C(R a ) 2 —.
6. The method of claim 1 , wherein R2 is hydrogen, and R3 is F or Cl.
7. The method of claim 1 , wherein —XR 1 is CH 2 cyclopropyl, optionally substituted with one or more of C1-C3alkyl, C1-C3alkoxy, and halo.
8. The method of claim 1 , wherein —XR 1 is CH 2 pyrazolyl, optionally substituted with one or more substituents selected from methyl and halo.
9. The method of claim 1 , wherein:
X is:
(i) —Y—[C(R a ) 2 ] a -A-[C(R b ) 2 ] b —B—;
(ii) direct bond; or
(iii) C═O, C(R j ) 2 —C(═O), C(═O)—C(R j ) 2 , SO 2 —NR k , NR k —SO 2 , C(═O)NR k or NR k —C(═O);
R1 is:
(i) monocyclic or bicyclic heteroaryl including from 5-10 ring atoms, which is optionally substituted with from 1-3 R o ; wherein from 1-4 of the ring atoms are a heteroatom independently selected from O, N, N—H, N—R o , and S;
(ii) C6-C10 aryl, which is optionally substituted with from 1-3 R o ;
(iii) C3-C10 cycloalkyl or C3-C10 cycloalkenyl, each of which is optionally substituted with from 1-3 R o ; or
(iv) hydrogen;
R o is independently selected from the group consisting of halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C1-C4)alkyl; C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6 alkyl) 2 N—; —N*(R o′ ) 2 , wherein R o′ —N*—R o′ together form a saturated ring having 5 or 6 ring atoms, in which 1 or 2 ring atoms are optionally a heteroatom independently selected from NH, N(C1-C6alkyl), O, or S; cyano; phenyl; heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ring atoms are a heteroatom independently selected from O, N, N—H, N—R o″ , and S, each of which is optionally substituted with from 1-3 R o″ ; and SO 2 —(C1-C6)alkyl;
R4 is hydrogen or halo;
R5 is hydrogen; and
(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 is fluoro; or (iii) R2 is a substituent other than hydrogen, and R3 is hydrogen.
10. The method of claim 9 , wherein X is CH 2 or (CH 2 ) 2-4 .
11. The method of claim 9 , wherein R1 is C3-C6 cycloalkyl, optionally substituted with from 1-3 R o .
12. The method of claim 1 , wherein:
X is —Y—[C(R a ) 2 ] a -A-[C(R b ) 2 ] b —B—;
R1 is:
(i) monocyclic or bicyclic heteroaryl including from 5-10 ring atoms, which is optionally substituted with from 1-3 R o ; wherein from 1-4 of the ring atoms are a heteroatom independently selected from O, N, N—H, N—R o , and S;
(ii) C6-C10 aryl, which is optionally substituted with from 1-3 R o ; or
(iii) C3-C10 cycloalkyl or C3-C10 cycloalkenyl, each of which is optionally substituted with from 1-3 R o ; or
(iv) hydrogen;
R o is independently selected from the group consisting of halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C1-C4)alkyl; C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6 alkyl) 2 N—; —N*(R o′ ) 2 , wherein R o′ —N*—R o′ together form a saturated ring having 5 or 6 ring atoms, in which 1 or 2 ring atoms are optionally a heteroatom independently selected from NH, N(C1-C6alkyl), O, or S; cyano; phenyl; heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ring atoms are a heteroatom independently selected from O, N, N—H, N—R o″ , and S, each of which is optionally substituted with from 1-3 R o″ ; and SO 2 —(C1-C6)alkyl;
R4 is hydrogen or halo;
R5 is hydrogen; and
(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 is fluoro; or (iii) R2 is a substituent other than hydrogen, and R3 is hydrogen.
13. The method of claim 1 , wherein:
X is —Y—[C(R a ) 2 ] a -A-[C(R b ) 2 ]—B—;
R1 is C3-C10cycloalkyl or C3-C10 cycloalkenyl, optionally substituted with from 1-3 R o ;
R o is independently selected from the group consisting of: halogen; C1-C6 alkyl;
fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C1-C4)alkyl; C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl) 2 N—; cyano; and SO 2 —(C1-C6)alkyl;
R4 is hydrogen or halo;
R5 is hydrogen; and
(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 is fluoro; or (iii) R2 is a substituent other than hydrogen, and R3 is hydrogen.
14. The method of claim 1 , wherein:
X is —Y—[C(R a ) 2 ] a -A-[C(R b ) 2 ] b —B—;
R1 is monocyclic or bicyclic heteroaryl including from 5-10 ring atoms, optionally substituted with from 1-3 R o ; wherein from 1-4 of the ring atoms are a heteroatom independently selected from O, N, N—H, N—R o , and S;
R o is independently selected from the group consisting of: halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C 1 -C 4 )alkyl; C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl) 2 N—; cyano; and SO 2 —(C1-C6)alkyl;
R4 is hydrogen or halo;
R5 is hydrogen; and
(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 is fluoro; or (iii) R2 is a substituent other than hydrogen, and R3 is hydrogen.
15. The method of claim 1 , wherein:
X is —Y—[C(R a ) 2 ] a -A-[C(R b ) 2 ] b —B—;
R1 is C6-C10 aryl, optionally substituted with from 1-3 R o ;
R o is independently selected from the group consisting of: halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C 1 -C 4 )alkyl; C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl) 2 N—; cyano; and SO 2 —(C1-C6)alkyl;
R4 is hydrogen or halo;
R5 is hydrogen; and
(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 is fluoro; or (iii) R2 is a substituent other than hydrogen, and R3 is hydrogen.
16. The method of claim 1 , wherein the disease or disorder is a neurological disorder selected from myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, Niemann Pick, Pitt Hopkins, spinal and bulbar muscular atrophy, and Alzheimer's disease.
17. A method of treating a disease or disorder wherein the disease or disorder is a neurological disorder selected from myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, Niemann Pick, Pitt Hopkins, spinal and bulbar muscular atrophy, and Alzheimer's disease; a cancer; an inflammatory disease; a memory impairment condition; or a drug addiction in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from the group consisting of:
18. A method of treating a disease or disorder mediated by HDAC1, HDAC2, or HDAC3 in a subject, the method comprising administering to the subject an effective amount of a compound having a structure of formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
R 1 —X is attached to only one of the ring nitrogen atoms;
X is:
(i) —Y—[C(R a ) 2 ] a -A-[C(R b ) 2 ] b —B—;
(ii) direct bond; or
(iii) C═O, C(R j ) 2 —C(═O), C(═O)—C(R j ) 2 , SO 2 —NR k , NR k —SO 2 , C(═O)NR k or NR k —C(═O);
wherein:
Y is bond, CR c ═CR d , O, NR e , or S(O) m ;
each of A and B is, independently, a bond, O, NR f , or S(O) m ;
a is 1, 2, or 3;
b is 0, 1, 2, or 3;
m is 0, 1, or 2;
each occurrence of R a and R b is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH 2 , OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano; or
one or more of the following can apply with respect to R a and R b :
any two R a , together with the carbons to which each is attached, together form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O, S(O) m and NR g ; or
one R a and one R b , together with the carbons to which each is attached, form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O)m and NR g ; or
any two R b , together with the carbons to which each is attached, form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the ring atoms is selected from O; S(O)m and NR g ;
each of R c and R d is independently selected from H, F, OH, C1-C6 alkyl, C3-C5 cycloalkyl, NH 2 , OCO—(C1-C6 alkyl), OCO—(C3-C5 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;
or R c and R d , together with the carbons to which each is attached form a C5-C7 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which from 1-2 of the heterocyclyl ring atoms are independently selected from 0, S(O), and NR g′ ;
each occurrence of R e , R f , R g and R g′ is independently selected from H, C1-C6 alkyl, —C(═O)H, —C(═O)R h , C(═O)O(C1-C6 alkyl), C(═O)N(R i ) 2 , and SO 2 —R h ; wherein R h is selected from C1-C6 alkyl, CH 2 -(heteroaryl including 5-10 ring atoms), CH 2 —(C6-C10 aryl), and C6-C10 aryl; and each occurrence of R i is independently selected from H, C1-C6 alkyl, CH 2 -(heteroaryl including 5-10 ring atoms), CH 2 —(C6-C10 aryl), and C6-C10 aryl;
each occurrence of R j is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH 2 , OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;
or R j —C—R j together form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O)m and NR j′ ;
each occurrence of R j′ and R k is independently selected from H, C1-C6 alkyl, —C(═O)H, —C(═O)R m , C(═O)O(C1-C6 alkyl), C(═O)N(R n ) 2 , and SO 2 —R m , wherein R m is selected from C1-C6 alkyl, CH 2 -(heteroaryl including 5-10 ring atoms), CH 2 —(C6-C10aryl), and C6-C10aryl; and each occurrence of R n is independently selected from H, C1-C6 alkyl, CH 2 -(heteroaryl including 5-10 ring atoms), CH 2 —(C6-C10 aryl), and C6-C10 aryl, and wherein the aryl and heteroaryl portion in R m and R n can be optionally substituted with 1-3 independently selected substituents F, C1-C6 alkyl, fluoro C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, or cyano;
further wherein:
(a) when each of A and B is a bond, and b is 0, then X has the following formula: —Y—[C(R a ) 2 ] a —;
(b) when b is 0 or 1, then A and B cannot both be heteroatoms; and
(c) when A or B serves as the point of connection of X to the nitrogen ring atoms, then A or B cannot be a heteroatom;
R1 is:
(i) monocyclic or bicyclic heteroaryl including from 5-10 ring atoms, which is optionally substituted with from 1-3 R o ; wherein from 1-4 of the ring atoms are a heteroatom independently selected from O, N, N—H, N—R o , and S;
(ii) C6-C10 aryl, which is optionally substituted with from 1-3 R o ;
(iii) C3-C10 cycloalkyl or C3-C10 cycloalkenyl, each of which is optionally substituted with from 1-6 R o ; or
(iv) hydrogen;
R4 is H or R o and each occurrence of R o is independently selected from the group consisting of halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C 1 -C 4 )alkyl; C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6 alkyl) 2 N—; —N*(R o′ ) 2 , wherein R o′ —N*—R o′ together form a saturated ring having 5 or 6 ring atoms, in which 1 or 2 ring atoms are optionally a heteroatom independently selected from NH, N(C1-C6alkyl), O, or S; formyl; formyl(C 1 -C 4 ) alkyl; cyano; cyano(C 1 -C 4 ) alkyl; benzyl; benzyloxy; (heterocyclyl)-(C0-C6) alkyl, wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms are a heteroatom independently selected from NH, N(alkyl), O, or S; phenyl; heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ring atoms are a heteroatom independently selected from O, N, N—H, N—R o″ , and S, each of which is optionally substituted with from 1-3 R o″ ; SO 2 —(O1-C6)alkyl; SO—(C1-C6)alkyl; and nitro;
each occurrence of R o″ is independently selected from the group consisting of halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C 1 -C 4 )alkyl; C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6 alkyl) 2 N—; formyl; formyl(C 1 -C 4 ) alkyl; cyano; cyano(C 1 -C 4 ) alkyl; benzyl; benzyloxy; (heterocyclyl)-(C0-C6) alkyl, wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms are a heteroatom independently selected from NH, N(C1-C6alkyl), 0, or S; phenyl; heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ring atoms are a heteroatom independently selected from O, N, N—H, N—(C1-C6 alkyl), and S; SO 2 —(C1-C6)alkyl; SO—(C1-C6)alkyl; and nitro;
R5 is selected from the group consisting of: hydrogen, halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C 1 -C 4 )alkyl; (C1-C6 alkyl)C(O)—; formyl; formyl(C 1 -C 4 ) alkyl; cyano; cyano(C 1 -C 4 ) alkyl; benzyl; (heterocyclyl)-(C0-C6)alkyl, wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms are a heteroatom independently selected from NH, N(C1-C6alkyl), O, or S; phenyl; heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ring atoms are a heteroatom independently selected from O, N, N—H, and S; SO 2 —(C1-C6)alkyl; SO—(C1-C6)alkyl; and nitro;
R2 is selected from H, F, Cl, CF 3 , CF 2 CF 3 , CH 2 CF 3 , OCF 3 , OCHF 2 , phenyl; or phenyl substituted with 1-3 R o ; and
R3 is H, F, or Cl.
19. The method of claim 18 , wherein the compound of formula (I) or salt thereof is selected from the group consisting of:
20. The method of claim 18 , wherein the disease or disorder is a neurological disease or disorder.