β3 adrenergic receptor agonists
View Patent ↗The present invention provides compounds of Formula (I), pharmaceutical compositions thereof, and methods of using the same in the treatment or prevention of diseases mediated by the activation of b3-adrenoceptor.
1. A compound of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof:
wherein
the dash bond “ ” means a single or double bond while conforming to the valency rule for the ring atoms;
m is 0, 1, 2 or 3;
n is 0, 1, 2, 3 or 4;
p is 0, 1 or 2;
U is —CH═ or —N═;
V is selected from the group consisting of:
(1) —O—,
(2) —N═, and
(3) —NR 3 —;
W is —N═ or —NR 3 —;
X is selected from the group consisting of:
(1) a bond, and
(2) C 1 -C 4 alkanediyl optionally substituted with 1 to 3 groups independently selected from:
(a) hydroxy,
(b) halogen,
(c) —CO 2 R 3 ,
(d) —CONR 3 R 3 , and
(e) —NR 3 R 3 ;
Z is selected from the group consisting of:
(1) phenyl,
(2) 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen,
(3) a C 5 -C 8 carbocyclic ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, and
(4) 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen;
each occurrence of R 1 is independently selected from the group consisting of:
(1) C 1 -C 4 alkyl optionally substituted with 1 to 3 groups independently selected from:
(a) hydroxy,
(b) halogen, and
(c) C 3 -C 8 cycloalkyl;
(2) C 3 -C 8 cycloalkyl,
(3) oxo, and
(4) halogen;
each occurrence of R 2 is independently selected from the group consisting of:
(1) hydroxy,
(2) halogen,
(3) oxo,
(4) —CO 2 R 3 ,
(5) C 3 -C 8 cycloalkyl,
(6) —S(O) p —C 1 -C 4 alkyl,
(7) C 1 -C 4 alkyl optionally substituted with 1 to 3 groups independently selected from
(a) hydroxy,
(b) halogen,
(c) —CO 2 R 3 ,
(d) —S(O) p —C 1 -C 4 alkyl,
(e) C 3 -C 8 cycloalkyl, and
(f) Z optionally substituted with 1 to 4 groups independently selected from hydroxyl, halogen, oxo, trifluoromethyl, trifluoromethoxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and —CO 2 R 3 , and
(8) Z optionally substituted with 1 to 4 groups independently selected from hydroxyl, halogen, oxo, trifluoromethyl, trifluoromethoxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —SO 2 —CH 3 , and —CO 2 R 3 ; and
each occurrence of R 3 is independently selected from the group consisting of:
(1) hydrogen, and
(2) C 1 -C 4 alkyl optionally substituted with 1 to 2 groups independently selected from phenyl, halogen, cyano and hydroxyl.
2. The compound of claim 1 , wherein V is —NH— and W is —N═.
3. The compound of claim 2 , wherein m is 0 and n is 0, 1, 2 or 3.
4. The compound of claim 3 , wherein X is selected from the group consisting of:
(1) a bond,
(2) —CH 2 —,
(3) —CH 2 CH 2 —,
(4) —CH(CH 3 )—
(5) —CH 2 CH 2 CH 2 —, and
(6) —CH(CH 3 )CH 2 —.
5. The compound of claim 3 , wherein Z is selected from the group consisting of:
(1) phenyl,
(2) a 5-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S,
(3) a 6-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S,
(4) a C 5 -C 6 carbocyclic ring fused to a 5-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S,
(5) a C 5 -C 6 carbocyclic ring fused to a 6-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S,
(6) a 5-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S fused to a 5-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S,
(7) a 5-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S fused to a 6-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S, and
(8) a 6-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S fused to a 6-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S.
6. The compound of claim 5 , wherein Z is selected from the group consisting of:
(1) phenyl,
(2) a 5-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S,
(3) a 6-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S,
(4) a C 5 -C 6 carbocyclic ring fused to a 5-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S,
(5) a 5-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S fused to a 5-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S, and
(6) a 5-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S fused to a 6-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S.
7. The compound of claim 6 wherein Z is selected from the group consisting of phenyl, thiazolyl, oxazolyl, pyridyl, dihydropyridyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, pyrimidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazinyl, dihydropyridazinyl, pyrrolidinyl, imidazolyl, pyrazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
8. The compound of claim 6 wherein Z is selected from the group consisting of phenyl, thiazolyl, oxazolyl, pyridyl, dihydropyridyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, pyrimidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazinyl, dihydropyridazinyl, pyrrolidinyl, imidazolyl, pyrazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
9. The compound of claim 1 wherein each occurrence of R 2 is independently selected from the group consisting of:
(1) hydroxy,
(2) fluoro,
(3) oxo,
(4) —CO 2 H,
(5) methyl, ethyl or propyl, each of which optionally substituted with 1 to 2 groups independently selected from hydroxy and halogen,
(6) —SO 2 —CH 3 , and
(7) Z optionally substituted with 1 to 3 groups independently selected from hydroxyl, halogen, oxo, trifluoromethyl, trifluoromethoxy, methyl, ethyl, and —CO 2 H.
10. The compound of claim 1 wherein each occurrence of R 3 is independently selected from the group consisting of:
(1) hydrogen,
(2) methyl, and
(3) ethyl.
11. A compound of Formulaic, or a pharmaceutically acceptable salt thereof:
wherein
n is 0, 1, 2, 3 or 4;
U is —CH═ or —N═;
X is selected from the group consisting of:
(1) a bond,
(2) —CH 2 —,
(3) —CH(CH 3 )—
(4) —CH 2 CH 2 —,
(5) —CH(CH 3 )CH 2 —, and
(6) —CH 2 CH 2 CH 2 —;
Z is selected from the group consisting of:
(1) phenyl,
(2) a 5-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S,
(3) a 6-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S,
(4) a C 5 -C 6 carbocyclic ring fused to a 5-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S,
(5) a 5-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S fused to a 5-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S, and
(6) a 5-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S fused to a 6-membered heterocyclic ring having 1 N ring atom and 0 to 2 additional hetero ring atoms independently selected from N, O and S;
each occurrence of R 2 is independently selected from the group consisting of:
(1) hydroxy,
(2) halogen,
(3) oxo,
(4) —CO 2 R 3 ,
(5) —SO 2 R 3 ,
(6) C 1 -C 4 alkyl optionally substituted with 1 to 3 groups independently selected from
(a) hydroxy,
(b) halogen,
(c) —CO 2 R 3 ,
(d) —SO 2 R 3 , and
(e) Z optionally substituted with 1 to 4 groups independently selected from hydroxyl, halogen, oxo, trifluoromethyl, trifluoromethoxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and —CO 2 R 3 , and
(7) Z optionally substituted with 1 to 4 groups independently selected from hydroxyl, halogen, oxo, trifluoromethyl, trifluoromethoxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —SO 2 R 3 , and —CO 2 R 3 ; and
each occurrence of R 3 is independently selected from the group consisting of:
(1) hydrogen, and
(2) C 1 -C 4 alkyl.
12. The compound of claim 11 , wherein Z is selected from the group consisting of: phenyl, thiazolyl, oxazolyl, pyridyl, dihydropyridyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, pyrimidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazinyl, dihydropyridazinyl, pyrrolidinyl, imidazolyl, pyrazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
13. The compound of claim 11 , wherein each occurrence of R 2 is independently selected from the group consisting of:
(1) hydroxy,
(2) halogen,
(3) oxo,
(4) —CO 2 H,
(5) —CO 2 CH 3 ,
(6) methyl, ethyl or propyl, each of which optionally substituted with 1 to 2 groups independently selected from hydroxy, halogen and Z optionally substituted with 1 to 4 groups independently selected from hydroxyl, halogen, oxo, trifluoromethyl, trifluoromethoxy, methyl, ethyl, —CO 2 H, and —CO 2 CH 3 ,
(7) —SO 2 —CH 3 , and
(8) Z optionally substituted with 1 to 4 groups independently selected from hydroxyl, halogen, oxo, trifluoromethyl, trifluoromethoxy, methyl, ethyl and —CO 2 H.
14. The compound of claim 11 , wherein each occurrence of R 2 is independently selected from the group consisting of:
(1) hydroxy,
(2) fluoro,
(3) oxo,
(4) —CO 2 H,
(5) methyl or ethyl, each of which optionally substituted with 1 to 2 groups independently selected from hydroxy, halogen and Z optionally substituted with 1 to 3 groups independently selected from hydroxyl, halogen, oxo, trifluoromethyl, methyl, ethyl, and —CO 2 H,
(6) —SO 2 —CH 3 , and
(7) Z optionally substituted with 1 to 3 groups independently selected from hydroxyl, halogen, oxo, trifluoromethyl, methyl, ethyl, and —CO 2 H.
15. The compound of claim 1 selected from those listed in Tables 1, 2 and 3
TABLE 1
Example
Number
U
R
1
CH
2
CH
3
CH
4
CH
5
CH
6
CH
7
CH
8
CH
9
CH
10
CH
11
CH
12
CH
13
CH
14
CH
15
CH
16
CH
17
CH
18
CH
19
CH
20
CH
21
CH
22
CH
23
CH
24
CH
25a Isomer 1
CH
25b Isomer 2
CH
26
N
27
N
28
N
29
N
30
N
31
N
32
N
33
N
34
N
35
N
36
N
37
N
38
N
39
N
40
N
41
N
42
N
TABLE 2
MS
Human β3 agonist
Example
Isomer
MW
(MH) +
functional activity
43
1
458.6
459.1
+++++
44
2
458.6
459.1
+++++.
16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
17. A method for the treatment of a disease or disorder mediated by the activation of β3-adrenoceptor, wherein said method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .
18. The method of claim 17 wherein the disease or disorder is selected from the group consisting of (1) overactive bladder, (2) urinary incontinence, (3) urge urinary incontinence, and (4) urinary urgency.
19. A method for the treatment of a disease or disorder mediated by the activation of β3-adrenoceptor, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 and a second active agent.