Dimers of covalent NFKB inhibitors
View Patent ↗Provided herein are compounds and methods for modulating the NFκB pathway. More particularly, provided are inhibitors of the NFκB pathway and the uses of such inhibitors in regulating diseases and disorders, e.g., to treat cancer, autoimmune diseases, inflammatory diseases, diabetes, cardiovascular diseases, or neurological diseases.
1. A compound, or pharmaceutically acceptable salt thereof, having the structure of Formula I:
wherein
X is O, S, or NR 4 ;
L is C 1-18 alkylene or C 2-18 alkenylene optionally interrupted with one or more of (i) non-adjacent heteroatom(s) selected from O, S, and NR 4 , (ii) C(O)NR 4 , (iii) C 6-10 aryl, (iv) 5-10 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S, (v) 3-12 membered cycloalkyl ring, and (vi) 3-7 membered heterocycloalkyl ring having 1-3 ring heteroatoms selected from O, S, and N, and said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 4 ;
each R 1 is independently selected from the group consisting of C 1-6 alkyl, halo, CN, N(R 4 ) 2 , OR 4 , NO 2 , CO 2 R 4 , (C═O)R 4 , CON(R 4 ) 2 , NR 4 (C═O)R 5 , C 6-10 aryl, and 5-10 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S, and said alkyl can be optionally substituted with 1 to 3 R 3 ;
two R 2 are provided as a pair, together with the carbon atom to which they are attached form a ring having the structure:
wherein * is the carbon atom to which each R 2 is attached, Z is O or NR 4 , and R 5 is C 1-6 alkyl, C 2-6 alkenyl, C 6-10 aryl, or 3-7 membered heterocycloalkyl ring having 1-3 ring heteroatoms selected from O, S, and N
each remaining R 2 is independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, OR 4 , COR 4 , CO 2 R 4 , CON(R 4 ) 2 , N(R 4 ) 2 , and SR 4 , or a pair of two R 2 together with the carbon atom to which they are attached form a saturated or unsaturated 4-8 membered cycloalkyl or heterocycloalkyl ring, wherein the heterocycloalkyl ring has 1 or 2 ring heteroatoms selected from O, S, and N, and wherein said alkyl, alkenyl, alkynyl, cycloalkyl ring, and heterocycloalkyl ring are optionally substituted with 1 to 3 R 3 , with the proviso that at least one R 2 or one pair of two R 2 together forming a ring comprise an α,β-unsaturated moiety;
each R 3 is independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, CN, N(R 4 ) 2 , OR 4 , NO 2 , oxo, ═S, ═NR 4 , CO 2 R 4 , (C=O)R 4 , CON(R 4 ) 2 , C 6-10 aryl, and 5-10 membered heteroaryl having 1-4 ring heteroatoms selected from N, O, and S, and wherein said alkyl, alkenyl, and alkynyl are optionally substituted with 1 to 3 R 4 ;
each R 4 is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein said alkyl, alkenyl, and alkynyl are optionally substituted with one or more substituents selected from the group consisting of halo, CN, NH 2 , OH, and C 1-6 alkoxy; and
n is 0-4.
2. The compound or salt of claim 1 , wherein Z is O or NH.
3. The compound or salt of claim 1 , wherein L is selected from the group consisting of uninterrupted C 1-18 alkylene,
Y 1 , Y 2 , and Y 3 are each independently O or NR 4 , and indicates that the double bond is cis or trans.
4. The compound or salt of claim 1 , wherein L is uninterrupted C 1-18 alkylene.
5. The compound or salt of claim 4 , wherein L is
(i) C 7 alkylene, or
(ii) C 12 alkylene.
6. The compound or salt of claim 3 , wherein
(i) at least one of Y 1 and Y 2 is O, or
(ii) at least one of Y 1 and Y 2 is NR 4 .
7. The compound or salt of claim 6 , wherein
(i) each of Y 1 and Y 2 are O, or
(ii) each of Y 1 and Y 2 are NR 4 .
8. The compound or salt of claim 3 , wherein R 4 is H or C 1-6 alkyl.
9. The compound or salt of claim 1 , wherein L is C 2-18 alkenylene.
10. The compound or salt of claim 9 , wherein L comprises
(i) one carbon-carbon double bond, or
(ii) two carbon-carbon double bonds.
11. The compound or salt of claim 9 , wherein L is
and indicates that the double bond is cis or trans.
12. The compound or salt of claim 1 , wherein L is
13. The compound or salt of claim 1 , wherein L is C 1-18 alkylene or C 2-18 alkenylene interrupted by at least one phenyl.
14. The compound or salt of claim 3 , wherein L is selected from the group consisting of
15. The compound or salt of claim 14 , wherein
(i) Y 3 is O, or
(ii) Y 3 is NR 4 , wherein R 4 is methyl.
16. The compound or salt of claim 1 , wherein L is
17. A compound, as recited in Table 1, or a pharmaceutically acceptable salt thereof:
TABLE 1
Compound
#
Structure
40-059
36-286
40-039
36-202
36-239
36-252
36-254
36-204
36-256
36-258
36-242
36-280
36-297
40-014
36-252P
36-252N
P1
P2
P3
P4
P5
P6
P7
P8
P9
P10
P11
P12
P13
P14
P15
P16
P17
P18
40-038
P19
P20
P21
P22
P23
P24
P25
P26
P27
P28
or
P29
18. A method of treating a disease or disorder capable of being modulated by NFκB pathway inhibition, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or salt of claim 1 .
19. The method of claim 18 , wherein the disease or disorder is selected from the group consisting of cancer, autoimmune diseases, inflammatory diseases, diabetes, cardiovascular diseases, and neurological diseases.
20. The compound or salt of claim 17 , wherein the compound is compound 36-252: