Cyclic guanidines, compositions containing such compounds and methods of use
View Patent ↗The present invention relates to cyclic guanidines, compositions containing such compounds and methods of treatment. The compounds are glucagon receptor antagonists and thus are useful for treating, preventing or delaying the onset of type 2 diabetes mellitus.
1. A compound represented by formula I:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
R 1 represents H or is independently selected from the group consisting of:
a) OH, halo, CO 2 R a , C(O)NR b R c , NR b R c , CN or S(O) p R d ;
b) C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, OC 1-10 alkyl, OC 3-10 alkenyl and OC 3-10 alkynyl, said groups being optionally substituted with:
(1) 1-5 halo groups up to a perhaloalkyl group;
(2) 1 oxo group;
(3) 1-2 OH groups;
(4) 1-2 C 1--10 alkoxy groups, each optionally substituted with: up to five halo or a perhaloalkoxy, 1 OH or CO 2 R a group;
(5) 1 CO 2 R a or S(O) p R d ;
(6) 1-2 Aryl, Hetcy or HAR groups, each optionally substituted as follows:
(a) 1-5 halo groups,
(b) 1 OH, CO 2 R a , CN, S(O) p R d , NO 2 or C(O)NR b R C ,
(c) 1-2 C 1-10 alkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl, and 1-2 OH or CO 2 R a groups; and
(d) 1-2 phenyl rings, each of which is optionally substituted as follows: 1-5 halo groups up to perhalo, 1-3 C 1-10 alkyl or alkoxy groups, each being further optionally substituted with 1-5 halo up to perhalo, or 1-2 hydroxy or CO 2 R a groups;
c) Aryl, HAR, Hetcy, —O-Aryl, —O-HAR and —O-Hetcy, each optionally substituted as set forth below:
(1) 1-3 C 1-10 alkyl, C 2-10 alkenyl or C 2-10 alkynyl groups optionally substituted with 1-5 halo groups; 1-2 OH groups; phenyl optionally substituted with 1-3 halo, C 1-6 alkyl or C 1-6 alkoxy groups, the alkyl and alkoxy groups being further optionally substituted with 1-3 halo groups; CO 2 R a ; CN or S(O) p R d groups; and
(2) 1-3 C 1-10 alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups, 1-2 OH; phenyl optionally substituted with 1-3 halo, C 1-6 alkyl or C 1-6 alkoxy groups, the alkyl and alkoxy groups being further optionally substituted with 1-3 halo groups; CO 2 R a ; CN or S(O) p R d groups;
said Aryl, HAR, Hetcy —O-Aryl, —O-HAR and —O-Hetcy group c) being further optionally substituted on carbon by a group selected from the group consisting of;
(3) 1-5 halo groups;
(4) 1-2 OH groups;
(5) 1 S(O) p R d , NO 2 or CN group;
(6) 1-2 CO 2 R a ;
(7) —C(O)NR b R c ;
each R 2 represents H or is independently selected from the group consisting of:
a) OH, halo, CO 2 R a , C(O)NR b R C , NR b R C , CN or S(O) p R d ;
b) C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, OC 1-10 alkyl, OC 3-10 alkenyl and OC 3-10 alkynyl, said groups being optionally substituted with:
(1) 1-5 halo groups up to a perhaloalkyl group;
(2) 1 oxo group;
(3) 1 OH group;
(4) 1 C 1-10 alkoxy group, each optionally substituted with: up to five halo or a perhaloalkoxy, 1 OH or CO 2 R a group;
(5) 1 CO 2 R a or S(O) p R d ;
(6) 1 Aryl, Hetcy or HAR group, each optionally substituted as follows:
(a) 1-5 halo groups,
(b) 1 OH, CO 2 R a , CN, S(O) p R d , NO 2 or C(O)NR b R C ,
(c) 1-2 C 1-10 alkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl, and 1-2 OH or CO 2 R a groups; and
(d) 1-2 phenyl rings, each of which is optionally substituted as follows: 1-5 halo groups up to perhalo; 1-3 C 1-10 alkyl or alkoxy groups, each being further optionally substituted with 1-5 halo up to perhalo; and 1-2 hydroxy or CO 2 R a groups;
c) Aryl, HAR, Hetcy, —O-Aryl, —O-HAR and —O-Hetcy, each optionally substituted as set forth below:
(1) 1-3 C 1-10 alkyl, C 2-10 alkenyl or C 2-10 alkynyl groups optionally substituted with 1-5 halo groups, 1-2 OH, phenyl, CO 2 R a , CN or S(O) p R d groups;
(2) 1-3 C 1-10 alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups, 1-2 OH, phenyl, CO 2 R a , CN or S(O) p R d groups;
said Aryl, HAR or Hetcy group c) being further optionally substituted on carbon by a group selected from the group consisting of;
(3) 1-5 halo groups up to perhalo;
(4) 1 OH group;
(5) 1 S(O) p R d , NO 2 or CN group;
(6) 1 CO 2 R a ;
R 3 selected from the group consisting of:
a) C 1-10 alkyl or C 2-10 alkenyl, each optionally substituted with
1-5 halo groups up to perhalo;
1-2 OH, C 1-3 alkoxy or haloC 1-3 alkoxy groups;
1-2 NR C R d groups; and
1-2 Aryl, HAR or Hetcy groups, each optionally substituted with 1-3 halo groups and 1-2 groups selected from CN, NO 2 , C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy and haloC 1-3 alkoxy groups,
b) Aryl, HAR or Hetcy, each optionally substituted with 1-3 halo groups and 1-2 groups selected from CN, NO 2 , C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy and haloC 1-3 alkoxy groups;
R 4 is independently selected from the group consisting of: Aryl, HAR or Hetcy, each optionally substituted as set forth below:
(1) 1-3 C 1-14 alkyl, C 2-10 alkenyl or C 2-10 alkynyl groups optionally substituted with 1-5 halo groups, 1-2 OH, CO 2 R a , CN or S(O) p R d groups or phenyl optionally substituted as follows: 1-5 halo groups up to perhalo; 1-3 C 1-10 alkyl or alkoxy groups, each being further optionally substituted with 1-5 halo up to perhalo, or 1-2 hydroxy or CO 2 R a groups;
(2) 1-3 C 1-10 alkoxy or C 3-10 alkenyloxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups, 1-2 OH, CO 2 R a , CN, S(O) p R d , and phenyl optionally substituted as follows: 1-5 halo groups up to perhalo; 1-3 C 1-10 alkyl or alkoxy groups, each being further optionally substituted with 1-5 halo up to perhalo, or 1-2 hydroxy or CO 2 R a groups;
(3) 1-2 Aryl, HAR or Hetcy, OAryl, OHAR or OHetcy groups, each optionally substituted as follows:
(i) 1-3 halo groups;
(ii) 1-2 C 1-10 alkyl, C 2-10 alkenyl or C 2-10 alkynyl groups each optionally substituted with 1-5 halo groups, 1-2 OH, phenyl, CO 2 R a , CN or S(O) p R d groups;
(iii) 1-2 C 1-10 alkoxy groups the alkyl portion of which being optionally substituted with 1-5 halo groups, 1-2 OH, phenyl, CO 2 R a , CN or S(O) p R d groups; and
(iv) 1-2 CO 2 R a , S(O) p R d , CN, NR b R c , NO 2 or OH groups;
said Aryl, HAR or Hetcy group R 4 being further optionally substituted on carbon by a group selected from the group consisting of;
(4) 1-5 halo groups;
(5) 1-2 OH groups;
(6) 1 S(O) p R d , NO 2 or CN group;
(7) 1-2 CO 2 R a ;
R 5 represents H or C 1-6 alkyl;
R 6 is selected from the group consisting of H, OH, F or C 1-3 alkyl;
R 7 is H or F, or R 6 and R 7 are taken in combination and represent oxo;
R 8 represents H or C 1-6 alkyl, optionally substituted with OH and 1-5 halo groups up to perhalo;
R 9 represents H, halo, OH, C 1-6 alkyl, optionally substituted with 1-5 halo groups up to perhalo, or C 1-6 alkoxy, optionally substituted with 1-3 halo groups up to perhalo,
or when R 9 is ortho to the benzylic group, R 8 and R 9 can be taken together and represent a —(CH 2 ) 2-4 —or a —O—(CH 2 ) 1-3 —group;
R a is H or C 1-10 alkyl, optionally substituted with phenyl, OH, OC 1-6 alkyl, CO 2 H, CO 2 C 1-6 alkyl and 1-3 halo groups;
R b is H or C 1-10 alkyl;
R C is H or is independently selected from:
(a) C 1-10 alkyl, optionally substituted with OH, OC 1-6 alkyl, CO 2 H, CO 2 C 1-6 alkyl, and 1-3 halo groups;
(b) Aryl or Ar-C 1-6 alkyl, each optionally substituted with 1-5 halos and 1-3 members selected from the group consisting of: CN, OH, C 1-10 alkyl and OC 1-10 alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo;
(c) Hetcy or Hetcy-C 1-6 alkyl, optionally substituted with 1-5 halo groups and 1-3 groups selected from: oxo, C 1-10 alkyl and OC 1-10 alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; and
(d) HAR or HAR-C 1-6 alkyl, optionally substituted with 1-5 halo groups and 1-3 groups selected from: C 1-10 alkyl and OC 1-10 alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo;
R d is C 1-10 alkyl, Aryl or Ar-C 1-10 alkyl;
m is an integer selected from 0, 1 and 2;
n is an integer selected from 0 to 6;
p is an integer selected from 0, 1 and 2, and
when at least one of m and n is other than 0, Z is selected from CO 2 R a , 5-tetrazolyl and 5-(2-oxo-1,3,4-oxadiazolyl), and when both m and n are 0, Z is selected from 5-tetrazolyl and 5-(2-oxo-1,3,4-oxadiazolyl).
2. A compound in accordance with claim 1 wherein R 1 is selected from the group consisting of: H, halo, C 1-10 alkyl and OC 1-10 alkyl, said alkyl and O-alkyl groups being optionally substituted with 1-5 halo groups up to a perhaloalkyl or perhaloalkoxy.
3. A compound in accordance with claim 2 wherein R 1 is selected from the group consisting of: H, halo, C1-4 alkyl, C1-4 alkoxy, said alkyl and alkoxy being optionally substituted with 1-3 halo groups.
4. A compound in accordance with claim 1 wherein each R 2 represents H or is independently selected from the group consisting of:
a) halo or S(O) p R d ; wherein p is 2 and R d represents C 1-10 alkyl;
b) C 1-10 alkyl, C 2-10 alkenyl, OC 1-10 alkyl and OC 3-10 alkenyl, said groups being optionally substituted with:
(1) 1-5 halo groups up to a perhaloalkyl group;
(2) 1 C 1-10 alkoxy group, each optionally substituted with: up to five halo or perhaloalkoxy, 1 OH or CO 2 R a group;
(3) 1 Aryl or HAR group, each optionally substituted as follows:
(a) 1-5 halo groups,
(b) 1-2 C 1-10 alkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl, and 1-2 OH or CO 2 R a groups;
c) Aryl or HAR, each optionally substituted with:
(1) 1-2 C 1-10 alkyl groups optionally substituted with 1-5 halo groups;
(2) 1-2 C 1-10 alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups;
said Aryl or HAR being further optionally substituted on carbon by 1-3 halo groups; up to perhalo.
5. A compound in accordance with claim 4 wherein one R 2 group represents H and the other represents H or is selected from the group consisting of:
a) halo or S(O) p R d ; wherein p is 2 and R d represents C 1-10 alkyl;
b) C 1-10 alkyl, C 2-10 alkenyl, OC 1-10 alkyl or OC 3-10 alkenyl, said groups being optionally substituted with:
(1) 1-5 halo groups up to a perhaloalkyl group;
(2) 1 C 1-10 alkoxy group, each optionally substituted with: up to five halo or a perhaloalkoxy, 1 OH or CO 2 R a group;
(3) 1 Aryl or HAR group, each optionally substituted as follows:
(a) 1-5 halo groups,
(b) 1-2 C110 alkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl, and 1-2 OH or CO 2 R a groups;
c) Aryl or HAR, each optionally substituted with:
(1) 1-2 C 1-10 alkyl groups optionally substituted with 1-5 halo groups;
(2) 1-2 C 1-10 alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups;
said Aryl or HAR being further optionally substituted on carbon by 1-3 halo groups; up to perhalo. Within this subset, all other variables are as originally defined with respect to formula I.
6. A compound in accordance with claim 5 wherein:
one R 2 group represents H and the other represents H or a member selected from the group consisting of:
a) halo or S(O) p R d ; wherein p is 2 and R d represents C 1-2 alkyl;
b) C 1-4 alkyl, C 2-4 alkenyl, OC 1-4 alkyl or OC 3-4 alkenyl, said groups being optionally substituted with:
(1) 1-5 halo groups up to a perhaloalkyl group;
(2) 1 C 1-4 alkoxy group, optionally substituted with: up to 3 halo or a perhaloalkoxy group;
(3) 1 Aryl or HAR group, each optionally substituted as follows:
(a) 1-3 halo groups,
(b) 1 C 1-4 alkyl or alkoxy group, each optionally substituted with: 1-3 halo up to perhaloalkyl, groups;
c) Aryl or HAR, each optionally substituted with:
(1) 1-2 C 1-4 alkyl groups optionally substituted with 1-3 halo groups;
(2) 1-2 C 1-4 alkoxy groups, the alkyl portion of which is optionally substituted with 1-3 halo groups;
said Aryl or HAR being further optionally substituted on carbon by 1-3 halo groups; up to perhalo.
7. A compound in accordance with claim 1 wherein R 3 is selected from the group consisting of:
a) C 1-6 alkyl optionally substituted with:
1-3 halo groups up to perhalo;
1 OH, C 1-3 alkoxy or haloC 1-3 alkoxy group;
1 NR c R d group; and
1 Aryl or HAR group, each optionally substituted with 1-3 halo groups and 1-2 groups selected from C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy and haloC 1-3 alkoxy groups,
b) Aryl or HAR, each optionally substituted with 1-3 halo groups and 1-2 groups selected from C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy and haloC 1-3 alkoxy groups.
8. A compound in accordance with claim 7 wherein R 3 is selected from the group consisting of:
a) C 1-6 alkyl optionally substituted with:
1-3 halo groups up to perhalo;
1 C 1-3 alkoxy or haloC 1-3 alkoxy group;
1 NR c R d group; wherein R c and R d are independently selected from H, C 1-3 alkyl and phenyl; and
1 Aryl or HAR group, each optionally substituted with 1-3 halo groups and 1-2 groups selected from C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy and haloC 1-3 alkoxy groups,
b) Aryl or HAR, each optionally substituted with 1-3 halo groups and 1 group selected from: C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy and haloC 1-3 alkoxy.
9. A compound in accordance with claim 1 wherein:
R 4 represents an Aryl or HAR group, each optionally substituted as set forth below:
(1) 1-2 C 1-10 alkyl or C 2-10 alkenyl groups, which are optionally substituted with 1-3 halo groups, or phenyl optionally substituted with 1-2 halo, C 1-4 alkyl or alkoxy groups, each being further optionally substituted with 1-3 halo groups;
(2) 1-2 C 1-10 alkoxy or C 3-10 alkenyloxy groups, which are optionally substituted with 1-3 halo groups, 1-2 OH or S(O) p R d , and phenyl optionally substituted as follows: 1-3 halo groups up to perhalo; 1-2 C 1-6 alkyl or alkoxy groups, each being further optionally substituted with 1-3 halo up to perhalo, or 1-2 hydroxy or CO 2 R a groups;
(3) 1-2 Aryl, HAR or Hetcy, OAryl, OHAR or OHetcy groups, each optionally substituted as follows:
(i) 1-3 halo groups;
(ii) 1-2 C 1-3 alkyl or C 2-4 alkenyl groups each optionally substituted with 1-3 halo groups, and 1 of OH, phenyl, CO 2 R a , CN and S(O) p R d ;
(iii) 1-2 C 1-3 alkoxy groups the alkyl portion of which being optionally substituted with 1-3 halo groups, and 1 of OH, phenyl, CO 2 R a , CN or S(O) p R d; and
(iv) 1-2 CO 2 R a , S(O) p R d , CN, NR b R c , NO 2 or OH groups;
said Aryl, HAR or Hetcy group R4 being further optionally substituted on carbon by a group selected from the group consisting of;
(4) 1-5 halo groups;
(5) 1-2 OH groups;
(6) 1 S(O) p R d , NO 2 or CN group.
10. A compound in accordance with claim 1 wherein R 5 represents H or CH 3 .
11. A compound in accordance with claim 1 wherein R 8 is selected from the group consisting of H and C 1-3 alkyl.
12. A compound in accordance with claim 1 wherein R 6 and R 7 represent H.
13. A compound in accordance with claim 9 wherein R 9 represents H.
14. A compound in accordance with claim 1 wherein m is 0 and n is an integer selected from 0 to 2.
15. A compound in accordance with claim 1 wherein when n is 1 or 2, Z is selected from CO 2 R a and 5-tetrazolyl, when both m and n are 0, Z is 5-tetrazolyl.
16. A compound in accordance with claim 1 wherein:
R 1 is selected from the group consisting of: H, halo, C 1-10 alkyl and OC 1-10 alkyl, said alkyl and O-alkyl groups being optionally substituted with 1-5 halo groups up to a perhaloalkyl or perhaloalkoxy;
each R 2 represents H or is independently selected from the group consisting of:
a) halo or S(O) p R d ; wherein p is 2 and R d represents C 1-10 alkyl;
b) C 1-10 alkyl, C 2-10 alkenyl, OC 1-10 alkyl and OC 3-10 alkenyl, said groups being optionally substituted with:
(1) 1-5 halo groups up to perhaloalkyl;
(2) 1 C 1-10 alkoxy group, each optionally substituted with: up to five halo or perhaloalkoxy, 1 OH or CO 2 R a group;
(3) 1 Aryl or HAR group, each optionally substituted as follows:
(a) 1-5 halo groups,
(b) 1-2 C 1-10 alkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl, and 1-2 OH or CO 2 R a groups;
c) Aryl or HAR, each optionally substituted with:
(1) 1-2 C 1-10 alkyl groups optionally substituted with 1-5 halo groups;
(2) 1-2 C 1-10 alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups;
said Aryl or HAR being further optionally substituted on carbon by 1-3 halo groups; up to perhalo;
R 3 selected from the group consisting of:
a) C 1-6 alkyl optionally substituted with:
1-3 halo groups up to perhalo;
1 OH, C 1-3 alkoxy or haloC 1-3 alkoxy group;
1NR c R d group; and
1 Aryl or HAR group, each optionally substituted with 1-3 halo groups and 1-2 groups selected from C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy and haloC 1-3 alkoxy;
b) Aryl or HAR, each optionally substituted with 1-3 halo groups and 1-2 groups selected from C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy and haloC 1-3 alkoxy;
R 4 represents an Aryl or HAR group, each optionally substituted as set forth below:
(1) 1-2 C 1-10 alkyl or C 2-10 alkenyl groups, which are optionally substituted with 1-3 halo groups, or phenyl optionally substituted with 1-2 halo, C 1-4 alkyl or alkoxy groups, each being further optionally substituted with 1-3 halo groups;
(2) 1-2 C 1-10 alkoxy or C 3-10 alkenyloxy groups, which are optionally substituted with 1-3 halo groups, 1-2 OH or S(O) p R d , and phenyl optionally substituted as follows: 1-3 halo groups up to perhalo; 1-2 C 1-6 alkyl or alkoxy groups, each being further optionally substituted with 1-3 halo up to perhalo, or 1-2 hydroxy or CO2R a groups;
(3) 1-2 Aryl, HAR or Hetcy, OAryl, OHAR or OHetcy groups, each optionally substituted as follows:
(i) 1-3 halo groups;
(ii) 1-2 C 1-3 alkyl or C 2-4 alkenyl groups each optionally substituted with 1- 3 halo groups, and 1 of OH, phenyl, CO2R a , CN and S(O) p R d ;
(iii) 1-2 C 1-3 alkoxy groups the alkyl portion of which being optionally substituted with 1-3 halo groups, and 1 of OH, phenyl, CO2R a , CN and S(O) p R d ; and
(iv) 1-2 CO 2 R a , S(O) p R d , CN, NR b R c , NO 2 or OH groups;
said Aryl, HAR or Hetcy group R 4 being further optionally substituted on carbon by a group selected from the group consisting of;
(4) 1-5 halo groups;
(5) 1-2 OH groups;
(6) 1 S(O) p R d , NO 2 or CN group;
R 5 H or CH 3 ;
R 8 is selected from the group consisting of H and C 1-3 alkyl;
R 6 , R 7 R 9 represents H;
and m is 0 and n is an integer selected from 0 to 2, such that when n is 1 or 2, Z is selected from CO 2 R a and 5-tetrazolyl, and when both m and n are 0, Z is 5-tetrazolyl.
17. A compound in accordance with claim 16 wherein R 1 is selected from the group consisting of: H, halo, Cl-4 alkyl, C1-4 alkoxy, said alkyl and alkoxy being optionally substituted with 1-3 halo groups.
18. A compound in accordance with claim 1 selected from Table 1a or 1b below:
TABLE 1a
Cpd
R 1
R 2a
R 2b
R 3
R 4
1
H
H
H
—Me
2
Cl
Cl
H
—Et
3
Cl
H
H
—Me
4
Cl
Cl
H
—Et
5
—OCF 3
H
H
—Me
6
Cl
H
—O(CH 2 ) 2 CH 3
—Et
7
—CF 3
Cl
H
—Me
8
Cl
Cl
H
—Me
9
Cl
H
Cl
—Me
10
—CF 3
H
H
—Me
11
Cl
Cl
H
—Me
12
—CF 3
H
H
—Me
13
H
Cl
H
—Me
14
Cl
Cl
H
—Me
18
—CF 3
H
H
—Et
19
H
H
H
—Me
20
—OMe
H
H
—Me
22
Cl
Cl
H
—Me
23
Cl
Cl
H
—Me
24
Cl
Cl
H
—Me
26
—CF 3
H
H
—Me
27
—OnPr
H
H
—Me
28
Cl
Cl
H
—Me
31
Cl
Cl
H
—Et
32
Cl
Cl
H
—Me
33
Cl
Cl
H
—Me
34
Cl
Cl
H
—Me
35
Cl
Cl
H
—Me
36
Cl
Cl
H
—Me
37
Cl
Cl
H
—Me
38
Cl
Cl
H
—Me
39
—OMe
H
H
—Me
40
Cl
Cl
H
—Me
41
Cl
Cl
H
42
—OMe
H
H
—Me
43
Cl
H
—OnBu
—Me
44
H
—OnPr
H
—Me
45
Cl
Cl
H
—Me
46
Cl
Cl
H
—Me
47
Cl
Cl
H
—CH 2 CH 2 F
48
Cl
Cl
H
iPr
49
Cl
Cl
H
—(CH 2 ) 2 OMe
50
Cl
Cl
H
—(CH 2 ) 2 NMe 2
51
CF 3
H
H
Me
52
CF 3
H
CF 3
Me
53
Cl
Cl
H
—(CH 2 ) 3 OMe
54
CF 3
H
H
Me
55
CF 3
H
Br
Me
56
Cl
Cl
H
—(CH 2 ) 3 NMe 2
57
OMe
H
H
Me
58
Cl
H
OMe
Me
59
CF 3
H
Et
Me
60
Cl
H
OMe
Me
61
H
—OnPr
H
Me
62
CF 3
H
—CH═CH 2
Me
63
CF 3
H
SO 2 Me
Me
64
CF 3
H
H
Me
65
CF 3
H
Et
Me
66
CF 3
H
Me
Me
67
CF 3
H
Et
Me
68
CF 3
H
Et
Me
69
Cl
H
OiPr
Me
70
Cl
H
OnPr
Me
71
CF 3
H
Me
72
Cl
H
OEt
Me
73
CF 3
H
H
Me
74
Cl
H
OMe
Me
75
CF 3
H
Et
Me
76
OMe
H
H
Me
77
CF 3
H
OnBu
Me
78
CF 3
H
Et
Me
79
L
H
OMe
Me
80
F
H
H
Me
81
CF 3
H
OMe
Me
82
Cl
H
OH
Me
83
OMe
H
H
Me
84
CF 3
H
OnPr
Me
85
CF 3
H
OMe
Me
86
CF 3
H
OMe
Me
87
H
H
OnPr
Me
88
CF 3
H
OnPr
Me
90
CF 3
H
OEt
Me
91
CF 3
H
Et
Et
92
CF 3
H
Et
Et
95
CF 3
H
Cl
Me
96
CF 3
H
H
Me
97
H
OnPr
H
Me
TABLE 1b
Cpd
R 1
R 2a
R 2b
R 3
R 4
15
H
Cl
H
Me
17
Cl
Cl
H
Me
21
OMe
H
H
Me
25
Cl
Cl
H
Me
29
CF 3
H
H
Me
30
CF 3
H
H
Me
89
Cl
H
OnPr
Et
93
H
H
OnPr
Me
94
CF 3
H
H
Me
or a pharmaceutically acceptable salt or solvate thereof.
19. A pharmaceutical composition comprising a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.
20. A method of treating type 2 diabetes mellitus in a mammalian patient in need of such treatment comprising administering to said patient a compound in accordance with claim 1 in an amount that is effective to treat said type 2 diabetes mellitus.