Patent Application
20150218183
Diabetes is characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or after administration of glucose during an oral glucose tolerance test. In Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose utilization. In Type 2 diabetes, or noninsulin-dependent diabetes mellitus (NIDDM), insulin is still produced by islet cells in the pancreas. Patients with Type 2 diabetes have a resistance to the effects of insulin in stimulating glucose and lipid metabolism in the main insulin-sensitive tissues, including muscle, liver and adipose tissues. These patients often have normal levels of insulin, and may have hyperinsulinemia (elevated plasma insulin levels), as they compensate for the reduced effectiveness of insulin by secreting increased amounts of insulin (Polonsky, Int. J. Obes. Relat. Metab. Disord. 24 Suppl 2:S29-31, 2000). Insulin resistance is not primarily caused by a diminished number of insulin receptors but rather by a post-insulin receptor binding defect that is not yet completely understood. This lack of responsiveness to insulin results in insufficient insulin-mediated activation of uptake, oxidation and storage of glucose in muscle, and inadequate insulin-mediated repression of lipolysis in adipose tissue and of glucose production and secretion in the liver. Eventually, a patient may be become diabetic due to the inability to properly compensate for insulin resistance. In humans, the beta cells within the pancreatic islets initially compensate for insulin resistance by increasing insulin output. The onset of Type 2 diabetes due to insufficient increases (or actual declines) in beta cell mass is apparently due to increased beta cell apoptosis relative to non-diabetic insulin resistant individuals (Butler et al., Diabetes 52:102-110, 2003).
Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with obesity, hypertension, and alterations of the lipid, lipoprotein and apolipoprotein metabolism, as well as other metabolic and hemodynamic disease. Patients with Type 2 diabetes mellitus have a significantly increased risk of macrovascular and microvascular complications, including atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, effective therapeutic control of glucose homeostasis, lipid metabolism, obesity, and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
Patients who have insulin resistance often exhibit several symptoms that together are referred to as Syndrome X or Metabolic Syndrome. According to one widely used definition, a patient having Metabolic Syndrome is characterized as having three or more symptoms selected from the following group of five symptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) low high-density lipoprotein cholesterol (HDL); (4) high blood pressure; and (5) elevated fasting glucose, which may be in the range characteristic of Type 2 diabetes if the patient is also diabetic. Each of these symptoms is defined clinically in the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III), National Institutes of Health, 2001, NIH Publication No. 01-3670. Patients with Metabolic Syndrome, whether or not they have or develop overt diabetes mellitus, have an increased risk of developing the macrovascular and microvascular complications that occur with Type 2 diabetes, such as atherosclerosis and coronary heart disease.
There are several available treatments for Type 2 diabetes, each of which has its own limitations and potential risks. Physical exercise and a reduction in dietary intake of calories often dramatically improve the diabetic condition and are the usual recommended first-line treatment of Type 2 diabetes and of pre-diabetic conditions associated with insulin resistance. Compliance with this treatment is generally very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of fat and carbohydrates. Pharmacologic treatments for diabetes have largely focused on three areas of pathophysiology: (1) hepatic glucose production (biguanides, such as phenformin and metformin), (2) insulin resistance (PPAR agonists, such as rosiglitazone, troglitazone, engliazone, balaglitazone, MCC-555, netoglitazone, T-131, LY-300512, LY-818 and pioglitazone), (3) insulin secretion (sulfonylureas, such as tolbutamide, glipizide and glimipiride); (4) incretin hormone mimetics (GLP-1 derivatives and analogs, such as exenatide and liraglutide); and (5) inhibitors of incretin hormone degradation (DPP-4 inhibitors, such as sitagliptin).
Many of the current treatments for diabetes have unwanted side effects. Phenformin and metformin can induce lactic acidosis, nausea/vomiting, and diarrhea. Metformin has a lower risk of side effects than phenformin and is widely prescribed for the treatment of Type 2 diabetes. The currently marketed PPAR gamma agonists are modestly effective in reducing plasma glucose and hemoglobinA1C, and do not greatly improve lipid metabolism or the lipid profile. Sulfonylureas and related insulin secretagogues can cause insulin secretion even if the glucose level is low, resulting in hypoglycemia, which can be fatal in severe cases. The administration of insulin secretagogues must therefore be carefully controlled. There remains a need for treatments for diabetes that work by novel mechanisms of action and that exhibit fewer side effects.
AMP-activated protein kinase (AMPK) has been identified as a regulator of carbohydrate and fatty acid metabolism that helps maintain energy balance in response to environmental and nutritional stress. There is evidence that activation of AMPK results in a number of beneficial effects on lipid and glucose metabolism by reducing glucogenesis and de novo lipogenesis (fatty acid and cholesterol synthesis), and by increasing fatty acid oxidation and skeletal muscle glucose uptake. Inhibition of ACC, by phosphorylation by AMPK, leads to a decrease in fatty acid synthesis and to an increase in fatty acid oxidation, while inhibition of HMG-CoA reductase, by phosphorylation by AMPK, leads to a decrease in cholesterol synthesis (Carling, D. et. al., FEBS Letters 223:217 (1987)).
In the liver, AMPK activation results in a decrease in fatty acid and cholesterol synthesis, inhibiting hepatic glucose production and increasing fatty acid oxidation. It has been shown that AMP-activated protein kinase regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle via glycerol-3-phosphate acyltransferase (Muoio, D. M. et. al., Biochem. J. 338:783 (1999)). Another substrace of AMPK, hepatocyte nuclear factor-4α, has been shown to be involved in type-1 maturity onset diabetes (Leclerc, I. et. al., Diabetes 50:1515 (2001)). Additional processes believed to be regulated through AMPK activation include the stimulation of glucose transport in skeletal muscle and the regulation of key genes in fatty acid and glucose metabolism in the liver (Hardie, D. G. and Hawley, S. A., Bioessays 23: 1112 (2001), Kemp, B. E. et. al., Biochem. Soc. Transactions 31:162 (2003), Musi, N. and Goodyear, L. J. Current Drug Targets-Immune, Endocrine and Metabolic Disorders 2:119 (2002); Lochhead, P. A. et. al., Diabetes 49:896 (2000); and Zhou, G. et. al., J. of Clin. Invest. 108: 1167 (2001).
In vivo studies have demonstrated the following beneficial effects of both acute and chronic administration of AICAR, an AMPK activator, in rodent models of obesity and type 2 diabetes: 1) an improvement in glucose homeostasis in insulin-resistant diabetic (ob/ob) mice; 2) a decrease in blood glucose concentrations in ob/ob and db/db mice and a blood glucose reduction of 35% following 8 weeks of administration; and 3) a reduction in metabolic disturbances and a reduction of blood pressure in rats displaying characteristics of insulin resistance syndrome (Bergeron, R. et. al., Diabetes 50:1076 (2001); Song, S. M. et. al., Diabetologia 45:56 (2002); Halseth, A. E. et. al., Biochem. and Biophys. Res. Comm. 294:798 (2002); and Buhl, E. S. et. al., Diabetes 51: 2199 (2002)). A further study of 7 week AICAR administration in obese Zucker (fa/fa) rats lead to a reduction in plasma triglycerides and free fatty acids; an increase in HDL cholesterol; and a normalization of glucose metabolism as assessed by an oral glucose tolerance test (Minokoshi, Y. et. al., Nature 415: 339 (2002)). Expression of dominant negative AMPK in skeletal muscle of transgenic mice has demonstrated that the AICAR effect on stimulation of glucose transport is dependent on AMPK activation (Mu, J. et. al., Molecular Cell 7: 1085 (2001)).
Recent data also suggest that AMPK activation is involved in the glucose and lipid-lowering effects of the anti-diabetic drug metformin. It has been shown that the diabetes drug metformin can activate AMPK in vivo at high concentrations (Zhou, G. et. al., J. of Clin. Invest. 108: 1167 (2001); Musi, N. et. al. Diabetes 51: 2074 (2002)).
Based on these studies, it is expected that the in vivo activation of AMPK in the liver may result in the reduction of hepatic glucose output, an improvement in overall glucose homeostasis, a decrease in fatty acid and cholesterol synthesis, and an increase in fatty acid oxidation. Stimulation of AMPK in skeletal muscle is expected to result in an increase in glucose uptake and fatty acid oxidation with resulting improvement of glucose homeostasis, and an improvement in insulin action. Finally, the resulting increase in energy expenditure may lead to a decrease in body weight. The lowering of blood pressure has also been reported to be a consequence of AMPK activation.
Increased fatty acid synthesis is a characteristic of many tumor cells, therefore decreasing the synthesis of fatty acids via AMPK activation may also be useful as a cancer therapy. Activation of AMPK may also be useful to treat ischemic events in the brain (Blazquez, C. et. al., J. Neurochem. 73: 1674 (1999)); to prevent damage from reactive oxygen species (Zhou, M. et. al., Am. J. Physiol. Endocrinol. Metab. 279: E622 (2000)); and to improve local circulatory systems (Chen, Z.-P., et. al. AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Letters 443: 285 (1999)).
Compounds that activate AMPK may be useful to treat type 2 diabetes mellitus, obesity, hypertension, dyslipidemia, cancer, and metabolic syndrome, as well as cardiovascular diseases, such as myocardial infarction and stroke, by improving glucose and lipid metabolism and by reducing body weight. There is a need for potent AMPK activators that have pharmacokinetic and pharmacodynamic properties suitable for use as human pharmaceuticals.
Benzimidazole compounds are disclosed in WO 2010/051206; WO 2010/051176; WO 2010/047982; WO 2010/036613; WO 93/07124; WO 95/29897; WO 98/39342; WO 98/39343; WO 00/03997; WO 00/14095; WO 01/53272; WO 01/53291; WO 02/092575; WO 02/40019; WO 03/018061; WO 05/002520; WO 05/018672; WO 06/094209; U.S. Pat. No. 6,312,662; U.S. Pat. No. 6,489,476; US 2005/0148643; DE 3 316 095; JP 6 298 731; EP 0 126 030; EP 0 128 862; EP 0 129 506; and EP 0 120 403. AMPK activators are disclosed in WO 08/006432; WO 05/051298; WO 05/020892; US 2007/015665; US 2007/032529; US 2006/287356; and US 2005/038068. Azabenzimidazole compounds are disclosed in WO 2012/33149.
The present invention is concerned with novel benzimidazole derivatives of structural Formula I:
and pharmaceutically acceptable salts thereof. The compounds of structural formula I, and salts thereof, are activators of AMP-activated protein kinase (AMPK) and are useful in the treatment, prevention and suppression of diseases, disorders and conditions mediated by activation of AMP-activated protein kinase. As AMPK activators, the compounds of structural formula I may be useful to treat Type 2 diabetes mellitus, insulin resistance, hyperglycemia, dyslipidemia, lipid disorders, obesity, hypertension, Metabolic Syndrome and atherosclerosis.
The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier. The present invention also relates to methods for the treatment, control or prevention of disorders, diseases, and conditions that are responsive to activation of AMP-activated protein kinase in a subject in need thereof by administering the compounds and pharmaceutical compositions of the present invention. The present invention also relates to the use of compounds of the present invention for manufacture of a medicament useful in treating diseases, disorders and conditions are responsive to the activation of AMP-activated protein kinase. The present invention is also concerned with treatment of these diseases, disorders and conditions by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent useful to treat the disease, disorder and condition. The invention is further concerned with processes for preparing the compounds of this invention.
The present invention is concerned with novel compounds of structural Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X is selected from:
wherein A is selected from: CH2, NH, NC1-6alkyl, O and S, and wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb;
Z is selected from:
In one embodiment of the present invention, T is CR3; U is CR1; V is CR2; and W is CR4. In a class of this embodiment, T is CR3; U is CR1; V is CR2; and W is CR4, wherein R3 is hydrogen or halogen. In another class of this embodiment, T is CR3; U is CR1; V is CR2; and W is CR4, wherein R3 is hydrogen or halogen; and R2 is halogen. In another class of this embodiment, T is CR3; U is CR1; V is CR2; and W is CR4, wherein R3 is hydrogen or halogen; R2 is halogen; and R4 is hydrogen.
In another embodiment of the present invention, T is —CR3—, U is —CR1—, V is —CR2—, and W is —CR4—. In a class of this embodiment, T is —CR3—, wherein R3 is hydrogen; U is —CR1—; V is —CR2—, wherein R2 is Cl; and W is —CR4—, wherein R4 is hydrogen. In another class of this embodiment, T is —CR3—, wherein R3 is F; U is —CR1—; V is —CR2—, wherein R2 is F; and W is —CR4—, wherein R4 is hydrogen.
In another embodiment of the present invention, T is —CR3—.
In another embodiment of the present invention, U is —CR1—.
In another embodiment of the present invention, V is —CR2—.
In another embodiment of the present invention, W is —CR4—.
In another embodiment of the present invention, T is —CR3—, wherein R3 is H, and V is —CR2, wherein R2 is Cl.
In another embodiment of the present invention, T is —CR3—, wherein R3 is H, and V is —CR2, wherein R2 is F.
In another embodiment of the present invention, T is —CR3—, wherein R3 is H or F, and V is —CF. In another embodiment of the present invention, T is —CF, and V is —CF.
In another embodiment of the present invention, X is selected from: —CH2—, —CHF—, —CF2—, —S—, —O—, —O—CH2—, —O—CH2CH2—, —NH—, —C(O)—, —NHC(O)—, —C(O)NH—, —NHSO2—, —SO2NH—, and —CO2—, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: hydroxy, halogen, NH2, C1-6alkyl, CO2H, CO2C1-6alkyl, COC1-6alkyl, phenyl and —CH2phenyl, and wherein each NH is unsubstituted or substituted with 1 substituent selected from: C1-6alkyl, CO2H, CO2C1-6alkyl, COC1-6alkyl, phenyl and —CH2phenyl.
In another embodiment of the present invention, X is selected from: —S—, —O—, and —NH—. In another embodiment of the present invention, X is —O—. In another embodiment of the present invention, X is —S—. In another embodiment of the present invention, X is —NH—.
In another embodiment of the present invention, Y is selected from:
wherein A is selected from: CH2, NH, NC1-6alkyl, O and S, and wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb.
In another embodiment of the present invention, Y is selected from:
wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb.
In another embodiment of the present invention, Y is selected from:
wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb. In a class of this embodiment, Y is:
wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb. In another class of this embodiment, Y is:
wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb.
In another embodiment of the present invention, Y is:
wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb. In a class of this embodiment, Y is:
wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb. In another class of this embodiment, Y is:
wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb.
In another embodiment of the present invention, Z is selected from: NR5, —S—, and —O—. In a class of this embodiment, Z is NR5. In another class of this embodiment, Z is —S—. In another class of this embodiment, Z is —O—.
In another embodiment of the present invention, each R1 and R2 is independently selected from: hydrogen, halogen, CN, CF3, —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, —(CH2)pC3-10cycloalkyl, —(CH2)C3-7cycloalkyl-aryl, —(CH2)pC3-7cycloalkyl-heteroaryl, —(CH2)pC4-10cycloalkenyl, —(CH2)pC4-7cycloalkenyl-aryl, —(CH2)pC4-7cycloalkenyl-heteroaryl, —(CH2)pC2-10cycloheteroalkyl, —(CH2)pC2-10cycloheteroalkenyl, —(CH2)paryl, —(CH2)paryl-C1-8 alkyl, —(CH2)paryl-C2-8 alkenyl, —(CH2)paryl-C2-8alkynyl-C1-8 alkyl, —(CH2)paryl-C2-8alkynyl-C3-7cycloalkyl, —(CH2)paryl-C2-8alkynyl-C3-7cycloalkenyl, —(CH2)paryl-C2-8alkynyl-C2-10cycloheteroalkyl, —(CH2)paryl-C2-8alkynyl-C2-10cycloheteroalkenyl, —(CH2)paryl-C2-8alkynyl-aryl, —(CH2)paryl-C2-8alkynyl-heteroaryl, —(CH2)paryl-C3-7cycloalkyl, —(CH2)paryl-C2-10cycloheteroalkyl, —(CH2)paryl-C2-10cycloheteroalkenyl, —(CH2)paryl-aryl, —(CH2)paryl-heteroaryl, —(CH2)pheteroaryl, —(CH2)pheteroaryl-C3-7cycloalkyl, —(CH2)pheteroaryl-C2-10cycloheteroalkyl —(CH2)pheteroaryl-C2-10cycloheteroalkenyl, —(CH2)pheteroaryl-aryl, —(CH2)pheteroaryl-heteroaryl, —C2-6alkenyl-alkyl, —C2-6alkenyl-aryl, —C2-6alkenyl-heteroaryl, —C2-6alkenyl-C3-7cycloalkyl, —C2-6alkenyl-C3-7cycloalkenyl, —C2-6alkenyl-C2-7cycloheteroalkyl, —C2-6alkenyl-C2-7cycloheteroalkenyl, —C2-6alkynyl-(CH2)1-3—O-aryl, —C2-6alkynyl-alkyl, —C2-6alkynyl-aryl, —C2-6alkynyl-heteroaryl, —C2-6alkynyl-C3-7cycloalkyl, —C2-6alkynyl-C3-7cycloalkenyl, —C2-6alkynyl-C2-7cycloheteroalkyl, —C2-6alkynyl-C2-7cycloheteroalkenyl, and —C(O)NH—(CH2)0-3phenyl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: halogen, CF3, —OH, —NH2, —C1-6alkyl, —OC1-6alkyl, —NHC1-6alkyl, and —N(C1-6alkyl)2, and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra, provided that at least one of and only one of R1 and R2 is selected from the group consisting of: hydrogen, halogen, —CN, —CF3, —C1-6alkyl, —C2-6 alkenyl and —C2-6alkynyl. In a class of this embodiment, at least one of and only one of R1 and R2 is selected from halogen. In a subclass of this class, at least one of and only one of R1 and R2 is selected from: F and Cl.
In another embodiment of the present invention, each R1 and R2 is independently selected from halogen, —(CH2)paryl-C2-10cycloheteroalkyl, —(CH2)paryl-aryl, and —(CH2)paryl-heteroaryl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: halogen, CF3, —OH, —NH2, —C1-6alkyl, —OC1-6alkyl, —NHC1-6alkyl, and —N(C1-6alkyl)2, and wherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra, provided that at least one of and only one of R1 and R2 is selected from the group consisting of: halogen. In a class of this embodiment, at least one of and only one of R1 and R2 is selected from: F and Cl.
In another embodiment of the present invention, each R1 and R2 is independently selected from: halogen, aryl-C2-10cycloheteroalkyl, aryl-aryl, and aryl-heteroaryl, wherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra, provided that at least one of and only one of R1 and R2 is selected from halogen. In a class of this embodiment, at least one of and only one of R1 and R2 is selected from: F and Cl.
In another embodiment of the present invention, each R1 and R2 is independently selected from: halogen, phenyl-dihydropyrrolopyrazole, biphenyl, phenyl-naphthalene, phenyl-thiazole, phenyl-pyrazine, phenyl-furan, phenyl-pyrazole, phenyl-pyrimidine, and phenyl-imidazole, wherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra, provided that at least one of and only one of R1 and R2 is selected from halogen. In a class of this embodiment, at least one of and only one of R1 and R2 is selected from: F and Cl.
In another embodiment of the present invention, each R1 and R2 is independently selected from: aryl-aryl, wherein each aryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra, provided that at least one of and only one of R1 and R2 is selected from halogen. In a class of this embodiment, at least one of and only one of R1 and R2 is selected from: F and Cl.
In another embodiment of the present invention, each R1 and R2 is independently selected from: biphenyl, wherein each phenyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra, provided that at least one of and only one of R1 and R2 is selected from halogen. In a class of this embodiment, at least one of and only one of R1 and R2 is selected from: F and Cl.
In another embodiment of the present invention, each R1 is independently selected from: hydrogen, halogen, CN, CF3, —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, —(CH2)pC3-10cycloalkyl, —(CH2)pC3-7cycloalkyl-aryl, —(CH2)pC3-7cycloalkyl-heteroaryl, —(CH2)pC4-10cycloalkenyl, —(CH2)pC4-7cycloalkenyl-aryl, —(CH2)pC4-7cycloalkenyl-heteroaryl, —(CH2)pC2-10cycloheteroalkyl, —(CH2)pC2-10cycloheteroalkenyl, —(CH2)paryl, —(CH2)paryl-C1-8 alkyl, —(CH2)paryl-C2-8 alkenyl, —(CH2)paryl-C2-8alkynyl-C1-8 alkyl, —(CH2)paryl-C2-8alkynyl-C3-7cycloalkyl, —(CH2)paryl-C2-8alkynyl-C3-7cycloalkenyl, —(CH2)paryl-C2-8alkynyl-C2-10cycloheteroalkyl, —(CH2)paryl-C2-8alkynyl-C2-10cycloheteroalkenyl, —(CH2)paryl-C2-8 alkynyl-aryl, —(CH2)paryl-C2-8alkynyl-heteroaryl, —(CH2)paryl-C3-7cycloalkyl, —(CH2)paryl-C2-10cycloheteroalkyl, —(CH2)paryl-C2-10cycloheteroalkenyl, —(CH2)paryl-aryl, —(CH2)paryl-heteroaryl, —(CH2)pheteroaryl, —(CH2)pheteroaryl-C3-7cycloalkyl, —(CH2)pheteroaryl-C2-10cycloheteroalkyl-(CH2)pheteroaryl-C2-10cycloheteroalkenyl, —(CH2)pheteroaryl-aryl, —(CH2)pheteroaryl-heteroaryl, —C2-6alkenyl-alkyl, —C2-6alkenyl-aryl, —C2-6alkenyl-heteroaryl, —C2-6alkenyl-C3-7cycloalkyl, —C2-6alkenyl-C3-7cycloalkenyl, —C2-6alkenyl-C2-7cycloheteroalkyl, —C2-6alkenyl-C2-7cycloheteroalkenyl, —C2-6alkynyl-(CH2)1-3—O-aryl, —C2-6alkynyl-alkyl, —C2-6alkynyl-aryl, —C2-6alkynyl-heteroaryl, —C2-6alkynyl-C3-7cycloalkyl, —C2-6alkynyl-C3-7cycloalkenyl, —C2-6alkynyl-C2-7cycloheteroalkyl, —C2-6alkynyl-C2-7cycloheteroalkenyl, and —C(O)NH—(CH2)0-3phenyl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: halogen, CF3, —OH, —NH2, —C1-6alkyl, —OC1-6alkyl, —NHC1-6alkyl, and —N(C1-6alkyl)2, and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra.
In another embodiment of the present invention, each R1 is independently selected from: —(CH2)pC3-10cycloalkyl, —(CH2)pC3-7cycloalkyl-aryl, —(CH2)pC3-7cycloalkyl-heteroaryl, —(CH2)pC4-10cycloalkenyl, —(CH2)pC4-7cycloalkenyl-aryl, —(CH2)pC4-7cycloalkenyl-heteroaryl, —(CH2)pC2-10cycloheteroalkyl, —(CH2)pC2-10cycloheteroalkenyl, —(CH2)paryl, —(CH2)paryl-C1-8 alkyl, —(CH2)paryl-C2-8 alkenyl, —(CH2)paryl-C2-8alkynyl-C1-8 alkyl, —(CH2)paryl-C2-8alkynyl-C3-7cycloalkyl, —(CH2)paryl-C2-8alkynyl-C3-7cycloalkenyl, —(CH2)paryl-C2-8alkynyl-C2-10cycloheteroalkyl, —(CH2)paryl-C2-8alkynyl-C2-10cycloheteroalkenyl, —(CH2)paryl-C2-8alkynyl-aryl, —(CH2)paryl-C2-8alkynyl-heteroaryl, —(CH2)paryl-C3-7cycloalkyl, —(CH2)paryl-C2-10cycloheteroalkyl, —(CH2)paryl-C2-10cycloheteroalkenyl, —(CH2)paryl-aryl, —(CH2)paryl-heteroaryl, —(CH2)pheteroaryl, —(CH2)pheteroaryl-C3-7cycloalkyl, —(CH2)pheteroaryl-C2-10cycloheteroalkyl —(CH2)pheteroaryl-C2-10cycloheteroalkenyl, —(CH2)pheteroaryl-aryl, —(CH2)pheteroaryl-heteroaryl, —C2-6alkenyl-alkyl, —C2-6alkenyl-aryl, —C2-6alkenyl-heteroaryl, —C2-6alkenyl-C3-7cycloalkyl, —C2-6alkenyl-C3-7cycloalkenyl, —C2-6alkenyl-C2-7cycloheteroalkyl, —C2-6alkenyl-C2-7cycloheteroalkenyl, —C2-6alkynyl-(CH2)1-3—O-aryl, —C2-6alkynyl-alkyl, —C2-6alkynyl-aryl, —C2-6alkynyl-heteroaryl, —C2-6alkynyl-C3-7cycloalkyl, —C2-6alkynyl-C3-7cycloalkenyl, —C2-6alkynyl-C2-7cycloheteroalkyl, —C2-6alkynyl-C2-7cycloheteroalkenyl, and —C(O)NH—(CH2)0-3phenyl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: halogen, CF3, —OH, —NH2, —C1-6alkyl, —OC1-6alkyl, —NHC1-6alkyl, and —N(C1-6alkyl)2, and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra.
In another embodiment of the present invention, each R1 is independently selected from: —(CH2)paryl-C3-7cycloalkyl, —(CH2)paryl-C2-10cycloheteroalkyl, —(CH2)paryl-C2-10cycloheteroalkenyl, —(CH2)paryl-aryl, —(CH2)paryl-heteroaryl and —(CH2)pheteroaryl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: halogen, CF3, —OH, —NH2, —C1-6alkyl, —OC1-6alkyl, —NHC1-6alkyl, and —N(C1-6alkyl)2, and wherein each cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra.
In another embodiment of the present invention, each R1 is independently selected from: -aryl-C3-7cycloalkyl, -aryl-C2-10cycloheteroalkyl, -aryl-C2-10cycloheteroalkenyl, -aryl-aryl, -aryl-heteroaryl and -heteroaryl, wherein each cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra.
In another embodiment of the present invention, each R1 is independently selected from: phenyl-cyclopropyl, phenyl-cyclobutyl, phenyl-cyclohexyl, phenyl-pyrrolidine, phenyl-piperazine, phenyl-azetidine, phenyl-dihyrothiopyran, phenyl-dihydropyrrolopyrazole, biphenyl, phenyl-naphthalene, phenyl-thiazole, phenyl-pyrazine, phenyl-furan, phenyl-pyrazole, phenyl-pyrimidine, phenyl-imidazole, and benzodioxane, wherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra.
In another embodiment of the present invention, each R1 is independently selected from: phenyl-cyclobutyl, phenyl-cyclohexyl, phenyl-pyrrolidine, phenyl-piperazine, phenyl-azetidine, phenyl-dihyrothiopyran, biphenyl, phenyl-naphthalene, phenyl-thiazole, phenyl-pyrazine, phenyl-furan, phenyl-pyrazole, phenyl-pyrimidine, phenyl-imidazole, and benzodioxane, wherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra.
In another embodiment of the present invention, each R1 is independently selected from: —(CH2)paryl-C2-10cycloheteroalkyl, —(CH2)paryl-aryl, and —(CH2)paryl-heteroaryl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: halogen, CF3, —OH, —NH2, —C1-6alkyl, —OC1-6alkyl, —NHC1-6alkyl, and —N(C1-6alkyl)2, and wherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra.
In another embodiment of the present invention, each R1 is independently selected from: aryl-C2-10cycloheteroalkyl, aryl-aryl, and aryl-heteroaryl, wherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra.
In another embodiment of the present invention, each R1 is independently selected from: phenyl-dihydropyrrolopyrazole, biphenyl, phenyl-naphthalene, phenyl-thiazole, phenyl-pyrazine, phenyl-furan, phenyl-pyrazole, phenyl-pyrimidine, and phenyl-imidazole, wherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra.
In another embodiment of the present invention, each R1 is independently selected from: halogen and aryl-aryl, wherein each aryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra, provided that at least one of and only one of R1 and R2 is selected from halogen. In a class of this embodiment, at least one of and only one of R1 and R2 is selected from: F and Cl. In another subclass of this class, R2 is halogen. In another subclass of this class, R2 is Cl.
In another embodiment of the present invention, each R1 is independently selected from: halogen and biphenyl, wherein each phenyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra, provided that at least one of and only one of R1 and R2 is selected from halogen. In a class of this embodiment, at least one of and only one of R1 and R2 is selected from: F and Cl. In another subclass of this class, R2 is halogen. In another subclass of this class, R2 is Cl.
In another embodiment of the present invention, each each R1 is independently selected from: hydrogen, halogen, —CN, —CF3, —C1-6alkyl, —C2-6alkenyl and —C2-6alkynyl. In another embodiment of the present invention, each each R1 is independently selected from: halogen. In another embodiment of the present invention, each R1 is independently selected from: C1 and F. In a class of this embodiment, R1 is Cl. In another class of this embodiment, R1 is F.
In another embodiment of the present invention, R2 is independently selected from: hydrogen, halogen, CN, CF3, —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, —(CH2)pC3-10cycloalkyl, —(CH2)pC3-7cycloalkyl-aryl, —(CH2)pC3-7cycloalkyl-heteroaryl, —(CH2)pC4-10cycloalkenyl, —(CH2)pC4-7cycloalkenyl-aryl, —(CH2)pC4-7cycloalkenyl-heteroaryl, —(CH2)pC2-10cycloheteroalkyl, —(CH2)pC2-10cycloheteroalkenyl, —(CH2)paryl, —(CH2)paryl-C1-8 alkyl, —(CH2)paryl-C2-8 alkenyl, —(CH2)paryl-C2-8alkynyl-C1-8 alkyl, —(CH2)paryl-C2-8alkynyl-C3-7cycloalkyl, —(CH2)paryl-C2-8alkynyl-C3-7cycloalkenyl, —(CH2)paryl-C2-8alkynyl-C2-10cycloheteroalkyl, —(CH2)paryl-C2-8alkynyl-C2-10cycloheteroalkenyl, —(CH2)paryl-C2-8 alkynyl-aryl, —(CH2)paryl-C2-8alkynyl-heteroaryl, —(CH2)paryl-C3-7cycloalkyl, —(CH2)paryl-C2-10cycloheteroalkyl, —(CH2)paryl-C2-10cycloheteroalkenyl, —(CH2)paryl-aryl, —(CH2)paryl-heteroaryl, —(CH2)pheteroaryl, —(CH2)pheteroaryl-C3-7cycloalkyl, —(CH2)pheteroaryl-C2-10cycloheteroalkyl —(CH2)pheteroaryl-C2-10cycloheteroalkenyl, —(CH2)pheteroaryl-aryl, —(CH2)pheteroaryl-heteroaryl, —C2-6alkenyl-alkyl, —C2-6alkenyl-aryl, —C2-6alkenyl-heteroaryl, —C2-6alkenyl-C3-7cycloalkyl, —C2-6alkenyl-C3-7cycloalkenyl, —C2-6alkenyl-C2-7cycloheteroalkyl, —C2-6alkenyl-C2-7cycloheteroalkenyl, —C2-6alkynyl-(CH2)1-3—O-aryl, —C2-6alkynyl-alkyl, —C2-6alkynyl-aryl, —C2-6alkynyl-heteroaryl, —C2-6alkynyl-C3-7cycloalkyl, —C2-6 alkynyl-C3-7cycloalkenyl, —C2-6alkynyl-C2-7cycloheteroalkyl, —C2-6alkynyl-C2-7cycloheteroalkenyl, and —C(O)NH—(CH2)0-3phenyl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: halogen, CF3, —OH, —NH2, —C1-6alkyl, —OC1-6alkyl, —NHC1-6alkyl, and —N(C1-6alkyl)2, and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra.
In another embodiment of the present invention, R2 is independently selected from: —(CH2)pC3-10cycloalkyl, —(CH2)pC3-7cycloalkyl-aryl, —(CH2)pC3-7cycloalkyl-heteroaryl, —(CH2)pC4-10cycloalkenyl, —(CH2)pC4-7cycloalkenyl-aryl, —(CH2)pC4-7cycloalkenyl-heteroaryl, —(CH2)pC2-10cycloheteroalkyl, —(CH2)pC2-10cycloheteroalkenyl, —(CH2)paryl, —(CH2)paryl-C1-8 alkyl, —(CH2)paryl-C2-8 alkenyl, —(CH2)paryl-C2-8alkynyl-C1-8 alkyl, —(CH2)paryl-C2-8alkynyl-C3-7cycloalkyl, —(CH2)paryl-C2-8alkynyl-C3-7cycloalkenyl, —(CH2)paryl-C2-8alkynyl-C2-10cycloheteroalkyl, —(CH2)paryl-C2-8alkynyl-C2-10cycloheteroalkenyl, —(CH2)paryl-C2-8alkynyl-aryl, —(CH2)paryl-C2-8alkynyl-heteroaryl, —(CH2)paryl-C3-7cycloalkyl, —(CH2)paryl-C2-10cycloheteroalkyl, —(CH2)paryl-C2-10cycloheteroalkenyl, —(CH2)paryl-aryl, —(CH2)paryl-heteroaryl, —(CH2)pheteroaryl, —(CH2)pheteroaryl-C3-7cycloalkyl, —(CH2)pheteroaryl-C2-10cycloheteroalkyl —(CH2)pheteroaryl-C2-10cycloheteroalkenyl, —(CH2)pheteroaryl-aryl, —(CH2)pheteroaryl-heteroaryl, —C2-6alkenyl-alkyl, —C2-6alkenyl-aryl, —C2-6alkenyl-heteroaryl, —C2-6alkenyl-C3-7cycloalkyl, —C2-6alkenyl-C3-7cycloalkenyl, —C2-6alkenyl-C2-7cycloheteroalkyl, —C2-6alkenyl-C2-7cycloheteroalkenyl, —C2-6alkynyl-(CH2)1-3—O-aryl, —C2-6alkynyl-alkyl, —C2-6alkynyl-aryl, —C2-6alkynyl-heteroaryl, —C2-6alkynyl-C3-7cycloalkyl, —C2-6alkynyl-C3-7cycloalkenyl, —C2-6alkynyl-C2-7cycloheteroalkyl, —C2-6alkynyl-C2-7cycloheteroalkenyl, and —C(O)NH—(CH2)0-3phenyl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: halogen, CF3, —OH, —NH2, —C1-6alkyl, —OC1-6alkyl, —NHC1-6alkyl, and —N(C1-6alkyl)2, and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra.
In another embodiment of the present invention, each R2 is independently selected from: —(CH2)paryl-C3-7cycloalkyl, —(CH2)paryl-C2-10cycloheteroalkyl, —(CH2)paryl-C2-10cycloheteroalkenyl, —(CH2)paryl-aryl, —(CH2)paryl-heteroaryl and —(CH2)pheteroaryl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: halogen, CF3, —OH, —NH2, —C1-6alkyl, —OC1-6alkyl, —NHC1-6alkyl, and —N(C1-6alkyl)2, and wherein each cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra.
In another embodiment of the present invention, each R2 is independently selected from: -aryl-C3-7cycloalkyl, -aryl-C2-10cycloheteroalkyl, -aryl-C2-10cycloheteroalkenyl, -aryl-aryl, -aryl-heteroaryl and -heteroaryl, wherein each cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra.
In another embodiment of the present invention, each R2 is independently selected from: phenyl-cyclopropyl, phenyl-cyclobutyl, phenyl-cyclohexyl, phenyl-pyrrolidine, phenyl-piperazine, phenyl-azetidine, phenyl-dihyrothiopyran, phenyl-dihydro-pyrrolopyrazole, biphenyl, phenyl-naphthalene, phenyl-thiazole, phenyl-pyrazine, phenyl-furan, phenyl-pyrazole, phenyl-pyrimidine, phenyl-imidazole, and benzodioxane, wherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra.
In another embodiment of the present invention, each R2 is independently selected from: phenyl-cyclobutyl, phenyl-cyclohexyl, phenyl-pyrrolidine, phenyl-piperazine, phenyl-azetidine, phenyl-dihyrothiopyran, biphenyl, phenyl-naphthalene, phenyl-thiazole, phenyl-pyrazine, phenyl-furan, phenyl-pyrazole, phenyl-pyrimidine, phenyl-imidazole, and benzodioxane, wherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra.
In another embodiment of the present invention, each R2 is independently selected from: —(CH2)paryl-C2-10cycloheteroalkyl, —(CH2)paryl-aryl, and —(CH2)paryl-heteroaryl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: halogen, CF3, —OH, —NH2, —C1-6alkyl, —OC1-6alkyl, —NHC1-6alkyl, and —N(C1-6alkyl)2, and wherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra.
In another embodiment of the present invention, each R2 is independently selected from: aryl-C2-10cycloheteroalkyl, aryl-aryl, and aryl-heteroaryl, wherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra.
In another embodiment of the present invention, each R2 is independently selected from: phenyl-dihydropyrrolopyrazole, biphenyl, phenyl-naphthalene, phenyl-thiazole, phenyl-pyrazine, phenyl-furan, phenyl-pyrazole, phenyl-pyrimidine, and phenyl-imidazole, wherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra.
In another embodiment of the present invention, each R2 is independently selected from: aryl-aryl, wherein each aryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra, provided that at least one of and only one of R1 and R2 is selected from halogen. In a class of this embodiment, at least one of and only one of R1 and R2 is selected from: F and Cl.
In another embodiment of the present invention, each R2 is independently selected from: biphenyl, wherein each phenyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra, provided that at least one of and only one of R1 and R2 is selected from halogen. In a class of this embodiment, at least one of and only one of R1 and R2 is selected from: F and Cl.
In another embodiment of the present invention, each R2 is independently selected from: hydrogen, halogen, —CN, —CF3, —C1-6alkyl, —C2-6alkenyl and —C2-6alkynyl. In another embodiment of the present invention, each R2 is independently selected from: halogen. In another embodiment of the present invention, each R2 is independently selected from: C1 and F. In a class of this embodiment, R2 is Cl. In another class of this embodiment, R2 is F.
In another embodiment of the present invention, R3 and R4 are each independently selected from: hydrogen, halogen, —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, —C3-10cycloalkyl, —C3-10cycloalkenyl, aryl, heteroaryl, —CN, —CF3, —OH, —OC1-6alkyl, —NH2, —NHC1-6alkyl, —N(C1-6alkyl)2, —SC1-6alkyl, —SOC1-6alkyl, —SO2C1-6alkyl, —NHSO2C1-6alkyl, NHC(O)C1-6alkyl, —SO2NHC1-6alkyl, and —C(O)NHC1-6alkyl.
In another embodiment of the present invention, R3 and R4 are each independently selected from: hydrogen and halogen. In a class of this embodiment, R3 and R4 are each independently selected from: hydrogen, Cl and F. In another class of this embodiment, R3 and R4 are each independently selected from: hydrogen and Cl. In another class of this embodiment, R3 and R4 are each independently selected from: hydrogen and F. In another class of this embodiment, R3 and R4 are hydrogen. In another class of this embodiment, R3 and R4 are Cl. In another class of this embodiment, R3 and R4 are F.
In another embodiment of the present invention, each R3 is independently selected from: hydrogen, halogen, —C1-6alkyl, —C2-6 alkenyl, —C2-6alkynyl, —C3-10cycloalkyl, —C3-10cycloalkenyl, aryl, heteroaryl, —CN, —CF3, —OH, —OC1-6alkyl, —NH2, —NHC1-6alkyl, —N(C1-6alkyl)2, —SC1-6alkyl, —SOC1-6alkyl, —SO2C1-6alkyl, —NHSO2C1-6alkyl, —NHC(O)C1-6alkyl, —SO2NHC1-6alkyl, and —C(O)NHC1-6alkyl.
In another embodiment of the present invention, R3 is selected from hydrogen, halogen, and C1-6alkyl. In a class of this embodiment, R3 is hydrogen. In a class of this embodiment, R3 is halogen.
In another embodiment of the present invention, R3 is independently selected from: hydrogen and halogen. In a class of this embodiment, R3 is independently selected from: hydrogen, Cl and F. In another class of this embodiment, R3 is independently selected from: hydrogen and Cl. In another class of this embodiment, R3 is independently selected from: hydrogen and F. In another class of this embodiment, R3 is hydrogen. In another class of this embodiment, R3 is Cl. In another class of this embodiment, R3 is F.
In another embodiment of the present invention, each R4 is independently selected from: hydrogen, halogen, —C1-6alkyl, —C2-6 alkenyl, —C2-6alkynyl, —C3-10cycloalkyl, —C3-10cycloalkenyl, aryl, heteroaryl, —CN, —CF3, —OH, —OC1-6alkyl, —NH2, —NHC1-6alkyl, —N(C1-6alkyl)2, —SC1-6alkyl, —SOC1-6alkyl, —SO2C1-6alkyl, —NHSO2C1-6alkyl, —NHC(O)C1-6alkyl, —SO2NHC1-6alkyl, and —C(O)NHC1-6alkyl.
In another embodiment of the present invention, R4 is selected from hydrogen, halogen, and —C1-6alkyl. In a class of this embodiment, R4 is hydrogen. In another class of this embodiment, R4 is halogen.
In another embodiment of the present invention, R4 is independently selected from: hydrogen and halogen. In a class of this embodiment, R4 is independently selected from: hydrogen, Cl and F. In another class of this embodiment, R4 is independently selected from: hydrogen and Cl. In another class of this embodiment, R4 is independently selected from: hydrogen and F. In another class of this embodiment, R4 is hydrogen. In another class of this embodiment, R4 is Cl. In another class of this embodiment, R4 is F.
In another embodiment of the present invention, R5 is selected from: hydrogen, —C1-6alkyl, —C1-6alkenyl, —(CH2)uOH, —CH2CO2H, and —CH2CO2C1-6alkyl. In a class of this embodiment, R5 is hydrogen.
In another embodiment of the present invention, each Ra is independently selected from the group consisting of: —(CH2)m-halogen, oxo, —(CH2)mOH, —(CH2)mN(Rj)2, —(CH2)mNO2, —(CH2)mCN, —C1-6alkyl, —(CH2)mCF3, —(CH2)mOCF3, —O—(CH2)m—OC1-6alkyl, —(CH2)mN(Rj)C(O)Rf, —(CH2)mN(Rj)CO2Rf, —(CH2)mC(═N—OH)N(Rj)2, —(CH2)mOC1-6alkyl, —(CH2)mO—(CH2)m—C3-7cycloalkyl, —(CH2)mO—(CH2)m—C2-7cycloheteroalkyl, —(CH2)mO—(CH2)m-aryl, —(CH2)mO—(CH2)m-heteroaryl, —(CH2)mSC1-6alkyl, —(CH2)mS(O)C1-6alkyl, —(CH2)mSO2C1-6alkyl, —(CH2)mSO2(CH2)m—C3-7cycloalkyl, —(CH2)mSO2(CH2)m—C2-7cycloheteroalkyl, —(CH2)mSO2(CH2)m-aryl, —(CH2)mSO2(CH2)m-heteroaryl, —(CH2)mSO2NH2, —(CH2)mSO2NHC1-6alkyl, —(CH2)mSO2NHC3-7cycloalkyl, —(CH2)mSO2NHC2-7cycloheteroalkyl, —(CH2)mSO2NH-aryl, —(CH2)mSO2NH-heteroaryl, —(CH2)mNHSO2C1-6alkyl, —(CH2)mNHSO2—C3-7cycloalkyl, —(CH2)mNHSO2—C2-7cycloheteroalkyl, —(CH2)mNHSO2-aryl, —(CH2)mNHSO2NH-heteroaryl, —(CH2)mN(Rj)—C1-6alkyl, —(CH2)mN(Rj)—C3-7cycloalkyl, —(CH2)mN(Rj)—C2-7cycloheteroalkyl, —(CH2)mN(Rj)—C2-7cycloheteroalkenyl, —(CH2)mN(Rj)-aryl, —(CH2)mN(Rj)-heteroaryl, —(CH2)mC(O)Rf, —(CH2)mC(O)N(Rj)2, —(CH2)mN(Rj)C(O)N(Rj)2, —(CH2)mCO2H, —(CH2)mOCOH, —(CH2)mCO2Rf, —(CH2)mOCORf, —(CH2)mC3-7cycloalkyl, —(CH2)mC3-7cycloalkenyl, —(CH2)mC2-6cycloheteroalkyl, —(CH2)mC2-6cycloheteroalkenyl, —(CH2)maryl, and —(CH2)mheteroaryl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —OH, —(CH2)1-3OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CHF, —CHF, —CF3, —CO2H, —CO2C1-6alkyl, —C3-7cycloalkyl, phenyl, CH2phenyl, heteroaryl and CH2heteroaryl, and wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —(CH2)1-5OH, —(CH2)1-5CN, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —(CH2)1-5CF3 optionally substituted with 1, 2 or 3 —OH, —CO2H, —CO2C1-6alkyl, —SO2C1-6alkyl, —C3-7cycloalkyl, phenyl, CH2phenyl, heteroaryl and CH2heteroaryl.
In another embodiment of the present invention, each Ra is independently selected from the group consisting of: —(CH2)m-halogen, oxo, —(CH2)mOH, —(CH2)mN(Rj)2, —(CH2)mCN, —C1-6alkyl, —(CH2)mCF3, —(CH2)mSO2C1-6alkyl, —(CH2)mSO2(CH2)m—C3-7cycloalkyl, —(CH2)mSO2(CH2)m—C2-7cycloheteroalkyl, —(CH2)mC(O)Rf, —(CH2)mC(O)N(Rj)2, —(CH2)mCO2H, —(CH2)mCO2Rf, —(CH2)mC3-7cycloalkyl, —(CH2)mC2-6cycloheteroalkyl, and —(CH2)mheteroaryl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —OH, —(CH2)1-3OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, —CO2C1-6alkyl, —C3-7cycloalkyl, phenyl, CH2phenyl, heteroaryl and CH2heteroaryl, and wherein alkyl, cycloalkyl, cycloheteroalkyl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —(CH2)1-5OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —(CF12)1-5CF3 optionally substituted with 1, 2 or 3 —OH, —CO2H, —CO2C1-6alkyl, —SO2C1-6alkyl, —C3-7cycloalkyl, phenyl, CH2phenyl, heteroaryl and CH2heteroaryl.
In another embodiment of the present invention, each Ra is independently selected from the group consisting of: halogen, oxo, —(CH2)mOH, N(Rj)2, —CN, —C1-6alkyl, CF3, —(CH2)mSO2C1-6alkyl, —SO2—C3-7cycloalkyl, SO2—C2-7cycloheteroalkyl, C(O)Rf, C(O)N(Rj)2, —(CH2)mCO2H, CO2Rf, C3-7cycloalkyl, C2-6cycloheteroalkyl, and heteroaryl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —OH, —(CH2)1-3OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, and —CO2C1-6alkyl, and wherein alkyl, cycloalkyl, cycloheteroalkyl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —(CH2)1-5OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —(CH2)1-5CF3 optionally substituted with 1, 2 or 3 —OH, —CO2H, —CO2C1-6alkyl, and —SO2C1-6alkyl. In a class of this embodiment, each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: —C1-6alkyl, and —CF3, and each alkyl, cycloalkyl, cycloheteroalkyl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —NH2, —C1-6alkyl, —CF3, and —CO2H.
In another embodiment of the present invention, each Ra is independently selected from the group consisting of F, —OH, oxo, —CH2OH, —C(CF3)2OH, —C(CH3)(CH2OH)2, —NH2, —CN, —CH3, —C(CH3)2OH, —CH2C(CH3)2OH, CF3, —CH2SO2CH3, —SO2CH3, —SO2-cyclopropyl, —SO2-piperidine, —C(O)azetidine, —C(O)pyrrolidine, —C(O)NHCH3, —CO2H, —(CH2)3CO2H, —CO2CH3, -cyclopropyl, piperidine, morpholine, pyrrolidine, tetrahydropyran, pyrazole, imidazole, pyrimidine, triazole, thiazole, oxazole, oxadiazole, and pyridazine, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —OH, —(CH2)1-3OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, and —CO2C1-6alkyl, and wherein alkyl, cycloalkyl, cycloheteroalkyl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —(CH2)1-5OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —(CH2)1-5CF3 optionally substituted with 1, 2 or 3 —OH, —CO2H, —CO2C1-6alkyl, and —SO2C1-6alkyl. In a class of this embodiment, each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: —C1-6alkyl, and —CF3, and each alkyl, cycloalkyl, cycloheteroalkyl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —NH2, —C1-6alkyl, —CF3, and —CO2H.
In another embodiment of the present invention, each Ra is independently selected from the group consisting of F, —OH, oxo, —C(CF3)2OH, —C(CH3)(CH2OH)2, —NH2, —CN, —CH3, —C(CH3)2OH, CF3, —CH2SO2CH3, —SO2CH3, —SO2-cyclopropyl, —SO2-piperidine, —C(O)azetidine, —C(O)pyrrolidine, —C(O)NHCH3, —CO2H, —(CH2)3CO2H, —CO2CH3, -cyclopropyl, piperidine, morpholine, pyrrolidine, tetrahydropyran, pyrazole, imidazole, pyrimidine, triazole, thiazole, oxazole, oxadiazole, and pyridazine, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —OH, —(CH2)1-3OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, and —CO2C1-6alkyl, and wherein alkyl, cycloalkyl, cycloheteroalkyl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —(CH2)1-5OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —(CH2)1-5CF3 optionally substituted with 1, 2 or 3 —OH, —CO2H, —CO2C1-6alkyl, and —SO2C1-6alkyl. In a class of this embodiment, each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: —C1-6alkyl, and —CF3, and each alkyl, cycloalkyl, cycloheteroalkyl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —NH2, —C1-6alkyl, —CF3, and —CO2H.
In another embodiment of the present invention, each Ra is independently selected from the group consisting of: —(CH2)m-halogen, —(CH2)mOH, —(CH2)mN(1=d)2, —(CH2)mCN, —C1-6alkyl, —(CH2)mCF3, —(CH2)mSO2C1-6alkyl, —(CH2)mSO2(CH2)m—C2-7cycloheteroalkyl, —(CH2)mC(O)Rf, —(CH2)mC(O)N(Rj)2, —(CH2)mCO2H, —(CH2)mCO2Rf, —(CH2)mC3-7cycloalkyl, —(CH2)mC2-6cycloheteroalkyl, and —(CH2)mheteroaryl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —OH, —(CH2)1-3OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, —CO2C1-6alkyl, —C3-7cycloalkyl, phenyl, CH2phenyl, heteroaryl and CH2heteroaryl, and wherein alkyl, cycloalkyl, cycloheteroalkyl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —(CH2)1-5 OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —(CH2)1-5CF3 optionally substituted with 1, 2 or 3 —OH, —CO2H, —CO2C1-6alkyl, —SO2C1-6alkyl, —C3-7cycloalkyl, phenyl, CH2phenyl, heteroaryl and CH2heteroaryl.
In another embodiment of the present invention, each Ra is independently selected from the group consisting of: halogen, —(CH2)mOH, N(R1)2, —CN, —C1-6alkyl, CF3, —(CH2)mSO2C1-6alkyl, SO2—C2-7cycloheteroalkyl, C(O)Rf, C(O)N(Rj)2, —(CH2)mCO2H, CO2Rf, C3-7cycloalkyl, C2-6cycloheteroalkyl, and heteroaryl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —OH, —(CH2)1-3OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, and —CO2C1-6alkyl, and wherein alkyl, cycloalkyl, cycloheteroalkyl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —(CH2)1-5OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —(CH2)1-5CF3 optionally substituted with 1, 2 or 3 —OH, —CO2H, —CO2C1-6alkyl, and —SO2C1-6alkyl. In a class of this embodiment, each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: —C1-6alkyl, and —CF3, and each alkyl, cycloalkyl, cycloheteroalkyl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —NH2, —C1-6alkyl, —CF3, and —CO2H.
In another embodiment of the present invention, each Ra is independently selected from the group consisting of F, —CH2OH, —C(CF3)2OH, —C(CH3)(CH2OH)2, —NH2, —CN, —CH3, —C(CH3)2OH, —CH2C(CH3)2OH, CF3, —CH2SO2CH3, —SO2CH3, —SO2-piperidine, —C(O)azetidine, —C(O)pyrrolidine, —C(O)NHCH3, —CO2H, —(CH2)3CO2H, —CO2CH3, -cyclopropyl, piperidine, morpholine, pyrrolidine, tetrahydropyran, pyrazole, imidazole, pyrimidine, triazole, thiazole, oxazole, oxadiazole, and pyridazine, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —OH, —(CH2)1-3OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, and —CO2C1-6alkyl, and wherein alkyl, cycloalkyl, cycloheteroalkyl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —(CH2)1-5OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —(CH2)1-5CF3 optionally substituted with 1, 2 or 3 —OH, —CO2H, —CO2C1-6alkyl, and —SO2C1-6alkyl. In a class of this embodiment, each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: —C1-6alkyl, and —CF3, and each alkyl, cycloalkyl, cycloheteroalkyl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —NH2, —C1-6alkyl, —CF3, and —CO2H.
In another embodiment of the present invention, each Ra is independently selected from the group consisting of F, —CH2OH, —C(CF3)2OH, —C(CH3)(CH2OH)2, —NH2, —CN, —CH3, —C(CH3)2OH, —CH2C(CH3)2OH, CF3, —CH2SO2CH3, —SO2CH3, —SO2-piperidine, —C(O)azetidine, —C(O)pyrrolidine, —C(O)NHCH3, —CO2H, —(CH2)3CO2H, —CO2CH3, -cyclopropyl, piperidine, morpholine, pyrrolidine, tetrahydropyran, pyrazole, imidazole, pyrimidine, triazole, thiazole, oxazole, oxadiazole, and pyridazine.
In another embodiment of the present invention, each Ra is independently selected from the group consisting of: —(CH2)mOH, —C1-6alkyl, —(CH2)mSO2C1-6alkyl, —(CH2)mC(O)Rf, —(CH2)mC(O)N(Rj)2, —(CH2)mC2-6cycloheteroalkyl, and —(CH2)mheteroaryl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —OH, —(CH2)1-3OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, —CO2C1-6alkyl, —C3-7cycloalkyl, phenyl, CH2phenyl, heteroaryl and CH2heteroaryl, and wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —(CH2)1-5OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —(CH2)1-5CF3 optionally substituted with 1, 2 or 3 —OH, —CO2H, —CO2C1-6alkyl, —SO2C1-6alkyl, —C3-7cycloalkyl, phenyl, CH2phenyl, heteroaryl and CH2heteroaryl.
In another embodiment of the present invention, each Ra is independently selected from the group consisting of: —(CH2)mOH, —C1-6alkyl, —SO2C1-6alkyl, —C(O)Rf, —C(O)N(Rj)2, —C2-6cycloheteroalkyl, and -heteroaryl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: —OH, —(CH2)1-3OH, and —C1-6alkyl, and wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —(CH2)1-5OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —(CH2)1-5CF3 optionally substituted with 1, 2 or 3 —OH, —CO2H, —CO2C1-6alkyl, —SO2C1-6alkyl.
In another embodiment of the present invention, each Ra is independently selected from the group consisting of: —C(CH3)(CH2OH)2, —C(CH3)2OH, —SO2CH3, —C(O)pyrrolidine, —C(O)NHCH3, morpholine, and pyrazole.
In another embodiment of the present invention, each Rb is independently selected from: hydrogen, —C1-6alkyl, —C1-6alkenyl, —(CH2)nC3-10cycloalkyl, —(CH2)nC3-10cycloalkenyl, —(CH2)nC2-10cycloheteroalkyl, —(CH2)nC2-10cycloheteroalkenyl, —(CH2)naryl, —(CH2)nheteroaryl, oxo, —(CH2)nCF3, —(CH2)nCN, —(CH2)t-halogen, —(CH2)s-OH, —(CH2)nNO2, —(CH2)nNH2, —(CH2)nNH(C1-6alkyl), —(CH2)nN(C1-6alkyl)2, —(CH2)nNHCO2H, —(CH2)nOC1-6alkyl, —(CH2)nOC1-6alkenyl, —(CH2)nCOC1-6alkyl, —(CH2)nCO2H, —(CH2)nOCOH, —(CH2)nCO2Ri, —(CH2)nOC(O)Ri, —(CH2)qC(O)N(Re)2, —(CH2)qCO2N(Re)2, —(CH2)nC(O)(CH2)nN(Rg)2, —(CH2)nOC(O)(CH2)nN(Rg)2, —(CH2)nN(Re)C(O)C1-6alkyl, —(CH2)nN(Re)SO2Ri, —(CH2)nSO2C1-6alkyl, —(CH2)nSO2N(Re)Rg, —(CH2)nSO2N(Re)C(O)Ri, —(CH2)nSO2N(Re)CO2Ri, —(CH2)nSO2N(Re)CON(Rg)2, —(CH2)nC(O)N(Re)SO2Ri, —(CH2)nN(Re)C(O)N(Rg)2, ═N(OH), and ═N(OC1-6alkyl), wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: —C1-6alkyl, —OH, halogen and —NH2 wherein each NH is unsubstituted or substituted with 1 substituent selected from Rc, and wherein each alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rc, or wherein two Rb substituents and the carbon to which they are attached may form a 3 to 6 membered cycloalkyl ring, a 3-6 membered cycloalkenyl ring, a 3-6 membered cycloheteroalkyl ring or a 3-6 membered cycloheteroalkenyl ring, wherein the ring is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rc. In a class of this embodiment, two Rb substituents and the carbon to which they are attached may form a 3-6 membered cycloheteroalkyl ring, wherein the ring is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rc.
In another embodiment of the present invention, each Rb is independently selected from: —(CH2)s-OH, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: —C1-6alkyl, —OH, halogen and —NH2 wherein each NH is unsubstituted or substituted with 1 substituent selected from Rc. In a class of this embodiment of the present invention, each Rb is —OH.
In another embodiment of the present invention, each Rb is —OH.
In another embodiment of the present invention, each Rc is independently selected from: halogen, oxo, —(CH2)rOH, —(CH2)rN(Re)2, —(CH2)rCN, —C1-6alkyl, —CF3, —C1-6alkyl-OH, —OCH2OC1-6alkyl, —(CH2)rOC1-6alkyl, —OCH2aryl, —(CH2)rSC1-6alkyl, —(CH2)rC(O)Rf, —(CH2)rC(O)N(Re)2, —(CH2)rCO2H, —(CH2)rCO2Rf, —(CH2)rC3-7cycloalkyl, —(CH2)rC2-6cycloheteroalkyl, —(CH2)raryl, and —(CH2)rheteroaryl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —OH, —CN, —N(Rh)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, —CO2C1-6alkyl, —C3-7cycloalkyl and heteroaryl, and wherein alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —N(Rh)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, —CO2C1-6alkyl, —C3-7cycloalkyl and heteroaryl. In a class of this embodiment, each Rc is independently selected from: oxo, —(CH2)rOH, —(CH2)rCO2H, and —(CH2)rCO2Rf, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —OH, —CN, —N(Rh)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, —CO2C1-6alkyl, —C3-7cycloalkyl and heteroaryl. In a subclass of this class, each Re is independently selected from: oxo, —OH, —CO2H and —CO2Rf.
In another embodiment of the present invention, each Rc is independently selected from: halogen, oxo, —(CH2)rOH, —(CH2)rN(Re)2, —(CH2)rCN, —C1-6alkyl, —CF3, —C1-6alkyl-OH, —OCH2OC1-6alkyl, —(CH2)rOC1-6alkyl, —OCH2aryl, —(CH2)rSC1-6alkyl, —(CH2)rC(O)Rf, —(CH2)rC(O)N(Re)2, —(CH2)rCO2H, and —(CH2)rCO2Rf, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —OH, —CN, —N(Rh)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, —CO2C1-6alkyl, —C3-7cycloalkyl and heteroaryl, and wherein alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —N(Rh)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, and —CO2C1-6alkyl.
In another embodiment of the present invention, each Rc is independently selected from: halogen, oxo, —(CH2)rOH, —(CH2)rN(Re)2, —(CH2)rCN, —C1-6alkyl, —CF3, and —C1-6alkyl-OH.
In another embodiment of the present invention, each Rc is independently selected from: halogen, oxo, and —C1-6alkyl.
In another embodiment of the present invention, each Re, Rg and Rh is independently selected from: hydrogen, —C1-6alkyl, and —O—C1-6alkyl, wherein alkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: —OH, oxo, halogen, C1-6alkyl, —OC1-6alkyl, —NH2, —NH(C1-6alkyl), and —N(C1-6alkyl)2.
In another embodiment of the present invention, each Re is independently selected from: hydrogen, —C1-6alkyl, and —O—C1-6alkyl, wherein alkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: —OH, oxo, halogen, C1-6alkyl, —OC1-6alkyl, —NH2, —NH(C1-6alkyl), and —N(C1-6alkyl)2.
In another embodiment of the present invention, each Rg is independently selected from: hydrogen, —C1-6alkyl, and —O—C1-6alkyl, wherein alkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: —OH, oxo, halogen, C1-6alkyl, —OC1-6alkyl, —NH2, —NH(C1-6alkyl), and —N(C1-6alkyl)2.
In another embodiment of the present invention, each Rh is independently selected from: hydrogen, —C1-6alkyl, and —O—C1-6alkyl, wherein alkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: —OH, oxo, halogen, C1-6alkyl, —OC1-6alkyl, —NH2, —NH(C1-6alkyl), and —N(C1-6alkyl)2.
In another embodiment of the present invention, each Rj is independently selected from: hydrogen, —C1-6alkyl, —C3-6 cycloalkyl, —C(O)Ri, —CO2Ri, and —SO2Ri, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: —OH, oxo, halogen, C1-6alkyl, —OC1-6alkyl, —NH2, —NH(C1-6alkyl), and —N(C1-6alkyl)2.
In another embodiment of the present invention each Rj is independently selected from: hydrogen and —C1-6alkyl. In a class of this embodiment, each Rj is independently selected from: hydrogen and —CH3.
In another embodiment of the present invention, each Rf and Ri is independently selected from: —C1-6alkyl, —(CH2)rC4-7cycloalkyl, —(CH2)rC4-7cycloalkenyl, —(CH2)rC3-7cycloheteroalkyl, —(CH2)rC3-7cycloheteroalkenyl, —(CH2)raryl, and —(CH2)rheteroaryl, wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, —CO2C1-6alkyl, —C3-7cycloalkyl, and heteroaryl. In a class of this embodiment, alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, and —CO2C1-6alkyl.
In another embodiment of the present invention, each Rf and Ri is independently selected from: C1-6alkyl and C3-7cycloheteroalkyl, wherein alkyl and cycloheteroalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —NH2, NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, and —CO2C1-6alkyl.
In another embodiment of the present invention, each Rf and Ri is independently selected from: CH3, azetidine, and pyrrolidine, wherein alkyl and cycloheteroalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, and —C1-6alkyl.
In another embodiment of the present invention, each Rf is independently selected from: —C1-6alkyl, —(CH2)rC4-7cycloalkyl, —(CH2)rC4-7cycloalkenyl, —(CH2)rC3-7cycloheteroalkyl, —(CH2)rC3-7cycloheteroalkenyl, —(CH2)raryl, and —(CH2)rheteroaryl, wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, —CO2C1-6alkyl, —C3-7cycloalkyl, and heteroaryl. In a class of this embodiment, alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, and —CO2C1-6alkyl. In another embodiment of the present invention, each Rf is independently selected from: C1-6alkyl and C3-7cycloheteroalkyl, wherein alkyl and cycloheteroalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —NH2, NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, and —CO2C1-6alkyl.
In another embodiment of the present invention, each Rf is independently selected from: CH3, azetidine, and pyrrolidine, wherein alkyl and cycloheteroalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, and —C1-6alkyl.
In another embodiment of the present invention, each Ri is independently selected from: —C1-6alkyl, —(CH2)rC4-7cycloalkyl, —(CH2)rC4-7cycloalkenyl, —(CH2)rC3-7cycloheteroalkyl, —(CH2)rC3-7cycloheteroalkenyl, —(CH2)raryl, and —(CH2)rheteroaryl, wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, —CO2C1-6alkyl, —C3-7cycloalkyl, and heteroaryl. In a class of this embodiment, alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, and —CO2C1-6alkyl.
In another embodiment of the present invention, each Ri is independently selected from: C1-6alkyl and C3-7cycloheteroalkyl, wherein alkyl and cycloheteroalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —NH2, NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, and —CO2C1-6alkyl.
In another embodiment of the present invention, each Ri is independently selected from: CH3, azetidine, and pyrrolidine, wherein alkyl and cycloheteroalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, and —C1-6alkyl. In another embodiment of the present invention, a is 1 or 2. In a class of this embodiment, a is 0. In another class of this embodiment, a is 1. In another class of this embodiment, a is 2.
In another embodiment of the present invention, b is 1 or 2. In a class of this embodiment, b is 0. In another class of this embodiment, b is 1. In another class of this embodiment, b is 2.
In another embodiment of the present invention, n is 0, 1, 2, 3 or 4. In a class of this embodiment, n is 1, 2 or 3. In another class of this embodiment, n is 0, 1 or 2. In another class of this embodiment, n is 0. In another class of this embodiment, n is 1. In another class of this embodiment, n is 2.
In another embodiment of the present invention, m is 0, 1, 2, 3, or 4. In a class of this embodiment, m is 0, 1, 2 or 3. In another class of this embodiment, m is 1, 2 or 3. In another class of this embodiment, m is 0, 1 or 2. In another class of this embodiment, m is 0 or 1. In another class of this embodiment, m is 0. In another class of this embodiment, m is 1.
In another embodiment of the present invention, p is 0, 1, 2 or 3. In a class of this embodiment, p is 1, 2 or 3. In another class of this embodiment, p is 0, 1 or 2. In another class of this embodiment, p is 0 or 2. In another class of this embodiment, p is 0. In another class of this embodiment, p is 1. In another class of this embodiment, p is 2.
In another embodiment of the present invention, q is 0, 1, 2, 3 or 4. In a class of this embodiment, q is 1, 2 or 3. In another class of this embodiment, q is 0, 1 or 2. In another class of this embodiment, q is 1 or 2. In another class of this embodiment, q is 0. In another class of this embodiment, q is 1. In another class of this embodiment, q is 2.
In another embodiment of the present invention, r is 0, 1 or 2. In a class of this embodiment, r is 0 or 1. In another class of this embodiment, r is 0. In another class of this embodiment, r is 1. In another class of this embodiment, r is 2.
In another embodiment of the present invention, s is 0, 1, 2, 3 or 4. In a class of this embodiment, s is 0, 1, 2 or 3. In a class of this embodiment, s is 0, 1 or 2. In another class of this embodiment, s is 0 or 1. In another class of this embodiment, s is 1 or 2. In another class of this embodiment, s is 0 or 2. In another class of this embodiment, s is 0. In another class of this embodiment, s is 1. In another class of this embodiment, s is 2. In another class of this embodiment, s is 3.
In another embodiment of the present invention, t is 0, 1, 2, 3 or 4. In a class of this embodiment, t is 0, 1, 2 or 3. In a class of this embodiment, t is 0, 1 or 2. In another class of this embodiment, t is 0 or 1. In another class of this embodiment, t is 1 or 2. In another class of this embodiment, t is 0 or 2. In another class of this embodiment, t is 0. In another class of this embodiment, t is 1. In another class of this embodiment, t is 2. In another class of this embodiment, t is 3.
In another embodiment of the present invention, u is 0, 1, 2, 3 or 4. In a class of this embodiment, u is 0, 1, 2 or 3. In a class of this embodiment, u is 0, 1 or 2. In another class of this embodiment, u is 0 or 1. In another class of this embodiment, u is 1 or 2. In another class of this embodiment, u is 0 or 2. In another class of this embodiment, u is 0. In another class of this embodiment, u is 1. In another class of this embodiment, u is 2. In another class of this embodiment, u is 3. In another class of this embodiment, u is 4.
Another embodiment of the present invention relates to compounds of structural formula I wherein:
Y is selected from:
wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb;
each R1 is independently selected from:
In a class of this embodiment, Y is:
wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb. In another class of this embodiment, Y is:
wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb.
In another class of this embodiment, Y is:
wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb. In another class of this embodiment, Y is:
wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb.
Another embodiment of the present invention relates to compounds of structural formula I wherein:
wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb; Z is NR5;
each R1 is independently selected from: aryl-aryl, wherein each aryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra;
R2 is halogen;
R3 is hydrogen or halogen;
R4 is hydrogen; and
R5 is hydrogen;
or a pharmaceutically acceptable salt thereof.
In a class of this embodiment, Y is:
wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb. In another class of this embodiment, Y is:
wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb.
In another embodiment of the present invention, the invention relates to compounds of structural formula Ia:
wherein Y is selected from:
wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb; or a pharmaceutically acceptable salt thereof.
In another embodiment of the present invention, the invention relates to compounds of structural formula Ib:
wherein Y is:
wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb; or a pharmaceutically acceptable salt thereof.
In another embodiment of the present invention, the invention relates to compounds of structural formula Ic:
wherein Y is:
wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb; or a pharmaceutically acceptable salt thereof.
In another embodiment of the present invention, the invention relates to compounds of structural formula Id:
wherein Y is:
wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb; or a pharmaceutically acceptable salt thereof.
In another embodiment of the present invention, the invention relates to compounds of structural formula Ie:
wherein Y is:
wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb; or a pharmaceutically acceptable salt thereof.
The compound of structural formula I, includes the compounds of structural formulas Ia, Ib, Ic, Id and Ie, and pharmaceutically acceptable salts, hydrates and solvates thereof.
Illustrative, but non-limiting, examples of the compounds of the present invention that are useful as activators of AMP-protein kinase are the following compounds:
and pharmaceutically acceptable salts thereof.
“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxy, alkanoyl, means carbon chains of up to 10 carbons which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.
“Alkenyl” means carbon chains up to 10 carbons which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. In one embodiment of the present invention, alkenyl is vinyl.
“Alkynyl” means carbon chains up to 10 carbons which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. In one embodiment, C2-8alkynyl means a carbon chain with 2 to 8 carbons that contains one carbon-carbon triple bond. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. In one embodiment of the present invention, alkynyl is ethynyl. In another embodiment, alkynyl is propargyl.
“Cycloalkyl” means mono- or bicyclic, spiro or bridged saturated carbocyclic rings, each having from 3 to 14 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and decahydronaphthyl, and the like. In one embodiment of the present invention, cycloalkyl is selected from cyclopentyl and cyclohexyl. In another embodiment of the present invention, cycloalkyl is selected from cyclopropyl, cyclopentyl, and cyclohexyl. In another embodiment of the present invention, cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In another embodiment, C3-7cycloalkyl is cyclopropyl.
“Cycloalkenyl” means nonaromatic, mono- or bicyclic, spiro or bridged carbocyclic rings, each having from 3 to 14 carbon atoms and containing at least one double bond. Examples of cycloalkyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooxtenyl, decahydronaphthyl, bicyclo[2.2.1]hept-5-en-2-yl, and the like.
“Cycloheteroalkyl” means nonaromatic, monocyclic, bicyclic, spiro or bridged saturated carbocyclic rings, each having from 2 to 14 carbon atoms and containing 1, 2, 3, 4 or 5 heteroatoms selected from N, NH, O and S. In one embodiment, C2-10cycloheteroalkyl means non-aromatic, mono- or bicyclic, spiro or bridged saturated carbocyclic rings, having from 2 to 10 carbon atoms and containing, 1, 2, 3, 4 or 5 heteroatoms selected from N, NH, O and S. In another embodiment, C2-6cycloheteroalkyl means non-aromatic, mono- or bicyclic, spiro or bridged saturated carbocyclic rings, having from 2 to 6 carbon atoms and containing, 1, 2, 3, 4 or 5 heteroatoms selected from N, NH, O and S. In another embodiment, C2-7cycloheteroalkyl means non-aromatic, mono- or bicyclic, spiro or bridged saturated carbocyclic rings, having from 2 to 7 carbon atoms and containing, 1, 2, 3, 4 or 5 heteroatoms selected from N, NH, O and S. In another embodiment, C3-7cycloheteroalkyl means non-aromatic, mono- or bicyclic, spiro or bridged saturated carbocyclic rings, having from 3 to 7 carbon atoms and containing, 1, 2, 3, 4 or 5 heteroatoms selected from N, NH, O and S. Examples of cycloheteroalkyl include tetrahydrofuranyl, azetidinyl, perhydroazepinyl, dihydrofuranyl, dioxanyl, oxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, piperidinyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dihydropyranyl, oxathiolanyl, dithiolanyl, 1,3-dithianyl, oxathianyl, thiomorpholinyl, dioxidoisothiazolidinyl, azacycloheptyl, diazobicyclo[3.2.1]-octane, and hexahydroindazolyl. The cycloheteroalkyl ring may be substituted on the ring carbons and/or the ring nitrogens. In one embodiment of the present invention, cycloheteroalkyl is selected from piperidine, pyrrolidine, oxazolidine, 1,3-oxazolidine-2,4-dione, thiazolidine, 1,3-thiazolidine-2,4-dione, imidazolidine, and hydantoin, and the like. In another embodiment of the present invention cycloheteroalkyl is selected from: morpholine, pyrrolidine, piperazine, and piperidine. In another embodiment of the present invention, cycloheteroalkyl is pyrrolidine. In another embodiment, C2-6cycloheteroalkyl is piperidine, morpholine, pyrrolidine, or tetrahydropyran. In another embodiment, C3-7cycloheteroalkyl is azetidine or pyrrolidine. In another embodiment, C3-7cycloheteroalkyl is azetidine, pyrrolidine or piperazine. In another embodiment, C2-7cycloheteroalkyl is piperidine. In another embodiment, C2-10cycloheteroalkyl is dihydropyrrolopyrazole.
In another embodiment, C2-10cycloheteroalkyl is a non-aromatic monocyclic, bicyclic, spiro or bridged carbocyclic ring having from 2 to 10 carbon atoms, and containing 1 or 2 heteroatoms selected from O. In another embodiment of the present invention, cycloheteroalkyl is dianhydro-mannitol. In another embodiment of the present invention, cycloheteroalkyl is 1, 4:3, 6-dianhydro-mannitol. In another embodiment of the present invention, cycloheteroalkyl is 1, 4:3, 6-dianhydro-D-mannitol. In another embodiment of the present invention, cycloheteroalkyl is hexahydrofuro[3,2-b]furan. In a class of this embodiment, cycloheteroalkyl is 2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan.
“Cycloheteroalkenyl” means aromatic monocyclic, bicyclic, spiro or bridged rings each having from 2 to 14 carbon atoms containing at least one double bond and containing 1, 2, 3, 4 or 5 heteroatoms selected from N, NH, O and S. Examples of cycloheteroalkenyl include 1,2,4-oxadiazol-5-one, 1,2,4-thiadiazol-5-one, 1,2,4-triazol-3-one, and 1,2,3,6-tetrahydropyridine, dihydro-1,3,4-oxadiazole, and [1,6]-dihydropyridine and the like. In one embodiment of the present invention, cycloheteroalkenyl is dihydro-1,3,4-oxadiazole. In another embodiment of the present invention, cycloheteroalkenyl is [1,6]-dihydropyridine.
In another embodiment, C2-10cycloheteroalkenyl is a non-aromatic, bicyclic carbocyclic ring having from 2 to 10 carbon atoms, and containing 1, 2 or 3 heteroatoms selected from N, and NH. In a class of this embodiment, cycloheteroalkenyl is dihydropyrrolo[3,4-c]pyrazole. In another class of this embodiment, cycloheteroalkenyl is 4,6-dihydropyrrolo[3,4-c]pyrazole.
In another embodiment, C2-6cycloheteroalkenyl is a non-aromatic, bicyclic carbocyclic ring having from 2 to 6 carbon atoms, and containing 1 or 2 heteroatoms selected from N, and NH. In a class of this embodiment, cycloheteroalkenyl is dihydroimidazole or tetrahydropyrimidine. In another class of this embodiment, cycloheteroalkenyl is 2,5 dihydro-1H-imidazole or 1,4,5,6-tetrahydropyrimidine. In another class of this embodiment, cycloheteroalkenyl is dihydroimidazole. In another class of this embodiment, cycloheteroalkenyl is 2,5 dihydro-1H-imidazole. In another class of this embodiment, cycloheteroalkenyl is tetrahydropyrimidine. In another class of this embodiment, cycloheteroalkenyl is 1,4,5,6-tetrahydropyrimidine. In another class of this embodiment, cycloheteroalkenyl is dihydrothiopyran. In another class of this embodiment, cycloheteroalkenyl is 3,6-dihydrothiopyran.
“Aryl” means a monocyclic, bicyclic or tricyclic ring system containing 5-14 carbon atoms, wherein at least one of the rings is aromatic. Aryl thus includes ring systems in which an aromatic ring is fused to a non-aromatic ring, such as a cycloalkyl or cycloalkenyl ring. Examples of aryl include phenyl, naphthalene, biphenyl, indane and 5,6,7,8-tetrahydronaphthalene, and the like. In one embodiment of the present invention, aryl is phenyl, naphthalene, biphenyl, indane, and 5,6,7,8-tetrahydronaphthalene. In another embodiment of the present invention, aryl is phenyl, naphthalene, indane and 5,6,7,8-tetrahydronaphthalene. In one class of this embodiment, aryl is phenyl or naphthalene. In another class of this embodiment, aryl is phenyl. In another class of this embodiment, aryl is naphthalene.
“Heteroaryl” means a monocyclic, bicyclic or tricyclic ring system containing 5-14 carbon atoms and containing 1, 2, 3, 4 or 5 heteroatoms selected from N, NH, O and S wherein at least one of the heteroatom containing rings is aromatic. Heteroaryl thus includes ring systems in which an aromatic heteroatom containing ring is fused to a non-aromatic ring, such as a cycloalkyl, cycloalkenyl, cycloheteroalkyl or cycloheteroalkenyl ring, and also includes ring systems in which an aryl ring is fused to a non-aromatic heteroatom containing ring, such as acycloheteroalkyl or cycloheteroalkenyl ring. Examples of heteroaryls include: pyrazole, pyridine, pyrazine, pyrimidine, thiazole, thiophene, benzoimidazole, quinoline, isoquinoline, indole, indazole, carbazole, benzotriazole, benzofuran, benzothiazole, benzothiophene, benzoisooxazole, benzodioxane, oxazole, furan, benzoxazole, isoxazole, indoline, isoindoline, tetrazole, imidazole, oxadiazole, thiadiazole, triazole, benzothiazole, benzopyrazole, imidazopyridine, benzodioxole, dihydropyridine, dihydropyrrolopyridine, dihydrobenzooxazine, benzodioxole, benzodioxine, pyrrolopyridine, triazolopyridine, dihydropyridooxazine, dihydropyrrolopyrazole, dihydrobenzoxazine, dihydroindole, dihydroisoindole, dihydrobenzoimidazole, dihydroquinoline, tetrahydroisoquinoline, tetrahydrocyclopentaindole, tetrahydroquinoxaline, and tetrahydropyridine. In one embodiment of the present invention, heteroaryl is selected from: imidazole, pyrazole, pyridine, pyrazine, pyrimidine, thiazole, thiophene, benzoimidazole, quinoline, isoquinoline, indole, indazole, carbazole, benzotriazole, benzofuran, benzothiazole, benzo[b]thiophene, benzo[d]isooxazole, 3,4-dihydro-2H-benzo[1,4]oxazine, benzo[1,3]dioxole, benzo[1,4]dioxine, 1H-pyrrolo[2,3-b]pyridine, 1,6-dihydro-pyridine, [1,2,4]triazolo[4,3-a]pyridine, 3,4 dihydropyrido[3,2-b][1,4]oxazine, 3,4-dihydro-2H-1,4-benzoxazine, 2,3-dihydro-1H-indole, 2,3-dihydro-1H-isoindole, 2,3-dihydrobenzoimidazole, 1,2-dihydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydrocyclopenta[b]indole, 1,2,3,4-tetrahydroquinoxaline, 1,2,3,6-tetrahydropyridine, benzodioxane, and 4,6-dihydropyrrolopyrazole. In another embodiment of the present invention, heteroaryl is tetrazole. In another embodiment, heteroaryl is selected from: pyrazole, pyridine, pyrimidine, isoxazole, imidazole, oxazole, triazole, tetrazole, oxadiazole, thiazole, thiadiazole, and benzoxazole. In another embodiment of this invention, heteroaryl is tetrazole. In another embodiment, heteroaryl is thiazole, pyrazine, furan, pyrazole, pyrimidine, and midazole. In another embodiment, heteroaryl is pyrazole, imidazole, pyrimidine, triazole, thiazole, oxazole, oxadiazole, or pyridazine.
In another embodiment of the present invention, dihydropyrrolopyrazole is 4,6-dihydropyrrolo[3,4-c]pyrazole.
In another embodiment of the present invention, dihydroimidazole is 4,5-dihydro-1H-imidazole.
“Halogen” includes fluorine, chlorine, bromine and iodine. In one embodiment of the present invention, halogen is selected from fluorine, chlorine, and bromine. In another embodiment of the present invention, halogen is selected from fluorine, and chlorine. In another embodiment of the present invention, halogen is fluorine. In another embodiment of the present invention, halogen is chlorine.
When any variable (e.g., R1, Ra, etc.) occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A squiggly line across a bond in a substituent variable represents the point of attachment.
Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a C1-5 alkylcarbonylamino C1-6alkyl substituent is equivalent to:
In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R1, R2, etc., are to be chosen in conformity with well-known principles of chemical structure connectivity and stability.
The term “substituted” shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.
Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of Formula I.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
Tautomers are defined as compounds that undergo rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.
Examples of tautomers include, but are not limited to:
In the compounds of general formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominately found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of structural formula I. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within structural formula I, can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
Compounds of the Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example MeOH or ethyl acetate or a mixture thereof. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active amine as a resolving agent or on a chiral HPLC column.
Alternatively, any enantiomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
It is generally preferable to administer compounds of the present invention as enantiomerically pure formulations. Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.
The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. The term “pharmaceutically acceptable salt” further includes all acceptable salts such as acetate, trifluoroacetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or pro-drug formulations.
It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
Compounds of the present invention are activators of the AMP-activated protein kinase. The methods of treatment of this invention comprise a method of activating AMPK-activated protein kinase and treating AMPK-activated protein kinase mediated diseases by administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of this invention that activate AMPK-activated protein kinase.
AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme composed of a catalytic α subunit and regulatory β and γ subunits. There are two genes encoding isoforms of both the α and β subunits (α1, α2, β1 and (β2) and three genes encoding isoforms of the γ subunit (γ1, γ2 and γ3) leading to 12 possible heterotrimeric combinations. The α2 isoform is predominately found in skeletal and cardiac muscle AMPK; both the α1 and α2 isoforms are found in hepatic AMPK; while in pancreatic islet β-cells the α1 isoform AMPK predominates. In particular, the compounds of structural formula I are activators of at least one heterotrimeric isoform of AMP-activated protein kinase.
An “activator” is a compound that either increases the activity (phosphorylation of downstream substrates) of fully phosphorylated AMPK or that increases the phosphorylation of AMPK.
The compounds of the present invention are efficacious in the treatment and prevention of diseases, disorders and conditions that are responsive to the activation of AMP-activated protein kinase. As AMPK activators, the compounds of the present invention may be useful for the treatment of Type 2 diabetes, insulin resistance, hyperglycemia, obesity, hyperinsulinemia, glucose intolerance, atherosclerosis, Metabolic Syndrome, hypertension, high hepatic glucose output, high blood glucose concentrations, nonalcoholic steatohepatitis, protection against ischemia and reperfusion damage, and lipid disorders, such as dyslipidemia, elevated levels of plasma triglycerides, elevated levels of free fatty acids, elevated levels of cholesterol, high levels of low density lipoprotein (LDL) and low levels of high density lipoprotein (HDL). The compounds of the present invention may also be useful for the treatment of cancer, hypoxia and glucocorticoid-induced apoptosis. The compounds of the present invention may also be useful for the treatment of sarcopenia by treating or preventing the loss of skeletal muscle mass, including but not limited to a loss of skeletal muscle mass due to aging.
One or more of the following diseases may be treated by the administration of a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a patient in need of treatment or prevention of: (1) non-insulin dependent diabetes mellitus (Type 2 diabetes); (2) hyperglycemia; (3) Metabolic Syndrome; (4) obesity; (5) hypercholesterolemia; (6) hypertriglyceridemia (elevated levels of triglyceride-rich-lipoproteins); (7) mixed or diabetic dyslipidemia; (8) low HDL cholesterol; (9) high LDL cholesterol; (10) atherosclerosis; (11) atherosclerosis, (12) hypertension, and (13) sarcopenia.
In one embodiment of the present invention, the compounds of Formula I may be useful for the treatment of one or more of the following diseases by administering a therapeutically effective amount to a patient in need of treatment: (1) Type 2 diabetes; (2) hyperglycemia; (3) Metabolic Syndrome; (4) obesity; (5) hypercholesterolemia; and (6) hypertension.
The compounds of structural Formula I may also be used for manufacturing a medicament for use in the treatment of one or more of the above diseases.
The compounds may also be effective in lowering glucose and lipids in diabetic patients and in non-diabetic patients who have impaired glucose tolerance and/or are in a pre-diabetic condition. The compounds may ameliorate hyperinsulinemia, which often occurs in diabetic or pre-diabetic patients, by modulating the swings in the level of serum glucose that often occurs in these patients. The compounds may also be effective in treating or reducing insulin resistance. The compounds may be effective in treating or preventing gestational diabetes.
The compounds, compositions, methods and medicaments as described herein may also be effective in: a) reducing the risks of adverse sequelae associated with metabolic syndrome, b) reducing the risk of developing atherosclerosis, c) delaying the onset of atherosclerosis, and/or d) reducing the risk of sequelae of atherosclerosis. Sequelae of atherosclerosis include angina, claudication, heart attack, stroke, and others. By keeping hyperglycemia under control, the compounds may also be effective in delaying or preventing vascular restenosis and diabetic retinopathy.
The compounds of this invention may also have utility in improving or restoring β-cell function, and may be useful in treating type 1 diabetes, and in delaying or preventing a patient with Type 2 diabetes from needing insulin therapy.
Other possible outcomes of treatment with the compounds of the present invention may be: 1) a decrease in fatty acid synthesis; 2) an increase in fatty acid oxidation and ketogenesis; 3) a decrease in cholesterol synthesis, lipogenesis, and triglyceride synthesis; 4) a decrease in blood glucose levels and concentration; 5) an improvement in glucose homeostasis; 6) a normalization of glucose metabolism; 7) a decrease in blood pressure; 8) an increase in HDL; 9) a decrease in LDL; 10) a decrease in plasma triglycerides; 11) a decrease in free fatty acids; 12) a decrease in hepatic glucose output; 13) an improvement in insulin action; 14) a decrease in blood pressure; 15) an improvement in insulin sensitivity; 16) a suppression of hepatic glucose output; 17) an inhibition of de novo lipogenesis; 18) stimulation of muscle glucose uptake; 19) modulation of insulin secretion by pancreatic (3 cells; 20) a decrease in body weight; 21) an increase in skeletal muscle mass; and 22) a prevention in the loss of skeletal muscle mass.
The compounds of the present invention may be efficacious in treating one or more of the following diseases: (1) Type 2 diabetes (also known as non-insulin dependent diabetes mellitus, or NIDDM), (2) hyperglycemia, (3) impaired glucose tolerance, (4) insulin resistance, (5) obesity, (6) lipid disorders, (7) dyslipidemia, (8) hyperlipidemia, (9) hypertriglyceridemia, (10) hypercholesterolemia, (11) low HDL levels, (12) high LDL levels, (13) atherosclerosis and its sequelae, (14) vascular restenosis, (15) abdominal obesity, (16) retinopathy, (17) metabolic syndrome, (18) high blood pressure (hypertension), and (19) insulin resistance.
One aspect of the invention provides potential methods for the treatment and control of mixed or diabetic dyslipidemia, hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, and/or hypertriglyceridemia, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I alone or with a cholesterol biosynthesis inhibitor, particularly an HMG-CoA reductase inhibitor such as lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, or ZD-4522. The compound of formula I may also be used advantageously in combination with other lipid lowering drugs such as cholesterol absorption inhibitors (for example stanol esters, sterol glycosides such as tiqueside, and azetidinones such as ezetimibe), ACAT inhibitors (such as avasimibe), CETP inhibitors (for example anacetrapib, torcetrapib, and those described in published applications WO2005/100298, WO2006/014413, and WO2006/014357), niacin and niacin receptor agonists, bile acid sequestrants, microsomal triglyceride transport inhibitors, and bile acid reuptake inhibitors. These combination treatments may be effective for the treatment or control of one or more related conditions selected from the group consisting of hypercholesterolemia, atherosclerosis, hyperlipidemia, hypertriglyceridemia, dyslipidemia, high LDL, and low HDL.
The present invention also provides potential methods and medicaments for the treatment, control, or prevention of Type 2 diabetes by administering the compounds and pharmaceutical compositions of the present invention alone or in combination with a therapeutically effective amount of another agent known to be useful to treat the condition. The present invention also relates to potential methods and medicaments for the treatment, control, or prevention of diabetes related disorders by administering the compounds and pharmaceutical compositions of the present invention alone, or in combination. The present invention also relates to potential methods and medicaments for the treatment and prevention of diabetes in pre-diabetic subject by administering the compounds and pharmaceutical compositions of the present invention alone, or in combination.
The present invention also relates to potential methods and medicaments for the treatment, control, or prevention of obesity by administering the compounds and pharmaceutical compositions of the present invention, alone or in combination with a therapeutically effective amount of another agent known to be useful to treat the condition. The present invention also relates to potential methods and medicaments for the treatment, control, or prevention of obesity related disorders by administering the compounds and pharmaceutical compositions of the present invention alone, or in combination. The present invention also relates to potential methods and medicaments for the treatment and prevention of obesity in overweight subject by administering the compounds and pharmaceutical compositions of the present invention alone, or in combination. The compounds may also be useful for the treatment of obesity related disorders.
The present invention also relates to potential methods and medicaments for the treatment, control, or prevention of hyperglycemia by administering the compounds and pharmaceutical compositions of the present invention, alone or in combination with a therapeutically effective amount of another agent known to be useful to treat the condition.
The present invention also relates to potential methods and medicaments for the treatment, control, or prevention of insulin resistance by administering the compounds and pharmaceutical compositions of the present invention, alone or in combination with a therapeutically effective amount of another agent known to be useful to treat the condition.
The present invention also relates to potential methods and medicaments for the treatment, control, or prevention of lipid disorders by administering the compounds and pharmaceutical compositions of the present invention, alone or in combination with a therapeutically effective amount of another agent known to be useful to treat the condition. The present invention also relates to potential methods and medicaments for the treatment, control, or prevention of dyslipidemia related disorders and lipid disorder-related disorders by administering the compounds and pharmaceutical compositions of the present invention alone, or in combination.
The present invention also relates to potential methods and medicaments for the treatment, control, or prevention of atherosclerosis by administering the compounds and pharmaceutical compositions of the present invention, alone or in combination with a therapeutically effective amount of another agent known to be useful to treat the condition.
The present invention also relates to potential methods and medicaments for the treatment, control, or prevention of hypertension by administering the compounds and pharmaceutical compositions of the present invention, alone or in combination with a therapeutically effective amount of another agent known to be useful to treat the condition. The present invention also relates to potential methods and medicaments for the treatment and prevention of hypertension in pre-hypertensive subject by administering the compounds and pharmaceutical compositions of the present invention alone, or in combination.
The present invention also relates to potential methods and medicaments for the treatment, control, or prevention of Metabolic Syndrome by administering the compounds and pharmaceutical compositions of the present invention, alone or in combination with a therapeutically effective amount of another agent known to be useful to treat the condition.
The compounds of the present invention wherein Y is a hexahydrofuro[3,2-b]furan derivative have the unexpected benefit of reduced inhibition of recombinant CYP2C9 or CYP2C8 isozymes, compared to analogous compounds wherein Y is phenyl. In particular, the compounds of the present invention wherein Y is a hexahydrofuro[3,2-b]furan derivative have the unexpected benefit of reduced inhibition of recombinant CYP2C9 or CYP2C8 isozymes, compared to analogous compounds wherein Y is benzoic acid.
Inhibition of a recombinant CYP isozyme is measured by using a probe substrate, which upon oxidation by human liver microsome, is converted to a metabolite which is monitored by LC-MS/MS. NADPH or NADPH regenerating system are used as electron donors for the microsome catalytic cycle. Control incubations containing no inhibitors performed to evaluate the 100% activities. The activity of the enzyme is evaluated in the presence of various concentrations of test compounds. Standard specific enzyme inhibitors are used as positive controls. Inhibition curves are generated and IC50 values are calculated for tested compounds.
Co-administration of CYP inhibitors with pharmaceutical agents that are metabolized by the enzyme can result in elevated circulating concentrations of the pharmaceutical agents. This can lead to adverse events.
The term “diabetes,” as used herein, includes both insulin-dependent diabetes mellitus (i.e., IDDM, also known as type 1 diabetes) and non-insulin-dependent diabetes mellitus (i.e., NIDDM, also known as Type 2 diabetes). Type 1 diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization. Type 2 diabetes, or insulin-independent diabetes (i.e., non-insulin-dependent diabetes mellitus), often occurs in the face of normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most of the Type 2 diabetics are also obese. The compositions of the present invention may be useful for treating both Type 1 and Type 2 diabetes. The term “diabetes associated with obesity” refers to diabetes caused by obesity or resulting from obesity. The compositions may be especially effective for treating Type 2 diabetes. The compositions of the present invention may also be useful for treating and/or preventing gestational diabetes mellitus.
Diabetes is characterized by a fasting plasma glucose level of greater than or equal to 126 mg/dl. A diabetic subject has a fasting plasma glucose level of greater than or equal to 126 mg/dl. A pre diabetic subject is someone suffering from prediabetes. Prediabetes is characterized by an impaired fasting plasma glucose (FPG) level of greater than or equal to 110 mg/dl and less than 126 mg/dl; or impaired glucose tolerance; or insulin resistance. A prediabetic subject is a subject with impaired fasting glucose (a fasting plasma glucose (FPG) level of greater than or equal to 110 mg/dl and less than 126 mg/dl); or impaired glucose tolerance (a 2 hour plasma glucose level of ≧140 mg/dl and <200 mg/dl); or insulin resistance, resulting in an increased risk of developing diabetes.
Treatment of diabetes mellitus refers to the administration of a compound or combination of the present invention to treat a diabetic subject. One outcome of treatment may be decreasing the glucose level in a subject with elevated glucose levels. Another outcome of treatment may be decreasing insulin levels in a subject with elevated insulin levels. Another outcome of treatment may be decreasing plasma triglycerides in a subject with elevated plasma triglycerides. Another outcome of treatment is decreasing LDL cholesterol in a subject with high LDL cholesterol levels. Another outcome of treatment may be increasing HDL cholesterol in a subject with low HDL cholesterol levels. Another outcome of treatment is increasing insulin sensivity. Another outcome of treatment may be enhancing glucose tolerance in a subject with glucose intolerance. Yet another outcome of treatment may be decreasing insulin resistance in a subject with increased insulin resistance or elevated levels of insulin. Prevention of diabetes mellitus, in particular diabetes associated with obesity, refers to the administration of a compound or combination of the present invention to prevent the onset of diabetes in a subject in need thereof. A subject in need of preventing diabetes is a prediabetic subject that is overweight or obese.
The term “diabetes related disorders” should be understood to mean disorders that are associated with, caused by, or result from diabetes. Examples of diabetes related disorders include retinal damage, kidney disease, and nerve damage.
The term “atherosclerosis” as used herein encompasses vascular diseases and conditions that are recognized and understood by physicians practicing in the relevant fields of medicine. Atherosclerotic cardiovascular disease, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease and peripheral vessel disease are all clinical manifestations of atherosclerosis and are therefore encompassed by the terms “atherosclerosis” and “atherosclerotic disease.” The combination comprised of a therapeutically effective amount of an anti-obesity agent in combination with a therapeutically effective amount of an anti-hypertensive agent may be administered to prevent or reduce the risk of occurrence, or recurrence where the potential exists, of a coronary heart disease event, a cerebrovascular event, or intermittent claudication. Coronary heart disease events are intended to include CHD death, myocardial infarction (i.e., a heart attack), and coronary revascularization procedures. Cerebrovascular events are intended to include ischemic or hemorrhagic stroke (also known as cerebrovascular accidents) and transient ischemic attacks. Intermittent claudication is a clinical manifestation of peripheral vessel disease. The term “atherosclerotic disease event” as used herein is intended to encompass coronary heart disease events, cerebrovascular events, and intermittent claudication. It is intended that persons who have previously experienced one or more non-fatal atherosclerotic disease events are those for whom the potential for recurrence of such an event exists. The term “atherosclerosis related disorders” should be understood to mean disorders associated with, caused by, or resulting from atherosclerosis.
The term “hypertension” as used herein includes essential, or primary, hypertension wherein the cause is not known or where hypertension is due to greater than one cause, such as changes in both the heart and blood vessels; and secondary hypertension wherein the cause is known. Causes of secondary hypertension include, but are not limited to obesity; kidney disease; hormonal disorders; use of certain drugs, such as oral contraceptives, corticosteroids, cyclosporin, and the like. The term “hypertension” encompasses high blood pressure, in which both the systolic and diastolic pressure levels are elevated (≧140 mmHg/≧90 mmHg), and isolated systolic hypertension, in which only the systolic pressure is elevated to greater than or equal to 140 mm Hg, while the diastolic pressure is less than 90 mm Hg. Normal blood pressure may be defined as less than 120 mmHg systolic and less than 80 mmHg diastolic. A hypertensive subject is a subject with hypertension. A pre-hypertensive subject is a subject with a blood pressure that is between 120 mmHg over 80 mmHg and 139 mmHg over 89 mmHg One outcome of treatment is decreasing blood pressure in a subject with high blood pressure. Treatment of hypertension refers to the administration of the compounds and combinations of the present invention to treat hypertension in a hypertensive subject. Treatment of hypertension-related disorder refers to the administration of a compound or combination of the present invention to treat the hypertension-related disorder. Prevention of hypertension, or a hypertension related disorder, refers to the administration of the combinations of the present invention to a pre-hypertensive subject to prevent the onset of hypertension or a hypertension related disorder. The hypertension-related disorders herein are associated with, caused by, or result from hypertension. Examples of hypertension-related disorders include, but are not limited to: heart disease, heart failure, heart attack, kidney failure, and stroke.
Dyslipidemias and lipid disorders are disorders of lipid metabolism including various conditions characterized by abnormal concentrations of one or more lipids (i.e. cholesterol and triglycerides), and/or apolipoproteins (i.e., apolipoproteins A, B, C and E), and/or lipoproteins (i.e., the macromolecular complexes formed by the lipid and the apolipoprotein that allow lipids to circulate in blood, such as LDL, VLDL and IDL). Hyperlipidemia is associated with abnormally high levels of lipids, LDL and VLDL cholesterol, and/or triglycerides. Treatment of dyslipidemia refers to the administration of the combinations of the present invention to a dyslipidemic subject. Prevention of dyslipidemia refers to the administration of the combinations of the present invention to a pre-dyslipidemic subject. A pre-dyslipidemic subject is a subject with higher than normal lipid levels, that is not yet dyslipidemic.
The terms “dyslipidemia related disorders” and “lipid disorder related disorders” should be understood to mean disorders associated with, caused by, or resulting from dyslipidemia or lipid disorders. Examples of dylipidemia related disorder and lipid disorder related disorders include, but are not limited to: hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high density lipoprotein (HDL) levels, high plasma low density lipoprotein (LDL) levels, atherosclerosis and its sequelae, coronary artery or carotid artery disease, heart attack, and stroke.
The term “obesity” as used herein is a condition in which there is an excess of body fat. The operational definition of obesity is based on the Body Mass Index (BMI), which is calculated as body weight per height in meters squared (kg/m2). “Obesity” refers to a condition whereby an otherwise healthy subject has a Body Mass Index (BMI) greater than or equal to 30 kg/m2, or a condition whereby a subject with at least one co-morbidity has a BMI greater than or equal to 27 kg/m2. An “obese subject” is an otherwise healthy subject with a Body Mass Index (BMI) greater than or equal to 30 kg/m2 or a subject with at least one co-morbidity with a BMI greater than or equal to 27 kg/m2. An overweight subject is a subject at risk of obesity. A “subject at risk of obesity” is an otherwise healthy subject with a BMI of 25 kg/m2 to less than 30 kg/m2 or a subject with at least one co-morbidity with a BMI of 25 kg/m2 to less than 27 kg/m2.
The increased risks associated with obesity occur at a lower Body Mass Index (BMI) in Asians. In Asian countries, including Japan, “obesity” refers to a condition whereby a subject with at least one obesity-induced or obesity-related co-morbidity, that requires weight reduction or that would be improved by weight reduction, has a BMI greater than or equal to 25 kg/m2. In Asian countries, including Japan, an “obese subject” refers to a subject with at least one obesity-induced or obesity-related co-morbidity that requires weight reduction or that would be improved by weight reduction, with a BMI greater than or equal to 25 kg/m2. In Asia-Pacific, a “subject at risk of obesity” is a subject with a BMI of greater than 23 kg/m2 to less than 25 kg/m2.
As used herein, the term “obesity” is meant to encompass all of the above definitions of obesity.
Obesity-induced or obesity-related co-morbidities include, but are not limited to, diabetes mellitus, non-insulin dependent diabetes mellitus—type 2, diabetes associated with obesity, impaired glucose tolerance, impaired fasting glucose, insulin resistance syndrome, dyslipidemia, hypertension, hypertension associated with obesity, hyperuricacidemia, gout, coronary artery disease, myocardial infarction, angina pectoris, sleep apnea syndrome, Pickwickian syndrome, fatty liver; cerebral infarction, cerebral thrombosis, transient ischemic attack, orthopedic disorders, arthritis deformans, lumbodynia, emmeniopathy, and infertility. In particular, co-morbidities include: hypertension, hyperlipidemia, dyslipidemia, glucose intolerance, cardiovascular disease, sleep apnea, and other obesity-related conditions.
Treatment of obesity and obesity-related disorders refers to the administration of the compounds of the present invention to reduce or maintain the body weight of an obese subject. One outcome of treatment may be reducing the body weight of an obese subject relative to that subject's body weight immediately before the administration of the compounds of the present invention. Another outcome of treatment may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy. Another outcome of treatment may be decreasing the occurrence of and/or the severity of obesity-related diseases. The treatment may suitably result in a reduction in food or calorie intake by the subject, including a reduction in total food intake, or a reduction of intake of specific components of the diet such as carbohydrates or fats; and/or the inhibition of nutrient absorption; and/or the inhibition of the reduction of metabolic rate; and in weight reduction in patients in need thereof. The treatment may also result in an alteration of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from weight loss.
Prevention of obesity and obesity-related disorders refers to the administration of the compounds of the present invention to reduce or maintain the body weight of a subject at risk of obesity. One outcome of prevention may be reducing the body weight of a subject at risk of obesity relative to that subject's body weight immediately before the administration of the compounds of the present invention. Another outcome of prevention may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy. Another outcome of prevention may be preventing obesity from occurring if the treatment is administered prior to the onset of obesity in a subject at risk of obesity. Another outcome of prevention may be decreasing the occurrence and/or severity of obesity-related disorders if the treatment is administered prior to the onset of obesity in a subject at risk of obesity. Moreover, if treatment is commenced in already obese subjects, such treatment may prevent the occurrence, progression or severity of obesity-related disorders, such as, but not limited to, arteriosclerosis, Type II diabetes, polycystic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
The obesity-related disorders herein are associated with, caused by, or result from obesity. Examples of obesity-related disorders include overeating and bulimia, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH-deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia. Further examples of obesity-related disorders are metabolic syndrome, also known as syndrome X, insulin resistance syndrome, sexual and reproductive dysfunction, such as infertility, hypogonadism in males and hirsutism in females, gastrointestinal motility disorders, such as obesity-related gastro-esophageal reflux, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, and kidney cancer.
The compounds of formula I may also be useful for treating or preventing obesity and obesity-related disorders in cats and dogs. As such, the term “mammal” includes companion animals such as cats and dogs.
The term “metabolic syndrome”, also known as syndrome X, is defined in the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III), National Institutes of Health, 2001, NIH Publication No. 01-3670. E. S. Ford et al., JAMA, vol. 287 (3), Jan. 16, 2002, pp 356-359. Briefly, a person is defined as having metabolic syndrome if the person has three or more of the following disorders: abdominal obesity, hypertriglyceridemia, low HDL cholesterol, high blood pressure, and high fasting plasma glucose. The criteria for these are defined in ATP-III. Treatment of metabolic syndrome refers to the administration of the combinations of the present invention to a subject with metabolic syndrome. Prevention of metabolic syndrome refers to the administration of the combinations of the present invention to a subject with two of the disorders that define metabolic syndrome. A subject with two of the disorders that define metabolic syndrome is a subject that has developed two of the disorders that define metabolic syndrome, but has not yet developed three or more of the disorders that define metabolic syndrome.
The terms “administration of” and or “administering a” compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual or mammal in need of treatment.
The administration of the compound of structural formula I in order to practice the present methods of therapy is carried out by administering an effective amount of the compound of structural formula I to the mammal in need of such treatment or prophylaxis. The need for a prophylactic administration according to the methods of the present invention is determined via the use of well known risk factors. The effective amount of an individual compound is determined, in the final analysis, by the physician or veterinarian in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of administration other drugs and treatments which the patient may concomitantly require, and other factors in the physician's judgment.
The usefulness of the present compounds in these diseases or disorders may be demonstrated in animal disease models that have been reported in the literature.
The magnitude of prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
For use where a composition for intravenous administration is employed, a suitable dosage range is from about 0.001 mg to about 100 mg in one embodiment from about 0.01 mg to about 50 mg, and in another embodiment from 0.1 mg to 10 mg of a compound of Formula I per kg of body weight per day.
In the case where an oral composition is employed, a suitable dosage range is, e.g. from about 0.01 mg to about 1000 mg of a compound of Formula I per day. In one embodiment, the range is from about 0.1 mg to about 10 mg per day. For oral administration, the compositions are preferably provided in the form of tablets containing from 0.01 to 1,000 mg, preferably 0.01, 0.05, 0.1, 0.5, 1, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 12.5, 15, 20, 25, 30, 40, 50, 100, 250, 500, 750 or 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
Another aspect of the present invention provides pharmaceutical compositions which comprises a compound of Formula I and a pharmaceutically acceptable carrier. The term “composition”, as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula I, additional active ingredient(s), and pharmaceutically acceptable excipients.
Any suitable route of administration may be employed for providing a mammal, particularly a human or a companion animal such as a dog or cat, with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, and nasal routes of administration, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (aerosol inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
For administration by inhalation, the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulizers, or as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device. The preferred delivery systems for inhalation are metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of Formula I in suitable propellants, such as fluorocarbons or hydrocarbons and dry powder inhalation (DPI) aerosol, which may be formulated as a dry powder of a compound of Formula I with or without additional excipients.
Suitable topical formulations of a compound of formula I include transdermal devices, aerosols, creams, solutions, ointments, gels, lotions, dusting powders, and the like. The topical pharmaceutical compositions containing the compounds of the present invention ordinarily include about 0.005% to 5% by weight of the active compound in admixture with a pharmaceutically acceptable vehicle. Transdermal skin patches useful for administering the compounds of the present invention include those known to those of ordinary skill in that art.
In practical use, the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
In addition to the common dosage forms set out above, the compounds of Formula I may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.
Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules (including timed release and sustained release formulations), pills, cachets, powders, granules or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion, including elixirs, tinctures, solutions, suspensions, syrups and emulsions. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet cachet or capsule contains from about 0.01 to 1,000 mg, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 25, 30, 40, 50, 75, 100, 125, 150, 175, 180, 200, 225, 250, 500, 750 and 1,000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
Additional suitable means of administration of the compounds of the present invention include injection, intravenous bolus or infusion, intraperitoneal, subcutaneous, intramuscular, intranasal, and topical, with or without occlusion.
Exemplifying the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. Also exemplifying the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. An illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
The dose may be administered in a single daily dose or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, based on the properties of the individual compound selected for administration, the dose may be administered less frequently, e.g., weekly, twice weekly, monthly, etc. The unit dosage will, of course, be correspondingly larger for the less frequent administration.
When administered via intranasal routes, transdermal routes, by rectal or vaginal suppositories, or through a continual intravenous solution, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
The following are examples of representative pharmaceutical dosage forms for the compounds of Formula I:
Compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases, disorders or conditions for which compounds of Formula I may be useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of Formula I is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula I. Examples of other active ingredients that may be combined with a compound of Formula I include, but are not limited to: other anti-diabetic agents, anti-dylipidemic agents, and anti-hypertensive agents, anti-obesity agents, and anorectic agents, which may be administered separately or in the same pharmaceutical compositions.
The present invention also provides a method for the treatment or prevention of an AMPK-activated protein kinase (AMPK) mediated disease, which method comprises administration to a patient in need of such treatment or at risk of developing an AMPK mediated disease of an amount of an AMPK activator and an amount of one or more active ingredients, such that together they give effective relief
In a further aspect of the present invention, there is provided a pharmaceutical composition comprising an AMPK activator and one or more active ingredients, together with at least one pharmaceutically acceptable carrier or excipient.
Thus, according to a further aspect of the present invention there is provided the use of an AMPK activator and one or more active ingredients for the manufacture of a medicament for the treatment or prevention of an AMPK mediated disease. In a further or alternative aspect of the present invention, there is provided a product comprising an AMPK activator and one or more active ingredients as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of an AMPK mediated disease. Such a combined preparation may be, for example, in the form of a twin pack.
It will be appreciated that for the potential treatment or prevention of diabetes, obesity, hypertension, Metabolic Syndrome, dyslipidemia, cancer, atherosclerosis, and related disorders thereof, a compound of the present invention may be used in conjunction with another pharmaceutical agent effective to treat that disorder.
The present invention also provides a potential method for the treatment or prevention of diabetes, obesity, hypertension, Metabolic Syndrome, dyslipidemia, cancer, atherosclerosis, and related disorders thereof, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of another pharmaceutical agent effective to threat that disorder, such that together they give effective relief
The present invention also provides a potential method for the treatment or prevention of diabetes, obesity, hypertension, Metabolic Syndrome, dyslipidemia, cancer, atherosclerosis, and related disorders thereof, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of another pharmaceutical agent useful in treating that particular condition, such that together they give effective relief
Examples of other active ingredients that may be administered separately or in the same pharmaceutical composition in combination with a compound of the formulas described herein include, but are not limited to:
(1) dipeptidyl peptidase-IV (DPP-4) inhibitors (e.g., sitagliptin, alogliptin, linagliptin, vildagliptin, saxagliptin, teneligliptin, omarigliptin);
(2) insulin sensitizers, including (i) PPARγ agonists, such as the glitazones (e.g. pioglitazone, AMG 131, MBX2044, mitoglitazone, lobeglitazone, IDR-105, rosiglitazone, and balaglitazone), and other PPAR ligands, including (1) PPARα/γ dual agonists (e.g., ZYH2, ZYH1, GFT505, chiglitazar, muraglitazar, aleglitazar, sodelglitazar, and naveglitazar); (2) PPARα agonists such as fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate), (3) selective PPARγ modulators (SPPARγM's), (e.g., such as those disclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408, and WO 2004/066963); and (4) PPARγ partial agonists; (ii) biguanides, such as metformin and its pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza™, Fortamet™, and GlucophageXR™; and (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., ISIS-113715 and TTP814);
(3) insulin or insulin analogs (e.g., insulin detemir, insulin glulisine, insulin degludec, insulin glargine, insulin lispro, SBS1000 and oral and inhalable formulations of insulin and insulin analogs);
(4) leptin and leptin derivatives and agonists;
(5) amylin and amylin analogs (e.g., pramlintide);
(6) sulfonylurea and non-sulfonylurea insulin secretagogues (e.g., tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, meglitinides, nateglinide and repaglinide);
(7) α-glucosidase inhibitors (e.g., acarbose, voglibose and miglitol);
(8) glucagon receptor antagonists (e.g., NOXG15, LY2409021);
(9) incretin mimetics, such as GLP-1, GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists (e.g., dulaglutide, semaglutide, albiglutide, exenatide, liraglutide, lixisenatide, taspoglutide, GSK2374697, ADX72231, RG7685, NN9924, ZYOG1, CJC-1131, and BIM-51077, including intranasal, transdermal, and once-weekly formulations thereof), and oxyntomodulin and oxyntomodulin analogs and derivatives;
(10) LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (e.g., simvastatin, lovastatin, pravastatin, crivastatin, fluvastatin, atorvastatin, pitavastatin and rosuvastatin), (ii) bile acid sequestering agents (e.g., colestilan, colestimide, colesevalam hydrochloride, colestipol, cholestyramine, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) inhibitors of cholesterol absorption, (e.g., ezetimibe), and (iv) acyl CoA:cholesterol acyltransferase inhibitors, (e.g., avasimibe);
(11) HDL-raising drugs, (e.g., niacin and nicotinic acid receptor agonists, and extended-release versions thereof; MK-524A, which is a combination of niacin extended-release and the DP-1 antagonist MK-524);
(12) antiobesity compounds;
(13) agents intended for use in inflammatory conditions, such as aspirin, non-steroidal anti-inflammatory drugs or NSAIDs, glucocorticoids, and selective cyclooxygenase-2 or COX-2 inhibitors;
(14) antihypertensive agents, such as ACE inhibitors (e.g., lisinopril, enalapril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (e.g., losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (e.g., aliskiren), beta blockers, and calcium channel blockers;
(15) glucokinase activators (GKAs) (e.g., AZD6370);
(16) inhibitors of 11β-hydroxysteroid dehydrogenase type 1, (e.g., such as those disclosed in U.S. Pat. No. 6,730,690, and LY-2523199);
(17) CETP inhibitors (e.g., anacetrapib, evacetrapib and torcetrapib);
(18) inhibitors of fructose 1,6-bisphosphatase, (e.g., such as those disclosed in U.S. Pat. Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and 6,489,476);
(19) inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2);
(20) AMP-activated Protein Kinase (AMPK) activators, such as MB 1055, ETC 1002;
(21) other agonists of the G-protein-coupled receptors: (i) GPR-109, (ii) GPR-119 (e.g., MBX2982, APD597, GSK1292263, HM47000, and PSN821), and (iii) GPR-40 (e.g., TAK875, MR 1704, TUG 469, TUG499, ASP 4178);
(22) SSTR3 antagonists (e.g., such as those disclosed in WO 2009/001836);
(23) neuromedin U receptor agonists (e.g., such as those disclosed in WO 2009/042053, including, but not limited to, neuromedin S (NMS));
(24) SCD inhibitors;
(25) GPR-105 antagonists (e.g., such as those disclosed in WO 2009/000087);
(26) SGLT inhibitors (e.g., ASP1941, SGLT-3, empagliflozin, dapagliflozin, canagliflozin, BI-10773, PF-04971729, remogloflozin, TS-071, tofogliflozin, ipragliflozin, and LX-4211);
(27) inhibitors of acyl coenzyme A:diacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGAT-2);
(28) inhibitors of fatty acid synthase;
(29) inhibitors of acyl coenzyme A:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2);
(30) agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR);
(31) ileal bile acid transporter inhibitors;
(32) PACAP, PACAP mimetics, and PACAP receptor 3 agonists;
(33) PPAR agonists;
(34) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;
(35) IL-1b antibodies, (e.g., XOMA052 and canakinumab);
(36) bromocriptine mesylate and rapid-release formulations thereof;
(37) GPR 120 agonists (such as KDT501.
Other suitable pharmaceutical agents of use in combination with a compound of the present invention, include, but are not limited to:
(b) anti-dyslipidemic agents such as (1) bile acid sequestrants such as, cholestyramine, colesevelem, colestipol, dialkylaminoalkyl derivatives of a cross-linked dextran; Colestid®; LoCholest®; and Questran®, and the like; (2) HMG-CoA reductase inhibitors such as atorvastatin, itavastatin, pitavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, simvastatin, rosuvastatin (ZD-4522), and other statins, particularly simvastatin; (3) HMG-CoA synthase inhibitors; (4) cholesterol absorption inhibitors such as FMVP4 (Forbes Medi-Tech), KT6-971 (Kotobuki Pharmaceutical), FM-VA12 (Forbes Medi-Tech), FM-VP-24 (Forbes Medi-Tech), stanol esters, beta-sitosterol, sterol glycosides such as tiqueside; and azetidinones such as ezetimibe, and those disclosed in WO 04/005247 and the like; (5) acyl coenzyme A-cholesterol acyl transferase (ACAT) inhibitors such as avasimibe, eflucimibe, pactimibe (KY505), SMP 797 (Sumitomo), SM32504 (Sumitomo), and those disclosed in WO 03/091216, and the like; (6) CETP inhibitors such as anacetrapib, JTT 705 (Japan Tobacco), torcetrapib, CP 532,632, BAY63-2149 (Bayer), SC 591, SC 795, and the like; (7) squalene synthetase inhibitors; (8) anti-oxidants such as probucol, and the like; (9) PPARα agonists such as beclofibrate, bezafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, gemcabene, and gemfibrozil, GW 7647, BM 170744 (Kowa), LY518674 (Lilly), GW590735 (GlaxoSmithkline), KRP-101 (Kyorin), DRF10945 (Dr. Reddy), NS-220/R1593 (Nippon Shinyaku/Roche, ST1929 (Sigma Tau) MC3001/MC3004 (MaxoCore Pharmaceuticals, gemcabene calcium, other fibric acid derivatives, such as Atromid®, Lopid® and Tricor®, and those disclosed in U.S. Pat. No. 6,548,538, and the like; (10) FXR receptor modulators such as GW 4064 (GlaxoSmithkline), SR 103912, QRX401, LN-6691 (Lion Bioscience), and those disclosed in WO 02/064125, WO 04/045511, and the like; (11) LXR receptor modulators such as GW 3965 (GlaxoSmithkline), T9013137, and XTCO179628 (X-Ceptor Therapeutics/Sanyo), and those disclosed in WO 03/031408, WO 03/063796, WO 04/072041, and the like; (12) lipoprotein synthesis inhibitors such as niacin; (13) renin angiotensin system inhibitors; (14) PPAR δ partial agonists, such as those disclosed in WO 03/024395; (15) bile acid reabsorption inhibitors, such as BARI 1453, SC4-35, PHA384640, S8921, AZD7706, and the like; and bile acid sequesterants such as colesevelam (WELCHOL/CHOLESTAGEL), colestipol, cholestyramine, and dialkylaminoalkyl derivatives of a cross-linked dextran, (16) PPARδ agonists such as GW 501516 (Ligand, GSK), GW 590735, GW-0742 (GlaxoSmithkline), T659 (Amgen/Tularik), LY934 (Lilly), NNC610050 (Novo Nordisk) and those disclosed in WO97/28149, WO 01/79197, WO 02/14291, WO 02/46154, WO 02/46176, WO 02/076957, WO 03/016291, WO 03/033493, WO 03/035603, WO 03/072100, WO 03/097607, WO 04/005253, WO 04/007439, and JP10237049, and the like; (17) triglyceride synthesis inhibitors; (18) microsomal triglyceride transport (MTTP) inhibitors, such as implitapide, LAB687, JTT130 (Japan Tobacco), CP346086, and those disclosed in WO 03/072532, and the like; (19) transcription modulators; (20) squalene epoxidase inhibitors; (21) low density lipoprotein (LDL) receptor inducers; (22) platelet aggregation inhibitors; (23) 5-LO or FLAP inhibitors; and (24) niacin receptor agonists including HM74A receptor agonists; (25) PPAR modulators such as those disclosed in WO 01/25181, WO 01/79150, WO 02/79162, WO 02/081428, WO 03/016265, WO 03/033453; (26) niacin-bound chromium, as disclosed in WO 03/039535; (27) substituted acid derivatives disclosed in WO 03/040114; (28) infused HDL such as LUV/ETC-588 (Pfizer), APO-A1 Milano/ETC216 (Pfizer), ETC-642 (Pfizer), ISIS301012, D4F (Bruin Pharma), synthetic trimeric ApoA1, Bioral Apo A1 targeted to foam cells, and the like; (29) IBAT inhibitors such as BARI143/HMR145A/HMR1453 (Sanofi-Aventis, PHA384640E (Pfizer), 58921 (Shionogi) AZD7806 (AstrZeneca), AK105 (Asah Kasei), and the like; (30) Lp-PLA2 inhibitors such as SB480848 (GlaxoSmithkline), 659032 (GlaxoSmithkline), 677116 (GlaxoSmithkline), and the like; (31) other agents which affect lipic composition including ETC1001/ESP31015 (Pfizer), ESP-55016 (Pfizer), AGI1067 (AtheroGenics), AC3056 (Amylin), AZD4619 (AstrZeneca); and
(c) anti-hypertensive agents such as (1) diuretics, such as thiazides, including chlorthalidone, chlorthiazide, dichlorophenamide, hydroflumethiazide, indapamide, and hydrochlorothiazide; loop diuretics, such as bumetanide, ethacrynic acid, furosemide, and torsemide; potassium sparing agents, such as amiloride, and triamterene; and aldosterone antagonists, such as spironolactone, epirenone, and the like; (2) beta-adrenergic blockers such as acebutolol, atenolol, betaxolol, bevantolol, bisoprolol, bopindolol, carteolol, carvedilol, celiprolol, esmolol, indenolol, metaprolol, nadolol, nebivolol, penbutolol, pindolol, propanolol, sotalol, tertatolol, tilisolol, and timolol, and the like; (3) calcium channel blockers such as amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, bepridil, cinaldipine, clevidipine, diltiazem, efonidipine, felodipine, gallopamil, isradipine, lacidipine, lemildipine, lercanidipine, nicardipine, nifedipine, nilvadipine, nimodepine, nisoldipine, nitrendipine, manidipine, pranidipine, and verapamil, and the like; (4) angiotensin converting enzyme (ACE) inhibitors such as benazepril; captopril; cilazapril; delapril; enalapril; fosinopril; imidapril; losinopril; moexipril; quinapril; quinaprilat; ramipril; perindopril; perindropril; quanipril; spirapril; tenocapril; trandolapril, and zofenopril, and the like; (5) neutral endopeptidase inhibitors such as omapatrilat, cadoxatril and ecadotril, fosidotril, sampatrilat, AVE7688, ER4030, and the like; (6) endothelin antagonists such as tezosentan, A308165, and YM62899, and the like; (7) vasodilators such as hydralazine, clonidine, minoxidil, and nicotinyl alcohol, nicotinic acid or salt thereof, and the like; (8) angiotensin II receptor antagonists such as candesartan, eprosartan, irbesartan, losartan, pratosartan, tasosartan, telmisartan, valsartan, and EXP-3137, FI6828K, and RNH6270, and the like; (9) α/β adrenergic blockers as nipradilol, arotinolol and amosulalol, and the like; (10) alpha 1 blockers, such as terazosin, urapidil, prazosin, bunazosin, trimazosin, doxazosin, naftopidil, indoramin, WHIP 164, and XEN010, and the like; (11) alpha 2 agonists such as lofexidine, tiamenidine, moxonidine, rilmenidine and guanobenz, and the like; (12) aldosterone inhibitors, and the like; (13) angiopoietin-2-binding agents such as those disclosed in WO 03/030833; and
(d) anti-obesity agents, such as (1) 5HT (serotonin) transporter inhibitors, such as paroxetine, fluoxetine, fenfluramine, fluvoxamine, sertraline, and imipramine, and those disclosed in WO 03/00663, as well as serotonin/noradrenaline re uptake inhibitors such as sibutramine (MERIDIA/REDUCTIL) and dopamine uptake inhibitor/Norepenephrine uptake inhibitors such as radafaxine hydrochloride, 353162 (GlaxoSmithkline), and the like; (2) NE (norepinephrine) transporter inhibitors, such as GW 320659, despiramine, talsupram, and nomifensine; (3) CB1 (cannabinoid-1 receptor) antagonist/inverse agonists, such as taranabant, rimonabant (ACCOMPLIA Sanofi Synthelabo), SR-147778 (Sanofi Synthelabo), AVE1625 (Sanofi-Aventis), BAY 65-2520 (Bayer), SLV 319 (Solvay), SLV326 (Solvay), CP945598 (Pfizer), E-6776 (Esteve), 01691 (Organix), ORG14481 (Organon), VER24343 (Vernalis), NESS0327 (Univ of Sassari/Univ of Cagliari), and those disclosed in U.S. Pat. Nos. 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736, 5,532,237, 5,624,941, 6,028,084, and 6,509367; and WO 96/33159, WO97/29079, WO98/31227, WO 98/33765, WO98/37061, WO98/41519, WO98/43635, WO98/43636, WO99/02499, WO00/10967, WO00/10968, WO 01/09120, WO 01/58869, WO 01/64632, WO 01/64633, WO 01/64634, WO 01/70700, WO 01/96330, WO 02/076949, WO 03/006007, WO 03/007887, WO 03/020217, WO 03/026647, WO 03/026648, WO 03/027069, WO 03/027076, WO 03/027114, WO 03/037332, WO 03/040107, WO 04/096763, WO 04/111039, WO 04/111033, WO 04/111034, WO 04/111038, WO 04/013120, WO 05/000301, WO 05/016286, WO 05/066126 and EP-658546 and the like; (4) ghrelin agonists/antagonists, such as BVT81-97 (BioVitrum), RC1291 (Rejuvenon), SRD-04677 (Sumitomo), unacylated ghrelin (TheraTechnologies), and those disclosed in WO 01/87335, WO 02/08250, WO 05/012331, and the like; (5) H3 (histamine H3) antagonist/inverse agonists, such as thioperamide, 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate), clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), and A331440, and those disclosed in WO 02/15905; and O-[3-(1H-imidazol-4-yl)propanol]carbamates (Kiec-Kononowicz, K. et al., Pharmazie, 55:349-55 (2000)), piperidine-containing histamine H3-receptor antagonists (Lazewska, D. et al., Pharmazie, 56:927-32 (2001), benzophenone derivatives and related compounds (Sasse, A. et al., Arch. Pharm. (Weinheim) 334:45-52 (2001)), substituted N-phenylcarbamates (Reidemeister, S. et al., Pharmazie, 55:83-6 (2000)), and proxifan derivatives (Sasse, A. et al., J. Med. Chem. 43:3335-43 (2000)) and histamine H3 receptor modulators such as those disclosed in WO 03/024928 and WO 03/024929; (6) melanin-concentrating hormone 1 receptor (MCH1R) antagonists, such as T-226296 (Takeda), T71 (Takeda/Amgen), AMGN-608450, AMGN-503796 (Amgen), 856464 (GlaxoSmithkline), A224940 (Abbott), A798 (Abbott), ATC0175/AR224349 (Arena Pharmaceuticals), GW803430 (GlaxoSmithkine), NBI-1A (Neurocrine Biosciences), NGX-1 (Neurogen), SNP-7941 (Synaptic), SNAP9847 (Synaptic), T-226293 (Schering Plough), TPI-1361-17 (Saitama Medical School/University of California Irvine), and those disclosed WO 01/21169, WO 01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO 02/076929, WO 02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO 02/094799, WO 03/004027, WO 03/13574, WO 03/15769, WO 03/028641, WO 03/035624, WO 03/033476, WO 03/033480, WO 04/004611, WO 04/004726, WO 04/011438, WO 04/028459, WO 04/034702, WO 04/039764, WO 04/052848, WO 04/087680; and Japanese Patent Application Nos. JP 13226269, JP 1437059, JP2004315511, and the like; (7) MCH2R (melanin concentrating hormone 2R) agonist/antagonists; (8) NPY1 (neuropeptide Y Y1) antagonists, such as BMS205749, BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, and GI-264879A; and those disclosed in U.S. Pat. No. 6,001,836; and WO 96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; (9) NPY5 (neuropeptide Y Y5) antagonists, such as 152,804, S2367 (Shionogi), E-6999 (Esteve), GW-569180A, GW-594884A (GlaxoSmithkline), GW-587081X, GW-548118X; FR 235,208; FR226928, FR 240662, FR252384; 1229U91, GI-264879A, CGP71683A, C-75 (Fasgen) LY-377897, LY366377, PD-160170, SR-120562A, SR-120819A,S2367 (Shionogi), JCF-104, and H409/22; and those compounds disclosed in U.S. Pat. Nos. 6,140,354, 6,191,160, 6,258,837, 6,313,298, 6,326,375, 6,329,395, 6,335,345, 6,337,332, 6,329,395, and 6,340,683; and EP-01010691, EP-01044970, and FR252384; and PCT Publication Nos. WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/27063, WO 00/107409, WO 00/185714, WO 00/185730, WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376, WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/20488, WO 02/22592, WO 02/48152, WO 02/49648, WO 02/051806, WO 02/094789, WO 03/009845, WO 03/014083, WO 03/022849, WO 03/028726, WO 05/014592, WO 05/01493; and Norman et al., J. Med. Chem. 43:4288-4312 (2000); (10) leptin, such as recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen); (11) leptin derivatives, such as those disclosed in U.S. Pat. Nos. 5,552,524; 5,552,523; 5,552,522; 5,521,283; and WO 96/23513; WO 96/23514; WO 96/23515; WO 96/23516; WO 96/23517; WO 96/23518; WO 96/23519; and WO 96/23520; (12) opioid antagonists, such as nalmefene (Revex®), 3-methoxynaltrexone, naloxone, and naltrexone; and those disclosed in WO 00/21509; (13) orexin antagonists, such as SB-334867-A (GlaxoSmithkline); and those disclosed in WO 01/96302, 01/68609, 02/44172, 02/51232, 02/51838, 02/089800, 02/090355, 03/023561, 03/032991, 03/037847, 04/004733, 04/026866, 04/041791, 04/085403, and the like; (14) BRS3 (bombesin receptor subtype 3) agonists; (15) CCK-A (cholecystokinin-A) agonists, such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623, PD170292, PD 149164, SR146131, SR125180, butabindide, and those disclosed in U.S. Pat. No. 5,739,106; (16) CNTF (ciliary neurotrophic factors), such as GI-181771 (Glaxo-SmithKline); SR146131 (Sanofi Synthelabo); butabindide; and PD170,292, PD 149164 (Pfizer); (17) CNTF derivatives, such as axokine (Regeneron); and those disclosed in WO 94/09134, WO 98/22128, and WO 99/43813; (18) GHS (growth hormone secretagogue receptor) agonists, such as NN703, hexarelin, MK-0677, SM-130686, CP-424,391, L-692,429 and L-163,255, and those disclosed in U.S. Pat. No. 6,358,951, U.S. Patent Application Nos. 2002/049196 and 2002/022637; and WO 01/56592, and WO 02/32888; (19) 5HT2c (serotonin receptor 2c) agonists, such as APD3546/AR10A (Arena Pharmaceuticals), ATH88651 (Athersys), ATH88740 (Athersys), BVT933 (Biovitrum/GSK), DPCA37215 (BMS), IK264; LY448100 (Lilly), PNU 22394; WAY 470 (Wyeth), WAY629 (Wyeth), WAY161503 (Biovitrum), R-1065, VR1065 (Vernalis/Roche) YM 348; and those disclosed in U.S. Pat. No. 3,914,250; and PCT Publications 01/66548, 02/36596, 02/48124, 02/10169, 02/44152; 02/51844, 02/40456, 02/40457, 03/057698, 05/000849, and the like; (20) Mc3r (melanocortin 3 receptor) agonists; (21) Mc4r (melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron), CHIR915 (Chiron); ME-10142 (Melacure), ME-10145 (Melacure), HS-131 (Melacure), NBI72432 (Neurocrine Biosciences), NNC 70-619 (Novo Nordisk), TTP2435 (Transtech) and those disclosed in PCT Publications WO 99/64002, 00/74679, 01/991752, 01/0125192, 01/52880, 01/74844, 01/70708, 01/70337, 01/91752, 01/010842, 02/059095, 02/059107, 02/059108, 02/059117, 02/062766, 02/069095, 02/12166, 02/11715, 02/12178, 02/15909, 02/38544, 02/068387, 02/068388, 02/067869, 02/081430, 03/06604, 03/007949, 03/009847, 03/009850, 03/013509, 03/031410, 03/094918, 04/028453, 04/048345, 04/050610, 04/075823, 04/083208, 04/089951, 05/000339, and EP 1460069, and US 2005049269, and JP2005042839, and the like; (22) monoamine reuptake inhibitors, such as sibutratmine (Meridia®/Reductil®) and salts thereof, and those compounds disclosed in U.S. Pat. Nos. 4,746,680, 4,806,570, and 5,436,272, and U.S. Patent Publication No. 2002/0006964, and WO 01/27068, and WO 01/62341; (23) serotonin reuptake inhibitors, such as dexfenfluramine, fluoxetine, and those in U.S. Pat. No. 6,365,633, and WO 01/27060, and WO 01/162341; (24) GLP-1 (glucagon-like peptide 1) agonists; (25) Topiramate (Topimax®); (26) phytopharm compound 57 (CP 644,673); (27) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (28) P3 (beta adrenergic receptor 3) agonists, such as rafebergron/AD9677/TAK677 (Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, GRC1087 (Glenmark Pharmaceuticals) GW 427353 (solabegron hydrochloride), Trecadrine, Zeneca D7114, N-5984 (Nisshin Kyorin), LY-377604 (Lilly), KT07924 (Kissei), SR 59119A, and those disclosed in U.S. Pat. No. 5,705,515, U.S. Pat. No. 5,451,677; and WO94/18161, WO95/29159, WO97/46556, WO98/04526 WO98/32753, WO 01/74782, WO 02/32897, WO 03/014113, WO 03/016276, WO 03/016307, WO 03/024948, WO 03/024953, WO 03/037881, WO 04/108674, and the like; (29) DGAT1 (diacylglycerol acyltransferase 1) inhibitors; (30) DGAT2 (diacylglycerol acyltransferase 2)inhibitors; (31) FAS (fatty acid synthase) inhibitors, such as Cerulenin and C75; (32) PDE (phosphodiesterase) inhibitors, such as theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram, and cilomilast, as well as those described in WO 03/037432, WO 03/037899; (33) thyroid hormone 13 agonists, such as KB-2611 (KaroBioBMS), and those disclosed in WO 02/15845; and Japanese Patent Application No. JP 2000256190; (34) UCP-1 (uncoupling protein 1), 2, or 3 activators, such as phytanic acid, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoic acid (TTNPB), and retinoic acid; and those disclosed in WO 99/00123; (35) acyl-estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001); (36) glucocorticoid receptor antagonists, such as CP472555 (Pfizer), KB 3305, and those disclosed in WO 04/000869, WO 04/075864, and the like; (37) 11β HSD-1 (11-beta hydroxy steroid dehydrogenase type 1) inhibitors, such as BVT 3498 (AMG 331), BVT 2733, 3-(1-adamantyl)-4-ethyl-5-(ethylthio)-4H-1,2,4-triazole, 3-(1-adamantyl)-5-(3,4,5-trimethoxyphenyl)-4-methyl-4H-1,2,4-triazole, 3-adamantanyl-4,5,6,7,8,9,10,11,12,3a-decahydro-1,2,4-triazolo[4,3-a][11]annulene, and those compounds disclosed in WO 01/90091, 01/90090, 01/90092, 02/072084, 04/011410, 04/033427, 04/041264, 04/027047, 04/056744, 04/065351, 04/089415, 04/037251, and the like; (38) SCD-1 (stearoyl-CoA desaturase-1) inhibitors; (39) dipeptidyl peptidase IV (DPP-4) inhibitors, such as isoleucine thiazolidide, valine pyrrolidide, sitagliptin (Januvia), saxagliptin, alogliptin, NVP-DPP728, LAF237 (vildagliptin), P93/01, TSL 225, TMC-2A/2B/2C, FE 999011, P9310/K364, VIP 0177, SDZ 274-444, GSK 823093, E 3024, SYR 322, TSO21, SSR 162369, GRC 8200, K579, NN7201, CR 14023, PHX 1004, PHX 1149, PT-630, SK-0403; and the compounds disclosed in WO 02/083128, WO 02/062764, WO 02/14271, WO 03/000180, WO 03/000181, WO 03/000250, WO 03/002530, WO 03/002531, WO 03/002553, WO 03/002593, WO 03/004498, WO 03/004496, WO 03/005766, WO 03/017936, WO 03/024942, WO 03/024965, WO 03/033524, WO 03/055881, WO 03/057144, WO 03/037327, WO 04/041795, WO 04/071454, WO 04/0214870, WO 04/041273, WO 04/041820, WO 04/050658, WO 04/046106, WO 04/067509, WO 04/048532, WO 04/099185, WO 04/108730, WO 05/009956, WO 04/09806, WO 05/023762, US 2005/043292, and EP 1 258 476; (40) lipase inhibitors, such as tetrahydrolipstatin (orlistat/XENICAL), ATL962 (Alizyme/Takeda), GT389255 (Genzyme/Peptimmune)Triton WR1339, RHC80267, lipstatin, teasaponin, and diethylumbelliferyl phosphate, FL-386, WAY-121898, Bay-N-3176, valilactone, esteracin, ebelactone A, ebelactone B, and RHC 80267, and those disclosed in WO 01/77094, WO 04/111004, and U.S. Pat. Nos. 4,598,089, 4,452,813, 5,512,565, 5,391,571, 5,602,151, 4,405,644, 4,189,438, and 4,242,453, and the like; (41) fatty acid transporter inhibitors; (42) dicarboxylate transporter inhibitors; (43) glucose transporter inhibitors; and (44) phosphate transporter inhibitors; (45) anorectic bicyclic compounds such as 1426 (Aventis) and 1954 (Aventis), and the compounds disclosed in WO 00/18749, WO 01/32638, WO 01/62746, WO 01/62747, and WO 03/015769; (46) peptide YY and PYY agonists such as PYY336 (Nastech/Merck), AC162352 (IC Innovations/Curis/Amylin), TM30335/TM30338 (7TM Pharma), PYY336 (Emisphere Tehcnologies), pegylated peptide YY3-36, those disclosed in WO 03/026591, 04/089279, and the like; (47) lipid metabolism modulators such as maslinic acid, erythrodiol, ursolic acid uvaol, betulinic acid, betulin, and the like and compounds disclosed in WO 03/011267; (48) transcription factor modulators such as those disclosed in WO 03/026576; (49) Mc5r (melanocortin 5 receptor) modulators, such as those disclosed in WO 97/19952, WO 00/15826, WO 00/15790, US 20030092041, and the like; (50) Brain derived neutotropic factor (BDNF), (51) Mc1r (melanocortin 1 receptor modulators such as LK-184 (Proctor & Gamble), and the like; (52) 5HT6 antagonists such as BVT74316 (BioVitrum), BVT5182c (BioVitrum), E-6795 (Esteve), E-6814 (Esteve), SB399885 (GlaxoSmithkline), SB271046 (GlaxoSmithkline), RO-046790 (Roche), and the like; (53) fatty acid transport protein 4 (FATP4); (54) acetyl-CoA carboxylase (ACC) inhibitors such as CP640186, CP610431, CP640188 (Pfizer); (55) C-terminal growth hormone fragments such as AOD9604 (Monash Univ/Metabolic Pharmaceuticals), and the like; (56) oxyntomodulin; (57) neuropeptide FF receptor antagonists such as those disclosed in WO 04/083218, and the like; (58) amylin agonists such as Symlin/pramlintide/AC137 (Amylin); (59) Hoodia and trichocaulon extracts; (60) BVT74713 and other gut lipid appetite suppressants; (61) dopamine agonists such as bupropion (WELLBUTRIN/GlaxoSmithkline); (62) zonisamide (ZONEGRAN/Dainippon/Elan), and the like; and
(e) anorectic agents suitable for use in combination with a compound of the present invention include, but are not limited to, aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex and sibutramine; and pharmaceutically acceptable salts thereof. A particularly suitable class of anorectic agent are the halogenated amphetamine derivatives, including chlorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine; and pharmaceutically acceptable salts thereof. Particular halogenated amphetamine derivatives of use in combination with a compound of the present invention include: fenfluramine and dexfenfluramine, and pharmaceutically acceptable salts thereof.
Specific compounds of use in combination with a compound of the present invention include: simvastatin, mevastatin, ezetimibe, atorvastatin, sitagliptin, metformin, sibutramine, orlistat, Qnexa, topiramate, naltrexone, bupriopion, phentermine, and losartan, losartan with hydrochlorothiazide. Specific CB1 antagonists/inverse agonists of use in combination with a compound of the present invention include: those described in WO03/077847, including: N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidyloxy)-2-methylpropanamide, N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide, N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide, and pharmaceutically acceptable salts thereof; as well as those in WO05/000809, which includes the following: 3-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-3-(3,5-difluorophenyl)-2,2-dimethylpropanenitrile, 1-{1-[1-(4-chlorophenyl)pentyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2-methylpropan-2-ol. 3-((S)-(4-chlorophenyl) {3-[(1S)-1-(3,5-difluorophenyl)-2-hydroxy-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile, 3-((S)-(4-chlorophenyl) {3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile, 3-((4-chlorophenyl) {3-[1-(3,5-difluorophenyl)-2,2-dimethylpropyl]azetidin-1-yl}methyl)benzonitrile, 3-((1S)-1-{1-[(S)-(3-cyanophenyl)(4-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile, 3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(4H-1,2,4-triazol-4-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, and 5-((4-chlorophenyl) {3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)thiophene-3-carbonitrile, and pharmaceutically acceptable salts thereof; as well as: 3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(S)-(3-{(1S)-1-[3-(5-amino-1,3,4-oxadiazol-2-yl)-5-fluorophenyl]-2-fluoro-2-methylpropyl}azetidin-1-yl)(4-chlorophenyl)methyl]benzonitrile, 3-[(S)-(4-cyanophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(S)-(3-{(1S)-1-[3-(5-amino-1,3,4-oxadiazol-2-yl)-5-fluorophenyl]-2-fluoro-2-methylpropyl}azetidin-1-yl)(4-cyanophenyl)methyl]benzonitrile, 3-[(S)-(4-cyanophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,2,4-oxadiazol-3-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]-methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile, 5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-1H-tetrazole, 5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-1-methyl-1H-tetrazole, 5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-2-methyl-2H-tetrazole, 3-[(4-chlorophenyl)(3-{2-fluoro-1-[3-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(4-chlorophenyl)(3-{2-fluoro-1-[3-fluoro-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(4-cyanophenyl)(3-{2-fluoro-1-[3-fluoro-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(4-cyanophenyl)(3-{2-fluoro-1-[3-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 5-{3-[(S)-{3-[(1S)-1-(3-bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}(4-chlorophenyl)methyl]phenyl}-1,3,4-oxadiazol-2(3H)-one, 3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile, 3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile, 3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile, 3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile, 3-((1S)-1-{1-[(S)-[3-(5-amino-1,3,4-oxadiazol-2-yl)phenyl](4-chlorophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile, 3-((1S)-1-{1-[(S)-[3-(5-amino-1,3,4-oxadiazol-2-yl)phenyl](4-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile, 3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile, 3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile, 5-[3-((S)-(4-chlorophenyl) {3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)phenyl]-1,3,4-oxadiazol-2(3H)-one, 5-[3-((S)-(4-chlorophenyl) {3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)phenyl]-1,3,4-oxadiazol-2(3H)-one, 4-{(S)-{3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}-benzonitrile, and pharmaceutically acceptable salts thereof.
Specific NPY5 antagonists of use in combination with a compound of the present invention include: 3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide, 3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide, N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide, trans-3′-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide, trans-3′-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide, trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaiso-benzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, and pharmaceutically acceptable salts and esters thereof.
Specific ACC-1/2 inhibitors of use in combination with a compound of the present invention include: 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one; (5-{1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}-2H-tetrazol-2-yl)methyl pivalate; 5-{l′-[(8-cyclopropyl-4-methoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinic acid; 1′-(8-methoxy-4-morpholin-4-yl-2-naphthoyl)-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one; and 1′-[(4-ethoxy-8-ethylquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one; and pharmaceutically acceptable salts and esters thereof. Specific MCH1R antagonist compounds of use in combination with a compound of the present invention include: 1-{4-[(1-ethylazetidin-3-yl)oxy]phenyl}-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one, 4-[(4-fluorobenzyl)oxy]-1-{4-[(1-isopropylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one, 1-[4-(azetidin-3-yloxy)phenyl]-4-[(5-chloropyridin-2-yl)methoxy]pyridin-2(1H)-one, 4-[(5-chloropyridin-2-yl)methoxy]-1-{4-[(1-ethylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one, 4-[(5-chloropyridin-2-yl)methoxy]-1-{4-[(1-propylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one, and 4-[(5-chloropyridin-2-yl)methoxy]-1-(4-{[(2S)-1-ethylazetidin-2-yl]methoxy}phenyl)pyridin-2(1H)-one, or a pharmaceutically acceptable salt thereof.
Specific DP-IV inhibitors of use in combination with a compound of the present invention are selected from Januvia, 7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine. In particular, the compound of formula I is favorably combined with 7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine, and pharmaceutically acceptable salts thereof.
Specific H3 (histamine H3) antagonists/inverse agonists of use in combination with a compound of the present invention include: those described in WO05/077905, including: 3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[2,3-d]-pyrimidin-4(3H)-one, 3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one, 2-ethyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one 2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4 (3H)-one, 3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2,5-dimethyl-4(3H)-quinazolinone, 3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone, 3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-5-methoxy-2-methyl-4(3H)-quinazolinone, 3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-5-fluoro-2-methyl-4(3H)-quinazolinone, 3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-7-fluoro-2-methyl-4(3H)-quinazolinone, 3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-methoxy-2-methyl-4(3H)-quinazolinone, 3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methyl-4(3H)-quinazolinone, 3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-8-fluoro-2-methyl-4(3H)-quinazolinone, 3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one, 3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one, 3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[4,3-d]pyrimidin-4(3H)-one, 6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one, 6-methoxy-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4 (3H)-one, 2,5-dimethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone, 2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)-quinazolinone, 5-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone, 6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone, 5-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone, 7-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone, 2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one, 5-fluoro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone, 2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 6-methoxy-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone, 6-methoxy-2-methyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone, and pharmaceutically acceptable salts thereof.
Specific CCK1R agonists of use in combination with a compound of the present invention include: 3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid; 3-(4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid; 3-(4-{[1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid; 3-(4-{[1-(3-ethoxyphenyl)-2-(2,4-difluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid; and 3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid; and pharmaceutically acceptable salts thereof.
Specific MC4R agonists of use in combination with a compound of the present invention include: 1) (5 S)-1′-{[(3R,4R)-1-tert-butyl-3-(2,3,4-trifluorophenyl)piperidin-4-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]; 2) (5R)-1′-{[(3R,4R)-1-tert-butyl-3-(2,3,4-trifluorophenyl)-piperidin-4-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]; 3) 2-(1′-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3-chloro-2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-yl)-2-methylpropanenitrile; 4) 1′-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]; 5) N-[(3R,4R)-3-({3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-1′H,5H-spiro[furo-[3,4-b]pyridine-7,4′-piperidin]-1′-yl}carbonyl)-4-(2,4-difluorophenyl)-cyclopentyl]-N-methyltetrahydro-2H-pyran-4-amine; 6) 2-[3-chloro-1′-({(1R,2R)-2-(2,4-difluorophenyl)-4-[methyl(tetrahydro-2H-pyran-4-yl)amino]-cyclopentyl}-carbonyl)-2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-yl]-2-methyl-propane-nitrile; and pharmaceutically acceptable salts thereof.
Suitable neurokinin-1 (NK-1) receptor antagonists may be favorably employed with the AMP-kinase activators of the present invention. NK-1 receptor antagonists of use in the present invention are fully described in the art. Specific neurokinin-1 receptor antagonists of use in the present invention include: (±)-(2R3R,2S3S)—N-{[2-cyclopropoxy-5-(trifluoromethoxy)-phenyl]methyl}-2-phenylpiperidin-3-amine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine; aperpitant; CJ17493; GW597599; GW679769; R673; R067319; R1124; R1204; SSR146977; SSR240600; T-2328; and T2763; or a pharmaceutically acceptable salts thereof.
The term “therapeutically effective amount” means the amount the compound of structural formula I that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disorder being treated. The novel methods of treatment of this invention are for disorders known to those skilled in the art. The term “mammal” includes humans, and companion animals such as dogs and cats.
The weight ratio of the compound of the Formula I to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formula I is combined with a DPIV inhibitor the weight ratio of the compound of the Formula I to the DPIV inhibitor will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the Formula I and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
The compounds of structural formula I of the present invention can be prepared according to the procedures of the following Schemes, Intermediates and Examples, using appropriate materials and are further exemplified by the following specific examples. Moreover, by utilizing the procedures described in the disclosure contained herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The Examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. The instant compounds are generally isolated in the form of their pharmaceutically acceptable salts, such as those previously described herein. The use of protecting groups for the amine and carboxylic acid functionalities to facilitate the desired reaction and minimize undesired reactions is well documented. Conditions required to remove protecting groups are found in standard textbooks such as Greene, T, and Wuts, P. G. M., Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, N.Y., 1991. CBZ and BOC are commonly used protecting groups in organic synthesis, and their removal conditions are known to those skilled in the art. All temperatures are degrees Celsius unless otherwise noted. Mass spectra (MS) were measured by electron-spray ion-mass spectroscopy.
Abbreviations used in the description of the preparation of the compounds of the present invention: ACN is acetonitrile; AcOH is acetic acid; aq or aq. is aqueous; Boc2O is t-butoxycarbonyl anhydride; n-BuLi is n-butyllithium; C is carbon; CPME is cyclopentyl methyl ether; CV is column volume(s); DAST is (diethylamino)sulfur trifluoride; DBU is 1,8-diazabicyclo[5.4.0]-undec-7-ene; DIBAL-H is di-isobutyl aluminum hydride; DCE is dichloroethane; DCM is dichloromethane; DEAD is diethyl azodicarboxylate; DIAD is diisopropyl azodicarboxylate; DIEA and DIPEA is diisopropylethyl amine; DMA is dimethyl acetal; DMAP is 4-(Dimethylamino)pyridine; DME is 1,2-dimethoxyethane; DMF is dimethyl formamide; DMSO is dimethyl sulfoxide; dppf DCM complex is 1,1′-bis(diphenyl-phosphino)ferrocene dichloromethane complex; DPPP is diphenyl phosphinopropane; EDC is N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide; Et2O is diethyl ether; EtOAc is ethyl acetate; dppf is 1,1′-Bis(diphenyl-phosphino)ferrocene; EtOH is ethanol; Et3N is triethyl amine; h is hour(s); HATU is O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate; Hex or hex is hexanes; HOBT is 1-Hydroxybenzotriazole; HPLC is high pressure liquid chromatography; ISCO Rf is the Rf determined via medium pressure liquid chromatography using a Teledyne ISCO RediSep® column; isomannide is 1,4:3,6-Di-anhydro-mannitol; KOAc is potassium acetate; L is liter; LC/MS and LC-MS is liquid chromatography/mass spectroscopy; KOTMS is potassium trimethylsilanolate; LAH is lithium aluminum hydride; M is molar; ml and mL is milliliter; Me is methyl, MeCN is acetonitrile; MeI is methyl iodide; MeMgBr is methyl magnesium bromide; MeOH is methanol; MgBr is magnesium bromide; min is minutes; mmol is millimole(s); m-CPBA is meta chloro per benzoic acid; MPLC is medium pressure liquid chromatography; MS is molecular sieves; MTBE is tert-butyl methyl ether; N is normal; NaOAc is sodium acetate; NBS is N-bromo succinamide; NIS is N-iodo succinamide; Pd2(dba)3 is tris(dibenzylideneacetone)-dipalladium(0); [PdCl2(dppf)]CH2Cl2 or PdCl2(dppf)-DCM is 1,1′-Bis(diphenylphosphino)-ferrocene-palladium(II)dichloride dichloromethane complex; PPh3 is triphenyl phosphine; PhSiH is phenyl silane; wt % is weight percent; psi is pounds per square inch; RT and rt is room temperature; Rt is retention time; Rochelles' Salt is potassium sodium tartrate; RuPhos is 2-Dicyclohexyl-phosphino-2′,6′-diisopropoxybiphenyl; sat or sat. is saturated; SEM is 2-(trimethylsilyl)ethoxymethyl; SEM-Cl and SEMCl is 2-(trimethylsilyl)-ethoxymethyl chloride; TBAF is tetrabutyl ammonium fluoride; TBSCl and TBDMSCl is ten-butyldimethylsilyl chloride; TEA is triethylamine; TESCl is chlorotriethylsilane; TFA is trifluoro acetic acid; THF is tetrahydrofuran; TMS is trimethylsilyl; Tosyl-Cl is p-toluene-sulfonyl chloride; and XPhos is 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.
Microwave (MW) reactions were performed with a single mode operating Biotage Emrys Optimizer in sealed reaction vials at the indicated fixed temperature held constant for the designated reaction time. The medium pressure liquid chromatography (MPLC) purifications were performed with Teledyne ISCO RediSep® normal-phase columns pre-packed with 35-60 micron silica gel. The LC-MS system contained an Applied Biosystems API150EX MS operating in a positive ion mode receiving 0.1 mL/min flowrate with a Shimadzu UV detector receiving 0.1 mL/min flowrate. Unless specified, the LC conditions were solvent A=0.05% TFA in acetonitrile; solvent B=0.05% TFA in water; flowrate=10 mL/min; column: Chromolith Performance RP-18e, 100×4.6 mm. Unless specified, the 1H NMRs were obtained in CD3OD at 500 MHz and spectra were recorded in units δ. C, H, N microanalyses were performed by Robertson Microlit Laboratories, Inc., Madison, N.J.
The following reaction schemes illustrate methods which may be employed for the synthesis of the compounds of structural formula I described in this invention. All substituents are as defined above unless indicated otherwise. Several strategies based upon synthetic transformations known in the literature of organic synthesis may be employed for the preparation of the compounds of general formula I.
Intermediate 1 may be purchased from Pharmatech.
Intermediate 2 may be prepared according to procedures disclosed in Ciaran, G. et. al., J. Med. Chem. 2008, 51, 6400-6409.
Methyl 4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-4-carboxylate (1.143 g, 3.38 mmol), 4,6-difluoro-5-iodo-2-(methylsulfonyl)-1H-benzo[d]imidazole (1.1 g, 3.07 mmol), potassium phosphate tribasic (1.956 g, 9.22 mmol) palladium tetrakis (177 mg, 0.154 mmol) and 2-methyl-THF (6 ml) were added together in a microwave vial and heated at 150° C. in the microwave for 30 minutes. Then the mixture was cooled to room temperature and partitioned between 2-MeTHF and water. The layers were separated and aqueous layer was extracted with 2-methyl-THF. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the desired product.
To a solution of methyl 4′-(4,6-difluoro-2-(methylsulfonyl)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxylate (1 g, 2.60 mmol) in THF, was added potassium carbonate (1.079 g, 7.80 mmol), followed by allyl bromide (0.338 ml, 3.90 mmol). The resulting mixture was heated to 60° C. for 16 h. The crude reaction was cooled to room temperature and diluted with EtOAc and filtered. The organic layer was washed with brine (×3) and dried over Na2SO4, filtered and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. LC-MS: calculated for C25H20F2N2O4S 482.11 observed m/e: 482.94 (M+H)+ (Rt: 2.33/4 min).
Intermediate 4 was synthesized using the same procedure as Intermediate 3 starting from the appropriate starting materials. LC-MS: calculated for C23H18F2N2O2S, 424.463, observed m/e: 424.93 (M+H)+
Intermediate 5 was synthesized according to procedures disclosed in WO2011/106273.
Intermediate 6 was synthesized according to procedures disclosed in WO2011/106273.
To a solution of commercially available isomannide (1802 mg, 12.33 mmol) and Cs2CO3 (2678 mg, 8.22 mmol) in anhydrous DMF (26 ml) was added dropwise 6-chloro-5-iodo-2-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (2001 mg, 4.11 mmol) in anhydrous DMF (26 ml) over 20 min. The mixture was stirred at room temperature for 4 hours, then diluted with EtOAc and washed with water. After concentration under reduced pressure, the residue was purified by column chromatography on silica gel Biotage™ 25 S, eluting with EtOAc/isohexane (gradient from 50% to 80% in 15 V) to give a yellow liquid. The yellow liquid was treated with formic acid (20 ml, 521 mmol) and saturated potassium hydrogen sulfate (2.22 ml, 4.11 mmol) and heated to 60° C. overnight. At 0° C., the reaction mixture was basified to pH 11 with NaOH (50/50% by weight). The mixture was then diluted with THF (10 ml) and stirred at room temperature for 45 min. Then the mixture was acidified to pH 7 with 2N HCl (aq.) and extracted by EtOAc. The organic phase was separated, washed with brine and dried over anhydrous Na2SO4. After concentration under reduced pressure, the title compound was obtained. LC-MS: calculated for C13H12ClIN2O4, 422.603, observed m/e: 422.71 (M+H)+ (Rt 2.62/5.5 min).
To a solution of isomannide (682 mg, 4.67 mmol) and Cs2CO3 (507 mg, 1.556 mmol) in anhydrous DMF (5 ml) was added dropwise 4,6-difluoro-5-iodo-2-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (380 mg, 0.778 mmol) in anhydrous DMF (5 ml) over 20 min. The mixture was stirred at room temperature for 4 hours, and then diluted with EtOAc and washed with water. After concentration under reduced pressure, the resulting residue was purified by column chromatography on silica gel Biotage™ 25 S, by eluting with EtOAc/isohexane (gradient from 50% to 80% in 15 V) to give the product. The desired product was dissolved in formic acid (4.5 ml, 117 mmol) and saturated potassium hydrogen sulfate (0.5 ml, 0.628 mmol). The reaction mixture was stirred at room temperature overnight and then heated to 60° C. for 3 hours. The reaction was cooled to 0° C., and basified to pH 11 with NaOH (50/50% by weight). The mixture was then diluted with THF (5 ml) and stirred at room temperature for 45 min. Then the mixture was acidified to pH 7 with concentrated aqueous HCl. and extracted with EtOAc. After concentration under reduced pressure, the title compound was obtained. LC-MS: calculated for C13H11F2IN2O4, 424.139, observed m/e: 424.76 (M+H)+ (Rt 2.55/5.5 min).
To a solution of 6-chloro-5-iodo-2-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (500 mg, 1.027 mmol) and Intermediate 2 (535 mg, 2.054 mmol) in anhydrous DMF (8 ml) was added Cs2CO3 (502 mg, 1.541 mmol). The mixture was stirred at room temperature overnight, and then diluted with EtOAc, and washed with water and brine. After concentration under reduced pressure, a solid was obtained. The solid was treated with formic acid (9 ml, 235 mmol) and aqueous saturated potassium hydrogen sulfate (1 ml, 1.027 mmol) overnight at 60° C. The reaction was cooled to 0° C., and basified to pH 11 with NaOH (50/50% by weight). The mixture was diluted with THF (10 ml) and stirred at room temperature for 45 min. At 0° C., the mixture was acidified to pH 7 with concentrated aqueous HCl. and extracted with EtOAc. The organic phase was washed with brine and dried over anhydrous Na2SO4. After concentration under reduced pressure, the title compound was obtained. LC-MS: calculated for C13H12ClIN2O4, 422.603, observed m/e: 422.71 (M+H)+ (Rt 2.63/5.5 min).
To a solution of 4,6-difluoro-5-iodo-2-(methylsulfonyl)-1-((2-(trimethylsilyl)-ethoxy)-methyl)-1H-benzo[d]imidazole (400 mg, 0.819 mmol) and Intermediate 2 (427 mg, 1.638 mmol) in anhydrous DMF (8 ml) was added Cs2CO3 (534 mg, 1.638 mmol) in anhydrous DMF (8 ml). The mixture was stirred at room temperature overnight, and then diluted with EtOAc and washed with water. After concentration under reduced pressure, a solid was obtained. The solid product was treated with formic acid (9 ml, 235 mmol) and aqueous saturated potassium hydrogen sulfate (1 ml, 0.819 mmol) overnight at 60° C. The reaction was then cooled to 0° C. and basified to pH 11 with NaOH (50/50% by weight). The mixture was diluted with THF (10 ml) and stirred at room temperature for 45 min. At 0° C., the mixture was acidified to pH 7 with concentrated aqueous HCl and extracted with EtOAc. The organic phase was washed with brine and dried over anhydrous Na2SO4. After concentration under reduced pressure, the title compound was obtained. LC-MS: calculated for C13H11F2IN2O4, 424.139, observed m/e: 424.75 (M+H)+ (Rt 2.57/5.5 min).
To a mixture of Cs2CO3 (97 g, 296.79 mmol, 2.00 equiv), (3R,3aR,6R,6aR)-hexahydrofuro[3,2-b]furan-3,6-diol (131 g, 896.39 mmol, 6.00 equiv) in N,N-dimethylformamide (730 mL) was added dropwise a solution of 4,6-difluoro-5-iodo-2-methanesulfonyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-1,3-benzodiazole and 5,7-difluoro-6-iodo-2-methanesulfonyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-1,3-benzodiazole (73 g mixture, 149.48 mmol, 1.00 equiv) in N,N-dimethylformamide (365 mL) with stirring at room temperature. The reaction was stirred for 4 h at room temperature, then cooled to 0° C. and quenched by the addition of 300 mL of water/ice. The resulting solution was extracted with 3×500 mL of ethyl acetate. The organic layers were combined, washed with 3×500 mL of water and 1×300 mL of brine, dried over anhydrous magnesium sulfate and concentrated under vacuum. The resulting residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:1-2:1) to give a mixture of (3R,3aR,6R,6aR)-6-[(4,6-difluoro-5-iodo-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1H-1,3-benzodiazol-2-yl)oxy]-hexahydrofuro[3,2-b]furan-3-ol and (3R,3aR,6R,6aR)-6-[(5,7-difluoro-6-iodo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-1,3-benzodiazol-2-yl)oxy]-hexahydrofuro[3,2-b]furan-3-ol as a yellow oil. LC-MS-(ES, m/z): 395 [M+H]+. H NMR (400 MHz, CDCl3, ppm): δ 7.15-7.13 (0.5H, d), 6.99-6.98 (0.5H, d), 5.69-5.62 (1H, m), 5.53-5.49 (1H, m), 5.46-5.34 (1H, m), 4.98-4.96 (1H, t), 4.62-4.60 (1H, t), 4.36-4.29 (2H, m), 4.17-4.09 (1H, m), 4.01-3.96 (1H, m), 3.68-3.55 (3H, m), 2.50 (1H, s), 0.94-0.90 (2H, m), 0.02-0.049 (9H, d).
To a solution of (3R,3aR,6R,6aR)-hexahydrofuro[3,2-b]furan-3,6-diol (148 g, 1.01 mol, 12.02 equiv) in N,N-dimethylformamide (900 mL) and DBU (77 g, 505.78 mmol, 6.01 equiv) was added dropwise a mixture of 6-chloro-5-iodo-2-methanesulfonyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-1,3-benzodiazole and 5-chloro-6-iodo-2-methanesulfonyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-1,3-benzodiazole (82 g mixture, crude, 1.00 equiv) in N,N-dimethylformamide (400 mL) with stirring at room temperature. The reaction was stirred for 2 h at room temperature, then cooled to 0° C., and quenched by the addition of 500 mL of water. The resulting solution was extracted with 3×1000 mL of ethyl acetate. The organic layers were combined, washed with 2×500 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:8-2:1) to give a mixture of (3R,3aR,6R,6aR)-6-(6-chloro-5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yloxy)-hexahydrofuro[3,2-b]furan-3-ol and (3R,3aR,6R,6aR)-6-[(5-chloro-6-iodo-1-[[2-(trimethylsilyl) ethoxy]methyl]-1H-1,3-benzodiazol-2-yl)oxy]-hexahydrofuro[3,2-b]furan-3-ol as an off-white solid. LC-MS (ES, m/z): 553 [M+H]−. H NMR (400 MHz, CDCl3, ppm): δ 8.03 (s, 1H), 7.82 (s, 1H), 7.67 (s, 1H), 7.50 (s, 1H), 5.65-5.61 (dd, 2H), 5.41-5.36 (m, 4H), 4.97-4.95 (m, 2H), 4.62-4.60 (m, 2H), 4.38-4.29 (m, 4H), 4.10-4.06 (m, 2H), 3.99-3.96 (m, 2H), 3.68-3.64 (dd, 2H), 3.59-3.55 (m, 4H), 2.63 (br, 2H), 0.95-0.91 (m, 4H), 0.02-0.01 (m, 18H).
Palladium(II) acetate (31.1 mg, 0.139 mmol) was added to a stirred suspension of (3R)-1-(4-bromophenyl)pyrrolidin-3-ol (211.5 mg, 1.070 mmol), bis(pinacolato)diboron (438.1 mg, 1.725 mmol), potassium acetate (326.8 mg, 3.33 mmol), and dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (113.1 mg, 0.237 mmol) in dioxane (10.5 ml). The reaction mixture was degassed (3×) and placed under nitrogen before being heated to 100° C. for 4 hours. Then the reaction mixture was allowed to cool to room temperature and partitioned between EtOAc (75 ml) and water (50 ml). The aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×30 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a dark residue. The residue was purified using an ISCO Rf and a 24 g silica gold column (CV=35.9 ml) and eluted as follows: 100% Hexane (1 CV), 0-40% EtOAc/Hexane gradient (20 CV), 40% EtOAc/Hexane (5 CV) at 35 ml/min. The product fractions were combined and evaporated under reduced pressure to give the title compound as a white residue. LC-MS: calculated for C16H24BNO3 289.18 observed m/e: 290.22 (M+H)+ (Rt 1.15/2 min)
To a stirred solution of diisopropylamine (4.86 ml, 3.45 g, 34.1 mmol) in anhydrous THF (48.0 ml) at 0° C. under nitrogen was added a solution of 2.5M n-butyllithium in hexanes (13.63 ml, 34.1 mmol), dropwise, over 5 minutes. The mixture was cooled to −78° and a solution of dihydro-2H-thiopyran-4(3H)-one (3.77 g, 32.4 mmol) in anhydrous THF (36.0 ml) was added dropwise over 10 minutes. After stirring at −78° C. for 15 minutes, 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (12.75 g, 35.7 mmol) was added as a solid in 5 portions over 10 minutes. The dry-ice bath was removed and the mixture was allowed to stir at room temperature for 18 hours. Then the mixture was diluted with diethyl ether (200 ml), washed with aqueous 1N NaOH (150 ml), washed with brine (100 ml), then dried over sodium sulfate. The organic layer was concentrated under reduced pressure and dried under high vacuum for 18 hours to provide the title compound as a red oil. 1H NMR (400 MHz, CDCl3) δ: 5.95 (d, J=8.0 Hz, 1H), 3.26 (m, 2H), 2.82 (m, 2H), 2.57 (m, 2H).
To a stirred solution of trans-racemic-2-phenylcyclohexanol (4.63 g, 26.3 mmol) and tin(II)trifluoromethanesulfonate (219 mg, 0.525 mmol) under nitrogen in anhydrous DCM (100 ml) at room temperature was added acetic anhydride (3.72 ml, 4.02 g, 39.4 mmol) in one portion. The mixture was stirred for 18 hours at room temperature, then poured into saturated aqueous sodium bicarbonate (200 ml), and extracted with DCM (2×200 ml). The combined organic layers were washed with brine (70 ml), dried over sodium sulfate, and concentrated under reduced pressure to provide the desired product as a light yellow oil. LC-MS: calculated for C14H18O2 218.29 observed m/e: 219.33 (M+H)+ (Rt 0.93/2 min).
To a stirred solution of trans-racemic-2-phenylcyclohexyl acetate (5.60 g, 25.7 mmol) under nitrogen in TFA (50 ml) at 0° C. was added N-iodosuccinimide (5.77 g, 25.7 mmol) portionwise over 5 minutes. The mixture was allowed to warm and stir at room temperature for 3 hours. The mixture was concentrated under reduced pressure. The resultant oil was chromatographed using an 80 g silica gel cartridge eluted with 0-20% ethyl acetate in hexanes over 15 column volumes. The desired product fractions were combined and concentrated under reduced pressure to provide the desired product as a yellow oil. LC-MS: calculated for C14H17IO2 344.19 observed m/e: 345.33 (M+H)+ (Rt 2.60/4 min).
Placed trans-racemic-2-(4-iodophenyl)cyclohexyl acetate (8.14 g, 23.65 mmol), potassium acetate (6.96 g, 70.9 mmol), and bis(pinacolato)diboron (6.31 g, 24.83 mmol) under nitrogen in anhydrous DMSO (30.0 ml). Pulled a hard vacuum, then introduced nitrogen (3×), then [1,1′-bis(diphyenylphosphino)ferrocene]dichloropalladium(II) (0.865 g, 1.182 mmol) was added. Pulled a hard vacuum, then introduced nitrogen (3×). The reaction mixture was stirred at 80° C. for 4.5 hours, allowed to cool to room temperature, then poured into water (200 ml) and extracted with diethyl ether (2×200 ml). The combined organic layers were washed with brine (80 ml), dried over sodium sulfate, and concentrated under reduced pressure. The resulting dark oil was chromatographed using an 80 g silica gel cartridge eluted with 5-10% ethyl acetate in hexanes over 15 column volumes. The desired product fractions were concentrated under reduced pressure to provide the title compound as a white solid. LC-MS: calculated for C20H29BO4 344.25 observed m/e: 344.00 (M+H)+ (Rt 2.87/4 min).
Example 107 was prepared according to the procedures in Example 49 omitting the final deprotection step. HPLC-mass spectum: 601.62 m/e.
5-([1,1′-biphenyl]-4-yl)-1-allyl-4,6-difluoro-2-(methylsulfonyl)-1H-benzo[d]imidazole (200.0 mg, 0.471 mmol), Intermediate 1 (245 mg, 0.942 mmol) and Cs2CO3 (307 mg, 0.942 mmol) in anhydrous DMA (4.5 ml) was stirred at room temperature over the weekend. Then the crude mixture was extracted with EtOAc and washed with water. The resulting residue was purified by column chromatography on silica gel Biotage™ 25 S, eluting with EtOAc/isohexane (gradient from 5% to 25% in 16V) to give a colorless oil. A mixture of the oil product (171 mg) and 1, 3-dimethylbarbituric acid (88 mg, 0.566 mmol) in anhydrous DMA (3 ml) was purged with N2 and then Pd(Ph3P)4 (98 mg, 0.085 mmol) was added under N2 flow. The mixture was heated to 75° C. overnight, and then extracted with EtOAc and washed with water (3 times). The organic phase was separated, washed with brine, and dried over anhydrous Na2SO4. After concentration under reduced pressure, the resulting residue was purified by column chromatography on silica gel Biotage™ 25 S, by eluting with EtOAc/isohexane (gradient from 20% to 30% in 15V) to give a yellow foam. To the yellow foam (91 mg, 0.161 mmol) was added TBAF in THF (4 ml, 4.00 mmol), and the mixture was stirred at room temperature for 1 hour. The resulting residue was purified by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.1% TFA (gradient from 15% to 100%), to give the title product. LC-MS: calculated for C25H20F2N2O4, 450.434, observed m/e: 451.08 (M+H)+ (Rt 3.34/5.5 min). 1H NMR δ (ppm) (CD3OD): 7.60-7.80 (m, 4H), 7.40-7.60 (m, 4H), 7.36 (t, J=7.5 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 5.48 (qt, J=5.5 Hz, 1H), 4.98 (t, J=5.0 Hz, 1H), 4.46 (t, J=5.0 Hz, 1H), 4.20-4.32 (m, 1H), 4.14 (d, J=5.0 Hz, 2H), 3.90 (m, 1H), 3.59 (t, J=8.5 Hz, 1H).
(4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)boronic acid (102 mg, 0.368 mmol) and (3R,3aR,6R,6aR)-6-((4,6-difluoro-5-iodo-1H-benzo[d]imidazol-2-yl)oxy)hexahydro furo[3,2-b]furan-3-ol (125 mg, 0.295 mmol) and potassium phosphate tribasic (0.57 ml, 1.140 mmol) were dissolved in anhydrous 1,4-Dioxane (4 ml). The mixture was purged with N2 for 15 min, and then PdCl2(dppf)-CH2Cl2 adduct (48.1 mg, 0.059 mmol) was added under N2 flow. The mixture was heated to 80° C. for 3 hours, then extracted with EtOAc and washed with water (3 times). The resulting residue was purified by preparative HPLC Reverse phase (C-18), by eluting with acetonitrile/water+0.1% TFA. After concentration under reduced pressure, the title compound was obtained as a off-white solid. LC-MS: calculated for C26H22F2N2O6S, 528.524, observed m/e: 528.87 (M+H)+ (Rt 2.84/5.5 min). 1H NMR δ (ppm) (CD3OD): 7.90-8.08 (m, 4H), 7.55-7.85 (m, 4H), 7.06 (d, J=9.5 Hz, 1H), 5.48 (m, 1H), 4.97 (m, 1H), 4.46 (t, J=4.5 Hz, 1H), 4.28 (m, 1H), 4.11 (m, 2H), 3.90 (m, 1H), 3.59 (t, J=8.5 Hz, 1H), 3.16 (s, 3H).
Step A: To a solution of (35,65)-hexahydrofuro[3,2-b]furan-3,6-diol (455 mg, 3.11 mmol) and DBU (0.1 ml, 0.663 mmol) in 2 ml of DMF was added dropwise a solution of methyl 4′-(1-allyl-4,6-difluoro-2-(methylsulfonyl)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxylate (250 mg, 0.518 mmol) in 1.5 ml of DMF over 15 minutes. The mixture was stirred at room temperature for 25 h. Then the crude reaction mixture was concentrated in vacuo, and the resulting residue was partitioned between EtOAc (50 ml) and water (50 ml). The organic phase was separated, and the aqueous phase was extracted with EtOAc (3×40 ml). The combined organic layers were washed with brine, then dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography of the resulting residue over silica (preparative TLC) eluting with 100% EtOAc afforded the title compound (Rf: 0.45-0.55) LC-MS: calculated for C30H26F2N2O6 548.18, observed m/e: 549.05 (M+H)+ (Rt: 2.12/4 min)
Step B: Methyl 4′-(1-allyl-4,6-difluoro-2-(((3S,6S)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxylate (217 mg, 039.6 mmol), palladium tetrakis (137 mg, 0.119 mmol) and 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (124 mg, 0.791 mmol) were dissolved in DMA (4 ml). The reaction mixture was heated at 75° C. under N2 overnight. Then the volatiles were removed in vacuo and the resulting residue was partitioned between EtOAc (50 ml) and water (50 ml). The organic phase was removed and the aqueous phase was extracted with EtOAc (3×40 ml). The combined organic layers were washed with brine, then dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography of the resulting residue over silica (preparative TLC) eluting with 5% Methanol in DCM afforded the title compound (Rf: 0.3) LC-MS: calculated for C27H22F2N2O6 508.14, observed m/e: 509.1 (M+H)+ (Rt: 2.07/4 min). 1H NMR (500 MHz, C2D6OS): δ 8.05 (d, 2H), 7.95 (d, 2H), 7.90 (d, 2H), 7.55 (d, 2H), 7.15 (b, 1H), 5.45 (q, 1H), 4.80 (t, 1H), 4.35 (t, 1H), 4.10 (m, 2H), 3.95 (m, 1H), 3.90 (s, 3H), 3.75 (t, 1H), 3.40 (t, 1H).
To a solution of the compound of Example 1 (93 mg, 0.183 mmol) in MeOH (2 ml) was added 2.5N NaOH (1 ml, 2.500 mmol). The reaction mixture was stirred at room temperature for 2 h. Then the volatiles were removed in vacuo and the resulting residue was dissolved in water (50 ml), acidified to pH 2 with 2N HCl, and extracted with EtOAc (3×50 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound. LC-MS: calculated for C26H20F2N2O6 494.13 observed m/e: 495.10 (M+H)+ (Rt: 1.84/4 min). 1H NMR (500 MHz, C2D6OS): δ 8.05 (d, 2H), 7.90 (dd, 4H), 7.55 (d, 2H), 7.15 (d, 1H), 5.45 (q, 1H), 4.80 (t, 1H), 4.35 (t, 1H), 4.10 (m, 2H), 3.90 (dd, 1H), 3.75 (t, 1H), 3.40 (t, 1H).
To a solution of Methyl 4′-(4,6-difluoro-2-(((3S,6S)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxylate (15 mg, 0.030 mmol) in THF (0.5 ml) was added LAH (15 mg, 0.395 mmol) at 0c. The reaction mixture was stirred at room temperature for 1 h, then diluted with water (50 ml) and extracted with EtOAc (2×50 ml). The combined organic layers were washed with water, then brine, dried over Na2SO4, filtered and concentrated. The purification of the resulting residue by mass directed HPLC eluting with 10-100% MeCN:H2O afforded the title compound. LC-MS: calculated for C26H22F2N2O5 480.15 observed m/e: 481.10 (M+H)+ (Rt: 1.74/4 min). 1H NMR (500 MHz, CD3OD): δ 7.65 (dd, 4H), 7.50 (d, 2H), 7.45 (d, 2H), 7.05 (d, 1H), 5.45 (q, 1H), 4.95 (t, 1H), 4.85 (s, 2H), 4.45 (t, 1H), 4.25 (m, 1H), 4.10 (m, 2H), 3.90 (t, 1H), 3.60 (t, 1H).
(4′-(4,6-difluoro-2-(((3S,6S)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)((R)-3-hydroxypyrrolidin-1-yl)methanone
4′-(4,6-difluoro-2-(((3S,6S)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]-imidazol-5-yl)-[1,1′-biphenyl]-4-carboxylic acid (34 mg, 0.069 mmol), (R)-pyrrolidin-3-ol (12 mg, 0.138 mmol), and HATU (53 mg, 0.139 mmol) were dissolved in DMF (1 ml). To this solution was added TEA (0.03 ml, 0.215 mmol) and the reaction mixture was stirred under N2 at room temperature for 24 h. The volatiles were removed in vacuo and the purification of the resulting residue by mass directed HPLC by eluting with 10-100% MeCN:H2O afforded the title compound. LC-MS: calculated for C30H27F2N3O6 563.19 observed m/e: 564.01 (M+H)+ (Rt: 1.64/4 min)1H NMR (500 MHz, CD3OD): δ 7.80 (m, 4H), 7.70 (d, 2H), 7.55 (d, 2H), 7.05 (d, 1H), 5.45 (q, 1H), 4.95 (t, 1H), 4.50 (t, 1H), 4.40 (b, 1H) 4.30 (m, 1H), 4.10 (m, 2H), 3.90 (t, 1H), 3.70 (m, 2H), 3.60 (m, 2H), 3.40 (d, 1H), 2.00 (m, 2H).
4′-(4,6-difluoro-2-(((3S,6S)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxylic acid (34 mg, 0.069 mmol), 3-methylazetidin-3-ol (12 mg, 0.138 mmol), and HATU (53 mg, 0.139 mmol) were dissolved in DMF (1 ml). To this solution was added TEA (0.03 ml, 0.215 mmol) and the reaction mixture was stirred under N2 at room temperature for 24 h. The volatiles were removed in vacuo and the purification of the resulting residue by mass directed HPLC eluting with 10-100% MeCN:H2O afforded the title compound. LC-MS: calculated for C30H22F2N3O6 563.19 observed m/e: 564.00 (M+H)+ (Rt: 1.69/4 min) 1H NMR (500 MHz, CD3OD): δ 7.80 (m, 6H), 7.60 (d, 2H), 7.10 (d, 1H), 5.50 (q, 1H), 5.00 (t, 1H), 4.45 (t, 1H), 4.30 (m, 4H), 4.20 (dd, 1H), 4.10 (m, 2H), 3.90 (t, 1H), 3.55 (t, 1H), 1.50 (s, 3H).
A mixture of (3R,3aR,6R,6aR)-6-((4,6-difluoro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (40.0 mg, 0.063 mmol), and 4-bromo-1,2-difluorobenzene (14.64 mg, 0.076 mmol) in anhydrous dioxane (0.4 ml) was purged with N2 and then chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (6.5 mg, 0.013 mmol) and tripotassium phosphate (0.191 ml, 0.191 mmol) were added under N2 flow. The mixture was heated to 60° C. overnight, then the reaction mixture was extracted with CH2Cl2 and washed with water. The organic layer was transferred out to 2 dram vial and the solvent was evaporated under reduced pressure. To the resulting residue was added 1 ml of 1:1 CH2Cl2 and TFA and the mixture was stirred at 25° C. for two hours. The desired product formed by UPLC. Then the reaction mixture was evaporated under reduced pressure to give an amber residue. The residue was dissolved with 1.5 ml DMSO, then filtered through a filter plate (0.45 micron) and submitted to High Throughput Purification group (HTP) for mass triggered reverse phase eluting with acetonitrile/water+0.1% TFA to give the title product. LC-MS: calculated for C25H18F4N2O4, 486.415, observed m/e: 487.12 (M+H)+ (Rt 1.00/2.00 min).
A mixture of (3R,3aR,6R,6aR)-6-((6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (40 mg, 0.064 mmol), and 2-bromonaphthalene (15.80 mg, 0.076 mmol) in anhydrous dioxane (0.4 ml) was purged with N2 and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium (II) (6.5 mg, 0.013 mmol) and tripotassium phosphate (0.191 ml, 0.191 mmol) were added under N2 flow. The mixture was heated to 60° C. overnight, then the reaction mixture was extracted with CH2Cl2 and washed with water. The organic layer was transferred out to 2 dram vial and the solvent was evaporated under reduced pressure. To the resulting residue was added 1 ml of 1:1 CH2Cl2 and TFA and the mixture was stirred at 25° C. for two hours. The desired product formed by UPLC. The solvent was evaporated under reduced pressure to give an amber residue. The residue was diluted with 1.5 ml DMSO, and then filtered through a filter plate (0.45 micron) and submitted to High Throughput Purification group (HTP) for mass triggered reverse phase eluting with acetonitrile/water+0.1% TFA to give the title product. LC-MS: calculated for C29H23ClN2O4, 498.13, observed m/e: 499.14 (M+H)+ (Rt 1.16/2.00 min).
Lithium hydroxide (0.970 ml, 2.91 mmol) was added to a stirred mixture of (3R,3aR,6R,6aR)-6-((6-chloro-5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (643.5 mg, 1.164 mmol), 1-(4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,4-triazole (485 mg, 1.397 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (95 mg, 0.116 mmol) in dioxane (9 ml)/water (2.4 ml). The reaction mixture was stirred under N2 at 60° C. for 90 min, and then cooled. Aqueous ammonium chloride (saturated, 100 mL) was added, and the mixture was extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with brine (saturated, 80 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel Isolute Flash Si; 20 g prepacked, and eluted with EtOAc/isohexane (0-100% EtOAc in hexane) to give (3R,3aR,6R,6aR)-6-((5-(4′-(1H-1,2,4-triazol-1-yl)-[1,1′-biphenyl]-4-yl)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol. TFA (2 mL, 26.0 mmol) was added to a stirred mixture of (3R,3aR,6R,6aR)-6-((5-(4′-(1H-1,2,4-triazol-1-yl)-[1,1′-biphenyl]-4-yl)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (643 mg, 0.995 mmol) in CH2Cl2 (2 ml). The mixture was stirred at room temperature for 1 h, then concentrated, and the resulting residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.1% TFA, to give title compound. LC-MS: calculated for C27H22ClN5O4, 515.14, observed m/e: 516.32 (M+H)+ (Rt 0.93/2 min). 1H NMR (400 MHz, cd3od): δ 9.08 (s, 1H); 8.12 (d, J=0.9 Hz, 1H); 7.77-7.86 (m, 4H); 7.65-7.68 (m, 2H); 7.44-7.47 (m, 2H); 7.44 (s, 1H); 7.29 (s, 1H); 5.37 (q, J=5.0 Hz, 1H); 4.88 (t, J=5.3 Hz, 1H); 4.37 (t, J=5.0 Hz, 1H); 4.19 (ddd, J=8.9, 6.8, 5.1 Hz, 1H); 4.01-4.08 (m, 2H); 3.81 (dd, J=8.3, 6.8 Hz, 1H); 3.49 (t, J=8.6 Hz, 1H).
1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (116.0 mg, 0.142 mmol) was added to a solution of (3R,3aR,6R,6aR)-6-((6-chloro-5-iodo-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (Intermediate 7) (300.0 mg, 0.710 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanol (292.0 mg, 1.065 mmol), and lithium hydroxide (51.0 mg, 2.130 mmol) in degassed 15% water in dioxane (6.02 mL). The reaction mixture heated under N2 at 80° C. for 3.5 h, then cooled to RT, and added to stirring EtOAc (200 mL)/water (200 mL). The aqueous layer was separated and back-extracted with EtOAc (5×150 mL). The organic layers combined, washed with brine (200 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. Flash chromatography of the resulting residue utilizing a 40 g silica RediSep Rf® Gold column and employing a 0-100% EtOAc/hexane gradient afforded the title compound. LC-MS: calculated for C23H23ClN2O5 442.13 observed m/e: 443.34 (M+H)′ (Rt 0.89/2.0 min).
Lithium hydroxide (1.004 ml, 3.01 mmol) was added to a stirred mixture of (3R,3aR,6R,6aR)-6-((4,6-difluoro-5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuroll[3,2-b]furan-3-ol (668 mg, 1.205 mmol), 1-(4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,4-triazole (502 mg, 1.446 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (98 mg, 0.120 mmol) in dioxane (9 ml)/water (2.4 ml) and the mixture was stirred under N2 at 60° C. overnight. Then the mixture was cooled, aqueous ammonium chloride (saturated, 100 mL) was added, and the mixture was extracted with ethyl acetate (3×80 mL). The combined organic fractions were washed with brine (saturated, 80 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel Isolute Flash Si; 20 g prepacked, eluting with EtOAc/isohexane (0-100% EtOAc in hexane) to give (3R,3aR,6R,6aR)-6-((5-(4′-(1H-1,2,4-triazol-1-yl)-[1,1′-biphenyl]-4-yl)-4,6-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol. TFA (3 mL, 38.9 mmol) was added to a stirred mixture of (3R,3aR,6R,6aR)-6-((5-(4′-(1H-1,2,4-triazol-1-yl)-[1,1′-biphenyl]-4-yl)-4,6-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (547 mg, 0.844 mmol) in CH2Cl2 (3 ml). The mixture was stirred at room temperature for 1 hour, and then concentrated. The resulting residue was purified by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.1% TFA to give the title product. LC-MS: calculated for C27H21F2N5O4, 517.16, observed m/e: 518.32 (M+H)+ (Rt 0.93/2 min). 1H NMR (400 MHz, dmso): δ 9.36 (s, 1H); 8.26 (s, 1H); 7.95 (q, J=8.7 Hz, 4H); 7.84 (d, J=8.3 Hz, 2H); 7.55 (d, J=7.9 Hz, 2H); 7.15 (d, J=9.4 Hz, 1H); 5.43 (d, J=5.7 Hz, 1H); 4.81 (t, J=5.0 Hz, 1H); 4.34 (t, J=4.8 Hz, 1H); 4.08 (dd, J=9.7, 6.1 Hz, 2H); 3.87 (t, J=6.1 Hz, 1H); 3.76 (t, J=7.4 Hz, 1H); 3.38-4.45 (m, 1H).
1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (154.0 mg, 0.189 mmol) was added to a solution of (3R,3aR,6R,6aR)-6-((4,6-difluoro-5-iodo-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (Intermediate 8, 400 mg, 0.943 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanol (388.0 mg, 1.415 mmol), and lithium hydroxide (67.8 mg, 2.830 mmol) in degassed 15% water in dioxane (8.0 mL). The reaction mixture heated under N2 at 80° C. for 4 h. Then the reaction mixture cool to RT and stirred with EtOAc (200 mL)/water (200 mL). The aqueous layer was separated and back-extracted with EtOAc (5×200 mL). The organic layers combined, washed with brine (200 mL), dried over Na2SO4, filtered, and the filtrate evaporated under reduced pressure. Flash chromatography of the resulting residue utilizing a 40 g silica RediSep Rf0 Gold column and employing a 0-100% EtOAc/hexane gradient afforded the title compound. LC-MS: calculated for C23H22F2N2O5 444.15 observed m/e: 445.39 (M+H)+ (Rt 0.90/2.0 min).
To a stirred solution of (3R,3aR,6R,6aR)-6-((6-chloro-5-(4-(3,6-dihydro-2H-thiopyran-4-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (360 mg, 0.599 mmol) in DCM (3.0 ml) under nitrogen at room temperature was added portion wise over 1 hour m-CPBA (77% w/w, 268 mg, 1.198 mmol). After stirring for 45 minutes, the reaction mixture was poured into 10% aqueous sodium thiosulfate (40 ml), and extracted with DCM (3×70 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (40 ml) and brine (40 ml), then dried over sodium sulfate and concentrated under reduced pressure. The resulting oil was dissolved in DCM (3.0 ml) and TFA (2.0 ml). The mixture was stirred at room temperature for 7.5 hours, and then concentrated under reduced pressure. The resulting oily residue was chromatographed using a Gilson reverse phase prep HPLC eluted with 10-90% acetonitrile in water (with 0.05% TFA). The desired product fractions were combined, frozen at −78° C., and lyophilized to dryness to provide the title compound as a white solid. LC-MS: calculated for C24H23ClN2O6S 502.97 observed m/e: 503.23 (M+H)+ (Rt 1.16/4 min).
To 3-(4-(4,6-difluoro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)phenyl)cyclobutanone (product from Suzuki coupling reaction above, 56 mg, 0.098 mmol)) in THF (1 ml) at −78° C. under N2 atmosphere was added dropwise DIBAL (1M in THF, 0.3 ml, 0.3 mmol). The reaction mixture was allowed to warm to 0° C. over 2 hours, then diluted with EtOAc (15 ml), and quenched by the dropwise addition of saturated aqueous NH4Cl solution (10 ml). The aqueous layer was separated and extracted with EtOAc (15 ml). The combined organic layers were washed with brine (25 ml), dried (Na2SO4), filtered and concentrated. The resulting crude material was purified (Isco system, 12 g gold cartridge, 30 ml flow rate) by eluting with 20/80 (1 min) to 100/0 (13 min) to 100/0 (15 min) of EtOAc/hexanes. The product containing fractions were combined and concentrated to give (3R,3aR,6R,6aR)-6-((4,6-difluoro-5-(4-(3-hydroxycyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol as a white foam. To a solution of (3R,3aR,6R,6aR)-6-((4,6-difluoro-5-(4-(3-hydroxycyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (42 mg, 0.073 mmol) in dichloromethane (1.5 ml) was added TFA (1 ml). The reaction mixture was stirred at room temperature for 3 hours, then concentrated. Twice methanol (10 ml) was added to the residue, followed by concentration. The resulting crude material was dissolved in DMSO (1.5 ml) and purified on a reverse phase HPLC (Waters Sunfire C18 column (19×100 mm), 5μ particle size, eluting with MeCN/H2O buffering with 0.16% TFA, 25 ml/min flow rate over 9 min) to provide the title compound as the TFA salt. LC-MS: observed m/e: 445.15 (M+H)+ (Rt 0.6/2 min).
Example 106 was prepared according to the procedures in Example 21. HPLC-mass spectum: 473.42 m/e.
1,1′-bis(diphenylphosphino)ferrocene-palladium-(II)dichloride dichloromethane complex (154.0 mg, 0.189 mmol) was added to a solution of (3R,3aR,6R,6aR)-6-((6-chloro-5-iodo-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol 2,2,2-trifluoroacetate (508.0 mg, 0.943 mmol), benzo[d][1,3]dioxol-5-ylboronic acid (235.0 mg, 1.415 mmol), and lithium hydroxide (67.8 mg, 2.830 mmol) in degassed 15% water in dioxane (8.0 mL). The reaction mixture placed under nitrogen before being heated under N2 at 80° C. for 3.5 h. The reaction mixture was then cooled to RT and added to stirring EtOAc (200 mL)/water (200 mL). The aqueous layer was separated and back-extracted with EtOAc (3×200 mL). The organic layers combined, washed with brine (200 mL), dried over Na2SO4, filtered, and the filtrate evaporated under reduced pressure. Flash chromatography of the resulting residue utilizing a 40 g silica RediSep Rf® Gold column and employing a 0-85% EtOAc/hexane gradient afforded the title compound. LC-MS: calculated for C20H17ClN2O6 416.08 observed m/e: 417.26 (M+H)+ (Rt 0.93/2.0 min).
The recombinant human AMPK complex 1 (containing α1β1γ1) or AMPK complex 7 (containing α2β1γ1) was obtained from baculovirus expression system. Recombinant viruses were generated by cotransfection of AMPK/pBacPak9 clones with Baculogold baculovirus DNA (Pharmingen) in spodoptera frugiperda 21 cells according to the manufacturer's instructions. Each round of virus amplification was performed for 5 days in Grace's medium containing 10% serum. Virus that had been subjected to three rounds of amplification was used for all protein production procedures. To express the AMPK complex, sf21 cells were adapted to serum free medium (SF900 II, Invitrogen) by sequential dilution from serum containing stocks into SF900II medium and maintained in shaker flasks at 90 rpm at 27° C. The recombinant AMPK enzyme complex was produced by triple infection, one recombinant virus for each of the subunits, in sf21 cells under serum free conditions. Cells were infected in log phase, 1×106 cells/ml, at a multiplicity of infection of ˜5. Cells were harvested by centrifugation at 10,000×g for 15 minutes after 72 hours of infection with viruses. The insect cell pellet from 2 liters of culture was resuspended in 50 ml lysis buffer (20 mM Tris-HCl, 50 mM NaCl, 50 mM NaF, 30 mM Na PPi, 0.25 M sucrose, 10 mM ZnCl2, 2 mM DTT, 0.4 mg/ml digitonin) and subjected to two cycles of freeze-thaw lysis in a dry-ice ethanol bath. Insoluble material was removed by centrifugation at 10,000×g and the supernatant was fractionated with use of polyethylene glycol (PEG). The protein fraction precipitating between 2.5 and 6% PEG was used for further purification using a Blue-Sepharose step (Zhou et al, J. Clin. Invest. 108, 1167-1174, 2001).
The in vitro AMPK activation assay is performed in a volume of 30 μl in a 384-well plate. Enzyme reactions were assembled in the microtiter plate by adding 15 μl of 2× enzyme in assay buffer (20 mM HEPES, pH 7.3, 5 mM MgCl2, 3 mM DTT, 0.01% Brij 35 and CamK Kinase, to activate AMPK) to wells which contained either DMSO or compound. The reaction was initiated with the addition of 15 μl 2× substrate mixture containing 200 μM ATP, and 3.0 μM fluorescently labeled SAMS (5-FAM-HMRSAMSGLHLVKRR-COOH) in assay buffer. After 45-minute incubation at 25° C., the reaction was stopped by the addition of 70 μl stop buffer (100 mM HEPES, pH 7.3, 40 mM EDTA, 0.015% Brij 35). Phosphorylated 5-FAM SAMS product is assessed using a Caliper EZ Reader LabChip microfluidics reader. Product conversion is determined by calculating the peak heights of the substrate and product and reporting the product/(product+substrate) peak ratio. The 10-point titration data were expressed as % maximum AMP activation. The results were plotted using 4 parameter fit and the inflection point reflecting 50% of the maximum activation was reported as the EC50. The % maximum AMP activation for selected compounds is provided in the table below.
The compounds of present invention, including the compounds of Examples 1-83, were tested in the in vitro AMPK activation assay using recombinant human AMPK complex 1 (containing α1β1γ1) or AMPK complex 7 (containing α2β1γ1), and were found to have greater than 50% maximum AMP activation of human AMPK complex 1 (containing α1β1γ1) or AMPK complex 7 (containing α2β1γ1), and EC50 values of less than 50 micromolar. Preferred compounds of the present invention were found to have EC50 values of less than 0.1 micromolar in the in vitro AMPK activation assay using recombinant human AMPK complex 1 or AMPK complex 7.
To assess the potential for AMPK activators to increase the phosphorylation of Acetyl COA Carboxylase (ACC) in liver and skeletal muscle, db/+ mice are dosed with AMPK activators at either 2 or 7 h prior to evaluation where phosphorylated ACC (p-ACC)/total ACC levels are compared in the tissues of vehicle and compound treated mice. Briefly, mice are anesthetized using gas anesthesia with 1-4% isoflurane administered to effect via nose cone. Once anesthetized, samples of liver and skeletal muscle (gastrocnemius) are removed, snap frozen in liquid nitrogen, and homogenized. Homogenates are analyzed for protein concentration and equal amounts of protein are assayed for total and phosphorylated ACC (p-ACC) levels using Meso Scale Discovery's Multi-array assay kit. MSD assay plates contain an electrode surface that is coated with streptavidin. Protein sample binds to streptavidin. The primary ACC or p-ACC specific antibody binds to protein and a secondary antibody labeled with MSD SULFO-TAG then binds to the primary antibody. The electrode surface of the MSD plate responds to an electrical stimulus and causes the SULFO-TAG labels bound to ACC and p-ACC to emit a light signal in proportion to the amount of p-ACC or total ACC present. The ratio of p-ACC/total ACC levels are determined for each sample and the ratio of p-ACC/total ACC levels for mice treated with AMPK activators is significantly elevated compared to the ratio of those treated with the vehicle control (significant elevations are described as differences where p<0.05).
To determine the effect of AMPK activators on Fatty Acid Synthesis (FAS) in the liver, the effect of oral pre-dosing of compounds on the amount of 3H incorporated into hepatic triglyceride is determined as described by Sakurai T, Miyazawa S, Shindo Y, and T. Hashimoto (Biochim Biophys Acta. 1974 Sep. 19; 360 (3):275-88). Briefly, mice (db/+, Jackson Laboratory, Maine) are orally dosed with AMPK activators at time=−8 h. Then at time=−1 h, mice are injected with 0.5 ml of 0.15 M NaCl containing 0.2 mCi of 3H water per 100 g of body weight. At time 0, mice are sacrificed via cervical dislocation and livers are harvested for FAS analysis. To analyze livers for FAS, samples of liver are heated at 90° C. for 5 hours in a 4 M KOH/50% ethanol solution. Then the alkaline hydrolysate of liver is extracted with hexane and acidified to a pH <2 with 10 M H2SO4. The fatty acids of liver are then extracted from acidified hydrolysate with additional hexane, dried down with a stream of warm air, then re-suspended in scintillation fluid, and counted on a beta counter. The amount of fatty acids synthesized per gram of liver is calculated based on the amount of 3H incorporated into hepatic triglyceride. The amount of 3H radiolabelled fatty acids synthesized in mice with treated with an AMPK activator is significantly less than the amount of 3H radiolabelled fatty acids synthesized in the control mice.
DIO mice are treated simultaneously with an effective dose of an AMPK-activated protein kinase activator.
Materials and Methods: Male C57BL/6NT mice (Taconic, 16-18 weeks old at the beginning of the drug administration) are used. Mice are given water and high fat diet D12492 (Research Diet Inc.) ad libitum. They are kept in an animal room which is maintained at 23±2 C temperature, 55±15% relative humidity and on a 12-hr light-dark cycle (7:00-19:00) during a quarantine and acclimatization period of 1 week. Animals are then administered vehicle (5 ml/kg of 0.5% methylcellulose in distilled water) by oral gavage twice-daily at 9 AM and 5 PM. After 9 days, stable body weight is observed. The following day (day −1), the mice are fasted for 4 hours and tail bled to determine the glucose and insulin levels. Animals are sorted into groups based on plasma glucose, insulin levels and body weight (n=8). The body weight and food in the hopper are recorded on day 0 before compound dosing is initiated. One of the groups is orally administered vehicle while the second group is administered an AMPK-activated protein kinase activator of the present invention at a dose of 30 mg/kg (5 ml/kg) twice-daily for 12 days by gavage. Body weight and food intake are measured every other day. On day 5, the animals are fasted 4 hours for measuring plasma glucose and insulin levels after morning dosing. At day 12, body weight and food intake are measured and animals receive their last morning dose. Mice again are fasted 4 hours, blood is collected at a set time point (t=0 min), and then challenged with dextrose orally (2 g/kg) Plasma glucose and insulin levels are determined from tail bleeds taken at 20 and 90 minutes after dextrose challenge. The plasma glucose and insulin excursion profile from t=0 to t=90 min is used to integrate an area under the curve (AUC) for each treatment. Percent inhibition values for each treatment are generated from the AUC data normalized to the C57BL/6NT mice feed with D7012. Preferred compounds of the present invention significantly reduce day 12 glucose and/or insulin AUC during the Oral Glucose Tolerance Test after an oral dose in the range of 0.1 to 100 mg/kg.
Adult DIO mice are used in these studies. After at least 2 days of acclimation to the vivarium conditions (controlled humidity and temperature, lights on for 12 hours out of 24 hours) food (D12492 (Research Diet Inc.) is removed from rodent cages. An AMPK activator of the present invention or the vehicle is administered orally, intraperitoneally, subcutaneously or intravenously before the return of a known amount of food to cage. The optimal interval between dosing and food presentation is based on the half-life of the compound based on when brain concentrations of the compound is the highest. Food remaining is measured at several intervals. Food intake is calculated as grams of food eaten per gram of body weight within each time interval and the appetite-suppressant effect of the AMPK activator is compared to the effect of the vehicle. The food intake of mice treated with an AMPK activator is significantly less than the food intake of control mice.
Adult DIO mice are used in these studies. Upon or soon after weaning, rats or mice are made obese due to exclusive access to diets containing fat and sucrose in higher proportions than in the control diet. The diet used to induce obesity is Research Diets D12451 chow (45% fat). The rodents ingest chow until they are significantly heavier and have a higher proportion of body fat than control diet rats, often 9 weeks. The rodents receive injections (1 to 4 per day) or continuous infusions of an AMPK activator of the present invention or the vehicle either orally, intraperitoneally, subcutaneously or intravenously. Food intake and body weights are measured daily or more frequently. Food intake is calculated as grams of food eaten per gram of body weight within each time interval and the appetite-suppressant and weight loss effect of the AMPK activator of the present invention is compared to the effect of the vehicle. The weight loss of mice treated with an AMPK activator is significantly greater than the weight loss of control mice.
Adult DIO mice are used in these studies. Upon or soon after weaning, rats or mice are made obese due to exclusive access to diets containing fat and sucrose in higher proportions than in the control diet. The diet used to induce obesity is Research Diets D12451 chow (45% fat). The rodents ingest chow until they are significantly heavier and have a higher proportion of body fat than control diet rats, often 9 weeks. The rodents receive injections (1 to 4 per day) or continuous infusions of an AMPK activator of the present invention or the vehicle either orally, intraperitoneally, subcutaneously or intravenously. Food intake and body weights are measured daily or more frequently. Food intake is calculated as grams of food eaten per gram of body weight within each time interval and the appetite-suppressant and weight loss effect of the AMPK activator of the present invention is compared to the effect of the vehicle. The weight loss of mice treated with an AMPK activator is significantly greater than the weight loss of control mice.
Adult DIO mice are used in these studies. Upon or soon after weaning, rats or mice are made obese due to exclusive access to diets containing fat and sucrose in higher proportions than in the control diet. The diet used to induce obesity is Research Diets D12451 chow (45% fat). The rodents ingest chow until they are significantly heavier and have a higher proportion of body fat than control diet rats, often 9 weeks. The rodents receive injections (1 to 4 per day) or continuous infusions of an AMPK activator of the present invention or the vehicle either orally, intraperitoneally, subcutaneously or intravenously. Food intake and body weights are measured daily or more frequently. Food intake is calculated as grams of food eaten per gram of body weight within each time interval and the appetite-suppressant and weight loss effect of the AMPK activator of the present invention is compared to the effect of the vehicle. The weight loss of mice treated with an AMPK activator is significantly greater than the weight loss of control mice.
Adult DIO mice are used in these studies. Upon or soon after weaning, rats or mice are made obese due to exclusive access to diets containing fat and sucrose in higher proportions than in the control diet. The diet used to induce obesity is Research Diets D12451 chow (45% fat). The rodents ingest chow until they are significantly heavier and have a higher proportion of body fat than control diet rats, often 9 weeks. The rodents receive injections (1 to 4 per day) or continuous infusions of an AMPK activator of the present invention or the vehicle either orally, intraperitoneally, subcutaneously or intravenously. Food intake and body weights are measured daily or more frequently. Food intake is calculated as grams of food eaten per gram of body weight within each time interval and the appetite-suppressant and weight loss effect of the AMPK activator of the present invention is compared to the effect of the vehicle. The weight loss of mice treated with an AMPK activator is significantly greater than the weight loss of control mice.
The scope of the claims should not be limited by the preferred embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for any of the indications for the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US13/55246 | 8/16/2013 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 61692056 | Aug 2012 | US |
