US20090312307A1 - Heterocyclo inhibitors of potassium channel function - Google Patents

Heterocyclo inhibitors of potassium channel function Download PDF

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US20090312307A1
US20090312307A1 US12/538,955 US53895509A US2009312307A1 US 20090312307 A1 US20090312307 A1 US 20090312307A1 US 53895509 A US53895509 A US 53895509A US 2009312307 A1 US2009312307 A1 US 2009312307A1
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alkyl
aryl
phenyl
heteroaryl
compound
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John Lloyd
Yoon T. Jeon
Heather Finlay
Lin Yan
Michael F. Gross
Serge Beaudoin
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Definitions

  • the present invention provides for heterocyclyl compounds useful as inhibitors of potassium channel function (especially inhibitors of the K v 1 subfamily of voltage gated K + channels, more especially inhibitors K v 1.5 which has been linked to the ultra-rapidly activating delayed rectifier K + current I Kur ) and to pharmaceutical compositions containing such compounds.
  • the present invention further provides for methods of using such compounds in the treatment of arrhythmia, I Kur -associated disorders, and other disorders mediated by ion channel function.
  • potassium channels that exhibit functional, pharmacological and tissue distribution characteristics have been cloned. These cloned potassium channels are useful targets in assays for identifying candidate compounds for the treatment of various disease states.
  • Potassium channels have turned out to be the most diverse family of ion channels discovered to date. They modulate a number of cellular events such as muscle contraction, neuroendocrine secretion, frequency and duration of action potentials, electrolyte homeostasis, and resting membrane potential.
  • Potassium channels are expressed in eukaryotic and procaryotic cells and are elements in the control of electrical and non-electrical cellular functions. Potassium channels have been classified according to their biophysical and pharmacological characteristics. Subclasses of these channels have been named based on amino acid sequence and functional properties. Salient among these are the voltage dependent potassium channels, for example voltage gated potassium channels (e.g., K v 1, K v 2, K v 3, K v 4).
  • voltage gated potassium channels e.g., K v 1, K v 2, K v 3, K v 4
  • Subtypes within these subclasses have been characterized as to their putative function, pharmacology and distribution in cells and tissues (Chandy et al., “Voltage-gated potassium channel genies” in Handbook of Receptors and Channels—Ligand and Voltage - gated Ion Channels , North, R. A. ed. (1995); Doupnik et al., Curr. Opin. Neurobiol., 5:268 (1995)).
  • K v 1 class of potassium channels is further subdivided depending on the molecular sequence of the channel, for example K v 1.1, K v 1.2, K v 1.3, K v 1.4, K v 1.5, K v 1.6, and K v 1.7.
  • Functional voltage-gated K + channels can exist as multimeric structures formed by the association of either identical or dissimilar subunits. This phenomena is thought to account for the wide diversity of K + channels. However, subunit compositions of native K + channels and the physiologic role that particular channels play are, in most cases, still unclear.
  • Membrane depolarization by K v 1.3 inhibition has been shown to be an effective method to prevent T-cell proliferation and therefore has applications in many autoimmune conditions.
  • Inhibition of K + channels in the plasma membrane of human T-lymphocytes has been postulated to play a role in eliciting immunosuppressive responses by regulating intracellular Ca ++ homeostasis, which has been found to be important in T-cell activation.
  • the K v 0.3 voltage-gated potassium channel is found in neurons, blood cells, osteoclasts and T-lymphocytes.
  • the Chandy and Cahalan laboratories proposed a hypothesis that blocking the K v 2.3 channel would elicit an immuxnosuppressant response. (Chandy et al., J. Exp. Med., 160:369 (1984); Decoursey et al., Nature, 307:465 (1984)).
  • the K + channel blockers employed in their studies were non-selective.
  • a peptide found in scorpion venom no specific inhibitor of the K v 1.3 channel existed to test this hypothesis.
  • a laboratory Price et al., Proc.
  • Margatoxin blocks only Kv1.3 in T-cells, and has immunosuppressant activity on both in in vitro and in vivo models. (Lin et al., J. Exp. Med., 177:637 (1993)).
  • the therapeutic utility of this compound is limited by its potent toxicity.
  • Recently, a class of compounds has been reported that may be an attractive alternative to the above mentioned drugs, see for example U.S. Pat. Nos. 5,670,504; 5,631,282; 5,696,156; 5,679,705; and 5,696,156. While addressing some of the activity/toxicity problems of previous drugs, these compounds tend to be of large molecular weight and are generally produced by synthetic manipulation of a natural product, isolation of which is cumbersome and labor intensive.
  • Immunoregulatory abnormalities have been shown to exist in a wide variety of autoimmune and chronic inflammatory diseases, including systemic lupus erythematosis, chronic rheumatoid arthritis, type I and II diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis and other disorders such as Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, ichthyosis, Graves ophthalmopathy and asthma.
  • each of these conditions may be quite different, they have in common the appearance of a variety of auto-antibodies and self-reactive lymphocytes. Such self-reactivity may be due, in part, to a loss of the homeostatic controls under which the normal immune system operates. Similarly, following a bone-marrow or an organ transplantation, the host lymphocytes recognize the foreign tissue antigens and begin to produce antibodies which lead to graft rejection.
  • autoimmune or a rejection process tissue destruction caused by inflammatory cells and the mediators they release.
  • Anti-inflammatory agents such as NSAIDs act principally by blocking the effect or secretion of these mediators but do nothing to modify the immunologic basis of the disease.
  • cytotoxic agents such as cyclophosphamide, act in such a nonspecific fashion that both the normal and autoimmune responses are shut off. Indeed, patients treated with such nonspecific immunosuppressive agents are as likely to succumb from infection as they are from their autoimmune disease.
  • Cyclosporin A which was approved by the US FDA in 1983 is currently the leading drug used to prevent rejection of transplanted organs.
  • FK-506 PROGRAF®
  • CsA and FK-506 act by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's foreign protein.
  • CsA was approved by the US FDA for the treatment of severe psoriasis and has been approved by European regulatory agencies for the treatment of atopic dermatitis. Though they are effective in fighting transplant rejection, CsA and FK-506 are known to cause several undesirable side effects including nephrotoxicity, neurotoxicity, and gastrointestinal discomfort. Therefore, a selective immunosuppressant without these side effects still remains to be developed. Potassium channel inhibitors promise to be the solution to this problem.
  • Atrial fibrillation (AF) and atrial flutter are the most common cardiac arrhythmias in clinical practice and are likely to increase in prevalence with the aging of the population.
  • AF affects more than 1 million Americans annually, represents over 5% of all admissions for cardiovascular diseases and causes more than 80,000 strokes each year in the United States.
  • AF is rarely a lethal arrhythmia, it is responsible for substantial morbidity and can lead to complications such as the development of congestive heart failure or thromboembolism.
  • Class I and Class III anti-arrhythmic drugs reduce the rate of recurrence of AF, but are of limited use because of a variety of potentially adverse effects including ventricular proarrhythmia. Because current therapy is inadequate and fraught with side effects, there is a clear need to develop new therapeutic approaches.
  • Anti-arrhythmic agents of Class III are drugs that cause a selective prolongation of the duration of the action potential without significant cardiac depression. Available drugs in this class are limited in number. Examples such as sotalol and amiodarone have been shown to possess interesting Class III properties (Singh, B. N. et al., “A Third Class of Anti-Arrhythmic Action: Effects on Atrial and Ventricular Intracellular Potentials and Other Pharmacological Actions on Cardiac Muscle, of MJ 1999 and AH 3747”, Br. J. Pharmacol., 39:675-689 (1970). and Singh B. N. et al., “The Effect of Amiodarone, a New Anti-Anginal Drug, on Cardiac Muscle”, Br. J.
  • Class III agents increase myocardial refractoriness via a prolongation of cardiac action potential duration.
  • prolongation of the cardiac action potential can be achieved by enhancing inward currents (i.e., Na + or Ca 2+ currents; hereinafter I Na and I Ca , respectively) or by reducing outward repolarizing potassium (K + ) currents.
  • the delayed rectifier (I K ) K + current is the main outward current involved in the overall repolarization process during the action potential plateau, whereas the transient outward (I tO ) and inward rectifier (I K1 ) K + currents are responsible for the rapid initial and terminal phases of repolarization, respectively.
  • I K consists of two pharmacologically and kinetically distinct K + current subtypes, I Kr (rapidly activating and deactivating) and I Ks (slowly activating and deactivating) (Sanguinetti et al., “Two Components of Cardiac Delayed Rectifier K + Current: Differential Sensitivity to Block by Class III Anti-arrhythmic Agents”, J. Gen. Physiol, 96:195215 (1990)).
  • Class III anti-arrhythmic agents currently in development including d-sotalol, dofetilide (UK-68,798), almokalant (H234/09), E-4031 and methanesulfonamide-N-[1′-6-cyano-1,2,3,4-tetrahydro-2-naphthalenyl)-3,4-dihydro-4-hydroxyspiro[2H-1-benzopyran-2,4′-piperidin]-6yl]monochloride, predominantly, if not exclusively, block I Kr .
  • amiodarone is a blocker of I Ks (Balser, J. R.
  • Reentrant excitation has been shown to be a prominent mechanism underlying supraventricular arrhythmias in man.
  • Reentrant excitation requires a critical balance between slow conduction velocity and sufficiently brief refractory periods to allow for the initiation and maintenance of multiple reentry circuits to coexist simultaneously and sustain AF.
  • Increasing myocardial refractoriness by prolonging action potential duration (APD) prevents and/or terminates reentrant arrhythmias.
  • Most selective Class III anti-arrhythmic agents currently in development, such as d-sotalol and dofetilide predominantly, if not exclusively, block I kr , the rapidly activating component of I K found both in the human atrium and ventricle.
  • I kr blockers increase APD and refractoriness both in atria and ventricle without affecting conduction per se, theoretically they represent potential useful agents for the treatment of arrhythmias like AF. These agents have a liability in that they have an enhanced risk of proarrhythmia at slow heart rates. For example, torsades de points has been observed when these compounds are utilized (Roden, D. M., “Current Status of Class III Anti-arrhythmic Drug Therapy”, Am. J. Cardiol., 72:44 B-49B (1993)). This exaggerated effect at slow heart rates has been termed “reverse frequency-dependence”, and is in contrast to frequency-independent or frequency-dependent actions (Hondeghem, L. M., “Development of Class III Anti-arrhythmic Agents”, J. Cadiovasc. Cardiol., 20(Suppl. 2):S17-S22).
  • the slowly activating component of the delayed rectifier potentially overcomes some of the limitations of I kr blockers associated with ventricular arrhythmias. Because of its slow activation kinetics however, the role of I ks in atrial repolarization may be limited due to the relatively short APD of the atrium. Consequently, although I ks blockers may provide distinct advantage in the case of ventricular arrhythmias, their ability to affect SVT is considered to be minimal.
  • the ultra-rapidly activating delayed rectifier K + current (I kur ) is believed to represent the native counterpart to a cloned potassium channel designated Kv1.5 and, while present in human atrium, it appears to be absent in human ventricle. Furthermore, because of its rapidity of activation and limited slow inactivation, I kur is believed to contribute significantly to repolarization in human atrium. Consequently, a specific blocker of I kur , that is a compound which blocks Kv1.5, would overcome the short coming of other compounds by prolonging refractoriness by retarding repolarization in the human atrium without causing the delays in ventricular repolarization that underlie arrhythmogenic after depolarizations and acquired long QT syndrome observed during treatment with current Class III drugs.
  • anti-arrhythmic agents of Class I according to the classification scheme of Vaughan-Williams (“Classification of Anti-arrhythmic Drugs” in Cardiac Arrhythmias , Sandoe, E. et al., eds., Sweden, Astra, Sodertalje, pp.
  • Beta-adrenoceptor blockers and calcium antagonists which belong to Class II and IV, respectively, have a defect in that their effects are either limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease. Their safety, however, is higher than that of the anti-arrhythmic agents of Class I.
  • the present invention provides heterocyclyl compounds of the following formula I, including enantiomers, diastereomers, and salts thereof, useful as inhibitors of potassium channel function (especially inhibitors of the K v 1 subfamily of voltage gated K + channels, more especially inhibitors of K v 1.5 which has been linked to the ultra-rapidly activating delayed rectifier K + current, I Kur ) for the treatment of disorders such as arrhythmia and I Kur -associated disorders:
  • n and p are independently 0, 1, 2 or 3 provided that the sum of m and p is at least 2;
  • Q is NR 1 , O, S, S(O) or S(O) 2 ;
  • R 1 is H
  • R 2 is heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, alkyl or cycloalkyl, any of which may be optionally independently substituted with one or more groups T 1 , T 2 or T 3 ;
  • J is a bond, C 1-4 alkylene optionally independently substituted with one or more groups T 1a , T 2a or T 3a , or C 1-4 alkenylene optionally independently substituted with one or more groups T 1a , T 2a or T 3a ;
  • R 4 is H, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, (aryl)alkyl or heteroaryl any of which may be optionally independently substituted with one or more groups T 1b , T 2b or T 3b ;
  • heteroaryl (heteroaryl)alkyl, aryl, (aryl)alkyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, (heterocyclo)alkyl, or alkyl any of which may be optionally independently substituted with one or more groups T 1c , T 2c or T 3c ;
  • R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 8a1 , R 8a2 , and R 8a3 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl, (heteroaryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, C(O)R 9 , —CO 2 R 9 , —C(O)—NR 9 R 10 , or —NR 9 R 10 any of which may be optional
  • R 6 and R 7 , or R 6a and R 7a together with the nitrogen atom to which they are attached may combine to form a 4 to 8 membered heterocyclo ring optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
  • R 6 or R 7 may combine with one of R 8 , R 8a or R 9 to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
  • R 8c is H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclo, heteroaryl, alkoxy or aryloxy any of which may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
  • R 8d is R 4 , COR 4 , CO 2 R 4 , SO 2 R 4 , CONR 6 R 7 , or SO 2 NR 6 R 7 ;
  • R 9 and R 10 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl, (heteroaryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, or (heterocyclo)alkyl any of which may be optionally independently substituted with one or more groups T 1f , T 2f or T 3f ;
  • R 9 and R 10 together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated ring which may be optionally independently substituted with one or more groups T 1f , T 2f or T 3f ;
  • W is ⁇ NR 8a1 , ⁇ N—CO 2 R 8a1 , ⁇ N—COR 8a1 , ⁇ N—CN, ⁇ N—SO 2 R 8a1 , or
  • X 1 is O, S, NR 8a2 or CH 2 ;
  • Z, Z 1 and Z 2 are independently ⁇ O, ⁇ S, ⁇ NR 8a3 or ⁇ N—CN;
  • R X is one or more optional substituents, attached to any available ring carbon atom, independently selected from T 1g , T 2g or T 3g ;
  • T 1-1g , T 2-2g , and T 3-3g are each independently
  • T 4 and T 5 are each independently
  • (1) are each independently hydrogen or a group provided in the definition of T 6 , or
  • T 7 and T 8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of T 1-1g , T 2-2g and T 3-3g , or
  • T 7 or T 8 together with T 9 , may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of T 1-1g , T 2-2g and T 3-3g , or
  • T 7 and T 8 or T 9 and T 10 together with the nitrogen atom to which they are attached may combine to form a group —N ⁇ CT 13 T 14 where T 13 and T 14 are each independently H or a group provided in the definition of T 6 ; and
  • T 11 and T 12 are each independently
  • the present invention provides novel methods for the prevention and treatment of arrhythmia and I Kur -associated disorders employing one or more compounds of the formula I, enantiomers, diastereomers or pharmaceutically acceptable salts thereof.
  • the present invention provides a novel method for the selective prevention and treatment of supraventricular arrhythmias.
  • Preferred compounds within the scope of formula I include compounds and salts thereof wherein one or more, and especially all of Q, R 2 , J and R 3 are selected from the following definitions:
  • Q is NR 1 or O
  • R 1 is H
  • R 2 is aryl, (aryl)alkyl or heteroaryl any of which may be optionally independently substituted with one or more T 1 , T 2 T 3 ;
  • J is a bond or methylene
  • R 3 is R 5 .
  • More preferred compounds within the scope of formula I include compounds and salts thereof wherein one or more, and especially all of Q, R 2 , J and R 3 are selected from the following definitions:
  • Q is NR 1 ;
  • R 1 is H
  • R 2 is aryl, (aryl)alkyl or heteroaryl (especially where aryl is phenyl and heteroaryl is thiophenyl) any of which may be optionally independently substituted with one or more T 1 , T 2 T 3 ;
  • J is a bond or methylene
  • R 3 is R 5 .
  • R 4 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, (aryl)alkyl, heteroaryl or (heteroaryl)alkyl any of which may be optionally independently substituted with one or more T 1b , T 2b T 3b ;
  • aryl (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo or (heterocyclo)alkyl any of which may be optionally independently substituted with one or more T 1c , T 2c T 3c ;
  • R 6 , R 6a , R 7 and R 7a are independently H, alkyl, alkenyl, alkynyl, aryl, (aryl)alkyl, (alkoxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, (hydroxy)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, (aryloxy)alkyl, —C(O)R 9 , —CO 2 R 9 , or —C(O)—NR 9 R 10 any of which may be optionally independently substituted with one or more T 1d , T 2d T 3d ;
  • R 8a is H, alkyl, or (aryl)alkyl
  • W is ⁇ N—CN
  • Z 1 is ⁇ O or ⁇ N—CN
  • T 1 , T 1b , T 1c , T 1d , T 2 , T 2b , T 2c , T 2d , T 3 , T 3b , T 3c and T 3d are independently halo, cyano, alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, haloalkyl, —OH, —OT 6 , —C(O) t T 6 , —SO 2 T 6 , -T 4 NT 7 T 8 , or -T 4 N(T 10 )T 5 -T 6 .
  • Preferred compounds generally have the structure
  • Preferred -JR 3 moieties include:
  • alk refers to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, etc.
  • Lower alkyl groups that is, alkyl groups of 1 to 6 carbon atoms, are generally most preferred.
  • substituted alkyl refers to alkyl groups substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , preferably selected from cyano, halo, oxo, hydroxy, —OT 6 , —C(O) t T 6 , OC(O)T 6 , -T 4 -NT 7 T 8 , -T 4 -N(T 9 )-T 5 -T 6 , —S(O) t T 6 or —S(O) t (T 9 )T 6 .
  • alkenyl refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms, preferably 2 to 4 carbon atoms, and at least one double carbon to carbon bond (either cis or trans), such as ethenyl.
  • substituted alkenyl refers to alkenyl groups substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , preferably selected from cyano, halo, oxo, hydroxy, —OT 6 , —C(O) t T 6 , —OC(O)T 6 , -T 4 -NT 7 T 8 , -T 4 -N(T 9 )-T 5 -T 6 , —S(O) t T 6 or —S(O) t N(T 9 )T 6 .
  • alkynyl refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms, preferably 2 to 4 carbon atoms, and at least one triple carbon to carbon bond, such as ethynyl.
  • substituted alkynyl refers to alkynyl groups substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , preferably selected from cyano, halo, oxo, hydroxy, —OT 6 , —C(O) t T 6 , —OC(O)T 6 , -T 4 -NT 7 T 8 , -T 4 -N(T 9 )-T 5 -T 6 , —S(O) t T 6 or —S(O) t N(T 9 )T 6 .
  • alkylene refers to a straight chain bridge of 1 to 4 carbon atoms connected by single bonds (e.g., —(CH 2 ) x — wherein x is 1 to 5), which may be substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , preferably selected from cyano, halo, oxo, hydroxy, —OT 6 , —C(O) t T 6 , —OC(T)T 6 -T 4 -NT 7 T 8 , -T 4 -N(T 9 )-T 5 -T 6 , —S(O) t T 6 or S(O) t N(T 9 )T 6 .
  • alkenylene refers to a straight chain bridge of 2 to 5 carbon atoms having one or two double bonds that is connected by single bonds and may be substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , preferably selected from cyano, halo, oxo, hydroxy, —OT 6 , —C(O) t T 6 , —OC(O)T 6 , -T 4 -NT 7 T 8 , -T 4 -N(T 9 )-T 5 -T 6 , —S(O) t T 6 or —S(O) t N(T 9 )T 6 .
  • alkenylene groups are —CH ⁇ CH—CH ⁇ CH—, —CH 2 —CH ⁇ CH—, —CH 2 —CH ⁇ CH—CH 2 —, —C(CH 3 ) 2 CH ⁇ CH— and —CH(C 2 H 5 )—CH ⁇ CH—.
  • alkynylene refers to a straight chain bridge of 2 to 5 carbon atoms that has a triple bond therein, is connected by single bonds, and may be substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g preferably selected from cyano, halo, oxo, hydroxy, —OT 6 , —C(O) t T 6 , —OC(O)T 6 , -T 4 -NT 7 T 8 , -T 4 -N(T 9 )-T 5 -T 6 , —S(O) t T 6 or S(O) n N(T 9 )T 6 .
  • Exemplary alkynylene groups are —C ⁇ C—, —CH 2 —C ⁇ C—, —CH(CH 3 )—C ⁇ C— and —C ⁇ C—CH(C 2 H 5 )CH 2 —
  • aromatic homocyclic i.e., hydrocarbon
  • bi- or tricyclic ring-containing groups preferably having 6 to 14 members such as phenyl, naphthyl and biphenyl, as well as such rings fused to a cycloalkyl, cycloalkenyl, heterocyclo, or heteroaryl ring. Examples include:
  • substituted aryl refers to aryl groups substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , preferably selected cyano, halo, oxo, hydroxy, —OT 6 , —C(O) t T 6 , —OC(O)T 6 , -T 4 -NT 7 T, -T 4 -N(T 9 )-T 5 -T 6 , —S(O) t T 6 or —S(O) t N(T 9 )T 6 .
  • cycloalkyl refers to saturated and partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 3 to 7 carbons forming the ring, and which may be fused to 1 or 2 aromatic or heterocyclo rings, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl,
  • substituted cycloalkyl refers to cycloalkyl groups substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , preferably selected from cyano, halo, oxo, hydroxy, —OT 6 , —C(O) t T 6 , —OC(O)T 6 , -T 4 -NT 7 T 8 , -T 4 -N(T 9 )-T 5 -T 6 , —S(O) t T 6 or —S(O) t N(T 9 )T 6 .
  • halogen and “Talo” refer to fluorine, chlorine, bromine and iodine.
  • heterocycle refers to fully saturated or partially or unsaturated cyclic groups (for example, 3 to 13 member monocyclic, 7 to 17 member bicyclic, or 10 to 20 member tricyclic ring systems, preferably containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring.
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be substituted or quaternized.
  • the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system.
  • the rings of multi-ring heterocycles may be either fused, bridged and/or joined through one or more spiro unions.
  • Exemplary heterocyclic groups include
  • substituted heterocycle refers to heterocycle, heterocyclic and heterocyclo groups substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , preferably selected from cyano, halo, oxo, hydroxy, —OT 6 , —C(O) t T 6 , —OC(O)T 6 , -T 4 -NT 7 T 8 , -T 4 -N(T 9 )-T 5 -T 6 , —S(O) t T 6 or —S(O) t N(T 9 )T 6 .
  • heteroaryl refers to a 5- 6- or 7-membered aromatic rings containing from 1 to 4 nitrogen atoms and/or 1 or 2 oxygen or sulfur atoms provided that the ring contains at least 1 carbon atom and no more than 4 heteroatoms.
  • the heteroaryl ring is linked through an available carbon or nitrogen atom.
  • such rings fused to a cycloalkyl, aryl, cycloheteroalkyl, or another heteroaryl ring.
  • One, two, or three available carbon or nitrogen atoms in the heteroaryl ring can be optionally substituted with substituents listed in the description of T 1 , T 2 and T 3 .
  • salts which are also within the scope of this invention.
  • Reference to a compound of the present invention herein is understood to include reference to salts thereof, unless otherwise indicated.
  • zwitterions inner salts
  • Pharmaceutically acceptable salts are preferred, although other salts are also useful, e.g., in isolation or purification steps which may be employed during preparation.
  • Salts of the compounds of the formula I may be formed, for example, by reacting a compound I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • the compounds of the present invention which contain a basic moiety may form salts with a variety of organic and inorganic acids.
  • Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, famarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2-hydroxyethanesulfon
  • the compounds of the present invention which contain an acidic moiety may form salts with a variety of organic and inorganic bases.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • the term “prodrug”, as employed herein, denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula I, or a salt and/or solvate thereof.
  • Solvates of the compounds of formula I are preferably hydrates.
  • All stereoisomers of the present compounds are contemplated within the scope of this invention.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • Z 1 is O and R 5 is —NR 6a R 7a may be prepared as described in Scheme 2.
  • nitrogen protecting groups include the benzyl (Bn), N-tert-butoxycarbonyl (Boc) and carbobeizyloxy (CBz) groups.
  • Bn benzyl
  • Boc N-tert-butoxycarbonyl
  • CBz carbobeizyloxy
  • the carboxylic acid moiety of compound 2 may be coupled with an amine R 6a R 7a using a variety of coupling procedures known in the literature to provide carboxamide compound 3.
  • the nitrogen atom of compound 3 may be deprotected and made to react with a carboxylic acid (e.g.; R 4 CO 2 H; shown in Scheme 1) in the presence of a coupling agent or an acid chloride (e.g.; R 4 COCl) in the presence of an acid scavenger such as triethylamine or polystyrene-diisoproplyethylamine resin to give compound 5 where Q is NR 1 and R 1 is
  • piperidine nitrogen atom of compound 4 may be made to react with a number of other readily available raw materials to provide compounds of formula I.
  • compound 4 may be made to react with sulfonyl chlorides (e.g.; R 8c SO 2 Cl) in the presence of an acid scavenger to provide compounds of formula I where Q is NR 1 and R 1 is
  • Compound 4 may made to react with isocyanates (e.g.; R 7 R 6 NCO) to provide compounds of formula I where Q is NR 1 and R 1 is
  • Compound 4 may be made to react with chloroformates (e.g.; R 4 OCOCl) in the presence of an acid scavenger to provide compounds of formula I where Q is NR 1 and R 1 is
  • Compound 4 may be made to react with certain heteroaryl groups (e.g., heteroaryl-X where X is a leaving group such as a halogen atom) in the presence of an acid scavenger to provide compound 5 where Q is NR 1 and R 1 is heteroaryl.
  • This reaction is may be performed in an organic solvent such a tetrahydrofuran or acetonitrile at elevated temperatures.
  • this reaction may be performed in the presence of a palladium catalyst to provide compound 5 where Q is NR 1 and R 1 is heteroaryl.
  • Z 1 is O and R 5 is —NR 6a R 7a may be prepared using as described in Scheme 3 and Scheme 4.
  • compound 1 may be made to react with diphenyl N-cyanocarbonimidate in a solvent such as tetrahydrofuran, acetonitrile or isopropanol to provide compound 2. Typically this reaction is conducted at elevated temperatures.
  • Compound 2 may be made to react with an amine HNR 6 R 7 to provide cyano guanidine compound 3 where Q is NR 1 and R 1 is
  • compound 1 may be made to react with compound 2 to provide sulfenyl urea compound 3 where Q is NR 1 and R 1 is
  • Compound 2 may be prepared by reacting 2-chloroethanol with chlorosulfonyl isocyanate followed by an amine HNR 6 R 7 in the presence of an acid scavenger such as triethylamine in an organic solvent such as dichloromethane.
  • an acid scavenger such as triethylamine in an organic solvent such as dichloromethane.
  • compound 1 may be made to react with dimethylsulfamoyl chloride in a solvent such as tetrahydrofuran or dichloromethane in the presence of an acid scavenger such as triethylamine or polystyrene-diisopropylethylamine resin to provide compound 3 where Q is NR 1 and R 1 is
  • R 6 and R 7 are each methyl.
  • Compound 1 may be made to react with sulfamide in a solvent such as 1,4-dioxane at elevated temperature to provide compound 3 where Q is NR 1 and R 1 is
  • R 6 and R 7 are each hydrogen.
  • Z 1 is O and R 5 is —NR 6a R 7a may be prepared using as described in Scheme 5.
  • the carboxylic acid compound 1 may be treated with thionyl chloride to convert the carboxylic acid to the acid chloride that is made to react with diazomethane in a solvent such as ethyl ether to produce a diazo intermediate compound 2.
  • the carboxylic acid moiety of compound 3 may be coupled with an amine HNR 6a R 7a using a variety of coupling procedures known in the literature to provide carboxamide compound 4.
  • the nitrogen atom of compound 3 may be deprotected and the nitrogen atom further derivatized (see Schemes 1-3) to provide compounds of formula I.
  • Z 1 is O
  • R 5 is —N 6a
  • R 7a and R 8a is hydrogen
  • Compound 1 may be made to react with diphenylphosphoryl azide in a solvent such as chlorobenzene at an elevated temperature to produce isocyanate compound 2.
  • Compound 2 may be made to react with an amine HNR 6a R 7a to produce the urea compound 3 where J is a bond, R 3 is
  • Z 1 is O
  • R 5 is NR 6a R 7a and R 8a is hydrogen.
  • Z 1 is O and R 8a is hydrogen may be prepared using as described in Scheme 7.
  • Isocyanate compound 1 may be made to react with an alcohol R 5 OH in a solvent such as chlorobenzene or tetrahydrofuran to provide compound 2 where J is a bond, R 3 is
  • Z 1 is O and R 8a is hydrogen.
  • Z 1 is O
  • R 5 is not NR 6a
  • R 7a and R 8a is hydrogen
  • Compound 1 (see Scheme 6; R 5 is tert-butyl) may be deprotected by treatment with trifluoroacetic acid in a solvent such as dichloromethane to provide amine compound 2.
  • the amino group of compound 2 may be made to react with a carboxylic acid (e.g.; R 5 CO 2 H; shown in Scheme 7) in the presence of a coupling agent or an acid chloride (e.g.; R 5 COCl) in the presence of an acid scavenger such as triethylamine or polystyrene-diisoproplyethylamine resin to give compound 3 where J is a bond, R 3 is
  • Z 1 is O, R 5 is not NR 6a R 7a and R 8a is hydrogen.
  • compound 2 may be made to react with a number of other readily available raw materials to provide compounds of formula I.
  • compound 2 may be made to react with sulfonyl chlorides (e.g.; R 5 SO 2 Cl) in the presence of an acid scavenger to provide compounds of formula I where J is a bond and R 3 is
  • Amine compound 1 may be made to react with a substituted aryl or heteroaryl compound where X is a halogen atom, triflate or similar leaving group to provide compound 2.
  • This reaction may be conducted in an organic solvent such a tetrahydrofuran or acetonitrile at an elevated temperature.
  • this reaction may be performed in the presence of a palladium catalyst to provide compound 2 where R 3 is R 5 , R 5 is NR 6a R 7a and R 6a is heteroaryl.
  • acid chloride compound 1 may be made to react compound 2 in an organic solvent such as dichloromethane to provide carboxamide compound 3. Cyclization of compound 2 in the presence of an acid such as acetic acid at elevated temperature provides compound 3 where R 3 is R 5 and R 5 is heteroaryl (e.g.; benzimidazole).
  • an acid such as acetic acid at elevated temperature provides compound 3 where R 3 is R 5 and R 5 is heteroaryl (e.g.; benzimidazole).
  • carboxylic acids or acid chlorides may be converted to a wide variety of heteroaryl groups.
  • compound 1 may be made to react with a 2-amino phenol to provide compounds of formula I where R 3 is R 5 and R 5 is heteroaryl (e.g.; benzoxazole).
  • Compound 1 may be made to react with a 2-amino benzenethiol to provide compounds of formula I where R 3 is R 5 and R 5 is heteroaryl (e.g.; benzthiazole).
  • Compound 1 may be made to react with an N-hydroxyamidine to provide compounds of formula 3 where R 3 is R 5 and R 5 is heteroaryl (e.g.; oxadiazole).
  • cyano compound 1 may be made to react with sodium azide in a solvent such as methyl sulfoxide at elevated temperatures to provide tetrazole compound 2.
  • Compound 2 may be made to react with T 1c -X where X is a leaving group such as a halogen atom or triflate to provide compound 3 where R 3 is R 5 and R 5 is heteroaryl (e.g.; tetrazole).
  • Z 1 is O
  • R 8a is hydrogen
  • Compound 1 may be made to react with bis(2-chloroethyl)ether under phase-transfer catalysis conditions to provide the cyclized product compound 2.
  • the nitrile group of compound 2 may be reduced using various methods, including treatment with lithium aluminum hydride or hydrogenation in the presence of platinum (IV) oxide, to provide the amine compound 3.
  • the amino group of compound 3 may be made to react with a carboxylic acid (e.g.; R 5 CO 2 H) in the presence of a coupling agent in an organic solvent such as tetrahydrofuran to provide the acylated product compound 4.
  • Additional compounds within the scope of the present invention can be prepared from the compounds obtained by the above described methods through conversion of the substituent groups to other functionality by the usual methods of chemical synthesis, as illustrated in the following examples.
  • cardiac arrhythmias including supraventricular arrhythmias, atrial arrhythmias, atrial flutter, atrial fibrillation, complications of cardiac ischemia, and use as heart rate control agents; angina pectoris including relief of Prinzmetal's symptoms, vasospastic symptoms and variant symptoms; gastrointestinal disorders including reflux esophagitis, functional dyspepsia, motility disorders (including constipation and diarrhea), and irritable bowel syndrome; disorders of vascular and visceral smooth muscle including asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, peripheral vascular disease (including intermittent claudication), venous insufficiency, impotence, cerebral and coronary spasm and Raynaud's disease; inflammatory and immunological disease including inflammatory bowel disease, rheumatoid arthritis, graft
  • inhibitors of the K v 1 subfamily of voltage-gated K + channels compounds of the present invention are useful to treat a variety of disorders including resistance by transplantation of organs or tissue, graft-versus-host diseases brought about by medulla ossium transplantation, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes uveitis, juvenile-onset or recent-onset diabetes mellitus, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, infectious diseases caused by pathogenicmicroorganisms, inflammatory and hyperproliferative skin diseases, psoriasis, atopical dermatitis, contact dermatitis, eczematous dermatitises, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullos
  • the compounds of the present invention are anti-arrhythmic agents which are useful in the prevention and treatment (including partial alleviation or cure) of arrhythmias.
  • inhibitors of K v 1.5 compounds within the scope of the present invention are particularly useful in the selective prevention and treatment of supraventricular arrhythmias such as atrial fibrillation, and atrial flutter.
  • supraventricular arrhythmias By “selective prevention and treatment of supraventricular arrhythmias” is meant the prevention or treatment of supraventricular arrhythmias wherein the ratio of the prolongation of the atrial effective refractory period to the prolongation of the ventricular effective refractory period is greater than 1:1. This ratio is preferably greater than 4:1, more preferably greater than 10:1, and most preferably such that prolongation of the atrial effective refractory response period is achieved without significantly detectable prolongation of the ventricular effective refractory period.
  • I Kur -associated condition is a disorder which may be prevented, partially alleviated or cured by the administration of an I Kur blocker.
  • the Kv1.5 gene is known to be expressed in stomach tissue, intestinal/colon tissue, the pulmonary artery, and pancreatic beta cells.
  • administration of an I Kur blocker could provide useful treatment for disorders such as: reflux esophagitis, functional dyspepsia, constipation, asthma, and diabetes.
  • Kv1.5 is known to be expressed in the anterior pituitary.
  • administration of an I Kur blocker could stimulate growth hormone secretion.
  • I Kur inhibitors can additionally be useful in cell proliferative disorders such as leukemia, and autoimmune diseases such as rheumatoid arthritis and transplant rejection.
  • the present invention thus provides methods for the prevention or treatment of one or more of the aforementioned disorders, comprising the step of administering to a subject in need thereof an effective amount of at least one compound of the present invention.
  • Other therapeutic agents such as those described below may be employed with the inventive compounds in the present methods.
  • such other therapeutic agent(s) may be administered prior to, simultaneously with or following the administration of the compound(s) of the present invention.
  • the present invention also provides pharmaceutical compositions comprising at least one of the compounds of the present invention or salts thereof capable of preventing or treating one or more of the aforementioned disorders in an amount effective therefore and a pharmaceutically acceptable vehicle or diluent.
  • the compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
  • the compounds of the present invention may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents.
  • the present compounds may, for example, be administered in a form suitable for immediate release or extended release.
  • Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.
  • the compounds of formula I may be administered to achieve chemical conversion to normal sinus rhythm, or may optionally be used in conjunction with electrical cardioconversion.
  • compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art.
  • the compounds of formula I may also be delivered through the oral cavity by sublingual and/or buccal administration.
  • Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used.
  • Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (AVICEL®) or polyethylene glycols (PEG).
  • Such formulations may also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g., Carbopol 934).
  • HPC hydroxy propyl cellulose
  • HPMC hydroxy propyl methyl cellulose
  • SCMC sodium carboxy methyl cellulose
  • maleic anhydride copolymer e.g., Gantrez
  • agents to control release such as polyacrylic copolymer (e.g., Carbopol 934).
  • Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
  • compositions for nasal aerosol or inhalation administration include solutions in saline which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
  • compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono or diglycerides, and fatty acids, including oleic acid.
  • suitable non-toxic, parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono or diglycerides, and fatty acids, including oleic acid.
  • compositions for rectal administration include suppositories which may contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).
  • a topical carrier such as Plastibase (mineral oil gelled with polyethylene).
  • the effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for an adult human of from about 0.001 to 100 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition.
  • Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats and the like, subject to the aforementioned disorders.
  • the compounds of the present invention may be employed alone or in combination with each other and/or other suitable therapeutic agents useful in the treatment of the aforementioned disorders or other disorders, including: other anti-arrhythmic agents such as Class I agents (e.g., propafenone), Class II agents (e.g., carvadiol and propranolol), Class III agents (e.g., sotalol, dofetilide, amiodarone, azimilide and ibutilide), Class IV agents (e.g., diltiazem and verapamil), 5HT antagonists (e.g., sulamserod, serraline and tropsetron), and dronedarone; calcium channel blockers (both L-type and T-type) such as diltiazem, verapamil, nifedipine, amlodipine and mybefradil; Cyclooxygenase inhibitors (i.e., COX-1 and/or COX-2 inhibitors) such
  • Dual ET/AII antagonist e.g., compounds disclosed in WO 00/01389, neutral endopeptidase NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat and geinopatrilat), nitrates, and combinations of such anti-hypertensive agents; antithrombotic/thrombolytic agents such as tissue plasminogen activator (tPA), recombinant tPA, tenecteplase (TNK), lanoteplase (nPA), factor VIIa inhibitors, factor Xa inhibitors, thrombin inhibitors (e.g., hirudin and argatroban), PAI-1 inhibitors (i.e., inactivators of tissue plasminogen activator inhibitors), ⁇ 2-antiplasmin inhibitors, streptokinase, urokinase, prour
  • tPA tissue plasminogen activator
  • squalene synthetase inhibitors such as squalene synthetase inhibitors, fibrates, and bile acid sequestrants (e.g., QUESTRAN®); antiproliferative agents such as cyclosporin A, TAXOL®, FK 506, and adriamycin; antitumor agents such as TAXOL®, adriamycin, epothilones, cisplatin and carboplatin; anti-diabetic agents such as biguanides (e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulins, meglitinides (e.g., repaglinide), sulfonylureas (e.g.,
  • Assays to determine the degree of activity of a compound as an inhibitor of other members of the K v 1 subfamily are also well known in the art.
  • inhibition of Kv1.1, K v 1.2 and K v 1.3 can be measured using procedures described by Grissmer, S. et al., Mol. Pharmacol, 45(6): 1227-1234 (June 1994).
  • Inhibition of Kv1.4 can be measured using procedures described by Petersen, K. R, et al., Pflugers Arch., 437(3):381392 (February 1999).
  • Inhibition of Kv1.6 can be measured using procedures described by Bowlby, M. R. et al., J. Neurophysiol., 73(6):2221-2229 (June 1995).
  • inhibition of Kv1.7 can be measured using procedures described by Kalmaii, K. et al., J. Biol. Chem., 273(10):5851-5857 (Mar. 6, 1998).
  • Compound 1 is commercially available.
  • Compound 1 was prepared using methodology described in Example 1.
  • Example 3 was prepared using methodology described in Example 2.
  • Compound 1 was prepared using methodology described in Example 1.
  • Compound 1 is commercially available.
  • Compound 2 Compound 2 is commercially available.
  • Compound 4 was prepared using methodology described in Example 1.
  • Compound 1 is commercially available.
  • Compound 1 is commercially available.
  • Compound 2 Compound 2 is commercially available.
  • Compound 3 was prepared using methodology described in Example 7 using 2-methoxy-ethylamine instead of 2,2,2-trifluoro-ethylamine.
  • Examples 18 to 22 were prepared using methodology described in Example 17.
  • Compound 1 is commercially available.
  • Examples 26 to 58 were prepared using methodology described in Example 24 and Example 25.
  • Examples 60 to 63 were prepared as described in Example 59.
  • Compound 1 was prepared using methodology described in Example 59.
  • Examples 65 to 73 were prepared using methodology described in Example 64.
  • Compound 1 is commercially available.
  • Examples 75 to 84 were prepared as described in Example 74.
  • Examples 86 to 93 were prepared as described in Example 85.
  • Compound 1 Compound 1. was prepared as described in Example 85.
  • Compound 1 Compound 1 was prepared as described in Example 85.
  • Compound 1 Compound 1 was prepared as described in Example 85.
  • Examples 97 to 269 were synthesized using methodology described in Example 94, Example 95 and Example 96.
  • Compound 1 Compound 1 were prepared using methodology described in Example 85.
  • Examples 271 to 274 were prepared using methodology described in Example 270.
  • Compound 1 Compound 1 was prepared as described in Example 85.
  • Compound 1 Compound 1 was prepared as described in Example 85.
  • Compound 2 Compound 1 was prepared as described in Example 85.
  • Examples 278 to 285 were prepared using methodology described in Example 277.
  • Compound 1 is commercially available.
  • Compound 1 Compound 1 was prepared as described in Example 286.
  • Examples 288 to 322 were prepared using methodology described in Example 287.
  • Compound 1 is commercially available.
  • Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.120 g, 0.271 mmol) was added to a solution of benzyl amine (0.030 mL, 0.271 mmol), 4-carboxymethyl-4-phenyl-piperidine-1-carboxylic acid benzyl ester (0.100 g, 0.247 mmol), triethylamine (0.103 mL, 0.741 mmol) in tetrahydrofuran (5 ml).
  • Compound 1 Compound 1 were prepared using methodology described in Example 323.
  • Examples 325 to 380 were synthesized using methodology described in Example 324.
  • Compound 1 was prepared using methodology described in Example 324. LRMS m/z 325 (M+H) + .
  • Compound 1 was prepared using methodology described in Example 324. LRMS m/z 325 (M+H) + .
  • Compound 1 was prepared using methodology described in Example 324. LRMS m/z 325 (M+H) + .
  • Compound 2 was prepared using methodology described in Example 25. LRMS m/z 470 (M+H) + .
  • Examples 384 and 385 was prepared using methodology described in Example 383.
  • Compound 1 was prepared using methodology described in Example 324. LRMS m/z 325 (M+H) + .
  • Compound 1 was prepared using methodology described in Example 324. LRMS m/z 325 (M+H) + .
  • Compound 1 was prepared using methodology described in Example 324. LRMS m/z 325 (M+1H) + .
  • Example 389 was prepared using methodology described in Example 388.
  • Compound 1 is commercially available.
  • Compound 1 is commercially available.
  • Compound 1 was prepared as described in Example 390.
  • Examples 393 to 530 were synthesized using methodology described in Example 391 and Example 392.
  • Compound 1 was prepared using methodology described in Example 390. LRMS m/z 352 (M+H) + .
  • Compound 1 was prepared using methodology described in Example 390. LRMS m/z 352 (M+H) + .
  • Example 523 was prepared using methodology described in Example 522.
  • Compound 1 was prepared using methodology described in Example 390. LRMS m/z 352 (M+H) + .
  • Examples 525 to 526 were prepared using methodology described in Example 524.
  • Compound 1 Compound 1 was prepared as described in Example 527.
  • Compound 1 Compound 1 was prepared as described in Example 527.
  • Compound 1 Compound 1 was prepared as described in Example 527.
  • Compound 2 was prepared using methodology described in Example 25. LRMS m/z 463 (M+H) + .
  • Compound 1 Compound 1 was prepared as described in Example 527.
  • Compound 1 Compound 1 was prepared as described in Example 527.
  • Compound 1 Compound 1 was prepared as described in Example 533.
  • Compound 2 was prepared using methodology described in Example 25. LRMS m/z 451 (M+H) + .
  • Example 537 was prepared using methodology described in Example 536.
  • Compound 1 is commercially available.
  • Compound 1 Compound 1 was prepared as described in Example 538.
  • Compound 1 Compound 1 was prepared as described in Example 538.
  • Compound 1 Compound 1 was prepared as described in Example 538.
  • Example 542 was prepared using methodology described in Example 541.
  • Compound 1 Compound 1 was prepared as described in Example 538.
  • Compound 1 was prepared using methodology described in Example 74. LRMS m/z 287 (M+H) + .
  • Compound 1 Compound 1 was prepared as described in Example 544.
  • Compound 1 Compound 1 was prepared as described in Example 544.
  • Compound 1 Compound 1 was prepared as described in Example 544.
  • Examples 549 to 598 were prepared using methodology described in Example 546, Example 547 and Example 548
  • Compound 1 Compound 1 was prepared as described in Example 545.
  • Compound 1 Compound 1 was prepared as described in Example 599.
  • Compound 5 were prepared using methodology described in Example 85 using hydrochloric acid instead of trifluoroacetic acid to accomplish nitrogen deprotection. LRMS m/z 334 (M+H) + .
  • Examples 602 to 626 were prepared as described in Example 601.
  • Compound 1 is commercially available.
  • Examples 628 to 646 were prepared as described in Example 627.
  • Compound 1 Compound 1 was prepared as described in Example 626.
  • Compound 1 Compound 1 was prepared as described in Example 626.
  • Examples 650 to 652 were prepared as described in Example 649.
  • Compound 1 is commercially available.
  • Compound 1 is commercially available.
  • Examples 655 to 695 were synthesized using methodology described in Example 1 and Example 654.
  • Examples 697 to 843 were prepared using methodology described in Example 15, Example 16, Example 17 and Example 696.
  • Examples 845 to 852 were prepared using methodology described in Example 844.
  • Examples 854 to 915 were prepared using methodology described in Example 25 and Example 853.
  • Compound 1 was prepared using methodology described in Example 653.
  • Examples 917 to 924 were prepared using methodology described in Example 916.
  • Examples 926 to 929 were prepared using methodology described in Example 925.
  • Compound 2 A solution of compound 1 (0.065 g; 0.21 mmol) in anhydrous acetonitrile (3 mL) was treated with 1,1-bis(methylthio)-2-nitroethylene (0.058 g; 0.35 mmol) and heated at 85° C. for 3 h. The solvent was removed by rotary evaporation and the crude residue was purified by recrystallization from ethyl acetate to give 0.068 g of compound 2 as a bright yellow solid. LRMS m/z 430 (M+H) + .
  • Compound 1 was prepared using methodology described in Example 653.
  • Examples 932 to 936 were prepared using methodology described in Example 931.

Abstract

Novel heterocyclo compounds useful as inhibitors of potassium channel function (especially inhibitors of the Kv1 subfamily of voltage gated K+ channels, especially inhibitors Kv1.5 which has been linked to the ultra-rapidly activating delayed rectifier K+ current IKur), methods of using such compounds in the prevention and treatment of arrhythmia and IKur-associated conditions, and pharmaceutical compositions containing such compounds.

Description

  • This application is a Divisional Application of copending, prior application Ser. No. 11/186,991 filed on Jul. 21, 2005, which is a Divisional Application of copending, prior application Ser. No. 10/417,355 filed on Apr. 16, 2003, now U.S. Pat. No. 7,005,436, which claims priority to U.S. Provisional Application Ser. No. 60/374,279, filed Apr. 19, 2002, the entirety of which is incorporated herein by reference.
    • FIELD OF THE INVENTION
  • The present invention provides for heterocyclyl compounds useful as inhibitors of potassium channel function (especially inhibitors of the Kv1 subfamily of voltage gated K+ channels, more especially inhibitors Kv1.5 which has been linked to the ultra-rapidly activating delayed rectifier K+ current IKur) and to pharmaceutical compositions containing such compounds. The present invention further provides for methods of using such compounds in the treatment of arrhythmia, IKur-associated disorders, and other disorders mediated by ion channel function.
    • BACKGROUND OF THE INVENTION
  • The importance of potassium channels was first recognized approximately fifty years ago when Hodgkin and Huxley discovered that potassium ions contributed to the current that excited the squid giant axon. Research in the area, however, was hampered by the lack of selective, high affinity ligands for potassium channels. But the advent of recombinant DNA techniques and single cell and whole cell voltage clamp techniques has changed the slow pace of the field. Indeed, potassium channels that exhibit functional, pharmacological and tissue distribution characteristics have been cloned. These cloned potassium channels are useful targets in assays for identifying candidate compounds for the treatment of various disease states. Potassium channels have turned out to be the most diverse family of ion channels discovered to date. They modulate a number of cellular events such as muscle contraction, neuroendocrine secretion, frequency and duration of action potentials, electrolyte homeostasis, and resting membrane potential.
  • Potassium channels are expressed in eukaryotic and procaryotic cells and are elements in the control of electrical and non-electrical cellular functions. Potassium channels have been classified according to their biophysical and pharmacological characteristics. Subclasses of these channels have been named based on amino acid sequence and functional properties. Salient among these are the voltage dependent potassium channels, for example voltage gated potassium channels (e.g., Kv1, Kv2, Kv3, Kv4). Subtypes within these subclasses have been characterized as to their putative function, pharmacology and distribution in cells and tissues (Chandy et al., “Voltage-gated potassium channel genies” in Handbook of Receptors and Channels—Ligand and Voltage-gated Ion Channels, North, R. A. ed. (1995); Doupnik et al., Curr. Opin. Neurobiol., 5:268 (1995)). For example, the Kv1 class of potassium channels is further subdivided depending on the molecular sequence of the channel, for example Kv1.1, Kv1.2, Kv1.3, Kv1.4, Kv1.5, Kv1.6, and Kv1.7. Functional voltage-gated K+ channels can exist as multimeric structures formed by the association of either identical or dissimilar subunits. This phenomena is thought to account for the wide diversity of K+ channels. However, subunit compositions of native K+ channels and the physiologic role that particular channels play are, in most cases, still unclear.
  • Membrane depolarization by Kv1.3 inhibition has been shown to be an effective method to prevent T-cell proliferation and therefore has applications in many autoimmune conditions. Inhibition of K+ channels in the plasma membrane of human T-lymphocytes has been postulated to play a role in eliciting immunosuppressive responses by regulating intracellular Ca++ homeostasis, which has been found to be important in T-cell activation.
  • The Kv0.3 voltage-gated potassium channel is found in neurons, blood cells, osteoclasts and T-lymphocytes. The Chandy and Cahalan laboratories proposed a hypothesis that blocking the Kv2.3 channel would elicit an immuxnosuppressant response. (Chandy et al., J. Exp. Med., 160:369 (1984); Decoursey et al., Nature, 307:465 (1984)). However, the K+ channel blockers employed in their studies were non-selective. Until research with the peptide margatoxin, a peptide found in scorpion venom, no specific inhibitor of the Kv1.3 channel existed to test this hypothesis. Although a laboratory (Price et al., Proc. Natl. Acad. Sci. USA, 86:10171 (1989)) showed that charybdotoxin would block Kv1.3 in human T-cells, charybdotoxin was subsequently shown to inhibit four different K+ channels (Kv1.3 and three distinct small conductance Ca++ activated K+ channels) in human T-lymphocytes, limiting the use of this toxin as a probe for the physiological role of Kv1.3 (Leonard et al., Proc. Natl. Acad. Sci. USA, 89:10094 (1992)). Margatoxin, on the other hand, blocks only Kv1.3 in T-cells, and has immunosuppressant activity on both in in vitro and in vivo models. (Lin et al., J. Exp. Med., 177:637 (1993)). The therapeutic utility of this compound, however, is limited by its potent toxicity. Recently, a class of compounds has been reported that may be an attractive alternative to the above mentioned drugs, see for example U.S. Pat. Nos. 5,670,504; 5,631,282; 5,696,156; 5,679,705; and 5,696,156. While addressing some of the activity/toxicity problems of previous drugs, these compounds tend to be of large molecular weight and are generally produced by synthetic manipulation of a natural product, isolation of which is cumbersome and labor intensive.
  • Immunoregulatory abnormalities have been shown to exist in a wide variety of autoimmune and chronic inflammatory diseases, including systemic lupus erythematosis, chronic rheumatoid arthritis, type I and II diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis and other disorders such as Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, ichthyosis, Graves ophthalmopathy and asthma.
  • Although the underlying pathogenesis of each of these conditions may be quite different, they have in common the appearance of a variety of auto-antibodies and self-reactive lymphocytes. Such self-reactivity may be due, in part, to a loss of the homeostatic controls under which the normal immune system operates. Similarly, following a bone-marrow or an organ transplantation, the host lymphocytes recognize the foreign tissue antigens and begin to produce antibodies which lead to graft rejection.
  • One end result of an autoimmune or a rejection process is tissue destruction caused by inflammatory cells and the mediators they release. Anti-inflammatory agents such as NSAIDs act principally by blocking the effect or secretion of these mediators but do nothing to modify the immunologic basis of the disease. On the other hand, cytotoxic agents, such as cyclophosphamide, act in such a nonspecific fashion that both the normal and autoimmune responses are shut off. Indeed, patients treated with such nonspecific immunosuppressive agents are as likely to succumb from infection as they are from their autoimmune disease.
  • Cyclosporin A (CsA), which was approved by the US FDA in 1983 is currently the leading drug used to prevent rejection of transplanted organs. In 1993, FK-506 (PROGRAF®) was approved by the US FDA for the prevention of rejection in liver transplantation. CsA and FK-506 act by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's foreign protein. In 1994, CsA was approved by the US FDA for the treatment of severe psoriasis and has been approved by European regulatory agencies for the treatment of atopic dermatitis. Though they are effective in fighting transplant rejection, CsA and FK-506 are known to cause several undesirable side effects including nephrotoxicity, neurotoxicity, and gastrointestinal discomfort. Therefore, a selective immunosuppressant without these side effects still remains to be developed. Potassium channel inhibitors promise to be the solution to this problem.
  • Atrial fibrillation (AF) and atrial flutter are the most common cardiac arrhythmias in clinical practice and are likely to increase in prevalence with the aging of the population. Currently, AF affects more than 1 million Americans annually, represents over 5% of all admissions for cardiovascular diseases and causes more than 80,000 strokes each year in the United States. While AF is rarely a lethal arrhythmia, it is responsible for substantial morbidity and can lead to complications such as the development of congestive heart failure or thromboembolism. Currently available Class I and Class III anti-arrhythmic drugs reduce the rate of recurrence of AF, but are of limited use because of a variety of potentially adverse effects including ventricular proarrhythmia. Because current therapy is inadequate and fraught with side effects, there is a clear need to develop new therapeutic approaches.
  • Anti-arrhythmic agents of Class III are drugs that cause a selective prolongation of the duration of the action potential without significant cardiac depression. Available drugs in this class are limited in number. Examples such as sotalol and amiodarone have been shown to possess interesting Class III properties (Singh, B. N. et al., “A Third Class of Anti-Arrhythmic Action: Effects on Atrial and Ventricular Intracellular Potentials and Other Pharmacological Actions on Cardiac Muscle, of MJ 1999 and AH 3747”, Br. J. Pharmacol., 39:675-689 (1970). and Singh B. N. et al., “The Effect of Amiodarone, a New Anti-Anginal Drug, on Cardiac Muscle”, Br. J. Pharmacol., 39:657-667 (1970)), but these are not selective Class III agents. Sotalol also possesses Class II effects which may cause cardiac depression and is contraindicated in certain susceptible patients. Amiodarone, also is not a selective Class III anti-arrhythmic agent because it possesses multiple electrophysiological actions and is severely limited by side effects (Nademanee, K., “The Amiodarone Odyssey”, J. Am. Coll. Cardiol., 20:1063-1065 (1992)). Drugs of this class are expected to be effective in preventing ventricular fibrillation. Selective class III agents, by definition, are not considered to cause myocardial depression or an induction of arrhythmias due to inhibition of conduction of the action potential as seen with Class I anti-arrhythmic agents.
  • Class III agents increase myocardial refractoriness via a prolongation of cardiac action potential duration. Theoretically, prolongation of the cardiac action potential can be achieved by enhancing inward currents (i.e., Na+ or Ca2+ currents; hereinafter INa and ICa, respectively) or by reducing outward repolarizing potassium (K+) currents. The delayed rectifier (IK) K+ current is the main outward current involved in the overall repolarization process during the action potential plateau, whereas the transient outward (ItO) and inward rectifier (IK1) K+ currents are responsible for the rapid initial and terminal phases of repolarization, respectively. Cellular electrophysiologic studies have demonstrated that IK consists of two pharmacologically and kinetically distinct K+ current subtypes, IKr (rapidly activating and deactivating) and IKs (slowly activating and deactivating) (Sanguinetti et al., “Two Components of Cardiac Delayed Rectifier K+ Current: Differential Sensitivity to Block by Class III Anti-arrhythmic Agents”, J. Gen. Physiol, 96:195215 (1990)). Class III anti-arrhythmic agents currently in development, including d-sotalol, dofetilide (UK-68,798), almokalant (H234/09), E-4031 and methanesulfonamide-N-[1′-6-cyano-1,2,3,4-tetrahydro-2-naphthalenyl)-3,4-dihydro-4-hydroxyspiro[2H-1-benzopyran-2,4′-piperidin]-6yl]monochloride, predominantly, if not exclusively, block IKr. Although, amiodarone is a blocker of IKs (Balser, J. R. et al., “Suppression of Time-Dependent Outward Current in Guinea Pig Ventricular Myocytes: Actions of Quinidine and Aniodarone”, Circ. Res., 69:519-529 (1991)), it also blocks INa and ICa, effects thyroid function, is as a nonspecific adrenergic blocker, and acts as an inhibitor of the enzyme phospholipase (Nademanee, K. “The Aniodarone Odyssey”, J. Am. Coll. Cardiol., 20:1063-1065 (1992)). Therefore its method of treating arrhythmia is uncertain. Most Class III agents that are known to be in development predominantly block IKr.
  • Reentrant excitation (reentry) has been shown to be a prominent mechanism underlying supraventricular arrhythmias in man. Reentrant excitation requires a critical balance between slow conduction velocity and sufficiently brief refractory periods to allow for the initiation and maintenance of multiple reentry circuits to coexist simultaneously and sustain AF. Increasing myocardial refractoriness by prolonging action potential duration (APD), prevents and/or terminates reentrant arrhythmias. Most selective Class III anti-arrhythmic agents currently in development, such as d-sotalol and dofetilide predominantly, if not exclusively, block Ikr, the rapidly activating component of IK found both in the human atrium and ventricle.
  • Since these Ikr blockers increase APD and refractoriness both in atria and ventricle without affecting conduction per se, theoretically they represent potential useful agents for the treatment of arrhythmias like AF. These agents have a liability in that they have an enhanced risk of proarrhythmia at slow heart rates. For example, torsades de points has been observed when these compounds are utilized (Roden, D. M., “Current Status of Class III Anti-arrhythmic Drug Therapy”, Am. J. Cardiol., 72:44 B-49B (1993)). This exaggerated effect at slow heart rates has been termed “reverse frequency-dependence”, and is in contrast to frequency-independent or frequency-dependent actions (Hondeghem, L. M., “Development of Class III Anti-arrhythmic Agents”, J. Cadiovasc. Cardiol., 20(Suppl. 2):S17-S22).
  • The slowly activating component of the delayed rectifier (Iks) potentially overcomes some of the limitations of Ikr blockers associated with ventricular arrhythmias. Because of its slow activation kinetics however, the role of Iks in atrial repolarization may be limited due to the relatively short APD of the atrium. Consequently, although Iks blockers may provide distinct advantage in the case of ventricular arrhythmias, their ability to affect SVT is considered to be minimal.
  • The ultra-rapidly activating delayed rectifier K+ current (Ikur) is believed to represent the native counterpart to a cloned potassium channel designated Kv1.5 and, while present in human atrium, it appears to be absent in human ventricle. Furthermore, because of its rapidity of activation and limited slow inactivation, Ikur is believed to contribute significantly to repolarization in human atrium. Consequently, a specific blocker of Ikur, that is a compound which blocks Kv1.5, would overcome the short coming of other compounds by prolonging refractoriness by retarding repolarization in the human atrium without causing the delays in ventricular repolarization that underlie arrhythmogenic after depolarizations and acquired long QT syndrome observed during treatment with current Class III drugs.
  • In intact human atrial myocytes an ultra-rapidly activating delayed rectifier K+ current Ikur which is also known as the sustained outward current, Isus or Iso, has been identified and this current has properties and kinetics identical to those expressed by the human K+ channel clone (hKv1.5, HK2) when isolated from human heart and stably expressed in human (HEK-293) cell lines (Wang et al., Circ. Res., 73:1061-1076 (1993); Fedida et al., Circ. Res., 73:210-216 (1993); Snyders et al., J. Gen. Physiol., 101: 513-543 (1993)) and originally cloned from rat brain (Swanson et al., 10, Neuron, 4:929-939). Although various anti-arrhythmic agents are now available on the market, those having both satisfactory efficacy and a high margin of safety have not been obtained. For example, anti-arrhythmic agents of Class I according to the classification scheme of Vaughan-Williams (“Classification of Anti-arrhythmic Drugs” in Cardiac Arrhythmias, Sandoe, E. et al., eds., Sweden, Astra, Sodertalje, pp. 449-472 (1981)) which cause a selective inhibition of the maximum velocity of the upstroke of the action potential (Vmax) are inadequate for preventing ventricular fibrillation. In addition, they have problems regarding safety, namely, they cause a depression of myocardial contractility and have a tendency to induce arrhythmias due to an inhibition of impulse conduction. Beta-adrenoceptor blockers and calcium antagonists which belong to Class II and IV, respectively, have a defect in that their effects are either limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease. Their safety, however, is higher than that of the anti-arrhythmic agents of Class I.
    • SUMMARY OF THE INVENTION
  • The present invention provides heterocyclyl compounds of the following formula I, including enantiomers, diastereomers, and salts thereof, useful as inhibitors of potassium channel function (especially inhibitors of the Kv1 subfamily of voltage gated K+ channels, more especially inhibitors of Kv1.5 which has been linked to the ultra-rapidly activating delayed rectifier K+ current, IKur) for the treatment of disorders such as arrhythmia and IKur-associated disorders:
  • Figure US20090312307A1-20091217-C00001
  • including enantiomers, diastereomers and salts thereof wherein
  • m and p are independently 0, 1, 2 or 3 provided that the sum of m and p is at least 2;
  • Q is NR1, O, S, S(O) or S(O)2;
  • R1 is H,
  • Figure US20090312307A1-20091217-C00002
  • —C(═NR8b)R8c, —SO2R8c, —OC(O)CCl3, —C(═S)R8c, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, perfluoroalkyl, cyano, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • R2 is heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, alkyl or cycloalkyl, any of which may be optionally independently substituted with one or more groups T1, T2 or T3;
  • J is a bond, C1-4 alkylene optionally independently substituted with one or more groups T1a, T2a or T3a, or C1-4 alkenylene optionally independently substituted with one or more groups T1a, T2a or T3a;
  • Figure US20090312307A1-20091217-C00003
  • R4 is H, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, (aryl)alkyl or heteroaryl any of which may be optionally independently substituted with one or more groups T1b, T2b or T3b;
  • R5 is
  • (a) —NR6aR7a, cyano, or
  • (b) heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, (heterocyclo)alkyl, or alkyl any of which may be optionally independently substituted with one or more groups T1c, T2c or T3c;
  • R6, R6a, R7, R7a, R8, R8a, R8a1, R8a2, and R8a3 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl, (heteroaryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, C(O)R9, —CO2R9, —C(O)—NR9R10, or —NR9R10 any of which may be optionally independently substituted with one or more groups T1d, T2d or T3d;
  • or R6 and R7, or R6a and R7a together with the nitrogen atom to which they are attached may combine to form a 4 to 8 membered heterocyclo ring optionally independently substituted with one or more groups T1d, T2d or T3d;
  • or one of R6 or R7, may combine with one of R8, R8a or R9 to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T1d, T2d or T3d;
      • or one of R6a or R7a, may combine with R8a1 to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T1d, T2d or T3d;
      • R8b is H, alkyl, aryl, cyano, nitro, acyl or —SO2(alkyl) were the alkyl and aryl groups may be optionally independently substituted with one or more groups T1d, T2d or T3d;
  • R8c is H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclo, heteroaryl, alkoxy or aryloxy any of which may be optionally independently substituted with one or more groups T1d, T2d or T3d;
  • R8d is R4, COR4, CO2R4, SO2R4, CONR6R7, or SO2NR6R7;
  • R9 and R10 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl, (heteroaryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, or (heterocyclo)alkyl any of which may be optionally independently substituted with one or more groups T1f, T2f or T3f;
  • or R9 and R10 together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated ring which may be optionally independently substituted with one or more groups T1f, T2f or T3f;
  • W is ═NR8a1, ═N—CO2R8a1, ═N—COR8a1, ═N—CN, ═N—SO2R8a1, or
  • Figure US20090312307A1-20091217-C00004
  • X1 is O, S, NR8a2 or CH2;
  • Z, Z1 and Z2 are independently ═O, ═S, ═NR8a3 or ═N—CN;
  • RX is one or more optional substituents, attached to any available ring carbon atom, independently selected from T1g, T2g or T3g;
  • T1-1g, T2-2g, and T3-3g are each independently
  • (1) hydrogen or T6, where T6 is
      • (i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl;
      • (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or
      • (iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of T1-1g, T2-2g and T3-3g,
  • (2) —OH or —OT6,
  • (3) —SH or —ST6,
  • (4) —C(O)tH, —C(O)tT6, or —O—C(O)T6, where t is 1 or 2,
  • (5) —SO3H, —S(O)tT6, or S(O)tN(T9)T6,
  • (6) halo,
  • (7) cyano,
  • (8) nitro,
  • (9) -T4-NT7T8,
  • (10) -T4-N(T9)-T5-NT7T8,
  • (11) -T4-N(T10)-T5-T6,
  • (12)-T4-N(T10)-T5-H,
  • (13) oxo;
  • T4 and T5 are each independently
  • (1) a single bond,
  • (2) -T11-S(O)t-T12-,
  • (3) -T11-C(O)-T12-,
  • (4) -T11-C(S)-T12-,
  • (5) -T11-O-T12-,
  • (6) -T11-S-T12-,
  • (7) -T11-O—C(O)-T12-,
  • (8) -T11-C(O)—O-T12,
  • (9) -T11-C(═NT9a)-T12-, or
  • (10) -T11-C(O)—C(O)-T12-;
  • T7, T8, T9, T9a and T10
  • (1) are each independently hydrogen or a group provided in the definition of T6, or
  • (2) T7 and T8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of T1-1g, T2-2g and T3-3g, or
  • (3) T7 or T8, together with T9, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of T1-1g, T2-2g and T3-3g, or
  • (4) T7 and T8 or T9 and T10 together with the nitrogen atom to which they are attached may combine to form a group —N═CT13T14 where T13 and T14 are each independently H or a group provided in the definition of T6; and
  • T11 and T12 are each independently
  • (1) a single bond,
  • (2) alkylene,
  • (3) alkenylene, or
  • (4) alkynylene.
  • The present invention provides novel methods for the prevention and treatment of arrhythmia and IKur-associated disorders employing one or more compounds of the formula I, enantiomers, diastereomers or pharmaceutically acceptable salts thereof. In particular the present invention provides a novel method for the selective prevention and treatment of supraventricular arrhythmias.
  • Preferred compounds within the scope of formula I include compounds and salts thereof wherein one or more, and especially all of Q, R2, J and R3 are selected from the following definitions:
  • Q is NR1 or O;
  • R1 is H,
  • Figure US20090312307A1-20091217-C00005
  • —C(═S)R8c, —C(═NR8b)R8c or heteroaryl;
  • R2 is aryl, (aryl)alkyl or heteroaryl any of which may be optionally independently substituted with one or more T1, T2 T3;
  • J is a bond or methylene; and
  • R3 is R5,
  • Figure US20090312307A1-20091217-C00006
  • More preferred compounds within the scope of formula I include compounds and salts thereof wherein one or more, and especially all of Q, R2, J and R3 are selected from the following definitions:
  • Q is NR1;
  • R1 is H,
  • Figure US20090312307A1-20091217-C00007
  • —C(═S)R8c, or heteroaryl;
  • R2 is aryl, (aryl)alkyl or heteroaryl (especially where aryl is phenyl and heteroaryl is thiophenyl) any of which may be optionally independently substituted with one or more T1, T2 T3;
  • J is a bond or methylene;
  • R3 is R5,
  • Figure US20090312307A1-20091217-C00008
  • R4 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, (aryl)alkyl, heteroaryl or (heteroaryl)alkyl any of which may be optionally independently substituted with one or more T1b, T2b T3b;
  • R5 is
  • (a) —NR6aR7a, or
  • (b) aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo or (heterocyclo)alkyl any of which may be optionally independently substituted with one or more T1c, T2c T3c;
  • R6, R6a, R7 and R7a are independently H, alkyl, alkenyl, alkynyl, aryl, (aryl)alkyl, (alkoxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, (hydroxy)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, (aryloxy)alkyl, —C(O)R9, —CO2R9, or —C(O)—NR9R10 any of which may be optionally independently substituted with one or more T1d, T2d T3d;
      • or R6 and R7, or R6a and R7a together with the nitrogen atom to which they are attached combine to form an optionally substituted 4 to 8 membered heterocyclo ring
  • Figure US20090312307A1-20091217-C00009
  • R8a is H, alkyl, or (aryl)alkyl;
  • R8c is
  • (a) alkyl, aryl, heteroaryl any of which may be optionally independently substituted with one or more T1d, T2d T3d, or
  • (b) —NR9R10;
  • W is ═N—CN;
  • Z1 is ═O or ═N—CN; and
  • T1, T1b, T1c, T1d, T2, T2b, T2c, T2d, T3, T3b, T3c and T3d are independently halo, cyano, alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, haloalkyl, —OH, —OT6, —C(O)tT6, —SO2T6, -T4NT7T8, or -T4N(T10)T5-T6.
  • Preferred compounds generally have the structure
  • Figure US20090312307A1-20091217-C00010
  • Preferred -JR3 moieties include:
  • Figure US20090312307A1-20091217-C00011
    • DETAILED DESCRIPTION OF THE INVENTION
  • The following are definitions of terms used in this specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated.
  • The terms “alk” or “alkyl” refer to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, etc. Lower alkyl groups, that is, alkyl groups of 1 to 6 carbon atoms, are generally most preferred. The term “substituted alkyl” refers to alkyl groups substituted with one or more groups listed in the definition of T1-1g, T2-2g and T3-3g, preferably selected from cyano, halo, oxo, hydroxy, —OT6, —C(O)tT6, OC(O)T6, -T4-NT7T8, -T4-N(T9)-T5-T6, —S(O)tT6 or —S(O)t(T9)T6.
  • The term “alkenyl” refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms, preferably 2 to 4 carbon atoms, and at least one double carbon to carbon bond (either cis or trans), such as ethenyl. The term “substituted alkenyl” refers to alkenyl groups substituted with one or more groups listed in the definition of T1-1g, T2-2g and T3-3g, preferably selected from cyano, halo, oxo, hydroxy, —OT6, —C(O)tT6, —OC(O)T6, -T4-NT7T8, -T4-N(T9)-T5-T6, —S(O)tT6 or —S(O)tN(T9)T6.
  • The term “alkynyl” refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms, preferably 2 to 4 carbon atoms, and at least one triple carbon to carbon bond, such as ethynyl. The term “substituted alkynyl” refers to alkynyl groups substituted with one or more groups listed in the definition of T1-1g, T2-2g and T3-3g, preferably selected from cyano, halo, oxo, hydroxy, —OT6, —C(O)tT6, —OC(O)T6, -T4-NT7T8, -T4-N(T9)-T5-T6, —S(O)tT6 or —S(O)tN(T9)T6.
  • The term “alkylene” refers to a straight chain bridge of 1 to 4 carbon atoms connected by single bonds (e.g., —(CH2)x— wherein x is 1 to 5), which may be substituted with one or more groups listed in the definition of T1-1g, T2-2g and T3-3g, preferably selected from cyano, halo, oxo, hydroxy, —OT6, —C(O)tT6, —OC(T)T6-T4-NT7T8, -T4-N(T9)-T5-T6, —S(O)tT6 or S(O)tN(T9)T6.
  • The term “alkenylene” refers to a straight chain bridge of 2 to 5 carbon atoms having one or two double bonds that is connected by single bonds and may be substituted with one or more groups listed in the definition of T1-1g, T2-2g and T3-3g, preferably selected from cyano, halo, oxo, hydroxy, —OT6, —C(O)tT6, —OC(O)T6, -T4-NT7T8, -T4-N(T9)-T5-T6, —S(O)tT6 or —S(O)tN(T9)T6. Exemplary alkenylene groups are —CH═CH—CH═CH—, —CH2—CH═CH—, —CH2—CH═CH—CH2—, —C(CH3)2CH═CH— and —CH(C2H5)—CH═CH—.
  • The term “alkynylene” refers to a straight chain bridge of 2 to 5 carbon atoms that has a triple bond therein, is connected by single bonds, and may be substituted with one or more groups listed in the definition of T1-1g, T2-2g and T3-3g preferably selected from cyano, halo, oxo, hydroxy, —OT6, —C(O)tT6, —OC(O)T6, -T4-NT7T8, -T4-N(T9)-T5-T6, —S(O)tT6 or S(O)nN(T9)T6. Exemplary alkynylene groups are —C≡C—, —CH2—C≡C—, —CH(CH3)—C≡C— and —C≡C—CH(C2H5)CH2—
  • The terms “ar” or “aryl” refer to aromatic homocyclic (i.e., hydrocarbon) mono-, bi- or tricyclic ring-containing groups preferably having 6 to 14 members such as phenyl, naphthyl and biphenyl, as well as such rings fused to a cycloalkyl, cycloalkenyl, heterocyclo, or heteroaryl ring. Examples include:
  • Figure US20090312307A1-20091217-C00012
  • and the like.
  • The term “substituted aryl” refers to aryl groups substituted with one or more groups listed in the definition of T1-1g, T2-2g and T3-3g, preferably selected cyano, halo, oxo, hydroxy, —OT6, —C(O)tT6, —OC(O)T6, -T4-NT7T, -T4-N(T9)-T5-T6, —S(O)tT6 or —S(O)tN(T9)T6.
  • The term “cycloalkyl” refers to saturated and partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 3 to 7 carbons forming the ring, and which may be fused to 1 or 2 aromatic or heterocyclo rings, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl,
  • Figure US20090312307A1-20091217-C00013
  • and the like.
  • The terms “substituted cycloalkyl” refers to cycloalkyl groups substituted with one or more groups listed in the definition of T1-1g, T2-2g and T3-3g, preferably selected from cyano, halo, oxo, hydroxy, —OT6, —C(O)tT6, —OC(O)T6, -T4-NT7T8, -T4-N(T9)-T5-T6, —S(O)tT6 or —S(O)tN(T9)T6.
  • The terms “halogen” and “Talo” refer to fluorine, chlorine, bromine and iodine.
  • The terms “heterocycle”, “heterocyclic”, “heterocyclyl”, “heterocyclic group” or “heterocyclo” refer to fully saturated or partially or unsaturated cyclic groups (for example, 3 to 13 member monocyclic, 7 to 17 member bicyclic, or 10 to 20 member tricyclic ring systems, preferably containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be substituted or quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system. The rings of multi-ring heterocycles may be either fused, bridged and/or joined through one or more spiro unions. Exemplary heterocyclic groups include
  • Figure US20090312307A1-20091217-C00014
  • and the like.
  • The terms “substituted heterocycle”, “substituted heterocyclic”, “substituted heterocyclic group” and “substituted heterocyclo” refer to heterocycle, heterocyclic and heterocyclo groups substituted with one or more groups listed in the definition of T1-1g, T2-2g and T3-3g, preferably selected from cyano, halo, oxo, hydroxy, —OT6, —C(O)tT6, —OC(O)T6, -T4-NT7T8, -T4-N(T9)-T5-T6, —S(O)tT6 or —S(O)tN(T9)T6.
  • The term “heteroaryl” as used herein alone or as part of another group refers to a 5- 6- or 7-membered aromatic rings containing from 1 to 4 nitrogen atoms and/or 1 or 2 oxygen or sulfur atoms provided that the ring contains at least 1 carbon atom and no more than 4 heteroatoms. The heteroaryl ring is linked through an available carbon or nitrogen atom. Also included within the definition of heteroaryl are such rings fused to a cycloalkyl, aryl, cycloheteroalkyl, or another heteroaryl ring. One, two, or three available carbon or nitrogen atoms in the heteroaryl ring can be optionally substituted with substituents listed in the description of T1, T2 and T3. Also an available nitrogen or sulfur atom in the heteroaryl ring can be oxidized. Examples of heteroaryl rings include
  • Figure US20090312307A1-20091217-C00015
    Figure US20090312307A1-20091217-C00016
    Figure US20090312307A1-20091217-C00017
  • Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.
  • The compounds of the present invention form salts which are also within the scope of this invention. Reference to a compound of the present invention herein is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, when a compound of formula I contains both a basic moiety and an acidic moiety, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps which may be employed during preparation. Salts of the compounds of the formula I may be formed, for example, by reacting a compound I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • The compounds of the present invention which contain a basic moiety may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, famarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.
  • The compounds of the present invention which contain an acidic moiety may form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term “prodrug”, as employed herein, denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula I, or a salt and/or solvate thereof. Solvates of the compounds of formula I are preferably hydrates.
  • To the extent that compounds of the present invention, and salts thereof may exist in their tautomeric form, all such tautomeric forms are contemplated herein as part of the present invention.
  • All stereoisomers of the present compounds, such as those which may exist due to asymmetric carbons on the various R and Z substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons) and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • The terms “including”, “such as”, “for example” and the like are intended to refer to exemplary embodiments and not to limit the scope of the present invention.
    • SCHEMES
  • Compounds of the formula I may be prepared using the sequence of steps outlined below.
  • Figure US20090312307A1-20091217-C00018
  • Compounds of the formula I may be prepared using the sequence of steps outlined in scheme 1. Specifically, compounds of the formula I where R2 is heteroaryl or substituted heteroaryl and R5 is aryl, substituted aryl, heteroaryl or substituted heteroaryl may be prepared using Scheme 1. Heteroaryl acetonitrile 1 is deprotonated and alkylated to form the N-protected piperidine ring 2. Reduction of nitrile 2 generates primary amine 3. The amine is subsequently acylated with Heterocyle 2 acyl chloride, deprotected and the resulting amine is taken onto final product carbamates, sulfonamides, sulfenyl ureas and cyanoguanidines.
  • Compounds of formula I where R3 is
  • Figure US20090312307A1-20091217-C00019
  • Z1 is O and R5 is —NR6aR7a may be prepared as described in Scheme 2.
  • Figure US20090312307A1-20091217-C00020
  • Protection of the nitrogen atom of compound 1 gives compound 2. One skilled in the art will recognize a variety of nitrogen protecting groups that are known in the literature. In this example, suitable nitrogen protecting groups include the benzyl (Bn), N-tert-butoxycarbonyl (Boc) and carbobeizyloxy (CBz) groups. The carboxylic acid moiety of compound 2 may be coupled with an amine R6aR7a using a variety of coupling procedures known in the literature to provide carboxamide compound 3. The nitrogen atom of compound 3 may be deprotected and made to react with a carboxylic acid (e.g.; R4CO2H; shown in Scheme 1) in the presence of a coupling agent or an acid chloride (e.g.; R4COCl) in the presence of an acid scavenger such as triethylamine or polystyrene-diisoproplyethylamine resin to give compound 5 where Q is NR1 and R1 is
  • Figure US20090312307A1-20091217-C00021
  • In addition to carboxylic acids or acid chlorides, one skilled in the art will recognize that the piperidine nitrogen atom of compound 4 may be made to react with a number of other readily available raw materials to provide compounds of formula I. For example, compound 4 may be made to react with sulfonyl chlorides (e.g.; R8cSO2Cl) in the presence of an acid scavenger to provide compounds of formula I where Q is NR1 and R1 is
  • Figure US20090312307A1-20091217-C00022
  • Compound 4 may made to react with isocyanates (e.g.; R7R6NCO) to provide compounds of formula I where Q is NR1 and R1 is
  • Figure US20090312307A1-20091217-C00023
  • Compound 4 may be made to react with chloroformates (e.g.; R4OCOCl) in the presence of an acid scavenger to provide compounds of formula I where Q is NR1 and R1 is
  • Figure US20090312307A1-20091217-C00024
  • Compound 4 may be made to react with certain heteroaryl groups (e.g., heteroaryl-X where X is a leaving group such as a halogen atom) in the presence of an acid scavenger to provide compound 5 where Q is NR1 and R1 is heteroaryl. This reaction is may be performed in an organic solvent such a tetrahydrofuran or acetonitrile at elevated temperatures. Alternatively, this reaction may be performed in the presence of a palladium catalyst to provide compound 5 where Q is NR1 and R1 is heteroaryl.
  • Additional compounds of formula I where R3 is
  • Figure US20090312307A1-20091217-C00025
  • Z1 is O and R5 is —NR6aR7a may be prepared using as described in Scheme 3 and Scheme 4.
  • Figure US20090312307A1-20091217-C00026
  • Referring to Scheme 2, compound 1 may be made to react with diphenyl N-cyanocarbonimidate in a solvent such as tetrahydrofuran, acetonitrile or isopropanol to provide compound 2. Typically this reaction is conducted at elevated temperatures. Compound 2 may be made to react with an amine HNR6R7 to provide cyano guanidine compound 3 where Q is NR1 and R1 is
  • Figure US20090312307A1-20091217-C00027
    • and W is N—CN.
  • Figure US20090312307A1-20091217-C00028
  • Referring to Scheme 3, compound 1 may be made to react with compound 2 to provide sulfenyl urea compound 3 where Q is NR1 and R1 is
  • Figure US20090312307A1-20091217-C00029
  • Compound 2 may be prepared by reacting 2-chloroethanol with chlorosulfonyl isocyanate followed by an amine HNR6R7 in the presence of an acid scavenger such as triethylamine in an organic solvent such as dichloromethane. One skilled in the art will recognize certain sulfenyl ureas may be prepared from commercially available raw materials. For example, compound 1 may be made to react with dimethylsulfamoyl chloride in a solvent such as tetrahydrofuran or dichloromethane in the presence of an acid scavenger such as triethylamine or polystyrene-diisopropylethylamine resin to provide compound 3 where Q is NR1 and R1 is
  • Figure US20090312307A1-20091217-C00030
  • and R6 and R7 are each methyl. Compound 1 may be made to react with sulfamide in a solvent such as 1,4-dioxane at elevated temperature to provide compound 3 where Q is NR1 and R1 is
  • Figure US20090312307A1-20091217-C00031
  • and R6 and R7 are each hydrogen.
  • Compounds of formula I where J is C1-alkylene (e.g.; CH2), R3 is
  • Figure US20090312307A1-20091217-C00032
  • Z1 is O and R5 is —NR6aR7a may be prepared using as described in Scheme 5.
  • Figure US20090312307A1-20091217-C00033
  • The carboxylic acid compound 1 may be treated with thionyl chloride to convert the carboxylic acid to the acid chloride that is made to react with diazomethane in a solvent such as ethyl ether to produce a diazo intermediate compound 2. Compound 2 may be irradiated under ultra-violet light (λ=365 mM) in a solvent such as methanol to provide an ester that may be hydrolyzed to the carboxylic acid compound 3 by treatment with aqueous lithium hydroxide. The carboxylic acid moiety of compound 3 may be coupled with an amine HNR6aR7a using a variety of coupling procedures known in the literature to provide carboxamide compound 4. The nitrogen atom of compound 3 may be deprotected and the nitrogen atom further derivatized (see Schemes 1-3) to provide compounds of formula I.
  • Compounds of formula I where J is a bond, R3 is
  • Figure US20090312307A1-20091217-C00034
  • Z1 is O, R5 is —N6aR7a and R8a is hydrogen may be prepared using as described in Scheme 6.
  • Figure US20090312307A1-20091217-C00035
  • Compound 1 may be made to react with diphenylphosphoryl azide in a solvent such as chlorobenzene at an elevated temperature to produce isocyanate compound 2. Compound 2 may be made to react with an amine HNR6aR7a to produce the urea compound 3 where J is a bond, R3 is
  • Figure US20090312307A1-20091217-C00036
  • Z1 is O, R5 is NR6aR7a and R8a is hydrogen.
  • Compounds of formula I where J is a bond, R3 is
  • Figure US20090312307A1-20091217-C00037
  • Z1 is O and R8a is hydrogen may be prepared using as described in Scheme 7.
  • Figure US20090312307A1-20091217-C00038
  • Isocyanate compound 1 may be made to react with an alcohol R5OH in a solvent such as chlorobenzene or tetrahydrofuran to provide compound 2 where J is a bond, R3 is
  • Figure US20090312307A1-20091217-C00039
  • Z1 is O and R8a is hydrogen.
  • Compounds of formula I where J is a bond, R3 is
  • Figure US20090312307A1-20091217-C00040
  • Z1 is O, R5 is not NR6aR7a and R8a is hydrogen may be prepared using as described in Scheme 8.
  • Figure US20090312307A1-20091217-C00041
  • Compound 1 (see Scheme 6; R5 is tert-butyl) may be deprotected by treatment with trifluoroacetic acid in a solvent such as dichloromethane to provide amine compound 2. The amino group of compound 2 may be made to react with a carboxylic acid (e.g.; R5CO2H; shown in Scheme 7) in the presence of a coupling agent or an acid chloride (e.g.; R5COCl) in the presence of an acid scavenger such as triethylamine or polystyrene-diisoproplyethylamine resin to give compound 3 where J is a bond, R3 is
  • Figure US20090312307A1-20091217-C00042
  • Z1 is O, R5 is not NR6aR7a and R8a is hydrogen. In addition to carboxylic acids or acid chlorides, one skilled in the art will recognize that compound 2 may be made to react with a number of other readily available raw materials to provide compounds of formula I. For example, compound 2 may be made to react with sulfonyl chlorides (e.g.; R5SO2Cl) in the presence of an acid scavenger to provide compounds of formula I where J is a bond and R3 is
  • Figure US20090312307A1-20091217-C00043
  • Compounds of formula I where R3 is R5, R5 is NR6aR7a and R6a is heteroaryl may be prepared as described in Scheme 9.
  • Figure US20090312307A1-20091217-C00044
  • Amine compound 1 may be made to react with a substituted aryl or heteroaryl compound where X is a halogen atom, triflate or similar leaving group to provide compound 2. This reaction may be conducted in an organic solvent such a tetrahydrofuran or acetonitrile at an elevated temperature. Alternatively, this reaction may be performed in the presence of a palladium catalyst to provide compound 2 where R3 is R5, R5 is NR6aR7a and R6a is heteroaryl.
  • Compounds of formula I where R3 is R5 and R5 is heteroaryl may be prepared as described in Scheme 10 and Scheme 11.
  • Figure US20090312307A1-20091217-C00045
  • Referring to Scheme 9, acid chloride compound 1 may be made to react compound 2 in an organic solvent such as dichloromethane to provide carboxamide compound 3. Cyclization of compound 2 in the presence of an acid such as acetic acid at elevated temperature provides compound 3 where R3 is R5 and R5 is heteroaryl (e.g.; benzimidazole). One skilled in the art will recognize that carboxylic acids or acid chlorides may be converted to a wide variety of heteroaryl groups. For example, compound 1 may be made to react with a 2-amino phenol to provide compounds of formula I where R3 is R5 and R5 is heteroaryl (e.g.; benzoxazole). Compound 1 may be made to react with a 2-amino benzenethiol to provide compounds of formula I where R3 is R5 and R5 is heteroaryl (e.g.; benzthiazole). Compound 1 may be made to react with an N-hydroxyamidine to provide compounds of formula 3 where R3 is R5 and R5 is heteroaryl (e.g.; oxadiazole).
  • Figure US20090312307A1-20091217-C00046
  • Referring to Scheme 10, cyano compound 1 may be made to react with sodium azide in a solvent such as methyl sulfoxide at elevated temperatures to provide tetrazole compound 2. Compound 2 may be made to react with T1c-X where X is a leaving group such as a halogen atom or triflate to provide compound 3 where R3 is R5 and R5 is heteroaryl (e.g.; tetrazole).
  • Compounds of formula I where R2 is alkyl, cycloalkyl or (aryl)alkyl may be prepared as described in Scheme 12.
  • Figure US20090312307A1-20091217-C00047
  • Protection of the nitrogen atom of compound 1 provides compound 2. Deprotonation of compound 2 with a base such as lithium diisopropylamide in an organic solvent such as tetrahydrofuran a low temperature followed by reaction with a benzyl halide, for example, provides compound 3 where R2 is (aryl)alkyl. One skilled in the art will recognize that aldehydes and ketone may also be made to react with compound 2 after deprotonation with lithium diisopropylamide. The cyano group of compound 3 may be reduced with lithium aluminum hydride in a solvent such as tetrahydrofuran to provide amino compound 4. Alternatively, the cyano group of compound 3 may be hydrolyzed with aqueous sodium hydroxide to provide carboxylic acid compound 5. Compounds of formula I may be prepared from compounds 4 and 5 as described previously.
  • Figure US20090312307A1-20091217-C00048
  • Compounds of the formula 1 where p=3>m=2, Q=NR1, R2=aryl may be prepared as described in Scheme 13. The lactam was prepared from intermediate cyclohexanone which was synthesized as described in J. Med. Chem., 821 (1998). The lactam nitrogen was protected using standard protecting group methodology and the lactam carbonyl group and the nitrile group were reduced either simultaneously or subsequently. The primary amine was acylated, the protecting group was removed and the azapene was further functionalized to the sulfinyl urea, the carbamate, the amide or alkylated directly.
  • Figure US20090312307A1-20091217-C00049
  • Compounds of formula I where Q is O, R3 is
  • Figure US20090312307A1-20091217-C00050
  • Z1 is O, and R8a is hydrogen may be prepared as described in Scheme 14. Compound 1 may be made to react with bis(2-chloroethyl)ether under phase-transfer catalysis conditions to provide the cyclized product compound 2. The nitrile group of compound 2 may be reduced using various methods, including treatment with lithium aluminum hydride or hydrogenation in the presence of platinum (IV) oxide, to provide the amine compound 3. The amino group of compound 3 may be made to react with a carboxylic acid (e.g.; R5CO2H) in the presence of a coupling agent in an organic solvent such as tetrahydrofuran to provide the acylated product compound 4.
  • Additional compounds within the scope of the present invention can be prepared from the compounds obtained by the above described methods through conversion of the substituent groups to other functionality by the usual methods of chemical synthesis, as illustrated in the following examples.
  • Compounds of formula I that contain chiral centers may be obtained in non-racemic form by non-racemic synthesis or resolution by methods well known to those skilled in the art. Compounds that are non-racemic are designated as “chiral” in the examples.
  • In the examples described below it may be necessary to protect reactive functionality such as hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in reactions. The introduction and removal of protecting groups are well known to those skilled in the art, for example see (Greene, T. W. in Protective Groups in Organic Synthesis, John Wiley and Sons, publ. (1991)).
    • UTILITY
  • Compounds within the scope of the present invention inhibit the Kv1 subfamily of voltage-gated K+ channels, and as such are useful in the treatment and/or prevention of various disorders: cardiac arrhythmias, including supraventricular arrhythmias, atrial arrhythmias, atrial flutter, atrial fibrillation, complications of cardiac ischemia, and use as heart rate control agents; angina pectoris including relief of Prinzmetal's symptoms, vasospastic symptoms and variant symptoms; gastrointestinal disorders including reflux esophagitis, functional dyspepsia, motility disorders (including constipation and diarrhea), and irritable bowel syndrome; disorders of vascular and visceral smooth muscle including asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, peripheral vascular disease (including intermittent claudication), venous insufficiency, impotence, cerebral and coronary spasm and Raynaud's disease; inflammatory and immunological disease including inflammatory bowel disease, rheumatoid arthritis, graft rejection, asthma, chronic obstructive pulmonary disease, cystic fibrosis and atherosclerosis; cell proliferative disorders including restenosis and cancer (including leukemia); disorders of the auditory system; disorders of the visual system including macular degeneration and cataracts; diabetes including diabetic retinopathy, diabetic nephropathy and diabetic neuropathy; muscle disease including myotonia and wasting; peripheral neuropathy; cognitive disorders; migraine; memory loss including Alzheimer's and dementia; CNS mediated motor dysfunction including Parkinson's disease, and ataxia; epilepsy; and other ion channel mediated disorders.
  • As inhibitors of the Kv1 subfamily of voltage-gated K+ channels compounds of the present invention are useful to treat a variety of disorders including resistance by transplantation of organs or tissue, graft-versus-host diseases brought about by medulla ossium transplantation, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes uveitis, juvenile-onset or recent-onset diabetes mellitus, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, infectious diseases caused by pathogenicmicroorganisms, inflammatory and hyperproliferative skin diseases, psoriasis, atopical dermatitis, contact dermatitis, eczematous dermatitises, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergies, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or inveterate asthma, late asthma and airway hyperresponsiveness, bronchitis, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns and leukotriene B4-mediated diseases, Coeliaz diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Good-pasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy, multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis, fibroid-lung, idiopathic interstitial pneumonia, dermatomyositis, leukodermia vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T cell lymphoma, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis, scleroderma, Wegener's granuloma, Sjögren's syndrome, adiposis, eosinophilic fascitis, lesions of gingiva, periodontium, alveolar bone, substantia osses dentis, glomerulonephritis, male pattern alopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth, muscular dystrophy; Pyoderma and Sezary's syndrome, Addison's disease, ischemia-reperfusion injury of organs which occurs upon preservation, transplantation or ischemic disease, endotoxin-shock, pseudomembranous colitis, colitis caused by drug or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer, pulmonary emphysema, cataracta, siderosis, retinitis, pigentosa, senile macular degeneration, vitreal scarring, corneal alkali burn, dermatitis erythema multiforme, linear IgA ballous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenis, metastatis of carcinoma and hypobaropathy, disease caused by histamine or leukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis sclerosing cholangitis, partial liver resection, acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock, or anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholic cirrhosis, hepatic failure, fulminant hepatic failure, late-onset hepatic failure, “acute-on-chronic” liver failure, augention of chemotherapeutic effect, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, trauma, and chronic bacterial infection.
  • The compounds of the present invention are anti-arrhythmic agents which are useful in the prevention and treatment (including partial alleviation or cure) of arrhythmias. As inhibitors of Kv1.5 compounds within the scope of the present invention are particularly useful in the selective prevention and treatment of supraventricular arrhythmias such as atrial fibrillation, and atrial flutter. By “selective prevention and treatment of supraventricular arrhythmias” is meant the prevention or treatment of supraventricular arrhythmias wherein the ratio of the prolongation of the atrial effective refractory period to the prolongation of the ventricular effective refractory period is greater than 1:1. This ratio is preferably greater than 4:1, more preferably greater than 10:1, and most preferably such that prolongation of the atrial effective refractory response period is achieved without significantly detectable prolongation of the ventricular effective refractory period.
  • In addition, the compounds within the scope of the present invention block IKur, and thus may be useful in the prevention and treatment of all IKur-associated conditions. An “IKur-associated condition” is a disorder which may be prevented, partially alleviated or cured by the administration of an IKur blocker. The Kv1.5 gene is known to be expressed in stomach tissue, intestinal/colon tissue, the pulmonary artery, and pancreatic beta cells. Thus, administration of an IKur blocker could provide useful treatment for disorders such as: reflux esophagitis, functional dyspepsia, constipation, asthma, and diabetes. Additionally, Kv1.5 is known to be expressed in the anterior pituitary. Thus, administration of an IKur blocker could stimulate growth hormone secretion. IKur inhibitors can additionally be useful in cell proliferative disorders such as leukemia, and autoimmune diseases such as rheumatoid arthritis and transplant rejection.
  • The present invention thus provides methods for the prevention or treatment of one or more of the aforementioned disorders, comprising the step of administering to a subject in need thereof an effective amount of at least one compound of the present invention. Other therapeutic agents such as those described below may be employed with the inventive compounds in the present methods. In the methods of the present invention, such other therapeutic agent(s) may be administered prior to, simultaneously with or following the administration of the compound(s) of the present invention.
  • The present invention also provides pharmaceutical compositions comprising at least one of the compounds of the present invention or salts thereof capable of preventing or treating one or more of the aforementioned disorders in an amount effective therefore and a pharmaceutically acceptable vehicle or diluent. The compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
  • The compounds of the present invention may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. The present compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. In the case where the compounds of formula I are being administered to prevent or treat arrhythmias, the compounds may be administered to achieve chemical conversion to normal sinus rhythm, or may optionally be used in conjunction with electrical cardioconversion.
  • Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The compounds of formula I may also be delivered through the oral cavity by sublingual and/or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used. Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (AVICEL®) or polyethylene glycols (PEG). Such formulations may also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g., Carbopol 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
  • Exemplary compositions for nasal aerosol or inhalation administration include solutions in saline which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
  • Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono or diglycerides, and fatty acids, including oleic acid.
  • Exemplary compositions for rectal administration include suppositories which may contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).
  • The effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for an adult human of from about 0.001 to 100 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats and the like, subject to the aforementioned disorders.
  • The compounds of the present invention may be employed alone or in combination with each other and/or other suitable therapeutic agents useful in the treatment of the aforementioned disorders or other disorders, including: other anti-arrhythmic agents such as Class I agents (e.g., propafenone), Class II agents (e.g., carvadiol and propranolol), Class III agents (e.g., sotalol, dofetilide, amiodarone, azimilide and ibutilide), Class IV agents (e.g., diltiazem and verapamil), 5HT antagonists (e.g., sulamserod, serraline and tropsetron), and dronedarone; calcium channel blockers (both L-type and T-type) such as diltiazem, verapamil, nifedipine, amlodipine and mybefradil; Cyclooxygenase inhibitors (i.e., COX-1 and/or COX-2 inhibitors) such as aspirin, indomethacin, ibuprofen, piroxicam, naproxen, CELEBREX®, VIOXX® and NSAIDs; anti-platelet agents such as GPIIb/IIIa blockers (e.g., abciximab, eptifibatide and tirofiban), P2Y12 antagonists (e.g., clopidogrel, ticlopidine and CS-747), thromboxane receptor antagonists (e.g., ifetroban), aspirin, and PDE-III inhibitors (e.g., dipyridamole) with or without aspirin; diuretics such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, and spironolactone; anti-hypertensive agents such as alpha adrenergic blockers, beta adrenergic blockers, calcium channel blockers, diuretics, renin inhibitors, ACE inhibitors, (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), A II antagonists (e.g., losartan, irbesartan, valsartan), ET antagonists (e.g., sitaxseltan, atrsentan and compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compounds disclosed in WO 00/01389), neutral endopeptidase NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat and geinopatrilat), nitrates, and combinations of such anti-hypertensive agents; antithrombotic/thrombolytic agents such as tissue plasminogen activator (tPA), recombinant tPA, tenecteplase (TNK), lanoteplase (nPA), factor VIIa inhibitors, factor Xa inhibitors, thrombin inhibitors (e.g., hirudin and argatroban), PAI-1 inhibitors (i.e., inactivators of tissue plasminogen activator inhibitors), α2-antiplasmin inhibitors, streptokinase, urokinase, prourokinase, anisoylated plasminogen streptokinase activator complex, and animal or salivary gland plasminogen activators; anticoagulants such as warfarin and heparins (including unfractionated and low molecular weight heparins such as enoxaparin and dalteparin); HMG-CoA reductase inhibitors such as pravastatin lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin); other cholesterol/lipid lowering agents such as squalene synthetase inhibitors, fibrates, and bile acid sequestrants (e.g., QUESTRAN®); antiproliferative agents such as cyclosporin A, TAXOL®, FK 506, and adriamycin; antitumor agents such as TAXOL®, adriamycin, epothilones, cisplatin and carboplatin; anti-diabetic agents such as biguanides (e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulins, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide and glipizide), biguanide/glyburide combinations (i.e., GLUCOVANCE®), thiozolidinediones (e.g., troglitazone, rosiglitazone and pioglitazone), PPAR-gamma agonists, aP2 inhibitors, and DP4 inhibitors; thyroid mimetics (including thyroid receptor antagonists) (e.g., thyrotropin, polythyroid, KB-130015, and dronedarone); Mineralocorticoid receptor antagonists such as spironolactone and eplerinone; growth hormone secretagoges; anti-osteoporosis agents (e.g., alendronate and raloxifene); hormone replacement therapy agents such as estrogen (including conjugated estrogens in premarin), and estradiol; antidepressants such as nefazodone and sertraline; antianxiety agents such as diazepam, lorazepam, buspirone, and hydroxyzine pamoate; oral contraceptives; anti-ulcer and gastroesophageal reflux disease agents such as famotidine, ranitidine, and omeprazole; anti-obesity agents such as orlistat; cardiac glycosides including digitalis and ouabain; phosphodiesterase inhibitors including PDE III inhibitors (e.g., cilostazol), and PDE V inhibitors (e.g., sildenafil); protein tyrosine kinase inhibitors; steroidal anti-inflammatory agents such as prednisone, and dexamethasone; and other anti-inflammatory agents such as ENBREL®.
  • The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
  • Assays to determine the degree of activity of a compound as an IKur inhibitor are well known. in the art and are described in references such as J. Gen. Physiol, 101(4):513-543 (April 1993), and Br. J. Pharmacol., 115(2):267-274 (May 1995).
  • Assays to determine the degree of activity of a compound as an inhibitor of other members of the Kv1 subfamily are also well known in the art. For example, inhibition of Kv1.1, Kv1.2 and Kv 1.3 can be measured using procedures described by Grissmer, S. et al., Mol. Pharmacol, 45(6): 1227-1234 (June 1994). Inhibition of Kv1.4 can be measured using procedures described by Petersen, K. R, et al., Pflugers Arch., 437(3):381392 (February 1999). Inhibition of Kv1.6 can be measured using procedures described by Bowlby, M. R. et al., J. Neurophysiol., 73(6):2221-2229 (June 1995). And inhibition of Kv1.7 can be measured using procedures described by Kalmaii, K. et al., J. Biol. Chem., 273(10):5851-5857 (Mar. 6, 1998).
  • Compounds within the scope of the present invention demonstrate activity in Kv1 assays such as the ones described above.
  • All documents cited in the present specification are incorporated herein by reference in their entirety.
  • The following examples and preparations describe the manner and process of making and using the invention and are illustrative rather than limiting. It is to be understood that there may be other embodiments which fall within the spirit and scope of the invention as defined by the claims appended hereto.
    • EXAMPLES Example 1
  • Figure US20090312307A1-20091217-C00051
    • 2-Methoxy-N-(4-thiophen-2-yl-piperidin-4-ylmethyl)-benzamide Synthesis
  • Figure US20090312307A1-20091217-C00052
  • Compound 1: Compound 1 is commercially available.
  • Compound 2: Compound 1 (20 g, 0.11 mol) was suspended in 200 mL dichloromethane. Benzoylchloride (17 mL, 0.14 mol) was added. At 0° C. TEA (42 mL, 0.30 mol) in dichloromethane (10 mL) was added slowly to the reaction mixture. The reaction mixture was stirred at room temperature for 14 h, diluted with ethyl acetate (500 mL), washed with saturated NaHCO3 (2×250 mL), 1N HC (2×250 mL), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using hexanes/ethyl acetate (4/1, 1/1) as eluent to give an orange oil compound 2, 25.85 g (94% yield).
  • Compound 3: NaH (6.0 g, 0.25 mol) was suspended in DMF (100 mL). At 0° C. 2-thiopheneacetonitrile (7.5 g, 0.061 mol) was added followed by the addition of compound 2 (12 g, 0.048 mol) in 100 mL DMF. The reaction was stirred at 0° C. for 0.5 h and then at ambient temperature for 14 h. The reaction mixture was poured into ice and extracted with ethyl acetate (250 mL). The aqueous layer was extracted with ethyl acetate (2×250 mL). The organic layers were combined and washed with 10% LiCl (2×200 mL), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel flash chromatography eluted with 2/1 and 1/1 hexane:ethyl acetate yielding 9.14 g (64% isolated yield) of compound 3 as a dark brown solid. HPLC Rt 2.87 min, Purity 100%, YMC S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220 nm. LCMS Rt 1.47 min, [M+1] 297.22 PHENOMENEX® S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) UV detection at 220 nm. H NMR (CDCl3) 1.74-2.32 ppm, 4H, m; 3.22-3.43 ppm, 2H, m; 3.78-3.84 ppm, 1H, broadpeak; 4.79 ppm, 1H, broad peak; 6.94 ppm, 1H, dd, J=5.0 Hz and 3.6 Hz; 7.08 ppm, 1H, dd, J=3.3 Hz and 1.1 Hz; 7.24 ppm, 1H, dd, J=5.0 Hz and 1.1 Hz; 7.34-7.42 ppm, 5H, m.
  • Compound 4: To a solution of compound 3 (2.1 g, 7.2 mmol) in THF (40 mL) was added LAH (20 mL, 20 mmol, 11.0M solution in THF). The reaction mixture was heated to reflux for 1 h then allowed to cool to ambient temperature. The solution was cooled to 0° C. and quenched with water (5.3 mL), 1N NaOH (3.4 mL) and water (5.3 mL). The quenched reaction mixture was stirred at ambient temperature for 0.5 h. The slurry was filtered through a CELITE® pad and the filtrate was concentrated. The residue was diluted with EtOAc (200 ml), washed with saturated NaHCO3 (2×100 mL), dried over MgSO4, filtered and concentrated to give a brown oil compound 4 sufficiently pure to be taken on to the next step. HPLC Rt 0.20 min and 0.59 min, Purity 100%, YMC S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220 nm. LCMS Rt 0.73 min, [M+1] 287.39 PHENOMENEX® S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TEA) UV detection at 220 nm. H NMR (CDCl3) 1.85 ppm, 2H, m; 2.05 2.08 ppm, 2H, m; 2.22-2.27 ppm, 2H, m; 2.67 ppm, 1H, s; 2.69 ppm, 2H, m; 3.44 ppm, 2H, s; 6.77-6.78 ppm, 1H, m; 6.94 ppm, 1H, dd, J=5.0 Hz and 33 Hz; 7.17-7.30 ppm, 6H, m.
  • Compound 5: Compound 4 was dissolved in dichloromethane (30 mL) and ortho-anisoyl chloride (1.1 mL, 7.4 mmol) was added followed by the addition of TEA (2.3 mL, 16 mmol). The reaction was stirred at ambient temperature for 14 h, diluted with dichloromethane (200 mL), washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated. The product amide compound 5 was eluted with 2:1 and 1:1 hexane:ethylacetate as a white foam (2.19 g, 77% yield for two steps). HPLC Rt 2.50 min, Purity 100%, YMC SS column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220 nm. LCMS Rt 1.36 min, [M+1] 421.27 PHENOMENEX® S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) L detection at 220 nm. H NMR (CD3OD) 1.98-2.00 ppm, 2H, m; 2.15-2.18 ppm, 2H, m; 2.44 ppm, 2H, m; 2.74-2.76 ppm, 2H, m; 3.53 ppm, 2H, s; 3.65 ppm, 2H, s; 3.77 ppm, 3H, s; 7.02-7.09 ppm, 4H, m; 7.25-7.31 ppm, 5H, m; 7.39-7.40 ppm, 1H, m; 7.45-7.48 ppm, 1H, m; 7.93-7.95 ppm, 1H, m.
  • Compound 6: Compound 5 (2.2 g, 5.2 mmol) was dissolved in dichloroethane (40 mL) and TEA (3.6 mL, 26 mmol) was added. At 0° C. chloroethyl chloroformate (1.1 mL, 10 mmol) in dichloroethane (20 mL) was added. The reaction mixture was stirred at ambient temperature for 1 h, then another 1.1 mL chloroethyl chloroformate in dichloroethane (20 mL) was added. The reaction was stopped till no starting material left according to LC-MS. The reaction mixture was concentrated and dried on oil pump for 0.5 h. MeOH (40 mL) was added to the residue and was heated to reflux for 4 h. The reaction mixture was concentrated and the residue was purified by a silica gel pad eluted with 1:1 EtOAc:hexane and then 1:1 MeOH:DCM yielding a pale yellow solid 2-methoxy-N-(4-thiophen-2-yl-piperidin-4-ylmethyl)-benzamide 6 (1.63 g, 95% yield). HPLC Rt 2.09 min, Purity 100%, YMC S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220 nm. LCMS Rt 1.20 min, [M+1] 331.41 PHENOMENEX® S5 column. 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) UV detection at 220 nm. H NMR (CDCl3) 2.01-2.04 ppm, 2H, m; 2.14-2.18 ppm, 2H, m; 2.92-2.94 ppm, 2H, m; 3.16 ppm, 2H, m; 3.64 ppm, 2H, s; 3.67 ppm, 3H, s; 6.82-6.86 ppm, 2H, m; 6.96-7.00 ppm, 2H, m; 7.23-7.25 ppm, 1H, m; 7.32-7.37 ppm, 1H, m; 8.09-8.11 ppm, 1H, m.
    • Example 2
  • Figure US20090312307A1-20091217-C00053
    • 4-[(2-Methoxy-benzoylamino)-methyl]-4-thiophen-2-yl-piperidine-1-carboxylic acid ethyl ester Synthesis
  • Figure US20090312307A1-20091217-C00054
  • Compound 1: Compound 1 was prepared using methodology described in Example 1.
  • Compound 2; Compound 1 (14 mg, 0.043 mmol) was dissolved in dichloromethane (0.20 mL). At ambient temperature TEA (12 μL, 0.086 mmol) was added followed by the addition of ethyl chloroformate (4.90 mg, 0.045 mmol) in dichloromethane (0.10 mL). The reaction mixture was stirred for 2.5 h and then concentrated. 4-[(2-Methoxy-benzoylamino)-methyl]-4-thiophen-2-yl-piperidine-1-carboxylic acid ethyl ester 2 (13.7 mg, 79% yield) was isolated by Prep-HPLC as a colorless oil. HPLC Rt 3.43 min, Purity 100%, YMC 85 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220 nm. LCMS Rt 1.78 min, [M+1] 403.17 YMC S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) UW detection at 220 nm. H NMR (CDCl3) 1.18 ppm, 3H, t, J=7.1 Hz; 1.81-1.84 ppm, 2H, m; 2.00-2.04 ppm, 2H, in; 3.18-3.25 ppm, 2H, m; 3.67 ppm, 3H, s; 3.73-377 ppm, 4H, m; 4.05 ppm, 2H, q, J=7.1 Hz; 6.83-6.88 ppm, 2H, m; 6.98-7.02 ppm, 2H, m; 7.25 ppm, 1H, dd, J=5.0 Hz and 0.76 Hz; 7.34-7.39 ppm, 1H, m; 7.83 ppm, 1H, m; 8.10 ppm, 1H, dd, J=7.8 Hz and 1.7 Hz.
    • Example 3
  • Example 3 was prepared using methodology described in Example 2.
  • Example Structure Name [M + 1]
    3
    Figure US20090312307A1-20091217-C00055
         		4-[(2-Methoxy-benzoylamino)-methyl]-4- thiophen-2-yl-piperidine-1-carboxylic acid tert-butyl ester 430
    • Example 4
  • Figure US20090312307A1-20091217-C00056
    • 2-Methoxy-N-[1-(propane-1-sulfonyl)-4-thiophen-2-yl-piperidin-4-ylmethyl]-benzamide Synthesis
  • Figure US20090312307A1-20091217-C00057
  • Compound 1: Compound 1 was prepared using methodology described in Example 1.
  • Compound 3: Compound 1 (14 mg, 0.043 mmol) was dissolved in dichloromethane (0.20 mL). At ambient temperature TEA (12 μL, 0.086 mmol) was added followed by the addition of propyl sulfonylchloride (6.4 mg, 0.045 mmol) in dichloromethane (0.10 mL). The reaction mixture was stirred for 1 h and then concentrated. 2-Methoxy-N-[1-(propane-1-sulfonyl)-4-thiophen-2-yl-piperidin-4-ylmethyl]-benzamide (14.5 mg, 77% yield) was isolated by Prep-HPLC as a colorless oil. HPLC Rt 3.21 min, Purity 100%, YMC S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220 nm. LCMS Rt 1.67 min, [M+1] 437.15 YMC S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) UV detection at 220 nm. H NMR (CDCl3) 0.97 ppm, 3H, t, J=7.5 Hz; 1.73-1.79 ppm, 2H, in; 1.92-1.98 ppm, 2H, m; 2.09-2.14 ppm, 2H, m; 2.78-2.82 ppm, 2H, m; 3.19-3.25 ppm, 2H, m; 3.40-3.45 ppm, 2H, m; 3.66 ppm, 3H, s; 3.71 ppm, 2H, d, J=6.2 Hz; 6.84-6.88 ppm, 2H, m; 6.99-7.03 ppm, 2H, m; 7.27 ppm, 1H, dd, J=5.0 Hz and 0.74 Hz; 7.37-7.41 ppm, 1H, m; 7.98 ppm, 1H, m; 8.07 ppm, 1H, dd, J=7.8 Hz and 1.8 Hz.
    • Examples 5 and 6
  • Examples 5 and 6 were synthesized using methodology described in Example 4.
  • Example Structure Name [M + 1]
    5
    Figure US20090312307A1-20091217-C00058
         		N-(1-Benzenesulfonyl-4-thiophen-2-yl- piperidin-4-ylmethyl)-2-methoxy- benzamide 470
    6
    Figure US20090312307A1-20091217-C00059
         		N-[1-(4-Fluoro-benzenesulfonyl)-4- thiophen-2-yl-piperidin-4-ylmethyl]-2- methoxy-benzamide 488
    • Example 7
  • Figure US20090312307A1-20091217-C00060
    • 2-Methoxy-N-[4-thiophen-2-yl-1-(2,2,2-trifluoro-ethylsulfamoyl)-piperidin-4-ylmethyl]-benzamide Synthesis
  • Figure US20090312307A1-20091217-C00061
  • Compound 1: Compound 1 is commercially available.
  • Compound 2: Compound 2 is commercially available.
  • Compound 3: Compound 1 (26 mg, 0.18 mmol) was dissolved in dichloromethane (0.50 mL). At 0° C. compound 2 (15 mg, 0.18 mmol) in dichloromethane (0.50 mL) was added and the reaction mixture was stirred for 1 h. Trifluoroethylamine (18 mg, 0.18 mmol) in dichloromethane (0.50 mL) was added followed by the addition of TEA (75 μL>, 0.54 mmol). The reaction mixture was stirred at ambient temperature for 2 h and then at 35° C. for 14 h. The reaction was diluted with dichloromethane (20 mL), washed with 1N HCl (10 mL), dried over MgSO4, filtered and concentrated to yield compound 3 sufficient pure to be taken to the next step.
  • Compound 4: Compound 4 was prepared using methodology described in Example 1.
  • Title Compound: Compound 4 (20 mg, 0.060 mmol) and TEA (130 μl 0.94 mmol) were dissolved into acetonitrile (1.0 mL). To this mixture compound 3 was added and the reaction mixture was heated at 95° C. for 14 h. The reaction was concentrated and the residue was purified by Prep HPLC yielding 2-methoxy-N-[4 thiophen-2-yl-1-(2,2,2-trifluoro-ethylsulfamoyl)-piperidin-4-ylmethyl]-benzamide (17.2 mg, 58% yield) as a clear oil. HPLC Rt 3.25 min, Purity 100%, YMC S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220 nm. LCMS Rt 1.66 min, [M+1] 492.14 YMC S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) UV detection at 220 nm. H NMR (CDCl3) 1.94-1.96 ppm, 2H, m; 2.01-2.12 ppm, 2H, m; 3.11-3.13 pm, 2H, m; 3.43 ppm, 2H, m; 3.56-3.59 ppm, 2H, m; 3.64 ppm, 2H, s; 3.66 ppm, 3H, s; 4.95 ppm, 1H, t, J=5.7 Hz; 6.85-6.86 ppm, 2H, m; 6.99-7.00 ppm, 2H, m; 7.25-7.26 ppm, 1H, m; 7.35-7.36 ppm, 1H, m; 7.75-7.78 ppm, 1H, m; 8.12 ppm, 1H, dd, J=6.2 Hz and 1.3 Hz.
    • Examples 8 to 14
  • Examples 8 to 14 were prepared using methodology described in Example 7.
  • Example Structure Name [M + 1]
    8
    Figure US20090312307A1-20091217-C00062
         		N-(1-Dimethylsulfamoyl-4-thiophen-2-yl- piperidin-4-ylmethyl)-2-methoxy- benzamide 437
    9
    Figure US20090312307A1-20091217-C00063
         		N-[1-(4-Fluoro-benzylsulfamoyl)-4- thiophen-2-yl-piperidin-4-ylmethyl]-2- methoxy-benzamide 517
    10
    Figure US20090312307A1-20091217-C00064
         		(4-Fluoro-benzyl)-carbamic acid 2-{4-[(2- methoxy-benzoylamino)-methyl]-4- thiophen-2-yl-piperidine-1- sulfonylamino}-ethyl ester 604
    11
    Figure US20090312307A1-20091217-C00065
         		2-Methoxy-N-(1-phenylsulfamoyl-4- thiophen-2-yl-piperidin-4-ylmethyl)- benzamide 485
    12
    Figure US20090312307A1-20091217-C00066
         		2-Methoxy-N-(1-methylsulfamoyl-4- thiophen-2-yl-piperidin-4-ylmethyl)- benzamide 423
    13
    Figure US20090312307A1-20091217-C00067
         		N-{1-[1-(4-Fluoro-phenyl)- ethylsulfamoyl]-4-thiophen-2-yl- piperidin-4-ylmethyl}-2-methoxy- benzamide 531
    14
    Figure US20090312307A1-20091217-C00068
         		2-Methoxy-N-(1-propylsulfamoyl-4- thiophen-2-yl-piperidin-4-ylmethyl)- benzamide 451
    • Example 15
  • Figure US20090312307A1-20091217-C00069
    • 2-Methoxy-N-(4-phenyl-1-sulfamoyl-piperidin-4-ylmethyl)-benzamide Synthesis
  • Figure US20090312307A1-20091217-C00070
  • Compound 1: Compound 1 is commercially available.
  • Compound 2: To 1-N-benzyl-4-phenyl-4-cyanopiperidine.HCl (10.0 g, 31.97 mmol) was added 220 mL of THF and the reaction flask was cooled to 0° C. Lithium aluminum hydride (4.85 g, 127.86 mmol) was added slowly and the reaction mixed 12 h at room temperature. The reaction was quenched by the addition of 5 mL of water, 15 mL of 15% aqueous solution of sodium hydroxide followed by 5 mL of water. The organic fraction was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give compound 2 that was used without further purification. LCMS Rt 1.70 min, [M+1] 281.0.
  • Compound 3: To a solution of 1N-benzyl-4-phenyl-4-aminomethylpiperidine (4.0 g, 14.26 mmol) and triethylamine (3.0 g, 21.39 mmol) in 18 mL of dichloromethane was added oanisoyl chloride (425 μL, 2.85 mmol) at 0° C. The reaction was stirred for 12 h and quenched with (100 mL) of 1 M hydrochloric acid. Dichoromethane (100 mL) was also added and the aqueous layer was washed with dichloromethane (50 mL portions, 2×). The organic fractions were combined and washed with 1 N sodium hydroxide (50 mL portions, 2×) followed by brine (100 mL). The organics were dried over anhydrous sodium sulfate and concentrated. 4.54 g (77% yield) of compound 3 was obtained. LCMS Rt 1.41 min, [M+1] 415.1.
  • Compound 4: To a solution of N-(1-benzyl-4-phenyl-piperidin-4-ylmethyl)-benzamide (4.54 g, 10.95 mmol) in ethanol (100 mL) was added 10% palladium/carbon (1.40 g). The reaction mixture was stirred in a hydrogen atmosphere (50 psi) for 78 h. After filtration, the filtrate was concentrated and purified using column chromatography o silica gel using 9:1:0.1 chloroform:methanol:ammonium hydroxide as the eluent to give a yellow oil. After lyophilization 2.7 g (76% yield) of compound 4 as a white/yellow powdery solid was obtained. LCMS Rt 1.43 min, [M+1] 325.3.
  • Title Compound: To compound 4 (50 mg, 0.154 mmol) in 1,4-dioxane (1.7 mL) was added sulfamide (148 mg, 1.54 mmol) and then stirred at 100° C. overnight. The solution was cooled to room temperature and the solvent was concentrated under reduced pressure. The crude material was diluted with dichloromethane (10 mL) and washed with water (10 mL) (2×), brine (10 mL) (1×) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a white solid. The crude was purified using preparative HPLC and lyophilized to give 54 mg (87% yield) of 2-methoxy-N-(4-phenyl-1-sulfamoyl-piperidin-4-ylmethyl)-benzamide. 1H NMR (CDCl3, rt): δ ppm) 2.11-2.19 (2H, m), 2.22-2.25 (2H, m), 3.24-3.26 (2H, m), 3.35-3.38 (2H, m), 3.57 (3H, s), 3.67 (2H, d, J=6 Hz), 4.43 (2H, s), 6.86 (1H, d, J=8.3 Hz), 7.05 (1H, t, J=7.5 Hz), 7.30-7.45 (6H, m), 7.63 (1H, s), 8.16 (1H, d, J=7.5). LCMS Rt 1.50 min, [M+1] 404.2.
    • Example 16
  • Figure US20090312307A1-20091217-C00071
    • N-(1-Dimethylsulfamoyl-4-phenyl-piperidin-4-ylmethyl)-2-methoxy-benzamide Synthesis
  • Figure US20090312307A1-20091217-C00072
  • Compound 1: Compound 1 was prepared as described in Example 15.
  • Title Compound: To compound 1 (35 mg, 0.1080 mmol) in tetrahydrofuran (1.5 mL) was added polystrene-diisopropylethylamine resin (394 mg, 1.4 mmol) and dimethylsulfamoyl chloride (35 μL, 0.324 mmol). The reaction was mixed overnight at room temperature. Excess dimethylsulfamoyl chloride (35 μL, 0.324 mmol) was added to the reaction to drive it to completion To the reaction was added AP-Trisamine (232 mg, 0.972 mmol) and the reaction mixed for 6 hr at room temperature. After filtration, the solvent was concentrated under reduced pressure. The crude material was purified using the preparative HPLC and lyophilized to give N-(1-dimethylsulfiamoyl-4-phenyl-piperidin-4-ylmethyl)-2-methoxy-benzamide 34.5 mg (73% yield). 1H NMR (CDCl3, rt): δ ppm) 1.94-1.99 (2H, m), 2.01-2.67 (2H, m), 2.79 (6H, s), 3.16-3.24 (2H, m), 3.42-3.5 (2H, m), 3.58 (3H, s), 3.74 (2H, d, J=6.3 Hz), 6.86 (1H, d, J=8.1 Hz), 7.05 (1H, t, J=7.5 Hz), 7.29-7.46 (6H, m), 7.59 (1H, s), 8.18 (1H, dd, J=1.7, 7.8 Hz). LCMS Rt 1.36 min, [M+1] 432.3.
    • Example 17
  • Figure US20090312307A1-20091217-C00073
    • 2-Methoxy-N-[1-(2-methoxy-ethylsulfamoyl)-4-phenyl-piperidin-4-ylmethyl]-benzamide Synthesis
  • Figure US20090312307A1-20091217-C00074
  • Compound 1: Compound 1 is commercially available.
  • Compound 2: Compound 2 is commercially available.
  • Compound 3: Compound 3 was prepared using methodology described in Example 7 using 2-methoxy-ethylamine instead of 2,2,2-trifluoro-ethylamine.
  • Compound 4: Compound 4 was as described in Example 15.
  • Title Compound: 2-Methoxy-N-[1-(2-methoxy-ethylsulfamoyl)-4-phenyl-piperidin-4-ylmethyl]-benzamide was prepared using methodology described in Example 7. 1H NMR (CDCl3 rt): δ ppm) 1.95-2.03 (2H, m), 2.2-2.29 (2H, m), 3.12-3.22 (4H, m), 3.30 (3H, s), 3.41-3.48 (4H, m), 3.58 (3H, s), 3.73 (2H, d, J=6.1 Hz), 4.55 (1H, t, J 5.8, 11.7 Hz), 6.86 (1H, d, J=8.2 Hz), 7.04 (1H, dt, J=0.9, 7.5 Hz), 7.28-7.45 (6H, m), 7.59 (1H, t, J=5.7, 8.65 Hz), 8.17 (1H, dd, J=2.0, 7.85 Hz). LCMS Rt 1.36 min, [M+1] 462.
    • Examples 18 to 22
  • Examples 18 to 22 were prepared using methodology described in Example 17.
  • Example Structure Name M + H
    18
    Figure US20090312307A1-20091217-C00075
         		N-(1-Benzylsulfamoyl-4-phenyl- piperidin-4-ylmethyl)-2-methoxy- benzamide 495
    19
    Figure US20090312307A1-20091217-C00076
         		2-Methoxy-N-(4-phenyl-1- propylsulfamoyl-piperidin-4-ylmethy)- benzamide 447
    20
    Figure US20090312307A1-20091217-C00077
         		N-[1-(4-Fluoro-benzylsulfamoyl)-4- phenyl-piperidin-4-ylmethyl]-2-methoxy- benzamide 513
    21
    Figure US20090312307A1-20091217-C00078
         		N-(1-Allylsulfamoyl-4-phenyl-piperidin- 4-ylmethyl)-2-methoxy-benzamide 445
    22
    Figure US20090312307A1-20091217-C00079
         		N-[1-(2-Hydroxy-ethylsulfamoyl)-4- phenyl-piperidin-4-ylmethyl]-2-methoxy- benzamide 449
    • Example 23
  • Figure US20090312307A1-20091217-C00080
    • 2-Methoxy-N-[1-(2-oxo-oxazolidine-3-sulfonyl)-4-phenyl-piperidin-4-ylmethyl]-benzamide Synthesis
  • Figure US20090312307A1-20091217-C00081
  • Compound 1: Compound 1 was prepared as described in Example 15.
  • Title Compound: A solution of chlorosulfonyl isocyanate (0.12 mL; 1.4 mmol) in dichloromethane (20 mL) was cooled to 0° C. and treated with 2-chloroethanol (0.094 mL; 1.3 mmol. After 2 h a solution of compound 1 (0.42 g; 1.3 mmol) and triethylamine (0.72 mL; 5.2 mmol) in dichloromethane (15 mL) was added dropwise. When the addition was complete the cooling bath was removed and the reaction mixture was allowed to stir at room temperature for 24 h. 20% aqueous hydrochloric acid was added and the organic layer was separated, washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated. The residue was purified by column chromatography on silica gel using 9:1 ethyl acetate:hexane as the eluent to give 0.3 g of 2-methoxy-N-[1-(2-oxo-oxazolidine-3-sulfonyl)-4-phenyl-piperidin-4-ylmethyl]-benzamide as a white solid. LCMS m/z 475 (M+H)+.
    • Example 24
  • Figure US20090312307A1-20091217-C00082
    • Synthesis
  • Figure US20090312307A1-20091217-C00083
  • Compound 1: Compound 1 is commercially available.
  • Compound 2: Trifluoroethylamine (6.6 mg, 0.067 mmol) and compound 1 (16 mg, 0.067 mmol) were added into iPrOH (1.0 mL). The reaction mixture was heated at 95° C. for 6 h.
  • Compound 3: Compound 3 was prepared as described in Example 1.
  • Title Compound: Compound 3 (20 mg, 0.060 mmol) in acetonitrile (0.50 mL) was added to compound 2 in iPrOH. The reaction was heated at 95° C. for 14 h and concentrated. The residue was purified through Prep HPLC to yield the title compound (4.4 mg, 15% yield) as a clear oil. HPLC Rt 3.13 min, Purity 91%, YMC S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220 nm. LCMS Rt 1.62 min, [M+1] 480.18 YMC S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) UV detection at 220 nm. H NMR (CDCl3) 1.91-1.99 ppm, 2H, m; 2.12-2.16 ppm, 2H, m; 3.40-3.47 ppm, 2H, m; 3.65-3.68 ppm, 5H, m; 3.77-3.83 ppm, 2H, m; 3.94-3.97 ppm, 2H, m; 5.32 ppm, 1H, m; 6.85-6.87 ppm, 2H, m; 6.98-7.02 ppm, 2H, m; 7.27 ppm, 1H, dd, J=5.0 Hz and 0.8 Hz; 7.35-7.40 ppm, 1H m; 7.82 ppm, 1H, m; 8.06-8.09 ppm, 1H, m.
    • Example 25
  • Figure US20090312307A1-20091217-C00084
    • Scheme
  • Figure US20090312307A1-20091217-C00085
  • Compound 1: Compound 1 was prepared as described in Example 15.
  • Compound 2: A solution of compound 1 (0.63 g; 1.9 mmol) in anhydrous acetonitrile (20 mL) was treated with diphenyl N-cyanocarbonimidate (0.95 g; 4.0 mmol) and the reaction mixture was heated to 85° C. After 19 h the acetonitrile was removed by evaporation and the residue was portioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated. Column chromatography on silica gel using 7:3 ethyl acetate:hexane as the eluent gave 0.89 g of compound 2 as a white solid. LCMS m/z=470 (M+H)+.
  • Title Compound: Compound 3 (0.1 g; 0.2 mmol) was treated with 7 N ammonia in methanol (1.5 mL) and heated to 45° C. in a sealed tube for 1 h. The methanol and ammonia was removed by evaporation and the residue was portioned between ethyl acetate and 1 N sodium hydroxide. The organic layer was separated, washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated. The crude product was purified by recrystallization from ethyl acetate to give 0.064 g of the title compound as white crystals. LCMS m/z=392 (M+H)+.
    • Examples 26 to 58
  • Examples 26 to 58 were prepared using methodology described in Example 24 and Example 25.
  • Example Structure Name [M + 1]
    26
    Figure US20090312307A1-20091217-C00086
         		519
    27
    Figure US20090312307A1-20091217-C00087
         		473
    28
    Figure US20090312307A1-20091217-C00088
         		439
    29
    Figure US20090312307A1-20091217-C00089
         		411
    30
    Figure US20090312307A1-20091217-C00090
         		392
    31
    Figure US20090312307A1-20091217-C00091
         		421
    32
    Figure US20090312307A1-20091217-C00092
         		501
    33
    Figure US20090312307A1-20091217-C00093
         		407
    34
    Figure US20090312307A1-20091217-C00094
         		435
    35
    Figure US20090312307A1-20091217-C00095
         		449
    36
    Figure US20090312307A1-20091217-C00096
         		461
    37
    Figure US20090312307A1-20091217-C00097
         		433
    38
    Figure US20090312307A1-20091217-C00098
         		437
    39
    Figure US20090312307A1-20091217-C00099
         		447
    40
    Figure US20090312307A1-20091217-C00100
         		431
    41
    Figure US20090312307A1-20091217-C00101
         		515
    42
    Figure US20090312307A1-20091217-C00102
         		447
    43
    Figure US20090312307A1-20091217-C00103
         		463
    44
    Figure US20090312307A1-20091217-C00104
         		435
    45
    Figure US20090312307A1-20091217-C00105
         		439
    46
    Figure US20090312307A1-20091217-C00106
         		465
    47
    Figure US20090312307A1-20091217-C00107
         		426
    48
    Figure US20090312307A1-20091217-C00108
         		426
    49
    Figure US20090312307A1-20091217-C00109
         		421
    50
    Figure US20090312307A1-20091217-C00110
         		408
    51
    Figure US20090312307A1-20091217-C00111
         		391
    52
    Figure US20090312307A1-20091217-C00112
         		484
    53
    Figure US20090312307A1-20091217-C00113
         		460
    54
    Figure US20090312307A1-20091217-C00114
         		495
    55
    Figure US20090312307A1-20091217-C00115
         		511
    56
    Figure US20090312307A1-20091217-C00116
         		445
    57
    Figure US20090312307A1-20091217-C00117
         		463
    58
    Figure US20090312307A1-20091217-C00118
         		487
    • Example 59
  • Figure US20090312307A1-20091217-C00119
    • Synthesis
  • Figure US20090312307A1-20091217-C00120
  • Compound 1: Compound 1 was prepared as described in Example 1.
  • Compound 2: To a solution of compound 1 (3.5 g, 12 mmol) in dry THF (70 mL) was added LAH (35 mL, 35 mmol, 1.0M solution in tetrahydrofuran). The reaction mixture was heated to reflux for 1.5 h then allowed to cool to ambient temperature. The solution was cooled to 0° C. and quenched with water (9.2 mL), 1N NaOH (5.8 mL) and water (9.2 mL). The quenched reaction mixture was stirred at ambient temperature for 0.5 h. The slurry was filtered through a CELITE® pad and the filtrate was concentrated. The residue was diluted with EtOAc (200 mL), washed with saturated NaHCO3 (2×100 mL), dried over MgSO4, filtered and concentrated to give a brown oil. This residue was dissolved in dichloromethane (75 mL) and carbonic acid di-tert-butyl ester (2.9 g, 13 mmol) and TEA (1.8 mL, 13 mmol) were added subsequently. The reaction mixture was stirred at ambient temperature for 18 h and then concentrated. The product compound 2 was purified by flash silica gel chromatography elution with 2:1 hexane:ethylacetate (3.5 g, 75% yield for two steps). HPLC Rt 2.44 min, Purity 100%, YMC S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220 nm. LCMS Rt 1.39 min, [M+1] 387.24 PHENOMENEX® S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) UV detection at 220 nm. H NMR (CDCl3) 1.32 ppm, 9H, s; 1.80 ppm, 2H, m; 1.96 ppm, 2H, m; 2.22 ppm, 2H, m; 2.55-2.58 ppm, 2H, m; 3.21 ppm, 2H, d, J=6.3 Hz; 3.35 ppm, 2H, s; 4.30 ppm, 1H, m; 6.76 ppm, 1H, dd, J=0.8 Hz and 3.4 Hz; 6.90-6.91 ppm, 1H, m; 7.13-7.21 ppm, 6H, m.
  • Compound 3: Compound 2 (1.7 g, 4.5 mmol) was dissolved in dichloroethane (35 mL) and TEA (3.1 mL, 22.4 mmol) was added. At 0° C. chloroethyl chloroformate (0.97 mL, 8.9 mmol) in dichloroethane (17 mL) was added. The reaction mixture was stirred at ambient temperature for 1 h, then another 1.0 mL chloroethyl chloroformate and 3.0 mL TEA were added. The reaction mixture was stirred at ambient temperature for a further 2 h then concentrated and dried under high vacuum for 0.5 h. MeOH (20 mL) was added to the residue and was heated to reflux for 4 h. The reaction mixture was concentrated and the residue was taken directly to the next step.
  • Compound 4: Compound 3 was dissolved in dichloromethane (60 mL). At ambient temperature TEA (1.9 mL, 13.4 mmol) was added followed by the addition of 4-Fluoro-benzenesulfonyl chloride (1.0 g, 5.4 mmol). The reaction mixture was stirred for 18 h and then concentrated. Compound 4 (1.44 g, 71% yield) was isolated as a white solid by column chromatography using 2:1 hexane:EtOAc. HPLC Rt 3.56 min, Purity 100%, YMC S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220 nm. LCMS Rt 1.82 min, [M+23] 477.13 YMC S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) W detection at 220 nm. H NMR (CDCl3) 1.32 ppm, 9H, s; 1.86-1.88 ppm, 2H, m; 2.03-2.06 ppm, 2H, m; 2.70-2.74 ppm, 2H, m; 3.13 ppm, 2H, d, J=6.6 Hz; 3.40-3.42 ppm, 2H, m; 4.30 ppm, 1H, m; 6.70 ppm, 1H, d, J=3.3 Hz; 6.87-6.89 ppm, 1H, m; 7.07-7.10 ppm, 1H, m; 7.13-7.14 ppm, 1H, m; 7.65-7.68 ppm, 2H, m.
  • Compound 5: Compound 4 (55 mg, 0.12 mmol) was dissolved in dichloromethane (1.3 mL). To this solution TFA (180 μL, 2.3 mmol) in dichloromethane (0.50 mL) was added and the reaction was stirred at ambient temperature till no starting material was detected according to LC-MS. The reaction mixture was concentrated and neutralized with TEA. To the concentrated residue was added diphenyl cyanocarbonimidate (32 mg, 0.13 mmol) and isopropyl alcohol (1.0 mL). The reaction mixture was heated to reflux for 18 h.
  • Title Compound: Cyclohexyl amine (19 mg, 0.19 mmol) was added to compound 5 and the reaction was heated at 95° C. for 24 h. The reaction mixture was concentrated and purified by Prep-HPLC YMC ODS S5 20×100 mm, 16 min gradient 40 to 100% MeOH (90% in water 0.1% TFA) at 20 mL/min UV detection at 220 nM to give the title compound as a yellow oil (23.8 mg, 39% yield). HPLC Rt 3.49 min, Purity 100%, YMC S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220 nm. LCMS Rt 1.81 min, [M+1] 504.24 YMC S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) UV detection at 220 nm. H NMR (CDCl3) 1.01-1.24 ppm, 5H, m; 1.56-1.58 ppm, 1H m; 1.66-1.77 ppm, 4H, m; 1.91-1.94 ppm, 2H, m; 2.15-2.18 ppm, 2H, m; 2.75-2.79 ppm, 2H, m; 2.98-3.01 ppm, 1H, m; 3.27 ppm, 2H, d, J=6.1 Hz; 3.45-3.47 ppm, 2H, m; 6.81 ppm, 1H, dd, J=3.9 Hz and 1.1 Hz; 6.98 ppm, 1H, dd, J=3.3 Hz and 4.9 Hz; 7.13-7.19 ppm, 2H, m; 7.25-7.29 ppm, 1H, m; 7.71-7.76 ppm, 2H, m.
    • Examples 60 to 63
  • Examples 60 to 63 were prepared as described in Example 59.
  • Example Structure Name [M + 1]
    60
    Figure US20090312307A1-20091217-C00121
         		435
    61
    Figure US20090312307A1-20091217-C00122
         		477
    62
    Figure US20090312307A1-20091217-C00123
         		541
    63
    Figure US20090312307A1-20091217-C00124
         		505
    • Example 64
  • Figure US20090312307A1-20091217-C00125
    • Synthesis
  • Figure US20090312307A1-20091217-C00126
  • Compound 1: Compound 1 was prepared using methodology described in Example 59.
  • Compound 2: To the solution of compound 1 (500 mg, 1.1 mmol) in dichloromethane (5.0 mL) was added TFA (3.0 mL) in dichloromethane (12 mL) and the reaction was stirred for 1.5 h. Then the mixture was concentrated and neutralized with TEA. At 0° C. 2-chloroethanol (74 μL, 1.1 mmol) in dichlormethane (7.5 mL) was added to the solutions of chlorosulfonyl isocyanate (96 μL, 1.1 mmol) in dichloromethane (7.5 μL). The reaction mixture was stirred at 0° C. for 1 h. The crude amine in dichloromethane (5.0 mL) and TEA (460 μL, 3.3 mmol) were added. The reaction was stirred for 18 h and concentrated. Compound 2 (260 mg, 47% yield) was purified as a white solid by column chromatography using 1:1 hexane:EtOAc. HPLC Rt 2.86 min, Purity 100%, YMC S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220 nm. LCMS Rt 1.48 min, [M+1] 504.08 YMC S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) V detection at 220 nm. H NMR (CDCl3) 1.86-1.96 ppm, 2H, m; 2.14-2.17 ppm, 2H, m; 2.56-2.62 ppm, 2H, m; 3.07 ppm, 2H, d, J=6.9 Hz; 3.51-3.53 ppm, 2H, m; 3.90 ppm, 2H, t, J=7.8 Hz; 4.32 ppm, 2H, t, J=7.8 Hz; 5.17 ppm, 1H, t, J=6.9 Hz; 6.75 ppm, 1H, d, J=3.4 Hz; 6.88-6.90 ppm, 1H, m; 7.07-7.09 ppm, 2H, m; 7.11-7.18 ppm, 1H, m; 7.63-7.67 ppm, 2H, m.
  • Title Compound: Cyclohexyl amine (7.7 mg, 0.078 mmol), TEA (130 μL) and compound 2 (26 mg, 0.052 mmol) were dissolved in acetonitrile (1.0 mL). The reaction was heated at 85° C. for 18 h and concentrated. The title compound was purified as an orange oil (24.1 mg, 90% yield) by Prep-HPLC YMC ODS S5 20×100 nm, 16 min gradient 40 to 100% MeOH (90% in water 0.1% TPA) at 20 mL/min UV detection at 220 nM. HPLC Rt 3.51 min, Purity 100%, YMC S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220 nm. LCMS Rt 1.82 min, [M+1] 516.16 YMC S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) UV detection at 220 nm. H NMR (CDCl3) 1.05-1.11 ppm, 3H, m; 1.16-1.21 ppm, 2H, m; 1.49-1.51 ppm, 1H, m; 1.59-1.63 ppm, 2H, m; 1.77-1.80 ppm, 2H, in; 1.88-1.92 ppm, 2H, m; 2.15-2.18 ppm, 2H, m; 2.62-2.68 ppm, 2H, m; 2.94-2.98 ppm, 3H, m; 3.43-3.45 ppm, 2H, m; 3.84 ppm, 1H, m; 6.73-6.74 ppm, 1H, m; 6.88-6.89 ppm, 1H, m; 7.01-7.11 ppm, 2H, m; 7.17 ppm, 1H, dd, J=1.1 Hz and 5.5 Hz; 7.65-7.67 ppm, 2H, m.
    • Examples 65 to 73
  • Examples 65 to 73 were prepared using methodology described in Example 64.
  • Example Structure Name [M + 1]
    65
    Figure US20090312307A1-20091217-C00127
         		447
    66
    Figure US20090312307A1-20091217-C00128
         		489
    67
    Figure US20090312307A1-20091217-C00129
         		515
    68
    Figure US20090312307A1-20091217-C00130
         		487
    69
    Figure US20090312307A1-20091217-C00131
         		539
    70
    Figure US20090312307A1-20091217-C00132
         		509
    71
    Figure US20090312307A1-20091217-C00133
         		553
    72
    Figure US20090312307A1-20091217-C00134
         		523
    73
    Figure US20090312307A1-20091217-C00135
         		503
    • Example 74
  • Figure US20090312307A1-20091217-C00136
    • 4-Benzylcarbamoyl-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester Synthesis
  • Figure US20090312307A1-20091217-C00137
  • Compound 1: Compound 1 is commercially available.
  • Compound 2; A solution of compound 1 (12.6 g; 33.4 mmol) in 100 mL of 1 N sodium hydroxide and 25 mL of tetrahydrofuran was treated with di-tert-butyl dicarbonate (10.3 g; 47.2 mmol) at room temperature. After stirring for 20 h, 10% aqueous hydrochloric acid was slowly added to neutralize the reaction mixture to pH=7. Ethyl acetate (approximately 300 mL) was added and the organic layer was separated, washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated to give compound 2 as a white solid (10.2 g) that was used without further purification. LCMS m/z=306 (M+H)+.
  • Title Compound: A solution of compound 2 (0.92 g; 3.0 mmol) in tetrahydrofuran (30 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.77 g; 4.0 mmol) and triethylamine (0.63 mL; 4.5 mmol) at room temperature. The reaction mixture was allowed to stir for 0.5 h at which time benzyl amine (0.39 mL; 3.6 mmol) was added and the reaction mixture was heated to 45° C. for 2 h. The tetrahydrofuran was removed by evaporation and the residue was treated with ethyl acetate (approximately 150 mL) and 5% aqueous hydrochloric acid (approximately 100 mL). The organic layer was separated, washed with saturated aqueous sodium chloride, dried (sodium sulfate), filtered and concentrated. Column chromatography on silica gel using 7:3 hexane:ethyl acetate as the eluent gave 0.93 g of 4-benzylcarbamoyl-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester as a white solid. LCMS m/z=396 (M+H)+.
    • Examples 75 to 84
  • Examples 75 to 84 were prepared as described in Example 74.
  • Example Structure Name M + H
    75
    Figure US20090312307A1-20091217-C00138
         		4-(2-Methoxy-benzylcarbamoyl)-4- phenyl-piperidine-1-carboxylic acid tert-butyl ester 425
    76
    Figure US20090312307A1-20091217-C00139
         		4-[2-(4-Methoxy-phenyl)- ethylcarbamoyl]-4-phenyl-piperidine- 1-carboxylic acid tert-butyl ester 439
    77
    Figure US20090312307A1-20091217-C00140
         		4-(2,4-Dimethoxy-benzylcarbamoyl)- 4-phenyl-piperidine-1-carboxylic acid tert-butyl ester 455
    78
    Figure US20090312307A1-20091217-C00141
         		4-[2-(2,6-Dichloro-phenyl)- ethylcarbamoyl]-4-phenyl-piperidine- 1-carboxylic acid tert-butyl ester 478
    79
    Figure US20090312307A1-20091217-C00142
         		4-Phenyl-4-(3-phenyl- propylcarbamoyl)-piperidine-1- carboxylic acid tert-butyl ester 423
    80
    Figure US20090312307A1-20091217-C00143
         		4-Pentylcarbamoyl-4-phenyl- piperidine-1-carboxylic acid tert-butyl ester 375
    81
    Figure US20090312307A1-20091217-C00144
         		4-(3-Methoxy-propylcarbamoyl)-4- phenyl-piperidine-1-carboxylic acid tert-butyl ester 377
    82
    Figure US20090312307A1-20091217-C00145
         		4-(4-Methoxy-benzylcarbamoyl)-4- phenyl-piperidine-1-carboxylic acid tert-butyl ester 425
    83
    Figure US20090312307A1-20091217-C00146
         		4-(3,4-Difluoro-benzylcarbamoyl)-4- phenyl-piperidine-1-carboxylic acid tert-butyl ester 431
    84
    Figure US20090312307A1-20091217-C00147
         		4-(4-Fluoro-benzylcarbamoyl)-4- phenyl-piperidine-1-carboxylic acid tert-butyl ester 413
    • Example 85
  • Figure US20090312307A1-20091217-C00148
    • 4-Phenyl-piperidine-4-carboxylic acid benzylamide Synthesis
  • Figure US20090312307A1-20091217-C00149
  • Compound 1: Compound 1 was prepared as described in Example 74.
  • Title Compound: A solution of compound 1 (0.93 g; 2.4 mmol) in 30 mL of dichloromethane was treated with 4 mL trifluoroacetic acid at room temperature. After stirring for 20 h, an additional 100 mL of dichloromethane was added followed by 100 mL 1 N sodium hydroxide. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated to give 0.67 g of 4-phenyl-piperidine-4-carboxylic acid benzylamide as a colorless oil that was used without further purification. LCMS m/z=295 (M+H)+.
    • Examples 86 to 93
  • Examples 86 to 93 were prepared as described in Example 85.
  • Example Structure Name M + H
    86
    Figure US20090312307A1-20091217-C00150
         		4-Phenyl-piperidine-4-carboxylic acid 2,4-dimethoxy-benzylamide 355
    87
    Figure US20090312307A1-20091217-C00151
         		(4-Phenyl-piperazin-1-yl)-(4-phenyl- piperidin-4-yl)-methanone 350
    88
    Figure US20090312307A1-20091217-C00152
         		4-Phenyl-piperidine-4-carboxylic acid 2-methoxy-benzylamide 325
    89
    Figure US20090312307A1-20091217-C00153
         		4-Phenyl-piperidine-4-carboxyic acid 4-methoxy-benzylamide 325
    90
    Figure US20090312307A1-20091217-C00154
         		4-Phenyl-piperidine-4-carboxylic acid [2-(4-methoxy-phenyl)-ethyl]-amide 339
    91
    Figure US20090312307A1-20091217-C00155
         		4-Phenyl-piperidine-4-carboxylic acid (3-phenyl-propyl)-amide 323
    92
    Figure US20090312307A1-20091217-C00156
         		4-Phenyl-piperidine-4-carboxylic acid pentylamide 275
    93
    Figure US20090312307A1-20091217-C00157
         		4-Phenyl-piperidine-4-carboxylic acid (3-methoxy-propyl)-amide 277
    • Example 94
  • Figure US20090312307A1-20091217-C00158
    • 4-Phenyl-1-(2-phenyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid benzylamide Synthesis
  • Figure US20090312307A1-20091217-C00159
  • Compound 1: Compound 1. was prepared as described in Example 85.
  • Title Compound; Compound 1 (0.015 g; 0.05 mmol) was dissolved in 1 mL acetonitrile. Polystyrene-diisopropylethylamine (PS-DIEA) resin (0.1 g) was added and the resulting suspension was treated with trans-2-phenyl-cyclopropanecarbonyl chloride (0.02 g; 0.1 mmol) and shaken at room temperature. After 21 h, polystyrene-trisamine (PS-trisamine) resin (0.1 g) was added and the reaction mixture was allowed to shake an additional 24 h. The reaction mixture was filtered and concentrated to give 0.015 g of 4-phenyl-1-(2-phenyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid benzylamide as a colorless oil. LCMS m/z=440 (M+H)+.
    • Example 95
  • Figure US20090312307A1-20091217-C00160
    • 1-(3-Fluoro-benzenesulfonyl)-4-phenylpiperidine-4-carboxylic acid benzylamide Synthesis
  • Figure US20090312307A1-20091217-C00161
  • Compound 1: Compound 1 was prepared as described in Example 85.
  • Title Compound: Compound 1 (0.015 g; 0.05 mmol) was dissolved in 1 mL anhydrous acetonitrile. Polystyrene-diisopropylethylamine (PS-DIEA) resin (0.1 g) was added and the resulting suspension was treated 3-fluoro-benzenesulfonyl chloride (0.02 g; 0.1 μmol) and shaken at room temperature. After 21 h, polystyrene-trisamine (PS-trisamine) resin (0.1 g) was added and the reaction mixture was allowed to shake an additional 24 h. The reaction mixture was filtered and concentrated to give 0.012 g of 1-(3-fluoro-benzenesulfonyl)-4-phenyl-piperidine-4-carboxylic acid benzylamide as a colorless oil. LCMS m/z=454 (M+H)+.
    • Example 96
  • Figure US20090312307A1-20091217-C00162
    • 4-Benzylcarbamoyl-4-phenyl-piperidine-1-carboxylic acid ethyl ester Synthesis
  • Figure US20090312307A1-20091217-C00163
  • Compound 1: Compound 1 was prepared as described in Example 85.
  • Title Compound: 4-Benzylcarbamoyl-4-phenylpiperidine-1-carboxylic acid ethyl ester was prepared using methodology described in Example 2. LCMS m/z=367 (M+H)+.
    • Examples 97 to 269
  • Examples 97 to 269 were synthesized using methodology described in Example 94, Example 95 and Example 96.
  • Example Structure Name M + H
    97
    Figure US20090312307A1-20091217-C00164
         		4-Phenyl-1-(2-phenyl- cyclopropanecarbonyl)-piperidine 4-carboxylic acid 2,4-dimethoxy- benzylamide 500
    98
    Figure US20090312307A1-20091217-C00165
         		1-(4-Methoxy-benzoyl)-4-phenyl- piperidine-4-carboxylic acid 2,4- dimethoxy-benzylamide 490
    99
    Figure US20090312307A1-20091217-C00166
         		1-[2-(4-Fluoro-phenyl)-acetyl]-4- phenyl-piperidine-4-carboxylic acid 2,4-dimethoxy-benzylamide 492
    100
    Figure US20090312307A1-20091217-C00167
         		1-[2-(3-Methoxy-phenyl)-acetyl]- 4-phenyl-piperidine-4-carboxylic acid 2,4-dimethoxy-benzylamide 504
    101
    Figure US20090312307A1-20091217-C00168
         		1-[2-(4-Chloro-phenoxy)-acetyl]-4- phenyl-piperidine-4-carboxylic acid 2,4-dimethoxy-benzylamide 524
    102
    Figure US20090312307A1-20091217-C00169
         		1-(3-Cyclopentyl-propionyl)-4- phenyl-piperidine-4-carboxylic acid 2,4-dimethoxy-benzylamide 480
    103
    Figure US20090312307A1-20091217-C00170
         		1-Butyryl-4-phenyl-piperidine-4- carboxylic acid 2,4-dimethoxy- benzylamide 426
    104
    Figure US20090312307A1-20091217-C00171
         		1-(2-Fluoro-benzoyl)-4-phenyl- piperidine-4-carboxylic acid 2,4- dimethoxy-beuzylamide 479
    105
    Figure US20090312307A1-20091217-C00172
         		1-Cyclohexanecarbonyl-4-phenyl- piperidine-4-carboxylic acid 2,4- dimethoxy-benzylamide 466
    106
    Figure US20090312307A1-20091217-C00173
         		(2-Phenyl-cyclopropyl)-[4-phenyl- 4-(4-phenyl-piperazine-1- carbonyl)-piperidin-1-yl]- methanone 495
    107
    Figure US20090312307A1-20091217-C00174
         		[1-(4-Methoxy-benzoyl)-4-phenyl- piperidin-4-yl]-(4-phenyl- piperazin-1-yl)-methanone 485
    108
    Figure US20090312307A1-20091217-C00175
         		2-(4-Fluoro-phenyl)-1-[4-phenyl-4- (4-phenyl-piperazine-1-carbonyl)- piperidin-1-yl]-ethanone 487
    109
    Figure US20090312307A1-20091217-C00176
         		2-(3-Methoxy-phenyl)-1-[4- phenyl-4-(4-phenyl-piperazine-1- carbonyl)-piperidin-1-yl]-ethanone 499
    110
    Figure US20090312307A1-20091217-C00177
         		2-(4-Chloro-phenoxy)-1-[4-phenyl- 4-(4-phenyl-piperazine-1- carbonyl)-piperidin-1-yl]-ethanone 519
    111
    Figure US20090312307A1-20091217-C00178
         		3-Cyclopentyl-1-[4-phenyl-4-(4- phenyl-piperazine-1-carbonyl)- piperidin-1-yl]-propan-1-one 475
    112
    Figure US20090312307A1-20091217-C00179
         		1-[4-Phenyl-4-(4-phenyl- piperazine-1-carbonyl)-piperidin-1- yl]-butan-1-one 421
    113
    Figure US20090312307A1-20091217-C00180
         		(2-Fluoro-phenyl)-[4-phenyl-4-(4- phenyl-piperazine-1-carbonyl)- piperidin-1-yl-methanone 473
    114
    Figure US20090312307A1-20091217-C00181
         		(1-Cyclohexanecarbonyl-4-phenyl- piperidin-4-yl)-(4-phenyl- piperazin-1-yl)-methanone 461
    115
    Figure US20090312307A1-20091217-C00182
         		4-Phenyl-1-(2-phenyl- cyclopropanecarbonyl)-piperidine- 4-carboxylic acid 4-methoxy- benzylamide 470
    116
    Figure US20090312307A1-20091217-C00183
         		1-(4-Methoxy-benzoyl)-4-phenyl- piperidine-4-carboxylic acid 4- methoxy-benzylamide 460
    117
    Figure US20090312307A1-20091217-C00184
         		1-[2-(4-Fluoro-phenyl)-acetyl]-4- phenyl-piperidine-4-carboxylic acid 4-methoxy-benzylamide 462
    118
    Figure US20090312307A1-20091217-C00185
         		1-[2-(3-Methoxy-phenyl)-acetyl]- 4-phenyl-piperidine-4-carboxylic acid 4-methoxy-benzylamide 474
    119
    Figure US20090312307A1-20091217-C00186
         		1-[2-(4-Chloro-phenoxy)-acetyl]-4- phenyl-pipendine-4-carboxylic acid 4-methoxy-benzylamide 494
    120
    Figure US20090312307A1-20091217-C00187
         		1-(3-Cyclopentyl-propionyl)-4- phenyl-piperidine-4-carboxylic acid 4-methoxy-benzylamide 450
    121
    Figure US20090312307A1-20091217-C00188
         		1-Butyryl-4-phenyl-piperidine-4- carboxylic acid 4-methoxy- benzylamide 396
    122
    Figure US20090312307A1-20091217-C00189
         		1-(2-Fluoro-benzoyl)-4-phenyl- piperidine-4-carboxylic acid 4- methoxy-benzylamide 448
    123
    Figure US20090312307A1-20091217-C00190
         		1-Cyclohexanecarbonyl-4-phenyl- piperidine-4-carboxylic acid 4- methoxy-benzylamide 436
    124
    Figure US20090312307A1-20091217-C00191
         		4-Phenyl-1-(2-phenyl- cyclopropanecarbonyl)-piperidine- 4-carboxylic acid 2- methoxy-benzylamide 470
    125
    Figure US20090312307A1-20091217-C00192
         		1-(4-Methoxy-benzoyl)-4-phenyl- piperidine-4-carboxylic acid 2- methoxy-benzylamide 460
    126
    Figure US20090312307A1-20091217-C00193
         		1-[2-(4-Fluoro-phenyl)-acetyl]-4- phenyl-piperidine-4-carboxylic acid 2-methoxy-benzylamide 462
    127
    Figure US20090312307A1-20091217-C00194
         		1-[2-(3-Methoxy-phenyl)-acetyl]- 4-phenyl-piperidine-4-carboxylic acid 2-methoxy-benzylamide 474
    128
    Figure US20090312307A1-20091217-C00195
         		1-[2-(4-Chloro-phenoxy)-acetyl]-4- phenyl-piperidine-4-carboxylic acid 2-methoxy-benzylamide 494
    129
    Figure US20090312307A1-20091217-C00196
         		1-(3-Cyclopentyl-propionyl)-4- phenyl-piperidine-4-carboxylic acid 2-methoxy-benzylamide 450
    130
    Figure US20090312307A1-20091217-C00197
         		1-Butyryl-4-phenyl-piperidine-4- carboxylic acid 2-methoxy- benzylamide 396
    131
    Figure US20090312307A1-20091217-C00198
         		1-(2-Fluoro-benzoyl)-4-phenyl- piperidine-4-carboxylic acid 2- methoxy-benzylamide 448
    132
    Figure US20090312307A1-20091217-C00199
         		1-Cyclohexanecarbonyl-4-phenyl- piperidine-4-carboxylic acid 2- methoxy-benzylamide 436
    133
    Figure US20090312307A1-20091217-C00200
         		1-(4-Methoxy-benzoyl)-4-phenyl- piperidine-4-carboxylic acid benzylamide 440
    134
    Figure US20090312307A1-20091217-C00201
         		1-[2-(4-Fluoro-phenyl)-acetyl]-4- phenyl-piperidine-4-carboxylic acid benzylamide 430
    135
    Figure US20090312307A1-20091217-C00202
         		1-[2-(3-Methoxy-phenyl)-acetyl]- 4-phenyl-piperidine-4-carboxylic acid benzylamide 444
    136
    Figure US20090312307A1-20091217-C00203
         		1-[2-(4-Chloro-phenoxy)-acetyl]-4- phenyl-piperidine-4-carboxylic acid benzylamide 464
    137
    Figure US20090312307A1-20091217-C00204
         		1-(3-Cyclopentyl-propionyl)-4- phenyl-piperidine-4-carboxylic acid benzylamide 420
    138
    Figure US20090312307A1-20091217-C00205
         		1-Butyryl-4-phenyl-piperidine-4- carboxylic acid benzylamide 365
    139
    Figure US20090312307A1-20091217-C00206
         		1-(2-Fluoro-benzoyl)-4-phenyl- piperidine-4-carboxylic acid benzylamide 417
    140
    Figure US20090312307A1-20091217-C00207
         		1-Cyclohexanccarbonyl-4-phenyl- piperidine-4-carboxylic acid benzylamide 406
    141
    Figure US20090312307A1-20091217-C00208
         		4-Phenyl-1-(2-phenyl- cyclopropanecarbonyl)-piperidine- 4-carboxylic acid (3-methoxy- propyl)-amide 422
    142
    Figure US20090312307A1-20091217-C00209
         		1-(4-Methoxy-benzoyl)-4-phenyl- piperidine-4-carboxylic acid (3- methoxy-propyl)-amide 412
    143
    Figure US20090312307A1-20091217-C00210
         		1-[2-(4-Fluoro-phenyl)-acetyl]-4- phenyl-piperidine-4-carboxylic acid (3-methoxy-propyl)-amide 414
    144
    Figure US20090312307A1-20091217-C00211
         		1-[2-(3-Methoxy-phenyl)-acetyl]- 4-phenyl-piperidine-4-carboxylic acid (3-methoxy-propyl)-amide 426
    145
    Figure US20090312307A1-20091217-C00212
         		1-[2-(4-Chloro-phenoxy)-acetyl]-4- phenyl-piperidine-4-carboxylic acid (3-methoxy-propy1)-amide 446
    146
    Figure US20090312307A1-20091217-C00213
         		1-(3-Cyclopentyl-propionyl)-4- phenyl-piperidine-4-carboxylic acid (3-methoxy-propyl)-amide 402
    147
    Figure US20090312307A1-20091217-C00214
         		1-Butyryl-4-phenyl-piperidine-4- carboxylic acid (3-methoxy- propyl)-amide 347
    148
    Figure US20090312307A1-20091217-C00215
         		1-(2-Fluoro-benzoyl)-4-phenyl- piperidine-4-carboxylic acid (3- methoxy-propyl)-amide 399
    149
    Figure US20090312307A1-20091217-C00216
         		1-Cyclohexanecarbonyl-4-phenyl- piperidine-4-carboxylic acid (3- methoxy-propyl)-amide 388
    150
    Figure US20090312307A1-20091217-C00217
         		4-Phenyl-1-(2-phenyl- cyclopropanecarbonyl)-piperidine- 4-carboxylic acid[2-(4-methoxy- phenyl)-ethyl]-amide 484
    151
    Figure US20090312307A1-20091217-C00218
         		1-(4-Methoxy-benzoyl)-4-phenyl- piperidine-4-carboxylic acid [2-(4- methoxy-phenyl)-ethyl]-amide 474
    152
    Figure US20090312307A1-20091217-C00219
         		1-[2-(4-Fluoro-phenyl)-acetyl]-4- phenyl-piperidine-4-carboxylic acid (2-(4-methoxy-phenyl)-ethyl]- amide 476
    153
    Figure US20090312307A1-20091217-C00220
         		1-[2-(3-Methoxy-phenyl)-acetyl]- 4-phenyl-piperidine-4-carboxylic acid [2-(4-methoxy-phenyl)-ethyl]- amide 488
    154
    Figure US20090312307A1-20091217-C00221
         		1-[2(4-Chloro-phenoxy)-acetyl]-4- phenyl-piperidine-4-carboxylic acid [2-(4-methoxy-phenyl)-ethyl]- amide 508
    155
    Figure US20090312307A1-20091217-C00222
         		1-(3-Cyclopentyl-propionyl)-4- phenyl-piperidine-4-carboxylic acid [2-(4-methoxy-phenyl)-ethyl]- amide 464
    156
    Figure US20090312307A1-20091217-C00223
         		1-Butyryl-4-phenyl-piperidine-4- carboxylic acid [2-(4-methoxy- phenyl)-ethyl]-amide 410
    157
    Figure US20090312307A1-20091217-C00224
         		1-(2-Fluoro-benzoyl)-4-phenyl- piperidine-4-carboxylic acid [2-(4- methoxy-phenyl)-ethyl]-amide 462
    158
    Figure US20090312307A1-20091217-C00225
         		1-Cyclohexanecarbonyl-4-phenyl- piperidine-4-carboxylic acid [2-(4- methoxy-phenyl)-ethyl]-amide 450
    159
    Figure US20090312307A1-20091217-C00226
         		4-Phenyl-1-(2-phenyl- cyclopropanecarbonyl)-piperidine 4-carboxylic acid (3-phenyl- propyl)-amide 468
    160
    Figure US20090312307A1-20091217-C00227
         		1-(4-Methoxy-benzoyl)-4-phenyl- piperidine-4-carboxylic acid (3- phenyl-propyl)-amide 458
    161
    Figure US20090312307A1-20091217-C00228
         		1-[2-(4-Fluoro-phenyl)-acetyl]-4- phenyl-piperidine-4-carboxylic acid (3-phenyl-propyl)-amide 460
    162
    Figure US20090312307A1-20091217-C00229
         		1-[2-(3-Methoxy-phenyl)-acetyl]- 4-phenyl-piperidine-4-carboxylic acid (3-phenyl-propyl)-amide 472
    163
    Figure US20090312307A1-20091217-C00230
         		1-[2-(4-Chloro-phenoxy)-acetyl]-4- phenyl-piperidine-4-carboxylic acid (3-phenyl-propyl)-amide 492
    164
    Figure US20090312307A1-20091217-C00231
         		1 -(3-Cyclopentyl-propionyl)-4- phenyl-piperidine-4-carboxylic acid (3-phenyl-propyl)-amide 448
    165
    Figure US20090312307A1-20091217-C00232
         		1-Butyryl-4-phenyl-piperidine-4- carboxylic acid (3-phenyl-propyl)- amide 394
    166
    Figure US20090312307A1-20091217-C00233
         		1-(2-Fluoro-benzoyl)-4-phenyl- piperidine-4-carboxylic acid (3- phenyl-propyl)-amide 446
    167
    Figure US20090312307A1-20091217-C00234
         		1-Cyclohexanecarbonyl-4-phenyl- piperidine-4-carboxylic acid (3- phenyl-propyl)-amide 434
    168
    Figure US20090312307A1-20091217-C00235
         		1-But-2-enoyl-4-phenyl-piperidine- 4-carboxylic acid 2,4-dimethoxy- benzylamide 424
    169
    Figure US20090312307A1-20091217-C00236
         		1-(3-Fluoro-benzenesulfonyl)-4- phenyl-piperidine-4-carboxylic acid 2,4-dimethoxy-benzylamide 514
    170
    Figure US20090312307A1-20091217-C00237
         		1-[4-Phenyl-4-(4-phenyl- piperazine-1-carbonyl)-piperidin-1- yl]-but-2-en-1-one 419
    171
    Figure US20090312307A1-20091217-C00238
         		[1-(3-Fluoro-benzenesulfonyl)-4- phenyl-piperidin-4-yl]-(4-phenyl- piperazin-1-yl)-methanone 509
    172
    Figure US20090312307A1-20091217-C00239
         		1-But-2-enoyl-4-phenyl-piperidine- 4-carboxylic acid 4-methoxy- benzylamide 394
    173
    Figure US20090312307A1-20091217-C00240
         		1-(3-Fluoro-benzenesulfonyl)-4- phenylpiperidine-4-carboxylic acid 4-methoxy-benzylamide 484
    174
    Figure US20090312307A1-20091217-C00241
         		1-But-2-enoyl-4-phenyl-piperidine- 4-carboxylic acid 2-methoxy- benzylamide 394
    175
    Figure US20090312307A1-20091217-C00242
         		1-(3-Fluoro-benzenesulfonyl)-4- phenyl-piperidine-4-carboxylic acid 2-methoxy-benzylamide 484
    176
    Figure US20090312307A1-20091217-C00243
         		1-But-2-enoyl-4-phenyl-piperidine- 4-carboxylic acid benzylamide 363
    177
    Figure US20090312307A1-20091217-C00244
         		1-But-2-enoyl-4-phenyl-piperidine- 4-carboxylic acid (3-methoxy- propyl)-amide 345
    178
    Figure US20090312307A1-20091217-C00245
         		1-(3-Fluoro-benzenesulfonyl)-4- phenylpipendine-4-carboxylic acid (3-methoxy-propyl)-amide 436
    179
    Figure US20090312307A1-20091217-C00246
         		1-But-2-enoyl-4-phenyl-piperidine- 4-carboxylic acid [2(4-methoxy- phenyl)-ethyl]-amide 408
    180
    Figure US20090312307A1-20091217-C00247
         		1-(3-Fluoro-benzenesulfonyl)-4- phenyl-piperidine-4-carboxylic acid [2-(4-methoxy-phenyl)-ethyl]- amide 498
    181
    Figure US20090312307A1-20091217-C00248
         		1-But-2-enoyl-4-phenyl-piperidine- 4-carboxylic acid (3-phenyl- propyl)-amide 392
    182
    Figure US20090312307A1-20091217-C00249
         		1-(3-Fluoro-benzenesulfonyl)-4- phenyl-piperidine-4-carboxylic acid (3-pbenyl-propyl)-amide 482
    183
    Figure US20090312307A1-20091217-C00250
         		4-Benzylcarbamoyl-4-phenyl- piperidine-1-carboxylic acid benzyl ester 430
    184
    Figure US20090312307A1-20091217-C00251
         		4-Phenyl-piperidine-1,4- dicarboxylic acid 4-benzylamide 1- [(1-phenyl-ethyl)-amide] 443
    185
    Figure US20090312307A1-20091217-C00252
         		1-(4-Ethyl-benzenesulfonyl)-4- phenyl-piperidine-4-carboxylic acid benzylamide 464
    186
    Figure US20090312307A1-20091217-C00253
         		4-Phenyl-1-(thiophene-2-sulfonyl)- piperidine-4-carboxylic acid benzylamide 442
    187
    Figure US20090312307A1-20091217-C00254
         		1-(3-Cyano-benzenesulfonyl)-4- phenyl-piperidine-4-carboxylic acid benzylamide 461
    188
    Figure US20090312307A1-20091217-C00255
         		1-(2-Fluoro-benzenesulfonyl)-4- phenyl-piperidine-4-carboxylic acid benzylamide 454
    189
    Figure US20090312307A1-20091217-C00256
         		1-(4-Fluoro-beuzenesulfonyl)-4- phenyl-piperidine-4-carboxylic acid benzylamide 454
    190
    Figure US20090312307A1-20091217-C00257
         		1-(4-Methoxy-benzenesulfonyl)-4- phenyl-piperidine-4-carboxylic acid benzylamide 466
    191
    Figure US20090312307A1-20091217-C00258
         		4-Phenyl-1-(toluene-3-sulfonyl)- piperidine-4-carboxylic acid benzylamide 450
    192
    Figure US20090312307A1-20091217-C00259
         		1-(2-Phenoxy-acetyl)-4-phenyl- piperidine-4-carboxylic acid benzylamide 430
    193
    Figure US20090312307A1-20091217-C00260
         		1-(2-Phenoxy-acetyl)-4-phenyl- piperidine-4-carboxylic acid (3- phenyl-propyl)-amide 458
    194
    Figure US20090312307A1-20091217-C00261
         		4-(3,4-Difluoro-benzylcarbamoyl)- 4-phenyl-piperidine-1-carboxylic acid benzyl ester 466
    195
    Figure US20090312307A1-20091217-C00262
         		1-(2-Phenoxy-acetyl)-4-phenyl- piperadine-4-carboxylic acid 3,4- difluoro-benzylamide 466
    196
    Figure US20090312307A1-20091217-C00263
         		1-(4-Fluoro-benzenesulfonyl)-4- phenyl-piperidine-4-carboxylic acid 3,4-difluoro-benzylamide 490
    197
    Figure US20090312307A1-20091217-C00264
         		4-Phenyl-piperidine-1,4- dicarboxylic acid 1-benzylamide 4- (3,4-difluoro-benzylamide) 465
    198
    Figure US20090312307A1-20091217-C00265
         		4-Phenyl-1-(3-phenyl-acryloyl)- piperidine-4-carboxylic acid 3,4- difluoro-benzylamide 462
    199
    Figure US20090312307A1-20091217-C00266
         		4-Phenyl-1-phenylacetyl- piperidine-4-carboxylic acid 3,4- difluoro-benzylamide 450
    200
    Figure US20090312307A1-20091217-C00267
         		1-Benzoyl-4-phenyl-piperidine-4- carboxylic acid 3,4-difluoro- benzylamide 435
    201
    Figure US20090312307A1-20091217-C00268
         		4-Phenyl-1-propionyl-piperidine-4- carboxylic acid 3,4-difluoro- benzylamide 387
    202
    Figure US20090312307A1-20091217-C00269
         		1-(2-Benzyloxy-acetyl)-4-phenyl- piperidine-4-carboxylic acid 3,4- difluoro-benzylamide 480
    203
    Figure US20090312307A1-20091217-C00270
         		4-(1-Benzyl-pyrrolidin-3- ylcarbamoyl)-4-phenyl-piperidine- 1-carboxylic acid benzyl ester 499
    204
    Figure US20090312307A1-20091217-C00271
         		4-(4-Methanesulfonyl- benzylcarbamoyl)-4-phenyl- piperidine-1-carboxylic acid benzyl ester 508
    205
    Figure US20090312307A1-20091217-C00272
         		4-(4-Fluoro-benzylcarbamoyl)-4- phenyl-piperidine-1-carboxylic acid benzyl ester 448
    206
    Figure US20090312307A1-20091217-C00273
         		4-[2-(3-Chloro-phenyl)- ethylcarbamoyl]-4-phenyl- piperidine-1-carboxylic acid benzyl ester 478
    207
    Figure US20090312307A1-20091217-C00274
         		4-Phenyl-4-[2-(3-trifluoromethyl- phenyl)-ethylcarbamoyl]- piperidine-1-carboxylic acid benzyl ester 512
    208
    Figure US20090312307A1-20091217-C00275
         		4-[(Naphthalen-1-ylmethyl)- carbamoyl)-4-phenyl-piperidine-1- carboxylic acid benzyl ester 480
    209
    Figure US20090312307A1-20091217-C00276
         		4-Phenyl-4-(4-trifluoromethyl- benzylcarbamoyl)-piperidine-1- carboxylic acid benzyl ester 498
    210
    Figure US20090312307A1-20091217-C00277
         		4-[(3-Methyl-benzo[b]thiophen-2- ylmethyl)-carbamoyl]-4-phenyl- piperidine-1-carboxylic acid benzyl ester 500
    211
    Figure US20090312307A1-20091217-C00278
         		4-(1-Benzyl-piperidin-4- ylcarbamoyl)-4-phenyl-piperidine- 1-carboxylic acid benzyl ester 513
    212
    Figure US20090312307A1-20091217-C00279
         		4-[2-(1-Methyl-pyrrolidin-2-yl)- ethylcarbamoyl]-4-phenyl- piperidine-1-carboxylic acid benzyl ester 451
    213
    Figure US20090312307A1-20091217-C00280
         		4-(Cyclopropylmethyl-carbamoyl)- 4-phenyl-piperidine-1-carboxylic acid benzyl ester 394
    214
    Figure US20090312307A1-20091217-C00281
         		4-Phenyl-4-(2-pyridin-2-yl- ethylcarbamoyl)-piperidine-1- carboxylic acid benzyl ester 445
    215
    Figure US20090312307A1-20091217-C00282
         		4-(Indan-1-ylcarbamoyl)-4-phenyl- piperidine-1-carboxylic acid benzyl ester 456
    216
    Figure US20090312307A1-20091217-C00283
         		4-(2-Morpholin-4-yl- ethylcarbamoyl)-4-phenyl- piperidine-1-carboxylic acid benzyl ester 453
    217
    Figure US20090312307A1-20091217-C00284
         		1-[3-(2-Chloro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid 4-fluoro-benzylamide 480
    218
    Figure US20090312307A1-20091217-C00285
         		1-[3-(2-Chloro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid (3-phenyl-propyl)-amide 490
    219
    Figure US20090312307A1-20091217-C00286
         		4-Phenyl-]-[3-(4-trifluoromethyl- phenyl)-propionyl]-piperidine-4- carboxylic acid 4-fluoro- benzylamide 514
    220
    Figure US20090312307A1-20091217-C00287
         		4-Phenyl-1-(3-phenyl-propynoyl)- piperidine-4-carboxylic acid 4- fluoro-benzylamide 458
    221
    Figure US20090312307A1-20091217-C00288
         		4-Phenyl-1-[3-(4-trifluoromethyl- phenyl)-propionyl]-piperidine-4- carboxylic acid (3-phenyl-propyl)- amide 524
    222
    Figure US20090312307A1-20091217-C00289
         		1-[3-(3,4-Difluoro-phenyl)- propionyl]-4-phenyl-piperidine-4- carboxylic acid (3-phenyl-propyl)- amide 492
    223
    Figure US20090312307A1-20091217-C00290
         		4-Phenyl-1-(3-phenyl-propynoyl)- piperidine-4-carboxylic acid (3- phenyl-propyl)-amide 452
    224
    Figure US20090312307A1-20091217-C00291
         		1-(4-Methoxy-benzenesulfonyl)-4- phenyl-piperidine-4-carboxylic acid (3-phenyl-propyl)-amide 494
    225
    Figure US20090312307A1-20091217-C00292
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid (biphenyl-2-ylmethyl)-amide 522
    226
    Figure US20090312307A1-20091217-C00293
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid 4-trifluoromethyl-benzylamide 514
    227
    Figure US20090312307A1-20091217-C00294
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid 4-fluoro-benzylamide 464
    228
    Figure US20090312307A1-20091217-C00295
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid 4-chloro-benzylamide 480
    229
    Figure US20090312307A1-20091217-C00296
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid 3-trifluoromethyl-benzylamide 514
    230
    Figure US20090312307A1-20091217-C00297
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid 3,5-bis-trifluoromethyl- benzylamide 582
    231
    Figure US20090312307A1-20091217-C00298
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid (thiophen-2-ylmethyl)-amide 452
    232
    Figure US20090312307A1-20091217-C00299
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid benzylamide 446
    233
    Figure US20090312307A1-20091217-C00300
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid 3-methyl-benzylamide 460
    234
    Figure US20090312307A1-20091217-C00301
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid 4-methyl-benzylamide 460
    235
    Figure US20090312307A1-20091217-C00302
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid 2-chloro-benzylamide 480
    236
    Figure US20090312307A1-20091217-C00303
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid indan-1-ylamide 472
    237
    Figure US20090312307A1-20091217-C00304
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid (1,2,3,4-tetrahydro- naphthalen-1-yl)-amide 486
    238
    Figure US20090312307A1-20091217-C00305
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid [2-(4-chloro-phenyl)-ethyl]- amide 494
    239
    Figure US20090312307A1-20091217-C00306
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid [2-(3-chloro-phenyl)-ethyl]- amide 494
    240
    Figure US20090312307A1-20091217-C00307
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid [2-(3-trifluoromethyl-phenyl)- ethyl]-amide 528
    241
    Figure US20090312307A1-20091217-C00308
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]- amide 488
    242
    Figure US20090312307A1-20091217-C00309
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid (2-thiophen-2-yl-ethyl)-amide 466
    243
    Figure US20090312307A1-20091217-C00310
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid [2-(1H-indol-3-yl)-ethyl]- amide 499
    244
    Figure US20090312307A1-20091217-C00311
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid (4-phenyl-butyl)-amide 488
    245
    Figure US20090312307A1-20091217-C00312
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid [2-(3-fluoro-phenyl)-ethyl]- amide 478
    246
    Figure US20090312307A1-20091217-C00313
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]- amide 478
    247
    Figure US20090312307A1-20091217-C00314
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid (2-phenoxy-ethyl)-amide 476
    248
    Figure US20090312307A1-20091217-C00315
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid cyclohexylmethyl-amide 452
    249
    Figure US20090312307A1-20091217-C00316
         		3-(4-Fluoro-phenyl)-1-{4-[2-(4- fluoro-phenyl)-piperidine-1- carbonyl]-4-phenyl-piperidin-1- yl}-propan-1-one 518
    250
    Figure US20090312307A1-20091217-C00317
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid (5-chloro-benzooxazol-2-yl)- amide 507
    251
    Figure US20090312307A1-20091217-C00318
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid (2-methyl-5-phenyl-2H- pyrazol-3-yl)-amide 512
    252
    Figure US20090312307A1-20091217-C00319
         		1-[3-(4-Fluoro-phenyl-propionyl]- 4-phenyl-piperidine-4-carboxylic acid (4-phenyl-thiazol-2-yl)-amide 515
    253
    Figure US20090312307A1-20091217-C00320
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid (1H-benzoimidazol-2- ylmethyl)-amide 486
    254
    Figure US20090312307A1-20091217-C00321
         		1-[3-(4-Fluoro-phenyl-propionyl[- 4-phenyl-piperidine-4-carboxylic acid methyl-pyridin-2-ylmethyl- amide 461
    255
    Figure US20090312307A1-20091217-C00322
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid methyl-pyridin-3-ylmethyl- amide 461
    256
    Figure US20090312307A1-20091217-C00323
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid [2-(2-methoxy-phenyl)-ethyl]- amide 490
    257
    Figure US20090312307A1-20091217-C00324
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxyiic acid [2-(4-bromo-phenyl)-ethyl]- amide 538
    258
    Figure US20090312307A1-20091217-C00325
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid (2-p-tolyl-ethyl)-amide 474
    259
    Figure US20090312307A1-20091217-C00326
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid [2-(2,5-dimethoxy-phenyl)- ethyl]-amide 520
    260
    Figure US20090312307A1-20091217-C00327
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid (2-benzo[1,3]dioxol-5-yl- ethyl)-amide 504
    261
    Figure US20090312307A1-20091217-C00328
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid [2-(3,4-dichloro-phenyl)- ethyl]-amide 528
    262
    Figure US20090312307A1-20091217-C00329
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid [2-(2,4-dimethyl-phenyl)- ethyl]-amide 488
    263
    Figure US20090312307A1-20091217-C00330
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid [2-(3,4-dimethyl-phenyl)- ethyl]-amide 488
    264
    Figure US20090312307A1-20091217-C00331
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid (2-o-tolyl-ethyl)-amide 474
    265
    Figure US20090312307A1-20091217-C00332
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid (2-m-tolyl-ethyl)-amide 474
    266
    Figure US20090312307A1-20091217-C00333
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-phenyl-piperidine-4-carboxylic acid (3-methyl-benzo[b]thiophen- 2-ylmethyl)-amide 516
    267
    Figure US20090312307A1-20091217-C00334
         		4-Phenyl-4-[(pyridin-2-ylmethyl)- carbamoyl]piperidine-1- carboxylic acid benzyl ester 431
    268
    Figure US20090312307A1-20091217-C00335
         		4-Phenyl-4-(pyridin-2- ylcarbamoyl)piperidine-1- carboxylic acid benzyl ester 416
    269
    Figure US20090312307A1-20091217-C00336
         		4-(2-Methoxy-pyridin-3- ylcarbamoyl)-4-phenyl-piperidine- 1-carboxylic acid benzyl ester 447
    • Example 270
  • Figure US20090312307A1-20091217-C00337
    • Synthesis
  • Figure US20090312307A1-20091217-C00338
  • Compound 1: Compound 1 were prepared using methodology described in Example 85.
  • Compound 2: A solution of compound 1 (1.26 g; 4.03 mmol) in anhydrous acetonitrile (25 mL) was treated with diphenyl N-cyanocarbonimidate (1.0 g; 4.2 mmol) and heated at 85° C. for 1.5 h. The acetonitrile was removed by evaporation and the crude residue was purified by column chromatography on silica gel using a 7:3 hexane:ethyl acetate to 1:1 hexane:ethyl acetate gradient as the eluent to give 0.51 g of compound 2 as a white solid. LCMS m/z 338 (M+H)+.
  • Title Compound. A solution of compound 2 (0.081 g; 0.18 mol) in isopropanol (5 mL) was treated with benzyl amine (0.04 mL; 0.37 mmol) and heated at 90° C. for 15 h. The isopropanol was removed by evaporation and the crude residue was purified by recrystallization from ethyl acetate/hexane to give 0.061 g of the title compound as white crystals. LCMS m/z=471 (M+H)+.
    • Examples 271 to 274
  • Examples 271 to 274 were prepared using methodology described in Example 270.
  • Example Structure Name M + H
    271
    Figure US20090312307A1-20091217-C00339
         		408
    272
    Figure US20090312307A1-20091217-C00340
         		423
    273
    Figure US20090312307A1-20091217-C00341
         		408
    274
    Figure US20090312307A1-20091217-C00342
         		380
    • Example 275
  • Figure US20090312307A1-20091217-C00343
    • 4-Phenyl-1-sulfamoyl-piperidine-4-carboxylic acid benzylamide Synthesis
  • Figure US20090312307A1-20091217-C00344
  • Compound 1: Compound 1 was prepared as described in Example 85.
  • Title Compound: 4-Phenyl-1-sulfamoyl-piperidine-4-carboxylic acid benzylamide was prepared using methodology described in Example 15. 1H NMR (CDCl3, rt); δ ppm) 2.15-2.24 (2H, m), 2.50-2.55 (2H, m), 3.21-3.27 (2H, m), 3.42-3.49 (2H, m), 4.28 (2H, s), 4.36 (2H, d, J=5.9 Hz), 5.47 (1H, bs), 7.02 (2H, d, J=7.5 Hz), 7.23 (2H, d, J=1.9 Hz), 7.30-7.41 (6H, m). LCMS Rt 1.45 min, [M+1] 374.0.
    • Example 276
  • Figure US20090312307A1-20091217-C00345
    • 1-Dimethylsulfamoyl-4-phenyl-piperidine-4-carboxylic acid benzylamide Scheme
  • Figure US20090312307A1-20091217-C00346
  • Compound 1: Compound 1 was prepared as described in Example 85.
  • Title Compound: 1-Dimethylsulfamoyl-4-phenyl-piperidine-4-carboxylic acid benzylamide was prepared using methodology described in Example 16. 1H NMR (CDCl3, rt): δ ppm) 2.13-2.22 (2H, m), 2.42-2.49 (2H, m), 2.80 (6H, s), 3.31-3.45 (4H, m), 4.34 (2H, d, J=5.7 Hz), 4.28 (2H, s), 5.47 (1H, bs), 7.02 (2H, t, J 5.0, Hz), 7.21-7.25 (2H, m), 7.27-7.41 (6H, m). LCMS Rt 1.59 min, [M+1] 402.0.
    • Example 277
  • Figure US20090312307A1-20091217-C00347
    • 1-(2-Methoxy-ethylsulfamoyl)-4-phenyl-piperidine-4-carboxylic acid benzylamide Scheme
  • Figure US20090312307A1-20091217-C00348
  • Compound 2: Compound 1 was prepared as described in Example 85.
  • Compound 2: Compound 2 was prepared as described in Example 17.
  • Title Compound: 1-(2-Methoxy-ethylsulfamoyl)-4-phenyl-piperidine-4-carboxylic acid benzylamide was prepared using methodology described in Example 17. 1H NMR (CDCl3, rt): δ ppm) 2.15-2.24 (2H, m), 2.44-2.51 (2H, m), 3.11-3.25 (2H, m), 3.30-3.43 (6H, m), 3.48 (2H, t, J=5.2 Hz), 4.34 (2H, d, J=5.7 Hz), 4.51 (1H, bs), 5.46 (1H, s), 7.01-7.25 (4H, m) 7, 7.29-7.41 (7H, m). LCMS Rt 1.47 min, [M+1] 432.3.
    • Examples 278 to 285
  • Examples 278 to 285 were prepared using methodology described in Example 277.
  • Example Structure Name M + H
    278
    Figure US20090312307A1-20091217-C00349
         		1-(4-Fluoro-benzylsulfamoyl)-4-phenyl- piperidine-4-carboxylic acid pyridin-2- ylamide 470
    279
    Figure US20090312307A1-20091217-C00350
         		1-(2-Methoxy-ethylsulfamoyl)-4-phenyl- piperidine-4-carboxylic acid pyridin-2- ylamide 420
    280
    Figure US20090312307A1-20091217-C00351
         		1-(4-Fluoro-benzylsulfamoyl)-4-phenyl- piperidine-4-carboxylic acid (2-methoxy- pyridin-3-yl)-amide 500
    281
    Figure US20090312307A1-20091217-C00352
         		1-(2-Methoxy-ethylsulfamoyl)-4-phenyl- piperidine-4-carboxylic acid (2-methoxy- pyridin-3-yl)-amide 450
    282
    Figure US20090312307A1-20091217-C00353
         		N-[1-(4-Fluoro-benzylsulfamoyl)-4- phenyl-piperidin-4-ylmethyl]-2-methoxy- benzamide 482
    283
    Figure US20090312307A1-20091217-C00354
         		N-(1-Benzylsulfamoyl-4-phenyl- piperidin-4-ylmethyl)-2-methoxy- benzamide 464
    284
    Figure US20090312307A1-20091217-C00355
         		2-Methoxy-N-(4-phenyl-1- propylsulfamoyl-piperidin-4-ylmethyl)- benzamide 416
    285
    Figure US20090312307A1-20091217-C00356
         		N-(1-Dimethylsulfamoyl-4-phenyl- piperidin-4-ylmethyl)-2-methoxy- benzamide 432
    • Example 286
  • Figure US20090312307A1-20091217-C00357
    • 4-Phenyl-1-(3-phenyl-propionyl)-piperidine-4-carboxylic acid (biphenyl-3-ylmethyl)-amide Synthesis
  • Figure US20090312307A1-20091217-C00358
  • Compound 1: Compound 1 is commercially available.
  • Compound 2: A suspension of compound 1 (3.53 g; 9.35 mmol) in 50 mL of tetrahydrofuran was treated with triethylamine (2.9 mL; 20.8 mmol) and the reaction mixture was cooled to 0° C. Hydrocinnamoyl chloride (1.92 g; 11.4 mmol) was added as a solution in 5 mL of tetrahydrofuran. The reaction mixture was allowed to slowly warm to room temperature and stirred for 18 h. The tetrahydrofuran was removed by evaporation and the residue was treated with ethyl acetate (approximately 150 mL) and 10% aqueous hydrochloric acid (approximately 100 mL). The organic layer was separated, washed with saturated aqueous sodium chloride, dried (sodium sulfate), filtered and concentrated. The crude product was purified by recrystallization from ethanol to give 1.02 g of compound 2 as a white solid. LCMS m/z=338 (M+H)+.
  • Compound 3: A suspension of compound 2 (0.23 g; 0.67 mmol) in 12 mL of dichloromethane was treated with triethylamine (0.14 mL; 1.0 mmol) followed by fluoro-N,N,N′-tetramethylformamidinium hexafluorophosphate (0.22 g; 0.83 mmol) at room temperature. After stirring for 1 h, the dichloromethane was removed by evaporation to give 0.23 g of compound 3 that was used in the next step without further purification. LCMS m/z 340 (M+H)+.
  • Title Compound. A solution of compound 3 (0.13 g; 0.39 mmol) in 15 mL of dichloromethane was treated with triethylamine (0.071 mL; 0.51 mmol) followed by 2-phenylbenzyl amine (0.074 mL; 0.043 mmol) at room temperature. After stirring for 8 h, an additional 50 mL of dichloromethane an 40 mL of 10% aqueous hydrochloric acid was added. The organic layer was separated, washed with saturated aqueous sodium chloride, dried (sodium sulfate), filtered and concentrated. Column chromatography on silica gel using 1:1 hexane:ethyl acetate as the eluent gave 0.16 g of 4-phenyl-1-(3-phenylpropionyl)-piperidine-4-carboxylic acid (biphenyl-3-ylmethyl)-amide as a white solid. m/z 504 (M+H)+.
    • Example 287
  • Figure US20090312307A1-20091217-C00359
  • 4-Phenyl-1-(3-phenylpropionyl)-piperidine-4-carboxylic acid methyl-phenethyl-amide
    • Synthesis
  • Figure US20090312307A1-20091217-C00360
  • Compound 1: Compound 1 was prepared as described in Example 286.
  • Title Compound: Compound 1 (0.015 g; 0.05 mmol) was dissolved in 1 mL acetonitrile. Polystyrene-diisopropylethylamine (PS-DIEA) resin (0.1 g) was added and the resulting suspension was treated with N-methylphenethylamine 0.02 g; 0.1 mmol) and shaken at room temperature. After 24 h, polystyrene-tosyl chloride, high loading (PS-TsCl) resin (0.2 g) was added and the reaction mixture was allowed to shake an additional 24 h. The reaction mixture was filtered and concentrated to give 0.010 g of 4-Phenyl-1-(3-phenyl-propionyl)-piperidine-4-carboxylic acid methyl-phenethyl-amide as a colorless oil. LCMS m/z 456 (M+H)+.
    • Examples 288 to 322
  • Examples 288 to 322 were prepared using methodology described in Example 287.
  • Example Structure Name M + H
    288
    Figure US20090312307A1-20091217-C00361
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid (biphenyl-3-ylmethyl)-amide 504
    289
    Figure US20090312307A1-20091217-C00362
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid 3- methyl-benzylamide 442
    290
    Figure US20090312307A1-20091217-C00363
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid 4- chloro-benzylamide 462
    291
    Figure US20090312307A1-20091217-C00364
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid (1- phenyl-ethyl)-amide 442
    292
    Figure US20090312307A1-20091217-C00365
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid (2- phenyl-propyl)-amide 456
    293
    Figure US20090312307A1-20091217-C00366
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid sec- butylamide 394
    294
    Figure US20090312307A1-20091217-C00367
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid indan- 2-ylamide 454
    295
    Figure US20090312307A1-20091217-C00368
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid 2,6- dimethoxy-benzylamide 488
    296
    Figure US20090312307A1-20091217-C00369
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid 3- trifluoromethyl-benzylamide 496
    297
    Figure US20090312307A1-20091217-C00370
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid cyclopentylamide 406
    298
    Figure US20090312307A1-20091217-C00371
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid benzyl-methyl-amide 442
    299
    Figure US20090312307A1-20091217-C00372
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid (2- hydroxy-indan-1-yl)-amide 470
    300
    Figure US20090312307A1-20091217-C00373
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid benzyl-(1-methyl-1H-imidazol-2- ylmethyl)-amide 522
    301
    Figure US20090312307A1-20091217-C00374
         		3-Phenyl-1-[4-phenyl-4-(4-pyridin- 2-yl-piperazine-1-carbonyl)- piperidin-1-yl]-propan-1-one 484
    302
    Figure US20090312307A1-20091217-C00375
         		3-Phenyl-1-[4-phenyl-4-(4- pyrimidin-2-yl-piperazine-1- carbonyl)-piperidin-1-yl]-propan-1- one 485
    303
    Figure US20090312307A1-20091217-C00376
         		1-{4-[4-(4-Chloro-phenyl)- piperazine-1-carbonyl]-4-phenyl- piperidin-1-yl}-3-phenyl-propan-1- one 517
    304
    Figure US20090312307A1-20091217-C00377
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid [2- (1H-indol-3-yl)-ethyl]-amide 481
    305
    Figure US20090312307A1-20091217-C00378
         		1-[4-(3,4-Dihydro-1H- isoquinoline-2-carbonyl)-4-phenyl- piperidin-1-yl]-3-phenyl-propan-1- one 454
    306
    Figure US20090312307A1-20091217-C00379
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid (5- phenyl-1H-pyrazol-3-yl)-amide 480
    307
    Figure US20090312307A1-20091217-C00380
         		1-{4-[4-(2-Chloro-phenyl)- piperazine-1-carbonyl]-4-phenyl- piperidin-1-yl}-3-phenyl-propan-1- one 517
    308
    Figure US20090312307A1-20091217-C00381
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid 3,4- difluoro-benzylamide 464
    309
    Figure US20090312307A1-20091217-C00382
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid (1- benzyl-pyrrolidin-3-yl)-amide 497
    310
    Figure US20090312307A1-20091217-C00383
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid 4- methanesulfonyl-benzylamide 506
    311
    Figure US20090312307A1-20091217-C00384
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid 4- fluoro-benzylamide 446
    312
    Figure US20090312307A1-20091217-C00385
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid [2-(3- chloro-phenyl)-ethyl]-amide 476
    313
    Figure US20090312307A1-20091217-C00386
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid [2-(3- trifluoromethyl-phenyl)-ethyl]- amide 510
    314
    Figure US20090312307A1-20091217-C00387
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid (naphthalen-1-ylmethyl)-amide 478
    315
    Figure US20090312307A1-20091217-C00388
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid 4- trifluoromethyl-benzylamide 496
    316
    Figure US20090312307A1-20091217-C00389
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid (3- methyl-benzo[b]thiophen-2- ylmethyl)-amide 498
    317
    Figure US20090312307A1-20091217-C00390
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid (1- benzyl-piperidin-4-yl)-amide 511
    318
    Figure US20090312307A1-20091217-C00391
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid [2-(1- methyl-pyrrolidin-2-yl)-ethyl]- amide 449
    319
    Figure US20090312307A1-20091217-C00392
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid cyclopropylmethyl-amide 392
    320
    Figure US20090312307A1-20091217-C00393
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid (2- pyridin-2-yl-ethyl)-amide 443
    321
    Figure US20090312307A1-20091217-C00394
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid indan- 1-ylamide 454
    322
    Figure US20090312307A1-20091217-C00395
         		4-Phenyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid (2- morpholin-4-yl-ethyl)-amide 451
    • Example 323
  • Figure US20090312307A1-20091217-C00396
    • 4-(Benzylcarbamoyl-methyl-4-phenyl-piperidine-1-carboxylic acid benzyl ester Synthesis
  • Figure US20090312307A1-20091217-C00397
  • Compound 1: Compound 1 is commercially available.
  • Compound 2: Benzyl chloroformate (4.75 mL, 33.1 mmol) was added dropwise to a solution of 4-phenyl-4-piperidinecarboxylic acid p-methylbenzenesulfonate (10.0 g, 26.5 mmol) in 1M sodium hydroxide (200 mL)/dichloromethane (100 mL). After 2 hours the reaction mixture was made acidic with 1M hydrochloric acid (pH=3), the organic layer was separated and the aqueous layer extracted with ethyl acetate (3×100 mL). The organic layers were collected, concentrated and crude product washed with water (3×50 mL) to give 8.52 g of 4-phenyl-piperidine-1,4-dicarboxylic acid monobenzyl ester. LRMS m/z 340.2 (M+H)+.
  • Compound 3: Thionyl chloride (4.29 mL, 58.9 mmol) was added to 4-Phenyl-piperidine-1,4-dicarboxylic acid monobenzyl ester (2.00 g, 5.89 mmol) and heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, taken up in ethyl ether (25 mL), cooled to 0° C. and diazomethane in ethyl ether was (30.0 mmole, 100 mL) added. After completion of the reaction, as monitored by thin layer chromatography, the excess diazomethane was quenched with acetic acid (5 mL). The reaction mixture was concentrated under reduced pressure and crude product purified by column chromatography to give 1.27 g of 4-(2-diazo-acetyl)-4-phenyl-piperidine-1-carboxylic acid benzyl ester.
  • Compound 4: 4-(2-Diazo-acetyl)-4-phenyl-piperidine-1-carboxylic acid benzyl ester (1.50 g, 4.12 mmol) in methanol (40 mL) was irradiated under UV (λ=365 nM) for 36 hours. The reaction mixture was concentrated under reduced pressure, crude product taken up in 3M lithium hydroxide (20 mL)/dioxane (20 mL) and heated to 60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to remove dioxane, made acidic with 6M hydrochloric acid, and extracted with ethyl acetate (6×50 mL). Organic layers were collected, concentrated and crude product purified by column chromatography to give 1.16 g of 4-carboxymethyl-4-phenyl-piperidine-1-carboxylic acid benzyl ester. 1H NMR (CD3Cl3, 300 MHz) δ 7.32 (m, 10H), 5.10 (s, 2H), 3.76 (d, 2H, J=13.4 Hz), 3.20 (t, 2H, J=10.7 Hz), 2.56 (s, 2H), 2.31 (d, 2H, J=13.6 Hz), 1.91 (t, 2H, J=13.0 Hz).
  • Title Compound: Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.120 g, 0.271 mmol) was added to a solution of benzyl amine (0.030 mL, 0.271 mmol), 4-carboxymethyl-4-phenyl-piperidine-1-carboxylic acid benzyl ester (0.100 g, 0.247 mmol), triethylamine (0.103 mL, 0.741 mmol) in tetrahydrofuran (5 ml). After 1 hour the mixture was diluted with ethyl ether (20 mL), washed with saturated aqueous sodium bicarbonate (20 mL) followed by water (2×10 mL). Organic layer collected, concentrated under reduced pressure and crude product purified by column chromatography to give 0.099 g of 4-(benzylcarbamoyl-methyl)-4-phenyl-piperidine-1-carboxylic acid benzyl ester. LRMS m/z 443.2 (M+H)+.
    • Example 324
  • Figure US20090312307A1-20091217-C00398
    • N-[2-(2-Fluoro-phenyl)-ethyl]-2-{1-[3-(4-fluorophenyl)-propionyl]-4-phenyl-piperidin-4-yl}-acetamide Synthesis
  • Figure US20090312307A1-20091217-C00399
  • Compound 1: Compound 1 were prepared using methodology described in Example 323.
  • Compound 2: Ammonium formate (1.00 g) was added to a solution of 4-{[2-(2-fluoro-phenyl)-ethylcarbamoyl]-methyl}-4-phenylpiperidine-1-carboxylic acid benzyl ester (0.520 g, 1.10 mmol) in methanol (50 mL) containing 10% palladium/carbon (0.500 g) and stirred for 4 h. The reaction mixture was filtered through CELITE® and concentrated under reduced pressure. The crude product was taken up in 1M sodium hydroxide (100 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were collected and concentrated under reduced pressure to give 0.328 g (87%) of N-[2-(2-fluoro-phenyl)-ethyl]-2-(4-phenyl-piperidin-4-yl)-acetamide. LRMS m/z 341.1 (M+H)+.
  • Title Compound: Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.311 g, 0.704 mmol) was added to a solution of N-[2-(2-fluoro-phenyl)-ethyl]-2-(4-phenyl-piperidin-4-yl)-acetamide (0.200 g, 0.587 mmol), 3-(4-Fluoro-phenyl)-propionic acid (0.118 g, 0.704 mmol) and triethylamine (0.245 mL, 1.76 mmol) in tetrahydrofuran (5 mL). After 1 hour the mixture was diluted with ethyl ether (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL) followed by water (2×10 mL). The organic layer was collected, concentrated under reduced pressure and crude product purified by column chromatography on silica gel to give 0.098 g (34%) of N-[2-(2-fluoro-phenyl)-ethyl]-2-{1-[3-(4-fluoro-phenyl)-propionyl]-4-phenyl-piperidin-4-yl}-acetamide. LRMS m/z 491.1 (M+H)+.
    • Examples 325 to 380
  • Examples 325 to 380 were synthesized using methodology described in Example 324.
  • Example Structure Name M + H
    325
    Figure US20090312307A1-20091217-C00400
         		4-Phenyl-4-{[(thiophen-2- ylmethyl)-carbamoyl]-methyl}- piperidine-1-carboxylic acid benzyl ester 450
    326
    Figure US20090312307A1-20091217-C00401
         		4-Phenyl-4-[(1-phenyl- ethylcarbamoyl)-methyl]- piperidine-1-carboxylic acid benzyl ester 458
    327
    Figure US20090312307A1-20091217-C00402
         		4-[(2-Methoxy-benzylcarbamoyl)- methyl]-4-phenyl-piperidine-1- carboxylic acid benzyl ester 474
    328
    Figure US20090312307A1-20091217-C00403
         		4-[(3-Methoxy-benzylcarbamoyl)- methyl]-4-phenyl-piperidine-1- carboxylic acid benzyl ester 474
    329
    Figure US20090312307A1-20091217-C00404
         		4-[(4-Methoxy-benzylcarbamoyl)- methyl]-4-phenyl-piperidine-1- carboxylic acid benzyl ester 474
    330
    Figure US20090312307A1-20091217-C00405
         		4-[(2,3-Dimethoxy- benzylcarbamoyl)-methyl]-4- phenyl-piperidine-1-carboxylic acid benzyl ester 504
    331
    Figure US20090312307A1-20091217-C00406
         		4-[(2,4-Dimethoxy- benzylcarbamoyl)-methyl]-4- phenyl-piperidine-1-carboxylic acid benzyl ester 504
    332
    Figure US20090312307A1-20091217-C00407
         		4-[(3-Methyl-benzylcarbamoyl)- methyl]-4-phenyl-piperidine-1- carboxylic acid benzyl ester 458
    333
    Figure US20090312307A1-20091217-C00408
         		4-[(4-Methyl-benzylcarbamoyl)- methyl]-4-phenyl-piperidine-1- carboxylic acid benzyl ester 458
    334
    Figure US20090312307A1-20091217-C00409
         		4-[(4-Fluoro-benzylcarbamoyl)- methyl]-4-phenyl-piperidine-1- carboxylic acid benzyl ester 462
    335
    Figure US20090312307A1-20091217-C00410
         		4-[(2-Chloro-benzylcarbamoyl)- methyl]-4-phenyl-piperidine-1- carboxylic acid benzyl ester 478
    336
    Figure US20090312307A1-20091217-C00411
         		4-[(4-Chloro-benzylcarbamoyl)- methyl]-4-phenyl-piperidine-1- carboxylic acid benzyl ester 478
    337
    Figure US20090312307A1-20091217-C00412
         		4-Phenyl-4-[(3-trifluoromethyl- benzylcarbamoyl)-methyl]- piperidine-1-carboxylic acid benzyl ester 512
    338
    Figure US20090312307A1-20091217-C00413
         		4-Phenyl-4-[(4-trifluoromethyl- benzylcarbamoyl)-methyl]- piperidine-1-carboxylic acid benzyl ester 512
    339
    Figure US20090312307A1-20091217-C00414
         		4-(Phenethylcarbamoyl-methyl)-4- phenyl-piperidine-1-carboxylic acid benzyl ester 458
    340
    Figure US20090312307A1-20091217-C00415
         		4-{[2-(2-Fluoro-phenyl)- ethylcarbamoyl]-methyl}-4-phenyl- piperidine-1-carboxylic acid benzyl ester 476
    341
    Figure US20090312307A1-20091217-C00416
         		4-{[2-(3-Fluoro-phenyl)- ethylcarbamoyl]-methyl}-4-phenyl- piperidine-1-carboxylic acid benzyl ester 476
    342
    Figure US20090312307A1-20091217-C00417
         		4-{[2-(4-Fluoro-phenyl)- ethylcarbamoyl]-methyl}-4-phenyl- piperidine-1-carboxylic acid benzyl ester 476
    343
    Figure US20090312307A1-20091217-C00418
         		4-Phenyl-4-{[2-(3-trifluoromethyl- phenyl)-ethylcarbamoyl]-methyl}- piperidine-1-carboxylic acid benzyl ester 526
    344
    Figure US20090312307A1-20091217-C00419
         		4-{[2-(4-Ethyl-phenyl)- ethylcarbamoyl]-methyl}-4-phenyl- piperidine-1-carboxylic acid benzyl ester 486
    345
    Figure US20090312307A1-20091217-C00420
         		4-{[2-(2,5-Dimethoxy-phenyl)- ethylcarbamoyl]-methyl}-4-phenyl- piperidine-1-carboxylic acid benzyl ester 518
    346
    Figure US20090312307A1-20091217-C00421
         		4-Phenyl-4-{[(pyridin-3-ylmethyl)- carbamoyl]-methyl}-piperidine-1- carboxylic acid benzyl ester 445
    347
    Figure US20090312307A1-20091217-C00422
         		4-Phenyl-4-{[(pyridin-4-ylmethyl)- carbamoyl]-methyl}-piperidine-1- carboxylic acid benzyl ester 445
    348
    Figure US20090312307A1-20091217-C00423
         		4-Phenyl-4-[(2-pyridin-4-yl- ethylcarbamoyl)-methyl]- piperidine-1-carboxylic acid benzyl ester 459
    349
    Figure US20090312307A1-20091217-C00424
         		2-{1-[3-(4-Fluoro-phenyl)- propionyl]-4-phenyl-piperidin-4- yl}-N-(1-phenyl-ethyl)-acetamide 474
    350
    Figure US20090312307A1-20091217-C00425
         		N-(1-Phenyl-ethyl)-2-[4-phenyl-1- (3-phenyl-propionyl)-piperidin-4- yl]-acetamide 456
    351
    Figure US20090312307A1-20091217-C00426
         		2-{1-[2-(4-Fluoro-phenyl)-acetyl]- 4-phenyl-piperidin-4-yl}-N-(1- phenyl-ethyl)-acetamide 460
    352
    Figure US20090312307A1-20091217-C00427
         		2-[1-(4-Fluoro-benzoyl)-4-phenyl- piperidin-4-yl]-N-(1-phenyl-ethyl)- acetamide 446
    353
    Figure US20090312307A1-20091217-C00428
         		2-[1-(2,3-Difluoro-benzoyl)-4- phenyl-piperidin-4-yl]-N-(1- phenyl-ethyl)-acetamide 464
    354
    Figure US20090312307A1-20091217-C00429
         		N-(1-Phenyl-ethyl)-2-[4-phenyl-1- (2,4,5-trifluoro-benzoyl)-piperidin- 4-yl]-acetamide 482
    355
    Figure US20090312307A1-20091217-C00430
         		N-[2-(2-Fluoro-phenyl)-ethyl]-2- [4-phenyl-1-(3-phenyl-propionyl)- piperidin-4-yl]-acetamide 474
    356
    Figure US20090312307A1-20091217-C00431
         		2-{1-[2-(4-Fluoro-phenyl)-acetyl]- 4-phenyl-piperidin-4-yl}-N-[2-(2- fluoro-phenyl)-ethyl]-acetamide 478
    357
    Figure US20090312307A1-20091217-C00432
         		2-[1-(4-Fluoro-benzoyl)-4-phenyl- piperidin-4-yl]-N-[2-(2-fluoro- phenyl)-ethyl]-acetamide 464
    358
    Figure US20090312307A1-20091217-C00433
         		2-[1-(2,3-Difluoro-benzoyl)-4- phenyl-piperidin-4-yl]-N-[2-(2- fluoro-phenyl)-ethyl]-acetamide 482
    359
    Figure US20090312307A1-20091217-C00434
         		N-[2-(2-Fluoro-phenyl)-ethyl]-2- [4-phenyl-1-(2,4,5-trifluoro- benzoyl)-piperidin-4-yl]-acetamide 500
    360
    Figure US20090312307A1-20091217-C00435
         		4-[(2-Methoxy-phenylcarbamoyl)- methyl]-4-phenyl-piperidine-1- carboxylic acid benzyl ester 460
    361
    Figure US20090312307A1-20091217-C00436
         		4-Phenyl-4-{[(pyridin-2-ylmethyl)- carbamoyl]-methyl}-piperidine-1- carboxylic acid benzyl ester 445
    362
    Figure US20090312307A1-20091217-C00437
         		4-Phenyl-4-[(1H-pyrazol-3- ylcarbamoyl)-methyl]-piperidine-1- carboxylic acid benzyl ester 419
    363
    Figure US20090312307A1-20091217-C00438
         		4-(Isoxazol-3-ylcarbamoylmethyl)- 4-phenyl-piperidine-1-carboxylic acid benzyl ester 420
    364
    Figure US20090312307A1-20091217-C00439
         		4-[(3-Methyl-isoxazol-5- ylcarbamoyl)-methyl]-4-phenyl- piperidine-1-carboxylic acid benzyl ester 435
    365
    Figure US20090312307A1-20091217-C00440
         		4-[(5-Methyl-isoxazol-3- ylcarbamoyl)-methyl]-4-phenyl- piperidine-1-carboxylic acid benzyl ester 435
    366
    Figure US20090312307A1-20091217-C00441
         		4-Phenyl-4-(thiazol-2- ylcarbamoylmethyl)-piperidine-1- carboxylic acid benzyl ester 437
    367
    Figure US20090312307A1-20091217-C00442
         		4-Phenyl-4-([1,3,4]thiadiazol-2- ylcarbamoylmethyl)-piperidine-1- carboxylic acid benzyl ester 438
    368
    Figure US20090312307A1-20091217-C00443
         		4-Phenyl-4-[(1H-tetrazol-5- ylcarbamoyl)-methyl]piperidine-1- carboxylic acid benzyl ester 421
    369
    Figure US20090312307A1-20091217-C00444
         		4-[(2-Ethyl-2H-pyrazol-3- ylcarbamoyl)-methyl]-4-phenyl- piperidine-1-carboxylic acid benzyl ester 448
    370
    Figure US20090312307A1-20091217-C00445
         		4-[(2,5-Dimethyl-2H-pyrazol-3- ylcarbamoyl)-methyl]-4-phenyl- piperidine-1-carboxylic acid benzyl ester 448
    371
    Figure US20090312307A1-20091217-C00446
         		4-(Benzothiazol-2- ylcarbamoylmethyl)-4-phenyl- piperidine-1-carboxylic acid benzyl ester 487
    372
    Figure US20090312307A1-20091217-C00447
         		4-[(3-Methyl-isothiazol-5- ylcarbamoyl)-methyl]-4-phenyl- piperidine-1-carboxylic acid benzyl ester 451
    373
    Figure US20090312307A1-20091217-C00448
         		4-Phenyl-4-[(5-phenyl-2H-pyrazol- 3-ylcarbamoyl)-methyl]-piperidine- 1-carboxylic acid benzyl ester 496
    374
    Figure US20090312307A1-20091217-C00449
         		4-Phenyl-4-[(5-phenyl-oxazol-2- ylcarbamoyl)-methyl]-piperidine-1- carboxylic acid benzyl ester 497
    375
    Figure US20090312307A1-20091217-C00450
         		4-[(5-Chloro-benzooxazol-2- ylcarbamoyl)-methyl]-4-phenyl- piperidine-1-carboxylic acid benzyl ester 505
    376
    Figure US20090312307A1-20091217-C00451
         		4-Phenyl-4-[(5-trifluoromethyl- [1,3,4]thiadiazol-2-ylcarbamoyl)- methyl]-piperidine-1-carboxylic acid benzyl ester 506
    377
    Figure US20090312307A1-20091217-C00452
         		4-[(2-Methyl-5-phenyl-2H-pyrazol- 3-ylcarbamoyl)-methyl]-4-phenyl- piperidine-1-carboxylic acid benzyl ester 510
    378
    Figure US20090312307A1-20091217-C00453
         		4-[(5-Oxo-1-phenyl-4,5-dihydro- 1H-pyrazol-3-ylcarbamoyl)- methyl]-4-phenyl-piperidine-1- carboxylic acid benzyl ester 512
    379
    Figure US20090312307A1-20091217-C00454
         		4-Phenyl-4-[(4-phenyl-thiazol-2- ylcarbamoyl)-methyl]-piperidine-1- carboxylic acid benzyl ester 513
    380
    Figure US20090312307A1-20091217-C00455
         		N-(2-methoxy-phenyl)-2-[4- phenyl-1-(3-phenyl-propionyl)- piperidin-4-yl]-acetamide 458
    • Example 381
  • Figure US20090312307A1-20091217-C00456
    • 2-[1-Fluorobenzenesulfonyl)-4-phenyl-piperidin-4-yl]-N-(2-methoxy-phenyl)-acetamide Synthesis
  • Figure US20090312307A1-20091217-C00457
  • Compound 1: Compound 1 was prepared using methodology described in Example 324. LRMS m/z 325 (M+H)+.
  • Title compound: 2-[1-(4-Fluoro-benzenesulfonyl)-4-phenyl-piperidin-4-yl]-N-(2-methoxy-phenyl)-acetamide was prepared using methodology described in Example 95. LRMS m/z 484 (M+H)+.
    • Example 382
  • Figure US20090312307A1-20091217-C00458
    • N-(2-Methoxy-phenyl)-2-(4-phenyl-1-pyrimidin-2-yl-piperidin-4-yl)-acetamide Synthesis
  • Figure US20090312307A1-20091217-C00459
  • Compound 1: Compound 1 was prepared using methodology described in Example 324. LRMS m/z 325 (M+H)+.
  • Title Compound: N-(2-Methoxy-phenyl)-2-(4-phenyl-1-pyrimidin-2-yl-piperidin-4-yl)-acetamide was prepared using methodology described in Example 521. LRMS m/z 403 (M+H)+.
    • Example 383
  • Figure US20090312307A1-20091217-C00460
    • Synthesis
  • Figure US20090312307A1-20091217-C00461
  • Compound 1: Compound 1 was prepared using methodology described in Example 324. LRMS m/z 325 (M+H)+.
  • Compound 2: Compound 2 was prepared using methodology described in Example 25. LRMS m/z 470 (M+H)+.
  • Title Compound: The title compound was prepared using methodology described in Example 25. LRMS m/z 421 (M+H)+.
    • Examples 384 and 385
  • Examples 384 and 385 was prepared using methodology described in Example 383.
  • Example Structure Name (M + H)
    384
    Figure US20090312307A1-20091217-C00462
         		483
    385
    Figure US20090312307A1-20091217-C00463
         		497
    • Example 386
  • Figure US20090312307A1-20091217-C00464
    • 2-(1-Dimethylsulfamoyl-4-phenyl-piperidin-4-yl)-N-(2-methoxyphenyl)-acetamide Synthesis
  • Figure US20090312307A1-20091217-C00465
  • Compound 1: Compound 1 was prepared using methodology described in Example 324. LRMS m/z 325 (M+H)+.
  • Title Compound: 2-(1-Dimethylsulfamoyl-4-phenyl-piperidin-4-yl)-N-(2-methoxy-phenyl)-acetamide was prepared using methodology described in Example 16. LRMS m/z 432 (M+H)+.
    • Example 387
  • Figure US20090312307A1-20091217-C00466
    • 2-(1-Cyano-4-phenyl-piperidin-4-yl)-N-(2-methoxy-phenyl)-acetamide Synthesis
  • Figure US20090312307A1-20091217-C00467
  • Compound 1: Compound 1 was prepared using methodology described in Example 324. LRMS m/z 325 (M+H)+.
  • Title Compound. 2-(1-Cyano-4-phenyl-piperidin-4-yl)-N-(2-methoxy-phenyl)-acetamide may prepared using methodology described in Example 521 using cyanogen bromide instead of 2-chloropyrimidine. LRMS m/z 350 (M+H)+.
    • Example 388
  • Figure US20090312307A1-20091217-C00468
    • 2-[1-(2-Methoxy-ethylsulfamoyl)-4-phenyl-piperidin-4-yl]-N-(2-methoxy-phenyl)-acetamide Synthesis
  • Figure US20090312307A1-20091217-C00469
  • Compound 1: Compound 1 was prepared using methodology described in Example 324. LRMS m/z 325 (M+1H)+.
  • Title Compound: 2-[1-(2-Methoxy-ethylsulfamoyl)-4-phenyl-piperidin-4-yl]-N-(2-methoxy-phenyl)-acetamide was prepared using methodology described in Example 17. LRMS m/z 462 (M+H)+.
    • Example 389
  • Example 389 was prepared using methodology described in Example 388.
  • Example Structure Name M + H
    389
    Figure US20090312307A1-20091217-C00470
         		N-(2-Methoxy-phenyl)-2-(4-phenyl- 1-propylsulfamoyl-piperidin-4-yl)- acetamide 447
    • Example 390
  • Figure US20090312307A1-20091217-C00471
    • 4-Benzyl-1-(3-phenyl-propionyl)-piperidine-4-carboxylic acid benzylamide Synthesis
  • Figure US20090312307A1-20091217-C00472
  • Compound 1: Compound 1 is commercially available.
  • Compound 2: A solution of compound 1 (0.86 g; 2.7 mmol) in tetrahydrofuran (25 mL) was treated with triethylamine (0.49 mL; 3.7 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.3 g; 2.9 mmol). After 0.5 h benzylamine (0.33 mL; 3.0 mmol) was added and the reaction mixture was heated to 50° C. for 15 h. The tetrahydrofuran was removed by evaporation and the residue was portioned between ethyl acetate and 5% aqueous hydrochloric acid. The organic layer was separated, washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated. Column chromatography on silica gel using 1:1 hexane:ethyl acetate as the eluent gave 0.81 g of compound 2 as a colorless oil. LRMS m/z 410 (M+H)+.
  • Compound 3: A solution of compound 2 (0.41 g; 10.0 mmol) in dichloromethane (15 mL) was treated with trifluoroacetic acid (2 mL) at room temperature. After 24 h additional dichloromethane (50 mL) and 1 N sodium hydroxide (40 mL) was added. The organic layer was separated, washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated to give compound 3 that was used in the next step without additional purification. LRMS m/z 309 (M+H)+.
  • Title Compound: A solution of compound 3 (0.16 g; 0.52 mmol) in tetrahydrofuran (20 mL) was treated with triethylamine (0.09 mL; 0.65 mmol) and hydrocinnamoyl chloride (0.1 g; 0.59 mmol) at room temperature. After 16 h the tetrahydrofuran was removed by evaporation and the residue was portioned between ethyl acetate and 5% aqueous hydrochloric acid. The organic layer was separated, washed with saturated sodium chloride, dried (anhydrous sodium sulfate) and concentrated. Column chromatography on silica gel using 1:1 hexane:ethyl acetate as the eluent gave 0.15 g of 4-benzyl-1-(3-phenyl-propionyl)-piperidine-4-carboxylic acid benzylamide as a white solid. LRMS m/z 442 (M+H)+.
    • Example 391
  • Figure US20090312307A1-20091217-C00473
    • 4-(2-Fluoro-benzyl)-1-[3-(4-fluoro-phenyl)-propionyl]-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]-amide Synthesis
  • Figure US20090312307A1-20091217-C00474
  • Compound 1: Compound 1 is commercially available.
  • Compound 2: Di-tert-butyl dicarbonate (12.66 g, 58.0 mmol) was added to a solution of piperidine-4-carboxylic acid (5.00 g, 38.7 mmol) in dioxane (100 mL) and saturated aqueous sodium bicarbonate (100 mL) and stirred at room temperature for 48 h. The reaction mixture was concentrated to 100 mL under reduced pressure and ethyl acetate (200 mL) was added. The solution was made acidic with 6M hydrochloric acid (pH=3), the organic layer collected and concentrated under reduced pressure to give 7.22 g of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester. LRMS m/z 228.1 (M−H)−.
  • Compound 3: Lithium diisopropylamide (10.9 mmol, 2M tetrahydrofuran) was added to a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.00 g, 4.36 mmol) in tetrahydrofuran (25 mL) at 0° C. After 1.5 h 2-fluorobenzyl bromide (0.788 mL, 6.54 mmol) was added, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with the addition of water (10 mL) followed by 1M hydrochloric acid (10 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL), the organic layers collected, concentrated under reduced pressure and crude product purified by column chromatography to give 0.330 g, (22%) of 4-(2-fluoro-benzyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester. 1H-NMR (CD3Cl3, 300 MHz) δ 7.11-7.00 (m, 5H), 4.00 (br., 2H), 2.92 (s, 2H), 2.90 (br., 2H), 2.05 (br., 2H), 1.46 (br., 2H), 1.44 (s, 9H).
  • Compound 4: Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.650 g, 1.47 mmol) was added to a solution of 2-(4-ethyl-phenyl)-ethylamine (0.235 mL, 1.47 mmol), 4-(2-fluoro-benzyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.330 g, 0.978 mmol) and triethylamine (0.409 mL, 2.93 mmol) in tetrahydrofuran (5 mL). After 1 hour the mixture was diluted with ethyl ether (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL) followed by water (2×10 mL). The organic layer was collected, concentrated under reduced pressure and crude product purified by column chromatography to give 0.301 g (65%) of 4-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-4-(2-fluoro-benzyl)-piperidine-1-carboxylic acid tert-butyl ester. LAMS m/z 469.1 (M+H)+.
  • Compound 5: Trifluoroacetic acid (20 mL) was added to a solution 4-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-4-(2-fluoro-benzyl)-piperidine-1-carboxylic acid tert-butyl ester (0.300 g, 0.64 mmol) in dichloromethane (50 mL). After 1 h the reaction mixture was concentrated under reduced pressure, the crude product taken up in 1 M sodium hydroxide (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were collected, concentrated under reduced pressure and crude product purified by column chromatography to give 0.188 g (80%) of 4-(2-fluoro-benzyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]-amide LRMS m/z 369.1 (M+H)+.
  • Title Compound: Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.266 g, 0.602 mmol) was added to a solution of 4-(2-fluoro-benzyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]-amide (0.185 g, 0.502 mmol), 3-(4-fluoro-phenyl)-propionic acid (0.101 g, 0.602 mmol) and triethylamine (0.210 mL, 1.51 mmol) in tetrahydrofuran (5 mL). After 1 h the mixture was diluted with ethyl ether (20 mL), washed with saturated aqueous sodium bicarbonate (20 mL) followed by water (2×10 mL). The organic layer was collected, concentrated under reduced pressure and the crude product purified by column chromatography to give 0.105 g (40%) of 4-(2-fluoro-benzyl)-1-[3-(4-fluoro-phenyl)-propionyl]-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]-amide LRMS m/z 519.2 (M+H)+.
    • Example 392
  • Figure US20090312307A1-20091217-C00475
    • 4-Benzyl-1-(4-fluoro-benzenesulfonyl)-piperidine-4-carboxylic acid benzylamide Synthesis
  • Figure US20090312307A1-20091217-C00476
  • Compound 1: Compound 1 was prepared as described in Example 390.
  • Title Compound: 4-Benzyl-1-(4-fluoro-benzenesulfonyl)-piperidine-4-carboxylic acid benzylamide was prepared using methodology described in Example 95. LRMS m/z 467 (M+H)+.
    • Examples 393 to 520
  • Examples 393 to 530 were synthesized using methodology described in Example 391 and Example 392.
  • Example Structure Name M + H
    393
    Figure US20090312307A1-20091217-C00477
         		4-Benzyl-4-benzylcarbamoyl- piperidine-1-carboxylic acid benzyl ester 444
    394
    Figure US20090312307A1-20091217-C00478
         		4-Benzyl-1-(2-phenoxy-acetyl)- piperidine-4-carboxylic acid benzylamide 444
    395
    Figure US20090312307A1-20091217-C00479
         		4-Benzyl-1-(3-phenyl-acryloyl)- piperidine-4-carboxylic acid benzylamide 440
    396
    Figure US20090312307A1-20091217-C00480
         		4-Benzyl-1-phenylacetyl- piperidine-4-carboxylic acid benzylamide 428
    397
    Figure US20090312307A1-20091217-C00481
         		1-Benzoyl-4-benzyl-piperidine-4- carboxylic acid benzylamide 414
    398
    Figure US20090312307A1-20091217-C00482
         		4-Benzyl-1-propionyl-piperidine-4- carboxylic acid benzylamide 365
    399
    Figure US20090312307A1-20091217-C00483
         		4-Benzyl-1-(2-benzyloxy-acetyl)- piperidine-4-carboxylic acid benzylamide 458
    400
    Figure US20090312307A1-20091217-C00484
         		4-Benzyl-4-(4-fluoro- benzylcarbamoyl)-piperidine-1- carboxylic acid tert-butyl ester 428
    401
    Figure US20090312307A1-20091217-C00485
         		4-Benzyl-4-(3-trifluoromethyl- benzylcarbamoyl)-piperidine-1- carboxylic acid tert-butyl ester 478
    402
    Figure US20090312307A1-20091217-C00486
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid 3- trifluoromethyl-benzylamide 510
    403
    Figure US20090312307A1-20091217-C00487
         		4-Benzyl-1-[3-(2-chloro-phenyl)- propionyl]-piperidine-4-carboxylic acid 3-trifluoromethyl-benzylamide 544
    404
    Figure US20090312307A1-20091217-C00488
         		4-Benzyl-1-(4-fluoro-benzyl)- piperidine-4-carboxylic acid 3- trifluoromethyl-benzylamide 486
    405
    Figure US20090312307A1-20091217-C00489
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid 4- fluoro-benzylamide 460
    406
    Figure US20090312307A1-20091217-C00490
         		4-Benzyl-1-[3-(2-chloro-phenyl)- propionyl]-piperidine-4-carboxylic acid 4-fluoro-benzylamide 494
    407
    Figure US20090312307A1-20091217-C00491
         		4-Benzyl-1-[3-(4-methoxy-phenyl)- propionyl]-piperidine-4-carboxylic acid 3-trifluoromethyl-benzylamide 540
    408
    Figure US20090312307A1-20091217-C00492
         		4-Benzyl-1-[3-(4-trifluoromethyl- phenyl)-propionyl]-piperidine-4- carboxylic acid 3-trifluoromethyl- benzylamide 578
    409
    Figure US20090312307A1-20091217-C00493
         		4-Benzyl-1-[3-(3,4-difluoro- phenyl)-propionyl]-piperidine-4- carboxylic acid 3-trifluoromethyl- benzylamide 546
    410
    Figure US20090312307A1-20091217-C00494
         		4-Benzyl-1-[3-(4-fluoro-phenyl)- acryloyl]-piperidine-4-carboxylic acid 3-trifluoromethyl-benzylamide 526
    411
    Figure US20090312307A1-20091217-C00495
         		4-Benzyl-1-(4-fluoro-benzoyl)- piperidine-4-carboxylic acid 3- trifluoromethyl-benzylamide 500
    412
    Figure US20090312307A1-20091217-C00496
         		4-Benzyl-1-[2-(4-chloro-phenoxy)- acetyl]-piperidine-4-carboxylic acid 3-trifluoromethyl-benzylamide 546
    413
    Figure US20090312307A1-20091217-C00497
         		4-Benzyl-1-[3-(4-methoxy-phenyl)- propionyl]-piperidine-4-carboxylic acid 4-fluoro-benzylamide 490
    414
    Figure US20090312307A1-20091217-C00498
         		4-Benzyl-1-[3-(4-trifluoromethyl- phenyl)-propionyl]-piperidine-4- carboxylic acid 4-fluoro- benzylamide 528
    415
    Figure US20090312307A1-20091217-C00499
         		4-Benzyl-1-[3-(3,4-difluoro- phenyl)-propionyl]-piperidine-4- carboxylic acid 4-fluoro- benzylamide 496
    416
    Figure US20090312307A1-20091217-C00500
         		4-Benzyl-1-(3-phenyl-propynoyl)- piperidine-4-carboxylic acid 4- fluoro-benzylamide 456
    417
    Figure US20090312307A1-20091217-C00501
         		4-Benzyl-1-(4-fluoro-benzoyl)- piperidine-4-carboxylic acid 4- fluoro-benzylamide 450
    418
    Figure US20090312307A1-20091217-C00502
         		4-Benzyl-1-[2-(4-chloro-phenoxy)- acetyl]-piperidine-4-carboxylic acid 4-fluoro-benzylamide 496
    419
    Figure US20090312307A1-20091217-C00503
         		4-Benzyl-1-(4-methoxy- benzenesulfonyl)-piperidine-4- carboxylic acid 4-fluoro- benzylamide 498
    420
    Figure US20090312307A1-20091217-C00504
         		4-(4-Fluoro-benzyl)-1-(3-phenyl- propionyl)-piperidine-4-carboxylic acid 3-trifluoromethyl-benzylamide 528
    421
    Figure US20090312307A1-20091217-C00505
         		1-(4-Fluoro-benzenesulfonyl)-4-(4- fluoro-benzyl)-piperidine-4- carboxylic acid 3-trifluoromethyl- benzylamide 554
    422
    Figure US20090312307A1-20091217-C00506
         		4-(4-Fluoro-benzyl)-4- phenethylcarbamoyl-piperidine-1- carboxylic acid tert-butyl ester 442
    423
    Figure US20090312307A1-20091217-C00507
         		4-[2-(4-Ethyl-phenyl)- ethylcarbamoyl]-4-(4-fluoro- benzyl)-piperidine-1-carboxylic acid tert-butyl ester 470
    424
    Figure US20090312307A1-20091217-C00508
         		4-(4-Fluoro-benzyl)-1-(3-phenyl- propionyl)-piperidine-4-carboxylic acid phenethyl-amide 474
    425
    Figure US20090312307A1-20091217-C00509
         		4-(4-Fluoro-benzyl)-1-(2-phenoxy- acetyl)-piperidine-4-carboxylic acid phenethyl-amide 476
    426
    Figure US20090312307A1-20091217-C00510
         		1-(4-Fluoro-benzenesulfonyl)-4-(4- fluoro-benzyl)-piperidine-4- carboxylic acid phenethyl-amide 500
    427
    Figure US20090312307A1-20091217-C00511
         		4-(4-Fluoro-benzyl)-1-(3-phenyl- propionyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]- amide 502
    428
    Figure US20090312307A1-20091217-C00512
         		4-(4-Fluoro-benzyl)-1-(2-phenoxy- acetyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]- amide 504
    429
    Figure US20090312307A1-20091217-C00513
         		1-(4-Fluoro-benzenesulfonyl)-4-(4- fluoro-benzyl)-piperidine-4- carboxylic acid [2-(4-ethyl- phenyl)-ethyl]-amide 528
    430
    Figure US20090312307A1-20091217-C00514
         		1-Benzenesulfonyl-4-benzyl- piperidine-4-carboxylic acid [2-(4- ethyl-phenyl)-ethyl]-amide 492
    431
    Figure US20090312307A1-20091217-C00515
         		4-Benzyl-1-(toluene-4-sulfonyl)- piperidine-4-carboxylic acid [2-(4- ethyl-phenyl)-ethyl]-amide 506
    432
    Figure US20090312307A1-20091217-C00516
         		4-Benzyl-1-(4-fluoro- benzenesulfonyl)-piperidine-4- carboxylic acid [2-(4-ethyl- phenyl)-ethyl]-amide 510
    433
    Figure US20090312307A1-20091217-C00517
         		4-Benzyl-1-(4-methoxy- benzenesulfonyl)-piperidine-4- carboxylic acid [2-(4-ethyl- phenyl)-ethyl]-amide 522
    434
    Figure US20090312307A1-20091217-C00518
         		4-Benzyl-1-(4-chloro- benzenesulfonyl)-piperidine-4- carboxylic acid [2-(4-ethyl- phenyl)-ethyl]-amide 526
    435
    Figure US20090312307A1-20091217-C00519
         		4-Benzyl-1-(4-trifluoromethoxy- benzenesulfonyl)-piperidine-4- carboxylic acid [2-(4-ethyl- phenyl)-ethyl]-amide 576
    436
    Figure US20090312307A1-20091217-C00520
         		4-Benzyl-1-[2-(4-fluoro-phenyl)- acetyl]-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]- amide 488
    437
    Figure US20090312307A1-20091217-C00521
         		4-Benzyl-1-(4-chloro-benzoyl)- piperidine-4-carboxylic acid [2-(4- ethyl-phenyl)-ethyl]-amide 490
    438
    Figure US20090312307A1-20091217-C00522
         		4-Benzyl-1-(2-phenyl- cyclopropanecarbonyl)-piperidine- 4-carboxylic acid [2-(4-ethyl- phenyl)-ethyl]-amide 496
    439
    Figure US20090312307A1-20091217-C00523
         		4-Benzyl-1-[2-(4-methoxy-phenyl)- acetyl]-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]- amide 500
    440
    Figure US20090312307A1-20091217-C00524
         		4-Benzyl-1-[2-(4-chloro-phenyl)- acetyl]-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]- amide 504
    441
    Figure US20090312307A1-20091217-C00525
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid [2-(2- methoxy-phenyl)-ethyl]-amide 486
    442
    Figure US20090312307A1-20091217-C00526
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid [2-(4- bromo-phenyl)-ethyl]-amide 535
    443
    Figure US20090312307A1-20091217-C00527
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid (2-p- tolyl-ethyl)-amide 470
    444
    Figure US20090312307A1-20091217-C00528
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid [2- (2,5-dimethoxy-phenyl)-ethyl]- amide 516
    445
    Figure US20090312307A1-20091217-C00529
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid (2- benzo[1,3]dioxol-5-yl-ethyl)-amide 500
    446
    Figure US20090312307A1-20091217-C00530
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid [2- (3,4-dichloro-phenyl)-ethyl]-amide 525
    447
    Figure US20090312307A1-20091217-C00531
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid [2- (2,4-dimethyl-phenyl)-ethyl]-amide 484
    448
    Figure US20090312307A1-20091217-C00532
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid [2- (3,4-dimethyl-phenyl)-ethyl]-amide 484
    449
    Figure US20090312307A1-20091217-C00533
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid (2-o- tolyl-ethyl)-amide 470
    450
    Figure US20090312307A1-20091217-C00534
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid (2-m- tolyl-ethyl)-amide 470
    451
    Figure US20090312307A1-20091217-C00535
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid (3- methyl-benzo[b]thiophen-2- ylmethyl)-amide 512
    452
    Figure US20090312307A1-20091217-C00536
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid [2-(4- chloro-phenyl)-ethyl]-amide 490
    453
    Figure US20090312307A1-20091217-C00537
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid [2-(4- ethyl-phenyl)-ethyl]-amide 484
    454
    Figure US20090312307A1-20091217-C00538
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid [2-(3- trifluoromethyl-phenyl)-ethyl]- amide 524
    455
    Figure US20090312307A1-20091217-C00539
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid 2- chloro-benzylamide 476
    456
    Figure US20090312307A1-20091217-C00540
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid phenethyl-amide 456
    457
    Figure US20090312307A1-20091217-C00541
         		4-Benzyl-1-(5-methyl-3-phenyl- isoxazole-4-carbonyl)-piperidine-4- carboxylic acid [2-(4-ethyl- phenyl)-ethyl]-amide 537
    458
    Figure US20090312307A1-20091217-C00542
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid [2-(4- fluoro-phenyl)-ethyl]-amide 474
    459
    Figure US20090312307A1-20091217-C00543
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid (3- phenyl-propyl)-amide 470
    460
    Figure US20090312307A1-20091217-C00544
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid 3- methyl-benzylamide 456
    461
    Figure US20090312307A1-20091217-C00545
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid 4- chloro-benzylamide 476
    462
    Figure US20090312307A1-20091217-C00546
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid [2-(2- fluoro-phenyl)-ethyl]-amide 474
    463
    Figure US20090312307A1-20091217-C00547
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid [2-(3- fluoro-phenyl)-ethyl]-amide 474
    464
    Figure US20090312307A1-20091217-C00548
         		4-Benzyl-1-(2-methoxy-acetyl)- piperidine-4-carboxylic acid [2-(4- ethyl-phenyl)-ethyl]-amide 424
    465
    Figure US20090312307A1-20091217-C00549
         		1-Benzoyl-4-benzyl-piperidine-4- carboxylic acid [2-(4-ethyl- phenyl)-ethyl]-amide 456
    466
    Figure US20090312307A1-20091217-C00550
         		4-Benzyl-1-phenylacetyl- piperidine-4-carboxylic acid [2-(4- ethyl-phenyl)-ethyl]-amide 470
    467
    Figure US20090312307A1-20091217-C00551
         		4-Benzyl-1-(4-methyl-benzoyl)- piperidine-4-carboxylic acid [2-(4- ethyl-phenyl)-ethyl]-amide 470
    468
    Figure US20090312307A1-20091217-C00552
         		4-Benzyl-1-(4-fluoro-benzoyl)- piperidine-4-carboxylic acid [2-(4- ethyl-phenyl)-ethyl]-amide 474
    469
    Figure US20090312307A1-20091217-C00553
         		4-Benzyl-1-(2-phenoxy-acetyl)- piperidine-4-carboxylic acid [2-(4- ethyl-phenyl)-ethyl]-amide 486
    470
    Figure US20090312307A1-20091217-C00554
         		4-Benzyl-1-cyclohexanecarbonyl- piperidine-4-carboxylic acid [2-(4- ethyl-phenyl)-ethyl]-amide 462
    471
    Figure US20090312307A1-20091217-C00555
         		4-Benzyl-1-(isoxazole-5-carbonyl)- piperidine-4-carboxylic acid [2-(4- ethyl-phenyl)-ethyl]-amide 447
    472
    Figure US20090312307A1-20091217-C00556
         		4-Benzyl-1-(2,4,5-trifluoro- benzoyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]- amide 510
    473
    Figure US20090312307A1-20091217-C00557
         		4-Benzyl-1-but-2-enoyl-piperidine- 4-carboxylic acid [2-(4-ethyl- phenyl)-ethyl]-amide 420
    474
    Figure US20090312307A1-20091217-C00558
         		4-Benzyl-1-pentanoyl-piperidine-4- carboxylic acid [2-(4-ethyl- phenyl)-ethyl]-amide 436
    475
    Figure US20090312307A1-20091217-C00559
         		4-Benzyl-1-(3-methyl-butyryl)- piperidine-4-carboxylic acid [2-(4- ethyl-phenyl)-ethyl]-amide 436
    476
    Figure US20090312307A1-20091217-C00560
         		1-Acetyl-4-benzyl-piperidine-4- carboxylic acid [2-(4-ethyl- phenyl)-ethyl]-amide 394
    477
    Figure US20090312307A1-20091217-C00561
         		4-Benzyl-1-(pyridine-4-carbonyl)- piperidine-4-carboxylic acid [2-(4- ethyl-phenyl)-ethyl]-amide 457
    478
    Figure US20090312307A1-20091217-C00562
         		4-Benzyl-1-(pyridine-2-carbonyl)- piperidine-4-carboxylic acid [2-(4- ethyl-phenyl)-ethyl]-amide 457
    479
    Figure US20090312307A1-20091217-C00563
         		4-Benzyl-1-(pyridine-3-carbonyl)- piperidine-4-carboxylic acid [2-(4- ethyl-phenyl)-ethyl]-amide 457
    480
    Figure US20090312307A1-20091217-C00564
         		4-Benzyl-1-(2-chloro-pyridine-3- carbonyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]- amide 491
    481
    Figure US20090312307A1-20091217-C00565
         		4-Benzyl-1-(3-piperidin-1-yl- propionyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]- amide 491
    482
    Figure US20090312307A1-20091217-C00566
         		4-Benzyl-1-(1H-indole-2- carbonyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]- amide 495
    483
    Figure US20090312307A1-20091217-C00567
         		4-Benzyl-1-(3-phenyl-propynoyl)- piperidine-4-carboxylic acid [2-(4- ethyl-phenyl)-ethyl]-amide 480
    484
    Figure US20090312307A1-20091217-C00568
         		4-Benzyl-1-(3-pyridin-3-yl- propionyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]- amide 485
    485
    Figure US20090312307A1-20091217-C00569
         		4-Benzyl-1-[2-(1-methyl-1H- imidazol-4-yl)-acetyl]-piperidine- 4-carboxylic acid [2-(4-ethyl- phenyl)-ethyl]-amide 474
    486
    Figure US20090312307A1-20091217-C00570
         		4-Benzyl-1-(6-methyl-pyridine-3- carbonyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]- amide 471
    487
    Figure US20090312307A1-20091217-C00571
         		4-Benzyl-1-(2-dimethylamino- acetyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]- amide 437
    488
    Figure US20090312307A1-20091217-C00572
         		4-Benzyl-1-(1H-indazole-3- carbonyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]- amide 496
    489
    Figure US20090312307A1-20091217-C00573
         		4-Benzyl-1-(pyrazine-2-carbonyl)- piperidine-4-carboxylic acid [2-(4- ethyl-phenyl)-ethyl]-amide 458
    490
    Figure US20090312307A1-20091217-C00574
         		4-Benzyl-1-(morpholine-4- carbonyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]- amide 465
    491
    Figure US20090312307A1-20091217-C00575
         		4-Benzyl-1-(2-oxo-imidazolidine- 4-carbonyl)-piperidine-4- carboxylic acid [2-(4-ethyl- phenyl)-ethyl]-amide 464
    492
    Figure US20090312307A1-20091217-C00576
         		4-Benzyl-1-(1H-pyrazole-4- carbonyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]- amide 446
    493
    Figure US20090312307A1-20091217-C00577
         		4-Benzyl-1-([1,2,3]thiadiazole-4- carbonyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]- amide 464
    494
    Figure US20090312307A1-20091217-C00578
         		4-Benzyl-1-[3-(4-chloro-phenyl)- propionyl]-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]- amide 518
    495
    Figure US20090312307A1-20091217-C00579
         		1-(1H-Benzoimidazole-5- carbonyl)-4-benzyl-piperidine-4- carboxylic acid [2-(4-ethyl- phenyl)-ethyl]-amide 496
    496
    Figure US20090312307A1-20091217-C00580
         		4-Benzyl-1-(1-cyano- cyclopropanecarbonyl)-piperidine- 4-carboxylic acid [2-(4-ethyl- phenyl)-ethyl]-amide 445
    497
    Figure US20090312307A1-20091217-C00581
         		4-Benzyl-1-(3-phenyl-propionyl)- piperidine-4-carboxylic acid [2-(4- chloro-phenyl)-ethyl]-(1-methyl- 1H-imidazol-2-ylmethyl)-amide 584
    498
    Figure US20090312307A1-20091217-C00582
         		4-Benzyl-1-(4-fluoro-benzoyl)- piperidine-4-carboxylic acid [2-(4- chloro-phenyl)-ethyl]-(1-methyl- 1H-imidazol-2-ylmethyl)-amide 574
    499
    Figure US20090312307A1-20091217-C00583
         		4-Benzyl-1-phenylacetyl- piperidine-4-carboxylic acid [2-(4- chloro-phenyl)-ethyl]-(1-methyl- 1H-imidazol-2-ylmethyl)-amide 570
    500
    Figure US20090312307A1-20091217-C00584
         		4-Benzyl-1-(2-phenoxy-acetyl)- piperidine-4-carboxylic acid [2-(4- chloro-phenyl)-ethyl]-(1-methyl- 1H-imidazol-2-ylmethyl)-amide 586
    501
    Figure US20090312307A1-20091217-C00585
         		4-Benzyl-1-[2-(4-chloro-phenoxy)- acetyl]-piperidine-4-carboxylic acid [2-(4-chloro-phenyl)-ethyl]-(1- methyl-1H-imidazol-2-ylmethyl)-amide 621
    502
    Figure US20090312307A1-20091217-C00586
         		1-Acetyl-4-benzyl-piperidine-4- carboxylic acid [2-(4-chloro- phenyl)-ethyl]-(1-methyl-1H- imidazol-2-ylmethyl)-amide 494
    503
    Figure US20090312307A1-20091217-C00587
         		4-Benzyl-1-cyclohexanecarbonyl- piperidine-4-carboxylic acid [2-(4- chloro-phenyl)-ethyl]-(1-methyl- 1H-imidazol-2-ylmethyl)-amide 562
    504
    Figure US20090312307A1-20091217-C00588
         		4-Benzyl-1-(3-methyl-butyryl)- piperidine-4-carboxylic acid [2-(4- chloro-phenyl)-ethyl]-(1-methyl- 1H-imidazol-2-ylmethyl)-amide 536
    505
    Figure US20090312307A1-20091217-C00589
         		4-Benzyl-1-(isoxazole-5-carbonyl)- piperidine-4-carboxylic acid [2-(4- chloro-phenyl)-ethyl]-(1-methyl- 1H-imidazol-2-ylmethyl)-amide 547
    506
    Figure US20090312307A1-20091217-C00590
         		4-Benzyl-1-(2-methoxy-acetyl)- piperidine-4-carboxylic acid [2-(4- chloro-phenyl)-ethyl]-(1-methyl- 1H-imidazol-2-ylmethyl)-amide 524
    507
    Figure US20090312307A1-20091217-C00591
         		1-Benzenesulfonyl-4-benzyl- piperidine-4-carboxylic acid [2-(4- chloro-phenyl)-ethyl]-(1-methyl- 1H-imidazol-2-ylmethyl)-amide 592
    508
    Figure US20090312307A1-20091217-C00592
         		4-Benzyl-1-(4-fluoro- benzenesulfonyl)-piperidine-4- carboxylic acid [2-(4-chloro- phenyl)-ethyl]-(1-methyl-1H- imidazol-2-ylmethyl)-amide 610
    509
    Figure US20090312307A1-20091217-C00593
         		1-[3-(4-Fluoro-phenyl)-propionyl]- 4-(4-methoxy-benzyl)-piperidine- 4-carboxylic acid [2-(4-ethyl- phenyl)-ethyl]-amide 532
    510
    Figure US20090312307A1-20091217-C00594
         		4-(3-Chloro-benzyl)-1-[3-(4- fluoro-phenyl)-propionyl]- piperidine-4-carboxylic acid [2-(4- ethyl-phenyl)-ethyl]-amide 536
    • Example 521
  • Figure US20090312307A1-20091217-C00595
    • 4-Benzyl-1-pyrimidin-2-yl-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]-amide Synthesis
  • Figure US20090312307A1-20091217-C00596
  • Compound 1: Compound 1 was prepared using methodology described in Example 390. LRMS m/z 352 (M+H)+.
  • Title Compound: A solution of compound 1 (0.05 g; 0.14 mmol) in anhydrous acetonitrile (1 mL) was treated with 2-chloropyrimidine (0.024 g; 0.21 mmol) and diisopropyl ethylamine (0.036 mL; 0.21 mmol) and heated at 90° C. for 1 h. The acetonitrile was removed by evaporation and the crude residue was purified by preparative HPLC to give 4-benzyl-1-pyrimidin-2-yl-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]-amide as a white solid. LRMS m/z 430 (M+H)+.
    • Example 522
  • Figure US20090312307A1-20091217-C00597
    • 4-Benzyl-1-dimethylsulfamoyl-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]-amide Synthesis
  • Figure US20090312307A1-20091217-C00598
  • Compound 1: Compound 1 was prepared using methodology described in Example 390. LRMS m/z 352 (M+H)+.
  • Title Compound: 4-Benzyl-1-dimethylsulfamoyl-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]-amide was prepared using methodology described in Example 16. LRMS m/z 458 (M+H)+.
    • Example 523
  • Example 523 was prepared using methodology described in Example 522.
  • Example Structure Name M + H
    523
    Figure US20090312307A1-20091217-C00599
         		4-Benzyl-1-dimethylsulfamoyl- piperidine-4-carboxylic acid [2-(4- chloro-phenyl)-ethyl]-(1-methyl- 1H-imidazol-2-ylmethyl)-amide 559
    • Example 524
  • Figure US20090312307A1-20091217-C00600
    • 4-Benzyl-1-(2-methoxy-ethylsulfamoyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]-amide
  • Figure US20090312307A1-20091217-C00601
  • Compound 1: Compound 1 was prepared using methodology described in Example 390. LRMS m/z 352 (M+H)+.
  • Title Compound: 4-Benzyl-1-(2-methoxy-ethylsulfamoyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]-amide was prepared using methodology described in Example 17. LRMS m/z 488 (M+H)+.
    • Examples 525 to 526
  • Examples 525 to 526 were prepared using methodology described in Example 524.
  • Example Structure Name M + H
    525
    Figure US20090312307A1-20091217-C00602
         		4-Benzyl-1-benzylsulfamoyl- piperidine-4-carboxylic acid [2-(4- ethyl-phenyl)-ethyl]-amide 521
    526
    Figure US20090312307A1-20091217-C00603
         		4-Benzyl-1-(4-fluoro- benzylsulfamoyl)-piperidine-4- carboxylic acid [2-(4-ethyl- phenyl)-ethyl]-amide 539
    • Example 527
  • Figure US20090312307A1-20091217-C00604
    • 1-[4-(Isoquinolin-1-ylaminomethyl)-4-phenyl-piperidin-1-yl]-3-phenyl-propan-1-one Synthesis
  • Figure US20090312307A1-20091217-C00605
  • Compound 1: A suspension of 1-benzyl-4-phenyl-piperidine-4-carbonitrile (6.24 g; 20 mmol) in tetrahydrofuran was cooled to 0° C. and treated with lithium aluminum hydride (3.04 g; 80 mmol). The reaction mixture was allowed slowly warm to room temperature overnight. The reaction was cooled in an ice-acetone bath and quenched with water (12 mL) and 15% aqueous sodium hydroxide (3 mL). The resulting slurry was filtered through CELITE® eluting with ethyl ether and evaporated to give 4.51 g of compound 1 as a colorless oil that was used in the next step without additional purification. LRMS m/z 281 (M+H)+.
  • Compound 2: Pd(OAc)2 (4.5 mg, 0.02 mmol), 2-(di-t-butylphosphino)biphenyl (11.9 mg, 0.04 mmol) and sodium t-butoxide (0.54 g, 5.6 mmol) were added to toluene (8 mL) and the mixture was sparged with argon. 1-Chloroisoquinoline (0.65 g, 4 mmol) and compound 1 (1.35 g, 4.8 mmol) were added and the reaction was heated at reflux under an argon atmosphere. After 48 hours a second portion of Pd(OAc)2 (4.5 mg, 0.02 mmol) and -(di-t-butylphosphino)biphenyl (11.9 mg, 0.04 mmol) was added. The reaction was allowed to reflux another 24 hours then diluted with water (8 mL). The mixture was filtered through CELITE® pad and portioned between ethyl acetate and water. The organic phase was separated, dried (anhydrous magnesium sulfate), filtered and concentrated. Column chromatography on silica gel using a dichloromethane to ethyl acetate gradient as the eluent gave 0.29 g compound 2. LRMS m/z 408 (M+H)+.
  • Compound 3: A solution of compound 2 (0.250 g) in methanol (20 mL) was treated with Pd(OH)2 (50 mg), placed under at atmosphere of hydrogen (60 psi) and heated to 40° C. until no starting material remained as judged by LCMS. The reaction mixture was filtered through CELITE® using ethyl acetate as the eluent and evaporated to give 0.19 g compound 3 that was used in the next step without further purification. LRMS m/z 318 (M+H)+.
  • Title Compound: 1-[4-(Isoquinolin-1-ylaminomethyl)-4-phenyl-piperidin-1-yl]-3-phenyl-propan-1-one was prepared using methodology described in Example 390. LRMS m/z 451 (M+H)+.
    • Example 528
  • Figure US20090312307A1-20091217-C00606
    • [1-(4-Fluoro-benzenesulfonyl)-4-phenyl-piperidin-4-ylmethyl]-isoquinolin-1-yl-amine Synthesis
  • Figure US20090312307A1-20091217-C00607
  • Compound 1: Compound 1 was prepared as described in Example 527.
  • Title Compound: [1-(4-Fluoro-benzenesulfonyl)-4-phenyl-piperidin-4-ylmethyl]-isoquinolin-1-yl-amine was prepared using methodology described in Example 95. LRMS m/z 477 (M+H)+.
    • Example 529
  • Figure US20090312307A1-20091217-C00608
    • Isoquinolin-1-yl-(4-phenyl-1-pyrimidin-2-yl-piperidin-4-ylmethyl)-amine Synthesis
  • Figure US20090312307A1-20091217-C00609
  • Compound 1: Compound 1 was prepared as described in Example 527.
  • Title Compound: Isoquinolin-1-yl-(4-phenyl-1-pyrimidin-2-yl-piperidin-4-ylmethyl)-amine was prepared using methodology described in Example 521. LRMS m/z 396 (M+H)+.
    • Example 530
  • Figure US20090312307A1-20091217-C00610
    • Synthesis
  • Figure US20090312307A1-20091217-C00611
  • Compound 1: Compound 1 was prepared as described in Example 527.
  • Compound 2: Compound 2 was prepared using methodology described in Example 25. LRMS m/z 463 (M+H)+.
  • Title Compound: The title compound was prepared using methodology described in Example 25. LRMS m/z 413 (M+H)+.
    • Example 531
  • Figure US20090312307A1-20091217-C00612
    • 4-(Isoquinolin-1-ylaminomethyl)-4-phenyl-piperidine-1 sulfonic acid dimethylamide Synthesis
  • Figure US20090312307A1-20091217-C00613
  • Compound 1: Compound 1 was prepared as described in Example 527.
  • Title Compound: 4-(Isoquinolin-1-ylaminomethyl)-4-phenyl-piperidine-1-sulfonic acid dimethylamide was prepared using methodology described in Example 16. LRMS m/z 426 (M+H)+.
    • Example 532
  • Figure US20090312307A1-20091217-C00614
    • 4-(Isoquinolin-1-ylaminomethyl)-4-phenyl-piperidine 1 sulfonic acid benzylamide Synthesis
  • Figure US20090312307A1-20091217-C00615
  • Compound 1; Compound 1. was prepared as described in Example 527.
  • Title Compound: 4-(Isoquinolin-1-ylaminomethyl)-4-phenylpiperidine-1-sulfonic acid benzylamide was prepared using methodology described in Example 17. LRMS m/z 488 (M+H)+.
    • Example 533
  • Figure US20090312307A1-20091217-C00616
    • 1-[4-Phenyl-1-(3-phenylpropionyl)-piperidin-4-ylmethyl]-1,3-dihydro-benzoimidazol-2-one Synthesis
  • Figure US20090312307A1-20091217-C00617
  • Compound 1: Compound 1 was prepared as described in Example 527.
  • Compound 2: A mixture of compound 1 (0.60 g, 2.14 μmol), 2-fluoronitrobenzene (0.25 mL, 2.35 mmol) and potassium carbonate (excess) in N,N-dimethylformamide, was stirred overnight at 70° C. The reaction was diluted with water (4 mL) then extracted with ethyl ether (4×15 mL). The combined extracts were evaporated and the residue was purified by column chromatography on silica gel using a dichloromethane to 1:1 dichloromethane/ethyl acetate gradient. Product fractions were combined and evaporated to give 0.75 g (87%) compound 2. LRMS m/z 403 (M+H)+.
  • Compound 3: Compound 2 (0.75 g, 1.87 mmol) was dissolved in methanol and a catalytic amount of 10% palladium/carbon was added. The mixture was stirred under H2 (balloon pressure) until the color disappeared. The reaction was filtered through a CELITE® pad and evaporated to give 0.58 g (84%) of compound 3.
  • LRMS m/z 373 (M+H)+.
  • Compound 4: A solution of compound 3 (76.3 mg, 0.206 mmol) in dichloromethane (4 mL) was treated with triethylamine (63 μL, 0.45 mmol) and a solution of diphosgene (13.7 μL, 0.113 mmol) in dichloromethane (2 mL). After stirring overnight, the reaction was quenched with saturated aqueous sodium bicarbonate and separated. The organic phase was dried (anhydrous magnesium sulfate), filtered and concentrated. Column chromatography on silica gel using dichloromethane as the eluent gave 0.077 g of compound 4. LRMS m/z 399 (M+H)+.
  • Compound 5: Compound 4 (63.1 mg, 0.159 mmol) was dissolved in methanol and Pd(OH)2/C (wet) was added. The mixture was hydrogenated at 60 psi and 50° C. overnight. The reaction was purified directly by column chromatography on silica gel using 59:40:1 methanol:chloroform:ammonium hydroxideas the eluent to give 10 mg (20%) of compound 5. LRMS m/z 508 (M+H)+.
  • Title Compound: 1-[4-Phenyl-1-(3-phenyl-propionyl)piperidin-4-ylmethyl]-1,3-dihydro-benzoimidazol-2-one was prepared using methodology described in Example 390. LRMS m/z 441 (M+1)+.
    • Example 534
  • Figure US20090312307A1-20091217-C00618
    • 1-[1-(4-Fluoro-benzenesulfonyl)-4-phenyl-piperidin-4-ylmethyl]-2-methyl-1H-benzoimidazole Synthesis
  • Figure US20090312307A1-20091217-C00619
  • Compound 1: Compound 1 was prepared as described in Example 533.
  • Compound 2; A solution of compound 1 (0.2508 g, 0.676 mmol) in acetic acid (2 mL) was treated with EEDQ (0.170 g, 0.678 mmol) and heated to 120° C. After 12 h, the reaction mixture was evaporated to dryness and the residue was portioned between ethyl acetate (4 mL) and saturated aqueous sodium bicarbonate (3 mL). The aqueous layers was separated and washed with dichloromethane (2×4 mL). The combined organic layers were combined, dried (anhydrous magnesium sulfate), filtered and concentrated. Column chromatography on silica gel using an ethyl acetate to 10% methanol:ethyl acetate gradient as the eluent gave 0.21 g of compound 2. LRMS m/z 397 (M+H)+.
  • Compound 3: Compound 3 was prepared using methodology described in Example 533. LRMS m/z 306 (M+H)+.
  • Title Compound: 1-[1-(4-Fluoro-benzenesulfonyl)-4-phenyl-piperidin-4-ylmethyl]-2-methyl-1H-benzoimidazole was prepared using methodology described in Example 95. LRMS m/z 464 (M+H)+.
    • Example 535
  • Figure US20090312307A1-20091217-C00620
    • 1-[4-(2-Methyl-benzoimidazol-1-ylmethyl)-4-phenyl-piperidin-1-yl]-3-phenyl-propan-1-one Synthesis
  • Figure US20090312307A1-20091217-C00621
  • Compound 1: Compound 1 was prepared as described in Example 534.
  • Title Compound: 1-[4-(2-Methyl-benzoimidazol-1-ylmethyl)-4-phenyl-piperidin-1-yl]-3-phenyl-propan-1-one was prepared using methodology described in Example 94. LRMS m/z 439 (M+H)+.
    • Example 536
  • Figure US20090312307A1-20091217-C00622
    • Synthesis
  • Figure US20090312307A1-20091217-C00623
  • Compound 1: Compound 1 was prepared as described in Example 534.
  • Compound 2: Compound 2 was prepared using methodology described in Example 25. LRMS m/z 451 (M+H)+.
  • Title Compound: The title compound was prepared using methodology described in Example 25. LRMS m/z 402 (M+H)+.
    • Example 537
  • Example 537 was prepared using methodology described in Example 536.
  • Example Structure Name M + H
    537
    Figure US20090312307A1-20091217-C00624
         		464
    • Example 538
  • Figure US20090312307A1-20091217-C00625
    • N-(4-Benzyl-piperidin-4-ylmethyl)-2-methoxy-benzamide Synthesis
  • Figure US20090312307A1-20091217-C00626
  • Compound 1: Compound 1 is commercially available.
  • Compound 2: To compound 1 (1.0 g, 9.08 mmol) in dichloromethane (30 mL) at 0° C. was added triethylamine (1.5 mL, 10.7 mmol) followed by benzoylchloride (1.1 mL, 9.08 mol). The reaction mixture was stirred at room temperature for 3 h, diluted with ethyl ether (100 mL), washed with saturated 1 N HCl, 1 N NaOH, water and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using Hexanes/EtOAc (2/1) as eluent to give a white solid compound 2, 1.41 g (73% yield). LCMS Rt 1.06 min, [M+1] 215.2.
  • Compound 3: To a solution of diisopropylamine (0.35 mL, 2.52 mmol) in dry tetrahydrofuran (2.5 mL) at 0° C. was added 1.58 mL (2.52 mmol) of 1.6 M n-BuLi in hexanes. After 30 minutes, the reaction mixture was cooled to 78° C. Compound 2 (360 mg, 1.68 mmol) in dry tetrahydrofuran (2.5 mL) was added dropwise. After 1 h, BnBr (0.22 mL, 1.85 mmol) was added. After stirring from −78° C. to room temperature over 2 h the reaction mixture was quenched with water and diluted with Et2O (30 mL). The organic phase was washed with 1 N HCl, water and brine. The aqueous phase was extracted with CH2Cl2. The combined organic phase was dried over Anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using hexanes/EtOAc (1/4) as eluent to give a white solid compound 3, 0.472 g (92% yield). NMR 1H(CDCl3) δ (ppm) 1.40-2.05 (4H, m), 2.89 (2H, s), 3.00-3.42 (2H, m), 3.70-3.90 (1H, bs), 4.70-4.90 (1H, bs), 7.26-7.43 (10H, m).
  • Compound 4: To compound 3 in dry tetrahydrofuran (5 mL) was added 231 mg (mmol) of LAH then stirred at 65° C. for 20 h. The solution was cooled to 0° C. and quenched with water (0.23 mL), 15% NaOH (0.69 mL) and water (0.23 mL). The quenched reaction mixture was stirred at ambient temperature for 0.5 h. The solid was filtered and washed with Et2O. The organic solution was dried over Na2SO4, filtered and concentrated to give a colorless oil compound 4 sufficiently pure to be taken on to the next step. LCMS [M+1] 295.2.
  • Compound 5: To compound 4 (1.52 mmol) in dichloromethane (5 mL) at 0° C. was added 0.43 mL (3.06 mmol) of Et3N followed by 0.25 mL (1.68 mmol) of o-anisoyl chloride. After stirring 2 hours from 0° C. to room temperature, the reaction mixture was diluted with Et2O (30 mL), washed with 1N NaOH, water, sat. sodium chloride, dried over anh. sodium sulfate and concentrated. The residue was purified by silica gel chromatography using EtOAc as eluent to give a light yellow syrup compound 5, 0.551 g (85% yield). NMR 1H(CDCl3) δ (ppm) 1.45-2.0 (4H, m), 2.02-2.70 (4H, m), 2.69 (2H, s), 3.40 (2H, d, J=5.9 Hz), 3.55 (2H, s), 4.00 (2H, s), 7.00 (1H, d, J=8.2 Hz), 7.08-7.40 (12H, m), 7.45 (1H, dt, J=1.7, 11.1 Hz), 8.05 (1 H, bs), 8.23 (1H, dd, J=1.8, 7.8 Hz). LCMS Rt 1.72 min, [M+1] 429.2.
  • Title Compound: N-(4-Benzyl-piperidin-4-ylmethyl)-2-methoxy-benzamide was prepared using methodology described in Example 1. LCMS [M+1] 339.1.
    • Example 539
  • Figure US20090312307A1-20091217-C00627
    • 4-Benzyl-4-[(2-methoxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid ethyl ester Synthesis
  • Figure US20090312307A1-20091217-C00628
  • Compound 1: Compound 1 was prepared as described in Example 538.
  • Title Compound: 4-Benzyl-4-[(2-methoxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid ethyl ester was prepared using methodology described in Example 2. NMR 1H(CDCl3) δ (ppm) 1.24 (3H, t, J=7.1 Hz), 1.47-1.51-(4H, m), 2.70 (2H, s), 3.41-3.50 (4H, m), 3.65-3.72 (2H, m), 4.01 (3H, s), 4.11 (2H, q, J=7.1 Hz), 7.02 (1H, d, =8.2 Hz), 7.09-7.33 (6H, m), 8.06 (1H, bs), 7.48 (1H, td, J=1.7, 7.5 Hz), 8.22 (1H, dd, J=2.2, 7.8 Hz). LCMS Rt 1.72 min, [M+1] 411.1.
    • Example 540
  • Figure US20090312307A1-20091217-C00629
    • N-[4-Benzyl-1-(3-phenyl-propionyl)-piperidin-4-ylmethyl]-2-methoxy-benzamide Synthesis
  • Figure US20090312307A1-20091217-C00630
  • Compound 1: Compound 1 was prepared as described in Example 538.
  • Title Compound: N-[4-Benzyl-1-(3-phenyl-propionyl)-piperidin-4-ylmethyl]-2-methoxy-benzamide was prepared using methodology described in Example 94. NMR 1H (CDCl3) δ (ppm) 1.26-1.38 (2H, m), 1.43-1.50 (2H, m), 2.59-2.64 (2H, m), 2.65 (2H, s), 2.93-2.98 (2H, m), 3.23-3.62 (5H, m), 3.95-4.05 (1H, m), 4.01 (3H, s), 7.02 (1H, d, J=8.2 Hz), 7.09-7.34 (11H, m), 7.45-7.55 (1H, m), 8.07 (1H, t, J=5.8 Hz), 8.21 (1H, dd, J=1.8, 7.8 Hz). LCMS Rt 1.77 min, [M+1] 471.1.
    • Example 541
  • Figure US20090312307A1-20091217-C00631
    • N-[4-Benzyl-1-(4-fluoro-benzylsulfamoyl)-piperidin-4-ylmethyl]-2-methoxy benzamide Synthesis
  • Figure US20090312307A1-20091217-C00632
  • Compound 1: Compound 1 was prepared as described in Example 538.
  • Title Compound: N-[4-Benzyl-1-(4-fluoro-benzylsulfamoyl)-piperidin-4-ylmethyl]-2-methoxy-benzamide was prepared using methodology described in Example 17. NMR 1H (CDCl3) δ (ppm) 1.50-1-70 (4H, m), 2.66 (2H, s), 3.20-3.50 (6H, m), 4.02 (3H, s), 4.19 (2H, d, J=5.0 Hz), 4.58 (1H, bs), 6.99-7.33 (10H, m), 7.48 (1H, td, J=1.7, 8.0 Hz), 8.08 (1H, bt, J=5.7 Hz), 8.20 (1H, dd, J=1.8, 7.8 Hz).
    • Example 542
  • Example 542 was prepared using methodology described in Example 541.
  • Example Structure Name (M + 1)+
    542
    Figure US20090312307A1-20091217-C00633
         		N-[4-Benzyl-1-(2-methoxy- ethylsulfamoyl)-piperidin-4-ylmethyl]- 2-methoxy-benzamide 476.2
    • Example 543
  • Figure US20090312307A1-20091217-C00634
    • N-(4-Benzyl-1-dimethylsulfamoyl-piperidin-4-ylmethyl)-2-methoxy-benzamide Synthesis
  • Figure US20090312307A1-20091217-C00635
  • Compound 1: Compound 1 was prepared as described in Example 538.
  • Title Compound: N-(4-Benzyl-1-dimethylsulfamoyl-piperidin-4-ylmethyl)-2-methoxybenzamide was prepared using methodology described in Example 16. LRMS m/z 446 (M+H)+.
    • Examples 544 and 545
  • Figure US20090312307A1-20091217-C00636
    • 4-[2-(4-Chloro-benzyl)-2H-tetrazol-5-yl]-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester and 4-[1-(4-Chloro-benzyl)-1H-tetrazol-5-yl]-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester Synthesis
  • Figure US20090312307A1-20091217-C00637
  • Compound 1: Compound 1 was prepared using methodology described in Example 74. LRMS m/z 287 (M+H)+.
  • Compound 2: Compound 1 (286 mg, 1.0 mmol), sodium azide (325 mg, 5.0 mmol) and ammonium chloride (268 mg, 5.0 mmol) in DMF (1.5 mL) was heated at 145° C. for 24 hours. After cooling to room temperature the reaction mixture was diluted with water (15 ml) and extracted with ethyl acetate (3×10 mL). The combined organic fractions were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using CHCl3/MeOH (95:5) as eluent to give a white solid compound 2, 250 mg (76% yield). NMR 1H (CDCl3) 6 μm) 1.42 (9H, s), 2.05-2.20 (2H, m), 2.60-3.30 (4H, m), 3.90 (2H, bd, J=13.6 Hz), 7.15-7.30 (5H, m).
  • Title Compounds: Compound 2 (240 mg, 0.73 mmol), K2CO3 (111 mg, 0.8 mmol), 4-chlorobenzyl bromide (164 mg, 0.8 mmol) in acetonitrile (6 mL) was heated at 70° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water, saturated sodium chloride, dried over anhydrous sodium chloride, filtered and concentrated. The residue was purified by silica gel chromatography using hexanes/ethyl acetate (3-1) as eluent to give a white solid 4-[2-(4-chloro-benzyl)-2H-tetrazol-5-yl]-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester, 244 mg (74% yield) NMR 1H (CDCl3) δ (ppm) 1.44 (9H, s), 2.10-2.25 (2H, m), 2.75-2.90 (4H, m), 3.95 (2H, bs), 5.68 (2H, s), 7.16-7.35 (9H, m). LCMS Rt 1.38 min, [M+1] 454.0 and white solid 4-[1-(4-chloro-benzyl)-1H-tetrazol-5-yl]-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester, 38 mg (11% yield) NMR 1H (CDCl3) δ (ppm) 1.43 (9H, s), 2.00-2.55 (4H, m), 2.75-2.90 (2H, m), 3.00 (1H, bs), 3.35 (1H, bs), 3.82 (2H, bs), 5.92 (2H, bs), 6.71 (2H, d, J=8.6 Hz), 7.09 (2H, d, J=1.4 Hz), 7.11 (1H, d, J=1.9 Hz), 7.22-7.38 (4H, m). LCMS Rt 1.38 min, [M+1] 454.2
    • Example 546
  • Figure US20090312307A1-20091217-C00638
    • 4-[2-(4-Chloro-benzyl)-2H-tetrazol-5-yl]-4-phenyl-piperidine-1-carboxylic acid ethyl ester Synthesis
  • Figure US20090312307A1-20091217-C00639
  • Compound 1: Compound 1 was prepared as described in Example 544.
  • Compound 2: Compound 1 (236 mg, 0.52 mmol) in dichloromethane (3 mL) and TFA (1 mL) was stirred at room temperature for 1 hour then concentrated. The residue was dissolved in ethyl acetate (20 mL), washed with 1N NaOH (2×5 mL), water, saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated to give an oil compound 2, 181 mg (98%). H NMR (CDCl3) δ (ppm) 1.24 (3H, t, J=7.0 Hz), 2.11 (2H, bs), 2.43 (2H, bs), 3.05 (1H, bs), 3.35 (1H, bs), 3.85-3.95 (2H, bs), 4.11 (2H, q, J=7.0 Hz), 4.91 (2H, s), 6.72 (2H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4 Hz), 7.10 (2H, d, J=6.1 Hz), 7.29-7.38 (3H, m). [M+1] 426.0
  • Title Compound: 4-[2-(4-Chloro-benzyl)-2H-tetrazol-5-yl]-4-phenyl-piperidine-1-carboxylic acid ethyl ester was prepared using methodology described in Example 2. LRMS m/z 455 (M+H)+.
    • Example 547
  • Figure US20090312307A1-20091217-C00640
    • {4-[2-(4-Chloro-benzyl)-2H-tetrazol-5-yl]-4-phenyl-piperidin-1-yl}-phenyl-methanone Synthesis
  • Figure US20090312307A1-20091217-C00641
  • Compound 1: Compound 1 was prepared as described in Example 544.
  • Title Compound: {4-[2-(4-Chlorobenzyl)-2H-tetrazol-5-yl]-4-phenyl-piperidin-1-yl}-phenyl-methanone was prepared using methodology described in Example 94. LRMS m/z 459 (M+H)+.
    • Example 548
  • Figure US20090312307A1-20091217-C00642
    • 4-[2-(4-Chloro-benzyl)-2H-tetrazol-5-yl]-4-phenyl-piperidine-1-carboxylic acid phenylamide Synthesis
  • Figure US20090312307A1-20091217-C00643
  • Compound 1: Compound 1 was prepared as described in Example 544.
  • Title Compound: 4-[2-(4-Chloro-benzyl)-2H-tetrazol-5-yl]-4-phenyl-piperidine-1-carboxylic acid phenylamide was prepared using methodology as described in Example 390. LRMS m/z 474 (M+H)+.
    • Examples 549 to 598
  • Examples 549 to 598 were prepared using methodology described in Example 546, Example 547 and Example 548
  • Example Structure Name (M + 1)+
    549
    Figure US20090312307A1-20091217-C00644
         		4-(2-Benzyl-2H-tetrazol-5-yl)-4- phenyl-piperidine-1-carboxylic acid ethyl ester 392.2
    550
    Figure US20090312307A1-20091217-C00645
         		4-Phenyl-4-[2-(3-trifluoromethoxy- benzyl)-2H-tetrazol-5-yl]-piperidine- 1-carboxylic acid ethyl ester 476.2
    551
    Figure US20090312307A1-20091217-C00646
         		4-[2-(3-Methyl-benzyl)-2H-tetrazol- 5-yl]-4-phenyl-piperidine-1- carboxylic acid ethyl ester 406.2
    552
    Figure US20090312307A1-20091217-C00647
         		4-[2-(3-Bromo-benzyl)-2H-tetrazol-5- yl]-4-phenyl-piperidine-1-carboxylic acid ethyl ester 470.1
    553
    Figure US20090312307A1-20091217-C00648
         		4-{2-[2-(3-Methoxy-phenyl)-2-oxo- ethyl]-2H-tetrazol-5-yl}-4-phenyl- piperidine-1-carboxylic acid ethyl ester 450.2
    554
    Figure US20090312307A1-20091217-C00649
         		4-[2-(3,4-Dichloro-benzyl)-2H- tetrazol-5-yl]-4-phenyl-piperidine-1- carboxylic acid ethyl ester 460.1
    555
    Figure US20090312307A1-20091217-C00650
         		4-[2-(4-Fluoro-3-trifluoromethyl- benzyl)-2H-tetrazol-5-yl]-4-phenyl- piperidine-1-carboxylic acid ethyl ester 478.2
    556
    Figure US20090312307A1-20091217-C00651
         		4-[2-(4-Methyl-benzyl)-2H-tetrazol- 5-yl]-4-phenyl-piperidine-1- carboxylic acid ethyl ester 406.2
    557
    Figure US20090312307A1-20091217-C00652
         		4-[2-(2-Oxo-2-phenyl-ethyl)-2H- tetrazol-5-yl]-4-phenyl-piperidine-1- carboxylic acid ethyl ester 420.2
    558
    Figure US20090312307A1-20091217-C00653
         		4-[2-(4-tert-Butyl-benzyl)-2H- tetrazol-5-yl]-4-phenyl-piperidine-1- carboxylic acid ethyl ester 448.2
    559
    Figure US20090312307A1-20091217-C00654
         		4-Phenyl-4-[2-(4-trifluoromethoxy- benzyl)-2H-tetrazol-5-yl]-piperidine- 1-carboxylic acid ethyl ester 476.2
    560
    Figure US20090312307A1-20091217-C00655
         		4-(2-Naphthalen-2-ylmethyl-2H- tetrazol-5-yl)-4-phenyl-piperidine-1- carboxylic acid ethyl ester 442.2
    561
    Figure US20090312307A1-20091217-C00656
         		4-[2-(3-Fluoro-4-trifluoromethyl- benzyl)-2H-tetrazol-5-yl]-4-phenyl- piperidine-1-carboxylic acid ethyl ester 478.2
    562
    Figure US20090312307A1-20091217-C00657
         		4-[2-(4-Bromo-benzyl)-2H-tetrazol-5- yl]-4-phenyl-piperidine-1-carboxylic acid ethyl ester 470.1
    563
    Figure US20090312307A1-20091217-C00658
         		4-[2-(3,5-Difluoro-benzyl)-2H- tetrazol-5-yl]-4-phenyl-piperidine-1- carboxylic acid ethyl ester 428.2
    564
    Figure US20090312307A1-20091217-C00659
         		4-[2-(2,4-Dichloro-benzyl)-2H- tetrazol-5-yl]-4-phenyl-piperidine-1- carboxylic acid ethyl ester 460.1
    565
    Figure US20090312307A1-20091217-C00660
         		4-[2-(2-Chloro-benzyl)-2H-tetrazol-5- yl]-4-phenyl-piperidine-1-carboxylic acid ethyl ester 426.1
    566
    Figure US20090312307A1-20091217-C00661
         		4-[2-(3-Chloro-benzyl)-2H-tetrazol-5- yl]-4-phenyl-piperidine-1-carboxylic acid ethyl ester 426.1
    567
    Figure US20090312307A1-20091217-C00662
         		4-[2-(4-Chloro-benzyl)-2H-tetrazol-5- yl]-4-phenyl-piperidine-1-carboxylic acid ethyl ester 426.1
    568
    Figure US20090312307A1-20091217-C00663
         		4-[2-(2-Oxo-propyl)-2H-tetrazol-5- yl]-4-phenyl-piperidine-1-carboxylic acid ethyl ester 358.2
    569
    Figure US20090312307A1-20091217-C00664
         		4-(2-Allyl-2H-tetrazol-5-yl)-4- phenyl-piperidine-1-carboxylic acid ethyl ester 342.2
    570
    Figure US20090312307A1-20091217-C00665
         		4-[2-(3-Methoxy-benzyl)-2H-tetrazol- 5-yl]-4-phenyl-piperidine-1- carboxylic acid ethyl ester 422.2
    571
    Figure US20090312307A1-20091217-C00666
         		4-[2-(4-Methoxy-benzyl)-2H-tetrazol- 5-yl]-4-phenyl-piperidine-1- carboxylic acid ethyl ester 422.2
    572
    Figure US20090312307A1-20091217-C00667
         		4-[2-(2-Methoxy-benzyl)-2H-tetrazol- 5-yl]-4-phenyl-piperidine-1- carboxylic acid ethyl ester 422.2
    573
    Figure US20090312307A1-20091217-C00668
         		4-[2-(3,5-Dimethoxy-benzyl)-2H- tetrazol-5-yl]-4-phenyl-piperidine-1- carboxylic acid ethyl ester 452.2
    574
    Figure US20090312307A1-20091217-C00669
         		4-[2-(2-Methyl-benzyl)-2H-tetrazol- 5-yl]-4-phenyl-piperidine-1- carboxylic acid ethyl ester 406.2
    575
    Figure US20090312307A1-20091217-C00670
         		4-Phenyl-4-[2-(2-trifluoromethoxy- benzyl)-2H-tetrazol-5-yl]-piperidine- 1-carboxylic acid ethyl ester 476.1
    576
    Figure US20090312307A1-20091217-C00671
         		4-[2-(4-Chloro-benzyl)-2H-tetrazol-5- yl]-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester 454.2
    577
    Figure US20090312307A1-20091217-C00672
         		4-[2-(2-Fluoro-benzyl)-2H-tetrazol-5- yl]-4-phenyl-piperidine-1-carboxylic acid ethyl ester 410.2
    578
    Figure US20090312307A1-20091217-C00673
         		4-[2-(3-Fluoro-benzyl)-2H-tetrazol-5- yl]-4-phenyl-piperidine-1-carboxylic acid ethyl ester 410.2
    579
    Figure US20090312307A1-20091217-C00674
         		4-[2-(4-Fluoro-benzyl)-2H-tetrazol-5- yl]-4-phenyl-piperidine-1-carboxylic acid ethyl ester 410.2
    580
    Figure US20090312307A1-20091217-C00675
         		4-Phenyl-4-[2-(2-trifluoromethyl- benzyl)-2H-tetrazol-5-yl]-piperidine- 1-carboxylic acid ethyl ester 460.2
    581
    Figure US20090312307A1-20091217-C00676
         		4-Phenyl-4-[2-(3-trifluoromethyl- benzyl)-2H-tetrazol-5-yl]-piperidine- 1-carboxylic acid ethyl ester 460.2
    582
    Figure US20090312307A1-20091217-C00677
         		4-Phenyl-4-[2-(4-trifluoromethyl- benzyl)-2H-tetrazol-5-yl]-piperidine- 1-carboxylic acid ethyl ester 460.2
    583
    Figure US20090312307A1-20091217-C00678
         		{4-[2-(4-Chloro-benzyl)-2H-tetrazol- 5-yl]-4-phenyl-piperidin-1-yl}-(4- fluoro-phenyl)-methanone 476.1
    584
    Figure US20090312307A1-20091217-C00679
         		{4-[2-(4-Chloro-benzyl)-2H-tetrazol- 5-yl]-4-phenyl-piperidin-1-yl}-p- tolyl-methanone 472.2
    585
    Figure US20090312307A1-20091217-C00680
         		1-{4-[2-(4-Chloro-benzyl)-2H- tetrazol-5-yl]-4-phenyl-piperidin-1- yl}-2-phenyl-ethanone 472.2
    586
    Figure US20090312307A1-20091217-C00681
         		1-{4-[2-(4-Chloro-benzyl)-2H- tetrazol-5-yl]-4-phenyl-piperidin-1- yl}-2-(4-fluoro-phenyl)-ethanone 490.2
    587
    Figure US20090312307A1-20091217-C00682
         		1-{4-[2-(4-Chloro-benzyl)-2H- tetrazol-5-yl]-4-phenyl-piperidin-1- yl}-2-p-tolyl-ethanone 486.2
    588
    Figure US20090312307A1-20091217-C00683
         		1-{4-[2-(4-Chloro-benzyl)-2H- tetrazol-5-yl]-4-phenyl-piperidin-1- yl}-3-phenyl-propan-1-one 486.2
    589
    Figure US20090312307A1-20091217-C00684
         		1-{4-[2-(4-Chloro-benzyl)-2H- tetrazol-5-yl]-4-phenyl-piperidin-1- yl}-3-(4-fluoro-phenyl)-propan-1-one 504.2
    590
    Figure US20090312307A1-20091217-C00685
         		1-{4-[2-(4-Chloro-benzyl)-2H- tetrazol-5-yl]-4-phenyl-piperidin-1- yl}-3-p-tolyl-propan-1-one 500.2
    591
    Figure US20090312307A1-20091217-C00686
         		1-{4-[2-(4-Chloro-benzyl)-2H- tetrazol-5-yl]-4-phenyl-piperidin-1- yl}-2-phenoxy-ethanone 488.1
    592
    Figure US20090312307A1-20091217-C00687
         		4-[2-(4-Chloro-benzyl)-2H-tetrazol-5- yl]-4-phenyl-piperidine-1-carboxylic acid benzyl ester 488.1
    593
    Figure US20090312307A1-20091217-C00688
         		1-{[2-(4-Chloro-benzyl)-2H-tetrazol- 5-yl]-4-phenyl-piperidin-1-yl}-2- methoxy-ethanone 426.2
    594
    Figure US20090312307A1-20091217-C00689
         		4-[2-(4-Chloro-benzyl)-2H-tetrazol-5- yl]-4-phenyl-piperidine-1-carboxylic acid (4-fluoro-phenyl)-amide 491.2
    595
    Figure US20090312307A1-20091217-C00690
         		4-[2-(4-Chloro-benzyl)-2H-tetrazol-5- yl]-4-phenyl-piperidine-1-carbothioic acid phenylamide 489.1
    596
    Figure US20090312307A1-20091217-C00691
         		{4-[2-(4-Chloro-benzyl)-2H-tetrazol- 5-yl]-4-phenyl-piperidin-1-yl}- pyridin-2-yl-methanone 459.2
    597
    Figure US20090312307A1-20091217-C00692
         		{4-[2-(4-Chloro-benzyl)-2H-tetrazol- 5-yl]-4-phenyl-piperidin-1-yl}- pyridin-2-yl-methanone 459.2
    598
    Figure US20090312307A1-20091217-C00693
         		1-{4-[2-(4-Chloro-benzyl)-2H- tetrazol-5-yl]-4-phenyl-piperidin-1- yl}-2-thiophen-2-yl-ethanone 478.1
    • Example 599
  • Figure US20090312307A1-20091217-C00694
    • 4-[1-(4-Chloro-benzyl)-1H-tetrazol-5-yl]-4-phenyl-piperidine-1-carboxylic acid ethyl ester Synthesis
  • Figure US20090312307A1-20091217-C00695
  • Compound 1: Compound 1 was prepared as described in Example 545.
  • Compound 2: Compound 1 (31 mg, 0.068 mmol) in dichloromethane (0.75 mL) and TFA (0.25 mL) was stirred at room temperature for 1.5 hour then concentrated. The residue was dissolved in ethyl acetate (10 mL), washed with 1N NaOH (2×5 mL), water, saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to give an oil compound 6, 20 mg (83%). H NMR (CDCl3) δ (ppm) 1.72 (1H, bs), 2.12-2.21 (2H, m), 2.46 (2H, bd, J=13.7 Hz), 2.94 (4H, bs), 4.92 (2H, s), 6.71 (2H, d, J=8.4 Hz), 7.12 (2H, d, J=6.4 Hz), 7.16 (2H, d, J=11.3 Hz), 7.21-7.36 (3H, m).
  • Title Compound: 4-[1-(4-Chloro-benzyl)-1H-tetrazol-5-yl]-4-phenyl-piperidine-1-carboxylic acid ethyl ester was prepared using methodology described in Example 2. H NMR (CDCl3) δ (ppm) 1.24 (3H, t, J=7.0 Hz), 2.11 (2H, bs), 2.43 (2H, bs), 3.05 (1H, bs), 3.35 (1H, bs), 3.85-3.95 (2H, bs), 4.11 (2H, q, J=7.0 Hz), 4.91 (2H, s), 6.72 (2H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4 Hz), 7.10 (2H, d, J=6.1 Hz), 7.29-7.38 (3H, m). [M+1] 426.0
    • Example 600
  • Figure US20090312307A1-20091217-C00696
    • 1-{4-[1-(4-Chloro-benzyl)-1H-tetrazol-5-yl]-4-phenyl-piperidin-1-yl}-3-phenyl-propan-1-one Synthesis
  • Figure US20090312307A1-20091217-C00697
  • Compound 1: Compound 1 was prepared as described in Example 599.
  • Title Compound: 1-{4-[1-(4-Chloro-benzyl)-1H-tetrazol-5-yl]-4-phenyl-piperidin-1-yl}-3-phenyl-propan-1-one was prepared using methodology described in Example 390. H NMR (CDCl3) δ (ppm) 1.72-1.77 (1H, m), 2.09-2.27 (2H, m), 2.48-2.62 (3H, m), 2.69-2.77 (1H, m), 2.92-2.96 (2H, m), 3.63 (2H, dd, J=3.0, 8.0 Hz), 4.31-4.35 (1H, m), 4.81 (1H, d, J=15.8 Hz), 4.98 (1H, d, J=15.8 Hz), 6.71 (2H, d, J=8.5 Hz), 6.71 (2H, d, J=8.5 Hz), 7.06-7.38 (8H, m). [M+1] 486.3
    • Example 601
  • Figure US20090312307A1-20091217-C00698
    • 1-[4-(5-Phenethyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-piperidin-1-yl]-3-phenyl-propan-1-one Synthesis
  • Figure US20090312307A1-20091217-C00699
    Figure US20090312307A1-20091217-C00700
  • Compound 1: Compound 1 was prepared as described in Example 74.
  • Compound 2: To hydroxylamine hydrochloride (4.25 g, 61.2 mmol) and sodium methoxide (3.30 g, 61.2 mmol) in PrOH (100 mL) was added compound 1 (5.8 g, 20.4 mmol). The reaction mixture was heated at reflux overnight, diluted with Ethyl acetate (200 mL), washed with water, sat. sodium chloride, dried over anhydrous sodium sulfate and concentrated to give a white solid compound 2, 4.60 g (72% yield). LCMS Rt 1.06 min, [M+1] 320.2.
  • Compound 3: Compound 2 (31 mg, 0.10 mmol), Et3N (15 mg, 0.15 mmol) and hydrocinnamoyl chloride (19 mg, 0.11 mmol) in tetrahydrofuran (0.5 mL) was stirred overnight. The reaction mixture was diluted with ethyl acetate (5 mL), washed with saturated sodium bicarbonate, water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a white solid compound 3, 0.03 g (66% yield).
  • Compound 4: To compound 3 (30 mg, 0.066 mmol) in dry tetrahydrofuran (0.5 mL) was added 0.13 mL (0.132 mmol) of tetrabutyl ammonium fluoride. After stirring for two hours at room temperature the reaction mixture was diluted with Ethyl acetate (5 mL), washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a white solid compound 4 sufficiently pure to be taken on to the next step.
  • Compound 5: Compound 5 were prepared using methodology described in Example 85 using hydrochloric acid instead of trifluoroacetic acid to accomplish nitrogen deprotection. LRMS m/z 334 (M+H)+.
  • Title Compound: 1-[4-(5-Phenethyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-piperidin-1-yl]-3-phenyl-propan-1-one was prepared using methodology described in Example 94. LRMS m/z 466 (M+H)+.
    • Examples 602 to 626
  • Examples 602 to 626 were prepared as described in Example 601.
  • Example Structure Name (M + H)+
    602
    Figure US20090312307A1-20091217-C00701
         		1-{4-[5-(2-Methoxy-phenyl)- [1,2,4]oxadiazol-3-yl]-4-phenyl- piperidin-1-yl}-3-phenyl-propan- 1-one 468.2
    603
    Figure US20090312307A1-20091217-C00702
         		1-[4-(5-Phenethyl- [1,2,4]oxadiazol-3-yl)-4-phenyl- piperidin-1-yl]-2-phenyl- ethanone 452.2
    604
    Figure US20090312307A1-20091217-C00703
         		2-(4-Fluoro-phenyl)-1-[4-(5- phenethyl-[1,2,4]oxadiazol- 3-yl)-4-phenyl-piperidin-1-yl]- ethanone 470.2
    605
    Figure US20090312307A1-20091217-C00704
         		1-[4-(5-Phenethyl- [1,2,4]oxadiazol-3-yl)-4-phenyl- piperidin-1-yl]-2-p-tolyl- ethanone 466.2
    606
    Figure US20090312307A1-20091217-C00705
         		3-(4-Fluoro-phenyl)-1-[4-(5- phenethyl-[1,2,4]oxadiazol-3-yl)- 4-phenyl-piperidin-1-yl]-propan- 1-one 484.2
    607
    Figure US20090312307A1-20091217-C00706
         		1-[4-(5-Phenethyl- [1,2,4]oxadiazol-3-y1)-4-phenyl- piperidin-1-yl]-3-p-tolyl-propan- 1-one 480.3
    608
    Figure US20090312307A1-20091217-C00707
         		1-{4-[5-(4-Chloro-benzyl)- [1,2,4]oxadiazol-3-yl]-4-phenyl- piperidin-1-yl}-2-phenyl- ethanone 472.2
    609
    Figure US20090312307A1-20091217-C00708
         		1-{4-[5-(4-Chloro-benzyl)- [1,2,4]oxadiazol-3-yl]-4-phenyl- piperidin-1-yl}-2-(4-fluoro- phenyl)-ethanone 490.2
    610
    Figure US20090312307A1-20091217-C00709
         		1-{4-[5-(4-Chloro-benzyl)- [1,2,4]oxadiazol-3-yl]-4-phenyl- piperidin-1-yl}-2-p-tolyl- ethanone 486.2
    611
    Figure US20090312307A1-20091217-C00710
         		1-{4-[5-(4-Chloro-benzyl)- [1,2,4]oxadiazol-3-yl]-4-phenyl- piperidin-1-yl}-3-phenyl-propan- 1-one 486.2
    612
    Figure US20090312307A1-20091217-C00711
         		1-{4-[5-(4-Chloro-benzyl)- [1,2,4]oxadiazol-3-yl]-4-phenyl- piperidin-1-yl}-3-(4-fluoro- phenyl)-propan-1-one 504.2
    613
    Figure US20090312307A1-20091217-C00712
         		1-{4-[5-(4-Chloro-benzyl)- [1,2,4]oxadiazol-3-yl]-4-phenyl- piperidin-1-yl}-3-p-tolyl-propan- 1-one 500.2
    614
    Figure US20090312307A1-20091217-C00713
         		1-{4-[5-(4-Chloro-benzyl)- [1,2,4]oxadiazol-3-yl]-4-phenyl- piperidin-1-yl}-2-phenoxy- ethanone 488.2
    615
    Figure US20090312307A1-20091217-C00714
         		[4-(5-Benzyl-[1,2,4]oxadiazol-3- yl)-4-phenyl-piperidin-1-yl]-(4- fluoro-phenyl)-methanone 442.2
    616
    Figure US20090312307A1-20091217-C00715
         		1-[4-(5-Benzyl-[1,2,4]oxadiazol- 3-yl)-4-phenyl-piperidin-1-yl]-2- phenyl-ethanone 438.2
    617
    Figure US20090312307A1-20091217-C00716
         		1-[4-(5-Benzyl-[1,2,4]oxadiazol- 3-yl)-4-phenyl-piperidin-1-yl]-2- (4-fluoro-phenyl)-ethanone 456.2
    618
    Figure US20090312307A1-20091217-C00717
         		1-[4-(5-Benzyl-[1,2,4]oxadiazol- 3-yl)-4-phenyl-piperidin-1-yl]-2- p-tolyl-ethanone 452.2
    619
    Figure US20090312307A1-20091217-C00718
         		1-[4-(5-Benzyl-[1,2,4]oxadiazol- 3-yl)-4-phenyl-piperidin-1-yl]-3- phenyl-propan-1-one 452.2
    620
    Figure US20090312307A1-20091217-C00719
         		1-[4-(5-Benzyl-[1,2,4]oxadiazol- 3-yl-4-pheny1-piperidin-1-yl]-3- (4-fluoro-phenyl)-propan-1-one 470.2
    621
    Figure US20090312307A1-20091217-C00720
         		1-[4-(5-Benzy1-[1,2,4]oxadiazol- 3-yl)-4-phenyl-piperidin-1-yl]-3- p-tolyl-propan-1-one 466.2
    622
    Figure US20090312307A1-20091217-C00721
         		1-[4-(5-Phenethyl- [1,2,4]oxadiazol-3-yl)-4-phenyl- piperidin-1-yl]-2-thiophen-2-yl- ethanone 458.2
    623
    Figure US20090312307A1-20091217-C00722
         		4-[5-(4-Chloro-benzyl)- [1,2,4]oxadiazol-3-yl]-4-phenyl- piperidine-1-carboxylic acid benzyl ester 488.2
    624
    Figure US20090312307A1-20091217-C00723
         		1-[4-(5-Benzyl-[1,2,4]oxadiazol- 3-yl)-4-phenyl-piperidin-1-yl]-2- thiophen-2-yl-ethanone 444.2
    625
    Figure US20090312307A1-20091217-C00724
         		1-{4-[5-(4-Methoxy-benzyl)- [1,2,4]oxadiazol-3-yl]-4-phenyl- piperidin-1-yl}-3-phenyl-propan- 1-one 482.2
    626
    Figure US20090312307A1-20091217-C00725
         		3-(4-Fluoro-phenyl-1-{4-[5-(4- methoxy-benzyl)- [1,2,4]oxadiazol-3-yl]-4-phenyl- piperidin-1-yl}-propan-1-one 500.2
    • Example 627
  • Figure US20090312307A1-20091217-C00726
    • 4-(5-Fluoro-1-methyl-1H-benzoimidazol-2-yl)-4-phenyl-piperidine-1-carboxylic acid benzyl ester Synthesis
  • Figure US20090312307A1-20091217-C00727
    Figure US20090312307A1-20091217-C00728
  • Compound 1: Compound 1 is commercially available.
  • Compound 2: 2,5-Difluoronitrobenzene (1.0 g, 6.29 mmol), methylamine hydrochloride (2.12 g, 31.43 mmol) and potassium carbonate (4.34 g, 31.43 mmol) in DMSO (10 mL) was stirred for 24 hours, diluted with Et2O (200 mL), washed with water (3 times), brine, dried over anhydrous sodium sulfate and concentrated to give compound 2 as an orange solid 1.1 g (100%).
  • Compound 3: Compound 2 (1.1 g, 6.29 mmol) and 10% Pd on charcoal (300 mg) in methanol (20 mL) was stirred under hydrogen for 24 hours, filtered over CELITE® and concentrated. The residue was purified by silica gel chromatography using Hexanes/Ethyl acetate (2:1) as eluent to give a white solid compound 3, 672 mg (74% yield). NMR 1H (CDCl3) δ (ppm) 2.83 (3H, s), 3.28 (3H, bs), 6.40-6.60 (3H, m).
  • Compound 4: Compound 4 was prepared as described in Example 323.
  • Compounds 5 and 6: Compound 4 (700 mg, 2.06 mmol) in thionyl chloride was heated at reflux for 2 hours then concentrated. The residue was dissolved in CH2Cl2 (3.5 mL) and cooled to 0° C. Compound 3 (289 mg, 2.06 mmol) in CH2Cl2 (3.5 mL) followed by Et3N (1.44 mL, 10.3 mmol) were added. After 1 hour the reaction mixture was diluted with Ethyl acetate (30 mL), washed with 1N NaOH, water, brine, dried over anh. sodium sulfate and concentrated. The residue was purified by silica gel chromatography using Hexanes/Ethyl acetate (2:1) as eluent to give a white solid compound 5 and compound 6521 mg (55% yield) as an inseparable mixture. LCMS Rt 1.42 min and 1.52, [M+1] 462.2.
  • Title Compound: The mixture of compound 5 and compound 6 (521 mg, 1.12 mmol) in glacial acetic acid (5 mL) was heated at reflux for 2 hours then concentrated. The residue was purified by silica gel chromatography using hexanes/ethyl acetate (2:1) as eluent to give a white solid 4-(5-fluoro-1-methyl-1H-benzoimidazol-2-yl)-4-phenyl-piperidine-1-carboxylic acid benzyl ester, 365 mg (73% yield). NMR 1H (CDCl3) δ (ppm) 2.05-2.40 (2H, m), 2.55-2.75 (2H, m), 3.22 (3H, s), 3.25-3.40 (1H, m), 3.50-3.70 (1H, m), 5.14 (2H, s), 7.01 (1H, dt, J=2.4, 9.1 Hz), 7.09-7.35 (13H, m), 7.48 (1H, dd, J=2.2, 9.4 Hz). LCMS Rt 1.41 min, [M+1] 442.2.
    • Examples 628 to 646
  • Examples 628 to 646 were prepared as described in Example 627.
  • Example Structure Name (M + 1)+
    628
    Figure US20090312307A1-20091217-C00729
         		4-(1H-Benzoimidazol-2-ylmethyl)- 4-phenyl-piperidine-1-carboxylic acid benzyl ester 426.2
    629
    Figure US20090312307A1-20091217-C00730
         		4-(1-Methyl-1H-benzoimidazol-2- ylmethyl)-4-phenyl-piperidine-1- carboxylic acid benzyl ester 440.2
    630
    Figure US20090312307A1-20091217-C00731
         		4-(1H-Benzoimidazol-2-yl)-4- phenyl-piperidine-1-carboxylic acid benzyl ester 412.2
    631
    Figure US20090312307A1-20091217-C00732
         		1-[4-(5-Fluoro-1-methyl-1H- benzoimidazol-2-yl)-4-phenyl- piperidin-1-yl]-3-phenyl-propan-1- one 442.2
    632
    Figure US20090312307A1-20091217-C00733
         		1-[4-(5-Fluoro-1-methyl-1H- benzoimidazol-2-yl)-4-phenyl- piperidin-1-yl]-2-phenoxy-ethanone 444.2
    633
    Figure US20090312307A1-20091217-C00734
         		5-Fluoro-2-[1-(4-fluoro- benzenesulfonyl)-4-phenyl- piperidin-4-yl]-1-methyl-1H- benzoimidazole 468.2
    634
    Figure US20090312307A1-20091217-C00735
         		485.2
    635
    Figure US20090312307A1-20091217-C00736
         		1-[4-(5-Fluoro-1-methyl-1H- benzoimidazol-2-yl)-4-phenyl- piperidin-1-yl]-2-(4-fluoro- phenoxy)-ethanone 462.2
    636
    Figure US20090312307A1-20091217-C00737
         		1-[4-(5-Fluoro-1H-benzoimidazol-2- yl)-4-phenyl-piperidin-1-yl]-3-(4- methoxy-phenyl)-propan-1-one 458.2
    637
    Figure US20090312307A1-20091217-C00738
         		1-[4-(5-Fluoro-1H-benzoimidazol-2- yl)-4-phenyl-piperidin-1-yl]-4- phenyl-butan-1-one 442.2
    638
    Figure US20090312307A1-20091217-C00739
         		1-[4-(5-Fluoro-1H-benzoimidazol-2- yl)-4-phenyl-piperidin-1-yl]-2-(3- trifluoromethyl-phenyl)-ethanone 482.2
    639
    Figure US20090312307A1-20091217-C00740
         		5-Chloro-2-[1-(3-fluoro- benzenesulfonyl)-4-phenyl- piperidin-4-yl]-1H-benzoimidazole 470.1
    640
    Figure US20090312307A1-20091217-C00741
         		5-Chloro-2-[1-(4-fluoro- benzenesulfonyl)-4-phenyl- piperidin-4-yl]-1H-1-benzoimidazole 470.1
    641
    Figure US20090312307A1-20091217-C00742
         		467.2
    642
    Figure US20090312307A1-20091217-C00743
         		495.2
    643
    Figure US20090312307A1-20091217-C00744
         		481.2
    644
    Figure US20090312307A1-20091217-C00745
         		1-[4-(1-Methyl-1H-benzoimidazol- 2-ylmethyl)-4-phenyl-piperidin-1- yl]-3-phenyl-propan-1-one 438.3
    645
    Figure US20090312307A1-20091217-C00746
         		2-[1-(4-Methoxy-benzenesulfonyl)- 4-phenyl-piperidin-4-ylmethyl]-1- methyl-1H-benzoimidazole 476.2
    646
    Figure US20090312307A1-20091217-C00747
         		4-(5-Chloro-1H-benzoimidazol-2- yl)-4-phenyl-piperidine-1-carboxylic acid ethyl ester 384.1
    • Example 647
  • Figure US20090312307A1-20091217-C00748
    • 4-tert-Butoxycarbonylamino-4-phenyl-piperidine-1-carboxylic acid benzyl ester Synthesis
  • Figure US20090312307A1-20091217-C00749
  • Compound 1: Compound 1 was prepared as described in Example 323.
  • Compound 2: A solution of compound 1 (0.62 g; 1.8 mmol) in tetrahydrofuran (40 mL) was cooled to 0° C. and treated with triethylamine (0.38 mL; 2.7 mmol) and diphenylphosphoryl azide (0.44 mL; 2.0 mmol). The cooling bath was removed and the reaction mixture was allowed to stir at room temperature 18 h. The tetrahydrofuran was removed by evaporation and the crude residue was purified by column chromatography on silica gel using 8:2 hexane:ethyl acetate as the eluent to give 0.67 g of compound 2. LRMS m/z 365 (M+H)+.
  • Title Compound: A solution of compound 2 (0.67 g; 1.8 mmol) in chlorobenzene (15 mL) was treated with t-butanol (25 mL) and heated at 115° C. for 20 h. The chlorobenzene was removed by evaporation and the residue was subjected to column chromatography on silica gel using an 8:2 hexane:ethyl acetate to 1:1 hexane:ethyl acetate gradient as the eluent to give 0.05 g of 4-tert-butoxycarbonylamino-4-phenyl-piperidine-1-carboxylic acid benzyl ester as a colorless oil LRMS m/z 411 (M+H)+ and 0.2 g compound 3 as a colorless oil LRMS m/z 337 (M+H)+.
    • Example 648
  • Figure US20090312307A1-20091217-C00750
    • 4-(2-Methoxy-benzoylamino)-4-phenyl-piperidine-1 carboxylic acid benzyl ester Synthesis
  • Figure US20090312307A1-20091217-C00751
  • Compound 1: Compound 1 was prepared as described in Example 626.
  • Compound 2: A solution of compound 1 (0.05 g; 0.1 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (1 mL) and allowed to stir at room temperature for 1 h at which time LCMS indicated complete consumption of compound 1. Additional dichloromethane (20 mL) and 1 N sodium hydroxide (20 mL) were added. The organic layer was separated, washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated to give 0.03 g of compound 2 that was used in the next step without additional purification. LCMS m/z=311 (M+H)+.
  • Title Compound: A solution of compound 2 (0.03 g; 0.009 mmol) in tetrahydrofuran (2 mL) was treated with triethylamine (0.1 mL; 0.7 mmol) and o-anisoyl chloride (0.05 g; 0.3 mmol) at room temperature. After stirring 15 h the tetrahydrofuran was removed by evaporation and the residue was purified by prep LC to give 0.011 g of compound 4-(2-methoxy-benzoylamino)-4-phenyl-piperidine-carboxylic acid benzyl ester as a white solid. LCMS m/z 461 (M+H)+.
    • Example 649
  • Figure US20090312307A1-20091217-C00752
    • 4-[3-(2-Methoxy-benzyl)ureido]-4-phenyl-piperidine-1-carboxylic acid benzyl ester Synthesis
  • Figure US20090312307A1-20091217-C00753
  • Compound 1: Compound 1 was prepared as described in Example 626.
  • Title Compound: A solution of compound 1 (0.05 g; 0.15 mmol) in anhydrous tetrahydrofuran (2 mL) was treated with 2-methoxybenzyl amine (0.041 g; 0.30 mmol) at room temperature. After stirring 2 h the tetrahydrofuran was removed by evaporation and the residue was purified by prep LC to give 0.015 g of 4-[3-(2-methoxy-benzyl)-ureido]-4-phenyl-piperidine-1-carboxylic acid benzyl ester as a white solid. LCMS m/z 475 (M+H)+.
    • Examples 650 to 652
  • Examples 650 to 652 were prepared as described in Example 649.
  • Example Structure Name M + H
    650
    Figure US20090312307A1-20091217-C00754
         		4-[3-(2-Methoxy-phenyl)-ureido]-4- phenyl-piperidine-1-carboxylic acid benzyl ester 461
    651
    Figure US20090312307A1-20091217-C00755
         		4-(3-Phenethyl-ureido)-4-phenyl- piperidine-1-carboxylic acid benzyl ester 459
    652
    Figure US20090312307A1-20091217-C00756
         		4-(3-Isoquinolin-1-yl-ureido)-4- phenyl-piperidine-1-carboxylic acid benzyl ester 482
    • Example 653
  • Figure US20090312307A1-20091217-C00757
    • 3-Amino-pyrazine-2-carboxylic acid (4-phenyl-piperidin-4-ylmethyl)-amide Synthesis
  • Figure US20090312307A1-20091217-C00758
  • Compound 1: Compound 1 is commercially available.
  • Compound 2: A solution of compound 1 (20 g; 90 mmol) in 1 N sodium hydroxide (200 mL) and tetrahydrofuran (50 mL) was treated with di-tert-butyl dicarbonate (19.7 g; 90.3 mmol) at room temperature. After stirring 24 h the reaction mixture was adjusted to pH=7 by the addition of 1 N hydrochloric acid and washed with ethyl acetate (2×100 mL). The organic layers were combined, washed with saturated aqueous sodium chloride, dried (sodium sulfate), filtered and concentrated. The crude product was recrystallized from the minimum amount of ethanol to give 20 g compound 2 as a white solid. LRMS m/z=287 (M+H)+.
  • Compound 3: A solution of compound 2 (4.5 g; 15.7 mmol) in ethanol (42.5 mL) and acetic acid (7.5 mL) was treated with platinum oxide (250 mg) and hydrogenated at 60 psi for 12 h. Analysis by thin layer chromatography indicated the reaction was not complete. Additional platinum oxide (124 mg) was added and the reaction mixture hydrogenated at 60 psi for another 12 h. The reaction mixture was filtered through CELITE® and concentrated to give 4.6 g of compound 3 as a colorless oil that was used without additional purification. LRMS m/z 291 (M+H)+.
  • Compound 4: A suspension of 3-amino-pyrazine-2-carboxylic acid (2.9 g; 20.8 mmol) in tetrahydrofuran (30 mL) was treated with triethylamine (7 mL; 50 mmol) followed by benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (8.8 g; 19.9 mmol) at room temperature. After 15 minutes of stirring the reaction mixture became homogeneous and compound 3 (4.6 g; 15.8 mmol) was added as a solution in tetrahydrofuran (20 mL). The reaction was heated at 60° C. for 12 h. The solvent was removed by rotary evaporation and the crude product was purified directly by column chromatography on silica gel using 1:1 ethyl acetate:hexane as the eluent to give 2.0 g of compound 4 as a white foam. LRMS m/z=412 (M+H)−.
  • Title Compound: A solution of compound 4 (1.9 g; 4.6 mmol) in anhydrous dichloromethane (50 mL) was treated with trifluoroacetic acid (50 mL) at room temperature. After stirring for 19 h the reaction mixture was made basic (pH=12) with 6 N NaOH and additional dichloromethane (100 mL) was added. The organic layer was separated, washed with saturated aqueous sodium chloride, dried (sodium sulfate), filtered and concentrated to give 1.4 g of the title compound as a white foam that was used without additional purification. LRMS m/z=312 (M+H)+.
    • Example 654
  • Figure US20090312307A1-20091217-C00759
    • 3-Amino-pyrazine-2-carboxylic acid [4-(3-fluoro-phenyl)-piperidin-4-ylmethyl]-amide Synthesis
  • Figure US20090312307A1-20091217-C00760
    Figure US20090312307A1-20091217-C00761
  • Compound 1: Compound 1 is commercially available.
  • Compound 2: Compound 1 (5.0 g, 28.0 mmol) was suspended in 100 mL of dichloromethane. Di-tert-butyl dicarbonate (6.1 g, 28.0 mmol) and diisopropylethylamine (10.7 mL, 61.6 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether (300 mL), washed with 1N hydrochloric acid (2×100 n mL), saturated sodium bicarbonate (100 mL), water (100 mL) and saturated aqueous sodium chloride (100 mL). The organic layer was dried (sodium sulfate) and concentrated. The crude residue was purified by silica gel chromatography using 9:1 hexane:diethyl ether as eluent to give 3.46 g of compound 2 as a colorless oil.
  • Compound 3: Sodium hydride (1.9 g, 79.0 mmol) was suspended in dimethylformamide (30 mL) and cooled to 0° C. 3-Fluorophenylacetonitrile (2.61 g, 19.3 mmol) was slowly added followed by the addition of compound 2 (3.68 g, 15.2 mmol) as a solution in dimethylformamide (30 mL). The reaction was stirred at 0° C. for 0.5 hours and was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into ice and extracted with ethyl acetate (200 mL). The aqueous layer was extracted with ethyl acetate (2×200 mL). The organic layers were combined and washed with 10% lithium chloride (2×100 mL), dried (sodium sulfate), filtered and concentrated. The crude residue was purified by flash chromatography on silica gel using 9:1 hexane:ethyl acetate as the eluent to give 4.04 g of compound 3 as a yellow oil. 1H NMR (CDCl3) δ1.48 (9H, s), 1.92 (2H, td, J=4.3, 13.1), 2.05 (2H, t, J=10.2), 3.19 (2H, t, J=12.4), 4.29 (2H, d, J=13.7), 7.01-7.45 (4H, m). LRMS m/z 305 (M+H)+.
  • Compound 4: Compound 3 (4.04 g, 13.27 mmol) in 50 mL of 15% acetic acid in ethanol was treated with platinum (IV) oxide (0.210 g, 0.925 mmol) and hydrogenated at 60 psi (Parr Apparatus) for 48 h. The reaction mixture was filtered through a thick pad of CELITE® and concentrated. To the concentrate was added 200 mL of diethyl ether and the organic solution was washed with 1N sodium hydroxide (2×50 mL) and dried (sodium sulfate), filtered and concentrated to give 4.07 g of compound 4. LRMS m/z 309 (M+H)+.
  • Compound 5: To compound 4 (0.562 g, 1.94 mmol) in 15 mL of tetrahydrofuran was added 3-aminopyrazine-2-carboxylic acid (0.270 g, 1.94 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (0.858 g, 1.94 mmol) and triethylamine (0.271 mL, 1.94 mmol). The reaction mixture was stirred for 2 hours at room temperature then diluted with diethyl ether (50 mL), washed with water (3×50 mL), saturated sodium chloride (50 mL) and dried over sodium sulfate. After filtration, the solvent was removed by rotary evaporation and the crude residue was purified using flash chromatography (1:1 hexane/diethyl ether) to give 0.69 g of compound 5. LRMS m/z 430 (M−H)+.
  • Title Compound; Compound 5 (0.691 g, 1.61 mmol) was suspended in tetrahydrofuran (5 mL) and 4 N hydrochloric acid in 1,4-dioxane (5 mL) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, dissolved in water (15 mL) and the aqueous layer was washed with diethyl ether (2×15 mL). 6 N Sodium hydroxide was added to basily the aqueous layer that was then extracted with dichloromethane (3×20 mL). The organic layers were combined, dried (sodium sulfate), filtered and concentrated to give 0.47 g of the title compound as a yellow solid which was used without additional purification.
  • LRMS m/z 330 (M+H)+.
    • Examples 655 to 695
  • Examples 655 to 695 were synthesized using methodology described in Example 1 and Example 654.
  • Example Structure Name M + H
    655
    Figure US20090312307A1-20091217-C00762
         		3-Ammo-pyrazine-2-carboxylic acid [1-benzyl-4-(4-fluoro- phenyl)-piperidin-4-ylmethyl]- amide 422
    656
    Figure US20090312307A1-20091217-C00763
         		N-[1-Benzyl-4-(2-fluoro- phenyl)-piperidin-4-ylmethyl}-2- hydroxy-6-methoxy-benzamide 450
    657
    Figure US20090312307A1-20091217-C00764
         		N-[4-(2-Fluoro-phenyl)- piperidin-4-ylmethyl]-2- methoxy-benzamide 343
    658
    Figure US20090312307A1-20091217-C00765
         		N-[4-(2-Fluoro-phenyl)- piperidin-4-ylmethyl]-2- hydroxy-6-methoxy-benzamide 359
    659
    Figure US20090312307A1-20091217-C00766
         		1-Benzoyl-4-(3-chloro-phenyl)- piperidine-4-carbonitrile 326
    660
    Figure US20090312307A1-20091217-C00767
         		1-Benzoyl-4-(2,5-difluoro- phenyl)-piperidine-4-carbonitrile 327
    661
    Figure US20090312307A1-20091217-C00768
         		C-[1-Benzyl-4-(3-chloro- phenyl)-piperidin-4-yl]- methylamine 316
    662
    Figure US20090312307A1-20091217-C00769
         		N-[1-Benzyl-4-(3-chloro- phenyl)-piperidin-4-ylmethyl]-2- methoxy-benzamide 450
    663
    Figure US20090312307A1-20091217-C00770
         		N-[1-Benzyl-4-(3-chloro- phenyl)-piperidin-4-ylmethyl]-2- hydroxy-6-methoxy-benzamide 466
    664
    Figure US20090312307A1-20091217-C00771
         		3-Aminopyrazine-2-carboxylic acid [1-benzyl-4-(3-chloro- pheny)-piperidin-4-ylmethyl]- amide 437
    665
    Figure US20090312307A1-20091217-C00772
         		N-[4-(3-Chloro-phenyl)- piperidin-4-ylmethyl]-2- methoxy-benzamide 360
    666
    Figure US20090312307A1-20091217-C00773
         		N-[4-(3-Chloro-phenyl)- piperidin-4-ylmethyl]-2- hydroxy-6-methoxy-benzamide 376
    667
    Figure US20090312307A1-20091217-C00774
         		3-Amino-pyrazine-2-carboxylic acid [4-(3-chloro-phenyl)- piperidin-4-ylmethyl]-amide 347
    668
    Figure US20090312307A1-20091217-C00775
         		4-Cyano-4-(2,5-difluoro- phenyl)-piperidine-1-carboxylic acid tert-butyl ester 323
    669
    Figure US20090312307A1-20091217-C00776
         		4-Cyano-4-(3-fluoro-phenyl]- piperidine-1-carboxylic acid tert-butyl ester 305
    670
    Figure US20090312307A1-20091217-C00777
         		4-Aminomethyl-4-(3-fluoro- phenyl)-piperidin-1-carboxylic acid tert-butyl ester 309
    671
    Figure US20090312307A1-20091217-C00778
         		4-(3-Fluoro-phenyl)-4-[(2- methoxy-benzoylamino)- methyl]-piperidine-1-carboxylic acid tert-butyl ester 444
    672
    Figure US20090312307A1-20091217-C00779
         		N-[4-(3-Fluoro-phenyl)- piperidin-4-ylmethyl]-2- methoxy-benzamide 343
    673
    Figure US20090312307A1-20091217-C00780
         		3-Amino-pyrazine-2-carboxylic acid [1-benzyl-4-(3-methoxy- pheny)-piperidin-4-ylmethyl]- amide 433
    674
    Figure US20090312307A1-20091217-C00781
         		4-{[(3-Amino-pyrazine-2- carbonyl)-amino]-methyl}-4-(3- fluoro-phenyl)-piperidine-1- carboxylic acid tert-butyl ester 430
    675
    Figure US20090312307A1-20091217-C00782
         		3-Amino-pyrazine-2-carboxylic acid [4-(3-methoxy-phenyl)- piperidin-4-ylmethyl]-amide 342
    676
    Figure US20090312307A1-20091217-C00783
         		3-Amino-pyrazine-2-carboxylic acid [4-(3-fluoro-phenyl)- piperidin-4-ylmethyl]-amide 330
    677
    Figure US20090312307A1-20091217-C00784
         		4-Aminomethy-4-(2,5-difluoro- phenyl)-piperidine-1-carboxylic acid tert-butyl ester 327
    678
    Figure US20090312307A1-20091217-C00785
         		4-(2,5-Difluoro-phenyl)-4-[(2- methoxy-benzoylamino)- methyl]-piperidine-1-carboxylic acid tert-butyl ester 462
    679
    Figure US20090312307A1-20091217-C00786
         		4-(2,5-Difluoro-phenyl)-4-[(2- hydroxy-6-methoxy- benzoylamino)-methyl]- piperidine-1-carboxylic acid tert-butyl ester 478
    680
    Figure US20090312307A1-20091217-C00787
         		4-{[(3-Amino-pyrazine-2- carbonyl)-amino]-methyl}-4- (2,5-difluoro-phenyl)-piperidine- 1-carboxylic acid tert-butyl ester 448
    681
    Figure US20090312307A1-20091217-C00788
         		N-[4-(2,5-Difluoro-phenyl)- piperidin-4-ylmethyl]-2- methoxy-benzamide 361
    682
    Figure US20090312307A1-20091217-C00789
         		3-Amino-pyrazine-2-carboxylic acid [4-(2,5-difluoro-phenyl)- piperidin-4-ylmethyl]-amide 348
    683
    Figure US20090312307A1-20091217-C00790
         		2,3-Dihydro-benzofuran-7- carboxylic acid (1-benzyl-4- phenyl-piperidin-4-ylmethyl)- amide 428
    684
    Figure US20090312307A1-20091217-C00791
         		N-(1-Benzyl-4-phenyl-piperidin- 4-ylmethyl-(5-chloro-2- methoxy-benzamide 450
    685
    Figure US20090312307A1-20091217-C00792
         		N-[1-Benzyl-4-(3-methoxy- phenyl)-piperidin-4-ylmethyl]-2- methoxy-benzamide 446
    686
    Figure US20090312307A1-20091217-C00793
         		2-Methoxy-N-[4-(3-methoxy- phenyl)-piperidin-4-ylmethyl]- benzamide 355
    687
    Figure US20090312307A1-20091217-C00794
         		N-(1-Benzyl-4-phenyl-piperidin- 4-ylmethyl)-2-hydroxy-6- methoxy-benzamide 432
    688
    Figure US20090312307A1-20091217-C00795
         		2-Hydroxy-6-methoxy-N-(4- phenyl-piperidin-4-ylmethyl)- benzamide 341
    689
    Figure US20090312307A1-20091217-C00796
         		4-(3-Fluoro-phenyl)-4-[(2- hydroxy-6-methoxy- benzoylamino)-methyl]- piperidine-1-carboxylic acid tert-butyl ester 460
    690
    Figure US20090312307A1-20091217-C00797
         		N-[1-Benzyl-4-(2-fluoro- phenyl)-piperidin-4-ylmethyl]-2- methoxy-benzamide 434
    691
    Figure US20090312307A1-20091217-C00798
         		4-(3,5-Difluoro-phenyl)-4-[(2- hydroxy-6-methoxy- benzoylamino)-methyl]- piperidine-1-carboxylic acid tert-butyl ester 478
    692
    Figure US20090312307A1-20091217-C00799
         		4-{[(3-Amino-pyrazine-2- carbonyl)-amino]-methyl}-4- (3,5-difluorophenyl)-piperidine- 1-carboxylic acid tert-butyl ester 448
    693
    Figure US20090312307A1-20091217-C00800
         		4-[(2-Hydroxy-6-methoxy- benzoylamino)-methyl]-4-(3- trifluoromethyl-phenyl)- piperidine-1-carboxylic acid tert-butyl ester 510
    694
    Figure US20090312307A1-20091217-C00801
         		4-{[(3-Amino-pyrazine-2- carbonyl)-amino]-methyl}-4-(3- trifluoromethyl-phenyl)- piperidine-1-carboxylic acid tert-butyl ester 481
    695
    Figure US20090312307A1-20091217-C00802
         		4-[(2-Methoxy-benzoylamino)- methyl]-4-(3-trifluoromethyl- phenyl)-piperidine-1-carboxylic acid tert-butyl ester 494
    • Example 696
  • Figure US20090312307A1-20091217-C00803
    • N-(1-Cyclohexylsulfamoyl-4-phenyl-piperidin-4-ylmethyl)-2-methoxy-benzamide Synthesis
  • Figure US20090312307A1-20091217-C00804
  • Compound 1: Compound 1 was prepared as described in Example 15.
  • Compound 2: Compound 2 was prepared as described in J. Org. Chem., 68:115-119 (2003).
  • Compound 3: Compound 2 (3.34 g, 8.6 mmol) was suspended in 15 mL of acetonitrile and cooled to 0° C. Compound 1 (2.14 g, 6.6 mmol) was slowly added. The reaction was allowed to warm to room temperature overnight. The reaction mixture was concentrated and purified directly by flash chromatography on silica gel using 3:1 ethylacetate/hexane as the eluent to give 1.92 g of compound 3. LRMS m/z 469 (M+H)+.
  • Compound 4: Compound 3 (1.9 g, 4.05 mmol) was suspended in 16 mL of dichloromethane and cooled to 0° C. A solution of methyl triflate (0.505 mL, 4.46 mmol) in dichloromethane (16 mL) was slowly added. The reaction was allowed to warm to room temperature, stirred for 2 h and concentrated. Compound 4 was used in the next step without further purification. LRMS m/z 483 (M+H)+.
  • Title Compound: To compound 4 (0.075 g, 0.118 mmol) and cyclohexylamine (0.016 mL, 0.142 mmol) was added 0.695 mL of acetonitrile. The reaction mixture was heated to 80° C. for 4 h and concentrated. The crude material was purified using preparative reverse phase HPLC to give 0.026 g of the title compound as a white solid. LRMS m/z 488 (M+H)+.
    • Examples 697 to 843
  • Examples 697 to 843 were prepared using methodology described in Example 15, Example 16, Example 17 and Example 696.
  • Example Structure Name M + H
    697
    Figure US20090312307A1-20091217-C00805
         		4-Phenyl-1-sulfamoyl- piperidine-4-carboxylic acid benzyl-methyl-amide 390
    698
    Figure US20090312307A1-20091217-C00806
         		1-(4-Fluoro- benzylsulfamoyl)-4-phenyl- piperidine-4-carboxylic acid benzyl-methyl-amide 498
    699
    Figure US20090312307A1-20091217-C00807
         		4-Phenyl-1-sulfamoyl- piperidine-4-carboxylic acid [2-(3-trifluoromethyl- phenyl)-ethyl]-amide 457
    700
    Figure US20090312307A1-20091217-C00808
         		1-(4-Fluoro- benzylsulfamoyl}-4-phenyl- piperidine-4-carboxylic acid [2-(3-trifluoromethyl- phenyl)-ethyl]-amide 566
    701
    Figure US20090312307A1-20091217-C00809
         		N-[1-(Imidazole-1-sulfonyl)- 4-phenyl-piperidin-4- ylmethyl]-2-methoxy- benzamide 457
    702
    Figure US20090312307A1-20091217-C00810
         		4-Phenyl-1-sulfamoyl- piperidine-4-carboxylic acid (biphenyl-3-ylmethyl)-amide 452
    703
    Figure US20090312307A1-20091217-C00811
         		1-(4-Fluoro- benzylsulfamoyl)-4-phenyl- piperidine-4-carboxylic acid (biphenyl-3-ylmethyl)-amide 560
    704
    Figure US20090312307A1-20091217-C00812
         		N-(4-Cyclohex-1-enyl-1- dimethylsulfamoyl- piperidin-4-ylmethyl)-2- methoxy-benzamide 438
    705
    Figure US20090312307A1-20091217-C00813
         		N-(4-Cyclohex-1-enyl-1- dimethylsulfamoyl- piperidin-4-ylmethyl)-2,4- dimethoxy-benzamide 468
    706
    Figure US20090312307A1-20091217-C00814
         		N-(4-Cyclohex-1-enyl-1- dimethylsulfamoyl- piperidin-4-ylmethyl)-2,6- dimethoxy-benzamide 468
    707
    Figure US20090312307A1-20091217-C00815
         		N-(4-Cyclohex-1-enyl-1- dimethylsulfamoyl- piperidin-4-ylmethyl)-2- trifluoromethoxy-benzamide 492
    708
    Figure US20090312307A1-20091217-C00816
         		N-(4-Cyclohex-1-enyl-1- dimethylsulfamoyl- piperidin-4-ylmethyl)-2- fluoro-benzamide 426
    709
    Figure US20090312307A1-20091217-C00817
         		4-Cyclohex-1-enyl-4-[(2- trifluoromethoxy- benzenesulfonylamino)- methyl]-piperidine-1- sulfonic acid dimethylamide 528
    710
    Figure US20090312307A1-20091217-C00818
         		4-Phenyl-4-[(2- trifluoromethoxy- benzenesulfonylamino)- methyl]-piperidine-1- sulfonic acid amide 496
    711
    Figure US20090312307A1-20091217-C00819
         		4-Phenyl-4-[(2- trifluoromethoxy- benzenesulfonylamino)- methyl]-piperidine-1- sulfonic acid 4-fluoro- benzylamide 604
    712
    Figure US20090312307A1-20091217-C00820
         		5-Chloro-2-methoxy-N-(4- phenyl-1-sulfamoyl- piperidin-4-ylmethyl)- benzamide 440
    713
    Figure US20090312307A1-20091217-C00821
         		5-Chloro-N-[1-(4-fluoro- benzylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 548
    714
    Figure US20090312307A1-20091217-C00822
         		4-Phenyl-1-sulfamoyl- piperidine-4-carboxylic acid methyl-[2-(3- trifluoromethyl-phenyl)- ethyl]-amide 472
    715
    Figure US20090312307A1-20091217-C00823
         		1-(4-Fluoro- benzylsulfamoyl)-4-phenyl- piperidine-4-carboxylic acid methyl-[2-(3- trifluoromethyl-phenyl)- ethyl]-amide 580
    716
    Figure US20090312307A1-20091217-C00824
         		2,3-Dihydro-benzofuran-7- carboxylic acid (4-phenyl-1- sulfamoyl-piperidin-4- ylmethyl)-amide 418
    717
    Figure US20090312307A1-20091217-C00825
         		2,3-Dihydro-benzofuran-7- carboxylic acid [1-(4-fluoro- benzylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-amide 526
    718
    Figure US20090312307A1-20091217-C00826
         		N-[4-(3,6-Dihydro-2H- pyran-4-yl)-1- dimethylsulfamoyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 440
    719
    Figure US20090312307A1-20091217-C00827
         		2-Methoxy-N-(1-sulfamoyl- 4-thiophen-3-yl-piperidin-4- ylmethyl)-benzamide 412
    720
    Figure US20090312307A1-20091217-C00828
         		N-[4-(4-Fluoro-phenyl)-1- sulfamoyl-piperidin-4- ylmethyl]-2-methoxy- benzamide 423
    721
    Figure US20090312307A1-20091217-C00829
         		4-[(4-Methyl-pyridin-2- ylamino)-methyl]-4-phenyl- piperidine-1-sulfonic acid dimethylamide 391
    722
    Figure US20090312307A1-20091217-C00830
         		N-[4-(3-Fluoro-phenyl)-1- sulfamoyl-piperidin-4- ylmethyl]-2-methoxy- benzamide 423
    723
    Figure US20090312307A1-20091217-C00831
         		N-(1-Dimethylsulfamoyl-4- phenyl-piperidin-4- ylmethyl)-2-fluoro- benzamide 422
    724
    Figure US20090312307A1-20091217-C00832
         		2,3-Dimethoxy-N-(4-phenyl- 1-sulfamoyl-piperidin-4- ylmethyl)-benzamide 436
    725
    Figure US20090312307A1-20091217-C00833
         		N-[4-(2-Fluoro-phenyl)-1- sulfamoyl-piperidin-4- ylmethyl]-2-methoxy- benzamide 423
    726
    Figure US20090312307A1-20091217-C00834
         		2-Methoxy-N-{4-phenyl-1- [(pyridin-2-ylmethyl)- sulfamoyl]-piperidin-4- ylmethyl}-benzamide 497
    727
    Figure US20090312307A1-20091217-C00835
         		2-Methoxy-N-[4-(3- methoxy-phenyl)-1- sulfamoyl-piperidin-4- ylmethyl]-benzamide 436
    728
    Figure US20090312307A1-20091217-C00836
         		Carbamic acid 2-{4-[(2- methoxy-benzoylamino)- methyl]-4-phenyl-piperidine- 1-sulfonylamino}-ethyl ester 493
    729
    Figure US20090312307A1-20091217-C00837
         		Ethylcarbamic acid 2-{4- [(2-methoxy-benzoylamino)- methyl]-4-phenyl-piperidine- 1-sulfonylamino}-ethyl ester 521
    730
    Figure US20090312307A1-20091217-C00838
         		2-Methoxy-N-[4-phenyl-1- (2-pyridin-4-yl- ethylsulfamoyl)-piperidin-4- ylmethyl]-benzamide 511
    731
    Figure US20090312307A1-20091217-C00839
         		N-(4-Phenyl-1-sulfamoyl- piperidin-4-ylmethyl)-2- trifluoromethoxy-benzamide 459
    732
    Figure US20090312307A1-20091217-C00840
         		2,6-Dimethoxy-N-(4-phenyl- 1-sulfamoyl-piperidin-4- ylmethyl)-benzamide 436
    733
    Figure US20090312307A1-20091217-C00841
         		Cyclopropyl-carbamic acid 2-{4-[(2-methoxy- benzoylamino)-methyl]-4- phenyl-piperidine-1- sulfonylamino}-ethyl ester 533
    734
    Figure US20090312307A1-20091217-C00842
         		2-Methoxy-N-[1-(2-methyl- imidazole-1-sulfonyl)-4- phenyl-piperidin-4- ylmethyl]-benzamide 471
    735
    Figure US20090312307A1-20091217-C00843
         		2-Methoxy-N-(1- methylsulfamoyl-4-phenyl- piperidin-4-ylmethyl)- benzamide 420
    736
    Figure US20090312307A1-20091217-C00844
         		N-(1-Ethylsulfamoyl-4- phenyl-piperidin-4- ylmethyl)-2-methoxy- benzamide 434
    737
    Figure US20090312307A1-20091217-C00845
         		N-(1-Cyclopropylsulfamoyl- 4-phenyl-piperidin-4- ylmethyl)-2-methoxy- benzamide 446
    738
    Figure US20090312307A1-20091217-C00846
         		2-Methoxy-N-{4-phenyl-1- [(tetrahydro-furan-2- ylmethyl)-sulfamoyl]- piperidin-4-ylmethyl}- benzamide 490
    739
    Figure US20090312307A1-20091217-C00847
         		N-[1-(Isopropyl-methyl- sulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 462
    740
    Figure US20090312307A1-20091217-C00848
         		2-Methoxy-N-{4-phenyl-1- [(pyridin-3-ylmethyl)- sulfamoyl]-piperidin-4- ylmethyl}-benzamide 497
    741
    Figure US20090312307A1-20091217-C00849
         		2-Methoxy-N-{4-phenyl-1- [(pyridin-4-ylmethyl)- sulfamoyl]-piperidin-4- ylmethyl}-benzamide 497
    742
    Figure US20090312307A1-20091217-C00850
         		N-[1-(2-Hydroxy- propylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 464
    743
    Figure US20090312307A1-20091217-C00851
         		(2-{4-[(2-Methoxy- benzoylamino)-methyl]-4- phenyl-piperidine-1- sulfonylamino}-ethyl)- carbamic acid tert-butyl ester 549
    744
    Figure US20090312307A1-20091217-C00852
         		N-{1-[(2-Hydroxy-ethyl)- methyl-sulfamoyl]-4-phenyl- piperidin-4-ylmethyl}-2- methoxy-benzamide 464
    745
    Figure US20090312307A1-20091217-C00853
         		N-(1-Dimethylsulfamoyl-4- phenyl-piperidin-4- ylmethyl)-2-methoxy- nicotinamide 435
    746
    Figure US20090312307A1-20091217-C00854
         		Quinoline-8-carboxylic acid (1-dimethylsulfamoyl-4- phenyl-piperidin-4- ylmethyl)-amide 455
    747
    Figure US20090312307A1-20091217-C00855
         		N-[1-(Cyclopropylmethyl- sulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 460
    748
    Figure US20090312307A1-20091217-C00856
         		N-[1-(3-Hydroxy- pyrrolidine-1-sulfonyl)-4- phenyl-piperidin-4- ylmethyl]-2-methoxy- benzamide 476
    749
    Figure US20090312307A1-20091217-C00857
         		N-[1-(2-Dimethylamino- ethylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 477
    750
    Figure US20090312307A1-20091217-C00858
         		N-[1-(2-Fluoro- ethylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 452
    751
    Figure US20090312307A1-20091217-C00859
         		N-[l-(Carbamoylmethyl- sulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 463
    752
    Figure US20090312307A1-20091217-C00860
         		1-{4-[(2-Methoxy- benzoylamino)-methyl]-4- phenyl-piperidine-1- sulfonyl}-pyrrolidine-2- carboxylic acid amide 503
    753
    Figure US20090312307A1-20091217-C00861
         		N-(1-Isopropylsulfamoyl-4- phenyl-piperidin-4- ylmethyl)-2-methoxy- benzamide 448
    754
    Figure US20090312307A1-20091217-C00862
         		N-[1-(2-Amino- ethylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 449
    755
    Figure US20090312307A1-20091217-C00863
         		2-Methoxy-N-{4-phenyl-1- [2-(pyrimidin-2-ylamino)- ethylsulfamoyl]-piperidin-4- ylmethyl}-benzamide 527
    756
    Figure US20090312307A1-20091217-C00864
         		2-Methoxy-N-{4-phenyl-1- [3-(pyrimidin-2-ylamino)- propylsulfamoyl]-piperidin- 4-ylmethyl}-benzamide 541
    757
    Figure US20090312307A1-20091217-C00865
         		2-Methoxy-N-[4-phenyl-1- (pyridin-4-ylsulfamoyl)- piperidin-4-ylmethyl]- benzamide 483
    758
    Figure US20090312307A1-20091217-C00866
         		2-Methoxy-N-[4-phenyl-1- (pyridin-3-ylsulfamoyl)- piperidin-4-ylmethyl]- benzamide 483
    759
    Figure US20090312307A1-20091217-C00867
         		2-Methoxy-N-[4-phenyl-1- (pyridin-2-ylsulfamoyl)- piperidin-4-ylmethyl]- benzamide 483
    760
    Figure US20090312307A1-20091217-C00868
         		N-[1-(4-Hydroxy-piperidine- 1-sulfonyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 490
    761
    Figure US20090312307A1-20091217-C00869
         		N-[1-(3,4-Difluoro- phenylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 518
    762
    Figure US20090312307A1-20091217-C00870
         		N-[1-(2,4-Difluoro- phenylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 518
    763
    Figure US20090312307A1-20091217-C00871
         		2-Methoxy-N-(4-phenyl-1- phenylsulfamoyl-piperidin- 4-ylmethyl)-benzamide 482
    764
    Figure US20090312307A1-20091217-C00872
         		N-[1-(2-Hydroxy- propylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 464
    765
    Figure US20090312307A1-20091217-C00873
         		N-[1-(2-Hydroxy-1-methyl- ethylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 464
    766
    Figure US20090312307A1-20091217-C00874
         		N-[1-(1-Hydroxymethyl- propylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 478
    767
    Figure US20090312307A1-20091217-C00875
         		N-[1-(2-Hydroxy- propylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 464
    768
    Figure US20090312307A1-20091217-C00876
         		N-[1-(1-Hydroxymethyl- propylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 478
    769
    Figure US20090312307A1-20091217-C00877
         		N-[1-(2-Hydroxy-1-methyl- ethylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 464
    770
    Figure US20090312307A1-20091217-C00878
         		2-Methoxy-N-[1-(2- phenoxy-ethylsulfamoyl)-4- phenyl-piperidin-4- ylmethyl]-benzamide 526
    771
    Figure US20090312307A1-20091217-C00879
         		{4-[(2-Methoxy- benzoylamino)-methyl]-4- phenyl-piperidine-1- sulfonylamino}-acetic acid methyl ester 478
    772
    Figure US20090312307A1-20091217-C00880
         		2-{4-[(2-Methoxy- benzoylamino)-methyl]-4- phenyl-piperidine-1- sulfonylamino}-propionic acid methyl ester 492
    773
    Figure US20090312307A1-20091217-C00881
         		2-{4-[(2-Methoxy- benzoylamino)-methyl]-4- phenyl-piperidine-1- sulfonylamino}-3-phenyl- propionic acid methyl ester 568
    774
    Figure US20090312307A1-20091217-C00882
         		N-(1-Dimethylsulfamoyl-4- phenyl-piperidin-4- ylmethyl)-2-hydroxy-6- methoxy-benzamide 450
    775
    Figure US20090312307A1-20091217-C00883
         		N-(1-Dimethylsulfamoyl-4- phenyl-piperidin-4- ylmethyl)-2-fluoro-6- methoxy-benzamide 452
    776
    Figure US20090312307A1-20091217-C00884
         		2-Difluoromethoxy-N-(1- dimethylsulfamoyl-4-phenyl- piperidin-4-ylmethyl)- benzamide 470
    777
    Figure US20090312307A1-20091217-C00885
         		3-Amino-pyrazine-2- carboxylic acid (1- dimethylsulfamoyl-4-phenyl- piperidin-4-ylmethyl)-amide 421
    778
    Figure US20090312307A1-20091217-C00886
         		N-[1-(4-Fluoro- phenylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 500
    779
    Figure US20090312307A1-20091217-C00887
         		2-Methoxy-N-[1-(methoxy- methyl-sulfamoyl)-4-phenyl- piperidin-4-ylmethyl]- benzamide 450
    780
    Figure US20090312307A1-20091217-C00888
         		N-(1-Hydroxysulfamoyl-4- phenyl-piperidin-4- ylmethyl)-2-methoxy- benzamide 422
    781
    Figure US20090312307A1-20091217-C00889
         		N-[1-(2-Fluoro- phenylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 500
    782
    Figure US20090312307A1-20091217-C00890
         		N-[1-(3-Fluoro- phenylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 500
    783
    Figure US20090312307A1-20091217-C00891
         		N-[1-(1,1-Dioxo-tetrahydro- 1lambda*6*-thiophen-3- ylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 524
    784
    Figure US20090312307A1-20091217-C00892
         		N-[1-(4-Hydroxymethyl- piperidine-1-sulfonyl)-4- phenyl-piperidin-4- ylmethyl]-2-methoxy- benzamide 504
    785
    Figure US20090312307A1-20091217-C00893
         		N-{1-[(2-Fluoro-phenyl)- methyl-sulfamoyl]-4-phenyl- piperidin-4-ylmethyl}-2- methoxy-benzamide 514
    786
    Figure US20090312307A1-20091217-C00894
         		N-{1-[(3-Fluoro-phenyl)- methyl-sulfamoyl]-4-phenyl- piperidin-4-ylmethyl}-2- methoxy-benzamide 514
    787
    Figure US20090312307A1-20091217-C00895
         		N-[1-(Hydroxy-methyl- sulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 436
    788
    Figure US20090312307A1-20091217-C00896
         		2-Methoxy-N-(1- methylsulfamoyl-4-phenyl- piperidin-4-ylmethyl)- benzamide 419
    789
    Figure US20090312307A1-20091217-C00897
         		N-(1-tert-Butylsulfamoyl-4- phenyl-piperidin-4- ylmethyl)-2-methoxy- benzamide 462
    790
    Figure US20090312307A1-20091217-C00898
         		N-[1-(4,4-Dimethyl- oxazolidine-3-sulfonyl)-4- phenyl-piperidin-4- ylmethyl]-2-methoxy- benzamide 490
    791
    Figure US20090312307A1-20091217-C00899
         		N-[1-(2,6-Dimethyl- morpholine-4-sulfonyl)-4- phenyl-piperidin-4- ylmethyl]-2-methoxy- benzamide 504
    792
    Figure US20090312307A1-20091217-C00900
         		N-[1-(4,4-Dimethyl-4,5- dihydro-imidazole-1- sulfonyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 487
    793
    Figure US20090312307A1-20091217-C00901
         		N-[1-(2-Hydroxy-1,1- dimethyl-ethylsulfamoyl)-4- phenyl-piperidin-4- ylmethyl]-2-methoxy- benzamide 478
    794
    Figure US20090312307A1-20091217-C00902
         		N-[1-(4-Hydroxy- benzylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 512
    795
    Figure US20090312307A1-20091217-C00903
         		N-[1-(3-Hydroxy- phenylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 498
    796
    Figure US20090312307A1-20091217-C00904
         		N-[1-(2-Hydroxy- cyclohexylsulfamoyl)-4- phenyl-piperidin-4- ylmethyl]-2-methoxy- benzamide 504
    797
    Figure US20090312307A1-20091217-C00905
         		2-Methoxy-N-[1-(2- methoxymethyl-pyrrolidine- 1-sulfonyl)-4-phenyl- piperidin-4-ylmethyl]- benzamide 504
    798
    Figure US20090312307A1-20091217-C00906
         		N-[1-(1-Hydroxymethyl-2- methyl-propylsulfamoyl)-4- phenyl-piperidin-4- ylmethyl]-2-methoxy- benzamide 492
    799
    Figure US20090312307A1-20091217-C00907
         		N-[1-(1-Hydroxymethyl-2- methyl-propylsulfamoyl)-4- phenyl-piperidin-4- ylmethyl]-2-methoxy- benzamide 492
    800
    Figure US20090312307A1-20091217-C00908
         		N-[1-(2-Cyclohexyl-1- hydroxymethyl- ethylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 546
    801
    Figure US20090312307A1-20091217-C00909
         		N-[1-(2-Hydroxy-indan-1- ylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 538
    802
    Figure US20090312307A1-20091217-C00910
         		N-[1-(2-Hydroxy-indan-1- ylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 538
    803
    Figure US20090312307A1-20091217-C00911
         		N-[1-(3-Hydroxy- pyrrolidine-1-sulfonyl)-4- phenyl-piperidin-4- ylmethyl]-2-methoxy- benzamide 476
    804
    Figure US20090312307A1-20091217-C00912
         		1-{4-[(2-Methoxy- benzoylamino)-methyl]-4- phenyl-piperidine-1- sulfonyl}-pyrrolidine-2- carboxylic acid methyl ester 518
    805
    Figure US20090312307A1-20091217-C00913
         		2-{4-[(2-Methoxy- benzoylamino)-methyl]-4- phenyl-piperidine-1- sulfonylamino}-3-methyl- butyric acid methyl ester 520
    806
    Figure US20090312307A1-20091217-C00914
         		2-Hydroxy-6-methoxy-N-{1- [(2-methoxy-ethyl)-methyl- sulfamoyl]-4-phenyl- piperidin-4-ylmethyl}- benzamide 494
    807
    Figure US20090312307A1-20091217-C00915
         		2-Hydroxy-6-methoxy-N-(4- phenyl-1-sulfamoyl- piperidin-4-ylmethyl)- benzamide 422
    808
    Figure US20090312307A1-20091217-C00916
         		N-[4-(3-Fluoro-phenyl)-1- sulfamoyl-piperidin-4- ylmethyl]-2-hydroxy-6- methoxy-benzamide 439
    809
    Figure US20090312307A1-20091217-C00917
         		N-[4-(3-Fluoro-phenyl)-1- (2-methyl-imidazole-1- sulfonyl)-piperidin-4- ylmethyl]-2-hydroxy-6- methoxy-benzamide 505
    810
    Figure US20090312307A1-20091217-C00918
         		N-[4-(3-Fluoro-phenyl)-1- (2-hydroxy-ethylsulfamoyl)- piperidin-4-ylmethyl]-2- hydroxy-6-methoxy- benzamide 484
    811
    Figure US20090312307A1-20091217-C00919
         		N-[1-(Cyclopropylmethyl- sulfamoyl)-4-(3-fluoro- phenyl)-piperidin-4- ylmethyl]-2-hydroxy-6- methoxy-benzamide 494
    812
    Figure US20090312307A1-20091217-C00920
         		N-[4-(3-Fluoro-phenyl)-1- (4-fluoro-phenylsulfamoyl)- piperidin-4-ylmethyl]-2- hydroxy-6-methoxy- benzamide 534
    813
    Figure US20090312307A1-20091217-C00921
         		N-[4-(3-Fluoro-phenyl)-1- (4-hydroxy- benzylsulfamoyl)-piperidin- 4-ylmethyl]-2-hydroxy-6- methoxy-benzamide 546
    814
    Figure US20090312307A1-20091217-C00922
         		N-[4-(3-Fluoro-phenyl)-1- (2-hydroxy-1-methyl- ethylsulfamoyl)-piperidin-4- ylmethyl]-2-hydroxy-6- methoxy-benzamide 498
    815
    Figure US20090312307A1-20091217-C00923
         		N-[4-(3-Fluoro-phenyl)-1- (1-hydroxymethyl- propylsulfamoyl)-piperidin- 4-ylmethyl]-2-hydroxy-6- methoxy-benzamide 512
    816
    Figure US20090312307A1-20091217-C00924
         		N-[4-(3-Fluoro-pheny-1- (2-hydroxy- propylsulfamoyl)-piperidin- 4-ylmethyl]-2-hydroxy-6- methoxy-benzamide 498
    817
    Figure US20090312307A1-20091217-C00925
         		N-[4-(3-Fluoro-phenyl)-1- (3-hydroxy-pyrrolidine-1- sulfonyl)-piperidin-4- ylmethyl]-2-hydroxy-6- methoxy-benzamide 510
    818
    Figure US20090312307A1-20091217-C00926
         		2-Hydroxy-6-methoxy-N-[1- (2-methyl-imidazole-1- sulfonyl)-4-phenyl- piperidin-4-ylmethyl]- benzamide 487
    819
    Figure US20090312307A1-20091217-C00927
         		Trifluoro- methanesulfonate3-{4-(3- fluoro-phenyl)-4-[(2- hydroxy-6-methoxy- benzoylamino)-methyl]- piperidine-1-sulfonyl}-1,2- dimethyl-3H-imidazol-1-ium 669
    820
    Figure US20090312307A1-20091217-C00928
         		N-[4-(3-Fluoro-phenyl)-1- (2-phenoxy-ethylsulfamoyl)- piperidin-4-ylmethyl]-2- hydroxy-6-methoxy- benzamide 560
    821
    Figure US20090312307A1-20091217-C00929
         		N-{4-(3-Fluoro-phenyl)-1- [(2-hydroxy-ethyl)-methyl- sulfamoyl]-piperidin-4- ylmethyl}-2-hydroxy-6- methoxy-benzamide 498
    822
    Figure US20090312307A1-20091217-C00930
         		N-{4-(3-Fluoro-phenyl)-1- [(tetrahydro-furan-2- ylmethyl)-sulfamoyl]- piperidin-4-ylmethyl}-2- hydroxy-6-methoxy- benzamide 524
    823
    Figure US20090312307A1-20091217-C00931
         		N-(1-Dimethylsulfamoyl-4- phenyl-piperidin-4- ylmethyl)-2-hydroxy- benzamide 420
    824
    Figure US20090312307A1-20091217-C00932
         		N-[1-Dimethylsulfamoyl-4- (3-trifluoromethyl-phenyl)- piperidin-4-ylmethyl]-2- hydroxy-benzamide 488
    825
    Figure US20090312307A1-20091217-C00933
         		N-[1-Dimethylsulfamoyl-4- (3-trifluoromethyl-phenyl)- piperidin-4-ylmethyl]-2- methoxy-benzamide 502
    826
    Figure US20090312307A1-20091217-C00934
         		N-[4-(2-Fluoro-phenyl)-1- sulfamoyl-piperidin-4- ylmethyl]-2-hydroxy-6- methoxy-benzamide 439
    827
    Figure US20090312307A1-20091217-C00935
         		N-[1-Dimethylsulfamoyl-4- (2-fluoro-phenyl)-piperidin- 4-ylmethyl]-2-hydroxy-6- methoxy-benzamide 468
    828
    Figure US20090312307A1-20091217-C00936
         		N-[4-(3-Chloro-phenyl)-1- sulfamoyl-piperidin-4- ylmethyl]-2-methoxy- benzamide 440
    829
    Figure US20090312307A1-20091217-C00937
         		N-[4-(3-Chloro-phenyl)-1- dimethylsulfamoyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 468
    830
    Figure US20090312307A1-20091217-C00938
         		N-[4-(3,5-Difluoro-phenyl)- 1-sulfamoyl-piperidin-4- ylmethyl]-2-methoxy- benzamide 441
    831
    Figure US20090312307A1-20091217-C00939
         		N-[4-(3,5-Difluoro-phenyl)- 1-dimethylsulfamoyl- piperidin-4-ylmethyl]-2- methoxy-benzamide 470
    832
    Figure US20090312307A1-20091217-C00940
         		N-[4-(3,5-Difluoro-phenyl)- 1-sulfamoyl-piperidin-4- ylmethyl]-2-hydroxy-6- methoxy-benzamide 457
    833
    Figure US20090312307A1-20091217-C00941
         		3-Amino-pyrazine-2- carboxylic acid [4-(3,5- difluoro-phenyl)-1- sulfamoyl-piperidin-4- ylmethyl]-amide 428
    834
    Figure US20090312307A1-20091217-C00942
         		3-Amino-pyrazine-2- carboxylic acid (4-phenyl-1- sulfamoyl-piperidin-4- ylmethyl)-amide 392
    835
    Figure US20090312307A1-20091217-C00943
         		2-Hydroxy-6-methoxy-N-[1- sulfamoyl-4-(3- trifluoromethyl-phenyl)- piperidin-4-ylmethyl]- benzamide 489
    836
    Figure US20090312307A1-20091217-C00944
         		3-Amino-pyrazine-2- carboxylic acid [1- sulfamoyl-4-(3- trifluoromethyl-phenyl)- piperidin-4-ylmethyl]-amide 460
    837
    Figure US20090312307A1-20091217-C00945
         		3-Amino-pyrazine-2- carboxylic acid [4-(3-chloro- phenyl)-1-sulfamoyl- piperidin-4-ylmethyl]-amide 427
    838
    Figure US20090312307A1-20091217-C00946
         		3-Amino-pyrazine-2- carboxylic acid [4-(3-fluoro- phenyl)-1-sulfamoyl- piperidin-4-ylmethyl]-amide 410
    839
    Figure US20090312307A1-20091217-C00947
         		N-[4-(2,5-Difluoro-phenyl)- 1-sulfamoyl-piperidin-4- ylmethyl]-2-methoxy- benzamide 441
    840
    Figure US20090312307A1-20091217-C00948
         		3-Amino-pyrazine-2- carboxylic acid [4-(2,5- difluoro-phenyl)-1- sulfamoyl-piperidin-4- ylmethyl]-amide 428
    841
    Figure US20090312307A1-20091217-C00949
         		2-Methoxy-N-[1-sulfamoyl- 4-(3-trifluoromethyl- phenyl)-piperidin-4- ylmethyl]-benzamide 472
    842
    Figure US20090312307A1-20091217-C00950
         		N-[4-(2,3-Difluoro-phenyl)- 1-sulfamoyl-piperidin-4- ylmethyl]-2-methoxy- benzamide 440
    843
    Figure US20090312307A1-20091217-C00951
         		3-Amino-pyrazine-2- carboxylic acid [4-(2,3- difluoro-phenyl)-1- sulfamoyl-piperidin-4- ylmethyl]-amide 427
    • Example 844
  • Figure US20090312307A1-20091217-C00952
    • 3-Aminopyrazine-2-carboxylic acid [1-(amino-methanesulfonylimino-methyl)-4-phenyl-piperidin-4-ylmethyl]-amide Synthesis
  • Figure US20090312307A1-20091217-C00953
  • Compound 1: Compound 1 was prepared as described in Example 653.
  • Compound 2: A solution of compound 1 (0.15 g; 0.47 mmol) in anhydrous acetonitrile (8 mL) at room temperature was treated with N-diphenoxymethylene-methanesulfonamide (for preparation see U.S. Pat. No. 4,871,765) (0.17 g; 0.5 mmol). The reaction mixture was heated to 85° C. for 2 h. The solvent was removed by rotary evaporation and the crude residue was purified directly by column chromatography on silica gel using 9:1 ethyl acetate hexane as the eluent to give 0.2 g of compound 2 as a white solid. LRMS m/z=510 (M+H)+.
  • Title Compound: Compound 2 (0.060 g; 0.12 mmol) was treated with 7 N ammonia in methanol (2 mL) and heated to 85° C. for 15 minutes in a sealed tube. The solvent was removed by rotary evaporation and the crude residue was purified directly by column chromatography on silica gel using 10:1 chloroform:methanol as the eluent to give 0.024 g of the title compound as a white solid. LRMS m/z=433 (M+H)+.
    • Examples 845 to 852
  • Examples 845 to 852 were prepared using methodology described in Example 844.
  • Example Structure Name M + H
    845
    Figure US20090312307A1-20091217-C00954
         		N-[1-(Methanesulfonylimino- phenoxy-methyl)-4-phenyl-piperidin- 4-ylmethyl]-2-methoxy-benzamide 523
    846
    Figure US20090312307A1-20091217-C00955
         		N-[1-(Amino-methanesulfonylimino- methyl)-4-phenyl-piperidin-4- ylmethyl]-2-methoxy-benzamide 446
    847
    Figure US20090312307A1-20091217-C00956
         		N-[1-(Cyclopropylamino- methanesulfonylimino-methyl)-4- phenyl-piperidin-4-ylmethyl]-2- methoxy-benzamide 486
    848
    Figure US20090312307A1-20091217-C00957
         		N-{1-[(Cyclopropylmethyl-amino)- methanesulfonylimino-methyl]-4- phenyl-piperidin-4-ylmethyl}-2- methoxy-benzamide 500
    849
    Figure US20090312307A1-20091217-C00958
         		N-(1-{Methanesulfonylimino- [(pyridin-2-ylmethyl)-amino]- methyl}-4-phenyl-piperidin-4- ylmethyl)-2-methoxy-benzamide 537
    850
    Figure US20090312307A1-20091217-C00959
         		N-{1-[Methanesulfonylimino-(2- pyridin-4-yl-ethylamino)-methyl]-4- phenyl-piperidin-4-ylmethyl}-2- methoxy-benzamide 551
    851
    Figure US20090312307A1-20091217-C00960
         		N-{1-[(2-Hydroxy-ethylamino)- methanesulfonylimino-methyl]-4- phenyl-piperidin-4-ylmethyl}-2- methoxy-benzamide 490
    852
    Figure US20090312307A1-20091217-C00961
         		N-{1-[(3-Imidazol-1-yl- propylamino)-methanesulfonylimino- methyl]-4-phenyl-piperidin-4- ylmethyl}-2-methoxy-benzamide 554
    • Example 853
  • Figure US20090312307A1-20091217-C00962
    • Synthesis
  • Figure US20090312307A1-20091217-C00963
  • Compound 1: Compound 1 was prepared as described in Example 653.
  • Compound 2: A solution of compound 1 (0.211 mg; 0.68 mmol) in anhydrous acetonitrile (5 mL) was treated with diphenyl N-cyanocarbonimide (0.180 mg; 0.76 mmol) and heated to 85° C. for 1 h. The solvent was removed by rotary evaporation and the crude residue was purified directly by column chromatography on silica gel using 7:3 ethyl acetate:hexane as the eluent to give 0.273 g of compound 2 as a white foam. LRMS m/z=457 (M+H)+.
  • Title Compound: Compound 2 (0.061 g; 0.13 mmol) was treated with 7 N ammonia in methanol (2 mL) and heated to 60° C. for 1 h in a sealed tube. The solvent was removed by rotary evaporation and the crude residue was purified by preparative reverse phase HPLC to give 0.030 g of the title compound as a white solid. LRMS m/z=379 (M+H)+.
    • Examples 854 to 915
  • Examples 854 to 915 were prepared using methodology described in Example 25 and Example 853.
  • Example Structure M + H
    854
    Figure US20090312307A1-20091217-C00964
         		411
    855
    Figure US20090312307A1-20091217-C00965
         		440
    856
    Figure US20090312307A1-20091217-C00966
         		503
    857
    Figure US20090312307A1-20091217-C00967
         		520
    858
    Figure US20090312307A1-20091217-C00968
         		478
    859
    Figure US20090312307A1-20091217-C00969
         		477
    860
    Figure US20090312307A1-20091217-C00970
         		499
    861
    Figure US20090312307A1-20091217-C00971
         		434
    862
    Figure US20090312307A1-20091217-C00972
         		408
    863
    Figure US20090312307A1-20091217-C00973
         		480
    864
    Figure US20090312307A1-20091217-C00974
         		551
    865
    Figure US20090312307A1-20091217-C00975
         		451
    866
    Figure US20090312307A1-20091217-C00976
         		489
    867
    Figure US20090312307A1-20091217-C00977
         		411
    868
    Figure US20090312307A1-20091217-C00978
         		440
    869
    Figure US20090312307A1-20091217-C00979
         		503
    870
    Figure US20090312307A1-20091217-C00980
         		503
    871
    Figure US20090312307A1-20091217-C00981
         		508
    872
    Figure US20090312307A1-20091217-C00982
         		478
    873
    Figure US20090312307A1-20091217-C00983
         		501
    874
    Figure US20090312307A1-20091217-C00984
         		423
    875
    Figure US20090312307A1-20091217-C00985
         		452
    876
    Figure US20090312307A1-20091217-C00986
         		515
    877
    Figure US20090312307A1-20091217-C00987
         		515
    878
    Figure US20090312307A1-20091217-C00988
         		478
    879
    Figure US20090312307A1-20091217-C00989
         		487
    880
    Figure US20090312307A1-20091217-C00990
         		409
    881
    Figure US20090312307A1-20091217-C00991
         		454
    882
    Figure US20090312307A1-20091217-C00992
         		438
    883
    Figure US20090312307A1-20091217-C00993
         		505
    884
    Figure US20090312307A1-20091217-C00994
         		427
    885
    Figure US20090312307A1-20091217-C00995
         		512
    886
    Figure US20090312307A1-20091217-C00996
         		505
    887
    Figure US20090312307A1-20091217-C00997
         		507
    888
    Figure US20090312307A1-20091217-C00998
         		429
    889
    Figure US20090312307A1-20091217-C00999
         		523
    890
    Figure US20090312307A1-20091217-C01000
         		494
    891
    Figure US20090312307A1-20091217-C01001
         		445
    892
    Figure US20090312307A1-20091217-C01002
         		416
    893
    Figure US20090312307A1-20091217-C01003
         		458
    894
    Figure US20090312307A1-20091217-C01004
         		408
    895
    Figure US20090312307A1-20091217-C01005
         		428
    896
    Figure US20090312307A1-20091217-C01006
         		465
    897
    Figure US20090312307A1-20091217-C01007
         		408
    898
    Figure US20090312307A1-20091217-C01008
         		492
    899
    Figure US20090312307A1-20091217-C01009
         		476
    900
    Figure US20090312307A1-20091217-C01010
         		555
    901
    Figure US20090312307A1-20091217-C01011
         		477
    902
    Figure US20090312307A1-20091217-C01012
         		415
    903
    Figure US20090312307A1-20091217-C01013
         		398
    904
    Figure US20090312307A1-20091217-C01014
         		507
    905
    Figure US20090312307A1-20091217-C01015
         		494
    906
    Figure US20090312307A1-20091217-C01016
         		428
    907
    Figure US20090312307A1-20091217-C01017
         		415
    908
    Figure US20090312307A1-20091217-C01018
         		447
    909
    Figure US20090312307A1-20091217-C01019
         		393
    910
    Figure US20090312307A1-20091217-C01020
         		423
    911
    Figure US20090312307A1-20091217-C01021
         		438
    912
    Figure US20090312307A1-20091217-C01022
         		425
    913
    Figure US20090312307A1-20091217-C01023
         		471
    914
    Figure US20090312307A1-20091217-C01024
         		428
    915
    Figure US20090312307A1-20091217-C01025
         		415
    • Example 916
  • Figure US20090312307A1-20091217-C01026
    • 3-Amino-pyrazine-2-carboxylic acid (4-phenyl 1-pyrimidin-2-yl-piperidin-4-ylmethyl)-amide Synthesis
  • Figure US20090312307A1-20091217-C01027
  • Compound 1: Compound 1 was prepared using methodology described in Example 653.
  • Title Compound: The title compound was prepared using methodology described in Example 521 and purified by preparative reverse phase HPLC to give a white solid. LRMS m/z 390 (M+H)+.
    • Examples 917 to 924
  • Examples 917 to 924 were prepared using methodology described in Example 916.
  • Example Structure Name M + H
    917
    Figure US20090312307A1-20091217-C01028
         		3-Amino-pyrazine-2- carboxylic acid [1-pyrimidin- 2-yl-4-(3-trifluoromethyl- phenyl)-piperidin-4-ylmethyl]- amide 459
    918
    Figure US20090312307A1-20091217-C01029
         		3-Amino-pyrazine-2- carboxylic acid [1-(4- methoxy-pyrimidin-2-yl)-4- phenyl-piperidin-4-ylmethyl]- amide 421
    919
    Figure US20090312307A1-20091217-C01030
         		3-Amino-pyrazine-2- carboxylic acid [4-phenyl-1- (4-trifluoromethyl-pyrimidin- 2-yl)-piperidin-4-ylmethyl]- amide 459
    920
    Figure US20090312307A1-20091217-C01031
         		3-Amino-pyrazine-2- carboxylic acid [4-(3-fluoro- phenyl)-1-pyrimidin-2-yl- piperidin-4-ylmethyl]-amide 409
    921
    Figure US20090312307A1-20091217-C01032
         		3-Amino-pyrazine-2- carboxylic acid [4-(3,5- difluoro-phenyl)-1-pyrimidin- 2-ylpiperidin-4-ylmethyl]- amide 410
    922
    Figure US20090312307A1-20091217-C01033
         		3-Amino-pyrazine-2- carboxylic acid [4-(2,5- difluoro-phenyl)-1-pyrimidin- 2-yl-piperidin-4-ylmethyl]- amide 427
    923
    Figure US20090312307A1-20091217-C01034
         		N-[4-(2,3-Difluoro-phenyl)-1- pyrimidin-2-yl-piperidin-4- ylmethyl]-2-methoxy- benzamide 439
    924
    Figure US20090312307A1-20091217-C01035
         		3-Amino-pyrazine-2- carboxylic acid [4-(2,3- difluoro-phenyl)-1-pyrimidin- 2-yl-piperidin-4-ylmethyl]- amide 426
    • Example 925
  • Figure US20090312307A1-20091217-C01036
    • 3-Amino-pyrazine-2-carboxylic acid (4-phenyl-1-pyrimidin-2-yl-piperidin-4-ylmethyl)-amide Synthesis
  • Figure US20090312307A1-20091217-C01037
  • Compound 1: Compound 1 was prepared as described in Example 653.
  • Title Compound: A solution of compound 1 (0.072 g; 0.23 mmol) in anhydrous acetonitrile (2 mL) was treated with polystyrene-diisopropylethylamine (300 mg) and hydrocinnamoyl chloride (0.045 g; 0.27 mmol) at room. temperature. The reaction was shaken for 24 h, filtered and concentrated by rotary evaporation. The crude residue was purified by preparative reverse phase HPLC to give 0.054 g of the title compound as white solid. LRMS m/z=444 (M+H)+.
    • Examples 926 to 929
  • Examples 926 to 929 were prepared using methodology described in Example 925.
  • Example Structure Name M + H
    926
    Figure US20090312307A1-20091217-C01038
         		4-{[(3-Amino-pyrazine-2- carbonyl)-amino]-methyl}-4- phenyl-piperidine-1-carboxylic acid ethyl ester 385
    927
    Figure US20090312307A1-20091217-C01039
         		3-Amino-pyrazine-2-carboxylic acid (1-benzoyl-4-phenyl- piperidin-4-ylmethyl)-amide 417
    928
    Figure US20090312307A1-20091217-C01040
         		3-Amino-pyrazine-2-carboxylic acid [4-phenyl-1-(pyridine-3- carbonyl)-piperidin-4-ylmethyl]- amide 418
    929
    Figure US20090312307A1-20091217-C01041
         		3-Amino-pyrazine-2-carboxylic acid [4-phenyl-1-(pyridine-4- carbonyl)-piperidin-4-ylmethyl]- amide 418
    • Example 930
  • Figure US20090312307A1-20091217-C01042
    • 3-Amino-pyrazine-2-carboxylic acid [1-(1-amino-2-nitro-vinyl)-4-phenyl-piperidin-4-ylmethyl]-amide Synthesis
  • Figure US20090312307A1-20091217-C01043
  • Compound 1: Compound 1 was prepared as described in Example 653.
  • Compound 2: A solution of compound 1 (0.065 g; 0.21 mmol) in anhydrous acetonitrile (3 mL) was treated with 1,1-bis(methylthio)-2-nitroethylene (0.058 g; 0.35 mmol) and heated at 85° C. for 3 h. The solvent was removed by rotary evaporation and the crude residue was purified by recrystallization from ethyl acetate to give 0.068 g of compound 2 as a bright yellow solid. LRMS m/z 430 (M+H)+.
  • Title Compound: Compound 2 (0.042 g; 0.098 mmol) was treated with 7 N ammonia in methanol (1 mL) and heated at 85° C. for 15 min in a sealed tube. The solvent was removed by rotary evaporation and the crude residue was purified directly by column chromatography on silica gel using 9:1 ethyl acetate:hexane as the eluent to give 0.018 g of the title compound as a white solid. LRMS m/z=398 (M+H)+.
    • Example 931
  • Figure US20090312307A1-20091217-C01044
    • 3-Amino-pyrazine-2-carboxylic acid [1-(3,5-dimethyl-isoxazole-4-sulfonyl)-4-phenyl-piperidin-4-ylmethyl]-amide Synthesis
  • Figure US20090312307A1-20091217-C01045
  • Compound 1: Compound 1 was prepared using methodology described in Example 653.
  • Title Compound: A solution of compound 1 (0.043 mg; 0.14 mmol) in anhydrous acetonitrile (1 mL) was treated with triethylamine (0.1 mL; 0.7 mmol) and 3,5-dimethyl-isoxazole-4-sulfonyl chloride (0.040 mg; 0.2 mmol) and allowed to stir at room temperature for 0.5 h. The solvent was removed by rotary evaporation and the crude residue was purified directly by column chromatography on silica gel using 1:1 ethyl acetate:hexane as the eluent to give 0.012 g of the title compound as a white solid. LRMS m/z 472 (M+H)+.
    • Examples 932 to 936
  • Examples 932 to 936 were prepared using methodology described in Example 931.
  • Example Structure Name M + H
    932
    Figure US20090312307A1-20091217-C01046
         		3-Amino-pyrazine-2- carboxylic acid [1-(3-fluoro- benzenesulfonyl)-4-phenyl- piperidin-4-ylmethyl]-amide 471
    933
    Figure US20090312307A1-20091217-C01047
         		3-Amino-pyrazine-2- carboxylic acid [1-(4-fluoro- benzenesulfonyl)-4-phenyl- piperidin-4-ylmethyl]-amide 471
    934
    Figure US20090312307A1-20091217-C01048
         		3-Amino-pyrazine-2- carboxylic acid [1-(3-cyano- benzenesulfonyl)-4-phenyl- piperidin-4-ylmethyl]-amide 478
    935
    Figure US20090312307A1-20091217-C01049
         		3-Amino-pyrazine-2- carboxylic acid [1-(2- methanesulfonyl- benzenesulfonyl)-4-phenyl- piperidin-4-ylmethyl]-amide 531
    936
    Figure US20090312307A1-20091217-C01050
         		3-Amino-pyrazine-2- carboxylic acid [4-phenyl-1- (propane-2-sulfonyl)- piperidin-4-ylmethyl]-amide 419
    • Example 937
  • Figure US20090312307A1-20091217-C01051
    • 1-{4-[(1H-Indazol-3-ylamino)-methyl]-4-phenyl-piperidin-1-yl}-3-phenyl-propan-1-one Synthesis
  • Figure US20090312307A1-20091217-C01052
  • Compound 1: Compound 1 was prepared as described in Example 653.
  • Compound 2: To compound 1 (0.89 g, 3.06 mmol) and triethylamine (0.95 g, 9.36 mmol) in dichloromethane (5 mL) was added 2-fluorobenzoyl chloride (0.53 g, 3.37 mmol). After 1 h, the reaction mixture was diluted with diethyl ether (20 mL) then washed with 1 N sodium hydroxide, water and saturated aqueous sodium chloride. The organic layer was separated, dried (sodium sulfate), filtered and concentrated. Purification by silica gel chromatography using 2:1 hexanes:ethyl acetate as the eluent gave compound 2 (344 mg, 27%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ1.43 (9H, s), 1.82-1.91 (2H, m), 2.15-2.20 (2H, m), 3.18-3.26 (2H, m), 3.68-3.74 (4H, m), 6.32-6.36 (1H, m), 7.03 (1H, dd, f 6.1, 12.0 Hz), 7.20-7.46 (7H, m), 8.03 (1H, td, J=1.8, 7.9 Hz). LRMS m/z 357 (M+H)+.
  • Compound 3: Compound 2 (340 mg, 0.82 mmol) and Lawesson's reagent (433 mg, 1.07 mmol) in toluene (3 mL) was heated at 100° C. for 3 h then cooled to room temperature. Water (1 mL), saturated aqueous sodium bicarbonate (3 mL) and ethyl acetate (3 mL) were added. After stirring for 20 min, the reaction mixture was diluted with ethyl acetate then washed with water and saturated aqueous sodium chloride. The organic layer was separated, dried (sodium sulfate), filtered and concentrated. Purification by silica gel chromatography using 3:1 hexanes:ethyl acetate as the eluent gave compound 3 (255 mg, 72%) as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ1.44 (9H, s), 1.94-1.98 (2H, m), 2.17-2.25 (2H, m), 3.27-3.34 (2H, m), 3.67-3.75 (2H, m), 4.15 (2H, d, J=5.0 Hz), 6.95-7.01 (1H, m), 7.15 (1H, td, J=1.0, 7.4 Hz), 7.27-7.63 (7H, m), 8.07 (1H, td, J=1.9, 8.0 Hz). LRMS m/z 429 (M+H)+.
  • Compound 4: Compound 3 (250 mg, 0.58 mmol) and hydrazine (187 mg, 5.80 mmol) in 1,4-dioxane (3 mL) was heated at 100° C. for 3 days then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (10 mL) then washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride. The organic layer was separated, dried (sodium sulfate), filtered and concentrated. Purification by silica gel chromatography using 3:1 hexanes:ethyl acetate as the eluent gave compound 4 (149 mg, 63%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ1.43 (9H, s), 1.90-1.97 (2H, m), 2.20-2.25 (2H, m), 3.16-3.25 (2H, m), 3.64 (2H, s), 3.64-3.69 (3H, m), 6.98 (1H, td, J=1.5, 7.9 Hz), 7.29-7.35 (5H, m), 7.42 (4H, d, J=4.4 Hz). LRMS m/z 407 (M+H)+.
  • Compound 5: Compound 4 (143 mg, 0.35 mmol) in dichloromethane (0.75 mL) and trifluoroacetic acid (0.25 mL) was stirred for 1.5 h then concentrated under reduced pressure. 1N Sodium hydroxide (5 mL) was added then extracted with dichloromethane (3×10 mL). The combined organic layers were dried (sodium sulfate), filtered and concentrated to give the compound 5 (107 mg, 100%) as a white solid. LRMS m/z 307 (M+H)+.
  • Title Compound: The title compound was prepared using methodology described in Example 390. LRMS m/z 440 (M+H)+.
    • Example 938
  • Figure US20090312307A1-20091217-C01053
    • 4-[(2-Methoxy-benzoylamino)-methyl]-4-phenyl-piperidine-1-carboxylic acid dimethylamide Synthesis
  • Figure US20090312307A1-20091217-C01054
  • Compound 1: Compound 1 was prepared as described in Example 15.
  • Compound 2: A solution of compound 1 (0.63 g; 1.9 mmol) in tetrahydrofuran (25 mL) was treated with triethylamine (0.33 mL; 2.4 mmol) and 4-nitro phenyl chloroformate (0.47 g; 2.3 mmol) at room temperature. After 24 h the solvent was removed by rotary evaporation and the crude residue was purified directly by column chromatography on silica gel using 1:1 ethyl acetate:hexane as the eluent to give 0.53 g of compound 2 as a white foam. LRMS m/z 491 (M+H)+.
  • Title Compound: Compound 2 (0.050 g; 0.10 mmol) was treated with 2 M dimethylamine in tetrahydrofuran (2 mL) and heated to 65° C. in a sealed tube for 12 h. The solvent was removed by rotary evaporation and the crude residue was purified by preparative reverse phase HPLC to give 0.018 g of the title compound as a white solid. LRMS m/z 396 (M+H)+.
    • Examples 939 to 942
  • Examples 939 to 942 were prepared using methodology described in Example 938.
  • Example Structure Name M + H
    939
    Figure US20090312307A1-20091217-C01055
         		N-[1-(3-Hydroxy-pyrrolidine-1- carbonyl)-4-phenyl-piperidin-4- ylmethyl]-2-methoxy-benzamide 440
    940
    Figure US20090312307A1-20091217-C01056
         		2-Methoxy-N-[1-(morpholine-4- carbonyl)-4-phenyl-piperidin-4- ylmethyl]-benzamide 440
    941
    Figure US20090312307A1-20091217-C01057
         		2-Methoxy-N-[4-phenyl-1-(pyrrolidine- 1-carbonyl)-piperidin-4-ylmethyl]- benzamide 424
    942
    Figure US20090312307A1-20091217-C01058
         		4-[(2-Methoxy-benzoylamino)-methyl]- 4-phenyl-piperidine-1-carboxylic acid isopropyl-methyl-amide 426
    • Example 943
  • Figure US20090312307A1-20091217-C01059
    • 2-Methoxy-N-(4-phenyl-piperidin-4-ylmethyl)-thiobenzamide Synthesis
  • Figure US20090312307A1-20091217-C01060
  • Compound 1: Compound 1 was prepared using methodology described in Example 653.
  • Compound 2: A solution of compound 1 (0.32 g; 0.76 mmol) and Lawesson's reagent (0.38 g; 0.95 mmol) in 10% pyridine in toluene (5 mL) was heated at reflux for 3 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (5 mL), water (2 mL) and saturated aqueous sodium bicarbonate (5 mL) and stirred for 0.5 h. Additional ethyl acetate was added and the organic layer was separated, washed with water and saturated aqueous sodium chloride, dried (sodium sulfate), filtered and concentrated. The crude residue was purified by column chromatography on silica gel using 3:1 hexane:ethyl acetate as the eluent to give 0.24 g of compound 2 as a yellow solid. LRMS m/z 442 (M+H)+.
  • Title Compound: Compound 2 (0.044 g; 0.10 mmol) was treated with 0.75 mL dichloromethane and 0.25 mL trifluoroacetic acid and the reaction mixture was stirred at room temperature for 0.5 h. The solvents were removed by rotary evaporation to give 0.040 g of the title compound as the trifluoroacetic acid salt as a white solid that was used without additional purification. LRMS m/z 341 (M+H)+.
    • Examples 944 to 947
  • Examples 944 to 947 were prepared using methodologies described in Example 943 and Example 15, Example 16 or Example 25.
  • Example Structure Name M + H
    944
    Figure US20090312307A1-20091217-C01061
         		N-(1-Dimethylsulfamoyl-4-phenyl- piperidin-4-ylmethyl)-2-methoxy- thiobenzamide 450
    945
    Figure US20090312307A1-20091217-C01062
         		2-Methoxy-N-(4-phenyl-1-sulfamoyl- piperidin-4-ylmethyl)-thiobenzamide 422
    946
    Figure US20090312307A1-20091217-C01063
         		487
    947
    Figure US20090312307A1-20091217-C01064
         		410
    • Example 948
  • Figure US20090312307A1-20091217-C01065
    • N-[1-(N-Ethylcarbamimidoyl)-4-phenyl-piperidin-4-ylmethyl]-2-methoxy-benzamide Synthesis
  • Figure US20090312307A1-20091217-C01066
  • Compound 1: Compound 1 was prepared using methodology described in Example 15.
  • Compound 2: Compound 2 was prepared as described in J. Org. Chem., 67:7553-7556 (2002).
  • Compound 3: A solution of compound 1 (0.63 g; 1.9 mmol) and compound 2 (0.45 g; 2.8 mmol) in tetrahydrofuran (15 mL) was heated at 50° C. for 24 h. The solvent was removed by rotary evaporation and the residue was treated with ethyl acetate (50 mL) and water (50 mL). The organic layer was separated, washed with water and saturated aqueous sodium chloride. The organic layer was separated, dried (sodium sulfate), filtered and concentrated to give 0.7 g of compound 3 as a light yellow foam that was used without additional purification. LRMS m/z 419 (M+H)+.
  • Title Compound: Compound 3 (0.059 g; 0.14 mmol) was treated with 2 M ethylamine in tetrahydrofuran (2.5 mL) and heated to 60° C. in a sealed tube for 48 h. The solvent was removed by rotary evaporation and the crude residue was purified by preparative reverse phase HPLC to give 0.022 mg of the title compound as the trifluoroacetic acid salt as a white solid. LRMS m/z 396 (M+H)+.
    • Example 949
  • Figure US20090312307A1-20091217-C01067
    • 3-Amino-pyrazine-2-carboxylic acid (4-p-tolyl-tetrahydro-pyran-4-ylmethyl)-amide Synthesis
  • Figure US20090312307A1-20091217-C01068
  • Compound 1: Compound 1 is commercially available.
  • Compound 2: A solution of compound 1 (0.71 g; 5 mmol), 4-methyl benzyl cyanide (0.66 g; 5 mmol) and hexadecyl tributyl phosphonium bromide (0.13 g; 0.25 mmol) in 50% NaOH in water (8 mL) was heated at 100° C. for 2 h. The reaction was cooled to room temperature, diluted with water (20 mL) and extracted with diethyl ether (3×10 mL). The combined organic layers were washed with water and saturated aqueous sodium chloride, dried (sodium sulfate), filtered and concentrated. The crude residue was purified by column chromatography on silica gel using 8.5:1.5 hexane:ethyl acetate as the eluent to give 0.776 g of compound 2 as a yellow oil. LRMS m/z 202 (M+H)+.
  • Compound 3: Compound 3 was prepared using methodology described in Example 15. LRMS m/z 206 (M+H)+.
  • Title Compound: The title compound was prepared using methodology described in Example 653. LRMS m/z 327 (M+H)+.
    • Examples 950 to 955
  • Examples 950 to 955 were prepared using methodology described in Example 949.
  • Example Structure Name M + H
    950
    Figure US20090312307A1-20091217-C01069
         		3-Amino-pyrazine-2-carboxylic acid (4-phenyl-tetrahydro-pyran-4- ylmethyl)-amide 313
    951
    Figure US20090312307A1-20091217-C01070
         		3-Amino-pyrazine-2-carboxylic acid [4-(4-chloro-phenyl)- tetrahydro-pyran-4-ylmethyl]- amide 348
    952
    Figure US20090312307A1-20091217-C01071
         		3-Amino-pyrazine-2-carboxylic acid [4-(3-fluoro-phenyl)- tetrahydro-pyran-4-ylmethyl]- amide 331
    953
    Figure US20090312307A1-20091217-C01072
         		3-Amino-pyrazine-2-carboxylic acid [4-(4-methoxy-phenyl)- tetrahydro-pyran-4-ylmethyl]- amide 343
    954
    Figure US20090312307A1-20091217-C01073
         		3-Amino-pyrazine-2-carboxylic acid [4-(2,4-difluoro-phenyl)- tetrahydro-pyran-4-ylmethyl]- amide 349
    955
    Figure US20090312307A1-20091217-C01074
         		3-Amino-pyrazine-2-carboxylic acid [4-(4-fluoro-phenyl)- tetrahydro-pyran-4-ylmethyl]- amide 331
    • Example 956
  • Figure US20090312307A1-20091217-C01075
    • 2-Methoxy-N-(4-phenyl-azepan-4-ylmethyl)-benzamide Synthesis
  • Figure US20090312307A1-20091217-C01076
  • Compound 1: Compound 1 is commercially available.
  • Compound 2: To a solution of ketone 1 (500 mg, 2.51 mmol) in glacial acetic acid (30 mL) was added concentrated sulfuric acid (0.3 mL) at room temperature. The solution was heated to 65° C. and sodium azide (0.50 g, 7.7 mmol) was added in 3 equal portions over 5 min at 65° C. After a further 5 min at 65° C., the reaction mixture was allowed to cool and stirred at ambient temperature for 16 h. The resulting slurry was poured cautiously into a saturated NaHCO3 solution (ca. 100 mL), transferred to a separation funnel and the aqueous portion extracted with dichloromethane (3×50mL). The combined organic portions were washed with NaHCO3 (20 ml), dried over Na2SO4, decanted and concentrated yielding a pale yellow oil. Methanol (ca. 5 mL) was added to the oil and the white precipitate was collected and dried under high vacuum (153 mg). The methanol solution was purified by preparative HPLC. YMC ODS S5 30×50 mm, 10 min gradient, 0-100% MeOH (90% in water, 0.1% TFA) UV detection 220 nM, 50 mL/min flow rate. The product retention time was 5.23 min. The product was neutralized with saturated NaHCO3 and extracted into dichloromethane. A further 119 mg of product was isolated and combined with the product isolated by precipitation, (combined mass 272 mg, yield 51%). HPLC Rt 2.17 min, Purity 98%, PHENOMENEX® Luna S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.1% PPA) UV detection at 220 nm. LCMS Rt 1.12 min, [M+1] 215.42 PHENOMENEX® S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TEA) UV detection at 220 nm. H NMR (DMSO) 1.98 ppm, 1H, multiplet; 2.10 ppm, 1H, multiplet; 2.30 ppm, 1H, multiplet; 2.78 ppm, 1H, multiplet; 3.21 ppm, 1H, multiplet; 3.43 ppm, 1H, multiplet; 7.31 ppm, 1H, t, J=7.9 Hz; 7.42 ppm, 2H, dd, J=7.9 Hz and J=7.9 Hz; 7.55 ppm, 2H, d, J=8.4 Hz; 7.82 ppm, 1H, s.
  • Compound 3: Benzoic anhydride (4.22 g, 18.7 mmol) and pyridine (3.1 mL, 37 mmol) were added to a suspension of compound 2 (2.00 g, 9.33 mmol) in toluene (20 mL). After heating at 100° C. for 18 hours, the reaction mixture was concentrated and purified by ISCO hexane/EtOAc, 0% EtOAc-10% EtOAc over 10 minutes, 10% EtOAc-30% EtOAc over 10 minutes, 30% EtOAc for 20 minutes, 30% EtOAc-100% EtOAc over 2 minutes, 100% EtOAc for 5 minutes. Compound 3 eluted at a retention time of 12.8 min as a white solid (2.62 g, 88% yield). HPLC Rt 3.08 min, Purity 86%, PHENOMENEX® Luna S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.1% PPA) UV detection at 220 nm. LCMS Rt 1.57 min, [M+1] 319.18 PHENOMENEX® S85 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TEA) UV detection at 220 nm. H NMR (CDCl3) 2.23 ppm, 2H, multiplet; 2.37 ppm, 1H, multiplet; 2.47 ppm, 1H, multiplet; 2.76 ppm, 1H, multiplet; 3.34 ppm, 1H, multiplet; 3.91 ppm, 1H, dd, J=12.0 and 16.0 Hz; 4.66 ppm, 1H, dd, J=12.0 and 16.0 Hz; 7.44 ppm, 8HS, multiplet; 7.57 ppm, 2H, multiplet.
  • Compound 4: To a solution of compound 3 (500 mg, 1.57 mmol) in CH2Cl2 (8 mL) and THF (4 mL) was added a 1.0 M solution of lithium aluminum hydride in THF (9.4 ml, 9.4 mmol) at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred for 18 hours. The reaction was quenched with H2O (1.7 mL), 1 N NaOH (1.0 mL) and H2O (1.7 mL). After stirring at room temperature for 30 minutes, the reaction was filtered and the filtrate was concentrated. The resulting residue was dissolved in CH2Cl2 (75 mL). The organic layer was washed with brine (25 mL), dried over MgSO4, filtered, concentrated, and the resulting residue was dissolved in CH2Cl2 (2.0 mL). The solution was added to a solution of O-anisic acid (215 mg, 1.42 mmol) and EDCI (296 mg, 1.54 mmol) in CH2Cl2 (2 mL). After 2 hours, the reaction mixture was concentrated and purified by ISCO Hexane/EtOAc; 0% EtOAc 30% EtOAc over 10 minutes, 30% EtOAc-50% EtOAc over 10 minutes, 50% EtOAc for 10 minutes, 50% EtOAc-100% EtOAc over 5 minutes, 100% EtOAc for 5 minutes. Compound N+2 eluted at a retention time of 13.3 min as a white solid compound (211 mg, 31%). HPLC Rt 2.40 min, Purity 100%, PHENOMENEX® Luna S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.1% PPA) WV detection at 220 nm. LCMS Rt 1.46 min, [M+1] 429.22 PHENOMENEX® S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) W detection at 220. H NMR (CDCl3) 1.63 ppm, 1H, multiplet; 1.75 ppm, 1H, multiplet; 1.89 ppm, 1H, multiplet; 1.99 ppm, 1H, multiplet; 2.22 ppm, 2H, multiplet; 2.61 ppm, 4H, multiplet; 2.92 ppm, 3H, s; 3.54 ppm, 2H, s; 3.64 ppm, 2H, d, J=4.0 Hz; 6.75 ppm, 1H, d, J=8.0 Hz; 6.96 ppm, 1H, t, J=6.0 Hz; 7.20 ppm, 6H, multiplet; 7.30 ppm, 5H, multiplet; 7.50 ppm, 1H, multiplet; 8.11 ppm, 1H, dd, J=4.0 and 8.0 Hz.
  • Title Compound: At 0° C. 1-chloroethyl chloroformate (159 μL, 1.48 mmol) was added to a solution of compound 4 (211 mg, 0.492 mmol) and TEA (341 μL, 2.45 mmol) in dichloroethane (5 mL). The reaction was allowed to warm up to room temperature and stirred for 3 hours. The reaction mixture was concentrated and dried on oil pump for 0.5 hours. The solution of the resulting residue in MeOH (5 mL) was heated under reflux for 5 hours and concentrated. Crude product was purified by preparative HPLC YMC ODS S5 30×100 mm Ballistic column 0-100% MeOH (90% in water, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm. Compound 5 eluted at a retention time of 6.6 mins and was isolated as a yellow oil (101.3 mg, yield 61%) H NMR (CDCl3) 1.60 ppm, 1H, multiplet; 1.91 ppm, 3H, multiplet; 2.34 ppm, 2H, multiplet; 3.22 ppm, 2H, multiplet; 3.36 ppm, 1H, multiplet; 3.52 ppm, 1H, multiplet; 3.53 ppm, 3H, s; 3.62 ppm, 2H, multiplet; 6.76 ppm, 1H, d, J=1.8 Hz; 6.80 ppm, 1H, d, J=7.9 Hz; 6.98 ppm, 1H, t, J=7.7 Hz; 7.06 ppm, 1H, d, J=1.8 Hz; 7.22 ppm, 1H, multiplet; 7.34 ppm, 3H, multiplet; 7.56 ppm, 1H, t, J=5.7 Hz; 8.11 ppm, 1H, dd, J=1.8 and 7.5 Hz.
    • Example 957
  • Figure US20090312307A1-20091217-C01077
    • N-(1-Benzyl-4-phenyl-azepan-4-ylmethyl)-2-methoxy-benzamide Synthesis
  • Figure US20090312307A1-20091217-C01078
  • Compound 1: Compound 1 was synthesized as described in Example 956.
  • Compound 2: NaH (95%) (71 mg, 2.8 mmol) was added to the suspension of compound 1 (500 mg, 2.33 mmol) in DMF (10 mL). After 30 minutes benzylbromide (333 μL, 2.80 mmol) was added and the reaction was stirred for 18 hours. LiCl (10%, 50 mL) was added. The aqueous layer was extracted with EtOAc (3×25 mL). The combined organic layers were dried over MgSO4, filtered, concentrated and purified by ISCO Hexane/EtOAc, 0% EtOAc to 10% EtOAc over 10 minutes, 10% EtOAc for 5 minutes, 10% EtOAc to 30% EtOAc over 10 minutes, 30% EtOAc for 10 minutes, 30% EtOAc to 100% EtOAc over 5 minutes. Compound N+1′ eluted at 23 min as a clear oil (454.7 mg, 64% yield).
  • Title Compound: At room temperature a 1.0 M solution of Lithium aluminum hydride in THF (480 mL, 0.480 mmol) was added to a solution of compound 2 (48.5 mg, 0.160 mmol) in THF (1 mL). After 3 hours the reaction mixture was quenched with H2O (60 μL), 1 N NaOH (36 μL) and H2O (60 μL). The reaction was stirred at room temperature for 0.5 hours, dried over MgSO4, filtered and concentrated. The solution of the resulting residue in CH2Cl2 (1 mL) was added to the mixture of o-anisic acid (27 mg, 0.18 mmol) and EDCI (37 mg, 0.19 mmol) in CH2Cl2 (1 mL). After 1 hours the reaction was concentrated and purified by preparative HPLC yielding compound N+2 as a yellow oil (17.5 mg, 26%).
    • Example 958
  • Figure US20090312307A1-20091217-C01079
    • 2-Methoxy-N-(4-phenyl-1-sulfamoyl-azepan-4-ylmethyl)-benzamide Synthesis
  • Figure US20090312307A1-20091217-C01080
  • Compound 1: Compound 1 was synthesized as described in Example 956.
  • Compound 2: At 0° C. N,N′-sulfuryl bis-2-methylimidazole mono-methyl triflate salt (317 mg, 0.390 mmol) was added to a solution of compound 1 (101 mg, 0.300 mmol) in acetonitrile (10 mL) followed by the addition of TEA (100 μL). The reaction was allowed to warm up to room temperature and stirred for 18 hours. The mixture was concentrated and purified by ISCO hexane (0.1% TEA)/EtOAc, 0% EtOAc-50% EtOAc over 15 minutes, 50% EtOAc for 15 minutes, 50% EtOAc-100% EtOAc over 5 minutes, 100% EtOAc for 5 minutes. Compound 2 eluted at a retention time of 26 min as a yellow oil (78.8 mg, 54% yield) H NMR (CDCl3) 1.58 ppm, 1H, multiplet; 1.89 ppm, 3H, multiplet; 2.35 ppm, 2H, multiplet; 2.45 ppm, 3H, s; 3.20 ppm, 2H, multiplet; 3.37 ppm, 1H, multiplet; 3.51 ppm, 1H, multiplet; 3.53 ppm, 3H, s; 3.62 ppm, 2H, multiplet; 6.76 ppm, 1H, d, J=1.8 Hz; 6.80 ppm, 2H, multiplet; 6.98 ppm, 1H, t, J=7.5 Hz; 7.06 ppm, 1H, d, J=1.8 Hz; 7.23 ppm, 2H, multiplet; 7.33 ppm, 3H, multiplet; 7.56 ppm, 1H, t, J=5.7 Hz; 8.10 ppm, 1H, dd, J=1.8 and 7.9 Hz
  • Title Compound: A solution of compound 2 (34 mg, 0.070 mmol) in CH2Cl2 (1 mL) was added methyl trifluoromethanesulfonate (8 mL, 0.08 mmol) at 0° C. After 1.5 hours, the reaction was concentrated to give crude product of compound 3 as a white foam. This product was used directly to the next step without further purification. A 2.0 M solution of NH3 in MeOH (170 μL, 0.35 mmol) was added to a solution of compound 4 and TEA (100 μL) in acetonitrile (1 mL). The reaction mixture was heated at 80° C. for 8 hours. The concentrated reaction mixture was purified by preparative HPLC YMC ODS S5 30×100 mm Ballistic column 10-100% MeOH (90% in water, 0.1% TFA) gradient over 12 min with flow rate 40 mL/min and UV detection at 220 nm. Compound 5 eluted at a retention time of 9.6 mins and was isolated as a clear oil (18.27 mg, 63% yield from compound 3). HPLC Rt 2.91 min, Purity 100%, PHENOMENEX® Luna S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.1% PPA) UV detection at 220 nm. LCMS Rt 1.60 min, [M+1] 418.17 YMC-ODS S5 column 4.6×33 mm, 2 min gradient 0 to 100% MeOH (90% in water, 10 mM NH4OAc) UV detection at 220 nm. H NMR (CDCl3) 1.65 ppm, 1H, multiplet; 1.84 ppm, 2H, multiplet; 1.99 ppm, 2N, multiplet; 2.25 ppm, 1H, multiplet; 2.37 ppm, 2N, multiplet; 3.23 ppm, 24, multiplet; 3.31 ppm, 1H, multiplet; 3.52 ppm, 3H, s; 3.57 ppm, 2N, s; 3.69 ppm, I, multiplet; 4.40 ppm, 2H, bs; 6.79 ppm, 1H, d, J=8.4 Hz; 6.97 ppm, 1H, t, J=7.5 Hz; 7.23 ppm, 1H, multiplet; 7.34 ppm, 5H, multiplet; 7.61 ppm, 1H, multiplet; 8.09 ppm, 1H, dd, J=1.7 and 7.9 Hz.
    • Examples 959 to 963
  • Compounds 959 to 963 were synthesized using methodology described in Example 958.
  • Example Structure Name [M + 1]
    959
    Figure US20090312307A1-20091217-C01081
         		2-Methoxy-N-[1-(2-methoxy- ethylsulfamoyl)-4-phenyl-azepan-4- ylmethyl]-benzamide 476
    960
    Figure US20090312307A1-20091217-C01082
         		N-[1-(2-Hydroxy-ethylsulfamoyl)-4-phenyl- azepan-4-ylmethyl]-2-methoxy-benzamide 462
    961
    Figure US20090312307A1-20091217-C01083
         		2-Methoxy-N-{1-[(2-methoxy-ethyl)- methyl-sulfamoyl]-4-phenyl-azepan-4- ylmethyl}-benzamide 490
    962
    Figure US20090312307A1-20091217-C01084
         		N-(1-Cyclopropylsulfamoyl-4-phenyl- azepan-4-ylmethyl)-2-methoxy-benzamide 458
    963
    Figure US20090312307A1-20091217-C01085
         		2-Methoxy-N-(1-methylsulfamoyl-4-phenyl- azepan-4-ylmethyl)-benzamide 432
    • Example 964
  • Figure US20090312307A1-20091217-C01086
    • N-(1-Dimethylsulfamoyl-4-phenyl-azepan-4-ylmethyl)-2-methoxy-benzamide Synthesis
  • Figure US20090312307A1-20091217-C01087
  • Compound 1: Compound 1 was synthesized as described in Example 956.
  • Title Compound: Dimethysulfomoyl chloride (3.44 mg, 0.0240 mmol) was added to a solution of compound 1 (6.76 mg, 0.0200 mmol) in CH2Cl2 (0.5 mL). TEA (5 μL) was added and the reaction was stirred at room temperature for 2 hours. The concentrated reaction mixture was purified by preparative HPLC YMC ODS S5 30×100 mm Ballistic column 20-100% MeOH (90% in water, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm. Compound 2 eluted at a retention time of 9.0 min and was isolated as a clear oil (5.7 mg, 64% yield). HPLC Rt 3.30 min, Purity 100%, PHENOMENEX®T Luna S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.1% PPA) UV detection at 220 nm. LCMS Rt 1.68 min, [M+1] 446.21 PHENOMENEX® S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 10 mM NH4OAc) UV detection at 220 nm. H NMR (CDCl3) 1.61 ppm, 1H, multiplet; 1.89 ppm, 3H, multiplet; 2.34 ppm, 2H, multiplet; 2.61 ppm, 6H, s; 3.18 ppm, 2H, multiplet; 3.26 ppm, 1H, multiplet; 3.54 ppm, 3H, s; 3.57 ppm, 3H, multiplet; 6.80 ppm, 1H, d, J=8.0 Hz; 6.98 ppm, 1H, t, J=8.0 Hz; 7.23 ppm, 1H, multiplet; 7.33 ppm, 5H, multiplet; 7.58 ppm, 1H, multiplet; 8.11 ppm, 1H, multiplet.
    • Example 965
  • Figure US20090312307A1-20091217-C01088
    • 4-Aminomethyl-4-(3-fluoro-phenyl)-azepane-1-carboxylic acid tert-butyl ester Synthesis
  • Figure US20090312307A1-20091217-C01089
  • Compound 1: Compound 1 was synthesized via the intermediate cyclohexanone according to the procedures described in J. Med. Chem., 821 (1998). The intermediate cyclohexanone was converted to the lactam as described for Example 956.
  • Compound 2: To a suspension of the crude compound 1 in THF (20 mL) was added subsequently di-tert-butyl dicarbonate (2.33 mL, 10.1 mmol) and dimethylaminopyridine (1.24 g, 10.1 mmol). After 3 hours the reaction mixture was concentrated. The resulting residue was dissolved in Ethyl acetate (100 mL). The organic layer was washed with 1 N HCl (2×50 mL) and dried over MgSO4. Evaporation and purification by ISCO (hexane/EtOAc, 0% EtOAc-10% EtOAc over 10 minutes, 10% EtOAc-30% EtOAc over 10 minutes, 30% EtOAc for 15 minutes, 30% EtOAc-100% EtOAc over 5 minutes, 100% EtOAc for 5 minutes) yielded compound 2 with a retention time of 16 min as a white solid (2.69 g, 88% from ketone) H NMR (CDCl3) 2.03 ppm, 1H, multiplet; 2.28 ppm, 3H, multiplet; 2.76 ppm, 1H, dd, J=7.2 and 15.6 Hz; 3.21 ppm, 1H, multiplet; 3.75 ppm, 1H, dd, J=10.5 and 16.3 Hz; 4.44 ppm, 1H, dd, J=6.5 and 15.9 Hz; 7.05 ppm, 1H, multiplet; 7.16 ppm, 1H, multiplet; 7.26 ppm, 1H, multiplet; 7.38 ppm, 1H, multiplet.
  • Compound 3: At −78° C. a 1.0 M solution of lithium triethylborohydride in THF (4.87 mL, 4.87 mmol) was added to a solution of compound 2 (1.35 g, 4.06 mmol) in THF (25 mL). After 30 minutes the reaction was quenched with saturated NaHCO3 (7.6 mL) and warmed to 0° C. At 0° C. H2O2 (12 drops) was added and the reaction was stirred for 20 minutes. THF was removed and the aqueous layer was extracted with CH2Cl2 (3×25 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The resulting thick oil was dissolved in CH2Cl2 (50 mL). At −78° C. triethylsilane (648 μL, 4.06 mmol) was added followed by drop wise addition of boron trifluoride etherate (566 μL, 4.47 mmol). After 30 minutes another portion of triethylsilane (648 μL, 4.06 mmol) and boron trifluoride etherate (566 μL, 4.47 mmol) were added and the reaction was continued to stir for 2 hours at −78° C. The reaction was quenched with saturated NaHCO3 (15 mL). The aqueous layer was extracted with CH2Cl2 (3×20 mL) and the combined organic layers were dried over MgSO4, filtered and concentrated to give crude compound 3 (1.19 g) as an oil. This crude product was used to the next step directly without further purification.
  • Title Compound: To a solution of crude compound 3 (1.19 g, 3.73 mmol) in MeOH (35 mL) was added cobalt (II) chloride hexahydrate (1.41 g, 7.46 mmol). The resulted purple mixture was stirred at room temperature for 10 minutes. At 0° C. NaBH4 (1.41 g, 37.3 mmol) was added in three portions over 25 minutes. The reaction mixture was stirred at room temperature for 2 hours, concentrated to give a black residue. The black residue was dissolved in 30% ammonium hydroxide solution (100 mL), extracted with ethyl acetate (3×50 mt). The combined organic layers were dried over MgSO4, filtered and concentrated to give a crude pink solid of compound 4 (1.46 g). This crude solid was used directly to the following acylation reaction.
    • Example 966
  • Figure US20090312307A1-20091217-C01090
    • N-[4-(3-Fluoro-phenyl)-azepan-4-ylmethyl]-2-methoxy-benzamide Synthesis
  • Figure US20090312307A1-20091217-C01091
  • Compound 1: The synthesis of Compound 1 is described for Example 965.
  • Compound 2: To a solution of crude compound 1 (729 mg, 2.26 mmol), o-anisic acid (345 mg, 2.26 mmol) and TEA (314 μL, 2.26 mmol) in CH2Cl2 (10 mL) was added PyBrOP (1.05 g, 2.26 mmol) at room temperature. After 3 hours, the reaction was concentrated and purified by flash chromatography using Hexane/EtOAc (2/1) to yield compound 2 as a white solid (536.2 mg, 58% from compound N+13). HPLC Rt 3.79 min, Purity 100%, PHENOMENEX® Luna S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.1% PPA) UV detection at 220 nm. LCMS Rt 2.04 min, [M+1] 357.43 PHENOMENEX® S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TEA) UV detection at 220 nm. H NMR (CDCl3) 1.38 ppm, 9H, d, J=12.8 Hz; 1.64 ppm, 1H, multiplet; 1.78 ppm, 3H, multiplet; 2.32 ppm, 2H, multiplet; 3.31 ppm, 3H, multiplet; 3.65 ppm, 6H, multiplet; 6.89 ppm, 1H, d, J=8.4 Hz; 6.99 ppm, 1H, multiplet; 7.06 ppm, 2H, multiplet; 7.16 ppm, 1H, d, J=7.5 Hz; 7.40 ppm, 2H, multiplet; 7.62 ppm, 1H, multiplet; 8.20 ppm, 1H, d, J=7.5 Hz.
  • Title Compound: To a solution of compound 2 (526 mg, 1.24 mmol) in CH2Cl2 (5 mL) was added a solution of TFA (1 mL) in CH2Cl2 (4 ml) at room temperature. After 1.5 hours the reaction was diluted with CH2Cl2 (50 mL) and was washed with saturated NaHCO3 (2×20 mL), dried over MgSO4, filtered and concentrated to give a crude product of compound N+18 as a white solid (483 mg, quantitative yield). The crude product was used directly to the next step without further purification.
    • Examples 967 to 970
  • Compounds 967 to 970 were prepared using the methodology described for Example 966 and Example 958.
  • Example Structure Name [M + 1]
    967
    Figure US20090312307A1-20091217-C01092
         		N-[4-(3-Fluoro-phenyl)-1-(2-methyl- imidazole-1-sulfonyl)-azepan-4-ylmethyl]-2- methoxy-benzamide 501
    968
    Figure US20090312307A1-20091217-C01093
         		N-[1-Cyclopropylsulfamoyl-4-(3-fluoro- phenyl)-azepan-4-ylmethyl]-2-methoxy- benzamide 476
    969
    Figure US20090312307A1-20091217-C01094
         		N-{4-(3-Fluoro-phenyl)-1-[(2-methoxy- ethyl)-methyl-sulfamoyl]-azepan-4- ylmethyl}-2-methoxy-benzamide 508
    970
    Figure US20090312307A1-20091217-C01095
         		N-[4-(3-Fluoro-phenyl)-1-sulfamoyl-azepan- 4-ylmethyl]-2-methoxy-benzamide 436
    • Example 971
  • Figure US20090312307A1-20091217-C01096
    • Synthesis
  • Figure US20090312307A1-20091217-C01097
  • Compound 1: The synthesis of Compound 1 is described for Example 965.
  • Compound 2: To a solution of crude compound 1 (729 mg, 2.26 mmol) and 3-aminopyrazine-2-carboxylic acid (377 mg, 2.26 mmol) in ethylene glycol dimethyl ether (10 mL) was added drop wise diethyl phosphoryl cyanide (411 μL, 2.71 mmol) and TEA (630 mL, 4.52 mmol) respectively at 0° C. The reaction was stirred at 0° C. for 1 hour and at 40° C. for 1 hour under N2. The mixture was diluted with EtOAc (100 mL) and washed with H2O (25 mL), saturated NaHCO3 (25 mL) and H2O (25 mL) successively. The organic layer was dried over MgSO4 and concentrated to afford the crude product, which was purified by ISCO Hexane/EtOAc; 0% EtOAc-50% EtOAc over 10 minutes, 50% EtOAc for 25 minutes, 50% EtOAc-100% EtOAc over 5 minutes, 100% EtOAc for 5 minutes. Compound 2 eluted at a retention time of 14 min as a yellow solid (432.7 mg, 51% from compound 1). HPLC Rt 3.67 min, Purity 100%, PHENOMENEX™ Luna S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.1% PPA) UV detection at 220 nm. LCMS Rt 1.90 min, [M+1] 344.45 PHENOMENEX® S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) UV detection at 220 nm. H NMR (CDCl3) 1.38 ppm, 9H, d, J=12.8 Hz; 1.62 ppm, 1H, multiplet; 1.71 ppm, 1H, multiplet; 1.87 ppm, 2H, multiplet; 2.34 ppm, 2H, multiplet; 3.17 ppm, 2H, multiplet; 3.38 ppm, 1H, multiplet; 3.46 ppm, 2H, multiplet; 3.67 ppm, 1H, multiplet; 6.99 ppm, 2H, multiplet; 7.11 ppm, 1H, multiplet; 7.37 ppm, 1H, multiplet; 7.71 ppm, 2H, multiplet; 8.11 ppm, 1H, s.
  • Title Compound: To a solution of compound 2 (457 mg, 1.03 mmol) in CH2Cl2 (5 mL) was added a solution of TFA (1 mL) in CH2Cl2 (4 mL) at room temperature. After 1.5 hours the reaction was diluted with CH2Cl2 (50 mL) and was washed with saturated NaHCO3 (2×20 mL), dried over MgSO4, filtered and concentrated to give a crude product of compound 3 as a yellow solid (291 mg, 82% crude yield). The crude product was used directly to the next step without further purification.
    • Examples 972 to 974
  • Compounds 972 to 974 were prepared using the methodology described for Example 971 and Example 961.
  • Example Structure Name [M + 1]
    972
    Figure US20090312307A1-20091217-C01098
         		N-[1-Dimethylsulfamoyl-4-(3-fluoro- phenyl)-azepan-4-ylmethyl]-2-methoxy- benzamide 464
    973
    Figure US20090312307A1-20091217-C01099
         		3-Amino-pyrazine-2-carboxylic acid [1- dimethylsulfamoyl-4-(3-fluoro-phenyl)- azepan-4-ylmethyl]-amide 451
    974
    Figure US20090312307A1-20091217-C01100
         		3-Amino-pyrazine-2-carboxylic acid [4- (3-fluoro-phenyl-1-(2-methyl-imidazole- 1-sulfonyl)-azepan-4-ylmethyl]-amide 488
    • Example 975
  • Figure US20090312307A1-20091217-C01101
  • Compound 1: Compound 1 was prepared as described in Example 671.
  • Compound 3: N-(tert-Butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide was made according to Organic Letters, 2001, Vol. 3, No. 14, 2241-2243. Compound 1119 mg, 0.058 mmol) was added to Compound 2 (20 mg, 0.064 mmol) in CH2Cl2 (1 mL) and was stirred at room temperature for 18 hours. The residue was concentrated and purified by preparative silica thin layer chromatography (25×25 cm plate, 1 mm thickness silica with UV indicator) using hexane/EtOAc (1/2) as eluent to yield compound 3 as a clear oil (26 mg, 87% yield) H NMR (CDCl3) 1.44 ppm, 9H, s; 1.64 ppm, 1H, multiplet; 1.98 ppm, 3H, multiplet; 2.37 ppm, 2H, multiplet; 3.24 ppm, 2H, multiplet; 3.49 ppm, 3H, multiplet; 3.81 ppm, In, multiplet; 6.99 ppm, 2H, multiplet; 7.35 ppm, 1H, multiplet; 7.67 ppm, 1H, multiplet; 7.69 ppm, 1H, d, J=4.0Hz; 8.00 ppm, 1H, s; 8.12 ppm, 1H, d, J=4.0 Hz.
  • Title Compound: At room temperature, a solution of TFA (0.25 mL) in CH2Cl2 (1 mL) was added to a solution of compound 3 (26 mg, 0.050 mmol. After 2 hours the reaction mixture was concentrated and purified by preparative HPLC YMC ODS S5 30×100 mm Ballistic column 20-100% MeOH (90% in water, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm. Compound 4 eluted at a retention time of 7.0 min and was isolated as a clear oil (20.2 mg, 95% yield). HPLC Rt 2.68 min, Purity 100%, PHENOMENEX® Luna S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.1% PPA) UV detection at 220 nm. LCMS Rt 1.39 min, [M+1] 423.31 PHENOMENEX® S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 10 mM NH4OAc) UV detection at 220 nm. H NMR (CDCl3) 1.66 ppm, 1H, multiplet; 1.90 ppm, 2H, multiplet; 2.00 ppm, 1H, multiplet; 2.30 ppm, 1H, multiplet; 2.41 ppm, 1H, multiplet; 3.16 ppm, 2H, multiplet; 3.41 ppm, 1H, multiplet; 3.51 ppm, 2H, multiplet; 3.66 ppm, 1H, multiplet; 7.00 ppm, 2H, multiplet; 7.10 ppm, 1H, d, J=8.0 Hz; 7.38 ppm, 1H, multiplet; 7.60 ppm, t, J=6.0 Hz; 7.81 ppm, 1H, d, J=4.0 Hz; 7.93 ppm, 1H, multiplet.

Claims (16)

1. A compound of formula I
Figure US20090312307A1-20091217-C01102
enantiomers, diastereomers, and salts thereof wherein
m and p are independently 0, 1, 2 or 3 provided that the sum of m and p is at least 2;
Q is NR1, O, S, S(O) or S(O)2;
R1 is H,
Figure US20090312307A1-20091217-C01103
 —C(═NR8b)R8c, —SO2R8c, —OC(O)CCl3, —C(═S)R8c, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, perfluoroalkyl, cyano, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
R2 is heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, alkyl or cycloalkyl, any of which may be optionally independently substituted with one or more groups T1, T2 or T3;
J is a bond, C1-4 alkylene optionally independently substituted with one or more groups T1a, T2a or T3a, or C1-4 alkenylene optionally independently substituted with one or more groups T1a, T2a or T3a;
Figure US20090312307A1-20091217-C01104
R4 is H, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, (aryl)alkyl or heteroaryl any of which may be optionally independently substituted with one or more groups T1b, T2b or T3b;
R5 is
(a) —NR6aR7a, cyano or
(b) heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, (heterocyclo)alkyl, or alkyl any of which may be optionally independently substituted with one or more groups T1c, T2c or T3c;
R6, R6a, R7, R7a, R8, R8a, R8a1, R8a2, and R8a3 are independently H, alkyl hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl, (heteroaryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, —C(O)R9, —CO2R9, —C(O)—NR9R10, or —NR9R10 any of which may be optionally independently substituted with one or more groups T1d, T2d or T3d;
or R6 and R7, or R6a and R7a together with the nitrogen atom to which they are attached may combine to form a 4 to 8 membered heterocyclo ring optionally independently substituted with one or more groups T1d, T2d or T3d;
or one of R6 or R7, may combine with one of R8, R8a or R9 to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T1d, T2d or T3d;
or one of R6a or R7a, may combine with R8a1 to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T1d, T2d or T3d;
R8b is H, alkyl, aryl, cyano, nitro, acyl or —SO2(alkyl) were the alkyl and aryl groups may be optionally independently substituted with one or more groups T1d, T2d or T3d;
R8c is H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclo, heteroaryl, alkoxy or aryloxy any of which may be optionally independently substituted with one or more groups T1d, T2d or T3d;
R8d is R4, COR4, CO2R4, SO2R4, CONR6R7, or SO2NR6R7;
R9 and R10 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl, (heteroaryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, or (heterocyclo)alkyl any of which may be optionally independently substituted with one or more groups T1f, T2f or T3f,
or R9 and R10 together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated ring which may be optionally independently substituted with one or more groups T1f, T2f or T3f;
W is ═NR8a1, ═N—CO2R8a1, ═N—COR8a1, ═N—CN, ═N—SO2R8a1, or
Figure US20090312307A1-20091217-C01105
X1 is O, S, NR8a2 or CH2;
Z, Z1 and Z2 are independently ═O, S, ═NR8a3 or ═N—CN;
RX is one or more optional substituents, attached to any available ring carbon atom, independently selected from T1g, T2g or T3g;
T1-1g, T2-2g, and T3-3g are each independently
(1) hydrogen or T6, where T6 is
(i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or
(iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of T1-1g, T2-2g and T3-3g
(2) —OH or —OT6,
(3) —SH or —ST6,
(4) —C(O)tH, —C(O)tT6, or —O—C(O)T6, where t is 1 or 2;
(5) —SO3H, —S(O)tT6, or S(O)tN(T9)T6,
(6) halo,
(7) cyano,
(8) nitro,
(9) -T4-NT7T8,
(10) -T4-N(T9)-T5-NT7T8,
(11) -T4-N(T10)-T5-T6,
(12) T4-N(T10)-T5-H,
(13) oxo;
T4 and T5 are each independently
(1) a single bond,
(2) -T11-S(O)t-T12-,
(3) -T11-C(O)-T12,
(4) -T11-C(S)T12-,
(5) -T11-O-T12-,
(6) -T11-S-T12-,
(7) -T11-O—C(O)-T12-,
(8) -T11-C(O)—O-T12-,
(9) -T11-C(═NT9a)-T12-, or
(10) -T11-C(O)—C(O)-T12-;
T7, T8, T9, T9a and T10
(1) are each independently hydrogen or a group provided in the definition of T6, or
(2) T7 and T8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of T1-1g, T2-2g and T3-3g, or
(3) T7 or T8, together with T9, may be alkylene or alkenylene completing a 3 to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of T1-1g, T2-2g and T3-3g, or
(4) T7 and T8 or T9 and T10 together with the nitrogen atom to which they are attached may combine to form a group —N═CT13T14 where T13 and T14 are each independently H or a group provided in the definition of T6; and
T11 and T12 are each independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene;
provided said compound is other than
(i) a compound of formula I
Figure US20090312307A1-20091217-C01106
where
R1i is H, alkyl, aralkyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)alkylene-CO2alkyl, —CO2alkyl, —CO2alkenyl, —CO2aralkyl, or —SO2alkyl; and
R8i is H, or alkyl;
(ii) a compound of formula iia, iib or iic
(a)
Figure US20090312307A1-20091217-C01107
(b)
Figure US20090312307A1-20091217-C01108
where
q is 0, 1 or 2; and
R1iib is H or —C(O)2alkyl;
(c)
Figure US20090312307A1-20091217-C01109
where
R1iic is H or alkyl; and
R8iic is H or alkyl;
(iii) a compound of formula iii
Figure US20090312307A1-20091217-C01110
where
R1iii is -alkylene-C(O)Ar where Ar is phenyl, alkylphenyl, xylyl, halophenyl, methoxyphenyl or thienyl; and
R2iii is thienyl, phenyl, halophenyl, methoxyphenyl, alkylphenyl xylyl, or trifluoromethylphenyl;
(iv) a compound of formula iv
Figure US20090312307A1-20091217-C01111
where
R1iv is
Figure US20090312307A1-20091217-C01112
where
T1h is alkyl, aryl, heteroaryl, (aryl)alkyl, (heteroaryl)alkyl, (cycloalkyl)alkyl, -alkylene-M-alkyl, -alkylene-M-alkylene-aryl, -alkylene-M-alkylene-heteroaryl, -alkylene-M-alkylene-cycloalkyl
where alkyl and alkylene groups may be optionally substituted with 1 to 5 halo, —S(O)qH, —S(O)qalkyl, or 1 to 3 hydroxy, alkoxy, carboxyl or —C(O)Oalkyl, and where the aryl and heteroaryl groups may be optionally substituted with phenyl, phenoxy,(aryl)alkoxy, (heteroaryl)alkoxy, halophenyl, 1 to 3 halo or alkyl, 1 to 3 methoxy, alkoxy, or cycloalkoxy, 1 to 3 trifluoromethyl or trifluoromethoxy, 1 to 2 methylenedioxy, S(O)qR5b, nitro, —NR5bR5b, —NR5bC(O)R5b, —C(O)R5b, —C(O)NR5bR5b, —SO2NR5bR5b, —NR5bSO2aryl, —NR5bSO2heteroaryl, or —NR5bSO2R5b;
M is O, SOq, NR5bC(O), C(O)NR5b, OC(O), C(O)O, —CR5b═CR5b, or —C≡C—;
T2h is H, alkyl, or cycloalkyl;
or T1h and T2h combine to form a 3 to 8-membered ring optionally including heteroatoms;
T3h is -LC(O)ANR6dR7d;
L is NR5c, O or CH2,
R5c is H, alkyl or R5c combines with T2h to form a 3 to 8-membered ring;
R6d and R7d are independently H, alkyl, or substituted alkyl where the substituents are selected from phenyl, phenoxy, 2-furyl, —C(O)Oalkyl, —S(O)qalkyl, 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 —OC(O)alkyl, or 1 to 3 alkoxy, or R6d and R7d may combine to form an unsaturated ring optionally containing additional heteroatoms;
A is a bond or
Figure US20090312307A1-20091217-C01113
 where r and 5 are independently 0-3;
Q1 is a bond, NR5b or O;
R15 and R15a are independently H, alkyl, trifluoromethyl, phenyl or optionally substituted alkyl where the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR5b, S(O)qR5b, C(O)OR5b, cycloalkyl, NR5bR5b, C(O)NR5bR5b, or R15 and R15a can independently be joined to one or both of R6d and R7d to form alkylene bridges between the terminal nitrogen and the alkyl portion of the R15 and R15a group, or R15 and R15a may combine to form a 3 to 7-membered ring;
R2iv is alkyl, cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three halo, methyl, methoxy or trifluoromethyl;
-Jiv-R3iv is —OR5b, —C(O)OR5c, —NR6bR7b,
Figure US20090312307A1-20091217-C01114
 or -Jiva-R3iva, where
Jiva is a bond or allylene optionally substituted with one or more halo or hydroxy;
R3iva is a 5 or 6-membered cycloalkyl or heterocyclo ring to which is fused an optionally substituted 5 or 6-membered aryl or heteroaryl ring where the optional substituents are selected from halo, methyl, methoxy or trifluoromethyl;
R5b is H, alkyl or cycloalkyl;
R5c is H, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, (aryl)alkyl, or (heteroaryl)alkyl where the aryl and heteroaryl groups are optionally substituted with 1 to 3 halo, methyl, methoxy or trifluoromethyl;
R6b is C(O)—R12a or SO2—R12a;
R7b is aryl or heteroaryl, each optionally substituted with 1 to 3 halo, methyl, methoxy or trifluoromethyl;
R6c is H, alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl each optionally substituted with 1 to 3 halo, methyl, methoxy, trifluoromethyl or trifluoromethoxy;
R7c is H or alkyl optionally substituted with phenyl, phenoxy, —C(O)Oalkyl, —SOqalkyl, 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 alkoxy, or 1 to 3 —OC(O)alkyl
or R6c and R7c may combine to form a cycloalkyl or heterocyclo ring optionally substituted with alkyl or cycloalkyl;
R12a is 4-morpholinyl, 4-(1-methylpiperazinyl), cycloalkyl or alkyl, each optionally substituted with 1 to 3 fluorine, hydroxy, methoxy, trifluoromethoxy, trifluoromethyl or cycloalkyl;
(v) a compound of formula v
Figure US20090312307A1-20091217-C01115
where
R1v is H, (alkoxy)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)allyl, cycloalkyl, or (cycloalkyl)alkyl wherein the alkyl moieties may be optionally substituted with 1 to 7 fluorines, and wherein the aryl, heteroaryl and heterocyclo moieties may be optionally independently substituted with 1 to 3 halo, alkyl, fluoroalkyl, phenyl, benzyl, hydroxy, acetyl, amino, cyano, nitro, alkoxy, (alkyl)amino and (dialkyl)amino;
T1 is hydroxy, (hydroxy)alkyl, (alkoxy)alkyl, NHSO2R16, C(OH)R16R17, halo, heteroaryl, or C(O)NHR16;
T2 is H, halo or alkyl;
R16 and R17 are independently H, alkyl, alkoxy and (alkoxy)alkyl wherein the alkyl moieties are optionally substituted with 1 to 7 fluorine atoms;
n is 0 or 1;
E and F are independently O, N, S or CH provided E and F cannot both be either O or S; and
T1c is H, aryl, halo, heteroaryl, heterocyclo, —SO2R18, —C(O)R18, —C(O)NR18R19, —COOR18, or —C(OH)R18R19;
R18 and R19 are independently H, (alkoxy)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, cycloalkyl, or (cycloalkyl)alkyl wherein the alkyl moieties may be optionally substituted with 1 to 7 fluorines, and wherein the aryl, heteroaryl and heterocyclo moieties may be optionally independently substituted with 1 to 3 halo, alkyl, fluoroalkyl, phenyl, benzyl, hydroxy, acetyl, amino, cyano, nitro, alkoxy, (alkyl)amino and (dialkyl)amino;
(vi) a compound of formula vi
Figure US20090312307A1-20091217-C01116
where
R1vi is alkyl optionally substituted with hydroxy or —OC(O)alkyl; and
R20 is H or —C(O)alkyl;
(vii) a compound of formula vii
Figure US20090312307A1-20091217-C01117
where
R1vii is (aryl)alkyl, (aryl)alkenyl, (alkoxy)alkyl, (aryloxy)alkyl, (arylalkoxy)alkyl, (cycloalkyloxy)alkyl, (heterocyclo)alkyl, or —X—CH2—Y-phenyl, where X is —CH2— or —C(O)—, and Y is —C(O)—, —C(═NOH)— or —CH2— optionally substituted with hydroxy;
R2i is —C(O)alkyl, —C(O)aryl, —C(O)Oalkyl, —O—C(O)alkyl, or C(O)NR6eR7e, where R6e and R7e are independently alkyl or combine to form an alkylene chain; and
T1vii is H, hydroxy or alkoxy;
(viii) a compound of formula viii
Figure US20090312307A1-20091217-C01118
where
R1viii is SO2R23 or a group
Figure US20090312307A1-20091217-C01119
R22 is H, alkyl, phenyl, benzyl or biphenyl, wherein alkyl is optionally substituted with biphenyl, carboxy, alkoxy, —C(O)alkyl, or C(O)N(H)alkyl, and wherein benzyl is optionally substituted with hydroxy, alkoxy or halo;
R23 is alkyl or phenyl, wherein phenyl is optionally substituted with 1 or 2 halo, methoxy, halomethoxy, —N(H)C(O)methyl, CF3, alkyl or CN;
Xvii is a bond, CH2 or CHMe;
R24 is H or —N(H)R25; and
R25 is
Figure US20090312307A1-20091217-C01120
(ix) a compound of formula ixa or ixb
Figure US20090312307A1-20091217-C01121
where
R1ix is H or alkyl;
R2ixa is heteroaryl or (heteroaryl)alkyl;
R2ixb is alkyl optionally substituted with C(O)tH or C(O)talkyl where t is 1 or 2;
R6a is alkyl optionally substituted with C(O)tH or C(O)talkyl;
R26b is optionally substituted heteroaryl, —NHR27, or —OR7; and
R27 is optionally substituted heteroaryl;
(x) a compound of formula x
Figure US20090312307A1-20091217-C01122
where
R1x is —C(O)—(CHR28)—NHR29;
R2x is phenyl, (phenyl)alkyl, tetrahydropyranyl, piperidyl, alkyl, cycloalkyl or (cycloalkyl)alkyl;
R26c is C(O)R30, —C(O)2alkyl, —CH2—R31, or —NR32R33;
R28 is H, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, aryloxy, (aryloxy)alkyl, aralkoxy or (aralkoxy)alkyl, any of which may be optionally substituted;
R29 is H or —C(O)—(CR34R34)s-het* where s is 0-2; R34 is H, alkyl, cycloalkyl, (cycloalkyl)alkyl, heteroaryl or (heteroaryl)alkyl; and het* is an optionally substituted N-containing heterocyclo ring fused to an optionally substituted aryl, heteroaryl, heterocyclo or cycloalkyl ring;
R30 is alkyl, heterocyclo, —NR35R36, where R35 and R36 are independently H, alkyl, cycloalkyl or (cycloalkyl)alkyl;
R31 is —S-alkyl, —S(O)-alkyl, —S(O)2-alkyl, —O-alkyl, —NR32R33, or triazolyl;
R32 and R33 are independently H, alkyl, —S(O)2alkyl, or —C(O)alkyl;
(xi) a compound of formula xi
Figure US20090312307A1-20091217-C01123
where
R1xi is
Figure US20090312307A1-20091217-C01124
R2xi is
Figure US20090312307A1-20091217-C01125
R3xi is
Figure US20090312307A1-20091217-C01126
 —C(O)—O-alkyl, or —C(O)—NH2;
R34 is phenyl or naphthyl optionally substituted with cyano or —C(O)NH2;
R35 is H or alkyl;
R30 is phenyl optionally substituted with alkoxy;
R37 is H, alkyl, or C(O)NH2;
T1xi is H. alkyl, alkoxy, haloalkoxy, cyano, nitro, —CH2NH2, —CH2N(H)(—C(O)OCH2-Phenyl), or —NH—SO2alkyl;
T1axi is H, alkyl, halo, alkoxy, haloalkoxy, or cyano;
T1bxi is H, alkyl, halo alkoxy or hydroxy;
T1cxi is H or alkyl;
(xii) a compound of formula xii
Figure US20090312307A1-20091217-C01127
where
R38 is H or methyl;
R39 is
Figure US20090312307A1-20091217-C01128
R40 is H or Cl;
v is 0 or 1;
(xiii) a compound of formula xiii
Figure US20090312307A1-20091217-C01129
wherein
m and p are independently 0, 1, or 2, provided that the sum of m and p is 2;
Q is NR1;
J is a bond or C1-4 alkylene optionally substituted with one or more groups T1a, T2a or T3a;
R1 is selected from
Figure US20090312307A1-20091217-C01130
 or —SO2R8c;
R2 is aryl, which may be optionally independently substituted with one or more groups T1, T2 or T3;
R3 is
Figure US20090312307A1-20091217-C01131
R5 is optionally substituted heteroaryl or (heteroaryl)alkyl wherein the hetero is pyrazine or pyridine, and either of these may be optionally independently substituted with one or more groups T1c, T2c or T3c;
R6, R7, R8 and R8a are independently H, alkyl, hydroxy, alkoxy, aryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, —C(O)R9, CO2R9, —C(O)—NR9R10, or —NR9R10), any of which may be optionally independently substituted with one or more groups T1d, T2d or T3d;
R8b is H, alkyl, aryl, cyano, nitro, acyl or —SO2(alkyl) wherein the alkyl and aryl groups may be optionally independently substituted with one or more groups T1d, T2d or T3d;
R8c is H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy or aryloxy, any of which may be optionally independently substituted with one or more groups T1d, T2d or T3d;
R9 and R10 are independently H, alkyl, hydroxy, alkoxy, aryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, or (aryl)alkyl, any of which may be optionally independently substituted with one or more groups T1f, T2f or T3f;
Z1 is ═O;
Rx is one or more optional substituents attached to any available ring carbon atom, each of which is independently selected from T1g, T2g or T3g,
T1-1g, T2-2g and T3-3g are independently
(1) hydrogen or T6, where T6 is
(i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, or (aryl)alkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or
(iii) a group (i) or (ii) which is independently substituted by one or more of the following groups (2) to (13);
(2) —OH or —OT6,
(3) —SH or —ST6,
(4) —C(O)tH, —C(O)tT6, or O—C(O)T6, where t is 1 or 2,
(5) —SO3H, —S(O)tT6, or S(O)tN(T9)T6,
(6) halo,
(7) cyano,
(8) nitro,
(9) -T4-NT7T8,
(10) -T4-N(T9) -T5-NT7T8,
(11) -T4-N(T10)-T5-T6,
(12) -T4-N(T10)-T5-H,
(13) oxo;
T4 and T5 are independently
(1) a single bond,
(2) -T11-S(O)t-T12-,
(3) -T11-C(O)-T12,
(4) -T11-C(S)-T12-,
(5) -T11-O-T12-,
(6) -T11-S-T12-,
(7) -T11-O—C(O)-T2-,
(8) -T11-C(O)—O-T12-,
(9) -T11-C(═NT9a)-T12-, or
(10) -T11-C(O)—C(O)-T12-;
T7, T8, T9, T9a and T10
(1) are independently hydrogen or a group provided in the definition of T6; and
T11 and T12 are independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene;
(xiv) a compound of formula xiv
Figure US20090312307A1-20091217-C01132
enantiomers, diastereomers, and salts thereof wherein
m and p are independently 0, 1, or 2 provided that the sum of m and p is 2;
Q is NR1;
R1 is
Figure US20090312307A1-20091217-C01133
R2 is aryl, which may be optionally independently substituted with one or more groups T1, T2 or T3;
J is a bond or C1-4 alkylene optionally independently substituted with one or more groups T1a, T2a or T3a;
R3 is —R5;
R4 is alkyl or aryl, both of which may be optionally independently substituted with one or more groups T1b, T2b or T3b;
R5 is —NR6aR7a;
R6a is indazolyl, which may be optionally independently substituted with one or more groups T1d, T2d or T3d;
R7a is H;
RX is one or more optional substituents, attached to any available ring carbon atom, independently selected from T1g, T2g or T3g; and
T1-1g, T2-2g and T3-3g are each independently hydrogen, alkyl, haloalkyl, aryl, —OH, -Oalkyl or halo.
2. A compound of claim 1 wherein
Q is NR1 or O;
R1 is H,
Figure US20090312307A1-20091217-C01134
—C(═S)R8c, C(═NR8b)R8c or heteroaryl;
R2 is aryl, (aryl)alkyl or heteroaryl any of which may be optionally independently substituted with one or more groups T1, T2 or T3;
J is a bond or methylene; and
R3 is R5,
Figure US20090312307A1-20091217-C01135
provided said compound is other than:
(i) a compound wherein Q is NR1; R1 is
Figure US20090312307A1-20091217-C01136
 J is a bond or methylene; and R3 is
Figure US20090312307A1-20091217-C01137
 or
(ii) a compound wherein Q is NR1; R1 is
Figure US20090312307A1-20091217-C01138
 R2 is aryl, which may be optionally independently substituted with one or more groups T1, T2 or T3; J is a bond or methylene; and R3 is R5.
3. A compound of claim 2 wherein
Q is NR1;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, (aryl)alkyl, heteroaryl or (heteroaryl)alkyl any of which may be optionally independently substituted with one or more T1b, T2b T3b;
R5 is
(a) —NR6aR7a, or
(b) aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo or (heterocyclo)alkyl any of which may be optionally independently substituted with one or more T1c, T2c T3c;
R6, R6a, R7 and R7a are independently H, alkyl, alkenyl, alkynyl, aryl, (aryl)alkyl, (alkoxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, (hydroxy)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, (aryloxy)alkyl, —C(O)R9, —CO2R9, or —C(O)—NR9R10 any of which may be optionally independently substituted with one or more T1d, T2d T3d;
or R6 and R7 or R6a and R7a together with the nitrogen atom to which they are attached combine to form an optionally substituted 4 to 8 membered heterocyclo ring optionally independently substituted with one or more groups T1d, T2d or T3d;
R8a is H, alkyl, or (aryl)alkyl where the alkyl and aryl groups may be optionally independently substituted with one or more groups T1d, T2d or T3d;
R8c is
(a) alkyl, aryl, heteroaryl any of which may be optionally independently substituted with one or more T1d, T2d T3d; or
(b) —NR9R10;
W is ═N—CN; and
Z1 is ═O or N—CN;
provided said compound is other than:
(i) a compound wherein:
R5 is
Figure US20090312307A1-20091217-C01139
R6 and R7 are independently H, alkyl, alkenyl, alkynyl, aryl, (aryl)alkyl, (alkoxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, (hydroxy)alkyl, (aryloxy)alkyl, —C(O)R9, —CO2R9, or —C(O)—NR9R10 any of which may be optionally independently substituted with one or more groups T1d, T2d or T3d;
R8a is H, alkyl, or (aryl)alkyl where the alkyl and aryl groups may be optionally independently substituted with one or more groups T1d, T2d or T3d;
R8c is
(a) alkyl or aryl, any of which may be optionally independently substituted with one or more groups T1d, T2d or T3d; or
(b) —NR9R10; and
Z1 is ═O; or
(ii) a compound wherein Q is NR1; R4 is alkyl which may be optionally independently substituted with one or more T1b, T2b T3b; R5 is —NR6aR7a; R6a is indazolyl, which may be optionally substituted with one or more groups T1d, T2d or T3d; and R7a is H.
4. A compound of claim 3 wherein T1, T1b, T1c, T1d, T2, T2b, T2c, T2d, T3, T3b, T3c and T3d are independently halo, cyano, alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, haloalkyl, —OH, —OT6, —C(O)tT6, —SO2T6, -T4NT7T8, or -T4N(T10)T5-T6.
5. A compound of claim 1 wherein:
R1* is
Figure US20090312307A1-20091217-C01140
 —C(═NR8b)R8c, —OC(O)CCl3, —C(═S)R8c, optionally substituted heterocyclo, cyano, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, or optionally substituted heteroaryloxy; and
R3 is
Figure US20090312307A1-20091217-C01141
provided said compound is other than a compound wherein;
Figure US20090312307A1-20091217-C01142
wherein
R8c is selected from H, —NR9R10, or alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, aryloxy, any of which may be optionally independently substituted with one or more groups T1d, T2d or T3d as defined hereinabove;
R9 and R10 are H or alkyl;
T1, T2 and T3 may each be present or absent and each may be selected from halo, —CF3 or —CN; and
T1c is selected from H or —NH2.
6. The compound of claim 1 where at least one of T1c, T2c or T3c is alkoxy.
7. A compound of claim 1 having the structure
Figure US20090312307A1-20091217-C01143
where R3** is heteroaryl or (heteroaryl)alkyl, either of which may be optionally substituted with one or more groups T1c, T2c or T3c.
8. A pharmaceutical composition comprising at least one compound of claim 1 together with a suitable vehicle or carrier therefor.
9. A pharmaceutical composition of claim 11 further comprising at least one additional therapeutic agent selected from anti-arrhythmic agents, calcium channel blockers, anti-platelet agents, anti-hypertensive agents, anti-thrombotic/anti-thrombolytic agents, anti-coagulants, HMG-CoA reductase inhibitors, anti-diabetic agents, thyroid mimetics, mineralocorticoid receptor antagonists, or cardiac glycosides.
10. The pharmaceutical composition of claim 12 wherein
(a) the additional anti-arrhythmic agent is selected from sotalol, dofetilide, diltiazem and verapamil;
(b) the anti-platelet agent is selected from clopidogrel, ifetroban and aspirin;
(c) the anti-hypertensive agent is selected from beta adrenergic blockers, ACE inhibitors, A II antagonists, ET antagonists, Dual ET/A II antagonists, and vasopepsidase inhibitors;
(d) the anti-thrombotic/anti-thrombolytic agent is selected from tPA, recombinant tPA, TNK, nPA, factor VIIa inhibitors, factor Xa inhibitors and thrombin inhibitors;
(e) the anti-coagulant is selected from warfarin and heparins;
(f) the HMG-CoA reductase inhibitor is selected from pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 and ZD-4522;
(g) the anti-diabetic agent is selected from biguanides and biguanide/glyburide combinations;
(h) the mineralocorticoid receptor antagonist is selected from spironolactone and eplerinone; and
(i) the cardiac glycoside is selected from digitalis and ouabain.
11. The pharmaceutical composition of claim 13 wherein
(a) the ACE inhibitors are selected from captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, and lisinopril; and
(b) the vasopepsidase inhibitors are selected from omapatrilat and gemopatrilat.
12. A method of treating IKur-associated disorders comprising the step of administering to a patient in need thereof an effective amount of at least one compound of claim 1.
13. The method of claim 12 wherein the IKur-associated condition is arrhythmia.
14. The method of claim 13 wherein the arrhythmia is a supraventricular arrhythmia.
15. The method of claim 14 wherein the supraventricular arrhythmia is atrial fibrillation.
16. The method of claim 14 wherein the supraventricular arrhythmia is atrial flutter.
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