Compounds, pharmaceutical composition and methods relating thereto
View Patent ↗New compounds are disclosed which have utility in the treatment of a variety of metabolic related conditions in a patient. The compounds of this invention have the structure (I): wherein X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , A, R 1 , R 2 , R 3 , R 4 , m, n, p, and q are as defined herein, including stereoisomers, esters, and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof in a patient in need thereof.
1. A compound of the formula (I):
wherein:
X 1 , X 2 , X 3 , and X 4 are independently —N— or —C(R 5 )—;
Y 1 is —N— and Y 2 —C(R 3 )—, or Y 1 is —C(R 3 )— and Y 2 is —N—;
A is —N(R 7 )—;
R 1 is R Alk , aryl-C 1-4 alkyl, heterocycle-C 1-4 alkyl, —C(═O)R 7 , —CO 2 R 6 , —SO 2 R 6 , —C(═O)N(R 7 ) 2 , —C(═S)N(R 7 ) 2 , aryl, or heterocycle, wherein each R A1k , alkyl, aryl and heterocycle are optionally substituted with 1-4 substituents independently of each other selected from R 9 ;
R 2 at each occurrence is independently C 1-4 alkyl, F, hydroxy, or C 1-4 alky-O—;
R 3 at each occurrence is independently H, halogen, CN, C 1-4 alkyl, C 1-4 alkyl-O— or C 1-4 alkyl-S—;
R 4 at each occurrence is independently H, halogen, or C 1-4 alkyl;
R 5 at each occurrence is independently H, halogen, cyano, hydroxy, R Alk , haloC 1-4 alkyl, —NO 2 , —C(═O)R 6 , —CO 2 R 6 , —C(═O)N(R 7 ) 2 , —SO 2 N(R 7 ) 2 , —S(═O)R 6 , —S(═O) 2 R 6 , C 1-6 alkyl-O—, haloC 1-4 alkyl-O—, —N(R 7 ) 2 , C 1-6 alkyl-S—, aryl, aryl-C 1-6 alkyl, heterocycle, heterocycle-C 1-6 alkyl, —NR 7 C(═O)R 6 , —NR 7 C(═O)N(R 7 ) 2 , —NR 7 C(═O)OR 7 , —NR 7 C(═NR 7 )N(R 7 ) 2 , or —NR 7 S(═O) 2 N(R 7 ) 2 wherein each R Alk , alkyl, aryl, and heterocycle are optionally substituted with 1-5 substituents independently of each other selected from R 9 ;
R 6 is R Alk , heterocycle, heterocycle-C 1-3 -alkyl, or aryl, wherein each R Alk , alkyl, heterocycle and aryl is optionally substituted with 1-4 substituents independently of each other selected from R 9 ;
R 7 at each occurrence is independently H or R Alk wherein each R Alk is optionally substituted with 1-4 substituents independently of each other selected from halogen, hydroxy, —N(R 8 ) 2 , C 1-4 alkyl-O—, and —CO 2 R 8 ;
R 8 at each occurrence is independently H or C 1-4 alkyl;
R 9 is at each occurrence is independently cyano, hydroxy, R Alk , aryl, aryl-C 1-3 -alkyl, heterocycle, halogen, oxo, C 1-4 haloalkyl, —NO 2 , —C(═O)H, —CO 2 R 8 , —OC(═O)R Alk , —C(═O)N(R 7 ) 2 , —SO 2 N(R 7 ) 2 , —S(═O)R Alk , —S(═O) 2 R Alk , C 1-6 alkoxy, haloC 1-4 alkoxy, —N(R 7 ) 2 , —SR 7 , —NR 7 C(═O)R Alk , —NR 7 C(═O)OR Alk or —NR 7 C(═O)N(R 7 ) 2 , wherein each R Alk , alkyl, aryl and heterocycle are optionally substituted with 1-4 substituents independently of each other selected from halogen, hydroxy, —N(R 8 ) 2 , C 1-4 alkyl-O—, —NR 7 CO 2 R 7 , —NR 7 SO 2 R 7 , and —CO 2 R 8 ;
R Alk at each occurrence is independently C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-3 -alkyl, C 4-8 -cycloalkenyl or C 4-8 -cycloalkenyl-C 1-3 -alkyl;
m is 0,1, or 2;
n is 0,1, or 2;
p is 0 or 1; and
q is 0,1, or 2,
a tautomer or stereoisomer thereof, or a salt thereof.
2. The compound according to claim 1 wherein R 1 is C 1-6 alkyl, aryl-C 1-4 alkyl, heterocycle-C 1-4 alkyl, aryl, or heterocycle, wherein each alkyl, aryl and heterocycle are optionally substituted with 1-4 substituents independently of each other selected from R 9 , or a salt thereof.
3. The compound according to claim 1 wherein R 1 is —C(═O)R 7 , —CO 2 R 6 , or —C(═O)N(R 7 ) 2 , or a salt thereof.
4. The compound according to claim 3 wherein R 1 is —CO 2 R 6 , or a salt thereof.
5. The compound according to claim 4 wherein R 6 is C 1-6 alkyl, or a salt thereof.
6. The compound according to claim 1 wherein n is 0, or a salt thereof.
7. The compound according to claim 1 wherein p and q are 1, or a salt thereof.
8. A pharmaceutically acceptable salt of the compound according to claim 1 .
9. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and/or diluents.
10. A method for treating type-2 diabetes or obesity in a patient in need thereof characterized in that a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, is administered to the patient.
11. A method for treating type-2 diabetes or obesity in a patient in need thereof comprising the step of administering to the patient a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents.
12. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, optionally together with one or more pharmaceutically acceptable carriers and/or diluents.
13. The compound according to claim 1 of the formula (I6):
wherein:
R 3 and R 31 are each H;
R 5 is halogen, —NO 2 or —S(═O) 2 —C 1-4 -alkyl;
R 6 is C 1-4 -alkyl, C 3-6 -cycloalkyl or C 3-6 -cycloalkyl-C 1-3 -alkyl, wherein each of the beforementioned groups is optionally substituted with 1 to 4 substituents independently of each other selected from F and C 1-3 -alkyl-O—; and
R 7 is H, C 1-4 -alkyl, C 3-4 -alkenyl or C 1-3 -alkyl-O—C 1-3 -alkyl,
a tautomer or stereoisomer thereof, or a salt thereof.
14. The compound according to claim 13 , wherein
R 5 is F, Cl, —NO 2 or —S(═O) 2 —CH 3 ; and
R 6 is i-propyl, sec-butyl, tert-butyl, cyclopropyl or cycloproyl-methyl-, all of which are optionally substituted with one or more F or C 1-3 -alkyl-O—.
15. The compound according to claim 1 selected from:
or a salt thereof.
16. A pharmaceutical composition comprising the compound of claim 13 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and/or diluents.
17. A pharmaceutical composition comprising a compound according to claim 13 , or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, optionally together with one or more pharmaceutically acceptable carriers and/or diluents.
18. A method for treating type-2 diabetes or obesity, characterized in that a compound according to claim 13 , or a pharmaceutically acceptable salt thereof, is administered to a patient in need thereof.
19. The method of claim 18 , wherein the method is for treating type-2 diabetes.
20. A method for treating type-2 diabetes or obesity, comprising the step of administering to the patient a therapeutically effective amount of a compound according to claim 13 , or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents to a patient in need thereof.
21. The method of claim 20 , wherein the method is for treating type-2 diabetes.
22. A pharmaceutically acceptable salt of the compound according to claim 13 .