CXCR3 RECEPTOR AGONISTS
Compounds are provided having the structure of the following Formula I: where R, R 1 , R 2 , R 3 a and R 3b are as defined herein. Pharmaceutical compositions comprising such compounds, as well as methods related to their manufacture and use, are also provided.
1 . A compound having the structure of Formula I:
or a stereoisomer, hydrate, solvate, isotope or pharmaceutically acceptable salt thereof, wherein:
R is hydrogen, hydroxy, cyano, halo or —OS(═O) 2 R 6 ;
R 1 is aryl or heteroaryl and substituted with 0-4 R 4 groups;
R 2 is aryl or heteroaryl and substituted with 0-3 R 5 groups,
or R 2 is —NR 8 R 9 ;
R 3a is hydrogen or alkyl and R 3b is a nitrogen- or amine-containing moiety of carbon, at least one nitrogen atom and hydrogen,
or R 3a and R 3b taken together with the carbon to which they are attached form a cyclic nitrogen- or amine-containing moiety of carbon, at least one nitrogen atom and hydrogen;
R 4 and R 5 are, at each occurrence, cyano, halo, alkyl, haloalkyl, aminoalkyl, hydroxyalkyl, hydroxy, alkoxy, phenyl, heterocyclyl, —S(═O) 2 R 6 , —C(═O)R 6 , —C(═O)OR 6 , —C(═O)NR 6 N 7 or —NR 6 R 7 ;
R 6 and R 7 are, at each occurrence, hydrogen or alkyl; and
R 8 is hydrogen or alkyl and R 9 is alkyl or aryl substituted with 0-4 R 4 groups,
or R 8 and R 9 taken together with the nitrogen atom to which they are attached form a heterocyclyl substituted with 0-4 R 4 groups and optionally substituted with oxo (═O) or thioxo (═S).
2 . The compound of claim 1 , wherein R 1 is aryl substituted with 0-4 R 4 groups.
3 . The compound of claim 1 , wherein R 1 is heteroaryl substituted with 0-4 R 4 groups.
4 . The compound of claim 1 , wherein R 2 is aryl substituted with 0-3 R 5 groups.
5 . The compound of claim 1 , wherein R 2 is heteroaryl substituted with 0-3 R 5 groups.
6 . The compound of claim 1 , wherein R 1 and R 2 are phenyl, and the compound has the structure of Formula II, or a stereoisomer, hydrate, solvate, isotope or pharmaceutically acceptable salt thereof:
7 . The compound of claim 1 , wherein R 1 is substituted with at least two R 4 groups.
8 . The compound of claim 1 , wherein R 1 is substituted with at least three R 4 groups.
9 . The compound of claim 1 , wherein R 1 is substituted with at least three R 4 groups individually selected from halo and alkyl.
10 . The compound of claim 1 , wherein R 2 is substituted with zero R 5 groups.
11 . The compound of claim 1 , wherein R 1 and R 2 are phenyl, R 3a is hydrogen, and the compound has the structure of Formula III, or a stereoisomer, hydrate, solvate, isotope or pharmaceutically acceptable salt thereof:
12 . The compound of claim 1 , wherein R 1 and R 2 are phenyl, R 3a is hydrogen, and the compound has the structure of Formula IV, or a stereoisomer, hydrate, solvate, isotope or pharmaceutically acceptable salt thereof:
13 . The compound of claim 1 , wherein R 2 is —NR 8 R 9 and the compound has the structure of Formula V, or a stereoisomer, hydrate, solvate, isotope or pharmaceutically acceptable salt thereof:
14 . The compound of claim 13 , wherein R 8 is hydrogen or alkyl and R 9 is alkyl or aryl substituted with 0-4 R 4 groups.
15 . The compound of claim 13 , wherein R 8 and R 9 taken together with the nitrogen atom to which they are attached form a heterocyclyl substituted with 0-4 R 4 groups and optionally substituted with oxo (═O) or thioxo (═S).
16 . The compound of claim 1 , wherein R 2 is —NR 8 R 9 and R 8 and R 9 taken together with the nitrogen atom to which they are attached form a heterocyclyl, and the compound has the structure of Formula VI, or a stereoisomer, hydrate, solvate, isotope or pharmaceutically acceptable salt thereof:
17 . The compound of claim 1 , wherein R 2 is —NR 8 R 9 and R 8 and R 9 taken together with the nitrogen atom to which they are attached form a heterocyclyl, and the compound has the structure of Formula VII, or a stereoisomer, hydrate, solvate, isotope or pharmaceutically acceptable salt thereof:
18 . The compound of claim 1 , wherein R 2 is —NR 8 R 9 and R 8 and R 9 taken together with the nitrogen atom to which they are attached form a heterocyclyl, and the compound has the structure of Formula VIII, or a stereoisomer, hydrate, solvate, isotope or pharmaceutically acceptable salt thereof:
19 . The compound of claim 1 , wherein R 2 is —NR 8 R 9 and R 8 and R 9 taken together with the nitrogen atom to which they are attached form a heterocyclyl, and the compound has the structure of Formula IX, or a stereoisomer, hydrate, solvate, isotope or pharmaceutically acceptable salt thereof:
20 . The compound of claim 1 , wherein R 2 is —NR 8 R 9 and R 8 and R 9 taken together with the nitrogen atom to which they are attached form a heterocyclyl, and the compound has the structure of Formula X, or a stereoisomer, hydrate, solvate, isotope or pharmaceutically acceptable salt thereof:
wherein R 14 is H or R 4 .
21 . The compound of claim 1 , wherein R 3a is hydrogen and R 3b is a nitrogen- or amine-containing moiety of carbon, at least one nitrogen atom and hydrogen.
22 . The compound of claim 21 , wherein R 3b is a nitrogen-containing heterocyclyl substituted with 0-4 R 4 groups, or wherein R 3b is alkyl substituted with —NR 10 R 11 , —N + R 10 R 11 R 12 , —NR 12 C(═O)NR 10 R 11 , —C(═O)NR 10 R 11 , —NR 12 C(═O)CH 2 NR 10 R 11 , —NR 12 N(═NR 12 NR 13 )NR 10 R 11 , —NR 10 SO 2 R 11 , or a nitrogen-containing heterocyclyl substituted with 0-4 R 4 groups, and wherein R 10 , R 11 , R 12 and R 13 are independently hydrogen, alkyl or haloalkyl.
23 . The compound of claim 22 , wherein R 3b is alkyl substituted with —NR 10 R 11 or —N + R 10 R 11 R 12 .
24 . The compound of claim 23 , wherein R 3b is —(CH 2 ) 2-4 NH 2 .
25 . The compound of claim 22 , wherein R 3b is alkyl substituted with —NR 12 N(═NR 13 )NR 10 R 11 .
26 . The compound of claim 22 , wherein R 3b is alkyl substituted with —C(═O)NR 10 R 11 , —NR 12 C(═O)NR 10 R 11 or —NR 12 C(═O)CH 2 NR 10 R 11 .
27 . The compound of claim 22 , wherein R 3b is alkyl substituted with a nitrogen-containing heterocyclyl substituted with 0-4 R 4 groups.
28 . The compound of claim 1 , wherein R 3a and R 3b taken together with the carbon to which they are attached form a cyclic nitrogen- or amine-containing moiety of carbon, at least one nitrogen atom and hydrogen.
29 . The compound of claim 28 , wherein R 3a and R 3b taken together with the carbon to which they are attached form a nitrogen-containing heterocyclyl substituted with 0-4 R 4 groups.
30 . The compound of claim 1 , wherein the compound is a compound of Table A.
31 . The compound of claim 1 , wherein the compound is a compound of Table B.
32 . The compound of claim 1 , wherein R 3a is H and the compound of claim 1 is a stereoisomer having the structure of Formula XI:
or a hydrate, solvate, isotope or pharmaceutically acceptable salt thereof.
33 . The compound of claim 1 , wherein R 3a and R 3b taken together with the carbon to which they are attached form a cyclic nitrogen- or amine-containing moiety of carbon, at least one nitrogen atom and hydrogen, and the compound of claim 1 is a stereoisomer having the structure of Formula XII:
34 . The compound of claim 1 wherein R is hydrogen.
35 . A pharmaceutical composition comprising a compound of claim 1 and at least one pharmaceutically acceptable excipient.
36 . A method for agonizing a chemokine receptor of a cell comprising contacting the cell with a compound of claim 1 .
37 . The method of claim 36 , wherein the chemokine receptor is CXCR3.
38 . A method for treating a disease or condition in a subject for which activation of a CXCR3 receptor is medically indicated, comprising administering to the subject a therapeutically acceptable amount of a compound of claim 1 .
39 . A method for treating rheumatoid arthritis, multiple sclerosis or inflammatory bowel disease in a subject in need thereof, comprising administering to the subject a therapeutically acceptable amount of a compound of claim 1 .