Compounds for disease treatment
The present disclosure provides compounds according to Formula (I), wherein X, R 2 , R 3 , R 4 , and R 5 are defined herein. Further disclosed herein are pharmaceutical compositions, orally administrable dosage forms, and methods for using such compounds in the treatment of various diseases and disorders including inflammation, autoimmune disorders, chronic pain and cancer. In particular embodiments, the present disclosure provides orally bioavailable compounds capable of selectively modulating an activity (e.g., inhibition) of the serine/threonine protein kinase TAK1 and/or related kinases.
1 . A compound according to Formula (I):
or a pharmaceutically acceptable salt or a tautomer thereof,
wherein;
X is NR 1 ;
R 1 is H, C 1-6 alkyl, C 1-6 carbonyl, C 1-6 carboxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cyclo(C 3-8 ) alkyl, or or substituted or unsubstituted heterocyclo(C 3-8 ) alkyl;
R 2 is C 1-6 alkoxy, substituted or unsubstituted —Y—(CH 2 ) n -aryl, substituted or unsubstituted —Y—(CH 2 ) n -heteroaryl, substituted or unsubstituted —Y—(CH 2 ) n -cyclo(C 3-8 ) alkyl, —NR 6 R 7 , C 1-6 alkyl-NR 6 R 7 , or C 1-6 alkoxy-NR 6 R 7 , wherein R 6 and R 7 are independently selected from the group consisting of H, C 1-6 alkyl, hetero-C 1-6 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl-C 1-6 alkyl; alternatively, R 6 and R 7 may be combined with the nitrogen atom to form a 5-, 6-, 7- or 8-membered, substituted or unsubstituted heterocycloalkane or substituted or unsubstituted heteroaromatic ring, wherein Y is selected from the group consisting of a bond, O and S, and wherein the subscript n is an integer from 0 to 6;
R 3 is H, C 1-6 alkyl, C 1-6 alkoxy, halogen, substituted or unsubstituted —Y—(CH 2 ) n -aryl, substituted or unsubstituted —Y—(CH 2 ) n -heteroaryl, substituted or unsubstituted —Y—(CH 2 ) n -cyclo(C 3-8 ) alkyl, —NR 8 R 9 , C 1-6 alkyl-NR 8 R 9 , or C 1-6 alkoxy-NR 8 R 9 , wherein R 8 and R 9 are independently selected from the group consisting of H, C 1-6 alkyl, hetero-C 1-6 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl-C 1-6 alkyl; alternatively, R 8 and R 9 may be combined with the nitrogen atom to form a 5-, 6-, 7- or 8-membered, substituted or unsubstituted heterocycloalkane or substituted or unsubstituted heteroaromatic ring, wherein Y is selected from the group consisting of a bond, O and S, and wherein the subscript n is an integer from 0 to 6;
R 4 is OH, C 1-6 alkoxy, NH 2 , NH(C 1-6 alkyl), or N(C 1-6 alkyl) (C 1-6 alkyl); and
R 5 is H, C 1-6 alkyl, C 1-6 alkoxy, or halogen;
wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 carbonyl and C 1-6 carboxy of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and Ry are optionally and independently substituted by halo, OH, NH 2 , NH(C 1-6 alkyl), or N(C 1-6 alkyl) (C 1-6 alkyl).
2 . The compound of claim 1 , wherein R 4 is NH 2 .
3 . The compound of claim 1 , wherein R 5 is H.
4 . The compound of claim 1 , wherein R 1 is H, C 1-6 alkyl, or substituted or unsubstitued cyclo(C 3-8 ) alkyl.
5 . The compound of claim 1 , wherein Ri is C 1-6 alkyl or substituted cyclohexyl.
6 . The compound of claim 1 , wherein R 3 is H.
7 . The compound of claim 1 , wherein R 2 is substituted or unsubstituted —Y—(CH 2 ) n -aryl, substituted or unsubstituted —Y—(CH 2 ) n -heteroaryl, substituted or unsubstituted —Y—(CH 2 ) n -cyclo(C 3-8 ) alkyl, —NR 6 R 7 , C 1-6 alkyl-NR 6 R 7 , or C 1-6 alkoxy-NR 6 R 7 , wherein R 6 and R 7 are independently selected from the group consisting of H, C 1-6 alkyl, hetero-C 1-6 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl-C 1-6 alkyl; alternatively, R 6 and R 7 may be combined with the nitrogen atom to form a 5-, 6-, 7- or 8-membered, substituted or unsubstituted heterocycloalkane or substituted or unsubstituted heteroaromatic ring, wherein Y is selected from the group consisting of a bond, O and S, and wherein the subscript n is an integer from 0 to 6.
8 . The compound of claim 1 , wherein R 2 is —NR 6 R 7 , C 1-6 alkyl-NR 6 R 7 , or C 1-6 alkoxy-NR 6 R 7 , wherein R 6 and R 7 are independently selected from the group consisting of H, C 1-6 alkyl, hetero-C 1-6 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl-C 1-6 alkyl; alternatively, R 6 and R 7 may be combined with the nitrogen atom to form a 5-, 6-, 7- or 8-membered, substituted or unsubstituted heterocycloalkane or substituted or unsubstituted heteroaromatic ring.
9 . The compound of claim 1 , wherein R 2 is —CH 2 —N(C 1-6 alkyl) (C 1-6 alkyl) or —CH 2 —NR 6 R 7 , wherein R 6 and R 7 are combined with the nitrogen atom to form a 5-, 6-, 7- or 8-membered, substituted or unsubstituted heterocycloalkane or substituted or unsubstituted heteroaromatic ring.
10 . The compound of claim 1 , wherein R 2 is —CH 2 —NR 6 R 7 , wherein R 6 and R 7 are combined with the nitrogen atom to form a 5- or 6-membered, substituted or unsubstituted heterocycloalkane or substituted or unsubstituted heteroaromatic ring.
11 . The compound of claim 1 , wherein R 2 is —CH 2 —NR 6 R 7 , wherein R 6 and R 7 are combined with the nitrogen atom to form a 6-membered, substituted or unsubstituted heterocycloalkane ring.
12 . The compound of claim 1 , wherein R 2 is substituted or unsubstituted piperidinomethyl.
13 . The compound of claim 1 , wherein the compound according to Formula (I) is selected from the group consisting of:
or a pharmaceutically acceptable salt, a tautomer, or a prodrug thereof.
14 . The compound of claim 1 , wherein the compound according to Formula (I) is:
or a pharmaceutically acceptable salt, a tautomer, or a prodrug thereof.
15 . A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier or excipient.
16 . The compound of claim 1 , wherein the compound has a ratio of IC 50 (IRAK) to IC 50 (TAK1) of at least about 25.
17 . A method of treating chronic pain in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound according to Formula (I):
or a pharmaceutically acceptable salt or a tautomer thereof,
wherein;
X is NR 1 ;
R 1 is H, C 1-6 alkyl, C 1-6 carbonyl, C 1-6 carboxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cyclo(C 3-8 ) alkyl, or or substituted or unsubstituted heterocyclo(C 3-8 ) alkyl;
R 2 is C 1-6 alkyl, C 1-6 alkoxy, substituted or unsubstituted —Y—(CH 2 ) n -aryl, substituted or unsubstituted —Y—(CH 2 ) n -heteroaryl, substituted or unsubstituted —Y—(CH 2 ) n -cyclo(C 3-8 ) alkyl, —NR 6 R 7 , C 1-6 alkyl-NR 6 R 7 , or C 1-6 alkoxy-NR 6 R 7 , wherein R 6 and R 7 are independently selected from the group consisting of H, C 1-6 alkyl, hetero-C 1-6 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl-C 1-6 alkyl; alternatively, R 6 and R 7 may be combined with the nitrogen atom to form a 5-, 6-, 7- or 8-membered, substituted or unsubstituted heterocycloalkane or substituted or unsubstituted heteroaromatic ring, wherein Y is selected from the group consisting of a bond, O and S, and wherein the subscript n is an integer from 0 to 6;
R 3 is H, C 1-6 alkyl, C 1-6 alkoxy, halogen, substituted or unsubstituted —Y—(CH 2 ) n -aryl, substituted or unsubstituted —Y—(CH 2 ) n -heteroaryl, substituted or unsubstituted —Y—(CH 2 ) n -cyclo(C 3-8 ) alkyl, —NR 8 R 9 , C 1-6 alkyl-NR 8 R 9 , or C 1-6 alkoxy-NR 8 R 9 , wherein R 8 and R 9 are independently selected from the group consisting of H, C 1-6 alkyl, hetero-C 1-6 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl-C 1-6 alkyl; alternatively, R 8 and R 9 may be combined with the nitrogen atom to form a 5-, 6-, 7- or 8-membered, substituted or unsubstituted heterocycloalkane or substituted or unsubstituted heteroaromatic ring, wherein Y is selected from the group consisting of a bond, O and S, and wherein the subscript n is an integer from 0 to 6;
R 4 is OH, C 1-6 alkoxy, NH 2 , NH(C 1-6 alkyl), or N(C 1-6 alkyl) (C 1-6 alkyl); and
R 5 is H, C 1-6 alkyl, C 1-6 alkoxy, or halogen;
wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 carbonyl and C 1-6 carboxy of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and Ry are optionally and independently substituted by halo, OH, NH 2 , NH(C 1-6 alkyl), or N(C 1-6 alkyl) (C 1-6 alkyl).
18 . The method of claim 17 , wherein the compound has a ratio of IC 50 (IRAK) to IC 50 (TAK1) of at least about 25, 50, 100, 500, 1,000 or 2,000.
19 . The method of claim 17 , wherein the compound has a blood plasma concentration of at least about 0.25, 0.5, 1.0, or 1.5 μM measured 2 hours after oral administration of 50 mg/kg of the compound to a subject.
20 . The method of claim 17 , wherein the subject is treatment refractory to a previously administered anti-inflammatory agent and wherein the anti-inflammatory agent is an anti-TNF biologic.