Antidiabetic heterocyclic compounds
View Patent ↗Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.
1. A compound of structural formula I:
or a pharmaceutically acceptable salt thereof; wherein
“a” is a single bond;
T is CH;
U is CR 1 ;
V is CR 2 ;
W is CH;
Y is selected from the group consisting of: —CR g R g ;
A is selected from the group consisting of:
(1) —C 1-6 alkyl-N(R n )—,
(2) —C 1-6 alkyl-C 6-14 cycloheteroalkyl, and
(3) —C 6-14 cycloheteroalkyl,
wherein A is unsubstituted or substituted with one to five substituents selected from R a ;
B is selected from the group consisting of:
(1) hydrogen,
(2) aryl,
(3) aryl-O—,
(4) aryl-C 1-10 alkyl-,
(5) aryl-C 1-10 alkyl-O—,
(6) C 3-6 cycloalkyl,
(7) C 3-6 cycloalkyl-C 1-10 alkyl-,
(8) C 3-6 cycloalkyl-C 1-10 alkyl-O—,
(9) C 3-6 cycloalkenyl,
(10) C 3-6 cycloalkenyl-C 1-10 alkyl-,
(11) C 3-6 cycloalkenyl-C 1-10 alkyl-O—,
(12) C 2-5 cycloheteroalkyl,
(13) C 3-6 cycloheteroalkyl-C 1-10 alkyl-,
(14) C 3-6 cycloheteroalkyl-C 1-10 alkyl-O—,
(15) heteroaryl,
(16) heteroaryl-O—,
(17) heteroaryl-C 1-10 alkyl-, and
(18) heteroaryl-C 1-10 alkyl-O—,
wherein B is unsubstituted or substituted with one to five substituents selected from R b ;
R 1 is selected from —C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R L , and wherein R 1 is substituted with a substituent selected from R 7 ;
R 2 is hydrogen;
R 3 is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —OR e ,
(4) —CN,
(5) —C 1-6 alkyl,
(6) —C 3-6 cycloalkyl, and
(7) —C 3-6 cycloalkyl-C 1-3 alkyl-,
wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R i ;
R 4 is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) OR e ,
(4) C 1-6 alkyl,
(5) C 1-6 alkyl-O—,
(6) C 3-6 cycloalkyl,
(7) C 3-6 cycloalkyl-O—,
(8) C 3-6 cycloalkyl-C 1-10 alkyl-,
(9) C 3-6 cycloalkyl-C 1-10 alkyl-O—,
(10) C 2-5 cycloheteroalkyl,
(11) C 2-5 cycloheteroalkyl-O—,
(12) C 2-5 cycloheteroalkyl-C 1-10 alkyl-,
(13) C 2-5 cycloheteroalkyl-C 1-10 alkyl-O—,
(14) aryl,
(15) aryl-O—,
(16) aryl-C 1-10 alkyl-,
(17) heteroaryl,
(18) heteroaryl-O—, and
(19) heteroaryl-C 1-10 alkyl-,
wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from R j ,
provided that when R 4 is selected from the group consisting of:
(1) OR e ,
(2) C 1-6 alkyl-O—,
(3) C 3-6 cycloalkyl-O—,
(4) C 3-6 cycloalkyl-C 1-10 alkyl-O—,
(5) C 2-5 cycloheteroalkyl-O—,
(6) C 2-5 cycloheteroalkyl-C 1-10 alkyl-O—,
(7) aryl-O—, and
(8) heteroaryl-O—,
then Y is selected from the group consisting of: —CR g R g ;
R 5 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —C 3-6 cycloalkyl,
wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R j ;
R 6 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —C 3-6 cycloalkyl,
wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R j ;
R 7 is selected from the group consisting of:
(1) —CO 2 R 8 ,
(2) —C 1-6 alkyl-CO 2 R 8 ,
(3) —C 1-6 alkyl-CONHSO 2 R m ,
(4) —C 1-6 alkyl-SO 2 NHCOR m ,
(5) —C 1-6 alkyl-tetrazolyl, and
(6) a cycloheteroalkyl selected from the group consisting of:
R 8 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —C 3-6 cycloalkyl, and
(4) aryl-C 1-6 -alkyl,
wherein each alkyl, cycloalkyl and aryl is unsubstituted or substituted with one to three substituents selected from R j ;
R a is selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) halogen,
(3) —OR e ,
(4) —NR c S(O) n R e ,
(5) —S(O) n R e ,
(6) —S(O) n NR c R d ,
(7) —NR c R d ,
(8) —C(O)R e ,
(9) —OC(O)R e ,
(10) —CO 2 R e ,
(11) —CN,
(12) —C(O)NR c R d ,
(13) —NR c C(O)R e ,
(14) —NR c C(O)OR e ,
(15) —NR c C(O)NR c R d ,
(16) —CF 3 ,
(17) —OCF 3 ,
(18) —OCHF 2 ,
(19) aryl,
(20) heteroaryl,
(21) —C 3-6 cycloalkyl,
(22) —C 3-6 cycloalkenyl, and
(23) —C 2-5 cycloheteroalkyl,
wherein each alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with —C 1-6 alkyl, halogen, —O—C 1-6 alkyl and —CF 3 ;
R b is independently selected from the group consisting of:
(1) —C 1-10 alkyl,
(2) —C 2-10 alkenyl,
(3) —CF 3 ,
(4) halogen,
(5) —CN,
(6) —OH,
(7) —OC 1-10 alkyl,
(8) —OC 2-10 alkenyl,
(9) —O(CH 2 ) p OC 1-10 alkyl,
(10) —O(CH 2 ) p C 3-6 cycloalkyl,
(11) —O(CH 2 ) p C 3-6 cycloalkyl-C 1-10 alkyl-,
(12) —O(CH 2 ) p C 2-5 cycloheteroalkyl,
(13) —O(CH 2 ) p C 2-5 cycloheteroalkyl-C 1-10 alkyl-,
(14) —O-aryl,
(15) —O-heteroaryl,
(16) —O-aryl-C 1-10 alkyl-,
(17) —O-heteroaryl-C 1-10 alkyl-,
(18) —O(CH 2 ) p NR c S(O) m R e ,
(19) —O(CH 2 ) p S(O) m R e ,
(20) —O(CH 2 ) p S(O) m NR c R d ,
(21) —O(CH 2 ) p NR c R d ,
(22) —C(O)R e ,
(23) —OC(O)R e ,
(24) —CO 2 R e ,
(25) —C(O)NR c R d ,
(26) —NR c C(O)R e ,
(27) —NR c C(O)OR e ,
(28) —NR c C(O)NR c R d ,
(29) —O(CH 2 ) p O—C 3-6 cycloalkyl,
(30) —O(CH 2 ) p O—C 2-5 cycloheteroalkyl,
(31) —OCF 3 ,
(32) —OCHF 2 ,
(33) —(CH 2 ) p C 3-6 cycloalkyl,
(34) —(CH 2 ) p C 2-5 cycloheteroalkyl,
(35) aryl,
(36) heteroaryl,
(37) aryl-C 1-10 alkyl-, and
(38) heteroaryl-C 1-10 alkyl-,
wherein each CH, CH 2 , alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with —C 1-6 alkyl, halogen, —O—C 1-6 alkyl and —CF 3 ;
R c and R d are each independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-10 alkyl,
(3) C 2-10 alkenyl,
(4) C 3-6 cycloalkyl,
(5) C 3-6 cycloalkyl-C 1-10 alkyl-,
(6) C 2-5 cycloheteroalkyl,
(7) C 2-5 cycloheteroalkyl-C 1-10 alkyl-,
(8) aryl,
(9) heteroaryl,
(10) aryl-C 1-10 alkyl-, and
(11) heteroaryl-C 1-10 alkyl-,
wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents independently selected from R f ;
each R e is independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-10 alkyl,
(3) —C 2-10 alkenyl,
(4) —C 3-6 cycloalkyl,
(5) —C 3-6 cycloalkyl-C 1-10 alkyl-,
(6) —C 2-5 cycloheteroalkyl,
(7) —C 2-5 cycloheteroalkyl-C 1-10 alkyl-,
(8) aryl,
(9) aryl-C 1-10 alkyl-,
(10) heteroaryl, and
(11) heteroaryl-C 1-10 alkyl-,
wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from R h ;
each R f is selected from the group consisting of:
(1) halogen,
(2) C 1-10 alkyl,
(3) —OH,
(4) —O—C 1-4 alkyl,
(5) —S(O) m —C 1-4 alkyl,
(6) —CN,
(7) —CF 3 ,
(8) —OCHF 2 , and
(9) —OCF 3 ,
wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, C 1-6 alkyl, cyano and S(O) 2 C 1-6 alkyl;
each R g is selected from the group consisting of:
(1) hydrogen,
(2) —C(O)R e , and
(3) —C 1-10 alkyl,
wherein each alkyl is unsubstituted or substituted with one to five halogens;
each R h is selected from the group consisting of:
(1) halogen,
(2) C 1-10 alkyl,
(3) —OH,
(4) —O—C 1-4 alkyl,
(5) —S(O) m —C 1-4 alkyl,
(6) —CN,
(7) —CF 3 ,
(8) —OCHF 2 , and
(9) —OCF 3 ,
wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, C 1-6 alkyl, cyano and S(O) 2 C 1-6 alkyl;
R i is independently selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) —OR e ,
(3) —NR c S(O) m R e ,
(4) halogen,
(5) —S(O) m R e ,
(6) —S(O) m NR c R d ,
(7) —NR c R d ,
(8) —C(O)R e ,
(9) —OC(O)R e ,
(10) —CO 2 R e ,
(11) —CN,
(12) —C(O)NR c R d ,
(13) —NR c C(O)R e ,
(14) —NR c C(O)OR e ,
(15) —NR c C(O)NR c R d ,
(16) —CF 3 ,
(17) —OCF 3 ,
(18) —OCHF 2 ,
(19) —C 3-6 cycloalkyl, and
(20) —C 2-5 cycloheteroalkyl;
R j is independently selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) —OR e ,
(3) —NR c S(O) m R e ,
(4) halogen,
(5) —S(O) m R e ,
(6) —S(O) m NR c R d ,
(7) —NR c R d ,
(8) —C(O)R e ,
(9) —OC(O)R e ,
(10) —CO 2 R e ,
(11) —CN,
(12) —C(O)NR c R d ,
(13) —NR c C(O)R e ,
(14) —NR c C(O)OR e ,
(15) —NR c C(O)NR c R d ,
(16) —CF 3 ,
(17) —OCF 3 ,
(18) —OCHF 2 ,
(19) —C 3-6 cycloalkyl, and
(20) —C 2-5 cycloheteroalkyl;
each R k is independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —C 1-6 alkyl-SO 2 C 1-6 alkyl,
(4) —CF 3 , and
(5) —CHF 2 ,
wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, —OC 1-6 alkyl, halogen, cyano, and —S(O) 2 C 1-6 alkyl;
each R L is independently selected from the group consisting of:
(1) —CO 2 C 1-6 alkyl,
(2) —C 1-10 alkyl,
(3) —C 2-10 alkenyl,
(4) —C 2-10 alkynyl,
(5) —C 3-6 cycloalkyl,
(6) —C 2-6 cycloheteroalkyl,
(7) aryl, and
(8) heteroaryl,
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1-4 substituents selected from C 1-6 alkyl, halogen, and —OC 1-6 alkyl;
each R m is independently selected from the group consisting of:
(1) —C 1-10 alkyl,
(2) —C 2-10 alkenyl,
(3) —C 3-6 cycloalkyl,
(4) —C 3-6 cycloalkyl-C 1-10 alkyl-,
(5) —C 2-5 cycloheteroalkyl,
(6) —C 2-5 cycloheteroalkyl-C 1-10 alkyl-,
(7) aryl,
(8) heteroaryl,
(9) aryl-C 1-10 alkyl-, and
(10) heteroaryl-C 1-10 alkyl-;
R n is selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-10 alkyl,
wherein each alkyl is unsubstituted or substituted with one to five halogens;
each n is independently selected from: 0, 1 or 2;
each m is independently selected from: 0, 1 or 2; and
each p is independently selected from: 0, 1, 2, 3, 4, 5 or 6.
2. The compound according to claim 1 wherein “a” is a single bond, and R 6 is present; or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1 wherein Y is —CH 2 ; or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1 wherein A is selected from the group consisting of:
(1) —C 1-6 alkyl-N(R n )—, and
(2) —C 6-14 cycloheteroalkyl,
wherein A is unsubstituted or substituted with one to five substituents selected from R a ; or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 wherein B is selected from the group consisting of:
(1) aryl-C 1-10 alkyl-, and
(2) heteroaryl,
wherein B is unsubstituted or substituted with one to five substituents selected from R b ; or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 1 wherein B is aryl-C 1-10 alkyl-, wherein B is unsubstituted or substituted with one to five substituents selected from R b ; or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 1 wherein R 3 is hydrogen; R 4 is hydrogen; R 5 is hydrogen; and R 6 is hydrogen; or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 1 wherein R 7 is —CO 2 R 8 ; or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1 wherein R 8 is hydrogen; or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 1 of structural Formula Ik:
wherein
“a” is a single bond, and R 6 is present;
T is CH;
U is CR 1 ;
V is CR 2 ;
W is CH;
Y is selected from the group consisting of: —CR g R g ;
A is selected from the group consisting of:
(1) —C 1-6 alkyl-N(R n )—,
(2) —C 1-6 alkyl-C 6-14 cycloheteroalkyl, and
(3) —C 6-14 cycloheteroalkyl,
wherein A is unsubstituted or substituted with one to five substituents selected from R a ;
B is selected from the group consisting of:
(1) aryl-C 1-10 alkyl-, and
(2) heteroaryl,
wherein B is unsubstituted or substituted with one to five substituents selected from R b ;
R 1 is selected from —C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R L , and wherein R 1 is substituted with a substituent selected from R 7 ;
R 2 is hydrogen;
R 3 is hydrogen;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is hydrogen;
R 7 is —CO 2 R 8 ;
R 8 is hydrogen;
or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 1 of structural formula In:
wherein
A is selected from the group consisting of:
(1) —C 1-6 alkyl-N(R n )—, and
(2) —C 6-14 cycloheteroalkyl,
wherein A is unsubstituted or substituted with one to five substituents selected from R a ;
B is aryl-C 1-10 alkyl-, wherein B is unsubstituted or substituted with one to five substituents selected from R b ;
R 1 is —C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R L , and wherein R 1 is substituted with a substituent selected from R 7 ;
R 2 is hydrogen;
R 3 is hydrogen;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is hydrogen;
R 7 is —CO 2 R 8 ;
R 8 is hydrogen;
or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 11 selected from:
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14. A pharmaceutical composition comprising
(1) a compound of claim 1 , or a pharmaceutically acceptable salt thereof;
(2) one or more compounds selected from the group consisting of:
(a) PPAR gamma agonists and partial agonists;
(b) biguanides;
(c) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;
(d) dipeptidyl peptidase IV (DP-IV) inhibitors;
(e) insulin or an insulin mimetic;
(f) sulfonylureas;
(g) α-glucosidase inhibitors;
(h) agents which improve a patient's lipid profile, said agents being selected from the group consisting of (i) HMG-CoA reductase inhibitors, (ii) bile acid sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARα agonists, (v) cholesterol absorption inhibitors, (vi) acyl CoA:cholesterol acyltransferase (ACAT) inhibitors, (vii) CETP inhibitors, and (viii) phenolic anti-oxidants;
(i) PPARα/γ dual agonists,
(j) PPARδ agonists,
(k) antiobesity compounds,
(l) ileal bile acid transporter inhibitors;
(m) anti-inflammatory agents;
(n) glucagon receptor antagonists;
(o) GLP-1;
(p) GIP-1;
(q) GLP-1 analogs;
(r) HSD-1 inhibitors;
(s) SGLT-2 inhibitors; and
(t) SGLT-1/SGLT-2 inhibitors; and
(3) a pharmaceutically acceptable carrier.
15. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a compound selected from simvastatin, ezetimibe and sitagliptin; and a pharmaceutically acceptable carrier.