HETEROCYCLIC RECEPTOR AGONISTS FOR THE TREATMENT OF DIABETES AND METABOLIC DISORDERS
4 Assignments
0 Petitions
Accused Products
Abstract
Compounds and methods are provided for the treatment of, inter alia, Type II diabetes and other diseases associated with poor glycemic control. The compounds of the invention are orally active.
-
Citations
61 Claims
-
1. A compound having the Formula I:
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)
-
2. A compound of claim 1, wherein two of X, Y and Z are independently selected from the group consisting of O, N, N(R3) and S.
-
3. A compound of claim 1, wherein each of X, Y and Z are independently selected from the group consisting of O, N, N(R3) and S.
-
4. A compound of claim 1, wherein the ring having X, Y and Z is selected from the group consisting of:
-
5. A compound of claim 1, wherein A is CR4.
-
6. A compound of claim 1, wherein r is 1, s is 0 or 1, q is 0 and Ar is phenyl or naphthyl, optionally substituted with from 1 to 5 R6 substituents.
-
7. A compound of claim 1, wherein r is 1, s is 0 or 1, q is 0 and Ar is a 5-membered heteroaryl ring, optionally substituted with from 1 to 3 R6 substituents.
-
8. A compound of claim 1, wherein r is 1, s is 0 or 1, q is 0 and Ar is a 5-membered heteroaryl ring selected from the group consisting of oxazolyl, thiazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, furanyl, thienyl, triazolyl, pyrrolyl, isoxazolyl, isothiazolyl, and pyrazolyl, each of which is optionally substituted with from 1 to 3 R6 substituents.
-
9. A compound of claim 1, wherein r is 1, s is 0 or 1, q is 0 and Ar is a 6-membered heteroaryl ring, optionally substituted with from 1 to 3 R6 substituents.
-
10. A compound of claim 1, wherein r is 1, s is 0 or 1, q is 0 and Ar is selected from the group consisting of pyridyl, pyrimidinyl and pyrazinyl, each of which is optionally substituted with from 1 to 3 R6 substituents.
-
11. A compound of claim 1, wherein r is 1, s is 0 or 1, q is 0, and n is 2.
-
12. A compound of claim 1, wherein r is 1, s is 0 or 1, q is 0, n is 2 and one CH2 of L is replaced by O, S or N(R5).
-
13. A compound of claim 1, wherein r is 1;
- s is 0 or 1;
q is 0;
n is 2 and one CH2 of L is replaced by O;
A is selected from the group consisting of CH, C(CH3), CF and C(OH);
the ring having X, Y and Z as ring members is selected from the group consisting of thiazole, oxazole, thiadiazole and oxadiazole.
- s is 0 or 1;
-
14. A compound of claim 13, wherein Ar is phenyl, optionally substituted with from 1 to 3 R6 substituents.
-
15. A compound of claim 14, wherein R1 is a 5- to 10-membered heteroaryl group, and is optionally substituted with from one to two substituents independently selected from halo, C1-10 alkyl, C1-10 haloalkyl, C3-7 cycloalkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, heteroaryl, CN, NO2, —
- ORa, —
NRaRb, —
CO2Ra, —
CONRaRb, —
NRaCORb, —
NRaCO2Rb, —
S(O)mRa, —
NRaS(O)2Rb, and —
SO2NRaRb.
- ORa, —
-
16. A compound of claim 15, wherein R1 is a pyridine or pyrimidine, and is optionally substituted with from one to two substituents independently selected from halo, C1-10 alkyl, C1-10 haloalkyl, C3-7 cycloalkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, heteroaryl, CN, NO2, —
- ORa, —
NRaRb, —
CO2Ra, —
CONRaRb, —
NRaCORb, —
NRaCO2Rb, —
S(O)mRa, —
NRaS(O)2Rb, and —
SO2NRaRb.
- ORa, —
-
17. A compound of claim 14, wherein R1 is selected from the group consisting of —
- X1—
CORa, —
X1—
CO2Ra, —
X1—
CONRaRb and —
SO2Ra.
- X1—
-
18. A compound of claim 17, wherein Ar is substituted with from 1 to 2 R6 substituents independently selected from the group consisting of halo, C1-10 alkyl, C1-10 haloalkyl, CN, NO2, —
- ORa, —
NRaRb, —
CORa, —
CO2Ra, —
CONRaRb, —
NRaCORb, —
NRaCO2Rb, —
S(O)mRa, —
NRaS(O)mRb, —
SO2NRaRb, a 4- to 5-membered heterocyclo group, and a 5- to 6-membered heteroaryl group.
- ORa, —
-
19. A compound of claim 18, wherein each R6 is independently selected from the group consisting of halo, —
- ORa, —
NRaRb, —
NRaCORb, —
NRaCO2Rb, —
S(O)mRa, —
NRaS(O)mRb, —
SO2NRaRb, a 4- to 5-membered heterocyclo group, and a 5- to 6-membered heteroaryl group.
- ORa, —
-
2. A compound of claim 1, wherein two of X, Y and Z are independently selected from the group consisting of O, N, N(R3) and S.
-
20. A compound of Formula II:
- View Dependent Claims (21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61)
-
21. A compound of claim 20, wherein R1 is selected from the group consisting of —
- X1—
CORa, —
X1—
CO2Ra, —
X1—
CONRaRb, SO2Ra, aryl, heteroaryl, substituted aryl and substituted heteroaryl.
- X1—
-
22. A compound of claim 21, wherein R1 is selected from the group consisting of pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, phenyl, substituted phenyl, imidazolyl, substituted imidazolyl, triazolyl, substituted triazolyl, oxazolyl, substituted oxazolyl, thiazolyl, substituted thiazolyl, oxadiazolyl, substituted oxadiazolyl, tetrazolyl, and substituted tetrazolyl.
-
23. A compound of claim 22, wherein said pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, and tetrazolyl is further substituted with from one to three substituents selected from the group consisting of halo, C1-10alkyl, C1-10haloalkyl, C3-7cycloalkyl, aryl, heteroaryl, NO2, —
- ORa, —
NRaRb, CO2Ra, —
CONRaRb, —
S(O)mRa, —
NRaS(O)2Rb, and —
SO2NRaRb.
- ORa, —
-
24. A compound of claim 20, wherein D is O.
-
25. A compound of claim 24, wherein R1 is —
- X1—
CORa, —
X1—
CO2Ra, —
X1—
CONRaRb, SO2Ra, aryl, heteroaryl, substituted aryl or substituted heteroaryl.
- X1—
-
26. A compound of claim 25, wherein R1 is selected from the group consisting of pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, phenyl, substituted phenyl, imidazolyl, substituted imidazolyl, triazolyl, substituted triazolyl, oxazolyl, substituted oxazolyl, thiazolyl, substituted thiazolyl, oxadiazolyl, substituted oxadiazolyl, tetrazolyl, and substituted tetrazolyl.
-
27. A compound of claim 26, wherein said pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, and tetrazolyl is further substituted with from one to three substituents selected from the group consisting of halo, C1-10alkyl, C1-10haloalkyl, C3-7 cycloalkyl, aryl, heteroaryl, NO2, —
- ORa, —
NRaRb, CO2Ra, —
CONRaRb, —
S(OmRa, —
NRaS(O)2Rb, and —
SO2NRaRb.
- ORa, —
-
28. A compound of claim 20, wherein J, K, T, and U are all C.
-
29. A compound of claim 28, wherein R1 is selected from the group consisting of —
- X1—
CORa, —
X1CO2Ra, —
X1—
CONRaRb, SO2Ra, aryl, heteroaryl, substituted aryl and substituted heteroaryl.
- X1—
-
30. A compound of claim 29, wherein R1 is selected from the group consisting of pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, phenyl, substituted phenyl, imidazolyl, substituted imidazolyl, triazolyl, substituted triazolyl, oxazolyl, substituted oxazolyl, thiazolyl, substituted thiazolyl, oxadiazolyl, substituted oxadiazolyl, tetrazolyl, and substituted tetrazolyl.
-
31. A compound of claim 30, wherein said pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, and tetrazolyl is further substituted with from one to three substituents selected from the group consisting of halo, C1-10alkyl, C1-10haloalkyl, C3-7 cycloalkyl, aryl, heteroaryl, NO2, —
- ORa, —
NRaRb, CO2Ra, —
CONRaRb, —
S(O)mRa, —
NRaS(O)2Rb, and —
SO2NRaRb.
- ORa, —
-
32. A compound of claim 31, wherein the subscript p is an integer of from 1 to 3 and each R7 is independently selected from the group consisting of halo, C1-10alkyl, C1-10haloalkyl, CN, NO2, —
- ORa, —
NRaRb, —
CORa, —
CO2Ra, —
CONRaRb, —
NRaCORb, —
NRaCO2Rb, —
S(O)mRa, —
NRaS(O)mRb, —
SO2NRaRb, a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said heterocyclo groups, said aryl and heteroaryl groups are optionally substituted with from one to four substituents independently selected from halo, oxo, C1-4 alkyl, C1-4haloalkyl, C3-7 cycloalkyl, CN, NO2, —
ORa—
NRaRb, —
CO2Ra, —
CONRaRb, NRaCORb, —
NRaCORb, —
S(O)mRa, —
NRaS O2Rb, and —
SO2NRaRb and wherein the subscript m is an integer of from 0 to 2.
- ORa, —
-
33. A compound of claim 20, wherein at least one of J, K, T, and U is N.
-
34. A compound of claim 33, wherein D is O.
-
35. A compound of claim 34, wherein R1 is selected from the group consisting of —
- X1—
CORa, —
X1CO2Ra, —
X1—
CONRaRb, SO2Ra, aryl, heteroaryl, substituted aryl and substituted heteroaryl.
- X1—
-
36. A compound of claim 35, wherein R1 is selected from the group consisting of pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, phenyl, substituted phenyl, imidazolyl, triazolyl, substituted triazolyl, substituted imidazolyl, thiazolyl, substituted thiazolyl, oxazolyl, substituted oxazolyl, oxadiazolyl, substituted oxadiazolyl, tetrazolyl, and substituted tetrazolyl.
-
37. A compound of claim 36, wherein said pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, and tetrazolyl is further substituted with from one to three substituents selected from the group consisting of halo, C1-10alkyl, C1-10haloalkyl, C3-7 cycloalkyl, aryl, heteroaryl, NO2, —
- ORa, —
NRaRb, CO2Ra, —
CONRaRb, S(O)mRa, —
NRaS(O)2Rb, and —
SO2NRaRb.
- ORa, —
-
38. A compound of claim 37, wherein the subscript p is an integer of from 1 to 3 and each R7 is independently selected from the group consisting of halo, C1-10alkyl, C1-10haloalkyl, CN, NO2, —
- ORa, —
NRaRb, —
CORa, —
CO2Ra, —
CONRaRb, —
NRaCORb, —
NRaCO2Rb, —
S(O)mRa, —
NRaS(O)mRb, —
SO2NRaRb, a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said heterocyclo groups, said aryl and heteroaryl groups are optionally substituted with from one to four substituents independently selected from halo, oxo, C1-4 alkyl, C1-4haloalkyl, C3-7 cycloalkyl, CN, NO2, —
ORa, —
NRaRb, —
CO2Ra, —
CONRaRb, —
NRaCORb, —
NRCO2Rb, —
S(O)mRa, —
NRaSO2Rb, and —
SO2NRaRb and wherein the subscript m is an integer of from 0 to 2.
- ORa, —
-
39. A compound of claim 20, wherein J, T, and U are all C;
- and D is O.
-
40. A compound of claim 39, wherein each R7 is a member independently selected from the group consisting of halo, C1-10 alkyl, C1-10 haloalkyl, CN, NO2, —
- ORa, —
NRaRb, CORa, —
CO2Ra, —
CONRaRb, —
NRaCORb, —
NRaCORb, —
S(O)mRa, NRaS(O)mRb, —
SO2NRaRb, a 4- to 5-membered heterocyclo group, and a 5- to 6-membered heteroaryl group and wherein the subscript m is an integer of from 0 to 2;
each R2 is a member independently selected from the group consisting of halo, C1-5alkyl, C1-5haloalkyl; and
the subscript q is an integer of from 0 to 2.
- ORa, —
-
41. A compound of claim 40, wherein each R7 is independently selected from the group consisting of halo, C1-5alkyl, C1-5haloalkyl, —
- SORa, —
SO2Ra, and 5-membered heteroaryl group.
- SORa, —
-
42. A compound of claim 41, wherein each R7 is independently selected from the group consisting of fluoro, chloro, methyl, ethyl, —
- CF3, —
SO2C1-3alkyl, imidazolyl, triazolyl, and tetrazolyl and wherein the subscript p is integer of from 1 to 2.
- CF3, —
-
43. A compound of claim 42, wherein R1 is selected from the group consisting of —
- X1—
CORa, —
X1—
CO2Ra, —
X1—
CONRaRb, SO2Ra, aryl, heteroaryl, substituted aryl and substituted heteroaryl.
- X1—
-
44. A compound of claim 43, wherein R1 is selected from the group consisting of is aryl, heteroaryl, substituted aryl and substituted heteroaryl.
-
45. A compound of claim 44, wherein R1 is selected from the group consisting of pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, phenyl, substituted phenyl, imidazolyl, triazolyl, substituted triazolyl, substituted imidazolyl, oxazolyl, substituted oxazolyl, thiazolyl, substituted thiazolyl, oxadiazolyl, substituted oxadiazolyl, tetrazolyl, and substituted tetrazolyl.
-
46. A compound of claim 43, wherein R1 is selected from the group consisting of pyrimidinyl, substituted pyrimidinyl, oxadiazolyl, substituted oxadiazolyl, and —
- X1—
CO2Ra and wherein X1 is a bond.
- X1—
-
47. A compound of claim 39, wherein X is S, Y is C, Z is N;
- R1 is selected from the group consisting of pyrimidinyl, substituted pyrimidinyl, pyridyl, and substituted pyridyl, each R7 is independently selected from the group consisting of fluoro and tetrazolyl.
-
49. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 20.
-
50. A method of treating a disease or condition selected from the group consisting of Type I diabetes, Type II diabetes and metabolic syndrome, said method comprising administering to a subject in need of such treatment an effective amount of a compound of claim 20.
-
51. The method of claim 50, wherein said disease is Type II diabetes.
-
52. A method of stimulating insulin production, said method comprising administering an effective amount of a compound of claim 20 to a mammal.
-
53. The method of claim 52, wherein said mammal is a human.
-
54. The method of claim 53, wherein insulin is produced by a beta cell of said mammal.
-
55. A method of stimulating glucose-dependent insulin secretion, said method comprising administering an effective amount of a compound of claim 20 to a mammal.
-
56. The method of claim 55, wherein said mammal is a human.
-
57. The method of claim 56, wherein insulin is produced by a beta cell of said mammal.
-
58. A method of lowering blood glucose in a mammal, said method comprising administering an effective amount of a compound of claim 20 to a mammal.
-
59. The method of claim 58 wherein said mammal is a human.
-
60. A method of lowering blood triglyceride levels in a mammal, said method comprising administering an effective amount of a compound of claim 20 to a mammal.
-
61. The method of claim 60 wherein said mammal is a human.
-
21. A compound of claim 20, wherein R1 is selected from the group consisting of —
-
48. A compound as disclosed in Examples 1 to 210.
Specification
- Resources
Thank you for your request. You will receive a custom alert email when the Litigation Campaign Assessment is available.
×
-
Current AssigneeCymaBay Therapeutics Inc. (Gilead Sciences Inc.)
-
Original AssigneeMetabolex Inc (Gilead Sciences Inc.)
-
InventorsJohnson, Jeffrey D., Chen, Xin, Zhu, Yan, Song, Jiangao, Cheng, Peng, Zhao, Zuchun, Ma, Jingyuan, Rabbat, Christopher J., Nashashibi, Imad, Murphy, Alison, Clemens, L. Edward, Wilson, Maria E.
-
Granted Patent
-
Time in Patent OfficeDays
-
Field of Search
-
US Class Current514/275
-
CPC Class CodesA61K 31/454 containing a five-membered ...A61K 31/506 not condensed and containin...A61P 13/12 of the kidneysA61P 27/02 Ophthalmic agentsA61P 3/00 Drugs for disorders of the ...A61P 3/04 Anorexiants; Antiobesity ag...A61P 3/06 AntihyperlipidemicsA61P 3/08 for glucose homeostasis pan...A61P 3/10 for hyperglycaemia, e.g. an...A61P 43/00 Drugs for specific purposes...A61P 9/00 Drugs for disorders of the ...A61P 9/10 for treating ischaemic or a...A61P 9/12 AntihypertensivesC07D 277/42 Amino or imino radicals sub...C07D 401/04 directly linked by a ring-m...C07D 401/14 containing three or more he...C07D 413/04 directly linked by a ring-m...C07D 413/14 containing three or more he...C07D 417/04 directly linked by a ring-m...C07D 417/14 containing three or more he...