FORM 2
The Patents Act, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
"ADAMANTYL-ACETAMIDE DERIVATIVES AS INHIBITORS OF THE 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1 ENZYME"
Abbott Laboratories, a company incorporated in the U.S.A. having its Registered Office at Dept. 377 Bldg. AP6A-1, 100 Abbott Park Road, Abbott Park, IL 60064-6008, USA.
The following specification particularly describes the invention and the manner in which it is to be performed

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ADAMANTYL-ACETAMIDE DERIVATIVES AS INHIBITORS OF THE H-BETA-HYDROXYSTEROID DEHY DROGENASE TYPE 1 ENZYME 5
Field of invention
The present invention relates to compounds which are inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme. The present invention further relates to the 10 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.
15 Background of the Invention
Insulin is a hormone which 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
20 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
25 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.,
30 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 macrovascular and/or microvascular complications including atherosclerosis, coronary heart disease, peripheral vascular disease, stroke, nephropathy, neuropathy, and retinopathy.
35 Insulin resistance, even in the absence of profound hyperglycemia, is a component of
the metabolic syndrome. Recently, diagnostic criteria for metabolic syndrome have been
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established. To qualify a patient as having metabolic syndrome, three out of the five following criteria must be met: elevated bbod 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
5 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.
10 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.
15 This may be 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
20 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
25 (e.g., nausea or diarrhea).
Alpha-ghicosidase 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.
30 Glitazones (i.e., 5-benzylthiazoUdine-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
3 5 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
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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-1") analogues and inhibitors
5 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-IB, or "PTP-IB").
Another method of treating or prophylactically treating diabetes mellitus includes
10 using inhibitors of 11-3-hydroxysteroid dehydrogenase Type 1 (1 1P-HSD1). 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 hypertensioa Glucocorticoids circulate in
IS the blood in an active form (Le., Cortisol in humans) and an inactive form (Le., cortisone in humans). 11 P-HSD 1, which is highly expressed in liver and adipose tissue, converts cortisone to Cortisol leading to higher local concentration of Cortisol Inhibition of 11P-HSD1 prevents or decreases the tissue specific amplification of glucocorticoid action thus imparting beneficial effects on blood pressure and glucose- and lipid-metabolism.
20 Thus, inhibiting 11 P-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 actioa
Summary of the Invention
25 One aspect of the present invention is directed toward a compound of formula (I)
A2
ca
wherein
or therapeutically acceptable salt or prodrug thereof, wherein
30 A1, A2, A3, and A4 are each independently selected from the group consisting of
hydrogen, alkyl, alkyl-NH-aflcyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfbnyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl, aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyL, -NR7-[C(R8 R9)]„-C(0)-R10, -
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0-[C(RMR12)]p-C(0)-R13, -OR14, -N(R,5R16), -COaR17, -C(0)-N(R18R19), -C(R20R21)-OR22,
and-CCR^R^NCR2^26);
n is 0 or 1;
p is 0 or 1;
5 R1 and R2 are each independently selected from the group consisting of hydrogen,
alkyl, alkoxyalkyl, alkyl-NH-alkyl, aryloxyalkyl, aryl-NH-alkyl, carboxyalkyl,
carboxycycloalkyl, heterocycleoxyalkyl, heterocycle-NH-alkyl, cycloalkyl, aryl, arylalkyl,
haloalkyl, heterocycle, heterocyclealkyl, heterocycle-heterocycle, and aryl-heterocycle, or
R'and R2 together with the atom to which they are attached form a heterocycle;
10 R3 and R4 are each independently selected from the group consisting of hydrogen,
alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and heterocycle, or R3 and R4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
or R and R together with the atoms to which they are attached form a non-aromatic
15 heterocycle;
R5 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R6 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, 20 cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R7 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl,
carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxy, hydroxy, alkoxy, cycloalkyloxy,
heterocycleoxy, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
25 R8 and R9 are each independently selected from the group consisting of hydrogen,
alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl,
heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or R8 and R9 together with the atom
to which they are attached form a ring selected from the group consisting of cycloalkyl and
non-aromatic heterocycle;
30 R10 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl,
cycloalkyl, carboxycycloalkyl, aryl, aryloxy, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -N(R27R28);
RuandR12 are each independently selected from the group consisting of hydrogen,
35 alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl,
heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or R11 and R12 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and
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non-aromatic heterocycle;
R13 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -5 N(R29R30);
R14 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R15andR16 are each independently selected from the group consisting of hydrogen, 10 alkyl, carboxyalkyl, cycloalkyl, caiboxycycbalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, 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, 15 carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R18andR19 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, 20 hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R18 and R19 together with the atom to which they are attached form a non-aromatic heterocycle;
R20, R21 and R22 are each independently selected from the group consisting of
hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and
25 heterocycle;
R23 and R24 are each independently selected from the group consisting of hydrogen,
alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl,
cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl,
cycloalkyl, aryl, and heterocycle;
30 R25andR26 are each independently selected from the group consisting of hydrogen,
alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl,
cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl,
hydroxy, alkoxy, cycloalkyloxy, aryloxy, heterocycleoxy, cycloalkyl, aryl, and heterocycle,
or R25 and R26 together with the atom to which they are attached form a heterocycle;
35 R27andR28 are each independently selected from the group consisting of hydrogen,
alkyl, carboxy, carboxyalkyl, cycbalkyl, cycbalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy,
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hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R27 and R28 together with the atom to which they are attached form a non-aromatic heterocycle; and
R2 and R30 are each independently selected from the group consisting of hydrogen,
5 alkyl, carboxy, carboxyalkyi, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyi,
aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R29 and R30 together with the atom to which they are attached form a non-aromatic heterocycle;
10 provided that if R6 is hydrogen, then at least one of A1, A2, A3 and A4 is not hydrogen.
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
15 that are mediated by excessive glucocorticoid action.
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.
20 Detailed description 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)
w
A3 R6R5 R4 R3
A1-4-LJ^A4o Ri A2
25 ax
wherein
or therapeutically acceptable salt or prodrug thereof, wherein A1, A2, A3, and A4 are each independently selected from the group consisting of hydrogen, alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, 30 cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl,
heterocyclesulfonyl, aryl, arylalkyi, aryloxyalkyl, carboxyalkyi, carboxycycloalkyl, halogen, haloalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, -NR7-[C(R8 R9)]„-C(0)-R10, -0-[C(RnR12)]p-C(0)-R13, -OR14, -N(R15R16), -C02R17, -C(0)-N(R18R19), -C(R20R21)-OR22, and -C(R23R24)-N(R25R26);
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nisOorl; pisOor 1;
R1 and R2 are each independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkyl-NH-alkyl, aryloxyalkyl, aryl-NH-alkyl, carboxyalkyl, 5 carboxycycloalkyl, heterocycleoxyalkyl, heterocycle-NH-alkyl, cyctoalkyl, aryl, arylalkyl, haloalkyl, heterocycle, heterocyclealkyl, heterocycle-heterocycle, and aryl-heterocycle, or R'and R2 together with the atom to which they are attached form a heterocycle;
R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and heterocycle, or R3 10 and R4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
or R2 and R3 together with the atoms to which they are attached form a non-aromatic heterocycle;
R5 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, 15 carboxycycloalkyl, cycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R6 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl,
cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl,
and heterocycleoxyalkyl;
20 R7 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl,
carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxy, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R8 and R9 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cyctoalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, 25 heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or R8 and R9 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R10 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cyctoalkyl, carboxycycloalkyl, aryl, aryloxy, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, 30 cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -N(R27R2S);
RnandR12 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, orRn and R12 together with the atom 35 to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R13 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl,
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cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyi, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -NCR^R30);
R is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl,
5 carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyi, haloalkyl, heterocycle, heterocyclealkyl, and
heterocycleoxyalkyl;
R15 and R16 ' are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycyctoalkyl, aryl, arylalkyl, aryloxyalkyi, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and 10 heterocyclesulfonyl, 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, aryloxyalkyi, heterocycle, heterocyclealkyl, and
heterocycleoxyalkyl;
15 R18 and R19 are each independently selected from the group consisting of hydrogen,
alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyi, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or Ru and R19 together with the atom to which they are attached form a non-aromatic 20 heterocycle;
R20, R21 and R22 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and heterocycle;
R23 and R24 are each independently selected from the group consisting of hydrogen, 25 alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, cycloalkyl, aryl, and heterocycle;
R2S and R26 are each independently selected from the group consisting of hydrogen,
alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl,
30 cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl,
hydroxy, alkoxy, cycloalkyloxy, aryloxy, heterocycleoxy, cycloalkyl, aryl, and heterocycle, or R25 and R26 together with the atom to which they are attached form a heterocycle;
R27 and R28 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, 35 aryloxy, aryloxyalkyi, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R27 and R28 together with the atom to which they are attached form a non-aromatic
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heterocycle; and
R^andR30 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cyctoalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, 5 hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R29 and R30 together with the atom to which they are attached form a non-aromatic heterocycle;
provided that if R6 is hydrogen, then at least one of A1, A2, A3 and A4 is not hydrogen.
Another aspect of the present invention is directed toward a therapeutically suitable 10 metabolite of a compound of formula (I).
Another aspect of the present invention is directed to a compound of formula (II)
H R4.R3
-crfi*
(H),
15 or a therapeutically suitable salt or prodrug thereof, wherein
A1 is selected'from the group consisting of alkyl, alkyl-NH-alkyl, alkylcarbonyl, aikylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl, aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, -20 NR7-[C(R8 R9)]„-C(0)-R10, -0-[C(R"R12)]p-C(0)-R13, -OR14, -N(R15R16), -C02R17, -C(0)-N(Rl8R19), -C^V^-OR22, and -CCR^-NCR^R2*);
R1 and R2 are each independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkyl-NH-alkyl, aryloxyalkyl, aryl-NH-alkyl, carboxyalkyl, carboxycycloalkyl, heterocycleoxyalkyl, heterocycle-NH-alkyl, cycloalkyl, aryl, arylalkyl, 25 haloalkyl, heterocycle, heterocyclealkyl, heterocycle-heterocycle, and aryl-heterocycle, or R1 and R2 together with the atom to which they are attached form a heterocycle;
R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and heterocycle, or R3 and R4 together with the atom to which they are attached form a ring selected from the group 30 consisting of cycloalkyl and non-aromatic heterocycle;
or R2 and R3 together with the atoms to which they are attached form a non-aromatic heterocycle;
R7 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxy, hydroxy, alkoxy, cycloalkyloxy, 35 heterocycleoxy, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
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R8 and R9 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyi, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyi, or R8 and R9 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and 5 non-aromatic heterocycle;
R10 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyi, aryl, aryloxy, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyi, and -N(R27R28);
10 R1! and R12 are each independently selected from the group consisting of hydrogen,
alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyi, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyi, or Ru and R12 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
15 R13 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl,
cycloalkyl, carboxycycloalkyi, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyi, and -N(R29R30);
R14 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl,
20 carboxycycloalkyi, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyi;
R15 and R16 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyi, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyi, alkylsufonyl, cycloalkylsulfonyl, arylsulfbnyl, and
25 heterocyclesulfonyl, 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, carboxycycloalkyi, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyi;
30 R18 and R19 are each independently selected from the group consisting of hydrogen,
alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyi, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyi, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfbnyl, and heterocyclesulfonyl, or R18 and R19 together with the atom to which they are attached form a non-aromatic
35 heterocycle;
R20, R21 and R22 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyi, cycloalkyl, haloalkyl, aryl, and
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heterocycle;
R23 and R24 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, 5 cycloalkyl, aryl, and heterocycle;
R25andR26 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcaifconyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, hydroxy, alkoxy, cycloalkyloxy, aryloxy, heterocycleoxy, cycloalkyl, aryl, and heterocycle, 10 or R25 and R26 together with the atom to which they are attached form a heterocycle;
R27andR28 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 15 R27 and R28 together with the atom to which they are attached form a non-aromatic heterocycle; and
R29 and R30 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, 20 hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R29 and R30 together with the atom to which they are attached form a non-aromatic heterocycle.
Another aspect of the present invention is directed to a compound of formula (HI),
H R4 R3
25
(in),
30
or a therapeutically suitable salt or prodrug thereof, wherein A1 is selected from the group consisting of alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl, aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, -NR7-[C(R8 R9)]„-C(0)-R10, -0-[C(RuR,2)]p-C(0)-R13, -OR14, -N(R15R16), -C02R17, -C(0)-N(R18R19), -C(R20R2l)-OR22, and -CCR^R^-NCR^R26);
35
R1 and R2 are each independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkyl-NH-alkyl, aryloxyalkyl, aryl-NH-alkyl, carboxyalkyl,
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carboxycycloalkyl, heterocycleoxyalkyl, heterocycle-NH-alkyl, cycloalkyl, aryl, arylalkyl, haloalkyl, heterocycle, heterocyciealkyl, heterocycle-heterocycle, and aryl-heterocycle;
R* and R* are each independently selected from the group consisting of hydrogen,
alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, aryl, and heterocycle;
5 R is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl,
carboxycycloalkyl, aryl, arylalkyl, arytoxyalkyl, aryloxy, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyciealkyl, and heterocycleoxyalkyl;
R8 and R9 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, arytoxyalkyl, 10 heterocycle, heterocyciealkyl, and heterocycleoxyalkyl, or R8 and R9 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R10 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl,
cycloalkyl, carboxycycloalkyl, aryl, aryloxy, arylalkyl, arytoxyalkyl, hydroxy, alkoxy,
15 cycloalkyloxy, heterocycleoxy, heterocycle, heterocyciealkyl, heterocycleoxyalkyl, and -
N(R27R28);
RnandR12 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, arytoxyalkyl, heterocycle, heterocyciealkyl, and heterocycleoxyalkyl, or R11 and R12 together with the atom 20 to which they are attached form a group consisting of cycloalkyl and non-aromatic heterocycle;
R13 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyciealkyl, heterocycleoxyalkyl, and -25 N(R29R3°);
R14 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, arytoxyalkyl, haloalkyl, heterocycle, heterocyciealkyl, and heterocycleoxyalkyl;
R15 and R16 are each independently selected from the group consisting of hydrogen, 30 alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyciealkyl, heterocycleoxyalkyl, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R13 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, 35 carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyciealkyl, and heterocycleoxyalkyl;
R18 and R19 are each independently selected from the group consisting of hydrogen,
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alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R18 and R19 together with the atom to which they are attached form a non-aromatic 5 heterocycle;
R20, R21 and R22 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and heterocycle;
R23 and R24 are each independently selected from the group consisting of hydrogen,
10 alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, cycloalkyl, aryl, and heterocycle;
R2S and R26 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl,
15 cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl,
hydroxy, alkoxy, cycloalkyloxy, aryloxy, heterocycleoxy, cycloalkyl, aryl, and heterocycle, or R25 and R26 together with the atom to which they are attached form a heterocycle;
R27 and R28 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl,
20 aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R27 and R28 together with the atom to which they are attached form a non-aromatic heterocycle; and
R29 and R30 are each independently selected from the group consisting of hydrogen,
25 alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cyctoalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R29 and R30 together with the atom to which they are attached form a non-aromatic heterocycle.
30 Another aspect of the present invention is directed to a compound of formula (IV),
w R*R3
(IV),
or a therapeutically suitable salt or prodrug thereof, wherein
35 A1 is selected from the group consisting of alkyl, alkyl-NH-alkyl, alkylcarbonyl,
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alkyfeulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl, aryloxyalkyl, carboxyalkyi, carboxycycloalkyl, halogen, haloalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, -NR7-[C(R8 R9)]n-C(0)-R10, -0-[C(RuR12)]p-C(0)-R13, -OR14, -N(RISR16), -CO2R17, -C(0)-5 N(R,8R19), -C(R20R2,)-OR22, and -CCR^^NO^R26); D is a non-aromatic heterocycle;
R andR are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyi, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl and heterocycle, orR3 and R4 together with the atom to which they are attached form a ring selected from the group 10 consisting of cycloalkyl and non-aromatic heterocycle;
R7 is selected from the group consisting of hydrogen, alkyl, carboxyalkyi, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxy, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R8andR9 are each independently selected from the group consisting of hydrogen,
15 alkyl, carboxy, carboxyalkyi, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl,
heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or R8 and R9 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R10 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyi, 20 cycloalkyl, carboxycycloalkyl, aryl, aryloxy, arylalkyl, aryloxyalkyl, hydroxy, alkoxy,
cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -N(R27R28);
R11 and R12 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyi, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, 25 heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or R11 and R12 together with the
atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R13 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyi, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, 30 cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -N(R29R30);
R14 is selected from the group consisting of hydrogen, alkyl, carboxyalkyi, cycloalkyl,
carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, habalkyi, heterocycle, heterocyclealkyl, and
heterocycleoxyalkyl;
35 R15 and R16 are each independently selected from the group consisting of hydrogen,
alkyl, carboxyalkyi, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and
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heterocyclesulfonyl, or R1S 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, heterocycle, heterocyclealkyl, and 5 heterocycleoxyalkyl;
R18andR19 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 10 R18 and R19 together with the atom to which they are attached form a non-aromatic heterocycle;
R20, R21 and R22 are each independently selected from the group consisting of
hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and
heterocycle;
15 R23 and R24 are each independently selected from the group consisting of hydrogen,
alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, cycloalkyl, aryl, and heterocycle;
R25 and R26 are each independently selected from the group consisting of hydrogen, 20 alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, hydroxy, alkoxy, cycloalkyloxy, aryloxy, heterocycleoxy, cycloalkyl, aryl, and heterocycle, or R23 and R26 together with the atom to which they are attached form a heterocycle;
R27 and R28 are each independently selected from the group consisting of hydrogen,
25 alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl,
aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy,
hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or
R27 and R28 together with the atom to which they are attached form a non-aromatic
heterocycle; and
30 R29 and R30 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
R29 and R30 together with the atom to which they are attached form a non-aromatic
35 heterocycle.
Another aspect of the present invention is directed to a compound of formula (V),
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H R4 R3
*&ftX
(V),
or a therapeutically suitable salt or prodrug thereof, wherein
A1 is selected from the group consisting of alkyl, alkyl-NH-alkyl, alkylcarbonyl,
5 alkylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl,
heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl, aryloxyalkyl, carboxyalkyl,
carboxycycloalkyl, halogen, hatoalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, -
NR7-[C(R8 R9)]„-C(0)-R10, -0-[C(RHR,2)]p-C(0)-R13, -OR14, -N(R15R16), -C02R17, -C(0>
N(R,8R19), -CCR^R^-OR22, and -CCR^R24)-^2^26);
10 G is selected from the group consisting of aryl and heterocycle;
R3andR4 are each independently selected from the group consisting of hydrogen,
alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and heterocycle, or R3
and R4 together with the atom to which they are attached form a ring selected from the group
consisting of cycloalkyl and non-aromatic heterocycle;
15 R7 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl,
carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxy, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R8 and R9 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, 20 heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or R8 and R9 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R10 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl,
cycloalkyl, carboxycycloalkyl, aryl, aryloxy, arylalkyl, aryloxyalkyl, hydroxy, alkoxy,
25 cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -
N(R27R28);
, R11 and R12 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or R11 and R12 together with the atom 30 to which they are attached form a non-aromatic heterocycle;
R13 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl,
cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy,
cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -
N(R29R30);
35 R14 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl,
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carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R15andR16 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cyctoalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle,
5 heterocyclealkyl, heterocycleoxyalkyl, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, 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, cyctoalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and
10 heterocycleoxyalkyl;
R18 and R19 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cyctoalkyl, cycloalkytoxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or
15 R18 and R19 together with the atom to which they are attached form a non-aromatic heterocycle;
R20, R21 and R22 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cyctoalkyl, haloalkyl, aryl, and heterocycle;
20 R23 and R24 are each independently selected from the group consisting of hydrogen,
alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, cyctoalkyl, aryl, and heterocycle;
R25 and R26 are each independently selected from the group consisting of hydrogen,
25 alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, hydroxy, alkoxy, cycloalkytoxy, aryloxy, heterocycleoxy, cyctoalkyl, aryl, and heterocycle, or R25 and R26 together with the atom to which they are attached form a heterocycle;
R27 and R28 are eadfcindependently selected from the group consisting of hydrogen,
30 alkyl, carboxy, carboxyalkyl, cyctoalkyl, cycloalkytoxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyli heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R27 and R28 together with the atom to which they are attached form a non-aromatic heterocycle; and
35 R29 and R30 are each independently selected from the group consisting of hydrogen,
alkyl, carboxy, carboxyalkyl, cyctoalkyl, cycloalkytoxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy,
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hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R29 and R30 together with the atom to which they are attached form a non-aromatic heterocycle.
Another aspect of the present invention is directed to a compound of formula (VI), 5
H R4 R3
(VI),
or a therapeutically suitable salt or prodrug thereof, wherein
A1 is selected from the group consisting of alkyl, alkyl-NH-alkyl, alkylcarbonyl,
10 alkylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl,
heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl, aryloxyalkyl, carboxyalkyl,
carboxycycloalkyl, halogen, haloalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, -
NR7-[C(R8 R9)]n-C(0)-R10, -0-[C(RuR12)]p-C(0)-R13, -OR14, -N(R15R16), -COaR17, -C(0)-
N(R18R19), -CCR^R^-OR22, and -CCR^R^NCR^R2*);
15 R3 and R4 are each independently selected from the group consisting of hydrogen,
alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and heterocycle, or R3 and R4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R7 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, 20 carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxy, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R8 and R9 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or R8 and R9 together with the atom 25 to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R10 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, aryloxy, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -30 N(R27R28);
Rn and R12 are each independently selected from the group consisting of hydrogen,
alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl,
heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or R11 and R12 together with the atom
to which they are attached form a non-aromatic heterocycle;
35 R13 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl,
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cycloalkyl, carboxycycloalkyi, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy,
cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -
N(R29R30);
R is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, 5 carboxycycloalkyi, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heterocycle, heterocyclealkyl, and
heterocycleoxyalkyl;
R"andR" ' are each independently selected from the group consisting of hydrogen,
alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyi, aryl, arylalkyl, aryloxyalkyl, heterocycle,
heterocyclealkyl, heterocycleoxyalkyl, alkylsufonyl, cycloalkylsulfonyl, arylsulfbnyl, and 10 heterocyclesulfonyl, or R13 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,
carboxycycloalkyi, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and
heterocycleoxyalkyl;
15 R18andR19 are each independently selected from the group consisting of hydrogen,
alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyi, aryl, arylalkyl,
aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy,
hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfbnyl, and heterocyclesulfonyl, or
R18 and R19 together with the atom to which they are attached form a non-aromatic 20 heterocycle;
R20, R21 and R22 are each independently selected from the group consisting of
hydrogen, alkyl, carboxyalkyl, carboxycycloalkyi, cycloalkyl, haloalkyl, aryl, and
heterocycle;
R23 and R24 are each independently selected from the group consisting of hydrogen, 25 alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyi, cycloalkylcarbonyl,
cycloalkylsulfonyl, arylcarbonyl, arylsulfbnyl, heterocyclecarbonyl, heterocyclesulfonyl,
cycloalkyl, aryl, and heterocycle;
R2S and R26 are each independently selected from the group consisting of hydrogen,
alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyi, cycloalkylcarbonyl, 30 cycloalkylsulfonyl, arylcarbonyl, arylsulfbnyl, heterocyclecarbonyl, heterocyclesulfonyl,
hydroxy, alkoxy, cycloalkyloxy, aryloxy, heterocycleoxy, cycloalkyl, aryl, and heterocycle,
or R25 and R26 together with the atom to which they are attached form a heterocycle;
R27 and R28 are each independently selected from the group consisting of hydrogen,
alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyi, aryl, arylalkyl, 35 aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy,
hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfbnyl, and heterocyclesulfonyl, or
R27 and R28 together with the atom to which they are attached form a non-aromatic
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heterocycle;
R™ and RJ0 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyi, heterocycleoxyalkyl, heterocycleoxy, 5 hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R2 and R30 together with the atom to which they are attached form a non-aromatic heterocycle; and
R31 is selected from the group consisting of alkyl, alkoxy, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkoxy, halogen, haloalkyl, heterocycle, heterocyclealkyi, heterocycleoxy, 10 heterocycleoxyalkyl and hydroxy.
Another aspect of the present invention is directed to a compound of formula (VII),
H R4 R3
^grs
(vn),
15 or a therapeutically suitable salt or prodrug thereof, wherein
A1 is selected from the group consisting of alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, cycbalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl, aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl, heterocycle, heterocyclealkyi, heterocycleoxyalkyl, -20 NR7-[C(R8 R9)]n-C(0)-R10, -0-[C(RnR12)]p-C(0)-R13, -OR14, -N(RI5R16), -COaR17 -C(O)-N(R,8R19), -C^V^-OR22, and -CCR^^-N^R26);
R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and heterocycle, or R3 and R4 together with the atom to which they are attached form a ring selected from the group 25 consisting of cycloalkyl and non-aromatic heterocycle;
R7 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxy, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyi, and heterocycleoxyalkyl;
R8 and R9 are each independently selected from the group consisting of hydrogen, 30 alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyi, and heterocycleoxyalkyl, or R8 and R9 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R10 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, 35 cycloalkyl, carboxycycloalkyl, aryl, aryloxy, arylalkyl, aryloxyalkyl, hydroxy, alkoxy,
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cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -NCR^R28);
R and R12 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, 5 heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or Rn and R12 together with the atom to which they are attached form a non-aromatic heterocycle;
R is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -10 N(R29R30);
R is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R1 and R16 are each independently selected from the group consisting of hydrogen, 15 alkyl, carboxyalkyl, cycbalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, 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, 20 carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R18 and R19 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, 25 hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R18 and R19 together with the atom to which they are attached form a non-aromatic heterocycle;
R20, R21 and R22 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and 30 heterocycle;
R23 and R24 are each independently selected from the group consisting of hydrogen,
alkyl, alkylcarbonyl, alkylsulfonyi, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl,
cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl,
cycloalkyl, aryl, and heterocycle;
3 5 R2i and R26 are each independently selected from the group consisting of hydrogen,
alkyl, alkylcarbonyl, alkylsulfonyi, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl,
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hydroxy, alkoxy, cycbalkytoxy, aryloxy, heterocycleoxy, cycloalkyl, aryl, and heterocycle, or R25 and R26 together with the atom 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, cycbalkytoxy, carboxycycloalkyl, aryl, arylalkyl, 5 aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfbnyl, arylsulfonyl, and heterocyclesulfonyl, or R27 and R28 together with the atom to which they are attached form a non-aromatic heterocycle;
R29andR30 are each independently selected from the group consisting of hydrogen,
10 alkyl, carboxy, carboxyalkyl, cycbalkyl, cycloalkyfoxy, carboxycycloalkyl, aryl, arylalkyl,
aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy,
hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfbnyl, arylsulfonyl, and heterocyclesulfonyl, or
R29 and R30 together with the atom to which they are attached form a non-aromatic
heterocycle; and
15 R31 is selected from the group consisting of alkyl, alkoxy, aryl, arylalkyl, aryloxy,
aryloxyalkyl, cycloalkoxy, habgen, haloalkyl, heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl and hydroxy.
Another aspect of the present invention is directed to a compound of formula (VIII)

20

-JErrV

(VHD,
or a therapeutically suitable salt or prodrug thereof, wherein
A1 is selected from the group consisting of-OH, -COjH, carboxyalkyl,
carboxycyctoalkyl, and -C(0>N(RI8R19);
25 E is selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R1 and R2 are each independently selected from the group consisting of hydrogen,
alkyl, alkoxyalkyl, alkyl-NH-alkyl, aryloxyalkyl, aryl-NH-alkyl, carboxyalkyl,
carboxycycloalkyl, heterocycleoxyalkyl, heterocycle-NH-alkyl, cycloalkyl, aryl, arylalkyl,
haloalkyl, heterocycle, heterocyclealkyl, heterocycle-heterocycle, and aryl-heterocycle; and
30 R18 and R19 are each independently selected from the group consisting of hydrogen,
alkyl, carboxy, carboxyalkyl, cycloalkyl, cycbalkytoxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R18 and R19 together with the atom to which they are attached form a non-aromatic
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heterocycle.
Another aspect of the present invention is directed to a compound of formula (IX),
5 (IX),
or a therapeutically suitable salt or prodrug thereof, wherein
A1 is selected from the group consisting of-OH, -CO2H, carboxyalkyl,
carboxycycloalkyl, and -C(0)-N(R18R19);
D is a non-aromatic heterocycle;
10 E is selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
and
R18 and R19 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, 15 hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfbnyl, arylsulfonyl, and heterocyclesulfbnyl, or R18 and R19 together with the atom to which they are attached form a non-aromatic heterocycle.
Another aspect of the present invention is directed to a method of inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme, comprising administering to a mammal, a 20 therapeutically effective amount of a compound of formula (I, II, ID, IV, V, VI, VII, VTH or IX).
Another aspect of the present invention is directed to a method of treating or prophylactically treating disorders in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme, comprising administering to a mammal, a therapeutically 25 effective amount of a compound of formula (I, II, m, IV, V, VI, VII, VTH or IX).
Another aspect of the present invention is directed to a method of treating or prophylactically treating non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome or diseases and conditions that are mediated by excessive glucocorticoid action, in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase 30 Type I enzyme, comprising administering to a mammal, a therapeutically effective amount of a compound of formula Q, II, HI, IV, V, VI, VII, Vffl or IX).
Another aspect of the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I, n, m, IV, V, VI, VII, VET! or IX) in combination with a pharmaceutical^ suitable carrier.
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As set forth herein, the invention includes administering a therapeutically effective amount of any of the compounds of formula I-IX and the salts and prodrugs thereof to a mammal. Preferably, the invention also includes administering a therapeutically effective amount of any of the compounds of formula I-DC to a human, and more preferably to a 5 human in need of being treated for or prophylactically treated for any of the respective disorders set forth herein.
Definition nf Terms
The term "alkoxy," as used herein, refers to an alkyl group, as defined herein, 10 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. 15 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, 20 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, 25 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-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
30 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, 35 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.
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The term "aryl," as used herein, refers to a monocyclio-ring system or a polycyclic-ring system wherein one or more of the fused rings are aromatic. Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
5 The aryl groups of this invention may be optionally substituted with 0,1, 2, 3, 4 or 5
substituents independently selected from alkenyl, alkenylthio, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkoxy, alkylcarbonylalkyl, alkylcarbonylalkylthio, alkylcarbonytoxy,
10 alkylcarbonylthio, alkylsulfinyl, alkylsulfinylalkyl, alkyl sulfonyl, alkylsulfonylalkyl, alkyltbio, alkylthioalkyl, alkylthioalkoxy, alkynyl, alkynyloxy, alkynyltbio, aryl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkoxy, carboxyalkyl, cyano, cyanoalkoxy, cyanoalkyl, cyanoalkylthio, 1,3-dioxolanyl, dioxanyl, dithianyl, ethylenedioxy, formyl, formylalkoxy, formylalkyl, haloalkenyl, haloalkenyloxy, haloalkoxy, haloalkyl,
15 haloalkynyl, haloalkynyloxy, halogen, heterocycle, heterocyclecarbonyl, heterocycleoxy,
heterocyclsulfonyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, mercapto, mercaptoalkoxy, mercaptoalkyl, methylenedioxy, nitro, R^N-, RfRgNalkyl, R^RgNcarbonyl and RfRgNsulfonyl, wherein Rf and Rg are members independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkylcarbonyl, alkylsulfbnyl, alkoxycarbonyl,
20 cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl and cycfoalkylsulfonyl, and wherem
substituent aryl, the aryl of arylcarbonyl, the aryl of aryloxy, the aryl of arylsulfonyl, the substituent heterocycle, 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 alkenyl,
25 alkenylthio, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkoxy, alkylcarbonylalkyl, alkylcarbonylalkylthio, alkylcarbonyloxy, alkylcarbonylthio, alkylsulfinyl, alkylsulfinylalkyl, alkyl sulfonyl, alkylsulfonylalkyl, alkyltbio, alkylthioalkyl, alkylthioalkoxy, alkynyl, alkynyloxy,
30 alkynyltbio, carboxy, carboxyalkoxy, carboxyalkyl, cyano, cyanoalkoxy, cyanoalkyl, cyanoalkyhbio, ethylenedioxy, formyl, formylalkoxy, formylalkyl, haloalkenyl, haloalkenyloxy, haloalkoxy, haloalkyl, haloalkynyl, haloalkynyloxy, halogen, hydroxy, hydroxyalkoxy, hydroxyalkyl, mercapto, mercaptoalkoxy, mercaptoalkyl, methylenedioxy, oxo, nitro, RfRgN-, RfRgNalkyl, RfRgNcarbonyl and RfRgNsulfonyl.
35 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-
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phenylpropyl, and 2-naphth-2-ylethyl.
The term "aryl-heterocycle," as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a heterocycle group, as defined herein. The term "aryl-NH-," as used herein, refers to an aryl group, as defined herein, 5 appended to the parent molecular moiety through a nitrogen atom.
The term "aryl-NH-alkyV 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. 10 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, 15 appended to the parent molecular moiety through a sulfonyl group, as defined herein.
Representative examples of arylsulfonyl include, but are not limited to, phenylsulfbnyl, 4-bromophenylsulfonyl and naphthylsulfonyl.
The term "carbonyl," as used herein refers to a -C(0)- group.
The term "carboxy," as used herein refers to a -C(0)-OH group.
20 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.
25 The term "cycloalkyl," as used herein, refers to a saturated cyclic hydrocarbon group
containing from 3 to 8 carbons. Examples of cycloalkyl include cyclopropyl, cyctobutyl, cyclopentyl, cyclohexyl, cyctoheptyl, and cyclooctyl.
The cycloalkyl groups of this invention may be substituted with 1, 2,3,4 or 5 substituents independently selected from alkenyl, alkenylthio, alkenyloxy, alkoxy, 30 alkoxyalkoxy, alkoxyalkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkoxy, alkylcarbonylalkyl, alkylcarbonylalkylthio, alkylcarbonyloxy, alkylcarbonylthio, alkylsulfinyl, alkylsulfinylalkyl, alkyl sulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkyhhioalkoxy, alkynyl, alkynyloxy, alkynylthio, carboxy, 35 carboxyalkoxy, carboxyalkyl, cyano, cyanoalkoxy, cyanoalkyl, cyanoalkylthio, formyl,
formylalkoxy, fonnylalkyl, hatoalkenyl, haloalkenyloxy, haloalkoxy, haloalkyl, haloalkynyl, haloalkynyloxy, halogen, hydroxy, hydroxyalkoxy, hydroxyalkyl, mercapto, mercaptoalkoxy,
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mercaptoalkyl, nitro, RfRgN-, RjRgNalkyl, RfRgNcarbonyl and RfRgNsulfbnyl, wherein Rf
and Rg are members independently selected from the group consisting of hydrogen, alkyl,
alkoxyalkyl, alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, cycloalkyl, cycloalkylalkyl,
cycloalkylcarbonyl and cycloalkylsulfonyl.
5 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 -CI, -Br, -I or -F.
10 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-chbro-3-fluoropentyl
The term "heterocycle" or "heterocyclic," as used herein, refers to a monocyclic or
15 bicyclic ring system. Monocyclic ring systems are exemplified by any 3- or 4-membered
ring containing a heteroatom independently selected from oxygen, nitrogen and sulfur; or a 5-, Q-, 7- or 8-membered ring containing one, two or three heteroatoms wherein the heteroatoms are independently members selected from nitrogen, oxygen and sulfur. The 5-membered ring has from 0-2 double bonds and the 6-, 7-, and 8-membered rings have from 0-
20 3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidinyl, azepinyl, aziridinyl, diazepinyl, 1,3-dioxoIanyl, dioxanyl, dithianyl, furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolyl, oxadiazolinyl, oxadiazolidinyl; oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl,
25 pyrazinyl, pyrazolyl, pyrazolinyl, pyrazoUdinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyaohdinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl, thiazolinyl, tbiazolidinyl, thienyl, thiomorpholinyl, l.l-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, triazinyl, triazolyl, and trithianyL Bicyclic ring systems are exemplified by any of the above
30 monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as
defined herein, or another heterocyclic monocyclic ring system. Bicyclic ring systems can also be bridged and are exemplified by any of the above monocyclic ring systems joined with a cycloalkyl group as defined herein, or another non-aromatic heterocyclic monocyclic ring system. Representative examples of bicyclic ring systems include but are not limited to, for
35 example, benzimidazolyl, benzoazepine, benzothiazolyl, benzothienyl, benzoxazolyl,
benzofuranyl, 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-
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pyrrolo[3,4-c]pyrrole, indazolyl, indolyl, indolinyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoindolinyl, isoquinolinyl, phthalazinyl, pyranopyridyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, 2,3,4,5-tetrahydro-lH-benzo[c]azepine, 2,3,4,5-tetrahydro-lH-benzo[£]azepine, 2,3,4,5-tetrahydro-lH-5 benzo[d]azepine, tetrahydroisoquinolinyl, tetrahydroquinolinyl, and thiopyranopyridyl. The heterocycles of this invention may be optionally substituted with 0,1, 2 or 3 substkuents independently selected fiom alkenyl, alkenylthio, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl,
10 alkylcarbonylalkoxy, alkylcarbonylalkyl, alkylcarbonylalkylthio, alkylcarbonyloxy, alkylcarbonylthio, alkylsulfinyl, alkylsulfinylalkyl, alkyl sulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkyhhioalkoxy, alkynyl, alkynyloxy, alkynylthio, aryl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkoxy, carboxyalkyl, cyano, cyanoalkoxy, cyanoalky], cyanoalkylthio, 1,3-dioxolanyl, dioxany], dithianyl, ethylenedioxy,
15 formyl, formylalkoxy, formylalkyl, haloalkenyl, haloalkenyloxy, haloalkoxy, haloalkyl, haloalkynyl, haloalkynyloxy, halogen, heterocycle, heterocyclecarbonyl, heterocycleoxy, heterocyclesulfonyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, mercapto, mercaptoalkoxy, mercaptoalkyl, methylenedioxy, oxo, nitro, RfRgN-, B^gNalkyl, RrflgNcarbonyl and RfRgNsulfonyl, wherein Rf and Rg are members independently selected from the group
20 consisting of hydrogen, alkyl, alkoxyalkyl, alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl and cycloalkylsulfonyl, and wherein substituent aryl, the aryl of arylcarbonyl, the aryl of aryloxy, the aryl of arylsulfonyl, the substituent heterocycle, the heterocycle of heterocyclecarbonyl, the heterocycle of heterocycleoxy, the heterocycle of heterocyclesulfonyl may be optionally substituted with 0,
25 1, 2 or 3 substituents independently selected from the group consisting of alkenyl,
alkenylthio, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkoxy, alkylcarbonylalkyl, alkylcarbonylalkylthio, alkylcarbonyloxy, alkylcarbonylthio, alkylsulfinyl, alkylsulfinylalkyl, alkyl sulfonyl,
30 alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkylthioalkoxy, alkynyl, alkynyloxy,
alkynylthio, carboxy, carboxyalkoxy, carboxyalkyl, cyano, cyanoalkoxy, cyanoalkyl, cyanoalkylthio, ethylenedioxy, formyl, formylalkoxy, formylalkyl, haloalkenyl, haloalkenyloxy, haloalkoxy, haloalkyl, haloalkynyl, haloalkynyloxy, halogen, hydroxy, hydroxyalkoxy, hydroxyalkyl, mercapto, mercaptoalkoxy, mercaptoalkyl, methylenedioxy,
35 oxo, 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.
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Representative examples of heterocyclealkyl include, but are not limited to, pyridin-3-ylmethyl and 2-pyrimidin-2-ylpropyL
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.
5 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 "heterocycieoxyalkyl," as used herein, refers to a heterocycleoxy, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined hereia
The term "heterocycle-NH-,n as used herein, refers to a heterocycle, as defined herein, 10 appended to the parent molecular moiety through a nitrogen atom.
The term "heterocycle-NH-alkyl,H 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 "heterocycle-heterocycle," as used herein, refers to a heterocycle, as defined 1S herein, appended to the parent molecular moiety through a heterocycle group, as defined herein.
The term "heterocyclcarbonyl," 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-
20 piperidinylcarbonyl, 4-morpholinylcarbonyl, pyridin-3-ylcarbonyl and quinolin-3-ylcarbonyl.
The term "heterocyclesulfbnyl," 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 heterocyclesulfbnyl include, but are not limited to, 1-
piperidinylsulfonyl, 4-morpholinylsulfonyl, pyridin-3-ylsulfonyl and quinolin-3-ylsulfbnyl.
25 The term "non-aromatic," as used herein, refers to a monocyclic or bicyclic ring
system that does not contain the appropriate number of double bonds to satisfy the rule for aromaticity. Representative examples of a "non-aromatic" heterocycles include, but are not limited to, piperidinyl, piperazinyl, homopiperazinyl, and pyrrolidinyl. Representative bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to 30 an aryl group as defined herein, a cycloalkyl group as defined herein, or another heterocyclic monocyclic ring system.
The term "oxo," as used herein, refers to a =0 group appended to the parent molecule through an available carbon atom.
The term "oxy," as used herein, refers to a -O- group.
35 The term "sulfonyl," as used herein, refers to a -S(0)2- group.
Salts
The present compounds may exist as therapeutically suitable salts. The term
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"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 5 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
10 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-phenylpropionate, picrate, oxalate,
1S 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.
20 Basic addition salts may be 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, dimethylamine, trimethylamine,
25 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.
30 Prodrugs
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
35 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
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"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
5 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,
10 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. Optical Isomers-Diastereomers-Geometric Isomers
Asymmetric centers may exist in the present compounds. Individual stereoisomers of
15 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
20 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
25 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.
30 Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble J. Org. Chem. 63: 2758-2760, 1998.
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 may be prepared.
The compounds of this invention may be prepared by a variety of procedures and
35 synthetic routes. Representative procedures and synthetic routes are shown in, but are not limited to, Schemes 1-5.
Abbreviations which have been used in the descriptions of the Schemes and the
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Examples that follow are: DCM for dichloromethane; DMAP for dimethylaminopyridine; DMF for N,N-dimethylfbrm amide; DMSO for dimethylsulfoxide; DAST for (diethylamino)sulfur trifluoride; DEPEA orHtinig's base for diisopropylethylamine; EDCI for (3-dimethylammopropyl)-3-ethylcarbodlimide HC1; EtOAc for ethyl acetate; EtOH for 5 ethanol; HATU for 0-(7-azabenzotriazol-l-yI)-N, N, JT, N'-tetramethyluronium hexafluoro-phosphate; HOBt for hydroxybenzotriazole hydrate; MeOH for methanol; THF for tetrahydrofuran; tosyl for para-toluene sulfonyl, mesyl for methane sulfonyl, triflate for trifluoromethane sulfonyl.
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Scheme 1


f5 „B x
R6
ikh

(D

(3)


(3)
Substituted adamantanes of general formula (5), wherein A1, A2, A3, A4, R1, R2, R3,
5 R4, and R6 are as defined in formula I, may be prepared as in Scheme 1. Substituted
adamantamines of general formula (1), purchased or prepared using methodology known to those in the art, may be treated with acylating agents such as chloroacetyl chloride or 2-bromopropionyl bromide of general formula (2), wherein X is chloro, bromo, or fhioro, Y is a leaving group such as CI (or a protected or masked leaving group), and R3 and R4 are defined
10 as in formula I, and a base such as diisopropylethylamine to provide amides of general
formula (3). Alternatively, acids of general formula (2) wherein X = OH may be coupled to substituted adamantamines of general formula (1) with reagents such as EDCI and HOBt to provide amides of general formula (3) (after conversion of Y into a leaving group Z wherein Z is chloro, bromo, iodo, -O-tosyl, -O-mesyl, or -O-triflate). Amides of general formula (3)
15 may be treated with amines of general formula (4) wherein R1 and R2 are as defined in
formula I to provide aminoamides of general formula (5). In some examples, A1, A2, A3, and/or A4 in amines of formula (1) may exist as a group further substituted with a protecting group such as hydroxy protected with acetyl or methoxymethyl. Examples containing a protected functional group may be required due to the synthetic schemes and the reactivity of
20 said groups and could be later removed to provide the desired compound. Such protecting
groups may 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,
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Wiley & Sons, Inc.
Scheme 2

(D

(7)


(7)
5 Substituted adamantanes of general formula (8), wherein A1, A2, A3, A4, R1, R2, R3,
R4, and R6 are as defined in formula I, may be prepared as in Scheme 2. Substituted adamantamines of general formula (1) may be purchased or prepared using methodology known to those in the art. The amines of general formula (1) may be coupled with protected amino acids of general formula (6) (wherein X is OH, R3 and R4 are defined as in formula I,
10 and Y is a protected or masked amino group) such as N-(tert-butoxycarbonyl)glycine with
reagents such as EDCI and HOBt to provide amides of general formula (7) after deprotection. Alternatively, amines of general formula (1) may be treated with activated protected amino acids of general formula (2), wherein Y is a protected or masked amino group, and a base such as diisopropylethylamine to provide amides of general formula (7) after deprotection.
15 Amides of general formula (7) may be treated with alkylating agents such as 1,5-
dibromopentane and a base like potassium carbonate to yield amides of general formula (8). Among other methods known to those in the art, amines of general formula (7) may be treated with aldehydes such as benzaldehyde and a reducing agent like sodium cyanoborohydride to yield amides of general formula (8). In some examples, A1, A2, A3,
20 and/or A4 in amines of formula (1) may be a functional group covered with a protecting group such as hydroxy protected with acetyl or methoxymethyL These protecting groups may be removed using methodology known to those in the art in amides of general formula
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(7) or (8). Alternatively a group such as chloro may be used and subsequently converted to hydroxyl by irradiating with microwaves in the presence of aqueous hydroxide.
Scheme 3

5 (9) (10)
Substituted adamantane amines of general formula (10), wherein A1, A2, A3, A4, and R5 are as defined in formula I, may be prepared as in Scheme 3. Substituted adamantane ketones of general formula (9) may be purchased or prepared using methodology known to those in the art. Ketones of general formula (9) may be treated with ammonia or primary
10 amines (R5NHa) followed by reduction with sodium borohydride to provide amines of
general formula (10). In some examples, A1, A2, A3, and/or A4 in ketones of formula (9) may be a functional group covered with a protecting group such as hydroxy protected with acetyl or methoxymethyl. These protecting groups may be removed using methodology known to those in the art in amines of general formula (10) or in compounds subsequently prepared
15 from ketones of general formula (9) or amines of general formula (10). Alternatively a group
such as chloro may be used and subsequently converted to hydroxyl by irradiating with microwaves in the presence of aqueous hydroxide.
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Scheme 4



HN
I
(11)

R? R3

# II Y

alkylation
and hydrolysis
*-

R? R3
(14)

R2



(14)
Coupling
^-
(15) (16)
Substituted adamantanes of general formula (16), wherein A1, A2, A3, A4, R1, R2, R3, 5 R4,Rs,andR6 are as defined in formula I, may be prepared as in Scheme 4. Amines of
general formula (11) may be purchased or prepared using methodology known to those in the art. The amines of general formula (11) may be reacted with reagents of general formula (12), wherein R3 and R4 are defined as in formula I and X is an alkoxy group, such as 2-bromopropionic acid methyl ester in the presence of a base like diisopropylethylamine to
10 provide esters of general formula (13). Esters of general formula (13) may be alkylated using a base like lithium diisopropylamide and an alkylating agent such as methyl iodide to yield acids of general formula (14), X = OH, after hydrolysis. Substituted adamantamines of general formula (15) may be purchased or prepared using methodology known to those in the art. Coupling of acids of general formula (14) and amines of general formula (15) with
15 reagents such as EDCI and HOBt may provide amides of general formula (16). In some examples A1, A2, A3 and/or A4 in amines of general formula (15) may contain a functional group such as carboxy protected with a methyl group. In amides of general formula (16), these protecting groups may be removed using methodology known to those skilled in the art.
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Scheme 5
/ j^ carboxylation \ / \"^

10

A2 A2
(17) (18)
Substituted adamantanes of general formula (18), wherein A2, A3, and A4 are as defined in formula I, may be prepared as in Scheme 5. Substituted adamantanes of general formula (17) may be purchased or prepared using methodology known to those in the art Polycycles of general formula (17) may be treated with oleum and formic acid followed by an alcohol GOH, where G is an alkyl, cycloalkyl, aryl, or acid protecting group, to provide polycycles of general formula (18); In some examples, G in formula (9) may be a protecting group such as methyl. These protecting groups may be removed using methodology known to those in the art from polycycles of general formula (18) or in compounds subsequently prepared from (18).
Scheme 6 R4. -R3
A3 _- R5
A'zt^A<
A2
(21)
carbonylation
- (22)

£zT~«0

A2 (22) A2 (24)
Substituted adamantanes of general formula (24), wherein A1, A2, A3, A4, R1, R2, R3, 15 R4,R5,andR6 are as defined in formula I, may be prepared as in Scheme 6. Substituted
adamantamines of general formula (19), wherein A1, A2, A3, and A4 are defined as in formula one I with the proviso that at least one is a hydroxyl group or a protected or masked hydroxyl
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group, may be purchased or prepared using methodology known to those in the art Substituted adamantamines of general formula (19) may be treated with acylating agents such as chloroacetyl chloride or 2-bromopropionyl bromide of general formula (20), wherein X is chloro, bromo, or fluoro, Y is a leaving group such as CI (or a protected or masked leaving
5 group), and R3 and R4 are defined as in formula I, and a base such as diisopropylethylamine to provide amides of general formula (21). Alternatively, acids of general formula (20) wherein X = OH may be coupled to substituted adamantamines of general formula (19) with reagents such as EDCI and HOBt to provide amides of general formula (21) (after conversion of Y into a leaving group Z wherein Z is chloro, bromo, iodo, -O-tosyl, -O-mesyl, or-O-
10 triflate). Hydroxyadamantanes, or protected or masked hydroxyl adamantanes which can be converted to the corresponding hydroxyadamantane, (21) may be carbonylated with reagents like oleum and formic acid to yield the corresponding adamantyl acid or ester (22), wherein A1, A2, A3, and A4 are defined as in formula one I with the proviso that at least one is a carboxy group or a protected carboxy group (CO2R17 wherein R17 is defined as in formula I).
15 Amides of general formula (22) may be treated with amines of general formula (23) wherein R1 and R2 are as defined in formula I to provide aminoamides of general formula (24). In some examples, A1, A2, A3, and/or A4 in amines of formula (24) may exist as a group further substituted with a protecting group such as carboxy protected as an alkyl ester. Examples containing a protected functional group may be required due to the synthetic schemes and the
20 reactivity of said groups and could be later removed to provide the desired compound. Such protecting groups may 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" 3ri ed. 1999, Wiley & Sons, Inc.

25

H02C-

A3 R°
* *6 I R? R3

*■ (25)

Scheme 7 Amide coupling
□18
R\ NH
/* R« (26) O

(27)

deprotection

V4IUU1

IT
R1

R19

A2

(28)

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10

Substituted adamantanes of general formula (28), wherein A2, A3, A4, R1, R2, R3, R4, R5, R6, R18, and R19 are as defined in formula I, may be prepared as in Scheme 7. Adamantyl acids of general formula (25) may be prepared as described herein or using methodology known to those in the art. The acids of general formula (25) may be coupled with amines of general formula (26) (wherein R18 and R19 are defined as in formula I) with reagents such as 0-(Benzotrialzol-l-yl)-l,l,3,3-tetramethyluronium tetrafhioroborate (TBTU) to provide amides of general formula (27). In some examples, A2, A3, A4, R1, R2, R3, R4, R3, R6, R18, and R19 in amines of formula (27) may contain a functional group covered with a protecting group such as carboxy protected as an ester. These protecting groups may be removed using methodology known to those in the art to provide amides of general formula (28).

Scheme 8
A3 R5
/ Tf N reduction /
-_[ f I] I *■ HOH2C-^. (
H02C-

A2

(29)

A2

(30)

Rl .R3
oxidation
(CO) +■ 0HC
I
A3 ' f?5

,R2

A2

(31)


amination
Substituted adamantanes of general formula (33), wherein A2, A3, A4, R1, R2, R3, R4, 15 Rs, R6, R25, and R26 are as defined in formula I, may be prepared as in Scheme 8. Acids of general formula (29) may be prepared as detailed herein or by using methodology known to those in the art. Acids (29) may be reduced using a reagent like borane to alcohols of general formula (30). Alcohols of general formula (30) may be oxidized with reagents such as tetrapropylammonium perruthenate to aldehydes of general formula (31). Aldehydes of 20 general formula (31) may be reductively animated with an amine of general formula (32),
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,25
wherein R" and R26 are as defined in formula I, and a reducing agent such as sodium cyanoborohydride to provide amines of general formula (33). In some examples, A2, A3, A4, R1, R2, R3, R4, R5, R6, R2S, and R26 in amines of formula (33) may be and/or contain a functional group covered with a protecting group such as such as carboxy protected as an ester. These protecting groups may be removed using methodology known to those in the art.
Scheme 9
R? .R3



(40)

A2 (42)

irj
y-^j-^A* °
(42)

-*• A1

*3 * f Rl ,R3

A2

(43)

1 A2 A3 A4 D3 IJ4 T,5
Substituted adamantanes of general formula (42), wherein A,A,A,A,R,R,R 10 and R6 are as defined in formula I and G is as defined in formula V, may be prepared as in Scheme 9. Diethanolamines of general formula (34) wherein P1 is an alkylsulfonyl or arylsulfonyl group may be purchased or prepared using methodology known to those in the
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10
15

art Diethanolamines (34) wherein P1 is an alkylsulfonyl or arylsulfonyl group can be prepared by reacting diethanolamine with a sulfonyl chloride like 2-nitrobenzenesulfbnylchloride in the presence of a base like triethylamine in a solvent like methylene chloride. The diols of general formula (34) may be converted to sulfonamides of general formula (35) (wherein L1 and L2 are CI, Br, I, OMs, or OTf) with reagents such as triflic anhydride. Sulfonamides of general formula (35) may be treated with aminoesters (36), wherein R3 and R4 are as defined in formula I and P2 is an alkyl group, and a base like sodium carbonate to yield piperazines of general formula (37). Piperazine sulfonamides (37) can be deprotected to provide piperazines (38). Amines (38) can be arylated, or heteroarylated, with a reagent like 2-bromo-5-trifluoromethyl-pyridine to give piperazines of general formula (39). Esters (39) may be converted to acids of general formula (40). Acids (40) can be coupled to adamantly amines of general formula (41), wherein A1, A2, A3, A4, and R6 are as defined in formula I, to give amides of general formula (42). In some examples, A1, A2, A3, A4, R3, R4, R5, and/or R6 in amines of formula (42) may contain a functional group covered with a protecting group such as such as carboxy protected as an ester. These protecting groups may be removed using methodology known to those in the art to give amides of general formula (43).

A3 f R6

Scheme 10

(44)

(45)

R2
HN
O
(45)
R1
20 (46) (47)
1 *i 1 A 1 *) 1
Substituted adamantanes of general formula (48), wherein A,A,A,A,R,R,R, R4, R5, and R6 are as defined in formula I, may be prepared as in Scheme 10. Substituted adamantamines of general formula (44), wherein A1, A2, A3, A4, and R6 are as defined in formula I, may be purchased or prepared using methodology known to those in the art. The
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amines of general formula (44) may be converted to isonitriles of general formula (45) with reagents such as methyl formate followed by treatment with phosphorous oxychloride in the presence of a base like triethylamine. Isonitriles of general formula (45) may be treated with aldehydes or ketones of general formula (46), amines of general formula (47), and an acid such as acetic acid to provide amides of general formula (48). In some examples, A1, A2, A3, A4, R, R, R, R, R, and/or R6 in compounds of formula (48) may contain a functional group covered with a protecting group such as carboxy protected as an ester. These protecting groups may be removed using methodology known to those in the art in amides of general formula (48).

,,31 ,32
. .. R31
VSA ^ RVy"OH - riP
CN CN
10
R33
R34 O (49)
(51)
Substituted benzodiazepines of general formula (52), wherein R , R , R , and R are defined as hetero cycle substituents (and equivalent to benzodiazepines of general fomula (53) wherein R1 and R2 are a subset of the substituents in formula (I)) may be prepared as in
15 Scheme 11. Substituted arenes of general formula (49), wherein R31, R32, R33, and R34 are
defined as heterocycle substituents and X and Y are independently halogen, -OH, or -Oalkyl, may be purchased or prepared using methodology known to those skilled in the art. Arenes of general formula (49) may be treated with reducing agents such as borane-tetrahydrofuran, to provide diols of general formula (50). Diols (50) may be converted to the corresponding
20 dihalides with reagents like thionyl chloride and then treated with cyanide using reagents like sodium cyanide in solvents like dimethylsulfoxide to yield the corresponding dinitriles of general formula (51). Dinitriles of general formula (51) may be treated with ammonia under reducing conditions like Raney nickel in the presence of hydrogen gas at high pressure in a solvent such as but not limited to ethanol to provide benzodiazepines of general formula (52).
25 Examples containing a protected functional group may be required due to the synthetic
schemes and the reactivity of unprotected functional groups. The protecting group could be later removed to provide the desired compound. Such protecting groups may be added or
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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. Benozdiazepines of general formula (52) may be converted into compounds of general formula (I) using methods described herein and by methodology known to those skilled in the 5 art.
Scheme 12

Substituted adamantanes of general formula (56) and (57), wherein A1, A2, A3, A4, R3, 10 R4,R5,andR6 are as defined in formula (I), G is defined as in formula (V), and Y is an alkylcarbonyl, alkylsulfbnyl, alkoxycarbonyl, alkylaminocarbonyl, arylcarbonyl, arylsulfonyl, aryloxycarbonyl, arylaminocarbonyl, heteroarylcarbonyl, heteroarylsulfonyl, heteroaryloxycarbonyl, heteroarylaminocarbonyl, arylalkylcarbonyl, arylalkylsulfonyl, arylalkoxycarbonyl, arylalkylaminocarbonyl, heteroarylalkylcarbonyl,
15 heteroarylalkylsulfonyl, heteroarylalkoxycarbonyl, or a heteroarylalkylaminocarbonyl group
may be prepared as in Scheme 12. Adamantyl piperazines of general formula (54) wherein X is an amine protecting group and A1, A2, A3, A4, R3, R4, R5, and R6 are as defined in formula (I) may be prepared as described herein or using methodology known to those skilled in the art. The protected piperazines of general formula (54) may be deprotected with reagents such
20 as palladium on carbon in the presence of hydrogen when X is a benzyloxycarbonyl group to
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provide amines of general formula (55). Amines of general formula (55) can be treated with acid chlorides, sulfonylchlorides, chloroformates, isocyanates, and other compounds to provide piperazines of general formula (56). Amines of general formula (55) can also be treated with aryl or heteroaryl halides and other compounds to provide compounds of general formula (57). In some examples, A1, A2, A3, A4, R3, R4, R5, R6, G, and Y of piperazines containing compounds of formulas (56) and (57) may or may not contain a functional group substituted with a protecting group such as carboxy protected as an ester. These protecting groups may be removed using methodology known to those skilled in the art to provide piperazines of general formulas (56) and (57).
10

f R6 f Rl J*3


,R2

Scheme 13

f R8 f "v J*

•*^y^ ° i
(58)
A2

NC

R1

A3 R5
A R6 ? R*
15

■*- HN, ^
(59)
(59)
Substituted adamantanes of general formulas (60), (61), and (62), wherein A2, A3, A4, Rl,R2,R3,R4,RJ,andR6 are as defined in formula (I), may be prepared as in Scheme 13. Amides of general formula (58), wherein A2, A3, A4, Rl, R2, R3, R4, R5, and R6 are as defined in formula (I), may be prepared as described herein or by using methodology known to those

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skilled in the art. Amides (58) may be dehydrated using a reagent such as but not limited to
trifluoroacetic anhydride to provide nitriles of general formula (59). Nitriles of general
formula (59) may be treated with reagents such as hydroxylamine hydrochloride and
potassium carbonate in a solvent such as ethanol followed by treatment with acetyl chloride
5 in a solvent such as pyridine to provide heterocycles of general formula (60). Nitriles of
general formula (59) may also be treated with reagents such as sodium azide and a Lewis acid such as zinc bromide in a solvent such as water to provide tetrazoles of general formula (61). Nitriles of general formula (59) may also be treated with reagents such as dimethylformamide and dimethylacetamide followed by heating with hydrazine in acetic acid to provide triazoles 10 of general formula (62). In some examples, A2, A3, A4, R1, R2, R3, R4, R3, and R6 of
adamantane containing compounds of formula (60), (61), and (62) may or may not contain a functional group substituted with a protecting group such as such as carboxy protected as an ester. These protecting groups may be removed using methodology known to those in the art.
15 Scheme 14

R36 l35!^) R41 R2
—- ^-frfr ■ "f
R38 Rgg^ R43 R1
(65) (66)
Piperazines of general formula (65) which are equivalent to compounds of general formula (66) wherein R35, R36, R37, R38, R3', R40, R41, R42, and R43 are defined as aryl or heteroaryl substituents and Y is a carbon or a nitrogen, may be prepared as in Scheme 14.
20 Arenes and heterocycles of general formula (63), wherein R35, R36, R37, R38, and R39 are
defined as aryl or heteroaryl substituents, X is a halogen, and Y is a carbon or a nitrogen may be purchased or prepared using methodobgy known to those skilled in the art. Piperazines of general formula (64) wherein R40, R41, R42, and R43 are defined as heterocycle substituents and P is a protecting group may be purchased or prepared using methodology known to those
25 skilled in the art. Arenes and heterocycles of general structure (63) may be coupled with
piperazines of general formula (64) by heating them together neat or in a solvent such as dimethylformamide in the presence of a base such as potassium carbonate to provide piperazines of general formula (65) following protecting group removal. Alternatively, this reaction may be conducted with palladium or other metal catalyst systems such as
30 tris(dibenzylideneacetone)dipalladium and 2,2'-bis(diphenylphosphino)-l,r-binaphthyl in the presence of a base such as sodium tert-butoxide in a solvent such as toluene. Examples containing a protected functional group may be required due to the synthetic schemes and the reactivity of other substituent groups which could be later removed to provide the desired
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compounds. Such protecting groups may 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. Piperazines of general formula (65) may be converted into compounds of general formula I using methods described herein and by methodology known to those skilled in the art.

T3 # f < R3 Scheme 15 A3 1 R5R6 ? R\ .R 3
r/H -Y a f r PV >VR!
■**» -w-v~-—A4 ° Yi —y^-A4 ° I
/ k2 (67) o \T m
f R6 f Rl R3
(68) . HN r? M "V VR!
*" H2N-~^J —-/^-A4 ° R1
A' 2 (69) A3 R5f R6 T Rl R3
Rr r. As- r V"
(69) R45 ^ ^7 ^A4 u R1
A2 (70)
Substituted adamantanes of general formula (70), wherein A2, A3, A4, RL, R2, R3, R4, 10 R5,andR6 are as defined in formula (I) and R44 and R4S are independently defined as R7, -[CtR'RV^CO-R10, R15, and R16 as defined in formula (I), may be prepared as in Scheme 15. Substituted adamantanols of general fonnula (67), wherein A2, A3, A4, R1, R2, R3, R4, R3, andR6 are as defined in formula (I), may be purchased, prepared using procedures described herein, or made by methodology known to those skilled in the art. The adamantanols of 15 general formula (67) may be converted to amides of general formula (68) with reagents such as acetonitrile in the presence of an acid such as trifluoroacetic acid. Amides of general fonnula (68) may be treated with another acid such as hydrochloric acid to provide amines of general formula (69). Amines of general formula (69) may undergo a variety of reactions such as acylation or sulfonylation with acetyl chloride or methanesulfonyl chloride in the • 20 presence of a base to provide substituted adamantanes of general formula (70). In some examples, A2, A3, A4, Rl, R2, R3, R4, R5, and/or R6 in compounds of formula (70) may
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contain a functional group substituted with a protecting group such as carboxy protected as an ester. These protecting groups may be removed using methodology known to those skilled in the art to provide compounds of general formula (70).
Scheme 16

f «■ r
MX'

R? R3
.R2
MeOjC

Rl ,R3
R47 £-—" J
A2 (72)
Substituted adamantanes of general formula (72), wherein A2, A3, A4, R1, R2, R3, R4, R5, and R6 are as defined in formula I and R46 and R47 are alkyl, cycloalkyl, aryl or heterocyclic groups may be prepared as in Scheme 16. Substituted adamantane esters of
10 general formula (71), wherein A2, A3, A4, R1, R2, R3, R4, R5, and R6 are as defined in formula I may be purchased, synthesized as described herein, or prepared using methodology known to those skilled in the art. The esters of general formula (71) may be converted to alcohols of general formula (72) with reagents such as methyl lithium In some examples, A2, A3, A4, R3, R4,R5, and/or R6 in amines of formula (72) may contain a functional group substituted with a
15 protecting group such as such as carboxy protected as an ester. These protecting groups may be removed using methodology known to those skilled in the art to provide adamantane alcohols of general formula (72).
A2 (7D
R1
Scheme 17

/4—y^A< ° '

,R2

I RB
*3 -* *f R« R3

1.

,R2

A2 (73)

(74)

HOjC
(74)
20 A2 (75)
Substituted adamantanes of general formula (75), wherein A2, A3, A4, R1, R2, R3, R4, Rs, and R6 are as defined in formula (I), may be prepared as in Scheme 17. Aldehydes of
general formula (73), wherein Az, AJ, A4, R, R2, R3, R , R , and R are as defined in formula
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(I) may be prepared by methods described herein or using methodology known to those skilled in the art. Aldehydes (73) may be converted to nitriles of general formula (74) with reagents such as p-tolylsulfonylmethyl isocyanide in solvents such as dimethoxyethane and ethanol in the presence of a base such as potassium tert-butoxide. Nitriles of general formula 5 (74) may be treated with an acid such as hydrobromic acid in a solvent such as acetic acid to provide acids of general formula (75). In some examples, A2, A3, A4, R3, R4, R5, and/or R6 in amines of formula (75) may contain a functional group substituted with a protecting group such as such as carboxy protected as an ester. These protecting groups may be removed using methodology known to those skilled in the art to provide acids of general formula (75). 10

1 O Q A 1 A K
Substituted adamantanes of general formula (79), wherein A, A , A , A, R, R, R, and R6 are as defined in formula (I), R48 and R50 are defined as heterocycle substituents, and 15 R51 is an aryl or heteroaryl group, may be prepared as in Scheme 18. Pyrazoles of general formula (76) wherein R48 and R50 are heterocycle substituents and R49 is a halogen may be purchased or prepared using methodology known to those skilled in the art. Pyrazoles of
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general formula (76) may be alkylated with a reagent like 2-(trichloromethyl)-propan-2-ol in the presence of a base such as sodium hydroxide in a solvent such as acetone to provide acids of general formula (77). The acids of general formula (77) may be coupled with adamantamines as described in Scheme 4 to provide pyrazoles of general formula (78). 5 Pyrazoles of general formula (78) may be coupled with boronic acids and related reagents such as 4-cyanophenylboronic acid in the presence of a catalyst such as but not limited to Pd(PPh3)2Cl2 to provide pyrazoles of general formula (79). In some examples, A1, A2, A3, A4, R3, R4, R5, R6, R48, R50 and/or R51 in amines of formula (79) may contain a functional group substituted with a protecting group such as such as carboxy protected as an ester.
10 These protecting groups may be removed using methodology known to those skilled in the art to provide compounds of general formula (79).
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
15 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
20 adamantane ring system are designated as being of Z or E relative configuatioii (for examples see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble J. Org. Chem. 63: 2758-2760, 1998).
25 Example 1
N-[(Z)-5-Hvdroxy-2-adamantyll-2-{4-[5-(trifluoromethvl)pvridin-2-yl]piperazin-l-
yl}acetftnidp.
Example 1A
30 Acetic acid 2-oxo-adamantan-5-vl ester
A solution of 5-hydroxy-2-adamantarione (2.6 g, 15.66 mmoles) in dichloromethane (DCM) (50 mL) was treated with dimethylaminopyridine (DMAP) (2.1 g, 17 mmoles) and acetic anhydride (2.3 mL, 23 mmoles) and stirred overnight at 50 °C. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl 35 acetate. The aqueous layer was extracted twice with ethyl acetate. Combined organic
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extracts were washed with water, dried (MgS04) and filtered. The filtrate was concentrated under reduced pressure to provide the title compound as an off-white solid.
Example 1R
5 (E)- and (ZVAcetic acid 2-anfiino-adamantan-5-yl ester
A solution of acetic acid 2-pxo-adamantan-S-yl ester (3.124 g, 15 mmoles), from Example 1 A, and 4A molecular serves (lg) in methanolic ammonia (7N, 50 mL) was stirred overnight at room temperature. The mixture was cooled in an ice bath, treated portionwise with sodium borohydride (2.27 g, 60 mmoles) and stirred at room temperature for 2 hours.
10 The suspension was filtered and concentrated under reduced pressure. The residue was taken into DCM (50 mL), acidified with IN HC1 to pH = 3 and the layers separated. The aqueous layer was basified with 2N NaOH to pH = 12 and extracted three times with 4:1 tetrahydrofuran:dichloromethane (THF:DCM). The combined organic extracts were dried (MgS04) and filtered. The filtrate was concentrated under reduced pressure to provide the
15 title compound as a white solid.
Example 1C
(E\- and (ZVAcetic acid 2-(2-<^or^acftty1amino)-adamantan-5-vl ester
A solution of (£)- and (Z)-acetic acid 2-amino-adamantan-5-yl ester (1.82 g, 8.69 20 mmoles), from Example IB, in DCM (30 mL) and diisopropylethylamine (DIPEA) (1.74 mL, 10 mmoles) was cooled in an ice bath and treated with chloroacetyl chloride (0.76 mL, 9.57 mmoles). The solution was stirred for 2 hours at room temperature and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, dried (MgSC^) and 25 filtered. The filtrate was concentrated under reduced pressure to provide the title compound as dark beige solid.
Example ID
30 N-[(Z)-5-Hydroxv-2-adamantvl1-2-(4-f5^trifluoromethvRpyridm-2-vllpiperazin-U
y1}ar.ftfomiHft
A solution of (£)- and (Z)-acetic acid 2-(2-chloroacetylamino)-adamantan-5-yl ester (2.1 g, 7.3 mmoles), from Example 1C, inMeOH (30 mL) and DIPEA (1.53 mL, 8.8 mmoles) was treated with l-(5-trifluoromethyl-pyridin-2-yl)-piperazine (2.04 g, 8.8 mmoles)
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and stirred for 6 hours at 70 °C. An aqueous solution of potassium carbonate (K2CO3) (15 mL) was added to the reaction and stirred overnight at 70 °C. MeOH was removed under reduced pressure and the residue was partitioned with DCM. The aqueous layer was extracted with DCM and the combined organic extracts washed twice with Water, dried
5 (MgSO/t) and filtered. The filtrate was concentrated under reduced pressure to provide an
off-white solid, which was purified by column chromatography (silica gel, 30-90% acetone in hexane) to provide the title compound as a white solid. *H MMR (300 MHz, CDCI3) 6 8.41 (s, IH), 7.65 (dd, J = 2.7, 9.1 Hz, IH,), 7.6 (s, IH), 6.65 (d, J = 9.1 Hz, IH), 3.98 (d, J = 8.5 Hz, IH), 3.69 (s, 4H), 3.09 (s, 2H), 2.67 (s, 4H), 2.19-2.15 (m, 3H), 1.79-1.38 (m,
10 10H); MS(APCI+) m/z 439 (M+H)+.
Example 2
N-f(£l-5-Hydroxv-2-adaTnantyl]-2-{4-[5-(trifluoromethyl)pyridm-2-yl]piperazin-l-
yl}acetamide
15 Purification of the concentrated filtrate from Example ID by column chromatography
(silica gel, 30-90% acetone in hexane) provided the title compound as a white solid. *H NMR(300 MHz, CDCI3) S 8.41 (s, IH), 7.67 (dd, J = 2.1, 9.1 Hz, IH), 7.6 (s, IH), 6.67 (d, J = 9.1 Hz, IH), 4.07 (d, J = 8.1 Hz, IH), 3.69 (s, 4H), 3.1 (s, 2H), 2.68 (s, 4H), 2.12-2.17 (m, 3H), 1.91 (m, 2H), 1.79-1.75 (m, 4H), 1.67 (m, 2H), 1.57 (s, IH), 1.36 (s, IH); MS(APCI+)
20 m/z439(M+H)+.
Example 3
N-[(£)-5-HydroxY-7--adamantvl]-2-{4-f5-ftrifluoromelJivl)pyridin-2-yl1piperazin-l-
yl}propanamide
25
Example 3A (£)- and (Z)-AcetlC acid 2-(2-hromn-propionylaminn)-ariaiparntaTi-5-y1 eatIsr
A solution of (£)-and (Z)-acetic acid 2-amino-adamantan-5-yI ester (0.54 g, 2.58 mmoles), from Example IB, in DCM (10 mL) and DIPEA (0.54 mL, 3.09 mmoles) was 30 cooled in an ice bath and treated with 2-bromopropionyl chloride (0.26 mL, 2.6 mmoles). The solution was stirred for 2 hours at room temperature and DCM was removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, dried (MgS04) and filtered. The filtrate was concentrated under reduced pressure to provide the title compound
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as a dark beige solid.
Example 3B
N-f(,^5-Hvdroxv-2-adamantvll-2-(4-f5-rtrifluorom<^vnpvridin-2-vllpiperazm-l-
5 vl}propanamidp.
A solution of (£)- and (Z)-acetic acid 2-(2-bromo-propionylamino)-adamantan-5-yl ester (0.746 g, 2.17 mmoles), from Example 3 A, in MeOH (10 mL) and DIPEA (0.416 mL, 2.39 mmoles) was treated with l-(5-trifluoromethyl-pyridin-2-yl)-piperazine (0.552 g, 2.39 mmoles) and stirred for 6 hours at 70 °C. Saturated aqueous K2CO3 (5 mL) was added to the
10 reaction mixture and the mixture stirred overnight at 70°C. The mixture was concentrated under reduced pressure and the residue partitioned by the addition of DCM. The aqueous layer was extracted with additional DCM (3x). The combined organic extracts were washed twice with water, dried (MgS04) and filtered. The filtrate was concentrated under reduced pressure to provide an off-white solid, which was purified by column chromatography (silica
15 gel, 30-90% acetone in hexane) to provide the title compound as a white solid. 'HNMR(300 MHz, CDCI3) 8 8.41 (s, IH), 7.65 (m, 2H), 6.67 (d, J = 8.8 Hz, IH), 4.03 (d, J = 8.5 Hz, IH), 3.69 (m, 4H), 3.15 (q, J = 7.1 Hz, IH), 2.63 (m, 4H), 2.15 (m, 3H), 1.9 (m, 2H), 1.77 (m, 4H), 1.66 (m, 2H), 1.52 (s, IH), 1.36 (s, IH), 1.28 (d, J = 7.1 Hz, 3H); MS(APCI+) m/z 453 (M+H)+
20
Example. 4 2-[(cis)-2.6-Dimethylmorphplm-4-y^
Example 4A
25 (£)- and (2V5-Chloro-2-adamantamine
A solution of 5-cbloro-2-adamantanone (4.8 g, 26 mmoles) and 4A molecular sieves (2 g) in methanolic ammonia (7N, 50 mL) was stirred overnight at room temperature, cooled in an ice bath, treated with the portionwise addition of sodium borohydride (3.93 g, 104 mmoles) and stirred at room temperature for 2 hours. The suspension was filtered and 30 concentrated under reduced pressure. The residue was taken into DCM (50 mL) and
acidified with IN HC1 to pH = 3. The layers were separated and the aqueous layer basified with 2N NaOH to pH = 12 and extracted three times with 4:1 THF:DCM. The combined organic extracts were dried (MgSCv), filtered and concentrated under reduced pressure to provide the title compound as a white solid.
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Example 4B
2-Bromo-N-[fJS)- and (ZV5-chloro-adamantan-2-yl]-propionamide A solution of (£)- and (Z)-5-chloro-2-adamantamine (1 g, 5.38 mmoles), from 5 Example 4A, in DCM (30 mL) and DIPEA (2.08 mL, 11.96 mmoles) was cooled in an ice bath and treated with 2-bromopropionyl chloride (0.65 mL, 6.46 mmoles) and the mixture stirred for 2 hours at room temperature. The mixture was concentrated under reduced pressure, partitioned between water and ethyl acetate. The organic layer was washed with aqueous saturated sodium* bicarbonate (2x), water (2x), dried (MgS04) and filtered. The 10 filtrate was concentrated under reduced pressure to provide the title compound as a tan solid.
Example 4C
2-f(cis)-2.6-Dimethylmorpholm-4-yl1-N-f^^ A solution of 2-bromo-N-[(£)~ and (Z)-5-chtoro-adamantan-2-yl]-propionamide (55
15 mg, 0.17 mmoles) from Example 4B in MeOH (1 mL) and DIPEA (0.1 mL) was treated with ciy-2,6-dimethylmorphohne (23 mg, 0.2 mmoles) and the mixture stirred overnight at 70 °C. The mixture was concentrated under reduced pressure. The residue dissolved in dioxane (0.1 mL) and 5N potassium hydroxide (0.4 mL) and irradiated by microwaves for 1 hour at 190 °C. The mixture was filtered through a Celite cartridge and washed with 1:1 DMSOrMeOH
20 (1.5mL). The title compound was isolated by reverse phase HPLC (20-100% acetonitrile in 0.1 % TFA in water) on a YMC ODS Guardpak column as a clear oil *H NMR (300 MHz, CDCfe) 8 7.65 (d, J - 8.3 Hz, 1H); 4.0 (d, J = 8.6 Hz, 1H), 3.67 (m, 2H), 3.03 (q, J = 7.0 Hz, 1H), 2.62 (t, J = 11.2 Hz, 2H), 2.11 (m, 3H), 1.97-1.8 (m, 3H), 1.77-1.65 (m, 4H), 1.65-1.52 (m, 4H), 1.23 (d; J = 7.1 Hz, 3H), 1.17 (dd, J = 5.8, 6.1 Hz, 6H); MS(APCI+) m/z 337
25 (M+H)+.
Faramplft 5
N-[(2^-5-Hydro^-7--?d?iTi«ntyl]-9--(4-hydroxvpiperidin-l-yl)propanamide
The title compound was prepared according to the method of Example 4C substituting 30 4-hydroxypiperidine for cw-2,6-dimethylmorpholine. !H NMR (300 MHz, CDCI3) 5 7.75 (s, 1H), 3.9 (d, J = 9.2 Hz, 1H), 3:74 (s, 1H), 3.12 (m, 1H), 2.77 (m, 2H), 2.43 (m, 1H), 2.25 (m, 2H), 2.15-1.93 (m, 10H), 1.75-1.6 (m, 8H), 1.23 (d, J = 6.8 Hz, 3H); MS(APCI+) m/z 323 (M+H)+.
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Example 6
N-r(i^-5-Hvdroxy-2-adamantyl]-2-(4-hvdroxvpiperidin-l-vnpropai|a^idft
The title compound was prepared according to the method of Example 4C substituting
4-hydroxypiperidine for cw-2,6-dimethylmorpholine. rH NMR (300 MHz, CDCU) 5 7.76 (d,
5 J - 2.4 Hz, IH), 4.0 (d, J = 8.1 Hz, IH), 3.74 (m, IH), 3.13 (q, J - 7.2 Hz, IH), 2.78 (m, 2H),
2.44 (t, 12.2, IH), 2.28 (t, J = 9.6 Hz, IH), 2.16-2.05 (m, 5H), 1.96-1.88 (m, 4H), 1.77-1.52 (m, 9H), 1.23 (d, J = 7.2 Hz, 3H); MS(APCI+) m/z 323 (M+H)+.
Example 7
10 2-Azepan-l-vl-N-[(£V5-hydroxy-2-adamantyl1pr9p^aiTiide
The title compound was prepared according to the method of Example 4C substituting
hexamethyleneimine for cw-2,6-dimethylmorpholine. !H NMR (300 MHz, CDCfe) 6 7.84 (s,
IH), 3.99 (d, J = 8.1 Hz, IH), 3.35 (d, J = 5.9 Hz, IH), 2.71-2.65 (bd, 4H), 2.16-2.10 (m, 3H),
1.89 (d, J =11.9 Hz, 2H), 1.77-1.65 (m, 14H), 1.52 (d, J = 12.8 Hz, 2H), 1.24 (d, J = 6.9 Hz,
15 3H); MS(APCI+) m/z 321 (M+H)+.
Example 8
(ffl-4-f(l4-r5-(TrifIuoromethvty
carbamate
20 A solution of N-[(£)-5-hydroxy-2-adamantyl]-2-{4-[5-(trifluoromethyl)pyridin-2-
yl]piperazin-l-yl}acetamide (44 mg, 0.1 mmoles) from Example 2 in DCM (1 mL) was treated with trichloroacetylisocyanate (13 uL, 0.11 mmoles) and stirred for 2 hours at room temperature. The solvent was removed under reduced pressure, the residue was dissolved in MeOH (1 mL) followed by the addition of saturated potassium carbonate (3 mL) and the
25 mixture stirred overnight at 50 °C. The mixture was concentrated under reduced pressure, partitioned with DCM and the aqueous layer extracted with additional DCM. The combined organic extracts were washed twice with water, dried (MgSO-t) and filtered. The filtrate was concentrated under reduced pressure to provide the title compound as a white solid. 'H NMR (300 MHz, CDCI3) 6 8.42 (s, IH), 7.64 (m, 2H), 6.67 (d, J = 9.2 Hz, IH), 4.4 (s, 2H), 4.12 (d,
30 1= 5.8 Hz, IH), 3.68 (s, 4H), 3.09 (s, 2H), 2.68 (s, 4H), 2.19-2.17 (m, 9H), 1.64-1.63 (m, 4H); MS(APC1+) m/z 482 (M+H)+.
Example 9
ffi-4-f(2-(4-[5-(Trifluoromethyl)p^
acetate
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A solution of N-[(£)-5-hydroxy-2-adamantyl]-2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl}acetamide (44 mg, 0.1 mmoles) from Example 2 in DCM (0.5 mL) and pyridine (0.5 mL) was treated with acetyl chloride (11 uL, 0.15 mmoles), catalytic amount of DMAP and stirred overnight at 50 °C. Solvents were removed under reduced pressure and 5 the residue was purified (silica gel, 10-30% acetone in hexane) to provide the title compound as a white solid. *H NMR (300 MHz, CDCfe) 8 8.41 (s, 1H), 7.64 (m, 2H), 6.65 (d, J = 9.2 Hz, 1H), 4.12 (d, J - 8.1 Hz, 1H), 3.68 (s, 4H), 3.09 (s, 2H), 2.68 (s, 4H), 2.21-2.14 (m, 7H), 1.98 (s, 3H), 1.64 (s, 2H), 1.26-1.22 (m, 4H); MS(APCI+) m/z 481 (M+H)+.
10 Example 10
N-[(2ft-5-(Acetylairano)-2-aQ^antvfl-2-{4-["5^
vl}acetamide
A solution of N-[(£)-5-hydroxy-2-adamantyl]-2-{4-[5-(1rifluoromethyl)pyridin-2-
yl]piperazin-l-yl}acetamide (44 mg, 0.1 mmoles) from Example 2 in TFA (0.5 mL) and
15 acetonitrile (0.1 mL) was stirred overnight at 100 °C. The mixture was adjusted to pH ~ 10
with 2N NaOH and extracted with DCM. The organic layer was washed with water (2x),
dried (MgS04) and filtered. The filtrate was concentrated under reduced pressure and
purified (silica gel, 10-35% acetone in hexane) to provide the title compound as a white solid.
*H NMR (300 MHz, CDCfe) 5 8.41 (s, 1H), 7.64 (m, 2H), 6.67 (d, J = 9 Hz, 1H), 5.16 (s,
20 1H), 4.10 (d, J = 8.4 Hz, 1H), 3.69 (s, 4H), 3.09 (s, 2H), 2.68 (s, 4H), 2.18-2.16 (d, 2H), 2.09
(d, 4H), 2.01 (d, 2H), 1.92 (s, 3H), 1.69-1.63 (m, 5H); MS(APCI+) m/z 480 (M+H)+.
Example 11 N-[fy^-5-Fluoro-2-adamRn^l]-2-{4-f5-ftrifluoromethvnpyridin-2-yl]piperazin-l-
25 yl}acetamirfe
A solution of N-[(£^5-hydroxy-2-adamantyl]-2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl}acetamide (66 mg, 0.15 mmoles) from Example 2 in DCM (0.5 mL) was cooled to -78 °C, treated with (diethylamino)sulfur trifluoride (DAST) (0.020 mL, 0.16 mmoles) and slowly warmed to room temperature over 6 hours. The mixture was quenched
30 with aqueous saturated sodium bicarbonate (0.1 mL), filtered through a Celite cartridge and purified (silica gel, 10-15% acetone in hexane) to provide the title compound as a white solid. 'H NMR (300 MHz, CDCI3) 5 8.42 (s, 1H), 7.63 (m, 2H), 6.68 (d, J = 9.2 Hz, 1H), 4.09 (d, J = 8.5 Hz, 1H), 3.69 (s, 4H), 3.09 (s, 2H), 2.69 (s, 4H), 2.27-2.22 (m, 3H), 2.06 (m, 2H), 1.94 (m, 4H), 1.58-1.54 (m, 4H); (APCI+) m/z 441 (M+H)+.
35
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Exampjft 12
N-f(Z^-5-Fluoro-2-adamantviy2-M-f5-rtriflunromethvnpvridin-2-vnpiperazin-l-
y1}acetamidf!
A solution of N-[(2)-5-hydroxy-2-adamanlyl]-2-{4-[5-(trifluoromethyl)pyridin-2-5 yl]piperazin-l-yl}acetamide (66 mg, 0.15 mmoles) from Example ID in DCM (0.5 mL) was cooled to -78 °C, treated with DAST (0.020 mL, 0.16 mmoles) and slowly warmed to room temperature for 6 hours. The mixture was quenched by the addition of aqueous saturated sodium bicarbonate (0.1 mL), filtered through a Celite cartridge and purified (silica gel, 10-15% acetone in hexane) to provide the title compound as a white solid. *H NMR (300 MHz, 10 CDCh) 5 8.42 (s, IH), 7.67 (m, 2H), 6.67 (d, J = 9.1 Hz, IH), 3:97 (s, IH), 3.7 (s, 4H), 3.1 (s, 2H), 2.68 (s, 4H), 2.29-2.24 (m, 3H), 1.91-1.7 (m, 10H); MS(APCI+) m/z 441 (M+H)+.
Example 13
N-[(^-S-Hydroxy-2-adamantyl1-2-r4-r5-memvlpvridk-2-vnpiperazin-l-yl]propanamide
15
Example 13 A
(£)- and (2V5-hvdroxy-2-adamantaniifie
A solution of 5-hydroxy-2-adamantanone (10 g, 60.161mmoles) and 4A molecular sieves (5 g) in methanolic ammonia (7N, 100 mL) was stirred overnight at room temperature.
20 The mixture was cooled in an ice bath, treated by the portionwise addition of sodium borohydride (9.1 g, 240.64 mmoles) and stirred at room temperature for 2 hours. The mixture was filtered and MeOH was removed under reduced pressure. The mixture was taken into DCM (100 mL), acidified with IN HC1 to pH = 3 and the layers separated. The aqueous layer was treated with 2N NaOH solution to pH = 12 and extracted three times with
25 4:1 THF:DCM. The combined organic extracts were dried (MgSC^) and filtered. The filtrate was concentrated under reduced pressure to provide the title compound as a white solid.
Example 13B
2-Bromo-N-[(£)- and (Z)-5-hydmxy-aHamantan-2-yl]-propionamide
30 A solution of (£)- and (Z)-5-hydroxy-2-adamantamine (Ig, 5.98 mmoles) from
Example 13A in DCM (30 mL) and DEPEA (2.08 mL, 11.96 mmoles) was cooled in an ice bath and treated with 2-bromopropionyl chloride (0.66 mL, 6.58 mmoles). The mixture was stirred for 2 hours at room temperature and DCM was removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was washed with
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saturated sodium bicarbonate, water, dried (MgS04) and filtered. The filtrate was concentrated under reduced pressure to provide the title compound as a dark beige solid. The isomers were separated by column chromatography (silica gel, 5-35% acetone in hexane) to furnish 2-bromo-N-[(£)-5-hydroxy-adamantan-2-yl]propionamide and 2-bromo-N-[(Z)-5-5 hydroxy-adamantan-2-ylJpropionamide.
Example 13C
1 -C5-Methvl-pyridin-2-yl)-piperazine A solution of piperazine (215 mg, 2.5 mmoles), 2-bromo-5-methyl-pyridine (172 mg, 10 1 mmoles) in dioxane (1 mL) and potassium carbonate (276 mg, 2 mmoles) was irradiated by microwaves for 60 minutes at 180 °C. The dioxane was removed under reduced pressure and the residue partitioned between aqueous potassium carbonate and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts washed twice with water, dried (MgSCU) and filtered. The filtrate was concentrated under reduced pressure and 15 the residue was purified (silica gel, 0-10% methanol in dichloromethane) to provide the title compound as a white solid.
Example 13D N-[(£)-5-Hydroxy-7-aHamfl^yrj-2-[4-(5-memvlpyridin-2-vl)p«pftra7in-i-yl]pmpanamide
20 A solution of2-bromo-N-[(£)-5-hydroxy-adamantan-2-yl]-propionamide( 36 mg,
0.12 mmoles) from Example 13B and l-(5-methyl-pyridin-2-yl)-piperazine (21 mg, 0.12 mmoles) from Example 13Q in MeOH (0.5 mL) and DEPEA (0.1 mL) was stirred overnight at 70 °C. The MeOH was removed under reduced pressure and the residue purified (silica gel, 10-40% acetone in hexane) to provide the title compound as a white solid. 'HNMR^OO
25 MHz, CDCls) 5 8.06 (d, J=5.3, 1H), 7.71 (s, 1H), 6.51 (s, 2H), 4.02 (d, J = 8.2 Hz, 1H), 3.56 (s, 4H), 3.12 (m, 1H), 2.68 (bd, 4H), 2.28 (s, 3H), 2.17-2.10 (m, 3H), 1.91-1.88 (d, J= 11.5 Hz, 2H), 1.76 (s, 4H), 1.66 (d, J= 12.5 Hz, 2H), 1.51 (m, 2H), 1.27 (m, 3H); MS(APCI+) m/z 399(M+H)+
30 Example 14
N-[(£)-5-HydVoxy-2-adamantyl]-2-methvl-2-(4-[5-riTifluoromethynpyridm-2-yl]piperazin-l-
yl}propanamide
Example 14A
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2-f4-f5-Trifluoromethvl-pvridin-2-vn-piperazin-l-vn-propioni? acid methyl after
A solution of l-(5-trifluoromethyl-pyridin-2-yl)-piperazine (0.9 g, 3.9 mmoles) in MeOH (13 mL) and DIPEA (1.5 mL) was treated with 2-bromo-propionic acid methyl ester (0.48 mL, 4.3 mmoles) and stirred overnight at 70 °C. The MeOH was removed under 5 reduced pressure and the residue was purified (silica gel, 10-40% acetone in hexane) to provide the title compound as a yellowish solid.
Example 14R
2-Methyl-2-f4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l-yl]-propionic acid methyl ester
10 A solution of 2-[4-(5-irifluorometidyl-pyridin-2-yl)-piperazin-l-yl]-propionic acid
methyl ester (1.23 g, 3.9 mmoles) from Example 14A in dry THF (3 mL) was added dropwise to a -65 °C solution of 1.8 N lithium diisopropylamine (LDA) in dry THF (2.4 mL) and stirred at this temperature for 1 hour. Methyl iodide (0.49 mL, 7.88 mmoles) was added and the mixture was allowed to sbwly warm to room temperature and stir for 2 hours at room 15 temperature. The mixture was quenched with ice/water and partitioned with ethyl acetate. The aqueous layer was extracted with ethyl acetate (3x) and the combined organic extracts washed with water, dried ( MgS04), filtered and the filtrate concentrated under reduced pressure. The residue was purified (silica gel, 10-30% acetone in hexane) to provide the title compound as a yellowish solid. 20
Example 14C 2-Methyl-2-f 4-f 5-1rifluoromethyl-pyridin-2-yl)-pippira7in-1 -yll-propionic acid A solution of 2-methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l-yl]-propionic acid methyl ester (1.05 g, 3.17 mmoles) from Example 14B in dioxane (10 mL) 25 was treated with 5N potassium hydroxide (10 mL) and stirred for 4 hours at 60 °C. The
dioxane was removed under reduced pressure, the residue was neutralized with IN HCl to pH = 7 and extracted three times with 4:1 THF:DCM. The combined organic extracts were dried (MgS04), filtered and the filtrate concentrated under reduced pressure to provide the title compound as a white solid. 30
Example 14D
N-[(^-5-Hvdroxy-2-adamantyl]-2-memyl-2-{4-[5-(trifluoromethynpyridin-2-vl]piperazin-l-
vl}propanamide A solution of 2-methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1 -yl]-
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propionic acid (159 mg, 0.5 mmoles) from Example 14C in DCM (5 mL) and DIPEA (0.5 mL) was treated with hydroxybenzotriazole hydrate (HOBt) (84 mg, 0.6 mmoles), 5-hydroxy-2-adamantamine (100 mg, 0.6 mmoles) from Example 13 A and 15 minutes later with (3-dimethylammopropyl)-3-ethylcarbodiimide HCl (EDCI) (115 mg, 0.6 mmoles). The
5 mixture was stirred overnight at room temperature after which the DCM was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts washed with saturated sodium bicarbonate, water, dried (MgSCU) and filtered. The filtrate was concentrated under reduced pressure and the crude product purified (silica gel, 10-40%
10 acetone in hexane) to provide the title compound as a white solid. 'HNMR^OOMHz,
CDCI3) 6 8.41 (s, 1H), 7.67 (m, 2H), 6.66 (d, J = 9.1 Hz, 1H), 4.0 (d, J = 7.8 Hz, 1H), 3.66 (m, 4H), 2.64 (m, 4H), 2.23-2.1 (m, 3H), 1.9-1.63 (m, 10H), 1.25 (s, 6H); MS(APCI+) m/z 467(M+H)+.
15
Hxymplft 15
(£)-4-{2-Methyl-2-f4-(5-trifluorometh^^
fldq^qntfine-l-carboxylic acid
20 Example 15A
Methyl 2-adamantanone-5-carboxylate
A solution of 5-hydroxy-2-adamantanone (2.0 g, 12.0 mmoO in 99% formic acid (12 mL) was added dropwise with vigorous gas evolution over 40 minutes to a rapidly stirred 30% oleum solution (48 mL) heated to 60 °C (W. J. le Noble, S. Srivastava, C. K. Cheung, J.
25 Org. Chem. 48: 1099-1101,1983). Upon completion of addition, more 99% formic acid (12 mL) was slowly added over the next 40 minutes. The mixture was stirred another 60 rninutes at 60 °C and then slowly poured into vigorously stirred methanol (100 mL) cooled to 0 °C. The mixture was allowed to slowly warm to 23 °C while stirring for 2 hours and then concentrated in vacuo. The residue was poured onto ice (30 g) and methylene chloride (100
30 mL) added. The layers were separated, and the aqueous phase extracted twice more with methylene chloride (100 mL aliquots). The combined methylene chloride solutions were concentrated in vacuo to 50 mL, washed with brine, dried over Na2SC>4, filtered, and concentrated in vacuo to provide the title compound as a pale yellow solid. *H NMR (300 MHz, DMSO-de) 8 3.61 (s, 3H), 2.47-2.40 (bs, 2H), 2.17-1.96 (m, 9H), 1.93-1.82 (m, 2H);
3 5 MS(DCI) m/z 209 (M+H)+
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Exflti^pfle 15R Methvl (£)- and (ZM-adamantamine-1-carboxylate A solution of methyl 2-adamantanone-5-carboxylate (2.0 g, 9.6 mmoles) from 5 Example 15A and 4A molecular sieves (1.0 g) in methanolic ammonia (7N, 17 mL) was
stirred overnight at room temperature. The reaction mixture was cooled in an ice bath, treated portionwise with sodium borohydride (1.46 g, 38.4 mmoles) and stirred at room temperature for 2 hours. The suspension was filtered and MeOH was removed under reduced pressure. The residue was taken into methylene chloride (200 mL) and acidified with 10% citric acid. 10 The pH of the solution was adjusted to neutral with saturated NaHCCb and then saturated
with NaCl. The layers were separated and the aqueous extracted twice more with methylene chloride. The combined organic extracts were dried over Na2S04 and filtered. The filtrate was concentrated under reduced pressure to provide the title compound as a light yellow solid. 'H NMR (300 MHz, CDCfe) 5 3.66 (s, 3H), 3.16 (m, 1H), 2.27-1.46 (m, 13H); MS(DCI) m/z 15 210(M+H)+.
Example 15C
Methyl (E)- and (Z)-4-{2-methyl-2-r4-(5-trifluoromethvl-pwidm-2-vl)-piperazin-l-vl1-
20 proptonylamino}-adqT"aflt?nft- * -carboxvlate
To a 0 °C, heterogeneous solution of 2-methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l-yl]-propionic acid (50 mg, 0.16 mmol) from Example 14C, methyl (£)- and (Zy 4-adamantamine-l-carboxylate (33 mg, 0.16 mmol) from Example 15B. tetrahydrofuran (1.3 mL), and Hunig's base (30 mg, 0.24 mmol) was added solid HATU (60 mg, 0.16 mmol). 25 The stirred reaction mixture was allowed to slowly warm to 23 °C as the ice bath melted overnight (16 hours). LC/MS analysis of the homogenous reaction mixture revealed complete consumption of starting materials. The reaction mixture was concentrated under reduced pressure, and the residue purified with flash silica gel (ethyl acetate/hexanes, 20-80% gradient) to afford the title compound as a mixture of EJZ structural isomers. Carried on as a 3 0 slightly impure EJZ mixture.
Example 15D (£)-4-{2-Methyl-2-["4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l-yn-propionylamino}-
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adamantane-1-carboxvlic acid
A stirred, 23 °C, homogenous solution of methyl (£)- and (2)-4-{2-methyl-2-[4-(5-ttifluorometoyl-pyridin-2-yty-piperazta-^ ^ (19 mg, 0.037 mmol) from Example 15C and methanol (0.5 mL) became cloudy upon
5 addition of 10% aqueous NaOH (1 mL). After stirring for J hour at 23 °C, the reaction
mixture was heated to 50 °C for 1 hour. The mixture was diluted with sat. aqueous NaHCC>3 and extracted three times with a tetrahydrofuran/methylene chloride solution (4/1). The combined organic extracts were dried over Na2S04, filtered, and concentrated under reduced pressure. The E/Z isomers were separated by radial chromatography with 2% methanol in
10 ethyl acetate/hexanes (4/1) as the ehiant to afford the title compound. XH NMR (500 MHz, DMSO-dg) 8 8.41 (s, 1H), 7.79 (dd, J « 2.5, 9 Hz, 1H), 7.71 (d, J - 7.5 Hz, 1H), 6.96 (d, J = 9.5 Hz, 1H), 3.79 (m, 1H), 3.66 (m, 4H), 2.54 (m, 4H), 1.95-1.70 (m, 11H), 1.58-1.52 (m, 2H), 1.13 (s, 6H); MS(DC1) m/z 495 (M+H)+.
15
Fbqifliplft 16
fffi4-({l-[4-(5-TrifluoromelJiyl^
qi^ipo)-^Hamflntane-l-carboxvlic acid
20
N. J\r-Bis-f2-hydroxy-^thyI>2-nitrobenz^n^i Ifnnflm j4, filtered, and concentrated under reduced pressure. The residue was purified by normal phase
30 HPLC on a Biotage pre-packed silica gel column eluting with ethyl acetate to afford the title compound. MS(ESI) m/z 291 (M+H)+
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Example 16B
MAlBis^2-trifluorn^9%ffl^Ufonyfo Triflic anhydride (13.6 g, 48.3 mmol) was added dropwise with stirring to a 0 °C solution of A^iV-bis-(2-hydroxyethyl)-2-nitrobenzenesulfonamide (7.00 g, 24.1 mmol) from 5 Example 16A and 2,4,6-collidine (5.85 g, 48.3 mmol) in anhydrous methylene chloride (50 mL) (J. A. Kozlowski, et aL, Bioorg. Med. Chem. Lett. 12: 791-794,2002). Reaction stirred two hours at 0 °C and then overnight at room temperature. Reaction diluted with chloroform, washed with saturated NaHC03 and brine, dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by normal phase HPLC on a Biotage pre-10 packed silica gel column eluting with 3:1 hexane.ethyl acetate to afford the thle compound. MS(ESI) m/z 555 (M+H)+
Example 16C
15 Methyl l-[4-(2-mtrobenzenesutfonyl)-piperazm-l-yl1^yclopropaneaiit>oxylate
A solution of A^A^-bis^-trifluoromethanesulfonyloxyethyl)^-nitrobenzenesulfonamide (1.83 g, 3.30 mmol) from Example 16B and methyl 1-aminocyclopropane-1-carboxylate HC1 (0.50 g, 3.30 mmol) in anhydrous acetonitrile (10 mL) was treated with sodium carbonate (1.40 g, 13.2 mmol) and heated overnight at 60 °C (J.
20 A. Kozlowski, et aL, Bioorg. Med. Chem. Lett. 12:791-794,2002). Reaction diluted with ethyl acetate, washed with water and brine, dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by normal phase HPLC on a Biotage prepacked silica gel column eluting with 3:1 hexane:ethyl acetate to afford the title compound. MS(ESI) m/z 370 (M+H)+.
25
Example 16D
Methyl l-f4-(54rifluoromethylpyridin-2-ylVpiperazin-l-yl]-cyclopropanecarboxylate
A solution of methyl l-[4-(2-nitrobenzenesulfonyl)-piperazin-l-yl]-
30 cyclopropanecarboxylate (0.60 g, 1.63 mmol) from Example 16C in anhydrous
dimethylformamide (5 mL) was treated with potassium carbonate (0.67 g, 4.88 mmol) and thiophenol (0.21 g, 1.95 mmol) and stirred one hour at room temperature. This reaction mixture was then treated with 2-bromo-5-trifluoromethyl pyridine (0.44 g, 1.95 mmol) and heated overnight at 80 °C. Reaction diluted with ethyl acetate, washed with water and brine,
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dried over NaaSC>4, filtered, and concentrated under reduced pressure. The residue was purified by normal phase HPLC on a Biotage pre-packed silica gel column ehiting with 9:1 hexane:ethyl acetate to afford the title compound. MS(ESI) m/z 330 (M+H)+.
5
Example 1 fiR
l-[4-(5-Trifluoromethylpyridm-2-vlVp^erazm-l-yl1-cyctopropanecarboxylicacid
A solution of methyl l-[4-(5-trifluoromethylpyridin-2-yl)-piperazin-l-yl]-cyclopropanecarboxylate (0.32 g, 0.96 mmol) from Example 16D in tetrahydrofuran (5 mL) 10 and methanol (2mL) was treated with 4 N sodium hydroxide (2.40 mL, 9.60 mmol) and stirred overnight at 60 °C. Reaction mixture concentrated under reduced pressure and dissolved in water. Solution neutralized with 1 N phosphoric acid (pH 7) and extracted three times with chloroform. Extracts dried over Na2SC>4, filtered, and concentrated under reduced pressure to afford the title compound without further purification. MS(ESI) m/z 316 (M+H)+.
15
Methvl (E)- and f2V4-fn-r4^5-trifluoromemvl-pvridin-2-vD-piperazin-l-vl1-cycbpropanecartiopy)}-flmjno)-adamantane-l-carboxylate
20 A solution of l-[4-(5-trifluoromethylpyridin-2-yl)-piperazin-l-yl]-
cyclopropanecarboxylic acid (60 mg, 0.19 mmol) from Example 16E, methyl (£)- and (Z)-4-
adamantamine-1-carboxylate (40 mg, 0.19 mmol) from Example 15B, and 0-(lH-
benzotriazol-l-yO-AWA^AT-te^^ (TBTU) (92 mg, 0.29
mmol) in o^methylformamide (3 mL) was treated, after stirring 5 minutes at room
25 temperature, with JV.iV-dusopropylethylamine (50 mg, 0.38 mmol) and stirred overnight at room temperature. Reaction diluted with ethyl acetate, washed with water, saturated NaHC03, and brine, dried over NajSO.*, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 8:2 to 6:4 hexane:ethyl acetate to afford the title compound. MS(ESI) m/z 507 (M+H)+.
30
Example 16G
(Jg)-4-(H-[4-(5-Trifluoromemyl-pyridin-2-yl)-piperazin-l-yl]-cvclopropanecarbonvl}-aminn)-adamantane-l-carboxvlic acid
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The title compound was prepared using the procedure described in Example 16E starting with methyl (£)- and (Z)-4-({l-[4-(5-trifIuoromethyl-pyridin-2-yl)-piperazin-l-yl]-cycIopropanecarbonyl)-amino)-adamantane-l-carboxyIate from Example 16F. The E and Z isomers were separated by flash chromatography on silica gel eluting with 20:1 to 10:1 5 methylene chloride:methanol to afford the title compound. *H NMR (400 MHz, DMSO-dg) 5 8.41 (s, IH), 8.23 (d, J = 7.5 Hz, IH ), 7.79 (dd, J = 2.5, 9 Hz, IH), 6.96 (d, J - 9.5 Hz, IH), 3.79 (m, IH), 3.70 (m, 4H), 2.50 (m, 4H), 2.00-1.70 (m, 11H), 1.60-1.52 (m, 2H), 1.05 (m, 2H), 0.96 (m, 2H); MS(ESI) m/z 493 (M+H)+.
10
Example 17
(£^4-({l-[4-(5-Trifluoromethvl-pvridin-2-yl)-piperazin-l-yl]-cyplopropanecarbonyl)-
amino)-adamantane-1 -carboxamide
The title compound was prepared according to the procedure outlined in Example 23 15 substituting (£)-4-({l-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l-yl]-
cycfopropanecarbonyl}-amino)-adamantane-l-carboxyIic acid from example 16G for (E)-4-{2-methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l-yl]-propionylammo}-adamantane-1-carboxylic acid. !H NMR (500 MHz, DMSO-d6) 5 8.47 (s, IH), 8.31 (d, J = 9.5 Hz, IH), 7.86 (dd, J = 2.5, 9 Hz, IH), 7.03 (d, J = 9.5 Hz, 2H), 6.75 (bs, IH), 3.88 (m, 20 IH), 3.77 (m, 4H), 2.57 (m, 4H), 2.05-1.80 (m, 1 IH), 1.61 (m, 2H), 1.12 (m, 2H), 1.03 (m, 2H); MS(ESI) m/z 492 (M+H)+.
Example 18
25 (£)-4- (2-[4-(5-Trifluoromethvl-pvridin-2-yl)-piperazin-1 - vl]-butyrylamino} -adamantane-1-
carboxamide
Example 18A
30 Methyl (£)- and (Z)-4-formylamino-adamantane-l-carboxylate
A solution of methyl (£)- and (Z)-4-adamantamine-l-carboxylate (12.7 g, 60.2 mmol) from Example 15B in methyl formate (60 mL) was treated with triethylamine (12.2 g, 120 mmol) and heated overnight at 50 °C in a high pressure tube. The reaction mixture was concentrated under reduced pressure. The residue was purified by normal phase HPLC on a 3 5 Biotage pre-packed silica gel column eluting with 7:3 ethyl acetate.hexane to afford the title
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compound. MS(DCI) m/z 238 (M+H)+.
Example 18B
5 Methvl (£)-4-isocyano-adamantane-l-carboxylate
A -10 °C solution of methyl (£)- and (Z)-4-fomylamino-adamantane-l-carboxylate (6.00 g, 25.3 mmol) from Example 18A and triethylamine (12.8 g, 127mmol) in anhydrous methylene chloride (30 mL) was treated dropwise with phosphorus oxychloride (5.82 g, 38.0 mmol) and reaction stirred one hour at -10 °C and then one hour at room temperature.
10 Reaction cooled back down to 0 °C and quenched with saturated sodium bicarbonate. Organic layer separated and aqueous layer extracted two times with methylene chloride. Combined extracts dried over Na2S04, filtered, and concentrated under reduced pressure. The E and Z isomers were separated by flash chromatography on silica gel eluting methylene chloride to provide the title compound. MS(DCI) m/z 220 (M+H)+.
15
Example 18C
Methyl (£^-4-{2-[4-(5-lrifluoromethyl-pyridin-2-yl)-piperazin-1 -vll-butyrvlamino I-
adamantane-1 -carboxylate
20 A heterogeneous solution of l-[5-trifluoromethyl)-2-pyridyl]piperazine (106 mg, 0.46
mmol), propionaldehyde (14 mg, 0.23 mmol), acetic acid (27 mg, 0.46 mmol), and dried 4 A molecular sieves (25 mg) in anhydrous methanol (2 mL) which had been stirring at room temperature for twenty minutes was treated with methyl (E)-4-isocyano-adamantane-l-carboxylate (50 mg, 0.23 mmol) from Example 18B and stirred two hours at room
25 temperature and overnight at 70 °C. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 7:3 to 1:1 hexane:ethyl acetate to provide the title compound. MS(ESI) m/z 509 (M+H)+.
30 Example 18D
(^4-{2-r4-(5-Trifluoromemyl-pyridm-2-ylVpiperazm-l-vll-butwvlamino}-adamantane-l-
carboxylic acid The title compound was prepared using the procedure described in Example 16E starting with methyl (E)-4-{2-[4-(5-trifluoromethyI-pyridin-2-yl)-piperazin-l-yl]-35 butvrylamino}-adamantane-l-carboxylate from Example 18C. MS(ESI) m/z 495 (M+H)*.
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Example 18E (^-4-(2-r4-(5-Trifluorome^vl-pwidin-2-yl)-piperazm-l-vn-butvrvlamino)-adamantane-l-
carboxamide
5 The title compound was prepared according to the procedure outlined in Example 23
substituting (£)^{2-[4-(5-trifluojromethyl-pyridm-2-yl)-piperazm-l-yl]-butyrylanu^ adamantane-1-carboxylic acid from example 18D for (£)-4-{2-methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazm-1 -yl]-propionylamino } -adamantane-1 -carboxylic acid. 'H NMR (500 MHz, DMSO-de) 5 8.39 (s, IH), 7.77 (dd, J = 2.5, 9 Hz, IH), 7.68 (d, J = 10 9.5 Hz, IH), 6.97 (s, IH), 6.94 (d, J = 9.5 Hz, IH), 6.71 (s, IH), 3.82 (m, IH), 3.58 (m, 4H), 3.12 (m, IH), 2.65 (m, 2H), 2.56 (m, 2H), 1.95-1.70 (m, 1 IH), 1.65 (m, IH), 1.55 (m, IH), 1.41 (m, 2H), 0.83 (m, 3H); MS(ESI) m/z 494 (M+H)+.
15 Example 19
(£)-4-{2-Cyclopropyl-2-f4-f5-trffluoromethyl-pvridm-2-vlVpiperazm-l-yll-acetylamino}-
adaijriantaTie- 1-carboxamide
20 Example 19A
(£V4-{2-Cyclopropyl-2-f 4^5-trifluoromethyl-pyridin-2-vlVpiperazin-1 -yl~|-acetylamino} -
adamantane-1-carboxylic acid
The title compound was prepared using the procedures described in Examples 18 C-D substituting cyclopropanecarboxaldehyde for propionaldehyde.
25
Example 19B
(J^-4-{2-Cyclopropyl-2-r4-(5-trifmoromethvl-pyridm-2-yl)-piperazm
a^qm^i?^ne-l-carboxamide
30 The title compound was prepared using the procedures described in Examples 23
substituting (£)-4-{2-cyclopropyl-2-[4-(5-trifluoromethyl-pyridin-2-yI)-piperazin-l-yl]-acetylamino}-adamantane-1-carboxylic acid from example 19A for (£)-4-{2-methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l-yl]-propionylamino}-adamantane-l-carboxylic acid. 'H NMR (500 MHz, DMSO-d6) 5 8.39 (s, IH), 7.78 (dd, J = 2.5, 9 Hz, IH), 7.56 (d, J =
35 9.5 Hz, IH), 6.98 (s, IH), 6.93 (d, J = 9.5 Hz, IH), 6.72 (s, IH), 3.82 (m, IH), 3.62 (m, 4H),
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2.79 (m, 2H), 2.53 (m, 2H), 2.22 (d, J - 9.5 Hz, IH), 1.95-1.70 (m, 1 IH), 1.43 (m, 2H), 0.99 (m, IH), 0.60 (m, IH), 0.41 (m, IH), 0.27 (m, 2H); MSflSSI) m/z 506 (M+H)+.
5 Example 20
(£V44{144-(5-Trifluoromethvl-pvridin-2-yl)-piperazin-l-yl]-cyctobutanecarbonvl%amin^
adamantane-1 -carboxamide
10 Example 20A
(ii^4-({l-[4-(5-Trifluorome&yl-pyridm^
adamantane-1-carboxylic acid
The title compound was prepared using the procedures described in Examples 18 C-D substituting cyclobutanone for propionaldehyde.
15
Example 20B
(£)-4^{l-f4-(5-Trifluoromemyl-pyqdin-2-yl)-piperazm-l-yn
ada^aTflaqe-1 -carboxam i de
20 The title compound was prepared using the procedures described in Examples 23 substituting (£)-4^{l-[4-(54rifmoromethyl-pyridin-2-yI)-piperazm-l-yl]-cyclobuta^ adamantane-1-carboxylic acid for (£)^{2-metiiyl-2-[4-(5-trirluoromethyl-pyridin-2-yl)-piperazm-l-yl]-propionylanimo}-adamantane-l-carboxylic acid. !H NMR (500 MHz, DMSO-de) 5 8.41 (s, IH), 7.80 (dd, J«2.5, 9 Hz, IH), 7.36 (d, J « 9.5 Hz, IH), 6.99 (s, IH),
25 6.97 (d, J - 9.5 Hz, IH), 6.73 (s, IH), 3.82 (m, IH), 3.63 (m, 4H), 2.53 (m, 4H), 2.22 (m, 2H), 2.14 (m, 2H), 1.95-1.60 (m, 13H), 1.46 (m, 2H); MS(ESI) m/z 506 (M+H)+.
Example 7.1
JV^[(^-5-HvdroxvmelJiv1-adamaiTteD-2-yl]-2-[4-(5-1rffluoromemyl-pyridm-2
30 yl"|-isobutvramide
A solution of (£)-4-{2-meUiyl-2-[4-(5-trh%oromethyl-pyridJn-2-yl)-piperazin-l-yl]-propionylajmmo}-adamantane-l-carboxylic acid (494 mg, 1 mmoles) in THF (2 mL) was cooled to 0 °C and treated with IN borane solution in THF (2 mL). The reaction was stirred at reflux for 20 hours and carefully quenched with water (4 mL) after cooling to room
3 5 temperature. The reaction mixture extracted three times with a tetrahydrofuran/methylene
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chloride solution (4/1). The combiaed organic extracts were dried over Na2S04, filtered, and
concentrated under reduced pressure. The residue was purified with flash silica gel
(acetone/hexanes, 10-40% gradient) to provide the title compound as a white solid. !H NMR
(300 MHz, CDC13) 5 8.41 (s, 1H), 7.77 (d,J= 11.5 Hz, 1H), 7.64 (d, J = 6.3 Hz, 1H), 6.66
5 (d, J= 9.1 Hz, 1H), 6.76 (s, 1H), 3.96 (bd, 1H), 3.66 (s, 4H), 3.25 (d, J = 5.4 Hz, 2H), 2.65 (s,
4H), 1.99 (s, 2H), 1.71-1.56 (m, 12H), 1.25 (s, 6H); MS(ESI+) m/z 481 (M+H)+
Example ID.
JV^f£)-5-Formyl-adamantan-2-yl1-2-[4-(5-n^
10 isnhiityramidft
A solution of N-[(£)-hydroxyme1hyl-adamantan-2-yl]-2-[4-(5-trifluoromethyl-
pyridin-2-yl)-piperazin-l-yl]-isobutyramide (400 mg, 0.83 mmoles) from Example 21 and 4A
molecular sieves in DCE (3 mL) were treated with 4-methylmoipholine-N-oxide (124 mg,
1.24 mmoles) and tetrapropylammonium perruthenate (15 mg, 0.04 mmoles).The reaction
15 was stirred at room temperature for 20 hours, filtered and washed with DCM DCM was
concentrated under reduced pressure to afford the title compound as a white solid.
Example 23
(2^4-{2-Methvl-2-|4-(5-1rifluQ;ro^
20 a faro^^ne-1 -carboxa, mide
A solution of (£)-4-{2-methyl-2-[4-(5-trifluoromemyl-pyridin-2-yl)-piperazin-l-yl]-propionylamino}-adamantane-l-carboxylic acid (100 mg, 0.21 mmoles) from Example 15 in DCM (2 mL) was treated with HOBt (33 mg, 0.22 mmoles) and EDC (46 mg, 0.24 mmoles) and stirred at room temperature for 1 hour. Excess of aqueous (35%) ammonia (2 mL) was
25 added and the reaction was stirred for additional 20 hours. The layers were separated and the aqueous extracted twice more with methylene chloride (2x2 mL). The combined organic extracts were dried over Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure to provide the crude title compound that was purified on reverse phase HPLC to provide the title compound. *H NMR (400 MHz, DMSO-de) 5 8.47 (s, 1H), 7.83 (d, J = 6.8
30 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.02 (d, J= 9.5 Hz, 2H), 6.76 (s, 1H), 3.86 (d, J = 7.9 Hz, 1H), 3.71 (s, 4H), 2.59 (s, 4H), 1.98-1.90 (m, 7H), 1.81-1.77 (m, 4H), 1.58 (d, J= 12.9 Hz, 2H), 1.18 (s, 6H); MS(ESI+) m/z 494 (M+H)+.
Example 24
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(J^-4-{2-Methyl-2-[4-fS-trifluoromethyl-pvridm-2-vn-piperazin-l-vl]-propionylamino}-adamantane-1-carboxylic acid hydrroryamirie
A solution of (£)^-{2-methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l-yl]-propionylamino}-adamantane-l-carboxylic acid (100 mg, 0.21 mmoles) from Example 15 in 5 DCM (2 mL) was treated with HOBt (33 mg, 0.22 mmoles) and EDC (46 mg, 0.24 mmoles) and stirred at room temperature for 1 hour. Excess of aqueous hydroxylamine (2 mL) was added and the reaction was stirred for additional 20 hours. The layers were separated and the aqueous extracted twice more with methylene chloride (2x2 mL). The combined organic extracts were dried over NaaSCv and filtered. The filtrate was concentrated under reduced
10 pressure to provide the crude title compound that was purified on reverse phase HPLC to provide the title compound. *H NMR (400 MHz, Py-d5) 5 8.67 (s, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 4.3 (d, J = 8.3 Hz, 1H), 3.74 (s, 4H), 2.57 (s, 4H), 2.29 (s, 4H), 2.18 (s, 2H), 2.11 (s, 2H), 1.97 (s, 1H), 1.86 (d, J= 13.5 Hz, 2H)), 1.62 (d, J = 13.3 Hz, 2H), 1.31 (s, 6H); MS(ESI+) m/z 510 (M+H)+
15
Example 25
(£V4- {2-j'4-f 5-Trifluonnethyl-pvridin-2-yl)-piperazin-1 -yl1-acety|f»m jnp } -adamantane-1 -
carboxylic acid
20 Example 25A
2-Chloro-jy-rf.E)- and (2V5-hvdroyy-adamantqn-2-v^-acetamide A solution of (£)- and (Z)-5-hydroxy-2-adamantamine (1.7 g, 10 mmoles) in DCM (33 mL) and DPEA (1.47 g, 11.4 mmoles) was cooled in an ice bath and treated with 2-chloroacetyl chloride (0.88 mL, 11 mmoles). The mixture was stirred for 2.5 hours at room
25 temperature and DCM was removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated 1 N HC1, water, brine, dried (NasSC^), filtered, and concentrated in vacuo. The isomers were separated by column chromatography (silica gel, 10-30% acetone in hexane) to furnish 2-chloro-iV-[(^-5-hydroxy-adamantan-2-yl]a(»tanu^eand2-chloro-^-[(Z)-5-hydroxy-adamantan-2-
30 yfjacetamide.
Example 25B Methyl (£)-4-(2-chlp^p-ar^y)aTTiino)-adamantane-1 -carboxylate A solution of 2-chloro-#-[(E)-5-hydroxy-adamantan-2-yl]acetamide (0.5 g, 2.1 mmol)
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from Example 25A in 99% formic acid (3 mL) was added dropwise by addition funnel with vigorous gas evolution to a rapidly stirred 30% oleum solution (13 mL) heated.to 60 °C (W. J. le Noble, S. Srivastava, C. K. Cheung, J. Org. Chem. 48: 1099-1101,1983). Upon completion of addition, more 99% formic acid (3 mL) was slowly added by addition funnel. 5 The mixture was stirred another 60 minutes at 60 °C and then slowly poured into vigorously stirred ice water. The mixture was allowed to slowly warm to 23 °C, filtered and washed with water to neutral pH. The precipitate was dried in a vacuum oven, taken into MeOH (3 mL) and treated with thionyl chloride at 0 °C (0.25 mL, 3.5 mmoles). The reaction mixture was stirring at room temperature for 3 hours and then MeOH was evaporated under reduced 10 pressure to provide the title compound as an off-white solid.
Example 25C
(i^-{2-[4-(5-Trifluomethvl-pyridm^
carboxylic acid
15 A solution of methyl (£)-4-(2-cbJoro-acetylamino)-adamantane-l-carboxylate (0.075
g, 0.26 mmoles) from Example 25B, in MeOH (1.5 mL) and DIPEA (0.05 mL, 0.29 mmoles) was treated with l-(5-trifluoromethyl-pyridin-2-yl)-piperazine (0.091 g, 0.39 mmoles) and stirred for 2 hours at 80 °C. The cooled reaction mixture was purified on reverse phase HPLC and hydrolyzed with 3N HC1 at 60 °C over 6 hours. Drying of the reaction mixture
20 under reduced pressure provided the title compound as a white solid. *H NMR (300 MHz,
DMSO-de) 5 10.48 (bs, 1H), 8.56 (d, J - 7.2 Hz, 1H), 8.48 (bs, 1H), 7.92 (dd, J = 2.4, 9.0 Hz, 1H), 7.07 (d, J = 9.0 Hz, 1H), 4.51 (m, 2H), 4.06 (s, 2H), 3.89 (m, 1H), 3.56 (m, 2H), 3.41 (m, 2H), 3.21 (bs, 2H), 1.90 (m, 9H), 1.80 (m, 2H), 1.47 (m, 2H); MS(DCI+) m/z 467 (M+H)+.
25
Example 26 (^4-[2-(3.3-Difluoro-piperidm-l-yl)-acetylamino]-adamantane-l-carboxvlicacid
A solution of methyl (jE)-4-(2-chloro-acetylamino)-adamantane-l-carboxylate (0.075 g, 0.26 mmoles) from Example 25B, in MeOH (1.5 mL) and DIPEA (0.05 mL, 0.29 mmoles)
30 was treated with 3,3-difluoro-piperidine hydrochbride (0.062 g, 0.39 mmoles) and stirred for 2 hours at 80 °C. The cooled reaction mixture was purified on reverse phase HPLC and hydrolyzed with 3N HC1 at 60 °C over 6 hours. Drying of the reaction mixture under reduced pressure provided the hydrochloride salt of the title compound as a white solid. 'H NMR (300 MHz, DMSO-dfi) 5 8.45 (m, 1H), 3.97 (bs, 2H), 3.88 (m, 1H), 3.65 (m, 2H), 3.23 (m,
35 2H), 2.11 (m, 2H), 1.91 (m, 11H), 1.79 (m, 2H), 1.47 (m, 2H); MS(DCI+) m/z 357 (M+H)-70-

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Example 27
(£)-4-[2-(2-Trifluoromethyl-pyrrolidin-l -yfi-acetvlaTnino'1-adaiTiaTrtane-1 -carboxvlic acid A solution of methyl (£)-4-(2-chloro-acetylamino)-adamantane-l-carboxylate (0.075 g, 0.26 mmoles) from Example 25B, in MeOH (1.5 mL) and DIPEA (0.05 mL, 0.29 mmoles) 5 was treated with 2-trifluoromethylpyrrolidine (0.055 g, 0.39 mmoles) and stirred for 2 hours at 80 °C. The cooled reaction mixture was purified on reverse phase HPLC and hydrolyzed with 3N HC1 at 60 °C over 6 hours. Drying of the reaction mixture under reduced pressure provided the hydrochloride salt of the title compound as a white solid. *H NMR (300 MHz, DMSO-dg) 8 7.72 (d, J = 7.8 Hz, 1H), 3.79 (m, 2H), 3.54 (d, J = 16.5 Hz, 1H), 3.36 (d, J = 10 16.5 Hz, 1H), 3.07 (m, 1H), 2.72 (m, 1H), 2.10 (m, 1H), 1.82 (m, 14H), 1.48 (m, 2H); MS(DCI+) m/z 375 (M+H)+.
Example 28
(lft-4-{2-[4-(5-Trifluoromethyl-pyridm-2-^^
15 car^apiide
A solution of (^^{2-[4^5-trifluoromemyl-pyridm-2-yl)-piperazin-l-yl]-acetylamino}-adamantane-l-carboxylic acid (100 mg, 0.21 mmoles) from Example 25C in DCM (2 mL) was treated with HOBt (32 mg, 0.21 mmoles) and EDC (46 mg, 0.24 mmoles) and stirred at room temperature for 1 hour. Excess of aqueous (35%) ammonia (2 mL) was
20 added and the reaction was stirred for additional 20 hours. The layers were separated and the aqueous extracted twice more with methylene chloride (2x2 mL). The combined organic extracts were dried over Na2S04 and filtered. The filtrate was concentrated under reduced pressure to provide the crude title compound that was purified on reverse phase HPLC to afford the title compound. 'H NMR (400 MHz, Py-d5) 6 8.64 (s, 1H), 7. 9 (d, J = 7.6 Hz,
25 1H), 7.77 (d, J = 9.2 Hz, 1H), 6.82 (d, J = 9.2 Hz, 1H), 4.39 (d, J - 8.3 Hz, 1H), 3.72 (t, J =
4:9 Hz, 4H), 3.25 (s, 2H), 2.62 (t, J - 4.9 Hz, 4H), 2.26 (m, 4H), 2.17 (s, 4H), 1.96 (m, 3H), 1.6 (d J = 12.6 Hz, 2H); MS(ESI+) m/z 466 (M+H)+.
Example 29
30 (J£M-r242-Trifluoromethyl-pyn-oh\lm^^
A solution of (^-4-[2-(2-trifluoromethyl-pyrrolidin-l-yl)-acetylamino]-adamantane-1-carboxylic acid (74 mg, 0.2 mmoles) from Example 27 in DCM (2 mL) was treated with HOBt (33 mg, 0.22 mmoles) and EDC (46 mg, 0.24 mmoles) and stirred at room temperature for 1 hour. Excess of aqueous (35%) ammonia (2 mL) was added and the reaction was stirred
35 for additional 20 hours. The layers were separated and the aqueous extracted twice more with
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methylene chloride (2x2 mL). The combined organic extracts were dried over Na2SC>4 and
filtered. The filtrate was concentrated under reduced pressure to provide the crude title
compound which was purified on reverse phase HPLC to afford the title compound. !H NMR
(300 MHz, CDC13) 5 7.6 (d, J = 6.4 Hz, IH), 5.57-5.2 (bd, 2H), 4.05 (d, J = 8.1 Hz, IH), 3.56
5 (d, J = 17 Hz, IH), 3.32 (m, 2H), 3.22 (m, IH), 2.58 (q, J = 7.4 Hz, IH), 2.08-1.90 (m, 13H),
1.77 (m, 2H), 1.65 (m, 2H); MS(ESI+) m/z 374 (M+H)+.
Example 30
fff)-4-[2-(3.3-Dffluoro-piperidm-l-vl)-^^
10 A solution of (£)-4-[2-(3,3-difluoro-piperidm-l-yl)-acetylamino]-adamantane-l-
carboxylic acid (71 mg, 0.2 mmoles) from Example 26 in DCM (2 mL) was treated with HOBt (33 mg, 0.22 mmoles) and EDC (46 mg, 0.24 mmoles) and stirred at room temperature for 1 hour. Excess of aqueous (35%) ammonia (2 mL) was added and the reaction was stirred for additional 20 hours. The layers were separated and the aqueous extracted twice more
15 with methylene chloride. The combined organic extracts were dried over NajSCU and filtered. The filtrate was concentrated under reduced pressure to provide the crude title compound which was purified on reverse phase HPLC to afford the title compound. *H NMR (300 MHz, CDC13) 5 7.74 (d, J = 8.5 Hz, IH), 5.54-5.18 (bd, 2H), 4.06 (d, J - 8.5 Hz, IH), 3.12 (s, 2H), 2.78 (t, J = 11.2 Hz, 2H), 2.62 (bs, 2H), 2.08-1.80 (m, 15H), 1.6 (m, 2H); MS(ESI+)
20 m/z 356 (M+H)+.
Evftmp1ft31
(£M-[2-(3-Fluoropyn^ohdm-l-yl)-propionylamino]-adamantane-l-carbox
25 Example 31A
(E)-4-(2-Bromo-propinfly1prn ino)-adamantane-1 -carboxvlic acid
A solution of 2-bromo-JV-[(E)-5-hydroxy-adamantan-2-yl]-propionamide from Example 13B(4.0 g, 13.25 mmol) in 99% formic acid (13 mL) was added dropwise with vigorous gas evolution over 40 minutes to a rapidly stirred 30% oleum solution (40 mL) 30 heated to 60 °C (W. J. le Noble, S. Srivastava, C. K. Cheung, J. Org. Chem. 48: 1099-1101, 1983). Upon completion of addition, more 99% formic acid (13 mL) was slowly added over the next 40 minutes. The mixture was stirred another 60 minutes at 60 °C and then slowly poured into vigorously stirred iced water (100 mL) cooled to 0 °C. The mixture was allowed to slowly warm to 23 °C while stirring, filtered and washed with water to neutral pH (1L).
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The precipitate was dried in a vacuum oven to provide the title compound as a white solid.
Example 3 IB (£^-4-(2-Bromo-propionylarr(inoVadamantane-l-carboxamide
A solution of (£)^-(2-bromo-propionylamino)-adamantane-l-carboxylic acid (330
5 mg, 1 mmol) from Example 31A in DCM (5 mL) was treated with HOBt (168 mg, 1.1 mmol)
and EDC (230 mg, 1.2 mmoles) and stirred at room temperature for 1 hour. Excess of aqueous (35%) ammonia (5 mL) was added and the reaction was stirred for additional 2 hours. The layers were separated and the aqueous extracted twice more with methylene chloride (2x5 mL). The combined organic extracts were dried over Na2SC>4 and filtered. The 10 filtrate was concentrated under reduced pressure. The residue was taken into MeOH and formed a white precipitate that was filtered to provide the title compound as a white solid.
Example 31C
(2?M-r2-f3-Fhioropynoh\im-l-yl)-pr^^
A solution of (£)-4-(2-bromo-propionylamino)-adamantane-l-carboxamide (33 mg,
15 0.1 mmol) from Example 31B and the hydrochloride of (3i?)-3-fluoropyrrolidine (15 mg,
0.12 mmol) in MeOH (0.5 mL) and DIPEA (0.1 mL) was stirred overnight at 70 °C. The MeOH was removed under reduced pressure and the residue purified on reverse phase HPLC to provide the title compound as a mixture of 2 diastereomers. *H NMR (400 MHz, Py-ds) 5 7.7 (two d, 1H), 5.2-5.08 (bd, 2H), 4.32 (m, 1H), 3.56 (s, 4H), 3.29-2.95 (m, 2H), 2.6-2.5 20 (m, 2H), 2.25-2.0 (m, 10H), 1.95 (m, 3H), 1.37 (two d, 3H), 1.4 (t, 2H); MS(ESI+) m/z 338 (M+H)+.
Example VL
(E)-4-[2-(3.3-Diffaoropiperidme-l-yl)-prop
25 A solution of (£)-4-(2-bromo-propionylamino)-adamantane-l-carboxamide (33 mg,
0.1 mmoles) and the hydrochloride of 3,3-difluoropiperidine (19 mg, 0.12 mmol) from Example 3 IB in MeOH (0.5 mL) and DIPEA (0.1 mL) was stirred overnight at 70 °C. The MeOH was removed under reduced pressure and the residue purified on reverse phase HPLC to provide the title compound as a white solid. 'HNMR (400 MHz, Py-d5) 8 7.92 (d, J = 7.7
30 Hz, 1H), 7.51 (s, 2H), 4.32 (d, J = 7.7 Hz, 1H), 3.42 (q, J = 7 Hz, 1H), 2.92 (q, J = 10.7 Hz, 1H), 2.78 (q, J =11.6 Hz, 1H), 2.5 (m, 2H), 2.27-2.10 (m, 8H), 1.98-1.88 (m, 5H), 1.68 (m, 2H), 1.55 (m, 2H), 1.32 (d, 3H); MS(ESI+) m/z 370 (M+H)+.
Kvawmlft 33
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f^-4-[2-f2-Trifraoromet]ivlpyrroUdm-l-vlVpropionvlamino]-adamantane-l-carboxamide A solution of (jE)-4-(2-brorjQ»-propionylaniinD)-adamantane-l-carboxamide (33 mg, 0.1 mmol) from Example 3 IB and the hydrochloride of 2-trifhioromethylpyrrolidine (21 mg, 0.12 mmol) in MeOH (0.5 mL) and DIPEA (0.1 mL) was stirred overnight at 70 °C. The 5 MeOH was removed under reduced pressure and the residue purified on reverse phase HPLC to provide the title compound as a mixture of 4 diastereomers. !H NMR (400 MHz, Py-d5) 5 7.81 (d, IH), 4.32 (two d, IH), 3.8 (two m, 2H), 3. 2 (two m, IH), 2.7 (two m, IH), 2.48-1.5 (m, 17H), 1.47 (two d, 3H); MS(ESI+) mlz 388 (M+H)+.
10 Example 34
(iTM-{2-[4-(5-Chloro-pvridm-2-ylVpiperaz^
1-carboxylic acid
Rrample 34A
15 2-Bromo-iV:-f(fi)- and rZV5-hvdroxv-adamantan-2-vl1-2-methyl-prnp)niiqmid<>
A solution of (£)- and (Z)-5-hydroxy-2-adamantamine (8.7 g, 52 mmol) from Example 13A in DCM (150 mL) and DIPEA (25 mL) was cooled in an ice bath and treated with 2-bromoisobutyryl bromide(7.2 mL, 58 mmol) in DCM (25 mL). The mixture was stirred for 2 hours at room temperature and DCM was removed under reduced pressure. The
20 residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water, dried (MgSO-t) and filtered. The filtrate was concentrated under reduced pressure to provide the title compound as a dark beige solid. The isomers were separated by column chromatography (silica gel, 5-35% acetone in hexane) to furnish 2-bromo-^-[(£)-5-hydroxy-adamantan-2-yl]-2-methyl-propionamide and 2-bromo-N-
25 [(Z)-5-hydroxy-adamantan-2-yl]-2-methyl-propionamide.
Example 34B Methyl Cr£)-4-(,2-bromo-2-methyl-propionylamino)-a^arnaTitane-l-carboxvlate A solution of 2-bromo-iV-[(£)-5-hydroxy-adamantan-2-yl]-2-methyl-propionamide 30 (7.84 g, 24.8 mmol) from Example 34A in 99% formic acid (25 mL) was added dropwise
with vigorous gas evolution over 40 minutes to a rapidly stirred 30% oleum solution (75 mL) heated to 60 °C (W. J. le Noble, S. Srivastava, C. K. Cheung, J. Org. Chem. 48: 1099-1101, 1983). Upon completion of addition, more 99% formic acid (25 mL) was slowly added over the next 40 minutes. The mixture was stirred another 60 minutes at 60 °C and then slowly
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poured into vigorously stirred iced water (300 mL) cooled to 0 °C. The mixture was allowed to slowly warm to 23 °C, filtered and washed with water to neutral pH (1L). The precipitate was dried in a vacuum oven, taken into MeOH and treated with thionyl chloride at 0 °C (2 mL, 28 mmol). The reaction mixture was stirring at room temperature for 3 hours and then 5 MeOH was evaporated under reduced pressure to provide the title compound as an off-white solid.
Example 34C
(2l^-{2-r4-(5-CWoro-pvridin-2-vlVpiperaz^
10 1-carboxylic acid
A two phase suspension of methyl (E)-4-(2-bromo-2-methyl-propionylaniino)-adamantane-1-carboxylate (36 mg, 0.1 mmol) from Example 34B, l-(5-chloro-2-pyridyl)piperazine (20 mg, 0.11 mmol) and tetrabutylammonium bromide (3 mg, 0.01 mmol) in DCM (0.2 mL) and 50% NaOH (0.2 mL) was stirred at room temperature for 20 hours.
15 After that the reaction mixture was diluted with water and DCM and layers separated.
Organic layer was washed with water (2x2 mL), dried (MgS04) and filtered. The filtrate was concentrated under reduced pressure to provide crude methyl ester of the title compound that was purified on reverse phase HPLC and hydrolyzed with 3N HCL at 60°C over 6 hours. Drying of the reaction mixture under reduced pressure provided the title compound as a white
20 solid. *H NMR (400 MHz, Py-ds) 6 8.38 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 6.8 (d, J - 9 Hz, 1H), 4.31 (d, J = 8.1 Hz, 1H), 3.64 (s, 4H), 2.59 (s, 4H), 2.25 (m, 4H), 2.17 (s, 2H), 2.11 (s, 2H), 1.96(s, 1H), 1.87(d,J= 14.4Hz,2H), 1.62(d, J= 12.8Hz,2H), 1.31 (s, 6H); MS(ESI+)m/z461 (M+H)+.
Example 35
25 (E)-4-[2-Methvl-2-( 1.2.4.5-tetrahvdro-benzo rd]azepin-3 -vlVpropinnylam inn]-adamantane-1 -
carboxvlic acid The title compound was prepared according to the procedure outlined in Example 34C substituting 2,3,4,5-tetrahydro-lH-benzo[d]azepine for l-(5-chloro-2-pyridyI)piperazine. !H NMR (400 MHz, Py-dj) 8 7.85 (d, J = 7.8 Hz, 1H), 7.24 (m, 4H), 4.33 (d, J = 7.5 Hz, 1H), 30 2.9 (m, 4H), 2.56 (s, 4H), 2.32 (q, J = 14 Hz, 4H), 2.22 (s, 1H), 2.16 (s, 1H), 2.01 (s, 1H), 1.88 (d, J = 12.8 Hz, 2H), 1.78 (m, 2H), 1.65 (d, J = 13.4 Hz, 2H), 1.28 (s, 6H); MS(ESI+) m/z411(M+H)+.
Example 36
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(ffl^-[2-Methvl-2-f4-w-tolvl-rL41diflzepftn^
acid The title compound was prepared according to the procedure outlined in Example 34C substituting l-/w-tolyl-[l,4]diazepane for l-(5-chloro-2-pyridyl)piperazine. 'H NMR (400 5 MHz, Py-d5) 6 7.27 (t, J = 7.7 Hz, IH), 6.74 (s, IH), 6.69 (d, J = 6.4 Hz, 1 H), 6.65 (d, J = 8.6 Hz, 1 H), 4.3 (d, J = 7.3 Hz, IH), 3.54 (t, J = 8 Hz, 2H), 2.8 (s, IH), 2. 5 (s, IH), 2.3 (s, 3H), 2.25 (m, 5H), 2.16 (m, 5H), 1.93 (m, 3H), 1.79 (m, 2H), 1.58 (m, 2H), 1.31 (s, 6H), 1.27 (t, J = 7.4 Hz, 2H); MS(ESI+) m/z 454 (M+H)+.
10 Example 37
f£^-r2-Methvl-2-r4-phenvl-pipe^
The title compound was prepared according to the method of procedure outlined in Example 34C substituting 4-phenyl-piperidine for l-(5-chloro-2-pyridyl)piperazine. *H NMR (400 MHz, Py-ds) 8 7.96 (d, J - 8.1 Hz, IH), 7,41 (m, 4H), 7.29 (m, IH), 4.3 (d, J - 8.1 15 Hz, IH), 2.93 (d, J = 11.6 Hz, 2H), 2.53 (m, IH), 2.31-2.12 (m, 10H), 1.90 (m, 5H), 1.77 (m, 2H), 1.6 (d, J = 12.8 Hz, 2H), 1.35 (s, 6H); MS(ESI+) m/z 425 (M+H)+.
Example 38
^-4-f244-(4-CMoro-phenvlVp^Deridin-l-vl1-2-methvl-nmpionvlamino)-adamantane-l-
20 carboxvlic acid
The title compound was prepared according to the procedure outlined in Example 34C substituting 4-(4-chloro-phenyl)-piperidine for l-(5-chloro-2-pyridyl)piperazine. !H NMR (400 MHz, Py-d5) 5 7.92 (d, J = 8.1 Hz, IH), 7,42 (d, J = 8.5 Hz, 2H), 7.29 (d, J - 8.7 Hz, 2H), 4.3 (d, J - 8.1 Hz, IH), 2.93 (d, J -11.6 Hz, 2H), 2.48 (m, IH), 2.31-2.12 (m, 10H), 25 1.90 (m, 5H), 1.77 (m, 2H), 1.6 (d, J = 13.1 Hz, 2H), 1.35 (s, 6H); MS(ESI+)Wz 459 (M+H)+.
Example 39
(jS>4-{2-[5-(6-CMoro-pvridm-3-ylVhexahydrQ-pyrrolof3.4-c1pyrro
30 propionylamino}-adamantane-l -carboxamide
Example 39A (i>4-{2-r5-(6-CMoro-pwidm-3-yl)-hexahydro-pyiTotor3.4-c]pyrrol-2-vl]-2-methyl-
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prnpJQnylflnrino}-ariamantane-l-rarboxylicacid
The title compound was prepared according to the procedure outlined in Example 34C substituting 2,3,4,5-tetrahydro-lH-benzofdjazepine for l-(5-chloro-2-pyridyl)piperazine.
5 Example 39B
(JjM-{2-f5-(6-Chloro-pyridm-3-ylVfe
propiony1amjnn}-adamantane-l-carboxamide The title compound was prepared according to the procedure outlined in Example 23 substituting (i^-{2-[5-(6-chbro-pyridb-3-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-10 methyl-propionylarnino}-adamantane-l-carboxylic acid for (£)-4-{2-methyl-2-[4-(5-
trifhioromethyl-pyridin-2-yl)-piperazin-l -yl]-propionylamino} -adamantane-1 -carboxylic acid. JHNMR (400 MHz, Py-dj) 8 7.98 (d, J = 3.1 Hz, IH), 7.73 (d, J - 8.1 Hz, IH), 7.32 (d, J = 8.6 Hz, IH), 6.98 (m, IH), 4.23 (d, J = 8.1 Hz, IH), 3.32 (m, 2H), 3.12 (m, 2H), 2.76 (s, 2H), 2.59 (m, 4H), 2.16 (m, 4H), 2.01 (s, 4H), 1.6 (m, 3H), 1.38 (m, 2H), 1.31 (s, 6H); 15 MS(ESI+) m/z 486 (M+H)+.
Example 40
(i^-{2-f4-(5-Fluoro-pyridin-3-yl)-[1,4]Hiay.epan-l-yl]-2-methyl-propionylamino}-
adamantane-1 -carhnxamide
20
Pyaipple 40^
(j^-{244-(5"Fluoro-pyriQ^-3-ylVri.41dlazepan-l-vl1-2-methyl-propionvlamm^
a.da^ia^tane-l -carboxylic acid
The title compound was prepared according to the procedure outlined in Example 34C 25 substituting l-(5-fluoro-pyridin-3-yl)-[l,4]diazepane for l-(5-chloro-2-pyridyl)piperazine.
Example 40B
Y^-4-{2-f4-f5-Fluoro-pvridui-3-vlV[1.41diazepan-l-yll-2-methyl-propionylamino}-
adamantane- 1-carboxamide
30 The title compound was prepared according to the procedure outlined in Example 23
substituting (£)-4-{2-[4-(5-fluoro-pyridin-3-yl)-[l ,4]diazepan-l -yl]-2-methyl-propionylamino}-adamantane-l-carboxylic acid for (£)-4-{2-methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazm-l-yl]-propk)nylammo}-adamantane-l-carboxylic acid. 'H NMR (400
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MHz, Py-dj) 5 8.28 (s, IH), 8.13 (s, IH), 7.44 (d, J = 8 Hz, IH), 7.0 (d, J = 8 Hz, IH), 4.25 (d, J = 8.1 Hz, IH), 3.5 (m, 4H), 2.73 (s, 2H), 2.45 (s, 2H), 2.23 (m, 4H), 2.14 (s, 2H), 2.06 (s, 2H), 1.9 (s, IH), 1.79 (m, 2H), 1.66 (d, J = 12.8 Hz, 2H), 1.55 (d, J = 12.8 Hz, 2H), 1.29 (s, 6H); MS(ESI+) m/z 458 (M+H)+.
Rvamplft 41
(£>4-[2-Methyl-2-(3-pvridm-3-vl-3.9-dia^
adamantane-1 -carboxam i de
10 Example 41A
(£)-4-[2-Methyl-2^3-pwidin-3-yl0.9-diaza-bicycIof4.2.1]non-9-vlVpropiory1aminn]-
flrtamappine-l-carboxylic acid
The title compound was prepared according to the procedure outline in Example 34C substituting 3-pyridin-3-yI-3,9-diaza-bicyclo[4.2.1]nonane for l-(5-chloro-2-15 pyridyl)piperazine.
Example 41B
(£)^[2-Methvl-2-(3-pyridm-3-yl-3.9^iaza-bicyclor4.2.1]non-9-yf>-propionylaTTimn]-
adamantanft-1 -r-arWannide
20 The title compound was prepared according to the procedure outlined in Example 23
substituting (£)-4-[2-methyl-2-(3-pyridin-3-yl-3,9-diaza-bicyclo[4.2.1]non-9-yl)-propionylamino]-adamantane-l-carboxylic acid for (£)-4-{2-methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazm-l-yl]-propionylanu^o}-aJamantane-l-carboxylic acid. *H NMR (300 MHz, CDCls) 8 7.84 (s, IH), 3.99 (d, J - 8.1 Hz, IH), 3.35 (d, J - 5.9 Hz, IH), 2.71-2.65 (bd,
25 4H), 2.16-2.10 (m, 3H), 1.89 (d, J = 11.9Hz, 2H), 1.77-1.65 (m, 14H), 1.52 (d, J= 12.8 Hz,
2H), 1.24 (d, J = 6.9 Hz, 3H); MS(ESI+) m/z 466 (M+H)+.
Example. 42
(£V4-r2-Methyl-2-(2-trifmoromethyl-py^^
30 carboxamide
Example 42A (£M-r2-Methvl-2-(2-trifluoromeliivl-pyrroUdin-l-yl)-propiony1amjnn]-ariamantane-l-
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carboxylic acid The title compound was prepared according to the procedure outlined in Example 34C substituting 2-trifluoromethylpyrrolidine for l-(5-chloro-2-pyridyl)piperazine.
5 Example 42B
(iiM-[2-Methyl-2-(2-trifhoromethv^
carboxyamide
The title compound was prepared according to the procedure outlined in Example 23 substituting (E)-4-[2-methyl-2-(2-trifluoromethyl-pyrrolidin-1 -yl)-propionylamino]-
10 adamantane-1-carboxylic acid for (£)^{2-methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-
piperazm-l-yl]-propionylamino}-adamantane-l-carboxylic acid. lH NMR (400 MHz, Py-ds) 6 7.43 (d, J - 7.8 Hz, IH), 5.54 (bs, IH), 5.18 (bs, IH), 3.99 (d, J = 8.1 Hz, IH), 3.68 (m, IH), 3.05 (m, IH), 2.82 (m, IH), 2.05-1.9 (m, 12H), 1.77 (d, J = 13.1 Hz, 3H), 1.65 (m, 2H), 1.35 (s, 3H); 1.21 (s, 3H); MS(ESI+) m/z 402 (M+H)+.
15
Example. 43
(J5M-r2-(3,3-Difluoro-piperidto-l-yn-2-m^
carhnxamide
20
Example 43 A
(E)-4-[2-(3.3-Difluoro-piperidin-l-ylV2-methy
acid
The title compound was prepared according to the procedure outlined in Example 34C 25 substituting 3,3-difluoropiperidine for l-(5-chloro-2-pyridyl)piperazine.
Example 43B
(E^-^-fSJ-Difluoro-piperidm-l-yft^-methyl-propionvlaminnl-aHflTnantane-l-
carboxamide
30 The title compound was prepared according to the procedure outlined in Example 23
substituting (2s)-4-[2-(3,3 -difluoro-piperidin-1 -yl)-2-methyl-propionylamino]-adamantane-1 -carboxylic acid for (£)-4-{2-methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l-yl]-propionylamino}-adamantane-l-carboxylic acid. lH NMR (400 MHz, Py-ds) 5 7.71 (s, IH),
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5.55 (bs, 1H), 5.22 (bs, 1H), 3.96 (d, J = 8.1 Hz, 1H), 2.71 (s, 2H), 2.54 (s, 2H), 2.05-1.9 (m, 11H), 1.8 (m, 4H), 1.6 (d, J = 13.1 Hz, 2H), 1.23 (s, 6H); MS(ESI+) m/z 384 (M+H)+.
Example 44
5 (£)-4-[2-(3-Fluoro-pvrroUdin-l-yR-2-methyl-propionylamino]-adamantane-l-carboxamide
T^qtpplp. 44 A
(gM-(2-Bromo-2-methyl-propiony1aminnVadamantanfi-^ -carboxvlic acid
A solution of 2-bromo-^-[(i^5-hyd^xy-adamantan-2-yl]-2-methyl-propionamide 10 (7.84 g, 24.8 mmol) from Example 34A in 99% formic acid (25 mL) was added dropwise
with vigorous gas evolution over 40 minutes to a rapidly stirred 30% oleum solution (75 mL) heated to 60 °C (W. J. le Noble, S. Srivastava, C. K. Cheung, J. Org. Chem. 48:1099-1101, 1983). Upon completion of addition, more 99% formic acid (25 mL) was slowly added over the next 40 minutes. The mixture was stirred another 60 minutes at 60 °C and then slowly 15 poured into vigorously stirred iced water (300 mL) cooled to 0 °C. The mixture was allowed to slowly warm to 23 °C, filtered and washed with water to neutral pH (1L). The precipitate was dried in a vacuum oven, to provide the title compound as an white solid.
Example 44B
20 (ii^-(2-Bromo-2-memyl-propiotiYlH^
A solution of (1.72 g, 5 mmol) in (£)-4-(2-bromo-2-methyl-propionylamino)-adamantane-1-carboxylic acid from Example 44A in DCM (15 mL) was treated with HOBt (841 mg, 1.1 mmol) and EDC (1.15 g, 6 mmol) and stirred at room temperature for 1 hour. Excess of aqueous (35%) ammonia (15 mL) was added and the reaction was stirred for
25 additional 2 hours. The layers were separated and the aqueous extracted twice more with
methylene chloride (2x15 mL). The combined organic extracts were dried over Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure. The residue was taken into MeOH and formed a white precipitate that was filtered to provide the title compound as a white solid.
30
Example 44C
fii>4-[2-f3-Fluoro-pvrrohdm-l-yl)-2-methy^
A two phase suspension of (jE^-(2-bromo-2-methyl-propionylamino)-adamantane-l-
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carboxamide (35 mg, 0.1 mmol) from Example 44B, (3iQ-3-fluoropyrrolidine (14 mg, 0.11 mmol) and tetrabutylammonium bromide (3 mg, 0.01 mmol) in DCM (0.2 mL) and 50% NaOH (0.2 mL) was stirred at room temperature for 20 hours. After that the reaction mixture was diluted with water and DCM and layers separated. Organic layer was washed with water 5 (2x2 mL), dried (MgS04) and filtered. The filtrate was concentrated under reduced pressure to provide the title compound as a white solid. *H NMR (300 MHz, Py-d5) 8 7.91 (d, J = 7.7 Hz, 1H), 5.19-5.06 (bd, 1H), 4.29 (d, J =» 8.0 Hz, 1H), 3.0 (m, 1H), 2.91 (m, 1H), 2.58 (m, 1H), 2.39 (q, J «= 7.6 Hz,, 1H), 2.27-2.01 (m, 7H), 1.96-1.85 (m, 6H), 1.53 (m, 3H), 1.35 (d, 6H); MS(ESI+) m/z 352 (M+H)+. 10
Example 45
(£^-{2-r4-(5-Trffluomethvl-pvridm-2^
q^rhny^nnide
A solution of (£)-4-(2-biomo-propbnylamino)-adamantane-l-carboxamide (0.075 g, 15 0.23 mmol) from Example 3 IB in MeOH (1.0 mL) and DIPEA (0.044 mL, 0.25 mmol) was treated with l-(5-trifluoromethyl-pvridin-2-yl)-piperazine (0.058 g, 0.25 mmol) and stirred for 48 hours at 70 °C. The cooled reaction mixture was purified on reverse phase HPLC and drying of the reaction mixture under reduced pressure provided the TFA salt of the title compound as a white solid. *H NMR (400 MHz, Py-d3) 5 8.66 (s, 1H), 7.93 (d, J = 8 Hz, 20 1H), 7.77 (dd, J = 2.8, 9.2 Hz, 1H), 7.62 (s, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.36 (m, 1H), 3.74 (m, 4H), 3.33 (q, J = 6.8 Hz, 1H), 2.67 (m, 2H), 2.57 (m, 2H), 2.27 (m, 4H), 2.16 (m, 5H), 1.94 (m, 3H), 1.60 (m, 2H), 1.34 (d, J - 6.8 Hz, 3H); MS(DCI+) m/z 480 (M+H)+
25 Example 46
(fi)-4-[2-(3.3-Difluoro-piperidin-1 -yl)-2-methyl-propionvlamino]-adamantane-1 -carboxylic
acid 3.4-dimethoxy-benzylamide
A solution of Example 43A (35.0 mg, 0.09mmol) in DMA (5 mL) was treated with TBTU (O- (Benzotrialzol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate) (43.3 mg,
30 0.135 mmol), 3,4-dimethoxy-benzylamine (18.0 mg, 0.108 mmol) and DIEA (Ethyl-
diisopropyl-amine) (0.033 ml, 0.18mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase -HPLC to provide the title compound. !H NMR (400 MHz, DMSO-D6) 5 ppm 1.12 (s, 6 H) 1.49 - 1.58 (m, 2 H) 1.64 - 1.74 (m, 4 H) 1.77 -1.84 (m, 2
35 H) 1.84 - 2.00 (m, 9 H) 2.43 - 2.49 (m, 2 H) 2.69 (m, 2 H) 3.72 (s, 3 H) 3.73 (s, 3 H) 3.79 (m,
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1 H) 4.19 (d, .7=5.83 Hz, 2 H) 6.72 (dd, .7=7.98 Hz, 1.53Hz, 1 H) 6.81 (d, J=l.53 Hz, 1 H) 6.87 (d, 7=7.98 Hz, 1 H) 7.59 (d, 7=7.98 Hz, 1 H) 7.94 (t, 7=5.83 Hz, 1 H); MS(ESI+) m/z 534 (M+H)+.
5
Example 47
(i^-[({4-[2-(3J-Diffaoro-piperidm-l-yl)-2-^
carbonyl}-argipn)-methyll-benzoicacid
A solution of Example 43 A (71.0 mg, 0.18mmol) in DMF (8 mL) was treated with
10 TBTU (O- (Benzotrialzol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate) (77 mg, 0.27 mmol), 4-aminomethyl-benzoic acid methyl ester (36.0 mg, 0.216 mmol) and DIEA (Ethyl-diisopropyl-amine) (0.066 ml, 0.36 mmol). The mixture was stirred at room temperature for 12 hours. Then DCM (15 mL) and H20 (5 mL) were added to reaction mixture. The layers were separated and the organic phase were dried over Na2SC>4 and filtered. The filtrate was
15 concentrated under reduced pressure. The residue was purified by reverse phase -HPLC to provide white powder with MS(ESI+) m/z 532. The white powder was dissolved in THF (2 mL). HjO (2 mL) and LiOH (24 mg, 1 mmol) were added to the THF solution. The reaction mixture was stirred for at room temperature for 12 hours. Then DCM (15 mL) and H2O (5 mL) were added to reaction mixture. The layers were separated and the organic phase was
20 dried over NajSCU and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase -HPLC to provide the title compound. 'H NMR (500 MHz, DMSO-D6) 5 ppm 1.12 (s, 6 H) 1.50 - 1.59 (m, 7=12.79 Hz, 2 H) 1.63 - 1.74 (m, 4 H) 1.82 (d, 7=2. 18 Hz, 2 H) 1.85 - 1.97 (m, 9 H) 2.44 - 2.49 (m, 2 H) 2.69 (t, .7=11.07 Hz, 2 H) 3.78 (d, .7=7.49 Hz, 1 H) 4.30 (d, .7=5.93 Hz, 2 H) 7.26 (d, .7=8.11 Hz, 2 H) 7.59 (d, .7=8.11
25 Hz, 1 H) 7.85 (d, 7=8.11 Hz, 2 H) 8.07 (t, 7=5.93 Hz, 1 H); MS(ESI+) m/z 518 (M+H)+.
Example 48
(J^-[2-(3.3-Difhioro-piperidm-l-yl)-2-mem^^
30 acid (furan-2-ylmethyl)-amide
A solution of Example 43A (35.0 mg, 0.09mmol) in DMF (5 mL) was treated with TBTU (O- (BenzotriaIzol-l-yl>l,l,3,3-tetramethyluronium tetrafluoroborate) (43.3 mg, 0.135 mmol), furfurylamine (10.5 mg, 0.108 mmol) and DIEA (Ethyl-diisopropyl-amine) (0.033 ml, 0.18 mmol). The mixture was stirred at room temperature for 12 hours. The 3 5 reaction mixture was concentrated under reduced pressure. The residue was purified by
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reverse phase -HPLC to provide the title compound. 'H NMR (400 MHz, DMSO-D6) 8 ppm 0.85 - 1.01 (s, 6 H) 1.40 - 1.55 (m, 2 H) 1.55 - 1.79 (m, 19 H) 2.24 - 2.34 (m, 2 H) 3.50 - 3.58 (m, 1 H) 6.93 - 7.01 (m, 3 H) 7.07 (t, J±1.61 Hz, 2 H) 7.26 (t, .£=5.52 Hz, 1 H) 7.37 (d, ^7.98 Hz, 1 H); MS(ESI+) m/z 464 (M+H)+.
Example. 49
(2i^-(2-f3.3-Difluoro-piperidinrl-vl)-2-metfo^
acid fthiazol-5-ylmethylVamide
10 A solution of Example 43 A (35.0 mg, 0.09mmol) in DMA (5 mL) was treated with
TBTU (0- (Benzotrialzol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate) (43.3 mg, 0.135 mmol), thiazol-5-yl-methylamine (12.0 mg, 0.108 mmol) and DIEA (Ethyl-diisopropyl-amine) (0.033 ml, 0.18 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was
15 purified by reverse phase-HPLC to provide the title compound. *H NMR (400 MHz, DMSO-
D6) 5 ppm 1.12 (s, 6 H) 1.48 - 1.59 (m, 2 H) 1.64 - 1.76 (m, 4 H) 1.80 - 1.85 (m, 2 H) 1.86 -2.00 (m, 9 H) 2.44 - 2.49 (m, 2 H) 2.69 (t, J=\ 1.51 Hz, 2 H) 3.78 (d, J==7.67 Hz, 1 H) 4.39 (d, >6.14 Hz, 2 H) 7.26 (s, 1 H) 7.59 (d, Ml.61 Hz, 1 H) 8.03 (t, >6.14 Hz, 1 H) 9.01 - 9.05 (m, 1 H); MS(ESI+) m/z 481(M+H)+.
Example 50
(j^-f2-(3J-Difluoro-piperidin-l-vrH2-m
acid 2-methoxy-benzylamide
25 A solution of Example 43 A (3 5.0 mg, 0.09mmol) in DMA (5 mL) was treated with
TBTU (O- (Benzotrialzol-l-yl^l.l^.S^etramethyluronium tetrafluoroborate) (43.3 mg, 0.135 mmol), 2-methoxy-benzylamine (15.0 mg, 0.108 mmol) and DIEA (Ethyl-diisopropyl-amine) (0.033 mL 0.18 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by
3 0 reverse phase -HPLC to provide the title compound. 'H NMR (400 MHz, DMSO-D6) 8 ppm 1.10 - 1.15 (m, 6 H) 1.51 - 1.99 (m, 17 H) 2.44 - 2.49 (m, 2 H) 2.64 - 2.74 (m, 2 H) 3.58 -3.60 (m, 1 H) 3.80 (s, 3 H) 4.22 (d, ^=5.83 Hz, 2 H) 6.86 - 6.93 (m, 1 H) 6.94 - 6.98 (m, 1 H) 7.02 - 7.07 (m, 1 H) 7.17 - 7.24 (m, 1 H) 7.57 - 7.63 (m, 1 H) 7.79 - 7.85 (m, 1 H); MS(ESI+) m/z 504 (M+H)+.
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Example 51
(^-4^2-Memyl-2-phenylaniino-propionylamino)-adamantane-l-carboxamide
(jE^4-(2-Memyl-2Tphenylamino-propionylamino)-adamantane-l-carboxylie acid 5 (MS(ESI+) m/z 357 (M+H)*) was prepared according to the method of Example 34
substituting aniline for l-(5-chloro-2-pyridyl) piperazine. A solution of (E)-4-(2-methyl-2-
phenylamino-propionylamino)-adamantane-l-carboxylic acid (23.6 mg, 0.07mmol) inDCM
(1 mL) was treated with HOBt (10 mg, 0.073mmol) and EDC (15.4 mg, 0.08 mmol) and
stirred at room temperature for 1 hour. Excess of aqueous (30%) ammonia (1 mL) was added
10 and the reaction was stirred at room temperature for additional 2 hours. The reaction mixture
was concentrated under reduced pressure. The residue was purified by reverse phase -HPLC
to provide the title compound. *H NMR (300 MHz, DMSO-D6) 6 ppm 1.24 - 1.34 (m, 2 H)
1.37 (s, 6 H) 1.38 -1.48 (m, 2 H) 1.59 -1.89 (m, 9 H) 3.78 (d, >7.$0Hz, 1H) 5.81 (s, 1 H)
6.53 (d, 2 H) 6.60 (m, 1 H) 6.69 (s, 1 H) 6.95 (s, 1H) 7.03 -7.13 (m, 2 H) 7.26 (d, 1H);
15 MS(ESI+) m/z 3 56 (M+H)+.
Example 52
(j5^-[2-Methyl-2-(3-pyridm-3-vl-3.9-diaza-bicvclo[4.2.11non-9-yl)-propbnylamino]-
ariamflntftne-1-carboxamide
20
Example 52A
(J^-[2-Methvl-2-(3-pyridfa-3-vl-3.9-dira^
adamantane-1-carboxylic acid
The title compound was prepared according to the method outlined in Example 34C 25 substituting 3-pyridin-3-yl-3,9-diaza-bicyclo[4.2.1]nonane for l-(5-chloro-2-pyridyl)piperazine.
Example 52B
(E)-4-[2-Methvl-2-(3 -pyridin-3 -yl-3.9-diaza-bicvclo \ 4.2.11non-9-yl)-propionvlamino]-
30 adamantane-1 -carboxamide
The title compound was prepared according to the method outlined in Example 23 substhuting(£)-4-[2-methyl-2-(3-pyridin-3-yl-3,9-diaza-bicyclo[4.2.1]non-9-yl)-propionylamino]-adamantane-l-carboxylic acid for (£)-4-{2-methyl-2-[4-(5-trifluoromethyl-
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pyridin-2-yl)-piperazia-l-yl]-propionylamino}-adamantane-l-carboxylic acid. ]H NMR (400 MHz, Py-ds) 5 8.56 (d, J = 2.4 Hz, IH), 8.18 (d, J = 3 Hz, IH), 7.32 (d, J = 7.7 Hz, IH), 7.18 (m, 2H),, 4.31 (d, J = 7.7 Hz, IH), 3.74 (d, J = 13.5 Hz, IH), 3.56 (m, 2H), 3.40 (m, 2H), 3.1 (d, J = 13.5 Hz, IH), 2.29-2.04 (m, 12H), 1.95-1.85 (m, 2H), 1.7701.74 (m, 2H), 1.57 (m, 5 2H), 1.4 (m, IH), 1.31 (s, 6H); MS(BSI+) m/z 466 (M+H)+.
Example 53
ffi-4-{2-Methvl-2-f5-f3-trifhiorome^
adairiantane-1-carboxylic acid
10 The title compound was prepared according to the method outlined in Example 34C
substituting l-(3-trifluoromethyl-phenyl)-[l,5]diazocane for l-(5-chloro-2-pyridyl)piperazine. *H NMR (400 MHz, Py-d3) 5 7.42 (t, J = 7.8 Hz, IH), 7.07 (d, J = 7.6 Hz, IH), 7.03 (s, IH), 6.91 (d, J - 8.6 Hz, IH), 4.25 (s, IH), 3.55 (s, 4H), 2.53 (s, 4H), 2.26 (m, 4H), 2.16 (s, 4H), 1.94 (m, 2H), 1.76 (s, 5H), 1.58 (m, 2H), 1.33 (s, 6H); MS(ESI+) m/z
15 522(M+H)+.
Example 54
(£V4-{2-f7-f5-Bromo-pyridin-2-yl)-3.7-diaza-bicvclo|'3.3.1Tnon-3-yl1-2-methyl-pmpfo^y|ami^o}-adamantane-1-r.flrbo^tT1idft
20
Example 54A
(^-4-{2-r7-f5-Bromo-pyridin-2-yl)-3.7-diaza-bicyctof3.3.11non-3-yll-2-methyl-propionylajnino}-adamantane-l-carboxylic acid
The title compound was prepared according to the method outlined in Example 34C 25 substituting 3-(5-bromo-pyridin-2-yl)-3,7-diaza-bicyclo[3.3. ljnonane for.
Example 54B
(E^-4-(2-r7-/5-Bromo-pvridin-2-vlV3.7-diaza-bicvclof3.3. nnon-3-vri-2-methvl-propionvlamino) -adamantane-1 -carboxamide
30 The title compound was prepared according to the method outlined in Example 23
substituting (£)-4-{2-[7-(5-bromo-pyridin-2-yl)-3,7diaza-bicyclo[3.3.1]non-3-yl]-2-methyl-propionylamino}-adamantane-l-carboxylic acid for (£)-4-{2-methyl-2-[4-(5-trifluoromethyl-pyridm-2-yl)-piperazm-l-yI]-propionylamino}-adamantane-l-carboxylic acid. *H NMR (400
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MHz, Py-d3) 8 8.48 (s, IH), 7.69 (m, IH), 7.14 (d, J = 4.1 Hz, IH), 6.55 (d, J = 9.2 Hz, IH), 4.03 (d, J = 6.1 Hz, IH), 3.8 (d, J = 12.6 Hz, 2H), 3.18 (m, 2H), 2.75 (d, J = 11 Hz, 2H), 2.32-2.14 (m, 9H), 2.04-2.0 (m, 4H), 1.69 (s, IH), 1.5-1.39 (m, 3H), 1.20 (s, 6H), 1.15 (d, J = 12.6 Hz, 2H); MS(ESI+) m/z 545 (M+H)+.
Example 56
JVa-r2-(4-Chlorophenvnel^yl]-A^-[(£)-5-h.ydroxv-2-adamantyl1alamnamide The title compound was prepared according to the method of Example I3D 10 substitutmg 2-(4-cWoro-phenyl)-ethylaniine for l-(5-methyl-pyridin-2-yl)-piperazine. *H NMR (500 MHz, Py-dj) 5 8.42 (d, J= 6.39 Hz, IH), 7.30-7.27 (m, 2H), 7.23-7.20 (m, 2H), 4.36-4.25 (m, IH), 4.10-3.99 (m, IH), 3.34-3.15 (m, 2H), 3.13-2.92 (m, 2H), 2.30-2.21 (m, 2H), 2.17-2.02 (m, 3H), 2.01-1.95 (m, 5H), 1.94-1.81 (m, 2H), 1.61 (d, J = 6.84 Hz, 3H), 1.50-1.43 (m, 2H); MS(ESI) m/z 377 (M+H)+.
Example 57
2-(4-Ben2rylpiperidin-l-yl)-N-[ffi)-5-hydroxy-^-aHqi^anty|]pfnpaTiaTriiH<»
The title compound was prepared according to the method of Example 13D 20 substituting 4-benzyl-piperidine for l-(5-methyl-pyridin-2-yl)-piperazine. *H NMR (500
MHz, Py-dj) 8 8.45 (m, IH), 7.36 (dd, J = 7.5,7.5 Hz, 2H), 7.27 (m, IH), 7.20 (m, 2H), 4.31 (m, IH), 3.87 (bs, IH), 3.13 (m, 2H), 2.66 (m, IH), 2.51 (d, J= 6.5 Hz, 2H), 2.42 (m, IH), 2.28 (m, IH), 2.24 (m, IH), 2.10 (m, 3H), 1.98 (m, 6H), 1.65 (m, 3H), 1.54 (bs, IH), 1.51 (bs, IH), 1.47 (m, 2H), 1.44 (d,V= 6.5 Hz, 3H); MS(ESI) m/z 397 (M+H)+. 25
Eyamplft 58
N-[(£)-5-Hydroxv-2-adamantvll-2-f6.7.9.10-tetrahvdro-8H-fl.31dioxolor4.5-g]|"31benzazepin-8-yl)propanamide
30
Example 58A
(4-Hydroxymethy-l .3-benzodioxol -5-yDmethanol
A solution of 1.0 M borane-tetrahydrofuran complex (200 mL, 200 mmoles) at 0 °C was treated portion-wise over 30 minutes with 5-formyl-benzo[l,3]dioxole-4-carboxylic acid
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(10 g, 51.5 mmoles) (F. E. Ziegler, K. W. Fowler, J. Org. Chem.41: 1564-1566, 1976). Following the final addition, the mixture was stirred one hour at room temperature. The mixture was cooled to 0 °C, quenched with water, and concentrated under reduced pressure to remove the tetrahydrofbran. The aqueous residue was acidified with 3N aqueous HC1, and the product extracted with chloroform. The combined extracts were dried over Na2S04, filtered, and concentrated under reduced pressure to afford the title compound. MS(DCI) m/z 182 (M+H)+
10 Example 58B
4.5-BisfcMoromethyl)-1.3-benzodioxole
A 0 °C solution of (4-hydroxymethy-l,3-benzodioxol -5-yl)methanol (8.55 g, 47.0 mmoles) from Example 58A in anhydrous methylene chloride (50 mL) was treated dropwise with tbionyl chloride (17 mL, 235 mmoles). The mixture was stirred one hour at room 15 temperature and then concentrated under reduced pressure to afford the title compound. MS(DCI) m/z 218 (M+H)+.
Example 58C
20 (5-Cyanomcthyl-l .3-benzodioxol-4-yDacetonitrile
A 0 °C suspension of sodium cyanide (7.4 g, 150 mmoles) in anhydrous dimethyl sulfoxide (80 mL) was treated portionwise with 4,5-bis(chloromethyl)-l,3-benzodioxole (10.2 g, 47.0 mmoles) from Example 58B. The mixture was stirred two hours at room temperature. Ice was added to the mixture, and the solids that formed were filtered off and
25 washed with water. Solids were dissolved in chloroform, and solution washed with dilute aqueous NaOH, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by normal phase HPLC on a Biotage pre-packed silica gel column eluting with 7:3 hexane:ethyl acetate to afford the title compound. MS(DCI) m/z 201 (M+H)+.
30
Example 58D 7.8.9.10-Tetrahvdro-6//--fl.3]dioxolor4.5-g]r3]benzazepine
(5-Cyanomethyl-l,3-benzodfoxol-4-yl)acetonitrile (6.00 g, 30.0 mmoles) from 35 Example 58C was reductively cyclized with Raney-Nickel (1.21 g) under a hydrogen
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atmosphere and high pressure (1100 p.s.i.) in a 10% ammonia in ethanol solution (121 mL) at 100 °C for one hour. The mixture was cooled, and the catalyst filtered off and washed with hot ethanol. The mixture was concentrated under reduced pressure, and the residue purified by normal phase HPLC on a Biotage pre-packed silica gel column eluting with 7:3 methylene 5 chloride:methanol to afford the title compound. MS(DCI) m/z 192 (M+H)+..
Example 58F.
N-[(^-S-Hvdroxv-2-adamantvll-2-(;6.7.9.10-tetrahvdro-8H-ri.31dioxolor4.5-
10 g][31benzazepin-8-yl)prnpanamide
The title compound was prepared according to the method of Example 13D substituting 7,8,9,10-tetrahydro-6#-[l,3]dioxolo[4,5-g][3]beiizazepine from example 58D for l-(5-methyl-pyridin-2-yl)-piperazine. !H NMR (400 MHz, DMSO-d6) 8 7.75 (d, J= 8 Hz, 1H), 6.60 (m, 2H), 5.93 (s, 2H), 3.77 (m, 1H), 3.39 (q, J= 6.76 Hz, 1H), 2.80 (m, 4H), 2.65-15 2.50 (m, 4H), 2.05-1.90 (m, 3H), 1.80-1.55 (m, 8H), 1.40 (m, 2H), 1.03 (d, J= 6.86 Hz, 3H); MS(ESI)m/z413 (M+H)+.
Example 59
20 N-[(^-5-Hvdroxv-2-adamantyl]-2-(4-pyridin-2-vlpiperazin-l-vl)propanamide
The title compound was prepared according to the method of Example 13D substituting l-pyridin-2-yl-piperazine for l-(5-methyl-pyridm-2-yl)-piperazine. !HNMR (500 MHz, Py-d3) 5 8.40 (ddd, 7= 0.89, 2.00,4.85 Hz, 1H), 7.89 (d, 7= 7.99 Hz, 1H), 7.53 (ddd, J= 2.03, 7.10, 8.58 Hz, 1H), 6.81 (dt, J= 0.80, 8.63 Hz, 1H), 6.68 (ddd, J= 0.83,4.85, 25 7.09 Hz, 1H), 5.81-6.00 (bs, 1H), 4.30-4.35 (m, 1H), 3.62-3.75 (m, 4H), 3.30 (q, 7= 6.98 Hz, 1H), 2.66-2.72 (m, 2H), 2.56-2.62 (m, 2H), 2.20-2.26 (m, 2H), 2.08-2.13 (m, 3H), 1.96-2.02 (m, 4H), 1.81-1.88 (m, 2H), 1.50-1.56 (m, 2H), 1.34 (d, J= 6.98 Hz, 3H); MS(ESI) m/z 385 (M+H)+.
30
Kxamplp. 60
2-[4-(4-Fluorophenyl)piperazin-l-vl'l-N-[(£)-5-hydroxy-2-adamantyl]propanamide
The title compound was prepared according to the method of Example 13D substituting l-(4-fluoro-phenyl)-piperazine for l-(5-methyl-pyridin-2-yl)-piperazine. !H
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NMR (500 MHz, Py-d5) 5 7.86 (d, 7 = 7.93 Hz, IH), 7.12-7.16 (m, 2H), 6.98-7.02 (m, 2H), 4.29-4.38 (m, IH), 3.32 (q, 7= 6.97 Hz, IH), 3.11-3.25 (m, 4H), 2.71-2.81 (m, 2H), 2.59-2.69 (m, 2H), 2.21-2.28 (m, 2H), 2.07-2.15 (m, 3H), 1.96-2.03 (m, 4H), 1.81-1.89 (m, 2H), 1.50-1.59 (m, 2H), 1.37 (d, 7= 6.97 Hz, 3H); MS(ESI) m/z 402 (M+H)+.
Example 61
N-r(^-5-Hvdroxv-2-adamantyl1-2-f4-(4-methoxyphenyl)piperazin-1 -vl]propanamide The title compound was prepared according to the method of Example 13D 10 substituting l-(4-methoxy-phenyl)-piperazinefor l-(5-methyl-pyridin-2-yl)-piperazine. JH NMR (500 MHz, Py-d3) 5 7.89 (d, 7= 7.97 Hz, IH), 7.00-7.10 (m, 4H), 5.89-5.92 (bs, IH), 4.28-4.38 (m, IH), 3.70 (s, 3H), 3.32 (q, 7= 6.97Hz, IH), 3.12-3.25 (m,-4H), 2.72-2.82 (m, 2H), 2.60-2.71 (m, 2H), 2.19-2.28 (m, 2H), 2.05-2.14 (m, 3H), 1.97-2.02 (m, 4H), 1.82-1.89 (m, 2H), 1.49-1.56 (m, 2H), 1.38 (d, 7= 6.97 Hz, 3H); MS(ESI) m/z 414 (M+H)+. 15
Example 62
2-[4-(5-Cyanopyridm-2-yl)piperazm-l-yl]-N-[(fo
The title compound was prepared according to the method of Example 13D
20 substitutmg6-piperazm-l-yl-iiicotmonitrilefor l-(5-methyl-pyridin-2-yf)-piperazine. ]H
NMR (500 MHz, Py-d5) 5 8.64 (dd, J= 0.72, 2.35 Hz, IH), 7.88 (d, 7= 7.86 Hz, IH), 7.74
(dd, 7= 2.38, 8.99 Hz, IH), 6.77 (dd, 7= 0.82, 9.05 Hz, IH), 4.28-4.37 (m, IH), 3.65-3.82
(m, 4H), 3.35 (q, 7= 6.96 Hz, IH), 2.63-2.73 (m, 2H), 2.55-2.60 (m, 2H), 2.20-2.29 (m, 2H),
2.07-2.15 (m, 3H), 1.96-2.04 (m, 4H), 1.82-1.92 (m, 2H), 1.52-1.59 (m, 2H), 1.34 (d, 7= 6.95
25 Hz, 3H); MS(ESI) m/z 410 (M+H)+.
Example 63 2-[4-(2-Furoyl)piperazin-l-yl]-N-|"(£)-5-hydroxy-2-adamantyl1propanamide
30 The title compound was prepared according to the method of Example 13D
substituting furan-2-yl-piperazin-l-yl-methanone for l-(5-methyl-pyridin-2-yl)-piperazine. 'H NMR (500 MHz, Py-d5) 5 7.84 (d, 7= 7.86 Hz, IH), 7.74 (dd, 7= 0.87, 1.75 Hz, IH), 7.23 (dd, 7= 0.83, 3.39 Hz, IH), 6.55 (dd, 7= 1.72, 3.43 Hz, IH), 5.70-6.05 (bs, IH), 4.30-4.37 (m, IH), 3.79-3.94 (m, 4H), 3.32 (q, 7= 6.97 Hz, IH), 2.55-2.67 (m, 2H), 2.49-2.55 (m,
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2H), 2.19-2.28 (m, 2H), 2.09-2.14 (m, 2H), 1.98-2.03 (m, 4H), 1.92-1.98 (m, IH), 1.81-1.88 (m, 2H), 1.50-1.58 (m, 2H), 1.31 (d, J= 6.94 Hz, 3H); MS(ESI) m/z 402 (M+H)+.
5 Example 64
2-(1.3-Dihydro-2H-isoindol-2-ylVN-[(J^-5-hydroxv-?-nrfarnantvilpropanamide
The title compound was prepared according to the method of Example 13D substituting 2,3-dihydro-lH-isoindole for l-(5-methyl-pyridin-2-yl)-piperazine. JHNMR (500 MHz, Py-d5) 8 7.62 (d, J= 7.64 Hz, IH), 7.24-7.30 (m, 4H), 4.32-4.40 (m, IH), 4.09-10 4.13 (m, 2H), 4.00-4.04 (m, 2H), 3.51 (q, J= 6.82 Hz, IH), 2.23-2.28 (m, 2H), 2.08-2.12 (m, 2H), 1.98 (q, 7= 2.94 Hz, IH), 1.95-1.97 (m, 2H), 1.93-1.95 (m, 2H), 1.74-1.83 (m, 2H), 1.49 (d, 7= 6.78 Hz, 3H), 1.39-1.45 (m, 2H); MS(ES1) m/z 341 (M+H)+.
15 Example 65
N-r(^-5-Hydrnyy-2-adaTnqnty1]-2-{4-[4-(trifluoromethyRphenvl1piperazin-l-
y|}p^r>panamiHe
The title compound was prepared according to the method of Example 13D
substituting l-(4-trifluoromethyl-phenyl)-piperazine for l-(5-methyl-pyridin-2-yl)-piperazine.
20 JH NMR (500 MHz, Py-dj) 8 7.87 (d, J== 7.88 Hz, IH), 7.62-7.66 (m, 2H), 7.07 (d, J= 8.57
Hz, 2H), 4.29-4.39 (m, IH), 3.29-3.40 (m, 5H), 2.71-2.77 (m, 2H), 2.62-2.68 (m, 2H), 2.20-2.30 (m, 2H), 2.11-2.14 (m, 3H), 1.95-2.06 (m, 4H), 1.80-1.92 (m, 2H), 1.53-1.58 (m, 2H), 1.37 (d, J= 6.97 Hz, 3H); MS(ESI) m/z 452 (M+H)+.
25
P.vamplft 66 and Example 67
f2lS)-N-rf£^-5-Hvdroxy-2-aHamantvl1-2-{4-f5-(trifluoromethylVyridin-2-yllpiperazin-l-yl}prnpan^mideajidf2J?VN-rffi)-5-Hvdroxv-?--?d»^a"tyl]-2-{4-[5-(tiifluoromethyl)pyridin-
2-vl]piperazin-l-vl}propanamide
30 The two enantiomers of Example 3, ^-[(£)-5-hydroxy-2-adamantyl]-2-{4-[5-
(trifluoromethyl)pyridin-2-yl]piperazin-l-yl}propanamide, were separated by chiral chromatography (Chiralcel OD Chiral Technologies Column; Isocratic mobile phase, 12% ethanol in hexanes, 1.0 mL/minutes, 10 minutes runtime; 254 nm and 210 nm UV detection; retention times: 6.8 min and 8.3 min.). Spectral information is identical as with earlier
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racemic material. JH NMR (300 MHz, CDC13) 8 8.41 (s, IH), 7.65 (m, 2H), 6.67 (d, J = 8.8 Hz, IH), 4.03 (d, J = 8.5 Hz, IH), 3.69 (m, 4H), 3.15 (q, J = 7.1 Hz, IH), 2.63 (m, 4H), 2.15 (m, 3H), 1.9 (m, 2H), 1.77 (m, 4H), 1.66 (m, 2H), 1.52 (s, IH), 1.36 (s, IH), 1.28 (d, J = 7.1 Hz, 3H); MS(APCI+) m/z 453 (M+H)+. 5
Example 68
2-[3-(4-CMorophenoxv)azetidm-l-vl1-N-ff£)-5-hvdroxv-2-adamantyllprnpanaTnjrie
The title compound was prepared according to the method of Example 13D substituting 3-(4-chloro-phenoxy)-azetidine for l-(5-methyl-pyridin-2-yl)-piperazine. !H 10 NMR (500 MHz, Py-d5) 8 7.37-7.42 (m, IH), 7.34-7.37 (m, 2H), 6.89-6.94 (m, 2H), 5.88-5.89 (bs, IH), 4.24-4.32 (m, IH), 3.92-3.96 (m, IH), 3.76-3.80 (m, IH), 3.32 (dd, 7= 5.20, 7.79 Hz, IH), 3.27 (dd, 7= 5.25, 7.83 Hz, IH), 3.18 (q, 7= 6.76 Hz, IH), 2.19-2.29 (m, 2H), 2.06-2.13 (m, 2H), 2.02-2.05 (m, IH), 1.94-2.00 (m, 4H), 1.80-1.88 (m, 2H), 1.44-1.52 (m, 2H), 1.30 (d, 7 = 6.78 Hz, 3H); MS(ESI) m/z 405 (M+H)+.
Example 69
2-f4-(2-Fluorophenoxy^piperidin-Uvl]-N-[ffi)-5-hydroxy-2-ariaTnantyl]prnpananjidft
The title compound was prepared according to the method of Example 13D
20 substituthg4-(2-fluoro-phenoxy)-piperidkeforl-(5^ JH
NMR (300 MHz, CDCfe) 8 1.25 (d, 7= 7.04 Hz, 3H), 1.55-1.58 (m, IH), 1.63-1.72 (m, 2H), 1.75-1.80 (m, 4H), 1.82-1.97 (m, 5H), 1.98-2.14 (m, 4H), 2.14-2.23 (m, 2H), 2.29-2.40 (m, IH), 2.48 (ddd, J= 11.72, 9.01, 2.90 Hz, IH), 2.77-2.90 (m, 2H), 3.12 (q, 7= 7.01 Hz, IH), 3.98-4.04 (m, IH), 4.24-4.34 (m, IH), 6.89-7.13 (m, 4H), 7.73 (d,7= 8.31 Hz, IH); 25 MS(APCI+) m/z 417 (M+H)+.
Example 70
2-f3-(2-Fluorophenoxy)piperidin-l-yl1-N-r('£V5-hydroxy-2-adamantyl]propanamide
30 The title compound was prepared according to the method of Example 13D
substituting 3-(2-fluoro-phenoxy)-piperidine for l-(5-methyl-pyridin-2-yl)-piperazine. JH NMR (500 MHz, CDCfe) 8 1.20-1.30 (m, 4H), 1.45-1.48 (m, 2.5H), 1.65-1.67 (m, 1.5H), 1.68-1.73 (m, 5H), 1.80-1.90 (m, 4H), 1.99 (m, IH), 2.00-2.09 (m, 2H), 2.48 (m, 0.5H), 2.6 (m, IH), 2.7 (m, 0.5H), 2.8 (m, IH), 3.09-3.17 (m, 0.5H), 3.25 (m, 0.5H), 3.65-3.70 (m,
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0.5H), 3.87-3.90 (m, 0.5H), 3.95 (m, IH), 4.00-4.04 (m, 0.5H), 4.28-4.34 (m, 0.5H), 6.87-7.09 (m, 4H), 7.83 (m, IH); MS(APCI+) m/z 417 (M+H)+.
5 Example 71
2-[3-f3-Fluorophenoxv)pyrrolidig-l-yl]-N-frg)-5-hvdroxv-2-adamantvllpfopanamide The title compound was prepared according to the method of Example 13D substituting 3-(3-fluorophenoxy)-pyrrolidine for l-(5-methyl-pyridin-2-yl)-piperazine. !H NMR (500 MHz, CDC13) 8 1.29-1.35 (m, 4H), 1.55-1.58 (m, 2H), 1.70-1.76 (m, 6H), 1.87 10 (m, 2H), 2.07 (m, 3H), 2.14 (m, IH), 2.3 (m, IH), 2.40 (m, 0.5H), 2.6 (m, 1.5H), 2.90 (m,
IH), 2.97 (m, 0.5H), 3.05 (m, 0.5H), 3.13 (m, IH), 3.98-4.04 (m, IH), 4.78 (s, IH), 6.5-6.63 (m, 2H) 6.64 (m, 0.5H), 6.77 (m, 0.5H), 6.95 (m, 0.5H), 7.21 (m, 0.5H), 7.39 (m, 0.5H), 7.51 (m, 0.5H); MS(APCI+) m/z 403 (M+H)+.
15
Example 72
A^-[2-(3.4-Dic&orophenyl)ethyl]-J^-f(^
The title compound was prepared according to the method of Example 13D substituting [2-(3,4-dichloro-phenyl)-ethyl]-methyl-amine for l-(5-methyl-pyridin-2-yl)-
20 piperazine. JH NMR (500 MHz, CDCI3) 8 7.35 (d, 7= 8.12 Hz, IH), 7.27-7.33 (m, IH), 7.04 (dd, 7=2.05, 8.16 Hz, IH), 3.87-3.95 (m, IH), 3.16-3.29 (m, IH), 2.71-2.84 (m, 4H), 2.24-2.26 (m, 3H), 2.04-2.12 (m, IH), 1.96-2.02 (m, IH), 1.91-1.96 (m, IH), 1.80-1.88 (m, 2H), 1.69-1.75 (m, 4H), 1.37-1.49 (m, 4H), 1.27-1.34 (m, IH), 1.17-1.24 (m, 3H); MS(APCI+) m/z426(M+H)+
25
Example 73
JV2-r2-f4-Chlorophenvl>l-methvlethvll-^1-|'rg)-5-hvdroxv-2-adamantyll-Wa-
methvlalaninamide
30 The title compound was prepared according to the method of Example 13D
substituting [2-(4-chloro-phenyl)-l-methyl-ethyl]-methyl-amine for l-(5-methyl-pyridin-2-yi)-piperazine. !H NMR (500 MHz, CDCI3) 8 7.4 (d, 0.5H), 7.24 (d, 2H), 7.15 (d, 0.5H), 7.11 (m, 2H), 3.88 (t, IH), 3.32 (m, 0.5H), 3.26 (m, 0.5H), 3.18 (m, 0.5H), 3.12 (m, 0.5H), 2.84 (m, 0.5H), 2.75 (m, 0.5H), 2.65 (m, 0.5H), 2.6 (m, 0.5H), 2.2 (d, 3H), 2.06 (m, IH),
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1.88-1.94 (m, 1H), 1.84 (m, 2H), 1.68-1.73 (m, 4H), 1.36-1.41 (m, 3H), 1.33-1.32 (m, 1.5H), 1.29 (m, 1H), 1.21-1.26 (m, 2.5H), 1.02-1.07 (dd, 3H); MS(APCI+) m/z 405 (M+H)+.
5 Example 74
2-(S-CMoro-2.3-dmvdro-lH-mdol-l-yl)-N-[(£)-5-hvdroxv-2-adaniqntvl1propanamide The title compound was prepared according to the method of Example 13D substituting 5-chloro-2,3-dihydro-lH-indole for l-(5-methyl-pyridin-2-yl)-piperazine. *H NMR (500 MHz, CDCk) 5 7.08-7.09 (m, 1H), 7.01 (dd, J= 2.17, 8.30 Hz, 1H), 6.90-6,99 10 (m, 1H), 6.35 (d, J= 8.32 Hz, 1H), 4.00-4.05 (m, 1H), 3.87 (q, J= 7.09 Hz, 1H), 3.37-3.51 (m, 2H), 2.99 (t, 7= 8.15 Hz, 2H), 2.02-2.11 (m, 3H), 1.84-1.90 (m, 2H), 1.72-1.76 (m,2H), 1.71-1.72 (m, 2H), 1.44-1.48 (m, 2H), 1.40-1.43 (m, 2H), 1.40 (d, J= 7.09 Hz, 3H); MS(APCI+) m/z 375 (M+H)+.
15
Example 75 2-f4-r6-CMoropvridm-3-yl)pip«^yin-l-yl]-N-[(^-5-hydroxy-2-adqn?antyl]propaTiaff7idi>
Example 75A
Benzyl 4-(2-{[(^-5-hydroxy-2-at^anty1]aT^ino}-l-mbthvl-2-oxoethvnpiperazine-l-
20 carboxylate
The title compound was prepared and used in the next step according to the method of Example 13D substituting piperazine-l-carboxylic acid benzyl ester for l-(5-methyl-pyridin-2-yI)-piperazine. MS(APCI+) m/z 442 (M+H)+.
25 Example 75B
A^-("(£)-5-Hydroxy-2-adamantyl]-2-piperazin-l-ylpropanatTiide
A suspension of the product from Example 75 A and 5% Pd/C in MeOH (0.5 mL) was stirred under hydrogen atmosphere at room temperature overnight. The mixture was filtered, concentrated and carried on to the next step. MS(APCI+) m/z 308 (M+H)+.
30
Example 75C 2-[4-(6-CMoropyridm-3-yl)piperazin-l-yl]-N-f(£)-5-hvdroxy-2-adamantvllpropanamide
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A suspension of jV-[(£)-5-hydroxy-2-adamantyl]-2-piperazin-l-ylpropanamide from Example 75B (21.5 mg, 0.07 mmoles), 2-chloro-5-iodopyridine (20.5 mg, 0.07 mmoles), copper iodide (I) (2 mg, 0.01 mmoles), ethylene glycol (0.008 mL, 0.14 mmoles), potassium phosphate (32.7 mg, 0.154 mmoles) in isopropanol (0.7 mL) was stirred for 48 hours at 80
5 °C. The mixture was filtered, taken into DCM and purified by column chromatography (silica gel, 10-50% acetone in hexane) to provide the title compound. 'H NMR (400 MHz, CDCfe) 5 8.03 (s, 1H), 7.57 (d, J * 9.2 Hz, 1H), 7.19 (s, 1H), 4.02 (d, J= 8 Hz 1H), 3.23 (m, 4H), 3.13 (q, J = 7.1 Hz, 1H), 2.54 (m, 4H), 1.95-1.89 (m, 3H), 1.77 (m, 6H), 1.58 (m, 4 H) 1.13 (d, J = 7 Hz, 3H); MS(APCI+) m/z 419 (M+H)+.
10
Ryamplft 76 N-[(£)-5-Hvdroxy-2-adamantyl]-2-(3-phenvlazetidin-l-vl)propanamide The title compound was prepared according to the method of Example 13D 15 substituting 3-phenyl azetidine for 1 -(5-methyl-pyridin-2-yl)-piperazine. !H NMR (500
MHz, DMSO-ds) 5 7.32-7.36 (m, 3H), 7.29-7.32 (m, 2H), 7.18-7.22 (m, 1H), 3.71-3.75 (m, 1H), 3.57-3.67 (m, 3H), 3.16-3.20 (m, 2H), 2.94 (q, 7= 6.76 Hz, 1H), 1.98-2.02 (m, 1H), 1.90-1.96 (m, 2H), 1.70-1.76 (m, 2H), 1.64-1.69 (m, 2H), 1.57-1.63 (m, 4H), 1.34-1.41 (m, 2H), 1.03 (d, J = 6.86 H z, 3H); MS(ES1) m/z 355 (M+H)+ 20
Example 77
(^N-Methvl-4-[(2-methvl-2-f4-[5-(trifluoromelJiyl)pyridm-2-yl]piperazin-l-vl}propanoynanriinn]adamantane-l-carboxamide
25 The title compound was prepared according to the method of Example 24 substituting
methylamine for hydroxylamine. *H NMR (400 MHz, CDC13) 8 8.36-8.45 (m, 1H), 7.71-7.81 (m, 1H), 7.64 (dd,y=2.38, 8.98 Hz, 1H), 6.66 (&,J= 8.96 Hz, 1H), 5.53-5.61 (m, 1H), 3.95-4.11 (m, 1H), 3.61-3.69 (m, 4H), 2.80 (d, /= 4.74 Hz, 3H), 2.59-2.70 (m, 4H), 2.00-2.08 (m, 3H), 1.96-1.99 (m, 4H), 1.85-1.91 (m, 2H), 1.69-1.78 (m, 2H), 1.59-1.67 (m, 2H),
30 1.25 (s, 6H); MS(APCI+) m/z 508 (M+H)+.
Example 78
(i^N-Methoxy-4-[(2-methyl-2-{4-f5-(trifluoromethvl)pvridm-2-yl]piperazin-l-
35 vl)propanoyl)amino]adamantapft-l-carhn7fa^Tiide
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The title compound was prepared according to the method of Example 24 substituting
methoxyamine for hydroxylamine. JH NMR (400 MHz, CDCfe) 5 8.41 (s, IH), 7.78 (d, J =
8.3 Hz, IH), 7.64 (d, J = 6.5 Hz, IH), 6.66 (d, J = 8.9 Hz, IH), 4.0 (d, J = 8.3 Hz, IH), 3.75
(s, 3H), 3.65 (s, 4 H), 2.65 (s, 4H), 2.03 (s, 4H), 1.99 (s, 3H), 1.90 (s, 2H), 1.73 (d, J = 13.5
5 Hz, 2H)), 1.62 (d, J = 13.5 Hz, 2H), 1.25 (s, 6H); MS(APCI+) m/z 524 (M+H)+.
Example 79
N-[(^-5-(Aminnmethvl)-2-adamantyl]-2-methyl-2-{4-[5-ftrifmoromethvl)pyridm-2^
10 vllpiperazin-1 -vl}propanamide
A solution of A^-[(£)-5-fonnyl-adamantan-2-yl]-2-[4-(5-trifluoromethyI-pyridin-2-yl)-piperazin-l-yl]-isobutyramide (48 rug, 0.1 mmoles) from Example 22, and 4A molecular serves (50 mg) in methanolic ammonia (7N, 2 mL) was stirred overnight at room temperature. The mixture was cooled in an ice bath, treated portionwise with sodium
15 borohydride (15 mg, 0.4 mmoles) and stirred at room temperature for 2 hours. The
suspension was filtered and concentrated under reduced pressure. The residue was taken into DCM (2 mL), acidified with IN HC1 to pH = 3 and the layers separated. The aqueous layer was basified with 2N NaOH to pH =" 12 and extracted three times with DCM. The combined organic extracts were dried (MgSC^) and filtered. The filtrate was concentrated under
20 reduced pressure and purified on reverse phase HPLC to provide the title compound. ]H
NMR (500 MHz, Py-d3) 8 8.67 (s, IH), 7.82 (d, J= 8.1 Hz, IH), 7.79 (d, 7= 2.5, 9.1 Hz, IH), 6.86 (d, J= 8.9 Hz, IH), 4.22 (d, J= 8.1 Hz, IH), 3.73 (s, 4H), 3.05 (s, 2 H), 2.57 (m, 4H), 2.07 (s, 2H), 1.96 (s, IH), 1.82-1.92 (m, 8H), 1.55-1.58 (d, J= 13.1 Hz, 2H), 1.30 (s, 6H); MS(ESI+) m/z 480 (M+H)+.
25
Example 80
N-|"fJEl-5-Hvdroxv-2-adamantvn-l-fr4-(trifluoromethyDben7:y11aiT|iTi9}cvclopropanecarhoxfimide
30
Example 80A
ferf-Butvl 1 -({ [(E)-5-hydroxy-2-ariamanty1]aminr>} carbonyl)cvclopropylcarbamate The title compound was prepared according to the method of Example 16F using a mixture of (£)- and (2)- 5-hydroxy-2-adamantamine from example 13A and l-(W-t-Boc-
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amino)cyclopropanecarboxylic acid. The (E)-isomer was isolated by normal phase HPLC on a Biotage pre-packed silica gel column eluting with 4:1 ethyl acetate.hexane to afford the title compound. MS(ESI)m/z351 (M+H)+
5 Example 80B
l-Amino-JV-rf£)-5-hvdroxy-2-ada.niant.vl1cvclopropanecqrhnxamidft
A solution of tert-butyl l-({[(£)-5-hydroxy-2-adamantyl]amino}carbonyl)cycbpropylcarbamate (0.50 g, 1.43 mmoles) from Example 80A in methylene chloride (3 mL) was treated with trichloroacetic acid (1 mL) and stirred two 10 hours at room temperature. The mixture was concentrated under reduced pressure. The
residue was dissolved in saturated NaHC03, and the product extracted with chloroform. The combined extracts were dried over Na2S04, filtered, and concentrated under reduced pressure to afford the title compound. MS(ESI) m/z 251 (M+H)+.
15 Example 80C
N-rf£)-5-Hvdroxv-2-adamantvn-l-{ ^4-(trifluoromethynben7ynaminn}cyclopropai?ftp-arb9^g)njjde
A solution of l-amino-7V'-[(JE)-5-hydroxy-2-adamantyl]cyclopropanecarboxamide from example 80B (0.050 g, 0.20 mmoles), 4-(trifluoromethyl)benzaldehyde (0.034 g, 0.20
20 mmoles), and acetic acid (0.048 g, 0.80 mmoles) in dichloroethane (2 mL) was treated, after stirring two hours at room temperature, with sodium triacetoxyborohydride (0.085 g, 0.40 mmoles). The mixture was stirred overnight at room temperature. The mixture was quenched with saturated NaHCCfe, and the product extracted into ethyl acetate. The combined extracts were washed with saturated NaHCC>3 and brine, dried over NajSCvt,
25 filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (20-100% acetonitrile in 0.1% TFA in water) on a YMC ODS Guardpak column to afford the title compound. *H NMR (400 MHz, DMSO-d6) 5 8.72 (rn, 1H), 8.22 (m, 1H), 7.80-7.70 (m, 2H), 7.60-7.40 (m, 2H), 4.15 (m, 1H), 4.03 (m, 2H), 1.90 (m, 2H), 1.70-1.50 (m,5H), 1.40-1.20 (m,4H), 1.08 (m, 2H), 0.89 (t,J= 6Hz, 2H), 0.76 (t,.7=6 Hz, 2H);
30 MS(ESI)m/z409(M+H)+
Example 82 N-rfi^-5-Hydrn^-2-adaiTi^^ty11-1-piperidin-l-ylcyclopropanftr.arhnyatTiide
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Example 89. A
Methvl 1 -piperidin-1 -ylcvclopropanecarboxylate
A mixture of methyl 1-anunocyclopropane-l-carboxylate (0.50 g, 4.35 mmoles), . 5 powdered potassium carbonate (2.40 g, 17.4 mmoles), and tetrabutylammonium bromide
(0.140 g, 0.43 mmoles) in anhydrous acetonitrile (12 mL) was treated with 1,5-diiodopentane (1.70 g, 5.22 mmoles). The mixture was stirred for three days at 90 °C. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified on an Alltech pre-packed silica gel column eluting with 10 ethyl acetate to afford the title compound. MS(DCI) m/z 184 (M+H)+. Vaidyanathan, G.; Wilson, J. W. J. Org. Chem. 1989, 54, 1810-1815.
Example 82B
1-Piperidin-1-vlcvclopropanecarboxvlic acid
15 The title compound was prepared according to the method of Example 16E
substituting methyl 1 -piperidin- 1-ylcyclopropanecarboxylate from example 82A for methyl l-[4-(5-trifluoromemylpyridin-2-yl)-piperazin-l-yl]-cyclopropanecarboxylate. MS(DCI)m/z 170 (M+H)+.
20
Example 82C jy-f^-S-Hydrox^^-a^nirtantyl^-l-piperidm-l-ylcyclopropanecarboxamide
The title compound was prepared according to the method of Example 16F using (£)-and (2)-5-hydroxy-2-adamantamine from Example 13 A and I-piperidin-1-
25 ylcyclopropanecarboxylic acid from Example 82B. The (£)-isomer was isolated on an
Alltech pre-packed silica gel column eluting with ethyl acetate to afford the title compound. 'HNMR (500 MHz, DMSO-dg) 6 8.32 (m, 1H), 4.44 (m, 1H), 3.75 (m, 1H), 2.32 (m, 2H), 2.06 (m, 1H), 1.91 (m, 2H), 1.80-1.40 (m, 15H), 1.39 (m, 2H), 1.00 (ro, 2H) , 0.76 (m, 2H); MS(ESI)m/z319(M+H)+.
30
Example 83
2-Methvl-N-rr£^-5-f5-methvl-1.2.4-oxadiazol-3-vlV2-adamantvn-2-(4-r5-ftrifluoromethvl)p vridin-2-yl]piperazin-1 -yl) propanamide
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Example 83 A 2-Bromo-A^-r(^S-g^nn-2-arianianty11-9-inemylpropanamide
A solution of (£)-4-(2-bromo-2-methyl-propionylamino)-adamantane-l-carboxamide 5 (343 mg, 1 mmoles) from Example 44B in dioxane (7 mL) and pyridine (0.7 mL) was cooled to 0°C, treated with trifluoroacetic acid anhydride (0.1 mL) and stirred at room temperature for 4 hours. Solvents were removed under reduced pressure and the residue partitioned between water and DCM. Organics were washed with water, dried (MgSC>4) and filtered. The filtrate was concentrated under reduced pressure to provide the title compound. 10
Example 83B
JV-[(£)-5-Cyano-2-adamantvl1-2-memyl-2-(4-[5-(tt^
y1}pmpanamiHft
A two phase suspension of 2-bromo-iV-[(E)-5-cyano-2-adamantyl]-2-15 methylpropanamide (300 mg, 0.92 mmoles) from Example 83 A, l-(5-trifluoromethyl-
pyridin-2-yl)piperazine (34 mg, 1 mmoles) and tetrabutylammonium bromide (30 mg, 0.1 mmoles) in DCM (7 mL) and 50% NaOH (7 mL) was stirred at room temperature for 20 hours. After that the mixture was diluted with water and DCM and layers separated. Organic layer was washed with water (2x2 mL), dried (MgSCM) and filtered. The filtrate was 20 concentrated under reduced pressure to provide crude material that was purified by column chromatography (silica gel, 10-40% acetone in hexane) to provide the title compound. MS(ESI+) m/z 476 (M+H)+
Example 83C
25 2-Methvl-N-[f£^-5-r5-methvl-1.2.4-oxadiazol-3-vlV2-adamantvll-2-(4-r5-
(trifluoromethyl)pyridin-2-yl]piperazin-l-yl}prnpaTiatiriiflp.
A solution of i^-[(£)-5-cyano-2-adamantyl]-2-methyl-2-{4-[5-(lTifluoromemyl)pyridm-2-yl]piperazin-l-yl}propanamide (95 mg, 0.2 mmoles) from Example 83B, hydroxylamine hydrochloride (70 mg, 1 mmoles) and potassium carbonate 30 (138 mg, 1 mmoles) in ethanol (1 mL) was refluxed overnight, filtered hot, and washed with hot ethanol. The solvent was concentrated under reduced pressure; the residue was taken into pyridine (1 mL), treated at 80°C with acetyl chloride (28 uL, 0.4 mmoles) and stirred at 100°C overnight. The solvent was concentrated under reduced pressure and the residue purified by reverse phase HPLC to provide the title compound. !H NMR (300 MHz, Py-ds)
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5 8.68 (s, IH), 7.88 (d, J = 8 Hz, IH), 7.79 (d, J = 8.9 Hz, IH), 6.87 (d, J = 8.2 Hz, IH), 4.33 (d, J = 8.0 Hz, IH), 3.76 (s, 4H), 2.59 (m, 4H), 2.41 (s, 3H), 2.27-1.86 (m, 1 IH), 1.65 (m, 2H), 1.32 (d, 6H); MS(ESI+) m/z 533 (M+H)+.
5
Example 84
2-Methvl-N-r(ia-5-(2H-tefraazol-5-vll2-adam^
yl]pipearazin-1 -yl}pir>panamidp.
A suspension of A^-[(£)-5-cyano-2-adamantyl]-2-methyl-2-{4-[5-10 (trifluoromethyl)pyridin-2-yl]piperazin-l-yl}propanamide (95 mg, 0.2 mmoles) from
Example 83B, sodium azide (14.3 mg, 0.22 mmoles) and zinc bromide (45 mg, 0.2 mmoles)
in water (0.5 mL) with a drop of isopropanol was stirred at 120 °C for 72 hours. The solvent
was concentrated under reduced pressure and the residue purified by reverse phase HPLC to
provide the title compound. *H NMR (300 MHz, Py-d5) 5 8.69 (s, IH), 7.89 (d, J = 7.9 Hz,
15 IH), 7.8 (d, J = 9.1 Hz, IH), 6.89 (d, J = 8.8 Hz, IH), 4.36 (d, J = 7.7 Hz, IH), 3.76 (s, 4H),
2.58 (m, 4H), 2.39 (m, 4H), 2.26 (s, 2H), 2.16 (s, 2H), 2.02 (s, IH), 1.92 (d, J = 12.9 Hz, 2H), 1.65 (d, J = 12.9 Hz, 2H), 1.32 (s, 6H); MS(ESI+) m/z 519 (M+H)+.
20 Example 85
(7jJ)-4-f('2-{4-rr(4-Chlorophenvl)sulfonyl](cycloprnpyl)apiino1pipeqdin-l-vl}propanoyl)amino1adamantane-1 -carboxamide
A solution of (£)-4-(2-bromo-propionylamino)-adamantane-l-carboxamide (33 mg, 0.1 mmoles) from Example 3 IB, 4-cbloro-/V'-cyclopropyl-N-piperidin-4.-yl-,
25 benzenesulfonamide (12 mg, 0.12 mmoles) in MeOH (0.5 mL) and DEPEA (0.1 mL) was stirred overnight at 70 °C. The MeOH was removed under reduced pressure and the residue purified on reverse phase HPLC to provide the title compound. !H NMR (500 MHz, CDCfe) 5 7.96 (d, J = 6.6 Hz, IH), 5.54-5.34 (m, 2H),4.68-4.78 (m, IH), 4.00 (d, J = 7.8 Hz, IH), 3. 2 (q, J = 7.2 Hz, IH), 2.8 (m, IH), 2.53-2.59 (m, 3H), 1.55-2.07 (m, 17H), 1.22 (d, J = 7.2 Hz,
30 3H); MS(ESI+) m/z 352 (M+H)+.
Example 86 N-[(^-5-Hvdroxy-2-adamantyl]-2-memvl-2-r2-(trifluoromethyl)pyrrohdin-l-yllpropanamide
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A two phase suspension of 2-bromo-N-[(JE)-5-hydroxy-adamantan-2-yl]-2-methyl-propionamide (32 mg, 0.1 mmoles) from Example 34A, hydrochloride of 2-trifluoromethylpyrrolidine (21 mg, 0.12 mmoles) and tetrabutylammonhim bromide (3 mg, 0.01 mmoles) in DCM (0.2 mL) and 50% NaOH (0.2 mL) was stirred at room temperature
5 for 20 hours. The mixture was diluted with water and DCM and the layers separated. The
organic layer was washed with water (2x2 mL), dried (MgSCU) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified on reverse phase HPLC to provide the title compound. 'H NMR (400 MHz, Py-d5) 6 7.33-7.43 (m, IH), 5.87-5.91 (bs, IH), 4.21-4.31 (m, IH), 3.97 (qd, J= 7.93, 4.80 Hz, IH), 3.06 (ddd, J= 10.70, 7.46, 5.92 Hz,
10 IH), 2.82 (dt, J= 10.69, 6.94 Hz, IH), 2.20-2.25 (m, IH), 2.14-2.19 (m, IH), 2.04-2.13 (m,
3H), 1.89-2.03 (m, 5H), 1.70-1.87 (m, 4H), 1.58-1.70 (m, IH), 1.48-1.58 (m, 2H), 1.48 (s, 3H), 1.34 (s, 3H); MS(ESI+) m/z 375 (M+H)+.
15 Trample. 87
fiM-({2-ff3.SV3-Ffaoropvrrohd^
The title compound was prepared according to the method of Example 44C
substituting (35)-3-fluoropyrrolidine for (3J?>3-frooropyrrolidine. *H NMR (300 MHz, Py-
20 d5) 6 7.91 (d, J = 7.7 Hz, IH), 5.19-5.06 (m, IH), 4.29 (d, J = 8.0 Hz, IH), 3.0 (m, IH), 2.91
(m, IH), 2.58 (m, IH), 2.39 (q, J = 7.6 Hz,, IH), 2.27-2.01 (m, 7H), 1.96-1.85 (m, 6H), 1.53 (m, 2H), 1.35 (m, 6H); MS(ESI+) m/z 352 (M+H)+.
25 Example 88
Methyl (£M- {["2-methyl-2-(4-pvridin-2-ylpiperazin-1 -yl)propanoyr|a.minn } adamantane-1 -
carboxylate
The title compound was prepared according to the method of Example 34C substituting l-pyridin-2-yl-piperazine for l-(5-chloro-2-pyridyl)piperazine and isolating the 30 ester before hydrolysis. 'H NMR (500 MHz, Py-ds) 5 8.38-8.46 (m, IH), 7.88 (d, J= 8.10 Hz, IH), 7.55 (ddd, J= 1.83, 7.02, 8.62 Hz, IH), 6.85 (d, J= 8.56 Hz, IH), 6.70 (dd, 7= 5.03, 6.87 Hz, IH), 4.18-4.26 (m, IH), 3.68 (s, 4H), 3.62 (s, 3H), 2.55-2.64 (m, 4H), 1.98-2.08 (m, 6H), 1.92-1.94 (m, 2H), 1.86-1.90 (m, IH), 1.75-1.84 (m, 2H), 1.48-1.56 (m, 2H), 1.30 (s, 6H); MS(ESI+) m/z 441 (M+H)+.
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Example 89
(jE^-4-{f2-Methyl-2-f4-pyridin-2-vlpiperazin-l-yl)prop?nny1]aminn}adamgntanp-1-
carboxylic acid
5 The title compound was prepared according to the procedure outlined in Example 34C
substituting l-pyridin-2-yl-piperazine for l-(5-chloro-2-pyridyl)piperazine. *H NMR (500 MHz, Py-d5) 5 14.49-15.26 (bs, IH), 8.39-8.46 (m, IH), 7.91 (d, /= 8.10 Hz, IH), 7.53-7.57 (m, IH), 6.85 (d, 7= 8.54 Hz, IH), 6.70 (t, J= 5.96 Hz, IH), 4.27-4.35 (m, IH), 3.63-3.76 (m, 4H), 2.57-2.65 (m, 4H), 2.26-2.33 (m, 2H), 2.20-2.26 (m, 2H), 2.15-2.17 (m, 2H), 2.09-
10 2.12 (m, 2H), 1.94-1.96 (m, IH), 1.81-1.90 (m, 2H), 1.56-1.65 (m, 2H), 1.31 (s, 6H);
MS(ESI+) m/z 427 (M+H)+.
Example 90
15 f£V4-f{2-Methvl-2-f(2^-2-methvl-4-pvridin-2-vlpiperazin-l-
yl]prnpan9y1}amifin)a^a|naffta^e-l-carboxvlicacid
The title compound was prepared according to the procedure outlined in Example 34C substituting (35)-3-methyl-l-pyridin-2-yl-piperazine for l-(5-chloro-2-pyridyl)piperazine. !H NMR (500 MHz, Py-d5) 5 8.37-8.43 (m, IH), 8.13-8.23 (m, IH), 7.53 (ddd, J= 1.87,6.94, 20 8.67 Hz, IH), 6.84 (d, J= 8.58 Hz, IH), 6.68 (dd, J= 4.94, 7.12 Hz, IH), 4.25-4.30 (m, IH), 4.19-4.23 (m, IH), 4.05-4.12 (m, IH), 3.31-3.42 (m, 2H), 3.17-3.27 (m, IH), 2.96-3.07 (m, IH), 2.40-2.52 (m, IH), 2.20-2.31 (m, 4H), 2.08-2.17 (m, 4H), 1.93-1.98 (m, IH), 1.86-1.93 (m, 2H), 1.57-1.63 (m, 2H), 1.42 (s, 6H), 1.16 (d, J= 6.24 Hz, 3H); MS(ESI+) m/z 441 (M+H)+. .
Example 91
(EV4-{ |T2-Methvl-2-(4-pyridin-2-vlpippira7:in-1 -yftpropanoyl] aminn } adamantane-1 -
carboxamide
30 The title compound was prepared according to the method of Example 23 substituting
(£)-4-[2-methyl-2-(4-pyridin-2-yl-piperazin-l-yl)-propionylammo]-adamantane-l-carboxylic acid for (£)-4-{2-methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l -yl]-propionylamino}-adamantane-l-carboxylic acid. JH NMR (500 MHz, Py-ds) 5 8.41-8.44 (m, IH), 7.90 (d, 7= 8.14 Hz, IH), 7.68-7.70 (bs, IH), 7.61-7.63 (bs, IH), 7.55 (ddd, J= 1.81,
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6.98, 8.62 Hz, IH), 6.85 (d, 7= 8.53 Hz, IH), 6.70 (dd, 7= 4.83, 7.08 Hz, IH), 4.25-4.34 (m, IH), 3.67-3.70 (m, 4H), 2.55-2.63 (m, 4H), 2.21-2.31 (m, 4H), 2.15 (s, 2H), 2.07-2.12 (m, 2H), 1.95 (s, IH), 1.79-1.88 (m, 2H), 1.54-1.63 (m, 2H), 1.30 (s, 6H); MS(ESI+) m/z 426 (M+H)+.
5
Example 92 2-Methvl-N-KE)-5-(4H-1.2.4-nTazol-3-v^^
yflpipera7iin-l-yl}propanarnirie
10 A solution of (£)-4-{2-methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l-yl]-
propionylamino)-adamantane-l-carboxamide (28 mg, 0.06 mmoles) from Example 23 in DMF-DMA (1 mL, 1/1 mixture) was heated at 100 °C for 3 hours. The mixture was cooled and concentrated under reduced pressure. The residue was heated in acetic acid (2 mL) to 90 °C and treated with 9 uL of hydrazine. The mixture was cooled and the solvent was removed
15 under reduced pressure. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried (MgSC>4) and filtered.. The filtrate was concentrated under reduced pressure to provide an off-white solid that was purified by reverse phase HPLC to provide the title compound. lH NMR. (500 MHz, Py-d5) 5 8.67-8.68 (m, IH), 8.46 (s, IH),
20 7.89 (d, 7= 8.11 Hz, IH), 7.79 (dd, 7= 2.57, 9.12 Hz, IH), 6.87 (d, 7= 9.00 Hz, IH), 4.36-4.42 (m, IH), 3.70-3.81 (m, 4H), 2.55-2.64 (m, 4H), 2.37-2.49 (m, 4H), 2.31-2.32 (m, 2H), 2.16-2.23 (m, 2H), 2.00-2.07 (m, IH), 1.88-1.97 (m, 2H), 1.65-1.74 (m, 2H), 1.32 (s, 6H); MS(APCI+) m/z 518 (M+H)+.
25
Example 93
(jE^-4-{[2-(3.3-Difluoropiperidm-l-yl)-2-methylpropanovllfttnino}-N-(pvridin-4-
vlmethvfladamantane-1 -carboxamide A solution of Example 43 A (35.0 mg, 0.09 mmoles) in DMF (5 mL) was treated with 30 TBTU (O- (ben2»trialzol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate) (43.3 mg, 0.135 mmoles), 4-(aminomethyl)pyridine (12.1 mg, 0.108 mmoles) and D1EA (ethyl-diisopropyl-amine) (0.033 mL, 0.18 mmoles). The mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC to provide the title compound. JH NMR (300 MHz, DMSO-35 d6) 8 8.76 (d, 7=6.44 Hz, 2H) 8.33 (t, 7=5.93 Hz, IH) 7.71 (d, 7=6.44 Hz, 2H) 7.61 (d, 7=7.80
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Hz, IH) 4.45 (d, >5.76 Hz, 2H) 3.80 (d, J=7.80 Hz, IH) 2.73 (m, 2H) 1.88 - 1.98 (m, 10H) 1.84 (m, 2H) 1.66 - 1.78 (m, 5H) 1.50 - 1.61 (m, 2H) 1.15 (s, 6H); MS(ESI+) m/z 464 (M+H)+.
5
Example 94
(JJM-[(2-Methyl-2-(4-f4-(trifluoromelJiyl)phenvl1piperazin-l-yl}propanoy1)a.tn ipp]adamantane-1 -carboxvlic acid
The title compound was prepared according to the procedure outlined in Example 34C 10 substituting l-(4-trifluorometiiyl-phenyl)-pq)erazinefor l-(5-chloro-2-pyridyl)piperazine. !H NMR (400 MHz, Py-d5) 67.85 (d, J*7.98Hz, IH), 7.66 (d,J= 8.51 Hz, 2H), 7.11 (d, J= 8.44 Hz, 2H), 4.27-4.37 (m, IH), 3.31-3.38 (m, 4H), 2.59-2.68 (m, 4H), 2.19-2.35 (m, 4H), 2.09-2.19 (m, 4H), 1.94-1.99 (m, IH), 1.84-1.90 (m, 2H), 1.59-1.66 (m, 2H), 1.34 (s, 6H); MS(ESI+) m/z 494 (M+H)+. 15
Example 95
(£V4-({2-Methvl-2-f (2J?)-2-methvl-4-f5-melJivlpyridin-2-yl)pipftrayiii-l -yl1propanoy1}^ipn)adamantane-l-carboxylicacid
20
Example 95A T3i?)-3-MethyH-(5-methylpyridin-2-vl)piperazine
A solution of 2-cUoro-5-methyl-pyridine^l27 mg, lmmoles), (2i?)-2-methyl-25 piperazine (200 mg, 2 mmoles) in EtOH (3 mL) was heated in microwave to 180 °C for 5
minutes. The mixture was cooled, concentrated under reduced pressure and partitioned with DCM and the saturated aqueous sodium bicarbonate layer. The aqueous solution was extracted three times with additional DCM. The combined organic extracts were washed twice with water, dried (MgS(>4) and filtered. The filtrate was concentrated under reduced 30 pressure to provide the crude title compound.
Example 95B r^4-rf2-Methvl-2-r(2/ft-2-methvl-4-r5-methvlpvridin-2-vnpiperazin-l-
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vllpropanovl>amino)adamantane-l-carboxylic acid
The title compound was prepared according to the procedure outlined in Example 34C substituting (3i?)-3-methyl-l-(5-methylpyridin-2-yl)piperazine from Example 95A for l-(5-chloro-2-pyridyl)piperazine. *H NMR. (400 MHz, Py-dj) 6 8.27 (s, 1H), 8.2 (d, J = 7.3 Hz, 5 1H), 7.37 (d, J = 9.7 Hz, 1H), 6.83 (d, J - 8.5 Hz, 1H), 4.28 (d, J = 4.6 Hz, 1H),4.18 (d, J = 7.3 Hz, 1H),4.03 (d, J = 6.7Hz, 1H), 3.18 (t, J= 10.1 Hz, 1H),2.45 (d, J= 11.6Hz, 1H), 2.26 (m, 4H), 2.14 (s, 3H), 2.12 (m, 5H), 1.94 (s, 1H), 1.87 (d, J = 12.5 Hz, 2H), 1.60 (m, 4H), 1.43 (s, 6H), 1.18 (d, J = 6.4 Hz, 3H); MS(ESI+) m/z 455 (M+H)+.
10
Example 96
(g)-4-({2-[(3iS)-3-Fluoropiperidin-l-yl1propa^^
A solution of (£)-4-(2-bromo-propionylamino)-adamantane-l-carboxamide (33 mg, 0.1 mmoles) from Example 3 IB and the hydrochloride of (3iS)-3-fluoropiperidine (12 mg,
15 0.12 mmoles) in MeOH (0.5 mL) and DIPEA (0.1 mL) was stirred overnight at 70 °C. The MeOH was removed under reduced pressure and the residue purified on reverse phase HPLC to provide the title compound. *H NMR (500 MHz, CDCk) 8 7.96 (d, J - 6.6 Hz, 1H), 5.54-5.34 (m, 2H), 4.68-4.78 (m, 1 H), 4.00 (d, J = 7.8 Hz, 1H), 3. 2 (q, J = 7.2 Hz, 1H), 2.8 (m, 1H), 2.53-2.59 (m, 3H), 1.55-2.07 (m, 17H), 1.22 (d, J = 7.2 Hz, 3H); MS(ESI+) m/z 352
20 (M+H)+.
Example 97
(^-4-r(~f2^-2-M-r5-n:iffluoromemynpvridin-2-vl1piperazin-l-
25 vl}propanoy1)aminn]ajfiamanta.nft-1-rjirhr>Yan(iiHe
Example 97A
(2.S)-2-(4-r5-(TrifluoromethvDpvridin-2-yl1piperazin-l-vl}propanoicacid
30 A solution of 1 -(5-trifluoromethyl-pyridin-2-yl)-piperazine (2.77 g, 11.99 mmoles) in
DCM (42 mL) and TEA (4.2 mL) was treated with (2R)-2-bromo-propionic acid (1.19 mL, 13.2 mmoles) and stirred overnight at 35 °C. The DCM was removed under reduced pressure to provide crude title compound as a yellowish solid that was used in the next step. MS(APCI+) m/z 304 (M+H)+.
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Example 97B
Methvl r^-4-rf f2iyV2-H-r5-rtrifluoromethvnpvridin-2-vl1pipea-azin-1 -
5 yl}propanoytyftrninp]adamantane-l-carboxvlate
The title compound was prepared according to the method of Example 15C substituting (25)-2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl}propanoic acid for 2-melliyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1 -yl]-propionic acid. MS(APCI+) m/z 495 (M+H)+.
Example 97C
f£M-rff25V2-{4-[5-rrrifluoromemvnpvridm-2-vl1pi|)erazin-l-yl}propanoynaminn]adamantane-l-caiboxvlicacid
15
20
The title compound was prepared according to the method of Example 15D substituting methyl (j^-4-[((2iS)-2-{4-[5-(trifJuoromethyl)pyridin-2-yl]piperazin-l-yl}propanoyl)amino3adamantane-l-carboxylate for methyl (E)-4-{2-methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l -yl]-propionylamino} -adamantane-1 -carboxylate. MS(APCI+) m/z 481 (M+H)+.
Example 97D f£M-fff2^2-{4-f5-frrifluoromethvnpvridin-2-vllpiperazin-l-
25 The title compound was prepared according to the method of Example 23 substituting
(JE0-4-[((25>2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl}propanoyl)amino]adamantane-l-carboxylic acid for (E)-4-{2-methyl-2-[4-(5-trifhioromethyl-pyridin-2-yl)-piperazin-1 -yl]-propionylamino} -adamantane-1 -carboxylic acid. !HNMR (400 MHz, Py-d3) 8 8.66 (s, IH), 7.94 (d, J= 7.88 Hz, IH), 7.78 (dd, J = 2.59,
30 9.02 Hz, IH), 7.61-7.64 (bs, IH), 7.58-7.61 (bs, IH), 6.84 (d, /= 8.96 Hz, IH), 4.34-4.39 (m, IH), 3.66-3.81 (m, 4H), 3.34 (q, J= 6.96 Hz, IH), 2.64-2.72 (m, 2H), 2.55-2.62 (m, 2H), 2.27-2.33 (m, 2H), 2.21-2.27 (m, 2H), 2.16-2.18 (m, 2H), 2.12-2.19 (m, 2H), 1.96-2.00 (m, IH), 1.89-1.96 (m, 2H), 1.57-1.64 (m, 2H), 1.35 (d, J= 7.06 Hz, 3H); MS(DCI+) m/z 480 (M+H)+.
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Example 98
r£V4-[ff2J^-2-{4-rS-rrrifluoromethvnpvridin-2-vl]pipera7.ia-l-
5 vl}propanoy1)aminQ]adamantane,-l-carboxamide
Example 98A
(2R)-2-{4-[5-(Trifluoromethvl)pyridin-2-yl]piperazin-l-yl}propanoicacid A solution of l-(5-tri£luoromethyl-pyridin-2-yl)-piperazine (2.77 g, 11.99 mmoles) in 10 DCM (42 mL) and TEA (4.2 mL) was treated with (2iS>2-bromo-propionic acid (1.19 mL,
13.2 mmoles) and stirred overnight at 35 °C. The DCM was removed under reduced pressure to provide crude title compound.
15 Example 98B
Methvl (£)^-rff2/amign]aH^i^antage-l-carfaoxamide
The title compound was prepared according to the method of Example 23 substituting
5 (£)-4-[((2^)-2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-l-
yl}propanoyl)amino]adamantane-l-carboxylic acid for (E)-4-{2-methyl-2-[4-(5-trifluoromethyl-pyridm-2-yl)-piperazm-l-yl]-propionylamino}-adamantane-l-carboxylic acid. 'H NMR (400 MHz, Py-d5) 5 8.63-8.65 (m, IH), 7.93 (d, J= 7.94 Hz, IH), 7.76 (dd, J = 2.59, 9.04 Hz, IH), 7.58-7.66 (m, 2H), 6.83 (d, J= 9.03 Hz, IH), 4.32-4.37 (m, IH), 3.64-
10 3.79 (m, 4H)> 3.32 (q, 7= 6.94 Hz, IH), 2.61-2.74 (m, 2H), 2.50-2.61 (m, 2H), 2.18-2.35 (m,
4H), 2.08-2.18 (m, 4H), 1.94-1.98 (m, IH), 1.87-1.94 (m, 2H), 1.53-1.65 (m, 2H), 1.33 (d, J = 6.95 Hz, 3H); MS(DCI+) m/z 480 (M+H)+.
15 T?^Tnp1p. 99
(jEM-[({2-rrrifluoromethyl)-4-[5-(trifluoromethvnpyridin-2-vl1pipera^ vl}acetynamino]adamantape-T -caihmcam'iAp.
20 Example 99A
1 -Benzvl-3-(trifluoromethvDpiperazine
The title compound was prepared according to the method described in the following reference, Jenneskens, Leonardus W.; Mahy, Jan; Berg, Ellen M. M. de Brabander-van.; Hoef, Ineke van der; Lugtenburg, Johan; Reel. Trav. Chim. Pays-Bas; 114; 3; 1995; 97-102. 25 Purification by reverse phase HPLC afforded the trifiuoroacetic acid salt of the title compound. MS(DCI+) m/z 245 (M+H)+.
Example 99B
Methyl (^^-("{^-benzyl^-flrifluoromethyOpipfirnzin-l-yllacetY^^niiTi^adamantane-l-
30 carboxvlate
A solution of the trifuoroacetic acid salt of l-benzyl-3-(trifluoromethyl)piperazine from Example 99A (100 mg), methyl (£)-4-(2-chloro-acetylamino)-adamantane-l-carboxylate from Example 25B (55 mg, 0.19 mmoles), and methanol (1.5 mL) was treated with DIEA (100 uL), and the reaction mixture warmed to 80 C for 24 h. The reaction
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mixture was concentrated under reduced pressure and purified by reverse phase HPLC to afford the title compound. MS(APCI+) m/z 494 (M+H)+.
5 Example 99C
Methyl (gM-(lf2-(triffaoromethvl)piperazto^^
To a solution of methyl (i^-({[4-benzyl-2-(trifluoromethyl)piperazin-l-yl]acetyl}amino)adamantane-l-carboxylate from Example 99B (50 mg, 0.10 mmoles), cyclohexene (1 mL), and methanol (1 mL) was added 10% Pd/C (30 mg), and the reaction
10 mixture heated to 70 C for 16h. The reaction mixture was cooled to 23 C, additional
cyclohexene (1 mL) and 10% Pd/C (30 mg) was added, and the reaction mixture heated to 80 C for 2h. The reaction mixture was .cooled to 23 C and filtered through Celite. The filtrate was concentrated under reduced pressure to afford the title compound that was carried on crude. See also reference in 99A. MS(APCI+) m/z 404 (M+H)+.
15
Example 99D
Memvl(ffl-4-[({2-(trifluoromethyl)-4-r5-(t^
vl}acetyl)^Tninn]^darnantane-l-carboxvlate
20 Solid methyl (^^({[2-(trifluoromethyl)piperazm-l-yl]acetyl}amino)adamantane-l-
carboxylate from Example 99C (20 mg, 0.05 mmoles) and solid 2-bromo-5-trifhioromethyl-pyridine (160 mg, 0.71 mmoles) were combined in a small vial with a stirring bar. The vial was gently warmed until the two solids melted between 45-50 C, and then the temperature was raised to 120 C for 14h. The reaction mixture was cooled to 23 C, and the residue was
25 purified using radial chromatography (0-100% acetone/hexanes) to afford the title compound. MS(APCI+) m/z 549 (M+H)+.
Example 99E
30 (£V4-[({2-(Trifluoromemvl)-4-f5-ftrifMoromethyl)pyridin-2-yl]piperazm
vl)acety1)amino]adamantane-l-carboxvlicacid
A slightly heterogeneous solution of methyl (jE)-4-[({2-(trifluoromethyl)-4-[5-(trifluoromethyl)pyridm-2-yl]piperazm-l-yl}acetyl)amino]adamantane-l-carboxylatefrom Example 99D (14 mg), dioxane (0.1 mL), and 3N HC1 (0.75 mL) was warmed to 50 C for 3 5 20h. The reaction mixture was cooled and concentrated under reduced pressure to afford the
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title compound as the hydrochloride salt. MS(DCI+) m/z 535 (M+H)+.
Rvamplft QQT?
5 (E}-4-\ (^-nrrifluoromcthylW-rS-flrifiuoromethynpyridm^-vllpiperazin-1 -
y1}ace^y1)aminn]aHflmantane-l-^rhnvftniide
The hydrochloride salt of (£)^[({2-(trifluoromethyl)-4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl}acetyl)amino]adamantane-l-carboxylic acid from Example 99E (12 mg, 0.023 mmoles), EDCI (5.7 mg, 0.030 mmoles), HOBt (33 mg, 0.025 mmoles), methylene
10 chloride (1.7 mL), 1,4-dioxane (50 uL) and triethylamine (50 uL) were combined and stirred at 23 C for lh. Aqueous NH4OH (1 niL, 30%) was added, and the reaction mixture stirred another 16 hours. The layers were separated and the aqueous phase extracted additionally with methylene chloride (2x). The combined methylene chloride extracts were dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified using
15 radial chromatography (80% acetone/hexanes) to afford the title compound. 'H NMR (400 MHz, Py-ds) 6 8.63 (s, IH), 8.01 (d, J= 7.36 Hz, IH), 7.77 (d, J = 6.75 Hz, 2H), 7.68 (s, IH), 6.75 (d, J= 9.21 Hz, IH), 4.79 (d, J= 11.35 Hz, IH), 4.42 (d, J= 7.36 Hz, IH), 3.98 - 4.11 (m, 2H), 3.79 - 3.92 (m, 2H), 3.70 - 3.79 (m, IH), 3.47 - 3.57 (m, IH), 3.24 - 3.35 (m, IH), 3.09 - 3.21 (m, IH), 2.30 - 2.39 (m, 2H), 2.12 - 2.30 (m, 6H), 1.90 - 2.03 (m, 3H), 1.58 (m,
20 2H); MS(DCI+) m/z 480 (M+H)+.
Example 100
(£)-4-[(Cyclopropyl{4-f 5-ftrifmoromethvl)pyridin-2-vnpiperazin-1 -
25 y1}ap.t»ty))^j|in]fldqTTiantane-l-carboxylicacid
The title compound was prepared according to the methods of Examples 18C-D
substituting cyclopropanecarboxaldehyde for propionaldehyde. !H NMR (500 MHz, DMSO-
d6) 8 8.39 (bs, IH), 7.78 (dd, J = 2.5, 9 Hz, IH), 7.49 (d, J = 9.5 Hz, IH), 6.97 (s, IH), 3.78
(m, IH), 3.62 (m, 4H), 2.79 (m, 2H), 2.55 (m, 2H), 2.21 (d, J = 9.5 Hz, IH), 1.90-1.65 (m,
30 1 IH), 1.42 (m, 2H), 0.99 (m, IH), 0.60 (m, IH), 0.42 (m, IH), 0.27 (m, 2H); MS(ESI) m/z
507 (M+H)+.
Example 101
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(£V4-{[(l-(4-f5-rrrifluoromethvl')pyridin-2-yl]pipera7fin-l-vl> cyclobutvflcarbon v1]a m inn } adamantane-1 -carboxvlic acid
The title compound was prepared according to the methods of Examples 18C-D
substituting cyclobutanone for propionaldehyde. *H NMR (500 MHz, DMSO-d6) 8 8.41 (bs,
5 IH), 7.79 (dd, J = 2.5, 9 Hz, IH), 7.36 (d, J = 9.5 Hz, IH), 6.97 (d, J = 9.5 Hz, IH), 3.78 (m,
IH), 3.65 (m, 4H), 2.53 (m, 4H), 2.22 (m, 2H), 2.12 (m, 2H), 1.90-1.60 (m, 13H), 1.43(m, 2H); MS(ESI) m/z 507 (M+H)+.
10 Kvample 102
(£^-4-fl2-r9-(6-Chloropvridin-3-vlV3.9-diazabicvclof4.2.11non-3-vll-2-methvlpropanny1}aminn)adRmantan6-l-Cai^n,gftfn^ft
Example 102 A
15 (:£M-fa-r9-r6^Chloropvridm-3-vlV3.9-diazabic^cter4.2.1Tnon-3-vl1-2-
methv1propannv1}atninn)flfiftniantane-l-carboxvlicacid
The title compound was prepared according to the method of Example 34C substituting 9-(6-chloropyridin-3-yl)-3,9-diazabicyclo[4.2.1]nonane for l-(5-chloro-2-pyridyl)piperazine. MS(ESI+) m/z 501 (M+H)+. 20
Example 102B
f£^-4-a2-r9-(6-Chk>ropvridin-3-vlV3.9-diazabicvclof4.2.11non-3-vl1-2-methvlpropaD»y1}flminn)aHamantane-1-cqrhnTamide
The title compound was prepared according to the method of Example 23 substituting 25 (£>4-({2-[9-(6-chloropyridin-3-yl>3,9-diazabicyclo[4.2.1]non-3-yl]-2-
methylpropanoyl}amino)adamantane-l-carboxylic acid from Example 102A for (E)-4-{2-
memyl-2-[4-(5-triimoromethyl-pyridm-2-y^
1-carboxylic acid. *H NMR (400 MHz, CDCb) 8 7.78 (s, IH), 7.10 (d, J = 8.6 Hz, IH), 7.02
(d, IH), 6.98 (m, IH), 5.54-5.19 (d, 2 H), 4.33 (m, 2 H), 3.95 (d, J = 8.1 Hz, IH), 2.99 (m,
30 IH), 1.88-2.58 (m, 18H), 1.13-1.21 (d, 6H) 8 MS(ESI+) m/z 500 (M+H)+.
Ev^mnlft 103
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f^-4-^{2-r4-(2.3-Dichlorophenvnpipefaan-l-yl]-2-methvlDropajiov1}amino)adajnantane-l-
carboxylic acid
The title compound was prepared according to the method of Example 34C substituting l-(2,3-dichloro-phenyl)-piperazine for l-(5-chloro-2-pyridyl)piperazine. *H 5 NMR (500 MHz, Py-d3) 5 7.89 (d, J= 8.09 Hz, IH), 7.28 (dd, J= 1.43, 7.96 Hz, IH), 7.21 (d, J= 6.71 Hz, IH), 7.07 (dd, J= 1.48, 8.04 Hz, IH), 4.29-4.37 (m, IH), 3.05-3.18 (m, 4H), 2.70-2.72 (m, 4H), 2.21-2.35 (m, 4H), 2.11-2.19 (m, 4H), 1.95-2.01 (m, IH), 1.85-1.93 (m, 2H), 1.60-1.69 (m, 2H), 1.36 (s, 6H); MS(ESI) m/z 494 (M+H)+.
10
Example 104
(£V4-{|"2-Methyl-2-(4-phenvlpiperay.in-1 -yl)propanov11a^inr>) adama^anf»-i-carboxylic acid
The title compound was prepared according to the method of Example 34C substituting 1-phenyl-piperazine for l-(5-chloro-2-pyridyl)piperazine. *H NMR (500 MHz, 15 Py-dj) 5 7.89 (d, J= 8.11 Hz, IH), 7.36-7.42 (m, 2H), 7.10-7.14 (m, 2H), 0.95-6.99 (m, IH), 4.30-4.38 (m, IH), 3.23-3.30 (m, 4H), 2.61-2.66 (m, 4H), 2.30-2.41 (m, 4H), 2.23-2.27 (m, 2H), 2.09-2.15 (m, 2H), 1.91-1.98 (m, IH), 1.83-1.87 (m, 2H), 1.58-1.66 (m, 2H), 1.32 (s, 6H); MS(ESI) m/z 426 (M+H)+.
20
Example 105
f£V4-((2-Methyl-2-r4-f4-methvlphenyl)pipt^^in-1-yl]propanovT}aminn)aHaiT|antaTift-1-
carboxvlic acid
The title compound was prepared according to the method of Example 34C 25 substituting 1-p-tolyl-piperazine for l-(5-chloro-2-pyridyl)piperazine. 2H NMR (500 MHz, Py-ds) 5 7.91 (d, J = 8.12 Hz, IH), 7.20 (d, 7= 8.55 Hz, 2H), 7.06 (d, 7= 8.09 Hz, 2H), 4.27-4.36 (m, IH), 3.22-3.29 (m, 4H), 2.63-2.71 (m, 4H), 2.20-2.34 (m, 7H), 2.15-2.16 (m, 2H), 2.09-2.14 (m, 2H), 1.90-1.95 (m, IH), 1.81-1.89 (m, 2H), 1.56-1.63 (m, 2H), 1.34 (s, 6H); MS(ESI)m/z440(M+H)+.
Rxai^plft 106
(Jj^-(f2-r4-fO-Benzotmazol-2-vflpiperaz^
1-carboxylic acid
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The title compound was prepared according to the method of Example 34C substituting 2-piperazin-l-yl-benzothiazole for l-(5-chloro-2-pyridyl)piperazine. *H NMR (500 MHz, Py-d5) 5 7.88 (d, 7= 7.96 Hz, IH), 7.83 (d, 7= 7.76 Hz, IH), 7.78 (d, 7= 8.02 Hz, IH), 7.42 (t, 7= 7.53 Hz, IH), 7.19 (t, 7= 7.46 Hz, IH), 4.27-4.35 (m, IH), 3.69-3.76 (m, 5 4H), 2.54-2.61 (m, 4H), 2.20-2.34 (m, 4H), 2.14-2.19 (m, 2H), 2.10-2.12 (m, 2H), 1.96-2.00 (m, IH), 1.80-1.90 (m, 2H), 1.58-1.67 (m, 2H), 1.31 (s, 6H); MS(ESI) m/z 483 (M+H)+.
Example 107
10 (£V-4-( (2-[4-f3.4-Dichlorophenvl>piperazin-1 -vl"|-2-methvlpropano vl) amino'todamantanft-1 -
carboxylic acid The title compound was prepared according to the method of Example 34C substituting l-(3,4-dichloro-phenyl)-piperazine for l-(5-chloro-2-pyridyl)piperazine. lH NMR (500 MHz, Py-d3) 8 7.85 (d, 7= 8.05 Hz, IH), 7.43 (d, 7= 8.88 Hz, IH), 7.24 (d, 7= 15 2.80 Hz, IH), 6.94 (dd, 7= 2.87, 8.94 Hz, IH), 4.28-4.37 (m, IH), 3.21-3.30 (m, 4H), 2.61-2.68 (m, 4H), 2.20-2.34 (m, 4H), 2.16-2.17 (m, 2H), 2.10-2.15 (m, 2H), 1.93-1.98 (m, IH), 1.83-1.92 (m, 2H), 1.58-1.67 (m, 2H), 1.34 (s, 6H); MS(ESI) m/z 494 (M+H)+.
20 Example 108
(£)-4-({2-Methvl-2-r4-(3-methylphenyl)piperazm-l-yl]propaiinYl}flTniTio^adamantane-l-
carboxylic acid
The title compound was prepared according to the method of Example 34C substituting 1-w-tolyl-piperazine for l-(5-chloro-2-pyridyl)piperazine. *H NMR (500 MHz, 25 Py-dj) 5 7.92 (d, 7= 8.09 Hz, IH), 7.31 (t, 7= 7.73 Hz, IH), 6.92-7.02 (m, 2H), 6.80 (d, 7= 7.35 Hz, IH), 4.28-4.36 (m, IH), 3.28-3.31 (m, 4H), 2.64-2.72 (m, 4H), 2.32 (s, 3H), 2.26-2.31 (m, 2H), 2.20-2.26 (m, 2H), 2.09-2.18 (m, 4H), 1.91-1.95 (m, IH), 1.81-1.89 (m, 2H), 1.56-1.63 (m, 2H), 1.34 (s, 6H); MS(ESI) m/z 440 (M+H)+.
30
Example 109
f:£V4-|"(2-Methyl-2-{4-[2-(trifluoromethyl)phenynpiperazin-l-vl}propanoyl)amino]adamantane-l-carboxvlicacid
The title compound was prepared according to the method of Example 34C
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substituting l-(2-trifluoromethyl-phenyl)-piperazine for l-(5-chloro-2-pyridyl)piperazine. *H
NMR (500 MHz, Py-d5) 6 7.94 (d, J= 8.06 Hz, IH), 7.74 (d, J= 7.67 Hz, IH), 7.58-7.60 (m,
IH), 7.55 (t, J= 8.77 Hz, IH), 7.28 (t, J= 7.40 Hz, IH), 4.28-4.37 (m, IH), 3.01-3.08 (m,
4H), 2.66-2.73 (m, 4H), 2.28-2.35 (m, 2H), 2.23-2.26 (m, 2H), 2.16-2.20 (m, 2H), 2.13-2.15
5 (m, 2H), 1.97-1.99 (bs, IH), 1.88-1.95 (m, 2H), 1.60-1.69 (m, 2H), 1.34 (s, 6H); MS(ESI)
m/z494(M+H)+.
Example 110
10 (2iM-({2-r4-(2.4-Diffaorophenyl)pipCTa
carboxvlic acid
The title compound was prepared according to the method of Example 34C substituting l-(2,4-difluoro-phenyl)-piperazine for l-(5-chloro-2-pyridyl)piperazme. lH NMR (500 MHz, Py-d5) 5 7.89 (d, J== 8.07 Hz, IH), 7.14 (ddd, J= 2.72, 8.65,11.87 Hz, IH), 15 7.05 (td, J= 5.88, 9.23 Hz, IH), 6.94^7.01 (m, IH), 4.28-4.37 (m, IH), 3.09-3.17 (m, 4H), 2.65-2.72 (m, 4H), 2.27-2.35 (m, 2H), 2.20-2.27 (m, 2H), 2.16-2.18 (m, 2H), 2.07-2.15 (m, 2H), 1.94-1.98 (m, IH), 1.84-1.92 (m, 2H), 1.58-1.68 (m, 2H), 1.34 (s, 6H); MS(ESI) m/z 462(M+H)+.
Rvample 111
(EV4-({2-Methvl-2-f4-(6-me1faylpvridm-2^
1-carboxvlic acid
The title compound was prepared according to the method of Example 34C
25 substituting l-(6-methyl-pyridin-2-yl)-piperazine for l-(5-chforo-2-pyridyl)piperazine. JH
NMR (500 MHz, Py-dj) 8 7.93 (d, J= 8.10 Hz, IH), 7.47 (t, J= 7.80 Hz, IH), 6.68 (d, 7=
8.41 Hz, IH), 6.59 (d, J= 7.20 Hz, IH), 4.27-4.36 (m, IH), 3.70 (s, 4H), 2.58-2.66 (m, 4H),
2.48 (s, 3H), 2.26-2.34 (m, 2H), 2.20-2.26 (m, 2H), 2.13-2.19 (m, 3H), 2.09-2.12 (m, 2H),
1.91-1.97 (m, IH), 1.81-1.88 (m, 2H), 1.55-1.64 (m, 2H), 1.31 (s, 6H); MS(ESI) m/z 441
30 (M+H)+.
Example 112 (£V4-(f2-Methvl-2-f4-pvpmidm-2-ylpipt^?7iprl-YOpropanov11q^,ino}ad^Tri^ntane-1-
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carboxylic acid
The title compound was prepared according to the method of Example 34C
substituting 2-piperazin-l-yl-pyrimidine for l-(5-chloro-2-pyridyl)piperazine. lH NMR (500
MHz, Py-d3) 8 8.47 (d, 7= 4.68 Hz, 2H), 7.90 (d, 7= 8.17 Hz, IH), 6.53 (t, J= 4.68 Hz, IH),
5 4.26-4.34 (m, IH), 3.95-4.02 (m, 4H), 2.52-2.59 (m, 4H), 2.25-2.31 (m, 2H), 2.21-2.25 (m,
2H), 2.15-2.17 (m, 2H), 2.09-2.13 (m, 2H), 1.96-2.00 (m, IH), 1.83-1.90 (m, 2H), 1.58-1.67 (m, 2H), 1.30 (s, 6H); MS(ESI) m/z 428 (M+H)+.
10 Krample 113
f£V4-({2-[4-(4-Fluorophenyl)piperazin-l-yl1-2-methylpropanov1}amino)adamantane-l-
carboxylic acid
The title compound was prepared according to the method of Example 34C
substituting l-(4-fluoro-phenyl)-piperazine for l-(5-chloro-2-pyridyl)piperazine. 'HNMR
15 (500 MHz, Py-d5) 5 7.88 (d, J= 8.07 Hz, IH), 7.14-7.19 (m, 2H), 7.02-7.08 (m, 2H), 4.27-
4.35 (m, IH), 3.17-3.24 (m, 4H), 2.62-2.71 (m, 4H), 2.26-2.33 (m, 2H), 2.21-2.25 (m, 2H), 2.14-2.18 (m, 2H), 2.10-2.14 (m, 2H), 1.91-1.97 (m, IH), 1.83-1.89 (m, 2H), 1.56-1.65 (m, 2H), 1.34 (s, 6H); MS(ESI) m/z 444 (M+H)+.
20
Ripple 114
f£V1-f(2-Methyl-2-{4-[3-ftrifhiorome^yl^henvl1p^)erazin-l-yl}propanov^aminn]adamantane-l-carboxvlicacid
The title compound was prepared according to the method of Example 34C 25 substituting l-(3-trifluoromethyl-phenyl)-piperazinefor l-(5-chloro-2-pyridyl)piperazine. XH NMR (500 MHz, Py-ds) 5 7.86 (d, J= 8.06 Hz, IH), 7.43 (t, J= 8.01 Hz, IH), 7.39-7.40 (m, IH), 7.22-7.26 (m, IH), 7.19-7.21 (m, IH), 4.28-4.36 (m, IH), 3.28-3.35 (m, 4H), 2.63-2.72 (m, 4H), 2.26-2.34 (m, 2H), 2.21-2.25 (m, 2H), 2.14-2.16 (m, 2H), 2.10-2.14 (m, 2H), 1.92-1.98 (m, IH), 1.82-1.90 (m, 2H), 1.56-1.66 (m, 2H), 1.35 (s, 6H); MS(ESI) m/z 494 (M+H)+.
Example 115
(^-4-rf2-Methvl-2-{4-f3-ftrifhiorome1hvnpvridin-2-vl1piperazin-l-vnpropanoy^aminnlaHamantane-l-carboxvlicacid
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The title compound was prepared according to the method of Example 34C
substituting l-(3-trifluoromethyl-pyridin-2-yl)-piperazine for l-(5-chloro-2-
pyridyl)piperazine. ^NMR (500 MHz, Py-d5) 5 8.54 (dd, 7= 1.25, 4.52Hz, IH), 7.96 (dd,
7= 1.84, 7.72 Hz, IH), 7.91 (d, 7= 8.09 Hz, IH), 7.02 (dd, 7= 4.76, 7.41 Hz, IH), 4.25-4.35
5 (m, IH), 3.47 (s, 4H), 2.68-2.74 (m, 4H), 2.25-2.33 (m, 2H), 2.20-2.23 (m, 2H), 2.14 (s, 2H),
2.08-2.13 (m, 2H), 1.92 (s, IH), 1.83-1.90 (m, 2H), 1.55-1.61Xm, 2H), 1.34 (s, 6H); MS(ESI) m/z495(M+H)+.
10 Example 116
(JJVt-({2-[4-(3-CMorophenyl)pipCTa7:in-1-yl]-2-methvlpropanovl}aminr>)adamantane-l-
carboxylic acid
The title compound was prepared according to the method of Example 34C
substituting l-(3-chloro-phenyl)-piperazine for l-(5-chloro-2-pyridyl)piperazine. 'HNMR.
15 (500 MHz, Py-d5) 5 7.86 (d, 7= 8.06 Hz, IH), 7.26 (t, 7= 8.06 Hz, IH), 7.17 (t, 7= 2.15 Hz,
IH), 6.96 (dd, 7= 2.13, 8.05 Hz, 2H), 4.27-4.35 (m, IH), 3.22-3.30 (m, 4H), 2.60-2.68 (m, 4H), 2.26-2.31 (m, 2H), 2.21-2.26 (m, 2H), 2.14-2.17 (m, 2H), 2.10-2.14 (m, 2H), 1.92-1.98 (m, IH), 1.91 (s, 2H), 1.57-1.66 (m, 2H), 1.33 (s, 6H); MS(ESI) m/z 460 (M+H)+.
20
Example 117
(£V4-({2-[4-(4-Acetvlphenyl)piperazin-l -yl]-2-methvlpropanoyl > aminoWamantane-1 -
carboxylic acid
The title compound was prepared according to the method of Example 34C 25 substituting l-(4-piperazin-l-yl-phenyl)-ethanone for l-(5-chloro-2-pyridyl)piperazine. *H NMR (500 MHz, Py-d5) 5 8.09-8.22 (m, 2H), 7.80-7.89 (m, IH), 7.09 (d, 7= 8.90 Hz, IH), 4.28-4.36 (m, IH), 3.38-3.45 (m, 4H), 2.57-2.67 (m, 4H), 2.55 (s, 3H), 2.21-2.34 (m, 4H), 2.09-2.20 (m, 4H), 1.93-1.99 (m, 2H), 1.82-1.91 (m, 2H), 1.58-1.67 (m, 2H), 1.33 (s, 6H); MS(ESI)m/z468(M+H)+.
Example 118
(^V-N.N-Dimethvl-4-f(2-me^vl-2-{4-[5-(trifluoromemyl)pyridin-2-yl]piperazin-l-yl}pr9r?n9y1)aTTiinn]adamantane-l-carboxamide
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From Example 15D (£)-4-{2-methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l-yl]-propionylamino}-adamantane-l-carboxylic acid (0.04 mmoles) dissolved in DMA (0.7 mL) was mixed with TBTU (0.04 mmoles) dissolved in DMA (0.7 mL). Dimethylamine hydrochloride (0.05mmoles) dissolved in DMA (0.3 mL) was added, followed by addition of 5 DD2A (0.08 mmoles) dissolved in DMA (0.7 mL). The mixture was shaken at room
temperature overnight. The solvent was stripped down and the crude mixture was purified using reverse phase HPLC. !H NMR (500 MHz, Py-d5) 8 8.68 (s, IH), 7.88 (d, 7=8.24 Hz, IH), 7.80 (dd, 7=2.29, 9.00 Hz, IH), 6.89 (d, 7=9.15 Hz, IH), 4.26 (d, 7=7.93 Hz, IH), 3.76 (s, 4H), 2.95 (s, 6H), 2.59 (t, 7=4.73 Hz, 4H), 2.19 - 2.26 (m, 2H), 2.07 - 2.19 (m, 6H), 1.97 10 (s, IH), 1.81 - 1.91 (m, 2H), 1.61 (d, 7=12.82 Hz, 2H), 1.32 (s, 6H); MS(ESI) m/z 522 (M+H)+.
Example 119
15 N-[(ift-5^Ar.p.ty1aminnW-qHqmflntvl>2-{4-[^
vl)propanamide
The title compound was prepared according to the method of Example 10 substituting N-[(£)-5-hydVoxy-2-adamantyl]-2-{4-[5-(trifluorometibiyi)pyridm-2-yl]piperaa yl}propananudeforN-[(^5-hydroxy-2-adamantyl]-2-{4-[5^trifluoromethyl)pyridin-2-
20 yl]piperazin-l-yl}acetamide. !H NMR (300 MHz, DMSO-de) 8 8.40 (d, 7 = 2.55 Hz, IH),
7.78 (dd, 7= 2.61, 9.14 Hz, IH), 7.69 (d, 7= 7.69 Hz, IH), 7.35 (s, IH), 6.95 (d, 7= 9.11 Hz, IH), 3.74-3.88 (m, IH), 3.55-3.70 (m, 4H), 3.25 (q, 7= 6.82 Hz, IH), 2.49-2:69 (m, 4H), 1.86-2.00 (m,9H), 1.77-1.85 (m,2H), 1.74(s,3H), 1.36-1.52(m, 2H), 1.11 (d,7=6.83Hz, 3H); MS(APCI) m/z 494 (M+H)+.
25
Example 120
(£)-4-{[2>MelJiyl-2-(4-pvriTnidm-2-ylpiperazm-l-yl)propanoyllaniino}adqman^ne-U
carboxamide
30 The title compound was prepared according to the procedure outlined in Example 23
substituting (£)-4-[2-memyl-2-(4-pyriinidin-2-yl-piperazb-1 -yl)-propionylamino]-adamantane-1-carboxylic acid for (E)-4-{2-methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l-yl]-propionylamino}-adamantane-l-carboxylic acid. JHNMR (500 MHz, Py-dj) 5 7.35 (d, 7= 4.67 Hz, 2H), 6.81 (d, 7= 7.93 Hz, IH), 6.57-6.61 (bs, 2H), 5.43 (t, 7= 4.68 35 Hz, IH), 3.11-3.20 (m, IH), 2.76-2.93 (m, 4H), 1.40-1.44 (m, 4H), 1.13-1.19 (m, 2H), 1.08-
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1.12 (m, 2H), 1.03 (d, J= -0.21 Hz, 2H), 0.93-0.99 (m, 2H), 0.81-0.86 (m, IH), 0.68-0.76 (m, 2H), 0.43-0.49 (m, 2H), 0.17 (s, 6H); MS(ESI) m/z 427
5 Example 121
(ffl-4-{[2-Methyl-2-(4-pyrazfo-2-yIpipRrazin-l-yI)pro^
carhmratniHft
Example 121A
10 (E)-4- {[2-Methyl-2-(4-pyrazin-2-ylpiperazin-1 -vf)propano vl] amino) adamantane-1 -
carboxvlic acid
The title compound was prepared according to the method of Example 34C substituting 3,4,5,6-tetrahydro-2H-[l,2']bipyrazinyl for l-(5-chloro-2-pyridyl)piperazine.
15 Example, 121B
fi^-{|2-Me1iivl-2-(4-pyiram-2-y1pipftrazin-^
carhoxamirip.
The title compound was prepared according to the procedure outlined in Example 23 substituting (E)-4- {[2-methyl-2-(4-pyrazin-2-ylpiperazin-1 -yl)propanoyr|amino} adamantane-
20 1-carboxylic acid from Example 121A for (£5-4-{2-memyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazm-l-yl]-propionylamino}-adamantane-l-carboxylic acid. *H NMR. (500 MHz, Py-ds) 6 8.51-8.51 (m, IH), 8.22-8.23 (m, IH), 8.06-8.07 (m, IH), 7.86 (d, J= 8.12 Hz, IH), 7.69-7.72 (bs, IH), 7.62-7.65 (bs, IH), 4.26-4.35 (m, IH), 3.67-3.71 (m, 4H), 2.56-2.61 (m, 4H), 2.27-2.32 (m, 2H), 2.22-2.27 (m, 2H), 2.16-2.18 (m, 2H), 2.10-2.13 (m, 2H), 2.01 (s,
25 IH), 1.81-1.91 (m, 3H), 1.56-1.65 (m, 2H), 1.31 (s, 6H); MS(ESI) m/z 427 (M+H)+.
Example 122
(£)-4-({2-[4-(4-Fluorophenvl)piperazin-l-yl1-2-melJivlpropanovl}aminn)adamantane-l-
30 carhoxamide
The title compound was prepared according to the method of Example 23 substituting (£)-4-{2-[4-(4-fluoro-phenyl)-piperazm-l-yl]-2-methyl-propionylanimo}-adamantane-l-carboxylic acid for (£)-4-{2-:nemyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l-yl]-propionylamino}-adamantan)adamantane-l-carh9Tt;anriidft
The title compound was prepared according to the method of Example 44C
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substituting l-(6-methyl-pyridin-3-yl)-[l,4]diazepane for (lR)-3-fluoropyrrolidine, lH NMR (400 MHz, Py-ds) 8 8.03 (s, IH), 7.38 (d, J = 8 Hz, IH), 7.03 (m, 2H), 3.95 (d, J = 8.1 Hz, IH), 3.56 (m, 4H), 2.82 (s, 2H), 2.57 (s, 2H), 2.48 (s, 3H), 1.98 (m, 8H), 1.89 (s, 5H), 1.65 (m, 2H), 1.29 (s, 6H); MS(ESI+) m/z 454 (M+H)+.
5
Example 12S
(£V4-rf2-{4-[3-CMoro-5-rti^uoromethvnpvridin-2-vl1oiperazin-l-vl>-2-methylpropanoyl)amiTin]qdamanfanR-l-carboxvlicacid
10 The title compound was prepared according to the method of Example 34C
substituting l-(3-cUoro-5-1rifluoromethyl-pyridin-2-yl)-piperazine for l-(5-chloro-2-pyridyl)piperazine. *H NMR (400 MHz, Py-d5) 8 8.57 (d, J= 2.02 Hz, IH), 8.05 (d, J= 2.18 Hz, IH), 7.88 (d, J= 8.12 Hz, IH), 4.27-4.38 (m, IH), 3.61-3.70 (m, 4H), 2.65-2.76 (m, 4H), 2.20-2.36 (m, 4H), 2.14-2.18 (m, 2H), 2.09-2.14 (m, 2H), 1.93-2.00 (m, IH), 1.85-1.91 (m,
15 2H), 1.58-1.66 (m, 2H), 1.36 (s, 6H).
Example 126
4-f2-(rff£)-4-{r2-f3.3-Difhioropiperidin-l-yl)-2-methvlpropanovnaminol-l-
20 ariamaTftyflcarbonvl]ammn}^hyl)benzoicacid
A solution of (f^-4-[2-(3,3-d^fhioro-pq)eridin-l-yl)-2-methyl-propionylamino]-adamantane-1-carboxylic acid from Example 43A (71.0 mg, 0.18 mmoles) in DMF (8 mL) was treated with TBTU (O- (benzotrialzol-l-yl)-l,l,3,3-tetramethyhironium tetrafiuoroborate) (77 mg, 0.27 mmoles), 4-(2-amino-ethyl)-benzoic acid methyl ester (41.0
25 mg, 0.22 mmoles) and DIEA (ethyl-diisopropyl-amine) (0.066 mL, 0.36 mmoles). The
mixture was stirred at room temperature for 12 hours. DCM (15 mL) and HaO (5 mL) were added to the mixture, the layers were separated and the organic phase was dried over Na^SC^ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC to provide a white powder with MS(ESI+) m/z 546. The white
30 powder was dissolved in THF (2 mL).and H2O (2 mL) and then LiOH (24 mg, 1 mmoles) was added. The mixture was stirred at room temperature for 12 hours. The mixture was neutralized (pH=6) with HC1 (2.0 N). DCM (15 mL) and H20 (5 mL) were added to the reaction mixture. The layers were separated and the organic phase was dried over Na2S(>4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified
35 by reverse phase HPLC to provide the title compound. 'H NMR (300 MHz, DMSO-d6)
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6 7.81 - 7.90 (m, 2H) 7:58 (d, 7= 7.80 Hz, IH) 7.50 (t, 7= 5.59 Hz, IH) 7.29 (d, 7= 8.48 Hz, 2H) 3.70 - 3.80 (m, IH) 3.23 - 3.34 (m, 2H) 2.78 (t, 7= 7.12Hz, 2H) 2.62 - 2.74 (m, 2H) 1.83 - 2.03 (m, 7H) 1.80 (s, 4H) 1.72 (d,7=2.37Hz, 6H) 1.43 - 1.57 (m, 2H) 1.12 (s, 6H); MS(ESI+) m/z 532 (M+H)+. 5
Example 129
N-f(2i^5-[(>le1Jiylsulfonvl)amh^
vllpiperazin-1 -yl)propananiid<>
10
Example 129A
>J-[(/^-5-Aminn-2-adamantyl]-2-{4-[5^tTifluoromethvl)pyridm-2-yllpipCTa7Hn-l-
y1}propanamirie
N-[(^-5-(Acetylainino)-2-adamaiityl]-2-{4-[5-(trifluoromethyl)pyridin-2-15 yl]piperazin-l-yl}propanamide from Example 119 (45 mg) was treated with 5N HCl at 100 C for 48h. The mixture was cooled and concentrated in vacuo to afford the title compound as the dihydrochloride salt. MS(DCI+) m/z 452 (M+H)+.
Example 129B
20 N-(f£V5-r(Methvlsutfonvftaminn]-2-adamM
vl]piperazin-l-yl}propa"«miHp.
A 0 °C solution of N-[(J^5-amino-adamantan-2-yl]-2-[4^5-trifluoromethyl-pyridin-2-yl)-piperazin-l-yl]-propionamide from Example 129A (13 mg, 0.029 mmoles) and DDEA (6 uL) in methylene chloride (1 mL) was treated with methane sulfonyl chloride (2.5 uL).
25 After 5 minutes, the reaction was warmed to 23 °C for 16 hours. The mixture was filtered through a silica gel plug (0-100% acetone/hexanes) and the resultant solution concentrated under reduced pressure. The residue was purified by radial chromatography (0-100% acetone/hexanes) to afford the title compound. !H NMR (400 MHz, Py-d5) 8 8.66 (s, IH), 8.26 (s, IH), 7.91 (d, 7= 7.98 Hz, IH), 7.78 (dd, 7= 2.03, 9.05 Hz, IH), 6.84 (d, 7= 8.90 Hz,
30 IH), 4.33 (d, 7= 7.67 Hz, IH), 3.66 - 3.82 (m, 4H), 3.34 (q, 7= 7.06 Hz, IH), 3.14 (s, 3H),
2.64 - 2.73 (m, 2H), 2.54 - 2.64 (m, 2H), 2.16 - 2.35 (m, 8H), 2.05 (s, IH), 1.88 (m, 2H), 1.57 (m, 2H), 1.35 (d, 7=7.06 Hz, 3H); MS(DCI) m/z 530 (M+H)+.
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Example 131
N-rf£)-5-fl-Hvdroxv-l-methvlethvn-2-adamantvn-2-methvl-2-{4-[5-ftrifluoromethvl)pyridin-2-yllpiperazin-1 -yl}propanamide
A solution of methyl 4-{2-methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l-
5 yl]-propionylamino}-adamantane-l-carboxylate from Example 15C (70 mg, 0.138 mmoles)
and tetrahydrofuran (5 mL) cooled to -78 °C was treated with methyl lithium (0.26 mL, 1.6
M solution in ether). The mixture was slowly warmed to 23 °C and stirred for 16 hours. The
mixture was quenched with saturated NH4CI solution, and the tetrahydrofuran was removed
under reduced pressure. The aqueous solution was extracted with methylene chloride (3x),
10 and the combined extracts concentrated under reduced pressure. The residue was purified by
silica gel chromatography (0-100% acetone/hexanes) to afford the title compound. JH NMR
(400 MHz, Py-ds) 5 8.67 (s, IH), 7.88 (d, J= 7.67 Hz, IH), 7.79 (d, 7= 9.21 Hz, IH), 6.87
(d, J= 8.90 Hz, IH), 4.26 (d, J= 8.29 Hz, IH), 3.76 (s, 4H), 2.59 (s, 4H), 2.08 - 2.17 (m,
2H), 1.81 - 2.04 (m, 10H), 1.60 (m, 2H), 1.33 (s, 6H), 1.29 (s, 6H); MS(DCI) m/z 509
15 (M+H)+.
Evnmp1ft132
(fo4-{[2-Methyl-2-(4-phenylpipera7n^
The title compound was prepared according to the procedure outlined in Example 23
20 substimting(£^-[2-memyl-2-(4-phenyl-piperazm-l-yl)-propionylammo]-adamajitane-l-
carboxylic acid for (^-4-{2-me1hyl-2-[4-(5-lTifmorome^yl-pyridin-2-yi)-piperazin-l-yl]-
propionylamino}-adamantane-l-carboxylic acid. !H NMR (500 MHz, Py-ds) 5 7.88 (d, J=*
8.11 Hz, IH), 7.67-7.72 (m, IH), 7.61-7.65 (m, IH), 7.35-7.43 (m, 2H), 7.11 (d, J= 8.07 Hz,
2H), 6.97 (t, J= 1.12 Hz, IH), 4.26-4.34 (m, IH), 3.26 (s, 4H), 2.62-2.66 (m, 4H), 2.26-2.32
25 (m, 2H), 2.21-2.26 (m, 2H), 2.13-2.18 (m,.2H), 2.08-2.13 (m, 2H), 1.93 (s, IH), 1.78-1.88
(m, 2H), 1.56-1.60 (m, 2H), 1.32 (s, 6H); MS(ESI) m/z 425 (M+H)+.
Rvat)rip1<» 133
30 (2?M-({2-r4-(2-MethoxyphenyRpippraz^
carhnvamiHft
The title compound was prepared according to the method of Example 44C substituting l-(2-methoxy-phenyl)-piperazmefor(3i?)-3-fluoropyrrolidine. !H NMR (300 MHz, Py-dj) 5 7.96 (d, J = 8.2 Hz, IH), 6.98-7.12 (m, 4H), 4.32 (d, J = 8.2 Hz, IH), 3.82 (s,
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3H), 3.22 (s, 4H), 2.71 (s, 4H), 2.23-2.31 (m, 4H), 2.14-2.16 (m, 3H), 1.87-1.98 (m, 4H), 1.6 (d, J = 12.5 Hz, 2H), 1.33 (s, 6H); MS(ESI+) m/z 455 (M+H)+.
5 Example 134
(£^-4-ffN.2-Dimethyl-N-phenvlalanyl)aTninn1adamantaae-1-r.arhnyafniHft
Example 134A
(£V4-f(W^2-Dimethvl-J\^phft»)y1a1any1)aminn]adamantane-l-carboxylie acid
10 The title compound was prepared according to the method of Example 34C
substituting N-methylaniline for l-(5-chloro-2-pyridyl)piperazine. MS(ESI+) m/z 371 (M+H)+.
Example. 134R
15 (7JM-ffl>l2-Dime&yl-N-phenylalanyl)^
The title compound was prepared according to the procedure outlined in Example 23 substituting (£)-4-[(i\A,2-dimethyl-JV--phenylalanyl)amino]adamantane-l-carboxylic acid for (£)-4-{2-[5-(6-chloro-pyridmO-yl)-hexahydro-pyrrolo[3,4-c]pym>lr2-yrj-2-methyl-propionylamino}-adamantane-l-carboxylic acid. The product was purified by reverse phase 20 HPLC to provide the title compound as a TFA salt. *H NMR (400 MHz, DMSO-d«) 5 7.38 (d, >7.98 HZi IH) 7.23 (t, >7.98 Hz, 2H) 7.03 (d, 2H) 6.90 - 6.98 (m, 2H) 6.68 (s, IH) 3.77 (d, IH) 2.81 (s, 3H) 1.74 - 1.85 (m, 7H) 1.70 (s, 2H) 1.54 (d,'2H) 1.39 (d, 2H) 1.20 - 1.29 (s, 6H); MS(ESI+) m/z 370 (M+H)+.
25
Example 135
(li>4-f{2-[4-(2ADimetiioxvphenyl)p^
1-carboxamide
The title compound was prepared according to the method of Example 44C 30 substituting l-(2,4-dimetlioxy-phenyl)-piperazinefor(37?)-3-fluoropyrrolidine. 'HNMR
(300 MHz, Py-d5) 8 7.98 (d, J - 8.2 Hz, IH), 7.05 (d, J = 8.3 Hz, IH), 6.79(s, IH), 6.65 (d, J = 8.3 Hz, IH), 4.32 (d, J = 8.2 Hz, IH), 3.82 (s, 3H), 3.74 (s, 3H), 3.18 (s, 4H), 2.72 (s, 4H), 2.23-2.31 (m, 4H), 2.14-2.16 (m, 3H), 1.87-1.98 (m, 4H), 1.62 (d, J = 12.5 Hz, 2H)), 1.33 (s,
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6H); MS(ESI+) m/z 485 (M+H)+.
Example 136
5 (iTM-({2-[4-f2J-Dicyanophenyl)pipera2m-l-vl]-2-methylpropanovnamino^ad^niRtifanR-1-
carhoxanii^ft
The title compound was prepared according to the method of Example 44C
substituting l-(2,3-dicyano-phenyl)-piperazine for (3#)-3-fluoropyrrolidhie. 'HNMRpOO
MHz, Py-d5) 5 7.75 (m, 1H), 7.4-7.54 (m, 2H), 7.17 (m, 1H), 4.32 (d, J - 8.2 Hz, 1H), 3.39
10 (s, 4H), 2.72 (s, 4H), 2.23-2.31 (m, 2H), 2.04-2.17 (m, 6H), 1.82-1.98 (m, 3H), 1.62 (d, J =
12.5 Hz, 2H)), 1.32 (s, 6H); MS(ESI+) m/z 475 (M+H)+.
Example 137
15 N-[(lfl-5-(Cyanomemvl)-2-adamantyl1-2-me^
vl1piperazin-l-vl}propanamide Asohtionofi^-[(i^-5-fbnnyl-adamantan-2-yl]-2-[4-(5-trifluoromethyl-pyridm-2-yl)-piperazin-l-yl]-isobutyramide (230 mg, 0.48 mmoles) from Example 22 and (p-tolylsulfonyl)methyl isocyanide (TosMIC, 121 mg, 0.624 mmoles) in DME (2 mL) and EtOH
20 (0.5 mL) was cooled to 0 °C and treated portion-wise with solid potassium /ert-butoxide (134.7 mg, 1.2 mmoles) while maintaining the temperature at 5-10 °C. The mixture was stirred at room temperature for 0.5 hour and at 35-40 °C for another 0.5 hour before filtration and washing with DME. The filtrate was concentrated under reduced pressure, loaded onto a short aluminium oxide column and washed with 500/100 mL of hexane/DCM. The solvent
25 was concentrated under reduced pressure to provide the title compound. *H MMR (400 MHz, CDClg) 5 8.40-8.42 (bs, 1H), 7.71-7.79 (m, 1H), 7.65 (dd, J= 2.52, 9.03 Hz, 1H), 6.66 (d, J= 8.98 Hz, 1H), 3.95-4.00 (m, 1H), 3.62-3.70 (m, 4H), 2.59-2.70 (m, 4H), 2.15 (s, 2H), 2.01-2.06 (m, 2H), 1.74-1.76 (m, 4H), 1.65-1.73 (m, 4H), 1.56-1.65 (m, 3H), 1.25 (s, 6H); MS(ESI+) m/z 490 (M+H)+.
30
Example 138
(£M-f{2-Methyl-2-r4-(4-nm-ophenyl)p^
carboxvlic acid
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A two phase suspension of (£)-4-(2-bromo-2-m3thyl-propionylammo)-adamantane-l-
carboxamide (36 mg, 0.1 mmoles) from Example 44B, l-(5-chloro-2-pyridyl)piperazine (20
mg, 0.11 mmoles) and tetrabutylammonium bromide (3 mg, 0.01 mmoles) in DCM (0.2 mL)
and 50% NaOH (0.2 mL) was stirred at room temperature for 20 hours. The mixture was
5 diluted with water and DCM and the layers separated. The organic layer was washed with
water (2x2 mL), dried (MgSO-O and filtered. The filtrate was concentrated under reduced
pressure. The crude methyl ester of the title compound that was purified on reverse phase
HPLC and hydrolyzed with 3N HCL at 60 °C for 20 hours. Drying of the mixture under
reduced pressure provided the hydrochloride of the title compound. *H NMR (500 MHz, Py-
10 d5) 6 8.38-8.46 (m, IH), 7.88 (d, /= 8.10 Hz, IH), 7.55 (ddd, J= 1.83,7.02, 8.62 Hz, IH),
6.85 (d, J= 8.56 Hz, IH), 6.70 (dd, J = 5.03, 6.87 Hz, IH), 4.18-4.26 (m, IH), 3.68 (s, 4H), 3.62 (s, 3H), 2.55-2.64 (m, 4H), 1.98-2.08 (m, 6H), 1.92-1.94 (m, 2H), 1.86-1.90 (m, IH), 1.75-1.84 (m, 2H), 1.48-1.56 (m, 2H), 1.30 (s, 6H); MS(ESI+) m/z 461 (M+H)+.
15
Example 139
(£V4-f{2-[4-f2.4-Dichlorophenyl)piperazm-l-yl]-2-methylpropanoY0fim'nn)a^^m»^aP^-1-
carboxvlic acid
The title compound was prepared according to the method of Example 34C 20 substituting l-(2,4-dichloro-phenyl)-piperazine for l-(5-chloro-2-pyridyI)piperazine. *H NMR (400 MHz, Py-d5) 6 7.83-7.96 (m, IH), 7.31 (dd, J= 2.30, 8.59 Hz, IH), 7.10 (d, 7= 8.57 Hz, IH), 4.28-4.38 (m, IH), 3.07-3.15 (m, 4H), 2.71-2.75 (m, 4H), 2.27-2.36 (m, 2H), 2.21-2.27 (m, 2H), 2.15-2.18 (m, IH), 2.10-2.15 (m, 2H), 1.95-2.01 (m, IH), 1.85-1.95 (m, 2H), 1.57-1.69 (m, 4H), 1.36 (s, 6H); MS(ESI+) m/z 495 (M+H)+. 25
Example 140
{(Jj>4-[(2-Methyl-2-{4-r5-ftrifhiorome^
adamantyl}acetic acid
30 A solution of (J^-N-(5-cyanomethyl-adamantan-2-yl)-2-[4-(5-trifluoromethyl-
pyridin-2-yl)-piperazin-l-yl]-isobutyrarnide (25 mg, 0.05 mmoles) from Example 137 in acetic acid (0.5 mL) and 48% HBr (2.5 mL) was stirred overnight at 120 °C. The solvents were concentrated and the residue was purified on reverse phase HPLC to provide the title compound. *H NMR (400 MHz, Py-dg) 8 8.67 (s, IH), 7.83 (d, J - 8.3 Hz, IH), 7.78 (d, J =
35 7.1 Hz, IH), 6.86 (d, J = 8.9 Hz, IH), 4.23 (d, J - 8.3 Hz, IH), 3.75 (s, 4H), 2.59 (s, 4H), 2.31
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(s, 2 H), 2.08 (s, 3H), 1.92-1.84 (m, 7H), 1.73 (s, 1 H), 1.62 (m, 3H), 1.31 (s, 6H); MS(ESI+) m/z 508 (M+H)+.
5 foaniple 141
(£V4-f{2-[4-(4-Cnloro-2-fluorophenyl>piperazia-l-vll-2-methvlpropan"Yl}flmiP9)arfaroantane-l-carboxvlicacid
The title compound was prepared according to the procedure outlined in Example 34C substituting l-(4-chloro-2-fluoro-phenyl)-piperazine for l-(5-chloro-2-pyridyl)piperazine. *H 10 NMR (500 MHz, Py-d5) 5 7.87 (d, J= 8.09 Hz, IH), 7.30 (dd, J= 2.40,12.30 Hz, IH), 7.17-7.20 (m, IH), 7.01 (t, J= 8.96 Hz, IH), 4.29-4.35 (m, IH), 3.11-3.18 (m, 4H), 2.63-2.70 (m, 4H), 2.21-2.35 (m, 4H), 2.10-2.19 (m, 4H), 1.95-1.98 (bs, IH), 1.85-1.91 (m, 2H), 1.58-1.67 (m, 2H), 1.34 (s, 6H); MS(ESI+) m/z 479 (M+H)+.
15
Example 142
(£)-4-[(2-Methyl-2-{4-f4-(trifluoromethyl)pyrimidm-2-yHp1'pf'ra"t|-* -vl}propanpy1^?"memyl-pyrimidine for l-(5-chloro-2-
pyridyl)piperazine. *H NMR (500 MHz, Py-d5) 5 8.67 (d, J= 4.76 Hz, IH), 7.87 (d, J= 8.10 Hz, IH), 6.89 (d, J= 4.77 Hz, IH), 4.28-4.36 (m, IH), 3.84-4.04 (m, 4H), 2.49-2.58 (m, 4H), 2.22-2.34 (m, 4H), 2.17-2.19 (m, 2H), 2.09-2.15 (m, 2H), 1.98-2.00 (bs, IH), 1.82-1.90 (m, 2H), 1.60-1.67 (m, 2H), 1.31 (s, 6H); MS(ESI)m/z 496 (M+H)+.
Kyample 143
CEV4-({2-[4-(3-Chloro-4-fluorophenyl)piperazin-l-yl1-2-methvlpropanoyl}aminn^adatnantanfi-1 -carboxylic acid
30 The title compound was prepared according to the method of Example 34C
substituting l-(3-chloro-4-fluoro-phenyl)-piperazine for l-(5-chk>ro-2-pyridyl)piperazine. 'H NMR (500 MHz, Py-d5) 8 7.87 (d, J= 8.07 Hz, IH), 7.19-7.23 (m, 2H), 6.90-7.00 (m, IH), 4.28-4.37 (m, IH), 3.13-3.27 (m, 4H), 2.62-2.71 (m, 4H), 2.27-2.34 (m, 2H), 2.22-2.26 (m, 2H), 2.15-2.17 (m, 2H), 2.10-2.15 (m, 2H), 1.93-1.97 (m, IH), 1.83-1.91 (m, 2H), 1.57-1.65
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(m, 2H), 1.34 (s, 6H); MS(ESI) m/z 478 (M+H)+.
Example 144
5 (i^-({2-f4-(4-CyaiiophenvRpipera7.in-U^^
carboxvlic acid
The title compound was prepared according to the method of Example 34C substituting 4-piperazin-1 -yl-benzonitiile for 1 -(5-chloro-2-pyridyl)piperazine. *H NMR (500 MHz, Py-ds) 5 7.83 (d, J= 8.07 Hz, IH), 7.64 (d, 7= 8.57 Hz, 2H), 7.02 (d, 7= 8.62 Hz, 10 2H), 4.28-4.36 (m, IH), 3.36 (s, 4H), 2.56-2.65 (m, 4H), 2.27-2.34 (m, 2H), 2.23-2.26 (m, 2H), 2.17 (s, 2H), 2.13 (s, 2H), 1.97 (s, IH), 1.81-1.91 (m, 2H), 1.58-1.67 (m, 2H), 1.33 (s, 6H); MS(ESI) m/z 451 (M+H)+.
15 Example 145
(.g>-4-({2-f4-f4-Bromophenyl)piperazin-l -vl"{-2-methvlpropanovl}amino'>ariamantajie-1 -
carboxvlic acid
The title compound was prepared according to the method of Example 34C
substituting l-(4-bromo-phenyl)-piperazine for l-(5-chloro-2-pyridyl)piperazine. 'HNMR
20 (500 MHz, Py-ds) 8 7.87 (d, J= 8.08 Hz, IH), 7.51-7.54 (m, 2H), 6.96-7.00 (m, 2H), 4.28-
4.35 (m, IH), 3.19-3,27 (m, 4H), 2.59-2.68 (m, 4H), 2.26-2.34 (m, 2H), 2.20-2.26 (m, 2H), 2.15-2.17 (m, 2H), 2.11-2.13 (m, 2H), 1.94-1.96 (m, IH), 1.82-1.89 (m, 2H), 1.58-1.65 (m, 2H), 1.33 (s, 6H); MS(ESI) m/z 504 (M+H)+.
25
Example 146
(£V4-({2-r4-f5-CbJoro-2-methoxvphenyl)piperazin-l-yll-2-methvlpropanovl)aminnteriainantane-1-carboxvlic acid
The title compound was prepared according to the method of Example 34C 30 substituting l-(5-chloro-2-methoxy-phenyl)-piperazine for l-(5-chloro-2-pyridyl)piperazine. *H NMR (500 MHz, Py-d5) 5 7.92 (d, J= 8.12 Hz, IH), 7.10-7.12 (m, 2H), 6.90 (d, J= 8.67 Hz, IH), 4.29-4.37 (m, IH), 3.80 (s, 3H), 2.99-3.33 (m, 4H), 2.66-2.74 (m, 4H), 2.29-2.35 (m, 2H), 2.24-2.29 (m, 2H), 2.17-2.20 (m, 2H), 2.12-2.15 (m, 2H), 1.94-1.97 (bs, IH), 1.87-1.92 (m, 2H), 1.58-1.66 (m, 2H), 1.34 (s, 6H); MS(ESI) m/z 490 (M+H)+.
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Example 147
(ii^4-({2-r4-(2-CMorophenyl)pipera7^
5 carboxylic acid
The title compound was prepared according to the method of Example 34C substituting l-(2-chloro-phenyl)-piperazine for l-(5-chloro-2-pyridyl)piperazine. !HNMR (500MHz, Py-d5)S 7.91 (d,7= 8.10Hz, IH), 7.52 (d, 7 =7.82Hz, IH), 7.29(t, 7= 7.59Hz, IH), 7.17 (d, 7= 7.85 Hz, IH), 7.05 (t, 7= 7.54 Hz, IH), 4.29-4.37 (m, IH), 2.98-3.26 (m, 10 4H), 2.69-2.74 (m, 4H), 2.21-2.36 (m, 4H), 2.10-2.20 (m, 4H), 1.95-1.99 (m, IH), 1.85-1.92 (m, 2H), 1.59-1.68 (m, 2H), 1.35 (s, 6H); MS(ESI) m/z 460 (M+H)+.
Tfrafliple 148
15 f^^-a2-r4-r2-Cvanopheny1)pipera*in-^^
carboxylic acid
The title compound was prepared according to the method of Example 34C
substituting 2-piperazin-l-yl-benzonitrile for l-(5-chloro-2-pyridyl)piperazine. 'HNMR
(500 MHz, Py-dj) 5 7.84 (d, 7= 8.09 Hz, IH), 7.69 (dd, 7= 1.48, 7.70 Hz, IH), 7.47-7.52 (m,
20 IH), 7.10 (d, 7= 8.29 Hz, IH), 7.03 (t, J= 7.50 Hz, IH), 4.28-4.36 (m, IH), 3.23-3.42 (m,
4H), 2.69-2.77 (m, 4H), 2.27-2.35 (m, 2H), 2.23-2.26 (m, 2H), 2.15-2.19 (m, 2H), 2.09-2.15 (m, 2H), 1.96-1.98 (bs, IH), 1.83-1.92 (m, 2H), 1.58-1.67 (m, 2H), 1.31 (s, 6H); MS(ESI) m/z451(M+H)+.
25
Ryample 149
(£)-4-r{2-[4-(2-Fhiorophenvl)pipCTfty.in-l-vl]-2-methylproparnYl}yi^inn)?dflniqntanft-^-
carboxylic acid
The title compound was prepared according to the method of Example 34C 30 substituting l-(2-fluoro-phenyl)-piperazinefor l-(5-chloro-2-pyridyl)piperazine. 'HNMR (500 MHz, Py-dj) S 7.89 (d, 7= 8 Hz, IH), 7.21 (m, IH), 7.15 (dd, 7= 7.5, 7.5 Hz, IH), 7.09 (dd, J= 8, 8 Hz, IH), 7.02 (m, IH), 4.32 (bd, J= 8.5 Hz, IH), 3.19 (bs, 4H), 2.68 (m, 4H), 2.27 (m, 4H), 2.17 (bs, 2H), 2.13 (bs, 2H), 1.96 (bs, IH), 1.88 (bd, 7= 13.5 Hz, 2H), 1.62 (bd, 7= 12.5 Hz, 2H), 1.34 (s, 6H); MS(ESI) m/z 444 (M+H)+.
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Example 150
(^4-({2-MelJivl-2-[4-(2-methvlphenvDpiperazm-l-vllpropannv1}amiTio)adamantane-l-
5 carboxvlic acid
The title compound was prepared according to the method of Example 34C substituting 1-o-tolyl-piperazine for l-(5-chtoro-2-pyridyl)piperazine. 'H NMR (500 MHz, Py-ds) 5 7.94 (d, J= 8.10 Hz, IH), 7.26-7.32 (m, 2H), 7.17 (d, J= 8.24 Hz, IH), 7.11 (t, J= 7.31 Hz, IH), 4.29-4.37 (m, IH), 2.97-3.01 (m, 4H), 2.66-2.70 (m, 4H), 2.39 (s, 3H), 2.28-10 2.35 (m, 2H), 2.22-2.28 (m, 2H), 2.17 (s, 2H), 2.14 (s, 2H), 1.96 (s, IH), 1.86-1.93 (m, 2H), 1.58-1.68 (m, 2H), 1.37 (s, 6H); MS(ESI) m/z 440 (M+H)+
Brample 151
15 (£)-4-f(2-r4-(4-CMorophenyl)ptpera7.in-l-vl1-2-methylpropanovl}aTninn)adamantane-l-
carboxylic acid
The title compound was prepared according to the method of Example 34C substituting l-(4-chloro-phen.yl)-piperazine for l-(5-chloro-2-pyridyl)piperazine. *H NMR (500 MHz, Py-ds) 5 7.87 (d, J= 8.07 Hz, IH), 7.37-7.42 (m, 2H), 7.01-7.05 (m, 2H), 4.28-20 4.36 (m, IH), 3.23 (s, 4H), 2.60-2.68 (m, 4H), 2.26-2.34 (m, 2H), 2.22-2.25 (m, 2H), 2.15-2.17 (m, 2H), 2.10-2.14 (m, 2H), 1.93-1.97 (m, IH), 1.81-1.89 (m, 2H), 1.58-1.64 (m, 2H), 1.33 (s, 6H); MS(ESI) m/z 460 (M+H)+.
25 Example 152
(£)-4-((2-[4-f3 -Chloropwidin-2-vfipiperazin-l -Yll-2-methvlpropanoyl} apiino^adamantane-1 -
carboxvlic acid
The title compound was prepared according to the method of Example 34C substituting l-(3-chloro-pyridin-2-yl)-piperazinefor l-(5-chloro-2-pyridyl)piperazine. !H 30 NMR (500 MHz, Py-d5) 5 8.30 (dd, J= 0.92,4.58 Hz, IH), 7.71 (dd, J= 1.55, 7.64 Hz, IH), 6.89 (dd, J= 4.64,7.71 Hz, IH), 4.31-4.36 (m, IH), 3.46-3.83 (m, 4H), 2.76-3.02 (m, 4H), 2.26-2.31 (m, 2H), 2.20-2.25 (m, 2H), 2.14-2.16 (m, 4H), 1.98-2.08 (m, 2H), 1.92-1.98 (m, IH), 1.56-1.63 (m, 2H), 1.44 (s, 6H); MS(ESI+) m/z 462 (M+H)+.
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Example 153
(£)-4-[(2-{4-[2-Chloro-4-(trifluoromethyDphenvnpipera2in-l-yl}-2-methvlpropannynaTnino]adamantane-l-cart>oxvlicacid
5 The title compound was prepared according to the method of Example 34C
substituting l-(2-chloro-4-trifluoromethyl-phenyl)-piperazine for l-(5-chloro-2-pyridyl)piperazine. *HNMR (500 MHz, Py-dj) 8 7.88-8.10 (m, IH), 7.85 (d, J= 2.18 Hz, IH), 7.55-7.61 (m, IH), 7.18-7.25 (m, IH), 4.30-4.39 (m, IH), 3.06-3.49 (m, 4H), 2.57-2.97 (m, 4H), 2.28-2.34 (m, 2H), 2.22-2.28 (m, 2H), 2.17-2.18 (m, 2H), 2.12-2.17 (m, 2H), 1.97-
10 2.04 (m, IH), 1.85-1.97 (m, 2H), 1.60-1.69 (m, 2H), 1.39 (s, 6H); MS(ESI+) m/z 529 (M+H)+.
Example 154
15 (J^4-({2-K3Jg)-3-Fluoropvn-ohdm-l-vl1-2-methvlpropanovl>fiiirtinnVN-rpvridin-3-
vlmethvftadamantane-1 -p-arhmramide
Example 154 A
(E)-4-({2-f(3j;V3-Fhioropyrrolidin-l-yl]-2-methylpropanny1}aminn)adamanfa^<^-l-
20 carboxylic acid
The title compound was prepared according to the method of Example 34C
substituting (3J2)-3-fluoro-pyrrolidine (356.0 mg, 4 mmoles) for l-(5-chloro-2-pyridyl)
piperazine. !H NMR (300 MHz, DMSO-de) 8 10.83 - 11.15 (m, IH), 7.69 - 7.86 (d, J= 4.80
Hz, IH), 3.78 - 3.90 (m, IH), 3.60 (d, J= 4.75 Hz, IH), 2.16 - 2.37 (m, 2H), 1.92 - 2.09 (m,
25 4H), 1.76 - 1.94 (m, 8H), 1.54 - 1.66 (m, 6H), 1.38 - 1.51 (m, 3H), 1.21 - 1.33 (m, IH);
• MS(ESI+)m/z353(M+H)+.
Example 154B
(^M-({2-ff3J?V3-Fluoropyn:oUdm-l-yl]-2-me11iylpropa""y1}^minnVN-fpvridin-^
30 vlmethvfladamantane-1 -carboxamide
A solution of (£)-4-({2-[(3i0-3-fluoropyrrolidin-l-yl]-2-methylpropanoyl}amino)adamantane-l-carboxylic acid from Example 154A (21.0 mg, 0.06 mmoles) in DMF (5 mL) was treated with TBTU (O- (benzotrialzol-l-yl>l,1,3,3-tetramethyluronium tetrafluoroborate) (26.0 mg, 0.08 mmoles), 3-(aminomethyl)pyridine
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(8.0 mg, 0.07 mmoles) and DIEA (ethyl-diisopropyl-amine) (0.02 mL, 0.11 mmoles). The mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC to provide the title compound. 'HNMR (400MHz, DMSO-d6) 5 8.39 - 8.49 (m, 2H), 8.09 (t, J= 6.10 Hz, IH), 5 7.71 (d, J= 8.29 Hz, IH), 7.59 (d, J= 7.67 Hz, IH), 7.33 (dd, J= 7.67,4.91 Hz, IH), 4.27 (d, J = 6.14 Hz, 2H), 3.79 (d, J= 7.98 Hz, IH), 2.81 - 2.93 (m, 2H), 2.65 - 2.74 (m, IH), 2.41 -2.49 (m, IH), 2.03 - 2.22 (m, IH), 1.85 - 1.99 (m, 8H), 1.80 (s, 2H), 1.66 - 1.76 (m, 2H), 1.46 - 1.57 (m, 2H), 1.17 (s, 6H); MS(ESI+) m/z 443 (M+H)+.
10
Example 155
(E)-4-{ f 2-Methyl-2-(3 -phenylpiperidin-1 -yl)prf»pannYMaiT1'nr>} afom,antane-1 -carhoyfln^H e.
The title compound was prepared according to the method of Example 44C
substituting 3-phenyl-piperidine for (37?)-3-fluoropyrrolidine. XH NMR (300 MHz, Py-ds)
15 5 7.94 (s, IH), 7.35-7.42 (m, 2 H), 7.28-7.33 (m, 3 H), 4.27 (d, J = 8.0 Hz, IH), 3.0 (m, IH),
2.91 (m, IH), 2.04-2.34 (m, 11H), 1.93 (m, 4H), 1.74 (m, 1H), 1.50-1.68 (m, 4H), 1.33 (d, J = 5.8 Hz, 6H); MS(ESI+) m/z 424 (M+H)+.
20 Example 156
f£V4-f{2-f4-(2-Chloro-4-methvlphenvl>)piperazin-l-vn-2-methylprop^ti^y)[}a]jT|ijpn)adnniantane-l-carboxvlicacid
The title compound was prepared according to the method of Example 34C
substituting l-(2-chloro-4-methyl-phenyl)-piperazinefor l-(5-chloro-2-pyridyl)piperazine.
25 !H NMR (500 MHz, Py-d5) 5 7.94-8.12 (bs, IH), 7.31 (s, IH), 7.06-7.12 (m, 2H), 4.30-4.39
(m, IH), 3.04-3.34 (m, 4H), 2.67-2.92 (m, 4H), 2.28-2.35 (m, 2H), 2.22-2.28 (m, 2H), 2.11-2.21 (m, 7H), 1.87-2.04 (m, 3H), 1.57-1.68 (m, 2H), 1.39 (s, 6H); MS(ESI+) m/z 475 (M+H)+.
30
Example 157
(^-4-({2-[4-(,2-Fluorophenvl)piperidin-l-yl1-2-methvlpropanoyl}aminn'^?)Hamftntanf>-l-
carboxylic acid The title compound was prepared according to the method of Example 34C
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substituting 4-(2-fluoro-phenyI)-piperidine for l-(5-chloro-2-pyridyl)piperazine. JH NMR (500 MHz, Py-dj) 8 1.45 (s, 6H), 1.59-1.63 (m, 2H), 1.89-1.99 (m, 3H), 2.15-2.30 (m, 10H), 2.99-3.05 (m, 2H), 3.15-3-25 (m, IH), 4.34 (m, IH), 7.14-7.245 (m, 4H), 7.95 (m, IH); MS(ESI+) m/z 443 (M+H)+. 5
Example. 158
(2?M-({2-Methyl-2-[4-(2-methvlphenvDpiper^
carboxvlic acid
10 The title compound was prepared according to the method of Example 34C
substituting l-(3-chloro-pyridin-2-yl)-piperazine for l-(5-chloro-2-pyridyl)piperazine. 'H NMR (500 MHz, Py-d5) 5 8.30 (dd, J= 0.92, 4.58 Hz, IH), 7.71 (dd, 7= 1.55, 7.64 Hz, IH), 6.89 (dd, J= 4.64,7.71 Hz, IH), 4.31-4.36 (m, IH), 3.46-3.83 (m, 4H), 2.76-3.02 (m, 4H), 2.26-2.31 (m, 2H), 2.20-2.25 (m, 2H), 2.14-2.16 (m, 4H), 1.98-2.08 (m, 2H), 1.92-1.98 (m,
15 IH), 1.56-1.63 (m, 2H), 1.44 (s, 6H); MS(ESI+) m/z 462 (M+H)+.
P.yflmplft 15?
fgM-(r2-r4-(2-ChJoro-4-fluorophenvnpippr»^p-1-y|1-7-
20 methvltMopanovl}amino^adamantane-l-^An^tp^ft
Example 159A
1 -f2-Chloro-4-fluorophenyl)piperazine
A suspension of l-bromo-2-chloro-4-fluorobenzene (4.19 g, 20 mmoles), piperazine (10.32 g, 120 mmoles), sodium tert-butoxide (2.3 g, 1.5 mmoles),
25 tris(dibenzylideneacetone)dipalladium (366 mg, 0.4 mmoles) and racemic (±)-2,2'-
bis(diphenylphosphino)-l,r-binaphthyl (747 mg, 1.2 mmoles) in toluene (2 mL) was heated to 120 °C overnight. The mixture was cooled, filtered and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-5% 2N methanolic ammonia in DCM) to provide the title compound.
30
Example 159B
r^V4-rf2-r4-(2-Chk)ro-4-fluorophenvnpipftr?^it]-Vy11-7-methylpropanoyl}aminn)adaTnantane-l-carbnyapoide
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The title compound was prepared according to the method of Example 44C substituting l-(2-chloro-4-fluorophenyl)piperazine from Example 159A for (3R)-3-fluoropyrrolidine. *H NMR (400 MHz, Py-ds) 8 7.83-7.93 (m, IH), 7.58-7.66 (m, 2H), 7.33-7.41 (m, IH), 7.04-7.18 (m, 2H), 4.26-4.34 (m, IH), 3.03-3.13 (m, 4H), 2.67-2.75 (m, 4H), 5 2.27-2.33 (m, 2H), 2.22-2.27 (m, 2H), 2.11-2.18 (m, 4H), 1.94-2.00 (m, IH), 1.85-1.93 (m, 2H), 1.58-1.66 (m, 2H), 1.35 (s, 6H); MS(ESI+) m/z 477 (M+H)+.
Example 160
10 (£M-((2-[4-(2-Furovnpiperazm-l-y^
acid
Example 160 A
Memyl(ffl-4-({2-[4-(2-furoyl)pip^a7in-1-y|l^^
15 carfaoxylate
The hydrochloride salt of methyl (JE)-4[2-(4-pq)erazin-l-yl)-2-methyl-propionyl-amino]-adamantane-l-caboxylate (70 mg, 0.18 mmoles), TBTU (62 mg, 0.193 mmoles), and furoic acid (22 mg, 0.192 mmoles) were suspended in dimethylacetamide (0.5 mL). Diisopropylamine (525 mg, 4.07 mmoles) was added and the solution was kept at room 20 temperature for 18 hours. To the mixture was added toluene and the solution concentrate under reduced pressure. More toluene was added and the solution was washed with H3PO4, water, and finally KHCO3 before drying (MgSO-t) and removing the solvents in vacuum to afford the title compound. MS(ESI) m/z 458 (M+H)+.
25 Example 160B
(EV4-( {2-[4-(2-FuroyDpiperazin-1 -yl]-2-methylpropannyl} am inn)adamantane-1 -carboxylic
acid
The title compound was prepared according to the method of Example 164B substituting methyl (£)-4-({2-[4-(2-furoyl)piperazin-l-yl]-2-3 0 methylpropanoyl} amino)adamantane-1 -carboxylate from Example 160A for methyl (E)-4-[(2-{4-[(4-chlorophenyl)sulfonyl]piperazin-1 -yl) -2-methylpropanoyl)amino]adamantane-1 -carboxylate. *H NMR (300 MHz, CDCI3) 8 7.73 (d, J = 8 Hz, IH), 7.49 )d, J = 1 Hz, IH), 7.02 (d, J = 3 Hz, IH), 6.49 (dd, J - 3Hz, 1Hz, IH), 4.01 (d, J = 8 Hz, IH), 3.82 (br. s, 4H), 2.60 (m, 4H), 1.93-2.10 (m, 9H), 1.73 (d, J = 12 Hz, 2H), 1.65 (d, J - 12 Hz, 2H), 1.22 (s,
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6H); MS(ESI+) m/z 444 (M+H)+
Example Ifil
5 (£V4-('(2-[4-(2-Chloro-4-cvanophenvnpiperazin-l-yl1-2-
methvlpropanny1)ainiTir>)aHaTnflntane-l -carboxvlic acid
KxamplftlfilA
3-Chloro-4-pipftray.in-1 -vlbenzonitrile
10 A solution of 3-chtero-4-fhioro-benzonitrile (236 mg, 1.52 mmoles), piperazine (784
mg, 9.1 mmoles) and potassium carbonate (276 mg, 2 mmoles) in acetonitrile (5 mL) was heated to 100 °C overnight. The mixture was cooled, filtered and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-5% 2N methanolic ammonia in DCM) to provide the title compound. MS(APCI+) m/z
15 222(M+H)+.
Example! 61B
(£V4-({2-r4-(^-CM)nr9-4-cyanopbfttiYl)pipera?jn-l-yl]-2-methvlpropano vl} aminnladamantane-1 -carboxylic acid
20 The title compound was prepared according to the procedure outlined in Example 34C
substituting 3-chloro-4-piperazin-l-yIbenzonitrile from Example 161A for l-(5-chloro-2-pyridyl)piperazine. *H NMR (400 MHz, Py-d3) 5 7.84-7.85 (m, IH), 7.82-7.85 (m, IH), 7.58-7.63 (m, IH), 7.13 (d, J= 8.34 Hz, IH), 4.28-4.38 (m, IH), 3.10-3.33 (m, 4H), 2.71 (s, 4H), 2.20-2.36 (m, 4H), 2.11-2.19 (m, 4H), 1.97 (s, IH), 1.83-1.93 (m, 2H), 1.59-1.69 (m,
25 2H), 1.36 (s, 6H); MS(ESI+) m/z 486 (M+H)+.
Example 162
(£V4-r{2-r4-(2-Chloro-4-fluorophenvnpiperazin-l-vl1-2-
30 methylpropano vl) amino^adamantane-1 -carboxvlic acid
A sample of (£)-4-{2-[4-(2]adamantane-l-carboxylicacid
30
Example J 64A
fert-Butyl 4-(2-{f(£)-5-(methoxvcarbonvlV2-adamantv1}aiTiino}-1, l-dimethvl-2-oxoethvl)piperay.inft-l -r-arboxvlate
The title compound was prepared according to the method of Example 34C
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substituting piperazine-1-carboxylic acid tert-butyl ester for l-(5-chloro-2-pyridyl)piperazine and isolating the ester before hydrolysis. MS(DCI+) m/z 464 (M+H)+.
5 Example 164B
Methyl (£)-4-[(2-methyl-?-piperazin-l -vlpropam>yr>aminn]aHaTnantane-1 -carboxylate
A 0 °C solution of tert-butyl 4-(2-{[(£)-5-(memoxycarbonyl)-2-adarnantyl]amino}-l,l-dimethyl-2-oxoelJiyl)piperazine-l-carboxylate from Example 164A (250 mg, 0.54 mmoles) in methanol (3 mL) was slowly treated with acetyl chloride (0.15 mL). After 5 10 minutes, the solution was warmed to 23 °C and stirred for 16 hours. The mixture was
concentrated in vacuo to afford the title compound as the hydrochloride salt. MS(DCI+) m/z 364 (M+H)+.
15 Example 164C
Methvlf£^-4-f(2-{4-[(4-cMorophenyl)sulfbnyI1piperazin-l-vl}-2-methylpropanovnaminnj^^aTpaptane-l-carboxvlate The hydrochloride salt of methyl (£)-4-[(2-methyl-2-piperazin-l-ylpropanoyl)amino]adamantane-l-carboxylate from Example 164B (70 mg, 0.18 mmoles) 20 was suspended in CHCU (0.5 mL) in a 4 mL vial with rapid stirring. Diisopropylethylamine (70 mg, 0.54 mmoles) was added followed by 4-chlorobenzene sulfbnyl chloride (44 mg, 0.208 mmoles). The solution was stirred at room temperature for 15 hours. Toluene was added, and the solution was washed with KHCO3 and thenjiilute H3PO4. After drying (Na2SC>4), the tobene was removed under reduced pressure and the residue crystallized from 25 1:1 ether:heptane to afford the title compound. MS(ESI) m/z 538 (M+H)+.
Example 164D
f£)-4-r(2-{4-[f4-Chlorophenvnsulfonvnpiperazin-l-vn-2-
30 methylpropan9yl)atninn]adaniantane-l -carboxylic acid
A solution of methyl (E)-4-[(2-{4-[(4-chforophenyl)sulfbnyl]piperazin-l-yl}-2-methylpropanoyl)amino]adamantane-l-carboxylate from Example 164C (50 mg) in 50% aqueous NaOH (30 mg), methanol (0.8 mL), and water (0.25 mL) was stirred and heated at 55 °C for 1 hour. The solution was cooled and concentrated under reduced pressure, and the 35 residue dissolved in water (1 mL). The solution was acidified by addition of solid KH2PO4.
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The resultant mixture was extracted with CHC13, dried (Na2S04), and filtered. The filtrate
was concentrated and the residue crystallized from ether to afford the title compound. JH
NMR (500 MHz, CDCb) 5 7.73 (d, J = 9Hz, 2H), 7.55 (d, J = 9Hz, 2H), 7.40 (d, J = 8Hz,
IH), 3.93 (d, J = 8Hz, IH), 3.05 (br.s, 4H), 2.60 (m, 4H), 2.02 (d, J - 12Hz, 2H), 1.95 (d, J =
5 12Hz, 2H), 1.92 (m, 5H), 1.55 (d, J = 13Hz, 2H), 1,44 (d, J = 13Hz, 2H), 1.18 (s, 6H);
MS(ESI+) m/z 524 (M+H)+.
Example 165
10 (£>^{2-f4-(2.4-DifluoropheayI)piperidin-l-vl]-2-methylpropanoyl}amino^adaiTiaTitaTie-l-
carboxvlic acid
The title compound was prepared according to the procedure outlined in Example 34C substituting 4-(2,4-difiuoro-phenyl)piperidine for l-(5-chloro-2-pyridyl)piperazine. lH NMR (500 MHz, Py-ds) 5 7.96 (d, J= 8.07 Hz, IH), 7.37 (td, J= 6.46, 8.60 Hz, IH), 7.10 (ddd, 7= 15 2.40, 8.82,11.03 Hz, IH), 6.97-7.06 (m, IH), 4.27-4.35 (m, IH), 2.89-2.98 (m, 2H), 2.79-2.88 (m, IH), 2.26-2.34 (m, 2H), 2.10-2.26 (m, 8H), 1.75-1.96 (m, 7H), 1.57-1.65 (m, 2H), 1.35 (s, 6H); MS(ESI+) m/z 461 (M+H)+.
20 Example 166
(£)-4-({2-f4-(4-Cyano-2-fluorophenyl)piperazin-l-vl1-2-methylpropanovl}aiyinr>)ariai^antane-l-carboxylie acid
25 Example 166 A
3-Fluoro-4-piperazin-l-vlbenzonitrile
A solution of 4-chloro-3-fluoro-benzonitrile (236 mg, 1.52 mmoles), piperazine (784 mg, 9.1 mmoles) and potassium carbonate (276 mg, 2 mmoles) in acetonitrile (5 mL) was heated to 100 °C overnight. The mixture was cooled and filtered, and the filtrate was 30 concentrated under reduced pressure. The crude residue was purified by column
chromatography (silica gel, 0-5% 2N methanolic ammonia in DCM) to provide the title compound. MS(APCI+) m/z 206 (M+H)+.
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(JE>4-({2-r4-('4-Cyano-2-fluorophenynpiperazin-l-vl1-2-methvlpropanov1}amiTi^)a^amantane-l-carboxvlicacid
The title compound was prepared according to the procedure outlined in Example 34C
substituting 3-fluoro-4-piperazin-l-ylbenzonitrile from Example 166A for l-(5-cbJoro-2-
5 pyridyl)piperazine. 'H NMR (400 MHz, Py-dj) 8 7.84-7.85 (m, IH), 7.82-7.85 (m, IH),
7.58-7.63 (m, IH), 7.13 (d, 7= 8.34Hz, IH), 4.28-4.38 (m, IH), 3.10-3.33 (m, 4H), 2.71 (s, 4H), 2.20-2.36 (m, 4H), 2.11-2.19 (m, 4H), 1.97 (s, IH), 1.83-1.93 (m, 2H), 1.59-1.69 (m, 2H), 1.36 (s, 6H); MS(BSI+) m/z 486 (M+H)+.
10
Tfrrample 167
(J^-4-[(2-Memvl-2-{3-memyl-4-[5-(lrifmoromethvnpvridin-2-yl]piperazin-l-yl}propanoyflaroinn]adamantane-l -carboxvlic acid
15 Example 167A
2-Memvl-l-f5-ftrifluoromemvnpvridin-?-YllPT?niiirinft A suspension of 3-methyl-piperazine-l-carboxylic acid tert-butyl ester (200 mg, 1 mmoles), 2-bromo-5-trifluoromethyl-pyridine (339 mg, 1.5 mmoles), sodium ferf-butoxide (144 mg, 1.5 mmoles), tris(dibenzylideneacetone)dipalladium (4.6 mg, 0.005 mmoles) and
20 tri-t-butylptosphine (8 mg, 0.04 mmoles) in toluene (2 mL) was heated to 120 °C overnight. The mixture was cooled, filtered and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-20% acetone in hexane), and the ester was hydrolyzed stirring in 4N HC1 in dioxane (5 mL) for 4 hours at room temperature. The solvent was concentrated under reduced pressure to provide the
25 hydrochloride of the title compound. MS(APCI+) m/z 246 (M+H)+.
Example 167B
^-4-[(2-Methvl-2-{3-methyl-4-[5-(trifluoromethynpvridm-2-vllpipfira7.in-1-
yl) propanoyflaminoladamantane-1 -carboxvlic acid
3 0 The title compound was prepared according to the procedure outlined in Example 34C
substituting 2-methyl-l-[5-(trifluoromethyl)pyridin-2-yl]piperazine from Example 167A for l-(5-chloro-2-pyridyl)piperazine. JH NMR (400 MHz, Py-d5) 8 8.7 (s, IH), 7.8 (d, J - 8.8 Hz, IH), 7.73 (d, J = 7.6 Hz, IH), 6.85 (d, J - 8.9 Hz, IH), 4.32 (d, J = 7.7 Hz, IH), 3.22 (t, J = 12.5 Hz, IH), 2.86 (d, J = 10.7 Hz, IH), 2.76 (d, J = 11.3 Hz, IH), 2.45 (d, J = 9 Hz, IH),
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2.15-2.3 (m, 8H), 2.1 (s, 1H), 1.97 (s, 1H), 1.89 (d, J = 12.5 Hz, 2H), 1.63 (d, J = 12.5 Hz, 2H), 1.34 (d, J = 6.7 Hz, 3H), 1.32 (s, 6H); MS(ESI+) m/z 509 (M+H)+.
5 Tftrflmplfi 168
f^-4-f(2-f4-(4-C>yanophenvl)-3.5-dimethvl-lH-pvrazol-l-vl1-2-methvlpropanoyl}amipn)adamantane-l-carboxylicacid
10 Example 168 A
2-(,4-Broror>-3 ,S-^imethvl-lff-pvrazol-l-vlV2-methvlpropanoic acid
To a cold (0 °C), well stirred suspension of NaOH (1.6 g, 40 mmoles) and 4-bromo-3,5-dimethylpyrazole (1.75 g, 10 mmoles) in acetone (100 mL), was added 2-(trichloromethyl)-propan-2-ol (3.54 g, 20 mmoles) portion-wise over 1 hour. The mixture
15 was allowed to warm to room temperature overnight. The solvent was evaporated under reduced pressure. The residue was dissolved in water (100 mL) and washed with ether (50 mL). The aqueous phase was separated and acidified with cone. HCl 'to pH - 3. The mixture was extracted with CH2CI2 (3 x 50 mL) and the combined organics dried over NaiSCU. A colorless oil was obtained after the removal of the solvent under reduced pressure.
20 MS(DCI+) m/z 263 (M+H)+.
Example 168B
Methvn^-^fP-^bromo-S.S-dimethvl-lH-pvrazol-l-vn-a-
25 methvlpropat)ov^ftmi^n}adamitntane-l-carboxylate
To a DMF (20 mL) solution of 2-(4-bromo-3,5-dimethyl-l#-pyrazol-l-yl)-2-methylpropanoic acid from Example 168A (2.00 g, 7.66 mmoles) and methyl 4-adamantamine-1-carboxylate from Example 15B (1.71g, 7.66 mmoles), was added 0-(lH-benzolxiazol-l-yO-^HN'N'-tetramemyluroniumtetrafluoroborate (TBTU 3.36 g, 10.47
30 mmoles) followed by N,N-diisopropylethylamine (DDEA, 6.1 mL, 34.9 mmoles). The
mixture was stirred at room temperature overnight and then diluted with ethyl acetate (150 mL). The organic layer was washed with water (3x30 mL), brine (30 mL), dried over NajSOij, filtered, concentrated under reduced pressure to provide the crude product as dark brown oil. The residue was chromatographed on a Biotage flash 40 M ehiting with 70:30
3 5 hexane/ethyl acetate to afford the title compound. MS(ESI) m/z 452 (M+H)+.
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Example 168C
Methvlf^-4-((2-f4-r4-cvanoDhenvn-3.5-dimethvl-l//-pyrazol-l-yn-2-
5 methvlpropanoyl) amino^adamantane-1 -carboxylate
To a solution of methyl (£)-4-{[2-(4-bromo-3,5-dimethyl-ljy-pyrazol-l-yl)-2-methylpropanoyl]amino}adamantane-l-carboxylate from Example 168B (91 mg, 0.2 mmoles) in isopropanol (1 mL) was added 4-cyanophenylboronic acid (36 mg, 0.24 mmoles), Pd(PPh3)aCl2 (15 mg, 0.02 mmoles), and K2CO3 (83 mg, 0.6 mmoles). The mixture was 10 heated to 85 °C for 3 hours in sealed tube. It was diluted with ethyl acetate (10 mL) and washed with water (2x1 mL) and brine. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by flash chromatography with 30% ethyl acetate/hexane to provide the title compound. MS(ESI) m/z 475 (M+H)+.
15 Example IfiST)
rJgM-f(2-|"4-(;4-CvanophenylV3.5-dimethvl-lH-pvrazol-l-vn-2-methvlpropanoyl) amino)adamantane-1 -carboxylic acid
To a solution of methyl (£)-4-({2-[4-(4-cyanophenyl)-3,5-dimethyl-l//-pyrazol-l-yl]-2-methylpropanoyl}amino)adamantane-l-carboxylate from Example 168C (50 mg, 0.11
20 mmoles) in THF (0.2 mL) and water (0.1 mL) at room temperature was added lithium
hydroxide (27 mg, 0.66 mmoles). The resultant mixture was stirred at room temperature overnight. The reaction was acidified with a IN HC1 solution to pH = 3 and extracted with CH2CI2 (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide the title compound. JH NMR (300 MHz, CD3OD) 6 7.79 (d, J=
25 8.24 Hz, 2H), 7.43 (d, J= 8.24 Hz, 2H), 6.14 (m, 1H), 3.92 (m, 1H), 2.24 (s, 3H), 2.22 (s, 3H), 1.87 - 1.99 (m, 9H), 1.86 (s, 6H), 1.51 - 1.57 (m, 4H); MS(ES1) m/z 461 (M+H)+.
Example 169
30 (£V4-a2-r4-f4-Cvanophenvn-3.5-dimethvl-lH-pvrazol-l-vll-2-
methylpropanoyl}amino)ariarnantane-l-carbnyqmidft
To a DMF(0.2 mL) solution of (JE)-4-({2-[4-(4-cyanophenyI)-3,5-dimethyl-lH-pyrazol-l-yl]-2-methylpropanoyl}amino)adamantane-l-carboxylic acid from Example 168D (30 mg, 0.065 mmoles), was added 0-(lH-benzotriazol-l-yl)-N,N,N'N'-tetramethyluronium
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tetrafluoroborate (32 mg, 0.098 mmoles) followed by N,N-diisopropylethylamine (0.057 mL,
0.326 mmoles) and ammonium hydroxide (0.018 mL, 0.13 mmoles). The mixture was stirred
at room temperature overnight. It was diluted with ethyl acetate (10 mL), washed with water
(2x2 mL) and brine (3 mL), dried over NajSCV The crude product was obtained after
5 concentration. The residue was purified by HPLC to afford the title compound. 'HNMR
(500 MHz, CDC13) 5 7.71 (d, J= 8.24 Hz, 2H), 7.29 (d, 7= 8.24 Hz, 2H), 6.09 (s, IH), 5.67 (s, 1H),5.56 (m, IH), 3.97 (d, J= 7.93 Hz, IH), 2.27 (s, 3H), 2.23 (s, 3H), 1.91 - 1.97 (m, 7H), 1.90 (s, 6H), 1.83 - 1.86 (m, 2H), 1.52 (m, 2H), 1.36 (m, 2H); MS(ESI) m/z 460 (M+H)+ 10
Example 171 f£)^-{[2-Methyl-N-(3-methylpheny1)j}adarnantane-l-carbpyafniHft
The title compound was prepared according to the method of Example 51 substituting 15 w-tolylamine for phenylamine. lH NMR (500 MHz, DMSO-d<5) 5 7.26 (d, J= 8.24 Hz, IH), 6.92 - 6.99 (m, 2H), 6.70 (s, IH), 6.44 (d, /= 7.32 Hz, IH), 6.32 - 6.37 (m, 2H), 5.71 (s, IH), 3.78 (d, J= 7.93 Hz, IH), 2.15 (s, 3H), 1.73 - 1.85 (m, 6H), 1.71 (s, IH), 1.67 (s, 2H), 1.44 (s, IH), 1.39 - 1.42 (m, IH), 1.36 (s, 6H), 1.32 (s, IH), 1.30 (s, IH); MS(ESI+) m/z 370 (M+H)+.
20
Example 172
tert-Butyl4^2-{[(£)-5^aminnr.ai4K>nvl)-2-adaTTiantyl]amin9}-ll1-dimethyl-2-oxbethyDpiperazinft-1 -fiarboxylate
A solution of piperazine-1-carboxylic acid tert-butyl ester (20.0 mg, 0.11 mmoles) in 25 anhydrous toluene (2 mL) was treated with sodium hydride (3.6 mg, 1.5 mmoles). The
reaction mixture was stirred at room temperature under nitrogen for 2 hours. Then (£)-4- (2-bromo-2-methyl-propionylamino)-adamantane-l-carboxamide (35.0 mg, O.lmmol) from Example 44B was added to the mixture. This reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 12 hours. The reaction mixture was concentrated under reduced 30 pressure. The residue was purified by reverse phase HPLC to provide the title compound. *H NMR (500 MHz, DMSO-dg) 5 7.63 (d, 7= 8.24 Hz, IH), 7.00 (s, IH), 6.72 (s, IH), 3.76 (d, J = 8.24 Hz, IH), 2.34 - 2.41 (m, 4H), 1.92 (m, 2H), 1.86 (m, 3H), 1.81 - 1.84 (m, 4H), 1.73 -1.78 (m, 3H), 1.67 - 1.72 (m, 2H), 1.52 -1.55 (m, IH), 1.49 - 1.52 (m, 2H), 1.39 (s, 9H), 1.07 - 1.12 (s, 6H); MS(ESI+) m/z 449 (M+H)+. 35
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Example 173 (2R)-2-f(3i?V3-Fluoropvn-oUdm-l-yl]-N-[(iE^-5-hydroxv-2-adamantyl1prnpanaiT>iriR
5 Example 173 A
(25)-2-Bromo-JV-[(£V5-hvdroxy-2-adaTnant.y1]prnpanati(iidft
A solution of (2jS)-2-bromo-propionic acid (1.53 g, 10 mmoles) in DCM (100 mL) was treated with hydroxybenzotriazole hydrate (HOBt) (1.68 g, 11 mmoles), (£)- and (Z)-5-hydroxy-2-adamantamine (1.67 g, 10 mmoles) from Example 13 A and 15 minutes later with
10 (3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (EDCI) (2.4 g, 12 mmoles). The mixture was stirred overnight at room temperature after which the DCM was removedunder reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts washed with saturated sodium bicarbonate, water, dried (MgS04) and filtered. The filtrate was concentrated under
15 reduced pressure and the crude product purified (silica gel, 10-40% acetone in hexane) to provide the title compound. MS(APCI+) m/z 302, 304 (M+H)+.
Example 173B
f2flV2-r(3Jgy3-Fluoropyrroudm-l-vl1-^
20 A solution of (25)-2-bromo-iV-[(£)-5-hydroxy-2-adamantyl]propanamide (100 mg,
0.33 mmoles) from Example 173A and the hydrochloride of (3i?)-3-fluoropyrrolidine (41 mg, 0.33 mmoles) in DCM (1 mL) and TEA (0.1 mL) was stirred overnight at 50 °C. The DCM was removed under reduced pressure, and the residue was purified on reverse phase HPLC to provide the title compound. *H NMR (300 MHz, CDCb) 5 7.42 (s, 1H), 5.12-5.23 (d, J= 55
25 Hz, 1 H), 4.01 (d, J = 8.5 Hz, 1H), 2.93-3.16 (m, 3H), 2.20-2.50 (m, 2H), 2.23-2.1 (m, 5H),
1.9-1.88 (m, 2H), 1.7-1.8 (m, 6 H), 1.5-1.53 (m, 2 H) 1.33 (d, J= 5,2 Hz, 3H); MS(APCI+) m/z 311 (M+H)+.
30
Example 174
(£)-4-({2-[4-(2-Bromophenyl)piperazin-l-yl1-2-methvlpropanovl}aiT)inn^adamantane-l-
carboxylic acid
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Example 174A
Metiiyl(E)-4-((2-r4-(2-bromopb.envnpiperazin-l-yl]-2-
5 methylpropftnnY|}ainino^adamantane-l^carboxylate
The title compound was prepared according to the method of Example 34C substituting l-(2-bromo-phenyl)-piperazine for l-(5-chloro-2-pyridyl)piperazine and isolating the ester before hydrolysis to the acid. MS(DCI) m/z 518 (M+H)+.
10 Example 174B
(£)-4-({2-[4-(2-Bromophenyl)piperazin-l-yl1-2-methylpropanoyl}amino^adamantane-l-
carboxylic acid
A solution of methyl (E)-4-({2-[4-(2-bromophenyl)piperazin-l-yl]-2-methylpropanoyl}amino)adamantane-l-carboxylate (50 mg, 0.10 mmol) in tetrahydrofuran (1
15 mL) was treated with potassium trimethylsilanolate (25 mg, 0.19 mmol, tech. 90%), and the reaction mixture warmed to 40 °C for sixteen hours. The reaction mixture was cooled to 23 °C, diluted with methylene chloride, and quenched with IN HC1 (190 uL). The layers were separated and the aqueous phase extracted additionally with methylene chlorjde (2x). The combined organic phases were dried (Na2S04), filtered, and concentrated under reduced
20 pressure. The solid residue was triturated with diethyl ether to afford the title compound. JH NMR (400 MHz, Py-d5) 5 7.90 (d, 7=7.98 Hz, IH), 7.71 (d, 7=7.98 Hz, IH), 7.33 (dd, 7=7.67 Hz, IH), 7.15 - 7.20 (m, IH), 6.98 (dd, 7=7.52 Hz, IH), 4.32 (d, 7=7.67 Hz, IH), 3.05 - 3.22 (m, 4H), 2.67 - 2.80 (m, 4H), 2.20 - 2.35 (m, 4H), 2.15 (d, 7=13.20 Hz, 4H), 1.84 - 2.00 (m, 3H), 1.63 (d, 7=12.58 Hz, 2H), 1.35 (s, 6H); MS(DCI) m/z 504 (M+H)+.
25
Example 175 (£)^{P^-(3-CMorophenyl)-2-methylalanyl]aTninn}?damantanft-l-carboxamide
The title compound was prepared according to the method of Example 51 substituting 30 3-chloro-phenylamine for phenylamine. *H NMR (400 MHz, DMSO-4?) 8 7.18 (d, 7= 7.98 Hz, IH), 7.08 (t, 7= 8.13 Hz, IH), 6.94 (s, IH), 6.67 (d, 7= 1.84 Hz, IH), 6.62 (dd, 7= 7.98, 1.23 Hz, IH), 6.51 (t, 7= 2.15 Hz, IH), 6.45 - 6.49 (m, IH), 6.13 (s, IH), 3.75 - 3.81 (m, IH), 1.76 - 1.82 (m, 7= 4.91, 4.30 Hz, 5H), 1.70 -1.76 (m, 2H), 1.65 - 1.69 (m, 7= 3.07 Hz, 2H), 1.44 - 1.47 (m, IH), 1.40 - 1.44 (m, 7= 1.23 Hz, IH), 1.38 (s, 6H), 1.31 - 1.34 (m, IH), 1.27 -
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1.31 (m, IH); MS(ESI+) m/z 390 (M+H)+.
Example 176
(E)-A- i fN-(3 -MethoxyphenylV2-methyla lany 1]aminn } aria mantane-1 -carboxamide
5 The title compound was prepared according to the method of Example 51 substituting
3-methoxy phenylamine for phenylamine. *H NMR (400 MHz, DMSO-dS) 5 6.91 - 7.04 (m, 2H), 6.68 (d, J = 5.52 Hz, IH), 6.20 (dd, J= 8.13,1.99 Hz, IH), 6.07 - 6.17 (m, 2H), 5.81 (s, IH), 3.76 (t, J= 6.14 Hz, 2H), 3.64 (s, 3H), 1.98 (s, 2H), 1.88 (s, 2H), 1.70 - 1.84 (m, 2H), 1.68 (s, 2H), 1.46 (s, IH), 1.43 (s, IH), 1.36 (s, 6H), 1.33 (s, IH), 1.30 (s, IH); MS(ESI+) m/z 10 386 (M+H)+.
Ryawplft 177
fEM-({2-[4^4-CvanophenvlV3.5-dmethvM^
15 (\ 3-thiaznl-5-ylmethyl)ada^iaTi^ane-l-carpnxftm'dft
The title compound was prepared according to the method of Example 169 substituting C-thiazol-5-yl-methylamine for ammonium hydroxide: JH NMR (300 MHz, CDC13) 8 8.87 (s, IH), 7.70 (d, 7= 8.24 Hz, 2H), 7.30 (s, IH), 7.29 (d, J= 8.24 Hz, 2H), 6.55 (s, IH), 5.53 (m, IH), 4.56 - 4.62 (m, 2H), 3.96 (m, IH), 2.26 (s, 3H), 2.22 (s, 3H), 1.91 -20 2.01 (m, 7H), 1.89 (s, 6H), 1.82 - 1.87 (m, 2H), 1.46 - 1.55 (m, 2H), 1.30 - 1.39 (m, 2H); MS(ESI) m/z 557 (M+H)+.
Example 178
25 fJgV4-f{2-f4-(6-Chloropvrimidin-4-vl>)piperazin-l-vn-2-
methylpropanoyl}amino)aHatTiantane-l-carboxylicacid
A solution of methyl (i^-4-(2-memyl-2-piperazin-l-yl-propionylaniino)-adamantane-1-carboxylate from Example 164B (1.0 mmole), 4,6-dichloro-pyrimidine (1.2 mmoles), and dioxane (0.8 mL) was heated in a microwave reactor to 130 °C for 1 hour. The cooled 30 reaction mixture was directly purified by HPLC. The methyl ester was hydrolyzed with aq. LiOH in methanol to afford the title compound. 'H NMR (300 MHz, CD3OD), 8 8.28 (s, IH), 6.83 (s, IH), 3.93 (bs, IH), 3.75 (bs, 4H), 2.62 (t, J= 6 Hz, 4H), 2.02-1.63 (m, 14H), 1.22 (s, 6H); MS(ESI) m/z 462 (M+H)+.
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Example 179
r£V4-('(2-[4-f6-Chloropyridazin-3-vl^piperazin-l-yl1-2-methylpropanoy1}^mino)adamantane-l-carboxylicacid
The title compound was prepared according to the method of Example 178 substituting 3,6-dichloro-pyridazine for 4,6-dichloro-pyrimidine. !H NMR (300 MHz, CD3OD), 8 7.44 (d, J= 9 Hz, 1H), 7.53 (d, 7= 9 Hz, 1H), 3.93 (bs, 1H), 3.65 (bs, 4H), 2.66 (t, J= 6 Hz, 4H), 2.02-1.63 (m, 14H), 1.24 (s, 6H); MS(ESI), m/z 462 (M+H)+.
10
RvamplftlRO
r^4-a244-f2-ChtoropvrimidJ"-4-y1)pipftrfiTin..l-vl1-2-methvlpropanoyl} am inr>)ariam arcane-1 -carboxvlic acid
The title compound was prepared according to the method of Example 178 15 substituting 2,4-dicMoro-pyrimidine for 4,6-dichloro-pyrimidine. '-H NMR (3 00 MHz,
CDsOD), 6 8.00 (d, J= 6 Hz, 1H), 6.72 (d, J= 6 Hz, 1H), 3.93 (bs, 1H), 3.75 (bs, 4H), 2.63 (t, 7= 6 Hz, 4H), 2.07-1.63 (m, 14H), 1.24 (s, 6H); MS(ESI), m/z 462 (M+H)+.
20 Example 181
N^[((f£n^-K.2-Melhvl-2-{4-f5-(trifluoromethynpvridin-2-vnpiperazin-l-yl}prnpan9yl)amino]-l-adamantvl}ami«n)carhonyllglvcine
Example 181A
25 iy-f(2ft-5-Isocyanato-2-adamantvll-2-me^
1 -vl}propanamide
Asohationof(£)-4-{2-meinyl-2-[4-(5-trifluorome1iiyl-pyridin-2-yl)-piperazin-l-yl]-propionylamino}-adamantane-l-carboxylic acid (1.48 g, 3 mmoles) from Example 15D in toluene (10 mL) was treated with diphenylphosphoryl azide (991 mg, 3.6 mmoles) and TEA 30 (0.54 mL), and the reaction mixture was stirred at 90 °C overnight. The solvent was removed under reduced pressure to provide the crude title compound. MS(APCI+) m/z 492 (M+H)+.
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Example 18 IB
N-ff{(£n^r(2-Methvl-2-{4-[5-ftrifluoromethvnpvridin-2-vnpiperazin-l-v1}propanovflanyno1-l-adamanty1}ftTTiino)carbonvl1glvcine
A solution of iV-[(E)-5-isocyanato-2-adamantyl]-2-methyl-2-{4-[5-
5 (trifluoromethyl)pyridin-2-yl]piperazin-l-yl}propanamide (250 mg, 0.51 mmoles) from
Example 181A in dioxane (0.5 mL) was treated with the hydrochloride salt of glycine methyl ester (125.6 mg, 1 mmole), and the reaction mixture was stirred at 70 °C overnight. The dioxane was concentrated under reduced pressure. The crude product was purified (silica gel, 10-40% acetone in hexane) to provide methyl ester of the title that was hydro lyzed by stirring
10 in 3N HC1 at 60° C overnight. The reaction mixture was cooled to 23 °C and concentrated under reduced pressure to provide the hydrochloride salt of the title compound. ^NMR (500 MHz, Py-4-f{2-Methvl-2-f4-(1.3-tMazol-2-vnpiperazin-l-yl]propanoyl}amino^adamantane-l-
carboxylic acid
The title compound was prepared according to the method of Example 34C substituting l-thiazol-2-yl-piperazine for l-(5-chloro-2-pyridyl)piperazine. *H NMR (400 5 MHz, CDC13) 6 7.72 (d, J= 8.0 Hz, IH), 7.16 (d, J= 3.7 Hz, IH), 6.55 (d, J= 3.7 Hz, IH), 3.38 (bs, 4H), 2.99 (ap t, J= 5.1 Hz, IH), 2.61 (bs, 4H), 1.79-1.94 (m, 9H), 1.51-1.61 (m, 4H), 1.18 (s, 6H); MS(ESI) m/z 433 (M+H)+.
10 Example 185
(EM-{[>I-(4-Methoxvphenyl)-2-methyl3fa
A solution of 4-methoxy-phenylamine (25.0 mg, 0.2 mmoles) in anhydrous toluene (3 mL) was treated with sodium hydride (7.2 mg, 3.0 mmoles). The reaction mixture was stirred at room temperature under nitrogen for 2 hours. Then (£)-4-(2-bromo-2-methyl-
15 propionylamino)-adamantane-l-carboxamide(35.0 mg, 0.1 mmol) fromJBxarnple44B was added to the mixture. This reaction mixture was stirred at 100 °C under nitrogen for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC to provide the title compound. *H NMR (500 MHz, DMSO-d6) 8 7.41 (d, 7= 8.01 Hz, IH) 6.97 (s, IH) 6.67 - 6.77 (m, 7= 8.85 Hz, 3H) 6.51 (d, 7= 8.85
20 Hz, 2H) 5.44 (s, IH) 3.79 (d, 7= 7.94 Hz, IH) 3.63 (s, 3H) 1.73 -1.86 (m, 7H) 1.69 (s, 2H) 1.47 (m, 2 H) 1.34 - 1.38 (m, 2H) 1.32 (s, 6H); MS(ESI+) m/z 386 (M+H)+.
Example 186
25 6^4-({N-[4-(Dmiethylamino)phenyl]-2-methylalanvl}amino)adamantane-l-carboxamide
The title compound was prepared according to the method of Example 185 substituting N,N-dimethyl-benzene-l,4-diamine (27.0 mg, 0.2 mmoles) for 4-methoxy-phenylamine. *H NMR (500 MHz, DMSO-cfc) 5 7.48 (s, IH), 6.97 (s, IH), 6.71 (s, IH), 6.58 - 6.69 (m, 2H), 6.44 - 6.59 (m, 2H), 5.19 - 5.40 (m, IH), 3.80 (s, IH), 2.74 (s, 6H), 1.94 -30 2.09 (m, IH), 1.72 - 1.91 (m, 6H), 1.69 (s, 2H), 1.43 - 1.56 (m, 2H), 1.33 - 1.41 (m, IH), 1.31 (s, 6H), 1.21 - 1.27 (m, IH); MS(ESI+) m/z 399 (M+H)+.
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(ifl-4-({2-Methvl-N-r4-(trifluoromet^
The title compound was prepared according to the method of Example 185 substituting 4-trifluoromethyl-phenylamine (32.2 nig, 0.2 mmoles) for 4-methoxy-phenylamine. ltt NMR (500 MHz, DMSO-cfe) 8 7.40 (d, 7= 8.54 Hz, 2H), 7.14 (d, J= 7.93 Hz, IH), 6.96 (s, IH), 6.70 (s, IH), 6.62 (d, 7= 8.54 Hz, 2H), 6.49 (s, IH), 3.78 (d, J= 7.81 Hz, IH), 1.93 - 2.10 (m, IH), 1.72 - 1.85 (m, 6H), 1.62 - 1.72 (m, 3H), 1.42 (s, 6H), 1.38 (s, IH), 1.21 - 1.31 (m, 2H); MS(ESI+) m/z 424 (M+H)+.
10 Example 188
(i^-({2-Methvl-N-f3-(trifluorometh^
The title compound was prepared according to the method of Example 185
substituting 3-trifluoromethyl-phenylamine (32.2 mg, 0.2 mmoles) for 4-methoxy-
phenylamine. 'H NMR (500 MHz, DMSO-^f) 8 7.29 (t, 7= 7.93 Hz, IH), 6.96 (s, IH), 6.91
15 (d, J= 7.63 Hz, IH), 6.79 (d, J= 8.24 Hz, IH), 6.75 (s, IH), 6.70 (s, IH), 6.32 (s, IH), 3.78
(d, 7= 7.63 Hz, IH), 1.71 - 1.85 (m, 7H), 1.63 - 1.71 (m, 2H), 1.40 (s, 6H), 1.37 (s, 2H), 1.23 -1.31 (m, 2H); MS(ESI+) m/z 424 (M+H)+.
20 RvattiplRl89
(£V4-({2-[4-(2-Hvdroxvphenvl)piperazin-1 -yl]-2-methylpropanoyl} amino)adamantane-1 ■
carboxylic acid
25 Example 189A
Methyl (£)-4-(f2-f4-(2-methoxvphenyl)piperazin-l-yn-2-methylpropanoyl} am ino)adamantane-1 -carboxvlate
The title compound was prepared according to the method of Example 34C substituting l-(2-methoxy-phenyl)-piperazine for l-(5-chloro-2-pyridyl)piperazine and 3 0 isolating the ester before hydrolysis to the acid. MS(DCI) m/z 470 (M+H)+.
Example 189B
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Methyl (E)-4-((2-\4-(2-h.vdroxvphenyftpiperazin-1 -yll-2-methylpropanf>yl}amino^adamantane-l-carboxvlate
To a O °C solution of methyl (£)-4-({2-[4-(2-methoxyphenyI)piperazJn-l-yl]-2-memylpropanoyl}amino)adamantane-l-carboxylate from Example 189A (20 mg, 0.043
5 mmoles) in methylene chloride (2 mL) was added boron tribromide (0.26 mL, 1.0 M solution in methylene chloride), and the reaction mixture warmed to 23 °C for 1 hour and 45 °C for 16 hours. The reaction mixture was cooled to 0 °C and methanol (1 mL) was slowly added. The reaction was warmed to 40 °C for 4 hours, cooled to 23 °C, and concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with saturated aqueous
10 NaHC03 and brine. The ethyl acetated solution was dried (NajSO^, filtered, and
concentrated under reduced pressure. The residue was purified (flash silica gel, 0-40% methanol in methylene chloride) to provide the title compound. MS(DCI) m/z 456 (M+H)+.
Example 189C
15 (Jfo4-({2-[4-(2-HydroxvphenyI)pipera7.in-1^
carboxylic acid
The title compound was prepared according to the method of Example 174B substituting methyl (£)-4-({2-[4-(2-hydroxyphenyl)piperazin-1 -yl]-2-methylpropanoyl}amino)adamantane-l-carboxylate for methyl (£)-4-({2-[4-(2-
20 bromophenyl)piperazin-1 -yl]-2-methylpropanoyl} amino)adamantane-1 -carboxylate. !H NMR (500 MHz, Py-d5) 5 ppm 7.98 (d, J= 8.24 Hz, 1H), 7.28 (dd, J= 7.93, 1.53 Hz, 1H), 7.22 - 7.24 (m, 1H), 7.10 - 7.15 (m, 1H), 7.00 - 7.05 (m, 1H), 4.31 (d, J= 7.93 Hz, 1H), 3.27 (s, 4H), 2.68 (s, 4H), 2.20 - 2.33 (m, 4H), 2.10-2.19 (m, J= 20.14Hz, 4H), 1.93 - 1.98 (m, 1H), 1.87 - 1.93 (m, J= 13.12 Hz, 2H), 1.58 - 1.65 (m, 2H), 1.31 (s, 6H); MS(APCI) m/z 442
25 (M+H)+.
Example 190
4-(2-{r(£)-5-fAmiiincarbonyl)-2-adamantyl1aminol-l.l-dimethyl-2-oxoethvl)-N-(tert-
30 butyl)piperazine-1 -carboxamide
Example 190 A Methyl r£)-4-[(2-{4-r(tert-butylfminn)r.arhonyl1piperazin-l-yl}-2-
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metiivlprGpanovfiamiriojadamantane-1 -carboxylate
To a 23 °C solution of methyl (£)-4-(2-methyl-2-piperazin-l-yl-propionylamino)-adamantane-1 -carboxylate from Example 164B (50 mg, 0.114 mmoles) and methylene chloride (1 mL) was added ter/-butyl isocyanate (12 mg, 0.114 mmoles) and DBEA (37 mg, 0.285 nmoles). The reaction mixture was stirred for 1 hour. The reaction mixture was purified (flash silica gel, 0-50% acetone in methylene chloride) to afford the title compound. MS(DCI)m/z463(M+H)+.
10 Example 190B
(£V4-[(2-(4-[(ter^Biity1amiiin)<^rbonyl]piperazin-l-yl}-2-methylpropanoyl)amino1a^aff|qntane-l-carboxylicacid
The title compound was prepared according to the method of Example 174B substituting methyl (£)-4-[(2-{4-[(ter/-butylamino)carbonyl]piperazin-l-yl}-2-15 methylpropanoyl)amino]adamantane-l -carboxylate for methyl (E)-4-({2-[4-(2-
bromophenyl)piperazin-1 -yl]-2-methylpropanoyl} amino)adamantane-1 -carboxylate. MS(DCI) m/z 449 (M+H)+
Example 190C
20 4-(2-{[(ffl-5-(AminocaAonvl)-?.-adamantyl]amm^
butyl)piperazine-1 -carboxamide
The title compound was prepared according to the method of Example 23 substituting (£)-4-[(2-{4-[(tert-butylamino)carbonyl]piperazin-1 -yl} -2-methylpropanoyl)amino]adamantane-l-carboxylic acid from Example 190B for (£)-4-{2-
25 methyl-2-[4-(5-trifluoromethyl-pyridm-2-yl)-piperazin-l-yl]-propionylammo)-adajnajitane-1-carboxylic acid. 'H NMR (400 MHz, Py-d5) 5 7.80 (d, J= 7.98 Hz, IH), 7.59 - 7.65 (m, 2H), 6.09 (s, IH), 4.23 (d, J= 7.98 Hz, IH), 3.59 - 3.68 (m, 4H), 2.45 (t, 7= 4.60 Hz, 4H), 2.16 - 2.29 (m, 4H), 2.11 - 2.16 (m, 2H), 2.00 - 2.06 (m, 2H), 1.87 - 1.93 (m, IH), 1.72 - 1.80 (m, 2H), 1.49 - 1.57 (m, 1 IH), 1.22 (s, 6H); MS(DCI) m/z 448 (M+H)+.
30
Example 191
N-f(ift-5-(7omylaminoy2-adamantyll-2-methyl-^^
yllpiperazin-1 -yl}propanamide
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Erafliple191A
iV^(ifl-5-amino-2-adairiantyl]-2-meftvl-2^
yl)propanamide
A solution of N-[(^-5-isocyanato-adaniantan-2-yl]-2-[4-(5-lTifhioromethyl-pyridin-2-yl)-piperazin-l-yl]-isobutyramide (1.47 g, 1.5 mmoles) from Example 181A in dioxane (5 mL) was treated with 5N HCl and stirred at 70 °C overnight. The solvents were concentrated under reduced pressure to provide the crude hydrochloride of the title compound. MS(APCI+) m/z 466 (M+H)+.
10
Example 191B
N-[(^-5-(Fnrmvlamino)-2-adamantvl]-2-methvl-2-{4-[5^trifhioromethyl)pvridin-2-
y|]pipftrazin-| -y|} propanamide
A solution ofN-[(J5^5-armTO-adamaTitan-2-yl]-2-[4^5-lrifluoromelhyl-pyridin-2-yl)-15 piperazin-l-yl]-isobutyramide (83 mg, 0.1 mmoles) in ethyl formate (0.5 mL) and TEA (0.1 mL) was stirred at 70 °C for 3 days. The solvents were removed under reduced pressure, and the residue was purified by reverse phase HPLC to provide the title compound. *H NMR (500 MHz, Py-dj) 5 8.68 (s, 2H), 7.85 (d, J= 7.93 Hz, 1H), 7.80 (dd, J= 8.85, 2.44 Hz, 1H), 6.88 -6.92 (m, 1H), 4.30 (d, J= 7.63 Hz, 1H), 3.76 (s, 4H), 2.54 - 2.61 (m, 4H), 2.29 - 2.38 (m, 20 4H), 2.14 (s, 2H), 2.02 (s, 2H), 1.88 - 1.95 (m, 1H), 1.82 (m, 2H), 1.61 (m, 2H), 1.29 - 1.34 (m, 6H); MS(ESI+) m/z 494 (M+H)+.
Biological Data:
Measurement of Inhibition Constants:
25 The ability of test compounds to inhibit human 11P-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 1 ip-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 1 lp-HSD inhibitor, 18P-glycyrrhetinic acid.
30 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 P-scintillation counter. The 1 ip-HSD-1 assay was carried out in 96-well microliter plates in a total volume of 220 ul. To start the assay, 188 ul of master mix which contained 17.5 nM TH-cortisone,
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157.5 nM cortisone, and 181 mMNADPHwas 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 u.1 of titrated compounds was then added in 5 triplicate to the substrate. Reactions were initiated by the addition of 10 uJ of 0.1 mg/ml
E.coli lysates overexpressing 110-HSD-l enzyme. After shaking and incubating plates for 30 minutes at room temperature, reactions were stopped by adding 10 ul of 1 mM glycyrrhetinic acid. The product, tritiated Cortisol, was captured by adding 10 u.1 of 1 uM monoclonal anti-cortisol antibodies and 100 ui SPA beads coated with anti-mouse antibodies. After shaking
10 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
15 IC50 curves were generated. This assay was applied to 11 {J-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 1 10-HSD-l assay described above, and show selectivity for human 11 p-HSD-1 over human 110-HSD-2, as indicated in Table 1.
20 Table 1. Human 110-HSD-l and llfl-HSD-2 enzymatic SPA assay.
Compound 110-HSD-l ICsofnM) 113-HSD-2IC30(nM)
A 110 >10,000
B 92 >10,000
C 150 >10,000
D 140 >10,000
E 82 >10,000
F 53 >30,000
G 37 >30,000
H 35 >30,000
I 67 >30,000
J 80 >10,000
K 58 >10,000
L 200 >10,000
M 160 >30,000
The data in Table 1 indicates that the compounds of the present invention are active in the human 11 P-HSD-1 enzymatic SPA assay described above, and show selectivity for 110-
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HSD-1 over 1 ip-HSD-2. The llp-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 11P-HSD-2 greater than 1000 nM, and preferably greater than 10,000 nM. Generally, the ICso ratio for 5 11 P-HSD-2 to 11P-HSD-1 of a compound is at least 10 or greater, and preferably 100 or greater.
Mouse Dehvdrocorticosterone Challenge Model
Male CD-I (18-22 g) mice (Charles River, Madison, WI.) were group housed and
10 allowed free access to food and water. Mice are brought into a quiet procedure room for acclimation the night before the study. Animals are dosed with vehicle or compound at various times (pretreatment period) before being challenged with 11-dehydrocorticosterone (Steraloids Inc., Newport, R.I.). Thirty minutes after challenge, the mice are euthanized with C02 and blood samples (EDTA) are obtained by cardiac puncture and immediately placed on
15 ice. Blood samples were then spun, the plasma was removed, and the samples frozen until further analysis was performed. Corticosterone levels were obtained by ELISA (American Laboratory Prod., Co., Windham,, NH.) or HPLC/mass spectroscopy.
Table 2. Plasma corticosterone levels following vehicle, 11 dehydrocorticosterone (11-

DHC), or Compounds N, O and P (followed by 11-DHC) treatment.
Pretreatment Period Time (hours) vehicle 11-DHC Compounddose at 30mpk Compounddose at 100mpk
Compound N 0.5 231+51 1478+180 1297+121 742+119
16 151+23 1200 + 86 1402 ±99 1422+129
Compound O 0.5 359+67 1648+151 1095 +33
16 253+45 2003 ±260 1167 +211
Compound P 1.0 90+18 1521±150 100+18
16 191+33 1963 +170 1924 + 148
ob/ob Mouse Model of Type 2 Diabetes.
Male B6.VLepob(-/-) (pb/ob) mice and their lean lktermates (Jackson Laboratory, Bar Harbor, Maine) were group housed and allowed free access to food (Purina 5015) and water. 25 Mice were 6-7 weeks old at the start of each study. On day 0, animals were weighed and postprandial glucose levels determined (Medisense Precision-X™ glucometer, Abbott Laboratories). Mean postprandial glucose levels did not differ significantly from group to
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group (n=10) at the start of the studies. Animals were weighed, and postprandial glucose measurements were taken weekly throughout the study. On the last day of the study, 16 hours post dose (unless otherwise noted) the mice were euthanized via C02, and blood samples (EDTA) were taken by cardiac puncture and immediately placed on ice. Whole 5 blood measurements for HbAlc were taken with hand held meters (Ale NOW, Metrika Inc., Sunnyvale CA). Blood samples were then spun and plasma was removed and frozen until further analysis. The plasma triglyceride levels were determined according to instructions by the manufacturer (Infinity kit, Sigma Diagnostics, St. Louis MO).
10 Table 3. Plasma glucose, HbAlc, and triglyceride levels.following three weeks of twice

daily dosini i with vehicle or Compounds N, 0 and P
Control Compound Compound
ob/ob dose at 30 mpk dose at 100 mpk
CompoundN Glucose mg/dL 338 ± 13 295± 31 263 ± 21
HHbAlc 6.9 + 0.3 7.6± 0.6 6.4 ± 0.5
Triglycerides mg/dL 348 + 31 255± 22 282 ± 36
Compound 0 Glucose mg/dL 359 ±14 193± 19
%HbAlc 9.0 + 0.3 6.7 ±0.3
Triglycerides mg/dL 390 ± 24 143+ 19
FFA mEq/L 1.74±.13 1.16 + .15
CompoundP Glucose mg/dL 359 ±14 259± 34 146 ±9
HHbAlc 9.Q±0.3 7.0+1.0 6.0± 0.4
Triglycerides mg/dL 390 ± 24 186 ±24 117± 14
FFAmEa/L 1.74+ .13 1.56+ .13 0.97+ .11
Mouse Model of High Fat Diet Induced Obesity.
15 Male C57BL/6 J. mice were placed on a high fat diet (Research Diets D 12492i, 60
kcal% fat) for 16 weeks, starting at 5-6 weeks age, with free access to food and water. Age-matched mice on low fat diet (Research Diets D12450Bi) served as lean controls. Individually housed mice were 22-23 weeks old at the start of each study, and conditioned for 7 days to daily oral gavage with vehicle at 15:00h. On day 0, prior to the start of the studies,
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10
15

mean body weights did not differ significantly from group to group (n=10), except for the group on low fat diet. Additional mice (n=8 per group) were used for evaluation of insulin sensitivity by insulin tolerance test (ITT). Animals and food were weighed, and postprandial glucose measurements were taken twice each week throughout the 28 day study. Mice were dosed twice a day at 08:00h and 15:00h by oral gavage. On day 28,16 hours post dose (unless otherwise noted) the mice were euthanized via CO2, and blood samples (EDTA) were taken by cardiac puncture and immediately placed on ice. Blood samples were centrifuged and plasma was removed and frozen until further analysis. The plasma insulin levels were determined according to instructions by the manufacturer (Mouse Insulin Elisa, Alpco Diagnostics, Windham NH). On day 26, starting at approximately 06:001^ 8 mice from Compound F 30 mg/kg, DIO and lean vehicle groups were fasted for 4h in clean cages, with water available ad libitum. Blood glucose was determined by tail snip (time 0), and regular human insulin (Lilly Humulin-R™, 0.2S U/kg, 10 ml/kg IP diluted in sterile saline containing 1% bovine serum albumin) was given. Blood glucose was determined (Medisense Precision-X™ ghicometer, Abbott Laboratories) at 30,60, 90 and 120 min post-injection, and the area under the blood glucose vs time response curve (AUC) was reported.

Table 4. Body weight loss, plasma insulin level and insulin sensitivity following four weeks of twice daily dosing with vehicle or Compounds O and P.
Control DIO Mice CompoundO 10 mpk Compound O 30 mpk Compound P 30 mpk Control Lean Mice
Body Weight 2.78±0.49 -0.99+0.61 -7.53+1.01 -1.14+J3.95 -0.04+0.34
Change (g)
Insulin (ng/ml) 3.58±0.52 2.44+0.25 1.12+0.24 2.52+0.36 0.94+0.11
nTAUC(mg/dl -4288± nd -8582± 1816 nd -9574+929
* min) 1080
20 (nd-not determined)
The compounds of this invention are selective inhibitors of the 11 B-HSD-1 enzyme.
Their utility in treating or prophylactically treating type 2 diabetes, high blood pressure,
dyslipidemia, obesity, metabolic syndrome, and other diseases and conditions is believed to
derive from the biochemical mechanism described below.
25
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 30 action may lead to insulin resistance, type 2 diabetes, dyslipidemia, visceral obesity and
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hypertension. Cortisol and cortisone are the major active and inactive forms of glucocorticoids in humans, respectively, 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
5 circulating hormone concentration and the density of receptors in the target tissues. In the
last decade, it was discovered that tissue glucocorticoid levels may also be controlled by 11(3-hydroxysteroid dehydrogenases enzymes (1 ip-HSDs). There are two 1 Ip-HSD isozymes which have different substrate affinities and cofactors. The 1 ip-hydroxysteroid dehydrogenases type 1 enzyme (110-HSEM) is a low affinity enzyme with Km for cortisone
10 in the micromolar range that prefers NADPH/NADP* (nicotinamide adenine dinucleotide phosphate) as cofactors. 1lP-HSD-l 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 ip-HSD-1 is capable of acting both as a reductase and a dehydrogenase. However, many studies have shown that it functions primarily as a reductase
15 in vivo and in intact cells. It converts inactive 11-ketogtucocorticoids (i.e., cortisone or
dehydrocorticosterone) to active ll-hydroxyglucocorticoids (Le., Cortisol or corticosterone), and thereby amplifies glucocorticoid action in a tissue-specific manner.
With only 20% homology to 11 p-HSD-1, the 11 P-hydroxysteroid dehydrogenases type 2 enzyme (1 ip-HSD-2) is a NAD+-dependent (nicotinamide adenine dinucleotide-
20 dependent), high affinity dehydrogenase with a Km for Cortisol in the nanomolar range. 11P-HSD-2 is found primarily in mineralocorticoid target tissues, such as kidney, colon, and placenta. Glucocorticoid action is initiated by the binding of glucocorticoids to receptors, such as glucocorticoid receptors and mineralocorticoid receptors. Through binding to its receptor, the main mineralocorticoid aldosterone controls the water and electrolyte balance in
25 the body. However, the mineralocorticoid receptors have a high affinity for both Cortisol and aldosterone. 1 ip-HSD-2 converts Cortisol to inactive cortisone, therefore preventing the exposure of non-selective mineralocorticoid receptors to high levels of Cortisol. Mutations in the gene encoding 1 ip-HSD-2 cause Apparent Mineralocorticoid Excess Syndrome (AME), which is a congenital syndrome resulting in hypokaleamia and severe hypertension. Patients
30 have elevated Cortisol levels in mineralocorticoid target tissues due to reduced 1 IP-HSD-2 activity. The AME symptoms may also be induced by administration of the 1 IP-HSD-2 inhibitor glycyrrhetinic acid. The activity of 1 ip-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.
35 The effects of elevated levels of Cortisol are also observed in patients who have
Cushing's syndrome (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 la: Melmed S., Ed. The
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Pituitary. 2n ed.; Maiden, MA: Blackwell; 592-612, 2002), which is a disease characterized by high levels of Cortisol in the blood stream. Patients with Cushing's syndrome often develop many of the symptoms of type 2 diabetes, obesity, metabolic syndrome and dyslipidemia including insulin resistance, central obesity, hypertension, glucose intolerance, 5 etc.
The compounds of this invention are selective inhibitors of 11 p-HSD-1 when comparing to lip-HSD-2. Previous studies (B. R. Walker, et aL; J. of Clin. Endocrinology and Met., 80:3155-3159,1995) have demonstrated that administration of 11 p-HSD-1 inhibitors improves insulin sensitivity in humans. However, these studies were carried out
10 using the nonselective 11P-HSD-1 inhibitor carbenoxolone. Inhibition of 11P-HSD-2 by carbenoxolone causes serious side effects, such as hypertension.
Although Cortisol is an important and well-recognized anti-inflammatory agent (Baxer, J., Pharmac. Ther., 2:605-659,1976), if present in large amount, it also has detrimental effects. For example, Cortisol antagonizes the effects of insulin in the liver
15 resulting in reduced insulin sensitivity and increased ghiconeogenesis. 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.
Since glucocorticoids are potent regulators of glucose and lipid metabolism, excessive glucocorticoid action may lead to insulin resistance, type 2 diabetes, dyslipidemia, visceral
20 obesity and hypertension. The present invention relates to the administration of a therapeutically effective dose of an 11 P-HSD-1 inhibitor for the treatment, control, amelioration, and/or delay of onset of diseases and conditions that are mediated by excess or uncontrolled, amounts or activity of Cortisol and/or other corticosteroids. Inhibition of the 1 lP-HSD-renzyme limits the conversion of inactive cortisone to active Cortisol. Cortisol
25 may cause, or contribute to, the symptoms of these diseases and conditions if it is present in excessive amounts.
Dysregulation of glucocorticoid activity has been linked to metabolic disorders, including type 2 diabetes, metabolic syndrome, Cushing's Syndrome, Addison's Disease, and others. Glucocorticoids upregulate key gluconeogenic enzymes in the liver such as PEPCK
30 and G6Pase, and therefore lowering local glucocorticoid levels in this tissue is expected to improve glucose metabolism in type 2 diabetics. 11 P-HSD-1 receptor whole-body knockout mice, and mice overexpressing 11 P-HSD-2 in fat (resulting in lower levels of active glucocorticoid in fat) have better glucose control than their wild type counterparts (Masuzaki, et al.; Science. 294:2166-2170,2001; Harris, et aL; Endocrinology, 142:114-120,2001;
35 Kershaw, etaL; Diabetes. 54: 1023-1031,2005). Therefore, specific 11 P-HSD-1 inhibitors could be used for the treatment or prevention of type 2 diabetes and/or insulin resistance. By reducing insulin resistance and maintaining serum glucose at normal
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concentrations, compounds of this invention may also have utility in the treatment and prevention of the numerous conditions that often accompany type 2 diabetes and insulin resistance, including the metabolic syndrome, obesity, reactive hypoglycemia, and diabetic dyslipidemia. The following diseases, disorders and conditions are related to type 2 diabetes, 5 and some or all of these may be treated, controlled, prevented and/or have their onset
delayed, by treatment with the compounds of this invention: hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, abdominal obesity,
10 neurodegenerative disease, retinopathy, nephropathy, neuropathy, metabolic syndrome and other disorders where insulin resistance is a component.
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
15 LDL, and reduced HDL. Animal data supporting the role of HSD1 in the pathogenesis of the metabolic syndrome is extensive (Masuzaki, etal.; Science. 294: 2166-2170,2001; Paterson et al; Proc Natl. Acad Sci. USA. 101: 7088-93,2004; Montague and O'Rahilly; Diabetes. 49: 883-888,2000). Thus, administration of an effective amount of an 1 ip-HSD-1 inhibitor may be useful in the treatment or control of the metabolic syndrome. Furthermore,
20 administration of an 11 (3-HSD-l inhibitor may be useful in the treatment or control of obesity by controlling excess Cortisol, independent of its effectiveness in treating or prophylactically treating NBDDM. Long-term treatment with an 11P-HSD-1 inhibitor may also be useful in delaying the onset of obesity, or perhaps preventing it entirely if the patients use an lip-HSD-1 inhibitor in combination with controlled diet and exercise. Potent, selective 11 (3-
25 HSD-1 inhibitors should also have therapeutic value in the treatment of the ghicocorticoid-related effects characterizing the metabolic syndrome, or any of the following related conditions: hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglycidemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis, vascular restenosis, pancreatitis, obesity, neurodegenerative
30 disease, retinopathy, nephropathy, hepatic steatosis or related liver diseases, and Syndrome X, and other disorders where insulin resistance is a component.
llp-HSD-1 is expressed in pancreatic islet cells, where active glucocorticoids have a negative effect on glucose stimulated insulin secretion (Davani et al.;. Biol Chem. 10: 34841-34844, 2000; Tadayyon and Smith. Expert Opin. Investig. Drugs. 12: 307-324,
35 2003; Billaudel and Sutter. J. Endocrinol. 95: 315-20,1982.). It has been reported that the conversion of dehydrocorticosterone to corticosterone by 1 ip-HSD-1 inhibits insulin secretion from isolated murine pancreatic beta cells. Incubation of isolated islets with an
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11 P-HSD-1 inhibitor improves glucose stimulated insulin secretion. An earlier study
suggested that glucocorticoids reduce insulin secretion in vivo. (B. Billaudel et al, Horm.
Metab. Res. 11: 555-560,1979). Therefore, inhibition of 11 P-HSD-1 enzyme in the pancreas
may improve glucose stimulated insulin release.
5 Glucocorticoids may bind to and activate glucocorticoid receptors (and possibly
mineralocorticoid receptors) to potentiate the vasoconstrictive effects of both catecholamines and angiotensin II (M. Pirpiris et al., Hypertension, 19:567-574,1992, C. Kernel et al., Steroids, 58: 580-587,1993, B. R. Walker and B. C. Williams, Clin. Sci. 82:597-605,1992/ The 11 P-HSD-1 enzyme is present in vascular smooth muscle, which is believed to control
10 the contractile response together with 11P-HSD-2. High levels of Cortisol in tissues where
the mineralocorticoid receptor is present may lead to hypertensioa Therefore, administration of a therapeutic dose of an 11 P-HSD-1 inhibitor should be effective in treating or prophylactically treating, controlling, and ameliorating the symptoms of hypertensioa 11 P-HSD-1 is expressed in mammalian brain, and published data indicates that
15 glucocorticoids may cause neuronal degeneration and dysfunction, particularly in the aged (deQuervamefa/.;#«mM>/Ge/ie/. 13: 47-52,2004; Belanoffe/a/. 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. (See, A. M. Issa et al., J. Neurosci., 10:3247-3254,1990, S. J. Lupien etal, Nat. NeuroscL,
20 1:69-73 1998, J. L. Yau et al., Neuroscience, 66: 571-581,1995/ Chronic excessive Cortisol
levels in the brain may result in neuronal loss and neuronal dysfunction. (See, D. S. Kerr et aL, Psychobiology 22: 123-133, 1994, C. Woolley, Brain Res. 531: 225-231, 1990, P. W. Landfield, Science, 272: 1249-1251,1996). Furthermore, ghicocorticoid-induced acute psychosis exemplifies a more pharmacological induction of this response, and is of major
25 concern to physicians when treating patients with these steroidal agents (Wolkowhz et al.;
Arm NY Acad Sci. 1032: 191-4,2004). Thekkapat er a/have recently shown that 11P-HSD-1 mRNA is expressed in human hippocampus, frontal cortex and cerebellum, and that treatment of elderly diabetic individuals with the non-selective 11 P-HSD-1 and 1 lp-HSD-2 inhibitor carbenoxolone improved verbal fluency and memory (JProc Natl Acad Sci USA.
30 101: 6743-9,2004). Therefore, administration of a therapeutic dose of an 11 p-HSD-1
inhibitor may reduce, ameliorate, control and/or prevent the cognitive impairment associated with aging, neuronal dysfunction, dementia, and steroid-induced acute psychosis.
Cushing's syndrome is a life-threatening metabolic disorder characterized by chronically elevated glucocorticoid levels caused by either excessive endogenous production
35 of Cortisol from the adrenal glands, or by the administration of high doses of exogenous glucocorticoids, such as prednisone or dexamethasone, as part of an anti-inflammatory treatment regimen. Typical Cushingoid characteristics include central obesity, diabetes
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and/or insulin resistance, dyslipidemia, hypertension, reduced cognitive capacity, dementia, osteoporosis, atherosclerosis, moon faces, buffalo hump, skin thinning, and sleep deprivation among others (Principles and Practice of Endocrinology and Metabolism. Edited by Kenneth Becker, Lippincott Williams and Wilkins Pulishers, Philadelphia, 2001; pg 723-8). It is 5 therefore expected that potent, selective 11 P-HSD-1 inhibitors would be effective for the treatment of Cushing's disease.
As previously described above, 11 P-HSD-1 inhibitors may be effective in the treatment of many features of the metabolic syndrome including hypertension and dyslipidemia. The combination of hypertension and dyslipidemia contribute to the
10 development of atherosclerosis, and therefore it would be expected that administration of a therapeutically effective amount of an 110-HSD-1 inhibitor would treat, control, delay the onset of, and/or prevent atherosclerosis and other metabolic syndrome-derived cardiovascular diseases.
One significant side effect associated with topical and systemic glucocorticoid therapy
15 is corticosteroid-induced glaucoma. This condition results 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 Sci. 44: 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 P-HSD-1, and consistent with the expression of
20 11 P-HSD-1, is the finding of elevated ratios of Cortisol:cortisone in the aqueous humor (Rauz etal.;Imest Ophthalmol Vis Sci. 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 etal.; QJM. 96: 481-490, 2003.) Treatment of patients with the nonselective 1 ip-HSD-1 and 1 lp-HSD-2 inhibitor
25 carbenoxolone for 4 and 7 days significantly lowered intraocular pressure by 10% and 17% respectively, and lowered local Cortisol generation within the eye (Rauz et al.; QJM. 96: 481-490,2003). Therefore, administration of 11P-HSD-1 specific inhibitors could be used for the treatment of glaucoma.
In certain disease states, such as tuberculosis, psoriasis, and stress in general, high
30 glucocorticoid activity shifts the immune response to a humoral response, when in fact a cell based response may be more beneficial to the patients. Inhibition of 11 p-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 p-HSD-1 specific inhibitors
35 could be used for the treatment of tuberculosis, psoriasis, stress in general, and diseases or conditions where high glucocorticoid activity shifts the immune response to a humoral response.
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Glucocorticoids are known to cause a variety of skin related side effects including skin thinning, and impairment of wound healing (Anstead, G.M. Adv Wound Care. 11: 277-85, 1998; Beer, etal; VitamHorm. 59: 217-39, 2000). lip-HSD-1 is expressed in human skin fibroblasts, and it has been shown that the topical treatment with the non-selective 11 p-5 HSD-1 and 11P-HSD-2 inhibitor glycerrhetinic acid increases the potency of topically
applied hydrocortisone in a skin vasoconstrictor assay (Hammami, MM, and Siiteri, PK. J. Out. Endocrinol. Metab. 73: 326-34,1991). Advantageous effects of selective lip-HSD-1 inhibitors on wound healing have also been published (WO 2004/11310). It is therefore expected that potent, selective 11P-HSD-1 inhibitors would treat wound healing or skin
10 thinning due to excessive glucocorticoid activity.
Excess glucocorticoids decrease bone mineral density and increase fracture risk. This effect is mainly mediated by inhibition of osteoblastic bone formation, which results in a net bone loss (C. H. Kim et al. J. Endocrinol. 162: 371-379, 1999, C. G. Bellows et aL 23: 119-125,1998, M. S. Cooper et aL, Bone 27: 375-381,2000). Glucocorticoids are also known to
15 increase bone resorption and reduce bone formation in mammals (Turner et al.; Calcif Tissue Int. 54: 311-5,1995; Lane,NEe/o/. MedPediatr Oncol. 41: 212-6,2003). llp-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 etal; Bone, 23: 119-125,2000; Cooper etal; J. Bone Miner Res. 17: 979-
20 986,2002). In surgical explants obtained from orthopedic operations, lip-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
25 asthma. These steroidal agents have been shown to increase expression of 1 lp-HSD-1
mRNA and activity in human osteoblasts (Cooper et al.; J. Bone Miner Res. 17: 979-986, 2002). Similar results have been shown in primary osteoblast cells and MG-63 osteosarcoma cells where the inflammatory cytokines TNF alpha and IL-1 beta increase 1 ip-HSD-1 mRNA expression and activity (Cooper et al; J. Bone Miner Res. 16: 1037-1044,2001). These
30 studies suggest that 11 p-HSD-1 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 non-selective 1 lp-HSD-1 and 11 P-HSD-2 inhibitor carbenoxolone showed a significant decrease in markers of bone resorption (Cooper et al; Bone. 27: 375-81,2000). Therefore, administration of an 11P-
3 5 HSD-1 specific inhibitor may be useful for preventing bone loss due to glucocorticoid-induced or age-dependent osteroporosis.
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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
5 suitable, solid, semi-solid or liquid fillers, diluents, encapsulating material, formulation
auxiliary and the like. 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,
10 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. Examples of therapeutically suitable excipients include, but are not limited to, sugars, cellulose and derivatives thereof, oils, glycols, solutions, buffers, colorants, releasing agents,
15 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
The present drug compounds may also be microencapsulated with one or more excipients. Tablets, dragees, capsules, pills, and granules may also be prepared using
20 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.
25 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,
30 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
3 5 methods known in the art.
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
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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.
5 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
10 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. For a given dosage form, disorders of the present invention may be treated,
15 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 (HX) is administered to a patient to treat and/or prophylatically treat disorders modulated by the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme. The
20 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,
25 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 (HX). 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 (HX). For example,
30 pharmaceutically active metabolites include, but are not limited to, compounds made by
adamantane hydroxylation or polyhydroxylation of any of the compounds of formulas (HX). 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).
35 Administration and Dose Ranges
Any suitable route of administration may be employed for providing a mammal,
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especially a human, with an effective dose of a compound of the present invention. For
example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be
employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions,
capsules, creams, ointments, aerosols, and the like. Preferably compounds of Formula I are
5 administered orally.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
10 When treating or preventing diabetes mellitus and/or hyperglycemia or
hypertriglyceridemia or other diseases for which compounds of Formula (I) are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses
15 two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
20 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
25 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.
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We claim: 1. A compound according to formula (I),
J£JLMR* R3 *
A2
(1), or therapeutically acceptable sah or prodrug thereof, wherein
A1, A2, A3, and A4 are each independently selected from the group consisting of
hydrogen, alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfbnyl, cycloalkyl,
cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl,
heterocyclesulfonyl, aryl, arylalkyl, aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen,
haloalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, -NR7-[C(R8 R^VCCOy-R10, -
0-[C(RnR12)]p-C(0)-R13, -OR14, -N(R15R16), -COaR17, -C(0)-N(R,8R1'), -CCR20R2I)-OR22,
and-CCR^^-NCR^R26);
n is 0 or 1;
p is 0 or 1;
R1 and R2 are each independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkyl-NH-alkyl, aryloxyalkyl, aryl-NH-alkyl, carboxyalkyl, carboxycycloalkyl, heterocycleoxyalkyl, heterocycle-NH-alkyl, cyctoalkyl, aryl, arylalkyl, haloalkyl, heterocycle, heterocyclealkyl, heterocycle-heterocycle, and aryl-heterocycle, or R*and R2 together with the atom to which they are attached form a heterocycle;
R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and heterocycle, or R3 and R4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
or R2 and R3 together with the atoms to which they are attached form a non-aromatic heterocycle;
Rs is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R6 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R7 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl,
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carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxy, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R and R are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or R8 and R9 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R10 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, aryloxy, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -NCR^R28);
Ru and R12 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or Rn and R12 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R13 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -N(R29R30);
R14 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycyctoalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R1S and R16 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, 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, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R18 and R19 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 R18 and R19 together with the atom to which they are attached form a non-aromatic heterocycle;
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^_ Oft — O 1 AA
R , R and R are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and heterocycle;
R^andR24 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, cycloalkyl, aryl, and heterocycle;
R2JandR26 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, hydroxy, alkoxy, cycloalkybxy, aryloxy, heterocycleoxy, cycloalkyl, aryl, and heterocycle, or R2S and R25 together with the atom to which they are attached form a heterocycle;
R27 and R28 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycbalkyloxy, carboxycycfoalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycbalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R27 and R28 together with the atom to which they are attached form a non-aromatic heterocycle; and
R29 and R30 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycbalkyl, cycbalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryfoxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R29 and R30 together with the atom to which they are attached form a non-aromatic heterocycle;
provided that if R6 is hydrogen, then at least one of A1, A2, A3 and A4 is not hydrogen.
2. The compound according to claim 1, comprising a therapeutically suitable metabolite
of a compound of formula (I).
3. A compound according to formula (II),
H R4 .R3
o-jrrW
(n),
or a therapeutically suitable salt or prodrug thereof, wherein
A1 is selected from the group consisting of alkyl, alkyl-NH-alkyl, alkylcarbonyl,
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alkylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfbnyl, heterocyclecarbonyl, heterocyclesulfbnyl, aryl, arylalkyl, aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, -NR7-[C(R8R9)]n-C(0>R,°, -0-[C(RuR12)]p-C(0)-R13, -OR14, -N(R15R16), -CO2R17, -0(0)-N(R,8R19), -C(R20R2,)-OR22, and -CCR^-N^R26);
R1 and R2 are each independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkyl-NH-alkyl, aryloxyalkyl, aryl-NH-alkyl, carboxyalkyl, carboxycycloalkyl, heterocycleoxyalkyl, heterocycle-NH-alkyl, cycloalkyl, aryl, arylalkyl, haloalkyl, heterocycle, heterocyclealkyl, heterocycle-heterocycle, and aryl-heterocycle, or R1 and R2 together with the atom to which they are attached form a heterocycle;
R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and heterocycle, or R3 and R4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
or R2 and R3 together with the atoms to which they are attached form a non-aromatic heterocycle;
R7 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxy, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R8 and R9 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or R8 and R9 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R10 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, aryloxy, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -N(R27R28);
RnandR12 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or Rn and R12 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R13 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -NCR.2^30);
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R14 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyi, aryloxyalkyl, haloalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R15 and R16 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyi, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, 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, arylalkyi, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R1* and R19 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyi, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R18 and R19 together with the atom to which they are attached form a non-aromatic heterocycle;
R20, R21 and R22 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and heterocycle;
R23 and R24 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, cycloalkyl, aryl, and heterocycle;
R25 and R26 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, hydroxy, alkoxy, cycloalkyloxy, aryloxy, heterocycleoxy, cycloalkyl, aryl, and heterocycle, or R25 and R26 together with the atom to which they are attached form a heterocycle;
R27 and R28 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyi, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R27 and R28 together with the atom to which they are attached form a non-aromatic heterocycle; and
R29 and R30 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyi,
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aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R29 and R30 together with the atom to which they are attached form a non-aromatic heterocycle.
4. A compound according to formula (HI),
H R4 R3
(m),
or a therapeutically suitable salt or prodrug thereof, wherein
A1 is selected from the group consisting of alkyl, alkyl-NH-alkyl, alkylcarbonyl, aflcylsulfonyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl, aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen, habalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, -NR7-[C(R8 R^jn-CCO^R10, -6-[C(RuRia)VC(0>R13, -OR14, -N(R15R16), -COjR17, -C(0> N(R,8R19), -CCR^-OR22, and -C^^NCR2^26);
R1 and R2 are each independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkyl-NH-alkyl, aryloxyalkyl, aryl-NH-alkyl, carboxyalkyl, carboxycycloalkyl, heterocycleoxyalkyl, heterocycle-NH-alkyl, cycloalkyl, aryl, arylalkyl, haloalkyl, heterocycle, heterocyclealkyl, heterocycle-heterocycle, and aryl-heterocycle;
R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, aryl, and heterocycle;
R7 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxy, hydroxy, alkoxy, cycloalkytoxy, heterocycleoxy, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R8 and R9 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or R8 and R9 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R10 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, aryloxy, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, cycloalkytoxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -N(R27R28);
Ru and R12 are each independently selected from the group consisting of hydrogen,
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alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyi, aryloxyalkyl, . heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or R11 and R12 together with the atom to which they are attached form a group consisting of cycloalkyl and non-aromatic heterocycle;
R13 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cyctoalkyl, carboxycycloalkyl, aryl, arylalkyi, arytoxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -N(R29R30);
R14 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyi, aryloxyalkyl, haloalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R1S and R16 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cyctoalkyl, carboxycycloalkyl, aryl, arylalkyi, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, 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, arylalkyi, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R18 and R19 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyi, arytoxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R18 and R19 together with the atom to which they are attached form a non-aromatic heterocycle;
R20, R21 and R22 are each independently selected, from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and heterocycle;
R23 and R24 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, cycloalkyl, aryl, and heterocycle;
R25 and R26 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, hydroxy, alkoxy, cycloalkyloxy, arytoxy, heterocycleoxy, cycloalkyl, aryl, and heterocycle, or R25 and R26 together with the atom to which they are attached form a heterocycle;
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R27andR28 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, aikylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R27 and R28 together with the atom to which they are attached form a non-aromatic heterocycle; and
R29 and R30 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, aikylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R29 and R30 together with the atom to which they are attached form a non-aromatic heterocycle.
5. * A compound according to formula (TV),
H R'R3
(IV),
or a therapeutically suitable salt or prodrug thereof, wherein
A1 is selected from the group consisting of alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl, aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, -NR7-[C(R8 R^ln-CXCO-R10, -0-[CCR"R12)]p-C(0)-R13, -OR14, -N(RI5R16), -C02R17, -C(O)-N(Rl8R19), -CCR'V^OR22, and -C^^NCR2^26);
D is a non-aromatic heterocycle;
R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl and heterocycle, orR3 and R4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R7 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxy, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R8 and R9 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or R8 and R9 together with the atom
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to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R10 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, aryloxy, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -
N(R27R28);
R11 and R12 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or Rn and R12 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R13 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -NCR25^30);
R14 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heterocycle; heterocyclealkyl, and heterocycleoxyalkyl;
R15 and R16 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, 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, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R18 and R19 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 R18 and R19 together with the atom to which they are attached form a non-aromatic heterocycle;
R20, R21 and R22 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and heterocycle;
R23 and R24 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl,
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cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, cycloalkyl, aryl, and heterocycle;
R25 and R26 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, hydroxy, alkoxy, cycloalkyloxy, aryloxy, heterocycleoxy, cycloalkyl, aryl, and heterocycle, or R25 and R26 together with the atom to which they are attached form a heterocycle;
R27 and R28 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 R27 and R28 together with the atom to which they are attached form a non-aromatic heterocycle; and
R29 and R30 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, cycbalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R29 and R30 together with the atom to which they are attached form a non-aromatic heterocycle.
6. A compound according to formula (V),
H R4 R3
(V),
or a therapeutically suitable salt or prodrug thereof, wherein
A1 is selected from the group consisting of alkyl, alkyl-NH-aflcyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl, aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, -NR7-[C(R8 R9)]n-C(0)-R10, -0-[C(RnR12)]p-C(0)-R13, -OR14, -N(R1SR16), -COaR17, -C(0> N(R18R19), -CCR^-OR22, and -CCR^R^Nfl^R26);
G is selected from the group consisting of aryl and heterocycle;
R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and heterocycle, or R and R4 together with the atom to which they are attached form a ring selected from the group
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consisting of cycloalkyl and non-aromatic heterocycle;
R7 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxy, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R8 and R9 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or R8 and R9 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R10 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, aryloxy, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -N(R27R28);
R11 and R12 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or Ru and R12 together with the atom to which they are attached form a non-aromatic heterocycle;
R13 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -NCR^R30);
R14 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R15 and R16 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycyctoalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, alkylsufonyl, cyctoalkylsulfbnyl, arylsulfonyl, and heterocyclesulfonyl, 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, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R18 and R19 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 R18 and R19 together with the atom to which they are attached form a non-aromatic
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heterocycle;
R20, R21 and R22 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and heterocycle;
R23andR24 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyciesulfonyl, cycloalkyl, aryl, and heterocycle;
R25andR26 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyciesulfonyl, hydroxy, alkoxy, cycloalkyloxy, aryloxy, heterocycleoxy, cycloalkyl, aryl, and heterocycle, or R25 and R26 together with the atom to which they are attached form a heterocycle;
R27andR28 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 heterocyciesulfonyl, or R27 and R28 together with the atom to which they are attached form a non-aromatic heterocycle; and
R29 and R30 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, cycbalkylsulfonyl, arylsulfonyl, and heterocyciesulfonyl, or R29 and R30 together with the atom to which they are attached form a non-aromatic heterocycle.
7. A compound of formula (VI),
H FT RJ
•&i
(VI), or a therapeutically suitable sah or prodrug thereof, wherein A1 is selected from the group consisting of alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycbalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyciesulfonyl, aryl, arylalkyl, arybxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, -
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NR7-[C(R8 R9)]„-C(0)-R10, -CHCCR^R"^-^-^3, -OR14, -N(R15R16), -C02R17, -C(O)-N(R18R19), -C^V^-OR22, and -C^R^-Nfl^R26);
R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and heterocycle, or R3 and R4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R7 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxy, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R8 and R9 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or R8 and R9 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R10 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, aryloxy, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy„heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -Nfl^R28);
R11 and R12 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl* heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or Ru and R12 together with the atom to which they are attached form a non-aromatic heterocycle;
R13 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -NCR2^30);
R14 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R15andR16 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R1S 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, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
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R18 and R19 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycbalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycieoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycbalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R18 and R19 together with the atom to which they are attached form a non-aromatic heterocycle;
R20, R21 and R22 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, habalkyl, aryl, and heterocycle;
R23 and R24 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycbalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, cycbalkyl, aryl, and heterocycle;
R25 and R26 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycbalkyl, cycloalkylcarbonyl, cycbalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, hydroxy, alkoxy, cycbalkyfoxy, arybxy, heterocycleoxy, cycbalkyl, aryl, and heterocycle, or R25 and R26 together with the atom to which they are attached form a heterocycle;
R27 and R28 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycbalkyl, cycbalkyfoxy, carboxycycbalkyl, aryl, arylalkyl, arybxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycieoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycbalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R27 and R28 together with the atom to which they are attached form a non-aromatic heterocycle;
R29 and R30 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycbalkyl, cycbalkyfoxy, carboxycycloalkyl, aryl, arylalkyl, arybxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycieoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycbalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R29 and R30 together with the atom to which they are attached form a non-aromatic heterocycle; and
R31 is selected from the group consisting of alkyl, alkoxy, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkoxy, habgen, habalkyl, heterocycle, heterocyclealkyl, heterocycleoxy, heterocycieoxyalkyl and hydroxy.
8. A compound of formula (VH),
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H FT R3
R31
«"
(vn),
or a therapeutically suitable salt or prodrug thereof, wherein
A1 is selected from the group consisting of alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cyctoalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl, aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, -NR7-[C(R8 R9)]n-C(0)-R10, -0-[C(R1,R12)]p-C(0)-R13, -OR14, -N(R15R16), -COjR17, -C(0)-N(R18R19), -C(R20R21)-OR22, and -C(R23R24)-N(R25R26);
R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and heterocycle, or R3 and R4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R7 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxy, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R8andR9 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cyctoalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or R8 and R9 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R10 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cyctoalkyl, carboxycycloalkyl, aryl, aryloxy, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -N(R27R28);
RnandR12 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cyctoalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl, or Ru and R12 together with the atom to which they are attached form a non-aromatic heterocycle;
R13 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycleoxy, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, and -N(R29R30);
R14 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heterocycle, heterocyclealkyl, and
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heterocycleoxyalkyl;
R15 and R16 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, caiboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, alkylsufonyl, cycloalkykulfonyl, arylsulfonyl, and heterocyclesulfonyl, 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, heterocycle, heterocyclealkyl, and heterocycleoxyalkyl;
R18 and R19 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 R18 and R19 together with the atom to which they are attached form a non-aromatic heterocycle;
R20, R21 and R22 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, and heterocycle;
R23 and R24 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonylj alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, cycloalkyl, aryl, and heterocycle;
. R25 and R26 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, hydroxy, alkoxy, cycloalkyloxy, aryloxy, heterocycleoxy, cycloalkyl, aryl, and heterocycle, or R23 and R26 together with the atom to which they are attached form a heterocycle;
R27 and R28 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 R27 and R28 together with the atom to which they are attached form a non-aromatic heterocycle;
R29 and R30 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, cycloalkykulfonyl, arykulfonyl, and heterocyclesulfonyl, or
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R and R together with the atom to which they are attached form a non-aromatic heterocycle; and
R31 is selected from the group consisting of alkyl, alkoxy, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkoxy, halogen, haloalkyl, heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl and hydroxy.
9. A compound according to formula (Vm)
rrrBY^-R2 «iQ I if
(vnr>,
or a therapeutically suitable salt or prodrug thereof, wherein
A1 is selected from the group consisting of-OH, -CO2H, carboxyalkyl, carboxycycloalkyl, and -C(0)-N(R18R19);
E is selected from the group consisting of cycloalkyl and non-aromatic heterocycle;
R1 and R2 are each independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkyl-NH-alkyl, aryloxyalkyl, aryl-NH-alkyl, carboxyalkyl, carboxycycloalkyl, heterocycleoxyalkyl, heterocycle-NH-alkyl, cycloalkyl, aryl, arylalkyl, haloalkyl, heterocycle, heterocyclealkyl, heterocycle-heterocycle, and aryl-heterocycle; and
R18 and R19 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 R18 and R19 together with the atom to which they are attached form a non-aromatic heterocycli.
10. A compound according to formula (DC),
OX),
or a therapeutically suitable salt or prodrug thereof, wherein A1 is selected from the group consisting of-OH, -CO2H, carboxyalkyl, carboxycycloalkyl, and -C(0)-N(R18R19);
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D is a non-aromatic heterocycle;
E is selected from the group consisting of cycloalkyi and non-aromatic heterocycle; and
R18 and R1 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyi, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R18 and R19 together with the atom to which they are attached form a non-aromatic heterocycle.
11. A compound selected from the group consisting of
N-[(Z^-5-hydroxy-2-adamantyl]-2-{4-[5-(trifluoromethyl)pyridm-2-yl]piperazin-l-yl} acetamide;
N-[(E)-5-hya^oxy-2-arfamantyl]-2-{4-[5-(trifluoromethyl)pyridin-2-yl]pipera2in-l-yl}acetamide;
N-[(E)-5-hydroxy-2-adamantyl]-2-{4-[5-(triffa^ yl}propanamide;
2-[(cis)-2,6-dimemylmoipholin-4-yl]-N-[(E)-5-hydroxy-2-adamantyl]propanamide;
N-[(Z)-5-hydroxy-2-adamantyl]-2-(4-hydroxypiperidin-l -yl)propanamide;
N-[(E)-5-hydroxy-2-adamantyl]-2-(4-hydroxypiperidin-1 -yl)propanamide;
2-azepan-1-yl-N-t(E)-5-hydroxy-2-adamantyl]propanamide;
(E)-4-[({4-[5-(trifluoromelJiyl)pyridm-2-yl]piperazin-l-yl}acetyl)amino]-l-adamantyl carbamate;
(E)-4-[(2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1 -yl} acetyl)amino]-1 -adamantyl acetate;
N-[(E)-5-(acetylammo)-2-adamantyl]-2-{4-[5-(triiluoromethyl)pyridin-2-yl]piperazin-1 -yl} acetamide;
' N-[(E)-5-fluoro-2-adamantyl]-2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1 -yl} acetamide;
N-[(Z)-5-fluoro-2-adamantyl]-2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl} acetamide;
N-[(E)-5-hydroxy-2-adamantyl]-2-[4-(5-methylpyridin-2-yl)piperazin-l-yl]propanamide;
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N-[(E)-5-hydroxy-2-adamantyl]-2-methyl-2-{4-t5-(trifluoromethyl)pyridin-2-yl]piperazin-l -yl}propanamide;
(EH-{2-Methyl-2-[4-(5-tid^ororiiethyl-pyridin-2-yl)-piperaziQ-l-yl]-propionylamino} -adamantane-1 -carboxylic acid;
(E)-4-({ 1 -[4-(5-Trifluoromethyl-pyridin-2-yl)-piperazin-1 -yl]-cyclopropanecarbonyl} -amino)-adamantane-1 -carboxylic acid;
(E)-4-({l-[4-(5-Trifluoromethyl-pyridin-2-yl)-piperazin-l-yl]-cyclopropanecarbonyl} -amino)-adamantane-1 -carboxyamide;
(E)-4-{2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l-yl]-butyrylamino}-adamantane-1 -carboxyamide;
(E)-4-{2-Cyclopropyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l-yl]-acetylamino}-adamantane-l-carboxyamide;
(E)-4-({ l-[4-(5-Ttrifluoromethyl-pyridin-2-yl)-piperazin-l -yl]-cyclobutanecarbonyl}-amino)-adamantane-l- carboxamide;
(E)-N-(5-Hydroxymelhyl-adamantan-2-yl)-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-isobutyramide;
(E)-N-(5-Foimyl-adamantan-2-yl)-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l-yl]-isobutyramide;
(E)-4-{2-methyl-2-[4-(5-triftaoromethyl-pyridifl-2-yl)-pipera2in-l-yl]-propionylamino}-adamantane-l-carboxyamide;
(E)-4-{2-methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperaziii-l-yl]-propionylamino}-adamantane-l-carboxylic acid hydroxyamide;
(E)-4- {2-[4-(5-Trifluormetbyl-pyridin-2-yl)-piperazin-1 -yl]-acetylamino } -adamantane-1-carboxylic acid;
(E)-4-[2-(3,3-Difluoro-piperidm-l-y^-acetylaniko]-adamantane-l-carboxylicacid;
(E)- 4-[2-(2-Trifluoromethyl-pyrrolidin-l -yl)-acetylamino]-adamantane-1 -carboxylic acid;
(E)-4-{2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l-yl]-acetylamino}-adamantane-1 -carboxyamide;
(E)-4-[2-(2-trifluoromethyl-pyrrolidin-1 -yl)-acetylamino]-adamantane-1 -carboxyamide;
(E)-4-[2-(3,3-difluoro-piperidm-l-yI)-acetylarmBo]-adainantane-l-«irboxyamide;
(E)-4-[2-(3-fboropyrroUdin-l-yl)-propionylamino]-adamantane-l-carboxyamide;
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(E)-4-[2-(3,3-difluoropiperidine-1 -yl)-propionylamino]-adamantane-1 -carboxyamide;
(E)-4-[2-(2-trifluoromethylpyrrolidin-1 -yl)-propionylamino]-adamantane-1 -carboxyamide;
(E)-4-{2-[4-(5-Chloro-pyridin-2-yl)-piperazin-l-yl]-2-methyl-propionylamino}-adamantane-1-carboxylic acid;
(E)-4-[2-Methyl-2-(lJ2,4,5-tetrahydro-benzo[d]azepk-3-yl)-propbnylamino]-adamantane-1-carboxylic acid;
(E)-4-[2-Methyl-2-(4-m-tolyl-[l,4]diazepaJi-l-yl)-propionylainino]-adamantane-l-carboxylic acid;
(E)-4-[2-Metb.yl-2-(4-phenyl-piperidin-1 -yl)-propionylamino]-adamantane-1 -carboxylic acid;
(E)-4-{2-[4-(4-Chloro-phenyl)-piperidin-l-yl]-2-methyl-propionylamino}-adamantane-1-carboxylic acid;
(EH-{2-[5-(6-CWoro-pyridm-3-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-methyl-propionylamino}-adamantane-l-carboxyamide;
(E)-4-{2-[4-(5-Fluoro-pyridm-3-yl)-[l)4]diazepan-l-yl]-2-methyl-propionylamino}-adamantane-1 -carboxyamide;
(E)-4-[2-methyl-2-(3-pyridk-3-yl-3,9-diazbicyclo[4.2.1]non-9-yl)-propionylamino]-adamantane-1 -carboxyamide;
(B)-4-[2-methyl-2-(2-trifluoromethyl-pyn-oHdin-l-yl)-propionylamino]-adamantane-1-carboxyamide;
(E)-4-[2-(3,3-difluoro-pq)eridin-l-yl)-2-metb.yl-propionylamino]-adamantane-l-carboxyamide;
(E)-4-[2-(3 -fluoro-pyrrolidin-1 -yl)-2-methyl-propionylamino]-adamantane-1 -carboxyamide;
(E)-4-{2-[4-(5-Trifluormethyl-pyridin-2-yl)-piperaziri-l-yl]-acetylamino}-adamantane-1-carboxamide;
(E)-4-[2-(3,3-Difluoro-piperidin-1 -yl)-2-methyl-propbnylamino]-adamantane-1 -carboxylic acid 3,4-dimethoxy-benzylamide;
f^-4-[({4-[2-(3,3-Difluoro-piperidin-l-yl)-2-methyl-propionylamino]-adamantane-l-carbonyl}-amino)-methyl]-benzoic acid;
(E>4-[2-(3,3-Difluoro-piperidin-l-yl)-2-methyl-propionylamino]-adamaritane-l-
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carboxylic acid (furan-2-ylmethyI)-amide;
(E^-[2-(3,3-Difluoro-piperidin-l-yl)-2-methyl-propionylainmo]-adaniantane-l-carboxylic acid (thiazol-5-ylmethyl)-amide;
(E)-4-[2-(3,3-Difluoro-piperidin-1 -yl)-2-methyl-propionylamino]-adamantane-1 -carboxylic acid 2-methoxy-benzylamide;
(^-4-(2-Methyl-2-phenylamiQo-propionylamino)-adamantane-l-carboxyamide;
(E)^-[2-melJiyl-2-(3-pyridin-3-yl-3,9-diazbicyclo[4.2.1]non-9-yl)-propionylamino]-adamantane-1 -carboxyamide;
(EH-{2-methyl-2-[5-(3-trifluoromethyl-phenyl)-[l,5]diazocan-l-yl]-propionylamino } -adamantane-1 -carboxylic acid;
(E)-4-{2-[7-(5-bromo-pyridin-2-yl)-3>7-diazbicyclo[3.3. l]non-3-yl]-2-methyl-propionylamino} -adamantane-1 -carboxyamide;
iV8-[2-(4-CUorophenyl)ethyl]-7/1-[(J^-5-hydroxy-2-adamantyl]alatdnamide;
2-(4-benzylpiperidm-l-yl)-N-[(£)-5-hydroxy-2-adamantyl]propanamide;
N-f^-S-hydroxy^-adamantyll^^T.Q.lO-tetrahydro-SH-tl.Sldioxolo^S-g][3]benzazepin-8-yl)propanamide;
N-[(£)-5-hydroxy-2-adamantyl]-2-(4-pyridin-2-ylpiperazin-1 -yl)propanamide;
2-[4-(4-fluorophenyl)piperazin-l-yl]-N-[(£)-5-hydroxy-2-adamantyl]propanamide;
N-[(£)-5-hydroxy-2-adamantyl]-2-[4-(4-methoxyplienyl)piperazin-l-yl]propanamide;
2-[4-(5-cyanopyridin-2-yl)piperazin-1 -yl]-N-[(£)-5-hydroxy-2-adamantyl]propanamide;
2-[4-(2-furoyl)piperazin-l-yl]-N-[(lR,3S>5-hydroxy-2-adamantyl]propanamide;
2-(l,3-dihydro-2H-isoindol-2-yl)-N-[(JE)-5-hydroxy-2-adamantyl]propanamide;
N-[(£)-5-hydroxy-2-adamantyl]-2-{4-[4-(trifluoromethyl)phenyl]piperazin-l-yl}propanamide;
(2S)-N-[(E)-5-b.ydroxy-2-adamantyri-2-{4-[5-(trifluorometb.yl)pyridin-2-yr|piperazin-l-yl}propanamide;
(2R)-N-[CE)-5-hydroxy-2-adamantyl]-2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl}propanamide; .
2-[3-(4-cbJorophenoxy)azetidm-l-yl]-N-[(£)-5-hydroxy-2-adamantyl]propanamide;
2-[4-(2-fluorophenoxy)piperidm-l-yl]-N-[(E)-5-hydroxy-2-adamantyl]propanamide;
2-[3-(2-fluorophenoxy)piperidin-l-yl]-N-[(£)-5-hydroxy-2-adamantyl]propanamide;
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2-[3-(3-fhiorophenoxy)pyn^oUdin-l-yl]-N-[(^-5-hydroxy-2-adamaiityl]propanamide; ^-^-(S^-diclilorophenyOethyll-JV'-K^-S-hydroxy^-adamantyll-iV2-methylalaninamide;
i^-P-C^cMoropheny^l-methylethyq-^-tCEJ-S-hydroxy^-adamantyll-JV8-methylalaninamide;
2-(5-chloro-2,3-dihydro-lH-indol-l-yl)-N-[(£)-5-hydroxy-2-adamantyl]propanamide;
2-[4-(6-chloropyridin-3-yl)piperazin-l-yl]-N-[(£)-5-hydroxy-2-adamantyl]propanamide;
N-[(£)-5-hydroxy-2-adamantyl]-2-(3-phenylazetidin-l-yl)propanamide;
(^N-methyM-[(2-methyl-2-{4-[5^trifluoromethyl)pyridin-2-yl]piperazin-1 -yl}propanoyl)amino]adamantane-l-caiboxamide;
(£)-N-methoxy^[(2-methyl-2-{4-[5-(trifluorpmethyl)pyridk-2-yl]piperazin-l-yl}propanoyl)amino]adamantane-l-carboxamide;
N-[(ii}-5-(ammomethyl)-2-adamantyl]-2-methy^ yl]piperazin-1 -yl}propanamide;
N-[(£)-5-hydroxy-2-adamantyl]-l-{[4-(trifluoromethyl)benzyl]amino}cyclopropanecarboxamide;
N-[{£)-5-cyano-2-adaman1yl]-2-methyl-2-{4-[5^trifluoromethyl)pyridin-2-yl]piperazin-l-yl}propanamide;
N-[(J^-5-hydroxy-2-adamantyl]-1 -piperidin-1 -ylcyclopropanecarboxamide;
2-me%l-N-[(£)-5-(5-methyl-l>2,4^xadiazol-3-yl>2-adamaiityl]-2-{4-[5-(trifboromethyl)pyridin-2-yl]pipera2dn-l-yl}propanamide;
2-methyl-N-[(£)-5-(2H-tetraazDl-5-yl>2-adamaiityl]-2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl}propanamide;
(JE)-4-[(2-{4-[[(4-chlorophenyl)sulfbnyl](cyclopropyl)amino]piperidin-l-yl}propanoyl)amino]adamantane-l-carboxamide;
N-[(£)-5-hydroxy-2-adamantyl]-2-methyl-2-X2-(trifboromcthyl)pyrrolidin-1 -yljpropanamide;
(£)-4-({2-[(3S)0-fluoropyrrolidin-l-yl]-2-methylpropanoyl}amino)adamantane-l-carboxamide;
methyl (£)-4-{[2-methyl-2-(4-pyridin-2-ylpiperazin-l-y])propanoyl]amino } adamantane-1 -carboxylate;
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(E)-4- {[2-methy l-2-(4-pyridin-2-ylpiperazin-1 ryl)propanoyl] amino } adamantane-1 -carboxylic acid;
(£)-4-({2-methyl-2-[(2S>2-methyl-4-pyridin-2-ylpiperazin-l-yl]propanoyl}amino)adamantane-l-carboxylic acid;
(£)-4-{[2-methyl-2-(4-pyridm-2-ylpiperazm-l-yl)propanoyl]amino}adamantane-l-carboxamide;
2-methyl-N-[(£)-5-(4H-l,2,4-triazol-3-yl)-2-adamantyl]-2-{4-[5-(trifboromethyl)pyridin-2-yl]piperazin-l-yl}propanamide;
(i^4-{[2-(3,3-difkoiopiperidm-l-yl)-2-methylpropanoyl]ammo}-N-(pyridin-4^ ylmetb.yl)adamantane-l-carboxamide;
(E)-4-[(2-metb.yl-2- {4-[4-(trifluoromethyl)phenyl]piperazin-1 -yl}propanoyl)amino]adamantane-l -carboxylic acid;
(£)-4-({2-methyl-2-[(2R)-2-methyl-4-(5-methylpyridin-2-yl)piperazin-1 -yl]propanoyl}amino)adamantane-l-carboxylic acid;
(£)-4-({2-[(3S)-3-fluoropiperidm-l-yl]propanoyl}amino)adamantane-l-carboxamide;
(£>4-[((2S>2-{4-[5-(liifluoromethyI)pyridin-2-yl]piperazin-l-yl}propanoyl)ammo]adamantane-l-carb-3,9-diazabicycto[4.2.1]non-3-yl]-2-methylpropanoyl} amino)adamantane-1 -carboxamide;
(£)-4-({2-[4-(2,3-dichloropb.enyl)piperazin-l-yl]-2-methylpropanoyl}amino)adamantane-l-carboxylicacid;
(£)-4- {[2-methyl-2-(4-phenylpiperazin-1 -yl)propanoyl]amino } adamantane-1 -carboxylic acid;
(i£)-4-({2-methyl-2-[4-(4-metb.ylphenyl)piperazin-l-
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yl]propanoyl} amino)adamantane-1-carboxylic acid;.
(£>4-({2-[4-(l»3-ben20thiazol-2-y])piperazin-l-yl]-2-memylpropanoyl}ammo)adamantane-l-carboxylicacid;
(£)-4-({2-[4-(3,4-dichlorophenyl)piperazia-l-yl]-2-methylpropanoyl} amino)adamantane-1 -carboxylic acid;
(£)-4-({2-methyl-2-[4-(3-methylplienyl)piperaziii-1 -yl]propanoyl}amino)adamantane-l -carboxylic acid;
(£)-4-[(2-methyl-2-{4-[2-(trifboromethyl)phenyl]piperazin-l-yl}propanoyl)amino]adamantane-l-carboxylicacid;
(E)-4-({2-[4-(2J4-difluorophenyl)piperazin-l-yl]-2-methylpropanoyl}amino)adamantane-l -carboxylic acid;
(jE>4-({2-methyl-2-[4-(6-methylpyridin-2-y])piperazin-l-yl]propanoyl}amino)adamantane-l-carboxylic acid;
(£)-4-{ [2-methyl-2-(4-pyrimidin-2-ylpiperazin- l-yl)propanoyl]amino } adamantane-1 -carboxylic acid;
(£)-4-({2-[4-(4-fluorophenyl)pipeirazin-l-yl]-2-methylpropanoyl}amino)adamaiitane-1-carboxylic acid;
(£)-4-[(2-methyl-2-{4-[3-(ti^uoromethyl)phenyl]piperazin-l-yl}propanoyl)amino]adamantane-l -carboxylic acid;
(£>4-[(2-methyl-2-{4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl}propanoyl)amino]adamantaae-1 -carboxylic acid;
(£^-({2-[4-(3-cUorophenyl)piperazin-l-yl]-2-methylpropanoyl}amino)adamantane-1-carboxylic acid;
(£)-4-({2-[4-(4-acetylphenyl)piperazin-1 -yl]-2-methylpropanoyl} amino)adamantane-1-carboxylic acid;
(£)-N,N-dimethyl-4-[(2-methy 1-2- {4-[5-(trifluorometh.yl)pyridin-2-yl]piperazin-1 -yl}propanoyl)amino]adamantane-l-carboxamide;
N-[(£)-5-(acetylamino)-2-adamantyl]-2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1 -yl}propanamide;
(£)-4- {[2-methyl-2-(4-pyrimidin-2-ylpiperazin-1 -yl)propanoyl]amino } adamantane-1 -carboxamide;
(E)-4- {[2-methy l-2-(4-pyrazin-2-ylpiperazin-1 -yl)propanoyl] amino } adamantane-1 -
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carboxamide;
(£H-({2-[4K4-fluor°phenyl)piperazin-l-yl]-2-methylpropanoyl}amino)adamantane-1-carboxamide;
(£)-4-({2-[4-(3-cyanopyridin-2-yl)piperazin-l-yl]-2-methylpropanoyl} amino)adamantane-1 -carboxamide;
(£)-4-({2-metb.yl-2-[4-(6-methylpyridin-3-y])-l>4-diazepan-l-yl]propanoyl}amino)adamantane-l-carboxamide;
(£)-4-[(2-{4-[3-cUoro-5-(trifmoromethyl)pyridin-2-yl]piperaziii-l-yl}-2-me1hylpropanoyl)amino]adamantane-1 -carboxylic acid;
4-(2-{[((£)-4-{[2-(3,3-difluoiopipexidm-l-yl)-2-methylpropaiK>yl]amino}-l-adamantyl)carbonyl] amino} ethyl)benzoic acid;
N-{(£)-5-[(methylsulfonyl)aiiuno]-2-adamantyl}-2-{4-[5-(trifluoromethyQpyridm-2-yl]piperazin-1 -yl}propanamide;
N-[(£)-5-(l -hydroxy-1 -methylethyl)-2-adamantyl]-2-methyl-2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl}propanamide;
(£)-4- {[2-methyl-2-(4-phenylpiperazin-1 -yl)propanoyl]amino } adamantane-1 -carboxamide;
(£)-4-({2-[4-(2-metb.oxyphenyl)piperazin-l-yl]-2-methylpropanoyl} amino)adamantane-l -carboxamide;
(£)-4-[(N,2-dimethyl-N-phenylalanyl)amino]adamantane-l-carboxamide;
(£)-4-({2-[4-(2,4-dimethDxyphenyl)piperazin-l-yl]-2-methylpropano yl} amino)adamantane-1 -carboxamide;
(£)-4-({2-[4-(2J3-dicyanophenyl)piperazin-l-yl]-2-methylpropanoyl}amino)adamantane-l-carboxamide;
N-[(^-5-(cyanomethyl)-2-adamantyl]-2-methyl-2-{4-[5-(lrifmoromethyl)pyridin-2-yl]piperazin-l-yl}propanamide;
(£)-4-({2-methyl-2-[4-(4-i]itrophenyi)piperazin-l-yl]propanoyl}amiiK>)adam carboxylic acid;
(E)-4-({2-[4-(2,4-dichlorophenyl)piperazin-l-yl]-2-methylpropanoyl}amino)adamantane-l-carboxylic acid;
{(£^-[(2-methyl-2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperaziii-l-yl}propanoyI)amino]-l-adamantyl}aceticacid;
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(£)-4-({2-[4-(4-chloro-2-fluorophenyl)piperazin-1 -yl]-2-methylpropanoyl}amino)adamantane-l-carboxylic acid;
(£)-4-[(2-methyl-2-{4-[4^trifluoromethyl)pyrimidin-2-yl]piperaziii-l-yl}propanoyl)amino]adamantane-l -carboxylic acid;
(£)-4-({2-[4-(3-chloro-4-fluorDphenyl)piperazin-l -yl]-2-methylpropanoyl}amino)adamantane-l-carboxylicacid;
(£)-4-({2-[4-(4-cyanophenyl)piperazin-l-yl]-2-methylpropanoyl}amino)adamantane-1-carboxylic acid;
(E)-4-( {2-[4-(4-bromophenyl)piperazin-1 -yl]-2-methylpropanoyl} amino)adamantane-1-carboxylic acid;
(£)-4-({2-[4-(5-chloro-2-metbjOxyphenyl)piperazin-l-yl]-2-methylpropanoyl}amino)adamantane-l-carboxylic acid;
(£)-4-({2-[4-(2-cUoropb^ny^piperazh-l-yl]-2-methylpropaiK)yl}amino)adama^ 1-carboxylic acid;
(£^-({2-[4^2-cyanophenyl)pipera2dn-l-yl]-2-melhylpropanoyl}aniino)adamaiitane-1-carboxylic acid;
(£)-4-({2-[4-(2-fluorophenyl)piperazm-l^ 1-carboxylic acid;
(£)-4-({2-methyl-2-[4-(2-metb.ylphenyl)piperazih-l-yl]propanoyl}amino)adamantane-l-carboxylicacid;
(i^-({2-[4-(4-cWorophenyl)piperazin-l-yl]-2-methylpropanoyl}ainino)adamantane-1-carboxylic acid;
(£)-4-({ 2-[4-(3 -chloropyridin-2-yl)piperazin-1 -yl]-2-methylpropanoyl} amino)adamantane-1 -carboxylic acid;
(£)-4-[(2-{4-[2-cUorc^-(trifluoromethyl)phenyl]piperazin-l-yl}-2-methylpropanoyl)amino]adamantane-l-carboxylicacid;
(J^-4-({2-[(3R)-3-fluoropyrroUdin-l-yl]-2-methylpropanoyl}amino)-N-(pyridin-3-ylmethyl)adamantane-l-carboxamide;
(Ey4- {[2-methyl-2-(3 -phenylpiperidin-1 -yl)propanoyl] amino } adamantane-1 -carboxamide;
(£)-4-({2-[4-(2-cbJoro-4-methylphenyl)piperazin-l-yl]-2-methylpropanoyl} amino)adamantane-1 -carboxylic acid;
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(£)-4-({2-[4-(2-fluorophenyl)piperidin-1 -yl]-2-methylpropanoyl} amino)adamantane-1-carboxylic acid;
(£)-4-({2-methyl-2-[4-(2-methylphenyl)piperidin-l-yl]propanoyl}amino)adamantane-1-carboxylic acid;
(£)-4-({2-[4-(2-cbIoro-4-fluorophenyl)pipera2in-l-yl]-2-methylpropanoyl} amino)adamantane-1 -carboxamide;
(£)^-({2-[4-(2-fiu-oyl)piperazin-l-yl]-2-methylpropanoyl}amino)adamantane-l-carboxylic acid;
(£)-4-({2-[4-(2-chloro-4-cyanophenyl)piperazin-l-yl]-2-methylpropanoyl} amino)adamantane-1 -carboxylic acid;
(£)-4-({2-[4-(2-cbJoro-4-fhjoropheny])piperaziii-1 -yl]-2-methylpropanoyl} amino)adamantane-1 -carboxylic acid;
(£)-4-[(2-methyl-2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1 -yl}propanoyl)amino]-l-adamantyl carbamate;
(E)-4-[(2- {4-[(4-chlorophenyl)sulfonyl]pipexazin-1 -yl} -2-methylpropanoyl)amino]adamantane-l-carboxylicacid;
(JE)-4-({2-[4-(2,4-difluorophenyl)piperidin-l-yl]-2-methylpropanoyl}amino)adamantane-l-carboxylicacid;
(£)-4-({2-[4-(4-cyano-2-fluoropb.enyl)piperazin-1 -yl]-2-methylpropanoyl} amino)adamantane-l -carboxylic acid;
(^-4-[(2-methyl-2-{3-methyl-4-[5-(trifluoromethyl)pyridin-2-yl]piperazm yl}propanoyl)amino]adamantane-l-carboxylicacid;
(£)-4-({2-[4-(4-cyanophenyl)-3)5-dimethyl-lH-pyrazol-l-yl]-2-methylpropano yl} amino)adamantane-1 -carboxylic acid;
(£)-4-({2-[4-(4-cyanophenyl)-3,5-dimethyi-lH-pyrazol-l-yl]-2-methylpropanoyl} amino)adamantane-1 -carboxamide;
(£)-4-{[2-methyl-N-(3-methylphenyl)danyl]amino}adaiimntane-l-carboxamide;
0
tert-butyl 4-(2- {[(£)-5-(aminoGarbonyl)-2-adamantyl]amino}-1,1 -dimethyl-2-oxoethyl)piperazine-1 -carboxylate;
(2R)-2-[(3R)-3-fluoropyrrolidin-l-yl]-N-[(£)-5-bydroxy-2-adamantyl]propanamide;
(£)-4-({2-[4-(2-bromopheny0pipexazm-l-yl]-2-methylpropanoyl}aimjio)adamantane-1-carboxylic acid;
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(^-4-{|KK3-cUorophemyl)-2-methylalanyl]amino}adamantanerl-carboxamide;
(£)-4-{|K^3-metiioxypheny^2-methylalanyl]amijio}adamaiitane-l-carboxamide;
(EH-CC^^-^y^opieny^.S-dimethyl-lH-pyrazol-l-yl]^-methylpropanoyl} amino)-N-(l ,3-thiazol-5-yImethyl)adamantane-l -carboxamide;
(£)^({2-[4^6-cbJoropyrimidin-4-yl)piperazin-l-yl]-2-methylpropanoyl} amino)adamantane-1 -carboxylic acid;
(£)-4-({2-[4-(6-chloropyridaziii-3-yl)piperazin-l-yl]-2-methylpropanoyl} amino)adamautane-1 -carboxylic acid;
(£)-4-({2-[4-(2-chloropyrimidin-4-yl)piperazin-1 -yl]-2-methylpropanoyl}amino)adamantane-l-carboxylic acid;
N-[({(£)-4-[(2-methyl-2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl}propanoyl)amino]-1 -adamantyl} amino)carbonyl]glycine;
(£)-4-({2-[4-(5-cyanopyridin-2-yl)piperazin-1 -yl]-2-methylpropanoyl} amino)adamantane-1 -carboxylic acid;
(£)-4-({2-[4-(3-chloro-5-cyanopyridin-2-yl)piperazin-l-yl]-2-methylpropanoyl} amino)adamantane-l -carboxylic acid;
(£^-({2-methyl-2-[4-(l,3-tiiiazol-2-yl)piperazin-l-yl]propanoyl}amino)adamaQtane-1-carboxylic acid;
(£)-4-{[N-(4-methoxyphenyl)-2-methylda^
(i5^K{N-[4-(dimethylamiiK))phenyl]-2-methylalanyl}ainino)adamantane-l-carboxamide;
(£)-4-({2-methyl-N-[4-(trifluoromethyl)pb.enyl] alanyl} amino)adamantane-1 -carboxamide;
(£)-4-({2-methyl-N-[3-(trifluoromethyl)phenyl]alanyl}amino)adamantane-l-carboxamide;
(£)-4-({2-[4-(2-hydroxyphenyl)piperazin-l:yl]-2-methylpropanoyl}amiao)adamantane-l-carboxylic acid;
4-(2-{[(£)-5-(ambocarbonyl)-2-adamantyl]amino}-lJ-d,imethyl-2-oxoetb.yl)-N-(tert-butyl)piperazine-l-carboxamide; and
N-[(£)-5-(formylamino)-2-adamantyl]-2-methyl-2- {4-[5-(trifluoromethyI)pyridin-2-yl]piperazin-l-yl}propanamide.
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12. A method of inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme, comprising administering to a mammal, a therapeutically effective amount of a compound of formula (I, n, m, IV, V, VI, VII, VIE or IX).
13. A method of treating or prophylactically treating disorders in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme, comprising administering to a mammal, a therapeutically effective amount of a compound of formula (I, n, m, IV, V, VI,
vn,vmorix),
14. A method of treating or prophylactically treating non-insulin dependent type 2
diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome or 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 a compound of formula (I, n, IE, IV, V, VI,
vn,vmorDQ.
14. A pharmaceutical composition comprising a therapeutically effective amount of a
compound of formula (I, n, m, IV, V, VI, Vn, VTfl or IX) in combination with a
pharmaceutical^ suitable carrier.

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