Thio-substituted arylmethanesulfinyl derivatives
View Patent ↗The present invention is related to chemical compositions, processes for the preparation thereof and uses of the composition. Particularly, the present invention relates to compositions of compounds of Formula (A): wherein Ar, X, Y, R 1 , R 2 , R 3 , and q are as defined herein; and their use in the treatment of diseases, including treatment of sleepiness, promotion of wakefulness, treatment of Parkinson's disease, cerebral ischemia, stroke, sleep apneas, eating disorders, stimulation of appetite and weight gain, treatment of attention deficit hyperactivity disorder (“ADHD”), enhancing function in disorders associated with hypofunctionality of the cerebral cortex, including, but not limited to, depression, schizophrenia, fatigue, in particular, fatigue associated with neurologic disease, such as multiple sclerosis, chronic fatigue syndrome, and improvement of cognitive dysfunction.
1. A compound of formula (A):
wherein :
Ar is C 6 -C 10 aryl wherein:
C 6 -C 10 aryl is optionally substituted with one to three groups selected from F, Cl, Br, I, OR 22 , OR 25 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl, C(═O)R 22 , CO 2 R 22 , OC(═O)R 22 , C(═O)NR 23 R 24 , NR 21 C(═O)R 22 , NR 21 CO 2 R 22 , OC(═O)NR 23 R 24 , NR 21 C(═S)R 22 , and S(O) y R 22 ;
X is O, S(O) y , N(R 10 ), OC(R 22 ) 2 , (R 22 ) 2 CO, C(R 22 ) 2 NR 21 , NR 21 C(R 22 ) 2 , C(═O)N(R 21 ), NR 21 C(═O), S(O) 2 —NR 22 , NR 22 S(O) 2 , C(R 22 ) 2 C(R 22 ) 2 , CR 21 ═CR 21 , or C≡C;
Y is C 1 -C 6 alkylene; or (C 1 -C 4 alkylene) m -Z—(C 1 -C 4 alkylene) n ; wherein said alkylene groups are optionally substituted with one to three R 20 groups;
Z is O, NR 10A , S(O) y , CR 21 ═CR 21 , C≡C, C 6 -C 10 arylene, 5-10 membered heteroarylene, 3-6 membered heterocycloalkylene, or C 3 -C 6 cycloalkylene, wherein said arylene, heteroarylene, heterocycloalkylene, and cycloalkylene groups are optionally substituted with one to three R 20 groups;
R 1 is selected from NR 12 R 13 , C(═O)NR 12 R 13 , C(═NR 11 )NR 12 R 13 , OC(═O)NR 12 R 13 , NR 21 C(═O)NR 12 R 13 , and NR 21 S(O) 2 NR 12 R 13 ;
R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OR 22 , OR 25 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl, C(═O)R 22 , CO 2 R 22 , OC(═O)R 22 , C(═O)NR 23 R 24 , NR 21 C(═O)R 22 , NR 21 CO 2 R 22 , OC(═O)NR 23 R 24 , NR 21 C(═S)R 22 , and S(O) y R 22 ;
R 10 and R 10A are each independently selected from H, C 1 -C 6 alkyl, C 6 -C 10 aryl, C(═O)R 14 , and S(O) y R 14 ; wherein said alkyl and aryl groups are optionally substituted with one to three R 20 groups;
R 11 at each occurrence is independently selected from H, C 3 -C 7 alkyl and C 6 -C 10 aryl;
wherein said alkyl and aryl group are optionally substituted with one to three R 20 groups;
R 12 and R 13 together with the nitrogen to which they are attached, form a 3-7 membered heterocyclic ring;
wherein said heterocyclic ring is optionally substituted with one to three R 20 groups;
R 14 at each occurrence is independently selected from C 1 -C 6 alkyl, C 6 -C 10 aryl, and arylalkyl; wherein said alkyl, aryl and arylalkyl groups are optionally substituted with one to three R 20 groups;
R 20 at each occurrence is independently selected from F, Cl, Br, I, OR 22 , OR 25 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 -C 6 alkyl optionally substituted by one to three OH, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl, C(═O)R 22 , CO 2 R 22 , OC(═O)R 22 , C(═O)NR 23 R 24 , NR 21 C(═O)R 22 , NR 21 CO 2 R 22 , OC(═O)NR 23 R 24 , NR 21 C(═S)R 22 , and S(O) y R 22 ;
R 21 at each occurrence is independently selected from H and C 1 -C 6 alkyl;
R 22 at each occurrence is independently selected from H, C 1 -C 6 alkyl, and C 6 -C 10 aryl;
R 23 and R 24 at each occurrence are each independently selected from H, C 1 -C 6 alkyl, and C 6 -C 10 aryl, or R 23 and R 24 , together with the nitrogen to which they are attached, form a 3-7 membered heterocyclic ring;
R 25 at each occurrence is independently the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;
m is 0 or 1;
n is 0 or 1;
q is 1 or 2;
y is 0, 1, or 2;
Ar—X is positioned ortho or para to —CH 2 —S(O) q —Y—R 1 ;
with the exclusion of the compounds wherein:
Y is C 2 alkylene substituted with one to three C 1 -C 6 alkylene and/or NR 23 R 24 and/or NR 21 CO 2 R 22 , and
R 1 is C(═O)NR 12 R 13 ;
or a stereoisomeric form, mixture of stereoisomeric forms or a pharmaceutically acceptable salt form thereof.
2. A compound as defined in claim 1 , wherein Y is C 1 -C 6 alkylene, (C 1 -C 4 alkylene) m -Z 1 —(C 1 -C 4 alkylene) n , or C 1 -C 4 alkylene-Z 2 —C 1 -C 4 alkylene, wherein:
said alkylene groups are optionally substituted with one to three R 20 groups;
Z 1 is CR 21 ═CR 21 , C≡C, C 6 -C 10 arylene, 5-10 membered heteroarylene, 3-6 membered heterocycloalkylene, or C 3 -C 6 cycloalkylene; wherein said arylene, heteroarylene, heterocycloalkylene, and cycloalkylene groups are optionally substituted with one to three R 20 groups; and
Z 2 is O, NR 10A , or S(O) y .
3. A compound as defined in claim 1 , wherein q is 1.
4. A compound as defined in claim 1 , wherein R 1 is selected from NR 12 R 13 ; C(═O)NR 12 R 13 ; C(═NR 11 )NR 12 R 13 ; and NR 21 C(═O)NR 12 R 13 .
5. A compound as defined in claim 4 , wherein R 1 is C(═O)NR 12 R 13 .
6. A compound as defined in claim 3 , wherein R 1 is selected from C(═O)NR 12 R 13 , OC(═O)NR 12 R 13 , and NR 21 S(O) 2 NR 12 R 13 .
7. A compound as defined in claim 1 , wherein X is O, S(O) y ,N(R 10 ).
8. A compound as defined in claim 1 , wherein X is OC(R 22 ) 2 , C(R 22 ) 2 O, C(R 22 ) 2 NR 21 , NR 21 C(R 22 ) 2 , C(═O)N(R 21 ), NR 21 C(═O), S(O) 2 NR 22 , NR 22 S(O) 2 , C(R 22 ) 2 C(R 22 ) 2 .
9. A compound as defined in claim 8 , wherein X is OC(R 22 ) 2 , C(R 22 ) 2 NR 21 , C(═O)N(R 21 ), S(O) 2 —NR 22 .
10. A compound as defined in claim 1 , wherein Y is C 1 -C 6 alkylene.
11. A compound as defined in claim 10 , wherein Y is CH 2 .
12. A compound as defined in claim 2 , wherein Y is (C 1 -C 4 alkylene) m -Z 1 —(C 1 -C 4 alkylene) n .
13. A compound as defined in claim 12 , wherein Z 1 is C 6 -C 10 arylene or C 3 -C 6 cycloalkylene.
14. A compound as defined in claim 13 , wherein Z 1 is phenylene.
15. A compound as defined in claim 12 , wherein Z 1 is 5-10 membered heteroarylene or 3-6 membered heterocyloalkylene.
16. A compound as defined in claim 12 , wherein Z 1 is CR 21 ═CR 21 or C≡C.
17. A compound as defined in claim 2 , wherein Y is C 1 -C 4 alkylene-Z 2 —C 1 -C 4 alkylene.
18. A compound as defined in claim 17 , wherein Z 2 is O.
19. A compound as defined in claim 1 , with the structure:
wherein:
Ar is optionally substituted with one to three groups selected from F, Cl, Br, I, OR 22 , OR 25 , NR 23 R 24 , NHOH, NO 2 , CN, C 1 -C 6 alkyl, phenyl, arylalkyl, and C(═O)R 22 ;
X is O, S(O) y , N(R 10 ), OC(R 22 ) 2 , C(R 22 ) 2 O, C(R 22 ) 2 NR 21 , NR 21 C(R 22 ) 2 , C(═O)N(R 21 ), NR 21 C(═), S(═O) 2 NR 22 , NR 22 S(═O) 2 ;
Y is C 1 -C 6 alkylene;
C 1 -C 4 alkylene-Z 1 —(C 1 -C 4 alkylene) n ; or
C 1 -C 4 alkylene-Z 2 —C 1 -C 4 alkylene;
wherein said alkylene groups are optionally substituted with one to three R 20 groups;
Z 1 is CR 21 ═CR 21 , C≡C, C 6 -C 10 arylene, 5-10 membered heteroarylene, 3-6 membered heterocycloalkylene, or C 3 -C 6 cycloalkylene;
Z 2 is O, NR 10A , or S(O) y ;
R 1 is selected from C(═O)NR 12 R 13 , C(═NR 11 )NR 12 R 13 , OC(═O)NR 12 R 13 , NR 21 C(═O)NR 12 R 13 , and NR 21 S(O) 2 NR 12 R 13 ;
R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OR 22 , OR 25 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl, C(═O)R 22 ;
R 10 and R 10A are each independently selected from H, C 1 -C 6 alkyl, C(═O)R 14 , and S(O) y R 14 ; wherein said alkyl groups are optionally substituted with one to three R 20 groups;
R 11 at each occurrence is independently selected from H or C 3 -C 7 alkyl, wherein said alkyl group is optionally substituted with one to three R 20 groups;
R 12 and R 13 together with the nitrogen to which they are attached, form a 3-7 membered heterocyclic ring; wherein said heterocyclic ring is optionally substituted with one to three R 20 groups;
R 14 at each occurrence is independently selected from C 1 -C 6 alkyl, C 6 -C 10 aryl, and arylalkyl; wherein said alkyl, aryl and arylalkyl groups are optionally substituted with one to three R 20 groups;
R 20 at each occurrence is independently selected from F, Cl, Br, I, OR 22 , OR 25 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , phenyl, benzyl, C(═O)R 22 , CO 2 R 22 , OC(═O)R 22 , C(═O)NR 23 R 24 , NR 21 C(═O)R 22 , NR 21 CO 2 R 22 , OC(═O)NR 23 R 24 , NR 21 C(═S)R 22 , and S(O) y R 22 ;
R 21 at each occurrence is independently selected from H and C 1 -C 6 alkyl;
R 22 at each occurrence is independently selected from H, C 1 -C 6 alkyl, and C 6 -C 10 aryl;
R 23 and R 24 at each occurrence are each independently selected from H, and C 1 -C 6 alkyl, or R 23 and R 24 , together with the nitrogen to which they are attached, form a 3-7 membered heterocyclic ring;
R 25 at each occurrence is independently the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;
n is 0 or 1;
y is 0, 1, or 2;
or a stereoisomeric form, mixture of stereoisomeric forms or a pharmaceutically acceptable salt form thereof.
20. A compound as defined in claim 19 , wherein:
Y is C 1 -C 6 alkylene, C 1 -C 4 alkylene-Z 1 —C 1 -C 4 alkylene, or C 1 -C 4 alkylene-Z 2 —C 1 -C 4 alkylene, wherein said alkylene groups are optionally substituted with one to three C 1 -C 6 alkyl groups;
Z 1 is CR 21 ═CR 21 , C≡C, or phenyl;
Z 2 is O, NR 10A , or S(O) y ;
X is O, S(O) y , N(R 10 ), OC(R 22 ) 2 , C(R 22 ) 2 O, C(R 22 ) 2 NR 21 , NR 21 C(R 22 ) 2 , C(═O)N(R 21 ), NR 21 C(═O), S(O) 2 NR 22 , NR 22 S(O) 2 ; and
R 1 is C(═O)NR 12 R 13 .
21. A compound as defined in claim 19 , having the structure of formula (Ib):
or a stereoisomeric form, mixture of stereoisomeric forms or a pharmaceutically acceptable salt form thereof.
22. A compound as defined in claim 21 , wherein X is O, S(O) y , N(R 10 ), OC(R 22 ) 2 , C(R 22 ) 2 O, C(R 22 ) 2 NR 21 , NR 21 C(R 22 ) 2 , C(═O)N(R 21 ), NR 21 C(═O), S(O) 2 —NR 22 , or NR 22 S(O) 2 .
23. A compound as defined in claim 22 , wherein X is O, S(O) y , or NH.
24. A compound as defined in claim 22 , wherein X is OCH 2 , CH 2 O, CH 2 NH, NHCH 2 , C(═O)NH, NHC(═O), S(O) 2 NH, or NHS(O) 2 .
25. A compound as defined in claim 22 , wherein X is NH, O—CH 2 , CH 2 NH, C(═O)NH, or S(O) 2 —NH.
26. A compound as defined in any of claim 1 , 19 , or 21 , wherein R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OR 22 , OR 25 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl, and C(═O)R 22 .
27. A compound as defined in claim 21 , wherein Y is C 1 -C 6 alkylene.
28. A compound as defined in claim 27 , wherein Y is CH 2 .
29. A compound as defined in claim 21 , wherein Y is (C 1 -C 4 alkylene) n -Z 1 —C 1 -C 4 alkylene and Z 1 is phenyl, 5 or 6 membered heteroarylene, CR 21 ═CR 21 , or C≡C.
30. A compound selected in accordance with the following table, wherein :
TABLE 1
Ex.
Posi-
No.
Ar
X
tion*
R 2
R 3
q
Y—R 1
13
3,4-DiClPh
O
para
H
H
0
CH 2 CO—N-
piperazinyl-N-Boc
14
3,4-DiClPh
O
para
H
H
0
CH 2 CO—N-
piperazinyl
19
3,4-DiClPh
O
para
H
H
1
CH 2 CO—N-
piperazinyl
16
4-ClPh
S
para
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
23
4-ClPh
S
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
24
4-ClPh
SO
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
Ph
O
meta
H
H
0
CH 2 CO—N-
pyrrolidinyl
31
Ph
O
meta
H
H
1
CH 2 CO—N-
pyrrolidinyl
Ph
O
meta
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
35
Ph
O
meta
H
H
1
CH 2 CO-1-(4-
acetyl)-piperazinyl
4-OCH 3 Ph
O
para
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
37
4-OCH 3 Ph
O
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
4-OCH 3 Ph
O
para
H
H
0
CH 2 CO—N-
piperazinyl
38
4-OCH 3 Ph
O
para
H
H
1
CH 2 CO—N-
piperazinyl
11
3,4-DiClPh
O
para
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
22
3,4-DiClPh
O
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
27
3,4-DiClPh
O
para
H
H
2
CH 2 CO-1-(4-acetyl)-
piperazinyl
3,4-DiClPh
O
ortho
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
40
3,4-DiClPh
O
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
3,4-DiClPh
O
para
H
H
0
CH 2 CO-1-(4-
carboxamide)-
piperazinyl
41
3,4-DiClPh
O
para
H
H
1
CH 2 CO-1-(4-
carboxamide)-
piperazinyl
2-ClPh
O
para
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
46
2-ClPh
O
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
2-ClPh
O
para
H
H
0
CH 2 CO—N-
piperazinyl
47
2-ClPh
O
para
H
H
1
CH 2 CO—N-
piperazinyl
4-FPh
O
para
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
48
4-FPh
O
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
95
4-FPh
O
para
H
H
2
CH 2 CO-1-(4-acetyl)-
piperazinyl
4-FPh
O
ortho
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
49
4-FPh
O
ortho
H
H
1
CH 2 CO-1-(4-
acetyl)-piperazinyl
2-Naphthyl
O
ortho
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
53
2-Naphthyl
O
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
2-ClPh
O
ortho
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
57
2-ClPh
O
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
2-Naphthyl
O
para
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
58
2-Naphthyl
O
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
2-BiPh
O
ortho
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
59
2-BiPh
O
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
2-BiPh
O
para
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
60
2-BiPh
O
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
4-ClPh
O
para
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
61
4-ClPh
O
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
4-OCH 3 Ph
O
para
H
H
0
CH 2 CO-1-(4-methyl)-
piperazinyl
62
4-OCH 3 Ph
O
para
H
H
1
CH 2 CO-1-(4-methyl)-
piperazinyl
3,4-DiClPh
O
para
H
H
0
CH 2 CO-1-(4-
ethylcarboxylate)-
piperazinyl
63
3,4-DiClPh
O
para
H
H
1
CH 2 CO-1-(4-
ethylcarboxylate)-
piperazinyl
4-FPh
O
para
H
H
0
CH 2 CO-1-(4-
hydroxyethyl)-
piperazinyl
64
4-FPh
O
para
H
H
1
CH 2 CO-1-(4-
hydroxyethyl)-
piperazinyl
3,4-DiClPh
O
ortho
H
H
0
CH 2 CO-1-(4-
hydroxyethyl)-
piperazinyl
65
3,4-DiClPh
O
ortho
H
H
1
CH 2 CO-1-(4-
hydroxyethyl)-
piperazinyl
4-FPh
O
para
H
H
0
CH 2 CO-1-(4-methyl)-
piperazinyl
66
4-FPh
O
para
H
H
1
CH 2 CO-1-(4-methyl)-
piperazinyl
4-FPh
O
para
H
H
0
CH 2 CO-1-(4-
ethylcarboxylate)-
piperazinyl
68
4-FPh
O
para
H
H
1
CH 2 CO-1-(4-
ethylcarboxylate)-
piperazinyl
4-OCH 3 Ph
O
para
H
H
0
CH 2 CO-1-(4-
ethylcarboxylate)-
piperazinyl
69
4-OCH 3 Ph
O
para
H
H
1
CH 2 CO-1-(4-
ethylcarboxylate)-
piperazinyl
4-ClPh
S
para
H
H
0
CH 2 CO-1-(4-
ethylcarboxylate)-
piperazinyl
70
4-ClPh
S
para
H
H
1
CH 2 CO-1-(4-
ethylcarboxylate)-
piperazinyl
71
4-ClPh
SO
para
H
H
1
CH 2 CO-1-(4-
ethylcarboxylate)-
piperazinyl
3,4-DiClPh
O
ortho
H
H
0
CH 2 CO-1-(4-
ethylcarboxylate)-
piperazinyl
72
3,4-DiClPh
O
ortho
H
H
1
CH 2 CO-1-(4-
ethylcarboxylate)-
piperazinyl
Ph
O
ortho
H
H
0
CH 2 CO—N-
pyrrolidinyl
98
Ph
O
ortho
H
H
1
CH 2 CO—N-
pyrrolidinyl
Ph
O
para
H
H
0
CH 2 CO—N-
pyrrolidinyl
101
Ph
O
para
H
H
1
CH 2 CO—N-
pyrrolidinyl
Ph
O
ortho
H
H
0
CH 2 CO-1-(4-
hydroxy)-piperidinyl
106
Ph
O
ortho
H
H
1
CH 2 CO-1-(4-
hydroxy)-piperidinyl
Ph
O
ortho
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
107
Ph
O
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
Ph
O
meta
H
H
0
CH 2 CO-1-(4-
hydroxy)-piperidinyl
109
Ph
O
meta
H
H
1
CH 2 CO-1-(4-
hydroxy)-piperidinyl
110
Ph
O
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
112
Ph
O
para
H
H
1
CH 2 CO-1-(4-
hydroxy)-piperidinyl
116
4-ClPh
CONH
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
121
2,4-DiOCH 3 Ph
CONH
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
122
3,4-DiOCH 3 Ph
CONH
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
123
4-FPh
CONH
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
124
3,4-DiClPh
CONH
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
4-ClPh
S
ortho
H
H
0
CH 2 CO—N-
piperazinyl
73
4-ClPh
S
ortho
H
H
1
CH 2 CO—N-
piperazinyl
2,3-DiClPh
O
ortho
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
74
2,3-DiClPh
O
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
2,5-DiClPh
O
ortho
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
75
2,5-DiClPh
O
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
2,4-DiClPh
O
para
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
78
2,4-DiClPh
O
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
2,4-DiClPh
O
ortho
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
79
2,4-DiClPh
O
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
3,5-DiClPh
O
ortho
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
82
3,5-DiClPh
O
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
3,5-DiClPh
O
para
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
83
3,5-DiClPh
O
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
2,5-DiClPh
O
para
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
86
2,5-DiClPh
O
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
3,4-DiClPh
S
para
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
87
3,4-DiClPh
S
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
2,3-DiClPh
O
para
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
90
2,3-DiClPh
O
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
2,6-DiClPh
O
para
H
H
0
CH 2 CO-1-(4-acetyl)-
piperazinyl
91
2,6-DiClPh
O
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
135
Ph
NH
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
136
Ph
NH
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
134
4-OCH 3 Ph
NH
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
131
4-FPh
SO 2 NH
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
137
4-OCH 3 Ph
NH
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
138
4-FPh
NH
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
139
4-ClPh
NH
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
140
4-FPh
NH
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
128
3,4-DiClPh
CONH
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
129
4-FPh
CONH
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
141
3,4-DiClPh
NH
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
132
4-ClPh
SO 2 NH
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
147
4-FPh
CH 2 NH
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
133
3,4-DiClPh
SO 2 NH
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
148
3,4-DiClPh
CH 2 NH
para
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
149
4-FPh
CH 2 NH
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
146
3,4-DiClPh
CH 2 NH
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
130
3,4-DiClPh
SO 2 NH
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
145
2-Furyl
CH 2 NH
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
144
2-Thienyl
CH 2 NH
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
142
2-Thienyl
CONH
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
143
2-Furyl
CONH
ortho
H
H
1
CH 2 CO-1-(4-acetyl)-
piperazinyl
17
4-ClPh
O
para
2′-
H
0
CH 2 CO-1-(4-acetyl)-
Cl
piperazinyl
25
4-ClPh
O
para
2′-
H
1
CH 2 CO-1-(4-acetyl)-
Cl
piperazinyl
Ph = phenyl,
ClPh = chlorophenyl,
DiClPh = di-chlorophenyl,
FPh = fluorophenyl;
*Position: the position refers to the position of the ArX lateral side chain as compared to —CH 2 —S(O) q —Y—R 1 group on the central benzyl ring;
ortho is position 2′, meta is position 3′ and para is position 4′;
or a stereoisomeric form, mixture of stereoisomeric forms or a pharmaceutically acceptable salt form thereof.
31. A pharmaceutical composition, comprising a compound of claim 1 or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt form thereof, in admixture with one or more pharmaceutically acceptable excipients.