Imidazole quinoline-based immune system modulators
The present invention relates to a compound of Formula I: or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein the symbols are as defined in the specification; a pharmaceutical composition comprising the same; and a method for treating or preventing autoimmunity disease using the same.
1. A compound of Formula I or a pharmaceutically acceptable salt thereof,
wherein
X is absent or is a cycloalkyl, aryl, or pyridyl;
each occurrence of R 2 and R 3 is independently hydrogen, alkyl, cycloalkyl, alkoxy, or —(CH 2 ) p NR a R b , or R 2 and R 3 together with the carbon atom to which they are bonded optionally form a (C 3 -C 7 )cycloalkyl;
n is an integer of 2-4;
each q is an integer of 1-2;
Y is NR 9 or O;
R 9 is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, CH 2 CMe 3 , Ph, CH 2 Ph, C(═O)R 12 , (CH 2 ) p OR a , or (CH 2 ) p′ NR b R c , wherein R 12 is alkyl or phenyl; and p′ is 2-4;
or said R 8 and R 9 together with the nitrogen atom to which they are bonded optionally form a heterocycle selected from the group consisting of
in which R d is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, CH 2 CMe 3 , Ph, or CH 2 Ph;
R 4 is hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , alkyl, cycloalkyl, alkenyl, aryl, OR a , —CH 2 OR a , SR a , S(═O)R a , S(═O) 2 R a , NR b R c , S(═O) 2 NR b R c , C(═O)OR a , C(═O)R a , C(═O)NR b R c , OC(═O)R a , OC(═O)NR b R c , NR b C(═O)OR a , or NR b C(═O)R a ;
R 5 and R 6 are each independently hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , alkyl, cycloalkyl, alkenyl, aryl, OR a , SR a , S(═O)R a , S(═O) 2 R a , NR b R c , S(═O) 2 NR b R c , C(═O)OR a , C(═O)R a , C(═O)NR b R c , OC(═O)R a , OC(═O)NR b R c , NR b C(═O)OR a , NR b C(═O)R a , alkaryl, or NR b (CH 2 ) p NR b R c ;
L is alkyl or alkenyl containing from 2 to 10 carbon atoms;
R 7 is NR 10 R 11 ;
R 10 and R 11 are each independently hydrogen, alkyl, cycloalkyl, alkenyl, aryl or alkylaryl, or R 10 and R 11 together with the nitrogen atom to which they are bonded form a heterocycle selected from the group consisting of
in which R d is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, CH 2 CMe 3 , Ph, or CH 2 Ph;
p is an integer of 0, 1, 2, 3, 4, 5, or 6;
each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, or aryl;
each occurrence of R b , and R c is independently hydrogen, alkyl, cycloalkyl, or aryl; and
wherein
when X is cycloalkyl, aryl, or pyridyl, R 1 is hydrogen or alkyl, and R 8 is hydrogen or alkyl, or R 1 and R 8 together form
in which R d is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, CH 2 CMe 3 , Ph, or CH 2 Ph; and
when X is absent, R 1 is hydrogen or alkyl, and R 8 is hydrogen or alkyl.
2. The compound of claim 1 , wherein X is cycloalkyl.
3. The compound of claim 1 , wherein X is pyridyl.
4. The compound of claim 1 , wherein L is alkyl or alkenyl containing from 2 to 4 carbon atoms.
5. The compound of claim 1 having the structure of Formula II:
wherein
each occurrence of R 1 is independently hydrogen or (C 1 -C 4 )alkyl;
each occurrence of R 2 and R 3 is independently hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )alkoxy, or —(CH 2 ) p NR a R b , or R 2 and R 3 together with the carbon atom to which they are bonded optionally form a (C 3 -C 6 )cycloalkyl;
p is an integer of 0, 1, 2, 3, 4, 5, or 6;
R 8 is hydrogen or (C 1 -C 4 )alkyl;
R 9 is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, CH 2 CMe 3 , Ph, CH 2 Ph, C(═O)R 12 , (CH 2 ) p OR a , or (CH 2 ) p′ NR b R c , wherein R 12 is (C 1 -C 4 )alkyl or phenyl; R a , R b and R c are each independently hydrogen, or (C 1 -C 4 )alkyl; and p′ is 2-4;
or said R 8 and R 9 together with the nitrogen atom to which they are bonded optionally form a 3- to 7-membered heterocycle selected from the group consisting of
in which R d is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, CH 2 CMe 3 , Ph, or CH 2 Ph;
or R 1 and R 8 together form
in which R d is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, CH 2 CMe 3 , Ph, or CH 2 Ph;
R 4 is hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , (C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 6 )alkenyl, aryl, OR a , —CH 2 OR a , SR a , S(═O)R a , S(═O) 2 R a , NR b R c , S(═O) 2 NR b R c , C(═O)OR a , C(═O)R a , C(═O)NR b R c , OC(═O)R a , OC(═O)NR b R c , NR b C(═O)OR a , or NR b C(═O)R a ;
R 5 and R 6 are each independently hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , (C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 6 )alkenyl, aryl, OR a , SR a , S(═O)R a , S(═O) 2 R a , NR b R c , S(═O) 2 NR b R c , C(═O)OR a , C(═O)R a , C(═O)NR b R c , OC(═O)R a , OC(═O)NR b R c , NR b C(═O)OR a , NR b C(═O)R a , alkaryl, or NR b (CH 2 ) p NR b R c ; and
m is an integer of 2-6.
6. The compound of claim 1 having the structure of Formula III:
wherein
each occurrence of R 1 is hydrogen or (C 1 -C 4 )alkyl;
each occurrence of R 2 and R 3 is independently hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )alkoxy, or —(CH 2 ) p NR a R b , or R 2 and R 3 together with the carbon atom to which they are bonded optionally form a (C 3 -C 6 )cycloalkyl;
p is an integer of 0, 1, 2, 3, 4, 5, or 6;
R 8 is hydrogen or (C 1 -C 4 )alkyl;
R 9 is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, CH 2 CMe 3 , Ph, CH 2 Ph, C(═O)R 12 , (CH 2 ) p OR a , or (CH 2 ) p′ NR b R c , wherein R 12 is (C 1 -C 4 )alkyl or phenyl; and p′ is 2-4;
each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, or aryl;
each occurrence of R b , and R c is independently hydrogen, alkyl, cycloalkyl, or aryl;
R 4 is hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , (C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 6 )alkenyl, aryl, OR a , —CH 2 OR a , SR a , S(═O)R a , S(═O) 2 R a , NR b R c , S(═O) 2 NR b R c , C(═O)OR a , C(═O)R a , C(═O)NR b R c , OC(═O)R a , OC(═O)NR b R c , NR b C(═O)OR a , or NR b C(═O)R a ; and
m is an integer of 2-6.
7. The compound of claim 5 , wherein R 10 and R 11 are each independently hydrogen, (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkylaryl.
8. The compound of claim 5 , wherein R 10 and R 11 together with the nitrogen atom to which they are bonded form a heterocycle selected from the group consisting of
in which R d is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, CH 2 CMe 3 , Ph, or CH 2 Ph.
9. The compound of claim 1 , wherein NR 10 R 11 and NR 8 R 9 are each independently a heterocycle selected from the group consisting of
in which R d is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, or t-Bu.
10. The compound of claim 1 , wherein NR 10 R 11 and NR 8 R 9 are each independently a heterocycle selected from the group consisting of
in which R d is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, or t-Bu.
11. The compound of claim 1 , wherein X is cycloalkyl or aryl.
12. The compound of claim 1 , wherein X is absent.
13. The compound of claim 1 , wherein R 1 is H.
14. The compound of claim 1 , wherein R 2 and R 3 are each independently H.
15. A compound of claim 1 selected from the group consisting of the compounds 4-6, 8-15, 17-20, 25-34, 36-39, 41-43, 50-51, 53, 55, 59-61, 65, 67-68, and 70 from Tables 1-2:
TABLE 1
Compound No.
X
L
R 7
R 4
R 5 , R 6
4
—(CH 2 ) 2 —
N(CH 3 ) 2
CH 3
H, H
5
—(CH 2 ) 2 —
N(CH 3 ) 2
CH 2 OEt
H, H
6
—(CH 2 ) 2 —
N(CH 3 ) 2
CH 3 , CH 3
8
—(CH 2 ) 2 —
SH
H, H
9
—(CH 2 ) 2 —
Br
H, H
10
—(CH 2 ) 2 —
Cl
H, H
11
—(CH 2 ) 2 —
SCH 3
H, H
12
—(CH 2 ) 2 —
SO 2 CH 3
H, H
13
—(CH 2 ) 2 —
OCH 3
H, H
14
—(CH 2 ) 2 —
N(CH 3 ) 2
OH
15
—(CH 2 ) 2 —
H
H, H
17
—(CH 2 ) 2 —
CH 2 OEt
H, H
18
—(CH 2 ) 2 —
CH 2 OEt
H, H
19
—(CH 2 ) 2 —
H
CH 3 , CH 3
20
—(CH 2 ) 2 —
N(CH 3 ) 2
OH
H, H;
and
TABLE 2
Example No.
L
R 7
R 4
R 5 , R 6
25
—(CH 2 ) 4 —
H
H, H
26
—(CH 2 ) 3 —
CH 3
H, H
27
—(CH 2 ) 4 —
N(CH 3 ) 2
CH 2 OEt
H, H
28
—(CH 2 ) 5 —
N(CH 3 ) 2
CH 2 OEt
H, H
29
—(CH 2 ) 2 —
N(CH 3 ) 2
OH
CH 3 , Et
30
—(CH 2 ) 2 —
N(Et) 2
OH
H, H
31
—(CH 2 ) 4 —
N(CH 3 ) 2
CH 2 OEt
H,
32
—(CH 2 ) 2 —
NEtPh
Et
Et, Et
33
—(CH 2 ) 2 —
N(CH 3 ) 2
CH 3
H, H
34
—(CH 2 ) 5 —
N(CH 3 ) 2
CH 2 OEt
H, H
36
—(CH 2 ) 4 —
CH 3
F, H
37
—(CH 2 ) 4 —
n-Pr
CH 3 , n-Bu
38
—(CH 2 ) 2 —
CH 3
CH 3 , n-Bu
39
—(CH 2 ) 2 —
N(CH 3 ) 2
CH 2 OEt
F, Cl
41
—(CH 2 ) 2 —
N(CH 3 ) 2
CH 2 OEt
Cl, H
42
—(CH 2 ) 2 —
N(CH 3 ) 2
CH 2 OEt
Cl, Cl
43
—(CH 2 ) 2 —
N(CH 3 ) 2
CH 2 OEt
H, H
50
—(CH 2 ) 3 —
NHBn
OH
H, H
51
—(CH 2 ) 2 —
NHBn
CH 2 OEt
H, H
53
—(CH 2 ) 2 —
NHMe
CH 2 OEt
H, H
55
—(CH 2 ) 2 —
Et
H, OCF 3
59
—(CH 2 ) 2 —
Et
R 5 = H, R 6 = n- propyl
60
—(CH 2 ) 2 —
CH 2 OEt
R 5 = H, R 6 = H
61
—(CH 2 ) 2 —
NMe 2
CH 2 OEt
R 5 = H, R 6 = H
65
—(CH 2 ) 2 —
CH 2 OEt
R 5 = H, R 6 = H
67
—(CH 2 ) 2 —
NMe 2
H
R 5 = H, R 6 = H
68
—(CH 2 ) 2 —
NMe 2
OH
R 5 = H, R 6 = H
70
—(CH 2 ) 2 —
H
R 5 = H, R 6 = H.
16. A pharmaceutical composition comprising at least one compound according to claim 1 and a pharmaceutically-acceptable carrier or diluent.
17. A method of inhibiting TLR-mediated immunostimulation in a mammalian species in need thereof, comprising administering to the mammalian species a therapeutically effective amount of at least one compound according to claim 1 .
18. A method of inhibiting TLR-mediated immunostimulatory signaling, comprising contacting a cell expressing a TLR with an effective amount of at least one compound according to claim 1 .
19. The compound of claim 6 , wherein R 10 and R 11 are each independently hydrogen or (C 1 -C 4 )alkyl.
20. The compound of claim 6 , wherein R 7 is NR 10 R 11 , in which R 10 and R 11 together with the nitrogen atom to which they are bonded form a heterocycle selected from the group consisting of
in which R d is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, CH 2 CMe 3 , Ph, or CH 2 Ph.