Antidiabetic tricyclic 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 A:
or a pharmaceutically acceptable salt thereof; wherein
X is selected from the group consisting of:
(1) oxygen, and
(2) NR 7 ;
T is CH;
U is CH;
V is N;
W is CH;
A is selected from the group consisting of:
wherein A is unsubstituted or substituted with one to six substituents selected from R a , and wherein two R a substituents together with the carbon atom to which they are attached may form a 3-6 membered cycloalkyl ring or a 3-6 membered cycloheteroalkyl ring containing 0 to 3 heteroatoms independently selected from oxygen, sulfur, and NR 8 , and wherein each 3-6 membered cycloalkyl and each 3-6 membered cycloheteroalkyl ring is unsubstituted or substituted with 1 to 4 substituents selected from: —C 1-6 alkyl, —O—C 1-6 alkyl, halogen and OH;
B is selected from the group consisting of:
(1) C 1-6 alkyl,
(2) aryl,
(3) aryl-O—,
(4) C 3-6 cycloalkyl-,
(5) C 3-6 cycloalkyl-C 1-10 alkyl-,
(6) C 3-6 cycloalkyl-C 1-10 alkyl-O—,
(7) C 2-5 cycloheteroalkyl-,
(8) C 3-6 cycloheteroalkyl-C 1-10 alkyl-,
(9) C 3-6 cycloheteroalkyl-C 1-10 alkyl-O—,
(10) heteroaryl,
(11) heteroaryl-O—,
(12) aryl-C 1-10 alkyl-, and
(13) heteroaryl-C 1-10 alkyl-;
wherein B is unsubstituted or substituted with one to six substituents selected from R b ;
each R 1 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —OR e ,
(4) —CN,
(5) —C 1-6 alkyl, and
(6) —C 3-6 cycloalkyl,
wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R i ;
R 2 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 ;
each R 3 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —OR e ,
(4) —C 1-6 alkyl,
(5) —C 2-6 alkenyl,
(6) —C 2-6 alkynyl,
(7) —C 3-6 cycloalkyl, and
(8) —C 2-6 cycloheteroalkyl,
wherein each alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to three substituents selected from R L ;
each R 4 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —OR e ,
(4) —C 1-6 alkyl,
(5) —C 2-6 alkenyl,
(6) —C 2-6 alkynyl,
(7) —C 3-6 cycloalkyl, and
(8) —C 2-6 cycloheteroalkyl,
wherein each alkyl, alkenyl, alkynyl, and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R L ;
R 5 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-3 alkyl, and
(3) halogen;
R 6 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-3 alkyl, and
(3) halogen, or
R 5 and R 6 can together form oxo;
R 7 is selected from the group consisting of:
(1) hydrogen,
(2) —C(O)R e , and
(3) —C 1-10 alkyl,
wherein —C 1-10 alkyl is unsubstituted or substituted with one to five fluorines;
each R 8 is selected from the group consisting of:
(1) hydrogen,
(2) —C(O)R e , and
(3) —C 1-10 alkyl,
wherein —C 1-10 alkyl is unsubstituted or substituted with one to five fluorines;
each R 9 is selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-6 alkyl,
wherein —C 1-6 alkyl is unsubstituted or substituted with one to five fluorines;
each R a is independently selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) —O—C 1-6 alkyl,
(3) halogen,
(4) oxo,
(5) —OR e ,
(6) —N(R c )S(O) m R e ,
(7) —S(O) m R e ,
(8) —S(O) m NR c R d ,
(9) —NR c R d ,
(10) —C(O)R e ,
(11) —OC(O)R e ,
(12) —CO 2 R e ,
(13) —CN,
(14) —C(O)NR c R d ,
(15) —N(R c )C(O)R e ,
(16) —N(R c )C(O)OR e ,
(17) —N(R c )C(O)NR c R d ,
(18) —CF 3 ,
(19) —OCF 3 ,
(20) —OCHF 2 ,
(21) —(CH 2 ) p —C 3-6 cycloalkyl,
(22) —(CH 2 ) p —C 2-10 cycloheteroalkyl,
(23) —(CH 2 ) p -aryl, and
(24) —(CH 2 ) p -heteroaryl,
wherein R a is unsubstituted or substituted with one to three substituents selected from R m ;
each R b is independently selected from the group consisting of:
(1) —C 1-10 alkyl,
(2) —O—C 1-10 alkyl,
(3) —C 2-10 alkenyl,
(4) halogen,
(5) —OH,
(6) —OC 2-10 alkenyl,
(7) —O(CH 2 )pOC 1-10 alkyl,
(8) —O(CH 2 )pC 3-6 cycloalkyl,
(9) —O(CH 2 )pC 2-10 cycloheteroalkyl,
(10) —O(CH 2 )p-aryl,
(11) —O(CH 2 )p-heteroaryl,
(12) —N(R c )S(O) m R e ,
(13) —S(O) m R e ,
(14) —O(CH 2 )p-S(O) m R e ,
(15) —S(O) m NR c R d ,
(16) —NR c R d ,
(17) —C(O)R e ,
(18) —OC(O)R e ,
(19) —CO 2 R e ,
(20) —CN,
(21) —C(O)NR c R d ,
(22) —N(R c )C(O)R e ,
(23) —N(R c )C(O)OR e ,
(24) —N(R c )C(O)NR c R d ,
(25) —O(CH 2 )pO-C 3-6 cycloalkyl,
(26) —O(CH 2 )pO-C 2-10 cycloheteroalkyl,
(27) —CF 3 ,
(28) —OCF 3 ,
(29) —OCHF 2 ,
(30) —(CH 2 )p-C 3-6 cycloalkyl,
(31) —(CH 2 )p-C 2-10 cycloheteroalkyl,
(32) —(CH 2 )p-aryl, and
(33) —(CH 2 )p-heteroaryl,
wherein each R b is unsubstituted or substituted with one to five substituents selected from R k ;
each R c and R d 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 2-6 cycloheteroalkyl,
(7) C 2-6 cycloheteroalkyl-C 1-10 alkyl-,
(8) aryl,
(9) heteroaryl,
(10) aryl-C 1-10 alkyl-, and
(11) heteroaryl-C 1-10 alkyl-, or
R c and R d together with the atom(s) to which they are attached form a cycloheteroalkyl ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R g , and wherein each R c and R d 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) heteroaryl,
(10) aryl-C 1-10 alkyl-, and
(11) heteroaryl-C 1-10 alkyl-,
wherein each R e 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) —OC 1-6 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, cyano, and —S(O) 2 CH 3 ;
each R g is selected from the group consisting of:
(1) hydrogen,
(2) —C(O)R e , and
(3) —C 1-10 alkyl,
wherein alkyl is unsubstituted or substituted with one to five fluorines;
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, cyano, and —S(O) 2 CH 3 ;
R i is independently selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) —OR e ,
(3) —N(R 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) —N(R c )C(O)R e ,
(14) —N(R c )C(O)OR e ,
(15) —N(R 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) —N(R 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) —N(R c )C(O)R e ,
(14) —N(R c )C(O)OR e ,
(15) —N(R 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) halogen,
(2) —C 1-6 alkyl,
(3) —OH,
(4) oxo,
(5) —OC 1-6 alkyl,
(6) —SO 2 —C 1-6 alkyl,
(7) —C 1-6 alkyl-SO 2 C 1-6 alkyl,
(8) —CN,
(9) —CF 3 ,
(10) —OCHF 2 ,
(11) —OCF 3 ,
(12) —NH 2 ,
(13) —NHSO 2 C 1-6 alkyl,
(14) —NHC(O)C 1-6 alkyl,
(15) ═N(OCH 3 ),
(16) —P(O)(OH) 2 , and
(17) —P(O)(OC 1-6 alkyl) 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;
R L is selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) halogen,
(3) —OR e ,
(4) —N(R c )S(O) m R e ,
(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) —N(R c )C(O)R e ,
(14) —N(R c )C(O)OR e ,
(15) —N(R 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 m is independently selected from the group consisting of:
(1) halogen,
(2) —C 1-6 alkyl,
(3) —OH,
(4) oxo,
(5) —OC 1-6 alkyl,
(6) —SO 2 —C 1-6 alkyl,
(7) —C 1-6 alkyl-SO 2 C 1-6 alkyl,
(8) —CN,
(9) —CF 3 ,
(10) —OCHF 2 ,
(11) —OCF 3 ,
(12) —NH 2 ,
(13) —NHSO 2 C 1-6 alkyl,
(14) —NHC(O)C 1-6 alkyl,
(15) ═N(OCH 3 ),
(16) —P(O)(OH) 2 , and
(17) —P(O)(OC 1-6 alkyl) 2 ,
wherein each C 1-10 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;
n is 1;
each m is independently 0, 1 or 2;
each p is independently selected from: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and
q is independently selected from: 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
2. A compound of structural formula I:
wherein
X is selected from the group consisting of:
(1) oxygen, and
(2) NR 7 ;
T is CH;
U is CH;
V is N;
W is CH;
A is selected from the group consisting of:
wherein A is unsubstituted or substituted with one to six substituents selected from R a , and wherein two R a substituents together with the carbon atom to which they are attached may form a 3-6 membered cycloalkyl ring or a 3-6 membered cycloheteroalkyl ring containing 0 to 3 heteroatoms independently selected from oxygen, sulfur, and NR 8 , and wherein each 3-6 membered cycloalkyl and each 3-6 membered cycloheteroalkyl ring is unsubstituted or substituted with 1 to 4 substituents selected from: —C 1-6 alkyl, —O—C 1-6 alkyl, halogen and OH
B is selected from the group consisting of:
(1) aryl,
(2) aryl-O—,
(3) C 3-6 cycloalkyl-,
(4) C 3-6 cycloalkyl-C 1-10 alkyl-,
(5) C 3-6 cycloalkyl-C 1-10 alkyl-O—,
(6) C 2-5 cycloheteroalkyl-,
(7) C 3-6 cycloheteroalkyl-C 1-10 alkyl-,
(8) C 3-6 cycloheteroalkyl-C 1-10 alkyl-O—,
(9) heteroaryl,
(10) heteroaryl-O—,
(11) aryl-C 1-10 alkyl-, and
(12) heteroaryl-C 1-10 alkyl-;
wherein B is unsubstituted or substituted with one to six substituents selected from R b ;
each R 1 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —OR e ,
(4) —CN,
(5) —C 1-6 alkyl, and
(6) —C 3-6 cycloalkyl,
wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R 1 ;
R 2 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 ;
each R 3 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —OR e ,
(4) —C 1-6 alkyl,
(5) —C 2-6 alkenyl,
(6) —C 2-6 alkynyl,
(7) —C 3-6 cycloalkyl, and
(8) —C 2-6 cycloheteroalkyl,
wherein each alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to three substituents selected from R L ;
each R 4 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —OR e ,
(4) —C 1-6 alkyl,
(5) —C 2-6 alkenyl,
(6) —C 2-6 alkynyl,
(7) —C 3-6 cycloalkyl, and
(8) —C 2-6 cycloheteroalkyl,
wherein each alkyl, alkenyl, alkynyl, and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R L ;
R 5 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-3 alkyl, and
(3) halogen;
R 6 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-3 alkyl, and
(3) halogen, or
R 5 and R 6 can together form oxo;
R 7 is selected from the group consisting of:
(1) hydrogen,
(2) —C(O)R e , and
(3) —C 1-10 alkyl,
wherein —C 1-10 alkyl is unsubstituted or substituted with one to five fluorines;
each R 8 is selected from the group consisting of:
(1) hydrogen,
(2) —C(O)R e , and
(3) —C 1-10 alkyl,
wherein —C 1-10 alkyl is unsubstituted or substituted with one to five fluorines;
each R a is independently selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) —O—C 1-6 alkyl,
(3) halogen,
(4) oxo,
(5) —OR e ,
(6) —N(R c )S(O) m R e ,
(7) —S(O) m R e ,
(8) —S(O) m NR c R d ,
(9) —NR c R d ,
(10) —C(O)R e ,
(11) —OC(O)R e ,
(12) —CO 2 R e ,
(13) —CN,
(14) —C(O)NR c R d ,
(15) —N(R c )C(O)R e ,
(16) —N(R c )C(O)OR e ,
(17) —N(R c )C(O)NR c R d ,
(18) —CF 3 ,
(19) —OCF 3 ,
(20) —OCHF 2 ,
(21) —(CH 2 ) p —C 3-6 cycloalkyl,
(22) —(CH 2 ) p —C 2-10 cycloheteroalkyl,
(23) —(CH 2 ) p -aryl, and
(24) —(CH 2 ) p -heteroaryl,
wherein R a is unsubstituted or substituted with one to three substituents selected from R m ;
each R b is independently selected from the group consisting of:
(1) —C 1-10 alkyl,
(2) —O—C 1-10 alkyl,
(3) —C 2-10 alkenyl,
(4) halogen,
(5) —OH,
(6) —OC 2-10 alkenyl,
(7) —O(CH 2 )pOC 1-10 alkyl,
(8) —O(CH 2 )pC 3-6 cycloalkyl,
(9) —O(CH 2 )pC 2-10 cycloheteroalkyl,
(10) —O(CH 2 )p-aryl,
(11) —O(CH 2 )p-heteroaryl,
(12) —N(R c )S(O) m R e ,
(13) —S(O) m R e ,
(14) —O(CH 2 )p-S(O) m R e ,
(15) —S(O) m NR c R d ,
(16) —NR c R d ,
(17) —C(O)R e ,
(18) —OC(O)R e ,
(19) —CO 2 R e ,
(20) —CN,
(21) —C(O)NR c R d ,
(22) —N(R c )C(O)R e ,
(23) —N(R c )C(O)OR e ,
(24) —N(R c )C(O)NR c R d ,
(25) —O(CH 2 )pO-C 3-6 cycloalkyl,
(26) —O(CH 2 )pO-C 2-10 cycloheteroalkyl,
(27) —CF 3 ,
(28) —OCF 3 ,
(29) —OCHF 2 ,
(30) —(CH 2 )p-C 3-6 cycloalkyl,
(31) —(CH 2 )p-C 2-10 cycloheteroalkyl,
(32) —(CH 2 )p-aryl, and
(33) —(CH 2 )p-heteroaryl,
wherein each R b is unsubstituted or substituted with one to five substituents selected from R k ;
each R c and R d 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 2-6 cycloheteroalkyl,
(7) C 2-6 cycloheteroalkyl-C 1-10 alkyl-,
(8) aryl,
(9) heteroaryl,
(10) aryl-C 1-10 alkyl-, and
(11) heteroaryl-C 1-10 alkyl-, or
R c and R d together with the atom(s) to which they are attached form a cycloheteroalkyl ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R g , and wherein each R c and R d 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) heteroaryl,
(10) aryl-C 1-10 alkyl-, and
(11) heteroaryl-C 1-10 alkyl-,
wherein each R e 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) —OC 1-6 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, cyano, and —S(O) 2 CH 3 ;
each R g is selected from the group consisting of:
(1) hydrogen,
(2) —C(O)R e , and
(3) —C 1-10 alkyl,
wherein alkyl is unsubstituted or substituted with one to five fluorines;
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, cyano, and —S(O) 2 CH 3 ;
R i is independently selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) —OR e ,
(3) —N(R 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) —N(R c )C(O)R e ,
(14) —N(R c )C(O)OR e ,
(15) —N(R 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) —N(R 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) —N(R c )C(O)R e ,
(14) —N(R c )C(O)OR e ,
(15) —N(R 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) halogen,
(2) —C 1-6 alkyl,
(3) —OH,
(4) oxo,
(5) —OC 1-6 alkyl,
(6) —SO 2 —C 1-6 alkyl,
(7) —C 1-6 alkyl-SO 2 C 1-6 alkyl,
(8) —CN,
(9) —CF 3 ,
(10) —OCHF 2 ,
(11) —OCF 3 ,
(12) —NH 2 ,
(13) —NHSO 2 C 1-6 alkyl,
(14) —NHC(O)C 1-6 alkyl,
(15) ═N(OCH 3 ),
(16) —P(O)(OH) 2 , and
(17) —P(O)(OC 1-6 alkyl) 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;
R L is selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) halogen,
(3) —OR e ,
(4) —N(R c )S(O) m R e ,
(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) —N(R c )C(O)R e ,
(14) —N(R c )C(O)OR e ,
(15) —N(R 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 m is independently selected from the group consisting of:
(1) halogen,
(2) —C 1-6 alkyl,
(3) —OH,
(4) oxo,
(5) —OC 1-6 alkyl,
(6) —SO 2 —C 1-6 alkyl,
(7) —C 1-6 alkyl-SO 2 C 1-6 alkyl,
(8) —CN,
(9) —CF 3 ,
(10) —OCHF 2 ,
(11) —OCF 3 ,
(12) —NH 2 ,
(13) —NHSO 2 C 1-6 alkyl,
(14) —NHC(O)C 1-6 alkyl,
(15) ═N(OCH 3 ),
(16) —P(O)(OH) 2 , and
(17) —P(O)(OC 1-6 alkyl) 2 ,
wherein each C 1-10 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;
n is 1;
each m is independently 0, 1 or 2;
each p is independently selected from: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and
q is independently selected from: 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1 of structural formula Ia
or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1 wherein R 1 is hydrogen; or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 wherein X is oxygen; or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 1 wherein A is selected from the group consisting of:
wherein A is unsubstituted or substituted with one to six substituents selected from R a , and wherein two R a substituents together with the carbon atom to which they are attached may form a 3-6 membered cycloalkyl ring or a 3-6 membered cycloheteroalkyl ring containing 0 to 3 heteroatoms independently selected from oxygen, sulfur, and NR 8 , and wherein each 3-6 membered cycloalkyl ring and each 3-6 membered cycloheteroalkyl ring is unsubstituted or substituted with 1 to 4 substituents selected from: —C 1-6 alkyl, —O—C 1-6 alkyl, halogen and OH;
or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 1 wherein A is selected from the group consisting of:
wherein A is unsubstituted or substituted with one to six substituents selected from R a ;
or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 1 wherein B is selected from the group consisting of:
(1) aryl, and
(2) heteroaryl,
wherein each aryl and heteroaryl is unsubstituted or substituted with one to six substituents selected from R b ;
or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1 wherein B is selected from the group consisting of:
(1) phenyl,
(2) pyridine and
(3) benzimidazole,
wherein each phenyl, pyridine and benzimidazole is unsubstituted or substituted with one to six substituents selected from R b ;
or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 1 wherein R 3 and R 4 are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen, and
(3) —C 1-6 alkyl,
wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R L ; or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 1 wherein R 3 and R 4 are hydrogen; or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1 wherein R 2 is hydrogen; or a pharmaceutically acceptable salt thereof.
13. The compound according to claim 1 wherein R 5 and R 6 are selected from the group consisting of:
(1) hydrogen, and
(2) halogen;
or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 1 wherein R 5 and R 6 are hydrogen; or a pharmaceutically acceptable salt thereof.
15. The compound according to claim 1 wherein the absolute stereochemistry at the two stereogenic carbon centers is indicated below:
or a pharmaceutically acceptable salt thereof.
16. The compound according to claim 1 of structural formula Ia
wherein:
X is oxygen;
T is CH;
U is CH;
V is N;
W is CH;
A is selected from the group consisting of:
wherein A is unsubstituted or substituted with one to six substituents selected from R a , and wherein two R a substituents together with the carbon atom to which they are attached may form a 3-6 membered cycloalkyl ring or a 3-6 membered cycloheteroalkyl ring containing 0 to 3 heteroatoms independently selected from oxygen, sulfur, and NR 8 , and wherein each 3-6 membered cycloalkyl ring and each 3-6 membered cycloheteroalkyl ring is unsubstituted or substituted with 1 to 4 substituents selected from: —C 1-6 alkyl, —O—C 1-6 alkyl, halogen and OH;
B is selected from the group consisting of:
(1) aryl, and
(2) heteroaryl,
wherein each aryl and heteroaryl is unsubstituted or substituted with one to six substituents selected from R b ;
R 1 and R 2 are hydrogen;
R 3 and R 4 are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen, and
(3) —C 1-6 alkyl,
wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R L ;
R 5 and R 6 are selected from the group consisting of:
(1) hydrogen, and
(2) halogen; and
n is 1;
or a pharmaceutically acceptable salt thereof.
17. The compound according to claim 1 of structural formula Ia
wherein:
X is oxygen;
T is CH;
V is N;
W is CH;
A is selected from the group consisting of:
wherein A is unsubstituted or substituted with one to six substituents selected from R a ;
B is selected from the group consisting of:
(1) phenyl,
(2) pyridine, and
(3) benzimidazole,
wherein each phenyl, pyridine and benzimidazole is unsubstituted or substituted with one to six substituents selected from R b ;
R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are hydrogen; and
n is 1;
or a pharmaceutically acceptable salt thereof.
18. A compound selected from:
or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
20. 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.
21. 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.
22. 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.