Pyrazole amide derivatives, compositions containing such compounds and methods of use
View Patent ↗Pyrazole amides are disclosed. The compounds are useful for treating type 2 diabetes and related conditions. Pharmaceutical compositions and methods of treatment are also included.
1. A compound represented by formula I:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
Y represents —C(O)—N(R 5 )— or —O—;
one of A and B represents —C(O)—NH—R 1 and the other represents
R 1 represents H or is independently selected from the group consisting of:
a) C 1-16 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 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;
b) Aryl, HAR, Hetcy, each optionally substituted as set forth below:
(1) 1-3 C 1-10 alkyl or alkoxy groups optionally substituted as follows: 1-5 halo groups; 1-2 OH groups; CO 2 R a ; CN; S(O) p R d ; phenyl optionally substituted as follows: (i) 1-5 halo groups, (ii) 1 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
(2) phenyl optionally substituted as follows: (i) 1-5 halo groups, (ii) 1 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;
said Aryl, HAR, Hetcy group b) 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 is H or is selected from the group consisting of:
(a) halo, OH, CO 2 R a , CN, SO p R d , NO 2 ,
(b) C 1-6 alkyl or OC 1-6 alkyl optionally substituted with: (1) 1-5 halo groups up to a perhaloalkyl group; (2) CO 2 R a CN, S(O) p R d or OH; (3) phenyl optionally substituted as follows: (i) 1-5 halo groups, (ii) 1 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;
R 3 is H or C 1-3 alkyl;
R 5 is H or C 1-6 alkyl;
R 6 is selected from the group consisting of H, OH, F and 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) and
X is CH or N.
2. A compound in accordance with claim 1 wherein:
Y represents —C(O)—N(R 5 )— or —O—;
one of A and B represents —C(O)—NH—R 1 and the other represents
R 1 represents H or is independently selected from the group consisting of:
a) C 1-10 alkyl optionally substituted with:
(1) 1-3halo groups;
(2) 1 oxo group;
(3) 1 OH groups;
(4) 1-2 C 1-4 alkoxy groups, each optionally substituted with:
up to three halo groups;
(5) 1 CO 2 R a or S(O) p R d ;
(6) 1 Aryl, Hetcy or HAR group, optionally substituted as follows:
(a) 1-3 halo groups,
(b) 1 CO 2 R a , CN, S(O) p R d , NO 2 or C(O)NR b R c ,
(c) 1-C 1-6 alkyl or alkoxy group, each optionally substituted with: 1-3 halo groups; and
(d) 1 phenyl ring, optionally substituted as follows: 1-3 halo groups, 1-2 C 1-3 alkyl or alkoxy groups, each being further optionally substituted with 1-3 halo groups;
b) Aryl, HAR, Hetcy, each optionally substituted as set forth below:
(1) 1-2 C 1-6 alkyl or alkoxy groups optionally substituted as follows: 1-3 halo groups; OH, CO 2 R a ; CN; S(O) p R; phenyl optionally substituted as follows: (i) 1-3 halo groups, (ii) 1 CO 2 R a , CN, S(O) p R d , NO 2 or C(O)NR b R c group, (iii) 1-2 C 1-6 alkyl or alkoxy groups, each optionally substituted with: 1-3 halo, and 1-2 OH or CO 2 R a groups; and
(2) phenyl optionally substituted as follows: (i) 1-3 halo groups, (ii) 1 CO 2 R a , CN, S(O) p R d , NO 2 or C(O)NR b R c group, (iii) 1-2 C 1-6 alkyl or alkoxy groups, each optionally substituted with: 1-3 halo groups;
said Aryl, HAR, Hetcy group b) being further optionally substituted on carbon by a group selected from the group consisting of;
(3) 1-3 halo groups;
(4) 1 OH, S(O) p R d , NO 2 , CN, CO 2 R a or —C(O)NR b R c group;
each R 2 is H or is selected from the group consisting of:
(a) halo, CO 2 R a , CN, SO p R d , NO 2 ,
(b) C 1-6 alkyl or OC 1-6 alkyl optionally substituted with: (1) 1-3 halo groups up to a perhaloalkyl group; (2) CO 2 R a CN, S(O) p Ror OH; (3) phenyl optionally substituted as follows: (i) 1-3 halo groups, (ii) 1 CO 2 R a , CN, S(O) p R, NO 2 or C(O)NR b R c group, (iii) 1-2 C 1-6 alkyl or alkoxy groups, each optionally substituted with: 1-5 halo groups;
R 3 and R 5 are H or C 1-3 alkyl;
R 6 is selected from the group consisting of H, OH, F and C 1-3 alkyl;
R 7 is H or F;
R a is H or C 1-6 alkyl, optionally substituted with phenyl, OH, OC 1-4 alkyl, CO 2 H, CO 2 C 1-6 alkyl and 1-3 halo groups;
R b is H or C 1-3 alkyl;
R c is H or is independently selected from:
(a) C 1-6 alkyl, optionally substituted with OH, OC 1-4 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 1-3 halos and 1 member selected from the group consisting of: CN, OH, C 1-6 alkyl and OC 1-6 alkyl, said alkyl and alkoxy being further optionally substituted with 1-3 halo groups up to perhalo;
(c) Hetcy or Hetcy-C 1-6 alkyl, optionally substituted with 1-3 halo groups and 1 group selected from: oxo, C 1-6 alkyl and OC 1-6 alkyl, said alkyl and alkoxy being further optionally substituted with 1-3 halo groups up to perhalo; and
(d) HAR or HAR-C 1-6 alkyl, optionally substituted with 1-5 halo groups and 1 group selected from: C 1-6 alkyl and OC 1-6 alkyl, said alkyl and alkoxy being further optionally substituted with 1-3 halo groups up to perhalo;
R d is C 1-6 alkyl, Aryl or Ar—C 1-6 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) and
X is CH or N.
3. A compound in accordance with claim 1 wherein: Y represents —C(O)—NR 5 —.
4. A compound in accordance with claim 1 wherein A represents —C(O)NH—R 1 .
5. A compound in accordance with claim 1 wherein Y represents O.
6. A compound in accordance with claim 5 wherein R 5 represents H.
7. A compound in accordance with claim 1 wherein B represents —C(O)NH—R 1 .
8. A compound in accordance with claim 6 wherein R 1 represents H, C 1-10 alkyl, or aryl optionally substituted with C 1-6 alkyl, OC 1-6 alkyl, haloC 1-6 alkyl and haloC 1-6 alkoxy.
9. A compound in accordance with claim 1 wherein each R 2 is independently selected from the group consisting of: H, halo, C 1-6 alkyl and OC 1-6 alkyl.
10. A compound in accordance with claim 1 wherein X represents CH.
11. A compound in accordance with claim 1 wherein m and n represent 0, 1 or 2, such that the sum of m and n is 0, 1, 2 or 3.
12. A compound in accordance with claim 1 wherein Z represents tetrazole or CO 2 H.
13. A compound in accordance with claim 1 wherein:
X represents CH;
Y represents —C(O)—NH—;
A represents —C(O)NH—R 1 wherein R 1 represents a member selected from the group consisting of: H, C 1-10 alkyl, aryl-C 1-6 alkyl or aryl optionally substituted with one of C 1-6 alkyl, OC 1-6 alkyl, haloC 1-6 alkyl and haloC 1-6 alkoxy;
B represents
each R 2 is independently selected from the group consisting of: H, halo, C 1-6 alkyl and OC 1-6 alky;
R 3 represents H;
n and m represent 0, 1 or 2, such that the sum of m and n is 0, 1, 2 or 3 and
Z represents tetrazole or CO 2 H.
14. A compound in accordance with claim 1 selected from the following tables:
TABLE 1
R 2
R 1
Ph
Ph
4-CF 3 Ph
3-CF 3 Ph
3-CF 3 Ph
3-CFO 3 Ph
4-CFO 3 Ph
4- t BuPh
Bn
t Bu
4-FPh
3,4-diFPh
4-cHexylPh
3-MeOPh
4-MeOPh
Ph
4-CF 3 Ph
4-CF 3 Ph
3-CF 3 Ph
3-CFO 3 Ph
4-CFO 3 Ph
4- t BuPh
Bn
CF 3 CH 2
4-FPh
3,4-diFPh
3-MeOPh
4-MeOPh
4-cHexylPh
TABLE 2
R 2
R 1
4-CF 3 O
4-FPh
3,5-diF
4-FPh
3,4-diF
4-FPh
4-CF 3 O
3,4-diF
2,4,5-triF
3,5-diCl
4-CF 3 OPh
4-CF 3 O
4-CF 3 OPh
3,5-diF
4-CF 3 OPh
3,4-diF
4-CF 3 OPh
3,5-diF
3,4-diF
2,4,5-triF
4-CF 3 OPh
TABLE 3
R 2
R 1
4-CF 3 O
4-FPh
3,5-diF
4-CF 3 OPh
4-CF 3 O
3,5-diF
3,4-diF
2,4,5-triF
2,4,5-triF
4-CF 3 OPh
4-CF 3 O
4-CF 3 OPh
3,4-diF
4-CF 3 OPh
4-CF 3 O
3,5-diF
3,4-diF
2,4,5-triF
3,5-diCl
4-CF 3 OPh
TABLE 4
R 2
R 1
3,4-diCl
3,5-diF
4-CF 3 OPh
3,4-diF
4-CF 3 OPh
3,5-diF
TABLE 5
R 2
R 1
3,4-diF
3,5-diF
3,5-diF
TABLE 6
R 2
R 1
3,4-diCl
3,4-diF
3,5-diF
3,4-diCl
3,4-diF
3,5-diF
TABLE 7
R 2
R 1
3,4-diCl
Ph
3,4-diCl
4-CF 3 Ph
3,4-diCl
4-CF 3 OPh
3,4-diCl
4-CF 3 O
3,4-diCl
3-CF 3 Ph
3,4-diCl
3-CF 3 OPh
3,4-diCl
4- t BuPh
4-CF 3 O
4-CF 3 OPh
4-CF 3 O
TABLE 8
R 2
R 1
3,4-diCl
Ph
3,4-diCl
4-CF 3 Ph
3,4-diCl
4-CF 3 O
4-CF 3 OPh
4-CF 3 O
3,4-diCl
3-CF 3 Ph
3,4-diCl
4- t BuPh
3,4-diCl
4-CF 3 O
or a pharmaceutically acceptable salt or solvate thereof.
15. A pharmaceutical composition comprising a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.
16. 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.
17. A method of delaying the onset of type 2 diabetes mellitus in a mammalian patient in need thereof, comprising administering to the patient a compound in accordance with claim I in an amount that is effective to delay the onset of said type 2 diabetes mellitus.
18. A method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment which comprises administering to said patient an effective amount of a compound in accordance with claim 1 .
19. A method of treating non-insulin dependent diabetes mellitus in a mammalian patient in need of such treatment comprising administering to the patient an anti-diabetic effective amount of a compound in accordance with claim 1 .
20. A method of treating obesity 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 obesity.
21. A method of treating Syndrome X 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 Syndrome X.
22. A method of treating a lipid disorder selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL 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 lipid disorder.
23. A method of treating atherosclerosis in a mammalian patient in need of such treatment, comprising administering to said patient a compound in accordance with claim 1 in an amount effective to treat atherosclerosis.