# Patent

## Title
Potassium channel inhibitors

## Abstract

The present invention relates to compounds having the structure useful as potassium channel inhibitors to treat cardiac arrhythmias, and the like.

## Background
CROSS REFERENCE TO RELATED APPLICATION
This application is a U.S. National Phase application under 35 U.S.C. §371 of PCT Application Ser. No. PCT/US2005/026868, filed Jul. 27, 2005, which claims priority under 35 U.S.C. §119(e) from U.S. Provisional Application Ser. No. 60/592,177, filed Jul. 29, 2004.


BACKGROUND OF THE INVENTION
The present invention relates broadly to compounds that are useful as potassium channel inhibitors. Compounds in this class may be useful as Kv1.5 antagonists for treating and preventing cardiac arrhythmias, and the like.
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice and is likely to increase in prevalence with the aging of the population. While AF is rarely fatal, it can impair cardiac function and lead to complications such as the development of congestive heart failure, thromboembolism, or ventricular fibrillation.
Currently available antiarrhythmic agents have been developed for the treatment of ventricular and atrial/supraventricular arrhythmias. Malignant ventricular arrhythmias are immediately life-threatening and require emergency care. Drug therapy for ventricular arrhythmia includes Class Ia (eg. procainamide, quinidine), Class Ic (eg. flecamide, propafenone), and Class III (amiodarone) agents, which pose significant risks of proarrhythmia. These Class I and III drugs have been shown to convert AF to sinus rhythm and to prevent recurrence of AF (Mounsey, J P, DiNarco, J P, Circulation, 102:2665-2670), but pose an unacceptable risk of potentially lethal ventricular proarrhythmia and thus may increase mortality (Pratt, C M, Moye, L A, Am J Cardiol., 65:20 B-29B, 1990; Waldo et al, Lancet, 348:7-12, 1996; Torp-Pedersen et al, Expert Opin. Invest. Drugs, 9:2695-2704, 2000). These observations demonstrate a clear unmet medical need to develop safer and more efficacious drugs for the treatment of atrial arrhythmias. Class III antiarrhythmic agents cause a selective prolongation of the APD without significant depression of cardiac conduction or contractile function. The only selective Class III drug approved for clinical use in atrial fibrillation is dofetilide, which mediates its anti-arrhythmic effects by blocking IKr, the rapidly activating component of IK found in both atrium and ventricle in humans (Mounsey, J P, DiMarco, J P, Circulation, 102:2665-2670). Since IKr blockers increase APD and refractoriness both in atria and ventricle without affecting conduction per se, theoretically they represent potentially useful agents for the treatment of arrhythmias like AF (Torp-Pedersen, et al, Expert Opin. Invest. Drugs, 9:2695-2704, 2000). However, these agents have the major liability of an enhanced risk of proarrhythmia at slow heart rates.
The ultrarapid delayed rectifier K+ current, IKur, has been observed specifically in human atrium and not in ventricle. The molecular correlate of IKur in the human atrium is the potassium channel designated Kv1.5. 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 shortcoming of other compounds by prolonging refractoriness through retardation of the repolarization in the human atrium without causing the delays in ventricular repolarization that underlie arrhythmogenic afterdepolarizations and acquired long QT syndrome observed during treatment with current Class III drugs. Kv1.5 blockers exhibiting these properties have been described (Peukert et al, J. Med. Chem., 46:486-498, 2003; Knobloch et al, Naunyn-Schmedieberg's Arch. Pharmacol. 366:482-287, 2002; Merck & Co., Inc. WO0224655, 2002).
The compounds described in this invention represent a novel structural class of Kv1.5 antagonist.
SUMMARY OF THE INVENTION
The invention concerns compounds of formula I which antagonize the Kv1.5 potassium channel:




The compounds of this invention are useful in the treatment and prevention of cardiac arrhythmias, and the like. Also within the scope of this invention are pharmaceutical formulations comprising a compound of Formula I and a pharmaceutical carrier.


DETAILED DESCRIPTION OF THE DISCLOSURE
The invention includes compounds of formula I:




or a pharmaceutically acceptable salt, wherein:

    A is selected from the group consisting of
    
        1) an aryl ring,
        2) a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, and the heteroaryl ring is selected from the group consisting of:
        
            a) a 5-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S,
            b) a 6-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S, and
            c) an 8-, 9- or 10-membered unsaturated bicyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S;
        
        
        3) C1-C10 alkyl, wherein any stable atom is independently unsubstituted or substituted with a group selected from R4,
        4) a C3-C10 cycloalkyl ring, wherein any stable ring atom is independently unsubstituted or substituted with a group selected from R4, and
        5) a 4-6 membered saturated heterocyclic ring with 1, 2 or 3 heteroatom ring atoms selected from the group consisting of N, O and S, said aryl, heteroaryl, cycloalkyl, and saturated heterocyclic ring is unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein any stable S or N heteroaryl or heterocyclic ring atom is unsubstituted or substituted with oxo;
    
    
    B is a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, and wherein the heteroaryl ring is selected from the group consisting of
    
        a) a 5-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S,
        b) a 6-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S, and
        c) an 8-, 9- or 10-membered unsaturated bicyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S;
        said heteroaryl ring is unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein any stable S or N heteroaryl ring atom is unsubstituted or substituted with oxo;
    
    
    C is selected from the group consisting of
    
        1) an aryl ring, wherein any stable aryl ring atom is independently unsubstituted or substituted with a group selected from R4,
        2) a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, and the heteroaryl ring is selected from the group consisting of:
        
            a) a 5-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S,
            b) a 6-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S, and
            c) an 8-, 9- or 10-membered unsaturated bicyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S;
        
        
        3) a C3-C10 cycloalkyl ring, wherein any stable ring atom is independently unsubstituted or substituted with a group selected from R4,
        4) a 4-6 membered saturated heterocyclic ring with 1, 2 or 3 heteroatom ring atoms selected from the group consisting of N, O and S, wherein any stable ring atom is independently unsubstituted or substituted with a group selected from R4,
        5) C1-C10 alkyl, wherein any stable atom is independently unsubstituted or substituted with a group selected from R4,
        6) C(O)R5,
        7) C(O)OR5, and
        8) C(O)N(R5)2, wherein two R5 groups can be linked to form a ring, said aryl, heteroaryl, cycloalkyl, and saturated heterocyclic ring is unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein any stable S or N heteroaryl or heterocyclic ring atom is unsubstituted or substituted with oxo;
    
    
    X is selected from the group consisting of H, OR5, NR5R5, F, CN, S(O)0-2R5, C(O)OR5, and C(O)N(R5)2;
    Y is selected from the group consisting of






    
    
        13) a nitrogen-containing heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a nitrogen atom, and wherein the heteroaryl ring is selected from the group consisting of:
        
            a) a 5-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S,
            b) a 6-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S, and
            c) an 8-, 9- or 10-membered unsaturated bicyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S;
        
        
        said nitrogen-containing heteroaryl ring is unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein any stable S or N heteroaryl or heterocyclic ring atom is unsubstituted or substituted with oxo;
    
    
    G, each time it occurs, is independently selected from the group consisting of H2 and O;
    Z is selected from the group consisting of C(R6)2, NR5, NC(O)R5, NC(O)OR5, NC(O)N(R5)2, NS(O)1-2R5, S(O)0-2, —N(R5)C(O)—, —C(R5)═C(R6)— and O;
    Ra, in each instance in which it appears, is independently selected from the group consisting of
    
        1) hydrogen,
        2) C1-C6 alkyl,
        3) halogen,
        4) aryl,
        5) heterocycle,
        6) C3-C10 cycloalkyl, and
        7) OR5,
        said alkyl, aryl, heterocycle and cycloalkyl is unsubstituted or substituted with at least one substituent selected from R6;
    
    
    R2 and R3 are independently selected from the group consisting of
    
        1) hydrogen,
        2) (CRa2)nOR5,
        3) (CRa2)nN(R5)2,
        4) (CRa2)nC(O)R5,
        5) (CRa2)nC(O)OR5,
        6) (CRa2)nR5,
        7) (CRa2)nS(O)mR5,
        8) (CRa2)nS(O)mN(R5)2,
        9) C(O)R5,
        10) C(O)OR5,
        11) C(O)N(R5)2,
        12) S(O)mR5,
        13) S(O)mN(R5)2,
        14) (CRa2)nN(R5)(CRa2)nC(O)N(R5)2,
        15) (CRa2)nC(O)N(R5)2,
        16) (CRa2)nN(R5)(CRa2)nC(O)OR5, and
        17) (CRa2)nN(R5)S(O)mR5;
    
    
    R4, in each instance in which it appears, is independently selected from the group consisting of
    
        1) hydrogen,
        2) halogen,
        3) NO2,
        4) CN,
        5) CR4═C(R5)2,
        6) C≡CR5,
        7) (CRa2)nOR5,
        8) (CRa2)nN(R5)2,
        9) (CRa2)nC(O)R5,
        10) (CRa2)nC(O)OR5,
        11) (CRa2)nR5,
        12) (CRa2)nS(O)mR5,
        13) (CRa2)nS(O)mN(R5)2,
        14) OS(O)mR5,
        15) N(R5)C(O)R5,
        16) N(R5)S(O)mR5,
        17) (CRa2)nN(R6)R5,
        18) (CRa2)nN(R5)(CRa2)nC(O)N(R5)2,
        19) (CRa2)nN(R5)(CRa2)nC(O)OR5,
        20) N(R5)(CRa2)nR5,
        21) N(R5)(CRa2)nN(R5)2, and
        22) (CRa2)nC(O)N(R5)2;
    
    
    R5, in each instance in which it appears, is independently selected from the group consisting of
    
        1) hydrogen,
        2) unsubstituted or substituted C1-C6 alkyl,
        3) unsubstituted or substituted C3-C10 cycloalkyl,
        4) unsubstituted or substituted aryl,
        5) unsubstituted or substituted heterocycle,
        6) CF3,
        7) unsubstituted or substituted C2-C6 alkenyl, and
        8) unsubstituted or substituted C2-C6 alkynyl,
        or in the case where R5 is attached to a nitrogen atom that is disubstituted with R5, each R5 is independently selected from C1-C6 alkyl, and the nitrogen atom together with each R5 form a ring;
    
    
    R6, in each instance in which it appears, is independently selected from the group consisting of
    
        1) hydrogen,
        2) unsubstituted or substituted C1-C6 alkyl,
        3) halogen,
        4) OR5,
        5) CF3,
        6) unsubstituted or substituted aryl,
        7) unsubstituted or substituted C3-C10 cycloalkyl,
        8) unsubstituted or substituted heterocycle,
        9) S(O)mN(R5)2,
        10) C(O)OR5,
        11) C(O)R5,
        12) CN,
        13) C(O)N(R5)2,
        14) N(R5)C(O)R5,
        15) N(R5)C(O)OR5,
        16) N(R5)C(O)N(R5)2,
        17) OC(O)N(R5)2,
        18) S(O)mR5,
        19) OS(O)mR5,
        20) NO2,
        21) N(R5)2;
        22) SC(O)R5,
        23) N(R5)S(O)mR5,
    
    
    R7 is independently selected from the group consisting of
    
        1) S(O)mN(R5)2,
        2) C(O)OR5,
        3) C(O)R5,
        4) C(O)N(R5)2, and
        5) S(O)mR5;
    
    
    m is independently 0, 1 or 2;
    n is independently 0, 1, 2, 3, 4, 5 or 6;
    u is 0, 1 or 2; and
    v is 0, 1 or 2.


An embodiment of the invention is a compound or a pharmaceutically acceptable salt there of wherein

    B is a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, and wherein the heteroaryl ring is selected from the group consisting of pyridine and pyrimidine, wherein the heteroaryl ring is unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein the N heteroaryl ring atom is unsubstituted or substituted with oxo; and
    X is selected from the group consisting of hydrogen, OH, OCH3 and F.


A preferred embodiment of the invention is a compound or a pharmaceutically acceptable salt thereof wherein

    A is selected from the group consisting of
    
        1) a phenyl ring,
        2) a pyridyl ring, wherein the point of attachment to the pyridyl ring is a carbon atom, and
        3) C1-C10 alkyl, wherein any stable atom is independently unsubstituted or substituted with a group selected from R4,
        wherein the phenyl ring and pyridyl ring are unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein the N pyridyl ring atom is unsubstituted or substituted with oxo; and
    
    
    C is selected from the group consisting of
    
        1) an aryl ring, wherein any stable aryl ring atom is independently unsubstituted or substituted with a group selected from R4,
        2) a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, and the heteroaryl ring is selected from the group consisting of:
        
            a) a 5-membered unsaturated monocyclic ring with 1, 2, or 3 heteroatom ring atoms selected from the group consisting of N, O or S,
            b) a 6-membered unsaturated monocyclic ring with 1 or 2 N atoms, and
            c) an 8-, 9- or 10-membered unsaturated bicyclic ring with 1 or 2 heteroatom ring atoms selected from the group consisting of N, O or S,
        
        
        wherein any stable atom is independently unsubstituted or substituted with a group selected from R4;
        3) a cyclopropyl ring, wherein any stable ring atom is independently unsubstituted or substituted with a group selected from R4,
        4) a 4-6 membered saturated heterocyclic ring with 1 or 2 heteroatom ring atoms selected from the group consisting of N and O, wherein any stable ring atom is independently unsubstituted or substituted with a group selected from R4, and
        5) C1-C6 alkyl, wherein any stable atom is independently unsubstituted or substituted with a group selected from R4.
    
    


A more preferred embodiment of the invention is a compound or a pharmaceutically acceptable salt thereof wherein

    B is a pyridyl ring, wherein the point of attachment to the pyridyl ring is a carbon atom, and wherein the pyridyl ring is unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein the N atom is unsubstituted or substituted with oxo;
    X is selected from the group consisting of hydrogen, OH, OCH3 and F;
    A is selected from the group consisting of
    
        1) a phenyl ring,
        2) a pyridyl ring, wherein the point of attachment to the pyridyl ring is a carbon atom, and
        3) —C(CH3)3,
        wherein the phenyl ring and pyridyl ring are unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein the N pyridyl ring atom is unsubstituted or substituted with oxo;
    
    
    C is selected from the group consisting of












    Y is selected from the group consisting of







































Another embodiment of the invention includes compounds of formula I:




wherein:

    A is selected from the group consisting of
    
        1) an aryl ring,
        2) a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, and the heteroaryl ring is selected from the group consisting of:
        
            a) a 5-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S,
            b) a 6-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S, and
            c) an 8-, 9- or 10-membered unsaturated bicyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S;
        
        
        3) C1-C10 alkyl, wherein any stable atom is independently unsubstituted or substituted with a group selected from R4,
        4) a C3-C10 cycloalkyl ring, wherein any stable ring atom is independently unsubstituted or substituted with a group selected from R4, and
        5) a 4-6 membered saturated heterocyclic ring with 1, 2 or 3 heteroatom ring atoms selected from the group consisting of N, O and S,
        said aryl, heteroaryl, cycloalkyl, and saturated heterocyclic ring is unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein any stable S or N heteroaryl or heterocyclic ring atom is unsubstituted or substituted with oxo;
    
    
    B is a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, and wherein the heteroaryl ring is selected from the group consisting of
    
        a) a 5-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S,
        b) a 6-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S, and
        c) an 8-, 9- or 10-membered unsaturated bicyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S;
        said heteroaryl ring is unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein any stable S or N heteroaryl ring atom is unsubstituted or substituted with oxo;
    
    
    C is selected from the group consisting of
    
        1) an aryl ring, wherein any stable aryl ring atom is independently unsubstituted or substituted with a group selected from R4,
        2) a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, and the heteroaryl ring is selected from the group consisting of:
        
            a) a 5-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S,
            b) a 6-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S, and
            c) an 8-, 9- or 10-membered unsaturated bicyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S;
        
        
        3) a C3-C10 cycloalkyl ring, wherein any stable ring atom is independently unsubstituted or substituted with a group selected from R4,
        4) a 4-6 membered saturated heterocyclic ring with 1, 2 or 3 heteroatom ring atoms selected from the group consisting of N, O and S, wherein any stable ring atom is independently unsubstituted or substituted with a group selected from R4,
        5) C1-C10 alkyl, wherein any stable atom is independently unsubstituted or substituted with a group selected from R4,
        6) C(O)R5,
        7) C(O)OR5, and
        8) C(O)N(R5)2, wherein two R5 groups can be linked to form a ring,
        said aryl, heteroaryl, cycloalkyl, and saturated heterocyclic ring is unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein any stable S or N heteroaryl or heterocyclic ring atom is unsubstituted or substituted with oxo;
    
    
    X is selected from the group consisting of H, OR5, NR5R5, F, CN, S(O)0-2R5, C(O)ORS, and C(O)N(R5)2;
    Y is selected from the group consisting of






    
    
        12) a nitrogen-containing heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a nitrogen atom, and wherein the heteroaryl ring is selected from the group consisting of:
        
            a) a 5-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S,
            b) a 6-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S, and
            c) an 8-, 9- or 10-membered unsaturated bicyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S;
        
        
        said nitrogen-containing heteroaryl ring is unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein any stable S or N heteroaryl or heterocyclic ring atom is unsubstituted or substituted with oxo;
    
    
    G is selected from the group consisting of H2 and O;
    Z is selected from the group consisting of C(R6)2, NR5, NC(O)R5, NC(O)OR5, NC(O)N(R5)2, NS(O)1-2R5, S(O)0-2, —N(R5)C(O)—, —C(R5)═C(R6)— and O;
    Ra, in each instance in which it appears, is independently selected from the group consisting of
    
        1) hydrogen,
        2) C1-C6 alkyl,
        3) halogen,
        4) aryl,
        5) heterocycle,
        6) C3-C10 cycloalkyl, and
        7) OR5,
         said alkyl, aryl, heterocycle and cycloalkyl is unsubstituted or substituted with at least one substituent selected from R6;
    
    
    R2 and R3 are independently selected from the group consisting of
    
        1) hydrogen,
        2) (CRa2)nOR5,
        3) (CRa2)nN(R5)2,
        4) (CRa2)nC(O)R5,
        5) (CRa2)nC(O)OR5,
        6) (CRa2)nR5,
        7) (CRa2)nS(O)mR5,
        8) (CRa2)nS(O)mN(R5)2,
        9) C(O)R5,
        10) C(O)OR5,
        11) C(O)N(R5)2,
        12) S(O)mR5,
        13) S(O)mN(R5)2,
        14) (CRa2)nN(R5)(CRa2)nC(O)N(R5)2, and
        15) (CRa2)nC(O)N(R5)2;
    
    
    R4, in each instance in which it appears, is independently selected from the group consisting of
    
        1) hydrogen,
        2) halogen,
        3) NO2,
        4) CN,
        5) CR4═C(R5)2,
        6) C≡CR5,
        7) (CRa2)nOR5,
        8) (CRa2)nN(R5)2,
        9) (CRa2)nC(O)R5,
        10) (CRa2)nC(O)OR5,
        11) (CRa2)nR5,
        12) (CRa2)nS(O)mR5,
        13) (CRa2)nS(O)mN(R5)2,
        14) OS(O)mR5,
        15) N(R5)C(O)R5,
        16) N(R5)S(O)mR5,
        17) (CRa2)nN(R6)R5,
        18) (CRa2)nN(R5)(CRa2)nC(O)N(R5)2,
        19) (CRa2)nN(R5)(CRa2)nC(O)OR5,
        20) N(R5)(CRa2)nR5,
        21) N(R5)(CRa2)nN(R5)2, and
        22) (CRa2)nC(O)N(R5)2;
    
    
    R5, in each instance in which it appears, is independently selected from the group consisting of
    
        1) hydrogen,
        2) unsubstituted or substituted C1-C6 alkyl,
        3) unsubstituted or substituted C3-C10 cycloalkyl,
        4) unsubstituted or substituted aryl,
        5) unsubstituted or substituted heterocycle,
        6) CF3,
        7) unsubstituted or substituted C2-C6 alkenyl, and
        8) unsubstituted or substituted C2-C6 alkynyl,
        or in the case where R5 is attached to a nitrogen atom that is disubstituted with R5, each R5 is independently selected from C1-C6 alkyl, and the nitrogen atom together with each R5 form a ring;
    
    
    R6, in each instance in which it appears, is independently selected from the group consisting of
    
        1) hydrogen,
        2) unsubstituted or substituted C1-C6 alkyl,
        3) halogen,
        4) OR5,
        5) CF3,
        6) unsubstituted or substituted aryl,
        7) unsubstituted or substituted C3-C10 cycloalkyl,
        8) unsubstituted or substituted heterocycle,
        9) S(O)mN(R5)2,
        10) C(O)OR5,
        11) C(O)R5,
        12) CN,
        13) C(O)N(R5)2,
        14) N(R5)C(O)R5,
        15) N(R5)C(O)OR5,
        16) N(R5)C(O)N(R5)2,
        17) OC(O)N(R5)2,
        18) S(O)mR5,
        19) OS(O)mR5,
        20) NO2, and
        21) N(R5)2;
    
    
    R7 is independently selected from the group consisting of
    
        1) S(O)mN(R5)2,
        2) C(O)OR5,
        3) C(O)R5,
        4) C(O)N(R5)2, and
        5) S(O)mR5;
    
    
    m is independently 0, 1 or 2;
    n is independently 0, 1, 2, 3, 4, 5 or 6;
    u is 0, 1 or 2; and
    v is 0, 1 or 2.


An embodiment of the invention is a compound wherein

    B is a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, and wherein the heteroaryl ring is selected from the group consisting of pyridine and pyrimidine, wherein the heteroaryl ring is unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein the N heteroaryl ring atom is unsubstituted or substituted with oxo; and
    X is selected from the group consisting of hydrogen, OH, OCH3 and F.


A preferred embodiment of the invention is a compound wherein

    A is selected from the group consisting of
    
        1) a phenyl ring,
        2) a pyridyl ring, wherein the point of attachment to the pyridyl ring is a carbon atom, and
        3) C1-C10 alkyl, wherein any stable atom is independently unsubstituted or substituted with a group selected from R4,
        wherein the phenyl ring and pyridyl ring are unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein the N pyridyl ring atom is unsubstituted or substituted with oxo; and
    
    
    C is selected from the group consisting of
    
        1) an aryl ring, wherein any stable aryl ring atom is independently unsubstituted or substituted with a group selected from R4,
        2) a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, and the heteroaryl ring is selected from the group consisting of:
        
            a) a 5-membered unsaturated monocyclic ring with 1, 2, or 3 heteroatom ring atoms selected from the group consisting of N, O or S,
            b) pyridine, and
            c) an 8-, 9- or 10-membered unsaturated bicyclic ring with 1 or 2 heteroatom ring atoms selected from the group consisting of N, O or S;
        
        
        3) a cyclopropyl ring, wherein any stable ring atom is independently unsubstituted or substituted with a group selected from R4,
        4) a 4-6 membered saturated heterocyclic ring with 1 or 2 heteroatom ring atoms selected from the group consisting of N and O, wherein any stable ring atom is independently unsubstituted or substituted with a group selected from R4, and
        5) C1-C6 alkyl, wherein any stable atom is independently unsubstituted or substituted with a group selected from R4.
    
    


A more preferred embodiment of the invention is a compound wherein

    B is a pyridyl ring, wherein the point of attachment to the pyridyl ring is a carbon atom, and wherein the pyridyl ring is unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein the N atom is unsubstituted or substituted with oxo;
    X is selected from the group consisting of hydrogen, OH, OCH3 and F;
    A is selected from the group consisting of
    
        1) a phenyl ring,
        2) a pyridyl ring, wherein the point of attachment to the pyridyl ring is a carbon atom, and
        3) —C(CH3)3,
        wherein the phenyl ring and pyridyl ring are unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein the N pyridyl ring atom is unsubstituted or substituted with oxo;
    
    
    C is selected from the group consisting of












    Y is selected from the group consisting of






























An example of a compound of the invention is a compound selected from the group consisting of

    (±)-2-Morpholin-4-yl-2-phenyl-1,1-dipyridin-3-yl-ethanol,
    (±)-3-methyl-2-morpholin-4-yl-1,1-dipyridin-3-ylbutan-1-ol,
    (±)-2-[(2-methoxyethyl)(methyl)amino]-2-phenyl-1,1-dipyridin-3-ylethanol,
    (±)-2-phenyl-2-piperidin-1-yl-1,1-dipyridin-3-ylethanol,
    (±)-2-phenyl-1,1-dipyridin-3-yl-2-pyrrolidin-1-ylethanol,
    (±)-tert-butyl 4-(2-hydroxy-1-phenyl-2,2-dipyridin-3-ylethyl)piperazine-1-carboxylate,
    2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-2-phenyl-1,1-dipyridin-3-ylethanol,
    (±)-2-(1,4-oxazepan-4-yl)-2-phenyl-1,1-dipyridin-3-ylethanol,
    (±)-2-phenyl-1,1-dipyridin-3-yl-2-thiomorpholin-4-ylethanol,
    (±)-2-(diethylamino)-2-phenyl-1,1-dipyridin-3-ylethanol,
    (±)-2-(7-azabicyclo[2.2.1]hept-7-yl)-2-phenyl-1,1-dipyridin-3-ylethanol,
    (±)-2-(3,3-difluoropyrrolidin-1-yl)-2-phenyl-1,1-dipyridin-3-ylethanol,
    (±)-2-phenyl-1,1-dipyridin-3-yl-2-[2-(trifluoromethyl)pyrrolidin-1-yl]ethanol,
    (±)-2-(2-isopropylpyrrolidin-1-yl)-2-phenyl-1,1-dipyridin-3-ylethanol,
    (2R)-2-cyclopropyl-1,1-dipyridin-3-yl-2-pyrrolidin-1-ylethanol,
    (±)-2-[cyclobutyl(ethyl)amino]-2-phenyl-1,1-dipyridin-3-ylethanol,
    (±)-2-[ethyl(2,2,2-trifluoroethyl)amino]-2-phenyl-1,1-dipyridin-3-ylethanol,
    (±)-2-(3-fluoropyrrolidin-1-yl)-2-phenyl-1,1-dipyridin-3-ylethanol,
    (±)-2-morpholin-4-yl-1,2-diphenyl-1-pyridin-2-yl-ethanol,
    2-morpholin-4-yl-2-phenyl-1-pyridin-2-yl-1-pyridin-3-ylethanol,
    (±)-2-phenyl-2-(phenylsulfonyl)-1,1-dipyridin-3-ylethanol,
    (±)-2-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-1,1-dipyridin-3-yl-2-pyrrolidin-1-ylethanol,
    (±)-1,2-diphenyl-2-(1H-pyrazol-1-yl)-1-pyridin-4-ylethanol,
    (±)-3-(2-hydroxy-1-phenyl-2,2-dipyridin-3-ylethyl)-1,3-oxazolidin-2-one,
    (±)-3-[2-hydroxy-1-(2-oxo-1,3-oxazolidin-3-yl)-2,2-dipyridin-3-ylethyl]benzonitrile,
    (±)-1-[1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]-3-methylimidazolidin-2-one,
    (±)-1-tert-butyl-3-[1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]imidazolidin-2-one,
    (±)-3-(2-hydroxy-1-pyridin-2-yl-2,2-dipyridin-3-ylethyl)-1,3-oxazolidin-2-one,
    (±)-2-(1H-pyrazol-1-yl)-2-pyridin-2-yl-1,1-dipyridin-3-ylethanol,
    (±)-2-(1H-pyrazol-1-yl)-1,1,2-tripyridin-3-ylethanol,
    (±)-1,1,2-tripyridin-3-yl-2-(1H-1,2,3-triazol-1-yl)ethanol,
    (±)-4-[2-hydroxy-2,2-dipyridin-3-yl-1-(2H-1,2,3-triazol-2-yl)ethyl]benzonitrile,
    (±)-3-[2-hydroxy-2,2-dipyridin-3-yl-1-(1H-1,2,3-triazol-1-yl)ethyl]benzonitrile,
    (±)-(1-benzyl-1H-pyrazol-5-yl)(dipyridin-3-yl)methanol,
    (±)-1-[1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]pyridin-2(1H)-one,
    (±)-1-[1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]pyrazin-2(1H)-one,
    (±)-2-[1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]pyridazin-3(2H)-one,
    (R)-1-(2-hydroxy-1-pyridin-2-yl-2,2-dipyridin-3-ylethyl)pyridin-2(1H)-one,
    (S)-1-(2-hydroxy-1-pyridin-2-yl-2,2-dipyridin-3-ylethyl)pyridin-2(1H)-one,
    (±)-3-(2-hydroxy-2,2-dipyridin-3-yl-1-pyrrolidin-1-ylethyl)benzonitrile,
    (±)-2-(4-fluorophenyl)-1,1-dipyridin-3-yl-2-pyrrolidin-1-ylethanol,
    (±)-2-(3-methoxyphenyl)-1,1-dipyridin-3-yl-2-pyrrolidin-1-ylethanol,
    2-[(2r)-2-(methoxymethyl)pyrrolidin-1-yl]-2-phenyl-1,1-dipyridin-3-ylethanol,
    (±)-2-(3-bromophenyl)-1,1-dipyridin-3-yl-2-pyrrolidin-1-ylethanol,
    (±)-2-(3,3-difluoroazetidin-1-yl)-2-(4-fluorophenyl)-1,1-dipyridin-3-ylethanol,
    (±)-2-(5-chloro-2-thienyl)-1,1-dipyridin-3-yl-2-pyrrolidin-1-ylethanol,
    2-[(3R,4R)-3,4-difluoropyrrolidin-1-yl]-2-phenyl-1,1-dipyridin-3-ylethanol,
    (±)-1-(2-hydroxy-1-phenyl-2,2-dipyridin-3-ylethyl)piperidin-3-ol,
    2-(4-fluorophenyl)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-1,1-dipyridin-3-ylethanol,
    (±)-2-(cyclobutylamino)-2-(4-fluorophenyl)-1,1-dipyridin-3-ylethanol,
    (±)-2-phenyl-1,1-dipyridin-3-yl-2-[(2,2,2-trifluoroethyl)-amino]ethanol,
    2-(benzyloxy)-N-[(1R)-2-hydroxy-1-phenyl-2,2-dipyridin-3-ylethyl]acetamide,
    N-[(1R)-1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]-3-pyridin-2-yl-1H-pyrazole-5-carboxamide,
    N-[(1R)-1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]-4-phenylbutanamide, benzyl[(1R)-1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]carbamate,
    N-[(1R)-1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]-1-phenyl-1H-pyrazole-4-carboxamide,
    (±)-2-phenyl-1,1-dipyridin-3-yl-2-(1H-pyrrol-1-yl)ethanol,
    (±)-3-(2-hydroxy-1-morpholin-4-yl-2,2-dipyridin-3-ylethyl)benzonitrile,
    (±)-3,3′-(1-fluoro-2-phenyl-2-pyrrolidin-1-ylethane-1,1-diyl)dipyridine,
    (±)-1-[1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]azetidin-3-ol,
    (±)-1-[1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]azetidin-3-yl phenylcarbamate,
    (±)-2-(3,3-difluoroazetidin-1-yl)-2-(4-fluorophenyl)-1-(1-oxidopyridin-3-yl)-1-pyridin-3-ylethanol,
    (±)-4-[1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethyl]morpholine,
    (±)-N-[1-(4-fluorophenyl)-2-phenyl-2-pyridin-3-ylethyl]-2-methoxyacetamide,
    (±)-4-[1-(4-fluorophenyl)-2-phenyl-2-pyridin-3-ylethyl]morpholine,
    (±)-1-[1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]pyrrolidin-2-one,
    (±)-4-[1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]morpholine,
    (±)-[1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl](2,2,2-trifluoroethyl)amine,
    (±)-4-[1-(3,4-dichlorophenyl)-2,2-dipyridin-3-ylethyl]morpholine,
    (±)-4-(1-pyridin-2-yl-2,2-dipyridin-3-ylethyl)morpholine,
    (±)-3,3′-[2-(4-fluorophenyl)-2-pyrrolidin-1-ylethane-1,1-diyl]dipyridine,
    (±)-4-[1-(4-fluorophenyl)-2-pyridin-2-yl-2-pyridin-3-ylethyl]morpholine,
    (±)-4-[1-(3-chlorophenyl)-2,2-dipyridin-3-ylethyl]morpholine,
    (±)-4-[1-(3,5-dichlorophenyl)-2,2-dipyridin-3-ylethyl]morpholine,
    (±)-[1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl](3,3,3-trifluoropropyl)amine,
    (±)-[1-(3-chlorophenyl)-2,2-dipyridin-3-ylethyl](2,2,2-trifluoroethyl)amine,
    (±)-[1-(3,5-dichlorophenyl)-2,2-dipyridin-3-ylethyl](2,2,2-trifluoroethyl)amine,
    (±)-[1-(3,4-dichlorophenyl)-2,2-dipyridin-3-ylethyl](2,2,2-trifluoroethyl)amine,
    (±)-3,3′-[2-(1,1-dioxidoisothiazolidin-2-yl)-2-(4-fluorophenyl)ethane-1,1-diyl]dipyridine,
    (±)-4-[1-(6-methoxypyridin-2-yl)-2-phenyl-2-pyridin-2-ylethyl]morpholine,
    (±)-4-[1-(6-bromopyridin-2-yl)-2,2-dipyridin-3-ylethyl]morpholine,
    (±)-6-(1-morpholin-4-yl-2,2-dipyridin-3-ylethyl)pyridin-2-amine,
    (±)-N-methyl-6-(1-morpholin-4-yl-2,2-dipyridin-3-ylethyl)pyridin-2-amine,
    (±)-methyl[6-(1-morpholin-4-yl-2,2-dipyridin-3-ylethyl)pyridin-2-yl]carbamate,
    (±)-[1-(3-bromophenyl)-2,2-dipyridin-3-ylethyl]{[1-(phenylsulfonyl)-1H-pyrrol-2-yl]methyl}amine,
    (±)-methyl 1-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]prolinate,
    (±)-3-{1-[2-(hydroxymethyl)pyrrolidin-1-yl]-2,2-dipyridin-3-ylethyl}benzonitrile,
    (±)-1-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]-N,N-dimethylprolinamide,
    (±)-[1-(3-bromophenyl)-2,2-dipyridin-3-ylethyl]-4-methylpiperazine-2,3-dione,
    (±)-3-[1-(6-bromopyridin-2-yl)-2,2-dipyridin-3-ylethyl]-1,3-oxazolidin-2-one,
    (±)-3-[1-(2-oxo-1,3-oxazolidin-3-yl)-2,2-dipyridin-3-ylethyl]benzonitrile,
    (±)-benzyl (1,2,2-tripyridin-3-ylethyl)carbamate,
    (±)-n-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]-2-phenylcyclopropanecarboxamide,
    (±)-3-(1-{[(1-phenyl-1h-pyrazol-4-yl)methyl]amino}-2,2-dipyridin-3-ylethyl)benzonitrile,
    (R)-3-(1-morpholin-4-yl-2,2-dipyridin-3-ylethyl)benzonitrile,
    (S)-3-(1-morpholin-4-yl-2,2-dipyridin-3-ylethyl)benzonitrile,
    (±)-3-[2-(4-fluorophenyl)-1-pyridin-3-yl-2-(2,2,2-trifluoroethoxy)ethyl]pyridine,
    (±)-3-[2-(4-fluorophenyl)-2-methoxy-1-pyridin-3-ylethyl]pyridine,
    (±)-3-[2-(cyclopentyloxy)-2-(4-fluorophenyl)-1-pyridin-3-ylethyl]pyridine,
    (±)-1-[1-(6-chloropyridin-2-yl)-2,2-dipyridin-3-ylethyl]pyridin-2(1H)-one,
    (±)-1-(1-pyridin-2-yl-2,2-dipyridin-3-ylethyl)pyridin-2(1H)-one,
    (R)-1-(1-pyridin-2-yl-2,2-dipyridin-3-ylethyl)pyridin-2(1H)-one,
    (S)-1-(1-pyridin-2-yl-2,2-dipyridin-3-ylethyl)pyridin-2(1)-one,
    (±)-2-[1-(1H-pyrazol-1-yl)-2,2-dipyridin-3-ylethyl]pyridine,
    (±)-2-[2-(4-fluorophenyl)-1-(1H-pyrazol-1-yl)-2-pyridin-3-ylethyl]pyridine,
    (±)-2-[2-(4-fluorophenyl)-1-(1H-pyrazol-1-yl)-2-pyridin-3-ylethyl]pyridine,
    (±)-2-[1-(4-fluorophenyl)-2-(1H-imidazol-1-yl)-2-pyridin-3-ylethyl]pyridine,
    (±)-1-(1,2,2-tripyridin-3-ylethyl)pyridin-2(1H)-one,
    (±)-2-[2,2-dipyridin-3-yl-1-(1H-1,2,3-triazol-1-yl)ethyl]pyridine,
    (±)-3-[2,2-dipyridin-3-yl-1-(1H-1,2,3-triazol-1-yl)ethyl]benzonitrile, and
    (±)-1-[1(2H)-yl)-2,2-dipyridin-3-ylethyl]pyridin-2(1H)-one.


The above-listed compounds are active in one or more of the assays for Kv1.5 described below.
Another embodiment of the invention is a method of treating or preventing a condition in a mammal, the treatment or prevention of which is effected or facilitated by Kv1.5 inhibition, which comprises administering an amount of a compound of Formula I that is effective at inhibiting Kv1.5.
A preferred embodiment is a method of treating or preventing cardiac arrhythmias, e.g. atrial fibrillation, atrial flutter, atrial arrhythmia, and supraventricular tachycardia, in a mammal, which comprises administering a therapeutically effective amount of a compound of Formula I.
Another preferred embodiment is a method of preventing thromboembolic events, such as stroke.
Another preferred embodiment is a method of preventing congestive heart failure.
Another preferred embodiment is a method of treating or preventing immunodepression or a disorder involving immunodepression, such as AIDS, cancer, senile dementia, trauma (including wound healing, surgery and shock) chronic bacterial infection, certain central nervous system disorders, and conditions including resistance by transplantation of organs or tissue, graft-versus-host diseases brought about by medulla ossium transplantation. Within this embodiment is a method for treating or preventing immunodepression by administering a compound of the invention with an immunosuppresant compound.
Another preferred embodiment is a method of treating or preventing gliomas including those of lower and higher malignancy, preferably those of higher malignancy.
Another preferred embodiment is a method for inducing in a patient having atrial fibrillation, a condition of normal sinus rhythm, in which the induced rhythm corresponds to the rhythm that would be considered normal for an individual sharing with the patient similar size and age characteristics, which comprises treating the patient with a compound of the invention.
Another preferred embodiment is a method for treating tachycardia, (i.e., rapid heart rate e.g. 100 beats per minute) in a patient which comprises treating the patient with an antitachycardia device (e.g. a defibrillator or a pacemaker) in combination with a compound of Claim 1.
The present invention also encompasses a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and the compound of Formula I or a pharmaceutically acceptable crystal form or hydrate thereof. A preferred embodiment is a pharmaceutical composition of the compound of Formula I, comprising, in addition, a second agent.
The compounds of the present invention may have asymmetric centers or asymmetric axes, and this invention includes all of the optical isomers and mixtures thereof. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included.
In addition compounds with carbon-carbon double bonds may occur in Z- and E-forms with all isomeric forms of the compounds being included in the present invention.










List of abbreviations:
















AAS
atomic absorption spectroscopy


AIDS
acquired immunodeficiency syndrome


AF
atrial fibrillation


ACE
angiotensin converting enzyme


ACN
acetonitrile


APD
action potential duration


CHO
Chinese hamster ovary


DAST
(diethylamino)sulfur trifluoride


DCM
dichloromethane


dba
dibenzylidineacetone


DMA
dimethylacetamide


DMF
dimethylformamide


DMSO
dimethylsulfoxide


dppf
1,1′-(diphenylphosphino)ferrocene


EDTA
ethylenediaminetetraacetic acid


EGTA
ethylenebis(oxyethylenenitrilo)tetraacetic acid


ESI
electrospray ionization


EtOAc
ethyl acetate


Et2O
diethyl ether


FAAS
flame atomic absorption spetroscopy


FBS
fetal bovine serum


HBSS
Hank's balanced salt solution


HEPES
N-2-hydroxyethylpiperazine-N′-2-ethanesulphonic acid


HPLC
high pressure liquid chromatography


HRMS
high resolution mass spectrum


i-BuOH
isobutanol


i-Pr2Net
N,N-diisopropylethylamine


INH
inhibition


LDA
lithium diisopropylamide


LiHMDS
lithium hexamethyldisilazide


LRMS
low resolution mass spectrum


LYS
lysate


MCPBA
m-chloroperbenzoic acid


MeOH
methanol


MS
mass spectrum


MsCl
methanesulfonyl chloride


n-BuLi
n-butyllithium


NMO
N-methylmorpholine-N-oxide


NMR
nuclear magnetic resonance


NSAID
non-steroidal antiinflammatory drug


PBS
phosphate-buffered saline


RT
room temperature


SUP
supernatant


TAFI
thrombin-activatable fibrinolysis inhibitor


TFA
trifluoroacetic acid


THF
tetrahydrofuran


TMSCHN2
trimethylsilyldiazomethane


TPAP
tetrapropylammonium perruthenate









As used herein except where noted, “alkyl” is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbon atoms. Commonly used abbreviations for alkyl groups are used throughout the specification, e.g. methyl may be represented by “Me” or CH3, ethyl may be represented by “Et” or CH2CH3, propyl may be represented by “Pr” or CH2CH2CH3, butyl may be represented by “Bu” or CH2CH2CH2CH3, etc. “C1-6 alkyl” (or “C1-C6 alkyl”) for example, means linear or branched chain alkyl groups, including all isomers, having the specified number of carbon atoms. C1-6 alkyl includes all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. “C1-4 alkyl” means n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. The term “alkoxy” represents a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
The term “alkenyl” includes both branched and straight chain unsaturated hydrocarbon groups containing at least two carbon atoms joined by a double bond. The alkene ethylene is represented, for example, by “CH2CH2” or alternatively, by “H2C≡CH2”. “C2-5 alkenyl” (or “C2-C5 alkenyl”) for example, means linear or branched chain alkenyl groups having from 2 to 5 carbon atoms and includes all of the pentenyl isomers as well as 1-butenyl, 2-butenyl, 3-butenyl, 1-propenyl, 2-propenyl, and ethenyl (or ethylenyl). Similar terms such as “C2-3 alkenyl” have an analogous meaning.
The term “alkynyl” includes both branched and straight chain unsaturated hydrocarbon groups containing at least two carbon atoms joined by a triple bond. The alkyne acetylyene is represented, for example, by “CHCH” or alternatively, by “HC≡CH”. “C2-5 alkynyl” (or “C2-C5 alkynyl”) for example, means linear or branched chain alkynyl groups having from 2 to 5 carbon atoms and includes all of the pentynyl isomers as well as 1-butynyl, 2-butynyl, 3-butynyl, 1-propynyl, 2-propynyl, and ethynyl (or acetylenyl). Similar terms such as “C2-3 alkynyl” have an analogous meaning.
Unless otherwise specifically noted as only “unsubstituted” or only “substituted”, alkyl, alkenyl and alkynyl groups are unsubstituted or substituted with 1 to 3 substituents on each carbon atom, with halo, C1-C20 alkyl, CF3, NH2, N(C1-C6 alkyl)2, NO2, oxo, CN, N3, —OH, —O(C1-C6 alkyl), C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C6 alkyl) S(O)0-2—, (C0-C6 alkyl)S(O)0-2(C0-C6 alkyl)-, (C0-C6 alkyl)C(O)NH—, H2N—C(NH)—, —O(C1-C6 alkyl)CF3, (C0-C6 alkyl)C(O)—, (C0-C6 alkyl)OC(O)—, (C0-C6 alkyl)O(C1-C6 alkyl)-, (C0-C6 alkyl)C(O)1-2(C0-C6 alkyl)-, (C0-C6 alkyl)OC(O)NH—, aryl, aralkyl, heterocycle, heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl, cyano-heterocycle and cyano-heterocyclylalkyl.
The term “C0” as employed in expressions such as “C0-6 alkyl” means a direct covalent bond. Similarly, when an integer defining the presence of a certain number of atoms in a group is equal to zero, it means that the atoms adjacent thereto are connected directly by a bond. For example, in the structure




wherein s is an integer equal to zero, 1 or 2, the structure is





when s is zero.

The term “C3-8 cycloalkyl” (or “C3-C8 cycloalkyl”) means a cyclic ring of an alkane having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). The terms “C3-7 cycloalkyl”, “C3-6 cycloalkyl”, “C5-7 cycloalkyl” and the like have analogous meanings.
The term “halogen” (or “halo”) refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro (F), chloro (Cl), bromo (Br), and iodo (I)).
The term “C1-6 haloalkyl” (which may alternatively be referred to as “C1-C6 haloalkyl” or “halogenated C1-C6 alkyl”) means a C1 to C6 linear or branched alkyl group as defined above with one or more halogen substituents. The term “C1-4 haloalkyl” has an analogous meaning. The term “C1-6 fluoroalkyl” has an analogous meaning except that the halogen substituents are restricted to fluoro. Suitable fluoroalkyls include the series (CH2)0-4CF3 (i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.).
The term “carbocycle” (and variations thereof such as “carbocyclic” or “carbocyclyl”) as used herein, unless otherwise indicated, refers to (i) a C3 to C8 monocyclic, saturated or unsaturated ring or (ii) a C7 to C12 bicyclic saturated or unsaturated ring system. Each ring in (ii) is either independent of, or fused to, the other ring, and each ring is saturated or unsaturated. The carbocycle may be attached to the rest of the molecule at any carbon atom which results in a stable compound. The fused bicyclic carbocycles are a subset of the carbocycles; i.e., the term “fused bicyclic carbocycle” generally refers to a C7 to C10 bicyclic ring system in which each ring is saturated or unsaturated and two adjacent carbon atoms are shared by each of the rings in the ring system. A fused bicyclic carbocycle in which one ring is saturated and the other is saturated is a saturated bicyclic ring system. A fused bicyclic carbocycle in which one ring is benzene and the other is saturated is an unsaturated bicyclic ring system. A fused bicyclic carbocycle in which one ring is benzene and the other is unsaturated is an unsaturated ring system. Saturated carbocyclic rings are also referred to as cycloalkyl rings, e.g., cyclopropyl, cyclobutyl, etc. Unless otherwise noted, carbocycle is unsubstituted or substituted with C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, aryl, halogen, NH2 or OH. A subset of the fused bicyclic unsaturated carbocycles are those bicyclic carbocycles in which one ring is a benzene ring and the other ring is saturated or unsaturated, with attachment via any carbon atom that results in a stable compound. Representative examples of this subset include the following:




The term “aryl” refers to aromatic mono- and poly-carbocyclic ring systems, wherein the individual carbocyclic rings in the polyring systems are fused or attached to each other via a single bond. Suitable aryl groups include phenyl, naphthyl, and biphenylenyl.
The term “heterocycle” (and variations thereof such as “heterocyclic” or “heterocyclyl”) broadly refers to (i) a stable 4- to 8-membered, saturated or unsaturated monocyclic ring, or (ii) a stable 7- to 12-membered bicyclic ring system, wherein each ring in (ii) is independent of, or fused to, the other ring or rings and each ring is saturated or unsaturated, and the monocyclic ring or bicyclic ring system contains one or more heteroatoms (e.g., from 1 to 6 heteroatoms, or from 1 to 4 heteroatoms) selected from N, O and S and a balance of carbon atoms (the monocyclic ring typically contains at least one carbon atom and the ring systems typically contain at least two carbon atoms); and wherein any one or more of the nitrogen and sulfur heteroatoms is optionally oxidized, and any one or more of the nitrogen heteroatoms is optionally quaternized. The heterocyclic ring may be attached at any heteroatom or carbon atom, provided that attachment results in the creation of a stable structure. When the heterocyclic ring has substituents, it is understood that the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results.
Unless otherwise specifically noted as only “unsubstituted” or only “substituted”, cycloalkyl, aryl and heterocycle groups are unsubstituted or substituted. As used herein, the terms “substituted C3-C10 cycloalkyl”, “substituted aryl” and “substituted heterocycle” are intended to include the cyclic group containing from 1 to 3 substituents in addition to the point of attachment to the rest of the compound. Preferably, the substituents are selected from the group which includes, but is not limited to, halo, C1-C20 alkyl, CF3, NH2, N(C1-C6 alkyl)2, NO2, oxo, CN, N3, —OH, —O(C1-C6 alkyl), C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C6 alkyl) S(O)0-2—, aryl-S(O)0-2—, (C0-C6 alkyl)S(O)0-2(C0-C6 alkyl)-, (C0-C6 alkyl)C(O)NH—, H2N—C(NH)—, —O(C1-C6 alkyl)CF3, (C0-C6 alkyl)C(O)—, (C0-C6 alkyl)OC(O)—, (C0-C6alkyl)O(C1-C6 alkyl)-, (C0-C6 alkyl)C(O)1-2(C0-C6 alkyl)-, (C0-C6 alkyl)OC(O)NH—, aryl, aralkyl, heteroaryl, heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl, cyano-heterocycle and cyano-heterocyclylalkyl.
Saturated heterocyclics form a subset of the heterocycles; i.e., the term “saturated heterocyclic” generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is saturated. The term “saturated heterocyclic ring” refers to a 4- to 8-membered saturated monocyclic ring or a stable 7- to 12-membered bicyclic ring system which consists of carbon atoms and one or more heteroatoms selected from N, O and S. Representative examples include piperidinyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl (or tetrahydrofuranyl).
Heteroaromatics form another subset of the heterocycles; i.e., the term “heteroaromatic” (alternatively “heteroaryl”) generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is an aromatic ring system. The term “heteroaromatic ring” refers a 5- or 6-membered monocyclic aromatic ring or a 7- to 12-membered bicyclic which consists of carbon atoms and one or more heteroatoms selected from N, O and S. In the case of substituted heteroaryl rings containing at least one nitrogen atom (e.g., pyridine), such substitutions can be those resulting in N-oxide formation. Representative examples of heteroaromatic rings include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.
Representative examples of bicyclic heterocycles include benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-1,4-dioxinyl (i.e.,




), imidazo(2,1-b)(1,3)thiazole, (i.e.,





), and benzo-1,3-dioxolyl (i.e.,





). In certain contexts herein,





is alternatively referred to as phenyl having as a substituent methylenedioxy attached to two adjacent carbon atoms.

Unless expressly stated to the contrary, an “unsaturated” ring is a partially or fully unsaturated ring. For example, an “unsaturated monocyclic C6 carbocycle” refers to cyclohexene, cyclohexadiene, and benzene.
Unless expressly stated to the contrary, all ranges cited herein are inclusive. For example, a heterocycle described as containing from “1 to 4 heteroatoms” means the heterocycle can contain 1, 2, 3 or 4 heteroatoms.
When any variable occurs more than one time in any constituent or in any formula depicting and describing compounds of the invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term “substituted” (e.g., as in “aryl which is optionally substituted with one or more substituents . . . ”) includes mono- and poly-substitution by a named substituent to the extent such single and multiple substitution (including multiple substitution at the same site) is chemically allowed.
In compounds of the invention having N-oxide moieties, e.g., pyridyl N-oxide moieties, the N-oxide moiety is structurally depicted using conventional representations. For example, a pyridyl-N-oxide portion is structurally depicted as




which have equivalent meanings.

For variable definitions containing terms having repeated terms, e.g., (CRiRj)r, where r is the integer 2, Ri is a defined variable, and Rj is a defined variable, the value of Ri may differ in each instance in which it occurs, and the value of Rj may differ in each instance in which it occurs. For example, if Ri and Rj are independently selected from the group consisting of methyl, ethyl, propyl and butyl, then (CRiRj)2 can be




Pharmaceutically acceptable salts include both the metallic (inorganic) salts and organic salts; a list of which is given in Remington's Pharmaceutical Sciences, 17th Edition, pg. 1418 (1985). It is well known to one skilled in the art that an appropriate salt form is chosen based on physical and chemical stability, flowability, hydro-scopicity and solubility. As will be understood by those skilled in the art, pharmaceutically acceptable salts include, but are not limited to salts of inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate or salts of an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate or palmoate, salicylate and stearate. Similarly pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium (especially ammonium salts with secondary amines). Preferred salts of this invention for the reasons cited above include potassium, sodium, calcium and ammonium salts. Also included within the scope of this invention are crystal forms, hydrates and solvates of the compounds of Formula I.
Methods for preparing the compounds of this invention are illustrated in the following schemes. Other synthetic protocols will be readily apparent to those skilled in the art. The examples illustrate the preparation of the compounds of Formula I and as such are not to be considered as limiting the invention set forth in the claims appended hereto. Example described hereinafter comprises a further embodiment of the present invention.




The variables C, B, and Y in the scheme are as defined in “Formula I”.

EXAMPLE 1
(±)-2-Morpholin-4-yl-2-phenyl-1,1-dipyridin-3-yl-ethanol




Step A:

Methyl α-bromophenylacetate (3.79 g, 16.5 mmol) was dissolved in 50 mL of dry ACN, to which triethylamine (3.46 mL, 24.8 mmol) and morpholine (1.73 mL, 19.8 mmol) were added and the mixture was stirred for 18 hours. The mixture was poured into water, extracted twice with EtOAc. The combined organic extracts were dried with Na2SO4, filtered and concentrated in vacuo, providing methyl morpholin-4-yl(phenyl)acetate. ESI+MS: 236.2 [M+H]+.
Step B:
3-Bromopyridine (8.37 mL, 13.9 mmol) was dissolved in 350 mL of dry Et2O and was cooled to −78° C. n-Butyl lithium (35.1 mL, 2.5M solution in hexanes, 87.8 mmol) was added dropwise via an addition funnel over 30 minutes. After stirring for 15 minutes, a 50 mL (4:1; Et2O/THF) solution of methyl morpholin-4-yl-(phenyl)acetate (6.88 g, 29.3 mmol) was added dropwise over 30 minutes. The reaction was stirred for 1 hour at −78° C. and was warmed to 0° C. and stirred for 30 minutes. The reaction was quenched with NaHCO3(aq sat) and poured into NaHCO3(aq sat), extracted 3× with EtOAc, dried Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100/0/0 to 92/8/0.8 CH2Cl2/MeOH NO4OH) to provide the titled compound.
1H NMR (500 MHz, CDCl3): δ 9.01 (d, J=1.9 Hz, 1H), 6.53 (dd, J=2.4, 0.7 Hz, 1H), 8.48 (dd, J=4.6, 1.5 Hz, 1H), 8.16 (dd, J=4.8, 1.6 Hz, 1H), 8.02 (dt, J=8.0, 2.3 Hz, 1H), 7.58 (d, J=8.3 Hz, 1H), 7.30-7.22 (m, 3H), 7.16-7.08 (m, 3H), 6.95 (dd, J=8.1, 4.9 Hz, 1H), 5.63 (br s, 1H), 4.55 (s, 1H), 3.59-3.51 (m, 4H), 2.41 (br dt, J=12.0, 4.7 Hz, 2H), 2.18 (br dt, J=11.7, 4.8 Hz, 2H). HRMS [M+H] C22H24N3O2 calcd 362.1863, found 362.1851.

The following compounds were made according to Scheme 1, where intermediates in the scheme were modified according to literature methods. Example 2 was isolated from a reaction of 2-pyridyllithium (prepared from 2-bromopyridine and t-butyl lithium) with methyl 3-morpholin-4-yl-3-phenylpropanoate. Example 51 was prepared from the corresponding secondary alcohol tert-butyldimethylsilyl ether by standard deprotection. Unless otherwise shown, structures of compounds in Examples 2-51, 58-121, 4-1 to 4-21, 123-201, 202-302, and 5-1 listed in the tables are represented by defining variables





and “Y” of the structure





EXAMPLES 2-51













Example
Compound
Name
MS (M + 1)


















2




(±)-3,3-dimethyl-1-morpholin-4-yl-1- phenyl-2-pyridin-2-ylbutan-2-ol (diastereomer A)
363.2069 (M + Na+)


 


3




(±)-2-morpholin-4-yl-1,1-dipyridin-3- ylpropan-1-ol
300.1701


 


4




(±)-1,1-dipyridin-3-yl-2-pyridin-4-yl- 2-pyrrolidin-1-ylethanol
347.1867


 


5




(±)-tert-butyl(2-hydroxy-1-phenyl- 2,2-dipyridin-2-ylethyl)carbamate
392.1966


 


6




(±)-2-morpholin-4-yl-1,1-dipyridin-3- ylbutan-1-ol
314.1864


 


7




(±)-2-morpholin-4-yl-1,1-dipyridin-3- ylpentan-1-ol
328.2019


 


8




(±)-3-methyl-2-morpholin-4-yl-1,1- dipyridin-3-ylbutan-1-ol
328.2019


 


9




(±)-2-morpholin-4-yl-1,1-dipyridin-3- ylhexan-1-ol
342.2173


 


10




(±)-2-morpholin-4-yl-1,1-dipyridin-3- ylheptan-1-ol
356.2330


 


11




(±)-2-morpholin-4-yl-1,1-dipyridin-3- yloctan-1-ol
370.2487


 


12




(±)-2-morpholin-4-yl-4-phenyl-1,1- dipyridin-3-ylbutan-1-ol
390.2176


 


13




(±)-2-[(2- methoxyethyl)(methyl)amino]-2- phenyl-1,1-dipyridin-3-ylethanol
364.2027


 


14




(±)-2-[bis(2-methoxyethyl)amino]-2- phenyl-1,1-dipyridin-3-ylethanol
408.2279


 


15




(±)-2-phenyl-2-piperidin-1-yl-1,1- dipyridin-3-ylethanol
360.2072


 


16




(±)-2-phenyl-1,1-dipyridin-3-yl-2- pyrrolidin-1-ylethanol
346.1910


 


17




(±)-tert-butyl 4-(2-hydroxy-1-phenyl- 2,2-dipyridin-3-ylethyl)piperazine-1- carboxylate
461.2537


 


18




(±)-4-(2-hydroxy-1-phenyl-2,2- dipyridin-3-ylethyl)piperazin-2-one
375.1803


 


19




(±)-2-(4-methoxypiperidin-1-yl)-2- phenyl-1,1-dipyridin-3-ylethanol
390.2167


 


20




2-[(1S,4S)-2-oxa-5- azabicyclo[2.2.1]hept-5-yl]-2-phenyl- 1,1-dipyridin-3-ylethanol(1:1 mixture diastereomers)
374.1846


 


21




(±)-2-(1,4-oxazepan-4-yl)-2-phenyl- 1,1-dipyridin-3-ylethanol
376.2001


 


22




(±)-2-[(2R,6S)-2,6- dimethylmorpholin-4-yl]-2-phenyl-1,1- dipyridin-3-ylethanol
390.2168


 


23




(±)-2-[(3- methoxypropyl)(methyl)amino]-2- phenyl-1,1-dipyridin-3-ylethanol
378.2167


 


24




(±)-2-phenyl-1,1-dipyridin-3-yl-2- thiomorpholin-4-ylethanol
378.1617


 


25




(±)-2-azetidin-1-yl-2-phenyl-1,1- dipyridin-3-ylethanol
332.1760


 


26




(±)-2-(dimethylamino)-2-phenyl-1,1- dipyridin-3-ylethanol
320.1752


 


27




(±)-2-(diethylamino)-2-phenyl-1,1- dipyridin-3-ylethanol
348.2064


 


28




(±)-2-[methoxy(methyl)amino]-2- phenyl-1,1-dipyridin-3-ylethanol
336.1698


 


29




(±)-2-(7-azabicyclo[2.2.1]hept-7-yl)-2- phenyl-1,1-dipyridin-3-ylethanol
372.2061


 


30




(±)-2-morpholin-4-yl-3-phenyl-1,1- dipyridin-3-ylpropan-1-ol
376.2035


 


31




(±)-2-(3,3-difluoropyrrolidin-1-yl)-2- phenyl-1,1-dypyridin-3-ylethanol
382.1717


 


32




(±)-2-(3,3-dimethylpyrrolidin-1-yl)-2- phenyl-1,1-dipyridin-3-ylethanol
374.2210


 


33




(±)-2-(2,5-dihydro-1H-pyrrol-1-yl)-2- phenyl-1,1-dipyridin-3-ylethanol
344.1762


 


34




(±)-2-phenyl-1,1-dipyridin-3-yl-2-[2- (trifluoromethyl)pyrrolidin-1- yl]ethanol(diastereomer A)
414.1798


 


35




(±)-2-phenyl-1,1-dipyridin-3-yl-2-[2- (trifluoromethyl)pyrrolidin-1- yl]ethanol(diastereomer B)
414.1810


 


36




(±)-2-(2-isopropylpyrrolidin-1-yl)-2- phenyl-1,1-dipyridin-3-ylethanol (diastereomer A)
388.3


 


37




(±)-2-(2-isopropylpyrrolidin-1-yl)-2- phenyl-1,1-dipyridin-3-ylethanol (diastereomer B)
388.3


 


38




(±)-2-(3-bromophenyl)-2-morpholin-4- yl-1,1-dipyridin-3-ylethanol
440.0978


 


39




(2R)-2-cyclopropyl-1,1-dipyridin-3-yl- 2-pyrrolidin-1-ylethanol
310.1915


 


40




(2S)-2-cyclopropyl-1,1-dipyridin-3-yl- 2-pyrrolidin-1-ylethanol
310.1913


 


41




(±)-2-[cyclohexyl(ethyl)amino]-2- phenyl-1,1-dipyridin-3-ylethanol
402.2542


 


42




(±)-2-[cyclopentyl(ethyl)amino]-2- phenyl-1,1-dipyridin-3-ylethanol
388.2376


 


43




(±)-2-[cyclobutyl(ethyl)amino]-2- phenyl-1,1-dipyridin-3-ylethanol
374.2234


 


44




(±)-2-[cyclopropyl(ethyl)amino]-2- phenyl-1,1-dipyridin-3-ylethanol
360.2067


 


45




(±)-2-[tert-butyl(ethyl)amino]-2- phenyl-1,1-dipyridin-3-ylethanol
376.2378


 


46




(±)-2-[ethyl(2,2,2- trifluoroethyl)amino]-2-phenyl-1,1- dipyridin-3-ylethanol
402.1807


 


47




(±)-2-[cyclobutyl(ethyl)amino]-2-(3,4- difluorophenyl)-1,1-dipyridin-3- ylethanol
410.2053


 


48




tert-butyl(1S)-2-hydroxy-1-phenyl- 2,2-dipyridin-3-ylethylcarbamate
392.1986


 


49




tert-butyl(1R)-2-hydroxy-1-phenyl- 2,2-dipyridin-3-ylethylcarbamate
392.1985


 


50




(±)-2-(3-fluoropyrrolidin-1-yl)-2- phenyl-1,1-dipyridin-3-ylethanol(1:1 mixture diastereomers)
364.1813


 


51




(±)-1-(2-hydroxy-1-phenyl-2,2- dipyridin-3-ylethyl)pyrrolidin-3-ol (1:1 mixture diastereomers)
362.1879













The variables C, B, A, and Y in the scheme are as defined in “Formula I”.

EXAMPLE 52
(±)-2-Morpholin-4-yl-1,2-diphenyl-1-pyridin-2-yl-ethanol (diastereomer A)




Step A:

N,O-Dimethylhydroxylamine hydrochloride (1.66 g, 17.0 mmol) was suspended in 20 mL of dry TVF and cooled to 0° C. Trimethylaluminum (8.50 mL, 2.0M solution in toluene, 17.0 mmol) was added slowly and stirred for 30 minutes. Methyl morpholin-4-yl-(phenyl)acetate (1.00 g, 4.25 mmol) was added to the cooled mixture in an 8 mL TIFF solution. The reaction was allowed to warm to ambient temperature while for 18 hours. The mixture was poured into 1N HCl(aq) and stirred for 1 hour. The mixture was then poured into NaHCO3(sat) and extracted 3× with EtOAc. The combined organic layers were washed 1× with brine, dried with Na2SO4, filtered and concentrated in vacuo to provide N-methoxy-N-methyl-2-morpholin-4-yl-2-phenylacetamide. HRMS [M+H] C14H21N2O3 calc'd 265.1547. found 265.1553.
Step B:
N-Methoxy-N-methyl-2-morpholin-4-yl-2-phenylacetamide (215 mg, 0.813 mmol) was dissolved in 10 mL of dry THF and cooled to −78° C. In a separate flask, 2-bromopyridine (97 μL, 1.0 mmol) was dissolved in 5 mL of dry THF and cooled to −78° C., to which was added tert-Butyl lithium (1.20 mL, 1.7M solution in pentane, 2.0 mmol) dropwise. After stirring for 30 minutes, the mixture transferred to the amide flask dropwise and stirred for approximately one hour. The mixture was quenched with NaHCO3(sat), warmed to ambient temperature and poured into water. The aqueous layer was extracted 3× with EtOAc and the combined organic extracts were dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100/0/0 to 9/1/0.1 CH2Cl2/MeOH/NH4OH), providing partially purified titled product. The residue was further purified by preparative reverse phase HPLC. The appropriate fractions were poured into NaHCO3(aq sat) and extracted twice with EtOAc. The combined organic extracts were dried with Na2SO4, filtered and concentrated in vacuo to provide 2-morpholin-4-yl-2-phenyl-1-pyridin-2-ylethanone. ESI+MS: 283.1 [M+H]+.
Step C:
2-Morpholin-4-yl-2-phenyl-1-pyridin-2-yl-ethanone (15 mg, 0.053 mmol) was dissolved in 3 mL of dry THF and cooled to −78° C. Phenylmagnesium bromide (159 μL, 1.0 M solution in TBH, 0.159 mmol) was added dropwise and the mixture was allowed to stir for 15 minutes. The reaction was quenched with 1 mL of aqueous NaHCO3(sat) and warmed to ambient temperature. The mixture was poured into NaHCO3 (sat) and extracted 2× with EtOAc. The combined organic extracts were dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC. The appropriate fractions were poured into NaHCO3(sat) and extracted 2× with EtOAc. The combined organic extracts were dried with Na2SO4, filtered and concentrated in vacuo to provide the titled compound.
1H NMR (500 MHz, CDCl3): δ 8.19 (d, J=4.6 Hz, 1H), 7.86 (d, J=7.6 Hz, 2H), 7.47-7.41 (m, 2H), 7.36-7.28 (m, 4H), 7.22 (t, J=7.2 Hz, 1H), 7.13-7.05 (m, 2H), 6.86 (ddd, J=6.5, 4.9, 1.4 Hz, 1H), 6.28 br s, 1H), 4.62 (br s, 1H), 3.56-3.39 (br m, 4H), 2.65-2.60 (br m, 2H), 2.42-2.20 (br m, 2H). HRMS [M+H] C23H25N2O2 calc'd 361.1911, found 361.1914.
The following compounds were made according to Scheme 2, where intermediates in the scheme were modified according to literature methods.
EXAMPLES 53-55













Example
Compound
Name
MS (M + 1)


















53




2-morpholin-4-yl-2-phenyl- 1-pyridin-2-yl-1-pyridin-3- ylethanol(diastereomer A)
362.1857


 


54




(±)-3-methyl-2-morpholin-4- yl-1-phenyl-1-pyridin-3- ylbutan-1-ol(diastereomer A)
327.2079


 


55




(±)-3-methyl-2-morpholin-4- yl-1-phenyl-1-pyridin-2- ylbutan-1-ol(diastereomer A)
327.2079













The variables C, B, A, and Y in the scheme are as defined in “Formula I”.

The following compound was made according to Scheme 3.
















56




2-[(2S)-2- (hydroxymethyl)pyrrolidin- 1-yl]-1,2-diphenyl-1-pyridin- 2-ylethanol(Diastereomer A)
375.2063













The variables C, B, A, and Y in the scheme are as defined in “Formula I”.

EXAMPLE 57
(±)-1-[1-(4-Fluorophenyl)-2-hydroxy-2,2-dipridin-3-ylethyl]pyridin-2(1H)-one




Step A:

n-BuLi (42 mL, 1.6M, 67 mmol) was added to a solution of 3-bromopyridine (5.9 mL, 9.74 g, 62 mmol) in ether (200 mL) at −78 C. The resulting yellow suspension was stirred for 1 h. A solution of nicotinaldehyde (5.3 mL, 6 g, 56 mmol) in ether (25 mL) was then added. After stirring for 0.5 h, the reaction mixture was allowed to warm gradually to 0 C. The reaction mixture was then quenched by addition of half saturated brine (100 mL). The resulting mixture was extracted once with ethyl acetate and once with chloroform. Drying (1:1 Na2SO4/K2CO3) and concentration gave dipyridin-3-ylmethanol as a very viscous orange oil which was used without further purification.
1HNMR (CD3OD, 400 MHz) δ 8.58 (d, 2H, J=1.74 Hz); 8.42 (dd, 2H, J=1.28, 4.85 Hz); 7.82 (m, 2H); 7.39 (m, 2H); 5.93 (s, 1H).
Step B:
To a solution of dipyridin-3-ylmethanol (9 g, 48 mmol) in 9:1 methylene chloride/acetonitrile (100 mL) was added powdered 4A molecular sieves (24 g) and NMO (8.5 g, 72 mmol). The resulting mixture was cooled in an ice bath and TPAP (0.85 g, 2.4 mmol) added carefully in 3 portions at 5 min intervals. After stirring for 15 min the ice bath was removed and stirring was continued at RT. After stirring for 3 days, the reaction mixture was filtered through Celite and the cake washed well with methylene chloride and then chloroform. The filtrate was concentrated to approximately 1⁄3 the original volume then silica gel was added. The remaining solvent was removed leaving the crude material adsorbed onto the silica gel as a dark green powder. This powder was layered on top of an equal volume of silica gel in a Buchner funnel and flushed with ether. These washings were discarded. The silica pad was then flushed repeatedly first with methylene chloride then with chloroform until no further product eluted. The dark red filtrate was concentrated to give a red brown solid. Trituration with ether gave dipyridin-3-ylmethanone as a white powder. The mother liquors were stripped and the residue chromatographed (eluting with 24:1 methylene chloride/methanol). The fractions enriched in product were combined, stripped, and the residue triturated with ether to give a second crop of pure ketone.
1HNMR (CD3OD, 400 MHz) δ 8.92 (m, 2H); 8.79 (m, 2H); 8.22 (m, 2H); 7.61 (m, 2H).
Step C:
NaH (0.61 g, 25 mmol) was added to a solution of 2-hydroxypyridine (2 g, 21 mmol) in DMF (20 mL) at 0 C. After stirring for 15 min, p-fluorobenzyl bromide (4.4 g, 2.9 mmol, 23 mmol) was added and the reaction mixture allowed to warm gradually to RT. The reaction mixture was quenched by addition of ice then poured into ether and extracted several times with ice water. The organic phase was then dried over Na2SO4, concentrated and the resulting yellow oil purified by normal phase Gilson chromatography eluting with 10% DCM, 70% Hexane, 20% EtOAc. 1-(4-Fluorobenzyl)pyridin-2(1H)-one was isolated as a white solid.
1HNMR (CD3OD, 400MHz) δ 7.67 (m, 1H); 7.50 (m, 1H); 7.34 (m, 2H); 7.05 (m, 2H); 6.54 (m, 1H); 6.37 (m, 1H); 5.15 (s, 2H).
Step D:
A solution of dipyridin-3-ylmethanone (1 g, 5.9 mmol) and 1-(4-fluorobenzyl)pyridin-2(1H)-one (1 g, 4.9 mmol) in THF (50 mL) was cooled to −78 C. To the resulting white suspension was added in a dropwise manner, LiHMDS (1M in THF, 6 mL). The resulting cream suspension was stirred for 30 min then allowed to warm up gradually to −30 C over 1 h. The reaction mixture was quenched with saturated NaHCO3 and then it was extracted once with ether and once with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. The resulting yellow oil was purified by normal phase Gilson chromatography eluting with 98% DCM, 2% methanol. The product was isolated as a white solid.
1HNMR (CD3OD, 400 MHz) δ 8.63 (s, 1H); 8.49 (br s, 1H); 8.36 (m, 3H); 7.93 (m, 1H); 7.75 (br s, 1H); 7.54 (br s, 2H); 7.34 (m, 3H); 7.15 (br s, 1H); 6.96 (m, 2H); 6.29 (m, 2H).
The following compounds were made according to Scheme 4, where intermediates in the scheme were modified according to literature methods. Examples 58-64 were prepared from 1-benzylpyrrolidine and the requisite ketone using the method of Kessar (Chem Rev. 1997, 97, 721). Example 120 was prepared by trifluoroacetic acid deprotection of the corresponding 1-(2,4-dimethoxybenzyl)-3-methyl-1H-pyrazol-1-yl derivative. Example 121 was prepared by hydrogenation of the corresponding pyridinone ring benzyl ether.
EXAMPLES 58-121 AND 4-1 to 4-21













Example
Compound
Name
MS (M + 1)


















58




(±)-1-(1H-indol-4-yl)-2- phenyl-1-pyridin-2-yl-2- pyrrolidin-1-ylethanol (1:1 mixture of diastereomers)
384.2059


 


59




(±)-1,2-diphenyl-1- pyridin-2-yl-2-pyrrolidin- 1-ylethanol (diastereomer a)
345.1966


 


60




(±)-1-(4-methoxypyridin- 2-yl)-1,2-diphenyl-2- pyrrolidin-1-ylethanol (diastereomer a)
375.2063


 


61




(±)-1-phenyl-2-pyridin- 2-yl-1-pyrrolidin-1- ylbutan-2-ol (diastereomer A)
297.1962


 


62




(±)-1-phenyl-2-pyridin- 2-yl-1-pyrrolidin-1- ylbutan-2-ol (diastereomer B)
297.1959


 


63




(±)-1-phenyl-2-pyridin- 2-yl-1-pyrrolidin-1- ylpropan-2-ol
283.1808


 


64




(±)-2-phenyl-2- (phenylsulfonyl)-1,1- dipyridin-3-ylethanol
417.1257


 


65




(±)-ethyl 3-hydroxy-3- phenyl-3-pyridin-2-yl-2- pyrrolidin-1-ylpropanoate (diastereomer A)
341.1855


 


66




(±)-3-hydroxy-N,N- dimethyl-3,3-dipyridin- 3-yl-2-pyrrolidin-1- ylpropanamide
341.2


 


67




(±)-3-morpholin-4-yl-3- oxo-1,1-dipyridin-3-yl-2- pyrrolidin-1-ylpropan-1- ol
383.2070


 


68




(±)-3-oxo-1,1-dipyridin- 3-yl-2,3-dipyrrolidin-1- ylpropan-1-ol
367.2124


 


69




(±)-2-(1,3-dimethyl-1H- 1,2,4-triazol-5-yl)-1,1- dipyridin-3-yl-2- pyrrolidin-1-ylethanol
365.2090


 


70




(±)-1,2-diphenyl-2-(1H- pyrazol-1-yl)-1-pyridin-4- ylethanol (diastereomer A)
342.1598


 


71




(±)-2-(1,3-dimethyl-1H- 1,2,4-triazol-5-yl)-1,1- dipyridin-3-yl-2- pyrrolidin-1-ylethanol
365.2090


 


72




(±)-4-ethyl-5-(2-hydroxy- 2,2-dipyridin-3-yl-1- pyrrolidin-1-ylethyl)-2,4- dihydro-3H-1,2,4-triazol- 3-one
381.2025


 


73




(±)-3-[1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3-ylethyl]- 1,3-oxazolidin-2-one
380.1444


 


74




(±)-3-(2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl)-1,3-oxazolidin-2- one
362.1542


 


75




(±)-3-[2-hydroxy-1-(2- oxo-1,3-oxazolidin-3-yl)- 2,2-dipyridin-3- ylethyl]benzonitrile
387.1464


 


76




(±)-1-[1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3-ylethyl]- 3-methylimidazolidin-2- one
393.1767


 


77




(±)-1-tert-butyl-3-[1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3- ylethyl]imidazolidin-2- one
435.2203


 


78




(±)-3-(2-hydroxy-1- pyridin-2-yl-2,2- dipyridin-3-ylethyl)-1,3- oxazolidin-2-one
363.1


 


79




(±)-2-(1H-pyrazol-1-yl)- 2-pyridin-2-yl-1,1- dipyridin-3-ylethanol
344.1502


 


80




(±)-2-(1H-pyrazol-1-yl)- 1,1-dipyridin-3-yl-2- pyridin-4-ylethanol
344.1507


 


81




(±)-2-(1H-pyrazol-1-yl)- 1,1,2-tripyridin-3- ylethanol
344.1504


 


82




(±)-methyl 1-(2-hydroxy- 1-pyridin-2-yl-2,2- dipyridin-3-ylethyl)-1H- pyrazole-3-carboxylate
402.1558


 


83




(±)-2-(5-fluoropyridin-2- yl)-2-(1H-pyrazol-1-yl)- 1,1-dipyridin-3-ylethanol
362.1413


 


84




(±)-1,1,2-tripyridin-3-yl- 2-(1H-1,2,3-triazol-1- yl)ethanol
345.1463


 


85




(±)-4-[2-hydroxy-2,2- dipyridin-3-yl-1-(2H- dipyridin-3-yl-1-(2H- 1,2,3-triazol-2- yl)ethyl]benzonitrile
369.1456


 


86




(±)-4-[2-hydroxy-2,2- dipyridin-3-yl-1-(1H- 1,2,3-triazol-1- yl)ethyl]benzonitrile
369.1457


 


87




(±)-3-[2-hydroxy-2,2- dipyridin-3-yl-1-(1H- 1,2,3-triazol-1- yl)ethyl]benzonitrile
369.1459


 


88




(±)-3-[2-hydroxy-2,2- dipyridin-3-yl-1-(2H- 1,2,3-triazol-2- yl)ethyl]benzonitrile
369.1454


 


89




(±)-2-(1H-imidazol-1-yl)- 2-phenyl-1,1-dipyridin-3- ylethanol
343.1553


 


90




(±)-(1-benzyl-1H- pyrazol-5-yl)(dipyridin-3- yl)methanol
343.1554


 


91




(±)-2-(3-methoxyphenyl)- 2-(1H-pyrazol-1-yl)-1,1- dipyridin-3-ylethanol
373.1673


 


92




(±)-2-(4-fluorophenyl)-2- (1H-pyrazol-1-yl)-1,1- dipyridin-3-ylethanol
361.1466


 


93




(±)-1-[1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3- ylethyl]pyridin-2(1H)-one
388.1461


 


94




(±)-3-[1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3- ylethyl]pyrimidin-4(3H)- one
389.1417


 


95




(±)-1-[1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3- ylethyl]pyrazin-2(1H)- one
389.1413


 


96




(±)-3-[2-hydroxy-1-(2- oxopyridin-1(2H)-yl)-2,2- dipyridin-3- ylethyl]benzonitrile
395.2


 


97




(±)-1-(2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl)pyridin-2(1H)-one
370.2


 


98




(±)-3-[2-hydroxy-1-(1H- pyrazol-1-yl)-2,2- dipyridin-3- ylethyl]benzonitrile
368.1506


 


99




(±)-2-[1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3- ylethyl]pyridazin-3(2H)- one
389.1416


 


100




(±)-4-[2-hydroxy-1-(2- oxopyridin-1(2H)-yl)-2,2- dipyridin-3- ylethyl]benzonitrile
395.1520


 


101




1-[1-(4-fluorophenyl)-2- hydroxy-2,2-dipyridin-3- ylethyl]pyridin-2(1H)-one (enantiomer A)
388.1


 


102




1-[1-(4-fluorophenyl)-2- hydroxy-2,2-dipyridin-3- ylethyl]pyridin-2(1H)-one (enantiomer B)
388.1


 


103




(±)-methyl 1-[1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3-ylethyl]- 2-oxo-1,2- dihydropyridine-3- carboxylate
446.1512


 


104




(±)-ethyl 1-(2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl)-1H-pyrazole-4- carboxylate
415.1786


 


105




(±)-1-[1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3- ylethyl]pyrimidin-2(1H)- one
389.2


 


106




(±)-1-[1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3-ylethyl]- 2-oxo-1,2- dihydropyridine-3- carbonitrile
413.1


 


107




(±)-1-(2-hydroxy-1- pyridin-2-yl-2,2- dipyridin-3- ylethyl)pyridin-2(1H)-one
371.1520


 


108




(±)-2-phenyl-1,1- dipyridin-3-yl-2-(1H- 1,2,3-triazol-1-yl)ethanol
344.1505


 


109




(±)-1-(2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl)pyrazin-2(1H)- one
371.1516


 


110




(±)-2-phenyl-1,1- dipyridin-3-yl-2-(2H- 1,2,3-triazol-2-yl)ethanol
344.1516


 


111




(±)-methyl 1-[1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3-ylethyl]- 6-oxo-1,6- dihydropyridine-3- carboxylate
446.5


 


112




(±)-5-bromo-1-[1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3- ylethyl]pyridin-2(1H)-one
468.2 (M + 2)


 


113




(±)-1-[1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3-ylethyl]- 6-oxo-1,6- dihydropyridine-3- carbonitrile
413.5


 


114




(±)-1-(2-hydroxy-1,2,2- tripyridin-3- ylethyl)pyridin-2(1H)-one
371.4


 


115




(±)-2-(2-hydroxy-1- pyridin-2-yl-2,2- dipyridin-3- ylethyl)pyridazin-3(2H)- one
372.5


 


116




(±)-2-(2-hydroxy-1,2,2- tripyridin-3- ylethyl)pyridazin-3(2H)-one
372.2


 


117




1-(2-hydroxy-1-pyridin-2- yl-2,2-dipyridin-3- ylethyl)pyridin-2(1H)-one (enantiomer A)
371.2


 


118




1-(2-hydroxy-1-pyridin-2- yl-2,2-dipyridin-3- ylethyl)pyridin-2(1H)-one (enantiomer B)
371.2


 


119




(±)-1-(2-hydroxy-1- pyridin-2-yl-2,2- dipyridin-3- ylethyl)pyrazin-2(1H)- one
372.3


 


120




(±)-2-(3-methyl-1H-1,2,4- triazol-5-yl)-1,1- dipyridin-3-yl-2- pyrrolidin-1-ylethanol
351.1


 


121




(±)-1-[1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3-ylethyl]- 4-hydroxypyridin-2(1H)- one
404.5


 










4-1 




(±)-1-phenyl-1,2- dipyridin-3-yl-2-(1H- 1,2,3-triazol-1-yl)ethanol (Diastereomer A)
344.1511


 


4-2 




(±)-1-phenyl-1,2- dipyridin-3-yl-2-(1H- 1,2,3-triazol-1-yl)ethanol (Diastereomer B)
344.1512


 


4-3 




(±)-1-phenyl-1-pyridin-2- yl-2-pyridin-3-yl-2-(1H- 1,2,3-triazol-1-yl)ethanol (Diastereomer A)
344.1504


 


4-4 




(±)-1-phenyl-1-pyridin-2- yl-2-pyridin-3-yl-2-(1H- 1,2,3-triazol-1-yl)ethanol (Diastereomer B)
344.1513


 


4-5 




(±)-4-[2-hydroxy-2,2- dipyridin-3-yl-1-(1H- 1,2,3-triazol-1- yl)ethyl]benzonitrile
369.1477


 


4-6 




(±)-1-(2-hydroxy-2- phenyl-2-pyridin-2-yl-1- pyridin-3-ylethyl)pyridin- 2(1H)-one
370.3


 


4-7 




(±)-1-(2-hydroxy-2- phenyl-1,2-dipyridin-3- ylethyl)pyridin-2(1H)-one (Diastereomer C)
370.3


 


4-8 




(±)-1-(2-hydroxy-2- phenyl-1,2-dipyridin-3- ylethyl)pyridin-2(1H)-one (Diastereomer D)
370.3


 


4-9 




(±)-1-(2-hydroxy-2- phenyl-2-pyridin-2-yl-1- pyridin-3-ylethyl)pyrazin- 2(1H)-one
371.3


 


4-10




(±)-2-(6-bromopyridin-3- yl)-1,1-dipyridin-3-yl-2- (1H-1,2,3-triazol-1- yl)ethanol
423.0582


 


4-11




(±)-3-[1-hydroxy-2-(2- oxopyridin-1(2H)-yl)-2- pyridin-2-yl-1-pyridin-3- ylethyl]benzonitrile (Diastereomer X)
395.2


 


4-12




(±)-3-[1-hydroxy-2-(2- oxopyridin-1(2H)-yl)-2- pyridin-2-yl-1-pyridin-3- ylethyl]benzonitrile (Diastereomer Y)
395.2


 


4-13




(±)-3-(2-hydroxy-1- pyridin-2-yl-2,2- dipyridin-3-ylethyl)-1,3- oxazinan-2-one
377.1607


 


4-14




(±)-3-[2-(6- bromopyridin-3-yl)-1- hydroxy-1-pyridin-3-yl-2- (1H-1,2,3-triazol-1- yl)ethyl]benzonitrile (Diastereomer A)
447.0558


 


4-15




(±)-3-[2-(6- bromopyridin-3-yl)-1- hydroxy-1-pyridin-3-yl-2- (1H-1,2,3-triazol-1- yl)ethyl]benzonitrile (Diastereomer B)
447.0559


 


4-16




(±)-3-[1-hydroxy-1,2- dipyridin-3-yl-2-(1H- 1,2,3-triazol-1- yl)ethyl]benzonitrile
369.1457


 


4-17




(±)-3-[1-hydroxy-2- pyridin-2-yl-1-pyridin-3- yl-2-(1H-1,2,3-triazol-1- yl)ethyl]benzonitrile (Diastereomer A)
369.1464


 


4-18




(±)-3-[1-hydroxy-2- pyridin-2-yl-1-pyridin-3- yl-2-(1H-1,2,3-triazol-1- yl)ethyl]benzonitrile (Diastereomer B)
369.1464


 


4-19




(±)-3-(2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl)-1,3-oxazinan-2- one
376.1646


 


4-20




(±)-3-[1-hydroxy-2-(2- oxo-1,3-oxazinan-3-yl)-2- pyridin-2-yl-1-pyridin-3- ylethyl]benzonitrile
401.1


 


4-21




(±)-1-(2-hydroxy-1-pyridin- 2-yl-2,2-dipyridin-3-ylethyl 2-oxo-1,2-dihydropyridine- carbonitrile
396.4













The variables C, B, and Y in the scheme are as defined in “Formula I”.

EXAMPLE 122
(±)-3-(2-hydroxy-2,2-dipyridin-3-yl-1-pyrrolidin-1-ylethyl)benzonitrile




Step A:

To a mixture of glyoxylic acid monohydrate (1.54 g), pyrrolidine (1.19 g), and 220 mL acetonitrile was added 3-bromophenyl boronic acid (3.35 g). The reaction was heated at 80 C for 93 h. After cooling to room temperature, volatiles were removed in vacuo, and the residue was dissolved in 75 mL of benzene and 38 mL of methanol. Trimethylsilyldiazomethane (2M in hexanes, 16.7 mL) was added via syringe, and the reaction was stirred at room temperature for 2.5 h. The volatiles were removed in vacuo, and the residue was purified by flash chromatography to provide 1.53 g of methyl (3-bromophenyl)(pyrrolidin-1-yl)acetate. MS 298, 300 (Br).
Step B:
A solution of 3-bromopyridine (1.62 g) in 40 mL of diethyl ether was cooled to −78 C. n-BuLi (2.87 M in hexanes, 3.6 mL) was added via syringe, and the resulting mixture was stirred for 15 min. A solution of methyl (3-bromophenyl)-(pyrrolidin-1-yl)acetate (1.53 g) in 10 mL of THF was added via cannula. The reaction was stirred for 5 min at −78 C then for 2.5 h at 0 C. After quenching with saturated aqueous NH4Cl, the mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3. The aqueous solution was extracted once with ethyl acetate, and the combined organic solutions were dried (Na2SO4) and concentrated in vacuo. Flash chromatography provided a solid that was triturated with diethyl ether to give 893 mg of 2-(3-bromophenyl)-1,1-dipyridin-3-yl-2-pyrrolidin-1-ylethanol. HRMS calcd for C22H23BrN3O (M+H)+: 424.1019; found: 424.1025. 1H NMR (CDCl3, 500 MHz) δ 9.11 (d, J=2.4 Hz, 1H); 8.51-8.48 (m, 2H); 8.14-8.11 (m, 2H); 7.60 (ddd, J=1.6, 2.3, 8.2 Hz, 1H); 7.46 (t, J=3.5 Hz, 1H); 7.29 (dd, J=4.8, 8.1 Hz, 1H); 7.20 (t, J=8.7 Hz, 2H); 6.97-6.92 (m, 2H); 5.94 (s, 1H); 4.44 (s, 1H); 2.26 (m, 4H); 1.63 (m, 4H).
Step C:
2-(3-bromophenyl)-1,1-dipyridin-3-yl-2-pyrrolidin-1-ylethanol (40 mg, 0.094 mmol), Pd2(dba)3 (3 mg, 0.003 mmol), dppf (4 mg, 0.008 mmol), Zn(CN)2 (22 mg, 0.189 mmol) and zinc powder (1 mg, 0.011 mmol) were combined in a flask, purged with argon, and then 1.5 mL DMA was added. This mixture was heated at 120° C. for 3.5 h then cooled to room temperature. The reaction mixture was then diluted with EtOAc and washed with 2N aqueous NH4OH (1×). The organic layer was dried over Na2SO4 and concentrated. The resulting viscous liquid was purified by reverse phase HPLC. Pure fractions were combined and extracted from saturated aqueous NaHCO3 with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4 and concentrated to yield the titled compound as a white solid (22 mg, 63%). HRMS calcd for C23H22N4O (M+H)+: 371.1853; found: 371.1867. 1H NMR (CDCl3, 500 MHz) δ 9.11 (d, J=2.2 Hz, 1H); 8.51 (dd, J=1.2, 4.6 Hz, 1H); 8.47 (d, J=1.9 Hz, 1H); 8.13 (m, 2H); 7.64 (s, 1H); 7.59 (m, 1H); 7.53 (br d, J=6.6 Hz, 1H); 7.37 (d, J=7.8 Hz, 1H); 7.31 (dd, J=4.6, 7.8 Hz, 1H); 7.21 (t, J=7.8 Hz, 1H); 6.94 (dd, J=4.6, 8.1 Hz, 1H); 5.71 (br, 1H); 5.30 (s, 1H); 2.25 (br d, J=26.9 Hz, 4H); 1.65 (s, 4H).
The following compounds were made according to Scheme 5, where intermediates in the scheme were modified according to literature methods. Example 181 was prepared by acid deprotection of the corresponding tert-butyl carbamate derivative. Examples 182-189 were prepared by fluoride-mediated deprotection of the corresponding primary or secondary tert-butyldimethylsilyl ethers. Example 192 was prepared by trifluoroacetic acid deprotection of Example 191, and Examples 193-201 were prepared in likewise fashion from the corresponding 4-methoxybenzyl amines.
EXAMPLES 123-201













Example
Compound
Name
MS (M + 1)


















123




(±)-2-(4-methoxyphenyl)- 1,1-dipyridin-3-yl-2- pyrrolidin-1-ylethanol
376.2047


 


124




(±)-2-(2-fluorophenyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
364.1817


 


125




(±)-2-(3-fluorophenyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
364.1816


 


126




(±)-2-(4-fluorophenyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
364.1817


 


127




(±)-2-(3,3- difluoropyrrolidin-1-yl)-2- (4-methoxyphenyl)-1,1- dipyridin-3-ylethanol
412.1849


 


128




(±)-2-(2-methoxyphenyl)- 1,1-dipyridin-3-yl-2- pyrrolidin-1-ylethanol
376.2039


 


129




(±)-2-(3-methoxyphenyl)- 1,1-dipyridin-3-yl-2- pyrrolidin-1-ylethanol
376.2042


 


130




(±)-2-(2-chlorophenyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
380.1536


 


131




(±)-2-(3-chlorophenyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
380.1525


 


132




(±)-2-(4-chlorophenyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
380.1546


 


133




(±)-2-(3,3- difluoropyrrolidin-1-yl)-2- (4-fluorophenyl)-1,1- dipyridin-3-ylethanol
400.1646


 


134




(±)-2-(3,4-difluorophenyl)- 1,1-dipyridin-3-yl-2- pyrrolidin-1-ylethanol
382.1722


 


135




(±)-2-(3,3- difluoropyrrolidin-1-yl)-2- (3-methoxyphenyl)-1,1- dipyridin-3-ylethanol
412.1837


 


136




(±)-2-(2,4-difluorophenyl)- 1,1-dipyridin-3-yl-2- pyrrolidin-1-ylethanol
382.1722


 


137




(±)-2-(3-methoxyphenyl)-2- piperidin-1-yl-1,1-dipyridin- 3-ylethanol
390.2173


 


138




(±)-2-(4-fluorophenyl)-2- piperidin-1-yl-1,1-dipyridin- 3-ylethanol
378.1973


 


139




(±)-2-(2-fluoro-3- methoxyphenyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
394.1929


 


140




(±)-2-(2,6-difluorophenyl)- 1,1-dipyridin-3-yl-2- pyrrolidin-1-ylethanol
382.1719


 


141




(±)-2-(3-methoxyphenyl)- 1,1-dipyridin-3-yl-2-[4- (trifluoromethyl)piperidin-1- yl]ethanol
458.2077


 


142




(±)-tert-butyl 7-[2-hydroxy- 1-(3-methoxyphenyl)-2,2- dipyridin-3-ylethyl]-2,7- diazaspiro[3.5]nonane-2- carboxylate
531.2993


 


143




2-[(2r)-2- (methoxymethyl)pyrrolidin- 1-yl]-2-phenyl-1,1-dipyridin- 3-ylethanol (1:1 mixture diastereomers)
390.2175


 


144




(±)-2-(4-tert-butylphenyl)- 1,1-dipyridin-3-yl-2- pyrrolidin-1-ylethanol
402.2554


 


145




(±)-2-(4-ethylphenyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
374.2264


 


146




(±)-2-(2-methylphenyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
360.2093


 


147




(±)-2-(3-methylphenyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
360.2079


 


148




(±)-2-(4-methylphenyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
360.2078


 


149




(±)-2-(4-propylphenyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
388.2379


 


150




(±)-2-(2-ethoxyphenyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
390.2184


 


151




(±)-2-(3-ethoxyphenyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
390.2188


 


152




(±)-2-(1,3-benzodioxol-5- yl)-1,1-dipyridin-3-yl-2- pyrrolidin-1-ylethanol
390.1819


 


153




(±)-1,1-dipyridin-3-yl-2- pyrrolidin-1-yl-2-[3- (trifluoromethoxy)phenyl]ethanol
430.1738


 


154




(±)-1,1-dipyridin-3-yl-2- pyrrolidin-1-yl-2-[4- (trifluoromethoxy)phenyl]ethanol
430.1736


 


155




(±)-2-(4-fluoro-2- methoxyphenyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
394.1921


 


156




(±)-2-(4-fluoro-2- methylphenyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
378.1975


 


157




(±)-2-(4-fluoro-3- methylphenyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
378.1970


 


158




(±)-2-[4-(1h-pyrazol-1- yl)phenyl]-1,1-dipyridin-3- yl-2-pyrrolidin-1-ylethanol
412.2120


 


159




(±)-1,1-dipyridin-3-yl-2- pyrrolidin-1-yl-2-[2- (trifluoromethoxy)phenyl]ethanol
430.1743


 


160




(±)-2-(4-fluoropiperidin-1- yl)-2-(3-methoxyphenyl)- 1,1-dipyridin-3-ylethanol
408.2091


 


161




(±)-2-(4,4-difluoropiperidin- 1-yl)-2-(3-methoxyphenyl)- 1,1-dipyridin-3-ylethanol
426.1988


 


162




(±)-2-(3,3-difluoropiperidin- 1-yl)-2-(3-methoxyphenyl)- 1,1-dipyridin-3-ylethanol
426.1995


 


163




(±)-2-(3-fluoropiperidin-1- yl)-2-(3-methoxyphenyl)- 1,1-dipyridin-3-ylethanol (1:1 mixture diastereomers)
408.2097


 


164




(±)-2-(2-bromophenyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
424.1021


 


165




(±)-2-(4-bromophenyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
424.1021


 


166




(±)-2-[allyl(methyl)amino]- 2-phenyl-1,1-dipyridin-3- ylethanol
346.1923


 


167




(±)-2-(3-bromophenyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
424.1025


 


168




2-[(3S)-3-fluoropyrrolidin-1- yl]-2-(3-methoxyphenyl)- 1,1-dipyridin-3-ylethanol (diastereomer A)
394.1931


 


169




(±)-2-(3,3-difluoroazetidin- 1-yl)-2-phenyl-1,1-dipyridin- 3-ylethanol
368.1568


 


170




(±)-2-(3,3-difluoroazetidin- 1-yl)-2-(4-fluorophenyl)-1,1- dipyridin-3-ylethanol
386.1466


 


171




(±)-1,1-dipyridin-3-yl-2- pyrrolidin-1-yl-2-(3- thienyl)ethanol
352.1485


 


172




(±)-2-(3-furyl)-1,1- dipyridin-3-yl-2-pyrrolidin- 1-ylethanol
336.1704


 


173




(±)-2-(1-benzothien-2-yl)- 1,1-dipyridin-3-yl-2- pyrrolidin-1-ylethanol
402.1649


 


174




(±)-2-(4-fluorophenyl)-2-(3- methoxyazetidin-1-yl)-1,1- dipyridin-3-ylethanol
380.1765


 


175




(±)-2-(5-chloro-2-thienyl)- 1,1-dipyridin-3-yl-2- pyrrolidin-1-ylethanol
386.1110


 


176




(±)-2-(3,3-difluoroazetidin- 1-yl)-2-(2-fluoro-3- methoxyphenyl)-1,1- dipyridin-3-ylethanol
416.1573


 


177




(±)-2-(3-chlorophenyl)-2- (3,3-difluoroazetidin-1-yl)- 1,1-dipyridin-ylethanol
402.1183


 


178




(±)-2-(3,3-difluoroazetidin- 1-yl)-2-(3-methoxyphenyl)- 1,1-dipyridin-3-ylethanol
398.1674


 


179




2-[(3R,4R)-3,4- difluoropyrrolidin-1-yl]-2- phenyl-1,1-dipyridin-3- ylethanol (diastereomer A)
382.1744


 


180




2-[(3R,4R)-3,4- difluoropyrrolidin-1-yl]-2- phenyl-1,1-dipyridin-3- ylethanol (diastereomer B)
382.1740


 


181




2-(3-chlorophenyl)-2- [(1S,4S)-2,5- diazabicyclo[2.2.1]hept-2- yl]-1,1-dipyridin-3-ylethanol (2:1 mixture diastereomers)
407.1617


 


182




(±)-1-(2-hydroxy-1-phenyl- 2,2-dipyridin-3- ylethyl)piperidin-3-ol (1:1 mixture diastereomers)
376.2010


 


183




(±)-3-[2-hydroxy-1-(3- hydroxypiperidin-1-yl)-2,2- dipyridin-3- ylethyl]benzonitrile (2:1 mixture diastereomers)
401.1947


 


184




(±)-1-[2-hydroxy-1-(3- methoxyphenyl)-2,2- dipyridin-3- ylethyl]piperidin-4-ol
406.2132


 


185




(3R)-1-[1-(3-chlorophenyl)- 2-hydroxy-2,2-dipyridin-3- ylethyl]pyrrolidin-3-ol (1:1 mixture diastereomers)
396.1490


 


186




(3R)-1-[1-(4-fluorophenyl)- 2-hydroxy-2,2-dipyridin-3- ylethyl]pyrrolidin-3-ol (1:1 mixture diastereomers)
380.1770


 


187




(3R)-1-{2-hydroxy-2,2- dipyridin-3-yl-1-[3- (trifluoromethoxy)phenyl]ethyl} pyrrolidin-3-ol (1:1 mixture diastereomers)
446.1694


 


188




2-(3-chlorophenyl)-2-[(2S)- 2- (hydroxymethyl)pyrrolidin- 1-yl]-1,1-dipyridin-3- ylethanol (diastereomer A)
410.1642


 


189




2-(4-fluorophenyl)-2-[(2S)- 2- (hydroxymethyl)pyrrolidin- 1-yl]-1,1-dipyridin-3- ylethanol (diastereomer A)
394.1943


 


190




(±)-1-(2-hydroxy-1-phenyl- 2,2-dipyridin-3-ylethyl)-n,n- dimethylpiperidine-3- sulfonamide (diastereomer A)
467.2109


 


191




(±)-2-[cyclobutyl(4- methoxybenzyl)amino]-2-(4- fluorophenyl)-1,1-dipyridin- 3-ylethanol
484.2425


 


192




(±)-2-(cyclobutylamino)-2- phenyl-1,1-dipyridin-3- ylethanol
346.1918


 


193




(±)-2-(cyclopentylamino)-2- phenyl-1,1-dipyridin-3- ylethanol
360.2075


 


194




(±)-2-(cyclohexylamino)-2- phenyl-1,1-dipyridin-3- ylethanol
374.2230


 


195




(±)-2-(ethylamino)-2- phenyl-1,1-dipyridin-3- ylethanol
320.1769


 


196




(±)-2-(cyclobutylamino)-2- (4-fluorophenyl)-1,1- dipyridin-3-ylethanol
364.1818


 


197




(±)-2-phenyl-1,1-dipyridin- 3-yl-2-[(2,2,2- trifluoroethyl)amino]ethanol
374.1471


 


198




(±)-2-phenyl-1,1-dipyridin- 3-yl-2-[(2,2,2- trifluoroethyl)amino]ethanol
376.2016


 


199




(±)-2-(3-chlorophenyl)-2- (cyclobutylamino)-1,1- dipyridin-3-ylethanol
380.1521


 


200




(±)-2-(4-fluorophenyl)-1,1- dipyridin-3-yl-2-[(2,2,2- trifluoroethyl)amino]ethanol
392.1378


 


201




(±)-2-(3-chlorophenyl)-1,1- dipyridin-3-yl-2-[(2,2,2- trifluoroethyl)amino]ethanol
408.1100









The following compounds were made from compounds in Examples 1-201, using methods known to those skilled in the art. Examples 202, 203, 281 and 284 were prepared by acid deprotection of Examples 48, 49, 142 and 17, respectively. Example 217 was prepared by acid deprotection of the corresponding tert-butyl carbamate. Examples 204-280, 282 and 285, were prepared from Examples 202, 203, 217 or 284 by acylations or reductive aminations or combinations of both. Example 283 was prepared by O-alkylation of Example 1. Example 286 was prepared by trifluoroacetic acid treatment of Example 77, and Example 287 was prepared from Example 286. Example 288 was prepared by MnO2 oxidation for Example 33. Examples 289 and 290 were prepared by reduction of Examples 82 and 104, respectively. The acid 291 was prepared from bromide 165 by palladium mediated carbonylation, and was converted to amides 292 and 293 by standard amide coupling. Amides 295 and 296 were prepared in likewise fashion from the carboxylic acid derived from carbonylation of bromide 167, and ester 294 was prepared from the same acid using trimethylsilyldiazomethane. Example 297 was prepared by hydrolysis of Example 103. Example 298 was prepared by palladium mediated cyanation of bromide 38. Example 299 was prepared from example 166 by olefin dihydroxylation, and Example 300 was prepared from example 299 by NaIO4 oxidative cleavage followed by sodium borohydride reduction. Example 301 prepared by oxidation of example 51, and 301 was converted to 302 using excess methyl Grignard.
EXAMPLES 202-302 AND 5-1













Example
Compound
Name
MS (M + 1)


















202




(2S)-2-amino-2-phenyl-1,1- dipyridin-3-ylethanol
292.1454


 


203




(2R)-2-amino-2-phenyl-1,1- dipyridin-3-ylethanol
292.1455


 


204




2-(benzyloxy)-N-[(1S)-2- hydroxy-1-phenyl-2,2- dipyridin-3- ylethyl]acetamide
440.1970


 


205




N-[(1S)-2-hydroxy-1-phenyl- 2,2-dipyridin-3-ylethyl]-2- methoxyacetamide
364.1657


 


206




1-hydroxy-N-[(1S)-2- hydroxy-1-phenyl-2,2- dipyridin-3- ylethyl]cyclopropane- carboxamide
376.1664


 


207




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-2- methoxyacetamide
364.2


 


208




2-(benzyloxy)-N-[(1R)-2- hydroxy-1-phenyl-2,2- dipyridin-3-ylethyl]- acetamide
440.1974


 


209




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]benzenesulfonamide
432.2


 


210




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-1- phenylmethanesulfonamide
446.3


 


211




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-2- phenoxyacetamide
426.4


 


212




(1R)-N2-benzoyl-N1-(2- hydroxy-1-phenyl-2,2- dipyridin-3- ylethyl)glycinamide
453.2


 


213




(1R)-N2-Boc-N1-(2-hydroxy- 1-phenyl-2,2-dipyridin-3- ylethyl)glycinamide
449.5


 


214




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-2- phenylethanesulfonamide
460.0


 


215




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-3- phenylpropane-1- sulfonamide
474.2


 


216




tert-butyl (1R)-1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3- ylethylcarbamate
410.1879


 


217




(2R)-2-amino-2-(4- fluorophenyl)-1,1-dipyridin- 3-ylethanol
310.2


 


218




N-[(1R)-1-(4-fluorophenyl)- 2-hydroxy-2,2-dipyridin-3- ylethyl]-5-phenylisoxazole- 3-carboxamide
481.3


 


219




N-[(1R)-1-(4-fluorophenyl)- 2-hydroxy-2,2-dipyridin-3- ylethyl]-3-phenylisoxazole- 5-carboxamide
481.3


 


220




N-[(1R)-1-(4-fluorophenyl)- 2-hydroxy-2,2-dipyridin-3- ylethyl]-3-phenyl-1H- pyrazole-5-carboxamide
480.6


 


221




N-[(1R)-1-(4-fluorophenyl)- 2-hydroxy-2,2-dipyridin-3- ylethyl]-3-pyrdin-2-yl-1H- pyrazole-5-carboxamide
481.3


 


222




N-[(1S)-2-hydroxy-1-phenyl- 2,2-dipyridin-3- ylethyl]cyclobutanecarboxamide
374.1886


 


223




N-[(1S)-2-hydroxy-1-phenyl- 2,2-dipyridin-3-ylethyl]-1- (trifluoromethyl)cyclobutane carboxamide
442.1736


 


224




N-ethyl-N′-[(1S)-2-hydroxy- 1-phenyl-2,2-dipyridin-3- ylethyl]urea
363.1816


 


225




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-3- methoxybenzamide
426.1801


 


226




(1R)-ethyl {[(2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl)amino]carbonyl} carbamate
407.1717


 


227




(1R)-N-ethyl-N′-(2-hydroxy- 1-phenyl-2,2-dipyridin-3- ylethyl)urea
363.1815


 


228




(1R)-N-(2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl)-N-phenylurea
411.1816


 


229




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]cyclopropane- carboxamide
360.1


 


230




(1R)-N-(2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl)cyclobutane- carboxamide
374.1855


 


231




(1R)-N-(2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl)-1- (trifluoromethyl)cyclobutane carboxamide
442.1714


 


232




benzyl[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]carbamate
426.1799


 


233




phenyl[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]carbamate
412.1655


 


234




(1R)-3,3,3-trifluoro-n-(2- hydroxy-1-phenyl-2,2- dipyridin-3- ylethyl)propanamide
402.1405


 


235




(2R)-2-phenyl-2-[(1H- pyrazol-5-ylmethyl)amino]- 1,1-dipyridin-3-ylethanol
372.1825


 


236




(1R)-3,3,3-trifluoro-2- hydroxy-N--(2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl)propanamide
418.1369


 


237




(1R)-2,2,2-trifluoro-N-(2- hydroxy-1-phenyl-2,2- dipyridin-3- ylethyl)acetamide
388.1283


 


238




(1R)-N-(2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl)-3- phenylpropanamide
424.2017


 


239




(1R)-N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-N-methylbenzamide
410.1860


 


240




(1R)-N-2-hydroxy-1- phenyl-(2,2-dipyridin-3- ylethyl)-2- methoxybenzamide
426.4


 


241




(1R)-N-(2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl)-2-phenylacetamide
410.1860


 


242




(1R)-2-(benzylamino)-2- phenyl-1,1-dipyridin-3- ylethanol
382.1912


 


243




(1R)-2- [(cyclopropylmethyl)amino]- 2-phenyl-1,1-dipyridin-3- ylethanol
346.1913


 


244




(1R)-2- [(cyclohexylmethyl)amino]- 2-phenyl-1,1-dipyridin-3- ylethanol
388.2381


 


245




(2R)-2- [(cyclopentylmethyl)amino]- 2-phenyl-1,1-dipyridin-3- ylethanol
374.2218


 


246




(1R)-N--(2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl)-4-phenylbutanamide
438.2174


 


247




tert-butyl[(1S)-1-({[(1R)-2- hydroxy-1-phenyl-2,2- dipyridin-3- ylethyl]amino}carbonyl)-3- phenylpropyl]carbamate
553.2786


 


248




tert-butyl[(1R)-1-({[(1R)-2- hydroxy-1-phenyl-2,2- dipyridin-3- ylethyl]amino}carbonyl)-3- phenylpropyl]carbamate
553.2787


 


249




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-4-oxo-4- phenylbutanamide
452.1950


 


250




(2S)-2-amino-N-[(1R)-2- hydroxy-1-phenyl-2,2- dipyridin-3-ylethyl]-4- phenylbutanamide
453.2269


 


251




(2R)-2-amino-N-[(1R)-2- hydroxy-1-phenyl-2,2- dipyridin-3-ylethyl]-4- phenylbutanamide
453.2268


 


252




trans-N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-2- phenylcyclopropanecarboxamide
436.2015


 


253




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-4-(methylamino)-4- phenylbutanamide
467.2435


 


254




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-3-(1H-indol-3- yl)propanamide
463.2127


 


255




(2S)--[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-2- [(methylsulfonyl)amino]-4- phenylbutanamide
531.2051


 


256




(2S)-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-2- [(methylsulfonyl)amino]-4- phenylbutanamide
531.2054


 


257




(2S)-2-(acetylamino)-N- [(1R)-2-hydroxy-1-phenyl- 2,2-dipyridin-3-ylethyl]-4- phenylbutanamide
495.2394


 


258




(2R)-2-(acetylamino)-N- [(1R)-2-hydroxy-1-phenyl- 2,2-dipyridin-3-ylethyl]-4- phenylbutanamide
495.2395


 


259




4-hydroxy-N-[(1R)-2- hydroxy-1-phenyl-2,2- dipyridin-3-ylethyl]-4- phenylbutanamide
454.2137


 


260




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-4-(5,6,7,8- tetrahydro-1,8-napthyridin- 2-yl)butanamide
494.2547


 


261




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-2-(4- phenylpiperazin-1- yl)acetamide
494.2552


 


262




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-2-(2-phenyl-1,3- thiazol-5-yl)acetamide
493.1699


 


263




2-(1,3-benzothiazol-2- ylthio)--N-[(1R)-2-hydroxy- 1-phenyl-2,2-dipyridin-3- ylethyl]acetamide
499.1249


 


264




3-(1-H-benzimidazol-1-yl)- N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]propanamide
464.2077


 


265




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-3-(1-H-pyrazol-1- yl)propanamide
414.1927


 


266




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-3-(3-methyl-1-h- pyrazol-1-yl)propanamide
428.2076


 


267




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-3-pyrazin-2- ylpropanamide
426.1920


 


268




3-(2-hydroxy-2,3-dihydro- 1,3-benzoxazol-2-yl)-N- [(1R)-2-hydroxy-1-phenyl- 2,2-dipyridin-3- ylethyl]propanamide
483.2040


 


269




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-1-(pyridin-3- ylmethyl)piperidine-4- carboxamide
494.2562


 


270




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-1-pyrimidin-2- ylpiperidine-4-carboxamide
481.2350


 


271




N-[(1R)-1-(4-fluorophenyl)- 2-hydroxy-2,2-dipyridin-3- ylethyl]-4-phenylbutanamide
456.2089


 


272




2-(benzyloxy)-N-[(1R)-1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3- ylethyl]acetamide
458.1885


 


273




benzyl [(1R)-1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3- ylethyl]carbamate
444.1725


 


274




2-phenylethyl [(1R)-2- hydroxy-1-phenyl-2,2- dipyridin-3- ylethyl]carbamate
440.1907


 


275




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-4-pyridin-4- ylbutanamide
439.2129


 


276




N-[(1R)-1-(4-fluorophenyl)- 2-hydroxy-2,2-dipyridin-3- ylethyl]-1-phenyl-1H- pyrazole-4-carboxamide
480.1830


 


277




N-[(1R)-1-(4-fluorophenyl)- 2-hydroxy-2,2-dipyridin-3- ylethyl]-4-(6-oxopyridazin- 1(6H)-yl)butanamide
474.1928


 


278




N-[(1R)-1-(4-fluorophenyl)- 2-hydroxy-2,2-dipyridin-3- ylethyl]pyrazolo[1,5- a]pyridine-2-carboxamide
454.1688


 


279




N-[(1R)-2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl]-5-phenyl-2- furamide
462.1818


 


280




(2R)-2-phenyl)-2-{[(1- phenyl-1h-pyrazol-4- yl)methyl]amino}-1,1- dipyridin-3-ylethanol
448.2136


 


 280a




(±)-N-[1-(4-fluorophenyl)-2- hydroxy-2,2-dipyridin-3- ylethyl]-5-propylisoxazole- 3-carboxamide
447.1849


 


281




(±)-2-(2,7- diazaspiro[3.5]non-7-yl)-2- (3-methoxyphenyl)-1,1- dipyridin-3-ylethanol
461.2435


 


282




(±)-2-phenyl-2-(N- hydroxyacetyl)-piperazin-1- yl-1,1-dipyridin-3-ylethanol
419.2097


 


283




(±)-4-(2-methoxy-1- phenyl-2,2-dipyridin-3- ylethyl)morpholine
376.2023


 


284




(±)-2-phenyl-2-piperazin- 1-yl-1,1-dipyridin-3- ylethanol
361.2020


 


285




(±)-2-(4-acetylpiperazin- 1-yl)-2-phenyl-1,1- dipyridin-3-ylethanol
403.2126


 


286




(±)-1-[1-(4-fluorophenyl)- 2-hydroxy-2,2-dipyridin- 3-ylethyl]imidaazolidin-2- one
379.1575


 


287




(±)-N-ethyl-3-[1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3-ylethyl]-2- oxoimidazolidine-1- carboxamide
450.1


 


288




(±)-2-phenyl-1,1- dipyridin-3-yl-2-(1H- pyrrol-1-yl)ethanol
342.1607


 


289




(±)-2-[3-(hydroxymethyl)-1H- pyrazol-1-yl]-2-pyridin-2-yl- 1,1-dipyridin-3-ylethanol
374.1624


 


290




(±)-2-[4-(hydroxymethyl)- 1H-pyrazol-1-yl]-2-phenyl- 1,1-dipyridin-3-ylethanol
373.2


 


291




(±)-4-(2-hydroxy-2,2- dipyridin-3-yl-1-pyrrolidin- 1-ylethyl)benzoic acid
390.1795


 


292




(±)-4-(2-hydroxy-2,2- dipyridin-3-yl-1-pyrrolidin- 1-ylethyl)-N- methylbenzamide
403.2108


 


293




(±)-4-(2-hydroxy-2,2- dipyridin-3-yl-1-pyrrolidin- 1-ylethyl)-N,N- dimethylbenzamide
417.2287


 


294




(±)-methyl 3-(2-hydroxy- 2,2-dipyridin-3-yl-1- pyrrolidin-1- ylethyl)benzoate
404.1956


 


295




(±)-3-(2-hydroxy-2,2- dipyridin-3-yl-1-pyrrolidin- 1-ylethyl)-N,N- dimethylbenzamide
417.2301


 


296




(±)-3-(2-hydroxy-2,2- dipyridin-3-yl-1-pyrrolidin- 1-ylethyl)-N- methylbenzamide
403.2147


 


297




(±)-1-[1-(4-fluorophenyl)-2- hydroxy-2,2-dipyridin-3- ylethyl]-2-oxo-1,2- dihydropyridine-3- carboxylic acid
432.1354


 


298




(±)-3-(2-hydroxy-1- morpholin-4-yl-2,2- dipyridin-3- ylethyl)benzonitrile
387.1817


 


299




(±)-3-[(2-hydroxy-1-phenyl- 2,2-dipyridin-3- ylethyl)(methyl)amino]propane- 1,2-diol (1:1 mixture diastereomers)
380.1959


 


300




(±)-2- [hydroxyethyl(methyl)amino]- 2-phenyl-1,1-dipyridin-3- ylethanol
350.1851


 


301




(±)-1-(2-hydroxy-1-phenyl- 2,2-dipyridin-3- ylethyl)pyrrolidin-3-one
360.1709


 


302




(±)-1-(2-hydroxy-1- phenyl-2,2-dipyridin-3- ylethyl)-3- methylpyrrolidin-3-ol (5:1 mixture diastereomers)
376.2009


 










5-1




(±)-N-[1-(4-fluorophenyl)-2- hydroxy-2,2-dipyridin-3- ylethyl]-5-propylisoxazole- 3-carboxamide
447.1849









The following fluorinated compounds were made by treatment of Examples 1-201 compounds with DAST, in accordance with literature methods. Structures of compounds 303-319 are represented by defining variables and “{circle around (C)}” of the structure




EXAMPLES 303-319













Example
Compound
Name
MS (M + 1)







303




(±)-3,3′-[2-(2,5-dihydro-1H- pyrrol-1-yl)-1-fluoro-2- phenylethane-1,1- diyl]dipyridine
346.1719


 


304




(±)-3,3′-[2-(3-chlorophenyl)- 2-(3,3-difluoroazetidin-1- yl)-1-fluoroethane-1,1- diyl]dipyridine
404.2


 


305




(3R)-1-[2-fluoro-1-(3- methoxyphenyl)-2,2- dipyridin-3- ylethyl]pyrrolidin-3-ol
394.1921


 


306




(±)-3,3′-[1-fluoro-2- pyrrolidin-1-yl-2-(3- thienyl)ethane-1,1- diyl]dipyridine
354.1448


 


307




(±)-3,3′-(1-fluoro-2-phenyl- 2-pyrrolidin-1-ylethane-1,1- diyl]dipyridine
348.1871


 


308




(±)-3,3-difluoro-1-[2-fluoro- 1-(2-fluoro-3- methoxyphenyl)-2,2- dipyridin-3-ylethyl]azetidine
418.3


 


309




(±)-3,3′-[1-fluoro-2-(4- fluorophenyl)-2-piperidin-1- ylethane-1,1-diyl]dipyridine
380.1938


 


310




(±)-3,3′-[1-fluoro-2-(4- methylphenyl)-2-pyrrolidin- ylethane-1,1- diyl]dipyridine
362.2031


 


311




(±)-3,3′-[2-(1,3- benzodioxol-5-yl)-1-fluoro- 2-pyrrolidin-1-ylethane-1,1- diyl]dipyridine
392.1822


 


312




(±)-N-ethyl-N-(2-fluoro-1- phenyl-2,2-dipyridin-3- ylethyl)cyclobutanamine
376.2190


 


313




(±)-3,3′-[2-(3,3- difluoropyrrolidin-1-yl)-1- fluoro-2-phenylethane-1,1- diyl]dipyridine
384.1681


 


314




(±)-3,3′-[1-fluoro-2-(4- fluoro-2-methylphenyl)-2- pyrrolidin-1-ylethane-1,1- diyl]dipyridine
380.1943


 


315




(±)-3-fluoro-N,N-dimethyl- 3,3-dipyridin-3-yl-2- pyrrolidin-1-ylpropanamide
343.1932


 


316




(±)-3,3′-{1-fluoro-2- pyrrolidin-1-yl-2-[4- (trifluoromethoxy)phenyl] ethane-1,1-diyl}dipyridine
432.1736


 


317




(±)-3,3′-[1-fluoro-2-(4- fluoro-3-methylphenyl)-2- pyrrolidin-1-ylethane-1,1- diyl]dipyridine
380.1957


 


318




(±)-4-(2-fluoro-2,2- dipyridin-3-yl-1-pyrrolidin- 1-ylethyl)benzonitrile
373.1834


 


319




(±)-3-(2-fluoro-2,2- dipyridin-3-yl-1-pyrrolidin- 1-ylethyl)benzonitrile
373.1828









The following compounds were made from 2-(3-{[tert-butyl(dimethyl)silyl]oxy}azetidin-1-yl)-2-(4-fluorophenyl)-1,1-dipyridin-3-ylethanol, which was prepared in accordance with scheme 5, using methods known to those skilled in the art. Unless otherwise shown, structures of compounds 320-334 and 335-342 are represented by defining variables




and “Y” of the structure





EXAMPLES 320-334













Example
Compound
Name
MS (M + 1)







320




(±)-1-[1-(4-fluorophenyl)-2- hydroxy-2,2-dipyridin-3- ylethyl]azetidin-3-ol
366.1595


 


321




(±)-1-[1-(4-fluorophenyl)-2- hydroxy-2,2-dipyridin-3- ylethyl]azetidin-3-yl methanesulfonate
444.1374


 


322




(±)-2-(3-aminoazetidin-1- yl)-2-(4-fluorophenyl)-1,1- dipyridin-3-ylethanol
365.1763


 


323




(±)-2-[3- (dimethylamino)azetidin-1- yl]-2-(4-fluorophenyl)-1,1- dipyridin-3-ylethanol
393.2064


 


324




(±)-N-{1-[1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3- ylethyl]azetidin-3- yl}methanesulfonamide
443.1534


 


325




(±)-N-{1-[1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3- ylethyl]azetidin-3- yl}acetamide
407.1857


 


326




(±)-2-(4-fluorophenyl)-2-[3- (methylthio)azetidin-1-yl]- 1,1-dipyridin-3-ylethanol
396.1554


 


327




(±)-1-[1-(4-fluorophenyl)-2- hydroxy-2,2-dipyridin-3- ylethyl]azetidin-3-yl carbamate
409.1667


 


328




(±)-1-[1-(4-fluorophenyl)-2- hydroxy-2,2-dipyridin-3- ylethyl]azetidin-3- sulfonamide
429.1357


 


329




(±)-1-[1-(4-fluorophenyl)-2- hydroxy-2,2-dipyridin-3- ylethyl]-N,N- dimethylazetidin-3- sulfonamide
457.1700


 


330




(±)-N-{1-[1-(4- fluorophenyl)-2-hydroxy- 2,2-dipyridin-3- ylethyl]azetidin-3-yl}-N′- phenylurea
484.2135


 


331




(±)-1-[1-(4-fluorophenyl)-2- hydroxy-2,2-dipyridin-3- ylethyl]azetidin-3-yl phenylcarbamate
485.1966


 


332




(±)-1-[1-(4-fluorophenyl)-2- hydroxy-2,2-dipyridin-3- ylethyl]azetidin-3-yl pyrrolidine-1-carboxylate
463.2154


 


333




(±)-1-[1-(4-fluorophenyl)-2- hydroxy-2,2-dipyridin-3- ylethyl]azetidin-3-yl methylcarbamate
423.1845


 


334




(±)-1-[1-(4-fluorophenyl)-2- hydroxy-2,2-dipyridin-3- ylethyl]azetidin-3-yl(4- fluorophenyl)carbamate
503.1897









The following compounds were made from compounds in Examples 1-201, using oxidation methods known to those skilled in the art. MCPBA oxidation was used to convert example 24 to 335, example 316 to 336 and 337, example 1 to 338, and example 16 to 339. Methyltrioxorhenium was used to convert example 1 to 340 and 341, and example 170 to 342
EXAMPLES 335-342













Example
Compound
Name
MS (M + 1)







335




(±)-2-(1,1- dioxidothiomorpholin-4-yl)- 2-phenyl-1,1-dipyridin-3- ylethanol
410.1513


 


336




(±)-2-(4-fluorophenyl)-2-[3- (methylsulfonyl)azetidin-1- yl]-1,1-dipyridin-3-ylethanol
428.1457


 


337




(±)-2-(4-fluorophenyl)-2-[3- (methylsulfonyl)azetidin-1- yl]-1-(1-oxidopyridin-3-yl)- 1-pyridin-3-ylethanol(1:1 mixture diastereomers)
444.1391


 


338




(±)-2-(4-oxidomorpholin-4- yl)-2-phenyl-1,1-dipyridin-3- ylethanol
378.1799


 


339




(±)-2-(1-oxidopyrrolidin-1- yl)-2-phenyl-1,1-dipyridin-3- ylethanol
362.1859


 


340




(±)-2-(4-oxidomorpholin-4- yl)-1,1-bis(1-oxidopyridin-3- yl)-2-phenylethanol
410.1711


 


341




(±)-2-morpholin-4-yl-1,1- bis(1-oxidopyridin-3-yl)-2- phenylethanol
394.1762


 


342




(±)-2-(3,3-difluoroazetidin- 1-yl)-2-(4-fluorophenyl)-1- (1-oxidopyridin-3-yl)-1- pyridin-3-ylethanol(1:1 mixture diastereomers)
402.1447













The variables C, B, A, and Y in the scheme are as defined in “Formula I”.

EXAMPLE 343
(±)-4-[1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethyl]morpholine




Step A:

Dipyridin-3-ylmethanone (1-1, 2.630 g, 14.28 mmol) was suspended in ethylene glycol (28 mL). KOH (1.682 g, 29.98 mmol) was added and the reaction was stirred at RT for 1 hr until most of the solids were dissolved. Hydrazine monohydrate (1.596 mL, 32.84 mmol) was added and the mixture was heated to 185° C. After 1 hr 45 min, the reaction was cooled to RT, diluted with H2O (150 mL), and extracted with CH2Cl2 (4×100 mL). The combined organics were washed with water, washed with brine (2×), dried over Na2SO4, filtered, and concentrated in vacuo to afford 3-(pyridin-3-ylmethyl)pyridine as a light yellow solid. 1H NMR (CDCl3) δ 8.52-8.49 (m, 4H), 7.47-7.45 (m, 2H), 7.25-7.22 (m, 2H), 3.99 (s, 2H). [M+H]+=171.2.
Step B:
LiHMDS (2.45 mL, 1.2 M in THF, 2.94 mmole) was added to a flame-dried round bottom flask. The mixture was cooled to 0° C. then 6-methoxypyridine-2-carbaldehyde (Comins, Daniel L.; Killpack, Michael O. J. Org. Chem. 1990, 55, 69-73, 161 mg, 1.18 mmole) was added. After 30 minutes di-3-pyridylmethane (200 mg, 1.18 mmole) in dry THF (2.0 mL) was added. After 2 hr the mixture was warmed to RT, quenched with saturated NH4Cl, and extracted with CH2Cl2(3×) and iBuOH (2×). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was taken up in MeOH (5 mL) and H2NOH (0.4 mL, 50% in H2O) was added. After 18 hr the mixture was concentrated. Flash column (gradient, 0-10% MeOH/CH2Cl2) gave 1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethanamine as a pale yellow oil (168 mg, 47%): 1H-NMR (500 MHz, CDCl3) δ 8.64 (d, J=1.95 Hz, 1H), 8.51 (dd, J=1.46 and 3.17 Hz, 1H), 8.36 (d, J=1.95 Hz, 1H), 8.32 (dd, J=1.46 and 3.18 Hz, 1H), 7.76 (d, J=7.82 Hz, 1H), 7.49 (d, J=8.06 Hz, 1H), 7.37-7.27 (m, 2H), 7.09 (m, 1H), 6.56 (d, J=7.08 Hz, 1H), 6.52 (d, J=7.81 Hz, 1H), 4.59 (d, J=9.28 Hz, 1H), 4.42 (d, J=9.28 Hz, 1H), 3.91 (s, 3H).
Step C:
To a solution of 1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethanamine (75 mg, 0.25 mmole) in CH3CN (1 mL) was added a solution of 2,2′-oxydiacetaldehyde in H2O (1.47 mL, 0.5 M, 0.73 mmole). After 10 minutes NaBH3CN (92 mg, 1.47 mmole) was added. After 2 hr 1N HCl (2 mL) was added.
After 1 hr the pH was adjusted to 8 and the mixture extracted with CH2Cl2 (3×) and iBuOH (1×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column (gradient, 0-10% MeOH/CH2Cl2) gave mixed fractions. Fractions containing the product were pooled and concentrated. The mixture was purified by reverse phase HPLC (5-100% CH3CN/H2O+0.1% TFA). Fractions containing the product were pooled, made basic with saturated NaHCO3, and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated to give the title compound (15 mg, 16%) as a white solid: 1H-NMR (500 MHz, CDCl3) δ 8.70 (bs, 1H), 8.48 (bs, 1H), 8.39 (bs, 1H), 8.26 (bd, J=3.9 Hz, 1H), 7.71 (d, J=7.82 Hz, 1H), 7.44-7.36 (m, 2H), 7.28 (m, 1H), 7.03 (m, 1H), 6.52 (m, 2H), 5.01 (d, J=11.72 Hz, 1H), 4.27 (d, J=11.72 Hz, 1H), 3.96 (s, 3H), 3.49 (m, 2H), 3.35 (m, 2H), 2.63 (m, 2H), 2.42 (m, 2H); HRMS, calc'd for C22H25N4O2 (M+1), 377.1972; found 377.1944.
The following compounds were made according to Scheme 6, where intermediates in the Scheme were modified according to literature methods. Example 347 was prepared by reaction of the corresponding (1-aryl-2,2-dipyridin-3-ylethyl)amine with 4-chlorobutyryl chloride followed by ring closure under basic conditions. Example 368 was prepared by reaction of the amine with 3-chloropropanesulfonyl chloride followed by ring closure under basic conditions. Examples 372, 375-378 were prepared by palladium catalyzed amination of 371 with the corresponding carbamate, amide, sulfonamide or urea. Example 373 was prepared by deprotection of 372. Example 379 was prepared by methylation of 372 and deprotection. Examples 380 and 381 were prepared from the corresponding (1-aryl-2,2-dipyridin-3-ylethyl)amine using the method of Tschaen et al. (J. Org. Chem. 1995, 60, 4324). Example 394 was prepared by treatment of the corresponding primary amine with methyl-4-bromo-2-oxopentanoate under reductive amination conditions. Ester reduction of the compound in example 394 provided example 395. Ester hydrolysis of the compound in example 394 provided the corresponding carboxylic acid, which was subjected to standard peptide coupling conditions to provide the amides in examples 396, 397, and 398. Example 401 was prepared by reductive amination of [1-(3-bromophenyl)-2,2-dipyridin-3-ylethyl]amine with methyl[methyl(2-oxoethyl)amino](oxo)acetate, according to a published procedure (Tetrahedron Lett. 2000, 41, 8735). Examples 405 and 406 were prepared by reaction of the corresponding (1-aryl-2,2-dipyridin-3-ylethyl)amine with 2-chloroethyl chloroformate followed by ring closure under basic conditions. Unless otherwise shown, structures of compounds 344-420 and 6-1 to 6-87 are represented by defining variables




and “Y” of the structure





EXAMPLES 344-420 AND 6-1 TO 6-87













Example
Compound
Name
MS (M + 1)







344




(±)-N-[1-(4-fluorophenyl)-2- phenyl-2-pyridin-3- ylethyl]methanesulfonamide
371.3


 


345




(±)-N-[1-(4-fluorophenyl)-2- phenyl-2-pyridin-3-ylethyl]-2- methoxyacetamide
365.1642


 


346




(±)-4-[1-(4-fluorophenyl)-2- phenyl-2-pyridin-3- ylethyl]morpholine
363.1862


 


347




(±)-1-[1-(4-fluorophenyl)-2,2- dipyridin-3-ylethyl]pyrrolidin-2- one
362.1663


 


348




(±)-4-[1-(4-fluorophenyl)-2,2- dipyridin-3-ylethyl]morpholine
364.1


 


349




(±)-[1-(4-fluorophenyl)-2,2- dipyridin-3-ylethyl](2,2,2- trifluoroethyl)amine
376.2


 


350




(±)-4-[1-(3,4-dichlorophenyl)- 2,2-dipyridin-3- ylethyl]morpholine
414.1111


 


351




(±)-4-(1-pyridin-2-yl-2,2- dipyridin-3-ylethyl)morpholine
347.1893


 


352




(±)-4-(1,2,2-tripyridin-3- ylethyl)morpholine
347.1896


 


353




(±)-N′-[1-(4-fluorophenyl)-2,2- dipyridin-3-ylethyl]-N,N- dimethylurea
365.1763


 


354




(±)-3,3′-[2-(4-fluorophenyl)-2- pyrrolidin-1-ylethane-1,1- diyl]dipyridine
348.1879


 


355




(±)-4-[1-(4-fluorophenyl)-2- pyridin-2-yl-2-pyridin-3- ylethyl]morpholine
364.1834


 


356




(±)-[1-(4-fluorophenyl)-2,2- dipyridin-3-ylethyl](2-pyridin-3- ylethyl)amine
399.2


 


357




(±)-N-[1-(4-fluorophenyl)-2,2- dipyridin-3- ylethyl]cyclobutanamine
347.9


 


358




(±)-4-[1-(3-chlorophenyl)-2,2- dipyridin-3-ylethyl]morpholine
380.1504


 


359




(±)-4-[1-(3,5-dichlorophenyl)- 2,2-dipyridin-3- ylethyl]morpholine
414.1114


 


360




(±)-[1-(4-fluorophenyl)-2,2- dipyridin-3-ylethyl](3,3,3- trifluoropropyl)amine
390.1


 


361




(±)-[1-(3-chlorophenyl)-2,2- dipyridin-3-ylethyl](2,2,2- trifluoroethyl)amine
392.1


 


362




(±)-[1-(3,5-dichlorophenyl)-2,2- dipyridin-3-ylethyl](2,2,2- trifluoroethyl)amine
426.0


 


363




(±)-[1-(3,4-dichlorophenyl)-2,2- dipyridin-3-ylethyl](2,2,2- trifluoroethyl)amine
427.8


 


364




(±)-N-[1-(3-chlorophenyl)-2,2- dipyridin-3-ylethyl]-3,3,3- trifluoropropan-1-amine
406.0


 


365




(±)-N-[1-(3,5- dichlorophenyl)-2,2- dipyridin-3-ylethyl]-3,3,3- trifluoropropan-1-amine
441.8


 


366




(±)-N-[1-(4-fluorophenyl)-2,2- dipyridin-3-ylethyl]-3- nitropyridin-2-amine
416.1


 


367




(±)-N-[1-(4-fluorophenyl)-2,2- dipyridin-3-ylethyl]-2- (methylsulfonyl)pyrimidin-4- amine
450.1


 


368




(±)-3,3′-[2-(1,1- dioxidoisothoazolidin-2-yl)-2-(4- fluorophenyl)ethane-1,1- diyl]dipyridine
398.1


 


369




(±)-4-[1-(6-methoxypyridin-2- yl)-2-phenyl-2-pyridin-2- ylethyl]morpholine
398.1830 (M + Na+)


 


370




(±)-N~2~-[1-(4-fluorophenyl)- 2,2-dipyridin-3-ylethyl]pyridine- 2,3-diamine
386.1


 


371




(±)-4-[1-(6-bromopyridin-2-yl)- 2,2-dipyridin-3- ylethyl]morpholine
425.1005


 


372




(±)-tert-butyl [6-(1-morpholin- 4-yl-2,2-dipyridin-3- ylethyl)pyridin-2-yl]carbamate
462.2547


 


373




(±)-6-(1-morpholin-4-yl-2,2- dipyridin-3-ylethyl)pyridin-2- amine
362.1957


 


374




(±)-N-methyl-6-(1-morpholin-4- yl-2,2-dipyridin-3- ylethyl)pyridin-2-amine
376.2126


 


375




(±)-methyl [6-(1-morpholin-4- yl-2,2-dipyridin-3- ylethyl)pyridin-2-yl]carbamate
420.2017


 


376




(±)-N-[6-(1-morpholin-4-yl-2,2- dipyridin-3-ylethyl)pyridin-2- yl]acetamide
404.2068


 


377




(±)-N-[6-(1-morpholin-4-yl-2,2- dipyridin-3-ylethyl)pyridin-2- yl]methanesulfonamide
440.1734


 


378




(±)-N-methyl-N′-[6-(1- morpholin-4-yl-2,2-dipyridin-3- ylethyl)pyridin-2-yl]urea
419.2182


 


379




(±)-N-[1-(4-fluorophenyl)-2,2- dipyridin-3-ylethyl]-3- phenylpropane-1-sulfonamide
476.1794


 


380




(±)-1-[1-(3-bromophenyl)-2,2- dipyridin-3-ylethyl]piperidin-4- one
436.1023


 


381




(±)-3-[1-(4-oxopiperidin-1-yl)- 2,2-dipyridin-3- ylethyl]benzonitrile
383.1859


 


382




(±)-1-[1-(3-bromophenyl)-2,2- dipyridin-3-ylethyl]piperidin-4- ol
438.1181


 


383




(±)-2-{[1-(3-bromophenyl)-2,2- dipyridin-3- ylethyl]amino}ethanol
398.0875


 


384




(±)-N-[1-(3-bromophenyl)-2,2- dipyridin-3-ylethyl]-3,3- difluoroazetidine-1- carboxamide
473.0779


 


385




(±)-[1-(3-bromophenyl)-2,2- dipyridin-3-ylethyl]{[1- (phenylsulfonyl)-1H-pyrrol-2- yl]methyl}amine
573.0959


 


386




(±)-N-[1-(3-bromophenyl)-2,2- dipyridin-3-ylethyl]-N′-(3- cyanophenyl)urea
498.0930


 


387




(±)-N-[1-(3-bromophenyl)-2,2- dipyridin-3-ylethyl]-N′-(4- cyanophenyl)urea
498.0930


 


388




(±)-N-[1-(3-bromophenyl)-2,2- dipyridin-3-ylethyl]-N′-[4- (methylthio)phenyl]urea
519.0850


 


389




(±)-N-[1-(3-bromophenyl)-2,2- dipyridin-3-ylethyl]-N′-phenylurea
473.0966


 


390




(±)-N-[1-(3-bromophenyl)-2,2- dipyridin-3-ylethyl]-N′- propylurea
439.1134


 


391




(±)-N-[1-(3-bromophenyl)-2,2- dipyridin-3-ylethyl]-N′-methylurea
411.0821


 


392




(±)-N-[1-(3-bromophenyl)-2,2- dipyridin-3-ylethyl]-N′- cyclohexylurea
479.1448


 


393




(±)-methyl N-[1-(3- cyanophenyl)-2,2-dipyridin-3- ylethyl]-beta-alaninate
387.1815


 


394




(±)-methyl 1-[1-(3- cyanophenyl)-2,2-dipyridin-3- ylethyl]prolinate(diastereomer A)
413.1978


 


395




(±)-3-{1-[2- (hydroxymethyl)pyrrolidin-1- yl]-2,2-dipyridin-3- ylethyl}benzonitrile (diastereomer A)
385.2020


 


396




(±)-1-[1-(3-cyanophenyl)-2,2- dipyridin-3-ylethyl]-N- methylprolinamide (diastereomer A)
412.2137


 


397




(±)-1-[1-(3-cyanophenyl)-2,2- dipyridin-3-ylethyl]-N,N- dimethylprolinamide (diastereomer A)
446.2291


 


398




(±)-1-[1-(3-cyanophenyl)-2,2- dipyridin-3-ylethyl]-N-(2- hydroxyethyl)prolinamide (diastereomer A)
442.2235


 


399




(±)-N1-benzyl-N2-[1-(3- cyanophenyl)-2,2-dipyridin-3- ylethyl]glycinamide
448.2143


 


400




(±)-3-{1-[(2- hydroxyethyl)amino]-2,2- dipyridin-3-ylethyl}benzonitrile
345.1


 


401




(±)-1-[1-(3-bromophenyl)-2,2- dipyridin-3-ylethyl]-4- methylpiperazine-2,3-dione
465.0928


 


402




(±)-N-[1-(3-cyanophenyl)-2,2- dipyridin-3-ylethyl]pyridine-2- carboxamide
406.1652


 


403




(±)-4-[1-(3,5-dibromophenyl)- 2,2-dipyridin-3- ylethyl]morpholine
502.0123


 


404




(±)-N-[1-(3-cyanophenyl)-2,2- dipyridin-3-ylethyl]-1H-1,2,4- triazole-3-carboxamide
396.1578


 


405




(±)-3-[1-(6-bromopyridin-2-yl)- 2,2-dipyridin-3-ylethyl]-1,3- oxazolidin-2-one
425.0603


 


406




(±)-3-[1-(2-oxo-1,3-oxazolidin- 3-yl)-2,2-dipyridin-3- ylethyl]benzonitrile
371.1473


 


407




(±)-1-phenyl-N-(1,2,2-tripyridin-3- ylethyl)-1H-pyrazole-4- carboxamide
447.1928


 


408




(±)-5-phenyl-N-(1,2,2- tripyridin-3-ylethyl)-2-furamide
447.1814


 


409




(±)-4-phenyl-N-(1,2,2- tripyridin-3-ylethyl)butanamide
423.2181


 


410




(±)-3-phenyl-N-(1,2,2- tripyridin-3- ylethyl)propanamide
409.2021


 


411




(±)-benzyl(1,2,2-tripyridin-3- ylethyl)carbamate
411.1805


 


412




(±)-2-(benzyloxy)-N-(1,2,2- tripyridin-3-ylethyl)acetamide
425.1955


 


413




(±)-2-phenyl-N-(1,2,2- tripyridin-3-ylethyl)acetamide
395.1867


 


414




(±)-N-(1,2,2-tripyridin-3- ylethyl)benzamide
381.1671


 


415




(±)-5-phenyl-N-(1,2,2- tripyridin-3- ylethyl)pentanamide
437.6


 


416




(±)-N-[1-(3-cyanophenyl)-2,2- dipyridin-3-ylethyl]-2-phenyl- cyclopropanecarboxamide
445.1980


 


417




(±)-N-[1-(3-cyanophenyl)-2,2- dipyridin-3-ylethyl]-5-phenyl-2- furamide
471.1780


 


418




(±)-N-benzyl-N′-[1-(3- cyanophenyl)-2,2-dipyridin-3- ylethyl]-N-methylurea
448.2105


 


419




(±)-N-benzyl-N′-[1-(3- cyanophenyl)-2,2-dipyridin-3- ylethyl]urea
434.1936


 


420




(±)-3-(1-{[(1-phenyl-1H- pyrazol-4-yl)methyl]amino}- 2,2-dipyridin-3- ylethyl)benzonitrile
457.7


 


6-1 




(S)-{1-[1-(3-bromophenyl)-2,2- dipyridin-3-ylethyl]piperidin-4- yl}ethanethioate
496.1062


 


6-2 




(±)-3-[1-(2,4- dioxoimidazolidin-1-yl)-2,2- dipyridin-3-ylethyl]benzonitrile
384.1


 


6-3 




(±)-3-[1-(2-oxomorpholin-4-yl)- 2,2-dipyridin-3- ylethyl)benzonitrile
385.1655


 


6-4 




(±)-3-[1-(2-hydroxymorpholin- 4-yl)-2,2-dipyridin-3- ylethyl]benzonitrile
387.1815


 


6-5 




(±)-1-[1-(3-cyanophenyl)-2,2- dipyridin-3-ylethyl]-N,N-bis(1- {1-[1-(3-cyanophenyl)-2,2- dipyridin-3-ylethyl]prolyl}- pyrrolidin-2-yl)prolinamide
452.2435


 


6-6 




(±)-3-(1-pyridin-2-yl-2,2- dipyridin-3-ylethyl)-1,3- oxazolidin-2-one
347.1487


 


6-7 




(±)-tert-butyl 2-{[1-(3- cyanophenyl)-2,2-dipyridin-3- ylethyl]amino}ethylcarbamate
444.2414


 


6-8 




(±)-3-[1-(2-oxo-1,3-oxazinan-3- yl)-2,2-dipyridin-3- ylethyl]benzonitrile
384.1655


 


6-9 




(±)-N-(2-{[1-(3-bromophenyl)-2,2- dipyridin-3-ylethyl]amino}ethyl)- methanesulfonamide
475.08


 


6-10




(±)-3-(1-morpholin-4-yl-2,2- dipyridin-3-ylethyl)phenol
362.1864


 


6-11




(±)-3-[1-(6-bromopyridin-2-yl)- 2,2-dipyridin-3-ylethyl]-1,3- oxazinan-2-one
439.0767


 


6-12




(±)-N-(2-{[1-(3-bromophenyl)- 2,2-dipyridin-3-ylethyl]amino}- ethyl)-n′-phenylurea
516.1428


 


6-13




(±)-N-(tert-butyl)-1-[1-(3- cyanophenyl)-2,2-dipyridin-3- ylethyl]prolinamide
454.261


 


6-14




(±)-1-[1-(3-cyanophenyl)-2,2- dipyridin-3-ylethyl]- piperidinylprolinamide
466.2577


 


6-15




(±)-1-[1-(3-cyanophenyl)-2,2- dipyridin-3-ylethyl]-N- cyclohexylprolinamide
480.1538


 


6-16




(±)-1-[1-(3-cyanophenyl)-2,2- dipyridin-3-ylethyl]-N- phenylprolinamide
474.2268


 


6-17




(±)-methyl 1-[1-(6- bromopyridin-2-yl)-2,2- dipyridin-3-ylethyl]prolinate
467.1065


 


6-18




(±)-3-(1-{[(1-phenyl-1H- pyrazol-4-yl)methyl]amino}- 2,2-dipyridin-3- ylethyl)benzonitrile
404.2073


 


6-19




(±)-methyl 1-[1-(4- fluorophenyl)-2,2-dipyridin-3- ylethyl]prolinate
406.192


 


6-20




(±)-methyl 1-[1-(6- aminopyridin-2-yl)-2,2- dipyridin-3-ylethyl]prolinate
404.2073


 


6-21




(±)-N-{1-[1-(3-cyanophenyl)- 2,2-dipyridin-3- ylethyl]piperidin-4-yl}-N- methylmethanesulfonamide
476.2107


 


6-22




(±)-3-[1-(2- oxopyrrolidin-1-yl)- 2,2-dipyridin-3- ylethyl]benzonitrile
369.172


 


6-23




(±)-1-[1-(3-cyanophenyl)-2,2- dipyridin-3-ylethyl]piperidin-4- yl phenylcarbamate
504.2386


 


6-24




(±)-1-[1-(4-fluorophenyl)-2,2- dipyridin-3-ylethyl]-N- methylprolinamide
405.2085


 


6-25




(±)-N-ethyl-1-[1-(4- fluorophenyl)-2,2-dipyridin-3- ylethyl]prolinamide
419.2228


 


6-26




(±)-N-{1-[1-(3-cyanophenyl)- 2,2-dipyridin-3- ylethyl]piperidin-4-yl}-N- methylcyclopropanesulfonamide
502.2268


 


6-27




(±)-3-[1-(1,1- dioxidoisothiazolidin-2-yl)-2,2- dipyridin-3-ylethyl]benzonitrile
405.1381


 


6-28




(±)-3-[1-(4,5-dihydro-1,3- thiazol-2-ylamino)-2,2- dipyridin-3-ylethyl]benzonitrile
471.1398


 


6-29




(±)-methyl 1-(1-pyridin-2-yl- 2,2-dipyridin-3-ylethyl)prolinate
389.1964


 


6-30




(±)-N-butyl-1-[1-(3- cyanophenyl)-2,2-dipyridin-3- ylethyl]prolinamide
454.2573


 


6-31




(±)-1-[1-(3-cyanophenyl)-2,2- dipyridin-3-ylethyl]-N- isobutylprolinamide
454.2603


 


6-32




(±)-1-[1-(3-cyanophenyl)-2,2- dipyridin-3-ylethyl]-N- cyclobutylprolinamide
452.2435


 


6-33




(±)-1-[1-(3-cyanophenyl)-2,2- dipyridin-3-ylethyl]-N- cyclopentylprolinamide
466.2597


 


6-34




(±)-1-[1-(4-fluorophenyl)-2,2- dipyridin-3-ylethyl]-N-pyridin- 2-ylprolinamide
468.2193


 


6-35




(±)-1-[1-(3-cyanophenyl)-2,2- dipyridin-3-ylethyl]-N-[4- (trifluoromethyl)pyridin-2- yl]prolinamide
543.2113


 


6-36




(±)-N-(5-chloropyridin-2-yl)-1- [1-(3-cyanophenyl)-2,2- dipyridin-3-ylethyl]prolinamide
509.1885


 


6-37




(±)-4-[1-(3-bromophenyl)-2,2- dipyridin-3-ylethyl]morpholin- 2-one
438.0836


 


6-38




(±)-N-{1-[1-(3-cyanophenyl)- 2,2-dipyridin-3- ylethyl]piperidin-4-yl}-N- cyclopropylmethanesulfonamide
502.2274


 


6-39




(±)-N-{1-[1-(3-cyanophenyl)- 2,2-dipyridin-3- ylethyl]piperidin-4-yl}-N- ethylmethanesulfonamide
490.2277


 


6-40




(±)-N-{1-[1-(3-cyanophenyl)- 2,2-dipyridin-3- ylethyl]piperidin-4-yl}-N- ethylcyclopropanesulfonamide
516.4


 


6-41




(±)-N-{1-[1-(3-cyanophenyl)- 2,2-dipyridin-3- ylethyl]piperidin-4-yl}-N- methylethanesulfonamide
490.2301


 


6-42




(±)-methyl 1-[1-(3- cyanophenyl)-2-pyrazin-2-yl-2- pyridin-3-ylethyl]prolinate
414.1946


 


6-43




(±)-2-{1-[1-(4-fluorophenyl)- 2,2-dipyridin-3- ylethyl]pyrrolidin-2-yl}-1H- benzimidazole
464.2278


 


6-44




(±)-methyl 1-[1-(6- methoxypyridin-2-yl)-2,2- dipyridin-3-ylethyl]prolinate
419.2099


 


6-45




(±)-3-{1-[2-(1H-benzimidazol- 2-yl)pyrrolidin-1-yl]-2,2- dipyridin-3-ylethyl}benzonitrile
471.2305


 


6-46




(±)-N-(tert-butyl)-1-[1-(6- methoxypyridin-2-yl)-2,2- dipyridin-3-ylethyl]prolinamide
460.2725


 


6-47




(±)-2-{1-[1-(6-methoxypyridin- 2-yl)-2,2-dipyridin-3- ylethyl]pyrrolidin-2-yl}-1H- benzimidazole
477.2426


 


6-48




(±)-tert-butyl 3-{[1-(3- cyanophenyl)-2,2-dipyridin-3- ylethyl]amino}piperidine-1- carboxylate
484.5


 


6-49




(±)-{1-[2-(6-aminopyridin-2-yl)- 1,2-dipyridin-3-ylethyl]- pyrrolidin-2-yl}methanol
376.2137


 


6-50




(±)-3-(1-{[(4-phenyl-1,3- thiazol-2-yl)methyl]amino}-2,2- dipyridin-3-ylethyl)benzonitrile
474.1764


 


6-51




(±)-3-(1-{[(2-phenyl-1,3- thiazol-5-yl)methyl]amino}-2,2- dipyridin-3-ylethyl)benzonitrile
474.1772


 


6-52




(±)-3-{2,2-dipyridin-3-yl-1- [(pyridin-2- ylmethyl)amino]ethyl}benzonitrile
392.1875


 


6-53




(±)-3-(1-{[3-(4-methoxy- phenoxy)benzyl]amino}-2,2- dipyridin-3-ylethyl)benzonitrile
513.2304


 


6-54




(±)-3-{2,2-dipyridin-3-yl-1- [(quinolin-3-ylmethyl)amino]- ethyl}benzonitrile
442.2035


 


6-55




(±)-3-(1-{[4- (methylthio)benzyl]amino}-2,2- dipyridin-3-ylethyl)benzonitrile
437.1817


 


6-56




(±)-3-{1-[(2,2-dimethylpent-4- en-1-yl)amino]-2,2-dipyridin-3- ylethyl}benzonitrile
397.2395


 


6-57




(±)-3-{1-[(4- propoxybenzyl)amino]-2,2- dipyridin-3-ylethyl}benzonitrile
449.2351


 


6-58




(±)-3-{1-[(biphenyl-4- ylmethyl)amino]-2,2-dipyridin- 3-ylethyl}benzonitrile
467.2251


 


6-59




(±)-3-{1-[(1-benzothien-2- ylmethyl)amino]-2,2-dipyridin- 3-ylethyl}benzonitrile
447.1645


 


6-60




(±)-3-(2,2-dipyridin-3-yl-1-{[3- (trifluoromethyl)benzyl]amino} ethyl)benzonitrile
459.1804


 


6-61




(±)-3-{1-[(4- cyanobenzyl)amino]-2,2- dipyridin-3-ylethyl}benzonitrile
416.1876


 


6-62




(±)-3-{1-[2-(3-methyl-1,2,4- oxadiazol-5-yl)pyrrolidin-1-yl]- 2,2-dipyridin-3- ylethyl}benzonitrile
437.2085


 


6-63




(±)-6-{1-[2-(3-methyl-1,2,4- oxadiazol-5-yl)pyrrolidin-1-yl]- 2,2-dipyridin-3-ylethyl}pyridin- 2-amine
428.2174


 


6-64




(±)-2-methoxy-6-{1-[2-(3- methyl-1,2,4-oxadiazol-5- yl)pyrrolidin-1-yl]-2,2- dipyridin-3-ylethyl}pyridine
443.2168


 


6-65




(±)-3-{2-(4-fluorophenyl)-2-[2- (3-methyl-1,2,4-oxadiazol-5- yl)pyrrolidin-1-yl]-1-pyridin-3- ylethyl}pyridine
430.2014


 


6-66




(±)-3-{1-[2-(3-methyl-1,2,4- oxadiazol-5-yl)pyrrolidin-1-yl]- 2-pyrazin-2-yl-2-pyridin-3- ylethyl}benzonitrile
438.2012


 


6-67




(±)-3-{1-[2-(3-methyl-1,2,4- oxadiazol-5-yl)pyrrolidin-1-yl]- 2-pyrazin-2-yl-2-pyridin-3- ylethyl}benzonitrile
438.2013


 


6-68




(±)-3-[1-(3-hydroxypiperidin-1- yl)-2,2-dipyridin-3-ylethyl]- benzonitrile (Diastereomer A)
385.2012


 


6-69




(±)-3-[1-(3-hydroxypiperidin-1- yl)-2,2-dipyridin-3-ylethyl]- benzonitrile (Diastereomer B)
385.2012


 


6-70




(±)-4-[2-(6-aminopyridin-2-yl)- 2-(3-hydroxypiperidin-1-yl)-1- pyridin-3-ylethyl]benzonitrile
400.2129


 


6-71




(±)-4-{2,2-dipyridin-3-yl-1- [(2,2,2-trifluoroethyl)amino]- ethyl}benzonitrile
383.145


 


6-72




(±)-4-{1-[(2-fluoroethyl)amino]- 2,2-dipyridin-3- ylethyl}benzonitrile
347.167


 


6-73




(±)-4-{1-[(2-difluoroethyl)amino]- 2,2-dipyridin-3-ylethyl}benzonitrile
365.1576


 


6-74




(±)-N-{1-[4-(methylthio)- phenyl]-2,2-dipyridin-3- ylethyl}-N-(2,2,2- trifluoroethyl)amine
404.1407


 


6-75




(±)-N-{1-[4-(methylsulfonyl)- phenyl]-2,2-dipyridin-3- ylethyl}-N-(2,2,2- trifluoroethyl)amine
436.1305


 


6-76




(±)-6-{2,2-dipyridin-3-yl-1- [(2,2,2- trifluoroethyl)amino]ethyl} pyridin-2-amine
374.1596


 


6-77




(±)-N-{1-[2- (methylthio)phenyl]-2,2- dipyridin-3-ylethyl}-N-(2,2,2- trifluoroethyl)amine
404.1411


 


6-78




(±)-N-{1-[2- (methylsulfonyl)phenyl]-2,2- dipyridin-3-ylethyl}-N-(2,2,2- trifluoroethyl)amine
436.1301


 


6-79




(±)-N-{1-[3- (methylthio)phenyl]-2,2- dipyridin-3-ylethyl}-N-(2,2,2- trifluoroethyl)amine
404.1404


 


6-80




(±)-N-{1-[3- (methylsulfonyl)phenyl]-2,2- dipyridin-3-ylethyl}-N-(2,2,2- trifluoroethyl)amine
436.1305


 


6-81




(±)-1-(2,3′-bipyridin-3-yl)-2,2- dipyridin-3-ylethanamine
354


 


6-82




(±)-1-(2,3′-bipyridin-3-yl)-2,2- dipyridin-3-yl-N-(2,2,2- trifluoroethyl)ethanamine
436.1


 


6-83




(±)-3-[1-(4-fluorophenyl)-2,2- dipyridin-3-ylethyl]-1,3- oxazolidin-2-one
364.0


 


6-84




(±)-3-[1-(4-chlorophenyl)-2,2- dipyridin-3-ylethyl]-1,3- oxazolidin-2-one
371.1


 


6-85




benzyl (±)-1-(4-chlorophenyl)- 2,2-dipyridin-3- ylethylcarbamate
444.0


 


6-86




(±)-4-[1-(2-oxo-1,3-oxazolidin- 3-yl)-2,2-dipyridin-3- ylethyl]benzonitrile
317.15


 


6-87




(±)-neopentyl 1-(4- chlorophenyl)-2,2-dipyridin-3- ylethylcarbamate
424













The variables C, B, A, and Y in the scheme are as defined in “Formula I”.

EXAMPLE 421
3-(1-morpholin-4-yl-2,2-dipyridin-3-ylethyl)benzonitrile (enantiomer B)




Step A:

In a flame dried flask under N2, 3-cyanobenzaldehyde (7.050 g, 53.76 mmol) was dissolved in anhydrous dioxane (100 mL). Ti(IV) ethoxide (28.183 mL, 134.40 mmol) was added followed by (S)-(−)-2-methyl-2-propanesulfinamide (7.167 g, 59.14 mmol). The r×n was heated to 110° C. After 2.5 hr the reaction was cooled to RT and brine (150 mL) was added. A precipitate formed and the reaction was rapidly stirred for 1 hr. The suspension was filtered through celite and the filter cake was washed with brine and ethyl acetate. The layers of the filtrate were separated. The aqueous layer was extracted with ethyl acetate (1×). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to afford (S)—N-[(3-cyanophenyl)methylidene]-2-methylpropane-2-sulfinamide as a light orange solid. 1H NMR (CD3OD) (8.61 (s, 1H), 8.26 (s, 1H), 8.22-8.20 (m, 1H), 7.94-7.92 (m, 1H), 7.72 (t, 1H, J=7.81 Hz), 1.28 (s, 9H).
Step B:
In a flame dried flask under N2, diisopropylamine (1.647 mL, 11.75 mmol) was dissolved in anhydrous THF (5 mL) and the solution was cooled to 0° C. nBuLi (2.5 M solution in hexanes, 4.406 mL, 11.02 mmol) was added and the reaction was stirred at 0° C. for 15 min. A solution of 3-(pyridin-3-ylmethyl)pyridine (1.250 g, 7.34 mmol) in anhydrous THF (15 mL) was slowly added and the reaction became dark red. After 15 min, a solution of (S)—N-[(3-cyanophenyl)methylidene]-2-methylpropane-2-sulfinamide (1.893 g, 8.08 mmol) in anhydrous THF (10 mL) was added. The reaction was stirred at 0° C. for 2.5 h and was quenched with saturated aqueous NH4Cl (150 mL). The product was extracted with ethyl acetate (4×100 mL). The combined organics were dried over Na2SO4, filtered, concentrated in vacuo and purified by reverse phase HPLC (DeltaPak C18, 47 mm×300 mm, 15 □, 0% CH3OH/100% H2O to 100% CH3OH/0% H2O). The fractions containing each diastereomer were separately combined and concentrated in vacuo to afford N-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]-2-methylpropane-2-sulfinamide as two diastereomers;
diastereomer A as a foamy white solid and diastereomer B as a white solid.
Diastereomer A: 1H NMR (CDCl3) δ 8.67 (s, 1H), 8.62 (d, 1H, J=4.64 Hz), 8.37 (d, 1H, J=4.64 Hz), 8.17 (d, 1H, J=1.95 Hz), 7.94-7.93 (m, 1H), 7.57 (s, 1H), 7.53-7.51 (m, 1H), 7.43 (dd, 1H, J=4.88 Hz), 7.39-7.37 (m, 2H), 7.32 (t, 1H, J=7.57 Hz), 7.13 (dd, 1H, J=4.64 Hz), 5.15 (d, 1H, J=10.75 Hz), 4.22 (d, 1H, J=10.98 Hz), 1.06 (s, 9H). [M+H]+=405.1.

Diastereomer B: 1H NMR (CDCl3) δ 8.66 (s, 1H), 8.54 (d, 1H, J=3.91 Hz), 8.37 (s, 2H), 7.73-7.71 (m, 1H), 7.55-7.50 (m, 3H), 7.47-7.45 (m, 1H), 7.39 (t, 1H, J=7.57 Hz), 7.43 (dd, 1H, J=4.88 Hz), 7.14 (dd, 1H, J=4.88 Hz), 5.16 (dd, 1H, J=7.57 Hz), 4.44 (d, 1×, J=10.74 Hz), 3.52 (d, 1H, J=7.81 Hz), 0.96 (s, 9H). [M+H]+=404.9.

Step C:

N-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]-2-methylpropane-2-sulfinamide (Diastereomer B, 1.567 g, 3.87 mmol) was dissolved in CH3OH (15 mL) and the solution was cooled to 0° C. HCl (4 M solution in dioxane, 2.905 mL, 11.62 mmol) was added drop-wise. The reaction was allowed to warm to RT and was stirred for 7 hr. The reaction was diluted with H2O and the pH was adjusted to pH=7 using saturated aqueous NaHCO3. The product was extracted with ethyl acetate (3×75 mL) followed by isobutanol (6×50 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to afford 3-(1-amino-2,2-dipyridin-3-ylethyl)benzonitrile as a foamy light yellow solid.
Enantiomer B: 1H NMR (CD3OD) δ 8.78 (d, 1H, J=1.53 Hz), 8.51 (d, 1H, J=3.66 Hz), 8.35 (d, 1H, J=1.53 Hz), 8.25-8.24 (m, 1H), 8.18-8.14 (m, 1H), 7.84-7.79 (m, 2H), 7.72-7.70 (m, 1H), 7.60-7.43 (m, 3H), 7.26 (dd, 1H, J=4.88 Hz), 5.13 (d, 1H, J=10.99 Hz), 4.53 (d, 1H, J=11.29 Hz). [M+H]+=301.1.

Step D:

According to the procedure in Example 343, Step C, 3-(1-Amino-2,2-dipyridin-3-ylethyl)benzonitrile (Enantiomer B, 0.503 g, 1.68 mmol) was converted to the title compound. The product was purified by reverse phase HPLC (5-95% CH3CN/H2O+0.05% NH4OH) followed by flash column chromatography (0-9% CH3OH/CH2Cl2). The fractions were combined and concentrated in vacuo to afford the title compound as a foamy white solid. Enantiomer B: 1H NMR (CDCl3) δ 8.67 (d, 1H, J=1.95 Hz), 8.51 (dd, 1H, J=1.22 Hz), 8.37 (d, 1H, J=2.20 Hz), 8.30 (dd, 1H, J=1.22 Hz), 7.69-7.67 (m, 1H), 7.52-7.50 (m, 1H), 7.43-7.37 (m, 4H), 7.29 (dd, 1H, J=4.88 Hz), 7.07 (dd, 1H, J=4.88 Hz), 4.62 (d, 1H, J=11.96 Hz), 4.37 (d, 1H, J=12.21 Hz), 3.53-3.50 (m, 2H), 3.49-3.37 (m, 2H), 2.50-2.47 (m, 2H), 2.29-2.26 (m, 2H). [M+H]+=371.1870.
The following compounds were made according to Scheme 7, where intermediates in the scheme were modified according to literature methods. Examples 7-3 and 7-4 were synthesized using the tert-butyl sulfonimine rather than the tert-butyl sulfinimine using literature procedures.
EXAMPLES 422-423 AND 7-1 TO 7-4















422




(±)-3-(1-morpholin-4-yl-2,2- dipyridin-3- ylethyl)benzamide
389.1989


 


423




(±)-3-{1- [(cyanomethyl)amino]-2,2- dipyridin-3- ylethyl}benzonitrile
340.1561


 


7-1




(±)-N-{1-[2- (methylthio)pyrimidin-4-yl]- 2,2-dipyridin-3-ylethyl}-n- (2,2,2-trifluoroethyl)amine
406.1318


 


7-2




(±)-4-{2- (2-fluoropyridin-3- yl)-2-pyridin-3-yl-1-[(2,2,2- trifluoroethyl)amino]ethyl} pyrimidin-2-amine (mixture of diastereomers)
393.1443


 


7-3




(±)-6-{2-(4-fluorophenyl)-1- pyridin-3-yl-2-[(2,2,2- trifluoroethyl)amino]ethyl} pyridin-2-amine (diastereomer 1)
391


 


7-4




(±)-6-{2-(4-fluorophenyl)-1- pyridin-3-yl-2-[(2,2,2- trifluoroethyl)amino]ethyl} pyridin-2-amine (diastereomer 2)
391













The variables C, B, A, and R5 in the scheme are as defined in “Formula I”.

EXAMPLE 424
(±)-3-[2-(4-fluorophenyl)-1-pyridin-3-yl-2-(2,2,2-trifluoroethoxy)ethyl]pyridine




Step A:

To the solution of 3-(pyridin-3-ylmethyl)pyridine (0.195 g, 1.15 mmol) in THF (5 mL) at −78° C. was added LDA (0.7 mL, 1.8 M) and stirred for 1 h. 4-Fluorobenzaldehyde (0.171 g, 1.37 mmol) in THF (1 mL) was added. The mixture was stirred at −78° C. for 10 min and at −45° C. for 0.5 h. The reaction was quenched with ice and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated to give a solid. The solid was triturated with CH2Cl2 to give 1-(4-fluorophenyl)-2,2-dipyridin-3-ylethanol. 1H-NMR (500 MHz, CDCl3) δ 8.60 (d, 1H, J=1.7), 8.45 (d, 1H, J=1.9), 8.38 (dd, 1H, J=4.7, 1.2), 8.27 (dd, 1H, J=4.6, 1.2), 7.91 (d, 1H, J=7.8), 7.76 (d, 1H, J=8.0), 7.34-7.29 (m, 3H), 7.19 (dd, 1H, J=7.8, 4.9), 7.02 (t, 2H, J=8.8), 5.68 (d, 1H, J=4.9), 5.45 (dd, 1H, J=8.5, 4.8), 4.34 (d, 1H, J=8.8). LRMS m/z (M+H) Calcd: 295.3. found: 295.1.
Step B:
To the solution of 1-(4-fluorophenyl)-2,2-dipyridin-3-ylethanol (0.2 g, 0.68 mmol) in THF (4 mL) was added i-Pr2NEt (0.4 mL, 2.3 mmol) at 0° C. followed by methanesulfonyl chloride (0.1 mL, 1.3 mmol). The reaction mixture was stirred for 10 h. Diluted with saturated NaHCO3 and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated to give 1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl methanesulfonate. LRMS m/z (M+H) Calcd: 373.4. found: 373.0.
Step C:
The mixture of 1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl methanesulfonate (0.1 g, 0.27 mmol) and i-Pr2NEt (0.1 mL) in CF3CH2OH (1 mL) was heated to reflux for 10 h. Diluted with aqueous Na2CO3 (2M) and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated. The residue was purified by reverse phase HPLC (5-100% CH3CN/H2O+0.1% TFA) to give the trifluoroacetate salt of (±)-3-[2-(4-fluorophenyl)-1-pyridin-3-yl-2-(2,2,2-trifluoroethoxy)ethyl]pyridine. 1H-NMR (500 MHz, CDCl3) δ 11.38 (broad, 2H), 8.68 (d, 2H, J=32.7), 8.55 (d, 2H, J=14.9), 8.0 (d, 1H, J=8.0), 7.75 (d, 1H, J=8.0), 7.58-7.60 (m, 1H), 7.40-7.42 (m, 1H), 7.08-7.11 (m, 2H), 6.99-7.02 (t, 2H, J=8.3), 5.16 (d, 1H, J=7.3), 4.40 (d, 1H, J=7.3), 3.63-3.76 (m, 2H). (LRMS m/z (M+H) Calcd: 377.3. found: 377.2.
The following compounds were made according to Scheme 8, where intermediates in the Scheme were modified according to literature methods.
EXAMPLES 425-427 AND 8-1 TO 8-2













Example
Compound
Name
MS (M + 1)







425




(±)-3-[2-(4-fluorophenyl)-2- methoxy-1-pyridin-3- ylethyl]pyridine
309.3


 


426




(±)-3-[2-(cyclopentyloxy)-2- (4-fluorophenyl)-1-pyridin- 3-ylethyl]pyridine
363.2


 


427




(±)-methyl [1-(4- fluorophenyl)-2,2-dipyridin- 3-ylethoxy]acetate
367.1


 


8-1




(±)-1-(2-morpholin-4- ylpyridin-3-yl)-2,2- dipyridin-3-ylethanol
363.182


 


8-2




(±)-1-{2-[methyl(pyridin-3- yl)amino]pyridin-3-yl}-2,2- dipyridin-3-ylethanol
384.1798













The variables C, B, A, and Y in the scheme are as defined in “Formula I”.

EXAMPLE 428
(±)-1-[1-(6-chloropyridin-2-yl)-2,2-dipyridin-3-ylethyl]pyridin-2(1H)-one




Step A:

To the solution of 2-chloro-6-chloromethylpyridine (1.62 g g, 10 mmol) in DMF (10 mL) was added 2-hydroxypyridine (0.95 g, 10 mmol) and Cs2CO3 (6.52 g, 20 mmol). The mixture was stirred overnight, then diluted with water and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated to give a solid. The solid was purified by silica gel chromatography (2-4% MeOH in CH2Cl2) to give 1-[(6-chloropyridin-2-yl)methyl]pyridin-2(1H)-one. 1H-NMR (500 MHz, CDCl3) δ 7.62 (t, 1H, J=7.8), 7.51 (dd, 1H, J=6.8, 2.0), 7.31-7.37 (m, 2H), 7.25 (d, 1H, 3=8.3), 6.59 (d, 1H, J=9.2), 6.21 (td, 1H, J=6.6, 1.3), 5.19 (s, 2H). LRMS m/z (M+H) Calcd: 221.7. found: 221.0.
Step B:
To the solution of 1-[(6-chloropyridin-2-yl)methyl]pyridin-2(1H)-one (0.3 g, 1.36 mmol) in THF (6 mL) at −78° C. was added LDA(0.83 mL, 1.8 M) and stirred at −78° C. for 1 h. The solution of 3-[chloro(pyridin-3-yl)methyl]pyridine (0.278 g, 1.36 mmol) in THF (3 mL) was added and the mixture was warmed to 0° C. and stirred at 0° C. for 1 h. The reaction was quenched with water and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated. The residue was purified by silica gel chromatography (3% MeOH in CH2Cl2) to give (±)-1-[1-(6-chloropyridin-2-yl)-2,2-dipyridin-3-ylethyl]pyridin-2(1H)-one. 1H-NMR (500 MHz, CDCl3) δ 8.58 (d, 1H, J=2.2), 8.53 (d, 1H, J=2.0), 8.42 (dd, 1H, J=4.6, 1.2), 8.35 (dd, 1H, J=4.6, 1.2), 7.92 (d, 1H, 3=6.6), 7.84 (d, 1H, J=8.0), 7.64 (d, 1H, J=8.0), 7.48 (t, 1H, J=7.7), 7.25-7.09 (m, 6H), 6.41 (d, 1H, J=9.0), 6.09 (t, 1H, J=6.7), 5.30 (d, 1H, J=12.2). LRMS m/z (M+H) Calcd: 389.8. found: 389.0.
The following compounds were made according to Scheme 9 where intermediates in the Scheme were modified according to literature methods. Unless otherwise shown, structures of compounds 429-437, 9-1 to 9-5 and 444-446 are represented by defining variables




and “Y” of the structure





EXAMPLES 429-437 and 9-1 to 9-5













Example
Compound
Name
MS (M + 1)







429




(±)-1-(1-pyridin-2-yl-2,2- dipyridin-3-ylethyl]pyridin- 2(1H)-one
355.0


 


430




(±)-2-[1-(1H-pyrazol-1-yl)- 2,2-dipyridin-3- ylethyl]pyridine
328.0


 


431




(±)-1-[2-(4-fluorophenyl)-1- pyridin-2-yl-2-pyridin-3- ylethyl]pyridin-2(1H)-one (Diastereomer A)
372.1499


 


432




(±)-1-[2-(4-fluorophenyl)-1- pyridin-2-yl-2-pyridin-3- ylethyl]pyridin-2(1H)-one (Diastereomer B)
372.1499


 


433




(±)-1-[2-(4-fluorophenyl)- 1,2-dipyridin-3- ylethyl]pyridin-2(1H)-one (Diastereomer A)
372.1500


 


434




(±)-1-[2-(4-fluorophenyl)- 1,2-dipyridin-3- ylethyl]pyridin-2(1H)-one (Diastereomer B)
372.1505


 


435




(±)-2-[2-(4-fluorophenyl)-1- (1H-pyrazol-1-yl)-2-pyridin- 3-ylethyl]pyridine (Diastereomer A)
345.1503


 


436




(±)-2-[2-(4-fluorophenyl)-1- (1H-pyrazol-1-yl)-2-pyridin- 3-ylethyl]pyridine (Diastereomer B)
345.1502


 


437




(±)-2-[1-(4-fluorophenyl)-2- (1H-imidazol-1-yl)-2- pyridin-3-ylethyl]pyridine (mixture of idiastereomers)
345.1503


 


438




(±)-1-(1,2,2-tripyridin-3- ylethyl)pyridin-2(1H)-one
355.5


 


439




(±)-2-(1-pyridin-2-yl-2,2- dipyridin-3- ylethyl)pyridazin-3(2H)-one
356.5


 


440




(±)-2-[2,2-dipyridin-3-yl-1- (1H-1,2,3-triazol-1- yl)ethyl]pyridine
329.3


 


441




(±)-3,3′,3′′-[2-(1H-1,2,3- triazol-1-yl)ethane-1,1,2- triyl]tripyridine
329.2


 


442




(±)-4-[2,2-dipyridin-3-yl-1- (1H-1,2,3-triazol-1- yl)ethyl]benzonitrile
353.3


 


443




(±)-3-[2,2-dipyridin-3-yl-1- (1H-1,2,3-triazol-1- yl)ethyl]benzonitrile
353.3


 


9-1




(±)-3,3′,3′′-[2-(1H-tetrazol-1- yl)ethane-1,1,2- triyl]tripyridine
330.1464


 


9-2




(±)-3-[2-pyridin-2-yl-1- pyridin-3-yl-2-(1H-1,2,3- triazol-1- yl)ethyl]benzonitrile
353.4


 


9-3




(±)-2-[2,2-dipyridin-3-yl-1- (4H-1,2,4-triazol-4- yl)ethyl]pyridine
329.1525


 


9-4




(±)-4-{2-(4-chlorophenyl)-1- [2-(methylthio)pyrimidin-4- yl]-2-pyridin-3- ylethyl}morpholine
427.1


 


9-5




(±)-4-[2-(4-chlorophenyl)-1- morpholin-4-yl-2-pyridin-3- ylethyl]pyrimidin-2-amine
396









The following compounds were made from Example 428 using methods known to those skilled in the art.

EXAMPLES 444-446













Example
Compound
Name
MS (M + 1)







444




(±)-1-(1-{6-[(2- hydroxyethyl)amino]pyridin- 2-yl}-2,2-dipyridin-3- ylethyl)pyridin-2(1H)-one
448.1


 


445




(±)-N-{6-[1-(2-oxopyridin- 1(2H)-yl)-2,2-dipyridin-3- ylethyl]pyridin-2- ylcarbamate
470.0


 


446




(±)-1-[1(2H)-yl)-2,2- dipyridin-3-ylethyl]pyridin- 2(1H)-one
370.1













The variables A, B, C, Y, and R5 in the scheme are as defined in “Formula I”.

EXAMPLE 447
(±)-6-[1-(3,3-difluoropyrrolidin-1-yl)-2,2-dipyridin-3-ylethyl]pyridin-2-amine




Step A:

To a solution of di-3-pyridylmethane (250 mg, 1.47 mmol) in dry TIE (5 mL) was added LDA (2.1 mL, 3.16 mmol) slowly at −78° C. After 30 min a solution of methyl 2-bromopyridine-6-carboxylate (349 mg, 1.62 mmol) in dry THF (3 mL) was added slowly. After 30 min the cooling bath was removed and the mixture allowed to warm to RT. After 4 hr the mixture was diluted with saturated NH4Cl and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column (100% EtOAc) gave 1-(6-bromopyridin-2-yl)-2,2-dipyridin-3-ylethanone as a yellow oil. 1H-NMR (500 MHz, CDCl3) δ 8.66 (m, 2 H), 8.53 (m, 2 H), 8.06 (dd, J=0.98 and 6.35 Hz, 1 H), 7.80 (m, 4 H), 7.28 (m, 2 H), 6.79 (s, 1 H).
Step B:
To a solution of 1-(6-bromopyridin-2-yl)-2,2-dipyridin-3-ylethanone (154 mg, 0.44 mmol) in dry 1,4-dioxane (2 mL) was added 3,3-difluoropyrrolidine hydrochloride (75 mg, 0.52 mmol), TEA (0.079 mL, 0.57 mmol), and Ti(OEt)4 (0.18 mL, 0.87 mmol). The mixture was heated to reflux. After 2 hr the mixture was cooled to RT, diluted with brine, and filtered through a pad of Celite. The pad was washed with EtOAc. The filtrate layers were separated and the aqueous layer extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated to a brown foam which was used in the next step without purification.
Step C:
To a solution of crude imine (134 mg, 0.3 mmol) in HOAc (3 mL) was added Zn dust (198 mg, 3.02 mmol) at RT. After 16 hr the mixture was filtered through a pad of Celite and concentrated. The residue was taken up in 1M NaOH and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column (gradient, 0-10% MeOH/CH2Cl2) gave 2-bromo-6-[1-(3,3-difluoropyrrolidin-1-yl)-2,2-dipyridin-3-ylethyl]pyridine as a yellow solid. 1H-NMR (500 MHz, CDCl3) δ 8.72 (s, 1 H), 8.49 (d, J=4.89 Hz, 1 H), 8.37 (s, 1 H), 8.27 (d, J=4.88 Hz, 1 H), 7.75 (d, J=7.57 Hz, 1 H), 7.43 (d, J=7.57 Hz, 1 H), 7.37 (t, J=7.32 Hz, 1 H), 7.30 (m, 2H), 7.04 (dd, J=4.89 and 2.93 Hz, 1 H), 6.88 (d, J=7.33 Hz, 1 H), 4.88 (d, J=11.71 Hz, 1 H), 4.53 (d, J=11.48 Hz, 1H), 3.10 (m, 1 H), 2.88 (m, 2 H), 2.70 (m, 1 H), 2.0 (m, 2 H).
Step D:
The 2-bromo-6-[1-(3,3-difluoropyrrolidin-1-yl)-2,2-dipyridin-3-ylethyl]pyridine (73 mg, 0.16 mmol), tert-butyl carbamate (23 mg, 0.2 mmol), Cs2CO3 (75 mg, 0.23 mmol), Pd2(dba)3 (3 mg, 0.003 mmol), and xantphos (6 mg, 0.01 mmol) were combined in dry 1,4-dioxane (1.5 mL). The mixture was degassed (3× pump/N2) then heated to 100° C. After 5 hr the mixture was cooled to RT, diluted with EtOAc, filtered through a pad of Celite, and concentrated. The residue was taken up in 1 mL CH2Cl2 to which was added 1 mL TFA at RT. After 90 min the mixture was concentrated. The residue was taken up in saturated NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column (gradient, 0-10% MeOH/CH2Cl2) gave the title compound as a yellow foam. 1H-NMR (500 MHz, CDCl3) δ 8.68 (d, J=2.20 Hz, 1 H), 8.47 (d, J=4.15 Hz, 1 H), 8.37 (d, J=2.19 Hz, 1 H), 8.25 (d, J=3.90 Hz, 1 H), 7.74 (d, J=8.06 Hz, 1 H), 7.41 (d, J=7.81 Hz, 1 H), 7.25 (m, 2 H), 7.02 (m 1 H), 6.27 (m, 2 H), 4.85 (d, J=11.47 Hz, 1 H), 4.39 (s, 2 H), 4.35 (d, J=11.72 Hz, 1 H), 3.10 (m, 1 H), 2.86 (m, 2 H), 2.67 (m, 1 H), 2.0 (m, 2 H); MS (M+H)+ 382.0.
Using the methodologies described below, representative compounds of the invention were evaluated and found to exhibit activity in the Kv1.5 assays, thereby demonstrating and confirming the utility of the compounds of this invention as Kv1.5 inhibitors and antiarrhythmics. Compounds of this type may exhibit forward rate-dependence, blocking the outward K+ currents to a greater extent or preferentially at faster rates of depolarization or heart rates. Such a compound could be identified in electrophysiological studies as described below. For example, during a train of depolarizations delivered at frequencies of 1 Hz and 3 Hz, the block is “rate-dependent” if the amount of block observed during a 10 second train at 3 Hz is greater than that at 1 Hz. A Kv1.5 blocker may also display use-dependence, during which the block of the outward K+ currents increases with use, or during repetitive depolarization of a cardiac cell. Use dependence of block occurs to a greater extent with each successive depolarization in a train or sequence of pulses or depolarizations at a given rate or frequency. For example, during a train of 10 depolarizations at a frequency of 1 Hz, the block is “use-dependent” if the amount of block is greater for the 10th pulse than for the 1st pulse of the train. A Kv1.5 blocker may exhibit both use-dependence and rate-dependence.
A Kv1.5 blocker may also be identified through electrophysiological studies of native IKur using cardiac myocytes or other tissue from various species including, but not limited to, human, rat, mouse, dog, monkey, ferret, rabbit, guinea pig, or goat. In native tissues Kv1.5 may exist as a homo-oligomer, or as a hetero-oligomer with other Kv family members, or may exist in a complex with a β-subunit. Compounds of this invention may block Kv1.5 homo- or hetero-oligomers or Kv1.5 in complexes with β-subunits.
Kv1.5 Assays
The high throughput Kv1.5 planar patch clamp assay is a systematic primary screen. It confirms activity and provides a functional measure of the potency of agents that specifically affect Kv1.5 potassium channels. Kiss et al. (Assay and Drug Dev. Tech., 1(1-2):127-135, 2003) and Schroeder et al. (J. of Biomol. Screen., 8(1); 50-64, 2003) describe the use of this instrument for Kv1.5 as well as other voltage gated ion channels.
Chinese hamster ovary cells (CHO) stably expressing the human Kv1.5 potassium channel alpha subunit, cloned from human heart, are grown to 90-100% confluence in Ham's F12 medium supplemented with 10% FBS, 100 U/ml penicillin, 100 μg/ml streptomycin, 1000 μg/ml G-418 sulfate. Cells are subcultured by treatment with Versene, then suspended in phosphate-buffered saline (PBS) and centrifuged The cell pellet is resuspended in PBS and the resulting suspension placed in the cell reservoir of the IonWorksTM HT instrument.
Electrophysiological recordings are performed with intracellular solution containing (mM): K-gluconate 100, KCl 40, MgCl2 3.2, EGTA 3, N-2-hydroxylethylpiperazine-Nt-2-ethanesulphonic acid (HEPES)5, adjusted to pH 7.3. Amphotericin (Sigma) is prepared as 30 mg/ml stock solution and diluted to a final working concentration of 0.1 mg/ml in internal buffer solution. The external solution is Dulbecco's PBS (Invitrogen) and contains (mM): CaCl2 0.90, KCl 2.67, K3PO4 1.47, MgCl2 0.50, NaCl 138, Na3PO4 8.10 and has a pH of 7.4. All compounds are prepared as 10 mM stock solutions in DMSO. Compounds are diluted into external buffer, then transferred from the drug plate to the Patchplate during the experiment (final DMSO concentration <0.66% vol.).
Kv1.5 ionic currents are recorded at room temperature. Membrane currents are amplified (RMS ̃10 pA) and sampled at 10 kHz. Leak subtraction was performed in all experiments by applying a 160 ms hyperpolarizing (10 mV) pre-pulses 200 ms before the test pulses to measure leak conductance. The patch clamp stimulus protocol is as follows:

    
    
        1. Patchplate wells are loaded with 3.5 μL of external buffer.
        2. Planar micropipette hole resistances (Rp) is determined by applying a 10 mV, 160 ms potential difference across each hole (Hole test).
        3. Cells are pipetted into the Patchplate and form high resistance seals with the 1-2 μm holes at the bottom of each Patchplate well. A seal test scan is performed to determine how many of the Patchplate wells have cells that have formed seals.
        4. In order to gain electrical access to the cells, intracellular solution containing amphotericin is circulated for 4 minutes on the bottom side of the Patchplate.
        5. Pre-compound addition test pulse is applied to each well on the Patchplate. Protocol: Cells are voltage clamped at a membrane holding potential of −80 mV for 15 seconds. This is followed by application of a 5 Hz stimulus train (27×150 ms depolarizations to +40 mV). The membrane potential steps to +40 mV evoke outward (positive) ionic currents.
        6. Compound is added to each well of the Patchplate. Compounds are allowed to incubate for 5 minutes.
        7. Post-compound addition test pulse protocol is applied. Protocol: Cells are voltage clamped at a membrane holding potential of −80 mV for 15 seconds. This is followed by application of a 5 Hz stimulus train (27×150 ms depolarizations to +40 mV).
    
    


Data analysis is conducted off-line. Paired comparisons between pre-drug and post-drug additions are used to determine the inhibitory effect of each compound. % inhibition of the peak control current during the 27th depolarization to +40 mV (in the 5 Hz train) is plotted as a function of antagonist concentration. The concentrations of drug required to inhibit current by 50% (IC50) are determined by fitting of the Hill equation to the concentration response data: % of Control=100×(1+([Drug]/IC50)p)−1
For each cell four arithmetic metrics are obtained:

    
    
        1) seal resistance
        2) baseline metric (the mean current at −70 mV from 5 to 45 ms before the first depolarization to +40 mV)
        3) current run up metric (pre-compound mean current amplitude during the 1st depolarization to +40 mV minus the pre-compound mean current amplitude during the 27th depolarization to +40 mV)
        4) peak current (maximum current amplitude during the 27th depolarization to +40 mV during the 5 Hz train).

All metrics are obtained during both the pre- and post-compound addition traces. Cells are eliminated from further analysis if:

        1) seal resistance is <50 MΩ
        2) baseline metric is >±100 pA during the pre-compound
        3) current run up metric is ≧−0.2 nA
        4) pre-read peak metric is <400 pA.

The above-listed compounds provide ≧20% inhibition at a concentration of 33 μM or less in the high throughput Kv1.5 planar patch clamp assay described above.

Atomic Absorption Spectroscopy Protocol:

    
    


This assay identifies agents that specifically block the human Kv1.5 K+ channel heterologously expressed in CHO cells as measured by Rb+ efflux using Flame Atomic Absorption Spectroscopy (FAAS). The application of FAAS for measuring ion channel activity was adapted from Terstappen et al, Anal. Biochem., 272:149-155, 1999.
CHO cells expressing human Kv1.5 are cultured as described above, then harvested with trypsin-EDTA and washed with medium.

    
    
        1. 40,000 cells per well are seeded in a 96-well cell culture plate (assay plate) and the cells are allowed to grow for 48 hours at 37° C.
        2. The medium is removed and 200 μl of Rb Load Buffer (Aurora Biomed, Vancouver, BC) is added for 3 hours at 37° C. under 5% CO2.
        3. The cells are washed 5 times with 200 μl Hank's Balanced Salt Solution (HBSS) followed by the addition of 100 μl HBSS containing test compound or 0.5% DMSO.
        4. After 10 min, 100 μl of HEPES-buffered saline containing 140 mM KCl is added and plate is incubated at RT for 5 min. with gentle shaking.
        5. Immediately thereafter, 150 μl of supernatant is transferred to a fresh 96 well plate and the remaining supernatant aspirated.
        6. 120 μl of Cell Lysis Buffer (Aurora Biomed, Vancouver, BC) is added to the assay plate and shaken for 10 min. prior to analysis.
        7. Rb content is measured in samples of supernatant (SUP) and lysate (LYS) using an ICR-8000 automated AAS instrument (Aurora Biomed, Vancouver, BC).

% FLUX=100%*(SUP/(LYS+SUP)). % INH=100%*(1−(A−B)/(C−B)), where A is % FLUX in the presence of tested compound, B is % FLUX in the presence of 10 mM (6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)-N,N-dimethylmethanaminium chloride, C is % FLUX in the presence of 0.25% DMSO.

    
    


The above-listed compounds provide ≧25% inhibition at a concentration of 25 μM or less in the AAS assay described above.
The compounds of this invention can be administered for the treatment or prevention of afflictions, diseases and illnesses according to the invention by any means that effects contact of the active ingredient compound with the site of action in the body of a warm-blooded animal. For example, administration, can be oral, topical, including transdermal, ocular, buccal, intranasal, inhalation, intravaginal, rectal, intracisternal and parenteral. The term “parenteral” as used herein refers to modes of administration which include subcutaneous, intravenous, intramuscular, intraarticular injection or infusion, intrasternal and intraperitoneal.
The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
For the purpose of this disclosure, a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.
The dosage administered will be dependent on the age, health and weight of the recipient, the extent of disease, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired. Usually, a daily dosage of active ingredient compound will be from about 1-500 milligrams per day. Ordinarily, from 10 to 100 milligrams per day in one or more applications is effective to obtain desired results. These dosages are the effective amounts for the treatment and prevention of afflictions, diseases and illnesses described above, e.g., cardiac arrhythmias such as atrial fibrillation, atrial flutter, atrial arrhythmia, and supraventricular tachycardia, thromboembolic events such as stroke and congestive heart failure, and immunodepression.
The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, troches, dragées, granules and powders, or in liquid dosage forms, such as elixirs, syrups, emulsions, dispersions, and suspensions. The active ingredient can also be administered parenterally, in sterile liquid dosage forms, such as dispersions, suspensions or solutions. Other dosages forms that can also be used to administer the active ingredient as an ointment, cream, drops, transdermal patch or powder for topical administration, as an ophthalmic solution or suspension formation, i.e., eye drops, for ocular administration, as an aerosol spray or powder composition for inhalation or intranasal administration, or as a cream, ointment, spray or suppository for rectal or vaginal administration.
Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene gycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol.
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.
For administration by inhalation, the compounds of the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulisers. The compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device. The preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of Formula I in suitable propellants, such as fluorocarbons or hydrocarbons.
For ocular administration, an ophthalmic preparation may be formulated with an appropriate weight percent solution or suspension of the compounds of Formula I in an appropriate ophthalmic vehicle, such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye.
Useful pharmaceutical dosage-forms for administration of the compounds of this invention include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injectables, and oral suspensions.
A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.
A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol. The solution is made to volume with water for injection and sterilized.
An aqueous suspension is prepared for oral administration so that each 5 milliliters contain 100 milligrams of finely divided active ingredient, 100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin.
The same dosage forms can generally be used when the compounds of this invention are administered stepwise or in conjunction with another therapeutic agent. When drugs are administered in physical combination, the dosage form and administration route should be selected depending on the compatibility of the combined drugs. Thus the term coadministration is understood to include the administration of the two agents concomitantly or sequentially, or alternatively as a fixed dose combination of the two active components.
Compounds of the invention can be administered as the sole active ingredient or in combination with a second active ingredient, including other antiarrhythmic agents having Kv1.5 blocking activities such as quinidine, propafenone, ambasilide, amiodarone, flecamide, sotalol, bretylium, dofetilide, almokalant, bepridil, clofilium, other compounds having Kv1.5 blocking activities such as clotrimazole, ketoconazole, bupivacaine, erythromycin, verapamil, nifedipine, zatebradine, bisindolylmaleimide, or other cardiovascular agents such as, but not limited to, ACE inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril erbumine, quinapril, ramipril, and trandolapril, angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan, cardiac glycosides such as digoxin, L-type calcium channel blockers, T-type calcium channel blockers, selective and nonselective beta blockers, an immunosuppresant compound, endothelin antagonists, thrombin inhibitors, aspirin, nonselective NSAIDs other than aspirin such as naproxen, warfarin, factor Xa inhibitors, low molecular weight heparin, unfractionated heparin, clopidogrel, ticlopidine, IIb/IIIa receptor antagonists such as tirofiban, 5HT receptor antagonists, integrin receptor antagonists, thromboxane receptor antagonists, TAFI inhibitors and P2T receptor antagonists. Compounds of the invention can also be administered as the sole active ingredient or in combination with a pacemaker or defibrillator device.

## Claims

1. A compound of the formula




or a pharmaceutically acceptable salt thereof, wherein
A is selected from the group consisting of
1) a phenyl ring, and
2) a pyridyl ring, wherein the point of attachment to the pyridyl ring is a carbon atom, wherein the phenyl ring and pyridyl ring are unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein the N pyridyl ring atom is unsubstituted or substituted with oxo; and

C is selected from the group consisting of
1) an aryl ring, wherein any stable aryl ring atom is independently unsubstituted or substituted with a group selected from R4, and
2) C1—C6 alkyl, wherein any stable atom is independently unsubstituted or substituted with a group selected from R4;

B is a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, and wherein the heteroaryl ring is selected from the group consisting of pyridine and pyrimidine, wherein the heteroaryl ring is unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein the N heteroaryl ring atom is unsubstituted or substituted with oxo;
X is OH;
Y is selected from the group consisting of




G, each time it occurs, is independently selected from the group consisting of H2 and O;
Z is selected from the group consisting of C(R6)2, NR5, NC(O)R5, NC(O)OR5, NC(O)N(R5)2, NS(O)1-2R5, S(O)0-2, —N(R5)C(O)—, —C(R5)═C(R6)— and O;
Ra, in each instance in which it appears, is independently selected from the group consisting of
1) hydrogen,
2) C1—C6 alkyl,
3) halogen,
4) aryl,
5) heterocycle,
6) C3—C10 cycloalkyl, and
7) OR5,

said alkyl, aryl, heterocycle and cycloalkyl is unsubstituted or substituted with at least one substituent selected from R6;
R4, in each instance in which it appears, is independently selected from the group consisting of
1) hydrogen,
2) halogen,
3) NO2,
4) CN,
5) CR4═C(R5)2,
6) C≡CR5,
7) (CRa2)nOR5,
8) (CRa2)nN(R5)2,
9) (CRa2)nC(O)R5,
10) (CRa2)nC(O)OR5,
11) (CRa2)nR5,
12) (CRa2)nS(O)mR5,
13) (CRa2)nS(O)mN(R5)2,
14) OS(O)mR5,
15) N(R5)C(O)R5,
16) N(R5)S(O)mR5,
17) (CRa2)nN(R6)R5,
18) (CRa2)nN(R5)(CRa2)nC(O)N(R5)2,
19) (CRa2)nN(R5)(CRa2)nC(O)OR5,
20) N(R5)(CRa2)nR5,
21) N(R5)(CRa2)nN(R5)2, and
22) (CRa2)nC(O)N(R5)2;

R5, in each instance in which it appears, is independently selected from the group consisting of
1) hydrogen,
2) unsubstituted or substituted C1—C6 alkyl,
3) unsubstituted or substituted C3—C10 cycloalkyl,
4) unsubstituted or substituted aryl,
5) unsubstituted or substituted heterocycle,
6) CF3,
7) unsubstituted or substituted C2—C6 alkenyl, and
8) unsubstituted or substituted C2—C6 alkynyl, or in the case where R5 is attached to a nitrogen atom that is disubstituted with R5, each R5 is independently selected from C1—C6 alkyl, and the nitrogen atom together with each R5 form a ring;

R6, in each instance in which it appears, is independently selected from the group consisting of
1) hydrogen,
2) unsubstituted or substituted C1—C6 alkyl,
3) halogen,
4) OR5,
5) CF3,
6) unsubstituted or substituted aryl,
7) unsubstituted or substituted C3—C10 cycloalkyl,
8) unsubstituted or substituted heterocycle,
9) S(O)m(R5)2,
10) C(O)OR5,
11) C(O)R5,
12) CN,
13) C(O)N(R5)2,
14) N(R5)C(O)R5,
15) N(R5)C(O)OR5,
16) N(R5)C(O)N(R5)2,
17) OC(O)N(R5)2,
18) S(O)mR5,
19) OS(O)mR5,
20) NO2,
21) N(R5)2,
22) SC(O)R5,
23) N(R5)S(O)mR5,

R7 is independently selected from the group consisting of
1) S(O)mN(R5)2,
2) C(O)OR5,
3) C(O)R5,
4) C(O)N(R5)2, and
5) S(O)mR5;

m is independently 0, 1 or 2;
n is independently 0, 1, 2, 3, 4, 5 or 6;
u is 0, 1 or 2; and
v is 0, 1 or 2 provided the compound is not

2. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
B is a pyridyl ring, wherein the point of attachment to the pyridyl ring is a carbon atom, and wherein the pyridyl ring is unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein the N atom is unsubstituted or substituted with oxo;
X is OH;
A is selected from the group consisting of
1) a phenyl ring, and
2) a pyridyl ring, wherein the point of attachment to the pyridyl ring is a carbon atom, wherein the phenyl ring and pyridyl ring are unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein the N pyridyl ring atom is unsubstituted or substituted with oxo;

C is selected from the group consisting of










Y is selected from the group consisting of

3. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
(±)-2-Morpholin-4-yl-2-phenyl-1,1-dipyridin-3-yl-ethanol,
(±)-3-methyl-2-morpholin-4-yl-1,1-dipyridin-3-ylbutan-1-ol,
(±)-2-[(2-methoxyethyl)(methyl)amino]-2-phenyl-1,1-dipyridin-3-ylethanol,
(±)-2-phenyl-2-piperidin-1-yl-1,1-dipyridin-3-ylethanol,
(±)-2-phenyl-1,1-dipyridin-3-yl-2-pyrrolidin-1-ylethanol,
(±)-tert-butyl 4-(2-hydroxy-1-phenyl-2,2-dipyridin-3-ylethyl)piperazine-1-carboxylate,
2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-2-phenyl-1,1-dipyridin-3-ylethanol,
(±)-2-(1,4-oxazepan-4-yl)-2-phenyl-1,1-dipyridin-3-ylethanol,
(±)-2-phenyl-1,1-dipyridin-3-yl-2-thiomorpholin-4-ylethanol,
(±)-2-(diethylamino)-2-phenyl-1,1-dipyridin-3-ylethanol,
(±)-2-(7-azabicyclo[2.2.1]hept-7-yl)-2-phenyl-1,1-dipyridin-3-ylethanol,
(±)-2-(3,3-difluoropyrrolidin-1-yl)-2-phenyl-1,1-dipyridin-3-ylethanol,
(±)-2-phenyl-1,1-dipyridin-3-yl-2-[2-(trifluoromethyl)pyrrolidin-1-yl]ethanol,
(±)-2-(2-isopropylpyrrolidin-1-yl)-2-phenyl-1,1-dipyridin-3-ylethanol,
(2R)-2-cyclopropyl-1,1-dipyridin-3-yl-2-pyrrolidin-1-ylethanol,
(±)-2-[cyclobutyl(ethyl)amino]-2-phenyl-1,1-dipyridin-3-ylethanol,
(±)-2-[ethyl(2,2,2-trifluoroethyl)amino]-2-phenyl-1,1-dipyridin-3-ylethanol,
(±)-2-(3-fluoropyrrolidin-1-yl)-2-phenyl-1,1-dipyridin-3-ylethanol,
(±)-2-morpholin-4-yl-1,2-diphenyl-1-pyridin-2-yl-ethanol,
2-morpholin-4-yl-2-phenyl-1-pyridin-2-yl-1-pyridin-3-ylethanol,
(±)-2-phenyl-2-(phenylsulfonyl)-1,1-dipyridin-3-ylethanol,
(±)-2-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-1,1-dipyridin-3-yl-2-pyrrolidin-1-ylethanol,
(±)-1,2-diphenyl-2-(1H-pyrazol-1-yl)-1-pyridin-4-ylethanol,
(±)-3-(2-hydroxy-1-phenyl-2,2-dipyridin-3-ylethyl)-1,3-oxazolidin-2-one,
(±)-3-[2-hydroxy-1-(2-oxo-1,3-oxazolidin-3-yl)-2,2-dipyridin-3-ylethyl]benzonitrile,
(±)-1-[1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]-3-methylimidazolidin-2-one,
(±)-1-tert-butyl-3-[1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]imidazolidin-2-one,
(±)-3-(2-hydroxy-1-pyridin-2-yl-2,2-dipyridin-3-ylethyl)-1,3-oxazolidin-2-one,
(±)-2-(1H-pyrazol-1-yl)-2-pyridin-2-yl-1,1-dipyridin-3-ylethanol,
(±)-2-(1H-pyrazol-1-yl)-1,1,2-tripyridin-3-ylethanol,
(±)-1,1,2-tripyridin-3-yl-2-(1H-1,2,3-triazol-1-yl)ethanol,
(±)-4-[2-hydroxy-2,2-dipyridin-3-yl-1-(2H-1,2,3-triazol-2-yl)ethyl]benzonitrile,
(±)-3-[2-hydroxy-2,2-dipyridin-3-yl-1-(1H-1,2,3-triazol-1-yl)ethyl]benzonitrile,
(±)-(1-benzyl-1H-pyrazol-5-yl)(dipyridin-3-yl)methanol,
(±)-1-[1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]pyridin-2(1H)-one,
(±)-1-[1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]pyrazin-2(1H)-one,
(±)-2-[1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]pyridazin-3(2H)-one,
(R)-1-(2-hydroxy-1-pyridin-2-yl-2,2-dipyridin-3-ylethyl)pyridin-2(1H)-one,
(S)-1-(2-hydroxy-1-pyridin-2-yl-2,2-dipyridin-3-ylethyl)pyridin-2(1H)-one,
(±)-3-(2-hydroxy-2,2-dipyridin-3-yl-1-pyrrolidin-1-ylethyl)benzonitrile,
(±)-2-(4-fluorophenyl)-1,1-dipyridin-3-yl-2-pyrrolidin-1-ylethanol,
(±)-2-(3-methoxyphenyl)-1,1-dipyridin-3-yl-2-pyrrolidin-1-ylethanol,
2-[(2r)-2-(methoxymethyl)pyrrolidin-1-yl]-2-phenyl-1,1-dipyridin-3-ylethanol,
(±)-2-(3-bromophenyl)-1,1-dipyridin-3-yl-2-pyrrolidin-1-ylethanol,
(±)-2-(3,3-difluoroazetidin-1-yl)-2-(4-fluorophenyl)-1,1-dipyridin-3-ylethanol,
(±)-2-(5-chloro-2-thienyl)-1,1-dipyridin-3-yl-2-pyrrolidin-1-ylethanol,
2-[(3R,4R)-3,4-difluoropyrrolidin-1-yl]-2-phenyl-1,1-dipyridin-3-ylethanol,
(±)-1-(2-hydroxy-1-phenyl-2,2-dipyridin-3-ylethyl)piperidin-3-ol,
2-(4-fluorophenyl)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-1,1-dipyridin-3-ylethanol,
(±)-2-(cyclobutylamino)-2-(4-fluorophenyl)-1,1-dipyridin-3-ylethanol,
(±)-2-phenyl-1,1-dipyridin-3-yl-2-[(2,2,2-trifluoroethyl)-amino]ethanol,
2-(benzyloxy)-N-[(1R)-2-hydroxy-1-phenyl-2,2-dipyridin-3-ylethyl]acetamide,
N-[(1R)-1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]-3-pyridin-2-yl-1H-pyrazole-5-carboxamide,
N-[(1R)-1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]-4-phenylbutanamide,
benzyl[(1R)-1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]carbamate,
N-[(1R)-1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]-1-phenyl-1H-pyrazole-4-carboxamide,
(±)-2-phenyl-1,1-dipyridin-3-yl-2-(1H-pyrrol-1-yl)ethanol,
(±)-3-(2-hydroxy-1-morpholin-4-yl-2,2-dipyridin-3-ylethyl)benzonitrile,
(±)-3,3′-(1-fluoro-2-phenyl-2-pyrrolidin-1-ylethane-1,1-diyl)dipyridine,
(±)-1-[1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]azetidin-3-ol,
(±)-1-[1-(4-fluorophenyl)-2-hydroxy-2,2-dipyridin-3-ylethyl]azetidin-3-yl phenylcarbamate,
(±)-2-(3,3-difluoroazetidin-1-yl)-2-(4-fluorophenyl)-1-(1-oxidopyridin-3-yl)-1-pyridin-3-ylethanol,
(±)-4-[1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethyl]morpholine,
(±)-N-[1-(4-fluorophenyl)-2-phenyl-2-pyridin-3-ylethyl]-2-methoxyacetamide,
(±)-4-[1-(4-fluorophenyl)-2-phenyl-2-pyridin-3-ylethyl]morpholine,
(±)-1-[1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]pyrrolidin-2-one,
(±)-4-[1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]morpholine,
(±)-[1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl](2,2,2-trifluoroethyl)amine,
(±)-4-[1-(3,4-dichlorophenyl)-2,2-dipyridin-3-ylethyl]morpholine,
(±)-4-(1-pyridin-2-yl-2,2-dipyridin-3-ylethyl)morpholine,
(±)-3,3′-[2-(4-fluorophenyl)-2-pyrrolidin-1-ylethane-1,1-diyl]dipyridine,
(±)-4-[1-(4-fluorophenyl)-2-pyridin-2-yl-2-pyridin-3-ylethyl]morpholine,
(±)-4-[1-(3-chlorophenyl)-2,2-dipyridin-3-ylethyl]morpholine,
(±)-4-[1-(3,5-dichlorophenyl)-2,2-dipyridin-3-ylethyl]morpholine,
(±)-[1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl](3,3,3-trifluoropropyl)amine,
(±)-[1-(3-chlorophenyl)-2,2-dipyridin-3-ylethyl](2,2,2-trifluoroethyl)amine,
(±)-[1-(3,5-dichlorophenyl)-2,2-dipyridin-3-ylethyl](2,2,2-trifluoroethyl)amine,
(±)-[1-(3,4-dichlorophenyl)-2,2-dipyridin-3-ylethyl](2,2,2-trifluoroethyl)amine,
(±)-3,3′-[2-(1,1-dioxidoisothiazolidin-2-yl)-2-(4-fluorophenyl)ethane-1,1-diyl]dipyridine,
(±)-4-[1-(6-methoxypyridin-2-yl)-2-phenyl-2-pyridin-2-ylethyl]morpholine,
(±)-4-[1-(6-bromopyridin-2-yl)-2,2-dipyridin-3-ylethyl]morpholine,
(±)-6-(1-morpholin-4-yl-2,2-dipyridin-3-ylethyl)pyridin-2-amine,
(±)-N-methyl-6-(1-morpholin-4-yl-2,2-dipyridin-3-ylethyl)pyridin-2-amine,
(±)-methyl[6-(1-morpholin-4-yl-2,2-dipyridin-3-ylethyl)pyridin-2-yl]carbamate,
(±)-[1-(3-bromophenyl)-2,2-dipyridin-3-ylethyl]{[1-(phenylsulfonyl)-1H-pyrrol-2-yl]methyl}amine,
(±)-methyl[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]prolinate,
(±)-3-{1-[2-(hydroxymethyl)pyrrolidin-1-yl]-2,2-dipyridin-3-ylethyl}benzonitrile,
(±)-1-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]-N,N-dimethylprolinamide,
(±)-1-[1-(3-bromophenyl)-2,2-dipyridin-3-yethyl]-4-methylpiperazine-2,3-dione,
(±)-3-[1-(6-bromopyridin-2-yl)-2,2-dipyridin-3-ylethyl]-1,3-oxazolidin-2-one,
(±)-3-[1-(2-oxo-1,3-oxazolidin-3-yl)-2,2-dipyridin-3-ylethyl]benzonitrile,
(±)-benzyl (1,2,2-tripyridin-3-ylethyl)carbamate,
(±)-n-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]-2-phenylcyclopropanecarboxamide,
(±)-3-(1-{[(1-phenyl-1h-pyrazol-4-yl)methyl]amino}-2,2-dipyridin-3-ylethyl)benzonitrile,
(R)-3-(1-morpholin-4-yl-2,2-dipyridin-3-ylethyl)benzonitrile,
(S)-3-(1-morpholin-4-yl-2,2-dipyridin-3-ylethyl)benzonitrile,
(±)-3-[2-(4-fluorophenyl)-1-pyridin-3-yl-2-(2,2,2-trifluoroethoxy)ethyl]pyridine,
(±)-3-[2-(4-fluorophenyl)-2-methoxy-1-pyridin-3-ylethyl]pyridine,
(±)-3-[2-(cyclopentyloxy)-2-(4-fluorophenyl)-1-pyridin-3-ylethyl]pyridine,
(±)-1-[1-(6-chloropyridin-2-yl)-2,2-dipyridin-3-ylethyl]pyridin-2(1H)-one,
(±)-1-(1-pyridin-2-yl-2,2-dipyridin-3-ylethyl)pyridin-2(1H)-one,
(R)-1-(1-pyridin-2-yl-2,2-dipyridin-3-ylethyl)pyridin-2(1H)-one,
(S)-1-(1-pyridin-2-yl-2,2-dipyridin-3-ylethyl)pyridin-2(1H)-one,
(±)-2-[1-(1H-pyrazol-1-yl)-2,2-dipyridin-3-ylethyl]pyridine,
(±)-2-[2-(4-fluorophenyl)-1-(1H-pyrazol-1-yl)-2-pyridin-3-ylethyl]pyridine,
(±)-2-[2-(4-fluorophenyl)-1-(1H-pyrazol-1-yl)-2-pyridin-3-ylethyl]pyridine,
(±)-2-[1-(4-fluorophenyl)-2-(1H-imidazol-1-yl)-2-pyridin-3-ylethyl]pyridine,
(±)-1-(1,2,2-tripyridin-3-ylethyl)pyridin-2(1H)-one,
(±)-2-[2,2-dipyridin-3-yl-1-(1H-1,2,3-triazol-1-yl)ethyl]pyridine,
(±)-3-[2,2-dipyridin-3-yl-1-(1H-1,2,3-triazol-1-yl)ethyl]benzonitrile,
(±)-1-[1(2H)-yl)-2,2-dipyridin-3-ylethyl]pyridin-2(1H)-one,
(±)-1-phenyl-1,2-dipyridin-3-yl-2-(1H-1,2,3-triazol-1-yl)ethanol,
(±)-1-phenyl-1-pyridin-2-yl-2-pyridin-3-yl-2-(1H-1,2,3-triazol-1-yl)ethanol,
(±)-4-[2-hydroxy-2,2-dipyridin-3-yl-1-(1H-1,2,3-triazol-1-yl)ethyl]benzonitrile,
(±)-1-(2-hydroxy-2-phenyl-2-pyridin-2-yl-1-pyridin-3-ylethyl)pyridin-2(1H)-one,
(±)-1-(2-hydroxy-2-phenyl-1,2-dipyridin-3-ylethyl)pyridin-2(1H)-one,
(±)-1-(2-hydroxy-2-phenyl-2-pyridin-2-yl-1-pyridin-3-ylethyl)pyrazin-2(1H)-one,
(±)-2-(6-bromopyridin-3-yl)-1,1-dipyridin-3-yl-2-(1H-1,2,3-triazol-1-yl)ethanol,
(±)-3-[1-hydroxy-2-(2-oxopyridin-1(2H)-yl)-2-pyridin-2-yl-1-pyridin-3-ylethyl]benzonitrile,
(±)-3-(2-hydroxy-1-pyridin-2-yl-2,2-dipyridin-3-ylethyl)-1,3-oxazinan-2-one,
(±)-3-[2-(6-bromopyridin-3-yl)-1-hydroxy-1-pyridin-3-yl-2-(1H-1,2,3-triazol-1-yl)ethyl]benzonitrile,
(±)-3-[1-hydroxy-1,2-dipyridin-3-yl-2-(1H-1,2,3-triazol-1-yl)ethyl]benzonitrile,
(±)-3-[1-hydroxy-2-pyridin-2-yl-1-pyridin-3-yl-2-(1H-1,2,3-triazol-1-yl)ethyl]benzonitrile,
(±)-3-(2-hydroxy-1-phenyl-2,2-dipyridin-3-ylethyl)-1,3-oxazinan-2-one,
(±)-3-[1-hydroxy-2-(2-oxo-1,3-oxazinan-3-yl)-2-pyridin-2-yl-1-pyridin-3-ylethyl]benzonitrile,
(S)-{1-[1-(3-bromophenyl)-2,2-dipyridin-3-ylethyl]piperidin-4-yl}ethanethioate,
(±)-3-[1-(2,4-dioxoimidazolidin-1-yl)-2,2-dipyridin-3-ylethyl]benzonitrile,
(±)-3-[1-(2-oxomorpholin-4-yl)-2,2-dipyridin-3-ylethyl]benzonitrile,
(±)-3-[1-(2-hydroxymorpholin-4-yl)-2,2-dipyridin-3-ylethyl]benzonitrile,
(±)-1-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]-N,N-bis(1-{1-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]prolyl}pyrrolidin-2-yl)prolinamide,
(±)-3-(1-pyridin-2-yl-2,2-dipyridin-3-ylethyl)-1,3-oxazolidin-2-one,
(±)-tert-butyl 2-{[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]amino}ethylcarbamate,
(±)-3-[1-(2-oxo-1,3-oxazinan-3-yl)-2,2-dipyridin-3-ylethyl]benzonitrile,
(±)-N-(2-{[1-(3-bromophenyl)-2,2-dipyridin-3-ylethyl]amino}ethyl)methanesulfonamide,
(±)-3-(1-morpholin-4-yl-2,2-dipyridin-3-ylethyl)phenol,
(±)-3-[1-(6-bromopyridin-2-yl)-2,2-dipyridin-3-ylethyl]-1,3-oxazinan-2-one,
(±)-N-(2-{[1-(3-bromophenyl)-2,2-dipyridin-3-ylethyl]amino}ethyl)-n′-phenylurea,
(±)-N-(tert-butyl)-1-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]prolinamide,
(±)-1-[(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]-piperidinylprolinamide,
(±)-1-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]-N-cyclohexylprolinamide,
(±)-1-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]-N-phenylprolinamide,
(±)-methyl 1-[1-(6-bromopyridin-2-yl)-2,2-dipyridin-3-ylethyl]prolinate,
(±)-3-(1-{[(1-phenyl-1H-pyrazol-4-yl)methyl]amino}-2,2-dipyridin-3-ylethyl)benzonitrile,
(±)-methyl 1-[1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]prolinate,
(±)-methyl 1-[1-(6-aminopyridin-2-yl)-2,2-dipyridin-3-ylethyl]prolinate,
(±)-N-{1-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]piperidin-4-yl}-N-methylmethanesulfonamide,
(±)-3-[1-(2-oxopyrrolidin-1-yl)-2,2-dipyridin-3-ylethyl]benzonitrile,
(±)-1-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]piperidin-4-yl phenylcarbamate,
(±)-1-[1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]-N-methylprolinamide,
(±)-N-ethyl-1-[1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]prolinamide,
(±)-N-{1-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]piperidin-4-yl}-N-methylcyclopropanesulfonamide,
(±)-3-[1-(1,1-dioxidoisothiazolidin-2-yl)-2,2-dipyridin-3-ylethyl]benzonitrile,
(±)-3-[1-(4,5-dihydro-1,3-thiazol-2-ylamino)-2,2-dipyridin-3-ylethyl]benzonitrile,
(±)-methyl 1-(1-pyridin-2-yl-2,2-dipyridin-3-ylethyl)prolinate,
(±)-N-butyl-1-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]prolinamide,
(±)-1-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]-N-isobutylprolinamide,
(±)-1-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]-N-cyclobutylprolinamide,
(±)-1-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]-N-cyclopentylprolinamide,
(±)-1-[1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]-N-pyridin-2-ylprolinamide,
(±)-1-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]-N-[4-(trifluoromethyl)pyridin-2-yl]prolinamide,
(±)-N-(5-chloropyridin-2-yl)-1-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]prolinamide,
(±)-4-[1-(3-bromophenyl)-2,2-dipyridin-3-ylethyl]morpholin-2-one,
(±)-N-{1-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]piperidin-4-yl}-N-cyclopropylmethanesulfonamide,
(±)-N-{1-[(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]piperidin-4-yl}-N-ethylmethanesulfonamide,
(±)-N-{1-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]piperidin-4-yl}-N-ethylcyclopropanesulfonamide,
(±)-N-{1-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]piperidin-4-yl}-N-methylethanesulfonamide,
(±)-methyl 1-[1-(3-cyanophenyl)-2-pyrazin-2-yl-2-pyridin-3-ylethyl]prolinate,
(±)-2-{1-[1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]pyrrolidin-2-yl}-1H-benzimidazole,
(±)-methyl 1-[1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethyl]prolinate,
(±)-3-{1-[2-(1H-benzimidazol-2-yl)pyrrolidin-1-yl]-2,2-dipyridin-3-ylethyl}benzonitrile,
(±)-N-(tert-butyl)-1-[1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethyl]prolinamide,
(±)-2-{1-[1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethyl]pyrrolidin-2-yl}-1H-benzimidazole,
(±)-tert-butyl 3-{[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]amino}piperidine-1-carboxylate,
(±)-{1-[2-(6-aminopyridin-2-yl)-1,2-dipyridin-3-ylethyl]pyrrolidin-2-yl}methanol,
(±)-3-(1-{[(4-phenyl-1,3-thiazol-2-yl)methyl]amino}-2,2-dipyridin-3-ylethyl)benzonitrile,
(±)-3-(1-{[(2-phenyl-1,3-thiazol-5-yl)methyl]amino}-2,2-dipyridin-3-ylethyl)benzonitrile,
(±)-3-{2,2-dipyridin-3-yl-1-[(pyridin-2-ylmethyl)amino]ethyl}benzonitrile,
(±)-3-(1-{[3-(4-methoxyphenoxy)benzyl]amino}-2,2-dipyridin-3-ylethyl)benzonitrile,
(±)-3-{2,2-dipyridin-3-yl-1-[(quinolin-3-ylmethyl)amino]ethyl}benzonitrile,
(±)-3-(1-{[4-(methylthio)benzyl]amino}-2,2-dipyridin-3-ylethyl)benzonitrile,
(±)-3-{1-[(2,2-dimethylpent-4-en-1-yl)amino]-2,2-dipyridin-3-ylethyl}benzonitrile,
(±)-3-{1-[(4-propoxybenzyl)amino]-2,2-dipyridin-3-ylethyl}benzonitrile,
(±)-3-{1-[(biphenyl-4-ylmethyl)amino]-2,2-dipyridin-3-ylethyl}benzonitrile,
(±)-3-{1-[(1-benzothien-2-ylmethyl)amino]-2,2-dipyridin-3-ylethyl}benzonitrile,
(±)-3-(2,2-dipyridin-3-yl-1-{[3-(trifluoromethyl)benzyl]amino}ethyl)benzonitrile,
(±)-3-{-[(4-cyanobenzyl)amino]-2,2-dipyridin-3-ylethyl}benzonitrile,
(±)-3-{1-[2-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl]-2,2-dipyridin-3-ylethyl}benzonitrile,
(±)-6-{1-[2-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl]-2,2-dipyridin-3-ylethyl}pyridin-2-amine,
(±)-2-methoxy-6-{1-[2-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl]-2,2-dipyridin-3-ylethyl}pyridine,
(±)-3-{2-(4-fluorophenyl)-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl]-1-pyridin-3-ylethyl}pyridine,
(±)-3-{1-[2-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl]-2-pyrazin-2-yl-2-pyridin-3-ylethyl}benzonitrile,
(±)-3-{1-[2-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl]-2-pyrazin-2-yl-2-pyridin-3-ylethyl}benzonitrile,
(±)-3-[1-(3-hydroxypiperidin-1-yl)-2,2-dipyridin-3-ylethyl]benzonitrile,
(±)-4-[2-(6-aminopyridin-2-yl)-2-(3-hydroxypiperidin-1-yl)-1-pyridin-3-ylethyl]benzonitrile,
(±)-4-{2,2-dipyridin-3-yl-1-[(2,2,2-trifluoroethyl)amino]ethyl}benzonitrile,
(±)-4-{1-[(2-fluoroethyl)amino]-2,2-dipyridin-3-ylethyl}benzonitrile,
(±)-4-{1-[(2,2-difluoroethyl)amino]-2,2-dipyridin-3-ylethyl}benzonitrile,
(±)-N-{1-[4-(methylthio)phenyl]-2,2-dipyridin-3-ylethyl}-N-(2,2,2-trifluoroethyl)amine,
(±)-N-{1-[4-(methylsulfonyl)phenyl]-2,2-dipyridin-3-ylethyl}-N-(2,2,2-trifluoroethyl)amine,
(±)-6-{2,2-dipyridin-3-yl-1-[(2,2,2-trifluoroethyl)amino]ethyl}pyridin-2-amine,
(±)-N-{1-[2-(methylthio)phenyl]-2,2-dipyridin-3-ylethyl}-N-(2,2,2-trifluoroethyl)amine,
(±)-N-{1-[2-(methylsulfonyl)phenyl]-2,2-dipyridin-3-ylethyl}-N-(2,2,2-trifluoroethyl)amine,
(±)-N-{1-[3-(methylthio)phenyl]-2,2-dipyridin-3-ylethyl}-N-(2,2,2-trifluoroethyl)amine,
(±)-N-{1-[3-(methylsulfonyl)phenyl]-2,2-dipyridin-3-ylethyl}-N-(2,2,2-trifluoroethyl)amine,
(±)-1-(2,3′-bipyridin-3-yl)-2,2-dipyridin-3-ylethanamine,
(±)-1-(2,3′-bipyridin-3-yl)-2,2-dipyridin-3-yl-N-(2,2,2-trifluoroethyl)ethanamine,
(±)-3-[1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]-1,3-oxazolidin-2-one,
(±)-3-[1-(4-chlorophenyl)-2,2-dipyridin-3-ylethyl]-1,3-oxazolidin-2-one,
benzyl(±)-1-(4-chlorophenyl)-2,2-dipyridin-3-ylethylcarbamate,
(±)-4-[1-(2-oxo-1,3-oxazolidin-3-yl)-2,2-dipyridin-3-ylethyl]benzonitrile,
(±)-neopentyl 1-(4-chlorophenyl)-2,2-dipyridin-3-ylethylcarbamate,
(±)-N-{1-[2-(methylthio)pyrimidin-4-yl]-2,2-dipyridin-3-ylethyl}-n-(2,2,2-trifluoroethyl)amine,
(±)-4-{2-(2-fluoropyridin-3-yl)-2-pyridin-3-yl-1-[(2,2,2-trifluoroethyl)amino]ethyl}pyrimidin-2-amine,
(±)-6-{2-(4-fluorophenyl)-1-pyridin-3-yl-2-[(2,2,2-trifluoroethyl)amino]ethyl}pyridin-2-amine,
(±)-1-(2-morpholin-4-ylpyridin-3-yl)-2,2-dipyridin-3-ylethanol,
(±)-1-{2-[methyl(pyridin-3-yl)amino]pyridin-3-yl}-2,2-dipyridin-3-ylethanol,
(±)-3,3′,3′′-[2-(1H-tetrazol-1-yl)ethane-1,1,2-triyl]tripyridine,
(±)-3-[2-pyridin-2-yl-1-pyridin-3-yl-2-(1H-1,2,3-triazol-1-yl)ethyl]benzonitrile,
(±)-2-[2,2-dipyridin-3-yl-1-(4H-1,2,4-triazol-4-yl)ethyl]pyridine,
(±)-4-{2-(4-chlorophenyl)-1-[2-(methylthio)pyrimidin-4-yl]-2-pyridin-3-ylethyl}morpholine,
(±)-4-[2-(4-chlorophenyl)-1-morpholin-4-yl-2-pyridin-3-ylethyl]pyrimidin-2-amine, and
(±)-6-[1-(3,3-difluoropyrrolidin-1-yl)-2,2-dipyridin-3-ylethyl]pyridin-2-amine.

4. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and the compound claim 1 or a pharmaceutically acceptable crystal form or hydrate thereof.

5. A pharmaceutical composition made by combining the compound of claim 1 and a pharmaceutically acceptable carrier.