BIPIPERIDINYL COMPOUNDS, COMPOSITIONS CONTAINING SUCH COMPOUNDS AND METHODS OF TREATMENT
Bipiperidinyl compounds of the formula I, are disclosed as useful for treating or preventing type 2 diabetes and similar conditions. Pharmaceutically acceptable salts and solvates are included as well. The compounds are useful as agonists of the g-protein coupled receptor GPR-119.
1 . A compound represented by formula I:
or a pharmaceutically acceptable salt or solvate thereof wherein:
ring
represents phenyl or a 5-10 membered mono or bicyclic Heteroaryl group containing at least one nitrogen atom, 0-2 additional nitrogen atoms, and 0-1 oxygen or sulfur atom;
ring
is selected from thiadiazole, pyridyl, pyrimidine and pyrazine;
(1) CN or OH;
(2) C 1-6 alkyl, OC 1-6 alkyl or C 3-6 cycloalkyl, said members being optionally substituted with 1-3 halo groups and 1-2 members selected from the group consisting of:
i) S(O) x C 1-3 alkyl, wherein x is 0, 1 or 2 and the alkyl portion is optionally substituted with 1-3 halo atoms;
ii) a 5-10 membered Heteroaryl moiety optionally substituted with 1-3 halo atoms or C 1-3 alkyl groups;
iii) C 1-3 alkoxy or haloC 1-3 alkoxy;
iv) CN;
v) NH 2 , NHC 1-3 alkyl and N(C 1-3 alkyl) 2 the alkyl portions being optionally substituted with 1-3 halo groups;
vi) OH;
vii) C(O)C 1-6 alkyl the alkyl portion being optionally substituted with 1-3 halo atoms;
viii) phenyl optionally substituted with 1-2 halo atoms or C 1-3 alkyl groups;
ix) C(O)NR d R e , wherein R d is selected from H and C 1-3 alkyl and R e is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, a 5-6 membered Heteroaryl group and phenyl;
x) C(O) 2 R e , wherein R e is as defined above;
xi) Heteroaryl optionally substituted with 1-2 halo or C 1-3 alkyl groups;
(3) S(O) x C 1-6 alkyl, and SO 2 NR d R e wherein the C 1-6 alkyl group is optionally substituted with 1-3 halo groups and x, R d and R e are as defined above;
(4) NH 2 , NH(C 1-6 alkyl) or N(C 1-6 alkyl) 2 , wherein the alkyl portions are optionally substituted with 1-3 halo groups and 1 group selected from i) through xi) above;
(5) C(O)NR d R e , wherein R d and R e are as defined above;
(6) C(O)C 1-6 alkyl optionally substituted with 1-3 halo atoms;
(7) CO 2 R e , wherein R e is as defined above;
(8) Phenyl, a 5-10 membered Heteroaryl or a 5-10 membered Heterocyclic moiety, each being optionally substituted with 1-3 halo atoms and 1-2 C 1-3 alkyl groups, and the remaining R 1 groups are H or halo;
each R 2 is H or halo, or 1-2 are H or halo and the remainder are selected from the group consisting of:
1) CN;
2) NR f R g , wherein R f and R g each represent H or C 1-3 alkyl,
3) C 1-6 alkyl or OC 1-6 alkyl, said alkyl and alkyl portion being optionally substituted with 1-3 halo groups and 0-1 of NR f R g , S(O) x C 1-3 alkyl, SO 2 NR f R g and phenyl;
4) S(O) x C 1-3 alkyl, and
5) SO 2 NR f R g ,
and at least one R 1 and R 2 group represents a moiety other than hydrogen.
2 . A compound in accordance with claim 1 wherein ring A represents a 5-6 membered monocyclic aryl or heteroaryl group containing at least one nitrogen atom and 0-2 additional nitrogen atoms, and 0-1 additional oxygen or sulfur atom.
3 . A compound in accordance with claim 2 wherein ring A represents a member selected from the group consisting of: phenyl, thiazole, thiadiazole, pyridyl, pyrimidine and pyrazine.
4 . A compound in accordance with claim 3 wherein ring A represents a member selected from the group consisting of: phenyl, pyridyl, pyrimidine and pyrazine.
5 - 7 . (canceled)
8 . A compound in accordance with claim 1 wherein:
each R 1 is H or halo, or 1-2 R 1 groups are selected from the group consisting of:
(1) CN;
(2) C 1-6 alkyl, optionally substituted with 1-3 halo groups and 1-2 members selected from the group consisting of:
i) S(O) x C 1-3 alkyl, wherein x is 0, 1 or 2;
ii) NH 2 , NHCH 3 and N(CH 3 ) 2 ;
iii) OH;
iv) C(O)C 1-4 alkyl;
v) phenyl optionally substituted with 1-2 halo atoms or C 1-3 alkyl groups;
vi) C(O)NR d R e , wherein R d is selected from H and CH 3 and R e is selected from H, CH 3 , CH 2 CH 3 , cyclopropyl, cyclopropylmethyl, a 5-6 membered Heteroaryl group and phenyl;
vii) C(O) 2 R e , wherein R e is as defined above;
viii) Heteroaryl optionally substituted with 1-2 halo or CH 3 groups;
(3) S(O) x C 1-6 alkyl, wherein the C 1-6 alkyl group is optionally substituted with 1-3 halo groups and x, R d and R e are as defined above;
(4) NH 2 , NH(C 1-3 alkyl) or N(C 1-3 alkyl) 2 , wherein the alkyl portions are optionally substituted with 1-3 halo groups;
(5) C(O)NR d R e , wherein R d and R e are as defined above;
(6) C(O)C 1-6 alkyl optionally substituted with 1-3 halo atoms;
(7) CO 2 R e , wherein R e is as defined above;
(8) Phenyl, a 5-6 membered Heteroaryl or a 5-6 membered Heterocyclic moiety, each being optionally substituted with 1-3 halo atoms and 1-2 C 1-3 alkyl groups,
and the remaining R 1 groups are H or halo, and at least one R 1 and R 2 group represents a moiety other than hydrogen.
9 . A compound in accordance with claim 8 wherein:
each R 1 is H or halo selected from F and Cl, or 1-2 R 1 groups are selected from the group consisting of:
(1) CN;
(2) C 1-6 alkyl, optionally substituted with 1-3 halo groups and 1-2 members selected from the group consisting of:
i) S(O) 2 CH 3 ;
ii) phenyl optionally substituted with 1-2 halo atoms or CH 3 groups;
iii) C(O)NR d R e , wherein R d is selected from H and CH 3 and Re is selected from H, CH 3 , CH 2 CH 3 , cyclopropyl, cyclopropylmethyl, cyclopropyl substituted with methyl, a 5-6 membered Heteroaryl group and phenyl;
(3) SO 2 C 1-2 alkyl, wherein the C 1-2 alkyl group is optionally substituted with 1-3 halo groups and x, R d and R e are as defined above;
(4) N(CH 3 ) 2 ;
(5) C(O)NR d R e , wherein R d and R e are as defined above;
(6) CO 2 H or CO 2 CH 3 ;
and the remaining R 1 groups are H or halo selected from F and Cl, and at least one R 1 and R 2 group represents a moiety other than hydrogen.
10 . A compound in accordance with claim 9 wherein:
1 R 1 group is selected from the group consisting of:
(1) CN;
(2) C 1-4 alkyl, optionally substituted with 1-3 fluoro groups and 1 member selected from the group consisting of:
i) SO 2 CH 3 ;
ii) phenyl optionally substituted with 1-2 fluoro, chloro or CH 3 groups;
iii) C(O)NR d R e , wherein R d is H and R e is selected from H, CH 3 , CH 2 CH 3 , cyclopropyl, cyclopropyl substituted with methyl and cyclopropylmethyl,
(3) SO 2 CH 3 ,
(4) N(CH 3 ) 2 ;
(5) C(O)NR d R e , wherein R d is H and R e is as defined above;
(6) CO 2 H or CO 2 CH 3 ;
and the remaining R 1 groups are H or halo selected from F and Cl, and at least one R 1 and R 2 group represents a moiety other than hydrogen.
11 . A compound in accordance with claim 1 wherein:
each R 2 is H or halo, or 1-2 are H or halo and the remainder are selected from the group consisting of:
1) CN;
2) NR f R g , wherein R f and R g each represent H or CH 3 ,
3) C 1-6 alkyl optionally substituted with 1-3 fluorine atoms; and
4) SO 2 C 1-3 alkyl,
and at least one R 1 and R 2 group represents a moiety other than hydrogen.
12 . A compound in accordance with claim 11 wherein:
each R 2 is H, Cl or F, or 1-2 are H, Cl or F and the remainder are selected from the group consisting of:
1) CN;
2) NH 2 or NHCH 3 ;
3) CH 3 or CF 3 ; and
4) SO 2 CH 3 ,
and at least one R 1 and R 2 group represents a moiety other than hydrogen.
13 . A compound in accordance with claim 1 wherein:
ring A represents a 5-6 membered monocyclic aryl or heteroaryl group containing at least one nitrogen atom and 0-2 additional nitrogen atoms, and 0-1 additional oxygen or sulfur atom;
ring B is selected from thiadiazole, pyridyl, pyrimidine and pyrazine;
each R 1 is H or halo, or 1-2 R 1 groups are selected from the group consisting of:
(1) CN;
(2) C 1-6 alkyl, optionally substituted with 1-3 halo groups and 1-2 members selected from the group consisting of:
i) S(O) x C 1-3 alkyl, wherein x is 0, 1 or 2;
ii) NH 2 , NHCH 3 and N(CH 3 ) 2 ;
iii) OH;
iv) C(O)C 1-4 alkyl;
v) phenyl optionally substituted with 1-2 halo atoms or C 1-3 alkyl groups;
vi) C(O)NR d R e , wherein R d is selected from H and CH 3 and R e is selected from H, CH 3 , CH 2 CH 3 , cyclopropyl, cyclopropylmethyl, a 5-6 membered Heteroaryl group and phenyl;
vii) C(O) 2 R e , wherein R e is as defined above;
viii) Heteroaryl optionally substituted with 1-2 halo or CH 3 groups;
(3) S(O) x C 1-6 alkyl, wherein the C 1-6 alkyl group is optionally substituted with 1-3 halo groups and x, R d and R e are as defined above;
(4) NH 2 , NH(C 1-3 alkyl) or N(C 1-3 alkyl) 2 , wherein the alkyl portions are optionally substituted with 1-3 halo groups;
(5) C(O)NR d R e , wherein R d and R 3 are as defined above;
(6) C(O)C 1-6 alkyl optionally substituted with 1-3 halo atoms;
(7) CO 2 R e , wherein R e is as defined above;
(8) Phenyl, a 5-6 membered Heteroaryl or a 5-6 membered Heterocyclic moiety, each being optionally substituted with 1-3 halo atoms and 1-2 C 1-3 alkyl groups,
and the remaining R 1 groups are H or halo, and
each R 2 is H or halo, or 1-2 are H or halo and the remainder are selected from the group consisting of:
1) CN;
2) NR f R g , wherein R f and R g each represent H or CH 3 ,
3) C 1-6 alkyl optionally substituted with 1-3 fluorine atoms; and
4) SO 2 C 1-3 alkyl,
and at least one R 1 and R 2 group represents a moiety other than hydrogen.
14 . A compound selected from the group consisting of:
1-(5-fluoro-2-methylpyrimidin-4-yl)-1′-(5-fluoropyrimidin-2-yl)-4,4′-bipiperidine;
1-(5-fluoro-2-methylpyrimidin-4-yl)-1′-pyrimidin-2-yl-4,4′-bipiperidine;
6-[1′-(5-chloropyrimidin-2-yl)-4,4′-bipiperidin-1-yl]pyrimidine-4-carbonitrile;
6-(1′-pyrimidin-2-yl-4,4′-bipiperidin-1-yl)pyrimidine-4-carbonitrile;
1-(5-bromopyrimidin-2-yl)-1′-[4-(methylsulfonyl)phenyl]-4,4′-bipiperidine;
1-(3-methylpyrazin-2-yl)-1′-[4-(methylsulfonyl)phenyl]-4,4′-bipiperidine;
N,N-dimethyl-5-{1′-[4-(methylsulfonyl)phenyl]-4,4′-bipiperidin-1-yl}-1,2,4-thiadiazol-3-amine;
methyl 4-{1′-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4′-bipiperidin-1-yl}benzoate;
4-{1′-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4′-bipiperidin-1-yl}benzoic acid;
N-cyclopropyl-4-{1′-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4′-bipiperidin-1-yl}benzamide;
4-{1′-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4′-bipiperidin-1-yl}-N,N-dimethylbenzamide;
N,N-dimethyl-5-(1′-{4-[(methylsulfonyl)methyl]phenyl}-4,4′-bipiperidin-1-yl)-1,2,4-thiadiazol-3-amine;
N,N-dimethyl-5-{1′-[6-(methylsulfonyl)-3-pyridinyl]-4,4′-bipiperidin-1-yl}-1,2,4-thiadiazol-3-amine;
5-{1′-[3-bromo-4-(methylsulfonyl)phenyl]-4,4′-bipiperidin-1-yl}-N,N-dimethyl-1,2,4-thiadiazol-3-amine;
6-{1′-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4′-bipiperidin-1-yl}-N-(1-methylcyclopropyl)nicotinamide;
4-{1′-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4′-bipiperidin-1-yl}-N-(1-methylcyclopropyl)benzamide;
4-{1′-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4′-bipiperidin-1-yl}-2-fluoro-N-(1-methylcyclopropyl)benzamide;
Ex.
Structure
14.1
13.29
14.2
13.30
14.3
13.31
14.4
13.32
14.5
13.33
14.6
13.34
14.7
13.35
14.8
13.36
14.9
15.1
14.10
15.2
14.11
15.3
14.12
15.4
14.13
15.5
14.14
15.6
14.14
15.7
14.15
15.8
14.15
16.1
14.16
16.2
14.17
16.3
14.18
16.4
14.19
16.5
14.20
16.6
14.21
16.7
14.22
16.8
14.23
16.9
14.24
16.10
14.25
16.11
14.26
17.1
14.27
17.2
14.28
17.3
14.29
17.4
14.30
17.5
14.31
18.1
14.32
18.2
14.33
18.3
14.34
18.4
14.35
18.5
19.4
18.6
19.5
18.7
19.6
18.8
19.7
18.9
19.8
18.10
19.9
18.11
19.10
18.12
19.11
18.13
19.12
18.14
19.13
18.15
19.14
18.16
19.15
18.17
19.16*
19.17
19.18
19.19
18.21
19.20
18.22
19.21
18.23
19.22
18.24
19.23
18.25
19.24
18.26
19.25
19.26
19.27
19.28
19.29
18.31
19.30
18.32
19.31
18.33
19.32
18.34
19.33
18.35
19.34
18.36
19.35
18.37
19.36
18.38
19.37
18.39
19.38
18.40
19.39
18.41
18.42
18.43
18.44
18.45
18.46
18.47
18.48
or a pharmaceutically acceptable salt or solvate thereof
15 . A pharmaceutical composition comprised of a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.
16 . A method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment which comprises administering to said patient a compound in accordance with claim 1 in an amount that is effective to treate hyperglycemia, diabetes or insulin resistance.
17 . A method treating type 2 diabetes in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with claim 1 in an amount that is effective to treat type 2 diabetes.
18 . A method of treating non-insulin dependent diabetes mellitus in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with claim 1 in an amount that is effective to treat non-insulin dependent diabetes mellitus.
19 . 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.
20 - 35 . (canceled)