Benzamidazoles, compositions containing such compounds and methods of use
View Patent ↗The present invention relates to substituted benzimidazoles, 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, 1OH 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 group, (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; (e) —NR a —C(O)—NR b R c ; (f) —NR a —CO 2 R c ; (g) —NR a —C(O)R c ; (h) —NR b R c ; (i) —NR a SO 2 R c ; (j) —SO 2 —NR b R c ; (k) —C(O)NR b R c and (1) —OC(O)—NR b R c ;
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) —NR a —C(O)—NR b R c ; (8) —NR a —CO 2 R c ; (9) —NR a —C(O)R c ; (10) —NR b R c ; (11) —NR a SO 2 R c ; (12) —SO 2 —NR b R c ; and (13) —C(O)NR b R c ; and when R 1 represents Hetcy containing a nitrogen atom, said nitrogen atom can be optionally substituted with a member selected from the group consisting of: (a) —C(O)NR b R c ; (b) —CO 2 R c ; (c) —C(O)R c ; and (d) —SO 2 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-l0 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 group, (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 represents H or is 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; and 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:
a) C 1-14 alkyl, C 2-10 alkenyl and C 2-10 alkynyl, said groups being optionally substituted with: (1) 1-5 halo groups up to perhaloalkyl; (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: (i) 1-5 halo groups, (ii) 1 OH, CO 2 R a , CN, S(O) p R d , NO 2 or C(O)NR b R c group, (iii) 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 (iv) 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;
b) Aryl, HAR or Hetcy, each optionally substituted as follows: (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 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 b) 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 ; (8) —NR a —C(O)—NR b R c ; (9) —NR a —CO 2 R c ; (10) —NR a —C(O)R c ; (11) —NR b R c ; (12) —NR a SO 2 R c ; (13) —SO 2 NR b R c ; (14) —C(O) NR b R c and —OC(O)—NR b R c ;
and when R 4 represents Hetcy containing a nitrogen atom, said nitrogen atom can be optionally substituted with a member selected from the group consisting of: (a) —C(O) NR b R c ; (b) —CO 2 R c ; (c) —C(O)R c ; and (d) —SO 2 R c ;
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 represents H.
3. A compound in accordance with claim 1 wherein one R 2 represents H, halo or C 1-6 alkyl, and the other is selected from the group consisting of: H, halo, OH, C 1-6 alkyl optionally substituted with 1-3 halo groups, C 1-6 alkoxy optionally substituted with 1-3 halo groups or 1 phenyl or heterocyclic ring, C 2-4 alkenyl or OC 2-4 alkenyl.
4. A compound in accordance with claim 1 wherein R3 is selected from the group consisting of: H, C2-4alkenyl and C1-6alkyl optionally substituted as follows: a) up to 3 halo groups; b) NRcRd wherein Rc and Rd are H or C1-4 alkyl; c) OH; and d) Aryl optionally substituted with 1-3 halo groups, C1-3 alkyl, OC1-3alkyl, CN, NO2, haloC1-3alkyl or O-haloC1-3alkyl.
5. A compound in accordance with claim 1 wherein R 4 is independently selected from the group consisting of:
(a) C 1-14 alkyl, optionally substituted with: (1) 1-5 halo groups up to perhaloalkyl; (2) 1-2 C 1-10 alkoxy groups, each optionally substituted with 1-5 halo groups up to perhaloalkoxy; (3) 1-2 Aryl groups, each optionally substituted as follows: (i) 1-5 halo groups, (ii) CN or NO 2 , (iii) 1-2 C 1-10 alkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl; and
(b) Aryl, HAR or Hetcy, each optionally substituted as follows: (1) 1-2 C 1-10 alkyl or C 2-10 alkenyl groups, optionally substituted with 1-5 halo groups, phenyl or CO 2 R a groups; (2) 1-2 C 1-10 alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo 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 or C 2-10 alkenyl, each optionally substituted with 1-3 halo groups; (iii) 1-2 C 1-10 alkoxy groups the alkyl portion of which being optionally substituted with 1-3 halo 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 b) 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 ; (8) —NR a —C(O)—NR b R c ; (9) —NR a —CO 2 R c ; (10) —NR a —C(O)R c ; (11) —NR b R c ; (12) —NR a SO 2 R c ; (13) —SO 2 —NR b R c ; (14) —C(O) NR b R c and (15) —OC(O)NR b R c ;
and when R 4 represents Hetcy containing a nitrogen atom, said nitrogen atom can be optionally substituted with a member selected from the group consisting of: (a) —C(O) NR b R c ; (b) —CO 2 R c ; (c) —C(O)R c ; and (d) —SO 2 R c .
6. A compound represented by formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 represents H;
one R 2 represents H, halo or C 1-6 alkyl, and the other is selected from the group consisting of: H, halo, OH, C 1-6 alkyl optionally substituted with 1-3 halo groups, C 1-6 alkoxy optionally substituted with 1-3 halo groups or 1 phenyl or heterocyclic ring, C 2-4 aalkenyl or OC 2-4 alkenyl;
R 3 is selected from the group consisting of: H, C 2-4 alkenyl and C 1-6 alkyl optionally substituted as follows: a) up to 3 halo groups; b) NR c R d wherein R c and R d are H or C 1-4 alkyl; c) OH; and d) Aryl optionally substituted with 1-3 halo groups, C 1-3 alkyl, OC 1-3 alkyl, CN, NO 2 , haloC 1-3 alkyl or O-haloC 1-3 alkyl;
R 4 is independently selected from the group consisting of:
(a) C 1-14 alkyl, optionally substituted with: (1) 1-5 halo groups up to perhaloalkyl; (2) 1-2 C 1-10 alkoxy groups, each optionally substituted with 1-5 halo groups up to perhaloalkoxy; (3) 1-2 Aryl groups, each optionally substituted as follows: (i) 1-5 halo groups, (ii) CN or NO 2 , (iii) 1-2 C 1-10 alkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl; and
(b) Aryl, HAR or Hetcy, each optionally substituted as follows: (1) 1-2 C 1-10 alkyl or C 2-10 alkenyl, optionally substituted with 1-5 halo groups, phenyl or C 2 R a groups; (2) 1-2 C 1-10 alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo 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 or C 2-10 alkenyl, each optionally substituted with 1-3 halo groups; (iii) 1-2 C 1-10 alkoxy groups the alkyl portion of which being optionally substituted with 1-3 halo 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 b) 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 ; (8) —NR a , —C(O)—NR b R c ; (9) —NR a —CO 2 R c ; (10) —NR a —C(O)R c ; (11) —NR b R c ; (12) —NR a SO 2 R c ; (13) —SO 2 —NR b R c ; (14) —C(O) NR b R c and (15) —OC(O)—NR b R c ;
and when R 4 represents Hetcy containing a nitrogen atom, said nitrogen atom can be optionally substituted with a member selected from the group consisting of: —C(O) NR b R c ; (b) —CO 2 R c ; (c) —C(O)R c ; and (d) —SO 2 R c ;
R 8 represents H or C 1-6 alkyl;
R 9 represents H or halo;
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 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).
7. A compound represented by formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 represents H;
one R 2 represents H, halo or C 1-6 alkyl, and the other is selected from the group consisting of: H, halo, OH, C 1-6 alkyl optionally substituted with 1-3 halo groups, C 1-6 alkoxy optionally substituted with 1-3 halo groups or 1 phenyl or heterocyclic ring, C 2-4 alkenyl or OC 2-4 alkenyl;
R 3 is selected from the group consisting of: H, C 2-4 alkenyl and C 1-6 alkyl optionally substituted as follows: a) up to 3 halo groups; b) NR c R d wherein R c and R d are H or C 1-4 alkyl; c) OH; and d) Aryl optionally substituted with 1-3 halo groups, C 1-3 alkyl, OC 1-3 alkyl, CN, NO 2 , haloC 1-3 alkyl or O-haloC 1-3 alkyl;
R 4 is independently selected from the group consisting of:
a) C 1-14 alkyl, optionally substituted with: (1) 1-5 halo groups up to perhaloalkyl; (2) 1-2 C 1-10 alkoxy groups, each optionally substituted with 1-5 halo groups up to perhaloalkoxy; (3) 1-2 Aryl groups, each optionally substituted as follows: (i) 1-5 halo groups, (ii) CN or NO 2 , and (iii) 1-2 C 1-10 alkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl; and
b) Aryl, HAR or Hetcy, each optionally substituted as follows: (1) 1-2 C 1-10 alkyl or C 2-10 alkenyl, optionally substituted with 1-5 halo groups, phenyl or CO 2 R a groups; (2) 1-2 C 1-10 alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups; (3) 1-2 Aryl, HAR or Hetcy, OAryl, OHAR or OHetcy groups, each optionally substituted as follows: (a) 1-3 halo groups; (b) 1-2 C 1-10 alkyl or C 2-10 alkenyl, each optionally substituted with 1-3 halo groups;
(c) 1-2 C 1-10 alkoxy groups the alkyl portion of which being optionally substituted with 1-3 halo groups, and
(d) 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 b) 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 ; (8) —NR a —C(O)—NR b R c ; (9) —NR a —CO 2 R c ; (10) —NR a —C(O)R c ; (11) —NR b R c ; (12) —NR a SO 2 R c ; (13) —SO 2 —NR b R c ; (14) —C(O) —NR b R c and (15) —OC(O)—NR b R c ;
and when R 4 represents Hetcy containing a nitrogen atom, said nitrogen atom can be optionally substituted with a member selected from the group consisting of: (a) —C(O) NR b R c ; (b) —CO 2 R c ; (c) —C(O)R c ; and (d) —SO 2 R c ;
R 8 and R 9 are taken in combination and represent —(CH 2 ) 2-4 ;
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 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 OC 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).
8. A compound in accordance with claim 1 falling within table A below:
TABLE A
Key to Compounds
wherein R 2 , R 3 and R 4 are in accordance with formula I and X is as shown below.
TABLE A
wherein
Cpd No.
R 2
R 3
R 4
X
1
5-Me
H
R4-1
X-1
2
5-Me
H
R4-2
X-1
3
5-Me
H
R4-1
X-3
4
5-Me
H
R4-2
X-3
5
5-OCF 3
H
R4-1
X-1
6
5-OCF 3
H
R4-2
X-3
7
5-OCF 3
H
R4-2
X-1
8
6-Me
Me
R4-2
X-3
9
5-Cl
H
R4-2
X-3
10
5-Cl
H
R4-1
X-3
11
6-Me
Me
R4-2
X-1
12
5-Cl
H
R4-2
X-1
13
5-Cl
H
R4-1
X-1
14
5-Me
Me
R4-1
X-3
15
5-Me
Me
R4-1
X-1
16
H
H
R4-2
X-3
17
H
H
R4-2
X-1
18
H
Me
R4-2
X-1
19
H
Me
R4-2
X-19
20
H
Me
R4-2
X-3
21
H
Me
R4-2
X-21
22
6-Me
Me
R4-2
X-21
23
5-Me
H
R4-2
X-21
24
H
Et
R4-2
X-3
25
H
Et
R4-2
X-1
26
H
Et
R4-2
X-21
27
H
n-Pr
R4-2
X-3
28
H
n-Pr
R4-2
X-1
29
H
n-Pr
R4-2
X-29
30
H
n-Pr
R4-2
X-21
31
5-Me
H
R4-2
X-29
32
H
cPentyl
R4-2
X-3
33
H
cPentyl
R4-2
X-1
34
H
cPentyl
R4-2
X-21
35
H
Et
R4-2
X-29
36
H
Benzyl
R4-2
X-3
37
H
Benzyl
R4-2
X-29
38
H
Benzyl
R4-2
X-1
39
H
Benzyl
R4-2
X-21
40
H
—CH 2 CH(Me) 2
R4-2
X-3
41
H
—CH 2 CH(Me) 2
R4-2
X-29
42
H
—CH 2 CH(Me) 2
R4-2
X-1
43
H
—CH 2 CH(Me) 2
R4-2
X-21
44
H
H
R4-2
X-29
45
H
H
R4-2
X-21
46
H
Me
R4-2
X-29
47
H
CH 2 CH 2 F
R4-2
X-3
48
H
CH 2 CH 2 F
R4-2
X-1
49
H
CH 2 CH 2 F
R4-2
X-21
50
H
CH 2 CH 2 F
R4-2
X-29
51
H
CH 2 CH═CH 2
R4-2
X-3
52
H
CH 2 CH═CH 2
R4-2
X-1
53
H
CH 2 CH═CH 2
R4-2
X-21
54
H
H
R4-54
X-3
55
H
H
R4-54
X-1
56
H
H
R4-54
X-21
57
H
Me
R4-54
X-3
58
H
Me
R4-54
X-1
59
H
Me
R4-54
X-21
60
5,6-di-Cl
H
R4-2
X-3
61
5,6-di-Cl
H
R4-2
X-29
62
5,6-di-Cl
H
R4-2
X-1
63
5,6-di-Cl
H
R4-2
X-21
64
5,6-di-Cl
Et
R4-2
X-3
65
5,6-di-Me
H
R4-2
X-3
66
5,6-di-Me
H
R4-2
X-29
67
5,6-di-Me
H
R4-2
X-1
68
5,6-di-Me
H
R4-2
X-21
69
H
Me
R4-2
X-70
70
H
CH 2 CH 2 OH
R4-2
X-3
71
H
CH 2 CH 2 OH
R4-2
X-1
72
H
CH 2 CH 2 OH
R4-2
X-21
73
5,6-di-Me
Me
R4-2
X-3
74
5,6-di-Me
Me
R4-2
X-29
75
5,6-di-Me
Me
R4-2
X-1
76
5,6-di-Me
Me
R4-2
X-21
77
5,6-di-Cl
Me
R4-2
X-3
78
5,6-di-Cl
Me
R4-2
X-1
79
5,6-di-Cl
Me
R4-2
X-21
80
5,6-di-F
H
R4-2
x-3
81
5,6-di-F
H
R4-2
x-1
82
5,6-di-F
H
R4-2
x-29
83
5,6-di-F
H
R4-2
x-21
84
H
Me
R4-2
x-85
85
H
Me
R4-2
X-86
86
5,6-di-F
Me
R4-2
X-3
87
5,6-di-F
Me
R4-2
X-1
88
5,6-di-F
Me
R4-2
X-21
89
H
(CH 2 ) 3 OH
R4-2
X-3
90
H
(CH 2 ) 3 OH
R4-2
X-21
91
H
Me
R4-95
X-3
92
H
Me
R4-95
X-21
93
H
(CH 2 ) 2 NMe 2
R4-2
X-3
94
H
R4-2
X-3
95
H
R4-2
X-21
96
H
R4-2
X-1
97
H
Phenyl
R4-2
X-3
98
H
Phenyl
R4-2
X-29
99
H
Phenyl
R4-2
X-1
100
H
Phenyl
R4-2
X-21
101
6-allyloxy
Et
R4-2
X-3
102
6-allyloxy
Et
R4-2
X-1
103
6-allyloxy
Et
R4-2
X-21
104
6-allyloxy
Et
R4-2
X-29
105
5,6-di-F
Et
R4-2
X-3
106
H
Me
R4-113
X-3
107
5,6-di-F
Et
R4-2
X-21
108
6-OH
Et
R4-2
X-3
109
6-OH
Et
R4-2
X-1
110
5,6-di-F
Et
R4-2
X-1
111
6-OH
Et
R4-2
X-21
112
6-OH
Et
R4-2
X-29
113
5-OMe
Me
R4-2
X-3
114
5-OMe
Me
R4-2
X-21
115
5-OMe
Me
R4-2
X-1
116
H
H
R4-122
X-3
117
H
H
R4-122
X-1
118
H
H
R4-122
X-21
119
H
H
R4-122
X-29
120
5-OH
Me
R4-2
X-3
121
5-OH
Me
R4-2
X-1
122
5-OH
Me
R4-2
X-21
123
5-allyloxy
Me
R4-2
X-3
124
5-allyloxy
Me
R4-2
X-1
125
5-benzyloxy
Me
R4-2
X-3
126
5-benzyloxy
Me
R4-2
X-1
127
6-allyloxy
Me
R4-2
X-3
128
6-allyloxy
Me
R4-2
X-1
129
6-allyloxy
Me
R4-2
X-21
130
6-allyloxy
Me
R4-2
X-29
131
H
R4-2
X-3
132
H
R4-2
X-3
133
H
R4-2
X-3
134
H
R4-2
X-21
135
H
R4-2
X-21
136
H
R4-2
X-21
137
H
R4-2
X-1
138
H
R4-2
X-1
139
H
R4-2
X-1
140
6-OH
Me
R4-2
X-3
141
6-OH
Me
R4-2
X-1
142
6-OH
Me
R4-2
X-21
143
6-OH
Me
R4-2
X-29
144
5-n-propyloxy
Me
R4-2
X-3
145
5-n-propyloxy
Me
R4-2
X-29
146
5-n-propyloxy
Me
R4-2
X-1
147
5-n-propyloxy
Me
R4-2
X-21
148
5-isopropyloxy
Me
R4-2
X-3
149
5-isopropyloxy
Me
R4-2
X-29
150
5-isopropyloxy
Me
R4-2
X-1
151
5-isopropyloxy
Me
R4-2
X-21
152
6-n-propyloxy
Me
R4-2
X-3
153
6-n-propyloxy
Me
R4-2
X-1
154
6-n-propyloxy
Me
R4-2
X-21
155
5-OMe
Me
R4-2
X-29
156
5-cyclo-pentyloxy
Me
R4-2
X-3
157
5-cyclo-pentyloxy
Me
R4-2
X-29
158
5-OCH 2 CH(Me) 2
Me
R4-2
X-3
159
5-OCH 2 CH(Me) 2
Me
R4-2
X-29
160
6-benzyloxy
Me
R4-2
X-3
161
6-isopropyloxy
Me
R4-2
X-3
162
6-OMe
Me
R4-2
X-3
163
6-benzyloxy
Me
R4-2
X-1
164
6-isopropyloxy
Me
R4-2
X-1
165
6-OMe
Me
R4-2
X-1
166
6-benzyloxy
Me
R4-2
X-21
167
6-isopropyloxy
Me
R4-2
X-21
168
6-OMe
Me
R4-2
X-21
169
5-benzyloxy
Me
R4-2
X-21
170
5-cyclopentyloxy
Me
R4-2
X-1
171
5-cyclopentyloxy
Me
R4-2
X-21
172
5-isobutyloxy
Me
R4-2
X-1
173
5-isobutyloxy
Me
R4-2
X-21
174
6-allyloxy
Me
R4-113
X-3
175
6-allyloxy
Me
R4-113
X-1
176
H
R4-2
X-3
177
6-allyloxy
Me
R4-113
X-21
178
H
R4-2
X-3
179
H
R4-2
X-21
180
H
R4-2
X-21
181
H
R4-2
X-1
182
H
R4-2
X-1
183
H
R4-2
X-3
184
H
R4-2
X-21
185
H
R4-2
X-1
186
H
R4-2
X-3
187
H
R4-2
X-21
188
H
R4-2
X-1
189
H
Me
R4-2
X-237
190
H
Me
R4-2
X-238
191
H
Me
R4-2
X-239
192
6-cyclopentyloxy
Me
R4-2
X-3
193
6-cyclopentyloxy
Me
R4-2
X-1
194
6-cyclopentyloxy
Me
R4-2
X-21
195
5-OMe
Me
R4-54
X-3
196
5-OMe
Me
R4-54
X-1
197
6-allyloxy
Me
R4-95
X-3
198
6-allyloxy
Me
R4-95
X-1
199
6-allyloxy
Me
R4-95
X-21
200
6-OH
Me
R4-95
X-3
201
5-OEt
Me
R4-2
X-3
202
5-cyclobutyloxy
Me
R4-2
X-3
203
5-cyclopropyl
Me
R4-2
X-3
methoxy
204
5-cyclopropyl
Me
R4-2
X-1
methoxy
205
5-cyclohexyl
Me
R4-2
X-3
methoxy
206
5-cyclohexyl
Me
R4-2
X-1
methoxy
207
5-OEt
Me
R4-2
X-1
208
5-cyclobutyloxy
Me
R4-2
X-1
209
5-OCH 2 CHF 2
Me
R4-2
X-3
210
5-OCH 2 CHF 2
Me
R4-2
X-1
211
5-cyclobutyl
Me
R4-2
X-3
methoxy
212
5-cyclobutyl
Me
R4-2
X-1
methoxy
213
5-cyclopentyl
Me
R4-2
X-3
methoxy
214
5-cyclopentyl
Me
R4-2
X-1
methoxy
215
6-n-propyloxy
Me
R4-95
X-3
216
5-CF 3
Me
R4-2
X-3
217
6-benzyloxy
Me
R4-95
X-3
218
5-CF 3
Me
R4-2
X-1
219
5-n-propyloxy
Me
R4-54
X-3
220
6-n-propyloxy
Me
R4-95
X-1
221
6-benzyloxy
Me
R4-95
X-1
222
6-OEt
Me
R4-2
X-3
223
6-cyclopropyl
Me
R4-2
X-3
methoxy
224
6-OCH 2 CH(Me) 2
Me
R4-2
X-3
225
6-OEt
Me
R4-2
X-1
226
6-cyclopropyl
Me
R4-2
X-1
methoxy
227
6-OCH 2 CH(Me) 2
Me
R4-2
X-1
228
H
Me
R4-54
X-237
229
5-Br
Me
R4-2
X-3
230
5-Br
Me
R4-2
X-1
231
H
Et
R4-2
X-226
232
H
Et
R4-2
X-227
233
6-OCH 2 CHF 2
Me
R4-2
X-3
234
6-OCH 2 CHF 2
Me
R4-2
X-1
235
5-OMe
Me
R4-2
X-244
236
H
Me
R4-245
X-3
237
6-cyclohexyloxy
Me
R4-2
X-3
238
H
Me
R4-122
X-3
249
5-n-propyloxy
Me
R4-2
X-237
240
5-cyclopentyloxy
Me
R4-54
X-3
241
5-cyclopentyloxy
Me
R4-54
X-1
242
5-n-propyloxy
Me
R4-54
X-1
243
6-cyclohexyl
Me
R4-2
X-3
methoxy
244
6-cyclohexyloxy
Me
R4-2
X-1
245
6-cyclohexyl
Me
R4-2
X-1
methoxy
246
H
Me
R4-256
X-1
247
6-
Me
R4-2
X-3
248
5-OMe
Me
R4-258
X-3
249
5-cyclopentyloxy
Me
R4-2
X-244
250
H
Me
R4-260
X-3
251
H
Me
R4-261
X-3
252
H
Me
R4-262
X-3
253
H
Me
R4-262
X-1
254
5-OMe
Me
R4-122
X-3
255
5-OMe
Me
R4-265
X-3
256
5-OMe
Me
R4-266
X-3
257
H
Me
R4-267
X-1
258
H
Me
R4-267
X-3
259
H
Me
R4-269
X-1
260
H
Me
R4-269
X-3
261
H
Me
R4-238
X-3
262
H
Me
R4-238
X-1
263
H
Me
R4-273
X-3
264
H
Me
R4-273
X-1
265
H
Me
R4-275
X-3
266
H
Me
R4-276
X-3
267
H
Me
R4-277
X-3
268
H
Me
R4-278
X-3
269
H
Me
R4-278
X-1
270
5-n-pentyloxy
Me
R4-122
X-3
271
5-n-propyloxy
Me
R4-122
X-3
272
H
Me
R4-282
X-1
273
H
Me
R4-282
X-3
274
H
Me
R4-284
X-3
275
H
Me
R4-284
X-1
276
5-OCF 3
Me
R4-95
X-3
277
5-CF 3
Me
R4-95
X-3
278
5-Cl
Me
R4-95
X-3
279
5-OMe
Me
R4-95
X-3
280
5-OMe
Me
R4-95
X-1
281
5-n-propyloxy
Me
R4-95
X-3
282
5-cyclopentyloxy
Me
R4-95
X-3
or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition which is comprised of a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.
10. 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 type 2 diabetes mellitus.