Pyrrole six-membered heteroaryl ring derivative, preparation method thereof, and medicinal uses thereof

Patent metadata

Field	Value
Publication number	US-9527851-B2
Application number	US-201214365497-A
Country	US
Kind code	B2
Filing date	Dec 19, 2012
Priority date	Dec 21, 2011
Publication date	Dec 27, 2016
Grant date	Dec 27, 2016

Abstract

The present invention relates to a pyrrole six-membered heteroaryl ring derivative, the preparation method therefor, and the medicinal uses thereof. Specifically, the present invention relates to a new pyrrole six-membered heteroaryl ring derivative as represented by formula (I), the preparation method therefor, a medicinal composition comprising the derivative, and a therapeutic method using same, and, in particular, the uses as a JAK inhibitor and an immunosuppressor. Substituents in formula (I) have the same definitions as in the description.

First claim

What is claimed is:

1. A compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:
A is CH or N;
L is a bond or alkyl;
R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH 2 ) n C(O)OR 15 , —OC(O)R 15 , —C(O)R 15 , —C(O)NR 16 R 17 , —NHC(O)R 15 , —NR 16 R 17 , —OC(O)NR 16 R 17 , —NHC(O)NR 16 R 17 and —S(O) m R 15 , wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH 2 ) n C(O)OR 15 , —OC(O)R 15 , —C(O)R 15 , —C(O)NR 16 R 17 , —NHC(O)R 15 , —NR 16 R 17 , —OC(O)NR 16 R 17 , —NHC(O)NR 16 R 17 , —S(O) m R 15 , —NHC(O)(O)R 15 , and —NHS(O) m R 15 ;
R 2 and R 4 are each independently selected from the group consisting of hydrogen and alkyl;
R and R 3 are each independently selected from the group consisting of hydrogen, halogen, and alkyl;
R 5 and R 6 are each independently selected from the group consisting of hydrogen, alkyl, and aryl, wherein the alkyl or aryl is optionally substituted with one or more groups selected from the group consisting of alkyl and halogen;
R 7 , R 8 , R 9 , and R 10 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, and halogen, or, R 7 and R 8 or R 9 and R 10 are taken together to form an oxo group;
R 11 , R 12 , R 13 , and R 14 are each independently selected from the group consisting of hydrogen, alkyl, and halogen, or, R 11 and R 12 or R 13 and R 14 are taken together to form an oxo group;
R 15 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more groups selected from the group consisting of alkyl, halogen, hydroxy, cyano, amino, nitro, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH 2 ) n C(O)OR 18 , —OC(O)R 18 , —C(O)R 18 , —C(O)NR 19 R 20 , —NHC(O)R 18 , —NR 19 R 20 , —OC(O)NR 19 R 20 , —NHC(O)NR 19 R 20 , —S(O) m R 18 , —NHC(O)(O)R 18 , and —NHS(O) m R 18 ;
R 16 and R 17 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more groups selected from the group consisting of alkyl, halogen, hydroxy, cyano, amino, alkoxy, cycloalkyl, heterocyclyl, hydroxyalkyl, alkynyl, aryl, heteroaryl, carboxyl, alkoxycarbonyl, and —OR 18 ;
R 18 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, hydroxyalkyl, aryl, and heteroaryl;
R 19 and R 20 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
m is 0, 1, or 2;
n is 0, 1, or 2;
p is 0, 1, or 2;
q is 0, 1, or 2;
s is 0, 1, or 2; and
t is 0, 1, or 2.

2. The compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , being a compound of formula (II), or a pharmaceutically acceptable salt thereof:

3. The compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , being a compound of formula (III), or a pharmaceutically acceptable salt thereof:

4. The compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , being a compound of formula (IV-a) or formula (IV-b), or a pharmaceutically acceptable salt thereof:

5. The compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , being a compound of formula (V-a) or formula (V-b), or a pharmaceutically acceptable salt thereof:

6. The compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , being a compound of formula (VI-a) or formula (VI-b), or a pharmaceutically acceptable salt thereof:

wherein t is 0 or 1.

7. The compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , being a compound of formula (VII-a) or formula (VII-b), or a pharmaceutically acceptable salt thereof:

8. The compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein L is a bond.

9. The compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is selected from the group consisting of alkyl, heteroaryl, —(CH 2 ) n C(O)OR 15 , —C(O)R 15 , —C(O)NR 16 R 17 and —S(O) 2 R 15 , wherein the alkyl or heteroaryl is optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, cyano, and —(CH 2 ) n C(O)OR 15 ;
R 15 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more groups selected from the group consisting of alkyl, halogen, hydroxy, cyano, amino, nitro, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH 2 ) n C(O)OR 18 , —OC(O)R 18 , —C(O)R 18 , —S(O) 2 R 18 , —NHC(O)(O)R 18 , —NHS(O) 2 R 18 , and —NR 19 R 20 ;
R 16 and R 17 are each independently selected from the group consisting of hydrogen, alkyl, and heteroaryl, wherein the heteroaryl is optionally substituted with one or more groups selected from the group consisting of alkoxy, cycloalkyl, hydroxyalkyl, alkynyl, and —OR 18 ;
R 18 is selected from the group consisting of hydrogen, alkyl, and hydroxyalkyl;
R 19 and R 20 are each independently selected from the group consisting of hydrogen and alkyl;
and n is 0, 1, or 2.

10. The compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 5 and R 6 are each independently selected from the group consisting of hydrogen and alkyl.

11. The compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 7 , R 8 , R 9 and

Assignees

• Jiangsu Hengrui Medicine Co
• Shanghai hengrui pharmaceutical co ltd

Inventors

• Zhang Xuejun
• Dong Qing
• Liu Bonian
• Zhu Yaoping
• Li Xiaotao
• Lan Jiong

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title