Substituted benzoazepines as toll-like receptor modulators
Provided are compositions and methods useful for modulation of signaling through the Toll-like receptors TLR7 and/or TLR8. The compositions and methods have use in treating or preventing disease, including cancer, autoimmune disease, fibrotic disease, cardiovascular disease, infectious disease, inflammatory disorder, graft rejection, or graft-versus-host disease.
1. A compound having the formula I:
or a pharmaceutically acceptable salt thereof,
wherein
is a double bond or a single bond;
R 2 and R 3 are independently selected from H and unsubstituted or substituted C 1 -C 6 alkyl, or R 2 and R 3 , together with the carbon atom to which they are attached, form a saturated carbocycle having from 3 to 7 members, or R 3 and one of R a or R b , together with the atoms to which they are attached, form a 5-7 member heterocyclic ring;
R 7 is selected from the group consisting of:
n is 0, 1, 2 or 3;
each R 8 is, independently, selected from unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, halogen, trihalomethyl, unsubstituted or substituted C 1 -C 6 alkoxycarbonyl, nitro, unsubstituted or substituted carbonylamino, unsubstituted or substituted sulfonamide, unsubstituted or substituted heterocycle comprising 1 or 2, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, and
R 9 is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, or —NR h R j ;
R f and R g are each, independently, H, unsubstituted or substituted C 1 -C 6 alkyl or R f and R g , together with the nitrogen atom to which they are attached, form a heterocycle comprising 1 or 2, 5- or 6-member rings and optionally 1-3 additional heteroatoms selected from N, O and S;
R h and R j are each, independently, H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl or R h and R j , together with the nitrogen atom to which they are attached, form a heterocycle comprising 1 or 2, 5- or 6-member rings and optionally 1-3 additional heteroatoms selected from N, O and S;
R 11 is H, unsubstituted or substituted C 1 -C 6 alkylcarbonyl, unsubstituted or substituted C 1 -C 6 alkoxycarbonyl, 3-7 member carbocycle substituted carbonyl, or 5-7 member heterocyclyl substituted carbonyl;
R 4 is H, halogen, unsubstituted C 1 -C 6 alkyl, or —C(O)NR c R d , or —C(O)OR 10 ;
R c and R d are independently selected from H and unsubstituted or substituted C 1 -C 6 alkyl, where the C 1 -C 6 alkyl is optionally substituted with aminocarbonyl or hydroxyl;
R 10 is selected from H and C 1 -C 6 alkyl, where the alkyl is optionally substituted with one or more —OH;
R a and R b are independently selected from H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl substituted amino, and R e , wherein the C 1 -C 6 alkyl is optionally substituted with one or more —OR 10 or R e , or R 3 and one of R a and R b together with the atoms to which they are attached, form a 5-7 member heterocyclic ring;
R e is selected from —NH 2 , —NH(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl) 2 ; and
R 1 is absent when is a double bond, or when is a single bond, R 1 is H, or R 1 and one of R a or R b are connected to form a saturated, partially unsaturated, or unsaturated heterocycle having 5-7 ring members and the other of R a or R b may be hydrogen or absent as necessary to accommodate ring unsaturation;
with the proviso that:
when R 7 is
then R 4 is not —COOR 10 where R 10 is C 1 -C 6 alkyl, or —CONR c R d where both R c and R d are unsubstituted C 1 -C 6 alkyl, and R a and R b are not both selected from H, unsubstituted C 1 -C 6 alkyl and R e .
2. The compound of claim 1 , wherein the compound is of formula II
or a pharmaceutically acceptable salt thereof,
wherein
R 7 is selected from the group consisting of:
n is 0, 1, 2 or 3;
each R 8 is, independently, selected from unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, halogen, trihalomethyl, unsubstituted or substituted C 1 -C 6 alkoxycarbonyl, unsubstituted or substituted carbonylamino, unsubstituted or substituted sulfonamide, unsubstituted or substituted heterocycle comprising 1 or 2, 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, and
R 9 is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy or —NR h R j ;
R f and R g are each, independently, H, unsubstituted or substituted C 1 -C 6 alkyl or R f and R g , together with the nitrogen atom to which they are attached, form a heterocycle comprising 1 or 2, 5- or 6-member rings and optionally 1-3 additional heteroatoms selected from N, O and S;
R h and R j are each, independently, H, unsubstituted or substituted C 1 -C 6 alkyl or R h and R j , together with the nitrogen atom to which they are attached, form a heterocycle comprising 1 or 2, 5- or 6-member rings and optionally 1-3 additional heteroatoms selected from N, O and S;
R 11 is H, unsubstituted or substituted C 1 -C 6 alkylcarbonyl, unsubstituted or substituted C 1 -C 6 alkoxycarbonyl, 3-7 member carbocycle substituted carbonyl, or 5-7 member heterocyclyl substituted carbonyl;
R 4 is selected from H, —C(O)NR c R d , —C(O)OR 10 , halogen, and unsubstituted C 1 -C 6 alkyl;
R c and R d are independently selected from H and unsubstituted or substituted C 1 -C 6 alkyl, where the C 1 -C 6 alkyl is optionally substituted with aminocarbonyl or hydroxyl;
R 10 is C 1 -C 6 alkyl optionally substituted with one or more —OH;
R a and R b are independently selected from H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl substituted amino, and R e , wherein the C 1 -C 6 alkyl is optionally substituted with one or more —OH, —OR 10 or R e , or R 3 and one of R a or R b together with the atoms to which they are attached, form a 5-7 member heterocyclic ring;
R e is selected from —NH 2 , —NH(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl) 2 .
3. The compound of claim 1 , wherein R 4 is H, halogen, unsubstituted C 1 -C 6 alkyl, —C(O)OR 10 , or —C(O)NR c R d , where both R c and R d are unsubstituted or substituted C 1 -C 6 alkyl.
4. The compound of claim 1 , wherein R 4 is —C(O)OR 10 , where R 10 is C 1 -C 6 alkyl.
5. The compound of claim 1 , wherein R 4 is —C(O)NR c R d in which both R c and R d are propyl or at least one of R c or R d is C 1 -C 6 alkyl substituted with one —OH.
6. The compound of claim 5 , wherein one of R c and R d is
and the other is propyl.
7. The compound of claim 1 , R 4 is Br, methyl or ethyl.
8. The compound of claim 1 , wherein R 7 is
and n is 1, 2 or 3.
9. The compound of claim 8 , wherein R 7 is not 3-methylphenyl nor 3,4-dichlorophenyl.
10. The compound of claim 1 , R 7 is
11. The compound of claim 1 , wherein at least one of R a and R b is not hydrogen, or one of R a and R b is unsubstituted or substituted C 1 -C 6 alkyl and the other is hydrogen, or one or more of R a and R b is C 1 -C 6 alkyl substituted with R e , or both R a and R b are unsubstituted or substituted C 1 -C 6 alkyl.
12. The compound of claim 1 , wherein one of R a and R b is R e and the other of R a and R b is hydrogen.
13. The compound of claim 1 , wherein at least one of R 2 and R 3 is not hydrogen, or R 2 and R 3 are connected to form a saturated carbocycle.
14. The compound of claim 1 wherein the compound is of the formula III:
or a salt thereof,
wherein R 2′ and R 3′ are independently selected from H and unsubstituted or substituted C 1 -C 6 alkyl, or R 2′ and R 3′ , together with the carbon atom to which they are attached, form a saturated carbocycle having from 3 to 7 members, or R 3′ and one of R a′ or R b′ , together with the atoms to which they are attached, form a 5-7 member heterocyclic ring;
R 4′ is C 1 -C 6 alkyl substituted with one or more —OH; and
R a′ and R b′ are independently selected from H and unsubstituted or substituted C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with one or more —OH, or R 3′ and one of R a′ or R b′ together with the atoms to which they are attached, form a 5-7 member heterocyclic ring.
15. The compound of claim 14 , wherein R 2′ and R 3′ are each H or both R 2′ and R 3′ are each methyl.
16. The compound of claim 14 , wherein R 2′ or R 3′ is unsubstituted or substituted C 1 -C 6 alkyl.
17. The compound of claim 14 , wherein R 2′ and R 3′ , together with the carbon atom to which they are attached, form a saturated carbocycle having from 3 to 7 members.
18. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
19. A compound selected from one of those with the following formula
wherein R 7 , R 4 , R 2 , R 3 , R a and R b are as shown in Table 1:
Compound
No.
R 7
R 4
R 2 , R 3
R a
R b
3010
COOH
H, H
H
H
3009
CONH-i-Pr
H, H
H
H
3058
COOEt
H, H
H
H
2937
COOEt
H, H
H
H
2882
COOEt
H, H
H
H
3096
2-methylphenyl
COOEt
H, H
H
H
3141
2-i-Pr-phenyl
COOEt
H, H
H
H
3287
3-methylphenyl
COOEt
H, H
H
H
3272
4-methylphenyl
COOEt
H, H
H
H
3162
2,6 -dimethylphenyl
COOEt
H, H
H
H
3264
2-methoxyphenyl
COOEt
H, H
H
H
3267
3-methoxyphenyl
COOEt
H, H
H
H
3098
4-methoxyphenyl
COOEt
H, H
H
H
3127
2-chlorophenyl
COOEt
H, H
H
H
3155
2,3-dichlorophenyl
COOEt
H, H
H
H
3102
3,4-dichlorophenyl
COOEt
H, H
H
H
3294
2-chloro-3-methylphenyl
COOEt
H, H
H
H
3386
2-chloro-3-methoxyphenyl
COOEt
H, H
H
H
3126
2-trifluoromethylphenyl
COOEt
H, H
H
H
3059
3-trifluoromethylphenyl
COOEt
H, H
H
H
3101
4-ethoxycarbonylphenyl
COOEt
H, H
H
H
3156
4-nitro
COOEt
H, H
H
H
3055
COOEt
H, H
H
H
3119
COOEt
H, H
H
H
3322
COOEt
H, H
H
H
3190
COOEt
H, H
H
H
3198
COOEt
H, H
H
H
3199
COOEt
H, H
H
H
3261
COOEt
H, H
H
H
3300
COOEt
H, H
H
H
3387
COOEt
H, H
H
H
3290
COOEt
H, H
H
H
3343
H, H
H
H
3342
H, H
H
H
3336
H, H
H
H
2946
COOEt
H, H
H
H
3128
COOEt
H, H
H
H
3125
COOEt
H, H
H
H
3046
COOEt
H, H
H
H
3093
COOEt
H, H
H
H
3057
COOEt
H, H
H
H
3197
COOEt
H, H
H
H
3094
COOEt
H, H
H
H
3095
COOEt
H, H
H
H,
or selected from those in Table 1A:
TABLE 1A
2935
3036
3142
3202
3254
2895
2968
2967
2930
3097
3448
3444
and a pharmaceutically acceptable salt thereof.