Antidiabetic substituted heteroaryl compounds
View Patent ↗The present invention relates to a compound represented by formula (I): and pharmaceutically acceptable salts thereof. The compounds of formula I 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
ring A is a monocyclic heteroaryl containing 1 to 2 N heteroatoms;
X is
(1) bond,
(2) —O—,
(3) NH,
(4) —(C 1-6 )alkyl-O—, wherein the alkyl or oxygen attaches to ring A,
(5) —O—(C 1-6 )alkyl-O—, or
(6) —(C 1-6 )alkyl-N(H)—, wherein the alkyl or nitrogen attaches to ring A;
R 1 is
(1) (C 3-7 )cycloalkyl,
(2) heterocycloalkyl containing 1 to 2 heteroatoms independently selected from the group consisting N, S, and O,
(3) heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S,
(4) —S(O) 2 (C 1-3 )alkyl, or
(6) —(CH 2 ) q -aryl,
wherein each heterocycloalkyl, heteroaryl, aryl, or cycloalkyl groups are unsubstituted or substituted with 1 to 2 substitutents each independently R 5 ;
R 2 is
(1) (C 1-6 )alkyl,
(2) halo(C 1-6 )alkyl,
(3) hydroxy(C 1-6 )alkyl, or
(4) halo;
R 3 is
(1) (C 1-6 )alkyl, or
(2) halo;
R 4 is
(1) hydrogen, or
(2) (C 1-3 )alkyl;
R 5 is
(1) oxo,
(2) hydroxy,
(3) (C 1-6 )alkyl,
(4) halo(C 1-6 )alkyl,
(5) hydroxy(C 1-6 )alkyl,
(6) cyano,
(7) phenyl,
(8) —S(O) 2 (C 1-3 )alkyl,
(9) —(C 1-3 )alkyl-S(O) 2 (C 1-3 )alkyl, or
(10) —(C 1-3 )alkyl-N(H)—S(O) 2 (C 1-3 )alkyl;
R 6 is
(1) hydrogen,
(2) (C 1-6 )alkyl, or
(3) (C 3-7 )cycloalkyl;
n is 0, 1, 2, or 3;
m is 0 or 1;
k is 0, 1, 2 or 3; and
q is 0,1,2, or 3.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is a bond, —O—, —N(H)—, —(CH 2 ) 3 —NH—, —(CH 2 ) 2 —NH—, —CH 2 —N(H)—, —(CH 2 ) 4 —O—, —(CH 2 ) 3 —O—, —(CH 2 ) 2 —O—, —CH 2 —O— or —O—(CH 2 ) 3 —O—.
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein ring A is pyridinyl or pyrimidinyl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.
5. A compound of structural formula I:
or a pharmaceutically acceptable salt thereof, wherein
ring A is a bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S;
X is
(1) bond,
(2) —O—,
(3) NH,
(4) —(C 1-6 )alkyl-O—, wherein the alkyl or oxygen attaches to ring A,
(5) —O—(C 1-6 )alkyl-O—, or
(6) —(C 1-6 )alkyl-N(H)—, wherein the alkyl or nitrogen attaches to ring A;
R 1 is
(1) (C 3-7 )cycloalkyl,
(2) heterocycloalkyl containing 1 to 2 heteroatoms independently selected from the group consisting N, S, and O,
(3) heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S,
(4) —S(O) 2 (C 1-3 )alkyl, or
(6) —(CH 2 ) q -aryl,
wherein each heterocycloalkyl, heteroaryl, aryl, or cycloalkyl groups are unsubstituted or substituted with 1 to 2 substitutents each independently R 5 ;
R 2 is
(1) (C 1-6 )alkyl,
(2) hydroxy(C 1-6 )alkyl, or
(3) halo;
R 3 is
(1) (C 1-6 )alkyl, or
(2) halo;
R 4 is
(1) hydrogen, or
(2) (C 1-3 )alkyl;
R 5 is
(7) oxo,
(8) hydroxy,
(9) (C 1-6 )alkyl,
(10) halo(C 1-6 )alkyl,
(11) hydroxy(C 1-6 )alkyl,
(12) cyano,
(7) phenyl,
(8) —S(O) 2 (C 1-3 )alkyl,
(9) —(C 1-3 )alkyl-S(O) 2 (C 1-3 )alkyl, or
(10) —(C 1-3 )alkyl-N(H)—S(O) 2 (C 1-3 )alkyl;
R 6 is
(1) hydrogen,
(2) (C 1-6 )alkyl, or
(3) (C 3-7 )cycloalkyl;
n is 0, 1, 2, or 3;
m is 0 or 1;
k is 0, 1, 2 or 3; and
q is 0, 1, 2, or 3.
6. The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein X is a bond, —O—, —N(H)—, —(CH 2 ) 3 —NH—, —(CH 2 ) 2 —NH—, —CH 2 —N(H)—, —(CH 2 ) 4 —O—, —(CH 2 ) 3 —O—, —(CH 2 ) 2 —O—, —CH 2 —O— or —O—(CH 2 ) 3 —O—.
7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein ring A is 1H-pyrazolo[4,3-b]pyridinyl, thiazolo[4,5-b]pyridinyl, or 1H-pyrrolo[2,3-b]pyridinyl.
8. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.
9. A compound of structural formula I-A:
or a pharmaceutically acceptable salt thereof, wherein
X is
(1) a bond,
(2) —O—,
(3) —(C 1-6 )alkyl-O—, wherein the alkyl or oxygen attaches to ring A
(4) —O—(C 1-6 )alkyl-O—, or
(5) —(C 1-6 )alkyl-N(H)—, wherein the alkyl or nitrogen attaches to ring A;
R 1 is
(1) (C 3-7 )cycloalkyl,
(2) heterocycloalkyl containing 1 to 2 heteroatoms independently selected from the group consisting of N, S, and O,
(3) heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S,
(4) —S(O) 2 (C 1-3 )alkyl, or
(5) —(CH 2 )q-aryl,
wherein each heterocycloalkyl, heteroaryl, aryl, or cycloalkyl groups are unsubstituted or substituted with 1 to 2 substitutents each independently R 5 ;
R 2 is
(1) (C 1-6 )alkyl,
(2) halo(C 1-6 )alkyl, or
(3) hydroxy(C 1-6 )alkyl;
R 3 is
(1) (C 1-6 )alkyl, or
(2) halo;
R 4 is
(1) hydrogen, or
(2) (C 1-3 )alkyl;
R 5 is
(1) oxo,
(2) hydroxy,
(3) (C 1-6 )alkyl,
(4) halo(C 1-6 )alkyl,
(5) hydroxy(C 1-6 )alkyl,
(6) cyano,
(7) phenyl,
(8) —S(O) 2 (C 1-3 )alkyl,
(9) —(C 1-3 )alkyl-S(O) 2 (C 1-3 )alkyl, or
(10) —(C 1-3 )alkyl-N(H)—S(O) 2 (C 1-3 )alkyl;
n is 0, 1, 2, or 3;
m is 0 or 1;
k is 0, 1, 2 or 3, and
q is 0, 1, 2, or 3.
10. A compound selected from
or a pharmaceutically acceptable salt, thereof.
11. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12. A method of treating type 2 diabetes mellitus in a patient in need of treatment comprising the administration to the patient of a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
13. 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 1 inhibitors; and
(t) SGLT 2 inhibitors; and
(3) a pharmaceutically acceptable carrier.