WO2006074330A2 - Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme - Google Patents

Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme Download PDF

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WO2006074330A2
WO2006074330A2 PCT/US2006/000402 US2006000402W WO2006074330A2 WO 2006074330 A2 WO2006074330 A2 WO 2006074330A2 US 2006000402 W US2006000402 W US 2006000402W WO 2006074330 A2 WO2006074330 A2 WO 2006074330A2
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WIPO (PCT)
Prior art keywords
group
hydrogen
adamantane
methyl
amino
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PCT/US2006/000402
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French (fr)
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WO2006074330A3 (en
Inventor
Jeffrey J. Rohde
Qi Shuai
James T. Link
Jyoti R. Patel
Jurgen Dinges
Bryan K. Sorensen
Hong Yong
Vince S. Yeh
Ravi Kurukulasuriya
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Abbott Laboratories
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Priority to JP2007550479A priority Critical patent/JP5133702B2/en
Priority to AU2006203918A priority patent/AU2006203918B2/en
Priority to KR1020077017918A priority patent/KR101302627B1/en
Priority to BRPI0606228-8A priority patent/BRPI0606228A2/en
Priority to CA002594116A priority patent/CA2594116A1/en
Priority to MX2007008239A priority patent/MX2007008239A/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to NZ555971A priority patent/NZ555971A/en
Priority to EP06717579A priority patent/EP1846362A2/en
Publication of WO2006074330A2 publication Critical patent/WO2006074330A2/en
Publication of WO2006074330A3 publication Critical patent/WO2006074330A3/en
Priority to IL184329A priority patent/IL184329A/en
Priority to IL213342A priority patent/IL213342A/en

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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • A61K31/16—Amides, e.g. hydroxamic acids
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    • C07C233/11—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/52—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to compounds that are inhibitors of the 11-beta- hydroxysteroid dehydrogenase Type 1 enzyme.
  • the present invention further relates to the use of inhibitors of 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme for the treatment of non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome and other diseases and conditions that are mediated by excessive glucocorticoid action.
  • Insulin is a hormone that modulates glucose and lipid metabolism. Impaired action of insulin (i.e., insulin resistance) results in reduced insulin-induced glucose uptake, oxidation and storage, reduced insulin-dependent suppression of fatty acid release from adipose tissue (i.e., lipolysis) and reduced insulin-mediated suppression of hepatic glucose production and secretion. Insulin resistance frequently occurs in diseases that lead to increased and premature morbidity and mortality.
  • Diabetes mellitus is characterized by an elevation of plasma glucose levels (hyperglycemia) in the fasting state or after administration of glucose during a glucose tolerance test. While this disease may be caused by several underlying factors, it is generally grouped into two categories, Type 1 and Type 2 diabetes.
  • Type 1 diabetes also referred to as Insulin Dependent Diabetes Mellitus (“IDDM”)
  • IDDM Insulin Dependent Diabetes Mellitus
  • type 2 diabetes also referred to as non-insulin dependent diabetes mellitus, or NIDDM
  • insulin resistance is a significant pathogenic factor in the development of hyperglycemia.
  • the insulin levels in type 2 diabetes patients are elevated (i.e., hyperinsulinemia), but this compensatory increase is not sufficient to overcome the insulin resistance.
  • Persistent or uncontrolled hyperglycemia in both type 1 and type 2 diabetes mellitus is associated with increased incidence of macro vascular and/or microvascular complications including atherosclerosis, coronary heart disease, peripheral vascular disease, stroke, nephropathy, neuropathy and retinopathy.
  • Insulin resistance is a component of the metabolic syndrome.
  • diagnostic criteria for metabolic syndrome have been established. To qualify a patient as having metabolic syndrome, three out of the five following criteria must be met: elevated blood pressure above 130/85 mmHg, fasting blood glucose above 110 mg/dl, abdominal obesity above 40" (men) or 35" (women) waist circumference and blood lipid changes as defined by an increase in triglycerides above 150 mg/dl or decreased HDL cholesterol below 40 mg/dl (men) or 50 mg/dl (women). It is currently estimated that 50 million adults, in the US alone, fulfill these criteria. That population, whether or not they develop overt diabetes mellitus, are at increased risk of developing the macrovascular and microvascular complications of type 2 diabetes listed above.
  • Type 2 diabetes Available treatments for type 2 diabetes have recognized limitations. Diet and physical exercise can have profound beneficial effects in type 2 diabetes patients, but compliance is poor. Even in patients having good compliance, other forms of therapy may be required to further improve glucose and lipid metabolism.
  • One therapeutic strategy is to increase insulin levels to overcome insulin resistance. This maybe achieved through direct injection of insulin or through stimulation of the endogenous insulin secretion in pancreatic beta cells.
  • Sulfonylureas e.g., tolbutamide and glipizide
  • meglitinide are examples of drugs that stimulate insulin secretion (i.e., insulin secretagogues) thereby increasing circulating insulin concentrations high enough to stimulate insulin-resistant tissue.
  • insulin and insulin secretagogues may lead to dangerously low glucose concentrations (i.e., hypoglycemia).
  • insulin secretagogues frequently lose therapeutic potency over time.
  • Alpha-glucosidase inhibitors e.g., acarbose
  • acarbose may delay carbohydrate absorption from the gut after meals, which may in turn lower blood glucose levels, particularly in the postprandial period.
  • these compounds may also cause gastrointestinal side effects.
  • Glitazones i.e., 5-benzylthiazolidine-2,4-diones
  • Glitazones are a newer class of compounds used in the treatment of type 2 diabetes. These agents may reduce insulin resistance in multiple tissues, thus lowering blood glucose. The risk of hypoglycemia may also be avoided.
  • Glitazones modify the activity of the Peroxisome Proliferator Activated Receptor ("PPAR") gamma subtype. PPAR is currently believed to be the primary therapeutic target for the main mechanism of action for the beneficial effects of these compounds.
  • Other modulators of the PPAR family of proteins are currently in development for the treatment of type 2 diabetes and/or dyslipidemia. Marketed glitazones suffer from side effects including bodyweight gain and peripheral edema.
  • GLP-I Glucagon-Like Peptide 1
  • DPP-IV Dipeptidyl Peptidase IV
  • GLP-I Glucagon-Like Peptide 1
  • DPP-IV Dipeptidyl Peptidase IV
  • Other examples include: Inhibitors of key enzymes involved in the hepatic glucose production and secretion (e.g., fructose- 1,6-bisphosphatase inhibitors) and direct modulation of enzymes involved in insulin signaling (e.g., Protein Tyrosine Phosphatase-1B, or "PTP-IB").
  • Another method of treating or prophylactically treating diabetes mellitus includes using inhibitors of 11- ⁇ -hydroxysteroid dehydrogenase Type 1 (1 l ⁇ -HSDl). Such methods are discussed in J.R. Seckl et al., Endocrinology, 142: 1371-1376, 2001 and references cited therein.
  • Glucocorticoids are steroid hormones that are potent regulators of glucose and lipid metabolism. Excessive glucocorticoid action may lead to insulin resistance, type 2 diabetes, dyslipidemia, increased abdominal obesity and hypertension. Glucocorticoids circulate in the blood in an active form (i.e., Cortisol in humans) and an inactive form (i.e., cortisone in humans).
  • 11 ⁇ -HSD 1 which is highly expressed in liver and adipose tissue, converts cortisone to Cortisol leading to higher local concentration of Cortisol. Inhibition of 1 l ⁇ -HSDl prevents or decreases the tissue specific amplification of glucocorticoid action thus imparting beneficial effects on blood pressure and glucose- and lipid-metabolism.
  • One aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof
  • a 1 , A 2 , A 3 and A 4 is selected from the group consisting of alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl 1 , arylalkyl, aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, haloalkyl, heterocyclealkyl, heterocycleoxyalkyl, -S(O) 2 -N(R 5 R 6 ), -NR 7 - [C(R 8 R 9 )] n -C(O)-R 10 , -OR 14a , -N(R 15 R 16 ),
  • D is selected from the group consisting of a bond, -C(R 27 R 28 )-X- and -C(R 27 R 28 )-
  • E is selected from the group consisting of a cycloalkyl, alkyl, aryl, heteroaryl and heterocycle, wherein the heteroaryl and the heterocycle are appended to the parent molecular moiety through an available carbon atom, or R 4 and E together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
  • X is selected from the group consisting of a bond, -N(R 31 )-, -O-, -S-, -S(O)- and - S(O) 2 -;
  • R 1 is selected from the group consisting of hydrogen and alkyl;
  • R 2 is selected from the group consisting of hydrogen, alkyl and cycloalkyl
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl, or R 3 and R 4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylcarbonyl, alkylsufonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxy, aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, or R 5 and R 6 together with the atom to which they are attached form
  • R 8 and R 9 are each independently selected from the group consisting of hydrogen and alkyl, or R and R taken together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
  • R 10 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl and -N(R R ); R 11 and R 12 are each independently selected from the group consisting of hydrogen and alkyl or R 11 and R 12 taken together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle; R 13 is selected from the group consisting of hydroxy and -N(R 34 R 35 ); R 14a is selected from the group consisting of carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,
  • R 15 and R 16 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocyclesulfonyl, alkylsufon
  • R 18 and R 19 are each independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylsufonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, or R 18 and R 19 together with the atom to which they are attached form a heterocycle;
  • R , R and R are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl;
  • R 23 and R 24 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl, arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, heterocycle, heterocyclecarbonyl and heterocyclesulfonyl;
  • R 25 and R 26 are each independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl, aryloxy, arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocyclecarbonyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, or R 25 and R 26 together with the nitrogen to which they are attached form a ring selected from the group consisting of heteroaryl and heterocycle;
  • R 27 and R 28 are each independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heteroaryl and heterocycle or R 27 and R 28 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R 27 and R 29 together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R 28 and R 4 together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
  • R 29 and R 3O are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, cycloalkyl, cycloalkyloxy, heteroaryl, heterocycle, and - N(R 36 R 37 ), or R 29 and R 30 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R 29 and R 4 together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R 29 and E together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
  • R 31 is selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycle and heteroaryl, or R 31 and E together with the atom to which they are attached form a ring selected from the group consisting of heteroaryl and heterocycle, or R 31 and R 4 together with the atoms to which they are attached form a heterocycle;
  • R and R are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R 32 and R 33 together with the atom to which they are attached
  • R 36 and R 37 are each independently selected from the group consisting of hydrogen, alkyl and aryl.
  • a further aspect of the present invention encompasses the use of the compounds of formula (I) for the treatment of disorders that are mediated by 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme, such as non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome and other diseases and conditions that are mediated by excessive glucocorticoid action, comprising administering a therapeutically effective amount of a compound of formula (I) .
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically suitable carrier.
  • One aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof
  • a 1 , A 2 , A 3 and A 4 is selected from the group consisting of alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl 1 , arylalkyl, aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, haloalkyl, heterocyclealkyl, heterocycleoxyalkyl, -S(O) 2 -N(R 5 R 6 ), -NR 7 - [C(R 8 R 9 )] n -C(O)-R 10 , -O-[C(R ⁇ R 12 )] p
  • D is selected from the group consisting of a bond, -C(R 27 R 28 )-X- and -C(R 27 R 28 )-
  • E is selected from the group consisting of a cycloalkyl, alkyl, aryl, heteroaryl and heterocycle, wherein the heteroaryl and the heterocycle are appended to the parent molecular moiety through an available carbon atom, or R 4 and E together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
  • X is selected from the group consisting of a bond, -N(R 31 )-, -O-, -S-, -S(O)- and -
  • R 1 is selected from the group consisting of hydrogen and alkyl
  • R 2 is selected from the group consisting of hydrogen, alkyl and cycloalkyl
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl, or R 3 and R 4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylcarbonyl, alkylsufonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxy, aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, or R 5 and R 6 together with the atom to which they are attached form
  • R 7 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, cafboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
  • R 8 and R 9 are each independently selected from the group consisting of hydrogen and alkyl, or R 8 and R 9 taken together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
  • R 10 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl and -N(R 32 R 33 ); R 11 and R 12 are each independently selected from the group consisting of hydrogen and alkyl or R 11 and R 12 taken together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
  • R 13 is selected from the group consisting of hydroxy and -N(R 34 R 35 );
  • R 14a is selected from the group consisting of carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
  • R 14b is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
  • R 15 and R 16 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocyclecarbony
  • R 17 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
  • R 18 and R 19 are each independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylsufonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxy, hetero
  • R 20 , R 21 and R 22 are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl;
  • R 23 and R 24 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl, arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, heterocycle, heterocyclecarbonyl and heterocyclesulfonyl;
  • R and R are each independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl, aryloxy, arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocyclecarbonyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, or R 25 and R 26 together with the nitrogen to which they are attached form a ring selected from the group consisting of heteroaryl and heterocycle;
  • R 27 and R 28 are each independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heteroaryl and heterocycle or R 27 and R 28 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R 27 and R 29 together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R and R together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
  • R 29 and R 30 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, cycloalkyl, cycloalkyloxy, heteroaryl, heterocycle, and -N(R 36 R 37 ), or R 29 and R 30 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R 29 and R 4 together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R 29 and E together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
  • R 31 is selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycle and heteroaryl, or R 31 and E together with the atom to which they are attached form a ring selected from the group consisting of heteroaryl and heterocycle, or R
  • Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein A 2 , A 3 and A 4 are hydrogen;
  • R 1 and R 2 are hydrogen; and A 1 , R 3 , R 4 , D and E are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (T), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
  • a 2 , A 3 and A 4 are hydrogen
  • R 1 and R 2 are hydrogen
  • D is a bond; and A 1 , R 3 , R 4 and E are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (T), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen; D is a bond;
  • E is selected from the group consisting of alkyl, aryl, and heteroaryl; and A 1 , R 3 , and R 4 are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I) 5 or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen; D is a bond;
  • E is selected from the group consisting of alkyl, aryl and heteroaryl; R 3 and R 4 are hydrogen; and
  • a 1 is selected from the group consisting of heteroaryl, -CO 2 R 17 , -C(O)-N(R 18 R 19 ), alkylsulfonyl and -S(O) 2 -N(R 5 R 6 ); wherein R 5 , R 6 , R 17 , R 18 and R 19 are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen;
  • E is selected from the group consisting of alkyl, aryl and heteroaryl;
  • R 3 is hydrogen;
  • R 4 is alkyl;
  • a 1 is selected from the group consisting of heteroaryl, -CO 2 R 17 , -C(O)-N(R 18 R 19 ), alkylsulfonyl and -S(O) 2 -N(R 5 R 6 ); wherein R 5 , R 6 , R 17 , R 18 and R 19 are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen; D is a bond;
  • E is selected from the group consisting of alkyl, aryl and heteroaryl
  • R 3 and R 4 are alkyl
  • a 1 is selected from the group consisting of heteroaryl, -CO 2 R 17 , -C(O)-N(R 18 R 19 ), alkylsulfonyl and -S(O) 2 -N(R 5 R 6 ); wherein R 5 , R 6 , R 17 , R 18 and R 19 are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (T), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein A 2 , A 3 and A 4 are hydrogen;
  • R 1 and R 2 are hydrogen
  • E is selected from the group consisting of alkyl, aryl and heteroaryl
  • R 3 and R 4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle; and A 1 is as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein A 2 , A 3 and A 4 are hydrogen;
  • R 1 and R 2 are hydrogen
  • E is selected from the group consisting of alkyl, aryl and heteroaryl
  • R 3 and R 4 together with the atom to which they are attached form a cycloalkyl ring
  • a 1 is selected from the group consisting of heteroaryl, -CO 2 R 17 , -C(O)-N(R 18 R 19 ), alkylsulfonyl and -S(O) 2 -N(R 5 R 6 ); wherein R 5 , R 6 , R 17 , R 18 and R 19 are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (T), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen;
  • E is selected from the group consisting of alkyl, aryl and heteroaryl
  • R 3 and R 4 together with the atom to which they are attached form a heterocycle ring
  • a 1 is selected from the group consisting of heteroaryl, -CO 2 R 17 , -C(O)-N(R 18 R 19 ), alkylsulfonyl and -S(O) 2 -N(R 5 R 6 ); wherein R 5 , R 6 , R 17 , R 18 and R 19 are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
  • a 2 , A 3 and A 4 are hydrogen
  • R 1 and R 2 are hydrogen
  • D is a bond; R 4 and E together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle; and
  • a 1 is selected from the group consisting of heteroaryl, -CO 2 R 17 , -C(O)-N(R 18 R 19 ), alkylsulfonyl and -S(O) 2 -N(R 5 R 6 ); wherein R 3 , R 5 , R 6 , R 17 , R 18 and R 19 are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula
  • a , A and A are hydrogen
  • R 1 and R 2 are hydrogen
  • R 3 is alkyl
  • a 1 is selected from the group consisting of heteroaryl, -CO 2 R 17 , -C(O)-N(R 18 R 19 ), alkylsulfonyl, and -S(O) 2 -N(R 5 R 6 ); wherein R 5 , R 6 , R 17 , R 18 and R 19 are as described in the summary of the invention; and
  • R 38 is selected from the group consisting of arylalkyl and heteroarylalkyl wherein the aryl of the arylalkyl and the heteroaryl of the heteroarylalkyl are each independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, halogen and haloalkyl.
  • Another aspect of the present invention is directed toward a compound of formula (III), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof,
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen;
  • R 3 is alkyl
  • a 1 is selected from the group consisting of heteroaryl, -CO 2 R 17 , -C(O)-N(R 18 R 19 ), alkylsulfonyl, and -S(O) 2 -N(R 5 R 6 ) ; wherein R 5 , R 6 , R 17 , R 18 and R 19 are as described in the summary of the invention; and R 38 is selected from the group consisting of arylalkyl and heteroarylalkyl wherein the aryl of the arylalkyl and the heteroaryl of the heteroarylalkyl are each independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, halogen and haloalkyl.
  • Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen;
  • D is selected from the group consisting of -C(R 27 R 28 )-X- and -C(R 27 R 28 )-C(R 29 R 30 )- X-; and R 27 , R 28 , R 29 , R 30 , X 5 A 1 , R 3 , R 4 and E are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein A 2 , A 3 and A 4 are hydrogen;
  • R 1 and R 2 are hydrogen
  • D is selected from the group consisting of -C(R 27 R 28 )-X- and -C(R 27 R 28 )-C(R 29 R 30 )-
  • E is selected from the group consisting of aryl and heteroaryl; and A 1 , R 3 , and R 4 are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen;
  • D is selected from the group consisting of -C(R 27 R 28 )-X- and -C(R 27 R 28 )-C(R 29 R 30 )-
  • Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen; D is selected from the group consisting of -C(R 27 R 28 )-X- and -C(R 27 R 28 )-C(R 29 R 30 )-
  • R 27 , R 28 , R 29 , and R 30 are each independently selected from the group consisting of hydrogen and alkyl;
  • E is selected from the group consisting of aryl and heteroaryl; X is a bond; R 3 and R 4 are hydrogen; and
  • a 1 is selected from the group consisting of heteroaryl, -CO 2 R 17 , -C(O)-N(R 18 R 19 ), alkylsulfonyl, and -S(O) 2 -N(R 5 R 6 ); wherein R 5 , R 6 , R 17 , R 18 and R 19 are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (T), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein A 2 , A 3 and A 4 are hydrogen;
  • R 1 and R 2 are hydrogen
  • D is selected from the group consisting of -C(R 27 R 28 )-X- and -C(R 27 R 28 )-C(R 29 R 30 )- X-; wherein R 27 , R 28 , R 29 , and R 30 are each independently selected from the group consisting of hydrogen and alkyl; E is selected from the group consisting of aryl and heteroaryl;
  • X is a bond
  • R 3 is hydrogen
  • R 4 is alkyl
  • a 1 is selected from the group consisting of heteroaryl, -CO 2 R 17 , -C(O)-N(R 18 R 19 ), alkylsulfonyl, and -S(O) 2 -N(R 5 R 6 ); wherein R 5 , R 6 , R 17 , R 18 and R 19 are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein A 2 , A 3 and A 4 are hydrogen;
  • R 1 and R 2 are hydrogen
  • D is selected from the group consisting of -C(R 27 R 28 )-X- and -C(R 27 R 28 )-C(R 29 R 30 )- X-; wherein R 5 R 5 R , and R are each independently selected from the group consisting of hydrogen and alkyl; E is selected from the group consisting of aryl and heteroaryl;
  • X is a bond
  • R 3 and R 4 are alkyl
  • a 1 is selected from the group consisting of heteroaryl, -CO 2 R 17 , -C(O)-N(R 18 R 19 ), alkylsulfonyl, and -S(O) 2 -N(R 5 R 6 ); wherein R 5 , R 6 , R 17 , R 18 and R 19 are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (T), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
  • a 2 , A 3 and A 4 are hydrogen
  • R 1 and R 2 are hydrogen
  • D is selected from the group consisting of -C(R 27 R 28 )-X- and -C(R 27 R 28 )-C(R 29 R 30 )- X-; wherein R 27 , R 28 , R 29 , and R 30 are as described in the summary of the invention;
  • E is selected from the group consisting of aryl and heteroaryl
  • X is a bond
  • R 3 and R 4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle; and A 1 is as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen;
  • D is selected from the group consisting of -C(R 27 R 28 )-X- and -C(R 27 R 28 )-C(R 29 R 30 )- X-; wherein R , R , R , and R are each independently selected from the group consisting of hydrogen and alkyl;
  • E is selected from the group consisting of aryl and heteroaryl; X is a bond;
  • R 3 and R 4 together with the atom to which they are attached form a cycloalkyl ring
  • a 1 is selected from the group consisting of heteroaryl, -CO 2 R 17 , -C(O)-N(R 18 R 19 ), alkylsulfonyl, and -S(O) 2 -N(R 5 R 6 ); wherein R 5 , R 6 , R 17 , R 18 and R 19 are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen;
  • D is selected from the group consisting of -C(R 27 R 28 )-X- and -C(R 27 R 28 )-C(R 29 R 30 )- X-; wherein R 5 R 5 R , and R are each independently selected from the group consisting of hydrogen and alkyl;
  • E is selected from the group consisting of aryl and heteroaryl
  • X is a bond
  • R 3 and R 4 together with the atom to which they are attached form a heterocycle ring
  • a 1 is selected from the group consisting of heteroaryl, -CO 2 R 17 , -C(O)-N(R 18 R 19 ), alkylsulfonyl, and -S(O) 2 -N(R 5 R 6 ); wherein R 5 , R 6 , R 17 , R 18 and R 19 are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
  • a 2 , A 3 and A 4 are hydrogen
  • R 1 and R 2 are hydrogen
  • D is selected from the group consisting of -C(R 27 R 28 )-X- and -C(R 27 R 28 )-C(R 29 R 30 )- X-; wherein R 27 , R 28 , R 29 , and R 30 are as described in the summary of the invention;
  • E is selected from the group consisting of aryl and heteroaryl
  • X is selected from the group consisting of -N(R 31 )- and -O-; and A 1 , R 3 , and R 4 are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
  • a 2 , A 3 and A 4 are hydrogen
  • R 1 and R 2 are hydrogen
  • D is selected from the group consisting of -C(R 27 R 28 )-X- and -C(R 27 R 28 )-C(R 29 R 30 )- X-; wherein R 5 R 5 R , and R are each independently selected from the group consisting of hydrogen and alkyl;
  • E is selected from the group consisting of aryl and heteroaryl;
  • X is selected from the group consisting of -N(R 31 )- and -0-;
  • R 3 and R 4 are hydrogen;
  • a 1 is selected from the group consisting of heteroaryl, -CO 2 R 17 , -C(O)-N(R 18 R 19 ), alkylsulfonyl, and -S(O) 2 -N(R 5 R 6 ); wherein R 5 , R 6 , R 17 , R 18 and R 19 are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen;
  • D is selected from the group consisting of -C(R 27 R 28 )-X- and -C(R 27 R 28 )-C(R 29 R 30 )- X-; wherein R 27 , R 28 , R 29 , and R 30 are each independently selected from the group consisting of hydrogen and alkyl;
  • E is selected from the group consisting of aryl and heteroaryl
  • X is selected from the group consisting of -N(R 31 )- and -O-;
  • R 3 is hydrogen
  • R 4 is alkyl
  • a 1 is selected from the group consisting of heteroaryl, -CO 2 R 17 , -C(O)-N(R 18 R 19 ), alkylsulfonyl, and -S(O) 2 -N(R 5 R 6 ); wherein R 5 , R 6 , R 17 , R 18 and R 19 are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen;
  • D is selected from the group consisting of -C(R 27 R 28 )-X- and -C(R 27 R 28 )-C(R 29 R 30 )- X-; wherein R 27 , R 28 , R 29 , and R 30 are each independently selected from the group consisting of hydrogen and alkyl;
  • E is selected from the group consisting of aryl and heteroaryl
  • X is selected from the group consisting of -N(R 31 )- and -O-;
  • R 3 and R 4 are alkyl
  • a 1 is selected from the group consisting of heteroaryl, -CO 2 R 17 , -C(O)-N(R 18 R 19 ), alkylsulfonyl, and -S(O) 2 -N(R 5 R 6 ); wherein R 5 , R 6 , R 17 , R 18 and R 19 are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein A 2 , A J and A 4 are hydrogen;
  • R 1 and R 2 are hydrogen
  • D is selected from the group consisting of -C(R 27 R 28 )-X- and -C(R 27 R 28 )-C(R 29 R 30 )- X-; wherein R 27 , R 28 , R 29 , and R 30 are each independently selected from the group consisting of hydrogen and alkyl;
  • E is selected from the group consisting of aryl and heteroaryl
  • X is selected from the group consisting of -N(R 31 )- and -O-;
  • R 3 and R 4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle; and
  • a 1 is selected from the group consisting of heteroaryl, -CO 2 R 17 , -C(O)-N(R 18 R 19 ), alkylsulfonyl, and -S(O) 2 -N(R 5 R 6 ); wherein R 5 , R 6 , R 17 , R 18 and R 19 are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
  • a 2 , A 3 and A 4 are hydrogen
  • R 1 and R 2 are hydrogen
  • D is selected from the group consisting of -C(R 27 R 28 )-X- and -C(R 27 R 28 )-C(R 29 R 30 )-
  • R , R , R , and R are each independently selected from the group consisting of hydrogen and alkyl;
  • E is selected from the group consisting of aryl and heteroaryl
  • X is selected from the group consisting of -N(R 31 )- and -0-
  • R 3 and R 4 together with the atom to which they are attached form a cycloalkyl ring
  • a 1 is selected from the group consisting of heteroaryl, -CO 2 R 17 , -C(O)-N(R 18 R 19 ), alkylsulfonyl, and -S(O) 2 -N(R 5 R 6 ); wherein R 5 , R 6 , R 17 , R 18 and R 19 are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen; D is selected from the group consisting of -C(R 27 R 28 )-X- and -C(R 27 R 28 )-C(R 29 R 30 )- X-; wherein R 27 , R 28 , R 29 , and R 30 are each independently selected from the group consisting of hydrogen and alkyl;
  • E is selected from the group consisting of aryl and heteroaryl
  • X is selected from the group consisting of -N(R 31 )- and -O-;
  • R 3 and R 4 together with the atom to which they are attached form a heterocycle ring
  • a 1 is selected from the group consisting of heteroaryl, -CO 2 R 17 , -C(O)-N(R 18 R 19 ), alkylsulfonyl, and -S(O) 2 -N(R 5 R 6 ); wherein R 5 , R 6 , R 17 , R 18 and R 19 are as described in the summary of the invention.
  • Exemplary compounds of the present invention having formula (I) include, but are not limited to,
  • Another embodiment of the present invention discloses a method of inhibiting 11- beta-hydroxysteroid dehydrogenase Type I enzyme, comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
  • Another embodiment of the present invention discloses a method of treating disorders in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme, comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
  • Another embodiment of the present invention discloses a method of treating non- insulin dependent type 2 diabetes in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I) .
  • Another embodiment of the present invention discloses a method of treating insulin resistance in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
  • Another embodiment of the present invention discloses a method of treating obesity in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula G ) .
  • Another embodiment of the present invention discloses a method of treating lipid disorders in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
  • Another embodiment of the present invention discloses a method of treating metabolic syndrome in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
  • Another embodiment of the present invention discloses a method of treating diseases and conditions that are mediated by excessive glucocorticoid action in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
  • Another embodiment of the present invention discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) in combination with a pharmaceutically suitable carrier.
  • alkenyl refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.
  • alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert- butoxy, pentyloxy and hexyloxy.
  • alkoxyalkyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2- ethoxyethyl, 2-methoxyethyl and methoxymethyl.
  • alkoxycarbonyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl.
  • alkyl refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
  • alkylcarbonyl refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-l-oxopropyl, 1-oxobutyl and 1-oxopentyl.
  • alkylsulfonyl refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl.
  • alkyl-NH refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a nitrogen atom.
  • alkyl-NH-alkyl refers to an alkyl-NH group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • aryl as used herein, means a phenyl group, or a bicyclic or a tricyclic fused ring system.
  • Bicyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety and fused to a monocyclic cycloalkyl group, as defined herein, a phenyl group, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein.
  • Tricyclic fused ring systems are exemplified by an aryl bicyclic fused ring system, as defined herein and fused to a monocyclic cycloalkyl group, as defined herein, a phenyl group, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein.
  • Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl and tetrahydronaphthyl.
  • aryl groups of this invention maybe optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylalkoxy, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkylalkoxy, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylalkoxy, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclealkoxy, heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl
  • the substituent aryl, the aryl of arylalkyl, the aryl of arylalkenyl, the aryl of arylalkoxy, the aryl of arylcarbonyl, the aryl of aryloxy, the aryl of arylsulfonyl, the cycloalkyl of cycloalkylalkoxy, the substituent heteroaryl, the heteroaryl of heteroarylalkyl, the heteroaryl of heteroarylalkenyl, the heteroaryl of heteroarylalkoxy, the heteroaryl of heteroarylcarbonyl, the substituent heterocycle, the heterocycle of heterocyclealkyl, the heterocycle of heterocyclealkoxy, the heterocycle of heterocyclecarbonyl, the heterocycle of heterocycleoxy, the heterocycle of heterocyclesulfonyl maybe optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
  • aryl 1 refers to a substituted phenyl group wherein the substituent is a member selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl and nitro, or a bicyclic or a tricyclic fused ring system.
  • Bicyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety, which is fused to a cycloalkyl group, as defined herein, a phenyl group, a heteroaryl, as defined herein, or a heterocycle as defined herein.
  • Tricyclic fused ring systems are exemplified by an aryl bicyclic fused ring system fused to a cycloalkyl group, as defined herein, a phenyl group, a heteroaryl, as defined herein, or a heterocycle as defined herein.
  • Bicyclic and tricyclic fused ring systems of this invention may be optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl, nitro, R f RgN-, R f R g Nalkyl, R f R g Ncarbonyl and RfR g Nsulfonyl, wherein R
  • arylalkenyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkenyl group, as defined herein.
  • arylalkyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3- phenylpropyl and 2-naphth-2-ylethyl.
  • arylalkoxy refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • arylcarbonyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and naphthoyl.
  • aryl-NH- refers to an aryl group, as defined herein, appended to the parent molecular moiety through a nitrogen atom.
  • aryl-NH-alkyl refers to an aryl-NH- group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • aryloxy refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of aryloxy include, but are not limited to phenoxy, naphthyloxy, 3- bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy and 3,5-dimethoxyphenoxy.
  • aryloxyalkyl refers to an aryloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • arylsulfonyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of arylsulfonyl include, but are not limited to, phenylsulfonyl, A- bromophenylsulfonyl and naphthylsulfonyl.
  • carbonyl refers to a -C(O)- group.
  • carboxyalkyl refers to a carboxy group as defined herein, appended to the parent molecular moiety through an alkyl group as defined herein.
  • carboxycycloalkyl refers to a carboxy group as defined herein, appended to the parent molecular moiety through an cycloalkyl group as defined herein.
  • cycloalkyl refers to a monocyclic, bicyclic, or tricyclic ring system.
  • Monocyclic ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Bicyclic fused ring systems are exemplified by a cycloalkyl group appended to the parent molecular moiety, which is fused to an additional cycloalkyl group, as defined herein, a phenyl group, a heteroaryl, as defined herein, or a heterocycle as defined herein.
  • Tricyclic fused ring systems are exemplified by a cycloalkyl bicyclic fused ring system fused to an additional cycloalkyl group, as defined herein, a phenyl group, a heteroaryl, as defined herein, or a heterocycle as defined herein.
  • Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms.
  • Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane and bicyclo[4.2.1]nonane.
  • Tricyclic ring systems are also exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge of between one and three carbon atoms.
  • Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.0 3 ' 7 ]nonane and tricyclo [3.3.1.1 3 ' 7 ] decane (adamantane).
  • cycloalkyl groups of this invention may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl, nitro, RfRgN-, R f RgNalkyl, RfR g Ncarbonyl and R f RgN
  • the substituent aryl, the aryl of arylalkyl, the aryl of arylcarbonyl, the aryl of aryloxy, the aryl of arylsulfonyl, the substituent heteroaryl, the heteroaryl of heteroarylalkyl, the heteroaryl of heteroarylcarbonyl, the substituent heterocycle, the heterocycle of heterocyclealkyl, the heterocycle of heterocyclecarbonyl, the heterocycle of heterocycleoxy, the heterocycle of heterocyclesulfonyl may be optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy, carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, RfRgN-, R f RgNalkyl, RfRgNcarbonyl and R
  • cycloalkylalkyl refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and 4-cycloheptylbutyl.
  • cycloalkylalkoxy refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • cycloalkylcarbonyl refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of cycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl, 2-cyclobutylcarbonyl and cyclohexylcarbonyl.
  • cycloalkyloxy refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein.
  • cycloalkylsulfonyl refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of cycloalkylsulfonyl include, but are not limited to, cyclohexylsulfonyl and cyclobutylsulfonyl.
  • halo refers to -Cl, -Br, -I or -F.
  • haloalkyl refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2- fluoroethyl, trifluoromethyl, pentafluoroethyl and 2-chloro-3-fluoropentyl.
  • heteroaryl refers to an aromatic monocyclic ring or an aromatic bicyclic ring system.
  • the aromatic monocyclic rings are five or six membered rings containing at least one heteroatom independently selected from the group consisting of N, O and S.
  • the five membered aromatic monocyclic rings have two double bonds and the six membered aromatic monocyclic rings have three double bonds.
  • the bicyclic heteroaryl groups are exemplified by a monocyclic heteroaryl ring appended to the parent molecular moiety and fused to a monocyclic cycloalkyl group, as defined herein, a monocyclic aryl group, as defined herein, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein.
  • heteroaryl include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indazolyl, indolyl, indolizinyl, isobenzofuranyl, isoindolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl.
  • heteroaryls of this invention may be optionally substituted with 1, 2 or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl, nitro, R f RgN-, RfR g Nalkyl, R f RgNcarbonyl
  • heteroarylalkyl refers to a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • heteroarylalkoxy refers to a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • heteroaryloxy refers to a heteroaryl, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein.
  • heteroaryloxyalkyl refers to a heteroaryloxy, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • heterocycle refers to a non-aromatic monocyclic ring or a non-aromatic bicyclic ring.
  • the non-aromatic monocyclic ring is a three, four, five, six, seven, or eight membered ring containing at least one heteroatom, independently selected from the group consisting of N, O and S.
  • monocyclic ring systems include, but are not limited to, azetidinyl, aziridinyl, diazepinyl, dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydrothienyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1- dioxido
  • bicyclic heterocycles are exemplified by a monocyclic heterocycle appended to the parent molecular moiety and fused to a monocyclic cycloalkyl group, as defined herein, a monocyclic aryl group, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein.
  • Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent atoms of the monocyclic ring are linked by a bridge of between one and three atoms selected from the group consisting of carbon, nitrogen and oxygen.
  • bicyclic ring systems include but are not limited to, for example, benzopyranyl, benzothiopyranyl, benzodioxinyl, 1,3-benzodioxolyl, cinnolinyl, 1,5- diazocanyl, 3,9-diaza-bicyclo[4.2.1]non-9-yl, 3,7-diazabicyclo[3.3.1]nonane, octahydro- pyrrolo[3,4-c]pyrrole, indolinyl, isoindolinyl, 2,3,4,5-tetrahydro-lH-benzo[c]azepine, 2,3,4,5-tetrahydro-lH-benzo[ ⁇ ]azepine, 2,3,4,5-tetrahydro-lH-benzo[cr
  • the heterocycles of this invention may be optionally substituted with 1, 2 or 3 substituents independently selected from oxo, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl, nitro, RfRgN-, RfR g Nalkyl, R f R g Ncarbonyl and R f R g Nsulfonyl, wherein R
  • the substituent aryl, the aryl of arylalkyl, the aryl of arylcarbonyl, the aryl of aryloxy, the aryl of arylsulfonyl, the heteroaryl, the heteroaryl of heteroarylalkyl, the substituent heterocycle, the heterocycle of heterocyclealkyl, the heterocycle of heterocyclecarbonyl, the heterocycle of heterocycleoxy, may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy, carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, R f R g N-, R f R g Nalkyl, R f R g Ncarbonyl and R f R g Nsulfonyl.
  • heterocyclealkyl refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of heterocyclealkyl include, but are not limited to, pyridin-3- ylmethyl and 2-pyrimidin-2-ylpropyl.
  • heterocyclealkylcarbonyl refers to a heterocyclealkyl, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • heterocyclealkoxy refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • heterocycleoxy refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein.
  • heterocycleoxyalkyl refers to a heterocycleoxy, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • heterocycle-NH- refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a nitrogen atom.
  • heterocycle-NH-alkyl refers to a heterocycle-NH-, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • heterocyclecarbonyl refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of heterocyclecarbonyl include, but are not limited to, 1- piperidinylcarbonyl, 4-morpholinylcarbonyl, pyridin-3-ylcarbonyl and quinolin-3-ylcarbonyl.
  • heterocyclesulfonyl refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of heterocyclesulfonyl include, but are not limited to, 1- piperidinylsulfonyl, 4-morpholinylsulfonyl, pyridin-3-ylsulfonyl and quinolin-3-ylsulfonyl.
  • hydroxy refers to an -OH group.
  • hydroxyalkyl refers to a hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • hydroxyalkyl include, but are not limited to, hydroxymethyl, 2- hydroxyethyl, 3-hydroxypropyl and 2-ethyl-4-hydroxyheptyl.
  • oxy refers to a -O- group.
  • sulfonyl refers to a -S(O) 2 - group.
  • the present compounds may exist as therapeutically suitable salts.
  • the term "therapeutically suitable salt,” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation and allergic response, commensurate with a reasonable benefit/risk ratio and effective for their intended use.
  • the salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid.
  • a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid.
  • the resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure.
  • salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, form ate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl ⁇ ro ⁇ ionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydro
  • amino groups of the compounds may also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.
  • Basic addition salts maybe prepared during the final isolation and purification of the present compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine.
  • a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine.
  • the present compounds may also exist as therapeutically suitable prodrugs.
  • therapeutically suitable prodrug refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation and allergic response, are commensurate with a reasonable benefit/risk ratio and are effective for their intended use.
  • prodrug refers to compounds that are rapidly transformed in vivo to the parent compounds of formula (I-IXc) for example, by hydrolysis in blood.
  • prodrug refers to compounds that contain, but are not limited to, substituents known as “therapeutically suitable esters.”
  • therapeuticically suitable ester refers to alkoxycarbonyl groups appended to the parent molecule on an available carbon atom.
  • a "therapeutically suitable ester” refers to alkoxycarbonyl groups appended to the parent molecule on one or more available aryl, cycloalkyl and/or heterocycle groups as defined herein.
  • Compounds containing therapeutically suitable esters are an example, but are not intended to limit the scope of compounds considered to be prodrugs.
  • prodrug ester groups include pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art.
  • Other examples of prodrug ester groups are found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • Asymmetric centers may exist in the present compounds.
  • Individual stereoisomers of the compounds are prepared by synthesis from chiral starting materials or by preparation of racemic mixtures and separation by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of the enantiomers on chiral chromatographic columns.
  • Starting materials of particular stereochemistry are either commercially available or are made by the methods described hereinbelow and resolved by techniques well known in the art.
  • Geometric isomers may exist in the present compounds.
  • the invention contemplates the various geometric isomers and mixtures thereof resulting from the disposal of substituents around a carbon-carbon double bond, a cycloalkyl group, or a heterocycloalkyl group. Substituents around a carbon-carbon double bond are designated as being of Z or E configuration and substituents around a cycloalkyl or heterocycloalkyl are designated as being of cis or trans configuration.
  • the invention contemplates the various isomers and mixtures thereof resulting from the disposal of substituents around an adamantane ring system.
  • the compounds of this invention can be prepared by a variety of procedures and synthetic routes. Representative procedures and synthetic routes are shown in, but are not limited to, Schemes 1-17. Abbreviations which have been used in the descriptions of the Schemes and the
  • Substituted adamantanes of general formula (3) wherein A 5 A 5 A , A , R 5 R , R 5 R 4 , D and E are as defined in formula I, may be prepared as in Scheme 1.
  • Substituted adamantamines of general formula (I) 5 purchased, prepared as described herein, or prepared using methodology known to those in the art, may be treated with an acylating agents of general formula (2), wherein Y is chloro, bromo, or fluoro and R 3 , R 4 , D and E are defined as in formula I, in the presence of a base such as diisopropylethylamine to provide amides of general formula (3).
  • a 1 , A 2 , A 3 and/or A 4 in amines of formula (1) and D and E in the reagents of formula (2) may exist as or contain a group further substituted with a protecting group such as a carboxylic acid protected as the methyl ester. Examples containing a protected functional group may be required due to the synthetic schemes and the reactivity of said groups and could be later removed to provide the desired compound.
  • Such protecting groups can be removed using methodology known to those skilled in the art or as described in T. W. Greene, P. G. M. Wuts "Protective Groups in Organic Synthesis" 3 rd ed. 1999, Wiley & Sons, Inc.
  • Substituted adamantane amines of general formula (5) wherein A 1 , A 2 , A 3 , A 4 and R 2 are as defined in formula I, may be prepared as in Scheme 2.
  • Substituted adamantane ketones of general formula (4) can be purchased, prepared as described herein, or prepared using methodology known to those skilled in the art.
  • Ketones of general formula (4) can be treated with ammonia or primary amines (R 2 NH 2 ) followed by reduction with reagents such as sodium borohydride or H 2 over Pd/C in a solvent like methanol to provide amines of general formula (5).
  • a 1 , A 2 , A 3 and/or A 4 in ketones of formula (4) may be a substituent with a functional group containing a protecting group such as a carboxylic acid protected as the methyl ester.
  • a protecting group such as a carboxylic acid protected as the methyl ester.
  • esters can be hydrolyzed and other protecting groups removed here to provide compounds of general formula (5) or in compounds subsequently prepared from (5) using methodology known to those skilled in the art.
  • Substituted adamantanes of general formula (7) wherein A 2 , A 3 and A 4 are as defined in formula I and G is alkyl, cycloalkyl, arylalkyl, or aryl, as defined in the definition of terms, or G is hydrogen or an acid protecting group, may be prepared as in Scheme 3.
  • Substituted adamantanes of general formula (6) can be purchased or prepared using methodology known to those in the art.
  • Tertiary alcohols of general formula (6) can be treated with oleum and formic acid followed by water or an alcohol GOH to provide polycycles of general formula (7).
  • G in formula (7) may be a protecting group such as methyl.
  • ester protecting groups can be removed from polycycles of general formula (7) or from compounds subsequently prepared from (7).
  • Substituted adamantanes of general formula (10), wherein A 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 4 , D, E, R 18 and R 19 are as defined in formula I, may be prepared as in Scheme 4.
  • Adamantane acids of general formula (8) may be prepared as described herein or using methodology known to those in the art.
  • the acids of general formula (8) may be coupled with amines of general formula (9) (wherein R 18 and R 19 are defined as in formula I) with reagents such as O-(benzotrialzol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU) to provide amides of general formula (10).
  • TBTU O-(benzotrialzol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate
  • R 18 and/or R 19 in amides of formula (10) may be a substituent with a functional group containing a protecting group, such as a carboxylic acid protected as the methyl ester.
  • a protecting group such as a carboxylic acid protected as the methyl ester.
  • esters can be hydrolyzed and other protecting groups removed using methodology known to those skilled in the art.
  • Esters of general formula (11) can be mono-alkylated or bis-alkylated to provide esters of general formula (12) wherein R 101 is the acid protecting group, P, as described above.
  • the bis-alkylation can be conducted either sequentially or in a one pot reaction.
  • Mono or bis-alkylation of esters of general formula (11) can be achieved in the presence of a base such as, but not limited to, sodium hydride, and an alkylating agent such as, but not limited to, alkyl halides (for example, methyl iodide, allyl bromide and the like).
  • the reaction is generally performed in a solvent such as, but not limited to, anhydrous N 5 N- dimethylformamide, at a temperature from about 0 0 C to about 23 0 C.
  • Removal of the protecting group P can be achieved using methodologies known to those skilled in the art or as described in T. W. Greene, P. G. M.
  • esters of formula (13), wherein P is C 1 -C 6 alkyl, unsubstituted or substituted aryl (for example, phenyl) or unsubstituted or substituted arylalkyl (for example, benzyl); and Y is Cl, Br, I, or triflate can be purchased, prepared as described herein, or prepared using methodologies known to those skilled in the art.
  • Esters of formula (13) can be converted to boronic esters of formula (14) when treated with a boron source like bis(pinacolato)diboron, a catalyst such as 1,1 '-bis(diphenylphosphino)ferrocenedichloropalladium (II), and a base like potassium acetate.
  • a boron source like bis(pinacolato)diboron
  • a catalyst such as 1,1 '-bis(diphenylphosphino)ferrocenedichloropalladium (II)
  • a base like potassium acetate.
  • the conversion is facilitated in a solvent such as, but not limited to, dimethyl sulfoxide, N,N-dimethylforrnamide or toluene, at a temperature of about 80 0 C to about 100 0 C.
  • Boronic esters of general formula (14) may be coupled with reagents of formula Z-Y, wherein Z is aryl or heteroaryl and Y is Cl, Br, I, or triflate, a catalyst such as 1,1 '-bis(diphenylphosphino)ferrocenedichloropalladium (II), and a base like sodium carbonate, to provide compounds of formula (15) wherein R 101 is an acid protecting group, P.
  • the reaction can be performed in a solvent system like N,N-dimethylformamide and water at a temperature of about 80 0 C to 90 0 C.
  • compounds of formula (13) wherein Y is Cl, Br, I, or triflate can be treated with a boronic acid or ester of formula (13 A) or Z-B(OR 102 ) 2 , wherein R 102 is hydrogen or alkyl, in the presence of a catalyst, such as but not limited to, bis(triphenylphospine)palladium (H) chloride or dichlorobis(tri-o-tolylphosphine)palladium (II), and a base such as triethylamine or sodium carbonate, to provide compounds of formula (15) wherein R 101 is an acid protecting group, P.
  • the reaction can be effected by heating at a temperature from about 50 0 C to about 180 0 C in solvents such as isopropanol, ethanol, dimethoxyethane, water or dioxane.
  • Acids of general formula (19), wherein R 101 is hydrogen, R 3 is as defined in formula (I) and A is a substituent of heterocycle as defined in the definition of terms, can be prepared from malonic acid di-ester of formula (16) wherein P is C 1 -C 6 alkyl or benzyl as shown in Scheme 7.
  • Malonic acid di-esters of general formula (16) wherein P is an acid protecting group such as C 1 -C 6 alkyl, unsubstituted or substituted aryl (for example, phenyl) or unsubstituted or substituted arylalkyl (for example, benzyl), can be purchased or prepared using methodologies known to those skilled in the art.
  • Malonic acid di-esters of general formula (16) can be treated with one molar equivalent of allyl bromide or 4-bromo-l-butene, using mono alkylation conditions for the conversion of (11) to (12) in Scheme 5, to provide compounds of formula (17).
  • Ozonolysis of the terminal olefin of di-ester (17) may be achieved in a solvent system like dichloromethane and methanol at a low temperature of about -78 0 C, by bubbling ozone through the solution, followed by purging the solution with nitrogen gas, and reduction of the intermediate ozonide with dimethyl sulfide to provide aldehyde di-esters of the general formula (18).
  • Thiazoles of formula (20) can be purchased or prepared using methodologies known to those skilled in the art.
  • Thiazoles of formula (20) may be alkylated by in situ activation with a chloroformate such as, but not limited to, ethyl chloroformate, followed by treatment of a nucleophile such as lithio diethylmalonate (prepared from a malonic acid di-ester in a solution such as tetrahydrofuran with a base such as lithium bis(trimethylsilyl)amide), to afford compounds of formula (21) wherein P 1 and P 2 are C 1 -C 6 alkyl.
  • a chloroformate such as, but not limited to, ethyl chloroformate
  • a nucleophile such as lithio diethylmalonate (prepared from a malonic acid di-ester in a solution such as tetrahydrofuran with a base such as lithium bis(trimethylsilyl)amide
  • the former can be conducted in a solvent such as, but not limited to, tetrahydrofuran, at a temperature around 0 0 C.
  • Treatment with the nucleophile can be effected in a solvent such as tetrahydrofuran and at a temperature around 23 0 C.
  • the lithio diethylmalonate may be formed in a solvent such as tetrahydrofuran.
  • the N-protected malonic acid di-ester adduct of general formula (21) may be oxidized with an agent such as tetrachloro-l,2-benzoquinone in a solvent such as dichloromethane at a temperature around 0 0 C to afford the di-ester of general formula (22).
  • Mono-decarboxylation of di-ester (22) may be achieved by heating in a solvent system such as water and dimethyl sulfoxide with a salt such as sodium chloride at a temperature near 180 0 C to provide esters of general formula (
  • Acids of formula (27) wherein R 101 is hydrogen, P 3 is -C(O)OCH 2 C 6 H 5 , and R 3 is as defined in formula (I) can be prepared from compounds of formula (24) where P is an acid protecting group such as, C 1 -C 6 alkyl, unsubstituted or substituted aryl (for example, phenyl) or unsubstituted or substituted arylalkyl (for example, benzyl), as shown in Scheme 9.
  • P is an acid protecting group such as, C 1 -C 6 alkyl, unsubstituted or substituted aryl (for example, phenyl) or unsubstituted or substituted arylalkyl (for example, benzyl), as shown in Scheme 9.
  • Compounds of formula (24) can be purchased or prepared using methodologies known to those skilled in the art.
  • Mono alkylation of compounds of formula (25) with halides of formula R 3 -X 3 wherein X 3 is Cl, Br or I, using reaction conditions as described in Scheme 5 provides compounds of formula (26).
  • Compounds of formula (28) can be purchased, prepared as described herein, or prepared using methodologies known to those skilled in the art.
  • Compounds of formula (28) wherein P is an acid protecting group can be reacted with compounds of formula 7 ⁇ -Y, wherein Y is Cl, Br, I, or triflate such as 6-chloronicotinonitrile, with a base such as sodium hydride, and in an anhydrous solvent system such as tetrahydrofuran and 1,3-dimethyl- 3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU) at a temperature ranging from 0 0 C to 23 0 C to provide esters of general formula (29), wherein R 101 is a protecting group, P.
  • G 3 is aryl or heteroaryl
  • R 103 is hydrogen, potassium, sodium, lithium, or C 1 -C 6 alkyl, can be prepared as shown in Scheme 11.
  • G 3 -Y wherein G 3 is aryl or heteroaryl and Y is Cl, Br, I or triflate can be purchased or prepared using methodologies known to those skilled in the art, as well as, alkyl trimethylsilyl ketene acetals of formula (30) wherein R 103 is C 1 -C 6 alkyl.
  • Adamantanes of general formula (34) wherein Y is Cl, Br or I, can be prepared as described herein or prepared using methodologies known to those skilled in the art.
  • Olefins of general formula (35) wherein Z 3 is either aryl or heteroaryl can be purchased or prepared using methodologies known to those skilled in the art.
  • Adamantanes of general formula (34) can be reacted with olefins of general formula (35), such as, but not limited to, 4- vinylpyridine; a catalyst such as, but not limited to, bis(triphenylphosphine)palladium (II) dichloride; a base such as, but not limited to, triethylamine; and, in a solvent system such as N,N-dimethylformamide at a temperature of near 150 0 C to provide adamantanes of general formula (36).
  • olefins of general formula (35) such as, but not limited to, 4- vinylpyridine
  • a catalyst such as, but not limited to, bis(triphenylphosphine)palladium (II) dichloride
  • a base such as, but not limited to, triethylamine
  • a solvent system such as N,N-dimethylformamide at a temperature of near 150 0 C to provide adamantanes of general formula (36).
  • Substituted adamantanes of general formula (37) can be prepared as described herein or prepared using methodologies known to those skilled in the art.
  • Substituted adamantanes of general formula (37) can be alkylated with alkylating agents Q-Y, wherein Q is alkyl, arylalkyl, heteroarylalkyl, heterocycle alkyl, or cycloalkylalkyl and Y is a leaving group like I, Br, Cl, or triflate, in the presence of a base like potassium carbonate and in a solvent like N,N-dimethylformamide to yield substituted adamantanes of general formula (38).
  • Substituted adamantanes of general formula (39), wherein Y is F, Cl, Br, or I, can be prepared as described herein or prepared using methodologies known to those skilled in the art.
  • Substituted adamantanes of general formula (39) can be condensed with amines of general formula R 1 ⁇ 111 NH, to provide compounds of formula (40).
  • the reaction can be conducted neat in a microwave synthesizer at a temperature near 150 0 C for a period of about 40 minutes.
  • R 4 , and D are as defined in formula I; G 8 is aryl or heteroaryl as defined in the definition of terms; Q 1 is C 1 -C 3 alkyl; and, R q and R r are independently hydrogen, alkyl, or heterocyclealkyl, or R q and R r together with the nitrogen to which they are attached form a heterocycle ring, can be prepared as shown in Scheme 16.
  • Substituted adamantanes of general formula (41) can be prepared as described herein or prepared using methodologies known to those skilled in the art.
  • Substituted adamantanes of general formula (41) can be halogenated with a reagent like N-halosuccinimde (for example, N-chlorosuccinirnide and the like) in the presence of a radical initiator like AIBN and in a solvent like carbon tetrachloride at a temperature near 80 0 C to yield substituted adamantanes of general formula (42), wherein Y is Cl, Br, or I.
  • N-halosuccinimde for example, N-chlorosuccinirnide and the like
  • Substituted adamantanes of general formula (42) when treated with amines of general formula R q R r NH in a solvent like dichloromethane at a temperature between 23 0 C and 40 0 C provide substituted adamantanes of general formula (43).
  • Substituted adamantanes of general formula (6) can be purchased or prepared using methodology known to those in the art. Substituted adamantanes of general formula (6) can be brominated with a reagent like hydrobromic acid in a solvent like water to provide bromides of general formula (44). Adamantanes of general formula (44) when treated with ethylene glycol and a catalytic amount of an acid like p-toluenesulfonic acid in a solvent like benzene provide adamantanes of general formula (45).
  • Bromides of general formula (45) can be (a) treated with Rieke zinc in a solvent like tetrahydrofuran; and (b) followed by treatment with reagent (46) (prepared as described in Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senanayake, C. H. J. Am. Chem. Soc. 2002, 124, 7880-7881) in a solvent like tetrahydrofuran to provide adamantanes of general formula (47).
  • reagent (46) prepared as described in Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senanayake, C. H. J. Am. Chem. Soc. 2002, 124, 7880-7881
  • Adamantanes of general formula (47) may be treated with lithium amide of formula LiNHR 5 R 6 (prepared in situ by reacting ammonia with lithium or amines of formula R 5 R 6 NH wherein R 5 and R 6 are other than hydrogen, with t-butyl lithium) in a solvent like tetrahydrofuran.
  • the resulting sulfanamides can be oxidized with a reagent like osmium tetroxide with a catalyst oxidant like NMO in a solvent like tetrahydrofuran to provide sulfonamides of general formula (48).
  • Adamantanes of general formula (48) can be deketalized with reagents like hydrochloric acid in a solvent mixture like water and tetrahydrofuran to provide ketones of formula (49).
  • Ketones of formula (49) can be treated with amines of formula R 2 NH 2 followed by reduction with reducing reagents such as, but not limited to, sodium borohydride or hydrogen over Pd/C in a solvent like methanol to provide amines of general formula (50).
  • a 2 , A 3 , A 4 , R 2 , R 5 and R 6 in amines of formula (50) may be a substituent with a functional group containing a protecting group such as a carboxylic acid protected as the methyl ester.
  • a protecting group such as a carboxylic acid protected as the methyl ester.
  • Such esters can be hydrolyzed and other protecting groups removed here or in compounds subsequently prepared from (50) using methodology known to those skilled in the art.
  • the reaction solution was cooled to 10 0 C in an ice bath. 20 volumes of 10% NaCl aq (4 L) were cooled to ⁇ 10 0 C, the crude reaction mixture was quenched into the brine solution in batches, maintaining an internal temperature ⁇ 70 0 C. The quenched reaction solution was combined with a second identical reaction mixture for isolation.
  • the combined product solutions were extracted 3x5 volumes with CH 2 Cl 2 (3x2.2 L) and the combined CH 2 Cl 2 layers were then washed 1x2 volumes with 10% NaCl (1 L).
  • the CH 2 Cl 2 solution was then extracted 3x5 volumes with 10% Na 2 CO 3 (3x2.2L).
  • the combined Na 2 CO 3 extracts were washed with 1x2 volumes with CH 2 Cl 2 (1 L).
  • the Na 2 CO 3 layer was then adjusted to pH 1-2 with concentrated HCl ( ⁇ 2 volumes, product precipitates out of solution).
  • the acidic solution was then extracted 3x5 volumes with CH 2 Cl 2 (3x2.2 L), and the organic layer was washed 1x2 volumes with 10% NaCl.
  • the organic solution was then dried over Na 2 SO 4 , filtered, concentrated to -1/4 volume, then chase distilled with 2 volumes EtOAc (1 L). Nucleation occurred during this distillation.
  • the suspension was then chase distilled 2x5 volumes (2x2 L) with heptane and cooled to room temperature.
  • the suspension was then filtered, and the liquors were recirculated 2x to wash the wet cake.
  • the resultant material was dried overnight at 50 0 C, 20 mm Hg to afford the title compound.
  • Example 1C E-4-amino-adamantane-l-carboxylic acid methyl ester hydrochloride Methanol (10 volumes, 85 mL) was cooled to 0 0 C. AcCl was added dropwise (5.0 equiv., 15.5 mL), and the solution was warmed to ambient temperature for 15-20 minutes. The product from Example IB (8.53 g, 43.7 mmol, 1.0 equiv.) was added and the reaction solution was heated to 45 0 C for 16 hours (overnight). Consumption of the starting aminoacid was monitored by LC/MS (APCI). The reaction solution was then cooled to room temperature, 10 volumes MeCN (85 mL) was added, distilled to ⁇ 1/4 volume
  • the methyl ester of the titled compound obtained from step A (50 mg, 0.12 mmol) was dissolved in 3 N HCl (1 mL), dioxane (0.25 mL), and 4 N HCl (1 mL). The homogenous acid solution was heated to 60 0 C for 24 hours, was cooled to 23 0 C, and was then concentrated under reduced pressure to provide the title compound.
  • the methyl ester of the titled compound was prepared according to the method of step
  • Example ID A of Example ID substituting 1 -phenyl- 1-cyclopropanecarboxylic acid for X-(A- chlorophenyl)-l-cyclobutanecarboxylic acid, and the crude methyl ester was purified by chromatography on flash silica gel with an eluant gradient of 20-40% ethyl acetate/hexanes.
  • the methyl ester of the titled compound was prepared according to the method of step A of Example ID substituting 2-methyl-2-phenyl propionic acid for l-(4-chlorophenyl)-l- cyclobutanecarboxylic acid, and the crude methyl ester was purified by chromatography on flash silica gel with an eluant gradient of 20-40% ethyl acetate/hexanes.
  • Step B The methyl ester obtained from step A (49 mg, 0.14 mmol) was dissolved in 3 N HCl (1 mL) and dioxane (0.25 mL), heated to 60 0 C for 24 hours, was cooled to 23 0 C, and was then concentrated under reduced pressure to provide the title compound.
  • Example 4 E-A- ⁇ [ 1 -(4-Chloro-phenyiy cyclobutanecarbonyri -amino ⁇ -adamantane- 1 -carboxylic acid amide A solution of the product from step B of Example ID (24 mg, 0.062 mmol) in DCM
  • Example 6 i?-4-f 2-Methyl-2-phenyl-propionylamino)-adamantane- 1 -carboxylic acid amide
  • the title compound was prepared according to the method of Example 4 substituting the product from step B of Example 3 for the product from step B of Example ID.
  • Example 7 iV -2-adamantyl-2-methyl-2-phenylpropanamide
  • 2-adamantanamine hydrochloride 38 mg, 0.20 mmol
  • 2- phenylisobutyric acid 30 mg, 0.19 mmol
  • O-benzotriazol-l-yl- ⁇ -V,N',iV ' '- tetramethyluronium tetrafiuoroborate TBTU
  • TBTU O-benzotriazol-l-yl- ⁇ -V,N',iV ' '- tetramethyluronium tetrafiuoroborate
  • DMA N,N-dimethylacetamide
  • DIEA 80 ⁇ L, 0.46 mmol
  • DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 urn particle size) using a gradient of 10% to 100% acetonitrile: aqueous ammonium acetate (10 mM) over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute on reverse phase HPLC to afford the title compound upon concentration under reduced pressure.
  • step A The methyl ester obtained from step A (47 mg, 0.11 mmol) was dissolved in 5 N aqueous HCl (1 mL) and 4 N HCl in dioxane (2 mL), heated to 60 0 C for 24 hours, was cooled to 23 0 C, and was then concentrated under reduced pressure to provide the title compound.
  • the title compound was prepared according to the method as described in Example 4 substituting the product of step B of Example 9A for the product of step B of Example ID, and with the exception that the crude title compound was purified by normal phase flash chromatography with MeOH/DCM (5:95) as eluant.
  • step A The methyl ester obtained from step A (51 mg, 0.13 mmol) was dissolved in 5 N aqueous HCl (1 mL) and 4 N HCl in dioxane (2 mL), heated to 60 0 C for 24 hours, was cooled to 23 C, and was then concentrated under reduced pressure to provide the title compound.
  • the title compound was prepared according to the method as described in Example 4, substituting the product of step B of Example 1OA for the product of step B of Example ID and with the exception that title compound was purified by normal phase flash chromatography with MeOH/DCM (5:95) as eluant.
  • the methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting l-(4-chlorophenyl)-l- cyclopentanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid, and with the exceptions that the methyl ester was purified by reverse phase chromatography.
  • the methyl ester obtained from step A (30 mg, 0.072 mmol) was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1 mL), heated to 60 0 C for 24 hours, was cooled to 23 0 C, and was then concentrated under reduced pressure to provide the title compound.
  • the title compound was prepared according to the method as described in Example 4, substituting the product of step B of Example 11 A for the product of step B of Example ID, and with the exception that title compound was purified by normal phase flash chromatography with MeOH/DCM (5:95) as eluant.
  • Step B The methyl ester obtained from step A (50 mg, 0.13 mmol) was dissolved in 5 N aqueous HCl (1 mL) and 4 N HCl in dioxane (2 mL), heated to 60 0 C for 24 hours, was cooled to 23 0 C, and was then concentrated under reduced pressure to provide the title compound.
  • the methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting 1 -phenyl- 1-cyclopentanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid, and with the exceptions that the methyl ester was purified by reverse phase chromatography.
  • the methyl ester obtained from step A (20 mg, 0.052 mmol) was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1 mL), heated to 60 0 C for 24 hours, was cooled to 23 0 C, and was then concentrated under reduced pressure to provide the title compound.
  • Example 13B E-4- [(I -phenylcyclopentvDcarbonyll amino ⁇ adamantane- 1 -carboxamide
  • the title compound was prepared according to the method as described in Example 4, substituting the product of step B of Example 13 A for the product of step B of Example ID, and with the exception that title compound was purified by normal phase flash chromatography with MeOH/DCM (5:95) as eluant.
  • Step A The methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting l-(3-fluorophenyl)-l- cyclopentanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid, and with the exceptions that the methyl ester was purified by reverse phase chromatography.
  • step A The methyl ester obtained from step A (41 mg, 0,10 mmol) was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1 mL), heated to 60 0 C for 24 hours, was cooled to 23 0 C, and was then concentrated under reduced pressure to provide the title compound.
  • Example 15A E-A-( ⁇ [ 1 -(2-chloro-4-fluoro ⁇ henyl)cyclopentyl]carbonvU amino)adamantane- 1 -carboxylic acid Step A
  • the methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting l-(2-chloro-4-fluorophenyl)-l- cyclopentanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid, and with the exceptions that the methyl ester was purified by reverse phase chromatography.
  • Step B The methyl ester obtained from step A (66 mg, 0.15 mmol) was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (2 mL), heated to 60 0 C for 24 hours, was cooled to 23 0 C, and was then concentrated under reduced pressure to provide the title compound.
  • step A The methyl ester obtained from step A (58 mg, 0.15 mmol) was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (2 mL), heated to 60 0 C for 24 hours, was cooled to 23 0 C, and was then concentrated under reduced pressure to provide the title compound.
  • the methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting l-(2-fluorophenyl)-l- cyclopentanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid, and with the exceptions that the methyl ester was purified by reverse phase chromatography.
  • Step B The methyl ester obtained from step A (56 mg, 0.14 mmol) was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (2 mL), heated to 60 0 C for 24 hours, was cooled to 23 0 C, and was then concentrated under reduced pressure to provide the title compound.
  • the methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting 1 -methyl- 1-cyclohexanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid, and with the exceptions that the methyl ester was purified by reverse phase chromatography.
  • step A The methyl ester obtained from step A (33 mg, 0.10 mmol) was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1 mL), heated to 60 0 C for 24 hours, was cooled to 23 0 C, and was then concentrated under reduced pressure to provide the title compound.
  • Example 18B E-A- ⁇ ⁇ ( 1 -methylcyclohexyDcarbonyll amino) adamantane- 1 -carboxamide
  • the title compound was prepared according to the method as described in Example 4, substituting the product of step B of Example 18A for the product of step B of Example ID.
  • the methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting l-(2,4-dichlorophenyl)-l- cyclopropanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid and with the exceptions that the methyl ester was purified by reverse phase chromatography.
  • step A The methyl ester obtained from step A (47 mg, 0.11 mmol) was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (2 mL), heated to 60 0 C for 24 hours, was cooled to 23 0 C, and was then concentrated under reduced pressure to provide the title compound.
  • the methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting l-(4-methoxyphenyl)-l- cyclopropanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid and with the exceptions that the methyl ester was purified by reverse phase chromatography.
  • Step B The methyl ester obtained from step A (43 mg, 0.11 mmol) was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1 mL), heated to 60 0 C for 24 hours, was cooled to 23 0 C, and was then concentrated under reduced pressure to provide the title compound.
  • the methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting l-(4-methylphenyl)-l- cyclopropanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid and with the exceptions that the methyl ester was purified by reverse phase chromatography.
  • step A The methyl ester obtained from step A (39 mg, 0.11 mmol) was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1 mL), heated to 60 0 C for 24 hours, was cooled to 23 0 C, and was then concentrated under reduced pressure to provide the title compound.
  • Example 22A To a solution of the product of Example 22A (3.7 g, 13.6 mmoles) in tetrahydrofuran (110.0 ml) and methanol (37.0 ml) was added 2 N sodium hydroxide (19.0 ml) and the solution was stirred at ambient temperature for about 16 hours. The reaction mixture was concentrated in vacuum down to the water layer, was cooled with an ice bath, and was acidified by addition of 2N hydrochloric acid. The precipitate was filtered off and was dried in vacuum to provide the title compound.
  • Example 22C To a solution of the product of Example 22C (300 mg, 0.7 mmoles) in 1,2- dimethoxyethane (6.0 ml) was added a solution of pyridine-4-boronic acid (127 mg, 1.0 mmoles) in ethanol (1.0 ml), dichlorobis(tri-o-tolylphosphine)palladium(II) (28 mg, 0.04 mmoles) and a 2M aqueous solution of sodium carbonate (1.7 ml, 3.5 mmoles) and the mixture was stirred under nitrogen in a heavy walled process vial in a microwave synthesizer (Personal Chemistry Smith Synthesizer) at about 140 0 C for about 10 min. The reaction mixture was concentrated in vacuum and the crude product was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (2 : 1) as the mobile phase to provide the title compound.
  • pyridine-4-boronic acid 127 mg, 1.0
  • Example 23C To a solution of the product of Example 23C (250 mg, 0.69 mmoles) in dioxane (9.0 ml) was added 2N hydrochloric acid (9.0 ml) and the mixture was heated to about 60 °C for about 18 hours. The mixture was cooled, concentrated down to the water layer, the precipitate was filtered off and was dried in vacuum to give the title compound.
  • Example 22F The title compound was prepared according to the method of Example 22F, substituting the product of Example 23D for the product of Example 22E.
  • Example 24D E-4-(2-Methyl-2-tMophen-3-yl-propionylaminoVadamantane- 1 -carboxylic acid
  • the title compound was prepared according to the method of Example 23D, substituting the product of Example 24C for the product of Example 23C.
  • Example 22F The title compound was prepared according to the method of Example 22F, substituting the product of Example 24D for the product of Example 22E.
  • Example 25B A solution of Example 25B (30 mg, 0.071 mmol), KOTMS (14 mg, 0.11 mmol) in THF (1 mL) was stirred for 12 hours at 23 0 C. The solvent was evaporated in vacuo to collect a solid. To the solid was added TBTU (40 mg, 0.12 mmol), DIEA (22 mg, 0.17 mmol) and DMF (0.5 mL) and stirred for 2 hours at 23 0 C. Ammonium hydroxide-30% by weight (2 mL) was added and stirred at 23 0 C for a further 30 minutes. The reaction was partitioned between EtOAc (8 mL) and water (3mL).
  • the organic layer was washed with water (3 mL), dried with MgSO 4 , filtered, and evaporated in vacuo.
  • the crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 urn particle size) using a gradient of 20% to 100% acetonitrile: water (0.1% TFA) over 18 min at a flow rate of 40 mL/min.to provide the title compound as the trifluoroacetic acid salt.
  • Example 22C The title compound was prepared according to the method of Example 22C substituting the product of Example 26C for the product of Example 22B .
  • Example 27A E-A- ( I " 1 -(4-Methox v-phenylVcyclopentanecarbonyl] -amino > -adamantane- 1 -carboxylic acid methyl etser A solution of the product of Example 1C (110 mg, 0.45 mmol), l-(4-methoxyphenyi)-
  • Example 22F The title compound was prepared according to the method of Example 22F substituting the product of Example 28 A for the product of Example 22E.
  • Example 30A was purified by flash chromatography (hexane/EtOAc 100:0 to 85:15) to provide Example 30A as an oil.
  • Example 3OA A solution of the product of Example 3OA (1.0 gm, 5 mmol) was dissolved in CH 2 Cl 2 MeOH 10:1 (15 mL) and cooled to -78°C. To the solution was bubbled O 3 over 20 minutes. The reaction solution was purged with N 2 for a further 10 minutes and dimethyl sulfide (DMS) (3.1 gm, 50 mmol) was added and the reaction warmed to ambient temperature and stirred for a further 2 hours. The solvent was evaporated in vacuo and product purified by flash column chromatography (hexane/EtOAc 100:0 to 70:30) to collect Example 30B as an oil.
  • DMS dimethyl sulfide
  • the crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 um particle size) using a gradient of 20% to 100% acetonitrile:water (0.1% TFA) over 18 min at a flow rate of 40 mL/min. to provide the title compound.
  • Example 31A A solution of the product of Example 31A (1.1 gm, 5.9 mmol) was dissolved in CH 2 Cl 2 /Me0H 10:1 (15 mL) and cooled to -78 0 C. To the solution was bubbled O 3 over 20 minutes. The reaction solution was purged with N 2 for a further 10 minutes and dimethyl sulfide (DMS) (3.6 gm, 59 mmol) was added and the reaction warmed to ambient temperature and stirred for a further 2 hours. The solvent was evaporated in vacuo and product purified by flash column chromatography (hexane/EtOAc 100:0 to 70:30) to collect Example 3 IB as an oil.
  • DMS dimethyl sulfide
  • Example 3 ID E-4-raminocarbonyl)-2-adamantyl1-l-benzyl-3-methyl-2-oxopyrrolidine-3-carboxamide
  • Example 1C (54 mg, 0.22 mmol), TBTU (92 mg, 0.29 mmol) and DIEA (57 mg, 0.45 mmol) in DMF (1.2 mL) was stirred for 2 hours at 23 0 C.
  • the reaction was partitioned between EtOAc (8 ml) and water (4 ml). The organic layer was separated and washed twice with water (4 mL each), dried with MgSO 4 , filtered and evaporated in vacuo.
  • the resulting oil was taken in THF (1 mL) and stirred with KOTMS (34 mg, 0.27 mmol) for 12 hours at 23 0 C. The solvent was evaporated in vacuo.
  • the crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 um particle size) using a gradient of 20% to 100% acetonitrile: water (0.1% TFA) over 18 min at a flow rate of 40 mL/min. to provide the title compound.
  • Example 32A 50 mg, 0.17 mmol
  • the product of Example 1C 52 mg, 0.21 mmol
  • TBTU 87 mg, 0.27 mmol
  • DIEA 54 mg, 0.42 mmol
  • the reaction was partitioned between EtOAc (8 ml) and water (4 ml). The organic layer was separated and washed twice with water (4 mL each), dried with MgSO 4 , filtered and evaporated in vacuo. The resulting oil was taken in THF (1 mL) and stirred with KOTMS (33 mg, 0.25 mmol) for 12 hours at 23 0 C. The solvent was evaporated in vacuo.
  • the crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 urn particle size) using a gradient of 20% to 100% acetonitriletwater (0.1% TFA) over 18 min at a flow rate of 40 mL/min. to provide the title compound.
  • Example 1C (48 mg, 0.19 mmol), TBTU (82 mg, 0.25 mmol) and DIEA (51 mg, 0.4 mmol) in DMF (1.2 mL) was stirred for 2 hours at 23 0 C.
  • the reaction was partitioned between EtOAc (8 ml) and water (4 ml). The organic layer was separated and washed twice with water (4 mL each), dried with MgSO 4 , filtered and evaporated in vacuo.
  • the resulting oil was taken in THF (1 mL) and stirred with KOTMS (31 mg, 0.24 mmol) for 12 hours at 23 0 C. The solvent was evaporated in vacuo.
  • the crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 urn particle size) using a gradient of 20% to 100% acetonitrile:water (0.1% TFA) over 18 min at a flow rate of 40 mL/min. to provide the title compound.
  • Example 34A A solution of the product of Example 31B (0.075 gm, 0.4 mmol), 3-chloro- benzylamine (68 mg, 0.47 mmol) and MP-triacetoxy borohydride (431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours at 23 0 C. The solution was filtered and evaporated in vacuo. The resulting oil was taken up in THF (1.2 mL) and stirred with KOTMS (77 mg, 0.6 mmol) at 23 0 C for 12 hours. The solvent was evaporated in vacuo to provide Example 34A.
  • Example 35B E-A- ⁇ 2-Methyl-2-[4-(l -methyl- lH-pyrazol-4-ylVphenyl]-propionylamino ⁇ -adamantane- 1 - carboxylic acid
  • the title compound was prepared according to the method of Example 23D, substituting the product of Example 35 A for the product of Example 23C.
  • Example 36D E-4-[2-(3-BromophenylV2-methylpropionylamino] -adamantane-1-carboxylic acid methlv ester
  • the title compound was prepared according to the method as described in Example
  • Example 27C The title compound was prepared according to the method as described in Example 27C, substituting the product of Example 36E for the product of Example 27B.
  • Example 22D The title compound was prepared according to the method of Example 22D, substituting 3,5-dimethyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane-2-yl)isoxazole for pyridine-4-boronic acid.
  • Example 37C E-4- ⁇ 2-[4-(3,5-Dimethyl-isoxazol-4-yl)-phenyl1-2-methyl-propionylamino ⁇ -adamantane-l- carboxylic acid amide
  • the title compound was prepared according to the method of 35C, substituting the product of Example 37B for the product of Example 35B.
  • the crude product was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm x 100 mm, 7 ⁇ m particle size) using a gradient of 10% to 100% acetonitrile : 0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 ml/min.
  • Example 38B E-A- [2-Methyl-2-(4- ⁇ yridin-3 -yl-phenyiVpropionylammo] -adamantane- 1 -carboxylic acid
  • the trifluoroacetic acid salt of the title compound was prepared according to the method of Example 35C, substituting the product of Example 38B for the product of Example 35B, and with the exception that the crude product was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm x 100 mm, 7 ⁇ m particle size) using a gradient of 10% to 100% acetonitrile : 0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 ml/min.
  • Example 39A E-4-( ⁇ [ " 4-(2-Methyl-2-thiophen-2-yl-propionylaminoVadamantane-l-carbonyl1-amino>- methvD-benzoic acid methyl ester
  • the title compound was prepared according to the method of Example 22C, substituting the product of Example 23D for Example 22B and substituting methyl A- (aminomethyl)-benzoate hydrochloride for the product of Example 1C.
  • Example 35C The title compound was prepared according to the method of Example 35C substituting the product of Example 4OB for the product of Example 35B.
  • Example 41 A Potassium: 3 -methyl- 1 -( 1 -methyl- 1 -phenyl-ethyl)-2-oxo-pyrrolidine-3 -carboxylate
  • Example 4 IA The solvent was evaporated in vacuo and the residue taken in THF (1.2 mL) and stirred with KOTMS (77 mg, 0.6 mmol) for 12 hours at 23 0 C. The solvent was evaporated in vacuo to provide Example 4 IA.
  • the crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 um particle size) using a gradient of 20% to 100% acetonitrile ".water (0.1% TFA) over 18 min at a flow rate of 40 mL/min. to provide the title compound.
  • Example 42A Potassium; 3 -methyl-2-oxo- 1 -(( 1 R)- 1 -phenylethvDpyrrolidine-3 -carboxylate
  • Example 42A A solution of the product of Example 3 IB (0.075 gm, 0.4 mmol), (R)-I- phenylethylamine (58 mg, 0.47 mmol) and MP-triacetoxy borohydride (431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours at 23 0 C. The solution was filtered and evaporated in vacuo. The resulting oil was taken up in toluene (1.5 mL) and heated at 100 0 C for 5 hours. The solvent was evaporated in vacuo and the residue taken in THF (1.2 mL) and stirred with KOTMS (77 mg, 0.6 mmol) for 12 hours at 23 0 C. The solvent was evaporated in vacuo to provide Example 42A as 1:1 mixture of diastereomers.
  • Example 42B E-4-raminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-l-rdRVl-phenylethyl1pyrrolidme-3- carboxamide
  • a solution of the product of Example 42 A 50 mg, 0.17 mmol
  • the product of Example 1C 52 mg, 0.21 mmol
  • TBTU 87 mg, 0.27 mmol
  • DIEA 51 mg, 0.4 mmol
  • the reaction was partitioned between EtOAc (8 ml) and water (4 ml).
  • the organic layer was washed with water (3 mL), dried with MgSO 4 , filtered and evaporated in vacuo.
  • the crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 ran particle size) using a gradient of 20% to 100% acetonitrile: water (0.1% TFA) over 18 min at a flow rate of 40 mL/min. to provide the title compound as a 1 : 1 mixture of diastereomers.
  • Example 43B A solution of the product of Example 31B (0.075 gm, 0.4 mmol), (S)-I- phenylethylamine (58 mg, 0.47 mmol) and MP-triacetoxy borohydride (431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours at 23 0 C. The solution was filtered and evaporated in vacuo. The resulting oil was taken up in toluene (1.5 mL) and heated at 100 0 C for 5 hours. The solvent was evaporated in vacuo and the residue taken in THF (1.2 mL) and stirred with KOTMS (77 mg, 0.6 mmol) at 23 0 C for 12 hours. The solvent was evaporated in vacuo to provide Example 43 A as a 1:1 mixture of diastereomers.
  • Example 43B A solution of the product of Example 31B (0.075 gm, 0.4 mmol), (S)-I- phenylethylamine (58 mg, 0.47
  • Example 1C (52 mg, 0.21 mmol), TBTU (87 mg, 0.27 mmol) and DIEA (51 mg, 0.4 mmol) in DMF (1.2 mL) was stirred at 23 0 C for 2 hours.
  • the reaction was partitioned between EtOAc (8 ml) and water (4 ml). The organic layer was separated and washed twice with water (4 mL each), dried with MgSO 4 , filtered and evaporated in vacuo.
  • the resulting oil was taken in THF (1 mL) and stirred with KOTMS (32 mg, 0.25 mmol) at 23 0 C for 12 hours. The solvent was evaporated in vacuo.
  • the crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 ran particle size) using a gradient of 20% to 100% acetonitrile: water (0.1% TFA) over 18 min at a flow rate of 40 niL/min. to provide the title compound as a 1:1 mixture of diastereomers.
  • Example 44A To a solution of the product of Example 44A (12.9 g, 40.7 mmoles) in dichloromethane (100.0 ml) was added tetrachloro-l,2-benzoquinone (10.0 g, 40.7 mmoles) in portions at about 0 °C, such that the mixture always had time to decolorize to a yellow- orange color. The mixture was then stirred for about 1 hour at 0 0 C and was then washed with saturated aqueous sodium bicarbonate solution (200.0 ml) and brine (100.0 ml).
  • Example 45B S-Methyl-piperidine-l ⁇ -dicarboxylic acid 1-benzyl ester To a -78 0 C solution of the product of Example 45A (6.0 g, 20.6 mmoles) in THF (50 mL) was added a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 22.7 mmoles). After 35 min, iodomethane (1.4 mL, 22.7 mmoles) was added and the reaction was slowly warmed to room temperature and stirred overnight. The reaction was quenched with aqueous sat. ammonium chloride and extracted with Et 2 O.
  • the organic layer was then rinsed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • the crude product was purified by silica gel chromatography employing a solvent gradient (hexane ⁇ 65:35 hexane:EtOAc). The resulting ester was hydrolyzed overnight at room temperature in THF (15 mL), H 2 O (10 mL), and EtOH (15 mL) with NaOH (2.5 g). The solution was concentrated under vacuum; the residue was dissolved in saturated ammonium chloride; and, the solution was extracted with ethyl acetate (3x). The combined ethyl acetate extracts were dried over sodium sulfate, filtered, and concentrated under vacuum to yield the title compound as a white solid.
  • Example 45B 2-phenylisobutyric acid
  • Example 1C 2-adamantanamine hydrochloride
  • Example 45D N-[E-4-(carbomethoxy)-2-adamantyl1-l-3-methylpiperidine-3-carboxamide A solution of the product of Example 45C (0.62 g, 1.32 mmoles) and 10% palladium on carbon (60 mg) in EtOAc (20 mL) was exposed to hydrogen (60 psi) at room temperature for 6 hours. The reaction was incomplete so EtOH was added and the reaction continued for an additional 8 h. The crude product was then filtered away from the catalyst using methanol and isolated after concentration in vacuo to provide the title compound.
  • Example 45D To a solution of the product of Example 45D (100 mg, 0.3 mmoles) and 4- chlorobenzaldehyde in dichloroethane (0.75 mL) and acetic acid (0.07 mL, 1,2 mmoles) was added sodium triacetoxyborohydride (127 mg, 0.6 mmoles). The resulting reaction mixture was stirred at room temperature overnight. The reaction was quenched with sat. aqueous NH 4 Cl and extracted with EtOAc. The organic layer was then rinsed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to provide a crude sample of the title compound.
  • Example 45E The crude product from Example 45E was hydrolyzed with an excess of NaOH at room temperature in a solution of water, EtOH, and tetrahydrofuran for 16 hours. The reaction was quenched with sat. aqueous NH 4 Cl and extracted with EtOAc. The organic layer was then rinsed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue, EDCI (80 mg, 0.42 mmoles), and 1-hydroxybenzotriazole hydrate (56.5 mg, 0.42 mmoles) were dissolved in DMF (0.75 mL) and stirred for 30 min at room temperature. Concentrated NH 4 OH (0.75 mL) was then added and stirring was continued overnight.
  • Example 27A The title compound was prepared according to the method as described in Example 27A, substituting the product of Example 46D for l-(4-methoxyphenyl)-l- cyclopentanecarboxylic acid.
  • Example 27C The title compound was prepared according to the method as described in Example 27C, substituting the product of Example 46G for the product of Example 27B.
  • Example 47 A A solution of the product of Example 30B (0.075 gm, 0.37 mmol), benzylamine (47 mg, 0.44 mmol) and MP-triacetoxy borohydride (420 mg, 0.92 mmol) in THF (2 mL) was stirred for 12 hours at 23 0 C. The solution was filtered and evaporated in vacuo. The resulting oil was taken up in THF (1.2 mL) and stirred with KOTMS (71 mg, 0.55 mmol) for 12 hours at 23 0 C. The solvent was evaporated in vacuo to provide Example 47 A.
  • the crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 um particle size) using a gradient of 20% to 100% acetonitrile:water (0.1% TFA) over 18 min at a flow rate of 40 mL/min. to provide the title compound.
  • Example 35 C The title compound was prepared according to the method of Example 35 C, substituting the product of Example 48E for the product of Example 35B.
  • Example 49C 2-rBenzofb]thiophen-3-ylV2-methylpropanoic acid The title compound was prepared according to the method of Example 22B substituting the product of Example 49B for the product of Example 22 A.
  • Example 50A The organic layer was dried with MgSO 4 , filtered, and evaporated in vacuo.
  • the crude product was purified by flash chromatography (hexane/EtOAc 100:0 to 80:20) to give the methyl ester of Example 50A.
  • MTBE Methyl t-butyl ether
  • Example 50B E-4- ⁇ [2-(5-fluoropyridin-2-ylV2-methylpropanoyl]amino)adamantane-l-carboxamide A solution of the product of Example 50A (30 mg, 0.15 mmol), the product of
  • Example 1C (45 mg, 0.18 mmol), TBTU (77 mg, 0.24 mmol) and DIEA (47 mg, 0.37 mmol) in DMF (1.2 mL) was stirred at 23 0 C for 3 hrs.
  • the reaction was diluted with EtOAc (10 mL) and washed twice with water (6 mL) and brine (6 mL).
  • the organic layer was dried with MgSO 4 , filtered, and evaporated in vacuo.
  • the residue was taken in THF (1 mL) and stirred with KOTMS (29 mg, 0.22 mmol) for 12 hours at 23 0 C. The solvent was evaporated in vacuo.
  • the crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 urn particle size) using a gradient of 20% to 100% acetonitrile:water (0.1% TFA) over 18 min at a flow rate of 40 mL/min. to provide the title compound as the trifluoroacetic acid salt.
  • Example 51A was isolated by filtration.
  • the crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 urn particle size) using a gradient of 20% to 100% acetonitrile: water (0.1% TFA) over 18 min at a flow rate of 40 niL/min. to provide the title compound as the trifluoroacetic acid salt.
  • test compounds to inhibit human 1 l ⁇ -HSD-1 enzymatic activity in vitro was evaluated in a Scintillation Proximity Assay (SPA).
  • SPA Scintillation Proximity Assay
  • Tritiated-cortisone substrate, NADPH cofactor and titrated compound were incubated with truncated human ll ⁇ -HSD-1 enzyme (24-287AA) at room temperature to allow the conversion to Cortisol to occur.
  • the reaction was stopped by adding a non-specific 11 ⁇ -HSD inhibitor, 18 ⁇ -glycyrrhetinic acid.
  • the tritiated Cortisol was captured by a mixture of an anti-cortisol monoclonal antibody and SPA beads coated with anti-mouse antibodies.
  • the reaction plate was shaken at room temperature and the radioactivity bound to SPA beads was then measured on a ⁇ -scintillation counter.
  • the 11- ⁇ HSD-l assay was carried out in 96-well microtiter plates in a total volume of 220 ⁇ l.
  • 188 ⁇ l of master mix which contained 17.5 nM 3 H-cortisone, 157.5 nM cortisone and 181 mM NADPH was added to the wells.
  • 1 mM G-6-P was also added.
  • E.coli lysates overexpressing 11 ⁇ -HSD- 1 enzyme After shaking and incubating plates for 30 minutes at room temperature, reactions were stopped by adding 10 ⁇ l of 1 mM glycyrrhetinic acid. The product, tritiated Cortisol, was captured by adding 10 ⁇ l of 1 ⁇ M monoclonal anti- cortisol antibodies and 100 ⁇ l SPA beads coated with anti-mouse antibodies. After shaking for 30 minutes, plates were read on a liquid scintillation counter Topcount. Percent inhibition was calculated based on the background and the maximal signal. Wells that contained substrate without compound or enzyme were used as the background, while the wells that contained substrate and enzyme without any compound were considered as maximal signal. Percent of inhibition of each compound was calculated relative to the maximal signal and IC 50 curves were generated. This assay was applied to 11 ⁇ -HSD-2 as well, whereby tritiated Cortisol and NAD + were used as substrate and cofactor, respectively.
  • Compounds of the present invention are active in the 11- ⁇ HSD-l assay described above and show selectivity for human 11- ⁇ -HSD-l over human 1 l- ⁇ -HSD-2, as indicated in Table 1.
  • the data in Table 1 demonstrates that compounds A, B, C and D are active in the human 1 l ⁇ -HSD-1 enzymatic SPA assay described above and the tested compounds show selectivity for l l ⁇ -HSD-1 over ll ⁇ -HSD-2.
  • the ll ⁇ -HSD-1 inhibitors of this invention generally have an inhibition constant IC 50 of less than 600 nM and preferably less than 50 nM.
  • the compounds preferably are selective, having an inhibition constant IC 50 against ll ⁇ - HSD-2 greater than 1000 nM and preferably greater than 10,000 nM.
  • the IC 50 ratio for 11 ⁇ -HSD-2 to 11 ⁇ -HSD- 1 of a compound is at least 10 or greater and preferably 100 or greater..
  • Metabolic stability screen each substrate (10 ⁇ M) was incubated with microsomal protein (0.1 - 0.5 mg/ml) in 5OmM potassium phosphate buffer (pH 7.4) in 48-Well plate.
  • the enzyme reaction was initiated by the addition of ImM NADPH 5 then incubated at 37°C in a Forma Scientific incubator (Marietta, OH, USA) with gentle shaking.
  • the reactions were quenched by the addition of 800 ⁇ l of ACN/MeOH (1:1, v/v), containing 0.5 ⁇ M of internal standard (IS), after 30 min incubation.
  • the parent remaining in the incubation mixture was determined by LC/MS.
  • the LC/MS system consisted of an Agilent 1100 series (Agilent Technologies, Waldbronn, Germany) and API 2000 (MDS SCIEX, Ontario, Canada).
  • a Luna C8(2) 50 x 2.0 mm, particle size 3 ⁇ m, Phenomenex, Torrance, CA, USA was used to quantify each compound at ambient temperature.
  • the mobile phase consisted of (A): 10 mM NH 4 AC (pH 3.3) and (B): 100% ACN and was delivered at a flow rate of 0.2 ml/min. Elution was achieved using a linear gradient of 0-100% B over 3 min, then held 100% B for 4 min and returned to 100% A in 1 min. The column was equilibrated for 7 min before the next injection.
  • the peak area ratios (each substrate over IS) at each incubation time were expressed as the percentage of the ratios (each substrate over IS) of the control samples (0 min incubation).
  • the parent remaining in the incubation mixture was expressed as the percentage of the values at 0 min incubation.
  • Compounds A, B, C and D contain a substituted adamantane, whereas the adamantane ring of Compounds E and F is unsubstituted.
  • the microsomal, metabolic, stability data in Table 2 demonstrates that substituted adamantane compounds of the present invention may exhibit an increase in metabolic stability compared to unsubstituted adamantane compounds which may lead to longer in vivo half lives and pharmacokinetic advantages over unsubstituted adamantanes.
  • Glucocorticoids are steroid hormones that play an important role in regulating multiple physiological processes in a wide range of tissues and organs.
  • glucocorticoids are potent regulators of glucose and lipid metabolism. Excess glucocorticoid action may lead to insulin resistance, type 2 diabetes, dyslipidemia, visceral obesity and hypertension.
  • Cortisol is the major active and cortisone is the major inactive form of glucocorticoids in humans, while corticosterone and dehydrocorticosterone are the major active and inactive forms in rodents.
  • the main determinants of glucocorticoid action were thought to be the circulating hormone concentration and the density of glucocorticoid receptors in the target tissues.
  • tissue glucocorticoid levels may also be controlled by 1 l ⁇ -hydroxysteroid dehydrogenases enzymes (1 l ⁇ -HSDs).
  • 1 l ⁇ -HSDs There are two 1 l ⁇ - HSD isozymes which have different substrate affinities and cofactors.
  • the 1 l ⁇ - hydroxysteroid dehydrogenases type 1 enzyme (1 l ⁇ -HSD-1) is a low affinity enzyme with K m for cortisone in the micromolar range that prefers NADPH/NADP + (nicotinamide adenine dinucleotide) as cofactors.
  • 11 ⁇ -HSD-1 is widely expressed and particularly high expression levels are found in liver, brain, lung, adipose tissue and vascular smooth muscle cells.
  • the 1 l ⁇ -hydroxysteroid dehydrogenases type 2 enzyme (11 ⁇ -HSD-2) is a NAD + -dependent, high affinity dehydrogenase with a K m for Cortisol in the nanomolar range.
  • 11 ⁇ -HSD-2 is found primarily in mineralocorticoid target tissues, such as kidney, colon and placenta.
  • Glucocorticoid action is mediated by the binding of glucocorticoids to receptors, such as mineralocorticoid receptors and glucocorticoid receptors. Through binding to its receptor, the main mineralocorticoid aldosterone controls the water and salts balance in the body.
  • 1 l ⁇ -HSD-2 converts Cortisol to inactive cortisone, therefore preventing the non-selective mineralocorticoid receptors from being exposed to high levels of Cortisol.
  • Mutations in the gene encoding 1 l ⁇ -HSD-2 cause Apparent Mineralocorticoid Excess Syndrome (AME), which is a congenital syndrome resulting in hypokaleamia and severe hypertension.
  • AME Patients have elevated Cortisol levels in mineralocorticoid target tissues due to reduced 11 ⁇ -HSD-2 activity.
  • the AME symptoms may also be induced by administration of 1 l ⁇ -HSD-2 inhibitor, glycyrrhetinic acid.
  • 1 l ⁇ -HSD-2 inhibitor glycyrrhetinic acid.
  • the activity of 11 ⁇ -HSD-2 in placenta is probably important for protecting the fetus from excess exposure to maternal glucocorticoids, which may result in hypertension, glucose intolerance and growth retardation.
  • the present invention describes selective ll ⁇ -HSD-1 inhibitors.
  • Glucocorticoid levels and/or activity may contribute to numerous disorders, including
  • Type II diabetes obesity, dyslipidemia, insulin resistance and hypertension.
  • Administration of the compounds of the present invention decreases the level of Cortisol and other 1 l ⁇ - hydroxysteroids in target tissues, thereby reducing the effects of glucucocrticoid activity in key target tissues.
  • the present invention could be used for the treatment, control, amelioration, prevention, delaying the onset of or reducing the risk of developing the diseases and conditions that are described herein.
  • glucocorticoids are potent regulators of glucose and lipid metabolism, glucocorticoid action may contribute or lead to insulin resistance, type 2 diabetes, dyslipidemia, visceral obesity and hypertension.
  • Cortisol antagonizes the insulin effect in liver resulting in reduced insulin sensitivity and increased gluconeogenesis. Therefore, patients who already have impaired glucose tolerance have a greater probability of developing type 2 diabetes in the presence of abnormally high levels of Cortisol.
  • Previous studies (B. R. Walker et al., J. of Clin. Endocrinology and Met., 80: 3155-3159, 1995) have demonstrated that administration of non-selective ll ⁇ -HSD-1 inhibitor, carbenoxolone, improves insulin sensitivity in humans. Therefore, administration of a therapeutically effective amount of an ll ⁇ -HSD-1 inhibitor may treat, control, ameliorate, delay, or prevent the onset of type 2 diabetes.
  • glucocorticoids in vivo has been shown to reduce insulin secretion in rats (B. Billaudel et al., Horm. Metab. Res. 11 : 555-560, 1979). It has also been reported that conversion of dehydrocorticosterone to corticosterone by 11 ⁇ -HSD-1 inhibits insulin secretion from isolated murine pancreatic ⁇ cells. (B. Davani et al., J. Biol. Chem., 275: 34841-34844, 2000), and that incubation of isolated islets with an ll ⁇ -HSD-1 inhibitor improves glucose-stimulated insulin secretion (H Orstater et al., Diabetes Metab. Res. Rev.. 21: 359-366, 2005). Therefore, administration of a therapeutically effective amount of an 1 l ⁇ -HSD-1 inhibitor may treat, control, ameliorate, delay, or prevent the onset of type 2 diabetes by improving glucose-stimulated insulin secretion in the pancreas.
  • Abdominal obesity is closely associated with glucose intolerance (C. T. Montaque et al., Diabetes, 49: 883-888, 2000), hyperinsulinemia, hypertriglyceridemia and other factors of metabolic syndrome (also known as syndrome X), such as high blood pressure, elevated VLDL and reduced HDL.
  • metabolic syndrome X also known as syndrome X
  • Animal data supporting the role of 11 ⁇ -HSD-1 in the pathogenesis of the metabolic syndrome is extensive (Masuzaki, et ah. Science. 294: 2166-2170, 2001; Paterson, J.M., et al; Proc Natl. Acad. Sd. USA. 101: 7088-93, 2004; Montague and O'Rahilly. Diabetes. 49: 883-888, 2000).
  • administration of a therapeutically effective amount of an 1 l ⁇ -HSD-1 inhibitor may treat, control, ameliorate, delay, or prevent the onset of obesity.
  • Long-term treatment with an 11 ⁇ -HSD-1 inhibitor may also be useful in delaying the onset of obesity, or perhaps preventing it entirely if the patients use an 1 l ⁇ - HSD-I inhibitor in combination with controlled diet, exercise, or in combination or sequence with other pharmacological approaches.
  • reducing insulin resistance and/or maintaining serum glucose at normal concentrations and/or reducing obestity compounds of the present invention also have utility in the treatment and prevention of conditions that accompany Type 2 diabetes and insulin resistance, including the metabolic syndrome or syndrome X, obesity, reactive hypoglycemia, and diabetic dyslipidemia.
  • 1 l ⁇ -HSD-I is present in multiple tissues, including vascular smooth muscle, where local glucocorticoid levels that are thought to increase insulin resistance, leading to reductions in nitric oxide production, and potentiation of the vasoconstrictive effects of both catecholamines and angiotensin II (M. Pirpiris et al., Hypertension, 19:567-574, 1992, C. Kornel et al., Steroids, 58: 580-587, 1993, B. R. Walker and B. C. Williams, Clin. Sci. 82:597-605, 1992; Hodge, G. et al Exp. Physiol 87: 1-8, 2002).
  • Transgenic mice overexpressing 1 l ⁇ -HSD-1 in liver and fat are also hypertensive, a phenotype believed to result from glucocorticoid activation of the renin angiotensin system (Paterson, J.M. et al, PNAS. 101: 7088-93, 2004; Masuzaki, H. et al, J. Clin. Invest. 112: 83-90, 2003). Therefore, administration of a therapeutically effective dose of an 11 ⁇ -HSD-1 inhibitor may treat, control, ameliorate, delay, or prevent the onset of hypertension.
  • Cushing's syndrome is a life-threatening metabolic disorder characterized by sustained and elevated glucocorticoid levels caused by the endogenous and excessive production of Cortisol from the adrenal glands.
  • Typical Cushingoid characteristics include central obesity, diabetes and/or insulin resistance, moon face, buffalo hump, skin thinning, dyslipidemia, osteoporosis, reduced cognitive capacity, dementia, hypertension, sleep deprivation, and atherosclerosis among others (Principles and Practice of Endocrinology and Metabolism. Edited by Kenneth Becker, Lippincott Williams and WiUrins Pulishers, Philadelphia, 2001; pg 723-8).
  • exogenous glucocorticoids such as prednisone or dexamethasone
  • Endogenous Cushings typically evolves from pituitary hyperplasia, some other ectopic source of ACTH, or from an adrenal carcinoma or nodular hyperplasia.
  • Administration of a therapeutically effective dose of an 1 l ⁇ -HSD-1 inhibitor may reduce local glucocorticoid concentrations and therefore treat, control, ameliorate, delay, or prevent the onset of Gushing' s disease and/or similar symptoms arising from glucocorticoid treatment.
  • glucocorticoids include glucocorticoid-induced acute psychosis which is of major concern to physicians when treating patients with these steroidal agents (Wolkowitz et al.; Ann NY Acad Sd. 1032: 191- 4, 2004).
  • Conditional mutagenesis studies of the glucocorticoid receptor in mice have also provided genetic evidence that reduced glucocorticoid signaling in the brain results in decreased anxiety (Tranche, F. et al. (1999) Nature Genetics 23: 99-103). Therefore, it is expected that potent, selective 1 l ⁇ -HSD-1 inhibitors would treat, control, ameliorate, delay, or prevent the onset of cognitive decline, dementia, steroid-induced acute psychosis, depression, and/or anxiety.
  • mice 1 l ⁇ -HSD-1 knockout mice are resistant to the dyslipidemic effects of a high fat diet and have an improved lipid profile vs wild type controls (Morton N.M. et al, JBC, 276: 41293-41300, 2001), and mice which overexpress 11 ⁇ -HSD-1 in fat exhibit the dyslipidemic phenotype characteristic of metabolic syndrome, including elevated circulating free fatty acids, and triclylgerides (Masuzaki, H., et al Science. 294: 2166-2170, 2001).
  • a selective 1 l ⁇ - HSD-I inhibitor has also been shown to reduce elevated plasma triglycerides and free fatty acids in mice on a high fat diet, and significantly reduce aortic content of cholesterol esters, and reduce progression of atherosclerotic plaques in mice (Hermanowski-Vosatka, A. et al. J. Exp. Med. 202: 517-27, 2005).
  • the administration of a therapeutically effective amount of an 11 ⁇ -HSD-1 inhibitor would therefore be expected to treat, control, ameliorate, delay, or prevent the onset of dyslipidemia and/or atherosclerosis.
  • Glucocorticoids are known to cause a variety of skin related side effects including skin thinning, and impairment of wound healing (Anstead, G. Adv Wound Care. 11 : 277- 85, 1998; Beer, et al; Vitam Horm. 59: 217-39, 2000).
  • ll ⁇ -HSD-1 is expressed in human skin fibroblasts, and it has been shown that the topical treatment with the non-selective HSD1/2 inhibitor glycerrhetinic acid increases the potency of topically applied hydrocortisone in a skin vasoconstrictor assay (Hammami, MM, and Siiteri, PK. J. Clin. Endocrinol. Metab. 73: 326-34, 1991).
  • Cortisol is an important and well-recognized anti-inflammatory agent (J. Baxer, Pharmac. Ther., 2:605-659, 1976), if present in large amount it also has detrimental effects.
  • high glucocorticoid activity shifts the immune response to a humoral response, when in fact a cell based response may be more beneficial to patients.
  • Inhibition of 11 ⁇ -HSD-1 activity may reduce glucocorticoid levels, thereby shifting the immuno response to a cell based response.
  • the cells that produce the majority of aqueous humor in the eye are the nonpigmented epithelial cells (NPE). These cells have been demonstrated to express 11 ⁇ -HSD- 1 , and consistent with the expression of 11 ⁇ -HSD- 1 , is the finding of elevated ratios of cortisolxortisone in the aqueous humor (Rauz et ah. Invest Ophthalmol Vis Sd. 42: 2037-2042, 2001). Furthermore, it has been shown that patients who have glaucoma, but who are not taking exogenous steroids, have elevated levels of Cortisol vs. cortisone in their aqueous humor (Rauz et al. QJM.
  • Glucocorticoids are known to increase bone resorption and reduce bone formation in mammals (Turner et al. Caldf Tissue Int. 54: 311-5, 1995; Lane, NE et al.
  • Glucocorticoids such as prednisone and dexamethasone
  • Glucocorticoids are also commonly used to treat a variety of inflammatory conditions including arthritis, inflammatory bowl disease, and asthma.
  • These steroidal agents have been shown to increase expression of 1 l ⁇ -HSD-1 mRNA and activity in human osteoblasts (Cooper et al; J. Bone Miner Res. 17: 979-986, 2002).
  • 11 ⁇ -HSD-I plays a potentially important role in the development of bone-related adverse events as a result of excessive glucocorticoid levels or activity.
  • the following diseases, disorders and conditions can be treated, controlled, prevented or delayed, by treatment with the compounds of this invention: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) lipid disorders, (5) hyperlipidemia, (6) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12), atherosclerosis and its sequelae, (13) vascular restensosis, (14) pancreatitis, (15) obdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropather, (19), neuropathy, (20) hypertension and other disorders where insulin resistance is a component, and (21) other diseases, disorders, and conditions that can benefit from reduced local glucocorticoid levels.
  • compositions of the present compounds comprise an effective amount of the same formulated with one or more therapeutically suitable excipients.
  • therapeutically suitable excipient generally refers to pharmaceutically suitable, solid, semi-solid or liquid fillers, diluents, encapsulating material, formulation auxiliary and the like.
  • therapeutically suitable excipients include, but are not limited to, sugars, cellulose and derivatives thereof, oils, glycols, solutions, buffers, colorants, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents and the like.
  • Such therapeutic compositions may be administered parenterally, intracisternally, orally, rectally, intraperitoneally or by other dosage forms known in the art.
  • Liquid dosage forms for oral administration include, but are not limited to, emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms may also contain diluents, solubilizing agents, emulsifying agents, inert diluents, wetting agents, emulsifiers, sweeteners, flavorants, perfuming agents and the like.
  • Injectable preparations include, but are not limited to, sterile, injectable, aqueous, oleaginous solutions, suspensions, emulsions and the like. Such preparations may also be formulated to include, but are not limited to, parenterally suitable diluents, dispersing agents, wetting agents, suspending agents and the like. Such injectable preparations may be sterilized by filtration through a bacterial-retaining filter. Such preparations may also be formulated with sterilizing agents that dissolve or disperse in the injectable media or other methods known in the art.
  • the absorption of the compounds of the present invention may be delayed using a liquid suspension of crystalline or amorphous material having poor water solubility.
  • the rate of absorption of the compounds generally depends upon the rate of dissolution and crystallinity. Delayed absorption of a parenterally administered compound may also be accomplished by dissolving or suspending the compound in oil.
  • Injectable depot dosage forms may also be prepared by microencapsulating the same in biodegradable polymers. The rate of drug release may also be controlled by adjusting the ratio of compound to polymer and the nature of the polymer employed. Depot injectable formulations may also prepared by encapsulating the compounds in liposomes or microemulsions compatible with body tissues.
  • Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, gels, pills, powders, granules and the like.
  • the drug compound is generally combined with at least one therapeutically suitable excipient, such as carriers, fillers, extenders, disintegrating agents, solution retarding agents, wetting agents, absorbents, lubricants and the like.
  • Capsules, tablets and pills may also contain buffering agents.
  • Suppositories for rectal administration may be prepared by mixing the compounds with a suitable non-irritating excipient that is solid at ordinary temperature but fluid in the rectum.
  • the present drug compounds may also be microencapsulated with one or more excipients.
  • Tablets, dragees, capsules, pills and granules may also be prepared using coatings and shells, such as enteric and release or rate controlling polymeric and nonpolymeric materials.
  • the compounds may be mixed with one or more inert diluents. Tableting may further include lubricants and other processing aids.
  • capsules may contain opacifying agents that delay release of the compounds in the intestinal tract.
  • Transdermal patches have the added advantage of providing controlled delivery of the present compounds to the body.
  • dosage forms are prepared by dissolving or dispensing the compounds in suitable medium.
  • Absorption enhancers may also be used to increase the flux of the compounds across the skin.
  • the rate of absorption may be controlled by employing a rate controlling membrane.
  • the compounds may also be incorporated into a polymer matrix or gel.
  • disorders of the present invention may be treated, prophylatically treated, or have their onset delayed in a patient by administering to the patient a therapeutically effective amount of compound of the present invention in accordance with a suitable dosing regimen.
  • a therapeutically effective amount of any one of compounds of formulas (I) is administered to a patient to treat and/or prophylatically treat disorders modulated by the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme.
  • the specific therapeutically effective dose level for a given patient population may depend upon a variety of factors including, but not limited to, the specific disorder being treated, the severity of the disorder; the activity of the compound, the specific composition or dosage form, age, body weight, general health, sex, diet of the patient, the time of administration, route of administration, rate of excretion, duration of the treatment, drugs used in combination, coincidental therapy and other factors known in the art.
  • the present invention also includes therapeutically suitable metabolites formed by in vivo biotransformation of any of the compounds of formula (I).
  • therapeutically suitable metabolite generally refers to a pharmaceutically active compound formed by the in vivo biotransform ation of compounds of formula (I).
  • pharmaceutically active metabolites include, but are not limited to, compounds made by adamantane hydroxylation or polyhydroxylation of any of the compounds of formulas(I).
  • the total daily dose (single or multiple) of the drug compounds of the present invention necessary to effectively inhibit the action of 11-beta-hydroxysteroid dehydrogenase type 1 enzyme may range from about 0.01 mg/kg/day to about 50 mg/kg/day of body weight and more preferably about 0.1 mg/kg/day to about 25 mg/kg/day of body weight.
  • Treatment regimens generally include administering from about 10 mg to about 1000 mg of the compounds per day in single or multiple doses.

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Abstract

The present invention relates to compounds that are inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme. The present invention further relates to the use of inhibitors of 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme for the treatment of non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome and other diseases and conditions that are mediated by excessive glucocorticoid action.

Description

Inhibitors of the 11-beta-hvdroxvsteroid dehydrogenase Type 1 enzyme
Field of invention
The present invention relates to compounds that are inhibitors of the 11-beta- hydroxysteroid dehydrogenase Type 1 enzyme. The present invention further relates to the use of inhibitors of 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme for the treatment of non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome and other diseases and conditions that are mediated by excessive glucocorticoid action.
Background of the Invention
Insulin is a hormone that modulates glucose and lipid metabolism. Impaired action of insulin (i.e., insulin resistance) results in reduced insulin-induced glucose uptake, oxidation and storage, reduced insulin-dependent suppression of fatty acid release from adipose tissue (i.e., lipolysis) and reduced insulin-mediated suppression of hepatic glucose production and secretion. Insulin resistance frequently occurs in diseases that lead to increased and premature morbidity and mortality.
Diabetes mellitus is characterized by an elevation of plasma glucose levels (hyperglycemia) in the fasting state or after administration of glucose during a glucose tolerance test. While this disease may be caused by several underlying factors, it is generally grouped into two categories, Type 1 and Type 2 diabetes. Type 1 diabetes, also referred to as Insulin Dependent Diabetes Mellitus ("IDDM"), is caused by a reduction of production and secretion of insulin. In type 2 diabetes, also referred to as non-insulin dependent diabetes mellitus, or NIDDM, insulin resistance is a significant pathogenic factor in the development of hyperglycemia. Typically, the insulin levels in type 2 diabetes patients are elevated (i.e., hyperinsulinemia), but this compensatory increase is not sufficient to overcome the insulin resistance. Persistent or uncontrolled hyperglycemia in both type 1 and type 2 diabetes mellitus is associated with increased incidence of macro vascular and/or microvascular complications including atherosclerosis, coronary heart disease, peripheral vascular disease, stroke, nephropathy, neuropathy and retinopathy.
Insulin resistance, even in the absence of profound hyperglycemia, is a component of the metabolic syndrome. Recently, diagnostic criteria for metabolic syndrome have been established. To qualify a patient as having metabolic syndrome, three out of the five following criteria must be met: elevated blood pressure above 130/85 mmHg, fasting blood glucose above 110 mg/dl, abdominal obesity above 40" (men) or 35" (women) waist circumference and blood lipid changes as defined by an increase in triglycerides above 150 mg/dl or decreased HDL cholesterol below 40 mg/dl (men) or 50 mg/dl (women). It is currently estimated that 50 million adults, in the US alone, fulfill these criteria. That population, whether or not they develop overt diabetes mellitus, are at increased risk of developing the macrovascular and microvascular complications of type 2 diabetes listed above.
Available treatments for type 2 diabetes have recognized limitations. Diet and physical exercise can have profound beneficial effects in type 2 diabetes patients, but compliance is poor. Even in patients having good compliance, other forms of therapy may be required to further improve glucose and lipid metabolism.
One therapeutic strategy is to increase insulin levels to overcome insulin resistance. This maybe achieved through direct injection of insulin or through stimulation of the endogenous insulin secretion in pancreatic beta cells. Sulfonylureas (e.g., tolbutamide and glipizide) or meglitinide are examples of drugs that stimulate insulin secretion (i.e., insulin secretagogues) thereby increasing circulating insulin concentrations high enough to stimulate insulin-resistant tissue. However, insulin and insulin secretagogues may lead to dangerously low glucose concentrations (i.e., hypoglycemia). In addition, insulin secretagogues frequently lose therapeutic potency over time.
Two biguanides, metformin and phenformin, may improve insulin sensitivity and glucose metabolism in diabetic patients. However, the mechanism of action is not well understood. Both compounds may lead to lactic acidosis and gastrointestinal side effects (e.g., nausea or diarrhea). Alpha-glucosidase inhibitors (e.g., acarbose) may delay carbohydrate absorption from the gut after meals, which may in turn lower blood glucose levels, particularly in the postprandial period. Like biguanides, these compounds may also cause gastrointestinal side effects.
Glitazones (i.e., 5-benzylthiazolidine-2,4-diones) are a newer class of compounds used in the treatment of type 2 diabetes. These agents may reduce insulin resistance in multiple tissues, thus lowering blood glucose. The risk of hypoglycemia may also be avoided. Glitazones modify the activity of the Peroxisome Proliferator Activated Receptor ("PPAR") gamma subtype. PPAR is currently believed to be the primary therapeutic target for the main mechanism of action for the beneficial effects of these compounds. Other modulators of the PPAR family of proteins are currently in development for the treatment of type 2 diabetes and/or dyslipidemia. Marketed glitazones suffer from side effects including bodyweight gain and peripheral edema.
Additional treatments to normalize blood glucose levels in patients with diabetes mellitus are needed. Other therapeutic strategies are being explored. For example, research is being conducted concerning Glucagon-Like Peptide 1 ("GLP-I") analogues and inhibitors of Dipeptidyl Peptidase IV ("DPP-IV") that increase insulin secretion. Other examples include: Inhibitors of key enzymes involved in the hepatic glucose production and secretion (e.g., fructose- 1,6-bisphosphatase inhibitors) and direct modulation of enzymes involved in insulin signaling (e.g., Protein Tyrosine Phosphatase-1B, or "PTP-IB").
Another method of treating or prophylactically treating diabetes mellitus includes using inhibitors of 11-β-hydroxysteroid dehydrogenase Type 1 (1 lβ-HSDl). Such methods are discussed in J.R. Seckl et al., Endocrinology, 142: 1371-1376, 2001 and references cited therein. Glucocorticoids are steroid hormones that are potent regulators of glucose and lipid metabolism. Excessive glucocorticoid action may lead to insulin resistance, type 2 diabetes, dyslipidemia, increased abdominal obesity and hypertension. Glucocorticoids circulate in the blood in an active form (i.e., Cortisol in humans) and an inactive form (i.e., cortisone in humans). 11 β-HSD 1 , which is highly expressed in liver and adipose tissue, converts cortisone to Cortisol leading to higher local concentration of Cortisol. Inhibition of 1 lβ-HSDl prevents or decreases the tissue specific amplification of glucocorticoid action thus imparting beneficial effects on blood pressure and glucose- and lipid-metabolism.
Thus, inhibiting 11 β-HSD 1 benefits patients suffering from non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome and other diseases and conditions mediated by excessive glucocorticoid action. Summary of the Invention
All patents, patent applications and literature references cited in the specification are herein incorporated by reference in their entirety.
One aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof
Figure imgf000005_0001
(I), wherein one of A1, A2, A3 and A4 is selected from the group consisting of alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl1, arylalkyl, aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, haloalkyl, heterocyclealkyl, heterocycleoxyalkyl, -S(O)2-N(R5R6), -NR7- [C(R8 R9)]n-C(O)-R10,
Figure imgf000005_0002
-OR14a, -N(R15R16), -CO2R17, -C(O)- N(R18R19), -C(R20R21)-OR22, -C(R23R24)-N(R25R26), and heterocycle, with the exception that 5 membered heterocycles may not contain two oxygen atoms, and the remaining members of the group consisting of A1, A2, A3 and A4 are each individually selected from the group consisting of hydrogen, alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl, aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, -S(O)2-N(R5R6), -NR7-[C(RS R^]n-C(O)-R10, -O-[C(RnR12)]p-C(O> R13, -OR14b, -N(R15R16), -CO2R17, -C(O)-N(R18R19), -C(R20R21)-OR22, and -C(R23R24)- N(R25R26); n is O or l; p is O or 1;
D is selected from the group consisting of a bond, -C(R27R28)-X- and -C(R27R28)-
Figure imgf000005_0003
E is selected from the group consisting of a cycloalkyl, alkyl, aryl, heteroaryl and heterocycle, wherein the heteroaryl and the heterocycle are appended to the parent molecular moiety through an available carbon atom, or R4 and E together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle; X is selected from the group consisting of a bond, -N(R31)-, -O-, -S-, -S(O)- and - S(O)2-; R1 is selected from the group consisting of hydrogen and alkyl;
R2 is selected from the group consisting of hydrogen, alkyl and cycloalkyl; R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl, or R3 and R4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
R5 and R6 are each independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylcarbonyl, alkylsufonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxy, aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, or R5 and R6 together with the atom to which they are attached form a heterocycle; R7 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
R8 and R9 are each independently selected from the group consisting of hydrogen and alkyl, or R and R taken together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
R10 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl and -N(R R ); R11 and R12 are each independently selected from the group consisting of hydrogen and alkyl or R11 and R12 taken together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle; R13 is selected from the group consisting of hydroxy and -N(R34R35); R14a is selected from the group consisting of carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl; R14b is selected from the group consisting of hydrogen, alkyl, carboxyalkyl,
• cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl; R15 and R16 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocyclesulfonyl, alkylsufonyl, cycloalkylsulfonyl and arylsulfonyl, or R15 and R16 together with the atom to which they are attached form a heterocycle; R17 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
R18 and R19 are each independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylsufonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, or R18 and R19 together with the atom to which they are attached form a heterocycle;
R , R and R are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl;
R23 and R24 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl, arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, heterocycle, heterocyclecarbonyl and heterocyclesulfonyl;
R25 and R26 are each independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl, aryloxy, arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocyclecarbonyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, or R25 and R26 together with the nitrogen to which they are attached form a ring selected from the group consisting of heteroaryl and heterocycle;
R27 and R28 are each independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heteroaryl and heterocycle or R27 and R28 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R27 and R29 together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R28 and R4 together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
R29 and R3Oare each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, cycloalkyl, cycloalkyloxy, heteroaryl, heterocycle, and - N(R36R37), or R29 and R30 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R29 and R4 together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R29 and E together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
R31 is selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycle and heteroaryl, or R31 and E together with the atom to which they are attached form a ring selected from the group consisting of heteroaryl and heterocycle, or R31 and R4 together with the atoms to which they are attached form a heterocycle; R and R are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R32 and R33 together with the atom to which they are attached form a heterocycle; R34 and R35 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R34 and R35 together with the atom to which they are attached form a heterocycle; and
R36 and R37 are each independently selected from the group consisting of hydrogen, alkyl and aryl. A further aspect of the present invention encompasses the use of the compounds of formula (I) for the treatment of disorders that are mediated by 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme, such as non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome and other diseases and conditions that are mediated by excessive glucocorticoid action, comprising administering a therapeutically effective amount of a compound of formula (I) .
According to still another aspect, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically suitable carrier.
Detailed description of the Invention
One aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof
Figure imgf000009_0001
(I)5 wherein one of A1, A2, A3 and A4 is selected from the group consisting of alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl1, arylalkyl, aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, haloalkyl, heterocyclealkyl, heterocycleoxyalkyl, -S(O)2-N(R5R6), -NR7- [C(R8 R9)]n-C(O)-R10, -O-[C(RπR12)]p-C(O)-R13, -OR14a, -N(R15R16), -CO2R17, -C(O)- N(R18R19), -C(R20R21)-OR22, -C(R23R24)-N(R25R26), and heterocycle, with the exception that 5 membered heterocycles may not contain two oxygen atoms, and the remaining members of the group consisting of A1, A2, A3 and A4 are each individually selected from the group consisting of hydrogen, alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl, aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, -S(O)2-N(R5R6), -NR7-[C(R8 R9)]n-C(O)-R10, -0-[C(R11R12^p-C(O)- R13, -OR14b, -N(R15R16), -CO2R17, -C(O)-N(R18R19), -C(R20R21)-OR22, and -C(R23R24)- N(R25R26); n is O or 1 ; p is O or 1;
D is selected from the group consisting of a bond, -C(R27R28)-X- and -C(R27R28)-
Figure imgf000010_0001
E is selected from the group consisting of a cycloalkyl, alkyl, aryl, heteroaryl and heterocycle, wherein the heteroaryl and the heterocycle are appended to the parent molecular moiety through an available carbon atom, or R4 and E together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle; X is selected from the group consisting of a bond, -N(R31)-, -O-, -S-, -S(O)- and -
S(O)2-;
R1 is selected from the group consisting of hydrogen and alkyl;
R2 is selected from the group consisting of hydrogen, alkyl and cycloalkyl;
R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl, or R3 and R4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
R5 and R6 are each independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylcarbonyl, alkylsufonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxy, aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, or R5 and R6 together with the atom to which they are attached form a heterocycle;
R7 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, cafboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
R8 and R9 are each independently selected from the group consisting of hydrogen and alkyl, or R8 and R9 taken together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
R10 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl and -N(R32R33); R11 and R12 are each independently selected from the group consisting of hydrogen and alkyl or R11 and R12 taken together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
R13 is selected from the group consisting of hydroxy and -N(R34R35);
R14a is selected from the group consisting of carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
R14b is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl; R15 and R16 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocyclesulfonyl, alkylsufonyl, cycloalkylsulfonyl and arylsulfonyl, or R15 and R16 together with the atom to which they are attached form a heterocycle;
R17 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl; R18 and R19 are each independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylsufonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, or R18 and R19 together with the atom to which they are attached form a heterocycle;
R20, R21 and R22 are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl;
R23 and R24 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl, arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, heterocycle, heterocyclecarbonyl and heterocyclesulfonyl;
R and R are each independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl, aryloxy, arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocyclecarbonyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, or R25 and R26 together with the nitrogen to which they are attached form a ring selected from the group consisting of heteroaryl and heterocycle;
R27 and R28are each independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heteroaryl and heterocycle or R27 and R28 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R27 and R29 together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R and R together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
R29 and R30are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, cycloalkyl, cycloalkyloxy, heteroaryl, heterocycle, and -N(R36R37), or R29 and R30 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R29 and R4 together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R29 and E together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle; R31 is selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycle and heteroaryl, or R31 and E together with the atom to which they are attached form a ring selected from the group consisting of heteroaryl and heterocycle, or R31 and R4 together with the atoms to which they are attached form a heterocycle; R32 and R33 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R32 and R33 together with the atom to which they are attached form a heterocycle; R34 and R35 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R34 and R35 together with the atom to which they are attached form a heterocycle; and R36 and R37 are each independently selected from the group consisting of hydrogen, alkyl and aryl.
Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; and A1, R3, R4, D and E are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (T), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is a bond; and A1, R3, R4 and E are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (T), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen; D is a bond;
E is selected from the group consisting of alkyl, aryl, and heteroaryl; and A1, R3, and R4 are as described in the summary of the invention. Another aspect of the present invention is directed toward a compound of formula (I)5 or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen; D is a bond;
E is selected from the group consisting of alkyl, aryl and heteroaryl; R3 and R4 are hydrogen; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl and -S(O)2-N(R5R6); wherein R5, R6, R17, R18 and R19 are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen;
D is a bond;
E is selected from the group consisting of alkyl, aryl and heteroaryl; R3 is hydrogen; R4 is alkyl; and A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl and -S(O)2-N(R5R6); wherein R5, R6, R17, R18 and R19 are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen; D is a bond;
E is selected from the group consisting of alkyl, aryl and heteroaryl;
R3 and R4 are alkyl; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl and -S(O)2-N(R5R6); wherein R5, R6, R17, R18 and R19 are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (T), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is a bond;
E is selected from the group consisting of alkyl, aryl and heteroaryl;
R3 and R4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle; and A1 is as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is a bond;
E is selected from the group consisting of alkyl, aryl and heteroaryl;
R3 and R4 together with the atom to which they are attached form a cycloalkyl ring; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl and -S(O)2-N(R5R6); wherein R5, R6, R17, R18 and R19 are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (T), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen;
D is a bond;
E is selected from the group consisting of alkyl, aryl and heteroaryl;
R3 and R4 together with the atom to which they are attached form a heterocycle ring; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl and -S(O)2-N(R5R6); wherein R5, R6, R17, R18 and R19 are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is a bond; R4 and E together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl and -S(O)2-N(R5R6); wherein R3, R5, R6, R17, R18 and R19 are as described in the summary of the invention. Another aspect of the present invention is directed toward a compound of formula
(II), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof,
Figure imgf000016_0001
(II) wherein t is 1 or 2;
A , A and A are hydrogen;
R1 and R2 are hydrogen;
R3 is alkyl; A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6); wherein R5, R6, R17, R18 and R19 are as described in the summary of the invention; and
R38 is selected from the group consisting of arylalkyl and heteroarylalkyl wherein the aryl of the arylalkyl and the heteroaryl of the heteroarylalkyl are each independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, halogen and haloalkyl.
Another aspect of the present invention is directed toward a compound of formula (III), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof,
Figure imgf000017_0001
(III) wherein t is 1 or 2;
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen;
R3 is alkyl;
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6) ; wherein R5, R6, R17, R18 and R19 are as described in the summary of the invention; and R38 is selected from the group consisting of arylalkyl and heteroarylalkyl wherein the aryl of the arylalkyl and the heteroaryl of the heteroarylalkyl are each independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, halogen and haloalkyl.
Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)- X-; and R27, R28, R29, R30, X5 A1, R3, R4 and E are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)-
X-; wherein R 3 R , R , R , and X are as described in the summary of the invention;
E is selected from the group consisting of aryl and heteroaryl; and A1, R3, and R4 are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)-
01 OSl OQ ^fi
X-; wherein R 5 R 5 R , and R are as described in the summary of the invention; E is selected from the group consisting of aryl and heteroaryl; X is a bond; and A1, R3, and R4 are as described in the summary of the invention. Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen; D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)-
X-; wherein R27, R28, R29, and R30 are each independently selected from the group consisting of hydrogen and alkyl;
E is selected from the group consisting of aryl and heteroaryl; X is a bond; R3 and R4 are hydrogen; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6); wherein R5, R6, R17, R18 and R19 are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (T), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)- X-; wherein R27, R28, R29, and R30 are each independently selected from the group consisting of hydrogen and alkyl; E is selected from the group consisting of aryl and heteroaryl;
X is a bond;
R3 is hydrogen;
R4 is alkyl; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6); wherein R5, R6, R17, R18 and R19 are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)- X-; wherein R 5 R 5 R , and R are each independently selected from the group consisting of hydrogen and alkyl; E is selected from the group consisting of aryl and heteroaryl;
X is a bond;
R3 and R4 are alkyl; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6); wherein R5, R6, R17, R18 and R19 are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (T), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)- X-; wherein R27, R28, R29, and R30 are as described in the summary of the invention;
E is selected from the group consisting of aryl and heteroaryl;
X is a bond;
R3 and R4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle; and A1 is as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)- X-; wherein R , R , R , and R are each independently selected from the group consisting of hydrogen and alkyl;
E is selected from the group consisting of aryl and heteroaryl; X is a bond;
R3 and R4 together with the atom to which they are attached form a cycloalkyl ring; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6); wherein R5, R6, R17, R18 and R19 are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)- X-; wherein R 5 R 5 R , and R are each independently selected from the group consisting of hydrogen and alkyl;
E is selected from the group consisting of aryl and heteroaryl;
X is a bond;
R3 and R4 together with the atom to which they are attached form a heterocycle ring; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6); wherein R5, R6, R17, R18 and R19 are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)- X-; wherein R27, R28, R29, and R30 are as described in the summary of the invention;
E is selected from the group consisting of aryl and heteroaryl;
X is selected from the group consisting of -N(R31)- and -O-; and A1, R3, and R4 are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)- X-; wherein R 5 R 5 R , and R are each independently selected from the group consisting of hydrogen and alkyl;
E is selected from the group consisting of aryl and heteroaryl; X is selected from the group consisting of -N(R31)- and -0-; R3 and R4 are hydrogen; and A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6); wherein R5, R6, R17, R18 and R19 are as described in the summary of the invention. Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)- X-; wherein R27, R28, R29, and R30 are each independently selected from the group consisting of hydrogen and alkyl;
E is selected from the group consisting of aryl and heteroaryl; X is selected from the group consisting of -N(R31)- and -O-;
R3 is hydrogen;
R4 is alkyl; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6); wherein R5, R6, R17, R18 and R19 are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)- X-; wherein R27, R28, R29, and R30 are each independently selected from the group consisting of hydrogen and alkyl;
E is selected from the group consisting of aryl and heteroaryl; X is selected from the group consisting of -N(R31)- and -O-;
R3 and R4 are alkyl; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6); wherein R5, R6, R17, R18 and R19 are as described in the summary of the invention. Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein A2, AJ and A4 are hydrogen;
R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)- X-; wherein R27, R28, R29, and R30 are each independently selected from the group consisting of hydrogen and alkyl;
E is selected from the group consisting of aryl and heteroaryl;
X is selected from the group consisting of -N(R31)- and -O-;
R3 and R4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle; and A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6); wherein R5, R6, R17, R18 and R19 are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)-
X-; wherein R , R , R , and R are each independently selected from the group consisting of hydrogen and alkyl;
E is selected from the group consisting of aryl and heteroaryl; X is selected from the group consisting of -N(R31)- and -0-; R3 and R4 together with the atom to which they are attached form a cycloalkyl ring; and A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6); wherein R5, R6, R17, R18 and R19 are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen; D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)- X-; wherein R27, R28, R29, and R30 are each independently selected from the group consisting of hydrogen and alkyl;
E is selected from the group consisting of aryl and heteroaryl; X is selected from the group consisting of -N(R31)- and -O-;
R3 and R4 together with the atom to which they are attached form a heterocycle ring; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6); wherein R5, R6, R17, R18 and R19 are as described in the summary of the invention.
Exemplary compounds of the present invention having formula (I) include, but are not limited to,
E-4- {[1 -(4-Chloro-phenyl)-cyclobutanecarbonyl] -amino} -adamantane- 1 -carboxylic acid; jE'-4-[(l-Phenyl-cyclopropanecarbonyl)-amino]-adamantane-l-carboxylic acid;
E-4-(2-Methyl-2-phenyl-propionylamino)-adamantane- 1 -carboxylic acid; E-4- { [ 1 -(4-Chloro-phenyl)-cyclobutanecarbonyl] -amino } -adamantane- 1 -carboxylic acid amide;
E-4-[(l-Phenyl-cyclopropanecarbonyl)-amino]-adamantane-l-carboxylic acid amide; E-4-(2-Methyl-2-phenyl-propionylamino)-adamantane-l -carboxylic acid amide;
E-4-( { [ 1 -(4-chlorophenyl)cyclohexyl] carbonyl} amino)adamantane- 1 -carboxamide; E-4-( { [ 1 -(4-chlorophenyl)cyclopropyl] carbonyl} amino)adamantane- 1 -carboxamide; E-4-({[l-(4-chlorophenyl)cyclopentyl]carbonyl}amino)adamantane-l-carboxamide; E-4- { [2-(4-chlorophenyl)-2-methylpropanoyl] amino} adamantane- 1 -carboxamide; E-4- {[(1 -phenylcyclopentyl)carbonyl]amino} adamantane- 1 -carboxamide;
E-4-({[l-(3-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-l-carboxamide; E-4-({[l-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-l- carboxamide;
E-4-( { [ 1 -(4-fluorophenyl)cyclopentyl]carbonyl} amino)adamantane- 1 -carboxamide; E-4-( {[ 1 -(2-fluoroρhenyl)cyclopentyl]carbonyl}amino)adamantane- 1 -carboxamide;
E-4- {[(1 -methylcyclohexyl)carbonyl]amino} adamantane- 1 -carboxamide; E-4-( {[ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl} amino)adamantane- 1 - carboxamide;
E-4-( { [ 1 -(4-methoxyphenyl)cyclopropyl]carbonyl} amino)adamantane-l - carboxamide;
E-4-({[l-(4-methylphenyl)cyclopropyl]carbonyl}amino)adaniantane-l-carboxamide; Ε-4- { [2-methyl-2-(4-pyridin-4-ylphenyl)propanoyl] amino} adamantane- 1 - carboxamide;
E-4-[(2-methyl-2-thien-2-ylpropanoyl)amino]adamantane-l-carboxamide;
E-4-[(2-methyl-2-thien-3-ylpropanoyl)amino]adamantane-l-carboxamide;
E-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)adamantane-l- carboxamide;
E-4-[(2-methyl-2-{4-[5-(trifluoromethyl)ρyridin-2 yl]phenyl}propanoyl)amino]adamantane-l-carboxamide;
E-4-( { [ 1 -(4-methoxyphenyl)cyclopentyl]carbonyl} amino)adamantane- 1 - carboxamide; E-4- { [2-(4-bromophenyl)-2-methylpropanoyl] amino } adamantane- 1 -carboxamide;
E-4-[5-(aminocarbonyl)-2-adamantyl]-3-methyl-l-(2-methylbenzyl)-2-oxopiρeridine- 3 -carboxamide;
E-4-(aminocarbonyl)-2-adamantyl]-l-benzyl-3-metliyl-2-oxopyrrolidine-3- carboxamide; Ε-4-(aminocarbonyl)-2-adamantyl]-3-methyl-l-(2-methylbenzyl)-2-oxopyrrolidme-3- carboxamide;
E-4-(aminocarbonyl)-2-adamantyl]-l-(2-chlorobenzyl)-3-methyl-2-oxopyrrolidine-3- carboxamide;
E-4-(aminocarbonyl)-2-adamantyl]-l-(3-chlorobenzyl)-3-methyl-2-oxopyrrolidine-3- carboxamide;
E-4-({2-methyl-2-[4-(l-methyl-lH-pyrazol-4- yl)phenyl]propanoyl} amino)adamantane- 1 -carboxamide;
E-4- { [2-(3 -bromophenyl)-2-methylpropanoyl] amino } adamantane- 1 -carboxamide;
E-4-({2-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-2- methylpropanoyl} amino)adamantane- 1 -carboxamide;
E-4-{[2-methyl-2-(4-pyridin-3-ylphenyl)propanoyl]amino}adamantane-l- carboxamide; 4-{[({(E)-4-[(2-methyl-2-thien-2-ylpropanoyl)amino]-l- adamantyl} carbonyl)amino]methyl}benzoic acid;
E-4-({2-methyl-2-[4-(lH-pyrazol-4-yl)phenyl]propanoyl}amino)adamantane-l- carboxamide; E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-l-(l-methyl-l-phenylethyl)-2- oxopyrrolidine-3-carboxamide;
E-4-(ammocarbonyl)-2-adaniantyl]-3-methyl-2-oxo- 1 -[(1R)- 1 - phenyle1%l]pyrrolidine-3-carboxamide;
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-l-[(lS)-l- phenylethyl]pyrrolidine-3 -carboxamide;
E-4-{[2-methyl-2-(13-tWazol-2-yl)propanoyl]amino}adamantane-l-carboxamide; E-4-(aminocarbonyl)-2-adamantyl]-l-(4-chlorobenzyl)-3-methylpiperidine-3- carboxamide;
E-4-{[2-(4-hydroxyphenyl)-2-methylpropanoyl]amino}adamantane-l-carboxamide; E-4-(aminocarbonyl)-2-adamantyl]-l-benzyl-3-methyl-2-oxopiperidine-3- carboxamide;
E-4-{[2-methyl-2-(4-phenoxyphenyl)propanoyl]amino}adamantane-l-carboxamide; E-4- { [2-( 1 -benzothien-3 -yl)-2-methylpropanoyl] amino } adamantane- 1 -carboxamide; E-4- {[2-(5-fluoropyridin-2-yl)-2-methylpropanoyl]amino} adamantane- 1 - carboxamide;
E-4-[(2-methyl-2-quinoxalin-2-ylpropanoyl)amino]adamantane-l-carboxamide; (E)-4-[(2-methyl-2-pyrazin-2-ylρropanoyl)amino]adamantane-l-carboxamide; N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-l-(2-pyridin-2- ylethyl)pyrrolidine-3 -carboxamide; methyl (E)-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane- 1 -carboxylate;
(E)-4-( {2-methyl-2- [3 -( 1 ,3 -thiazol-4-ylmethoxy)phenyl]propanoyl} amino)adamantane- 1 -carboxamide;
(E)-4-({2-methyl-2-[6-(methylamino)pyridin-3-yl]propanoyl}amino)adamantane-l- carboxamide; (E)-4-({2-methyl-2-[3-(morpholin-4-ylmethyl)phenyl]propanoyl}amino)adamantane-l- carboxamide;
(E)-4-( {2-methyl-2-[4-(trifluoromethyl)pyridin-2-yl]propanoyl} amino)adamantane- 1 - carboxamide;
(E)-4-[(2-{3-[2-(lH-imidazol-l-yl)ethoxy]phenyl}-2- methylpropanoyl)amino]adamantane-l-carboxamide; methyl (E)-4- { [( 1 -phenylcyclopropytycarbonyl j amino } adamantane- 1 -carboxylate; (E)-4-{[2-(6-fluoropyridin-3-yl)-2-metliylpropanoyl]amino}adamantane-l- carboxamide;
(E)-N-[3-(aminocarbonyl)benzyl]-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane- 1 -carboxamide;
N-[(E)-5-(aminocarbonyl)-2-adamantyl]-l-(2-chlorobenzyl)-3-methyl-2-oxoρiperidine- 3 -carboxamide;
N-[(E)-5-(ammocarbonyl)-2-adamantyl]-3-methyl-2-oxo-l-(pyridin-4- ylmethyl)pyrrolidine-3 -carboxamide;
(E)-A- { [2-methyl-2-(4-phenoxyphenyl)propanoyl] amino} adamantane-1 -carboxylic acid; N-[(E)-5-(aminosulfonyl)-2-adamantyl]-l-phenylcyclopropanecarboxamide;
(JΕ)-4-({3-[(5-cyanopyridin-2-yl)oxy]-2,2-dimethylpropanoyl}amino)adamantane-l- carboxamide;
N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-l-(l-pyridin-2- ylethyl)pyrrolidine-3 -carboxamide; (£)-4-[(2-methyl-3 -phenylpropanoyl)amino] adamantane- 1 -carboxamide;
(E)-4- { [2-methyl-2-(6-morpholin-4-ylpyridin-3 -yl)propanoyl] amino } adamantane- 1 - carboxamide; methyl (E)-4-({[l-(4-chlorophenyl)cyclobutyl]carbonyl}ammo)adamantane-l- carboxylate; N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-l-(pyridin-3- ylmethyl)pyrrolidine-3-carboxamide;
(E)-4-[(2-methyl-2-{6-[(2-morpholin-4-ylethyl)amino]pyridin-3- yl}propanoyl)amino]adamantane-l-carboxamide;
(E)-4-[(2-methyl-2-{4-[(Ε)-2-pyridin-4-ylvinyl]phenyl}propanoyl)ammo]adamantane- 1 -carboxamide;
N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(4-chlorophenyl)-2-methylpropanamide;
(JE)-4-({2-methyl-2-[3-(2-morpholin-4-ylethoxy)phenyl]ρropanoyl}amino)adamantane- 1-carboxamide;
(E)-4- { [2-(3 -cyanopyridin-2-yl)-2-methylpropanoyl] amino} adamantane- 1 - carboxamide;
(E)-4-( {2-methyl-2-[6-(4-methylpiperazin- 1 -yl)pyridin-3- yl]propanoyl} aniino)adamantane- 1 -carboxamide;
N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-l-(pyridin-2- ylmethyl)pyrrolidine-3-carboxamide;
(E)-N-[4-(aminosulfonyl)benzyl]-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane- 1-carboxamide; (E)-4-({2-methyl-2-[4-(pentyloxy)phenyl]propanoyl}amino)adamantane-l-carboxylic acid;
(E)-4-({2-methyl-2-[4-(l,3-thiazol-4-ylmethoxy)phenyl]propanoyl}amino)adamantane- 1-carboxylic acid;
(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-N-(l,3-thiazol-5-ylmethyl)adamantane-l- carboxamide;
(E)-4-({2-[4-(benzyloxy)phenyl]-2-methylpropanoyl}amino)adamantane-l-carboxylic acid;
(E)-4- {[2-(5-cyanopyridin-2-yl)-2-methylpropanoyl]amino} adamantane- 1 - carboxamide; (E)-4-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}adamantane-l-carboxylic acid;
4-[({[(E)-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]proρanoyl}amino)-l- adamantyljcarbonyl} amino)methyl]benzoic acid;
4- {[( {(E)-4-[(2-methyl-2-phenylpropanoyl)amino] - 1 - adamantyl} carbonyl)amino]methyl}benzoic acid; 3- {[( {(E)-4-[(2-methyl-2-ρhenylpropanoyl)amino]- 1 - adamantyl} carbonyl)amino]methyl}benzoic acid;
(E)-4-({[l-(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-l-carboxylic acid;
(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-N-(pyridin-4-ylmethyl)adamantane-l- carboxamide;
(E)-4-( { [ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl} amino)adamantane- 1 -carboxylic acid; (E)-N-(2-furylmethyl)-4-[(2-methyl-2-phenylpropanoyl)amino]adaniantane-l- carboxamide;
3-[(E)-4-({2-methyl-2-[5-(trifluoroniethyl)pyridm-2-yl]propanoyl}ainino)-l- adamantyl]- lH-pyrazole-5-carboxamide; (E)-4-[(2-methyl-2-phenylpropanoyl)amino]-N-(pyridin-3-ylmethyl)adamantane-l- carboxamide;
(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-N-(pyridin-2-ylmethyl)adamantane-l- carboxamide;
(E)-4-( {2- [4-(cyclohexylmethoxy)phenyl] -2-methylpropanoyl} amino)adamantane- 1 - carboxylic acid;
(£)-4-[(2-methyl-2-{4-[5-(trifluoromethyl)pyridin-2- yl]phenyl}propanoyl)amino]adamantane-l-carboxylic acid; and
N- [(JE)S -(aminosulfonyl)-2-adamantyl] - 1 -(2-chlorobenzyl)-3 -methyl-2- oxopyrrolidine-3-carboxamide. Another embodiment of the present invention discloses a method of inhibiting 11- beta-hydroxysteroid dehydrogenase Type I enzyme, comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
Another embodiment of the present invention discloses a method of treating disorders in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme, comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
Another embodiment of the present invention discloses a method of treating non- insulin dependent type 2 diabetes in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I) .
Another embodiment of the present invention discloses a method of treating insulin resistance in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I). Another embodiment of the present invention discloses a method of treating obesity in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula G).
Another embodiment of the present invention discloses a method of treating lipid disorders in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
Another embodiment of the present invention discloses a method of treating metabolic syndrome in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I). Another embodiment of the present invention discloses a method of treating diseases and conditions that are mediated by excessive glucocorticoid action in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
Another embodiment of the present invention discloses a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) in combination with a pharmaceutically suitable carrier.
Definition of Terms
The term "alkenyl" as used herein, refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.
The term "alkoxy" as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert- butoxy, pentyloxy and hexyloxy.
The term "alkoxyalkyl" as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2- ethoxyethyl, 2-methoxyethyl and methoxymethyl.
The term "alkoxycarbonyl" as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl.
The term "alkyl" as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
The term "alkylcarbonyl," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-l-oxopropyl, 1-oxobutyl and 1-oxopentyl.
The term "alkylsulfonyl" as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl.
The term "alkyl-NH" as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a nitrogen atom.
The term "alkyl-NH-alkyl" as used herein, refers to an alkyl-NH group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
The term "aryl" as used herein, means a phenyl group, or a bicyclic or a tricyclic fused ring system. Bicyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety and fused to a monocyclic cycloalkyl group, as defined herein, a phenyl group, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein. Tricyclic fused ring systems are exemplified by an aryl bicyclic fused ring system, as defined herein and fused to a monocyclic cycloalkyl group, as defined herein, a phenyl group, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein. Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl and tetrahydronaphthyl.
The aryl groups of this invention maybe optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylalkoxy, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkylalkoxy, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylalkoxy, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclealkoxy, heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl, nitro, RfRgN-, RfRgNalkyl, RfRgNcarbonyl and RfRgNsulfonyl, wherein Rf and Rg are independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, heterocyclealkyl and cycloalkylalkyl and wherein the cycloalkyl, the heterocycle of heterocyclealkyl and the cycloalkyl of cycloalkylalkyl as represented by Rf and Rg are each independently unsubstituted or substituted with 1, 2 or 3 substituent selected from the group consisting of alkyl, haloalkyl and halogen. The substituent aryl, the aryl of arylalkyl, the aryl of arylalkenyl, the aryl of arylalkoxy, the aryl of arylcarbonyl, the aryl of aryloxy, the aryl of arylsulfonyl, the cycloalkyl of cycloalkylalkoxy, the substituent heteroaryl, the heteroaryl of heteroarylalkyl, the heteroaryl of heteroarylalkenyl, the heteroaryl of heteroarylalkoxy, the heteroaryl of heteroarylcarbonyl, the substituent heterocycle, the heterocycle of heterocyclealkyl, the heterocycle of heterocyclealkoxy, the heterocycle of heterocyclecarbonyl, the heterocycle of heterocycleoxy, the heterocycle of heterocyclesulfonyl maybe optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy, carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, RfRgN-, RfRgNalkyl, RfRgNcarbonyl and RfRgNsulfonyl.
The term "aryl1" as used herein, refers to a substituted phenyl group wherein the substituent is a member selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl and nitro, or a bicyclic or a tricyclic fused ring system. Bicyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety, which is fused to a cycloalkyl group, as defined herein, a phenyl group, a heteroaryl, as defined herein, or a heterocycle as defined herein. Tricyclic fused ring systems are exemplified by an aryl bicyclic fused ring system fused to a cycloalkyl group, as defined herein, a phenyl group, a heteroaryl, as defined herein, or a heterocycle as defined herein. Bicyclic and tricyclic fused ring systems of this invention may be optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl, nitro, RfRgN-, RfRgNalkyl, RfRgNcarbonyl and RfRgNsulfonyl, wherein Rf and Rg are as described herein. Representative examples of aryl1 include, but are not limited to, anisole, aniline, anthracenyl, azulenyl, fluorenyl, naphthyl, and tetrahydronaphthyl.
The term "arylalkenyl" as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkenyl group, as defined herein. The term "arylalkyl" as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3- phenylpropyl and 2-naphth-2-ylethyl.
The term "arylalkoxy" as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. The term "arylcarbonyl" as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and naphthoyl.
The term "aryl-NH-" as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a nitrogen atom.
The term "aryl-NH-alkyl" as used herein, refers to an aryl-NH- group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
The term "aryloxy," as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of aryloxy include, but are not limited to phenoxy, naphthyloxy, 3- bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy and 3,5-dimethoxyphenoxy.
The term "aryloxyalkyl" as used herein, refers to an aryloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
The term "arylsulfonyl" as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of arylsulfonyl include, but are not limited to, phenylsulfonyl, A- bromophenylsulfonyl and naphthylsulfonyl.
The term "carbonyl" as used herein refers to a -C(O)- group.
The term "carboxy" as used herein refers to a -C(O)-OH group.
The term "carboxyalkyl" as used herein refers to a carboxy group as defined herein, appended to the parent molecular moiety through an alkyl group as defined herein. The term "carboxycycloalkyl" as used herein refers to a carboxy group as defined herein, appended to the parent molecular moiety through an cycloalkyl group as defined herein.
The term "cycloalkyl" as used herein, refers to a monocyclic, bicyclic, or tricyclic ring system. Monocyclic ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Bicyclic fused ring systems are exemplified by a cycloalkyl group appended to the parent molecular moiety, which is fused to an additional cycloalkyl group, as defined herein, a phenyl group, a heteroaryl, as defined herein, or a heterocycle as defined herein. Tricyclic fused ring systems are exemplified by a cycloalkyl bicyclic fused ring system fused to an additional cycloalkyl group, as defined herein, a phenyl group, a heteroaryl, as defined herein, or a heterocycle as defined herein. Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane and bicyclo[4.2.1]nonane. Tricyclic ring systems are also exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge of between one and three carbon atoms. Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.03'7]nonane and tricyclo [3.3.1.13'7] decane (adamantane).
The cycloalkyl groups of this invention may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl, nitro, RfRgN-, RfRgNalkyl, RfRgNcarbonyl and RfRgNsulfonyl, wherein Rf and Rg are independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl and cycloalkylalkyl. The substituent aryl, the aryl of arylalkyl, the aryl of arylcarbonyl, the aryl of aryloxy, the aryl of arylsulfonyl, the substituent heteroaryl, the heteroaryl of heteroarylalkyl, the heteroaryl of heteroarylcarbonyl, the substituent heterocycle, the heterocycle of heterocyclealkyl, the heterocycle of heterocyclecarbonyl, the heterocycle of heterocycleoxy, the heterocycle of heterocyclesulfonyl may be optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy, carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, RfRgN-, RfRgNalkyl, RfRgNcarbonyl and RfRgNsulfonyl.
The term "cycloalkylalkyl" as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and 4-cycloheptylbutyl.
The term "cycloalkylalkoxy" as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. The term "cycloalkylcarbonyl" as used herein, refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of cycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl, 2-cyclobutylcarbonyl and cyclohexylcarbonyl.
The term "cycloalkyloxy," as used herein, refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein. The term "cycloalkylsulfonyl," as used herein, refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of cycloalkylsulfonyl include, but are not limited to, cyclohexylsulfonyl and cyclobutylsulfonyl.
The term "halo" or "halogen," as used herein, refers to -Cl, -Br, -I or -F. The term "haloalkyl," as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2- fluoroethyl, trifluoromethyl, pentafluoroethyl and 2-chloro-3-fluoropentyl.
The term "heteroaryl," as used herein, refers to an aromatic monocyclic ring or an aromatic bicyclic ring system. The aromatic monocyclic rings are five or six membered rings containing at least one heteroatom independently selected from the group consisting of N, O and S. The five membered aromatic monocyclic rings have two double bonds and the six membered aromatic monocyclic rings have three double bonds. The bicyclic heteroaryl groups are exemplified by a monocyclic heteroaryl ring appended to the parent molecular moiety and fused to a monocyclic cycloalkyl group, as defined herein, a monocyclic aryl group, as defined herein, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein. Representative examples of heteroaryl include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indazolyl, indolyl, indolizinyl, isobenzofuranyl, isoindolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl.
The heteroaryls of this invention may be optionally substituted with 1, 2 or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl, nitro, RfRgN-, RfRgNalkyl, RfRgNcarbonyl and RfRgNsulfonyl, wherein Rf and Rg are as described herein. The substituent aryl, the aryl of arylalkyl, the aryl of arylalkenyl, the aryl of arylcarbonyl, the aryl of aryloxy, the aryl of arylsulfonyl, the substituent heteroaryl, the heteroaryl of heteroarylalkyl, the heteroaryl of heteroarylalkenyl, the substituent heterocycle, the heterocycle of heterocyclealkyl, the heterocycle of heterocyclecarbonyl, the heterocycle of heterocycleoxy, maybe optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy, carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, RfRgN-, RfRgNalkyl, RfRgNcarbonyl and RfRgNsulfonyl. The term "heteroarylalkenyl" as used herein, refers to a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkenyl group, as defined herein.
The term "heteroarylalkyl" as used herein, refers to a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
The term "heteroarylalkoxy" as used herein, refers to a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
The term "heteroaryloxy" as used herein, refers to a heteroaryl, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein.
The term "heteroaryloxyalkyl" as used herein, refers to a heteroaryloxy, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. The term "heterocycle" as used herein, refers to a non-aromatic monocyclic ring or a non-aromatic bicyclic ring. The non-aromatic monocyclic ring is a three, four, five, six, seven, or eight membered ring containing at least one heteroatom, independently selected from the group consisting of N, O and S. Representative examples of monocyclic ring systems include, but are not limited to, azetidinyl, aziridinyl, diazepinyl, dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydrothienyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1- dioxidothiomorpholinyl (thiomorpholine sulfone) and thiopyranyl. The bicyclic heterocycles are exemplified by a monocyclic heterocycle appended to the parent molecular moiety and fused to a monocyclic cycloalkyl group, as defined herein, a monocyclic aryl group, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein. Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent atoms of the monocyclic ring are linked by a bridge of between one and three atoms selected from the group consisting of carbon, nitrogen and oxygen.
Representative examples of bicyclic ring systems include but are not limited to, for example, benzopyranyl, benzothiopyranyl, benzodioxinyl, 1,3-benzodioxolyl, cinnolinyl, 1,5- diazocanyl, 3,9-diaza-bicyclo[4.2.1]non-9-yl, 3,7-diazabicyclo[3.3.1]nonane, octahydro- pyrrolo[3,4-c]pyrrole, indolinyl, isoindolinyl, 2,3,4,5-tetrahydro-lH-benzo[c]azepine, 2,3,4,5-tetrahydro-lH-benzo[έ]azepine, 2,3,4,5-tetrahydro-lH-benzo[cr|azepine, tetrahydroisoquinolinyl and tetrahydroquinolinyl. The heterocycles of this invention may be optionally substituted with 1, 2 or 3 substituents independently selected from oxo, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl, nitro, RfRgN-, RfRgNalkyl, RfRgNcarbonyl and RfRgNsulfonyl, wherein Rf and Rg are as described herein. The substituent aryl, the aryl of arylalkyl, the aryl of arylcarbonyl, the aryl of aryloxy, the aryl of arylsulfonyl, the heteroaryl, the heteroaryl of heteroarylalkyl, the substituent heterocycle, the heterocycle of heterocyclealkyl, the heterocycle of heterocyclecarbonyl, the heterocycle of heterocycleoxy, may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy, carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, RfRgN-, RfRgNalkyl, RfRgNcarbonyl and RfRgNsulfonyl.
The term "heterocyclealkyl" as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclealkyl include, but are not limited to, pyridin-3- ylmethyl and 2-pyrimidin-2-ylpropyl.
The term "heterocyclealkylcarbonyl" as used herein, refers to a heterocyclealkyl, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
The term "heterocyclealkoxy" as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. The term "heterocycleoxy" as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein. The term "heterocycleoxyalkyl" as used herein, refers to a heterocycleoxy, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. The term "heterocycle-NH-" as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a nitrogen atom.
The term "heterocycle-NH-alkyl" as used herein, refers to a heterocycle-NH-, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. The term "heterocyclecarbonyl" as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of heterocyclecarbonyl include, but are not limited to, 1- piperidinylcarbonyl, 4-morpholinylcarbonyl, pyridin-3-ylcarbonyl and quinolin-3-ylcarbonyl.
The term "heterocyclesulfonyl" as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of heterocyclesulfonyl include, but are not limited to, 1- piperidinylsulfonyl, 4-morpholinylsulfonyl, pyridin-3-ylsulfonyl and quinolin-3-ylsulfonyl.
The term "hydroxy" as used herein, refers to an -OH group.
The term "hydroxyalkyl" as used herein, refers to a hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2- hydroxyethyl, 3-hydroxypropyl and 2-ethyl-4-hydroxyheptyl.
The term "oxo" as used herein, refers to a =0 group.
The term "oxy" as used herein, refers to a -O- group. The term "sulfonyl" as used herein, refers to a -S(O)2- group.
The present compounds may exist as therapeutically suitable salts. The term "therapeutically suitable salt," refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation and allergic response, commensurate with a reasonable benefit/risk ratio and effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide the salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, form ate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylρroρionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like. The amino groups of the compounds may also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.
Basic addition salts maybe prepared during the final isolation and purification of the present compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts derived from methylamine, dimethylarnine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N- dibenzylphenethylamine, 1-ephenamine and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like, are contemplated as being within the scope of the present invention.
The present compounds may also exist as therapeutically suitable prodrugs. The term "therapeutically suitable prodrug," refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation and allergic response, are commensurate with a reasonable benefit/risk ratio and are effective for their intended use. The term "prodrug," refers to compounds that are rapidly transformed in vivo to the parent compounds of formula (I-IXc) for example, by hydrolysis in blood. The term "prodrug," refers to compounds that contain, but are not limited to, substituents known as "therapeutically suitable esters." The term "therapeutically suitable ester," refers to alkoxycarbonyl groups appended to the parent molecule on an available carbon atom. More specifically, a "therapeutically suitable ester," refers to alkoxycarbonyl groups appended to the parent molecule on one or more available aryl, cycloalkyl and/or heterocycle groups as defined herein. Compounds containing therapeutically suitable esters are an example, but are not intended to limit the scope of compounds considered to be prodrugs. Examples of prodrug ester groups include pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art. Other examples of prodrug ester groups are found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
Asymmetric centers may exist in the present compounds. Individual stereoisomers of the compounds are prepared by synthesis from chiral starting materials or by preparation of racemic mixtures and separation by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of the enantiomers on chiral chromatographic columns. Starting materials of particular stereochemistry are either commercially available or are made by the methods described hereinbelow and resolved by techniques well known in the art.
Geometric isomers may exist in the present compounds. The invention contemplates the various geometric isomers and mixtures thereof resulting from the disposal of substituents around a carbon-carbon double bond, a cycloalkyl group, or a heterocycloalkyl group. Substituents around a carbon-carbon double bond are designated as being of Z or E configuration and substituents around a cycloalkyl or heterocycloalkyl are designated as being of cis or trans configuration. Furthermore, the invention contemplates the various isomers and mixtures thereof resulting from the disposal of substituents around an adamantane ring system. Two substituents around a single ring within an adamantane ring system are designated as being of Z or E relative configuation. For examples, see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. Ie Noble J. Org. Chem. 63: 2758-2760, 1998.
Preparation of Compounds of The Invention The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes and Experimentals that illustrate a means by which the compounds of the invention can be prepared.
The compounds of this invention can be prepared by a variety of procedures and synthetic routes. Representative procedures and synthetic routes are shown in, but are not limited to, Schemes 1-17. Abbreviations which have been used in the descriptions of the Schemes and the
Examples that follow are: AcCl for acetyl chloride; DCM for dichloromethane; ATBN for 2,2'-azobis(2-methylpropionitrile); DMA for N,iV-dimethylacetamide; DIEA or Hunig's base forΛζN-diisopropylethylamine; DMAP for dimethylaminopyridine; DMF for N5N- dimethylformamide; DMSO for dimethylsulfoxide; DMPU for l,3-dimethyl-3,4,5,6- tetrahydro-2(lH)-pyrimidinone; EDCI or EDAC for (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride; EtOAc for ethyl acetate; EtOH for ethanol; Et2O for diethyl ether; HATU for O-(7-azabenzotriazol-l-yl)-N, N, N', N'-tetramethyluronium hexafluoro- phosphate; HOBt for hydroxybenzotriazole hydrate; KOTMS for potassium trimethylsilanolate; MeOH for methanol; MeCN for acetonitrile; MTBE for methyl t-butyl ether; NMO for iV-methylmorpholine N-oxide; TBTU for 0-b&azoiiiazol-l-yl-N,N,N',N'- tetramethyluronium tetrafluoroborate; THF for tetrahydrofuran; and, triflate for trifluoromethane sulfonyl
Scheme 1
Figure imgf000042_0001
(1 ) (3)
Substituted adamantanes of general formula (3), wherein A 5 A 5 A , A , R 5 R , R 5 R4, D and E are as defined in formula I, may be prepared as in Scheme 1. Substituted adamantamines of general formula (I)5 purchased, prepared as described herein, or prepared using methodology known to those in the art, may be treated with an acylating agents of general formula (2), wherein Y is chloro, bromo, or fluoro and R3, R4, D and E are defined as in formula I, in the presence of a base such as diisopropylethylamine to provide amides of general formula (3). Alternatively, acids of general formula (2) wherein Y = OH can be coupled to substituted adamantamines of general formula (1) with reagents such as EDCI and HOBt to provide amides of general formula (3). In some examples, A1, A2, A3 and/or A4 in amines of formula (1) and D and E in the reagents of formula (2) may exist as or contain a group further substituted with a protecting group such as a carboxylic acid protected as the methyl ester. Examples containing a protected functional group may be required due to the synthetic schemes and the reactivity of said groups and could be later removed to provide the desired compound. Such protecting groups can be removed using methodology known to those skilled in the art or as described in T. W. Greene, P. G. M. Wuts "Protective Groups in Organic Synthesis" 3rd ed. 1999, Wiley & Sons, Inc.
Scheme 2
Figure imgf000043_0001
(4) (5) Substituted adamantane amines of general formula (5), wherein A1, A2, A3, A4 and R2 are as defined in formula I, may be prepared as in Scheme 2. Substituted adamantane ketones of general formula (4) can be purchased, prepared as described herein, or prepared using methodology known to those skilled in the art. Ketones of general formula (4) can be treated with ammonia or primary amines (R2NH2) followed by reduction with reagents such as sodium borohydride or H2 over Pd/C in a solvent like methanol to provide amines of general formula (5). In some examples, A1, A2, A3 and/or A4 in ketones of formula (4) may be a substituent with a functional group containing a protecting group such as a carboxylic acid protected as the methyl ester. Such esters can be hydrolyzed and other protecting groups removed here to provide compounds of general formula (5) or in compounds subsequently prepared from (5) using methodology known to those skilled in the art.
Scheme 3
carboxylation
Figure imgf000043_0003
Figure imgf000043_0002
(6) (7)
Substituted adamantanes of general formula (7), wherein A2, A3 and A4 are as defined in formula I and G is alkyl, cycloalkyl, arylalkyl, or aryl, as defined in the definition of terms, or G is hydrogen or an acid protecting group, may be prepared as in Scheme 3. Substituted adamantanes of general formula (6) can be purchased or prepared using methodology known to those in the art. Tertiary alcohols of general formula (6) can be treated with oleum and formic acid followed by water or an alcohol GOH to provide polycycles of general formula (7). In some examples, G in formula (7) may be a protecting group such as methyl. Such ester protecting groups can be removed from polycycles of general formula (7) or from compounds subsequently prepared from (7).
Scheme 4
Figure imgf000044_0001
Substituted adamantanes of general formula (10), wherein A2, A3, A4, R1, R2, R3, R4, D, E, R18 and R19 are as defined in formula I, may be prepared as in Scheme 4. Adamantane acids of general formula (8) may be prepared as described herein or using methodology known to those in the art. The acids of general formula (8) may be coupled with amines of general formula (9) (wherein R18 and R19 are defined as in formula I) with reagents such as O-(benzotrialzol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU) to provide amides of general formula (10). In some examples, R18 and/or R19 in amides of formula (10) may be a substituent with a functional group containing a protecting group, such as a carboxylic acid protected as the methyl ester. Such esters can be hydrolyzed and other protecting groups removed using methodology known to those skilled in the art.
Scheme 5
Figure imgf000044_0002
(11 ) (12)
Acids of general formula (12), wherein R101 is hydrogen, and R3, R4, D and E are as defined in formula (I) can be prepared as shown in Scheme 5.
Esters of general formula (11) wherein P is an acid protecting group such as, but not limited to, C1-C6 alkyl, unsubstituted or substituted aryl (for example, phenyl) or unsubstituted or substituted arylalkyl (for example, benzyl), R3 and R4 are hydrogen, or one of R3 and R4 is hydrogen and the other is as defined in formula (T), can be purchased, prepared as described herein, or prepared using methodologies known to those skilled in the art. Esters of general formula (11) can be mono-alkylated or bis-alkylated to provide esters of general formula (12) wherein R101 is the acid protecting group, P, as described above. The bis-alkylation can be conducted either sequentially or in a one pot reaction. Mono or bis-alkylation of esters of general formula (11) can be achieved in the presence of a base such as, but not limited to, sodium hydride, and an alkylating agent such as, but not limited to, alkyl halides (for example, methyl iodide, allyl bromide and the like). The reaction is generally performed in a solvent such as, but not limited to, anhydrous N5N- dimethylformamide, at a temperature from about 0 0C to about 23 0C. Removal of the protecting group P can be achieved using methodologies known to those skilled in the art or as described in T. W. Greene, P. G. M. Wuts "Protective Groups in Organic Synthesis" 3rd ed. 1999, Wiley & Sons, Inc., to provide compounds of formula (12) wherein R101 is hydrogen. Typically, such transformation can be achieved by stirring with an acid (for example, hydrochloric acid and the like) or a base (for example, lithium hydroxide, sodium hydroxide and the like) in a solvent such as, but not limited to, dioxane, tetrahydrofuran, ethanol, and mixtures thereof, at ambient temperature or at elevated temperature (typically at about 50 0C to about 70 0C). Li cases where P is unsubstituted or substituted arylalkyl (for example, benzyl), hydrogenation can be employed to cleave the acid protecting group. Scheme 6
Figure imgf000045_0001
(15)
Synthesis of acids of general formula (15), wherein R101 is hydrogen, R3, R4, and D are as defined in formula (I), and G1 and Z are independently aryl or heteroaryl, is outlined in Scheme 6. Esters of formula (13), wherein P is C1-C6 alkyl, unsubstituted or substituted aryl (for example, phenyl) or unsubstituted or substituted arylalkyl (for example, benzyl); and Y is Cl, Br, I, or triflate can be purchased, prepared as described herein, or prepared using methodologies known to those skilled in the art. Esters of formula (13) can be converted to boronic esters of formula (14) when treated with a boron source like bis(pinacolato)diboron, a catalyst such as 1,1 '-bis(diphenylphosphino)ferrocenedichloropalladium (II), and a base like potassium acetate. The conversion is facilitated in a solvent such as, but not limited to, dimethyl sulfoxide, N,N-dimethylforrnamide or toluene, at a temperature of about 80 0C to about 100 0C. Boronic esters of general formula (14) may be coupled with reagents of formula Z-Y, wherein Z is aryl or heteroaryl and Y is Cl, Br, I, or triflate, a catalyst such as 1,1 '-bis(diphenylphosphino)ferrocenedichloropalladium (II), and a base like sodium carbonate, to provide compounds of formula (15) wherein R101 is an acid protecting group, P. The reaction can be performed in a solvent system like N,N-dimethylformamide and water at a temperature of about 80 0C to 90 0C.
Alternatively, compounds of formula (13) wherein Y is Cl, Br, I, or triflate can be treated with a boronic acid or ester of formula (13 A) or Z-B(OR102)2, wherein R102 is hydrogen or alkyl, in the presence of a catalyst, such as but not limited to, bis(triphenylphospine)palladium (H) chloride or dichlorobis(tri-o-tolylphosphine)palladium (II), and a base such as triethylamine or sodium carbonate, to provide compounds of formula (15) wherein R101 is an acid protecting group, P. The reaction can be effected by heating at a temperature from about 50 0C to about 180 0C in solvents such as isopropanol, ethanol, dimethoxyethane, water or dioxane.
Conversion of compounds of formula (15) wherein R101 is an acid protecting group, P, to compounds of formula (15) wherein R101 is hydrogen can be prepared using reaction conditions as described in Scheme 5.
Scheme 7
Figure imgf000047_0001
(16) (17) ozonolysis
Figure imgf000047_0002
Acids of general formula (19), wherein R101 is hydrogen, R3 is as defined in formula (I) and A is a substituent of heterocycle as defined in the definition of terms, can be prepared from malonic acid di-ester of formula (16) wherein P is C1-C6 alkyl or benzyl as shown in Scheme 7.
Malonic acid di-esters of general formula (16) wherein P is an acid protecting group such as C1-C6 alkyl, unsubstituted or substituted aryl (for example, phenyl) or unsubstituted or substituted arylalkyl (for example, benzyl), can be purchased or prepared using methodologies known to those skilled in the art. Malonic acid di-esters of general formula (16) can be treated with one molar equivalent of allyl bromide or 4-bromo-l-butene, using mono alkylation conditions for the conversion of (11) to (12) in Scheme 5, to provide compounds of formula (17). Ozonolysis of the terminal olefin of di-ester (17) may be achieved in a solvent system like dichloromethane and methanol at a low temperature of about -78 0C, by bubbling ozone through the solution, followed by purging the solution with nitrogen gas, and reduction of the intermediate ozonide with dimethyl sulfide to provide aldehyde di-esters of the general formula (18). Treatment of aldehyde di-ester (18) with a primary amine of formula A-NH2, wherein A is a substituent of heterocycle as defined in the definition of terms, a reducing agent like resin bound MP-triacetoxy borohydride, and in a solvent like tetrahydrofuran at a temperature around 23 0C, provides esters of general formula (19) wherein R101 is an acid protecting group, P. Removal of P using reaction conditions as outlined in Scheme 5 converts (19) wherein R101 is an acid protecting group, P, to compounds of formula (19) wherein R101 is hydrogen.
Scheme 8
Figure imgf000048_0001
d deeccaarrbbooxxyyllaattiioonn p1°y / °
Figure imgf000048_0003
Figure imgf000048_0002
Scheme 8 outlines the synthesis of esters of general formula (23), wherein P1 is an acid protecting group such as, but not limited to, C1-C6 alkyl, and X1 and X2 are substituents of heteoraryl as defined in the definition of terms, from thiazoles of formula (20).
Thiazoles of formula (20) can be purchased or prepared using methodologies known to those skilled in the art. Thiazoles of formula (20) may be alkylated by in situ activation with a chloroformate such as, but not limited to, ethyl chloroformate, followed by treatment of a nucleophile such as lithio diethylmalonate (prepared from a malonic acid di-ester in a solution such as tetrahydrofuran with a base such as lithium bis(trimethylsilyl)amide), to afford compounds of formula (21) wherein P1 and P2 are C1-C6 alkyl. The former can be conducted in a solvent such as, but not limited to, tetrahydrofuran, at a temperature around 0 0C. Treatment with the nucleophile can be effected in a solvent such as tetrahydrofuran and at a temperature around 23 0C. The lithio diethylmalonate may be formed in a solvent such as tetrahydrofuran. The N-protected malonic acid di-ester adduct of general formula (21) may be oxidized with an agent such as tetrachloro-l,2-benzoquinone in a solvent such as dichloromethane at a temperature around 0 0C to afford the di-ester of general formula (22). Mono-decarboxylation of di-ester (22) may be achieved by heating in a solvent system such as water and dimethyl sulfoxide with a salt such as sodium chloride at a temperature near 180 0C to provide esters of general formula (23).
Scheme 9
Figure imgf000049_0001
Acids of formula (27) wherein R101 is hydrogen, P3 is -C(O)OCH2C6H5, and R3 is as defined in formula (I) can be prepared from compounds of formula (24) where P is an acid protecting group such as, C1-C6 alkyl, unsubstituted or substituted aryl (for example, phenyl) or unsubstituted or substituted arylalkyl (for example, benzyl), as shown in Scheme 9.
Compounds of formula (24) can be purchased or prepared using methodologies known to those skilled in the art. Treatment of compounds of formula (24) with benzyl chloroformate and a base such as, but not limited to, sodium bicarbonate in water, provides compounds of formula (25) wherein P3 is -C(O)OCHaC6H5. Mono alkylation of compounds of formula (25) with halides of formula R3 -X3 wherein X3 is Cl, Br or I, using reaction conditions as described in Scheme 5 provides compounds of formula (26).
Conversion of compounds of formula (26) to compounds of formula (27) wherein R101 is hydrogen can be achieved using reaction conditions as described in Scheme 5 for removal of a protecting group, P.
Scheme 10 Z1-Y
1
Figure imgf000049_0002
Compounds of general formula (29), wherein R3, R4, R27, R28, R29, R30, and R31 are as defined in formula I; G2 is -N(R31)-, -O- or -S-; Z1 is aryl or heteroaryl; R101 is hydrogen or is an acid protecting group, P, such as, but not limited to, C1-C6 alkyl, unsubstituted or unsubstituted aryl (for example, phenyl) or unsubstituted or substituted arylalkyl (for example benzyl), can be prepared as shown in Scheme 10.
Compounds of formula (28) can be purchased, prepared as described herein, or prepared using methodologies known to those skilled in the art. Compounds of formula (28) wherein P is an acid protecting group can be reacted with compounds of formula 7} -Y, wherein Y is Cl, Br, I, or triflate such as 6-chloronicotinonitrile, with a base such as sodium hydride, and in an anhydrous solvent system such as tetrahydrofuran and 1,3-dimethyl- 3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU) at a temperature ranging from 0 0C to 23 0C to provide esters of general formula (29), wherein R101 is a protecting group, P.
Conversion of compounds of formula (29) wherein R101 is P to compounds of formula (29) wherein R101 is hydrogen can be achieved using reaction conditions as described in Scheme 5 for removal of a protecting group, P.
Scheme 11
Figure imgf000050_0001
(30) (31 )
Compounds of general formula (31), wherein R3 and R4 are as defined in formula (I),
G3 is aryl or heteroaryl, and R103 is hydrogen, potassium, sodium, lithium, or C1-C6 alkyl, can be prepared as shown in Scheme 11.
Compounds of formula G3 -Y wherein G3 is aryl or heteroaryl and Y is Cl, Br, I or triflate can be purchased or prepared using methodologies known to those skilled in the art, as well as, alkyl trimethylsilyl ketene acetals of formula (30) wherein R103 is C1-C6 alkyl. Compounds of formula G3-Y such as, but not limited to, 2-chloro-5-(trifluoro- methyl)pyridine can be reacted with an alkyl trimethylsilyl ketene acetal of formula (30) wherein R103 is C1-C6 alkyl such as, but not limited to, methyl or ethyl; a salt such as zinc fluoride; a catalyst such as tris(dibenzylideneacetone)diρalladium (0); a ligand such as tri-t- butylphosphine; and, in a solvent such as N,N-dimethylformamide at a temperature of about 90 0C to provide esters of general formula (31) wherein R103 is C1-C6 alkyl.
Numerous methodologies for the conversion of compounds of formula (31) wherein R103 is C1-C6 alkyl to compounds of formula (31) wherein R103 is hydrogen are described in "Protective Groups in Organic Synthesis" 3rd edition, 1999, Wiley & Sons, Inc. Additionally, one can obtain a salt of compounds of formula (31) where R101 is potassium, sodium, or lithium by stirring compounds of formula (31) wherein R103 is C1-C6 alkyl with a base such as, but not limited to, potassium trimethylsilanolate in a solvent such as, but not limited to, tetrahydrofuran, at ambient temperature.
Scheme 12
Figure imgf000051_0001
Compounds of formula (32) wherein Y is Cl, Br, I or triflate, G4 is aryl or heteroaryl as defined in the definition of terms, and A1, A2, A3, A4, R1, R2, R3, R4 and D are as defined in formula (I) can be prepared as described herein or prepared using methodologies known to those skilled in the art. Conversion of compounds of formula (32) to compounds of formula (33), depicted in Scheme 12, wherein Z2 is aryl or heteroaryl can be achieved using the series of reaction conditions as described in Scheme 6 for the transformation of (13) to (15).
Scheme 13
Figure imgf000051_0002
Adamantanes of general formula (36), wherein A1, A2, A3, A4, R1, R2, R3, R4 and D are as defined in formula (I), and G5 and Z3 are independently either aryl or heteroaryl as defined in the definition of terms, can be prepared as shown in Scheme 13.
Adamantanes of general formula (34) wherein Y is Cl, Br or I, can be prepared as described herein or prepared using methodologies known to those skilled in the art. Olefins of general formula (35) wherein Z3 is either aryl or heteroaryl can be purchased or prepared using methodologies known to those skilled in the art. Adamantanes of general formula (34) can be reacted with olefins of general formula (35), such as, but not limited to, 4- vinylpyridine; a catalyst such as, but not limited to, bis(triphenylphosphine)palladium (II) dichloride; a base such as, but not limited to, triethylamine; and, in a solvent system such as N,N-dimethylformamide at a temperature of near 150 0C to provide adamantanes of general formula (36). Scheme 14
Figure imgf000052_0001
Substituted adamantanes of general formula (38), wherein A1, A2, A3, A4, R1, R2, R3, R4, and D are as defined in formula (I); G6 is aryl or heteroaryl; and, Q is alkyl, arylalkyl, heteroarylalkyl, heterocycle alkyl, or cycloalkylalkyl, can be prepared as shown in Scheme 14.
Substituted adamantanes of general formula (37) can be prepared as described herein or prepared using methodologies known to those skilled in the art. Substituted adamantanes of general formula (37) can be alkylated with alkylating agents Q-Y, wherein Q is alkyl, arylalkyl, heteroarylalkyl, heterocycle alkyl, or cycloalkylalkyl and Y is a leaving group like I, Br, Cl, or triflate, in the presence of a base like potassium carbonate and in a solvent like N,N-dimethylformamide to yield substituted adamantanes of general formula (38).
Scheme 15
Figure imgf000052_0002
Substituted adamantanes of general formula (40), wherein A1, A2, A3, A4, R1, R2, R3, R4, and D are as defined in formula I; G7 is aryl or heteroaryl; and, Rk and Rm are independently hydrogen, alkyl, or heterocyclealkyl, or Rk and Rm together with the nitrogen to which they are attached form a heterocycle ring, can be prepared as shown in Scheme 15.
Substituted adamantanes of general formula (39), wherein Y is F, Cl, Br, or I, can be prepared as described herein or prepared using methodologies known to those skilled in the art. Substituted adamantanes of general formula (39) can be condensed with amines of general formula R1^111NH, to provide compounds of formula (40). The reaction can be conducted neat in a microwave synthesizer at a temperature near 150 0C for a period of about 40 minutes.
Scheme 16
Figure imgf000053_0001
R4, and D are as defined in formula I; G8 is aryl or heteroaryl as defined in the definition of terms; Q1 is C1-C3 alkyl; and, Rq and Rr are independently hydrogen, alkyl, or heterocyclealkyl, or Rq and Rr together with the nitrogen to which they are attached form a heterocycle ring, can be prepared as shown in Scheme 16.
Substituted adamantanes of general formula (41) can be prepared as described herein or prepared using methodologies known to those skilled in the art. Substituted adamantanes of general formula (41) can be halogenated with a reagent like N-halosuccinimde (for example, N-chlorosuccinirnide and the like) in the presence of a radical initiator like AIBN and in a solvent like carbon tetrachloride at a temperature near 80 0C to yield substituted adamantanes of general formula (42), wherein Y is Cl, Br, or I. Substituted adamantanes of general formula (42) when treated with amines of general formula RqRrNH in a solvent like dichloromethane at a temperature between 23 0C and 40 0C provide substituted adamantanes of general formula (43).
Figure imgf000054_0001
Substituted adamantanes of general formula (50), wherein A2, A3, A4, R2, R5 and R6 are as defined in formula I, can be prepared as shown in Scheme 17.
Substituted adamantanes of general formula (6) can be purchased or prepared using methodology known to those in the art. Substituted adamantanes of general formula (6) can be brominated with a reagent like hydrobromic acid in a solvent like water to provide bromides of general formula (44). Adamantanes of general formula (44) when treated with ethylene glycol and a catalytic amount of an acid like p-toluenesulfonic acid in a solvent like benzene provide adamantanes of general formula (45). Bromides of general formula (45) can be (a) treated with Rieke zinc in a solvent like tetrahydrofuran; and (b) followed by treatment with reagent (46) (prepared as described in Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senanayake, C. H. J. Am. Chem. Soc. 2002, 124, 7880-7881) in a solvent like tetrahydrofuran to provide adamantanes of general formula (47). Adamantanes of general formula (47) may be treated with lithium amide of formula LiNHR5R6 (prepared in situ by reacting ammonia with lithium or amines of formula R5R6NH wherein R5 and R6 are other than hydrogen, with t-butyl lithium) in a solvent like tetrahydrofuran. The resulting sulfanamides can be oxidized with a reagent like osmium tetroxide with a catalyst oxidant like NMO in a solvent like tetrahydrofuran to provide sulfonamides of general formula (48). Adamantanes of general formula (48) can be deketalized with reagents like hydrochloric acid in a solvent mixture like water and tetrahydrofuran to provide ketones of formula (49).
Ketones of formula (49) can be treated with amines of formula R2NH2 followed by reduction with reducing reagents such as, but not limited to, sodium borohydride or hydrogen over Pd/C in a solvent like methanol to provide amines of general formula (50). In some examples, A2, A3, A4, R2, R5 and R6 in amines of formula (50) may be a substituent with a functional group containing a protecting group such as a carboxylic acid protected as the methyl ester. Such esters can be hydrolyzed and other protecting groups removed here or in compounds subsequently prepared from (50) using methodology known to those skilled in the art.
It is understoond that the schemes described herein are for illustrative purposes and that routine experimentation, including appropriate manipulation of the sequence of the synthetic route, protection of any chemical functionality that are not compatible with the reaction conditions and deprotection are included in the scope of the invention. Protection and Deprotection of carboxylic acids and amines are known to one skilled in the art and references can be found in "Protective Groups in Organic Synthesis", T.W. Greene, P.G.M. Wuts, 3rd edition, 1999, Wiley & Sons, Inc.
The compounds and processes of the present invention will be better understood by reference to the following Examples, which are intended as an illustration of and not a limitation upon the scope of the invention. Further, all citations herein are incorporated by reference. Compounds of the invention were named by ACD/ChemSketch version 5.01
(developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada) or were given names consistent with ACD nomenclature. Adamantane ring system isomers were named according to common conventions. Two substituents around a single ring within an adamantane ring system are designated as being of Z or E relative confϊguation (for examples see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. Ie Noble J. Org. Chem. 63: 2758-2760, 1998).
Example 1 E-A- ( [" 1 -(4-Chloro-phenylVcyclobutanecarbonyr] -amino> -adamantane- 1 -carboxylic acid
Example IA
4-oxo-adamantane-l -carboxylic acid A 5L 4-neck flask equipped with N2 inlet/bubbler with H2O trap, overhead stirring, and an addition funnel was charged with 30% oleum (-10.5 volumes, 2.2 L, 8x500 g bottles + 100 mL), and heated to 50 0C under a slight N2 flow. 5-Hydroxy-2-adamantanone (220 g, 81wt% purity, 1.07 mol) was dissolved in 5 volumes HCO2H (-98%, 1.10 L) and added drop-wise to the warm oleum solution over 5 hours. The addition rate was adjusted to maintain the internal temperature between 70-90 0C. After stirring an additional 2 hours at 70 0C. The reaction solution was cooled to 10 0C in an ice bath. 20 volumes of 10% NaCl aq (4 L) were cooled to <10 0C, the crude reaction mixture was quenched into the brine solution in batches, maintaining an internal temperature <700C. The quenched reaction solution was combined with a second identical reaction mixture for isolation. The combined product solutions were extracted 3x5 volumes with CH2Cl2 (3x2.2 L) and the combined CH2Cl2 layers were then washed 1x2 volumes with 10% NaCl (1 L). The CH2Cl2 solution was then extracted 3x5 volumes with 10% Na2CO3 (3x2.2L). The combined Na2CO3 extracts were washed with 1x2 volumes with CH2Cl2 (1 L). The Na2CO3 layer was then adjusted to pH 1-2 with concentrated HCl (~ 2 volumes, product precipitates out of solution). The acidic solution was then extracted 3x5 volumes with CH2Cl2 (3x2.2 L), and the organic layer was washed 1x2 volumes with 10% NaCl. The organic solution was then dried over Na2SO4, filtered, concentrated to -1/4 volume, then chase distilled with 2 volumes EtOAc (1 L). Nucleation occurred during this distillation. The suspension was then chase distilled 2x5 volumes (2x2 L) with heptane and cooled to room temperature. The suspension was then filtered, and the liquors were recirculated 2x to wash the wet cake. The resultant material was dried overnight at 50 0C, 20 mm Hg to afford the title compound.
Example IB
E- and Z-4-amino-adamantane-l -carboxylic acid To 1.0 g (10 wt%) of 5% Pd/C is added 10.0 g of the product from Example IA followed by 200 mL (20 volumes) of 7M NH3 in MeOH. The reaction mixture is stirred under an atmosphere of H2 at RT for 16-24 hours. 200 mL of water is added and the catalyst is removed by filtration. The catalyst is washed with MeOH. Solvent is removed by distillation at a bath temperature of 35 0C until solvent stops coming over. Approximately 150 mL of a slurry remains. 300 mL of MeCN is added to the slurry, which is then stirred for three hours at RT. The slurry is filtered and washed once with 100 mL MeCN. The wet cake is dried at 500C and 20 mm Hg under N2 to afford the title compound with a 13.1 : 1.0 E:Z ratio by 1H-NMR (D2O).
Example 1C E-4-amino-adamantane-l-carboxylic acid methyl ester hydrochloride Methanol (10 volumes, 85 mL) was cooled to 0 0C. AcCl was added dropwise (5.0 equiv., 15.5 mL), and the solution was warmed to ambient temperature for 15-20 minutes. The product from Example IB (8.53 g, 43.7 mmol, 1.0 equiv.) was added and the reaction solution was heated to 45 0C for 16 hours (overnight). Consumption of the starting aminoacid was monitored by LC/MS (APCI). The reaction solution was then cooled to room temperature, 10 volumes MeCN (85 mL) was added, distilled to ~ 1/4 volume
(heterogeneous), and chase distilled 2x10 volumes with MeCN (2x85 mL). The resulting suspension was cooled to room temperature, filtered, and the filtrate was recirculated twice to wash the wet cake. The product was dried at 50 0C, 20 mm Hg overnight to afford the title compound.
Example ID
E-4- ([I -(4-Chloro-phenviy cyclobutanecarbonyl] -amino} -adamantane- 1 -carboxylic acid Step A
A solution of the product from Example 1C (50 mg, 0.20 mmol), l-(4-chlorophenyl)- 1-cyclobutanecarboxylic acid (39 mg, 0.19 mmol), and O-berizotriazol-l-yl--V)iV,i\r,iV'- tetramethyluronium tetrafluoroborate (TBTU) (65 mg, 0.20 mmol) in N,iV-dimethylacetamide (DMA) (2 mL) and DIEA (80 μL, 0.46 mmol) was stirred for 16 hours at 23 0C. The reaction mixture was analyzed by LC/MS and determined to be near completion. The reaction mixture was concentrated under reduced pressure. The residue was taken up in methylene chloride and washed with 1 N HCl (2x), saturated NaHCO3 (2x), water, and brine before drying over Na2SO4, filtering, and concentrating under reduced pressure. The resultant solid was triturated with ethyl acetate, dried under reduced pressure to provide the methyl ester of the titled compound. Step B
The methyl ester of the titled compound obtained from step A (50 mg, 0.12 mmol) was dissolved in 3 N HCl (1 mL), dioxane (0.25 mL), and 4 N HCl (1 mL). The homogenous acid solution was heated to 60 0C for 24 hours, was cooled to 23 0C, and was then concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, DMSOd6) δ 12.02 (s, IH), 7.40 (m, 4H), 6.87 (d, J = 6.6 Hz, IH), 3.68 (m, IH), 2.71 (m, 2H), 2.36 (m, 2H), 1.75 (m, 13H), 1.34 (m, 2H); MS (ESI+) m/z 389 (M+H)+.
Example 2
E-A- [(I -Phenyl-c yclopropanecarbonylV amino] -adamantane- 1 -carboxylic acid
The methyl ester of the titled compound was prepared according to the method of step
A of Example ID substituting 1 -phenyl- 1-cyclopropanecarboxylic acid for X-(A- chlorophenyl)-l-cyclobutanecarboxylic acid, and the crude methyl ester was purified by chromatography on flash silica gel with an eluant gradient of 20-40% ethyl acetate/hexanes.
Step B
The methyl ester obtained from step A (47 mg, 0.13 mmol) was dissolved in 3 N HCl
(1 mL), dioxane (0.25 mL), and 4 N HCl (1 mL), heated to 60 0C for 24 hours, was cooled to 23 0C, and was then concentrated under reduced pressure to provide the title compound. 1H
NMR (300 MHz, DMSOd6) δ 12.05 (s, IH), 7.43 (m, 4H), 7.36 (m, IH), 5.80 (d, J = 7.8 Hz,
IH), 3.72 (m, IH), 1.79 (m, 6H)5 1.71 (m, 3H), 1.40 (m, IH), 1.35 (m, 3H), 1.20 (m, 2H),
1.02 (m, 2H); MS (ESI+) m/z 341 (M+H)+.
Example 3
E-4-(2-Methyl-2-phenyl-propionylaminoV adamantane- 1 -carboxylic acid Step A
The methyl ester of the titled compound was prepared according to the method of step A of Example ID substituting 2-methyl-2-phenyl propionic acid for l-(4-chlorophenyl)-l- cyclobutanecarboxylic acid, and the crude methyl ester was purified by chromatography on flash silica gel with an eluant gradient of 20-40% ethyl acetate/hexanes. Step B The methyl ester obtained from step A (49 mg, 0.14 mmol) was dissolved in 3 N HCl (1 mL) and dioxane (0.25 mL), heated to 600C for 24 hours, was cooled to 23 0C, and was then concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 12.04 (s, IH), 7.34 (m, 4H), 7.24 (m, IH), 6.26 (d, J = 6.9 Hz, IH), 3.74 (m, IH), 1.87 (m, 2H), 1.81 (m, 4H), 1.74 (m, 3H), 1.55 (m, 2H), 1.49 (s, 6H), 1.35 (m, 2H); MS (ESI+) m/z 343 (M+H)+.
Example 4 E-A- { [ 1 -(4-Chloro-phenyiy cyclobutanecarbonyri -amino } -adamantane- 1 -carboxylic acid amide A solution of the product from step B of Example ID (24 mg, 0.062 mmol) in DCM
(2 mL) was treated with HOBt (12 mg, 0.090 mmol) and EDCI (20 mg, 0.10 mmol) and stirred at room temperature for 1 hour. Excess of aqueous (35%) ammonia (1 mL) was added and the reaction was stirred for 16 hours. The layers were separated and the aqueous extracted twice more with methylene chloride (2x2 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 um particle size) using a gradient of 10% to 100% acetonitrile:aqueous ammonium acetate (10 mM) over 8 minutes (10 minute run time) at a flow rate of 40 niL/minute on reverse phase HPLC to afford the title compound upon concentration under reduced pressure. 1H NMR (300 MHz, DMSO-d6) δ 7.40 (m, 4H), 6.94 (s, IH), 6.84 (d, J = 6.6 Hz, IH), 6.68 (s, IH), 3.69 (m, IH), 2.71 (m, 2H), 2.35 (m, 2H), 1.76 (m, 13H), 1.32 (m, 2H); MS (ESI+) m/z 388 (M+H)+.
Example 5 E-4-[ri-Phenyl-cyclopropanecarbonylVamino]-adamantane-l-carboxylic acid amide
The title compound was prepared according to the method of Example 4 substituting the product from step B of Example 2 for the product from step B of Example ID. 1H NMR (300 MHz, DMSO-d6) δ 7.42 (m, 4H), 7.36 (m, IH), 6.94 (s, IH), 6.68 (s, IH), 6.78 (d, J = 7.8 Hz, IH), 3.73 (m, IH), 1.75 (m, 7H), 1.65 (m, 2H), 1.35 (m, 4H), 1.18 (m, 2H), 1.02 (m, 2H); MS (ESI+) m/z 340 (M+H)+.
Example 6 i?-4-f 2-Methyl-2-phenyl-propionylamino)-adamantane- 1 -carboxylic acid amide The title compound was prepared according to the method of Example 4 substituting the product from step B of Example 3 for the product from step B of Example ID. 1H NMR (300 MHz, DMSOd6) δ 7.35 (m, 4H), 7.25 (m, IH), 6.96 (s, IH), 6.69 (s, IH), 6.23 (d, J = 7.2 Hz, IH), 3.74 (m, IH), 1.85 (m, 2H), 1.75 (m, 5H), 1.69 (m, 2H), 1.53 (m, 2H), 1.49 (s, 6H), 1.32 (m, 2H); MS (ESI+) m/z 342 (M+H)+.
Example 7 iV:-2-adamantyl-2-methyl-2-phenylpropanamide A solution of 2-adamantanamine hydrochloride (38 mg, 0.20 mmol), 2- phenylisobutyric acid (30 mg, 0.19 mmol), and O-benzotriazol-l-yl-λζ-V,N',iV''- tetramethyluronium tetrafiuoroborate (TBTU) (65 mg, 0.20 mmol) in N,N-dimethylacetamide (DMA) (2 mL) and DIEA (80 μL, 0.46 mmol) was stirred for 16 hours at 23 0C. The reaction mixture was analyzed by LC/MS and determined to be near completion. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in
DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 urn particle size) using a gradient of 10% to 100% acetonitrile: aqueous ammonium acetate (10 mM) over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute on reverse phase HPLC to afford the title compound upon concentration under reduced pressure. 1H NMR (300 MHz, DMSO-d6) δ 7.35 (m, 4H), 7.24 (m, IH), 6.16 (d, J = 6.9 Hz, IH), 3.78 (m, IH), 1.74 (m, 7H), 1.64 (m, 3H), 1.55 (m, 2H), 1.48 (s, 6H), 1.41 (m, 2H); MS (DCI+) m/z 298 (M+H)+.
Example 8 7V-2-adamantyl- 1 -phenylcyclopropanecarboxamide
The titled compound was prepared according to the method of Example 7 substituting 1 -phenyl cyclopropanecarboxylic acid for 2-phenylisobutyric acid. 1H NMR (300 MHz, DMSOd6) δ 7.43 (m, 4H), 7.37 (m, IH), 5.77 (d, J = 7.8 Hz, IH), 3.76 (m, IH), 1.68 (m, 10H), 1.42 (m, 2H), 1.35 (m, 2H), 1.21 (m, 2H), 1.01 (m, 2H); MS (DCI+) m/z 296 (M+H)+.
Example 9 E-4-f { [ 1 -r4-chlorophenyDcyclohexyllcarbonyl> amino)adamantane- 1 -carboxamide Example 9A
E-4-( j \ 1 -(4-chlorophenyl)cyclohexyncarbonyl> amino*)adamantane- 1 -carboxylic acid Step A The methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting l-(4-chlorophenyl)-l-cyclohexanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid, and with the exceptions that the methyl ester was purified by reverse phase chromatography. Upon work up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 urn particle size) using a gradient of 10% to 100% acetonitrile: aqueous ammonium acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40 mL/min. Step B
The methyl ester obtained from step A (47 mg, 0.11 mmol) was dissolved in 5 N aqueous HCl (1 mL) and 4 N HCl in dioxane (2 mL), heated to 60 0C for 24 hours, was cooled to 23 0C, and was then concentrated under reduced pressure to provide the title compound.
Example 9B E-4-( {[ 1 -(4-chlorophenyDcyclohexyl]carbonyl> amino)adamantane- 1 -carboxamide
The title compound was prepared according to the method as described in Example 4 substituting the product of step B of Example 9A for the product of step B of Example ID, and with the exception that the crude title compound was purified by normal phase flash chromatography with MeOH/DCM (5:95) as eluant. 1H NMR (500 MHz, DMSO- d6) δ ppm 7.36-7.42 (m, 4H), 6.95-6.96 (bs, IH), 6.69-6.70 (bs, IH), 6.57 (d, J= 6.56 Hz, IH), 3.72- 3.76 (m, IH), 2.36-2.44 (m, 2H), 1.84-1.86 (m, 2H), 1.73-1.82 (m, 5H), 1.64-1.73 (m, 6H), 1.49-1.56 (m, 3H), 1.36-1.51 (m, 2H), 1.32-1.36 (m, 2H), 1.23-1.30 (m, IH); MS (ESI+) m/z 415 (M+H)+.
Example 10
E-4-C l[ 1 -(4-chlorophenyDcyclopropylicarbonvU amino^adamantane- 1 -carboxamide Example IQA
E-4-dri-('4-chlorophenyl')cvcloρropyllcarbonyllamino)adaniantane-l-carboxylic acid Step A The methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting l-(4-chlorophenyl)-l- cyclopropanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid, and with the exceptions that the methyl ester was purified by reverse phase chromatography. Upon work up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 ran particle size) using a gradient of 10% to 100% acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40 mL/min. Step B
The methyl ester obtained from step A (51 mg, 0.13 mmol) was dissolved in 5 N aqueous HCl (1 mL) and 4 N HCl in dioxane (2 mL), heated to 60 0C for 24 hours, was cooled to 23 C, and was then concentrated under reduced pressure to provide the title compound.
Example IQB E-4-r{[l-(4-chlorophenvDcyclopropyl1carbonyl}amino)adamantane-l-carboxamide
The title compound was prepared according to the method as described in Example 4, substituting the product of step B of Example 1OA for the product of step B of Example ID and with the exception that title compound was purified by normal phase flash chromatography with MeOH/DCM (5:95) as eluant. 1H NMR (500 MHz, DMSO- d6) δ ppm 7.43-7.48 (m, 4H), 6.95-6.97 (bs, IH), 6.69-6.70 (bs, IH), 5.98 (d, J= 7.30 Hz, IH), 3.71- 3.76 (m, IH), 1.79-1.82 (m, 2H), 1.73-1.78 (m, 5H), 1.67-1.69 (m, 2H), 1.29-1.41 (m, 6H), 0.99-1.03 (m, 2H); MS (ESI+) m/z 373 (M+H)+.
Example 11 E-4-r{[l-(4-chlorophenvDcvclopentyl]carbonyl}amino)adamantane-l-carboxamide
Example 1 IA E-4-("{ri-r4-chlorophenvDcvclopentyl]carbonvUamino)adamantane-l-carboxylic acid Step A
The methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting l-(4-chlorophenyl)-l- cyclopentanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid, and with the exceptions that the methyl ester was purified by reverse phase chromatography. Upon work up, the residue was dissolved in DMS 0/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 urn particle size) using a gradient of 10% to 100% acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40 mL/min. Step B
The methyl ester obtained from step A (30 mg, 0.072 mmol) was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1 mL), heated to 600C for 24 hours, was cooled to 23 0C, and was then concentrated under reduced pressure to provide the title compound.
Example HB E-4-( {[ l-(4-chlorophenyl)cyclopentyl]carbonyl} aminoiadamantane- 1 -carboxamide
The title compound was prepared according to the method as described in Example 4, substituting the product of step B of Example 11 A for the product of step B of Example ID, and with the exception that title compound was purified by normal phase flash chromatography with MeOH/DCM (5:95) as eluant. 1H NMR (500 MHz, DMSO- d6) δ ppm 7.35-7.41 (m, 4H), 6.94-6.96 (bs, IH), 6.68-6.70 (bs, IH), 6.58 (d, J= 6.59 Hz, IH), 3.66- 3.70 (m, IH), 2.51-2.60 (m, 2H), 1.77-1.86 (m, 5H), 1.73-1.77 (m, 4H), 1.68-1.69 (m, 2H), 1.58-1.66 (m, 6H), 1.30-1.34 (m, 2H); MS (ESI+) m/z 401 (M+H)+.
Example 12 E-A- { [2-(4-chlorophenyl V2-methylproρanoyl] amino > adamantane- 1 -carboxamide
Example 12A
E-4- { [2-(4-chlorophenyl)-2-methylproρanoyl] amino > adamantane- 1 -carboxylic acid Step A The methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting 2-methyl-2-(4-chlorophenyl) propionic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid, and with the exceptions that the methyl ester was purified by reverse phase chromatography. Upon work up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 um particle size) using a gradient of 10% to 100% acetonitrileraqueous ammonium acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40 mL/min. Step B The methyl ester obtained from step A (50 mg, 0.13 mmol) was dissolved in 5 N aqueous HCl (1 mL) and 4 N HCl in dioxane (2 mL), heated to 600C for 24 hours, was cooled to 23 0C, and was then concentrated under reduced pressure to provide the title compound.
Example 12B
E-4-|[2-("4-chlorophenyl)-2-methylpropanoyl]amino>adamantane-l-carboxamide
The title compound was prepared according to the method as described in Example 4, substituting the product of step B of Example 12A for the product of step B of Example ID, and with the exception that title compound was purified by normal phase flash chromatography with MeOH/DCM (5:95) as eluant. 1H NMR (500 MHz, DMSO- d6) δ ppm 7.34-7.40 (m, 4H), 6.95-6.97 (bs, IH), 6.69-6.71 (bs, IH), 6.44 (d, J= 6.72 Hz, IH), 3.73- 3.77 (m, IH), 1.86-1.89 (m, 2H), 1.69-1.81 (m, 5H), 1.67-1.73 (m, 2H), 1.61-1.66 (m, 2H), 1.47 (s, 6H), 1.32-1.36 (m, 2H); MS (ESI+) m/z 375 (M+H)+.
Example 13
E-4- { [( 1 -phenylcyclopentyDcarbonyl] amino 1 adamantane- 1 -carboxamide
Example 13 A
E-4-{[(l-phenylcyclopentvπcarbonyl]amino>adamantane-l-carboxylic acid Step A
The methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting 1 -phenyl- 1-cyclopentanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid, and with the exceptions that the methyl ester was purified by reverse phase chromatography. Upon work up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 ran particle size) using a gradient of 10% to 100% acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40 mL/min. Step B
The methyl ester obtained from step A (20 mg, 0.052 mmol) was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1 mL), heated to 60 0C for 24 hours, was cooled to 23 0C, and was then concentrated under reduced pressure to provide the title compound.
Example 13B E-4- ( [(I -phenylcyclopentvDcarbonyll amino } adamantane- 1 -carboxamide The title compound was prepared according to the method as described in Example 4, substituting the product of step B of Example 13 A for the product of step B of Example ID, and with the exception that title compound was purified by normal phase flash chromatography with MeOH/DCM (5:95) as eluant. 1H NMR (500 MHz, DMSO- d6) δ ppm 7.38-7.40 (m, 2H), 7.30-7.34 (m, 2H), 7.20-7.24 (m, IH), 6.93-6.95 (bs, IH), 6.68-6.69 (bs, IH), 6.38 (d, J= 6.80 Hz, IH), 3.65-3.69 (m, IH), 2.51-2.58 (m, 2H), 1.78-1.90 (m, 4H), 1.71-1.78 (m, 5H), 1.65-1.69 (m, 2H), 1.60-1.64 (m, 4H), 1.51-1.56 (m, 2H), 1.28-1.32 (m, 2H); MS (ESI+) m/z 367 (M+H)+.
Example 14 E-4-( { [ 1 -D-fluorophenvDcyclopentylJcarbonyl} amino)adamantane- 1 -carboxamide
Example 14A
J-?-4-(([l-r3-fluorophenyl')cyclopentyl]carbonyl>amino)adamantane-l-carboxylic acid Step A The methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting l-(3-fluorophenyl)-l- cyclopentanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid, and with the exceptions that the methyl ester was purified by reverse phase chromatography. Upon work up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 urn particle size) using a gradient of 10% to 100% acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40 niL/min. Step B
The methyl ester obtained from step A (41 mg, 0,10 mmol) was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1 mL), heated to 60 0C for 24 hours, was cooled to 23 0C, and was then concentrated under reduced pressure to provide the title compound.
Example 14B E-4-( IfI-O -fluorophenyDcyclopentyl] carbonyll amino)adamantane- 1 -carboxamide
The title compound was prepared according to the method as described in Example 4, substituting the product of step B of Example 14A for the product of step B of Example ID. 1H NMR (300 MHz, DMSO- d6) δ ppm 7.31-7.40 (m, IH), 7.18-7.24 (m, 2H), 7.01-7.09 (m, IH), 6.93-6.96 (bs, IH), 6.68-6.70 (bs, IH), 6.60 (d, J= 6.55 Hz, IH), 3.64-3.71 (m, IH), 2.48-2.66 (m, 2H), 1.71-1.88 (m, 9H), 1.58-1.71 (m, 8H), 1.29-1.35 (m, 2H); MS (ESI+) m/z 385 (M+H)+.
Example 15 E-4-( { [ 1 -(2-chloro-4-fluorophenyl)cvclopentyl]carbonyll amino)adamantane- 1 -carboxamide
Example 15A E-A-( { [ 1 -(2-chloro-4-fluoroρhenyl)cyclopentyl]carbonvU amino)adamantane- 1 -carboxylic acid Step A
The methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting l-(2-chloro-4-fluorophenyl)-l- cyclopentanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid, and with the exceptions that the methyl ester was purified by reverse phase chromatography. Upon work up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 um particle size) using a gradient of 10% to 100% acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40 mL/min. Step B The methyl ester obtained from step A (66 mg, 0.15 mmol) was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (2 mL), heated to 60 0C for 24 hours, was cooled to 23 0C, and was then concentrated under reduced pressure to provide the title compound.
Example 15B
E-4-( {[ 1 -(2-chloro-4-fluorophenyl)cyclopentyl]carbonyU amino)adamantane-l -carboxamide The title compound was prepared according to the method as described in Example 4, substituting the product of step B of Example 15A for the product of step B of Example ID.
1H NMR (300 MHz5 DMSO- d6) δ ppm 7.61 (dd, J= 8.86, 6.18 Hz, IH), 7.43 (dd, J= 8.66, 2.77 Hz, IH), 7.24 (ddd, J= 8.81, 8.11, 2.80 Hz, IH), 6.94-6.96 (m, IH), 6.68-6.71 (bs, IH),
5.84 (d, J= 6.96 Hz, IH), 3.69-3.77 (m, IH), 2.35-2.51 (m, 2H), 1.92-2.08 (m, 2H), 1.53-
1.89 (m, 13H), 1.28-1.45 (m, 4H); MS (ESI+) m/z 419 (M+H)+.
Example 16 E-4-( (F 1 -(4-fluorophenyl)cyclopentyl]carbonyU amino)adamantane- 1 -carboxamide
Example 16A
E-4-( { \ 1 -(4-fluorophenyl)cyclopentyl] carbonyl) amino)adamantane- 1 -carboxylic acid Step A The methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting l-(4-fluorophenyl)-l- cyclopentanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid, and with the exceptions that the methyl ester was purified by reverse phase chromatography. Upon work up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 um particle size) using a gradient of 10% to 100% acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40 mL/min. Step B
The methyl ester obtained from step A (58 mg, 0.15 mmol) was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (2 mL), heated to 60 0C for 24 hours, was cooled to 23 0C, and was then concentrated under reduced pressure to provide the title compound.
Example 16B E-4-( { [ 1 -(4-fluorophenyDcvclopentvncarbonyll amino^adamantane- 1 -carboxamide
The title compound was prepared according to the method as described in Example 4, substituting the product of step B of Example 16A for the product of step B of Example ID. 1H NMR (300 MHz, DMSO- d6) δ ppm 7.37-7.45 (m, 2H), 7.10-7.17 (m, 2H), 6.93-6.96 (bs, IH), 6.67-6.70 (bs, IH), 6.50 (d, J= 6.65 Hz5 IH), 3.64-3.70 (m, IH), 2.51-2.61 (m, 2H), 1.54-1.86 (m, 17H), 1.27-1.37 (m, 2H); MS (ESI+) m/z 385 (M+H)+.
Example 17
E-4-r([l-(2-fluorophenyl)cvclopentyllcarbonyUammo)adamantane-l-carboxamide
Example 17A E-4-( ( [ 1 -(2-fluorophenyDc vclopentyljcarbonyl} amino)adamantane- 1 -carboxylic acid Step A
The methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting l-(2-fluorophenyl)-l- cyclopentanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid, and with the exceptions that the methyl ester was purified by reverse phase chromatography. Upon work up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 um particle size) using a gradient of 10% to 100% acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40 mL/min. Step B The methyl ester obtained from step A (56 mg, 0.14 mmol) was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (2 mL), heated to 60 0C for 24 hours, was cooled to 23 0C, and was then concentrated under reduced pressure to provide the title compound.
Example 17B
E-4-( { [ 1 -(l-fluorophenvDcyclopentylicarbonvU arnino)adarnantane- 1 -carboxamide The title compound was prepared according to the method as described in Example 4, substituting the product of step B of Example 17A for the product of step B of Example ID. 1H NMR (300 MHz, DMSO- d6) δ ppm 7.49 (td, J= 7.94, 1.80 Hz, IH), 7.29-7.37 (m, IH), 7.11-7.24 (m, 2H), 6.94-6.96 (bs, IH), 6.68-6.70 (bs, IH)5 6.02 (d, J= 6.93 Hz, IH), 3.67- 3.74 (m, IH), 2.34-2.53 (m, 2H)3 1.85-2.01 (m, 2H), 1.57-1.86 (m, 13H), 1.28-1.43 (m, 4H); MS (ESI+) m/z 385 (M+H)+.
Example 18 E-4- { [( 1 -methylcyclohexyDcarbonyl] amino } adamantane- 1 -carboxamide
Example 18A
E-4- ( [Y 1 -methylcyclohexyDcarbonyl] amino} adamantane- 1 -carboxylic acid Step A
The methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting 1 -methyl- 1-cyclohexanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid, and with the exceptions that the methyl ester was purified by reverse phase chromatography. Upon work up., the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 um particle size) using a gradient of 10% to 100% acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40 mL/min. Step B
The methyl ester obtained from step A (33 mg, 0.10 mmol) was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1 mL), heated to 60 0C for 24 hours, was cooled to 23 0C, and was then concentrated under reduced pressure to provide the title compound.
Example 18B E-A- { \( 1 -methylcyclohexyDcarbonyll amino) adamantane- 1 -carboxamide The title compound was prepared according to the method as described in Example 4, substituting the product of step B of Example 18A for the product of step B of Example ID. 1H NMR (300 MHz, DMSO- d6) δ ppm 6.96-6.99 (bs, IH), 6.66-6.72 (m, 2H), 3.74-3.80 (m, IH), 1.82-2.08 (m, 7H), 1.79-1.82 (m, 4H), 1.72-1.75 (m, 2H), 1.12-1.55 (m, 10H), 1.07 (s, 3H); MS (ESI+) m/z 319 (M+H)+.
Example 19
E-4-( { [ 1 -(2,4-dichlorophenyDcyclopropyl]carbonyl} amino)adamantane- 1 -carboxamide
Example 19A
E-4-( { [ 1 -(^-dichlorophenyDcyclopropyl] carbonyll amino)adamantane- 1 -carboxylic acid Step A
The methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting l-(2,4-dichlorophenyl)-l- cyclopropanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid and with the exceptions that the methyl ester was purified by reverse phase chromatography. Upon work up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 um particle size) using a gradient of 10% to 100% acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40 mL/min. Step B
The methyl ester obtained from step A (47 mg, 0.11 mmol) was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (2 mL), heated to 60 0C for 24 hours, was cooled to 23 0C, and was then concentrated under reduced pressure to provide the title compound.
Example 19B
E-4-(([l-(2,4-dichlorophenyπcvclopropyllcarbonyl}amino>adamantane-l-carboxamide The title compound was prepared according to the method as described in Example 4, substituting the product of step B of Example 19A for the product of step B of Example ID. 1H NMR (300 MHz, DMSO- d6) δ ppm 7.73 (d, J= 2.10 Hz, IH), 7.56 (d, J= 8.25 Hz, IH), 7.49 (dd, J= 8.27, 2.12 Hz, IH), 6.94-6.97 (bs, IH), 6.68-6.71 (bs, IH), 5.66 (d, J= 7.12 Hz, IH), 3.70-3.77 (m, IH), 1.80-1.84 (m, 2H), 1.71-1.78 (m, 5H), 1.68 (d, J= 3.09 Hz, 2H), 1.43-1.53 (m, 2H), 1.27-1.42 (m, 4H), 1.02-1.12 (m, 2H); MS (ESI+) m/z 407 (M+H)+.
Example 20
E-4-( { \ 1 -(4-methoxyphenvDc ycloprop yl] carbonyU amino)adamantane- 1 -carboxamide
Example 2OA E-4-( { [ 1 -(4-methoxyphenyDcycloprop yl] carbonyl } amino)adamantane- 1 -carboxylic acid Step A
The methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting l-(4-methoxyphenyl)-l- cyclopropanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid and with the exceptions that the methyl ester was purified by reverse phase chromatography. Upon work up, the residue was dissolved in DMS 0/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 urn particle size) using a gradient of 10% to 100% acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40 mL/min. Step B The methyl ester obtained from step A (43 mg, 0.11 mmol) was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1 mL), heated to 60 0C for 24 hours, was cooled to 23 0C, and was then concentrated under reduced pressure to provide the title compound.
Example 2OB
E-A-( { \ 1 -(4-methoxyphenyl)cyclopropyl] carbonyl} amino)adamantane- 1 -carboxamide
The title compound was prepared according to the method as described in Example 4, substituting the product of step B of Example 2OA for the product of step B of Example ID. 1H NMR (300 MHz, DMSO- d6) δ ppm 7.34-7.38 (m, 2H), 6.95-7.00 (m, 3H), 6.68-6.71 (bs, IH), 5.78 (d, J= 7.66 Hz, IH), 3.76 (s, 3H), 3.69-3.75 (m, IH), 1.72-1.77 (m, 7H)5 1.66-1.69 (m, 2H), 1.27-1.43 (m, 4H), 1.17-1.24 (m, 2H), 0.93-1.03 (m, 2H); MS (ESI+) m/z 369 (M+H)+. Example 21 E-4-( { \ 1 -(4-methylphenvDcvclopropyllcarbonyl> amino'jadamantane- 1 -carboxamide
Example 21A
E-4-(([l-r4-methylphenvDcvclopropyl1carbonyl>amino)adamantane-l-carboxylic acid Step A
The methyl ester of the title compound was prepared according to the method as described in step A of Example ID, substituting l-(4-methylphenyl)-l- cyclopropanecarboxylic acid for l-(4-chlorophenyl)-l-cyclobutanecarboxylic acid and with the exceptions that the methyl ester was purified by reverse phase chromatography. Upon work up, the residue was dissolved in DMS 0/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 urn particle size) using a gradient of 10% to 100% acetonitrile: aqueous ammonium acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40 mL/min. Step B
The methyl ester obtained from step A (39 mg, 0.11 mmol) was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1 mL), heated to 60 0C for 24 hours, was cooled to 23 0C, and was then concentrated under reduced pressure to provide the title compound.
Example 2 IB E-A-({ \ 1 -^-methylphenyDcyclopropyl] carbonyl} amino)adamantane- 1 -carboxamide
The title compound was prepared according to the method as described in Example 4, substituting the product of step B of Example 21A for the product of step B of Example ID. 1H NMR (300 MHz, DMSO- d6) δ ppm 7.30-7.34 (m, 2H), 7.20-7.25 (m, 2H), 6.94-6.97 (bs, IH), 6.68-6.70 (bs, IH), 5.80 (d, J= 7.62 Hz, IH), 3.69-3.76 (m, IH), 2.31 (s, 3H), 1.71-1.81 (m, 7H), 1.66-1.68 (m, 2H), 1.31-1.39 (m, 4H), 1.17-1.23 (m, 2H), 0.96-0.99 (m, 2H); MS (ESI+) m/z 353 (M+H)+.
Example 22 E-4-{r2-methyl-2-(4-pyridin-4-ylphenyl)propanoyl]aminoladamantane-l-carboxamide Example 22A
Ethyl 2-(4-bromophenylV2-methylpropanoate
A 60 % suspension of sodium hydride in mineral oil (3.3 g, 82.3 mmoles) was added to ΛζJV-dimethylformamide (60.0 ml) under a nitrogen atmosphere and the mixture was cooled to about - 10 0C. Iodomethane (5.1 ml, 82.3 mmoles) and subsequently ethyl 4- bromophenylacetate (5.0 g, 20.6 mmoles) were added over a period of about 30 min and the reaction mixture was then stirred for about 16 hours while being allowed to warm to room temperature. This suspension was then poured onto a mixture of ice and 2N hydrochloric acid (30.0 ml) and was extracted four times with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (2 : 1) as the mobile phase to provide the title compound.
Example 22B
2-(4-bromophenylV2-methylpropanoic acid
To a solution of the product of Example 22A (3.7 g, 13.6 mmoles) in tetrahydrofuran (110.0 ml) and methanol (37.0 ml) was added 2 N sodium hydroxide (19.0 ml) and the solution was stirred at ambient temperature for about 16 hours. The reaction mixture was concentrated in vacuum down to the water layer, was cooled with an ice bath, and was acidified by addition of 2N hydrochloric acid. The precipitate was filtered off and was dried in vacuum to provide the title compound.
Example 22C
E-4-[2-(4-Bromo-phenylV2-memyl-propionylamino]-adamantane- 1 -carboxylic acid methyl ester
A solution of the product of Example 22B (3.3 g, 13.5 mmoles), the product of Example 1C (3.3 g, 13.5 mmoles), O-benzotriazol-l-yl-ΛζΛζiV'.-V-tetramethyluronium tetrafluoroborate (8.6 g, 26.9 mmoles) and ΛζN-diisopropylethylamine (9.4 ml, 53.8 mmoles) in ΛζN-dimethylformamide (150.0 ml) was stirred at room temperature for about 16 hours under a nitrogen atmosphere. The solvent was evaporated in vacuum and the residue was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (2 : 1) as the mobile phase to provide the title compound..
Example 22D E-4-r2-Methyl-2-("4-pyridin-4-yl-phenyl)-propionylaminol-adamantane- 1 -carboxylic acid methyl ester
To a solution of the product of Example 22C (300 mg, 0.7 mmoles) in 1,2- dimethoxyethane (6.0 ml) was added a solution of pyridine-4-boronic acid (127 mg, 1.0 mmoles) in ethanol (1.0 ml), dichlorobis(tri-o-tolylphosphine)palladium(II) (28 mg, 0.04 mmoles) and a 2M aqueous solution of sodium carbonate (1.7 ml, 3.5 mmoles) and the mixture was stirred under nitrogen in a heavy walled process vial in a microwave synthesizer (Personal Chemistry Smith Synthesizer) at about 140 0C for about 10 min. The reaction mixture was concentrated in vacuum and the crude product was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (2 : 1) as the mobile phase to provide the title compound.
Example 22E
E-4-r2-Methyl-2-(4-pyridin-4-yl-phenylVpropionylammo1-adamantane-l-carboxylic acid To a solution of the product of Example 22D (125 mg, 0.29 mmoles) in dioxane (4.0 ml) was added 2N aqueous hydrochloric acid (4.0 ml) and the mixture was heated to about 60 °C for about 18 hours. The mixture was cooled, concentrated to dryness and the residue was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm x 100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile : 0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 ml/min to provide the title compound.
Example 22F E-4-r2-Methyl-2-f4-pyridin-4-yl-phenylVpropionylaminol-adamantane-l-carboxylic acid amide
A solution of the product of Example 22E (60 mg, 0.14 mmoles), N-(3- dimethylaminopropyl)-iV'-ethylcarbodiimide hydrochloride (110 mg, 0.57 mmoles) and 1- hydroxybenzotriazole hydrate (44 mg, 0.32 mmoles) in dichloromethane (4.0 ml) was stirred at ambient temperature under a nitrogen atmosphere for about 1 hour. A 0.5 M solution of ammonia in dioxane (2.9 ml, 1.43 mmoles) was added and stirring was continued for about 16 hours. The mixture was evaporated to dryness and the residue was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm x 100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile : 0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 ml/min to provide the title compound as the trifluoroacetic acid salt. 1H NMR (500 MHz, DMSO- d6) δ ppm 8.84-8.86 (m, 2H), 8.17-8.19 (m, 2H), 7.94-7.97 (m, 2H), 7.54-7.56 (m, 2H), 6.96-6.98 (bs, IH), 6.70-6.72 (bs, IH), 6.57 (d, J= 6.64 Hz, IH), 3.76- 3.80 (m, IH), 1.90-1.92 (m, 2H), 1.75-1.84 (m, 5H), 1.64-1.75 (m, 4H), 1.55 (s, 6H), 1.33- 1.37 (m, 2H); MS(ESI+) m/z 418 (M+H)+.
Example 23 E-4-[(2-methyl-2-thien-2-ylpropanoyl)amino]adamantane-l-carboxamide
Example 23A Ethyl 2-methyl-2-(miophen-2-yl)propanoate
The title compound was prepared according to the method of Example 22 A, substituting ethyl 2-(thiophen-2-yl)acetate for ethyl 4-bromophenylacetate.
Example 23B 2-Methyl-2-(thiophen-2-yDpropanoic acid
The title compound was prepared according to the method of Example 22B, substituting the product of Example 23 A for the product of Example 22 A.
Example 23 C E-4-(2-Methyl-2-thiophen-2-yl-propionylaminoVadamantane-l-carboxylic acid methyl ester
The title compound was prepared according to the method of Example 22C, substituting the product of Example 23B for the product of Example 22B.
Example 23D E-4-(2-Methyl-2-thioρhen-2-yl-propionylaminoVadamantane- 1 -carboxylic acid
To a solution of the product of Example 23C (250 mg, 0.69 mmoles) in dioxane (9.0 ml) was added 2N hydrochloric acid (9.0 ml) and the mixture was heated to about 60 °C for about 18 hours. The mixture was cooled, concentrated down to the water layer, the precipitate was filtered off and was dried in vacuum to give the title compound.
Example 23E E-4-(2-Methyl-2-thiophen-2- yl-propionylamino V adamantane- 1 -carboxylic acid amide
The title compound was prepared according to the method of Example 22F, substituting the product of Example 23D for the product of Example 22E. 1H NMR (500 MHz, DMSO- d6) δ ppm 7.46 (dd, J= 5.10, 1.20 Hz, IH), 7.10 (dd, J= 3.52, 1.21 Hz, IH), 7.02 (dd, J= 5.09, 3.52 Hz, IH), 6.95-6.97 (bs, IH), 6.69-6.71 (bs, IH), 6.24 (d, J= 7.11 Hz, IH), 3.68-3.72 (m, IH), 1.82-1.84 (m, 2H), 1.72-1.81 (m, 5H), 1.66-1.72 (m, 2H), 1.56 (s, 6H), 1.48-1.52 (m, 2H), 1.34-1.38 (m, 2H); MS(ESI+) m/z 347 (M+H)+.
Example 24
E-4-[(2-methyl-2-thien-3-ylpropanoyl)aminoladamantane-l-carboxamide
Example 24A
Ethyl 2-methyl-2-fthiophen-3-yl)propanoate
The title compound was prepared according to the method of Example 22 A substituting ethyl 2-(thiophen-3-yl)acetate for 4-bromophenylacetate.
Example 24B
2-Methyl-2-f thiophen-3 -yPpropanoic acid
The title compound was prepared according to the method of Example 22B, substituting the product of Example 24A for the product of Example 22 A.
Example 24C E-4-(2-Methyl-2-thiophen-3-yl-propionylamino)-adamantane-l -carboxylic acid methyl ester
The title compound was prepared according to the method of Example 22C, substituting the product of Example 24B for the product of Example 22B.
Example 24D E-4-(2-Methyl-2-tMophen-3-yl-propionylaminoVadamantane- 1 -carboxylic acid The title compound was prepared according to the method of Example 23D, substituting the product of Example 24C for the product of Example 23C.
Example 24E ■E-4'-(2-Methyl-2-thiophen-3 -yl-propionylaminoV adamantane- 1 -carboxylic acid amide
The title compound was prepared according to the method of Example 22F, substituting the product of Example 24D for the product of Example 22E. 1H NMR (500 MHz, DMSO- d6) δ ppm 7.54 (dd, J= 5.03, 2.90 Hz, IH), 7.41 (dd, J= 2.89, 1.44 Hz, IH), 7.12 (dd, J= 5.00, 1.40 Hz, IH), 6.95-6.97 (bs, IH), 6.69-6.70 (bs, IH), 6.01-6.07 (m, IH), 3.68-3.72 (m, IH), 1.76-1.82 (m, 7H), 1.69 (d, J= 3.14 Hz, 2H), 1.51 (s, 6H), 1.43-1.48 (m, 2H), 1.33-1.37 (m, 2H);MS(ESI+) m/z 347 (M+H)+.
Example 25
E-4-((2-methyl-2-[5-(trifluoromethvDpyridin-2-yl]propanoyUamino)adamantane-l- carboxamide
Example 25A
Potassium: 2-methyl-2-(5-trifluoromethyl-pyridin-2-ylVpropionate A solution of 2-chloro-5-(trifluoro-methyl)pyridine (328 mg, 1.8 mmol), methyl trimethylsilyl dimethylketene acetal (0.378 mg, 2.17 mmol), zinc fluoride (112 mg, 1.08 mmol), tris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.021 mmol) and tri-t- butylphosphine-10 wt% in hexane (172 mg, 0.084 mmol) in Argon degassed DMF (1.5 mL) was stirred at 900C for 12 hours. The reaction was taken up in EtOAc (25 mL) and washed with water (15 mL) followed by brine (15 mL). The organic layer was dried with MgSO4, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography (hexane/EtOAc 100:0 to 80:20) to give the methyl ester of the title compound. A solution of the methyl ester of the title compound (180 mg, 0.73 mmol), potassium trimethylsilanolate (KOTMS) (140 mg, 1.1 mmol) in THF (2 mL) was stirred for 12 hours at 23 0C. Methyl t- butyl ether (MTBE) 8 mL was added to the solution and the title compound was isolated by filtration.
Example 25B E-4-[2-Methyl-2-("5-tri£luoromethyl-ρyridin-2-vD-propionylainino1-adamantane-
1-carboxylic acid methyl ester
A solution of the product of Example 25A (50 mg, 0.184 mmol), the product of Example 1C (54 mg, 0.22 mmol), TBTU (94 mg, 0.294 mmol) and DIEA (58 mg, 0.46 mmol) in DMF (1.2 niL) was stirred for 3 hrs at 23 0C. The reaction was diluted with EtOAc (10 mL) and washed twice with water (6 mL) and brine (6 mL). The organic layer was dried with MgSO4, filtered and evaporated in vacuo to afford the title compound. The product was carried to the next step without further purification.
Example 25C
E-4-((2-methyl-2-[5-(trifluoromethvDpyridin-2-yl]propanoyl)amino')adamantane-l- carboxamide
A solution of Example 25B (30 mg, 0.071 mmol), KOTMS (14 mg, 0.11 mmol) in THF (1 mL) was stirred for 12 hours at 23 0C. The solvent was evaporated in vacuo to collect a solid. To the solid was added TBTU (40 mg, 0.12 mmol), DIEA (22 mg, 0.17 mmol) and DMF (0.5 mL) and stirred for 2 hours at 23 0C. Ammonium hydroxide-30% by weight (2 mL) was added and stirred at 23 0C for a further 30 minutes. The reaction was partitioned between EtOAc (8 mL) and water (3mL). The organic layer was washed with water (3 mL), dried with MgSO4, filtered, and evaporated in vacuo. The crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 urn particle size) using a gradient of 20% to 100% acetonitrile: water (0.1% TFA) over 18 min at a flow rate of 40 mL/min.to provide the title compound as the trifluoroacetic acid salt. 1H NMR (500 MHz, Chloroform- di) δ ppm 8.86-8.87 (m, IH), 7.94 (dd, J= 8.38, 2.40 Hz, IH), 7.59 (d, J= 8.33 Hz, IH), 7.41 (d, J= 7.48 Hz, IH), 6.13-6.18 (bs, IH), 5.80-5.84 (bs, IH), 3.93-3.97 (m, IH), 1.99-2.03 (m, 3H), 1.93-1.99 (m, 4H), 1.87-1.89 (m, 2H), 1.69 (s, 6H), 1.63-1.68 (m, 2H), 1.56-1.60 (m, 2H); MS(APCI+) m/z 410 (M+H)+.
Example 26
E-4-[(2-methyl-2-{4-[5-(trifluoromethyl)pyridin-2 yllphenyl}propanoyl)amino]adamantane- 1-carboxamide
Example 26A Ethyl 2-methyl-2-(4-(4,4.5.5-tetramethyl-l,3,2-dioxaborolan-2-vπphenvβpropanoate
A mixture of the product of Example 22A (500 mg, 1.84 mmoles), bis(pinacolato)diboron (735 mg, 2.90 mmoles), 1.1'- bis(diphenylphosphino)ferrocenedichloropalladium (II) (90 mg, 0.1.1 mmoles) and potassium acetate (903 mg, 9.20 mmoles) in dimethyl sulfoxide (11.0 ml) was heated to about 80°C under a nitrogen atmosphere for about two days. The mixture was cooled, diluted with benzene (28.0 ml) and was washed three times with water (18.0 ml each). The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (2 : 1) as the mobile phase to provide the title compound.
Example 26B
Ethyl 2-methyl-2-(4-(5-(trifluoromethyl)pyridin-2-yπphenvπpropanoate To a solution of the product of Example 26A (370 mg, 1.16 mmoles) and 2-bromo-5- (trifluoromethyl)pyridine (341 mg, 1.51 mmoles) in N,N-dimethylformamide (10.0 ml) were added l,r-bis(diphenylphosphino)ferrocenedichloropalladium (II) (28 mg, 0.04 mmoles) and a 2M aqueous solution of sodium carbonate (1.7 ml, 3.48 mmoles) and the reaction mixture was heated under a nitrogen atmosphere to about 80 °C for about 1 hour. Another portion of l,r-bis(diphenylphosphino)ferrocenedichloropalladium (II) (28 mg, 0.04 mmoles) was added and the mixture was heated to about 90 °C for about 2 hours. The solvent was evaporated in high vacuum, the residue was taken up in water (20.0 ml) and diethyl ether (20.0 ml), and was filtered through Celite. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic extracts were dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (2 : 1) as the mobile phase to provide the title compound.
Example 26C
2-Methyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)phenyl)propanoic acid The title compound was prepared according to the method of Example 22B, substituting the product of Example 26B for the product of Example 22A. Example 26D E-A- |2-Methyl-2- [4-(5 -trifluoromethyl-p yridin-2-ylVphenyll -propionylamino > -adamantane-
1-carboxylic acid methyl ester
The title compound was prepared according to the method of Example 22C substituting the product of Example 26C for the product of Example 22B .
Example 26E E-4-{2-Methyl-2-[4-r5-trifluoromethyl-pyridin-2-ylVphenyll-propionylamino>-adamantane-
1-carboxylic acid The title compound was prepared according to the method of Example 22E substituting the product of Example 26D for the product of Example 22D.
Example 26F E-4-{2-Methyl-2-[4-(5-trifluoromethyl-pyridin-2-ylVphenyll-propionylamino>-adamantane- 1-carboxylic acid amide
The trifluoroacetic acid salt of the title compound was prepared according to the method of Example 22F substituting the product of Example 26E for the product of Example 22E. 1H NMR (500 MHz, DMSO- d6) δ ppm 9.03-9.05 (m, IH)5 8.27 (dd, J= 8.46, 2.42 Hz, IH), 8.20 (d, J= 8.38 Hz, IH), 8.13-8.16 (m, 2H), 7.50-7.53 (m, 2H), 6.96-6.98 (bs, IH), 6.69-6.71 (bs, IH), 6.48 (d, J= 6.75 Hz, IH), 3.76-3.81 (m, IH), 1.88-1.91 (m, 2H), 1.74- 1.84 (m, 5H), 1.60-1.74 (m, 4H), 1.54 (s, 6H), 1.32-1.36 (m, 2H); MS(ESI+) m/z 486 (M+H)+.
Example 27 E-4-C { [ 1 -^-methoxyphenvDcyclopentyl'lcarbonyll amino)adamantane- 1 -carboxamide
Example 27A E-A- ( I" 1 -(4-Methox v-phenylVcyclopentanecarbonyl] -amino > -adamantane- 1 -carboxylic acid methyl etser A solution of the product of Example 1C (110 mg, 0.45 mmol), l-(4-methoxyphenyi)-
1-cyclopentanecarboxylic acid (100 mg, 0.45 mmol), and O-benzotriazol-l-yl-iV)iV,./V',iV)- tetramethyluronium tetrafluoroborate (TBTU) (219 mg, 0.68 mmol) in N,N-
19 dimethylfoπnainide (DMF) (2 mL) was stirred ten minutes at room temperature, and then, diisopropylethylamine (240 μL, 1.4 mmol) was added. Reaction stirred for 16 hours at room temperature. The reaction was diluted with ethyl acetate and washed successively with water, saturated sodium bicarbonate, IN phosphoric acid, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 20-30% ethyl acetate/hexane to provide the title compound.
Example 27B
-S-4- ([I -(4-Methoxy-phenylV cyclopentanecarbonyl] -amino } -adamantane- 1 -carboxylic acid A solution of the product of Example 27A (160 mg, 0.39 mmol) in THF (3 mL) was treated with aqueous 4N sodium hydroxide (1.00 mL, 3.9 mmol) and methanol (1 mL), and reaction stirred 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was taken up in water. The solution was acidified to pH 3 by the addition of aqueous IN phosphoric acid, and the product was extracted with chloroform (3X). The combined extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the title compound.
Example 27C E-A- { [ 1 -(4-Methoxy-phenyl)-cyclopentanecarbonyl] -amino I -adamantane- 1 -carboxylic acid amide
A solution of the product of Example 27B (130 mg, 0.330 mmol), 1- hydroxybenzotriazole (54 mg, 0.40 mmol), andiV-(3-dimethylaminopropyl)-iV- ethylcarbodiimide hydrochloride (EDAC) (76 mg, 0.40 mmol) in dimethylformamide (5 mL) was stirred two hours at room temperature. The reaction was treated with concentrated ammonium hydroxide (1 mL) and stirred 16 hours at room temperature. Reaction diluted with ethyl acetate and washed successively with water, saturated sodium bicarbonate, IN phosphoric acid, and brine before drying over Na2SO4, filtering, and concentrating under reduced pressure. Residue purified by flash chromatography on silica gel eluting with 5% methanol/ethyl acetate to provide the title compound. 1H NMR (500 MHz, DMSO- d6) δ ppm 7.29-7.31 (m, 2H), 6.94-6.95 (bs, IH), 6.86-6.89 (m, 2H), 6.68-6.69 (bs, IH), 6.32 (d, J = 6.82 Hz, IH), 3.73 (s, 3H), 3.64-3.70 (m, IH), 2.46-2.51 (m, 2H), 1.74-1.85 (m, 9H), 1.68 (d, J= 3.12 Hz, 2H), 1.53-1.62 (m, 6H), 1.30-1.34 (m, 2H); MS (ESI+) m/z 397 (M+H)+. Example 28 E-4- { r2-(4-bromophenylV2-methylpropano yl] amino} adamantane- 1 -carboxamide
Example 28A
E-4- r2-(4-Bromo-phenyl)-2-methyl-propionylammo] -adamantane- 1 -carboxylic acid
The title compound was prepared according to the method of Example 23D substituting the product of Example 22C for the product of Example 23C.
Example 28B
E-4-[2-(4-Bromo-phenyl)-2-methyl-propionylamino]-adamantane-l-carboxylic acid amide
The title compound was prepared according to the method of Example 22F substituting the product of Example 28 A for the product of Example 22E. 1H NMR (400 MHz, DMSO- d6) δ ppm 7.50-7.53 (m, 2H), 7.27-7.30 (m, 2H), 6.93-6.95 (bs, IH), 6.65-6.68 (bs, IH), 6.43 (d, J= 6.73 Hz, IH), 3.72-3.76 (m, IH), 1.86-1.89 (m, 2H), 1.77-1.79 (m, 5H), 1.61-1.73 (m, 4H), 1.47 (s, 6H), 1.32-1.37 (m, 2H); MS(DCI) m/z 419, 421 (M+H)+.
Example 30
E-4-[5-(aminocarbonylV2-adamantyl]-3-methyl-l-r2-methylbenzvD-2-oxopiperidine-3- carboxamide
Example 30A
2-But-3-enyl-2-methyl-malonic acid dimethyl ester
A stirred solution of NaH-60% by weight (0.517 gm, 12.94 mmol) in DMF (5 mL) was cooled to O0C and dimethyl methyl malonate (1.26 gm, 8.63 mmol) in 3 mL of DMF was added dropwise. The reaction was warmed to ambient and stirred for 15 minutes. A solution of 4-bromo-l-butene (1.28 gm, 9.49 mmol) in 1.5 mL of DMF was added to the reaction mixture and stirred for 12 hours at 23 0C. The reaction was partitioned between 10% NH4Cl (20 mL) and 30 mL of EtOAc. The organic layer was washed with water (20 mL), brine (20 mL), dried with MgSO4, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (hexane/EtOAc 100:0 to 85:15) to provide Example 30A as an oil. Exniϋle 3OB 2-Methyl-2-(3-oxo-propylVmalonic acid dimethyl ester
A solution of the product of Example 3OA (1.0 gm, 5 mmol) was dissolved in CH2Cl2MeOH 10:1 (15 mL) and cooled to -78°C. To the solution was bubbled O3 over 20 minutes. The reaction solution was purged with N2 for a further 10 minutes and dimethyl sulfide (DMS) (3.1 gm, 50 mmol) was added and the reaction warmed to ambient temperature and stirred for a further 2 hours. The solvent was evaporated in vacuo and product purified by flash column chromatography (hexane/EtOAc 100:0 to 70:30) to collect Example 30B as an oil.
Example 30C
Potassium: 3-Methyl-l-(2-methyl-benzyl)-2-oxo-piperidine-3-caboxylate A solution of the product of Example 30B (0.075 gm, 0.37 mmol), 2-methyl- benzylamine (53 mg, 0.44 mmol) and MP-triacetoxy borohydride (420 mg, 0.92 mmol) in
THF (2 mL) was stirred for 12 hours at 23 0C. The solution was filtered and evaporated in vacuo. The resulting oil was taken up in THF (1.2 mL) and stirred with KOTMS (71 mg, 0.55 mmol) at 23 0C for 12 hours. The solvent was evaporated in vacuo to provide the title compound as a white solid.
Example 30D E-r4-raminocarbonyl)-2-adamantyl]-3-methyl-l-r2-methylbenzyl')-2-oxopiperidme-3- carboxamide
A solution of the product of Example 30 C (50 mg, 0.167 mmol), the product of Example 1C (49 mg, 0.2 mmol), TBTU (85 mg, 0.26 mmol) and DIEA (53 mg, 0.42 mmol) in DMF (1.2 mL) was stirred for 2 hours at 23 0C. The reaction was partitioned between EtOAc (8 ml) and water (4 ml). The organic layer was separated and washed twice with water (4 mL each), dried with MgSO4, filtered and evaporated in vacuo. The resulting oil was taken in THF (1 mL) and stirred with KOTMS (32 mg, 0.25 mmol) at 23 0C for 12 hours. The solvent was evaporated in vacuo. The resulting solid was taken in DMF (1 mL) and stirred with TBTU (96 mg, 0.3 mmol) and DIEA (53 mg, 0.42 mmol) for 2 hours at 23 0C. Ammonium hydroxide-30% by weight (2 mL) was added and stirred for a further 30 minutes at 23 0C. The reaction was partitioned between EtOAc (8 mL) and water (3mL). The organic layer was washed with water (3 mL), dried with MgSO4 and evaporated in vacuo. The crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 um particle size) using a gradient of 20% to 100% acetonitrile:water (0.1% TFA) over 18 min at a flow rate of 40 mL/min. to provide the title compound. 1HNMR (500 MHz, CDCl3) δ ppm 8.25(d, J=8.1 Hz, IH), 7.19 (m, 2H), 7.13 (m, IH), 7.02 (d, J=7.5 Hz, IH), 6.6 (bs, IH), 5.82 (bs, IH), 4.93 (d, J=15.3, IH), 4.38 (d, J=15.3, IH), 4.01 (m, IH), 3.22 (m, 2H), 2.67 (m, IH), 2.28 (s, 3H), 2.1 (m, IH), 1.99 (m, 6H), 1.81 (m, 5H), 1.57 (m, 2H), 1.56 (s, 3H); MS(APCI) m/z 438 (M+H)
Example 31 E-4-(aminocarbonyl)-2-adamantyll-l-benzyl-3-methyl-2-oxopyrrolidine-3-carboxamide
Example 31 A
2-Allyl-2-methyl-malonic acid dimethyl ester
A stirred solution of NaH-60% by weight (0.493 gm, 12.34 mmol) in DMF (5 mL) was cooled to 00C and dimethyl methyl malonate (1.2 gm, 8.23 mmol) in 3 mL of DMF was added dropwise. The reaction was warmed to ambient temperature and stirred for 15 minutes. A solution of allyl bromide (1.18 gm, 9.86 mmol) in 1.5 mL of DMF was added to the reaction mixture and stirred for 12 hours at 23 0C. The reaction was partitioned between 10% NH4Cl (20 mL) and 30 mL of EtOAc. The organic layer was washed with water (20 mL), brine (20 mL), dried with MgSO4, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (hexane/EtOAC 100:0 to 85:15) to provide the title compound as an oil.
Example 3 IB
2-Methyl-2-f2-oxo-ethyr)-malonic acid dimethyl ester
A solution of the product of Example 31A (1.1 gm, 5.9 mmol) was dissolved in CH2Cl2/Me0H 10:1 (15 mL) and cooled to -780C. To the solution was bubbled O3 over 20 minutes. The reaction solution was purged with N2 for a further 10 minutes and dimethyl sulfide (DMS) (3.6 gm, 59 mmol) was added and the reaction warmed to ambient temperature and stirred for a further 2 hours. The solvent was evaporated in vacuo and product purified by flash column chromatography (hexane/EtOAc 100:0 to 70:30) to collect Example 3 IB as an oil.
Example 31C
Potassium: 1 -benzyl-S-methyl^-oxo-pyrrolidine-S-caboxylate A solution of the product of Example 3 IB (0.075 gm, 0.4 mmol), benzylamine (51 mg, 0.47 mmol) and MP-triacetoxy borohydride (431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours at 23 0C. The solution was filtered and evaporated in vacuo. The resulting oil was taken up in THF (1.2 mL) and stirred with KOTMS (77 mg, 0.6 mmol) for 12 hours at 23 0C. The solvent was evaporated in vacuo to provide Example 31C.
Example 3 ID E-4-raminocarbonyl)-2-adamantyl1-l-benzyl-3-methyl-2-oxopyrrolidine-3-carboxamide A solution of the product of Example 31 C (50 mg, 0.18 mmol), the product of
Example 1C (54 mg, 0.22 mmol), TBTU (92 mg, 0.29 mmol) and DIEA (57 mg, 0.45 mmol) in DMF (1.2 mL) was stirred for 2 hours at 23 0C. The reaction was partitioned between EtOAc (8 ml) and water (4 ml). The organic layer was separated and washed twice with water (4 mL each), dried with MgSO4, filtered and evaporated in vacuo. The resulting oil was taken in THF (1 mL) and stirred with KOTMS (34 mg, 0.27 mmol) for 12 hours at 23 0C. The solvent was evaporated in vacuo. The resulting solid was taken in DMF (1 mL) and stirred with TBTU (104 mg, 0.32 mmol) and DIEA (57 mg, 0.45 mmol) for 2 hours at 23 0C. Ammonium hydroxide-30% by weight (2 mL) was added and stirred for a further 30 minutes. The reaction was partitioned between EtOAc (8 mL) and water (3mL). The organic layer was washed with water (3 mL), dried with MgSO4 and evaporated in vacuo. The crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 um particle size) using a gradient of 20% to 100% acetonitrile: water (0.1% TFA) over 18 min at a flow rate of 40 mL/min. to provide the title compound. 1H NMR (400 MHz, Chloroform- dj) δ ppm 8.18-8.23 (m, IH), 7.29-7.35 (m, 3H), 7.19-7.21 (m, 2H), 5.48-5.70 (m, 2H), 4.51 (d, J= 14.73 Hz, IH), 4.43 (d, J= 14.58 Hz, IH), 3.99-4.05 (m, IH), 3.14-3.21 (m, 2H), 2.60-2.68 (m, IH), 2.09-2.15 (m, IH), 2.01-2.09 (m, 2H), 1.87-2.00 (m, 8H), 1.84-1.86 (m, IH), 1.57-1.66 (m, 2H), 1.48 (s, 3H); MS(APCI) m/z 410 (M+H) Example 32 E-4-(aminocarbonyl)-2-adamantyll-3-methyl-l-r2-methylbenzylV2-oxopyrrolidine-3- carboxamide
Example 32A
Potassium; 3-methyl-l-(2-methyl-benzyl)-2-oxo-pyrrolidme-3-carboxylate A solution of the product of Example 31B (0.075 gm, 0.4 mmol), 2-methyl- benzylamine (58 mg, 0.47 mmol) and MP-triacetoxy borohydride (431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours at 23 0C. The solution was filtered and evaporated in vacuo. The resulting oil was taken up in THF (1.2 mL) and stirred with KOTMS (77 mg, 0.6 mmol) for 12 hours at 23 0C. The solvent was evaporated in vacuo to provide Example 32A.
Example 32B
E-4-(aminocarbonyl)-2-adamantyl1-3-methyl-l-(2-methylbenzylV2-oxopyrrolidine-3- carboxamide
A solution of Example 32A (50 mg, 0.17 mmol), the product of Example 1C (52 mg, 0.21 mmol), TBTU (87 mg, 0.27 mmol) and DIEA (54 mg, 0.42 mmol) in DMF (1.2 mL) was stirred for 2 hours at 23 0C. The reaction was partitioned between EtOAc (8 ml) and water (4 ml). The organic layer was separated and washed twice with water (4 mL each), dried with MgSO4, filtered and evaporated in vacuo. The resulting oil was taken in THF (1 mL) and stirred with KOTMS (33 mg, 0.25 mmol) for 12 hours at 23 0C. The solvent was evaporated in vacuo. The resulting solid was taken in DMF (1 mL) and stirred with TBTU (98 mg, 0.31 mmol) and DIEA (54 mg, 0.42 mmol) for 2 hours. Ammonium hydroxide-30% by weight (2 mL) was added and stirred for a further 30 minutes at 23 0C. The reaction was partitioned between EtOAc (8 mL) and water (3mL). The organic layer was washed with water (3 mL), dried with MgSO4 and evaporated in vacuo. The crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 urn particle size) using a gradient of 20% to 100% acetonitriletwater (0.1% TFA) over 18 min at a flow rate of 40 mL/min. to provide the title compound. 1H NMR (400 MHz, Chloroform- dj) δ ppm 8.17-8.22 (m, IH), 7.12-7.24 (m, 3H), 7.08-7.11 (m, IH), 5.56-5.66 (m, IH), 5.34-5.43 (m, IH), 4.50-4.51 (m, 2H), 3.99-4.05 (m, IH), 3.07-3.17 (m, 2H), 2.65 (ddd, J= 13.33, 8.70, 7.16 Hz, IH), 2.28 (s, 3H), 2.08-2.15 (m, IH), 1.81-2.07 (m, HH), 1.53-1.68 (m, 2H), 1.49 (s, 3H); MS(APCI) m/z 424 (M+H)
Example 33
E-4-raminocarbonyl)-2-adamaiityl]-l-(2-chlorobenzyl)-3-methyl-2-oxopyrrolidme-3- carboxamide
Example 33A Potassium; l-(2-chloro-benzyl)-methyl-2-oxo-pyrrolidine-3-carboxylate
A solution of the product of 3 IB (0.075 gm, 0.4 mmol), 2-chϊoro-benzylamine (68 mg, 0.47 mmol) and MP-triacetoxy borohydride (431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours at 23 0C. The solution was filtered and evaporated in vacuo. The resulting oil was taken up in THF (1.2 mL) and stirred with KOTMS (77 mg, 0.6 mmol) for 12 hours at 23 0C. The solvent was evaporated in vacuo to provide Example 33A.
Example 33B
E-4-(aminocarbonyl)-2-adamantyl1-l-(2-chlorobenzyD-3-methyl-2-oxopyrrolidme-3- carboxamide A solution of the product of Example 33 A (50 mg, 0.16 mmol), the product of
Example 1C (48 mg, 0.19 mmol), TBTU (82 mg, 0.25 mmol) and DIEA (51 mg, 0.4 mmol) in DMF (1.2 mL) was stirred for 2 hours at 23 0C. The reaction was partitioned between EtOAc (8 ml) and water (4 ml). The organic layer was separated and washed twice with water (4 mL each), dried with MgSO4, filtered and evaporated in vacuo. The resulting oil was taken in THF (1 mL) and stirred with KOTMS (31 mg, 0.24 mmol) for 12 hours at 23 0C. The solvent was evaporated in vacuo. The resulting solid was taken in DMF (1 mL) and stirred with TBTU (92 mg, 0.29 mmol) and DIEA (51 mg, 0.4 mmol) for 2 hours at 23 0C. Ammonium hydroxide-30% by weight (2 mL) was added and stirred at 23 0C for a further 30 minutes. The reaction was partitioned between EtOAc (8 mL) and water (3mL). The organic layer was washed with water (3 mL), dried with MgS 04 and evaporated in vacuo. The crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 urn particle size) using a gradient of 20% to 100% acetonitrile:water (0.1% TFA) over 18 min at a flow rate of 40 mL/min. to provide the title compound. 1H NMR (400 MHz, Chloroform- di) δ ppm 8.13-8.19 (m, IH), 7.34-7.41 (m, " IH), 7.19-7.28 (m, 3H), 5.60-5.65 (bs, IH), 5.54-5.60 (bs, IH), 4.62-4.64 (m, 2H), 3.99-4.05 (m, IH), 3.15-3.30 (m, 2H), 2.63-2.73 (m, IH), 2.09-2.15 (m, IH), 1.80-2.08 (m, HH), 1.53- 1.66 (m, 2H), 1.49 (s, 3H); MS (PCI) m/z 444 (M+H).
Example 34 E-4-(aminocarbonyl)-2-adamantyll-l-(3-chlorobenzyl)-3-methyl-2-oxopyrrolidine-3- carboxamide
Example 34A Potassium: l-(3-chloro-benzyl)-3-methyl-2-oxo-pyrrolidine-3-carboxylate
A solution of the product of Example 31B (0.075 gm, 0.4 mmol), 3-chloro- benzylamine (68 mg, 0.47 mmol) and MP-triacetoxy borohydride (431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours at 23 0C. The solution was filtered and evaporated in vacuo. The resulting oil was taken up in THF (1.2 mL) and stirred with KOTMS (77 mg, 0.6 mmol) at 23 0C for 12 hours. The solvent was evaporated in vacuo to provide Example 34A.
Example 34B
E-4-(ammocarbonylV2-adamantyl]-l-(3-chlorobenzyl)-3-methyl-2-oxopyrrolidine-3- carboxamide
A solution of the product of Example 34A (50 mg, 0.16 mmol), the product of Example 1C (48 mg, 0.19 mmol), TBTU (82 mg, 0.25 mmol) and DIEA (51 mg, 0.4 mmol) in DMF (1.2 mL) was stirred for 2 hours at 23 0C. The reaction was partitioned between EtOAc (8 ml) and water (4 ml). The organic layer was separated and washed twice with water (4 mL each), dried with MgSO4, filtered and evaporated in vacuo. The resulting oil was taken in THF (1 mL) and stirred with KOTMS (31 mg, 0.24 mmol) at 23 0C for 12 hours. The solvent was evaporated in vacuo. The resulting solid was taken in DMF (1 mL) and stirred with TBTU (92 mg, 0.29 mmol) and DIEA (51 mg, 0.4 mmol) for 2 hours at 23 0C.
Ammonium hydroxide-30% by weight (2 mL) was added and stirred at 23 0C for a further 30 minutes. The reaction was partitioned between EtOAc (8 mL) and water (3mL). The organic layer was washed with water (3 mL), dried with MgSO4 and evaporated in vacuo. The crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C 8 column (25 mm X 100 mm, 7 urn particle size) using a gradient of 20% to 100% acetonitrile-.water (0.1% TFA) over 18 min at a flow rate of 40 mL/min. to provide the title compound. 1H NMR (400 MHz, Chloroform- di) δ ppm 8.11 (d, J= 7.93 Hz, IH), 7.26-7.29 (m, 2H), 7.18-7.20 (m, IH), 7.07-7.10 (m, IH), 5.64-5.79 (m, 2H), 4.44 (s, 2H), 3.99-4.04 (m, IH)5 3.18-3.23 (m, 2H), 2.68 (ddd, J= 15.66, 8.55, 7.17 Hz, IH), 2.02-2.15 (m, 3H), 1.88-2.02 (m, 8H), 1.81-1.88 (m, IH), 1.58-1.66 (m, 2H), 1.49 (s, 3H); MS (APCI) m/z 444.
Example 35
E-4-({2-methyl-2-[4-(l-methyl-lH-pyrazol-4-yl)phenyl]propanovUamino^adamantane-l- carboxamide
Example 35A
E-A- {2-Methyl-2-[4-( 1 -methyl- 1 H-pyrazol-4- vD-phenyl] -propionylammo } -adamantane- 1 - carboxylic acid methyl ester
The title compound was prepared according to the method of Example 22D substituting 1 -methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole for pyridine-4-boronic acid.
Example 35B E-A- {2-Methyl-2-[4-(l -methyl- lH-pyrazol-4-ylVphenyl]-propionylamino} -adamantane- 1 - carboxylic acid The title compound was prepared according to the method of Example 23D, substituting the product of Example 35 A for the product of Example 23C.
Example 35C
E-4-{2-Methyl-2-[4-fl-methyl-lH-pyrazol-4-ylVphenyl]-ρropionylamino>-adamantane-l- carboxylic acid amide
A solution of the product of Example 35B (240 mg, 0.55 mmoles), N-(3- dimethylaminopropyl)-iV'-ethylcarbodiimide hydrochloride (421 mg, 2.2 mmoles) and 1- hydroxybenzotriazole hydrate (167 mg, 1.24 mmoles) in dichloromethane (19 ml) was stirred at ambient temperature under a nitrogen atmosphere for about 1 hour. A 0.5 M solution of ammonia in dioxane (11.0 ml, 5.50 mmoles) was added and stirring was continued for about 2 hours. Ammonium hydroxide (9.5 ml) was added to the reaction mixture and stirring was continued for about 2 hours. The mixture was diluted with dichloromethane (60 ml), the layers were separated, the organic layer was dried (MgSO4), filtered and the filtrate was evaporated in vacuum. The residue was purified by flash column chromatography on silica gel using dichloromethane/methanol (15 : 1) as the mobile phase to provide the title compound. 1H NMR (500 MHz, DMSO-^) δ ppm 8.11 (s, IH), 7.83 (s, IH), 7.51-7.53 (m, 2H), 7.31-7.33 (m, 2H), 6.95-6.97 (bs, IH), 6.69-6.71 (bs, IH), 6.28 (d, J= 6.87 Hz, IH), 3.85 (s, 3H), 3.74-3.78 (m, IH), 1.84-1.89 (m, 2H), 1.73-1.82 (m, 5H), 1.67-1.70 (m, 2H), 1.54-1.60 (m, 2H), 1.49 (s, 6H), 1.31-1.37 (m, 2H); MS(ESI+) m/z 421 (M+H)+.
Example 36 E-A- { |"2-(3 -bromophenyl)-2-methylpropanoyl] amino ) adamantane- 1 -carboxamide
Example 36A
(3-BromophenvD-acetic acid methyl ester
A solution of 3-bromophenylacetic acid (2.0 g, 9.3 mmol) and 4-dimethylamino pyridine (1.1 g, 9.3 mmol) in methanol (20 mL) was treated with N-(3- dimethylaminopropyl)-iV-ethylcarbodiimide hydrochloride (EDAC) (2.1 g, 11 mmol). Reaction stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with water, saturated sodium bicarbonate, IN phosphoric acid, and brine before drying over Na2SO4, filtering, and concentrating under reduced pressure to provide the title compound.
Example 36B
2-(3-BromophenylV2-methylpropionic acid methyl ester A 00C solution of the product of Example 36A (2.1 g, 9.3 mmol) in anhydrous dimethylformamide (20 mL) was treated portion-wise with 60% sodium hydride (890 mg, 22 mmol) in mineral oil. The reaction mixture was stirred for twenty minutes at 0 0C, and methyl iodide (1.4 mL, 22 mmol) was then added. Ice bath was removed, and reaction mixture stirred 16 hours at room temperature. Reaction mixture quenched with saturated ammonium chloride, and product extracted with ethyl acetate (2X). The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Residue purified by normal phase HPLC on silica gel eluting with 10% ethyl acetate/hexane to provide the title compound.
Example 36C
2-(3 -BromophenylV 2-methylpropionic acid
The title compound was prepared according to the method as described in Example 27B, substituting the product of Example 36B for the product of Example 27 A.
Example 36D E-4-[2-(3-BromophenylV2-methylpropionylamino] -adamantane-1-carboxylic acid methlv ester The title compound was prepared according to the method as described in Example
27 A, substituting the product of Example 36C for l-(4-methoxyphenyl)-l- cyclopentanecarboxylic acid.
Example 36E E-4-[2-(3-Bromophenyl)-2-methylpropionylaminol -adamantane- 1 -carboxylic acid
The title compound was prepared according to the method as described in Example 27B, substituting the product of Example 36D for the product of Example 27A.
Example 36F E-4-[2-(θ-Bromophenyl)-2-methylpropionylamino] -adamantane-1-carboxylic acid amide
The title compound was prepared according to the method as described in Example 27C, substituting the product of Example 36E for the product of Example 27B. 1H NMR (400 MHz, DMSO-d6) δ 7.48 (m, IH), 7.42 (m, IH), 7.20 (m, 2H), 6.95 (bs, IH), 6.66 (bs, IH), 6.32 (d, J= 6 Hz, IH), 3.77 (m, IH), 1.95-1.60 (m, HH), 1.47 (s, 6H), 1.33 (m, 2H); MS (ESI+) m/z 419 (M+H)+.
Example 37 E-4-({2-r4-(3.5-dimethylisoxazol-4-yl)phenyll-2-methylpropanovUamino)adamantane-l- carboxamide
Example 37A E-4-{2-[4-(3,5-Dimethyl-isoxazol-4-ylVphenyl1-2-methyl-propionylamino)-adamantane-l- carboxylic acid methyl ester
The title compound was prepared according to the method of Example 22D, substituting 3,5-dimethyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane-2-yl)isoxazole for pyridine-4-boronic acid.
Example 37B E-4-{2-[4-(3,5-Dimethyl-isoxazol-4-ylVphenyll-2-methyl-propionylamino}-adamantane-l- carboxylic acid
The title compound was prepared according to the method of Example 23D5 substituting the product of Example 37A for the product of Example 23C.
Example 37C E-4-{2-[4-(3,5-Dimethyl-isoxazol-4-yl)-phenyl1-2-methyl-propionylamino}-adamantane-l- carboxylic acid amide The title compound was prepared according to the method of 35C, substituting the product of Example 37B for the product of Example 35B. The crude product was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm x 100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile : 0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 ml/min. 1H NMR (500 MHz, DMSO- d6) δ ppm 7.44-7.46 (m, 2H), 7.35-7.37 (m, 2H), 6.95-6.97 (bs, IH), 6.69-6.71 (bs, IH), 6.35 (d, J= 6.87 Hz5 IH), 3.74- 3.78 (m, IH)5 2.38 (s5 3H)5 2.21 (s, 3H), 1.87-1.89 (m, 2H), 1.73-1.83 (m, 5H)5 1.67-1.73 (m, 2H)5 1.56-1.60 (m, 2H)5 1.53 (s, 6H)5 1.32-1.36 (m, 2H); MS(ESI+) m/z 436 (MfH)+.
Example 38 E-4-{[2-methyl-2-r4-pyridin-3-ylphenyπpropanoyllamino>adamantane-l-carboxamide
Example 38A E-4-r2-Methyl-2-("4-pyridin-3-yl-phenylVpropionylamino]-adaniantane-l-carboxylic acid. methyl ester
The title compound was prepared according to the method of Example 22D, substituting pyridine-3-boronic acid for pyridme-4-boronic acid.
Example 38B E-A- [2-Methyl-2-(4-ρyridin-3 -yl-phenyiVpropionylammo] -adamantane- 1 -carboxylic acid
The title compound was prepared according to the method of Example 22E substituting the product of Example 38 A for the product of Example 22D.
Example 38C E-4- |~2-Methyl-2-(4-pyridin-3 -yl-phenylVpropionylaminol -adamantane- 1 -carboxylic acid amide
The trifluoroacetic acid salt of the title compound was prepared according to the method of Example 35C, substituting the product of Example 38B for the product of Example 35B, and with the exception that the crude product was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm x 100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile : 0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 ml/min. 1H NMR (400 MHz, DMSO- d6) δ ppm 9.07-9.08 (bs, IH), 8.72 (d, J = 5.06 Hz, IH), 8.47 (d, J= 8.03 Hz, IH), 7.77-7.83 (m, 3H), 7.50-7.53 (m, 2H), 6.94-6.96 (bs, IH), 6.66-6.69 (bs, IH), 6.48 (d, J= 6.68 Hz, IH), 3.76;3.81 (m, IH), 1.89-1.92 (m, 2H), 1.78-1.84 (m, 5H), 1.65-1.71 (m, 4H), 1.54 (s, 6H)5 1.33-1.38 (m, 2H); MS(ESI+) m/z 418 (M+H)+.
Example 39
4-(fαrE)-4-rr2-methyl-2-thien-2-ylpropanovnaminol-l- adamantyl>carbonyl)amino1methyl}benzoic acid
Example 39A E-4-({["4-(2-Methyl-2-thiophen-2-yl-propionylaminoVadamantane-l-carbonyl1-amino>- methvD-benzoic acid methyl ester The title compound was prepared according to the method of Example 22C, substituting the product of Example 23D for Example 22B and substituting methyl A- (aminomethyl)-benzoate hydrochloride for the product of Example 1C.
Example 39B E-4-({r4-(2-Methyl-2-thiophen-2-yl-propionylaminoVadamantane-l-carbonyll-amino>- methvD-benzoic acid
The title compound was prepared according to the method of Example 22B, substituting the product of Example 39A for the product of Example 22 A. 1H NMR (400 MHz, DMSO- d6) δ ppm 12.70-12.94 (bs, IH), 8.04-8.09 (m, IH), 7.85-7.88 (m, 2H), 7.46 (dd, J= 5.06, 1.22 Hz, IH), 7.28-7.36 (m, 2H), 7.10 (dd, J= 3.52, 1.23 Hz, IH), 7.02 (dd, J= 5.08, 3.54 Hz, IH), 6.25 (d, J= 7.10 Hz, IH), 4.30 (d, J= 5.87 Hz, 2H), 3.71-3.76 (m, IH), 1.75-1.86 (m, 9H), 1.57 (s, 6H), 1.48-1.55 (m, 2H), 1.37-1.42 (m, 2H); MS(ESI+) m/z 481 (M+H)+.
Example 40
■Z?-4-((2-methyl-2-|"4-(lH-ρyrazol-4-yl)phenyl]propanoyUammo)adamantane-l-carboxamide
Example 4OA
E-A- (2-Methyl-2- ["4-(I H-p yrazol-4-yD-phenyl] -propionylamino I -adamantane- 1 -carboxylic acid methyl ester
The title compound was prepared according to the method of Example 22D substituting l-tert-butoxycarbonyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole for pyridine-4-boronic acid.
Example 4OB
E-A- l2-Methyl-2- \A-( 1 H-pyrazol-4-yl")-phenyl] -propionylamino 1 -adamantane- 1 -carboxylic acid
The title compound was prepared according to the method of Example 22E substituting the product of Example 4OA for the product of Example 22D.
Example 4OC E-4-{2-Methyl-2-r4-(lH-pyrazol-4-ylVphenyll-propionylaminol-adamantane-l-carboxylic acid amide
The title compound was prepared according to the method of Example 35C substituting the product of Example 4OB for the product of Example 35B. 1H NMR (400 MHz, DMSO- d6) δ ppm 8.03 (s, 2H), 7.55-7.58 (m, 2H), 7.31-7.34 (m, 2H), 6.92-6.96 (bs, IH), 6.65-6.68 (bs, IH), 6.25 (d, J= 6.95 Hz, IH), 5.15-5.94 (bs, IH), 3.73-3.78 (m, IH), 1.85-1.88 (m, 2H), 1.73-1.83 (m, 5H), 1.68-1.70 (m, 2H), 1.55-1.60 (m, 2H), 1.49 (s, 6H), 1.31-1.36 (m, 2H); MS(ESI+) m/z 407 (M+H)+.
Example 41 E-4-f aminocarbonyl)-2-adamantyi] -3 -methyl- 1 -( 1 -methyl- 1 -phenylethvD-2-oxop yrrolidine-
3-carboxamide
Example 41 A Potassium: 3 -methyl- 1 -( 1 -methyl- 1 -phenyl-ethyl)-2-oxo-pyrrolidine-3 -carboxylate A solution of the product of Example 3 IB (0.075 gm, 0.4 mmol), 1 -methyl- 1-phenyl- ethylamine (65 mg, 0.47 mmol) and MP-triacetoxy borohydride (431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours at 23 0C. The solution was filtered and evaporated in vacuo. The resulting oil was taken up in toluene (1.5 mL) and heated at 1000C for 5 hours. The solvent was evaporated in vacuo and the residue taken in THF (1.2 mL) and stirred with KOTMS (77 mg, 0.6 mmol) for 12 hours at 23 0C. The solvent was evaporated in vacuo to provide Example 4 IA.
Example 41B
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-l-ri-methyl-l-phenylethylV2- oxopyrrolidine-3-carboxamide
A solution of the product of Example 41A (50 mg, 0.16 mmol), the product of Example 1C (48 mg, 0.19 mmol), TBTU (82 mg, 0.25 mmol) and DIEA (51 mg, 0.4 mmol) in DMF (1.2 mL) was stirred for 2 hours at 23 0C. The reaction was partitioned between EtOAc (8 ml) and water (4 ml). The organic layer was separated and washed twice with water (4 mL each), dried with MgSO4, filtered and evaporated in vacuo. The resulting oil was taken in THF (1 mL) and stirred with KOTMS (31 mg, 0.24 mmol) for 12 hours at 23 0C. The solvent was evaporated in vacuo. The resulting solid was taken in DMF (1 mL) and stirred with TBTU (92 mg, 0.29 mmol) and DIEA (51 mg, 0.4 mmol) for 2 hours at 23 0C. Ammonium hydroxide-30% by weight (2 mL) was added and stirred for a further 30 minutes. The reaction was partitioned between EtOAc (8 mL) and water (3mL). The organic layer was washed with water (3 mL), dried with MgSO4 and evaporated in vacuo. The crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 um particle size) using a gradient of 20% to 100% acetonitrile ".water (0.1% TFA) over 18 min at a flow rate of 40 mL/min. to provide the title compound. 1H NMR (500 MHz, Chloroform- d}) δ ppm 7.94 (d, J= 7.78 Hz, IH), 7.27-7.34 (m, 4H), 7.21- 7.25 (m, IH), 5.98-6.02 (bs, IH), 5.69-5.73 (bs, IH), 3.95-4.00 (m, IH), 3.39-3.47 (m, 2H), 2.69 (ddd, J= 13.17, 8.02, 6.58 Hz, IH), 2.03-2.06 (m, IH), 1.94-2.01 (m, 6H), 1.91 (ddd, J = 13.24, 7.44, 5.76 Hz, IH), 1.86-1.88 (m, 2H), 1.76-1.81 (m, IH), 1.75 (s, 3H), 1.72 (s, 3H), 1.64-1.69 (m, IH), 1.47-1.56 (m, 2H), 1.43 (s, 3H); MS (APCI) m/z 438 (M+H).
Example 42
E-4-(aminocarbonylV2-adamantyl]-3-methyl-2-oxo-l-f(lR)-l-phenylethyl]pyrrolidine-3- carboxamide
Example 42A Potassium; 3 -methyl-2-oxo- 1 -(( 1 R)- 1 -phenylethvDpyrrolidine-3 -carboxylate
A solution of the product of Example 3 IB (0.075 gm, 0.4 mmol), (R)-I- phenylethylamine (58 mg, 0.47 mmol) and MP-triacetoxy borohydride (431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours at 23 0C. The solution was filtered and evaporated in vacuo. The resulting oil was taken up in toluene (1.5 mL) and heated at 1000C for 5 hours. The solvent was evaporated in vacuo and the residue taken in THF (1.2 mL) and stirred with KOTMS (77 mg, 0.6 mmol) for 12 hours at 23 0C. The solvent was evaporated in vacuo to provide Example 42A as 1:1 mixture of diastereomers.
Example 42B E-4-raminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-l-rdRVl-phenylethyl1pyrrolidme-3- carboxamide A solution of the product of Example 42 A (50 mg, 0.17 mmol), the product of Example 1C (52 mg, 0.21 mmol), TBTU (87 mg, 0.27 mmol) and DIEA (51 mg, 0.4 mmol) in DMF (1.2 niL) was stirred for 2 hours at 23 0C. The reaction was partitioned between EtOAc (8 ml) and water (4 ml). The organic layer was separated and washed twice with water (4 mL each), dried with MgSO4, filtered and evaporated in vacuo. The resulting oil was taken in THF (1 mL) and stirred with KOTMS (32 mg, 0.25 mmol) for 12 hours at 23 0C. The solvent was evaporated in vacuo. The resulting solid was taken in DMF (1 mL) and stirred with TBTU (98 mg, 0.31 mmol) and DDEA (51 mg, 0.4 mmol) for 2 hours at 23 0C. Ammonium hydroxide-30% by weight (2 mL) was added and stirred for a further 30 minutes. The reaction was partitioned between EtOAc (8 mL) and water (3mL). The organic layer was washed with water (3 mL), dried with MgSO4, filtered and evaporated in vacuo. The crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 ran particle size) using a gradient of 20% to 100% acetonitrile: water (0.1% TFA) over 18 min at a flow rate of 40 mL/min. to provide the title compound as a 1 : 1 mixture of diastereomers. 1H NMR (500 MHz, Chloroform- df) δ ppm 8.3 (m, 2H), 7.38-7.22 (m, 10H), 6.34-6.18 (bs, 2H), 5.83-5.68 (bs, 2H), 5.52-5.41 (m, 2H), 4.06-3.95 (m, 2H), 3.31-3.18 (m, 2H), 3.01-2.78 (m, 2H), 2.62-2.44 (m, 4H), 2.1-1.87 (m, 24H), 1.56-1.53 (m, 6H), 1.47-1.43 (m, 6H); MS (APCI) m/z 424 (M+H).
Example 43
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-l-[(lS)-l-phenylethyl1ρyrrolidine-3- carboxamide
Example 43A Potassium: 3-methyl-2-oxo-l-((lS)-l-phenylethyl)pyrrolidine-3-carboxylate
A solution of the product of Example 31B (0.075 gm, 0.4 mmol), (S)-I- phenylethylamine (58 mg, 0.47 mmol) and MP-triacetoxy borohydride (431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours at 23 0C. The solution was filtered and evaporated in vacuo. The resulting oil was taken up in toluene (1.5 mL) and heated at 1000C for 5 hours. The solvent was evaporated in vacuo and the residue taken in THF (1.2 mL) and stirred with KOTMS (77 mg, 0.6 mmol) at 23 0C for 12 hours. The solvent was evaporated in vacuo to provide Example 43 A as a 1:1 mixture of diastereomers. Example 43B
E-4-(aminocarbonylV2-adamantyll-3-methyl-2-oxo-l-["(lS)-l-phenylethyllpyrrolidine-3- carboxamide A solution of the product of Example 43 A (50 mg, 0.17 mmol), the product of
Example 1C (52 mg, 0.21 mmol), TBTU (87 mg, 0.27 mmol) and DIEA (51 mg, 0.4 mmol) in DMF (1.2 mL) was stirred at 23 0C for 2 hours. The reaction was partitioned between EtOAc (8 ml) and water (4 ml). The organic layer was separated and washed twice with water (4 mL each), dried with MgSO4, filtered and evaporated in vacuo. The resulting oil was taken in THF (1 mL) and stirred with KOTMS (32 mg, 0.25 mmol) at 23 0C for 12 hours. The solvent was evaporated in vacuo. The resulting solid was taken in DMF (1 mL) and stirred with TBTU (98 mg, 0.31 mmol) and DIEA (51 mg, 0.4 mmol) at 23 0C for 2 hours. Ammonium hydroxide-30% by weight (2 mL) was added and stirred for a further 30 minutes. The reaction was partitioned between EtOAc (8 mL) and water (3mL). The organic layer was washed with water (3 mL), dried with MgSO4, filtered, and evaporated in vacuo. The crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 ran particle size) using a gradient of 20% to 100% acetonitrile: water (0.1% TFA) over 18 min at a flow rate of 40 niL/min. to provide the title compound as a 1:1 mixture of diastereomers. 1H NMR (500 MHz, Chloroform- di) δ ppm 8.29 (m, 2H), 7.34-7.18 (m, 10H), 6.30-6.14 (bs, 2H), 5.79-5.66 (bs, 2H), 5.48-5.37 (m, 2H), 4.06-3.95 (m, 2H), 3.31-3.18 (m, 2H), 3.01-2.78 (m, 2H), 2.62-2.44 (m, 4H), 2.1-1.87 (m, 24H), 1.56-1.53 (m, 6H), 1.47-1.43 (m, 6H); MS (APCI) m/z 424 (M+H)..
Example 44 E-4-{[2-methyl-2-(l,3-thiazol-2-yDpropanoyl]amino)adamantane-l-carboxamide
Example 44A
Diethyl 2-(3-(ethoxycarbonyl')-2.3-dihvdrothiazol-2-yl)malonate Ethyl chloroformate (6.46 ml, 67.8 mmoles) was added dropwise to a stirred solution of thiazole (5.0 g, 58.7 mmoles) in tetrahydrofuran (113.0 ml) at about 0 0C under a nitrogen atmosphere. After about 1 hour, a freshly prepared solution of lithio diethylmalonate (To a solution of diethylmalonate (10.3 ml, 67.8 mmoles) in tetrahydrofuran (17.0 ml) was added dropwise a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (67.8 ml, 67.8 mmoles) and the mixture was stirred at 23 0C for about 10 min) was added via cannula and the mixture was stirred at room temperature for about 18 hours. The mixture was diluted with diethyl ether (60.0 ml), was washed with saturated aqueous ammonium chloride (140.0 ml) and brine (120.0 ml). The organic layer was dried over MgSO4, filtered, concentrated in vacuum and the crude product was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (2 : 1) as the mobile phase to provide the title compound.
Example 44B Diethyl 2-(thiazol-2(3.H)-ylidene)malonate
To a solution of the product of Example 44A (12.9 g, 40.7 mmoles) in dichloromethane (100.0 ml) was added tetrachloro-l,2-benzoquinone (10.0 g, 40.7 mmoles) in portions at about 0 °C, such that the mixture always had time to decolorize to a yellow- orange color. The mixture was then stirred for about 1 hour at 0 0C and was then washed with saturated aqueous sodium bicarbonate solution (200.0 ml) and brine (100.0 ml). The organic layer was dried over MgSO4, filtered, concentrated in vacuum and the crude product was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (2 : 1) as the mobile phase to provide the title compound.
Example 44C
Ethyl 2-(thiazol-2-yl')acetate
A solution of the product of Example 44B (2.8 g, 11.5 mmoles), sodium chloride (1.3 g, 22.9 mmoles) and water (0.4 ml, 22.9 mmoles) in dimethyl sulfoxide (48.0 ml) was stirred at about 180 °C for about 30 min. The mixture was cooled, diluted with water (100.0 ml) and was extracted twice with (1 : 1) ethyl acetate/diethyl ether (80.0 ml each). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuum. The crude product was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (2 : 1) as the mobile phase to provide the title compound.
Example 44D
Ethyl 2-methyl-2-(thiazol-2-yl)propanoate The title compound was prepared according to the method of Example 22A substituting the product of Example 44C for ethyl 4-bromophenylacetate.
Example 44E
2-Methyl-2-(thiazol-2-yl)propanoic acid The title compound was prepared according to the method of Example 22B substituting the product of Example 44D for the product of Example 22A.
Example 44F
E-4-r2-Methyl-2-thiazol-2-yl-propionylaminoVadamantane-l-carboxylic acid methyl ester The title compound was prepared according to the method of Example 22C substituting the product of Example 44E for the product of Example 22B.
Example 44G
E-4-(2-Methyl-2-thiazol-2-yl-propionylaminoVadamantane- 1 -carboxylic acid The title compound was prepared according to the method of Example 23D substituting the product of Example 44F for the product of Example 23 C.
Example 44H
E-4-f 2-Methyl-2-thiazol-2-yl-propionylaminoV adarnantane- 1 -carboxylic acid amide The title compound was prepared according to the method of Example 35C substituting the product of Example 44G for the product of Example 35B. 1H NMR (400 MHz, DMSO- d6) δ ppm 7.86 (d, J= 3.30 Hz, IH)5 7.71 (d, J= 3.29 Hz, IH), 7.42 (d, J= 7.26 Hz, IH), 6.94-6.97 (bs, IH), 6.67-6.69 (bs, IH), 3.72-3.77 (m, IH), 1.82-1.88 (m, 3H), 1.75-1.82 (m, 4H), 1.71-1.74 (m, 2H), 1.62 (s, 6H), 1.57-1.64 (m, 2H), 1.39-1.47 (m, 2H); MS(ESI+) m/z 348 (M+H)+.
Example 45 E-4-(aminocarbonyl)-2-adamantyl]-l-(4-chlorobenzylV3-methvbiperidine-3-carboxamide
Example 45 A
Piperidine-l,3-dicarboxylic acid 1-benzyl ester 3-ethyl ester To a room temperature solution of 4.05 g (25.8 mmoles) of ethyl nipecotate and 4.33 g (51.5 mmoles) OfNaHCO3 in water (26 mL) was added benzyl chloroformate (4.1 mL, 28.3 ratnol). The reaction mixture was stirred at 23 0C under an atmosphere of N2 overnight. The crude products were diluted with water, extracted with Et2O, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane→70:30 hexane:EtOAc) to yield the title compound as a clear colorless oil.
Example 45B S-Methyl-piperidine-l^-dicarboxylic acid 1-benzyl ester To a -78 0C solution of the product of Example 45A (6.0 g, 20.6 mmoles) in THF (50 mL) was added a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 22.7 mmoles). After 35 min, iodomethane (1.4 mL, 22.7 mmoles) was added and the reaction was slowly warmed to room temperature and stirred overnight. The reaction was quenched with aqueous sat. ammonium chloride and extracted with Et2O. The organic layer was then rinsed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane→65:35 hexane:EtOAc). The resulting ester was hydrolyzed overnight at room temperature in THF (15 mL), H2O (10 mL), and EtOH (15 mL) with NaOH (2.5 g). The solution was concentrated under vacuum; the residue was dissolved in saturated ammonium chloride; and, the solution was extracted with ethyl acetate (3x). The combined ethyl acetate extracts were dried over sodium sulfate, filtered, and concentrated under vacuum to yield the title compound as a white solid.
Example 45 C N-[E-4-(carbomethoxy)-2-adamantyl]-l-(4-benzyloχycarbonyl)-3-methylpiperidine-3- carboxamide
The title compound was prepared according to the procedure outlined in Example 7, substituting the product of Example 45B for 2-phenylisobutyric acid and substituting the product of Example 1C for 2-adamantanamine hydrochloride.
Example 45D N-[E-4-(carbomethoxy)-2-adamantyl1-l-3-methylpiperidine-3-carboxamide A solution of the product of Example 45C (0.62 g, 1.32 mmoles) and 10% palladium on carbon (60 mg) in EtOAc (20 mL) was exposed to hydrogen (60 psi) at room temperature for 6 hours. The reaction was incomplete so EtOH was added and the reaction continued for an additional 8 h. The crude product was then filtered away from the catalyst using methanol and isolated after concentration in vacuo to provide the title compound.
Example 45E E-4-(carbomethoxyV2-adamantyl]-l-(4-chlorobenzyl)-3-methylpiperidine-3-carboxamide
To a solution of the product of Example 45D (100 mg, 0.3 mmoles) and 4- chlorobenzaldehyde in dichloroethane (0.75 mL) and acetic acid (0.07 mL, 1,2 mmoles) was added sodium triacetoxyborohydride (127 mg, 0.6 mmoles). The resulting reaction mixture was stirred at room temperature overnight. The reaction was quenched with sat. aqueous NH4Cl and extracted with EtOAc. The organic layer was then rinsed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide a crude sample of the title compound.
Example 45F E-4-(aminocarbonylV2-adamantyl]-l-(4-chlorobenzyl)-3-methylpiperidine-3-carboxamide
The crude product from Example 45E was hydrolyzed with an excess of NaOH at room temperature in a solution of water, EtOH, and tetrahydrofuran for 16 hours. The reaction was quenched with sat. aqueous NH4Cl and extracted with EtOAc. The organic layer was then rinsed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue, EDCI (80 mg, 0.42 mmoles), and 1-hydroxybenzotriazole hydrate (56.5 mg, 0.42 mmoles) were dissolved in DMF (0.75 mL) and stirred for 30 min at room temperature. Concentrated NH4OH (0.75 mL) was then added and stirring was continued overnight. The reaction was quenched with sat. aqueous NH4Cl and extracted with EtOAc. The organic layer was then washed with water (2x), rinsed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by reverse phase preparative HPLC (acetonitrile: 10 mM NH4OAc in H2O on a YMC prep ODS-A column) to provide the title compound. 1H NMR (500 MHz, Chloroform- di) δ ppm 8.74-8.79 (m, IH), 7.28-7.32 (m, 2H), 7.18-7.21 (m, 2H), 5.65-5.69 (bs, IH), 5.55-5.59 (bs, IH), 4.04-4.07 (m, IH), 3.56 (d, J = 12.82 Hz, IH), 3.43 (d, J= 12.82 Hz, IH), 3.00-3.05 (m, IH), 2.93-2.98 (m, IH), 2.08-2.13 (m, IH), 2.00-2.05 (m, IH), 1.93-2.00 (m, 6H), 1.90-1.94 (m, 2H), 1.83-1.90 (m, IH), 1.76- 1.82 (m, IH), 1.69-1.74 (m, IH), 1.61-1.69 (m, IH), 1.52-1.63 (m, 4H), 1.12 (s, 3H), 1.06- 1.15 (m, IH); MS (ESI+) m/z 444 (M+H)+.
Example 46 E-4-|[2-(4-hydroxyphenyl)-2-methylρropanoyl]amino|adarαantane-l-carboxamide
Example 46A
2-(4-HydroxyphenylVproprionic acid methyl ester
The title compound was prepared according to the method as described in Example 36A substituting 2-(4-hydroxyphenyl)-proprionic acid for 3-bromophenylacetic acid.
Example 46B
2-(4-AUyloxyphenyl)-proprionic acid methyl ester A solution of the product of Example 46A (2.6 g, 12 mmol) in anhydrous dimethylformamide (20 mL) was treated with potassium carbonate (3.3 g, 24 mmol) and allyl bromide (1.2 mL, 13 mmol), and reaction heated for 16 hours at 80 0C. Reaction mixture cooled and diluted with ethyl acetate. Mixture washed with water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Residue purified by normal phase HPLC on silica gel eluting with 3% ethyl acetate/hexane to provide the title compound.
Example 46C
2-(4-AllyloxyphenylV2-methylproprionic acid methyl ester A 0 0C solution of the product of Example 46B (1.9 g, 8.6 mmol) in anhydrous dimethylformamide (10 mL) was treated portion- wise with 60% sodium hydride (410 mg, 10 mmol) in mineral oil. The reaction mixture was stirred twenty minutes at 0 0C, and methyl iodide (1.4 mL, 22 mmol) was then added. Ice bath was removed, and reaction mixture stirred 16 hours at room temperature. Reaction mixture quenched with saturated ammonium chloride, and product extracted with ethyl acetate (2X). The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Residue purified by normal phase HPLC on silica gel eluting with 3% ethyl acetate/hexane to provide the title compound. Example 46D
2-(4-Allyloxyphenyl)-2-methylproprionic acid
The title compound was prepared according to the method as described in Example 27B, substituting the product of Example 46C for the product of Example 27A.
Example 46E E-4-[2-(4-AUyloxyphenyl)-2-methylpropionylamino] -adamantane-1-carboxylic acid methyl ester
The title compound was prepared according to the method as described in Example 27A, substituting the product of Example 46D for l-(4-methoxyphenyl)-l- cyclopentanecarboxylic acid.
Example 46F
E-4-[2-(4-HvdroxyphenylV2-methylpropionylamino] -adamantane- 1 -carboxylic acid methyl ester
A 0 0C solution of the product of Example 46E (1.4 g, 3.4 mmol) and tetrakis(triphenylphophine)palladium (390 mg, 0.34 mmol) in anhydrous methylene chloride (10 niL) was treated with phenyl silane (0.84 mL, 6.8 mmol). Reaction stirred ten minutes at 0 0C and two hours at room temperature. Reaction diluted with methylene chloride, washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. . Residue purified by normal phase HPLC on silica gel eluting with 30-40% ethyl acetate/hexane to provide the title compound.
Example 46G E-4-[2-r4-HvdroxyphenylV2-methylpropionylamino1 -adamantane- 1 -carboxylic acid
The title compound was prepared according to the method as described in Example 27B substituting the product of Example 46F for the product of Example 27 A.
Example 46H E-4-[2-(4-Hydroxyphenyl)-2-memylpropionylamino] -adamantane- 1-carboxylic acid amide
The title compound was prepared according to the method as described in Example 27C, substituting the product of Example 46G for the product of Example 27B. 1H NMR (500 MHz, DMSO- d6) δ ppm 9.24-9.38 (bs, IH), 7.15-7.17 (m, 2H), 6.95-6.97 (bs, IH), 6.69-6.74 (m, 3H), 6.69-6.70 (m, IH), 6.03 (d, J= 7.16 Hz, IH), 3.69-3.73 (m, IH), 1.80- 1.83 (m, 2H), 1.73-1.79 (m, 4H), 1.67-1.69 (m, 2H), 1.44-1.50 (m, 2H), 1.43 (s, 6H), 1.30- 1.36 (m, 2H); MS (ESI+) m/z 357 (M+H)+.
Example 47 E-4-(aminocarbonyl)-2-adamantyl1-l-benzyl-3-methyl-2-oxopiperidine-3-carboxamide
Example 47A Potassium: 1 -benzyl-3-methyl-2-oxo-piperidine-3-caboxylate
A solution of the product of Example 30B (0.075 gm, 0.37 mmol), benzylamine (47 mg, 0.44 mmol) and MP-triacetoxy borohydride (420 mg, 0.92 mmol) in THF (2 mL) was stirred for 12 hours at 23 0C. The solution was filtered and evaporated in vacuo. The resulting oil was taken up in THF (1.2 mL) and stirred with KOTMS (71 mg, 0.55 mmol) for 12 hours at 23 0C. The solvent was evaporated in vacuo to provide Example 47 A.
Example 47B
E-4-(aminocarbonyl)-2-adamantyl]-l-benzyl-3-methyl-2-oxopiperidine-3-carboxamide A solution of the product of Example 47A (50 mg, 0.17 mmol), the product of Example 1C (49 mg, 0.2 mmol), TBTU (87 mg, 0.27 mmol) and DIEA (54 mg, 0.42 mmol) in DMF (1.2 mL) was stirred for 2 hours at 23 0C. The reaction was partitioned between EtOAc (8 ml) and water (4 ml). The organic layer was separated and washed twice with water (4 mL each), dried with MgSO4, filtered and evaporated in vacuo. The resulting oil was taken in THF (1 mL) and stirred with KOTMS (32 mg, 0.25 mmol) for 12 hours at 23 0C. The solvent was evaporated in vacuo. The resulting solid was taken in DMF (1 mL) and stirred with TBTU (96 mg, 0.3 mmol) and DIEA (53 mg, 0.42 mmol) at 23 0C for 2 hours. Ammonium hydroxide-30% by weight (2 mL) was added and stirred for a further 30 minutes. The reaction was partitioned between EtOAc (8 mL) and water (3mL). The organic layer was washed with water (3 mL), dried with MgSO4 and evaporated in vacuo. The crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 um particle size) using a gradient of 20% to 100% acetonitrile:water (0.1% TFA) over 18 min at a flow rate of 40 mL/min. to provide the title compound. 1H NMR (500 MHz, Chloroform- di) δ ppm 8.17 (d, J= 7.93 Hz, IH), 7.27-7.34 (m, 3H), 7.21- 7.24 (m, 2H), 6.12-6.17 (bs, IH), 5.68-5.83 (m, IH), 4.95 (d, J= 14.58 Hz, IH), 4.29 (d, J= 14.59 Hz, IH), 3.97-4.02 (m, IH), 3.24-3.35 (m, 2H), 2.65 (ddd, J= 13.31, 5.72, 2.61 Hz, IH), 2.09-2.11 (m, IH), 1.96-2.05 (m, 6H), 1.85-1.90 (m, 3H), 1.64-1.83 (m, 4H), 1.55-1.63 (m, 2H), 1.54 (s, 3H); MS (APCI) m/z 424 (M+H).
Example 48 E-4- ( [2-methyl-2-(4-phenoxyphenyl)propanoyl] amino) adamantane- 1 -carboxamide
Example 48A
Methyl 2-(4-phenoxyphenyDacetate
To a solution of 4-phenoxyphenylacetic acid (1.0 g, 4.38 mmoles) in methanol (5.0 ml) was added concentrated sulfuric acid (0.05 ml, 0.88 mmoles) and the mixture was heated to reflux for about 5 hours. The mixture was cooled and concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate (20.0 ml) and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and evaporated to dryness to afford the title compound.
Example 48B
Methyl 2-methyl-2-(4-phenoxyphenyl)propanoate
The title compound was prepared according to the method of Example 22 A substituting the product of Example 48 A for ethyl-4-bromophenyl acetate.
Example 48C
2-Methyl-2-(4-phenoxyphenvDpropanoic acid
The title compound was prepared according to the method of Example 22B, substituting the product of Example 48B for the product of Example 22A.
Example 48D
■Z?-4-r2-Methyl-2-(4-phenoxy-phenyl)-propionylamino1-adamantane-l-carboχylic acid methyl ester The title compound was prepared according to the method of Example 22C, substituting the product of Example 48C for the product of Example 22B.
Example 48E E-4-[2-Methyl-2-(4-phenoxy-phenylVpropionylamino1-adamantane-l-carboxylic acid
The title compound was prepared according to the method of Example 23D, substituting the product of Example 48D for the product of Example 23C.
Example 48F E-4-[2-Methyl-2-(4-phenoxy-phenyl)-propionylamino1-adamantane-l-carboxylic acid amide
The title compound was prepared according to the method of Example 35 C, substituting the product of Example 48E for the product of Example 35B. 1H NMR (400 MHz, DMSO- d6) δ ppm 7.34-7.41 (m, 4H), 7.10-7.15 (m, IH), 6.93-7.01 (m, 5H), 6.66-6.68 (bs, IH), 6.22 (d, J= 6.94 Hz, IH), 3.72-3.77 (m, IH), 1.85-1.88 (m, 2H), 1.73-1.84 (m, 5H), 1.70-1.71 (m, 2H), 1.53-1.59 (m, 2H)5 1.49 (s, 6H), 1.33-1.38 (m, 2H); MS(ESI+) m/z 433 (M+Η)+.
Example 49
E-4- { \2-( 1 -benzothien-3 -ylV 2-methylproρanoyl] amino I adamantane- 1 -carboxamide
Example 49A
Methyl 2-(benzo[b]thiophen-3-yl)acetate
The title compound was prepared according to the method of Example 48 A substituting benzo[b]thiophene-3-acetic acid for 4-phenoxyphenylacetic acid.
Example 49B
Methyl 2-rbenzo["b1thiophen-3-yl)-2-methylpropanoate The title compound was prepared according to the method of Example 22 A substituting the product of Example 48 A for ethyl-4-bromophenylacetate.
Example 49C 2-rBenzofb]thiophen-3-ylV2-methylpropanoic acid The title compound was prepared according to the method of Example 22B substituting the product of Example 49B for the product of Example 22 A.
Example 49D 4-(2-Benzorb1thiophen-3-yl-2-methyl-propionylaminoVadamantane-l-carboxylic acid methyl ester
The title compound was prepared according to the method of Example 22C, substituting the product of Example 49C for the product of Example 22B.
Example 49E
4-(2-Benzo[b]thiophen-3-yl-2-methyl-propionylaminoVadamantane-l-carboxylic acid
The title compound was prepared according to the method of Example 23D substituting the product of Example 49D for the product of Example 23C.
Example 49F
4-(2-Benzorb]thiophen-3-yl-2-methyl-propionylamino)-adamantane-l-carboxylic acid amide The title compound was prepared according to the method of Example 35C substituting the product of Example 49E for the product of Example 35B. 1H NMR (400
MHz, DMSO- d6) δ ppm 7.97 (s, IH), 7.64-7.66 (m, 2H), 7.31-7.36 (m, 2H), 6.89-6.92 (bs, IH), 6.63-6.66 (bs, IH), 6.13 (d, J= 7.21 Hz, IH), 3.71-3.76 (m, IH), 1.66-1.79 (m, 6H)3
1.60 (s, 6H), 1.55-1.63 (m, 3H), 1.07-1.18 (m, 4H); MS(ESI+) m/z 397 (M+H)+.
Example 50
E-4-([2-("5-fluoropyridin-2-ylV2-methylpropanoyllammo}adamantane-l-carboxamide
Example 5OA
Potassium; 2-(5-fluoro-pyridin-2-ylV2-methyl-propionate
A solution of 2-bromo-5-fluoropyridine (315 mg, 1.8 mmol), methyl trimethylsilyl dimethylketene acetal (0.378 mg, 2.17 mmol), zinc fluoride (112 mg, 1.08 mmol), tris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.021 mmol) and tri-t-butylphosphine-10 wt% in hexane (172 mg, 0.084 mmol) in Argon degassed DMF (1.5 mL) was stirred at 9O0C for 12 hours. The reaction was taken up in EtOAc (25 mL) and washed with water (15 mL) followed by brine (15 mL). The organic layer was dried with MgSO4, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography (hexane/EtOAc 100:0 to 80:20) to give the methyl ester of Example 50A. A solution of the corresponding methyl ester (144 mg, 0.73 mmol), potassium trimethylsilanolate (KOTMS) (140 mg, 1.1 mmol) in THF (2 mL) was stirred for 12 hours at 23 0C. Methyl t-butyl ether (MTBE) 8 mL was added to the solution and Example 5OA was isolated by filtration.
Example 50B E-4-{[2-(5-fluoropyridin-2-ylV2-methylpropanoyl]amino)adamantane-l-carboxamide A solution of the product of Example 50A (30 mg, 0.15 mmol), the product of
Example 1C (45 mg, 0.18 mmol), TBTU (77 mg, 0.24 mmol) and DIEA (47 mg, 0.37 mmol) in DMF (1.2 mL) was stirred at 23 0C for 3 hrs. The reaction was diluted with EtOAc (10 mL) and washed twice with water (6 mL) and brine (6 mL). The organic layer was dried with MgSO4, filtered, and evaporated in vacuo. The residue was taken in THF (1 mL) and stirred with KOTMS (29 mg, 0.22 mmol) for 12 hours at 23 0C. The solvent was evaporated in vacuo. The residue solid was taken in DMF (1 mL) and added TBTU (86 mg, 0.27 mmol), DIEA (47 mg, 0.37 mmol) and stirred at 23 0C for 2 hours. Ammonium hydroxide-30% by weight (2 mL) was added and stirred for a further 30 minutes. The reaction was partitioned between EtOAc (8 mL) and water (3mL). The organic layer was washed with water (3 mL), dried with MgSO4, filtered and evaporated in vacuo. The crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 urn particle size) using a gradient of 20% to 100% acetonitrile:water (0.1% TFA) over 18 min at a flow rate of 40 mL/min. to provide the title compound as the trifluoroacetic acid salt. 1H NMR (500 MHz, Chloroform- dj) δ ppm 8.51-8.55 (m, IH), 7.58-7.64 (m, IH), 7.50-7.55 (m, 2H), 7.42-7.48 (bs, IH), 6.83-7.12 (bs, IH), 6.00-6.07 (bs, IH), 3.93-3.98 (m, IH), 2.02-2.07 (m, 3H), 1.94-1.97 (m, 4H), 1.87-1.90 (m, 2H), 1.70 (s, 6H), 1.66-1.72 (m, 2H), 1.56-1.62 (m, 2H); MS (APCI) m/z 360 (M+H).
Example 51 E-4-r(2-methyl-2-quinoxalin-2-ylpropanovπamino]adamantane-l-carboxamide
Example 51 A Potassium: 2-methyl-2-quinoxalin-2-yl-propionate
A solution of 2-chloroquinoxaline (295 mg, 1.8 mmol), methyl trimethylsilyl dimethylketene acetal (0.378 mg, 2.17 mmol), zinc fluoride (112 mg, 1.08 mmol), tris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.021 mmol) and tri-t-butylphosphine-10 wt% in hexane (172 mg, 0.084 mmol) in Argon degassed DMF (1.5 mL) was stirred at 900C for 12 hours. The reaction was taken up in EtOAc (25 mL) and washed with water (15 mL) followed by brine (15 mL). The organic layer was dried with MgSO4, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (hexane/EtOAc 100:0 to 80:20) to give the methyl ester of Example 51A. A solution of the corresponding methyl ester (168 mg, 0.73 mmol), potassium trimethylsilanolate (KOTMS) (140 mg, 1.1 mmol) in THF (2 mL) was stirred at 23 0C for 12 hours. Methyl t-butyl ether (MTBE) 8 mL was added to the solution and Example 51A was isolated by filtration.
Example 5 IB E-4-[r2-methyl-2-quinoxalin-2-ylpropanoyl)amino]adamantane-l-carboxamide
A solution of the product of Example 51A (30 mg, 0.12 mmol), the product of Example 1C (35 mg, 0.14 mmol), TBTU (61 mg, 0.19 mmol) and DIEA (38 mg, 0.3 mmol) in DMF (1.2 mL) was stirred at 23 0C for 3 hrs. The reaction was diluted with EtOAc (10 mL) and washed twice with water (6 mL) and brine (6 mL). The organic layer was dried with MgSO4, filtered and evaporated in vacuo. The residue was taken in THF (1 mL) and stirred with KOTMS (23 mg, 0.18 mmol) at 23 0C for 12 hours. The solvent was evaporated in vacuo. The residue solid was taken in DMF (1 mL) and added TBTU (69 mg, 0.22 mmol), DIEA (38 mg, 0.3 mmol) and stirred at 23 0C for 2 hours. Ammonium hydroxide-30% by weight (2 mL) was added and stirred for a further 30 minutes. The reaction was partitioned between EtOAc (8 mL) and water (3mL). The organic layer was washed with water (3 mL), dried with MgSO4, filtered, and evaporated in vacuo. The crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm X 100 mm, 7 urn particle size) using a gradient of 20% to 100% acetonitrile: water (0.1% TFA) over 18 min at a flow rate of 40 niL/min. to provide the title compound as the trifluoroacetic acid salt. 1H NMR (400 MHz, Chloroform- di) δ ppm 9.03 (s, IH), 8.12-8.16 (m, IH), 8.04- 8.08 (m, IH), 7.76-7.85 (m, 2H), 7.33-7.38 (m, IH), 6.28-6.41 (m, IH)5 5.69-5.82 (m, IH), 3.91-4.05 (m, IH), 1.96-2.04 (m, 4H), 1.89-1.97 (m, 4H), 1.84-1.88 (m, 2H), 1.83 (s, 6H), 1.62- 1.69 (m, 2H), 1.52- 1.59 (m, 2H); MS (APCI) m/z 393 (M+H).
Biological Data Measurement of Inhibition Constants:
The ability of test compounds to inhibit human 1 lβ-HSD-1 enzymatic activity in vitro was evaluated in a Scintillation Proximity Assay (SPA). Tritiated-cortisone substrate, NADPH cofactor and titrated compound were incubated with truncated human llβ-HSD-1 enzyme (24-287AA) at room temperature to allow the conversion to Cortisol to occur. The reaction was stopped by adding a non-specific 11 β-HSD inhibitor, 18β-glycyrrhetinic acid. The tritiated Cortisol was captured by a mixture of an anti-cortisol monoclonal antibody and SPA beads coated with anti-mouse antibodies. The reaction plate was shaken at room temperature and the radioactivity bound to SPA beads was then measured on a β-scintillation counter. The 11-βHSD-l assay was carried out in 96-well microtiter plates in a total volume of 220 μl. To start the assay, 188 μl of master mix which contained 17.5 nM 3H-cortisone, 157.5 nM cortisone and 181 mM NADPH was added to the wells. In order to drive the reaction in the forward direction, 1 mM G-6-P was also added. Solid compound was dissolved in DMSO to make a 10 mM stock followed by a subsequent 10-fold dilution with 3% DMSO in Tris/EDTA buffer (pH 7.4). 22 μl of titrated compounds was then added in triplicate to the substrate. Reactions were initiated by the addition of 10 μl of 0. lmg/ml
E.coli lysates overexpressing 11 β-HSD- 1 enzyme. After shaking and incubating plates for 30 minutes at room temperature, reactions were stopped by adding 10 μl of 1 mM glycyrrhetinic acid. The product, tritiated Cortisol, was captured by adding 10 μl of 1 μM monoclonal anti- cortisol antibodies and 100 μl SPA beads coated with anti-mouse antibodies. After shaking for 30 minutes, plates were read on a liquid scintillation counter Topcount. Percent inhibition was calculated based on the background and the maximal signal. Wells that contained substrate without compound or enzyme were used as the background, while the wells that contained substrate and enzyme without any compound were considered as maximal signal. Percent of inhibition of each compound was calculated relative to the maximal signal and IC50 curves were generated. This assay was applied to 11 β-HSD-2 as well, whereby tritiated Cortisol and NAD+ were used as substrate and cofactor, respectively.
Compounds of the present invention are active in the 11-βHSD-l assay described above and show selectivity for human 11-β-HSD-l over human 1 l-β-HSD-2, as indicated in Table 1.
Table 1. 11-β-HSD-l and ll-β-HSD-2 activity for representative compounds.
Figure imgf000112_0001
Figure imgf000113_0001
The data in Table 1 demonstrates that compounds A, B, C and D are active in the human 1 lβ-HSD-1 enzymatic SPA assay described above and the tested compounds show selectivity for l lβ-HSD-1 over llβ-HSD-2. The llβ-HSD-1 inhibitors of this invention generally have an inhibition constant IC50 of less than 600 nM and preferably less than 50 nM. The compounds preferably are selective, having an inhibition constant IC50 against llβ- HSD-2 greater than 1000 nM and preferably greater than 10,000 nM. Generally, the IC50 ratio for 11 β-HSD-2 to 11 β-HSD- 1 of a compound is at least 10 or greater and preferably 100 or greater..
Metabolic Stability Incubation conditions:
Metabolic stability screen: each substrate (10 μM) was incubated with microsomal protein (0.1 - 0.5 mg/ml) in 5OmM potassium phosphate buffer (pH 7.4) in 48-Well plate. The enzyme reaction was initiated by the addition of ImM NADPH5 then incubated at 37°C in a Forma Scientific incubator (Marietta, OH, USA) with gentle shaking. The reactions were quenched by the addition of 800 μl of ACN/MeOH (1:1, v/v), containing 0.5 μM of internal standard (IS), after 30 min incubation. Samples were then filtered by using Captiva 96-Well Filtration (Varian, Lake Forest, CA, USA) and analyzed by LC/MS (mass spectrometry). Liver microsomal incubations were conducted in duplicate. LC/MS analysis:
The parent remaining in the incubation mixture was determined by LC/MS. The LC/MS system consisted of an Agilent 1100 series (Agilent Technologies, Waldbronn, Germany) and API 2000 (MDS SCIEX, Ontario, Canada). A Luna C8(2) (50 x 2.0 mm, particle size 3 μm, Phenomenex, Torrance, CA, USA) was used to quantify each compound at ambient temperature. The mobile phase consisted of (A): 10 mM NH4AC (pH 3.3) and (B): 100% ACN and was delivered at a flow rate of 0.2 ml/min. Elution was achieved using a linear gradient of 0-100% B over 3 min, then held 100% B for 4 min and returned to 100% A in 1 min. The column was equilibrated for 7 min before the next injection.
The peak area ratios (each substrate over IS) at each incubation time were expressed as the percentage of the ratios (each substrate over IS) of the control samples (0 min incubation). The parent remaining in the incubation mixture was expressed as the percentage of the values at 0 min incubation. The percentage turnover is calculated using the following equation (%turnover = 100%turnover - %parent remaining) and is recorded as the percentage turnover in the Table 2.
Table 2. Microsomal metabolic stabilit .
Figure imgf000114_0001
Compounds A, B, C and D contain a substituted adamantane, whereas the adamantane ring of Compounds E and F is unsubstituted. The microsomal, metabolic, stability data in Table 2 demonstrates that substituted adamantane compounds of the present invention may exhibit an increase in metabolic stability compared to unsubstituted adamantane compounds which may lead to longer in vivo half lives and pharmacokinetic advantages over unsubstituted adamantanes.
Biochemical Mechanism
Glucocorticoids are steroid hormones that play an important role in regulating multiple physiological processes in a wide range of tissues and organs. For example, glucocorticoids are potent regulators of glucose and lipid metabolism. Excess glucocorticoid action may lead to insulin resistance, type 2 diabetes, dyslipidemia, visceral obesity and hypertension. Cortisol is the major active and cortisone is the major inactive form of glucocorticoids in humans, while corticosterone and dehydrocorticosterone are the major active and inactive forms in rodents. Previously, the main determinants of glucocorticoid action were thought to be the circulating hormone concentration and the density of glucocorticoid receptors in the target tissues. In the last decade, it was discovered that tissue glucocorticoid levels may also be controlled by 1 lβ-hydroxysteroid dehydrogenases enzymes (1 lβ-HSDs). There are two 1 lβ- HSD isozymes which have different substrate affinities and cofactors. The 1 lβ- hydroxysteroid dehydrogenases type 1 enzyme (1 lβ-HSD-1) is a low affinity enzyme with Km for cortisone in the micromolar range that prefers NADPH/NADP+ (nicotinamide adenine dinucleotide) as cofactors. 11 β-HSD-1 is widely expressed and particularly high expression levels are found in liver, brain, lung, adipose tissue and vascular smooth muscle cells. In vitro studies indicate that 1 lβ-HSD-1 is capable of acting both as a reductase and a dehydrogenase. However, many studies have shown that it is predominantly a reductase in vivo and in intact cells. It converts inactive 11-ketoglucocorticoids (i.e., cortisone or dehydrocorticosterone) to active 11-hydroxyglucocorticoids (i.e., Cortisol or corticosterone) and therefore amplifies the glucocorticoid action in a tissue-specific manner.
With only 20% homology to 1 lβ-HSD-1, the 1 lβ-hydroxysteroid dehydrogenases type 2 enzyme (11 β-HSD-2) is a NAD+-dependent, high affinity dehydrogenase with a Km for Cortisol in the nanomolar range. 11 β-HSD-2 is found primarily in mineralocorticoid target tissues, such as kidney, colon and placenta. Glucocorticoid action is mediated by the binding of glucocorticoids to receptors, such as mineralocorticoid receptors and glucocorticoid receptors. Through binding to its receptor, the main mineralocorticoid aldosterone controls the water and salts balance in the body. However, the mineralocorticoid receptors have a high affinity for both Cortisol and aldosterone. 1 lβ-HSD-2 converts Cortisol to inactive cortisone, therefore preventing the non-selective mineralocorticoid receptors from being exposed to high levels of Cortisol. Mutations in the gene encoding 1 lβ-HSD-2 cause Apparent Mineralocorticoid Excess Syndrome (AME), which is a congenital syndrome resulting in hypokaleamia and severe hypertension. AME Patients have elevated Cortisol levels in mineralocorticoid target tissues due to reduced 11 β-HSD-2 activity. The AME symptoms may also be induced by administration of 1 lβ-HSD-2 inhibitor, glycyrrhetinic acid. The activity of 11 β-HSD-2 in placenta is probably important for protecting the fetus from excess exposure to maternal glucocorticoids, which may result in hypertension, glucose intolerance and growth retardation. Due to the potential side effects resulting from llβ- HSD-2 inhibition, the present invention describes selective llβ-HSD-1 inhibitors. Glucocorticoid levels and/or activity may contribute to numerous disorders, including
Type II diabetes, obesity, dyslipidemia, insulin resistance and hypertension. Administration of the compounds of the present invention decreases the level of Cortisol and other 1 lβ- hydroxysteroids in target tissues, thereby reducing the effects of glucucocrticoid activity in key target tissues. The present invention could be used for the treatment, control, amelioration, prevention, delaying the onset of or reducing the risk of developing the diseases and conditions that are described herein.
Since glucocorticoids are potent regulators of glucose and lipid metabolism, glucocorticoid action may contribute or lead to insulin resistance, type 2 diabetes, dyslipidemia, visceral obesity and hypertension. For example, Cortisol antagonizes the insulin effect in liver resulting in reduced insulin sensitivity and increased gluconeogenesis. Therefore, patients who already have impaired glucose tolerance have a greater probability of developing type 2 diabetes in the presence of abnormally high levels of Cortisol. Previous studies (B. R. Walker et al., J. of Clin. Endocrinology and Met., 80: 3155-3159, 1995) have demonstrated that administration of non-selective llβ-HSD-1 inhibitor, carbenoxolone, improves insulin sensitivity in humans. Therefore, administration of a therapeutically effective amount of an llβ-HSD-1 inhibitor may treat, control, ameliorate, delay, or prevent the onset of type 2 diabetes.
Administration of glucocorticoids in vivo has been shown to reduce insulin secretion in rats (B. Billaudel et al., Horm. Metab. Res. 11 : 555-560, 1979). It has also been reported that conversion of dehydrocorticosterone to corticosterone by 11 β-HSD-1 inhibits insulin secretion from isolated murine pancreatic β cells. (B. Davani et al., J. Biol. Chem., 275: 34841-34844, 2000), and that incubation of isolated islets with an llβ-HSD-1 inhibitor improves glucose-stimulated insulin secretion (H Orstater et al., Diabetes Metab. Res. Rev.. 21: 359-366, 2005). Therefore, administration of a therapeutically effective amount of an 1 lβ-HSD-1 inhibitor may treat, control, ameliorate, delay, or prevent the onset of type 2 diabetes by improving glucose-stimulated insulin secretion in the pancreas.
Abdominal obesity is closely associated with glucose intolerance (C. T. Montaque et al., Diabetes, 49: 883-888, 2000), hyperinsulinemia, hypertriglyceridemia and other factors of metabolic syndrome (also known as syndrome X), such as high blood pressure, elevated VLDL and reduced HDL. Animal data supporting the role of 11 β-HSD-1 in the pathogenesis of the metabolic syndrome is extensive (Masuzaki, et ah. Science. 294: 2166-2170, 2001; Paterson, J.M., et al; Proc Natl. Acad. Sd. USA. 101: 7088-93, 2004; Montague and O'Rahilly. Diabetes. 49: 883-888, 2000). Therefore, administration of a therapeutically effective amount of an 1 lβ-HSD-1 inhibitor may treat, control, ameliorate, delay, or prevent the onset of obesity. Long-term treatment with an 11 β-HSD-1 inhibitor may also be useful in delaying the onset of obesity, or perhaps preventing it entirely if the patients use an 1 lβ- HSD-I inhibitor in combination with controlled diet, exercise, or in combination or sequence with other pharmacological approaches.
By reducing insulin resistance and/or maintaining serum glucose at normal concentrations and/or reducing obestity compounds of the present invention also have utility in the treatment and prevention of conditions that accompany Type 2 diabetes and insulin resistance, including the metabolic syndrome or syndrome X, obesity, reactive hypoglycemia, and diabetic dyslipidemia.
1 lβ -HSD-I is present in multiple tissues, including vascular smooth muscle, where local glucocorticoid levels that are thought to increase insulin resistance, leading to reductions in nitric oxide production, and potentiation of the vasoconstrictive effects of both catecholamines and angiotensin II (M. Pirpiris et al., Hypertension, 19:567-574, 1992, C. Kornel et al., Steroids, 58: 580-587, 1993, B. R. Walker and B. C. Williams, Clin. Sci. 82:597-605, 1992; Hodge, G. et al Exp. Physiol 87: 1-8, 2002). High levels of Cortisol in tissues where the mineralocorticoid receptor is present may lead to hypertension, as observed in Cushing's patients (See, D. N. Orth, N. Engl. J. Med. 332:791-803, 1995, M. Boscaro, et al., Lancet, 357: 783-791, 2001, X. Bertagna, et al, Cushing's Disease. In: Melmed S., Ed. The Pituitary. 2nd ed. Maiden, MA: Blackwell; 592-612, 2002). Transgenic mice overexpressing 1 lβ-HSD-1 in liver and fat are also hypertensive, a phenotype believed to result from glucocorticoid activation of the renin angiotensin system (Paterson, J.M. et al, PNAS. 101: 7088-93, 2004; Masuzaki, H. et al, J. Clin. Invest. 112: 83-90, 2003). Therefore, administration of a therapeutically effective dose of an 11 β-HSD-1 inhibitor may treat, control, ameliorate, delay, or prevent the onset of hypertension.
Cushing's syndrome is a life-threatening metabolic disorder characterized by sustained and elevated glucocorticoid levels caused by the endogenous and excessive production of Cortisol from the adrenal glands. Typical Cushingoid characteristics include central obesity, diabetes and/or insulin resistance, moon face, buffalo hump, skin thinning, dyslipidemia, osteoporosis, reduced cognitive capacity, dementia, hypertension, sleep deprivation, and atherosclerosis among others (Principles and Practice of Endocrinology and Metabolism. Edited by Kenneth Becker, Lippincott Williams and WiUrins Pulishers, Philadelphia, 2001; pg 723-8). The same characteristics can also arise from the exogenous administration of high doses of exogenous glucocorticoids, such as prednisone or dexamethasone, as part of an anti-inflammatory treatment regimen. Endogenous Cushings typically evolves from pituitary hyperplasia, some other ectopic source of ACTH, or from an adrenal carcinoma or nodular hyperplasia. Administration of a therapeutically effective dose of an 1 lβ-HSD-1 inhibitor may reduce local glucocorticoid concentrations and therefore treat, control, ameliorate, delay, or prevent the onset of Gushing' s disease and/or similar symptoms arising from glucocorticoid treatment. 1 lβ-HSD-1 is expressed in mammalian brain, and published data indicates that glucocorticoids may cause neuronal degeneration and dysfunction, particularly in the aged (de Quervain et al; Hum MoI Genet. 13: 47-52, 2004; Belanoff et al. J. Psychiatr Res. 35: 127-35, 2001). Evidence in rodents and humans suggests that prolonged elevation of plasma glucocorticoid levels impairs cognitive function that becomes more profound with aging. (Issa, A.M. et al. J. Neurosci. 10: 3247-54, 1990; Lupien, SJ et al. Nat. Neurosci. 1: 69-73, 1998; Yau, J.L.W. et al Pr oc Natl Acad Sd USA. 98: 4716-4712, 2001). Thekkapat et al has recently shown that 1 lβ-HSD-1 mRNA is expressed in human hippocampus, frontal cortex and cerebellum, and that treatment of elderly diabetic individuals with the nonselective HSD1/2 inhibitor carbenoxolone improved verbal fluency and memory (Proc Natl Acad Sd USA. 101: 6743-9, 2004). Additional CNS effects of glucocorticoids include glucocorticoid-induced acute psychosis which is of major concern to physicians when treating patients with these steroidal agents (Wolkowitz et al.; Ann NY Acad Sd. 1032: 191- 4, 2004). Conditional mutagenesis studies of the glucocorticoid receptor in mice have also provided genetic evidence that reduced glucocorticoid signaling in the brain results in decreased anxiety (Tranche, F. et al. (1999) Nature Genetics 23: 99-103). Therefore, it is expected that potent, selective 1 lβ-HSD-1 inhibitors would treat, control, ameliorate, delay, or prevent the onset of cognitive decline, dementia, steroid-induced acute psychosis, depression, and/or anxiety.
In Gushing' s patients, excess Cortisol levels contributes to the development of hypertension, dyslipidemia, insulin resistance, and obesity, conditions characteristic of metabolic syndrome (Orth, D.N. et al N. Engl. J. Med. 332:791-803, 1995; Boscaro, M. et al., Lancet, 357: 783-791, 2001, Bertagna, X. et al, Cushing's Disease. In: Melmed S., Ed. The Pituitary. 2nd ed. Maiden, MA: Blackwell; 592-612, 2002). Hypertension and dyslipidemia are also associated with development of atherosclerosis. 1 lβ-HSD-1 knockout mice are resistant to the dyslipidemic effects of a high fat diet and have an improved lipid profile vs wild type controls (Morton N.M. et al, JBC, 276: 41293-41300, 2001), and mice which overexpress 11 β-HSD-1 in fat exhibit the dyslipidemic phenotype characteristic of metabolic syndrome, including elevated circulating free fatty acids, and triclylgerides (Masuzaki, H., et al Science. 294: 2166-2170, 2001). Administration of a selective 1 lβ- HSD-I inhibitor has also been shown to reduce elevated plasma triglycerides and free fatty acids in mice on a high fat diet, and significantly reduce aortic content of cholesterol esters, and reduce progression of atherosclerotic plaques in mice (Hermanowski-Vosatka, A. et al. J. Exp. Med. 202: 517-27, 2005). The administration of a therapeutically effective amount of an 11 β-HSD-1 inhibitor would therefore be expected to treat, control, ameliorate, delay, or prevent the onset of dyslipidemia and/or atherosclerosis.
Glucocorticoids are known to cause a variety of skin related side effects including skin thinning, and impairment of wound healing (Anstead, G. Adv Wound Care. 11 : 277- 85, 1998; Beer, et al; Vitam Horm. 59: 217-39, 2000). llβ-HSD-1 is expressed in human skin fibroblasts, and it has been shown that the topical treatment with the non-selective HSD1/2 inhibitor glycerrhetinic acid increases the potency of topically applied hydrocortisone in a skin vasoconstrictor assay (Hammami, MM, and Siiteri, PK. J. Clin. Endocrinol. Metab. 73: 326-34, 1991). Advantageous effects of selective llβ-HSD-1 inhibitors such as BVT.2733 on wound healing have also been reported (WO 2004/11310). High levels of glucocorticoids inhibit blood flow and formation of new blood vessels to healing tissues. In vitro and in vivo models of angiogenesis have shown that systemic antagonism with the glucocorticoid receptor RU-486 enchances angiogenesis in subcutaneous sponges as well as in mouse myocardium following coronary artery ligation (Walker, et al, PNAS, 102: 12165-70, 2005). llβ-HSD-1 knockout mice also showed enhanced angiogenesis in vitro and in vivo within sponges, wounds, and infarcted myocardium. It is therefore expected that potent, selective 1 lβ -HSD-I inhibitors would treat, control, ameliorate, delay, or prevent the onset of skin thinning and/or promote wound healing and/or angiogenesis.
Although Cortisol is an important and well-recognized anti-inflammatory agent (J. Baxer, Pharmac. Ther., 2:605-659, 1976), if present in large amount it also has detrimental effects. In certain disease states, such as tuberculosis, psoriasis and stress in general, high glucocorticoid activity shifts the immune response to a humoral response, when in fact a cell based response may be more beneficial to patients. Inhibition of 11 β-HSD-1 activity may reduce glucocorticoid levels, thereby shifting the immuno response to a cell based response. (D. Mason, Immunology Today, 12: 57-60, 1991, G. A. W. Rook, Baillier's Clin. Endocrinol. Metab. 13: 576-581, 1999). Therefore, administration of 11 β-HSD-1 specific inhibitors could treat, control, ameliorate, delay, or prevent the onset of tuberculosis, psoriasis, stress, and diseases or conditions where high glucocorticoid activity shifts the immune response to a humoral response. One of the more significant side effects associated with topical and systemic glucocorticoid therapy is glaucoma, resulting in serious increases in intraocular pressure, with the potential to result in blindness (Armaly et al.; Arch Ophthalmol. 78: 193-7, 1967; Stokes et al; Invest Ophthalmol Vis Sd. AA: 5163-7, 2003; ). The cells that produce the majority of aqueous humor in the eye are the nonpigmented epithelial cells (NPE). These cells have been demonstrated to express 11 β-HSD- 1 , and consistent with the expression of 11 β-HSD- 1 , is the finding of elevated ratios of cortisolxortisone in the aqueous humor (Rauz et ah. Invest Ophthalmol Vis Sd. 42: 2037-2042, 2001). Furthermore, it has been shown that patients who have glaucoma, but who are not taking exogenous steroids, have elevated levels of Cortisol vs. cortisone in their aqueous humor (Rauz et al. QJM. 96: 481-490, 2003.) Treatment of patients with the nonselective HSD1/2 inhibitor carbenoxolone for 4 or 7 days significantly lowered intraocular pressure and local Cortisol generation within the eye (Rauz et al.; QJM. 96: 481-490, 2003.). It is therefore expected that potent, selective 11 β-HSD- 1 inhibitors would treat, control, ameliorate, delay, or prevent the onset of glaucoma.
Glucocorticoids (GCs) are known to increase bone resorption and reduce bone formation in mammals (Turner et al. Caldf Tissue Int. 54: 311-5, 1995; Lane, NE et al.
Med Pediatr Oncol. 41: 212-6, 2003). 11 β-HSD- 1 mRNA expression and reductase activity have been demonstrated in primary cultures of human osteoblasts in homogenates of human bone (Bland et al; J. Endocrinol. 161: 455-464, 1999; Cooper et al; Bone, 23: 119-125, 2000). In surgical explants obtained from orthopedic operations, llβ-HSD-1 expression in primary cultures of osteoblasts was found to be increased approximately 3 -fold between young and old donors (Cooper et al; J. Bone Miner Res. 17: 979-986, 2002). Glucocorticoids, such as prednisone and dexamethasone, are also commonly used to treat a variety of inflammatory conditions including arthritis, inflammatory bowl disease, and asthma. These steroidal agents have been shown to increase expression of 1 lβ-HSD-1 mRNA and activity in human osteoblasts (Cooper et al; J. Bone Miner Res. 17: 979-986, 2002). These studies suggest that 11 β -HSD-I plays a potentially important role in the development of bone-related adverse events as a result of excessive glucocorticoid levels or activity. Bone samples taken from healthy human volunteers orally dosed with the nonselective HSD1/2 inhibitor carbenoxolone showed a significant decrease in markers of bone resorption (Cooper et ah; Bone. 27: 375-81, 2000). It is therefore expected that potent, selective 1 lβ-HSD-1 inhibitors would treat, control, ameliorate, delay, or prevent the onset of conditions of glucocorticoid-induced or age-dependent osteoporosis
The following diseases, disorders and conditions can be treated, controlled, prevented or delayed, by treatment with the compounds of this invention: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) lipid disorders, (5) hyperlipidemia, (6) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12), atherosclerosis and its sequelae, (13) vascular restensosis, (14) pancreatitis, (15) obdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropather, (19), neuropathy, (20) hypertension and other disorders where insulin resistance is a component, and (21) other diseases, disorders, and conditions that can benefit from reduced local glucocorticoid levels. Therapeutic Compositions- Administration-Dose Ranges
Therapeutic compositions of the present compounds comprise an effective amount of the same formulated with one or more therapeutically suitable excipients. The term "therapeutically suitable excipient," as used herein, generally refers to pharmaceutically suitable, solid, semi-solid or liquid fillers, diluents, encapsulating material, formulation auxiliary and the like. Examples of therapeutically suitable excipients include, but are not limited to, sugars, cellulose and derivatives thereof, oils, glycols, solutions, buffers, colorants, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents and the like. Such therapeutic compositions may be administered parenterally, intracisternally, orally, rectally, intraperitoneally or by other dosage forms known in the art.
Liquid dosage forms for oral administration include, but are not limited to, emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms may also contain diluents, solubilizing agents, emulsifying agents, inert diluents, wetting agents, emulsifiers, sweeteners, flavorants, perfuming agents and the like.
Injectable preparations include, but are not limited to, sterile, injectable, aqueous, oleaginous solutions, suspensions, emulsions and the like. Such preparations may also be formulated to include, but are not limited to, parenterally suitable diluents, dispersing agents, wetting agents, suspending agents and the like. Such injectable preparations may be sterilized by filtration through a bacterial-retaining filter. Such preparations may also be formulated with sterilizing agents that dissolve or disperse in the injectable media or other methods known in the art.
The absorption of the compounds of the present invention may be delayed using a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the compounds generally depends upon the rate of dissolution and crystallinity. Delayed absorption of a parenterally administered compound may also be accomplished by dissolving or suspending the compound in oil. Injectable depot dosage forms may also be prepared by microencapsulating the same in biodegradable polymers. The rate of drug release may also be controlled by adjusting the ratio of compound to polymer and the nature of the polymer employed. Depot injectable formulations may also prepared by encapsulating the compounds in liposomes or microemulsions compatible with body tissues.
Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, gels, pills, powders, granules and the like. The drug compound is generally combined with at least one therapeutically suitable excipient, such as carriers, fillers, extenders, disintegrating agents, solution retarding agents, wetting agents, absorbents, lubricants and the like. Capsules, tablets and pills may also contain buffering agents. Suppositories for rectal administration may be prepared by mixing the compounds with a suitable non-irritating excipient that is solid at ordinary temperature but fluid in the rectum. The present drug compounds may also be microencapsulated with one or more excipients. Tablets, dragees, capsules, pills and granules may also be prepared using coatings and shells, such as enteric and release or rate controlling polymeric and nonpolymeric materials. For example, the compounds may be mixed with one or more inert diluents. Tableting may further include lubricants and other processing aids. Similarly, capsules may contain opacifying agents that delay release of the compounds in the intestinal tract.
Transdermal patches have the added advantage of providing controlled delivery of the present compounds to the body. Such dosage forms are prepared by dissolving or dispensing the compounds in suitable medium. Absorption enhancers may also be used to increase the flux of the compounds across the skin. The rate of absorption may be controlled by employing a rate controlling membrane. The compounds may also be incorporated into a polymer matrix or gel. For a given dosage form, disorders of the present invention may be treated, prophylatically treated, or have their onset delayed in a patient by administering to the patient a therapeutically effective amount of compound of the present invention in accordance with a suitable dosing regimen. In other words, a therapeutically effective amount of any one of compounds of formulas (I) is administered to a patient to treat and/or prophylatically treat disorders modulated by the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme. The specific therapeutically effective dose level for a given patient population may depend upon a variety of factors including, but not limited to, the specific disorder being treated, the severity of the disorder; the activity of the compound, the specific composition or dosage form, age, body weight, general health, sex, diet of the patient, the time of administration, route of administration, rate of excretion, duration of the treatment, drugs used in combination, coincidental therapy and other factors known in the art.
The present invention also includes therapeutically suitable metabolites formed by in vivo biotransformation of any of the compounds of formula (I). The term "therapeutically suitable metabolite", as used herein, generally refers to a pharmaceutically active compound formed by the in vivo biotransform ation of compounds of formula (I). For example, pharmaceutically active metabolites include, but are not limited to, compounds made by adamantane hydroxylation or polyhydroxylation of any of the compounds of formulas(I). A discussion of biotransformation is found in Goodman and Gilman's, The Pharmacological Basis of Therapeutics, seventh edition, MacMillan Publishing Company, New York, NY, (1985).
The total daily dose (single or multiple) of the drug compounds of the present invention necessary to effectively inhibit the action of 11-beta-hydroxysteroid dehydrogenase type 1 enzyme may range from about 0.01 mg/kg/day to about 50 mg/kg/day of body weight and more preferably about 0.1 mg/kg/day to about 25 mg/kg/day of body weight. Treatment regimens generally include administering from about 10 mg to about 1000 mg of the compounds per day in single or multiple doses. It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed aspects will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims

What is claimed,
1. A compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof
Figure imgf000125_0001
(I), wherein one of A1, A2, A3 and A4 is selected from the group consisting of alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl1, arylalkyl, aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, haloalkyl, heterocyclealkyl, heterocycleoxyalkyl, -S(O)2-N(R5R6), -NR7- [C(R8 R9)]n-C(0)-R10,
Figure imgf000125_0002
-OR14a, -N(R15R16), -CO2R17, -C(O)- N(R18R19), -C(R20R21)-OR22, -C(R23R24)-N(R25R26), and heterocycle, with the exception that 5 membered heterocycles may not contain two oxygen atoms, and the remaining members of the group consisting of A1, A2, A3 and A4 are each individually selected from the group consisting of hydrogen, alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl, aryloxyaUcyl, carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, -S(O)2-N(R5R6), -NR7-[C(R8 R9)]n-C(O)-R10, -0-[C(R11R12^p-C(O)- R13, -0R14b, -N(R15R16), -CO2R17, -C(O)-N(R18R19), -C(R20R21)-OR22, and -C(R23R24)- N(R25R26); n is O or 1; p is O or 1;
D is selected from the group consisting of a bond, -C(R27R28)-X- and -C(R27R28)-
Figure imgf000125_0003
E is selected from the group consisting of a cycloalkyl, alkyl, aryl, heteroaryl and heterocycle, wherein the heteroaryl and the heterocycle are appended to the parent molecular moiety through an available carbon atom, or R4 and E together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
X is selected from the group consisting of a bond, -N(R31)-, -O-, -S-, -S(O)- and - S(O)2-;
R1 is selected from the group consisting of hydrogen and alkyl;
R2 is selected from the group consisting of hydrogen, alkyl and cycloalkyl;
R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl, or R3 and R4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
R5 and R6 are each independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylcarbonyl, alkylsufonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxy, aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, or R5 and R6 together with the atom to which they are attached form a heterocycle;
R7 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
R8 and R9 are each independently selected from the group consisting of hydrogen and alkyl, or R8 and R9 taken together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
R10 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl and -N(R32R33);
R11 and R12 are each independently selected from the group consisting of hydrogen and alkyl or Rπ and R12 taken together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
R13 is selected from the group consisting of hydroxy and -N(R34R35); R14a is selected from the group consisting of carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
R14b is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
R15 and R16 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocyclesulfonyl, alkylsufonyl, cycloalkylsulfonyl and arylsulfonyl, or R15 and R16 together with the atom to which they are attached form a heterocycle;
R is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
R18 and R19 are each independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylsufonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, or R18 and R19 together with the atom to which they are attached form a heterocycle;
R20, R21 and R22 are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl;
R23 and R24 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl, arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, heterocycle, heterocyclecarbonyl and heterocyclesulfonyl;
R and R are each independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl, aryloxy, arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocyclecarbonyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, or R25 and R26 together with the nitrogen to which they are attached form a ring selected from the group consisting of heteroaryl and heterocycle;
R27 and R28are each independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heteroaryl and heterocycle or R27 and R28 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R27 and R29 together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R28 and R4 together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
R29 and R30are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, cycloalkyl, cycloalkyloxy, heteroaryl, heterocycle, and -N(R36R37), or R29 and R30 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R29 and R4 together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R29 and E together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
R31 is selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycle and heteroaryl, or R31 and E together with the atom to which they are attached form a ring selected from the group consisting of heteroaryl and heterocycle, or R31 and R4 together with the atoms to which they are attached form a heterocycle;
R32 and R33 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R32 and R33 together with the atom to which they are attached form a heterocycle;
R34 and R35 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R34 and R35 together with the atom to which they are attached form a heterocycle; and
R36 and R37 are each independently selected from the group consisting of hydrogen, alkyl and aryl.
2. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen; and
R1 and R2 are hydrogen.
3. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; and D is a bond.
4. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is a bond; and
E is selected from the group consisting of alkyl, aryl and heteroaryl.
5. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; D is a bond;
E is selected from the group consisting of alkyl, aryl and heteroaryl; R3 and R4 are hydrogen; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6).
6. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; D is a bond; E is selected from the group consisting of alkyl, aryl and heteroaryl; R3 is hydrogen; R4 is alkyl; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6).
7. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R and R are hydrogen; D is a bond;
E is selected from the group consisting of alkyl, aryl and heteroaryl; R3 and R4 are alkyl; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6).
8. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; D is a bond;
E is selected from the group consisting of alkyl, aryl and heteroaryl; R3 and R4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle.
9. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is a bond;
E is selected from the group consisting of alkyl, aryl and heteroaryl;
R3 and R4 together with the atom to which they are attached form a cycloalkyl ring; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6).
10. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is a bond;
R4 and E together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6).
11. The compound of claim 10 having formula (II), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof,
Figure imgf000131_0001
(II) wherein t is 1 or 2;
A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 is alkyl;
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6) ; and
R38 is selected from the group consisting of arylalkyl and heteroarylalkyl wherein the aryl of the arylalkyl and the heteroaryl of the heteroarylalkyl are each independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, halogen and haloalkyl.
12. The compound of claim 10 having formula (III), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof,
Figure imgf000132_0001
(πi) wherein t is 1 or 2;
A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 is alkyl;
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6) ; and
R38 is selected from the group consisting of arylalkyl and heteroarylalkyl wherein the aryl of the arylalkyl and the heteroaryl of the heteroarylalkyl are each independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, halogen and haloalkyl.
13. The compound according to claim 1, wherein A2, A3 and A are hydrogen;
R1 and R2 are hydrogen; and
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)- X-.
14. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)- X-; and
E is selected from the group consisting of aryl and heteroaryl.
15. The compound according to claim 1 , wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)-
X-;
E is selected from the group consisting of aryl and heteroaryl; and X is a bond.
16. The compound according to claim 1, wherein
A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)- X-;
E is selected from the group consisting of aryl and heteroaryl;
X is a bond;
R3 and R4 are hydrogen;
R 5 R 5 R 5 R are each independently selected from the group consisting of hydrogen and alkyl; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6).
17. The compound according to claim I5 wherein
A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)- X-;
E is selected from the group consisting of aryl and heteroaryl;
X is a bond;
R3 is hydrogen;
R4 is alkyl;
R27, R28, R29, R30 are each independently selected from the group consisting of hydrogen and alkyl; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6).
18. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)-
X-;
E is selected from the group consisting of aryl and heteroaryl;
X is a bond;
R3 and R4 are alkyl;
R 5 R , R , R are each independently selected from the group consisting of hydrogen and alkyl; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6).
19. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)- X-;
E is selected from the group consisting of aryl and heteroaryl;
X is a bond; and
R3 and R4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle.
20. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)-
X-;
E is selected from the group consisting of aryl and heteroaryl;
X is a bond;
R3 and R4 together with the atom to which they are attached form a cycloalkyl ring;
R , R , R 5 R are each independently selected from the group consisting of hydrogen and alkyl; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6).
21. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)-
X-;
E is selected from the group consisting of aryl and heteroaryl; and X is selected from the group consisting of -N(R31)- and -O-.
22. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R and R are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)-
X-;
E is selected from the group consisting of aryl and heteroaryl; X is selected from the group consisting of -N(R31)- and -O-; R3 and R4 are hydrogen;
R , R , R , R are each independently selected from the group consisting of hydrogen and alkyl; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6).
23. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)-
X-;
E is selected from the group consisting of aryl and heteroaryl; X is selected from the group consisting of -N(R31)- and -0-; R3 is hydrogen;
R4 is alkyl;
R27, R28, R29, R30 are each independently selected from the group consisting of hydrogen and alkyl; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6).
24. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)-
X-;
E is selected from the group consisting of aryl and heteroaryl;
X is selected from the group consisting of -N(R31)- and -O-;
R3 and R4 are alkyl;
R27, R28, R29, R30 are each independently selected from the group consisting of hydrogen and alkyl; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6).
25. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen; D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)-
Xs
E is selected from the group consisting of aryl and heteroaryl;
X is selected from the group consisting of -N(R31)- and -0-;
R3 and R4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
R27, R28, R29, R30 are each independently selected from the group consisting of hydrogen and alkyl; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6).
26. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is selected from the group consisting of -C(R27R28)-X- and -C(R27R28)-C(R29R30)-
X-;
E is selected from the group consisting of aryl and heteroaryl;
X is selected from the group consisting of -N(R31)- and -O-;
R3 and R4 together with the atom to which they are attached form a cycloalkyl ring;
R27, R28, R29, R30 are each independently selected from the group consisting of hydrogen and alkyl; and
A1 is selected from the group consisting of heteroaryl, -CO2R17, -C(O)-N(R18R19), alkylsulfonyl, and -S(O)2-N(R5R6).
27. The compound according to claim 1 selected from the group consisting of E-4-{[l-(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino}-adamantane-l-carboxylic acid;
E-4-[(l-Phenyl-cyclopropanecarbonyl)-amino]-adamantane-l-carboxylic acid;
E-4-(2-Methyl-2-phenyl-propionylamino)-adamantane- 1 -carboxylic acid;
E-A- { [ 1 -(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino} -adamantane- 1 -carboxylic acid amide;
E-4-[(l-Phenyl-cyclopropanecarbonyl)-ammo]-adamantane-l-carboxylic acid amide;
E-4-(2-Methyl-2-phenyl-propionylamino)-adamantane-l -carboxylic acid amide;
E-4-({[l-(4-chlorophenyl)cyclohexyl]carbonyl}amino)adamantane-l-carboxamide;
E-4-({[l-(4-chlorophenyl)cyclopropyl]carbonyl}amino)adamantane-l-carboxamide;
E-4-( {[ 1 -(4-chlorophenyl)cyclopentyl]carbonyl} amino)adamantane- 1 -carboxamide;
E-A- {[2-(4-chlorophenyl)-2-methylρropanoyl]amino} adamantane- 1 -carboxamide;
E-4-{[(l-phenylcyclopentyl)carbonyl]amino}adamantane-l-carboxamide;
E-4-({[l-(3-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-l-carboxamide;
E-4-({[l-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-l- carboxamide; E-4-( { [ 1 -(4-fluoroρhenyl)cyclopentyl]carbonyl} amino)adamantane- 1 -carboxamide;
E-4-({[l-(2-fluorophenyl)cyclopentyl]carbonyl}ammo)adamantane-l-carboxamide;
E-A- {[(1 -methylcyclohexyl)carbonyl]amino} adamantane-1 -carboxamide;
E-4-( {[ 1 -(2,4-dichlorophenyl)cyclopropyl] carbonyl} amino)adamantane- 1 - carboxamide;
E-4-( {[1 -(4-methoxyphenyl)cyclopropyl]carbonyl} amino)adamantane-l - carboxamide;
E-4-({[l-(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-l-carboxamide;
Ε-4- { [2-methyl-2-(4-pyridin-4-ylphenyl)propanoyl] amino } adamantane- 1 - carboxamide;
JE'-4-[(2-methyl-2-thien-2-ylpropanoyl)ammo]adamantane-l-carboxamide;
E-4- [(2-methyl-2-thien-3 -ylpropanoyl)amino] adamantane- 1 -carboxamide;
E-4-({2-methyl-2-[5-(trifluoromethyl)pyridm-2-yl]propanoyl}amino)adamantane-l- carboxamide;
E-4-[(2-methyl-2-{4-[5-(trifluoromethyl)pyridin-2 yl]phenyl}propanoyl)amino]adamantane-l-carboxamide;
E-A-{ {[ 1 -(4-methoxyphenyl)cyclopentyl]carbonyl} amino)adamantane- 1 - carboxamide;
E-A- {[2-(4-bromophenyl)-2-methylpropanoyl]amino} adamantane- 1 -carboxamide;
E-4-[5-(aminocarbonyl)-2-adamantyl]-3-methyl-l-(2-methylbenzyl)-2-oxopiperidine- 3-carboxamide;
JΕ'-4-(aminocarbonyl)-2-adamantyl]-l-benzyl-3-methyl-2-oxopyrrolidine-3- carboxamide;
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-l-(2-methylbenzyl)-2-oxopyrrolidine-3- carboxamide;
E-4-(aminocarbonyl)-2-adamantyl] - 1 -(2-chlorobenzyl)-3 -methyl-2-oxopyrrolidine-3 - carboxamide;
E-4-(aminocarbonyl)-2-adamantyl]-l-(3-chlorobenzyl)-3-methyl-2-oxopyrrolidine-3- carboxamide;
E-4-({2-methyl-2-[4-(l-methyl-lH-ρyrazol-4- yl)phenyl]propanoyl} amino)adamantane- 1 -carboxamide;
E-4-{[2-(3-bromophenyl)-2-methylpropanoyl]amino}adamantane-l-carboxamide; E-4-({2-[4-(3,5-dimemylisoxazol-4-yl)ρhenyl]-2- methylpropanoyl} amino)adamantane- 1 -carboxamide;
E-A- { [2-methyl-2-(4-pyridin-3 -ylphenyl)propanoyl] amino} adamantane- 1 - carboxamide;
4- {[( {(E)-4-[(2-methyl-2-thien-2-ylproρanoyl)amino]- 1 - adamantyl}carbonyl)amino]methyl}benzoic acid;
E-4-({2-methyl-2-[4-(lH-pyrazol-4-yl)phenyl]propanoyl}amino)adamantane-l- carboxamide;
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-l -(I -methyl- 1 -phenylethyl)-2- oxopyrrolidine-3-carboxamide; jΕ'-4-(aminocarbonyl)-2-adamantyl] -3 -methyl-2-oxo- 1-[(1R)-I- phenylethyl]pyrrolidine-3-carboxamide;
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-l-[(lS)-l- phenylethyl]pyrrolidine-3-carboxamide;
E-A- { [2-methyl-2-( 1 ,3 -thiazol-2-yl)propanoyl] amino } adamantane- 1 -carboxamide;
E-4-(aminocarbonyl)-2-adamantyl]-l-(4-chlorobenzyl)-3-methylpiperidine-3- carboxamide;
E-4-{[2-(4-hydroxyphenyl)-2-methylpropanoyl]amino}adamantane-l-carboxamide; jΕ'-4-(aminocarbonyl)-2-adamantyl]-l-benzyl-3-methyl-2-oxopiperidine-3- carboxamide;
E-A- { [2-methyl-2-(4-phenoxyphenyl)propanoyl] amino } adamantane- 1 -carboxamide;
E-A- { [2-( 1 -benzothien-3 -yl)-2-methylpropanoyl] amino } adamantane- 1 -carboxamide;
E-A- { [2-(5 -fluoropyridin-2-yl)-2-methylpropanoyl] amino } adamantane- 1 - carboxamide; and
E-A- [(2-methyl-2-quinoxalin-2-ylρropanoyl)amino] adamantane- 1 -carboxamide; or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof.
28. The compound according to claim 1 selected from the group consisting of (E)-4-[(2-methyl-2-pyrazin-2-ylpropanoyl)amino]adamantane-l-carboxamide; N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-l-(2-pyridin-2- ylethyl)pyrrolidine-3-carboxamide; methyl (E)-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane-l-carboxylate; (E)-4-( {2-methyl-2-[3-(l ,3-thiazol-4-ylmethoxy)phenyl]propanoyl} amino)adamantane- 1-carboxamide;
(E)-4-({2-methyl-2-[6-(methylamino)pyridin-3-yl]propanoyl}amino)adamantane-l- carboxaniide;
(E)-4-({2-methyl-2-[3-(morpholin-4-ylmethyl)phenyl]propanoyl}amino)adamantane-l- carboxamide;
(E)-4-( {2-methyl-2-[4-(trifluoromethyl)pyridin-2-yl]propanoyl} amino)adamantane-l - carboxamide;
(E)-4-[(2-{3-[2-(lH-imidazol-l-yl)emoxy]phenyl}-2- methylpropanoyl)amino] adamantane- 1 -carboxamide; methyl (E)-4- {[(l-phenylcyclopropytycarbonyljamino} adamantane-1-carboxylate;
(JE)-A- { [2-(6-fluoropyridin-3 -yl)-2-methylproρanoyl] amino} adamantane- 1 - carboxamide;
(E)-N-[3-(aminocarbonyl)benzyl]-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane- 1 -carboxamide;
N-[(E)-5-(aminocarbonyl)-2-adamantyl]-l-(2-chlorobenzyl)-3-methyl-2-oxopiperidme- 3-carboxamide;
N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-l-(pyridin-4- ylmethyl)pyrrolidine-3-carboxamide;
(E)-4-{[2-methyl-2-(4-phenoxyphenyl)propanoyl]amino}adamantane-l-carboxylic acid;
N-[(E)-5-(aminosulfonyl)-2-adamantyl]-l-phenylcycloρropanecarboxamide;
(E)-4-({3-[(5-cyanopyridin-2-yl)oxy]-2,2-dimethylpropanoyl}amino)adamantane-l- carboxamide;
N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-l-(l-pyridin-2- ylethyl)pyrrolidine-3-carboxamide;
(E)-4-[(2-methyl-3-phenylpropanoyl)amino]adamantane-l-carboxamide;
(E)-4-{[2-methyl-2-(6-morpholin-4-ylpyridin-3-yl)propanoyl]amino}adamantane-l- carboxamide; methyl (E)-4-({[l-(4-chlorophenyl)cyclobutyl]carbonyl}amino)adamantane-l- carboxylate;
N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-l-(ρyridin-3- ylmethyl)pyrrolidine-3-carboxamide;
(E)-4-[(2-methyl-2-{6-[(2-morpholin-4-ylethyl)amino]pyridin-3- yl}propanoyl)amino] adamantane- 1 -carboxamide;
(E)-4-[(2-methyl-2-{4-[(Ε)-2-pyridin-4-ylvinyl]phenyl}propanoyl)amino]adamantane- 1 -carboxamide;
N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(4-chlorophenyl)-2-methylpropanamide;
(E)-4-({2-methyl-2-[3-(2-moφholin-4-ylethoxy)phenyl]propanoyl}amino)adamantane- 1 -carboxamide;
(E)-A- { [2-(3 -cyanopyridin-2-yl)-2-methylpropanoyl] amino } adamantane- 1 - carboxamide;
(E)-4-({2-methyl-2-[6-(4-methylpiρerazin-l-yl)pyridin-3- yljpropanoyl} amino)adamantane- 1 -carboxamide;
N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-l-(pyridin-2- ylmethyl)pyrrolidine-3-carboxamide;
(E)-N-[4-(aminosulfonyl)benzyl]-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane- 1 -carboxamide;
(E)-4-({2-methyl-2-[4-(pentyloxy)phenyl]propanoyl}amino)adamantane-l-carboxylic acid;
(E)-4-( {2-methyl-2-[4-(l ,3-thiazol-4-ylmethoxy)phenyl]propanoyl} amino)adamantane- 1-carboxylic acid;
(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-N-(l,3-thiazol-5-ylmethyl)adamantane-l- carboxamide;
(E)-4-({2-[4-(benzyloxy)phenyl]-2-methylpropanoyl}amino)adamantane-l-carboxylic acid;
(E)-4-{[2-(5-cyanopyridin-2-yl)-2-methylpropanoyl]ammo}adamantane-l- carboxamide;
(E)-A- { [2-(4-chlorophenyl)-2-methylpropanoyl] amino } adamantane- 1 -carboxylic acid;
4-[({[(E)-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)-l- adamantyl]carbonyl} amino)methyl]benzoic acid;
4- { [( {(E)-4-[(2-methyl-2-phenylpropanoyl)amino] - 1 - adamantyl} carbonyl)amino]methyl}benzoic acid;
3-{[({(E)-4-[(2-methyl-2-ρhenylρroρanoyl)amino]-l- adamantyl}carbonyl)amino]methyl} benzoic acid;
(E)-4-({[l-(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-l-carboxylic acid;
(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-N-(pyridin-4-ylnietliyl)adamantane-l- carboxamide;
(E)-4-( { [ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl} amino)adamantane- 1 -carboxylic acid;
(-^-N-(2-furylmethyl)-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane-l- carboxamide;
3-[(E)-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)-l- adamantyl]-lH-pyrazole-5-carboxamide;
(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-N-(pyridin-3-ylmetliyl)adamantane-l- carboxamide;
(-^-4-[(2-methyl-2-phenylpropanoyl)amino]-N-(pyridin-2-ylniethyl)adaniantane-l- carboxamide;
(E)-4-({2-[4-(cyclohexylmethoxy)phenyl]-2-methylpropanoyl}amino)adamantane-l- carboxylic acid;
(E)-4-[(2-methyl-2-{4-[5-(trifluoromethyl)pyridin-2- yl]phenyl}propanoyl)amino]adamantane-l-carboxylic acid; and
N- [(E)-5-(aminosulfonyl)-2-adamantyl] - 1 -(2-chlorobenzyl)-3 -methyl-2-oxopyrrolidine- 3-carboxamide; or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof.
29. A method of inhibiting 11 -beta-hydroxysteroid dehydrogenase Type I enzyme, comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I) of claim 1.
30. A method of treating disorders in a mammal by inhibiting 11 -beta-hydroxysteroid dehydrogenase Type I enzyme, comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I) of claim 1.
31. A method of treating non-insulin dependent type 2 diabetes in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I) of claim 1.
32. A method of treating insulin resistance in a mammal by inhibiting 11 -beta- hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I) of claim 1.
33. A method of treating obesity in a mammal by inhibiting 11 -beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I) of claim 1.
34. A method of treating lipid disorders in a mammal by inhibiting 11 -beta- hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I) of claim 1.
35. A method of treating metabolic syndrome in a mammal by inhibiting 11 -beta- hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I) of claim 1.
36. A method of treating diseases and conditions that are mediated by excessive glucocorticoid action in a mammal by inhibiting 11 -beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I) of claim 1.
37 A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) of claim 1 in combination with a pharmaceutically suitable carrier.
PCT/US2006/000402 2005-01-05 2006-01-05 Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme WO2006074330A2 (en)

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BRPI0606228-8A BRPI0606228A2 (en) 2005-01-05 2006-01-05 11-beta-hydroxysteroid dehydrogenase type 1 enzyme inhibitors
CA002594116A CA2594116A1 (en) 2005-01-05 2006-01-05 Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
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JP2007550479A JP5133702B2 (en) 2005-01-05 2006-01-05 Inhibitors of 11-β-hydroxysteroid dehydrogenase type 1 enzyme
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EP06717579A EP1846362A2 (en) 2005-01-05 2006-01-05 Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
IL184329A IL184329A (en) 2005-01-05 2007-07-01 Amide containing an adamantyl moiety and a carbonyl-bearing substituent on the adamantyl moiety as inhibitor of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
IL213342A IL213342A (en) 2005-01-05 2011-06-02 Amide containing an adamantyl moiety and a carbonyl- bearing substituent on the adamantyl moiety as inhibitor of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007128761A2 (en) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Uses of dpp-iv inhibitors
WO2008142986A1 (en) 2007-05-18 2008-11-27 Shionogi & Co., Ltd. NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE HAVING 11 β-HYDROXYSTEROID DEHYDROGENASE TYPE I INHIBITORY ACTIVITY
JP2010501589A (en) * 2006-08-24 2010-01-21 ブリストル−マイヤーズ スクイブ カンパニー Cyclic 11-β hydroxysteroid dehydrogenase type I inhibitor
EP2150109A1 (en) * 2007-04-24 2010-02-10 High Point Pharmaceuticals, LLC Pharmaceutical use of substituted amides
WO2010044441A1 (en) * 2008-10-17 2010-04-22 塩野義製薬株式会社 Acetic acid amide derivative having inhibitory activity on vascular endothelial lipase
US8017638B2 (en) 2006-03-30 2011-09-13 Shionogi & Co., Ltd. Isoxazole derivative and isothiazole derivative having inhibitory activity on 11β-hydroxysteroid dehydrogenase type 1
US8324265B2 (en) 2005-11-21 2012-12-04 Shionogi & Co., Ltd. Heterocyclic compounds having type I 11β hydroxysteroid dehydrogenase inhibitory activity
US8822149B2 (en) 2007-05-24 2014-09-02 Pacific Edge Limited Prognosis prediction for melanoma cancer
US8952176B2 (en) 2005-06-07 2015-02-10 Shionogi & Co., Ltd. Heterocyclic compound having type I 11 β hydroxysteroid dehydrogenase inhibitory activity

Families Citing this family (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100222316A1 (en) 2004-04-29 2010-09-02 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8415354B2 (en) * 2004-04-29 2013-04-09 Abbott Laboratories Methods of use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US7880001B2 (en) * 2004-04-29 2011-02-01 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
TWI350168B (en) 2004-05-07 2011-10-11 Incyte Corp Amido compounds and their use as pharmaceuticals
EP1758580A4 (en) * 2004-06-24 2008-01-16 Incyte Corp N-substituted piperidines and their use as pharmaceuticals
US20050288317A1 (en) * 2004-06-24 2005-12-29 Wenqing Yao Amido compounds and their use as pharmaceuticals
EP1773773A4 (en) * 2004-06-24 2009-07-29 Incyte Corp Amido compounds and their use as pharmaceuticals
US7687665B2 (en) 2004-06-24 2010-03-30 Incyte Corporation 2-methylprop anamides and their use as pharmaceuticals
BRPI0514230A (en) * 2004-08-10 2008-06-03 Incyte Corp starch compounds and their use as pharmaceuticals
JP2008515956A (en) * 2004-10-12 2008-05-15 ノボ ノルディスク アクティーゼルスカブ 11.beta.-hydroxysteroid dehydrogenase type 1 active spiro compound
US8110581B2 (en) * 2004-11-10 2012-02-07 Incyte Corporation Lactam compounds and their use as pharmaceuticals
NZ554906A (en) * 2004-11-10 2011-01-28 Incyte Corp Lactam compounds and their use as pharmaceuticals
EP1824842A4 (en) * 2004-11-18 2009-08-26 Incyte Corp Inhibitors of 11- hydroxyl steroid dehydrogenase type 1 and methods of using the same
JP5078621B2 (en) * 2005-01-05 2012-11-21 アボット・ラボラトリーズ Adamantyl derivatives as inhibitors of 11-β-hydroxysteroid dehydrogenase type 1 enzyme
US8198331B2 (en) * 2005-01-05 2012-06-12 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US20090192198A1 (en) 2005-01-05 2009-07-30 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
GB0506133D0 (en) * 2005-03-24 2005-05-04 Sterix Ltd Compound
JP2009508963A (en) * 2005-09-21 2009-03-05 インサイト・コーポレイション Amide compounds and their use as pharmaceutical compositions
WO2007051811A2 (en) * 2005-11-01 2007-05-10 Transtech Pharma Pharmaceutical use of substituted amides
US20090124598A1 (en) * 2005-11-01 2009-05-14 Henrik Sune Andersen Pharmaceutical use of substituted amides
WO2007067504A2 (en) * 2005-12-05 2007-06-14 Incyte Corporation Lactam compounds and methods of using the same
WO2007084314A2 (en) * 2006-01-12 2007-07-26 Incyte Corporation MODULATORS OF 11-ß HYDROXYL STEROID DEHYDROGENASE TYPE 1, PHARMACEUTICAL COMPOSITIONS THEREOF, AND METHODS OF USING THE SAME
EP1979318A1 (en) * 2006-01-31 2008-10-15 Incyte Corporation Amido compounds and their use as pharmaceuticals
TW200808807A (en) * 2006-03-02 2008-02-16 Incyte Corp Modulators of 11-β hydroxyl steroid dehydrogenase type 1, pharmaceutical compositions thereof, and methods of using the same
US20070208001A1 (en) * 2006-03-03 2007-09-06 Jincong Zhuo Modulators of 11- beta hydroxyl steroid dehydrogenase type 1, pharmaceutical compositions thereof, and methods of using the same
WO2007107550A1 (en) * 2006-03-21 2007-09-27 High Point Pharmaceuticals, Llc Adamantane derivatives for the treatment of the metabolic syndrome
JP2009532418A (en) * 2006-04-07 2009-09-10 ハイ ポイント ファーマシューティカルズ，リミティド ライアビリティ カンパニー 11β-Hydroxysteroid dehydrogenase type 1 active compound
EP2013163A1 (en) * 2006-05-01 2009-01-14 Incyte Corporation Tetrasubstituted ureas as modulators of 11-beta hydroxyl steroid dehydrogenase type 1
WO2007137066A2 (en) * 2006-05-17 2007-11-29 Incyte Corporation HETEROCYCLIC INHIBITORS OF 11-β HYDROXYL STEROID DEHYDROGENASE TYPE I AND METHODS OF USING THE SAME
CA2655282A1 (en) * 2006-06-16 2007-12-21 High Point Pharmaceuticals, Llc Pharmaceutical use of substituted piperidine carboxamides
CA2657078A1 (en) * 2006-07-13 2008-01-17 High Point Pharmaceuticals, Llc 11beta-hydroxysteroid dehydrogenase type 1 active compounds
EP1878721A1 (en) * 2006-07-13 2008-01-16 Novo Nordisk A/S 4-Piperidylbenzamides as 11-beta-hydroxysteroid dehydrogenase type 1 inhibitors
EP1935420A1 (en) * 2006-12-21 2008-06-25 Merck Sante 2-Adamantyl-butyramide derivatives as selective 11beta-HSD1 inhibitors
JP2010519240A (en) * 2007-02-23 2010-06-03 ハイ ポイント ファーマシューティカルズ，リミティド ライアビリティ カンパニー N-adamantylbenzamide as an inhibitor of 11-beta-hydroxysteroid dehydrogenase
US8334305B2 (en) * 2007-02-23 2012-12-18 High Point Pharmaceuticals, Llc N-adamantyl benzamides as inhibitors of 11-β-hydroxysteroid dehydrogenase
US20110003852A1 (en) * 2007-02-23 2011-01-06 Soren Ebdrup N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase
AU2008219326B2 (en) * 2007-02-23 2012-12-13 Vtv Therapeutics Llc N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase
US8153798B2 (en) * 2007-03-09 2012-04-10 High Point Pharmaceuticals, Llc Indole- and benzimidazole amides as hydroxysteroid dehydrogenase inhibitors
WO2008119017A1 (en) * 2007-03-28 2008-10-02 High Point Pharmaceuticals, Llc 11beta-hsd1 active compounds
CA2683852A1 (en) * 2007-04-11 2008-10-23 High Point Pharmaceuticals, Llc Novel compounds
CL2008001839A1 (en) 2007-06-21 2009-01-16 Incyte Holdings Corp Compounds derived from 2,7-diazaspirocycles, inhibitors of 11-beta hydroxyl steroid dehydrogenase type 1; pharmaceutical composition comprising said compounds; Useful to treat obesity, diabetes, glucose intolerance, type II diabetes, among other diseases.
CN101743226B (en) * 2007-07-17 2012-10-10 霍夫曼-拉罗奇有限公司 Inhibitors of 11beta-hydroxysteroid dehydrogenase
JP5736098B2 (en) * 2007-08-21 2015-06-17 アッヴィ・インコーポレイテッド Pharmaceutical composition for treating central nervous system disorders
US8119658B2 (en) 2007-10-01 2012-02-21 Bristol-Myers Squibb Company Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors
EP2322505A4 (en) 2008-08-29 2011-10-19 Kowa Co 1-adamantylazetidin-2-one derivative and pharmaceutical preparation comprising same
EP2362730A4 (en) 2008-11-21 2012-08-29 High Point Pharmaceuticals Llc Adamantyl benzamide compounds
EP2243479A3 (en) 2009-04-20 2011-01-19 Abbott Laboratories Novel amide and amidine derivates and uses thereof
WO2010123838A2 (en) * 2009-04-20 2010-10-28 Abbott Laboratories Novel amide and amidine derivatives and uses thereof
US8871208B2 (en) * 2009-12-04 2014-10-28 Abbvie Inc. 11-β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors and uses thereof
JP5813106B2 (en) * 2010-06-25 2015-11-17 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Azaspirohexanone as an inhibitor of 11-β-HSD1 for the treatment of metabolic disorders
US8513430B2 (en) 2010-07-27 2013-08-20 High Point Pharmaceuticals, Llc Substituted thiazol-2-ylamine derivatives, pharmaceutical compositions, and methods of use as 11-beta HSD1 modulators
KR101409847B1 (en) * 2011-08-04 2014-06-27 현대약품 주식회사 A COMPOUND FOR INHIBITING 11β-HYDROXY STEROID DEHYDROGENASE 1, AND A PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
CA2860192C (en) * 2011-12-22 2020-10-27 Connexios Life Sciences Pvt. Ltd. Derivatives of aza adamantane and uses thereof
TW201808914A (en) 2016-05-05 2018-03-16 嘉來克生命科學有限責任公司 Modulators of the integrated stress pathway
TW201808903A (en) * 2016-05-05 2018-03-16 嘉來克生命科學有限責任公司 Modulators of the integrated stress pathway
TW201808888A (en) 2016-05-05 2018-03-16 嘉來克生命科學有限責任公司 Modulators of the integrated stress pathway
US11548893B2 (en) 2017-07-15 2023-01-10 Arisan Therapeutics Inc. Enantiomerically pure adamantane carboxamides for the treatment of filovirus infection
EP3704115A1 (en) 2017-11-02 2020-09-09 Calico Life Sciences LLC Modulators of the integrated stress pathway
TWI771621B (en) 2018-10-11 2022-07-21 美商嘉來克生命科學有限責任公司 Prodrug modulators of the integrated stress pathway

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004056744A1 (en) * 2002-12-23 2004-07-08 Janssen Pharmaceutica N.V. Adamantyl acetamides as hydroxysteroid dehydrogenase inhibitors
WO2004089470A2 (en) * 2003-04-11 2004-10-21 Novo Nordisk A/S New amide derivatives and pharmaceutical use thereof
US20050245534A1 (en) * 2004-04-29 2005-11-03 Link James T Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
US20050277647A1 (en) * 2004-04-29 2005-12-15 Link James T Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme

Family Cites Families (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US245534A (en) * 1881-08-09 James w
US3919313A (en) * 1973-07-23 1975-11-11 Schering Corp Novel 1-N-({60 -aminoacetyl) aminoadamantanes
SU740752A1 (en) 1977-12-29 1980-06-15 Научно-исследовательский институт фармакологии АМН СССР Method of preparing 1-hydroxy-4-amino- or 4-n-substituted adamantanes
SU803348A1 (en) 1979-10-12 1981-09-30 Предприятие П/Я В-2343 Oxyethylammonium derivatives of adamantane possessing antivirus activity
US4751292A (en) * 1985-07-02 1988-06-14 The Plant Cell Research Institute, Inc. Adamantyl purines
EP0336356A3 (en) 1988-04-05 1991-09-25 Abbott Laboratories Derivatives of tryptophan as cck antagonists
NZ234264A (en) 1989-06-29 1993-05-26 Warner Lambert Co N-substituted cycloalkyl and polycycloalkyl alpha-substituted trp-phe- and phenethylamine derivatives, and pharmaceutical compositions
US5631281A (en) * 1989-06-29 1997-05-20 Warner-Lambert Company N-substituted cycloalkyl and polycycloalkyl α-substituted Trp-Phe- and phenethylamine derivatives
EP0668290B1 (en) 1990-02-28 1998-11-11 Teikoku Seiyaku Kabushiki Kaisha Physiologically active substance well capable of permeating biomembrane
US5244915A (en) * 1990-08-31 1993-09-14 Warner-Lambert Company Amico acid derivatives cyclized at the c-terminal
JPH06506455A (en) 1991-02-08 1994-07-21 ケンブリッジ・ニューロサイエンス・インコーポレイテッド Novel method for identifying guanidine substitutes and their derivatives as neurotransmitter release modulators and neurotransmitter release blockers
US5576355A (en) 1993-06-04 1996-11-19 Mobil Oil Corp. Diamondoid derivatives for pharmaceutical use
US5395846A (en) 1993-06-25 1995-03-07 Rhone-Poulenc Rorer Pharmaceuticals Inc. Amino Bi- and tri-carbocyclic aklane bis-aryl squalene synthase inhibitors
WO1999002145A1 (en) 1997-07-07 1999-01-21 Cambridge Neuroscience, Inc. Combination drug therapies comprising aminoglycoside antibiotics and n,n'-disubstituted guanidines
CA2387892A1 (en) 1999-10-18 2001-04-26 University Of Connecticut Pyrazole derivatives as cannabinoid receptor antagonists
CN1307159C (en) * 2000-05-31 2007-03-28 参天制药株式会社 TNF-alpha prodn. inhibitors
AU2002255634A1 (en) 2001-03-01 2002-09-19 Smithkline Beecham Corporation Peptide deformylase inhibitors
EP1474139B1 (en) 2002-02-01 2007-11-21 Merck & Co., Inc. 11-beta-hydroxysteroid dehydrogenase 1 inhibitors useful for the treatment of diabetes, obesity and dyslipidemia
WO2003075660A1 (en) 2002-03-06 2003-09-18 Merck & Co., Inc. Method of treatment or prevention of obesity
US6793240B2 (en) 2002-07-25 2004-09-21 Autoliv Asp, Inc. Expandable section for inflatable curtains
AU2003269242A1 (en) 2002-10-11 2004-05-04 Astrazeneca Ab 1,4-disubstituted piperidine derivatives and their use as 11-betahsd1 inhibitors
KR20050059294A (en) 2002-10-24 2005-06-17 스테릭스 리미티드 Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1 and type 2
US20040122033A1 (en) * 2002-12-10 2004-06-24 Nargund Ravi P. Combination therapy for the treatment of obesity
US7348456B2 (en) * 2002-12-19 2008-03-25 Merck & Co., Inc. Substituted amides
JO2397B1 (en) * 2002-12-20 2007-06-17 ميرك شارب اند دوم كوربوريشن Triazole Derivatives As Inhibitors Of 11-Beta -Hydroxysteriod Dehydrogenase-1
TW200503994A (en) 2003-01-24 2005-02-01 Novartis Ag Organic compounds
US20060094699A1 (en) * 2003-04-11 2006-05-04 Kampen Gita Camilla T Combination therapy using an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor and a glucocorticoid receptor agonist to minimize the side effects associated with glucocorticoid receptor agonist therapy
EP1615697A2 (en) 2003-04-11 2006-01-18 Novo Nordisk A/S New pyrazolo[1,5-a] pyrimidine derivatives and pharmaceutical use thereof
JP2006522745A (en) 2003-04-11 2006-10-05 ノボ　ノルディスク　アクティーゼルスカブ Pharmaceutical use of substituted 1,2,4-triazoles
US7501405B2 (en) * 2003-04-11 2009-03-10 High Point Pharmaceuticals, Llc Combination therapy using an 11β-hydroxysteroid dehydrogenase type 1 inhibitor and an antihypertensive agent for the treatment of metabolic syndrome and related diseases and disorders
JP2006522747A (en) * 2003-04-11 2006-10-05 ノボ　ノルディスク　アクティーゼルスカブ Pharmaceutical use of condensed 1,2,4-triazole
JP2006522750A (en) 2003-04-11 2006-10-05 ノボ　ノルディスク　アクティーゼルスカブ Combination therapy using 11β-hydroxysteroid dehydrogenase type 1 inhibitors and antihypertensive agents to treat metabolic syndrome and related diseases and disorders
US7700583B2 (en) * 2003-04-11 2010-04-20 High Point Pharmaceuticals, Llc 11β-hydroxysteroid dehydrogenase type 1 active compounds
US20060100235A1 (en) * 2003-04-11 2006-05-11 Novo Nordisk A/S Pharmaceutical use of substituted 1,2,4-triazoles
CA2534221A1 (en) 2003-08-07 2005-02-24 Merck & Co., Inc. Pyrazole carboxamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1
WO2005042513A1 (en) 2003-10-23 2005-05-12 Sterix Limited Phenyl carboxamide and sulfonamide derivatives for use as 11-beta-hydroxysteroid dehydrogenase
GB0325745D0 (en) 2003-11-05 2003-12-10 Astrazeneca Ab Chemical compounds
GB0326029D0 (en) 2003-11-07 2003-12-10 Astrazeneca Ab Chemical compounds
AU2004305321A1 (en) 2003-12-19 2005-07-07 Pfizer Inc. Benzenesulfonylamino-pyridin-2-yl derivatives and related compounds as inhibitors of 11-beta-hydroxysteroid dehydrogenase type 1 (11-beta-hsd-1) for the treatment of diabetes and obesity
JP2007261945A (en) 2004-04-07 2007-10-11 Taisho Pharmaceut Co Ltd Thiazole derivative
GB0408771D0 (en) 2004-04-20 2004-05-26 Sterix Ltd Compound
US20050261302A1 (en) * 2004-04-29 2005-11-24 Hoff Ethan D Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme and their therapeutic application
EP1745019A1 (en) 2004-05-06 2007-01-24 Pfizer Inc. Novel compounds of proline and morpholine derivatives
MY148480A (en) 2004-05-24 2013-04-30 Amgen Inc Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
NZ551602A (en) * 2004-06-24 2010-11-26 Incyte Corp Amido compounds and their use as pharmaceuticals
US20050288317A1 (en) 2004-06-24 2005-12-29 Wenqing Yao Amido compounds and their use as pharmaceuticals
US7687665B2 (en) 2004-06-24 2010-03-30 Incyte Corporation 2-methylprop anamides and their use as pharmaceuticals
EP1758580A4 (en) * 2004-06-24 2008-01-16 Incyte Corp N-substituted piperidines and their use as pharmaceuticals
WO2006012227A2 (en) 2004-06-24 2006-02-02 Incyte Corporation Amido compounds and their use as pharmaceuticals
EP1773773A4 (en) 2004-06-24 2009-07-29 Incyte Corp Amido compounds and their use as pharmaceuticals
PT1773768T (en) 2004-07-30 2018-11-30 Exelixis Inc Pyrrole derivatives as pharmaceutical agents
US7915252B2 (en) 2004-08-06 2011-03-29 Merck Sharp & Dohme Sulfonyl compounds as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1
BRPI0514230A (en) 2004-08-10 2008-06-03 Incyte Corp starch compounds and their use as pharmaceuticals
EP1786774B1 (en) 2004-08-30 2009-10-14 Janssen Pharmaceutica N.V. Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
UA87328C2 (en) 2004-08-30 2009-07-10 Янссен Фармацевтика Н.В. N-2 adamantanyl-2-phenoxy-acetamide derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
JP2008515956A (en) 2004-10-12 2008-05-15 ノボ ノルディスク アクティーゼルスカブ 11.beta.-hydroxysteroid dehydrogenase type 1 active spiro compound
EP1807072B1 (en) 2004-10-29 2009-01-07 Eli Lilly And Company Cycloalkyl lactam derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
EP1812407A2 (en) 2004-11-02 2007-08-01 Pfizer, Inc. Novel compounds of substituted and unsubstituted adamantyl amides
EP1659113A1 (en) 2004-11-08 2006-05-24 Evotec AG Inhibitors of 11beta-hydroxy steroid dehydrogenase type 1 (11beta-HSD1)
EP1666467A1 (en) 2004-11-08 2006-06-07 Evotec AG 11Beta-HSD1 Inhibitors
EP1655283A1 (en) 2004-11-08 2006-05-10 Evotec OAI AG 11beta-HSD1 Inhibitors
NZ554906A (en) 2004-11-10 2011-01-28 Incyte Corp Lactam compounds and their use as pharmaceuticals
EP1888544A2 (en) 2004-12-17 2008-02-20 Takeda San Diego, Inc. Hydroxysteroid dehydrogenase inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004056744A1 (en) * 2002-12-23 2004-07-08 Janssen Pharmaceutica N.V. Adamantyl acetamides as hydroxysteroid dehydrogenase inhibitors
WO2004089470A2 (en) * 2003-04-11 2004-10-21 Novo Nordisk A/S New amide derivatives and pharmaceutical use thereof
US20050245534A1 (en) * 2004-04-29 2005-11-03 Link James T Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
US20050277647A1 (en) * 2004-04-29 2005-12-15 Link James T Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8952176B2 (en) 2005-06-07 2015-02-10 Shionogi & Co., Ltd. Heterocyclic compound having type I 11 β hydroxysteroid dehydrogenase inhibitory activity
US8324265B2 (en) 2005-11-21 2012-12-04 Shionogi & Co., Ltd. Heterocyclic compounds having type I 11β hydroxysteroid dehydrogenase inhibitory activity
US8017638B2 (en) 2006-03-30 2011-09-13 Shionogi & Co., Ltd. Isoxazole derivative and isothiazole derivative having inhibitory activity on 11β-hydroxysteroid dehydrogenase type 1
EP2351568A2 (en) 2006-05-04 2011-08-03 Boehringer Ingelheim International GmbH Uses of dpp-iv inhibitors
WO2007128761A2 (en) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Uses of dpp-iv inhibitors
JP2010501589A (en) * 2006-08-24 2010-01-21 ブリストル−マイヤーズ スクイブ カンパニー Cyclic 11-β hydroxysteroid dehydrogenase type I inhibitor
JP2010526777A (en) * 2007-04-24 2010-08-05 ハイ ポイント ファーマシューティカルズ，リミティド ライアビリティ カンパニー Pharmaceutical use of substituted amides
EP2150109A4 (en) * 2007-04-24 2011-05-04 High Point Pharmaceuticals Llc Pharmaceutical use of substituted amides
EP2150109A1 (en) * 2007-04-24 2010-02-10 High Point Pharmaceuticals, LLC Pharmaceutical use of substituted amides
CN101711106B (en) * 2007-04-24 2013-02-06 高点制药有限责任公司 Pharmaceutical use of substituted amides
WO2008142986A1 (en) 2007-05-18 2008-11-27 Shionogi & Co., Ltd. NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE HAVING 11 β-HYDROXYSTEROID DEHYDROGENASE TYPE I INHIBITORY ACTIVITY
JPWO2008142986A1 (en) * 2007-05-18 2010-08-05 塩野義製薬株式会社 Nitrogen-containing heterocyclic derivatives having type I 11β-hydroxysteroid dehydrogenase inhibitory activity
CN103288738B (en) * 2007-05-18 2016-03-16 盐野义制药株式会社 There is the nitogen-contained heterocycle derivant of 11beta-Hydroxysteroid dehydrogenase I type inhibit activities
CN101754954B (en) * 2007-05-18 2015-11-25 盐野义制药株式会社 There is the nitogen-contained heterocycle derivant of 11beta-Hydroxysteroid dehydrogenase I type inhibit activities
US8383622B2 (en) 2007-05-18 2013-02-26 Shionogi & Co., Ltd. Nitrogen-containing heterocyclic derivative having 11β-hydroxysteroid dehydrogenase type I inhibitory activity
CN103288738A (en) * 2007-05-18 2013-09-11 盐野义制药株式会社 Nitrogen-containing heterocyclic derivative having 11 beta-hydroxysteroid dehydrogenase type I inhibitory activity
JP4671369B2 (en) * 2007-05-18 2011-04-13 塩野義製薬株式会社 Nitrogen-containing heterocyclic derivatives having type I 11β-hydroxysteroid dehydrogenase inhibitory activity
US8822149B2 (en) 2007-05-24 2014-09-02 Pacific Edge Limited Prognosis prediction for melanoma cancer
JP5605844B2 (en) * 2008-10-17 2014-10-15 塩野義製薬株式会社 Acetic acid amide derivatives having vascular endothelial lipase inhibitory activity
US8957219B2 (en) 2008-10-17 2015-02-17 Shionogi & Co., Ltd. Acetic acid amide derivative having inhibitory activity on endothelial lipase
JPWO2010044441A1 (en) * 2008-10-17 2012-03-15 塩野義製薬株式会社 Acetic acid amide derivatives having vascular endothelial lipase inhibitory activity
WO2010044441A1 (en) * 2008-10-17 2010-04-22 塩野義製薬株式会社 Acetic acid amide derivative having inhibitory activity on vascular endothelial lipase

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ZA200705468B (en) 2010-03-31
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BRPI0606228A2 (en) 2009-06-09
CN101142172A (en) 2008-03-12
JP2008526874A (en) 2008-07-24
US7528282B2 (en) 2009-05-05
WO2006074330A3 (en) 2007-01-25
USRE41135E1 (en) 2010-02-16
NZ555971A (en) 2011-01-28
AU2006203918B2 (en) 2011-05-19
IL184329A0 (en) 2007-10-31
JP5133702B2 (en) 2013-01-30
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US20060149070A1 (en) 2006-07-06
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CN102816081A (en) 2012-12-12
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