US2019345133A1PendingUtilityA1
Cxcr3 receptor agonists
Est. expirySep 2, 2036(~10.1 yrs left)· nominal 20-yr term from priority
Inventors:Adam YeagerPhilip Stewart TurnbullLin ZhangJunhua FanJunko TamiyaMarcos SteinbergTom FowlerHanae BenelkebirRaffaele PasceriMaria IevaKevan GrantYang Tran
A61P 43/00A61P 29/00A61P 1/04A61P 25/00A61P 19/02C07D 401/06C07D 401/14C07D 405/12C07D 217/26C07D 401/12
39
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Claims
Abstract
Compounds are provided having the structure of the following Formula I: where R, R1, R2, R3a and R3b are as defined herein. Pharmaceutical compositions comprising such compounds, as well as methods related to their manufacture and use, are also provided.
Claims
exact text as granted — not AI-modified1 . 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 .Cited by (0)
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