Substituted pyrazoles, compositions containing such compounds and methods of use

1. A compound represented by formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is selected from the group consisting of:

(a) C 1-10 alkyl 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 8 group; (5) 1 CO 2 R 8 or S(O) p R 7 ; (6) 1-2 Aryl, Hetcy or HAR groups, each optionally substituted as follows: (i) 1-5 halo groups, (ii) 1 OH, CO 2 R 8 , CN, S(O) p R 7 , NO 2 or C(O)NR 9 R 10 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 8 groups; and (iv) 1-2 phenyl rings, each of which is optionally substituted as follows: 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 8 groups; (7) —NR 8 —C(O)—NR 9 R 10 ; (8) —NR 8 —CO 2 R 11 ; (9) —NR 8 —C(O)R 11 ; (10) —NR 9 R 10 ; (11) —NR 8 SO 2 R 11 ; (12) —SO 2 —NR 9 R 10 ; (13) —C(O)NR 9 R 10 and (14) —OC(O)—NR 9 R 10 ; or

(b) Aryl optionally substituted as follows: (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 8 , CN or S(O) p R 7 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 8 , CN or S(O) p R 7 groups; (3) 1-2 Aryl, HAR or Hetcy 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 11 , CN or S(O) p R 7 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 11 , CN or S(O) p R 7 groups; and (iv) 1-2 CO 2 R 11 , S(O) p R 7 , CN, NR 9 R 10 , NO 2 or OH groups;

said Aryl group 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 7 , NO 2 or CN group; (7) 1-2 CO 2 R 8 ; (8) —NR 8 —C(O)—NR 9 R 10 ; (9) —NR 8 —CO 2 R 11 ; (10) —NR 8 —C(O)R 11 ; (11) —NR 9 R 10 ; (12) —NR 8 SO 2 R 11 ; (13) —SO 2 —NR 9 R 10 ; (14) —C(O)NR 9 R 10 and (15) —OC(O)—NR 9 R 10 ;

R 2 represents monocyclic HAR or Hetcy selected from the group consisting of pyridinyl and piperidinyl, each optionally substituted as follows: (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 8 , CN or S(O) p R 7 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 8 , CN or S(O) p R 7 groups; (3) 1-2 Aryl, HAR or Hetcy 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 11 , CN or S(O) p R 7 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 11 , CN or S(O) p R 7 groups; and (iv) 1-2 CO 2 R 11 , S(O) p R 7 , CN, NR 9 R 10 , NO 2 or OH groups;

said monocyclic HAR or Hetcy selected from the group consisting of pyridinyl and piperidinyl 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 7 , NO 2 or CN group; (7) 1-2 CO 2 R 8 ; (8) —NR 8 —C(O)—NR 9 R 10 ; (9) —NR 8 —CO 2 R 11 ; (10) —NR 8 —C(O)R 11 ; (11) —NR 9 R 10 ; (12) —NR 8 SO 2 R 11 ; (13) —SO 2 —NR 9 R 10 ; (14) —C(O)NR 9 R 10 and (15) —OC(O)—NR 9 R 10 ;

R 3 and R 4 are H or C 1-10 alkyl;

R 5 represents H or F;

R 6 represents H, OH, F or C 1-3 alkyl, or R 5 and R 6 are taken in combination and represent oxo;

R 7 represents a member selected from the group consisting of: C 1-10 alkyl, Aryl or Ar—C 1-10 alkyl,

R 8 is H, 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 9 is H or C 1-10 alkyl;

R 10 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 11 is independently selected from the group consisting of: (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- 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;

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 8 , 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 of formula Ia, Ib, Ic, Id, Ie, If or Ig:

or a pharmaceutically acceptable salt thereof, wherein all variables are as originally defined with respect to formula I.

3. A compound in accordance with claim 1 wherein:

R 1 is selected from the group consisting of:

(a) C 1-10 alkyl optionally substituted with: (1) 1-5 halo groups up to a perhaloalkyl group; (2) 1-2 OH groups; (3) 1-2 C 1-10 alkoxy groups, each optionally substituted with up to five halo or a perhaloalkoxy group; (4) 1 CO 2 R 8 or S(O) p R 7 ; (5) 1-2 Aryl, Hetcy or HAR groups, each optionally substituted as follows: (i) 1-5 halo groups, (ii) 1 OH, CO 2 R 8 , CN, S(O) p R 7 , NO 2 or C(O)NR 9 R 10 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 8 groups; and (iv) 1-2 phenyl rings, each of which is optionally substituted as follows: 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 8 groups; and

(b) Aryl each optionally substituted as set forth below:

(1) 1-3 C 1-10 alkyl or C 2-10 alkenyl groups optionally substituted with 1-5 halo groups, 1-2 OH, phenyl, CO 2 R 8 , CN or S(O) p R 7 groups;

(2) 1-3 C 1-10 alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups, 1-2 phenyl, CN or S(O) p R 7 groups;

(3) 1-2 Aryl, HAR or Hetcy groups, each optionally substituted as follows: (i) 1-3 halo groups; (ii) 1-2 C 1-10 alkyl or C 2-10 alkenyl groups each optionally substituted with 1-5 halo groups, 1-2 OH, phenyl, CO 2 R 11 , CN or S(O) p R 7 groups; (iii) 1-2 C 1-10 alkoxy groups the alkyl portion of which being optionally substituted with 1-5 halo groups, 1-2 phenyl, CO 2 R 11 , CN or S(O) p R 7 groups; and (iv) 1-2 CO 2 R 11 , S(O) p R 7 , CN, NR 9 R 10 , NO 2 or OH groups;

said Aryl group 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 7 , NO 2 or CN group; (7) 1-2 CO 2 R 8 ; (8) —NR 8 —C(O)—NR 9 R 10 ; (9) —NR 8 —CO 2 R 11 ; (10) —NR 8 —C(O)R 11 ; (11) —NR 9 R 10 ; (12) —NR 8 SO 2 R 11 ; (13) —SO 2 —NR 9 R 10 ; (14) —C(O)NR 9 R 10 and (15) —OC(O)—NR 9 R 10 .

4. A compound in accordance with claim 3 wherein:

R 1 is selected from the group consisting of:

a) C 1-10 alkyl optionally substituted with: (1) 1-2 halo groups; (2) 1-2 C 1-6 alkoxy groups, each optionally substituted with up to 3 halo groups; (3) 1 Phenyl, Piperidinyl or Pyridinyl group, each optionally substituted as follows: (i) 1-2 halo groups, (ii) 1-2 C 1-3 alkyl or alkoxy groups, each optionally substituted with: 1-3 halo groups; and (iii) 1 phenyl ring, optionally substituted with 1-3 C 1-3 alkyl or alkoxy groups, each being further optionally substituted with 1-3 halo groups; and

b) Phenyl optionally substituted as follows: (1) 1 C 1-3 alkyl group optionally substituted with 1-3 halo groups, 1 phenyl or S(O) p R 7 group; (2) 1 C 1-3 alkoxy group, the alkyl portion of which is optionally substituted with 1-3 halo groups or 1 phenyl group; (3) 1 phenyl, pyridinyl, isoxazolyl or piperidinyl group, each optionally substituted as follows: (i) 1-3 halo groups; (ii) 1 C 1-6 alkyl group optionally substituted with 1-3 halo or 1 hydroxy group; (iii) 1 C 1-6 alkoxy group the alkyl portion of which being optionally substituted with 1-3 halo groups; and (iv) 1 CO 2 R 11 , S(O) p R 7 , CN, NR 9 R 10 , NO 2 or OH group; (4) 1-3 halo groups; (5) 1 OH group; (6) 1 S(O) p R 7 , NO 2 or CN group; (7) 1 CO 2 R 8 ; (8) —NR 9 R 10 ; (9) —C(O)NR 9 R 10 and (10) —OC(O)—NR 9 R 10 .

5. A compound in accordance with claim 4 wherein:

R 1 is selected from the group consisting of: a) C 1-10 alkyl optionally substituted with Phenyl, optionally substituted as follows: (i) 1-2 halo groups, (ii) 1-2 C 1-3 alkyl or alkoxy groups, each optionally substituted with: 1-3 halo groups; and (iii) 1 phenyl ring, optionally substituted with 1-3 C 1-3 alkyl or alkoxy groups, each being further optionally substituted with 1-3 halo groups; and

b) Phenyl optionally substituted as follows: (1) 1 C 1-3 alkyl group optionally substituted with 1-3 halo groups or 1 phenyl group; (2) 1 C 1-3 alkoxy group, the alkyl portion of which is optionally substituted with 1-3 halo groups or 1 phenyl group; (3) 1 phenyl, pyridinyl or isoxazolyl group, each optionally substituted as follows: (i) 1-3 halo groups; (ii) 1 C 1-6 alkyl group optionally substituted with 1-3 halo or 1 hydroxy group; (iii) 1 C 1-6 alkoxy group the alkyl portion of which being optionally substituted with 1-3 halo groups; and (iv) 1 CO 2 R 11 , S(O) p R 7 , CN, NR 9 R 10 , NO 2 or OH group; (4) 1-3 halo groups; (5) 1 OH group; (6) 1 CO 2 R 8 ; and (7) —NR 9 R 10 .

6. A compound in accordance with claim 1 wherein R 2 is selected from monocyclic HAR and Hetcy selected from the group consisting of pyridinyl and piperidinyl, each optionally substituted as follows: (1) 1-3 C 1-10 alkyl or C 2-10 alkenyl groups optionally substituted with 1-5 halo groups, 1-2 OH, phenyl, CO 2 R 8 , CN or S(O) p R 7 groups; (2) 1-3 C 1-10 alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups, 1-2 phenyl, CN or S(O) p R 7 groups; (3) 1-2 Aryl, HAR or Hetcy groups, each optionally substituted as follows: (i) 1-3 halo groups; (ii) 1-2 C 1-10 alkyl or C 2-10 alkenyl groups each optionally substituted with 1-5 halo groups, 1-2 OH, phenyl, CO 2 R 11 , CN or S(O) p R 7 groups; (iii) 1-2 C 1-10 alkoxy groups the alkyl portion of which being optionally substituted with 1-5 halo groups, 1-2 phenyl, CO 2 R 11 , CN or S(O) p R 7 groups; and (iv) 1-2 CO 2 R 11 , S(O) p R 7 , CN, NR 9 R 10 , NO 2 or OH groups;

said monocyclic HAR and Hetcy selected from the group consisting of pyridinyl and piperidinyl 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 7 , NO 2 or CN group; (7) 1-2 CO 2 R 8 ; (8) —NR 8 —C(O)—NR 9 R 10 ; (9) —NR 8 —CO 2 R 11 ; (10) —NR 8 —C(O)R 11 ; (11) —NR 9 R 10 ; (12) —NR 8 SO 2 R 11 ; (13) —SO 2 —NR 9 R 10 ; (14) —C(O)NR 9 R 10 and (15) —OC(O)—NR 9 R 10 ;

and when R 2 represents Hetcy selected from the group consisting of pyridinyl and piperidinyl, a nitrogen atom can be optionally substituted with a member selected from the group consisting of: (a) —CO 2 R 11 ; (b) —C(O)R 11 ; and (c) —SO 2 R 11 .

7. A compound in accordance with claim 6 wherein:

R 2 is selected from the group consisting of:

Pyridinyl and Piperidinyl, each optionally substituted as follows: (1) 1 C 1-3 alkyl group optionally substituted with 1-3 halo groups, 1 phenyl or S(O) p R 7 group; (2) 1 C 1-3 alkoxy group, the alkyl portion of which is optionally substituted with 1-3 halo groups or 1 phenyl group; (3) 1 phenyl, pyridinyl, isoxazolyl or piperidinyl group, each optionally substituted as follows: (i) 1-3 halo groups; (ii) 1 C 1-6 alkyl group optionally substituted with 1-3 halo or 1 hydroxy group; (iii) 1 C 1-6 alkoxy group the alkyl portion of which being optionally substituted with 1-3 halo groups; and (iv) 1 CO 2 R 11 , S(O) p R 7 , CN, NR 9 R 10 , NO 2 or OH group;

said Pyridinyl and Piperidinyl rings being further optionally substituted on carbon atoms by a group selected from the group consisting of: (4) 1-3 halo groups; (5) 1 OH group; (6) 1 S(O) p R 7 , NO 2 or CN group; (7) 1 CO 2 R 8 ; (8) —NR 9 R 10 ; (9) —C(O)NR 9 R 10 and (10) —OC(O)—NR 9 R 10 ;

and when R 2 represents piperidinyl, the piperidine nitrogen atom can be optionally substituted with a member selected from the group consisting of: (a) —CO 2 R 11 ; (b) C(O)R 11 ; and (c) —SO 2 R 11 .

8. A compound in accordance with claim 7 wherein:

R 2 is selected from the group consisting of:

Pyridinyl and Piperidinyl, each optionally substituted as follows: (1) 1 C 1-3 alkyl group optionally substituted with 1-3 halo groups or 1 phenyl group; (2) 1 C 1-3 alkoxy group, the alkyl portion of which is optionally substituted with 1-3 halo groups or 1 phenyl group; (3) 1 phenyl, pyridinyl or isoxazolyl group, each optionally substituted as follows: (i) 1-3 halo groups; (ii) 1 C 1-6 alkyl group optionally substituted with 1-3 halo or 1 hydroxy group; (iii) 1 C 1-6 alkoxy group the alkyl portion of which being optionally substituted with 1-3 halo groups; and (iv) 1 CO 2 R 11 , S(O) p R 7 , CN, NR 9 R 10 , NO 2 or OH group;

said Pyridinyl and Piperidinyl rings being further optionally substituted on carbon atoms by a group selected from the group consisting of: (4) 1-3 halo groups; (5) 1 OH group; (6) 1 CO 2 R 8 ; and (7) —NR 9 R 10 ;

and when R 2 represents piperidinyl, the piperidine nitrogen atom can be optionally substituted with a member selected from the group consisting of: (a) —CO 2 R 11 ; (b) —C(O)R 11 ; and (c) —SO 2 R 11 .

9. A compound in accordance with claim 1 wherein R 3 represents H or methyl.

10. A compound in accordance with claim 9 wherein R 3 represents H.

11. A compound in accordance with claim 1 wherein R 4 represents H or methyl.

12. A compound in accordance with claim 11 wherein R 4 represents H.

13. A compound in accordance with claim 1 wherein n represents 0 or 1; m represents 0 and Z represents tetrazolyl.

14. A compound in accordance with claim 1 wherein n represents 1 or 2; m represents 0 and Z represents CO 2 R 8 .

15. A compound in accordance with claim 1 wherein n represents 1;

m represents 1; R 5 represents H; R 6 represents OH, and Z represents CO 2 R 8 .

16. A compound in accordance with claim 1 wherein R 7 represents a member selected from the group consisting of: C 1-6 alkyl and Aryl.

17. A compound in accordance with claim 1 wherein R 8 is H or C 1-10 alkyl, optionally substituted with phenyl or 1-3 halo groups.

18. A compound in accordance with claim 1 selected from the group consisting of:

Cpd No.

Structure

 74

102

103

104

105

106

107

108

109

110

111

112

113

114

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

166

167

168

169

170

171

or a pharmaceutically acceptable salt 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.