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1. CA2759891 - GPR 119 MODULATORS

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters
What is claimed is:
1. A compound of the formula (I): in which
X is
R1 is -C(O)-O-R5 or
R2 is hydrogen, cyano, or methyl;
R3 is hydrogen, OH, halogen, cyano, CF3, OCF3, C1-C5 alkoxy, or C1-C5 alkyl;
R4 is SO2-R7 or -NH-(CH2)2-OH;
R5 is C1-C5 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl in which one carbon atom of said cycloalkyl moiety is optionally substituted with methyl or ethyl;
R6 is CF3, C1-C5 alkyl, halogen, cyano, or C3-C6 cycloalkyl;
R7 is C3-C6 cycloalkyl, C1-C5 alkyl, NH2, or -(CH2)2-OH;
R8 is hydrogen or C1-C5 alkyl,
R9 is hydrogen, C1-C5 alkyl, C3-C6cycloalkyl, -CH2-CH2-OH, -CH2-CH2-O-CH3, CH2-CH2-CH2-O-CH3, -CH2-CH2-CH2-OH, 3-oxetanyl, or 3-hydroxycyclobutyl,
R10 is hydrogen, cyano, nitro, CF3, OCF3, C3-C6 cycloalkyl, C1-C5 alkoxy, or
C1-C5 alkyl;
R11 is hydrogen, C1-C5 alkyl, or halogen; and
A1, A2, A3, and A4, are each independently CH, N-oxide, or N; with the proviso that: d) no more than 2 of A1, A2, A3, and A4 are N; e) no more than 1 of A1, A2, A3, and A4 are N-oxide; and f) when A1-A4 forms a phenyl ring, X is or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 in which X is
3. A compound according to claim 1 in which X is
4. A compound according to claim 1, 2, or 3 in which A1-A4 forms a ring in which one or two of A1, A2, A3, and A4 are N.
5. A compound according to claim 1, 2, 3 or 4 in which A1-A4 forms a pyridyl ring.
6. A compound according to any of claims 1-5 in which R4 is -SO2R7.
7. A compound according to any of claims 1-6 in which R1 is -C(O)-O-R5.
8. A compound according to any of claims 1-7 in which R3 is fluoro or hydrogen.
9. A compound according to any of claims 1-8 in which R2 is hydrogen or cyano.
10. A compound selected from the group consisting of:
Isopropyl 9-anti-({6-[5-(methyl sulfonyl)-2,3-dihydro-1H-indol-1-yl]pyrimidin-
yl}oxy)-3-oxa-7-azabicyclo[3.3.1 ]nonane-7-carboxylate; and
Isopropyl 9-syn-({6-[5-(methylsulfonyl)-2,3-dihydro-1H-indol-1-yl]pyrimidin-4yl }oxy )-3-oxa-7-azabicyclo[3 . 3.1 ] nonane-7-carboxylate;
or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising a compound according to any of claims 1-10, present in a therapeutically effective amount, in admixture with at least one pharmaceutically acceptable excipient.
12. The composition of claim 11 further comprising at least one additional pharmaceutical agent selected from the group consisting of an anti-obesity agent and an anti-diabetic agent.
13. The composition of Claim 12 wherein said anti-obesity agent is selected from the group consisting of dirlotapide, mitratapide, implitapide, R56918 (CAS No. 403987),
CAS No. 913541-47-6, lorcaserin, cetilistat, PYY3-36, naltrexone, oleoylestrone, obinepitide, pramlintide, tesofensine, leptin, liraglutide, bromocriptine, orlistat, exenatide,
AOD-9604 (CAS No. 221231-10-3) and sibutramine.
14. The composition of Claim 12 wherein said anti-diabetic agent is selected from the group consisting of metformin, acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, tolbutamide, tendamistat, trestatin, acarbose, adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, salbostatin, balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, troglitazone, exendin-3, exendin-4, trodusquemine, reservatrol, hyrtiosal extract, sitagliptin, vildagliptin, alogliptin and saxagliptin.
15. A method for the treatment of diabetes comprising the administration of an effective amount of compound according to any of claims 1 - 10 to a patient in need thereof.
16. A method for treating a metabolic or metabolic-related disease, condition or disorder comprising the step of administering to a patient a therapeutically effective amount of a compound of any one of claims 1 - 10.
17. A method for treating a condition selected from the group consisting of hyperlipidemia, type I diabetes, type II diabetes mellitus, idiopathic type I diabetes (Type
Ib), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction (e.g. necrosis and apoptosis), dyslipidemia, postprandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance, hyper apo
B lipoproteinemia, Alzheimer's, schizophrenia, impaired cognition, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and irritable bowel syndrome, comprising the administration of an effective amount of a compound according to any of claims
18. A method for treating a metabolic or metabolic-related disease, condition or disorder comprising the step of administering to a patient in need of such treatment two separate pharmaceutical compositions comprising
(i) a first composition according to claim 13, and, (ii) a second composition comprising at least one additional pharmaceutical agent selected from the group consisting of an anti-obesity agent and an anti-diabetic agent, and at least one pharmaceutically acceptable excipient.
19. The method of claims 20 wherein said first composition and said second composition are administered simultaneously.
20. The method of claim 20 wherein said first composition and said second composition are administered sequentially and in any order.
21. The use of a compound of claim 1 through 10 in the manufacture of a medicament for treating a disease, condition or disorder that modulates the activity of
G-protein-coupled receptor GPR119.
22. The use of a compound according to any of claims 1-12 in the preparation of a medicament for the treatment of diabetes or a morbidity associated with said diabetes.