# Patent

## Title
Pyrimidine compounds as delta opioid receptor modulators

## Abstract

Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula I as follows:




wherein R1, R2, R3, and L, A, and Ra are defined herein.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application 61/256,405, filed on Oct. 30, 2009, which is incorporated by reference herein in its entirety.


FIELD OF THE INVENTION
The present invention is directed to novel opioid receptor modulators of Formula (I). The invention further relates to methods for preparing such compounds, pharmaceutical compositions containing them, and their use in the treatment of opioid modulated disorders.
BACKGROUND OF THE INVENTION
The term “opiate” has been used to designate pharmacologically active alkaloids derived from opium, e.g., morphine, codeine, and many semi-synthetic congeners of morphine. After the isolation of peptide compounds with morphine-like actions, the term opioid was introduced to refer generically to all drugs with morphine-like actions. Included among opioids are various peptides that exhibit morphine-like activity, such as endorphins, enkephalins and dynorphins. However, some sources use the term “opiate” in a generic sense, and in such contexts, opiate and opioid are interchangeable. Additionally, the term opioid has been used to refer to antagonists of morphine-like drugs as well as to characterize receptors or binding sites that combine with such agents.
Opioids are generally employed as analgesics, but they may have many other pharmacological effects as well. Morphine and related opioids produce certain of their major effects on the central nervous and digestive systems. The effects are diverse, including analgesia, drowsiness, mood changes, respiratory depression, dizziness, mental clouding, dysphoria, pruritus, increased pressure in the biliary tract, decreased gastrointestinal motility, nausea, vomiting, and alterations of the endocrine and autonomic nervous systems.
When therapeutic doses of morphine are given to patients with pain, they report that the pain is less intense, less discomforting, or entirely gone. In addition to experiencing relief of distress, some patients experience euphoria. However, when morphine in a selected pain-relieving dose is given to a pain-free individual, the experience is not always pleasant; nausea is common, and vomiting may also occur. Drowsiness, inability to concentrate, difficulty in mentation, apathy, lessened physical activity, reduced visual acuity, and lethargy may ensue.
Two distinct classes of opioid molecules can bind opioid receptors: the opioid peptides (e.g., the enkephalins, dynorphins, and endorphins) and the alkaloid opiates (e.g., morphine, etorphine, diprenorphine and naloxone). Subsequent to the initial demonstration of opiate binding sites (Pert, C. B. and Snyder, S. H., Science (1973) 179:1011-1014), the differential pharmacological and physiological effects of both opioid peptide analogues and alkaloid opiates served to delineate multiple opioid receptors. Accordingly, three molecularly and pharmacologically distinct opioid receptor types have been described: delta, kappa and mu. Furthermore, each type is believed to have sub-types (Wollemann, M., J Neurochem (1990) 54:1095-1101; Lord, J. A., et al., Nature (1977) 267:495-499).
All three of these opioid receptor types appear to share the same functional mechanisms at a cellular level. For example, the opioid receptors cause inhibition of adenylate cyclase, and inhibition of neurotransmitter release via both potassium channel activation and inhibition of Ca2+ channels (Evans, C. J., In: Biological Basis of Substance Abuse, S. G. Korenman & J. D. Barchas, eds., Oxford University Press (in press); North, A. R., et al., Proc Natl Acad Sci USA (1990) 87:7025-29; Gross, R. A., et al., Proc Natl Acad Sci USA (1990) 87:7025-29; Sharma, S. K., et al., Proc Natl Acad Sci USA (1975) 72:3092-96). Although the functional mechanisms are the same, the behavioral manifestations of receptor-selective drugs differ greatly (Gilbert, P. E. & Martin, W. R., J Pharmacol Exp Ther (1976) 198:66-82). Such differences may be attributable in part to the anatomical location of the different receptors.
Delta receptors have a more discrete distribution within the mammalian CNS than either mu or kappa receptors, with high concentrations in the amygdaloid complex, striatum, substantia nigra, olfactory bulb, olfactory tubercles, hippocampal formation, and the cerebral cortex (Mansour, A., et al., Trends in Neurosci (1988) 11:308-14). The rat cerebellum is remarkably devoid of opioid receptors including delta opioid receptors.
There is a continuing need for new delta opioid receptor modulators as analgesics. There is a further need for delta opioid receptor selective agonists as analgesics having reduced side effects. There is also a need for delta opioid receptor antagonists as immunosuppressants, antiinflammatory agents, agents for the treatment of neurological and psychiatric conditions, agents for the treatment of urological and reproductive conditions, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents and agents for the treatment of respiratory diseases, having reduced side effects.
There is a continuing need for new opioid receptor modulators as analgesics. There is a further need for delta and mu opioid receptor agonists as analgesics having reduced side effects. There is a further need for mu opioid receptor agonists as analgesics having reduced side effects for the treatment of pain, immune function, esophageal reflux, and cough. There is also a need for delta opioid receptor agonists as analgesic agents, agents for the treatment of respiratory diseases, cardiovascular agents, agents for treating urological dysfunction, and agents for the treatment of neurological and psychiatric conditions. There is further need for dual delta opioid receptor/mu opioid receptor agonists.
SUMMARY OF THE INVENTION
The present invention is directed to a compound of Formula I




wherein

    R1 is selected from the group consisting of
    i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C1-4alkylthio, hydroxy, chloro, and fluoro; in addition, phenyl is optionally substituted with a single amino, C1-4alkylamino, di(C1-4alkyl)amino, di(C1-4alkyl)aminocarbonyl, C1-4alkylaminocarbonyl, hydroxy(C1-4)alkyl, aminocarbonyl, C1-4alkylcarbonylamino, C1-4alkoxycarbonylamino, ureido, C1-4alkylureido, di(C1-4alkyl)ureido, cyano, trifluoromethoxy, C1-4alkylsulfonyl, nitro, trifluoromethyl, bromo, piperazin-1-yl optionally substituted with 4-C1-4alkyl, morpholin-4-yl, phenyl, formamido, or pyridinyl substituent;
    
        and wherein the phenyl and pyridinyl substituents of the R1-phenyl are each optionally substituted with one substituent selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluoro, chloro, cyano, amino, and hydroxy;
    
    
    ii) pyrimidinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, and hydroxy; in addition, pyrimidinyl is optionally substituted with a single amino, C1-4alkylamino, di(C1-4alkyl)amino, di(C1-4alkyl)aminocarbonyl, C1-4alkylaminocarbonyl, hydroxy(C1-4)alkyl, aminocarbonyl, C1-4alkylcarbonylamino, C1-4alkoxycarbonylamino, ureido, C1-4alkylureido, di(C1-4alkyl)ureido, cyano, trifluoromethoxy, C1-4alkylsulfonyl, nitro, trifluoromethyl, bromo, piperazin-1-yl optionally substituted with 4-C1-4alkyl, morpholin-4-yl, formamido, pyrrol-1-yl, phenyl, pyridinyl, or piperidin-1-yl substituent;
    
        and, wherein the phenyl and pyridinyl substituents of the R1-pyrimidinyl are optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluoro, chloro, cyano, amino, and hydroxy;
    
    
    iii) pyridinyl optionally substituted with one to two substituents independently selected form the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, fluoro, chloro, and cyano; in addition, pyridinyl is optionally substituted with a single hydroxymethyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, C1-4alkylsulfonyl, aminocarbonyl, C1-4alkylaminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-4alkylcarbonylamino, C1-4alkoxyaminocarbonyl, ureido, C1-4alkylureido, di(C1-4alkyl)ureido, piperazin-1-yl, morpholin-4-yl, phenyl, or pyridinyl substituent;
    
        and, wherein the phenyl and pyridinyl substituents of the R1-pyridinyl are optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluoro, chloro, cyano, amino, and hydroxy; and
    
    
    iv) a G-substituent selected from the group consisting of naphthyl, pyrazolyl, thienyl, benzothiazolyl, benzimidazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, pyrazinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, isoxazolyl, oxazolyl, pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl, dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, benzothiophenyl, indazolyl, and 2,3-dihydrobenzo[1,4]dioxinyl;
    
        wherein G is optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkyl, C1-4alkoxy, fluoro, chloro, bromo, cyano, C1-4alkylcarbonyl, amino, C1-4alkylamino, and di(C1-4alkyl)amino;
    
    
    R2 is
    (i) phenyl optionally substituted with one to three substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluoro, chloro, and hydroxy; in addition, phenyl of R2 is optionally substituted with a single amino, C1-4alkylamino, di(C1-4alkyl)amino, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl, C1-4alkylaminocarbonyl, di(C1-4)alkylaminocarbonyl, C1-4alkylcarbonylamino, 2,2,2-trifluoroethoxy, cyano, C3-7cycloalkylcarbonylamino, hydroxy(C1-4)alkyl, C1-4alkoxy(C1-4)alkyl, C1-4alkoxy-(C1-4)alkoxy, C1-4alkylcarbonyloxy, C1-4alkylsulfonylamino, C1-4alkylsulfonyl, pyridinyl(C1-4)alkyl, benzyloxycarbonylamino, 4-methyl-piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, carboxy, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, C3-7cycloalkyl, C3-7cycloalkyl-(C1-3)alkyl, or C3-7cycloalkyl-(C1-3)alkoxy substituent;
    (ii) 1,2-dihydrobenzofuranyl, bound to O of Formula (I) at the benzo portion of the ring; and wherein the benzo portion of 1,2-dihydrobenzofuranyl is optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkyl, fluoro, chloro, bromo, cyano, C1-4alkylcarbonyl, amino, C1-4alkylamino, and di(C1-4alkylamino;
    or
    (iii) heteroaryl selected from the group consisting of benzothiazolyl, benzooxazolyl, pyridinyl, pyrimidinyl, indazolyl, quinolinyl, quinazolinyl, benzimidazolyl, pyrazinyl, triazinyl, benzothiophenyl, benzofuranyl, and isoquinolinyl;
    
        wherein heteroaryl of R2 is optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkyl, fluoro, chloro, bromo, cyano, C1-4alkylcarbonyl, amino, C1-4alkylamino, and di(C1-4alkylamino;
    
    
    A-L- is selected from the group consisting of a1-L1-; a2-L2-; a3-L3-; a4-L4-; and a5-L5-; wherein L1 is absent or C1-4alkyl;
    a1 is bound through a carbon atom to L1 and is selected from the group consisting of
    i) pyrrolidinyl optionally substituted at carbon with C1-4alkyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, aminomethyl, hydroxy, cyano, C1-4alkoxy, C1-4alkoxycarbonyl, or one to two fluoro substituents; and wherein pyrrolidinyl is optionally substituted at nitrogen with C1-4alkyl, phenyl(C1-4)alkyl, C1-4alkylcarbonyl, C1-4alkoxycarbonyl, or phenyl(C1-4)alkoxycarbonyl;
    ii) piperidinyl optionally substituted with C1-4alkyl, phenyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, aminomethyl, hydroxy, cyano, C1-4alkoxy, C1-4alkoxycarbonyl, phenyl(C1-4)alkyl, C1-4alkylcarbonyl, or phenyl(C1-4)alkoxycarbonyl;
    and
    iii) azetidinyl optionally substituted with 3-amino, 3-hydroxy, 3-C1-4alkoxy, C1-4alkyl, or aminomethyl;
    
        provided that when L1 is absent, a1 is attached to N(Ra) via a carbon atom other than that which is alpha to a nitrogen atom of a1;
        and provided that when a1 is substituted with a substituent containing an oxygen or nitrogen radical as a point of attachment to a1, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a1;
    
    
    L2 is C1-4alkyl;
    a2 is bound through a carbon atom to L2 and is selected from the group consisting of
    i) piperazinyl optionally substituted at carbon with C1-4alkyl, aminomethyl, cyano, or C1-4alkoxycarbonyl; and wherein piperazinyl is optionally substituted at nitrogen with C1-4alkyl, phenyl(C1-4)alkyl, C1-4alkylcarbonyl, C1-4alkoxycarbonyl, or phenyl(C1-4)alkoxycarbonyl;
    and
    ii) morpholinyl optionally independently substituted with phenyl(C1-4)alkyl or one to two C1-4alkyl substituents;
    L3 is methylene;
    a3 is imidazolyl optionally independently substituted with one to two C1-4alkyl substituents;
    L4 is (C2-6)alkyl; and when L4 is C3-6alkyl, L4 is optionally substituted with chloro, hydroxy or C1-4alkoxy; provided that the chloro, hydroxy, and C1-4alkoxy substituents are not alpha to a nitrogen-bearing carbon atom;
    a4 is selected from the group consisting of amino and C1-4alkylamino;
    provided that a4 is attached at a carbon atom other than that alpha to N(Ra);
    L5 is absent or C1-4alkyl;
    a5 is C3-7cycloalkyl substituted with RB; wherein RB is selected from the group consisting of amino, C1-4alkylamino, di(C1-4alkyl)amino, aminomethyl, C1-4alkylamino-methyl, and di(C1-4alkyl)amino-methyl;
    provided that when RB contains a nitrogen radical as the point of attachment to C3-7cycloalkyl, the attachment is at a carbon atom other than that alpha to N(Ra);
    or,
    A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of
    i) pyrrolidinyl wherein pyrrolidinyl is optionally substituted with C1-4alkyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, aminomethyl, cyano, C1-4alkoxy, C1-4alkoxycarbonyl, or phenyl;
    ii) piperazinyl optionally substituted with 4-C1-4alkyl; and wherein piperazinyl is optionally independently substituted at carbon with one to two C1-4alkyl substituents, 2-oxo, 3-oxo, trifluoromethyl, aminomethyl, or hydroxymethyl;
    iii) piperidinyl optionally substituted with one to two C1-4alkyl substituents, amino, C1-4alkylamino, di(C1-4alkyl)amino, aminomethyl, hydroxy, cyano, C1-4alkoxy, C1-4alkoxycarbonyl, phenyl, phenyl(C1-4)alkyl, or one to two fluoro substituents;
    and, wherein the phenyl and the phenyl portion of phenyl(C1-4)alkyl are optionally substituted with C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluoro, chloro, cyano, amino, or hydroxy;
    iv) azetidinyl optionally substituted with 3-amino or 3-aminomethyl;
    v) [1,4]diazepan-1-yl optionally substituted with one to two C1-4alkyl substituents;
    and
    vi) 3,6-diazoabicyclo[3.1.1]hept-3-yl optionally independently substituted with one to two C1-4alkyl substituents;
    Ra is hydrogen or C1-4alkylcarbonyl;
    provided that a compound of Formula (I) is other than a compound selected from the group consisting of
    a compound wherein R1 is 4-fluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    a compound wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is (S)-morpholin-3-yl, L2 is methyl, Ra is H, and X is O; a compound wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-(piperidin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    a compound wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    a compound wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2-methyl-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    a compound wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, RB is 2-amino, Ra is H, and X is O;
    and
    a compound wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-diethylaminocarbonyl-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.


The present invention is also directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I) or a pharmaceutically acceptable salt form thereof.
Also provided are processes for making a pharmaceutical composition comprising mixing a compound of Formula (I) and a pharmaceutically acceptable carrier.
The present invention is further directed to methods for treating or ameliorating an opioid receptor-modulated disorder. In particular, the methods of the present invention are directed to treating or ameliorating a opioid receptor-modulated disorder including, but not limited to, inflammatory pain, centrally mediated pain, peripherally mediated pain, visceral pain, structural related pain, cancer/pain, soft tissue injury related pain, progressive disease related pain, neuropathic pain and acute pain from acute injury, acute pain from trauma, acute pain from surgery, chronic pain from headache, chronic pain from neuropathic conditions, chronic pain from post-stroke conditions and chronic pain from migraine.
The present invention also provides methods for producing the instant compounds and pharmaceutical compositions and medicaments thereof.


DETAILED DESCRIPTION OF THE INVENTION
As used herein, the following terms are intended to have the following meanings:
“Ca-b” (where a and b are integers) refers to a radical containing from a to b carbon atoms inclusive. For example, C1-3 denotes a radical containing 1, 2 or 3 carbon atoms.
With reference to substituents, the term “independently” means that when more than one of such substituent is possible, such substituents may be the same or different from each other. Therefore, designated numbers of carbon atoms (e.g. C1-8) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
As used herein, unless otherwise noted, “alkyl” whether used alone or as part of a substituent group refers to straight and branched carbon chains having 1 to 8 carbon atoms or any number within this range. The term “alkoxy” refers to an —Oalkyl substituent group, wherein alkyl is as defined supra. Similarly, the terms “alkenyl” and “alkynyl” refer to straight and branched carbon chains having 2 to 8 carbon atoms or any number within this range, wherein an alkenyl chain has at least one double bond in the chain and an alkynyl chain has at least one triple bond in the chain. An alkyl and alkoxy chain may be substituted on a carbon atom. In substituent groups with multiple alkyl groups such as (C1-6alkyl)2amino- the C1-6alkyl groups of the dialkylamino may be the same or different.
“Halogenated alkyl” refers to a saturated branched or straight chain alkyl radical derived by removal of 1 hydrogen atom from the parent alkane; the parent alkyl chain contains from 1 to 8 carbon atoms with 1 or more hydrogen atoms replaced with halogen atoms up to and including replacement of all hydrogen atoms with halogen. Preferred halogenated alkyl groups include trifluoromethyl substituted alkyls, difluoromethyl substituted alkyls, and perfluorinated alkyls; more preferred fluorinated alkyls include trifluoromethyl and difluoromethyl.
“Halogenated alkoxy” refers to a radical derived from a halogenated alkyl, radical attached to an oxygen atom with the oxygen atom having one open valence for attachment to a parent structure.
The term “cycloalkyl” refers to saturated or partially unsaturated, monocyclic or polycyclic hydrocarbon of from 3 to 20 carbon atom members (preferably from 3 to 14 carbon atom members). Examples of such groups include, and are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or adamantyl. The term cycloalkyl includes a cycloalkyl ring fused to a benzene ring (benzo fused cycloalkyl), or a 5 or 6 membered heteroaryl ring (containing one of O, S or N and, optionally, one additional nitrogen) to form a heteroaryl fused cycloalkyl.
The term “heterocyclyl” refers to a nonaromatic monocyclic ring of 5 to 10 members in which 1 to 4 members are nitrogen or a nonaromatic monocyclic ring of 5 to 10 members in which zero, one or two members are nitrogen and up to two members are oxygen or sulfur; wherein, optionally, the ring contains zero, one or two unsaturated bonds. The term heterocyclyl includes a heterocyclyl ring fused to a benzene ring (benzo fused heterocyclyl), a 5 or 6 membered heteroaryl ring (containing one of O, S or N and, optionally, one additional nitrogen), a 5 to 7 membered cycloalkyl or cycloalkenyl ring, a 5 to 7 membered heterocyclyl ring (of the same definition as above but absent the option of a further fused ring) or fused with the carbon of attachment of a cycloalkyl, cycloalkenyl or heterocyclyl ring to form a spiro moiety. For instant compounds of the invention, the carbon atom ring members that form the heterocyclyl ring are fully saturated. Other compounds of the invention may have a partially saturated heterocyclyl ring. Additionally, heterocyclyl includes a heterocyclic ring bridged to form bicyclic rings. Preferred partially saturated heterocyclyl rings may have from one to two double bonds. Such compounds are not considered to be fully aromatic and are not referred to as heteroaryl compounds. Examples of heterocyclyl groups include, and are not limited to, pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl or 3-pyrrolinyl), pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl.
The term “aryl” refers to an unsaturated, aromatic monocyclic ring of 6 carbon members or to an unsaturated, aromatic polycyclic ring of from 10 to 14 carbon members. Examples of such aryl rings include, and are not limited to, phenyl, naphthalenyl or anthracenyl. Preferred aryl groups for the practice of this invention are phenyl and naphthalenyl.
The term “heteroaryl” refers to an aromatic ring of 5 or 6 members wherein the ring consists of carbon atoms and has at least one heteroatom member. Suitable heteroatoms include nitrogen, oxygen or sulfur. In the case of 5 membered rings, the heteroaryl ring contains one member of nitrogen, oxygen or sulfur and, in addition, may contain up to three additional nitrogens. In the case of 6 membered rings, the heteroaryl ring may contain from one to three nitrogen atoms. For the case wherein the 6 membered ring has three nitrogens, at most two nitrogen atoms are adjacent. The term heteroaryl includes a heteroaryl ring fused to a benzene ring (benzofused heteroaryl), a 5 or 6 membered heteroaryl ring (containing one of O, S or N and, optionally, one additional nitrogen), a 5 to 7 membered cycloalkyl ring or a 5 to 7 membered heterocyclic ring (as defined supra but absent the option of a further fused ring). Examples of heteroaryl groups include, and are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl; fused heteroaryl groups include indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl, benzotriazolyl, quinoxalinyl, quinolinyl, isoquinolinyl or quinazolinyl.
The term “arylalkyl” means an alkyl group substituted with an aryl group (e.g., benzyl, phenethyl). Similarly, the term “arylalkoxy” indicates an alkoxy group substituted with an aryl group (e.g., benzyloxy).
The term “halogen” refers to fluorine, chlorine, bromine and iodine. Substituents that are substituted with multiple halogens are substituted in a manner that provides compounds, which are stable.
The term “oxo” whether used alone or as part of a substituent group refers to an O═ to either a carbon or a sulfur atom. For example, phthalimide and saccharin are examples of compounds with oxo substituents.
Whenever the term “alkyl” or “aryl” or either of their prefix roots appear in a name of a substituent (e.g., arylalkyl, alkylamino) it shall be interpreted as including those limitations given above for “alkyl” and “aryl.” Designated numbers of carbon atoms (e.g., C1-C6) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root. For alkyl, and alkoxy substituents the designated number of carbon atoms includes all of the independent member included in the range specified individually and all the combination of ranges within in the range specified. For example C1-6 alkyl would include methyl, ethyl, propyl, butyl, pentyl and hexyl individually as well as sub-combinations thereof (e.g. C1-2, C1-3, C1-4, C1-5, C2-6, C3-6, C4-6, C5-6, C2-5, etc.).
The term “subject” as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
As used herein, the term “acyl” refers to alkylcarbonyl substituents.
As used herein, the term “a carbon atom which is alpha (α) to a nitrogen atom” is defined as a carbon atom that is adjacent to, and covalently bound to, a nitrogen atom, as illustrated hereinbelow.




Throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a “phenyl(C1-6)alkylaminocarbonyl(C1-6)alkyl” substituent refers to a group of the formula




Unless otherwise noted, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of formula (I) can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.
For purposes of the present invention, the term “opioid receptor-modulated” is used to refer to the condition of being affected by the modulation of an opioid receptor, including but not limited to, the state of being mediated by the opioid receptor.
DETAILED DESCRIPTION OF THE INVENTION
Embodiments of the present invention include those compounds of Formula (I) wherein

    a) R1 is selected from the group consisting of
    
        i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, hydroxy, chloro, and fluoro; in addition, phenyl is optionally substituted with a single amino, di(C1-4alkyl)amino, di(C1-4alkyl)aminocarbonyl, hydroxy(C1-4)alkyl, aminocarbonyl, C1-4alkylcarbonylamino, cyano, trifluoromethoxy, C1-4alkylsulfonyl, nitro, trifluoromethyl, or phenyl substituent;
        ii) pyrimidinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkoxy, C1-4alkylthio, and hydroxy; in addition, pyrimidinyl is optionally substituted with a single cyano, morpholin-4-yl, amino, di(C1-4alkyl)amino, or piperazin-1-yl optionally substituted with 4-C1-4alkyl substituent;
        iii) pyridinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, fluoro, chloro, and cyano; in addition, pyridinyl is optionally substituted with a single hydroxymethyl, amino, aminocarbonyl, C1-4alkylsulfonyl, or pyridinyl substituent;
        
            wherein the pyridinyl substituent of the R1-pyridinyl is optionally independently substituted with one to two substituents selected from the group consisting of chloro and methyl;
        
        
        and
        iv) a G-substituent selected from the group consisting of naphthyl, pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, pyrazinyl, quinoxalinyl, oxazolyl, pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl, dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl;
        wherein G is optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkyl, fluoro, and chloro;
    
    
    b) R1 is selected from the group consisting of
    
        i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, hydroxy, chloro, and fluoro; in addition, phenyl is optionally substituted with a single amino, di(C1-4alkyl)amino, di(C1-4alkyl)aminocarbonyl, hydroxy(C1-4)alkyl, aminocarbonyl, C1-4alkylcarbonylamino, cyano, trifluoromethoxy, C1-4alkylsulfonyl, nitro, trifluoromethyl, or phenyl substituent;
        ii) pyrimidinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkoxy, C1-4alkylthio, and hydroxy; in addition, pyrimidinyl is optionally substituted with a single cyano, morpholin-4-yl, amino, di(C1-4alkyl)amino, or piperazin-1-yl optionally substituted with 4-C1-4alkyl substituent;
        iii) pyridinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, fluoro, chloro, and cyano; in addition, pyridinyl is optionally substituted with a single hydroxymethyl, amino, C1-4alkylsulfonyl, or pyridinyl substituent;
        
            wherein the pyridinyl substituent of the R1-pyridinyl is optionally independently substituted with one to two substituents selected from chloro and methyl;
        
        
        and
        iv) a G-substituent selected from the group consisting of naphthyl, pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, pyrazinyl, quinoxalinyl, oxazolyl, pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl, dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl;
        wherein G is optionally independently substituted with one to two C1-4alkyl substituents;
    
    
    c) R1 is selected from the group consisting of
    
        i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-2alkoxy, hydroxy, chloro, and fluoro; in addition, phenyl is optionally substituted with a single amino, di(C1-4alkyl)amino, di(C1-4alkyl)aminocarbonyl, hydroxy(C1-4)alkyl, aminocarbonyl, C1-4alkylcarbonylamino, cyano, trifluoromethoxy, C1-4alkylsulfonyl, nitro, trifluoromethyl, or phenyl substituent;
        ii) pyrimidinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkoxy and C1-4alkylthio; in addition, pyrimidinyl is optionally substituted with a single cyano, morpholin-4-yl, di(C1-4alkyl)amino, or piperazin-1-yl optionally substituted with 4-C1-4alkyl substituent;
        iii) pyridinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, fluoro, chloro, and cyano; in addition, pyridinyl is optionally substituted with a single hydroxymethyl, amino, C1-4alkylsulfonyl, or pyridinyl substituent;
        
            wherein the pyridinyl substituent of the R1-pyridinyl is optionally independently substituted with one to two substituents selected from chloro and methyl;
        
        
        and
        iv) a G-substituent selected from the group consisting of naphthyl, pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, pyrazinyl, quinoxalinyl, pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl, dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl;
        wherein G is optionally substituted with one C1-4alkyl substituent;
    
    
    d) R1 is selected from the group consisting of
    
        i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-2alkoxy, hydroxy, and fluoro; in addition, phenyl is optionally substituted with a single amino, di(C1-4alkyl)amino, di(C1-4alkyl)aminocarbonyl, hydroxy(C1-4)alkyl, aminocarbonyl, C1-4alkylcarbonylamino, cyano, trifluoromethoxy, C1-4alkylsulfonyl, nitro, or trifluoromethyl substituent;
        ii) pyrimidinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkoxy and C1-4alkylthio; in addition, pyrimidinyl is optionally substituted with a single cyano, morpholin-4-yl, di(C1-4alkyl)amino, or piperazin-1-yl optionally substituted with 4-C1-4alkyl substituent;
        iii) pyridinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, fluoro, chloro, and cyano; in addition, pyridinyl is optionally substituted with a single hydroxymethyl or amino substituent;
        and
        iv) a G-substituent selected from the group consisting of pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, and benzo[1,2,5]oxadiazolyl;
        wherein G is optionally independently substituted with one C1-4alkyl substituent;
    
    
    e) R1 is selected from the group consisting of
    
        i) phenyl optionally substituted with a substituent selected from the group consisting of C1-2alkyl, C1-2alkoxy, hydroxy, and fluoro; or, phenyl is optionally substituted with one substituent selected from the group consisting of amino, di(C1-4alkyl)amino, di(C1-4alkyl)aminocarbonyl, hydroxymethyl, aminocarbonyl, C1-4alkylcarbonylamino, cyano, trifluoromethoxy, C1-2alkylsulfonyl, nitro, and trifluoromethyl;
        ii) pyrimidinyl optionally substituted with one to two substituents selected from the group consisting of C1-4alkoxy and C1-4alkylthio; or, pyrimidinyl is optionally substituted with one substituent selected from the group consisting of morpholin-4-yl, di(C1-4alkyl)amino, and piperazin-1-y optionally substituted with 4-methyl;
        iii) pyridinyl optionally substituted with one to two substituents selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, fluoro, and chloro; or, pyridinyl optionally substituted with one substituent selected from the group consisting of cyano, hydroxymethyl, and amino;
        and
        iv) a G-substituent selected from the group consisting of pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, and benzo[1,2,5]oxadiazolyl;
        wherein G is optionally independently substituted with one C1-4alkyl substituent;
    
    
    f) R2 is
    
        (i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, one to two fluoro substituents, chloro, and hydroxy; in addition, phenyl is optionally substituted with a single amino, fluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl, di(C1-4)alkylaminocarbonyl, C1-4alkylcarbonylamino, 2,2,2-trifluoroethoxy, cyano, C3-7cycloalkylcarbonylamino, hydroxy(C1-4)alkyl, C1-4alkoxy(C1-4)alkyl, C1-4alkoxy-(C1-4)alkoxy, C1-4alkylcarbonyloxy, C1-4alkylsulfonylamino, C1-4alkylsulfonyl, pyridinyl(C1-4)alkyl, benzyloxycarbonylamino, 4-methyl-piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, carboxy, piperidin-1-ylcarbonyl, or morpholin-4-ylcarbonyl substituent;
        or
        (ii) heteroaryl selected from the group consisting of benzothiazolyl, benzooxazolyl, and pyridinyl; wherein heteroaryl is optionally independently substituted with one to two C1-4alkyl substituents;
    
    
    g) R2 is
    
        (i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-2alkoxy, C1-4alkylthio, one to two fluoro substituents, chloro, and hydroxy; in addition, phenyl is optionally substituted with a single amino, fluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl, C1-4alkylcarbonylamino, C1-4alkylcarbonyloxy, 2,2,2-trifluoroethoxy, benzyloxycarbonylamino, hydroxy(C1-4)alkyl, or C1-4alkoxy(C1-4)alkyl substituent;
        or, (ii) heteroaryl selected from the group consisting of benzothiazolyl and benzooxazolyl; wherein heteroaryl is optionally independently substituted with one to two C1-4alkyl substituents;
    
    
    h) R2 is
    
        (i) phenyl optionally substituted with one to two substituents selected from the group consisting of C1-4alkyl, C1-2alkoxy, C1-4alkylthio, one to two fluoro substituents, chloro, and hydroxy; in addition, phenyl is optionally substituted with a single amino, fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl, C1-4alkylcarbonylamino, C1-4alkylcarbonyloxy, 2,2,2-trifluoroethoxy, or C1-4alkoxy(C1-4)alkyl substituent;
        or,
        (ii) heteroaryl selected from the group consisting of benzothiazolyl and benzooxazolyl; wherein heteroaryl is optionally independently substituted with one to two C1-4alkyl substituents;
    
    
    i) R2 is
    
        (i) phenyl optionally substituted with one to two substituents selected from the group consisting of C1-2alkyl, C1-2alkoxy, C1-2alkylthio, fluoro, 3-chloro, 4-chloro, and hydroxy; or phenyl is optionally substituted with one substituent selected from the group consisting of amino, difluoromethoxy, trifluoromethoxy, aminocarbonyl, C1-4alkylcarbonylamino, C1-4alkylcarbonyloxy, and 2,2,2-trifluoroethoxy;
        or,
        (ii) heteroaryl selected from the group consisting of benzothiazolyl and benzooxazolyl; wherein heteroaryl of R2 is optionally independently substituted with one to two C1-2alkyl substituents;
    
    
    j) R2 is
    
        (i) phenyl optionally substituted with one to two substituents selected from the group consisting of C1-2alkyl, C1-2alkoxy, C1-2alkylthio, one to two fluoro substituents, 3-chloro, 4-chloro, and hydroxy; or,
        phenyl is optionally substituted with one substituent selected from the group consisting of amino, difluoromethoxy, trifluoromethoxy, aminocarbonyl, C1-4alkylcarbonylamino, C1-4alkylcarbonyloxy, and 2,2,2-trifluoroethoxy;
        or,
        (ii) R2 is a heteroaryl selected from the group consisting of benzothiazolyl and benzooxazolyl; wherein heteroaryl of R2 is optionally independently substituted with one to two C1-2alkyl substituents;
    
    
    k) A-L- is selected from the group consisting of a1-L1-; a2-L2-; a3-L3-;
    
        a4-L4-; and a5-L5-;
        L1 is absent or C1-4alkyl;
        a1 is bound through a carbon atom to L1 and is selected from the group consisting of
        i) pyrrolidinyl optionally substituted at carbon with amino, hydroxy, or one to two fluoro substituents;
        ii) piperidinyl;
        and
        iii) azetidinyl;
        provided that when L1 is absent, a1 is attached to N(Ra) via a carbon atom other than that which is alpha to a nitrogen atom of a1;
        and provided that when a1 is substituted with a substituent containing an oxygen or nitrogen radical as a point of attachment to a1, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a1;
        L2 is C1-4alkyl;
        a2 is bound through a carbon atom to L2 and a2 is morpholinyl;
        L3 is methylene;
        a3 is imidazolyl optionally independently substituted with one to two C1-4alkyl substituents;
        L4 is (C2-6)alkyl;
        a4 is selected from the group consisting of amino and C1-4alkylamino;
        provided that a4 is attached at a carbon atom of (C2-6)alkyl other than that alpha to N(Ra);
        L5 is absent or C1-4alkyl;
        a5 is C3-7cycloalkyl substituted with RB; wherein RB is amino;
        provided that when RB contains a nitrogen radical as a point of attachment to C3-7cycloalkyl, the attachment is at a carbon atom other than that alpha to N(Ra);
        or,
        A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of
        i) pyrrolidin-1-yl wherein pyrrolidin-1-yl is optionally substituted with C1-4alkyl, amino, or aminomethyl;
        ii) piperazin-1-yl optionally substituted with 4-C1-4alkyl; and wherein piperazin-1-yl is optionally independently substituted at carbon with one to two C1-4alkyl substituents, 2-oxo, or 3-oxo;
        iii) piperidin-1-yl optionally substituted with one to two C1-4alkyl substituents or amino;
        iv) azetidin-1-yl optionally substituted with 3-amino or 3-aminomethyl;
        v) [1,4]diazepan-1-yl;
        and
        vi) 3,6-diazoabicyclo[3.1.1]hept-3-yl;
    
    
    l) A-L- is selected from the group consisting of a1-L1-; a2-L2-; a3-L3-;
    
        a4-L4-; and a5-L5-;
        L1 is absent or C1-2alkyl;
        a1 is bound through a carbon atom to L1 and is selected from the group consisting of
        i) pyrrolidinyl optionally substituted at carbon with hydroxy or one to two fluoro substituents;
        ii) piperidin-3-yl;
        and
        iii) azetidinyl;
        provided that when L1 is absent, a1 is attached to N(Ra) via a carbon atom other than that which is alpha to a nitrogen atom of a1;
        and provided that when a1 is substituted with a substituent containing an oxygen or nitrogen radical as a point of attachment to a1, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a1;
        L2 is C1-2alkyl;
        a2 is bound through a carbon atom to L2 and a2 is morpholinyl;
        L3 is methylene;
        a3 is imidazolyl optionally independently substituted with one to two C1-2alkyl substituents;
        L4 is (C2-4)alkyl;
        a4 is selected from the group consisting of amino and C1-4alkylamino;
        provided that a4 is attached at a carbon atom other than that alpha to N(Ra);
        L5 is absent or C1-4alkyl;
        a5 is C4-6cycloalkyl substituted with RB; wherein RB is amino;
        provided that when RB contains a nitrogen radical as the point of attachment to C5-6cycloalkyl, the attachment is at a carbon atom other than that alpha to N(Ra);
        or,
        A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of
        i) pyrrolidin-1-yl optionally substituted with amino or aminomethyl;
        ii) piperazin-1-yl optionally substituted with 4-C1-4alkyl; and wherein piperazin-1-yl is optionally independently substituted at carbon with one to two C1-4alkyl substituents;
        iii) piperidin-1-yl optionally substituted with amino;
        iv) azetidin-1-yl optionally substituted with 3-aminomethyl;
        and
        v) [1,4]diazepan-1-yl;
        provided that the position of a substituent containing a nitrogen radical as a point of attachment to the nitrogen-bound heterocyclyl is at a carbon atom other than that alpha to a heterocyclyl nitrogen atom;
    
    
    m) A-L- is selected from the group consisting of a1-L1-; a2-L2-; a3-L3-, a4-L4-; and a5-L5-;
    
        L1 is absent or C1-2alkyl;
        a1 is bound through a carbon atom to L1 and is selected from the group consisting of
        i) pyrrolidinyl optionally substituted at carbon with hydroxy or one to two fluoro substituents;
        and
        ii) piperidin-3-yl
        provided that when L1 is absent, a1 is attached to N(Ra) via a carbon atom other than that which is alpha to a nitrogen atom of a1;
        and provided that when a1 is substituted with a substituent containing an oxygen or nitrogen radical as a point of attachment to a1, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a1;
        L2 is C1-2alkyl;
        a2 is bound through a carbon atom to L2 and a2 is morpholinyl;
        L3 is methylene;
        a3 is imidazolyl optionally substituted with one to two methyl substituents;
        L4 is (C2-3)alkyl;
        a4 is amino, provided that a4 is attached at a carbon atom other than that alpha to N(Ra); L2 is methylene;
        L5 is absent or C1-2alkyl;
        a5 is C4-6cycloalkyl substituted with RB; wherein RB is amino;
        provided that when RB contains a nitrogen radical as the point of attachment to C5-6cycloalkyl, the attachment is at a carbon atom other than that alpha to N(Ra);
        or,
        A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of
        i) pyrrolidin-1-yl optionally substituted with amino;
        ii) piperazin-1-yl optionally independently substituted at carbon with one to two C1-4alkyl substituents;
        iii) piperidin-1-yl optionally substituted with amino; and
        iv) [1,4]diazepan-1-yl;
        provided that the position of a substituent containing an nitrogen radical as a point of attachment to the nitrogen-bound heterocyclyl is at a carbon atom other than that alpha to the heterocyclyl nitrogen atom
    
    
    n) A-L- is selected from the group consisting of a1-L1-; a2-L2-; a3-L3-, a4-L4-; and a5-L5-;
    
        L1 is absent or C1-2alkyl;
        a1 is bound through a carbon atom to L1 and is selected from the group consisting of
        i) pyrrolidinyl optionally substituted at carbon with hydroxy or one to two fluoro substituents;
        and
        ii) piperidin-3-yl
        provided that when L1 is absent, a1 is attached to N(Ra) via a carbon atom other than that which is alpha to a nitrogen atom of a1;
        and provided that when a1 is substituted with a substituent containing an oxygen or nitrogen radical as a point of attachment to a1, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a1;
        L2 is methylene;
        a2 is bound through a carbon atom to L2 and a2 is morpholinyl;
        L3 is methylene;
        a3 is imidazolyl optionally substituted with one to two methyl substituents;
        L4 is (C2-3)alkyl;
        a4 is amino, provided that a4 is attached at a carbon atom other than that alpha to N(Ra);
        L5 is absent or C1-2alkyl;
        a5 is C4-6cycloalkyl substituted with RB; wherein RB is amino;
        provided that when RB contains a nitrogen radical as the point of attachment to C5-6cycloalkyl, the attachment is at a carbon atom other than that alpha to N(Ra);
        or,
        A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of
        i) pyrrolidin-1-yl optionally substituted with amino;
        ii) piperazin-1-yl optionally independently substituted at carbon with one to two C1-2alkyl substituents;
        iii) piperidin-1-yl optionally substituted with amino; and
        iv) [1,4]diazepan-1-yl;
        provided that the position of a substituent containing an nitrogen radical as a point of attachment to the nitrogen-bound heterocyclyl is at a carbon atom other than that alpha to the heterocyclyl nitrogen atom;
    
    
    o) Ra is hydrogen;
    provided that a compound of Formula (I) is other than a compound selected from the group consisting of
    a compound wherein R1 is 4-fluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    a compound wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is (S)-morpholin-3-yl, L2 is methyl, Ra is H, and X is O; a compound wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-(piperidin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    a compound wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    a compound wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2-methyl-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    a compound wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, RB is 2-amino, Ra is H, and X is O;
    and
    a compound wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-diethylaminocarbonyl-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    
        and any combination of embodiments a) through o) above, provided that it is understood that combinations in which different embodiments of the same substituent would be combined are excluded;
        and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.
    
    


A further embodiment of the present invention is directed to a compound of Formula (I)




wherein

    R1 is selected from the group consisting of
    i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, hydroxy, chloro, and fluoro; in addition, phenyl is optionally substituted with a single amino, di(C1-4alkyl)amino, di(C1-4alkyl)aminocarbonyl, hydroxy(C1-4)alkyl, aminocarbonyl, C1-4alkylcarbonylamino, cyano, trifluoromethoxy, C1-4alkylsulfonyl, nitro, trifluoromethyl, or phenyl substituent;
    ii) pyrimidinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkoxy, C1-4alkylthio, and hydroxy; in addition, pyrimidinyl is optionally substituted with a single cyano, morpholin-4-yl, amino, di(C1-4alkyl)amino, or piperazin-1-yl optionally substituted with 4-C1-4alkyl substituent;
    iii) pyridinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, fluoro, chloro, and cyano; in addition, pyridinyl is optionally substituted with a single hydroxymethyl, amino, aminocarbonyl, C1-4alkylsulfonyl, or pyridinyl substituent;
    
        wherein the pyridinyl substituent of the R1-pyridinyl is optionally independently substituted with one to two substituents selected from chloro and methyl;
    
    
    and
    iv) a G-substituent selected from the group consisting of naphthyl, pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, pyrazinyl, quinoxalinyl, oxazolyl, pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl, dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl;
    
        wherein G is optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkyl, fluoro, and chloro;
    
    
    R2 is
    (i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, one to two fluoro substituents, chloro, and hydroxy; in addition, phenyl is optionally substituted with amino, fluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl, di(C1-4)alkylaminocarbonyl, C1-4alkylcarbonylamino, 2,2,2-trifluoroethoxy, cyano, C3-7cycloalkylcarbonylamino, hydroxy(C1-4)alkyl, C1-4alkoxy(C1-4)alkyl, C1-4alkoxy-(C1-4)alkoxy, C1-4alkylcarbonyloxy, C1-4alkylsulfonylamino, C1-4alkylsulfonyl, pyridinyl(C1-4)alkyl, benzyloxycarbonylamino, 4-methyl-piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, carboxy, piperidin-1-ylcarbonyl, or morpholin-4-ylcarbonyl;
    or,
    (ii) heteroaryl selected from the group consisting of benzothiazolyl, benzooxazolyl, and pyridinyl; wherein heteroaryl is optionally independently substituted with one to two C1-4alkyl substituents;
    A-L- is selected from the group consisting of a1-L1-; a2-L2-; a3-L3-;
    a4-L4-; and a5-L5-;
    L1 is absent or C1-4alkyl;
    a1 is bound through a carbon atom to L1 and is selected from the group consisting of
    i) pyrrolidinyl optionally substituted at carbon with amino, hydroxy, or one to two fluoro substituents;
    ii) piperidinyl;
    and
    iii) azetidinyl;
    provided that when L1 is absent, a1 is attached to N(Ra) via a carbon atom other than that which is alpha to a nitrogen atom of a1;
    and provided that when a1 is substituted with a substituent containing an oxygen or nitrogen radical as a point of attachment to a1, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a1;
    L2 is C1-4alkyl;
    a2 is bound through a carbon atom to L2 and a2 is morpholinyl;
    L3 is methylene;
    a3 is imidazolyl optionally independently substituted with one to two C1-4alkyl substituents;
    L4 is (C2-6)alkyl;
    a4 is selected from the group consisting of amino and C1-4alkylamino;
    provided that a4 is attached at a carbon atom of (C2-6)alkyl other than that alpha to N(Ra);
    L5 is absent or C1-4alkyl;
    a5 is C3-7cycloalkyl substituted with RB; wherein RB is amino;
    provided that when RB contains a nitrogen radical as a point of attachment to C3-7cycloalkyl, the attachment is at a carbon atom other than that alpha to N(Ra);
    or,
    A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of
    i) pyrrolidin-1-yl wherein pyrrolidin-1-yl is optionally substituted with C1-4alkyl, amino, or aminomethyl;
    ii) piperazin-1-yl optionally substituted with 4-C1-4alkyl; and wherein piperazin-1-yl is optionally independently substituted at carbon with one to two C1-4alkyl substituents, 2-oxo, or 3-oxo;
    iii) piperidin-1-yl optionally substituted with one to two C1-4alkyl substituents or amino;
    iv) azetidin-1-yl optionally substituted with 3-amino or 3-aminomethyl;
    v) [1,4]diazepan-1-yl;
    and
    vi) 3,6-diazoabicyclo[3.1.1]hept-3-yl;
    Ra is hydrogen or methylcarbonyl;
    provided that a compound of Formula (I) is other than a compound selected from the group consisting of a compound wherein R1 is 4-fluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    a compound wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is (S)-morpholin-3-yl, L2 is methyl, Ra is H, and X is O;
    a compound wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-(piperidin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    a compound wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    a compound wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2-methyl-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    and
    a compound wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, RB is 2-amino, Ra is H, and X is O;

and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.



A further embodiment of the present invention is directed to a compound of Formula (I)




wherein

    R1 is selected from the group consisting of
    i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, hydroxy, chloro, and fluoro; in addition, phenyl is optionally substituted with a single amino, di(C1-4alkyl)amino, di(C1-4alkyl)aminocarbonyl, hydroxy(C1-4)alkyl, aminocarbonyl, C1-4alkylcarbonylamino, cyano, trifluoromethoxy, C1-4alkylsulfonyl, nitro, trifluoromethyl, or phenyl substituent;
    ii) pyrimidinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkoxy, C1-4alkylthio, and hydroxy; in addition, pyrimidinyl is optionally substituted with a single cyano, morpholin-4-yl, amino, di(C1-4alkyl)amino, or piperazin-1-yl optionally substituted with 4-C1-4alkyl substituent;
    iii) pyridinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, fluoro, chloro, and cyano; in addition, pyridinyl is optionally substituted with a single hydroxymethyl, amino, C1-4alkylsulfonyl, or pyridinyl substituent;
    
        wherein the pyridinyl substituent of the R1-pyridinyl is optionally independently substituted with one to two substituents selected from chloro and methyl;
    
    
    and
    iv) a G-substituent selected from the group consisting of naphthyl, pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, pyrazinyl, quinoxalinyl, oxazolyl, pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl, dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl; wherein G is optionally independently substituted with one to two C1-4alkyl substituents;
    R2 is
    (i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-2alkoxy, C1-4alkylthio, one to two fluoro substituents, chloro, and hydroxy; in addition, phenyl is optionally substituted with amino, fluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl, C1-4alkylcarbonylamino, C1-4alkylcarbonyloxy, 2,2,2-trifluoroethoxy, benzyloxycarbonylamino, hydroxy(C1-4)alkyl, or C1-4alkoxy(C1-4)alkyl;
    or,
    (ii) heteroaryl selected from the group consisting of benzothiazolyl and benzooxazolyl; wherein heteroaryl is optionally independently substituted with one to two C1-4alkyl substituents;
    A-L- is selected from the group consisting of a1-L1-; a2-L2-; a3-L3-;
    a4-L4-; and a5-L5-;
    L1 is absent or C1-2alkyl;
    a1 is bound through a carbon atom to L1 and is selected from the group consisting of
    i) pyrrolidinyl optionally substituted at carbon with hydroxy or one to two fluoro substituents;
    ii) piperidin-3-yl;
    and
    iii) azetidinyl;
    provided that when L1 is absent, a1 is attached to N(Ra) via a carbon atom other than that which is alpha to a nitrogen atom of a1;
    and provided that when a1 is substituted with a substituent containing an oxygen or nitrogen radical as a point of attachment to a1, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a1;
    L2 is C1-2alkyl;
    a2 is bound through a carbon atom to L2 and a2 is morpholinyl;
    L3 is methylene;
    a3 is imidazolyl optionally independently substituted with one to two C1-2alkyl substituents;
    L4 is (C2-4)alkyl;
    a4 is selected from the group consisting of amino and C1-4alkylamino;
    provided that a4 is attached at a carbon atom other than that alpha to N(Ra);
    L5 is absent or C1-4alkyl;
    a5 is C4-6cycloalkyl substituted with RB; wherein RB is amino;
    provided that when RB contains a nitrogen radical as the point of attachment to C5-6cycloalkyl, the attachment is at a carbon atom other than that alpha to N(Ra);
    or,
    A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of
    i) pyrrolidin-1-yl optionally substituted with amino or aminomethyl;
    ii) piperazin-1-yl optionally substituted with 4-C1-4alkyl; and wherein piperazin-1-yl is optionally independently substituted at carbon with one to two C1-4alkyl substituents;
    iii) piperidin-1-yl optionally substituted with amino;
    iv) azetidin-1-yl optionally substituted with 3-aminomethyl;
    and
    v) [1,4]diazepan-1-yl;
    
        provided that the position of a substituent containing a nitrogen radical as a point of attachment to the nitrogen-bound heterocyclyl is at a carbon atom other than that alpha to a heterocyclyl nitrogen atom;
    
    
    Ra is hydrogen;
    provided that a compound of Formula (I) is other than a compound selected from the group consisting of
    a compound wherein R1 is 4-fluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    a compound wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is (S)-morpholin-3-yl, L2 is methyl, Ra is H, and X is O;
    a compound wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2-methyl-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    and
    a compound wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, RB is 2-amino, Ra is H, and X is O.

and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.



A further embodiment of the present invention is directed to a compound of Formula (I)




wherein

    R1 is selected from the group consisting of
    i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-2alkoxy, hydroxy, chloro, and fluoro; in addition, phenyl is optionally substituted with a single amino, di(C1-4alkyl)amino, di(C1-4alkyl)aminocarbonyl, hydroxy(C1-4)alkyl, aminocarbonyl, C1-4alkylcarbonylamino, cyano, trifluoromethoxy, C1-4alkylsulfonyl, nitro, trifluoromethyl, or phenyl substituent;
    ii) pyrimidinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkoxy and C1-4alkylthio; in addition, pyrimidinyl is optionally substituted with a single cyano, morpholin-4-yl, di(C1-4alkyl)amino, or piperazin-1-yl optionally substituted with 4-C1-4alkyl substituent;
    iii) pyridinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, fluoro, chloro, and cyano; in addition, pyridinyl is optionally substituted with a single hydroxymethyl, amino, C1-4alkylsulfonyl, or pyridinyl substituent;
    
        wherein the pyridinyl substituent of the R1-pyridinyl is optionally independently substituted with one to two substituents selected from chloro and methyl;
    
    
    and
    iv) a G-substituent selected from the group consisting of naphthyl, pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, pyrazinyl, quinoxalinyl, pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl, dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl;
    wherein G is optionally substituted with one C1-4alkyl substituent;
    R2 is
    (i) phenyl optionally substituted with one to two substituents selected from the group consisting of C1-4alkyl, C1-2alkoxy, C1-4alkylthio, one to two fluoro substituents, chloro, and hydroxy; in addition, phenyl is optionally substituted with a single amino, fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl, C1-4alkylcarbonylamino, C1-4alkylcarbonyloxy, 2,2,2-trifluoroethoxy, or C1-4alkoxy(C1-4)alkyl substituent;
    or,
    (ii) heteroaryl selected from the group consisting of benzothiazolyl and benzooxazolyl; wherein heteroaryl is optionally independently substituted with one to two C1-4alkyl substituents;
    A-L- is selected from the group consisting of a1-L1-; a2-L2-; a3-L3-; a4-L4-; and a5-L5-;
    L1 is absent or C1-2alkyl;
    a1 is bound through a carbon atom to L1 and is
    i) pyrrolidinyl optionally substituted at carbon with hydroxy or one to two fluoro substituents;
    ii) piperidin-3-yl
    or
    iii) azetidinyl;
    provided that when L1 is absent, a1 is attached to N(Ra) via a carbon atom other than that which is alpha to a nitrogen atom of a1;
    and provided that when a1 is substituted with a substituent containing a nitrogen radical as a point of attachment to a1, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a1;
    L2 is methylene;
    a2 is bound through a carbon atom to L2 and a2 is morpholinyl;
    L3 is methylene;
    a3 is imidazolyl optionally independently substituted with one to two C1-4alkyl substituents;
    L4 is (C2-3)alkyl;
    a4 is amino, provided that a4 is attached at a carbon atom other than that alpha to N(Ra);
    L5 is absent or C1-2alkyl;
    a5 is C4-6cycloalkyl substituted with RB; wherein RB is amino;
    provided that when RB contains a nitrogen radical as the point of attachment to C5-6cycloalkyl, the attachment is at a carbon atom other than that alpha to N(Ra);
    or,
    A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of
    i) pyrrolidin-1-yl optionally substituted with amino or aminomethyl;
    ii) piperazin-1-yl optionally independently substituted at carbon with one to two C1-4alkyl substituents;
    iii) piperidin-1-yl optionally substituted with amino;
    iv) azetidin-1-yl optionally substituted with 3-aminomethyl;
    and
    v) [1,4]diazepan-1-yl;
    provided that the position of a substituent containing an nitrogen radical as a point of attachment to the nitrogen-bound heterocyclyl is at a carbon atom other than that alpha to the heterocyclyl nitrogen atom;
    Ra is hydrogen;
    provided that a compound of Formula (I) is other than a compound selected from the group consisting of
    a compound wherein R1 is 4-fluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    a compound wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is (S)-morpholin-3-yl, L2 is methyl, Ra is H, and X is O;
    a compound wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2-methyl-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    and
    a compound wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, RB is 2-amino, Ra is H, and X is O;

and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.



A further embodiment of the present invention is directed to a compound of Formula (I)




wherein

    R1 is selected from the group consisting of
    i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-2alkoxy, hydroxy, and fluoro; in addition, phenyl is optionally substituted with a single amino, di(C1-4alkyl)amino, di(C1-4alkyl)aminocarbonyl, hydroxy(C1-4)alkyl, aminocarbonyl, C1-4alkylcarbonylamino, cyano, trifluoromethoxy, C1-4alkylsulfonyl, nitro, or trifluoromethyl substituent;
    ii) pyrimidinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkoxy and C1-4alkylthio; in addition, pyrimidinyl is optionally substituted with a single cyano, morpholin-4-yl, di(C1-4alkyl)amino, or piperazin-1-yl optionally substituted with 4-C1-4alkyl substituent;
    iii) pyridinyl optionally substituted with one to two substituents independently selected form the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, fluoro, chloro, and cyano; in addition, pyridinyl is optionally substituted with hydroxymethyl or amino;
    and
    iv) a G-substituent selected from the group consisting of pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, and benzo[1,2,5]oxadiazolyl;
    wherein G is optionally independently substituted with one C1-4alkyl substituent;
    R2 is
    (i) phenyl optionally substituted with one to two substituents selected from the group consisting of C1-2alkyl, C1-2alkoxy, C1-2alkylthio, fluoro, 3-chloro, 4-chloro, and hydroxy; or phenyl is optionally substituted with one substituent selected from the group consisting of amino, difluoromethoxy, trifluoromethoxy, aminocarbonyl, C1-4alkylcarbonylamino, C1-4alkylcarbonyloxy, and 2,2,2-trifluoroethoxy;
    or,
    (ii) heteroaryl selected from the group consisting of benzothiazolyl and benzooxazolyl; wherein heteroaryl of R2 is optionally independently substituted with one to two C1-2alkyl substituents;
    A-L- is selected from the group consisting of a1-L1-; a2-L2-; a3-L3-, a4-L4-; and a5-L5-;
    L1 is absent or C1-2alkyl;
    a1 is bound through a carbon atom to L1 and is
    i) pyrrolidinyl optionally substituted at carbon with hydroxy or one to two fluoro substituents;
    or
    ii) piperidin-3-yl;
    provided that when L1 is absent, a1 is attached to N(Ra) via a carbon atom other than that which is alpha to a nitrogen atom of a1;
    and provided that when a1 is substituted with a substituent containing an oxygen or nitrogen radical as a point of attachment to a1, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a1;
    L2 is methylene;
    a2 is bound through a carbon atom to L2 and a2 is morpholinyl;
    L3 is methylene;
    a3 is imidazolyl optionally substituted with one to two methyl substituents;
    L4 is (C2-3)alkyl;
    a4 is amino, provided that a4 is attached at a carbon atom other than that alpha to N(Ra);
    L5 is absent or C1-2alkyl;
    a5 is C4-6cycloalkyl substituted with RB; wherein RB is amino;
    provided that when RB contains a nitrogen radical as the point of attachment to C5-6cycloalkyl, the attachment is at a carbon atom other than that alpha to N(Ra);
    or,
    A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of
    i) pyrrolidin-1-yl optionally substituted with amino;
    ii) piperazin-1-yl optionally independently substituted at carbon with one to two C1-4alkyl substituents;
    iii) piperidin-1-yl optionally substituted with amino;
    and
    iv) [1,4]diazepan-1-yl;
    provided that the position of a substituent containing an nitrogen radical as a point of attachment to the nitrogen-bound heterocyclyl is at a carbon atom other than that alpha to the heterocyclyl nitrogen atom
    Ra is hydrogen;
    provided that a compound of Formula (I) is other than a compound selected from the group consisting of
    a compound wherein R1 is 4-fluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    a compound wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is (S)-morpholin-3-yl, L2 is methyl, Ra is H, and X is O;
    a compound wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2-methyl-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    and
    a compound wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, RB is 2-amino, Ra is H, and X is O;

and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.



A further embodiment of the present invention is directed to a compound of Formula (I)




wherein

    R1 is selected from the group consisting of
    i) phenyl optionally substituted with a substituent selected from the group consisting of C1-2alkyl, C1-2alkoxy, hydroxy, and fluoro; or, phenyl is optionally substituted with one substituent selected from the group consisting of amino, di(C1-4alkyl)amino, di(C1-4alkyl)aminocarbonyl, hydroxymethyl, aminocarbonyl, C1-4alkylcarbonylamino, cyano, trifluoromethoxy, C1-2alkylsulfonyl, nitro, and trifluoromethyl;
    ii) pyrimidinyl optionally substituted with one to two substituents selected from the group consisting of C1-4alkoxy and C1-4alkylthio; or, pyrimidinyl is optionally substituted with one substituent selected from the group consisting of morpholin-4-yl, di(C1-4alkyl)amino, and piperazin-1-yl optionally substituted with 4-methyl;
    iii) pyridinyl optionally substituted with one to two substituents selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, fluoro, and chloro; or, pyridinyl optionally substituted with one substituent selected from the group consisting of cyano, hydroxymethyl, and amino;
    and
    iv) a G-substituent selected from the group consisting of pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, and benzo[1,2,5]oxadiazolyl;
    
        wherein G is optionally independently substituted with one C1-4alkyl substituent;
    
    
    R2 is
    (i) phenyl optionally substituted with one to two substituents selected from the group consisting of C1-2alkyl, C1-2alkoxy, C1-2alkylthio, one to two fluoro substituents, 3-chloro, 4-chloro, and hydroxy; or, phenyl is optionally substituted with one substituent selected from the group consisting of amino, difluoromethoxy, trifluoromethoxy, aminocarbonyl, C1-4alkylcarbonylamino, C1-4alkylcarbonyloxy, and 2,2,2-trifluoroethoxy;
    or,
    (ii) heteroaryl selected from the group consisting of benzothiazolyl and benzooxazolyl; wherein heteroaryl of R2 is optionally independently substituted with one to two C1-2alkyl substituents;
    A-L- is selected from the group consisting of a1-L1-; a2-L2-; a3-L3-, a4-L4-; and a5-L5-;
    L1 is absent or C1-2alkyl;
    a1 is bound through a carbon atom to L1 and is
    i) pyrrolidinyl optionally substituted at carbon with hydroxy or one to two fluoro substituents;
    or
    ii) piperidin-3-yl;
    provided that when L1 is absent, a1 is attached to N(Ra) via a carbon atom other than that which is alpha to a nitrogen atom of a1;
    and provided that when a1 is substituted with a substituent containing an oxygen or nitrogen radical as a point of attachment to a1, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a1;
    L2 is methylene;
    a2 is bound through a carbon atom to L2 and a2 is morpholinyl;
    L3 is methylene;
    a3 is imidazolyl optionally substituted with one to two methyl substituents;
    L4 is (C2-3)alkyl;
    a4 is amino, provided that a4 is attached at a carbon atom other than that alpha to N(Ra);
    L5 is absent or C1-2alkyl;
    a5 is C4-6cycloalkyl substituted with RB; wherein RB is amino;
    provided that when RB contains a nitrogen radical as the point of attachment to C5-6cycloalkyl, the attachment is at a carbon atom other than that alpha to N(Ra);
    or,
    A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of
    i) pyrrolidin-1-yl optionally substituted with amino;
    ii) piperazin-1-yl optionally independently substituted at carbon with one to two C1-2alkyl substituents;
    iii) piperidin-1-yl optionally substituted with amino;
    and
    iv) [1,4]diazepan-1-yl;
    provided that the position of a substituent containing an nitrogen radical as a point of attachment to the nitrogen-bound heterocyclyl is at a carbon atom other than that alpha to the heterocyclyl nitrogen atom
    Ra is hydrogen;
    provided that a compound of Formula (I) is other than a compound selected from the group consisting of
    a compound wherein R1 is 4-fluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    a compound wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is (S)-morpholin-3-yl, L2 is methyl, Ra is H, and X is O;
    a compound wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2-methyl-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
    and
    a compound wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, RB is 2-amino, Ra is H, and X is O;

and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.



A further embodiment of the present invention is directed to a compound of Formula (I)




selected from the group consisting of:

    a compound of Formula (I) wherein R1 is 4-methoxy-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3-methoxy-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 2-methoxy-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is naphth-1-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is naphth-2-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-4-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is thien-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is furan-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-trifluoromethoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-aminocarbonyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methylcarbonylamino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3-hydroxy-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is quinolin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is quinolin-8-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 2-methyl-quinolin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 4-biphenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is quinolin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is dibenzothiophen-2-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 6-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 2-fluoro-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 6-fluoro-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 2-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 2,6-dihydroxy-pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3-cyano-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3-nitro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3-aminocarbonyl-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3-N,N-diethylaminocarbonyl-phenyl,
    
        R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    
    
    a compound of Formula (I) wherein R1 is 3-methanesulfonyl-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 4-hydroxy-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is indol-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 4H-[1,2,4]oxadiazol-5-on-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-fluoro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 6-methoxy-pyridin-3-yl, R2 is 4-fluoro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3-fluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 6-methoxy-pyridin-3-yl, R2 is 2-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 2-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3-diethylamino-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3-methylcarbonylamino-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 4-methylcarbonylamino-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 6-methoxy-pyridin-3-yl, R2 is 4-amino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3-amino-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-amino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is benzothiazol-2-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is thiazol-2-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is benzothiophen-2-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3-trifluoromethyl-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3-trifluoromethoxy-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 2-methylthio-pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 2-methoxy-pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3,5-difluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3,4-difluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3,5-difluoro-4-hydroxymethyl-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 2,4-dimethoxy-pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 6-methoxy-pyridin-3-yl, R2 is 4-hydroxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 2-ethoxy-pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrazol-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3,5-dimethyl-isoxazol-4-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 2,3-dihydrobenzofuran5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3-fluoro-4-methoxy-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrazol-4-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 2-methylthio-pyrimidin-4-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 1-methyl-pyrazol-4-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3-fluoro-5-methoxy-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3-fluoro-5-methyl-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 6-amino-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-6-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 6-hydroxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 6-hydroxy-pyridin-3-yl, R2 is 4-hydroxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is quinoxalin-6-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 1H-pyrrolo[2,3-b]pyridin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is benzo[1,2,5]oxadiazol-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4,4-difluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4R)
    a compound of Formula (I) wherein R1 is 2-amino-pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 2-dimethylamino-pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 2-(morpholin-4-yl)-pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 2-(4-methyl-pyrazin-1-yl)-pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is benzothiazol-6-yl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is benzothiazol-6-yl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 2-methyl-benzoxazol-6-yl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2-methyl-benzoxazol-6-yl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2-methyl-benzothiazol-6-yl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 2-methyl-benzothiazol-6-yl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3,5-dimethyl-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is benzo[1,3]dioxol-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3,5-dichloro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 6-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 3,5-difluoro-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 3,5-difluoro-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 3-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 3-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2,3-difluoro-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 2,3-difluoro-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 2,3-difluoro-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-ethoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-ethoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-ethoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-methylthio-pyridin-3-y, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-methanesulfonyl-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, and Ra is H; (racemic)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-difluoromethoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-difluoromethoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-difluoromethoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-n-propyloxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-n-propyloxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-n-propyloxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is indol-4-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is indol-6-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is indol-7-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrazin-2-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 2-cyano-pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-(2,2,2-trifluoro-ethoxy)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-(2,2,2-trifluoro-ethoxy)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-(2,2,2-trifluoro-ethoxy)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-n-butoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-n-butoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-n-butoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-chloro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-chloro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-chloro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-fluoro-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 3-fluoro-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 3-fluoro-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4R)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-cyano-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-cyano-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-fluoro-4-cyano-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-cyclopropylcarbonylamino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-isopropyloxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-isopropyloxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-isopropyloxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 3-cyano-5-fluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-hydroxymethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-hydroxymethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-hydroxymethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-fluoro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methylthio-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methylthio-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methylthio-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxymethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxymethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxymethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-hydroxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-diethylaminocarbonyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-pyrrolidin-1-ylcarbonyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-carboxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-piperidin-1-ylcarbonyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-(morpholin-4-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-carboxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-carboxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-carboxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-(pyrrolidin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-(piperidin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-(morpholin-4-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-diethylaminocarbonyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-(pyrrolidin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-(piperidin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-(morpholin-4-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-diethylaminocarbonyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-(pyrrolidin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-benzyloxycarbonylamino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-ethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-chloro-pyridin-3-yl, R2 is 4-ethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, Ra is methylcarbonyl; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-ethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 3-fluoro-4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-ethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-fluoro-4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-chloro-pyridin-3-yl, R2 is 3-fluoro-4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-fluoro-4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-benzyloxycarbonylamino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2,3-difluoro-4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-chloro-pyridin-3-yl, R2 is 2,3-difluoro-4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 2,3-difluoro-4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 2,3-difluoro-4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4R)
    a compound of Formula (I) wherein R1 is 5-chloro-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4R)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-ethyl-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4R)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4R)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-benzyloxycarbonylamino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-amino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, and Ra is H; (3S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 3-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-chloro-pyridin-3-yl, R2 is 3-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 3-methyl-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-methyl-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-fluoromethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, and Ra is H; (3S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is piperidin-4-yl, L1 is absent, and Ra is H;
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-(pyridin-3-ylmethyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-chloro-pyridin-3-yl, R2 is 3-methyl-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-methyl-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-methylcarbonylamino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-methanesulfonylamino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methanesulfonylamino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is azetidin-3-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-formamido-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-fluoromethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 3-methyl-4-fluoro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-methyl-4-fluoro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-trifluoromethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-trifluoromethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-methanesulfonyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-formamido-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-3-yl, L1 is absent, and Ra is H; (3R)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is piperidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is azetidin-3-yl, L1 is absent, and Ra is H;
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-chloro-pyridin-3-yl, R2 is 2-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 3-methylcarbonyloxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-chloro-pyridin-3-yl, R2 is 2-chloro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2-chloro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 3-hydroxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 2-chloro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-methylthio-pyridin-3-y, R2 is 2-chloro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-methylthio-pyridin-3-y, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4R)
    a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4R)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, and Ra is H; (3S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-3-yl, L1 is absent, and Ra is H; (3S)
    a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4R)
    a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4S)
    a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4S)
    a compound of Formula (I) wherein R1 is 5-methylthio-pyridin-3-y, R2 is 4-(2-methoxy-ethoxy)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-(2-methoxy-ethoxy)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-(2-methoxy-ethoxy)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-(2-methoxy-ethoxy)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, and Ra is H; (3S)
    a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, and Ra is H; (3R)
    a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, Ra is H; (3S)
    a compound of Formula (I) wherein R1 is 5-methylthio-pyridin-3-y, R2 is 3-methylcarbonyloxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 3-hydroxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 3-methylcarbonyloxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 3-methylcarbonyloxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-methylthio-pyridin-3-y, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, and Ra is H; (3S)
    a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-methylthiopyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, Ra is H; (3R)
    a compound of Formula (I) wherein R1 is 5-methylthiopyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-3-yl, L1 is absent, Ra is H; (3S)
    a compound of Formula (I) wherein R1 is 5-methoxypyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-3-yl, L1 is absent, Ra is H; (3S)
    a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-3-yl, L1 is absent, Ra is H; (3S)
    a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, Ra is H; (3R)
    a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, Ra is H; (3S)
    a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-fluoromethoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, Ra is H; (3R)
    a compound of Formula (I) wherein R1 is 6-fluoro-5-methylpyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 2,5-dimethyl-pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 6′-chloro-3,5′-dimethyl-[2,3′]bipyridinyl-5-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 6-chloro-4-methylpyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 6-chloro-5-methyl-pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is piperidin-2-yl, L1 is methyl, and Ra is H; (2R)
    a compound of Formula (I) wherein R1 is 2-chloro-5-methylpyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-hydroxymethyl-pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is 4-hydroxy-pyrrolidin-2-yl, L1 is methyl, Ra is H; (trans 2S,4R)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is -hydroxypyrrolidin-2-yl, L1 is methyl, and Ra is H; (cis 2R,4R)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is 4-hydroxy-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (cis 2S,4S)
    a compound of Formula (I) wherein R1 is 5-methoxypyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is 4-hydroxy-pyrrolidin-2-yl, L1 is methyl, Ra is H, (trans 2S,4R)
    a compound of Formula (I) wherein R1 is 5-methoxypyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is 4-hydroxy-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (cis 2R,4R)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is morpholin-2-yl, L2 is methyl, and Ra is H; (racemic)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is morpholin-2-yl, L2 is methyl, and Ra is H;
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is morpholin-2-yl, L2 is methyl, and Ra is H;
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is morpholin-3-yl, L2 is methyl, and Ra is H; (racemic)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is morpholin-3-yl, L2 is methyl, and Ra is H; (racemic)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is morpholin-3-yl, L2 is methyl, and Ra is H; (3S)
    a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is morpholin-3-yl, L2 is methyl, and Ra is H; (3S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is morpholin-3-yl, L2 is methyl, and Ra is H; (3S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a3-L3, a3 is imidazol-2-yl, L3 is methyl, and Ra is H;
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a3-L3, a3 is 3H-imidazol-4-yl, L3 is methyl, and Ra is H;
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a3-L3, a3 is 5-methyl-3H-imidazol-4-yl, L3 is methyl, R and Ra is H;
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a3-L3, a3 is 3-methyl-3H-imidazol-4-yl, L3 is methyl, and Ra is H;
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a3-L3, a3 is 2-ethyl-5-methyl-3H-imidazol-4-yl, L3 is methyl, and Ra is H;
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a3-L3, a3 is 3H-imidazol-4-yl, L3 is methyl, and Ra is H;
    a compound of Formula (I) wherein R1 is 5-methylthio-pyridin-3-y, R2 is 4-methoxy-phenyl, A-L- is a3-L3, a3 is 3H-imidazol-4-yl, L3 is methyl, and Ra is H;
    a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a3-L3, a3 is 3H-imidazol-4-yl, L3 is methyl, and Ra is H;
    a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a3-L3, a3 is 3H-imidazol-4-yl, L3 is methyl, and Ra is H;
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a4-L4, a4 is 2-amino, L4 is propyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a4-L4, a4 is 2-amino, L4 is ethyl, and Ra is H;
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a4-L4, a4 is 2-amino, L4 is 4-methyl-pentyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a4-L4, a4 is 2-amino, L4 is 4-methyl-pentyl, and Ra is H; (2S)
    a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a4-L4, a4 is 2-amino, L4 is ethyl, and Ra is H;
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a4-L4, a4 is 2-methylamino, L4 is ethyl, and Ra is H;
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (cis/trans mixture)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is methyl, and Ra is H; (2S,1R)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is methyl, and Ra is H; (2S,1R)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclobutyl, L5 is methyl, and Ra is H; (trans)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclobutyl, L5 is methyl, and Ra is H; (trans)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclobutyl, L5 is absent, and Ra is H; (cis/trans mixture)
    a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclobutyl, L5 is absent, and Ra is H; (cis/trans mixture)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (cis)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (racemic, cis/trans mixture)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (1RS,3SR racemic cis)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (1RS,2SR racemic single stereoisomer, unknown cis/trans)
    a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; racemic, mixture of cis/trans)
    a compound of Formula (I) wherein R1 is 5-methylthiopyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (racemic, mixture of cis and trans)
    a compound of Formula (I) wherein R1 is 5-methoxypyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (cis 1R,3S)
    a compound of Formula (I) wherein R1 is 5-methoxypyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, Ra is H; (cis 1S,3R)
    a compound of Formula (I) wherein R1 is 5-methoxypyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (trans, one enantiomer, absolute unknown)
    a compound of Formula (I) wherein R1 is 5-methoxypyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (trans, one enantiomer, absolute unknown)
    a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (racemic, mixture of cis and trans)
    a compound of Formula (I) wherein R1 is 5-methylthiopyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (cis 1S,3R)
    a compound of Formula (I) wherein R1 is 5-methylthiopyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (cis 1R,3S)
    a compound of Formula (I) wherein R1 is 5-methylthiopyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (trans, one enantiomer, absolute unknown)
    a compound of Formula (I) wherein R1 is 5-methylthiopyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (trans, one enantiomer, absolute unknown)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-cyclopropylphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form piperazin-1-yl;
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (cis 1S,3R)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (cis 1R,3S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (trans, one enantiomer, absolute unknown)
    a compound of Formula (I) wherein R1 is phenyl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form piperazin-1-yl;
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form piperazin-1-yl;
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-aminopyrrolidin-1-yl;
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form piperazin-1-yl;
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is, A-L- and Ra are taken to form, 3-aminopyrrolidin-1-yl 3S
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-aminopiperidin-1-yl; (3S)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-aminopiperidin-1-yl; (3R)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-aminomethylazetidin-1-yl;
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 2-aminomethylpyrrolidin-1-yl; (2R)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 4-aminopiperidin-1-yl;
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 2-aminomethylpyrrolidin-1-yl; (2R)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-oxopiperazin-1-yl;
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form [1,4]diazepan-1-yl;
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 2-oxopiperazin-1-yl;
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3,6-diaza-bicyclo[3.1.1]hept-3-ylamino;
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, v 3-aminopyrrolidin-1-yl; (3R)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-amino-azetidin-1-yl;
    a compound of Formula (I) wherein R1 is 5-methylthio-pyridin-3-y, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form piperazin-1-yl;
    a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form piperazin-1-yl;
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-methyl-piperazin-1-yl; (racemic)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 2-methyl-piperazin-1-yl; (2R)
    a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 2-methyl-piperazin-1-yl; (2S)
    a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form [1,4]-diazepan-1-yl;
    a compound of Formula (I) wherein R1 is 5-methylthiopyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form [1,4]-diazepan-1-yl;
    a compound of Formula (I) wherein R1 is 5-methylthiopyridin-3-yl, R2 is 4-methoxyphenyl and A-L- and Ra are taken together with the atoms to which they are attached to form 3-amino-pyrrolidin-1-yl; (3R)
    a compound of Formula (I) wherein R1 is 5-methoxypyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-amino-pyrrolidin-1-yl; (3R)
    a compound of Formula (I) wherein R1 is 5-methylthiopyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3,3-dimethyl-piperazin-1-yl;
    a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form piperazin-1-yl;
    a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-amino-pyrrolidin-1-yl; (3R)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 4-methyl-piperazin-1-yl;
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 2-methyl-piperazin-1-yl; (2S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3,3-dimethyl-piperazin-1-yl;
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-methyl-piperazin-1-yl; (3S)
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-methyl-piperazin-1-yl; (3R)
    a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form [1,4]diazepan-1-yl;
    a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3,5-dimethyl-piperazin-1-yl; (cis)
    a compound of Formula (I) wherein R1 is 5-methoxypyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 2-ethyl-piperazin-1-yl; (2S)
    a compound of Formula (I) wherein R1 is 5-methoxypyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-ethyl-piperazin-1-yl; (3R).


For use in medicine, salts of compounds of formula (I) refer to non-toxic “pharmaceutically acceptable salts.” Other salts may, however, be useful in the preparation of compounds of formula (I) or of their pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of compounds of formula (I) include acid addition salts which can, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
Furthermore, where the compounds of formula (I) carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.
Representative acids and bases which may be used in the preparation of pharmaceutically acceptable salts include the following: acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid;
and bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.
Embodiments of the present invention include prodrugs of compounds of formula (I). In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound. Thus, in the methods of treatment of embodiments of the present invention, the term “administering” encompasses the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to a patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
Where the compounds according to embodiments of this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention. The skilled artisan will understand that the term compound as used herein, is meant to include solvated compounds of Formula I.
Where the processes for the preparation of the compounds according to certain embodiments of the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
One embodiment of the present invention is directed to a composition comprising the (+)-enantiomer of a compound of formula (I) wherein said composition is substantially free from the (−)-isomer of said compound. In the present context, substantially free means less than 25%, preferably less than 10%, more preferably less than 5%, even more preferably less than 2% and even more preferably less than 1% of the (−)-isomer calculated as.




  
    
      %
      ⁢
      
        
      
      ⁢
      
        (
        +
        )
      
    
    -
    enantiomer
  
  =
  
    
      
        (
        
          
            mass
            ⁢
            
              
            
            ⁢
            
              (
              +
              )
            
          
          -
          enantiomer
        
        )
      
      
        
          
            
              
                (
                
                  
                    mass
                    ⁢
                    
                      
                    
                    ⁢
                    
                      (
                      +
                      )
                    
                  
                  -
                  enantiomer
                
                )
              
              +
            
          
        
        
          
            
              (
              
                
                  mass
                  ⁢
                  
                    
                  
                  ⁢
                  
                    (
                    -
                    )
                  
                
                -
                enantiomer
              
              )
            
          
        
      
    
    ×
    100
  




Another embodiment of the present invention is a composition comprising the (−)-enantiomer of a compound of formula (I) wherein said composition is substantially free from the (+)-isomer of said compound. In the present context, substantially free from means less than 25%, preferably less than 10%, more preferably less than 5%, even more preferably less than 2% and even more preferably less than 1% of the (+)-isomer calculated as




  
    
      %
      ⁢
      
        
      
      ⁢
      
        (
        -
        )
      
    
    -
    enantiomer
  
  =
  
    
      
        (
        
          
            mass
            ⁢
            
              
            
            ⁢
            
              (
              -
              )
            
          
          -
          enantiomer
        
        )
      
      
        
          
            
              
                (
                
                  
                    mass
                    ⁢
                    
                      
                    
                    ⁢
                    
                      (
                      +
                      )
                    
                  
                  -
                  enantiomer
                
                )
              
              +
            
          
        
        
          
            
              (
              
                
                  mass
                  ⁢
                  
                    
                  
                  ⁢
                  
                    (
                    -
                    )
                  
                
                -
                enantiomer
              
              )
            
          
        
      
    
    ×
    100.
  




During any of the processes for preparation of the compounds of embodiments of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
Even though the compounds of embodiments of the present invention (including their pharmaceutically acceptable salts and pharmaceutically acceptable solvates) can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent selected with regard to the intended route of administration and standard pharmaceutical practice. Thus, particular embodiments of the present invention are directed to pharmaceutical compositions comprising compounds of formula (I) and one or more than one pharmaceutically acceptable carrier, excipient or diluent.
By way of example, in the pharmaceutical and veterinary compositions of embodiments of the present invention, the compounds of formula (I) may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and/or solubilizing agent(s).
Tablets or capsules of the compounds may be administered one or two or more at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.
Alternatively, compounds of formula (I) can be administered by inhalation (intratracheal or intranasal) or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. For example, they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. They can also be incorporated, at a concentration of between 1% and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required. An alternative means of transdermal administration is by use of a skin patch.
For some applications, preferably the compositions are administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents.
The compositions (as well as the compounds alone) can also be injected parenterally, for example intracavernosally, intravenously, intramuscularly, subcutaneously, intradermally or intrathecally. In this case, the compositions will comprise a suitable carrier or diluent.
For parenteral administration, the compositions are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or monosaccharides to make the solution isotonic with blood.
For buccal or sublingual administration, the compositions may be administered in the form of tablets or lozenges, which can be formulated in a conventional manner.
By way of further example, pharmaceutical and veterinary compositions containing one or more of the compounds of formula (I) as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral, etc.). Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations also may be coated with substances such as sugars or be enterically-coated so as to modulate the major site of absorption. For parenteral administration, the carrier will usually consist of sterile water, and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
A therapeutically effective amount of compounds of formula (I) or a pharmaceutical composition thereof comprises a dose range from about 0.1 mg to about 3000 mg, in particular from about 1 mg to about 1000 mg or, more particularly, from about 10 mg to about 500 mg of active ingredient in a regimen of about 1 to 4 times per day for an average (70 kg) human; although, it is apparent to one skilled in the art that the therapeutically effective amount for active compounds of the invention will vary as will the conditions being treated.
For oral administration, a pharmaceutical composition is preferably provided in the form of tablets containing 0.01, 10.0, 50.0, 100, 150, 200, 250, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
Advantageously, compounds of formula (I) may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds of formula (I) can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those skilled in that art.
It is also apparent to one skilled in the art that the therapeutically effective dose for active compounds of formula (I) or a pharmaceutical composition thereof will vary according to the desired effect. Therefore, optimal dosages to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust the dose to achieve an appropriate therapeutic level. The above dosages are thus exemplary of the average case. There can be, of course, individual instances wherein higher or lower dosage ranges are merited, and such are within the scope of this invention.
Compounds of formula (I) may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of the compounds of formula (I) as analgesics is required for a subject in need thereof.
Examples of pain intended to be within the scope of the present invention include, but are not limited to, inflammatory pain, centrally mediated pain, peripherally mediated pain, visceral pain, structural or soft tissue injury related pain, progressive disease related pain, neuropathic pain and acute pain such as caused by acute injury, trauma or surgery and chronic pain such as headache and that caused by neuropathic conditions, post-stroke conditions, cancer, and migraine.
Compounds of the present invention are also useful as immunosuppressants, antiinflammatory agents, agents for the treatment and prevention of neurological and psychiatric conditions, for instance, depression and Parkinson's disease, agents for the treatment of urological and reproductive conditions, for instance, urinary incontinence and premature ejaculation, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents and cardioprotective agents and agents for the treatment of respiratory diseases.
The compounds of the present invention are also useful in treating pain caused by osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burn, sunburn, snake bite (in particular, venomous snake bite), spider bite, insect sting, neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, cellulites, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, post-operative ileus, cholecystitis, postmastectomy pain syndrome, oral neuropathic pain, Charcot's pain, reflex sympathetic dystrophy, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome, cluster headache, migraine headache, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, optic neuritis, postfebrile neuritis, migrating neuritis, segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngial neuralgia, migrainous neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, vidian neuralgia, inflammatory bowel disease, irritable bowel syndrome, sinus headache, tension headache, labor, childbirth, menstrual cramps, and cancer.
In regard to the use of the present compounds in treatment of the diseases or conditions such as those listed above, a therapeutically effective dose can be determined by persons skilled in the art by the use of established animal models. The therapeutically effective dose of the compounds of Formula (I) exemplified in such a treatment is from about 0.001 mg/kg/day to about 300 mg/kg/day. Particularly, the range is from about 0.5 to about 5.0 mg/kg of body weight per day; and more particularly, from about 1.0 to about 3.0 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day.
General Synthetic Methods
Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and illustrated in the schemes and examples that follow. Since the schemes are an illustration, the invention should not be construed as being limited by the chemical reactions and conditions described in the schemes. The various starting materials used in the schemes and examples are commercially available or may be prepared by methods well within the skill of persons versed in the art. The variables are as defined herein.
Abbreviations used in the instant specification, particularly the schemes and examples, are as follows:
















AcCl
acetyl chloride



AcOH
glacial acetic acid



aq.
aqueous



Bn or Bzl
benzyl



conc.
concentrated



DBU
1,8-diazabicyclo[5.4.0]undec-7-ene



DCM
dichloromethane



DMF
N,N-dimethylformamide



DMSO
dimethylsulfoxide



dppf
1,1′-bis(diphenylphosphino)ferrocene



ESI
electron-spray ionization



EtOAc
ethyl acetate



EtOH
ethanol



h or hrs
hour(s)



HATU
O-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-




tetramethyl-uronium-hexafluorophosphate



HPLC
high performance liquid chromatography



Me
methyl



MeOH
methanol



MHz
megahertz



min
minutes



MPLC
medium pressure liquid chromatography



MS
mass spectroscopy



NMR
nuclear magnetic resonance



NT
not tested



Ph
phenyl



Pd/C
palladium on activated carbon



Ph3P
triphenylphosphine



PPA
polyphosphoric acid



rt
room temperature



TBDMS
tetra-butyldimethylsilane



TEA/Et3N
triethylamine



TFA
trifluoroacetic acid



THF
tetrahydrofuran



TLC
thin layer chromatography



TMS
tetramethylsilane or tetramethylsilyl










Scheme A illustrates a route for the synthesis of compounds of Formula (I)-A wherein A-L is a1-L1- or a2-L2-.




The compound of formula A1 is either commercially available or can be made by known methods, including those described in the scientific literature. A compound of formula A1 may be treated with a compound of formula A2 under basic conditions to afford a compound of formula A3. The nitro group of a compound of formula A3 may be reduced to its corresponding primary amino group of formula A4 by the action of a reducing agent such as zinc, tin, or iron in acetic acid, or by catalytic hydrogenation. The resultant amino group of a compound of formula A4 may undergo a reductive alkylation with an amino-protected aldehyde (R is H) or ketone (R is methyl) of formula A5 (wherein P is an amino protecting group) in the presence of a hydride source such as triacetoxysodium borohydride to install the A-L- portion of compounds of the present invention. A compound of formula A6 may be coupled with an R1-substituted boronic acid of formula A7 in the presence of a transition metal catalyst such as Pd(dppf)Cl2 and a base such as potassium carbonate to afford a compound of formula A8. Similarly, R1 substituents may be installed under conventional Stille coupling conditions using appropriately substituted tin reagents. The amine of a compound of formula A8 may be deprotected under appropriate conditions known to those skilled in the art to afford a compound of formula (I)-A of the present invention. For example, Boc-protected amines may be deprotected under acidic conditions using reagents such as HCl, TFA, and the like. Likewise, Cbz-protected amines may be deprotected under acidic conditions or by catalytic hydrogenation.

Scheme B illustrates a route for the synthesis of compounds of Formula (I)-B wherein A-L is a1-L1- or a3-L3- and L is absent.




Compounds of formula B1 are either commercially available or can be made by known methods including those described in the scientific literature. A ketone of formula B1 wherein the A-ring is a1 or a3 may be reacted with a compound of formula A4 using the methods described in Scheme A to afford a compound of formula B2.

Scheme C illustrates a route for the synthesis of certain A-L- intermediates useful toward compounds of the present invention wherein A-L- is a3-L3- and L3 is C1-2alkyl.




Compounds of formula C1 are either commercially available or can be made by known methods described in the scientific literature. A compound of formula C1 (P is an amino protecting group), wherein the A-ring is C3-7cycloalkyl, may be oxidized using an oxidant such as Dess-Martin reagent to afford its corresponding aldehyde of formula C2. Compounds of formula C2 may be used in an analogous manner to a compound of formula A5 in Scheme A.

Scheme D illustrates a route for the synthesis of compounds of formula (I)-D wherein R1 is 4H-[1,2,4]oxadiazol-5-on-yl.




A compound of formula A6 may be converted to its corresponding cyanide of formula D1 by the action of zinc(II)cyanide in the presence of a palladium catalyst and DMF. Subsequent treatment of a compound of formula D1 with hydroxylamine under of microwave irradiation affords a compound of formula D2. A compound of formula D2 may be converted to a compound of formula D3 via condensation with CDI in the presence of an appropriate coupling agent such as DBU and the like. Deprotection of the amino functionality using conventional chemistry affords compounds of formula (I)-D.

Scheme E illustrates a route for the synthesis of compounds of formula (I)-E wherein Ra is C1-4alkylcarbonyl.




A compound of formula A8 may by acylated by the action of a suitable acylating agent, such as an acid chloride, anhydride, or the like to afford a compound of formula E1. Amino deprotection by the standard methods discussed herein affords a compound of formula (I)-E.

Scheme F illustrates a route for the synthesis of compounds of formula (I)-F wherein R2 is phenyl substituted with amino or a derivative thereof.




The compounds of formula F1 can be made in an analogous manner to a compound of formula A4 together with known methods described in the scientific literature. A compound of formula F1 may be converted to a compound of formula F2 via the synthetic sequences presented in Scheme A. The Cbz-amino protecting group may be removed with palladium catalyzed hydrogenation to afford the corresponding primary amino compound of formula F3. At this stage, the amino group may be treated with a variety of electrophilic reagents to afford desirable R2 substitutions of the present invention. For example, treatment with a C1-4alkylsulfonyl chloride affords a compound of formula (I)-F. Likewise, the amino group of F3 may be acylated using conventional acylating agents or treated with an alkylating agent to make additional amino derivatives.

Scheme G illustrates an alternate route for the synthesis of intermediates of formula A8.







Compounds of formula G1 are either commercially available or can be made by known methods described in the scientific literature. A compound of formula G1 may be condensed with a compound of formula G2 in the presence of alkoxide to afford a pyrimidine of formula G3. The hydroxy group may be converted to its corresponding chloride of formula G4 by the action of a chlorinating agent such as thionyl chloride, phosphorus trichloride, or the like. Nucleophilic addition of a compound of formula A2 affords a compound of formula G5, which may be saponified by treatment with hydroxide to afford a carboxylic acid of formula G6. Treatment with diphenylphosphorylazide in t-butanol leads to a Curtius arrangement to afford a Boc-protected amine of formula G7. Removal of the Boc protecting group provides the amine of formula G8 which may subsequently undergo a reductive alkylation with a compound of formula A5 to afford a compound of formula A8.

Scheme H illustrates a route for the synthesis of intermediates of formula H5 that may be useful for the preparation of compounds of formula (I) wherein R2 is di(C1-4alkyl)aminocarbonyl-substituted phenyl.




Compounds of formula H1 are either commercially available or can be made by known methods described in the scientific literature. A compound of formula I1 may be coupled with an appropriately substituted amine in the presence of a suitable coupling agent such as HATU to afford an amide of formula H2. Upon conventional deprotection of the phenolic group, a compound of formula H3 may be reacted with a compound of formula G4 to afford a compound of formula H4 wherein R2 is an aminocarbonyl-substituted phenyl ring. In a manner analogous to that of intermediate G5, a compound of formula H4 may be converted to a desired compound of formula H5 using the methods of Scheme G.

Scheme I illustrates a route for the preparation of compounds of Formulae-I2, I3, and I4 wherein R2 is phenyl substituted with hydroxy(C1-4)alkyl, fluoro(C1-4)alkyl, or pyridinyl(C1-4)alkyl, respectively.




A compound of formula I1 may be prepared according to the methods taught herein using conventional reagents. A compound of formula I1 may be coupled with a compound of formula A7 as described herein to afford an R1-substituted compound of formula I2. A compound of formula I2 may be treated with appropriate reagents to afford amino-deprotected compounds of Formula (I) wherein R2 is phenyl substituted with hydroxy(C1-4)alkyl. A compound of formula I2 may be converted to a fluoro-alkyl substituted compound of formula I3 by the action of DAST. Subsequent removal of protecting group P affords desired compounds of Formula (I) wherein R2 is phenyl substituted with fluoroC1-4)alkyl.

Furthermore, a compound of formula I3 may undergo a palladium-catalyzed cross coupling reaction with a pyridine boronic acid to afford compounds of formula I4, which upon removal of protecting group P result in compounds of Formula (I) wherein R2 is phenyl substituted with pyridinyl(C1-4)alkyl.
Scheme J illustrates a route for the preparation of compounds of formula (I)-J wherein A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl as defined herein.




Commercially available 2,4-dichloro-5-bromo-pyrimidine may be treated with HBr solution under acidic conditions to form 2,4,5-tribromo-pyrimidine, which may then be reacted with a compound of formula A2 to afford a compound of formula J1. A compound of formula J1 may undergo a palladium catalyzed substitution with a compound of formula A7 under conditions described herein to afford a compound of formula J2. A compound of formula J2 may undergo a second palladium catalyzed substitution with an amino-containing heterocycle (Het), as defined herein, to afford a compound of Formula (I)-J.

Scheme K illustrates a route for the preparation of compounds of formula (I)-K wherein A-L- is a3-L3 and L3 is absent.




A compound mixture of formula K1 is either commercially available or can be made by known methods described in the scientific literature. The free amine of a compound of formula K1 may be Cbz-protected using conventional synthetic methods and subsequently separated into its diastereomeric pairs, of formulae K2-a and K2-b, using normal phase column chromatography. A diastereomeric pair of formula K2-a may be further separated into its individual enantiomers, K2-a1 and K2-a2, using chiral column chromatography. At this stage, each enantiomer (a compound of formula K2-a1 is illustrated) may be Cbz-deprotected using standard palladium catalyzed hydrogenation to afford a compound of formula K3. A compound of formula K3 may be coupled with a compound of formula J2 as described herein to afford a compound of formula K4 which, upon deprotection of its amino group, affords a compound of formula (I)-K.

SPECIFIC EXAMPLES
Reagents were purchased from commercial sources. Nuclear magnetic resonance (NMR) spectra for hydrogen atoms were measured in the indicated solvent with tetramethylsilane (TMS) as the internal standard on a Bruker Avance or Varian (300 or 400 MHz) spectrometer. The values are expressed in parts per million downfield from TMS. The mass spectra (MS) were determined on a Micromass Platform LC or Agilent 1100 LCMS spectrometer as (ESI) m/z (M+H+) using an electrospray technique. Microwave accelerated reactions were performed using a CEM Discover or Biotage microwave instrument, and were contained in a sealed pressure vessel unless otherwise noted. Stereoisomeric compounds may be characterized as racemic mixtures or as separate diastereomers and enantiomers thereof using X-ray crystallography and other methods known to one skilled in the art. Unless otherwise noted, the materials used in the examples were obtained from readily available commercial suppliers or synthesized by standard methods known to one skilled in the art of chemical synthesis. The substituent groups, which vary between examples, are hydrogen unless otherwise noted.
Example 1







A. 2-Chloro-4-(4-methoxy-phenoxy)-5-nitro-pyrimidine (1b)
To a solution of 2,4-dichloro-5-nitro-pyrimidine (Compound 1a) (5.82 g; 30.0 mmol) in acetone (480 mL), cooled to 0° C., was added a solution of 4-methoxy-phenol (3.75 g; 30.0 mmol) in a mixture of 1 N NaHCO3 (aq) (30 mL) and H2O (120 mL) dropwise by an addition funnel. After completion of addition, the reaction mixture was allowed to warm to ambient temperature, and was then stirred at room temperature for 3 h. The resultant mixture was evaporated in vacuo, and the residue was washed sequentially with EtOAc, 1 N NaOH(aq), and H2O. The organic phase was washed sequentially with H2O and brine, and dried over Na2SO4. The mixture was filtered and the solvent was evaporated under reduced pressure to give the crude material. The crude material was recrystallized from Et2O-hexanes to afford Compound 1b (7.70 g; 91% yield) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ 9.17 (s, 1H), 7.13-7.15 (m, 2H), 6.98-7.01 (m, 2H), 3.87 (s, 3H); MS: m/z 282.0 (M+H)+.
B. 2-Chloro-4-(4-methoxy-phenoxy)-pyrimidin-5-ylamine (1c)
To a stirred solution of Compound 1b (7.72 g; 27.4 mmol) in a mixture of glacial acetic acid (60 mL) and MeOH (120 mL) was added zinc dust (5.38 g; 82.2 mol) in portions at ambient temperature. The reaction mixture was stirred at room temperature for 20 h. The resultant mixture was filtered through a microglass filter and the filtrate was neutralized to pH 7 with 2 N KOH(aq). The mixture was partitioned between CH2Cl2 and H2O. The organic phase was washed sequentially with H2O and brine, and dried over Na2SO4. The mixture was filtered and the solvent was removed under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 1c (5.52 g; 80% yield) as an orange-red solid. 1H-NMR (400 MHz, CDCl3): δ 7.94 (s, 1H), 7.12-7.14 (m, 2H), 6.95-6.97 (m, 2H), 3.85 (s, 3H); MS: m/z 252.0 (M+H)+.
C. 2-(S)-{[2-Chloro-4-(4-methoxy-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (1e)
To a solution of Compound 1c (4.45 g, 17.7 mmol) in 1,2-dichloroethane (80 mL) was added Boc-L-prolinal (Compound 1d) (5.0 g; 24.4 mmol) and glacial acetic acid (4.5 mL) at ambient temperature, and the mixture was stirred under a nitrogen atmosphere for 3 h. The mixture was then treated with NaB(OAc)3H (9.37 g; 44.2 mmol) and continually stirred at room temperature for 20 h. The resultant mixture was diluted with CH2Cl2, and washed with saturated NaHCO3 (aq) and H2O. The organic phase was washed sequentially with H2O and brine, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a Et2O—CH2Cl2 gradient to afford Compound 1e (6.54 g; 85% yield) as a pale-yellow solid. 1H-NMR (400 MHz, CDCl3): δ 7.73-7.79 (m, 1H), 7.07-7.14 (m, 2H), 6.91-6.98 (m, 2H), 5.73 (br. s, 0.6H), 4.77 (br. s, 0.4H), 4.20-4.30 (m, 1H), 3.85 (s, 3H), 3.21-3.58 (m, 4H), 1.81-2.11 (m, 4H), 1.46-1.49 (m, 9H); MS: m/z 435.1 (M+H)+.
D. 2-(S)-{[4-(4-Methoxy-phenoxy)-2-(5-methylsulfanyl-pyridin-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (1g)
To a teflon-lined septum sealed Schlenk tube, a mixture of Compound 1e (4.0 g; 9.20 mmol), 5-(methylthio)pyridin-3-yl boronic acid (Compound 1f) (2.32 g; 13.7 mmol), K2CO3 (2.50 g; 18.1 mmol) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) (0.45 g, 0.55 mmol) in a mixture of ethanol (18 mL) and H2O (4.5 mL) was irradiated in a microwave reactor at 130° C. for 30 min. The resultant mixture was diluted with EtOAc, washed with saturated NH4Cl(aq) and H2O. The organic phase was washed with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 1g (3.45 g; 72% yield) as pale-yellow solid. 1H-NMR (400 MHz, CDCl3): δ 9.00 (s, 1H), 8.40 (d, 1H), 8.21 (s, 1H), 7.99 (br. s, 1H), 7.12-7.18 (m, 2H), 6.93-6.96 (m, 2H), 5.77 (br. s, 0.6H), 4.90 (br. s, 0.4H), 4.22-4.32 (m, 1H), 3.86 (s, 3H), 3.18-3.56 (m, 4H), 2.47 (s, 3H), 1.80-2.15 (m, 4H), 1.46-1.52 (m, 9H); MS: m/z 524.2 (M+H)+.
E. CPD 107
[4-(4-Methoxy-phenoxy)-2-(5-methylsulfanyl-pyridin-3-yl)-pyrimidin-5-yl]-pyrrolidin-2-(S)-ylmethyl-amine
To a solution of Compound 1g (3.45 g; 6.59 mmol) in CH2Cl2 (20 mL) was added trifluoroacetic acid (4.9 mL; 66 mmol) at ambient temperature. The reaction mixture was stirred at room temperature for 20 h. The resultant mixture was adjusted to pH 12 with 1 N NaOH(aq). The resultant mixture was extracted with CH2Cl2 and H2O. The organic phase was washed with H2O, and dried over Na2SO4. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (35 mL), and treated with 1.0 M HCl in Et2O (6.6 mL; 6.6 mmol) at ambient temperature. The reaction mixture was stirred at room temperature for 20 h. The resultant mixture was concentrated in vacuo, before the residue was taken up in a small portion of MeOH/CH2Cl2, and then triturated with Et2O. A solid was collected by filtration and dried to afford an HCl salt of Compound 107 (2.33 g; 77% yield) as a pale-yellow solid. HCl salt- 1H-NMR (400 MHz, DMSO-d6): δ 9.06 (br. s, 1H), 8.83 (d, 1H), 8.66 (br. s, 1H), 8.42 (d, 1H), 8.25 (s, 1H), 8.05 (t, 1H), 7.25-7.29 (m, 2H), 7.04-7.09 (m, 2H), 6.36 (t, 1H), 3.83-3.87 (m, 1H), 3.81 (s, 3H), 3.56 (t, 2H), 3.35 (s, 3H), 3.17-3.26 (m, 2H), 2.12-2.18 (m, 1H), 1.87-2.01 (m, 2H), 1.70-1.76 (m, 1H); MS: m/z 424.2 (M+H)+.
Following the procedure described above for Example 1 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:
















Cpd
MS (M + H)+
Cpd
MS (M + H)+





















1
407.2
2
377.0



4
407.0
3
407.0



6
427.0
5
427.0



8
378.2
7
378.2



10
367.2
9
383.0



12
391.0
11
432.0



14
348.0
13
405.0



16
428.2
15
393.0



18
442.2
17
428.2



20
428.1
19
453.2



22
408.1
21
483.2



24
396.2
23
379.1



26
408.2
25
396.1



28
402.1
27
411.1



30
420.1
29
422.2



32
455.1
31
476.2



34
416.2
33
393.1



37
396.2
36
366.2



39
408.2
38
395.1



41
420.1
40
378.2



43
434.1
42
434.1



49
433.0
45
392.1



51
461.1
50
445.0



53
409.1
52
425.1



55
413.1
54
396.1



57
443.1
56
413.1



59
394.2
58
439.0



62
396.1
61
367.2



64
425.1
63
419.1



67
381.1
65
367.2



69
403.1
68
408.1



71
409.2
70
425.1



73
426.1
72
393.1



75
380.2
74
394.2



77
417.1
76
429.1



81
394.2
78
419.1



83
464.2
82
422.1



85
406.2
84
477.1



87
404.2
86
430.0



90
444.0
88
428.0



96
439.0
91
420.2



98
403.0
97
415.0



100
378.2
99
379.2



102
432.0
101
439.2



104
417.2
103
415.0



106
410.2
105
393.2



110
439.0
108
455.0



112
432.0
111
415.0



114
407.2
113
431.2



117
416.2
115
424.2



119
416.2
118
416.2



123
447.2
122
471.2



125
445.2
124
464.0



127
438.2
126
421.2



129
407.0
128
400.0



131
414.2
130
383.0



133
397.2
132
421.2



140
407.2
139
431.2



142
419.1
141
406.2



144
379.2
143
403.2



146
391.2
145
378.2



148
363.2
147
387.2



150
419.1
149
362.2



152
394.2
151
395.2



154
393.2
153
417.2



178
380.2
155
392.2



180
410.2
179
401.2



183
405.2
182
394.2



185
398.2
184
376.2



187
380.2
186
414.0



190
432.0
189
423.2



192
398.2
191
416.0



201
396.2
200
387.2



203
362.2
202
380.2



205
410.2
204
417.2



211
392.2
210
426.2



219
398.2
218
405.2



221
434.2
220
441.2



227
396.0
222
444.1



229
416.0
230
407.0



231
389.0
232
412.0



233
428.0
241
468.0



242
436.0
243
452.0



244
422.0
249
394.2



253
392.0
262
410.0



263
406.0
265
426.0



266
426.0
268
426.0










CPD 44
The title compound was prepared in an analogous manner to the preparation of Cpd 107 of Example 1, substituting (4-hydroxy-phenyl)-carbamic acid tert-butyl ester for 4-methoxy-phenol in procedure A, and substituting 4-methoxy-pyridin-3-yl boronic acid for 5-(methylthio)pyridin-3-yl boronic acid in procedure D. MS: m/z 393.2 (M+H)+.
CPD 46
The title compound was prepared in an analogous manner to the preparation of Cpd 107 of Example 1, substituting (4-hydroxy-phenyl)-carbamic acid tert-butyl ester for 4-methoxy-phenol in procedure A, and substituting pyridin-3-yl boronic acid for 5-(methylthio)pyridin-3-yl boronic acid in Procedure D. MS: m/z 363.2 (M+H)+.
CPD 60
The title compound was prepared in an analogous manner to the preparation of Cpd 107 of Example 1, substituting 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine-2-carbonitrile for 5-(methylthio)pyridin-3-yl boronic acid in Procedure D. TFA salt- 1H-NMR (400 MHz, DMSO-d6): δ 8.95 (s, 2H), 8.53 (br. s, 1H), 8.21 (s, 1H), 7.23-7.26 (m, 2H), 7.04-7.07 (m, 2H), 6.23 (t, 1H), 4.36 (q, 2H), 3.81-3.86 (m, 1H), 3.81 (s, 3H), 3.48-3.53 (m, 2H), 3.15-3.26 (m, 2H), 2.10-2.17 (m, 1H), 1.87-2.00 (m, 2H), 1.65-1.74 (m, 1H), 1.32 (t, 3H); MS: m/z 423.1 (M+H)+.
CPD 92
1H-NMR (400 MHz, CDCl3) δ 7.92 (1H, s), 7.60 (2H, s), 7.16-7.14 (2H, m), 6.94 (1H, s), 6.90-6.87 (2H, m), 3.86-3.80 (4H, m), 3.61-3.50 (2H, m), 3.29-3.23 (2H, m), 3.20-2.95 (1H, br s), 2.27 (6H, s), 2.14-2.09 (1H, m), 2.03-2.00 (1H, m), 1.95-1.90 (1H, m), 1.79-1.74 (1H, m); MS: m/z 405.2 (M+H)+.
CPD 93
1H-NMR (400 MHz, CDCl3) δ 7.90 (1H, s), 7.62-7.60 (1H, m), 7.52-7.51 (1H, m), 7.15-7.13 (2H, m), 6.94-6.91 (2H, m), 6.76-6.74 (1H, m), 5.94 (2H, s), 4.86-4.83 (1H, m), 3.84 (3H, s), 3.68-3.62 (1H, m), 3.42-3.26 (2H, m), 3.12-3.08 (2H, m), 2.10-2.02 (1H, m), 1.97-1.91 (1H, m), 1.89-1.80 (1H, m), 1.69-1.60 (1H, m); MS: m/z 421.2 (M+H)+.
CPD 94
1H-NMR (400 MHz, CD3OD) δ 8.12 (1H, s), 7.90-7.89 (2H, m), 7.37-7.36 (1H, m), 7.19-7.17 (2H, m), 7.05-7.03 (2H, m), 4.03-3.94 (1H, m), 3.68-3.56 (2H, m), 3.42-3.32 (2H, m), 3.31-3.29 (1H, m), 2.36-2.28 (1H, m), 2.19-2.05 (2H, m), 1.93-1.81 (1H, m); MS: m/z 445.0 & 447.0 (M+H)+.
CPD 95
1H-NMR (400 MHz, CDCl3) δ 9.33 (1H, s), 8.42-8.40 (1H, m), 8.00 (1H, m), 7.64-7.62 (1H, m), 7.16-7.12 (2H, m), 6.98-6.95 (2H, m), 5.94 (2H, s), 5.03-5.01 (1H, m), 3.87 (3H, s), 3.59-3.55 (1H, m), 3.35-3.29 (1H, m), 3.18-3.10 (1H, m), 3.05-2.94 (2H, m), 2.07-1.99 (1H, m), 1.92-1.79 (2H, m), 1.60-1.54 (1H, m); MS: m/z 403.2 (M+H)+.
CPD 121
The title compound was prepared in an analogous manner to the preparation of Cpd 107 of Example 1, substituting 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine-2-carbonitrile for 5-(methylthio)pyridin-3-yl boronic acid and substituting CH3CN for ethanol in Procedure D. TFA salt- 1H-NMR (400 MHz, CDCl3): δ 9.33 (s, 2H), 7.98 (s, 1H), 7.09-7.13 (m, 2H), 6.91-6.96 (m, 2H), 5.59 (t, 1H), 3.85-3.88 (m, 1H), 3.85 (s, 3H), 3.60-3.62 (m, 2H), 3.21-3.26 (m, 2H), 2.18-2.24 (m, 1H), 1.95-2.09 (m, 2H), 1.75-1.85 (m, 1H); MS: m/z 404.2 (M+H)+.
CPD 260
The title compound was prepared in an analogous manner the preparation of Cpd 107 of Example 1, substituting 4-fluoromethoxy-phenol1 for 4-methoxy-phenol in Procedure A, and substituting 5-methylpyridin-3-yl boronic acid for 5-(methylthio)pyridin-3-yl boronic acid in Procedure D. 1H-NMR (400 MHz, DMSO-d6): δ 9.36 (br. s, 1H), 9.02 (br. s, 1H), 8.86 (s, 1H), 8.42-8.43 (m, 1H), 8.24-8.28 (m, 1H), 8.16-8.19 (m, 1H), 6.86-7.38 (m, 4H), 6.34-6.43 (m, 1H), 5.85-5.98 (m, 1H), 5.76 (s, 2H), 3.81-4.14 (m, 1H), 3.52-3.61 (m, 2H), 3.15-3.27 (m, 2H), 2.33 (s, 3H), 2.11-2.19 (m, 1H), 1.84-2.03 (m, 2H), 1.63-1.77 (m, 1H); MS: m/z 410.0 (M+H)+. 1 4-Fluoromethoxy-phenol was prepared as illustrated in the following synthetic scheme and procedure.




A. 4-Fluoromethoxy-Phenol
To a solution of 1-(4-fluoromethoxy-phenyl)-ethanone (1.5 g; 8.9 mmol) in dichloromethane (30 mL) was added mCPBA (4.0 g; 17.8 mmol). The resulting mixture was stirred at room temperature for 4 h, then washed with saturated NaHCO3 (3×). The organic layer was dried over Na2SO4, concentrated under reduced pressure to give the crude material (3.77 g). The crude material (3.77 g) was dissolved in THF/MeOH/H2O (5/5/5 mL), then treated with LiOH (4.0 g; 108 mmol) at room temperature for 4 h. The reaction mixture was acidified with 2N HCl solution to pH 5. The mixture was extracted with EtOAc (3×). The organic phases were combined, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (1.3 g). This compound was used directly without further purification.
CPD 264
The title compound was prepared in an analogous manner to the preparation of Cpd 107 of Example 1, substituting 4-chloro-5-methylpyridin-3-yl boronic acid for 5-(methylthio)pyridin-3-yl boronic acid in Procedure D, and the title compound was obtained as a by-product of Cpd 266. 1H-NMR (400 MHz, DMSO-d6): δ 9.44 (br. s, 1H), 9.05 (br. s, 1H), 8.96 (d, 1H), 8.46 (d, 1H), 8.27 (s, 1H), 8.23 (d, 1H), 8.04 (d, 1H), 7.27-7.31 (m, 2H), 7.04-7.08 (m, 2H), 6.41 (br. s, 1H), 3.83-3.90 (m, 1H), 3.57-3.94 (m, 2H), 3.15-3.27 (m, 2H), 2.40 (s, 3H), 2.38 (s, 3H), 2.11-2.19 (m, 1H), 1.85-2.03 (m, 2H), 1.67-1.77 (m, 1H); MS: m/z 517.2 (M+H)+.
Example 2




A. 4,4-Difluoro-2-(S)-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2b)
To a solution of 4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (Compound 2a) (1.5 g; 6.0 mmol) in tetrahydrofuran (15 mL) was added borane-dimethylsulfide complex (3.79 mL; 7.58 mmol) dropwise at ambient temperature. The reaction mixture was refluxed for 2 h. The resultant mixture was allowed to cool to room temperature. The mixture was partitioned between EtOAc and H2O. The organic phase was washed with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 2b (1.2 g; 84% yield) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ4.08-4.23 (m, 2H), 3.61-3.87 (m, 4H), 2.45-2.57 (m, 1H), 2.15 (br.s, 1H), 1.49 (s, 9H).
B. 4,4-Difluoro-2-(S)-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2c)
To a solution of Compound 2b (1.33 g; 5.61 mmol) in CH2Cl2 (20 mL) was added 3,3,3-triacetoxy-3-iodophthalide (3.56 g; 8.39 mmol) at ambient temperature. The reaction mixture was stirred at room temperature for 2 h. The resultant mixture was diluted with EtOAc, and washed sequentially with saturated NaHCO3 (aq) and H2O. The organic phase was washed with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 2c (0.58 g; 44% yield) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ 9.59 (d, 1H), 4.28-4.45 (m, 1H), 3.77-3.89 (m, 2H), 2.43-2.63 (m, 2H), 1.46-1.51 (m, 9H).
Following the procedure described above for Example 2 and substituting the appropriate starting materials and purification methods known to those skilled in the art, the following aldehydes were prepared:




Example 3




A. 3-Oxo-piperidine-1-carboxylic acid tert-butyl ester (3b)
To a solution of 3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (Compound 3a) (0.25 g; 1.24 mmol) in anhydrous dichloromethane (9.0 mL) at 0° C. was added 1,1,1-tris(actyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-one (1.58 g; 3.72 mmol). The mixture was allowed to stir at room temperature under nitrogen for 2 h, to which was then added additional 1,1,1-tris(actyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.5 g; 1.18 mmol). Upon stirring for 20 h at room temperature, the reaction mixture was partitioned between dichloromethane and brine. The organic layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash column chromatography, eluting with 40% ethyl acetate in hexanes, to yield Compound 3b as an oil (0.24 g; 97% yield). 1H NMR (400 MHz, CDCl3): δ 4.0 (2H, br s), 3.60-3.57 (2H, m), 2.49-2.45 (2H, m), 2.01-1.95 (1H, m), 1.46 (9H, s).
Example 4




A. trans-(3-Formyl-cyclobutyl)-carbamic acid tert-butyl ester (4b)
To a solution of trans-(3-hydroxymethyl-cyclobutyl)-carbamic acid tert-butyl ester (Compound 4a) (0.2 g; 1.0 mmol) in anhydrous dichloromethane (8.0 mL) at 0° C. was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-one (0.84 g; 2.0 mmol). The reaction was allowed to stir at room temperature under nitrogen for 3 h, before partitioning the reaction mixture between dichloromethane and brine. The organic layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash column chromatography, eluting with 30% ethyl acetate in hexanes, to yield Compound 4b as a foam (0.2 g; 88% yield).
1H NMR (400 MHz, CDCl3): δ 9.82 (1H, d), 4.77 (1H, br s), 4.16-4.11 (1H, br s), 3.04-3.03 (1H, m), 2.69-2.64 (2H, m), 2.21-2.13 (2H, m), 1.44 (9H, s).
Following the procedure described above for Example 4 and substituting the appropriate starting materials and purification methods known to those skilled in the art, the following aldehydes were prepared:




1H NMR (400 MHz, CDCl3): δ 9.58 (1H, d), 4.53 (1H, br s), 3.75 (1H, br s), 2.12-2.0 (2H, m), 1.84-1.73 (2H, m), 1.54-1.15 (13H, m).




1H NMR (400 MHz, CDCl3): δ 9.59 (1H, br s), 4.9 (1H, br s), 4.26-4.24 (1H, m), 1.79-1.62 (2H, m), 1.45 (9H, s), 1.44-1.36 (1H, m), 0.98-0.96 (6H, m).
Following the procedure described above for Example 1 and substituting the appropriate reagents, starting materials (including the aldehydes or ketones which were prepared in Examples 2, 3, and 4), and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:
















Cpd
MS (M + H)+
Cpd
MS (M + H)+





















79
415.2
80
397.1



89
397.2
277
419.2



278
412.2
279
395.2



280
395.2
281
419.2



282
419.1
134
421.0



283
412.2
193
414.2



284
394.2
195
419.2



194
430.0
235
426.0



234
442.0
239
410.0



238
410.0
240
426.0










Additional compounds with NMR data (below table):

CPD 109
1H NMR (400 MHz, CDCl3): δ 9.30 (1H, s), 9.12 (2H, s), 8.07 (1H, s), 7.16-7.13 (2H, m), 6.97-6.95 (2H, m), 4.74-4.72 (1H, m), 3.87 (3H, s), 3.63-3.55 (1H, m), 3.30-3.26 (1, m), 2.95-2.91 (1H, m), 2.81-2.71 (2H, m), 2.05-1.99 (1H, m), 1.84-1.77 (1H, m), 1.68-1.57 (2H, m); MS: m/z 379.2 (M+H)+.
CPD 196
HCl salt-1H-NMR (400 MHz, DMSO-d6): δ 9.90 (br, s, 1H), 9.79 (br. s, 1H), 9.06 (d, 1H), 8.59 (dd, 1H), 8.34 (d, 1H), 8.32 (s, 1H), 7.53 (dd, 1H), 7.27-7.32 (m, 2H), 7.04-7.08 (m, 2H), 6.45 (t, 1H), 5.48 (dt, 1H), 4.04-4.11 (m, 1H), 3.81 (s, 3H), 3.42-3.80 (m, 5H), 1.91-2.09 (m, 1H); MS: m/z 396.2 (M+H)+
CPD 292
1H NMR (400 MHz, CDCl3): δ 9.42 (1H, d), 8.76 (1H, d), 8.57 (1H, t), 7.99 (1H, s), 7.15-7.13 (2H, m), 6.98-6.96 (2H, m), 4.98 (1H, t), 3.87 (3H, s), 3.33-3.26 (2H, m), 3.09-3.04 (1H, m), 1.26 (3H, d); MS m/z 377.0 (M+H)+.
CPD 293
1H NMR (400 MHz, CDCl3): δ 9.42 (1H, d), 8.76 (1H, d), 8.57 (1H, t), 8.0 (1H, s), 7.15-7.13 (2H, m), 6.98-6.96 (2H, m), 4.93 (1H, t), 3.88 (3H, s), 3.37-3.33 (2H, m), 3.12-3.09 (2H, m); MS: m/z 363.0 (M+H)+.
CPD 294
1H NMR (400 MHz, CDCl3): δ 9.42 (1H, d), 8.76 (1H, d), 8.58-8.57 (1H, m), 7.98 (1H, s), 7.16-7.14 (2H, m), 6.98-6.96 (2H, m), 5.0 (1H, br s), 3.87 (3H, s), 3.35-3.30 (1H, m), 3.19-3.14 (1H, m), 3.03-2.97 (1H, m), 1.84-1.77 (1H, m), 1.39-1.36 (2H, m), 1.0-0.95 (6H, dd); MS: m/z 419.2 (M+H)+.
CPD 295
1H NMR (400 MHz, CDCl3): δ 9.31 (2H, s), 9.12 (1H, s), 7.99 (1H, s), 7.16-7.14 (2H, m), 6.97-6.94 (2H, m), 5.0 (1H, br s), 3.87 (3H, s), 3.35-3.31 (1H, m), 3.2-3.14 (1H, m), 3.02-2.97 (1H, m), 1.84-1.77 (1H, m), 1.4-1.35 (2H, m), 1.0-0.95 (6H, dd); MS: m/z 395.2 (M+H)+.
CPD 298
1H NMR (400 MHz, CDCl3): δ 9.41-9.40 (2H, m), 8.76-8.75 (2H, m), 8.56-8.55 (2H, m), 7.98-7.96 (2H, d), 7.15-7.12 (4H, m), 6.99-6.96 (4H, m), 4.61-4.56 (1H, m), 4.35-4.33 (1H, m), 3.88-3.87 (6H, d), 3.70-3.65 (1H, m), 3.42-3.37 (2H, m), 3.02-2.98 (1H, m), 2.84-2.77 (2H, m), 2.25-2.22 (2H, m), 2.02-1.90 (4H, m), 1.86-1.75 (4H, m), 1.42-1.25 (8H, m); MS: m/z 417.2 (M+H)+.
CPD 299
1H NMR (400 MHz, CDCl3): δ 9.41 (1H, d), 8.75 (1H, d), 8.57 (1H, t), 7.99 (1H, s), 7.15-7.13 (2H, m), 6.98-6.96 (2H, m), 6.11 (1H, br s), 3.87 (3H, s), 3.37-3.34 (1H, m), 3.29-3.26 (1H, m), 2.54-2.48 (1H, m), 1.92-1.87 (2H, m), 1.77-1.74 (2H, m), 1.55-1.19 (5H, m); MS: m/z 431.0 (M+H)+.
CPD 300
1H NMR (400 MHz, CDCl3): δ 9.31 (2H, s), 9.11 (1H, s), 8.0 (1H, s), 7.15-7.13 (2H, m), 6.96-6.94 (2H, m), 5.98 (1H, br s), 3.86 (3H, s), 3.39-3.34 (1H, m), 3.29-3.25 (1H, m), 2.54-2.48 (1H, m), 1.91-1.88 (2H, m), 1.76-1.74 (2H, m), 1.55-1.19 (5H, m); MS: m/z 407.0 (M+H)+.
CPD 301
1H NMR (400 MHz, CDCl3): δ 9.41 (1H, s), 8.76 (1H, s), 8.57 (1H, s), 7.97 (1H, s), 7.14-7.12 (2H, m), 6.98-6.96 (2H, m), 4.43-4.40 (1H, m), 3.87 (3H, s), 3.73-3.69 (1H, br s), 3.36-3.33 (2H, m), 2.61-2.57 (1H, m), 2.30-2.22 (2H, m), 2.01-1.94 (2H, m); MS: m/z 403.2 (M+H)+.
CPD 302
1H NMR (400 MHz, CDCl3): δ 9.31 (2H, s), 9.12 (1H, s), 7.98 (1H, s), 7.14-7.12 (2H, m), 6.97-6.94 (2H, m), 4.40-4.37 (1H, m), 3.86 (3H, s), 3.71-3.65 (1H, br s), 3.36-3.32 (2H, m), 2.61-2.57 (1H, m), 2.30-2.22 (2H, m), 2.01-1.93 (2H, m); MS: m/z 379.2 (M+H)+.
CPD 303
1H NMR (400 MHz, CDCl3): δ 9.42 (4H, d), 8.76 (2H, d), 8.57-8.56 (2H, m), 7.88 (1H, s), 7.81 (1H, s), 7.15-7.12 (4H, m), 6.99-6.96 (4H, m), 4.63-4.59 (1H, m), 4.19-4.13 (1H, m), 3.88-3.81 (7H, m), 3.69-3.64 (1H, m), 3.38-3.34 (1H, m), 3.00-2.94 (1H, m), 2.39-2.33 (4H, m), 2.30-2.24 (4H, m); MS: m/z 389.2 (M+H)+.
CPD 304
1H NMR (400 MHz, CDCl3): δ 9.31 (4H, s), 9.12 (2H, s), 7.88 (1H, s), 7.81 (1H, s), 7.15-7.12 (4H, m), 6.98-6.95 (4H, m), 4.59-4.55 (1H, m), 4.17-4.13 (1H, m), 3.88-3.81 (7H, m), 3.68-3.66 (1H, m), 3.38-3.34 (1H, m), 3.00-2.94 (1H, m), 2.39-2.33 (4H, m), 2.29-2.23 (4H, m); MS: m/z 365.2 (M+H)+
Example 5




A. 5-[5-Amino-4-(4-methoxy-phenoxy)-pyrimidin-2-yl]-nicotinonitrile (5b)
Using an adaptation of the method described in Procedure D of Example 1, substituting Compound 5a for Compound 1f, the title Compound 5b was obtained. MS: m/z 320.1 (M+H)+.
B. Cpd 285
5-{4-(4-Methoxy-phenoxy)-5-[(5-methyl-3H-imidazol-4-ylmethyl)-amino]-pyrimidin-2-yl}-nicotinonitrile
Using an adaptation of the method described in Procedure C of Example 1, substituting Compound 5b for Compound 1c, and substituting 5-methyl-3H-imidazole-4-carbaldehyde for Compound 1d, the title Compound 285 was obtained as a free base. 1H-NMR (400 MHz, DMSO-d6): δ 11.79 (br. s, 1H), 9.21 (s, 1H), 8.94 (s, 1H), 8.51 (s, 1H), 8.31 (s, 1H), 7.47 (s, 1H), 7.27 (d, 2H), 7.05 (d, 2H), 6.44 (br. s, 1H), 4.03 (m, 2H), 3.81 (s, 3H), 2.23 (s, 3H); MS: m/z 414.0 (M+H)+.
Following the procedure described above for Example 5 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:
















Cpd
MS (M + H)+
Cpd
MS (M + H)+





















283
400.0
284
400.2



286
414.0
287
442.0



288
375.0
289
421.0



290
405.0
291
389.0










Example 6




A. 2-(S)-{[2-Cyano-4-(4-methoxy-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic Acid tert-Butyl Ester (6a)
A mixture of Compound 1e (0.4 g; 0.92 mmol), Zn(CN)2 (0.11 g; 0.92 mmol), and Pd(PPh3)4 (0.106 g; 0.092 mmol) in DMF (2.4 mL) was irradiated at 160° C. in a CEM microwave reactor for 16 min. Purification by preparative TLC, eluting with 1/1 EtOAc/hexanes, gave the product 6a (0.059 g; 15% yield). MS: m/z 426.2 (M+H)+.
B. 2-(S)-{[2-(N-Hydroxycarbamimidoyl)-4-(4-methoxy-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic Acid tert-Butyl Ester (6b)
To a microwave vessel was added NaHCO3 (0.03 g; 0.354 mmol), hydroxylamine hydrochloride (0.016 g; 0.236 mmol) and H2O (0.2 mL). A suspension of Compound 6a (0.05 g; 0.118 mmol) in EtOH (0.5 mL) was added to the vessel, and the reaction mixture was irradiated at 130° C. in a CEM microwave reactor for 32 min. Purification by preparative TLC, eluting with 1/1 EtOAc/hexanes, gave the product 6b (0.053 g; 98% yield). MS: m/z 456.2 (M+H)+.
C. 2-(S)-{[4-(4-Methoxy-phenoxy)-2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic Acid tert-Butyl Ester (6c)
To a solution of Compound 6b (0.038 g; 0.0828 mmol) and 1,1′-carbonyldiimidazole (0.015 g; 0.091 mmol) in CH3CN (1 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL, 0.33 mmol) and the resulting mixture was stirred at rt for 20 h. The reaction mixture was washed with water, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield Compound 6c. MS: m/z 485.3 (M+H)+.
D. Cpd 35
3-{4-(4-Methoxy-phenoxy)-5-[(pyrrolidin-2-(S)-ylmethyl)-amino]-pyrimidin-2-yl}-4H-[1,2,4]oxadiazol-5-one
To a solution of Compound 6c (150 mg; 0.31 mmol) in CH2Cl2 (4 mL) was added TFA (1 mL) and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and the resultant residue was purified by reverse phase HPLC to afford Compound 35 as a TFA salt. 1H-NMR (300 MHz, CD3OD): δ 8.16 (s, 1H), 7.18 (d, 2H), 7.00 (d, 2H), 3.97 (m, 1H), 3.83 (s, 3H), 3.61-3.66 (m, 2H), 3.34-3.40 (m, 2H), 2.27-2.35 (m, 1H), 2.04-2.19 (m, 2H), 1.82-1.92 (m, 1H); MS: m/z 385.2 (M+H)+.
Example 7




A. 2-(S)-{[4-(4-Methoxy-phenoxy)-2′-methylsulfanyl-[2,4]bipyrimidin-yl-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (7b)
To a teflon-lined septum-sealed Schlenk tube, a mixture of Compound 1e (213 mg; 0.49 mmol), 2-methylsulfanyl-4-tributylstannanyl-pyrimidine (Compound 7a) (305 mg; 0.735 mmol) and tetrakis-(triphenylphosphine)palladium(0) (57 mg; 0.049 mmol) in dioxane (1.0 mL) was irradiated in a Microwave reactor at 150° C. for 30 min. The resultant mixture was diluted with EtOAc, and washed with saturated NH4Cl(aq) and H2O. The organic phase was washed with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 7b (129 mg; 50% yield). 1H-NMR (400 MHz, CDCl3): δ 8.48-8.50 (m, 1H), 8.08-8.12 (m, 1H), 7.54-7.57 (m, 1H), 7.16-7.23 (m, 2H), 6.96-7.01 (m, 2H), 6.27 (br. s, 0.7H), 5.18 (br, 0.3H), 4.25-4.36 (m, 1H), 3.88 (s, 3H), 3.24-3.59 (m, 4H), 2.68 (s, 3H), 1.79-2.16 (m, 4H), 1.44-1.54 (m, 9H); MS: m/z 525.2 (M+H)+.
B. Cpd 66
[4-(4-Methoxy-phenoxy)-2′-methylsulfanyl-[2,4]bipyrimidinyl-5-yl]-pyrrolidin-2-(S)-ylmethyl-amine
Using an adaptation of the method described in Procedure E of Example 1, substituting Compound 7b for Compound 1g, the title Compound 66 was obtained as a HCl salt. 1H-NMR (400 MHz, DMSO-d6): δ 8.89 (br. s, 1H), 8.62 (d, 1H), 8.31 (s, 1H), 7.59 (d, 1H), 7.29-7.31 (m, 2H), 7.02-7.04 (m, 2H), 6.66 (t, 1H), 3.83 (t, 1H), 3.80 (s, 3H), 3.57-3.60 (m, 2H), 3.11-3.25 (m, 2H), 2.45 (s, 3H), 2.08-2.15 (m, 1H), 1.84-1.99 (m, 2H), 1.66-1.74 (m, 1H); MS: m/z 425.1 (M+H)+.
Following the procedure described above for Example 8 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:















Cpd
MS (M + H)+
Cpd
MS (M + H)+




















47
434.1
48
384.1



120
379.2









Example 8




A. 2-(S)-{[4-(4-Methoxy-phenoxy)-[2,5′]bipyrimidinyl-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (8b)
Using an adaptation of the method described in Procedure D of Example 1, substituting pyrimidine-5-boronic acid (Compound 8a) for Compound 1f, the title Compound 8b was obtained as a pale-yellow solid. 1H-NMR (400 MHz, CDCl3): δ 9.31 (s, 2H), 9.11 (s, 1H), 8.00-8.03 (m, 1H), 7.10-7.15 (m, 2H), 6.93-6.96 (m, 2H), 5.89 (br. s, 0.7H), 4.98 (br. s, 0.3; H), 4.21-4.35 (m, 1H), 3.86 (s, 3H), 3.19-3.56 (m, 4H), 1.80-2.14 (m, 4H), 1.43-1.46 (m, 9H); MS: m/z 479.2 (M+H)+.
B. Cpd 156
4-{5-[(Pyrrolidin-2-(S)-ylmethyl)-amino]-[2,5]bipyrimidinyl-4-yloxy}-phenol
To a solution of Compound 8b (100 mg; 0.21 mmol) in CH2Cl2 (10 mL) cooled to 0° C. was added BBr3-S(CH3)2 in CH2Cl2 (1.0 M, 1.5 mL) dropwise. The mixture was allowed to warm to ambient temperature, and then was refluxed at 70° C. for 5 h. An additional portion of BBr3-S(CH3)2 in CH2Cl2 (1.0 M, 1.5 mL) was added to the reaction mixture upon reaching room temperature. The reaction mixture was refluxed at 70° C. for 20 h. The reaction was adjusted topH 6 with 1 N NaOH(aq), and the organic phase was concentrated. The resultant residue was purified by reverse phase HPLC, eluting with a CH3CN—H2O gradient to afford Compound 156 (29.7 mg; 27% yield) as a HBr salt. 1H-NMR (400 MHz, DMSO-d6): δ 9.54 (s, 1H), 9.17 (s, 1H), 9.16 (s, 1H), 8.97 (br. s, 1H), 8.55 (br. s, 1H), 7.27 (d, 1H), 7.12-7.15 (m, 2H), 6.86-6.89 (m, 2H), 6.42 (t, 1H), 3.85 (br. s, 1H), 3.53-3.57 (m, 2H), 3.18-3.26 (m, 2H), 2.11-2.18 (m, 1H), 1.88-1.98 (m, 2H), 1.67-1.72 (m, 1H); MS: m/z 365.1 (M+H)+.
Example 9




A. 2-(S)-({Acetyl-[4-(4-methoxy-phenoxy)-[2,5]bipyrimidinyl-5-yl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (9a)
To a solution of Compound 8b (89 mg; 0.19 mmol) in CH2Cl2 (7 mL) was added acetyl chloride (0.1 mL) and pyridine (0.1 mL) at ambient temperature. The mixture was stirred at room temperature for 3 h. Diluted the resulted mixture with CH2Cl2. The organic phase was washed sequentially with H2O and brine, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to afford Compound 9a. The crude product was used in the next reaction without further purification. MS: m/z 521.3 (M+H)+.
B. Cpd 181
N-[4-(4-Methoxy-phenoxy)-[2,5′]bipyrimidinyl-5-yl]-N-pyrrolidin-2-(S)-ylmethyl-acetamide
To a solution of Compound 9a in CH2Cl2 (3 mL) was added trifluoroacetic acid (0.4 mL) at ambient temperature. The mixture was stirred at room temperature for 20 h. The solvent was evaporated under reduced pressure. The crude material was purified by reverse phase HPLC, eluting with a CH3CN—H2O gradient to afford Compound 181 (71.1 mg; 71% yield) as a TFA salt. 1H-NMR (400 MHz, DMSO-d6): δ 9.34 (s, 1H), 9.32 (s, 2H), 9.09 (br. s, 0.6H), 9.00 (s, 0.4H), 8.99 (s, 1H), 8.42 (br. s, 1H), 7.32 (d, 2H), 7.08 (d, 2H), 4.25-4.31 (m, 0.6H), 4.10-4.13 (m, 0.4H), 3.82 (s, 3H), 3.64-3.79 (m, 2H), 3.17-3.31 (m, 2H), 1.85-2.14 (m, 6H), 1.61-1.68 (m, 1H); MS: m/z 421.2 (M+H)+.
Example 10




A. 2-(S)-{[4-(3-Hydroxy-phenoxy)-2-(5-methoxy-pyridin-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (10a)
The title compound was prepared in a same manner to Compound 1g in Example 1. Using an adaptation of the method described in Procedure A-D, substituting 3-Hydroxy-phenol for 4-Methoxyphenol in Procedure A and substituting 5-Methoxy-pyridin-3-yl boronic acid for Compound 1f in Procedure D, the title Compound 10a was obtained. MS: m/z 494.2 (M+H)+.
B. 2-(S)-{[4-(3-Acetoxy-phenoxy)-2-(5-methoxy-pyridin-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (10b)
To a solution of Compound 10a (50 mg; 0.1 mmol) in tetrahydrofuran (5 mL), cooled to −78° C., was added acetyl chloride (0.009 mL; 0.12 mmol) and triethylamine (0.035 mL; 0.25 mmol). The mixture was stirred at −78° C. for 1 hour. Diluted the resulted mixture with EtOAc and H2O. The organic phase was washed sequentially with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a EtOAc-heptane gradient to afford Compound 10b (43 mg; 80% yield). MS: m/z 536.0 (M+H)+.
C. Cpd 250
Acetic acid 3-{2-(5-methoxy-pyridin-3-yl)-5-[(pyrrolidin-2-(S)-ylmethyl)-amino]-pyrimidin-4-yloxy}-phenyl ester
Using an adaptation of the method described in Procedure E of Example 1, substituting Compound 10b for Compound 1g, the title Compound 250 was obtained as a HCl salt. 1H-NMR (400 MHz, DMSO-d6): δ 9.67 (br. s, 1H), 9.37 (br. s, 1H), 8.75 (s, 1H), 8.44 (s, 1H), 8.35 (s, 1H), 7.99 (s, 1H), 7.55 (t, 1H), 7.31 (d, 1H), 7.26 (s, 1H), 7.11 (d, 1H), 6.63 (br. s, 1H), 3.88 (s, 3H), 3.84 (m, 1H), 3.62-3.68 (m, 2H), 3.13-3.25 (m, 2H), 2.28 (s, 3H), 2.10-2.18 (m, 1H), 1.85-2.02 (m, 2H), 1.68-1.76 (m, 1H); MS: m/z 436.0 (M+H)+.
Following the procedure described above for Example 10 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:















Cpd
MS (M + H)+
Cpd
MS (M + H)+








228
431.0
248
452.0



251
420.0









Example 11




A. [4-(5-Amino-2-chloro-pyrimidin-4-yloxy)-phenyl]-carbamic acid benzyl ester (11a)
The title compound was prepared in a same manner to Compound 1c in Example 1. Using an adaptation of the method described in Procedures A and B, substituting (4-hydroxy-phenyl)-carbamic acid benzyl ester (prepared according to the procedure disclosed in U.S. Pat. No. 3,933,470) for 4-methoxyphenol in Procedure A, the title Compound 11a was obtained. MS: m/z 371.2 (M+H)+.
B. [4-(5-Amino-2-pyridin-3-yl-pyrimidin-4-yloxy)-phenyl]-carbamic acid benzyl ester (11b)
To a teflon-lined septum sealed Schlenk tube, a mixture of Compound 11a (1.0 g; 2.7 mmol), pyridin-3-yl boronic acid (0.83 g; 6.75 mmol), Cs2CO3 (2.60 g; 8.1 mmol) and [1,1-Bis(diphenylphosphino)-ferrocene]dichloro-palladium(11) (0.49 g; 0.6 mmol) in a mixture of dioxane (15 mL) and EtOH (1 mL) was irradiated in a microwave reactor at 150° C. for 55 min. The reaction mixture was poured into water, diluted with EtOAc and the solid was collected by filtration. The organic phase was isolated and dried over MgSO4. and the reaction mixture was concentrated under reduced pressure. The resultant residue was purified by reverse phase HPLC, eluting with a CH3CN—H2O (0.5% TFA) gradient to afford Compound 11b (0.72 g; 42% yield based on di-TFA). 1H-NMR (300 MHz, MeOH-d4): δ 9.2 (s, 1H), 8.9 (d, 1H), 8.7 (d, 1H), 8.2 (s, 1H), 8.0 (m, 1H), 7.5 (d, 2H), 7.5-7.3 (m, 6H), 7.2 (m, 2H), 5.2 (s, 2H); MS: m/z 414.2 (M+H)+.
C. 2-(S)-{[4-(4-Benzyloxycarbonylamino-phenoxy)-2-pyridin-3-yl-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (11c)
To a solution of Compound 11b (0.55 g; 1.3 mmol) in 1,2-dichloroethane (25 ml) was added Boc-L-prolinal (0.37 mL; 1.9 mmol). To the reaction mixture was then added NaBH(OAc)3 (0.4 g; 1.9 mmol) portionwise, and the reaction mixture was continually stirred at room temperature for 5 h. The resultant mixture was diluted with water. After stirring for 10 min the organic phase was isolated, washed with brine, and dried over MgSO4. The solvent was evaporated in vacuo to afford Compound 11c. The compound was used in the next step without further purification.
D. Cpd 177
(4-{2-Pyridin-3-yl-5-[(pyrrolidin-2-(S)-ylmethyl)-amino]-pyrimidin-4-yloxy}-phenyl)-carbamic acid benzyl ester (11d)
To a solution of Compound 11c (80 mg; 0.13 mmol) in CH2Cl2 (3 mL) was added trifluoroacetic acid (0.5 mL). The reaction was stirred at room temperature for 3 h and the solvent was evaporated in vacuo to give a crude residue. The crude material was purified by reverse phase HPLC, eluting with a CH3CN—H2O gradient to afford Compound 177 (31.6 mg; 46% yield). 1H-NMR (300 MHz, MeOH-d4): δ 8.7 (d, 1H), 8.6 (d, 1H), 8.2 (s, 1H), 7.7 (m, 1H), 7.6 (m, 2H), 7.5-7.25 (m, 7H), 7.2 (m, 2H), 5.2 (s, 2H), 4.0 (m, 1H), 3.7 (m, 2H), 3.5-3.3 (m, 4H), 2.4 (m, 1H), 2.2 (m, 2H) 1.9 (m, 1H); MS: m/z 497.2 (M+H)+.
Following the procedure described for Example 11 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:















Cpd
MS (M + H)+
Cpd
MS (M + H)+








188
497.2
197
515.2









Example 12




A. 2-(S)-{[4-(4-Benzyloxycarbonylamino-phenoxy)-2-(5-fluoro-pyridin-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (12a)
The title compound was prepared according to the method described for Compound 11c in Example 11. Using an adaptation of the method described in Procedures A-C, substituting 5-fluoro-pyridin-3-yl boronic acid for pyridin-3-yl boronic acid in Procedure B, the title Compound 12a was obtained. MS: m/z 615.2 (M+H)+.
B. 2-(S)-{[4-(4-Amino-phenoxy)-2-(5-fluoro-pyridin-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (12b)
To a Parr bottle was placed 10% Pd/C (100 mg), Compound 12a (1.2 g; 1.9 mmol) and EtOH (35 mL). The reaction mixture was placed under a 50-psi H2 atmosphere and the reaction was shaken for 20 h. The catalyst was collected by vacuum filtration and the filtrate was evaporated in vacuo to afford Compound 12b. The compound was used in the next step without further purification. MS: m/z 481.0 (M+H)+.
C. Cpd 198
[4-(4-Amino-phenoxy)-2-(5-fluoro-pyridin-3-yl)-pyrimidin-5-yl]-pyrrolidin-2-(S)-ylmethyl-amine
Using an adaptation of the method described in Procedure D of Example 11, substituting Compound 12b for Compound 11c, the title Compound 198 (100% yield based on tri-TFA salt) was obtained. 1H-NMR (300 MHz, MeOH-d4): δ 8.8 (s, 1H), 8.3 (s, 1H), 8.2 (s, 1H), 8.0 (m, 1H), 7.6-7.4 (m, 4H), 4.0 (br. m, 1H), 3.6 (m, 2H), 3.5-3.2 (m, 4H), 2.2 (m, 1H), 2.0 (m, 2H), 1.8 (m, 1H); MS: m/z 381.2 (M+H)+.
Example 13




A. Cpd 213
N-(4-{2-(5-Fluoro-pyridin-3-yl)-5-[(pyrrolidin-2-(S)-ylmethyl)-amino]-pyrimidin-4-yloxy}-phenyl)-methanesulfonamide
To a solution of Compound 12b (30 mg; 0.062 mmol) and i-Pr2EtN (0.044 mL; 0.25 mmol) in CH2Cl2 (4 mL), cooled to 0° C., was added a solution of mesyl chloride (0.0044 mL; 0.062 mmol) in CH2Cl2 (2 mL) over 2 h. The reaction was then allowed to warm to room temperature and stirred at room temperature for 20 h. Water was added and the organic phase was isolated, dried over MgSO4 and filtered, TFA (0.5 mL) was added to the filtrate. The mixture was stirred at room temperature for 1 h. The solvent was evaporated in vacuo. The residue was purified by reverse phase HPLC, eluting with a CH3CN—H2O gradient to afford Compound 213 (3.4 mg; 7% yield). 1H-NMR (300 MHz, DMSO-d6): δ 8.9 (m, 1H), 8.6 (d, 1H), 8.45 (m, 1H), 8.3 (m, 2H), 7.7 (d, 2H), 7.5 (m, 1H), 7.25 (d, 2H), 3.85 (m, 1H), 3.5 (m, 2H), 3.2 (m, 2H), 3.1-2.7 (m, 2H), 2.6 (s, 3H), 2.1 (m, 1H), 1.95 (m, 1H), 1.7 (m, 1H); MS: m/z 459.1 (M+H)+.
Following the procedure described above for Example 13 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:















Cpd
MS (M + H)+
Cpd
MS (M + H)+








212
423.3
214
441.2



216
391.2
223
409.2









Example 14







A. 4-Hydroxy-2-pyridin-3-yl-pyrimidine-5-carboxylic acid ethyl ester (14c)
A suspension of Compound 14a (6.1 g; 38.64 mmol) in sodium ethoxide solution (21 wt. % in denatured ethanol) (100 mL) was stirred at room temperature for 10 min. To the mixture was added Compound 14b (7.81 mL; 38.65 mmol) at 0° C. The reaction was allowed to stir at room temperature for 5 h. Water (100 mL) was added to the reaction mixture, and the pH was adjusted to 5 with 2N HCl. The aqueous phase was extracted with CH2Cl2 (3×150 mL). The combined organic phases were dried over MgSO4 and concentrated. To the residue was added Et2O (100 mL). The solid (Compound 14c) was collected by filtration and dried. 1H NMR (300 MHz, CDCl3): δ 9.80 (s, 1H), 9.10 (s, 1H), 7.75-8.90 (m, 2H), 7.50 (dd, 1H), 4.50 (q, 2H), 1.50 (t, 3H); MS: m/z 246.1 (M+H)+.
B. 4-Chloro-2-pyridin-3-yl-pyrimidine-5-carboxylic acid ethyl ester (14d)
To a suspension of Compound 14c (5.05 g; 20.59 mmol) in DMF (70 mL) was added SOCl2 (3 mL; 41.23 mmol) dropwise at room temperature. The reaction was stirred at room temperature for 30 min, then poured into an ice water slurry of K2CO3 (3.41 g). The resultant solid (Compound 14d) was collected by filtration and dried. 1H NMR (300 MHz, CDCl3): δ 9.70 (s, 1H), 9.20 (s, 1H), 7.70-8.85 (m, 2H), 7.50 (dd, 1H), 4.50 (q, 2H), 1.45 (t, 3H); MS: m/z 264.1 (M+H)+.
C. 4-(3-Cyano-phenoxy)-2-pyridin-3-yl-pyrimidine-5-carboxylic acid ethyl ester (14e)
A mixture of Compound 14d (1.0 g; 3.79 mmol), 3-cyanophenol (0.587 g; 4.93 mmol) and Cs2CO3 (4.93 g; 15.13 mmol) in CH3CN (25 mL) was stirred at room temperature for 2 h. The suspension was poured into ice-water and extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried over MgSO4 and concentrated to afford Compound 14e. 1H NMR (300 MHz, CDCl3): δ 9.40 (s, 1H), 9.25 (s, 1H), 8.70 (d, 1H), 8.45 (m, 1H), 7.45-7.65 (m, 4H), 7.35 (m, 1H), 4.50 (q, 2H), 1.45 (t, 3H); MS: m/z 347.2 (M+H)+.
D. 4-(3-Cyano-phenoxy)-2-pyridin-3-yl-pyrimidine-5-carboxylic acid (14f)
To a suspension of Compound 14e (1.06 g; 3.06 mmol) in EtOH (50 mL) was added 0.5N NaOH (9 mL; 4.5 mmol). The reaction was stirred at room temperature for 2 h. The pH of the reaction mixture was adjusted to 2 with 1N HCl. The resultant white solid was collected by filtration to afford Compound 14f. 1H NMR (300 MHz, DMSO d6): δ 9.21 (s, 1H), 9.18 (d, 1H), 8.70 (d, 1H), 8.35 (dd, 1H), 7.95 (s, 1H), 7.85 (dd, 1H), 7.75 (m, 2H), 7.50 (dd, 1H); MS: m/z 319.2 (M+H)+.
E. [4-(3-Cyano-phenoxy)-2-pyridin-3-yl-pyrimidin-5-yl]carbamic acid tert-butyl ester (14g)
To a solution of Et3N (0.058 mL; 0.42 mmol) in tBuOH (9.35 mL) was added 4 Å molecular sieves (3g) and the mixture was refluxed for 30 min under a N2 atmosphere. Compound 14f (0.1 g; 0.31 mmol) and diphenylphosphorylazide (0.085 mL; 0.39 mmol) were added to the mixture and refluxed for 3 h under a N2 atmosphere. The reaction mixture was allowed to cool to room temperature, filtered and concentrated. The resulting residue was suspended in EtOAc (10 mL) and washed with water (10 mL) and brine (10 mL), dried over MgSO4 and concentrated. The crude product was purified by reverse phase HPLC to give Compound 14g. 1H NMR (300 MHz, CD3OD): δ 9.30 (s, 1H), 9.20 (s, 1H), 8.80 (d, 1H), 8.65 (d, 1H), 7.80 (dd, 1H), 7.70 (s, 1H), 7.65 (m, 3H), 1.50 (s, 9H); MS: m/z 390.3 (M+H)+.
F. 3-(5-Amino-2-pyridin-3-yl-pyrimidin-4-yloxy)-benzonitrile (15h)
To a solution of Compound 14g (0.78 g; 2.0 mmol) in CH2Cl2 (20 mL) was added TFA (4 mL). The mixture was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure to afford Compound 14h. The crude product was used in the next reaction without further purification. MS: m/z 290.3 (M+H)+.
G. 2-(S)-{[4-(3-Cyano-phenoxy)-2-pyridin-3-yl-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (14i)
To a suspension of Compound 14h (0.52 g; 1.8 mmol) and Compound 1d (0.505 mL; 2.69 mmol) in 1,2-dichloroethane (10 mL) was added acetic acid (0.103 mL; 1.8 mmol). The reaction was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (0.46 g; 2.17 mmol) was added to the mixture. The mixture was stirred at room temperature for 20 h. Additional sodium triacetoxyborohydride (0.92 g; 4.34 mmol) was added to the mixture. The reaction was stirred at room temperature for 6 h, diluted with EtOAc (50 mL), and washed with H2O (2×20 mL). The organic layer was dried over MgSO4 and concentrated. The crude product was purified by reverse phase HPLC to give Compound 14i. 1H NMR (300 MHz, MeOH-d4): δ 9.20 (s, 1H), 8.95 (d, 1H), 8.20 (d, 1H), 8.45 (s, 1H), 8.00 (dd, 1H), 7.65-7.8 (m, 4H), 4.20 (m, 1H), 3.3-3.6 (m, 4H), 1.9-2.1 (m, 4H), 1.5 (s, 9H); MS: m/z 473.4 (M+H)+.
H. Cpd 135
3-{2-Pyridin-3-yl-5-[(pyrrolidin-2-(S)-ylmethyl)-amino]-pyrimidin-4-yloxy}-benzonitrile
To a solution of Compound 14i (0.05 g; 0.106 mmol) in CH2Cl2 (2 mL) was added TFA (0.4 mL). The mixture was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure. The crude product was purified by reverse phase HPLC to give Compound 135 as a TFA salt. 1H NMR (300 MHz, MeOH-d4): δ 9.20 (s, 1H), 8.95 (d, 1H), 8.75 (d, 1H), 8.35 (s, 1H), 8.00 (dd, 1H), 7.60-7.80 (m, 4H), 4.00 (m, 1H), 3.70 (m, 2H), 3.40 (m, 2H), 2.4 (m, 1H), 2.15 (m, 2H), 1.9 (m, 1H); MS: m/z 373.2 (M+H)+.
Following the procedure described above for Example 14 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:















Cpd
MS (M + H)+
Cpd
MS (M + H)+








136
373.3
137
391.3









Example 15




A. N,N-Diethyl-3-methoxy-benzamide (15a)
To a solution of m-anisic acid (0.5 g; 3.29 mmol) and HATU (1.4 g; 3.68 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine (2 mL; 11.48 mmol). The reaction was stirred at room temperature for 30 min. Diethylamine (0.377 mL; 3.62 mmol) was added to the reaction. The mixture was stirred at room temperature for 1.5 d, diluted with H2O (5 mL), and extracted with EtOAc (2×5 mL). The organic layer was dried over MgSO4 and concentrated to afford Compound 15a. The crude product was used in the next reaction without further purification. MS: m/z 208.2 (M+H)+.
B. N,N-Diethyl-3-hydroxy-benzamide (15b)
To a solution of Compound 15a (0.68 g; 3.28 mmol) in CH2Cl2 (50 mL) was added BBr3 (1.0M in CH2Cl2) (16 mL; 16 mmol) dropwise at 0° C. The reaction was stirred at room temperature for 1 h. The mixture was quenched with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated to afford Compound 15b. The crude product was used in the next reaction without further purification. MS m/z 194.2 (M+H)+.
Following the procedure described above for Example 15 and substituting pyrrolidine for diethylamine in Procedure A, the Compound 15c was prepared:




Following the procedure described above for Example 14, substituting Compound 15c for Compound 14c RIGHT?; and substituting the appropriate reagents and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:















Cpd
MS (M + H)+
Cpd
MS (M + H)+








157
447.3
158
445.4









Example 16







A. 4-(2-Chloro-5-nitro-pyrimidin-4-yloxy)-benzoic acid ethyl ester (16a)
To a suspension of Compound 1a (2.0 g; 10.31 mmol) and 0.5N NaHCO3 (20 mL; 10 mmol) in acetone (60 mL) was added a solution of 4-hydroxy-benzoic acid ethyl ester (1.71 g; 10.29 mmol) in acetone (20 mL) dropwise at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The resultant residue was extracted with EtOAc (2×20 mL). The organic layer was washed with brine and dried over MgSO4 and concentrated. The crude product was purified by normal phase chromatography (SiO2) to give Compound 16a. 1H NMR (300 MHz, CDCl3): δ 9.20 (s, 1H), 8.20 (d, 2H), 7.25 (d, 2H), 4.45 (q, 2H), 1.4 (t, 3H); MS: m/z 324.1 (M+H)+.
B. 4-(5-Amino-2-chloro-pyrimidin-4-yloxy)-benzoic acid ethyl ester (16b)
To a solution of Compound 16a (2.12 g; 6.55 mmol) in AcOH (15 mL) and CH3OH (20 mL) was added Zn (2.57 g; 39.31 mmol) in portions at room temperature. The reaction mixture was stirred at room temperature for 6 h. The solid was collected by filtration and washed with CH3OH. The filtrate was concentrated. The residue was quenched with aqueous NaOH (<1 N) and adjusted to pH  ̃7, and extracted with EtOAc (2×20 mL). The organic layer was dried over MgSO4 and concentrated. The crude product was purified by normal phase chromatography (SiO2) to give Compound 16b. 1H NMR (300 MHz, CDCl3): δ 8.15 (d, 2H), 7.95 (s, 1H), 7.25 (d, 2H), 4.45 (q, 2H), 1.4 (t, 3H); MS: m/z 294.1 (M+H)+.
C. 2-(S)-{[2-Chloro-4-(4-ethoxycarbonyl-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (16c) and 4-(2-Chloro-5-ethylamino-pyrimidin-4-yloxy)-benzoic acid ethyl ester (16d)
To a suspension of Compound 16b (0.82 g; 2.79 mmol) and Boc-L-prolinal (Compound 1d) (0.67 g; 3.36 mmol) in 1,2-dichloroethane (10 mL) was added acetic acid (0.16 mL, 2.79 mmol). The reaction was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (0.89 g; 4.20 mmol) was added to the mixture. The mixture was stirred at room temperature for 20 h. Additional sodium triacetoxyborohydride (0.89 g; 4.20 mmol) was added to the mixture. The reaction was stirred at room temperature for 2 d, diluted with EtOAc (50 mL), and washed with H2O (2×20 mL). The organic layer was dried over MgSO4 and concentrated. The crude product was purified by normal phase chromatography (SiO2) to give Compound 16c and Compound 16d. Compound 16c—MS: m/z 477.3 (M+H)+. Compound 16d—MS: m/z 322.2 (M+H)+.
D. 2-(S)-{[4-(4-Ethoxycarbonyl-phenoxy)-2-pyridin-3-yl-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (16e)
To a suspension of Compound 16c (0.76 g; 1.59 mmol), pyridin-3-yl boronic acid (0.235 g; 1.91 mmol) and Cs2CO3 (1.30 g; 3.99 mmol) in a dioxane (10 mL)/EtOH (2 mL) mixture, was added 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride complex with dichloromethane (0.116 g; 0.159 mmol). The mixture was stirred at 80° C. for 4 h, and then cooled to room temperature. The solid was collected by filtration and washed with CH3OH. The filtrate was concentrated. The crude product was purified by reverse phase HPLC to give Compound 16e. MS: m/z 520.3 (M+H)+.
E. 2-(S)-{[4-(4-Carboxy-phenoxy)-2-pyridin-3-yl-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (16f)
To a suspension of Compound 16e (0.4 g; 0.77 mmol) in EtOH (10 mL) was added 0.5N NaOH (2.3 mL; 1.15 mmol). The reaction was stirred at room temperature for 3 h. Additional 0.5N NaOH (6 mL; 3 mmol) was added to the mixture. The reaction was stirred at room temperature for 3 h. The solution was adjusted to pH 2 with 1N HCl. The white solid was collected by filtration to afford Compound 16f. MS: m/z 492.3 (M+H)+.
F. 2-(S)-({4-[4-(Piperidine-1-carbonyl)-phenoxy]-2-pyridin-3-yl-pyrimidin-5-ylamino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (16 g)
To a solution of Compound 16f (0.08 g; 0.16 mmol) and HATU (0.065 g; 0.17 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (0.115 mL; 0.66 mmol). The reaction was stirred at room temperature for 30 min. Piperidine (0.017 mL; 0.17 mmol) was added to the reaction. The mixture was stirred at room temperature for 1 h, poured into H2O (3 mL), and extracted with EtOAc (2×5 mL). The organic layer was dried over MgSO4 and concentrated to afford Compound 16g. The crude product was used in the next reaction without further purification. MS: m/z 559.3 (M+H)+.
G. Cpd 160
Piperidin-1-yl-(4-{2-pyridin-3-yl-5-[(pyrrolidin-2-(S)-ylmethyl)-amino]-pyrimidin-4-yloxy}-phenyl)-methanone
To a solution of Compound 16g (0.089 g; 0.16 mmol) in CH2Cl2 (4 mL) was added TFA (0.8 mL). The mixture was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure. The crude product was purified by reverse phase HPLC to give Compound 160 as a TFA salt. 1H NMR (300 MHz, MeOH-d4): δ 9.21 (s, 1H), 8.95 (d, 1H), 8.75 (d, 1H), 8.35 (s, 1H), 7.95 (dd, 1H), 7.55 (d, 2H), 7.40 (d, 2H), 4.05 (m, 1H), 3.6-3.85 (m, 4H), 3.3-3.55 (m, 4H), 2.35 (m, 1H), 2.20 (m, 2H), 1.9 (m, 1H), 1.55-1.85 (m, 6H); MS: m/z 459.3 (M++H)+.
Following the procedure described above for Example 16 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:















Cpd
MS (M + H)+
Cpd
MS (M + H)+








161
461.2
162
474.3



166
445.4
167
459.3



168
461.4
169
474.3



170
465.3
171
463.4



172
477.3
173
479.3



174
492.3
175
447.3





176
463.4









CPD 159
Deprotection of Compound 16f was performed using TFA/CH2Cl2 as described in Procedure G of Example 16 to afford Compound 159 as a TFA salt. MS: m/z 392.3 (M+H)+.
CPD 163
The title compound was prepared in an analogous manner to Cpd 159, substituting 3-hydroxy-benzoic acid ethyl ester for 4-hydroxy-benzoic acid ethyl ester in Procedure A of Example 16. MS: m/z 392.3 (M+H)+.
CPD 164
The title compound was prepared in an analogous manner to Cpd 159, substituting 3-hydroxy-benzoic acid ethyl ester for 4-hydroxy-benzoic acid ethyl ester in Procedure A and substituting 5-fluoropyridin-3-yl boronic acid for pyridin-3-yl boronic acid in Procedure D of Example 16. MS: m/z 410.2 (M+H)+.
CPD 165
The title compound was prepared in an analogous manner to Cpd 159, substituting 5-fluoropyridin-3-yl boronic acid for pyridin-3-yl boronic acid in Procedure D of Example 16. MS: m/z 410.2 (M+H)+.
Example 17







A. 4-(4-tert-Butoxycarbonylaminophenoxy)-2-pyridin-3-ylpyrimidine-5-carboxylic acid ethyl ester (17a)
Using an adaptation of the method described in Procedure C of Example 14, substituting (4-hydroxyphenyl)carbamic acid t-butyl ester for 3-cyanophenol, the title Compound 17a was obtained. MS: m/z 437.3 (M+H)+.
B. 4-(4-tert-Butoxycarbonylaminophenoxy)-2-pyridin-3-ylpyrimidine-5-carboxylic acid (17b)
Using an adaptation of the method described in Procedure D of Example 14, substituting Compound 17a for Compound 14e, the title Compound 17b was obtained. MS: m/z 409.2 (M+H)+.
C. 4-(4-Aminophenoxy)-2-pyridin-3-ylpyrimidine-5-carboxylic acid (17c)
To a solution of Compound 17b (1.5 g; 3.6 mmol) in CH2Cl2 (30 mL) was adde TFA (10 mL). The solution was stirred at room temperature for 1.5 h, and the solvent was evaporated in vacuo. The residue was triturated with Et2O, collected the solid and dried to afford the title Compound 17c (2.25 g; 96% yield based on tri-TFA salt). MS: m/z 309.2 (M+H)+.
D. 4-[4-(Cyclopropanecarbonylamino)phenoxy]-2-pyridin-3-ylpyrimidine-5-carboxylic acid (17d)
To a solution of Compound 17c (0.5 g; 1.6 mmol) in CH2Cl2 (6 mL) was added Et3N (0.72 mL; 6.4 mmol) and cyclopropylcarbonyl chloride (0.19 mL; 2.1 mmol). The solution was stirred at room temperature for 1 h, then poured the reaction mixture into water. Filtered to collect the solid and dried to afford Compound 17d (410 mg; 68% yield). MS: m/z 376.1 (M+H)+.
E. {4-[4-(Cyclopropanecarbonylamino)phenoxy]-2-pyridin-3-ylpyrimidin-5-yl}-carbamic acid tert-butyl ester (17e)
Using an adaptation of the method described in Procedure E of Example 14, substituting Compound 17d for Compound 14f, the title Compound 17e (16% yield) was obtained. MS: m/z 448.2 (M+H)+.
F. Cyclopropanecarboxylic acid [4-(5-amino-2-pyridin-3-yl-pyrimidin-4-yloxy)-phenyl]amide (17f)
Using an adaptation of the method described in Procedure F of Example 14, substituting Compound 17e for Compound 14g, the title Compound 17f (78% yield) was obtained. The crude product was used in the next reaction without further purification. MS: m/z 347.3 (M+H)+.
G. 2-(S)-({4-[4-(Cyclopropanecarbonyl-amino)-phenoxy]-2-pyridin-3-yl-pyrimidin-5-ylamino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (17g)
Using an adaptation of the method described in Procedure G of Example 14, substituting Compound 17f for Compound 14h, the title Compound 17g was obtained. MS: m/z 531.3 (M+H)+.
H. Cpd 138
Cyclopropanecarboxylic acid (4-{2-pyridin-3-yl-5-[(pyrrolidin-2-(S)-ylmethyl)-amino]-pyrimidin-4-yloxy}-phenyl)-amide
Using an adaptation of the method described in Procedure H of Example 15, substituting Compound 17g for Compound 14i, the title Compound 138 (15% yield based on di-TFA salt) was obtained. 1H-NMR (300 MHz, DMSO-d6): δ 8.6 (d, 2H), 8.5 (m, 1H), 8.3 (m, 2H), 7.7 (m, 2H), 7.5 (m, 1H), 7.25 (m, 2H), 6.3 (m, 1H), 3.9 (m, 1H), 3.5 (m, 2H), 3.2 (m, 2H) 3.1-2.8 (m, 2H), 2.15 (m, 1H), 1.9 (m, 2H), 1.8-1.6 (m, 3H), 0.9 (d, 2H); MS: m/z 431.3 (M+H)+.
Example 18




A. 2-(S)-{[2-Chloro-4-(4-hydroxymethyl-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (18a)
The title compound was prepared in a same manner to Compound 1e in Example 1. Using an adaptation of the method described in Procedures A-C, substituting 4-hydroxymethyl-phenol for 4-methoxyphenol in Procedure A, the title Compound 18a was obtained. MS: m/z 435.2 (M+H)+.
B. 2-(S)-{[4-(4-Hydroxymethyl-phenoxy)-2-pyridin-3-yl-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (18b)
Using an adaptation of the method described in Procedure D of Example 1, substituting Compound 18a for Compound 1e and substituting pyridin-3-yl boronic acid for Compound 1f, the title Compound 18b (73% yield) was obtained. MS: m/z 478.2 (M+H)+.
C. 2-(S)-{[4-(4-Fluoromethyl-phenoxy)-2-pyridin-3-yl-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (18c)
To a solution of (diethylamino)sulfur trifluoride (0.036 mL; 0.28 mmol) in CH2Cl2 (2 mL), cooled to −78° C., was added a solution of Compound 18b (100 mg; 0.21 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred at −78° C. for 20 min. The resultant mixture was partitioned between EtOAc and H2O. The organic phase was washed with water and dried over Na2SO4. The mixture was filtered and the solvent removed under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 18c (50 mg; 50% yield). MS: m/z 480.2 (M+H)+.
D. Cpd 217
[4-(4-Fluoromethyl-phenoxy)-2-pyridin-3-yl-pyrimidin-5-yl]-pyrrolidin-2-(S)-ylmethyl-amine
Using an adaptation of the method described in Procedure E of Example 1, substituting Compound 18c for Compound 1g, the title Compound 217 was obtained as a HCl salt. 1H-NMR (400 MHz, MeOH-d4): δ 9.21 (br. s, 1H), 8.73-8.74 (m, 1H), 8.63 (br. s, 1H), 8.27-8.29 (m, 1H), 7.75 (br. s, 1H), 7.45-7.58 (m, 2H), 7.30-7.39 (m, 2H), 5.36-5.51 (m, 2H), 4.02-4.05 (m, 1H), 3.67-3.73 (m, 2H), 3.41-3.48 (m, 2H), 2.32-2.38 (m, 1H), 2.09-2.21 (m, 2H), 1.86-1.95 (m, 1H); MS: m/z 380.2 (M+H)+.
Following the procedure described above for Example 18 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compound of the present invention was prepared:













Cpd
MS (M + H)+








348
405.2









Example 19




A. 2-(S)-{[2-Chloro-4-(4-fluoromethyl-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (19a)
Using an adaptation of the method described in Procedure C of Example 18, substituting Compound 18a for Compound 18b, the title Compound 19a (23% yield) was obtained. MS: m/z 437.2 (M+H)+.
B. 2(S)-{[2-Pyridin-3-yl-4-(4-pyridin-3-ylmethyl-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (19b)
Using an adaptation of the method described in Procedure D of Example 1, substituting Compound 19a for Compound 1e and substituting pyridin-3-yl boronic acid for Compound 1f, the title Compound 19b (22% yield) was obtained. 1H-NMR (400 MHz, CDCl3): δ 9.26 (s, 1H), 8.55 (d, 1H), 8.51 (dd, 2H), 8.32 (d, 1H), 8.01-8.06 (m, 1H), 7.53 (d, 1H), 7.18-7.27 (m, 6H), 5.78 (br. s, 0.7H), 4.85 (br. s, 0.3; H), 4.21-4.32 (m, 1H), 4.04 (s, 2H), 3.21-3.54 (m, 4H), 1.84-2.14 (m, 4H); MS: m/z 539.3 (M+H)+.
C. Cpd 209
[2-Pyridin-3-yl-4-(4-pyridin-3-ylmethyl-phenoxy)-pyrimidin-5-yl]-pyrrolidin-2-(S)-ylmethyl-amine
Using an adaptation of the method described in Procedure E of Example 1, substituting Compound 19b for Compound 1g, the title Compound 209 was obtained as a HCl salt. 1H-NMR (400 MHz, MeOH-d4): δ 9.12 (br. s, 1H), 8.44-8.57 (m, 4H), 8.23 (s, 1H), 7.94 (d, 1H), 7.47-7.57 (m, 2H), 7.41 (d, 2H), 7.29 (d, 2H), 4.17 (s, 2H), 4.01-4.04 (m, 1H), 3.67-3.70 (m, 2H), 3.45-3.54 (m, 2H), 2.31-2.39 (m, 1H), 2.08-2.21 (m, 2H), 1.85-1.95 (m, 1H); MS: m/z 439.2 (M+H)+.
Example 20




A. 2,4,5-Tribromo-pyrimidine (20b)
To a pressure vessel, a suspension of 2,4-dichloro-5-bromo-pyrimidine (Compound 20a) (3.0 g; 13.2 mmol) in HBr solution (33 wt % in AcOH) (35 mL) was heated at 50° C. for 4 h before cooling in an ice bath. The reaction mixture was poured into ice/water (2-fold volume) and was extracted with EtOAc. The organic phase was washed sequentially with H2O and brine, and dried over Na2SO4. The mixture was filtered and the solvent evaporated under reduced pressure to give the crude material. The crude material was recrystallized from EtOAc-hexanes to afford Compound 20b (3.75 g; 90% yield) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ 8.58 (s, 1H); MS: m/z 314.8 (M+H)+.
B. 2,5-Dibromo-4-(4-methoxy-phenoxy)-pyrimidine (26c)
A mixture of Compound 20b (0.39 g; 1.23 mmol), K2CO3 (0.25 g, 1.85 mmol) and 4-methoxy-phenol (0.15 g; 1.23 mmol) in dioxane (4 mL) was heated at 65° C. for 20 h. The reaction mixture was filtered and the filtrate was diluted with EtOAc and H2O. The organic phase was washed sequentially with H2O and brine, and dried over Na2SO4. The mixture was filtered and the solvent evaporated under reduced pressure to give the crude material. Recrystallized the crude material from EtOAc-hexane to afford Compound 20c (0.42 g; 95% yield) as white solid. 1H-NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 7.10 (d, 2H), 6.95 (d, 2H), 3.84 (s, 3H); MS: m/z 359.0 (M+H)+.
C. 5-Bromo-4-(4-methoxy-phenoxy)-2-pyridin-3-yl-pyrimidine (20d)
Under argon pressure, a mixture of Compound 20c (2.27 g; 6.31 mmol), pyridine-3-boronic acid (853 mg; 6.94 mmol), Na2CO3 (1.34 g; 12.6 mmol) and [1,1′-Bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) (258 mg, 0.32 mmol) in dioxane (32 mL) was stirred at room temperature for 5 min, and then D.I. water (8 mL) was added. The whole mixture was heated at 55° C. under argon pressure for 20 h. Diluted the resulted mixture with EtOAc, washed with saturated NH4Cl(aq) and H2O. The organic phase was washed sequentially with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 20d (1.44 g; 64% yield) as off-white solid. 1H-NMR (400 MHz, CDCl3): δ 9.33 (dd, 1H), 8.77 (s, 1H), 8.64 (dd, 1H), 8.41 (dt, 1H), 7.32 (td, 1H), 7.16 (dd, 2H), 6.97 (dd, 2H), 3.87 (s, 3H); MS: m/z 358.0 (M+H)+.
D. 4-[4-(4-Methoxy-phenoxy)-2-pyridin-3-yl-pyrimidin-5-yl]-piperazine-1-carboxylic acid tert-butyl ester (20e)
To a dry Schlenk tube was added a mixture of Compound 20d (100 mg; 0.28 mmol), piperazine-1-carboxylic acid tert-butyl ester (52 mg; 0.56 mmol), Cs2CO3 (227 mg; 0.70 mmol), (Diphenylphosphino)ferrocene (54 mg; 0.10 mmol), and Tris(dibenzylideneacetone)dipalladium(0) (25.6 mg; 0.028 mmol). Sealed the tube with a teflon-lined septum, evacuated, and refilled with argon. Added dioxane (0.3 mL; reaction conc.>0.75M) to the mixture via syringe. The mixture was heated at 95° C. for 3 h. Diluted the resulted mixture with EtOAc, washed with saturated NH4Cl(aq) and H2O. The organic phase was washed sequentially with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 20e (104 mg; 80% yield). 1H-NMR (400 MHz, CDCl3): δ 9.28 (d, 1H), 8.58 (dd, 1H), 8.35 (dt, 1H), 8.22 (s, 1H), 7.29 (td, 1H), 7.14 (dd, 2H), 6.98 (dd, 2H), 3.87 (s, 3H), 3.66 (t, 4H), 3.25 (t, 4H), 1.56 (s, 9H); MS: m/z 464.2 (M+H)+.
E. Cpd 327
4-(4-Methoxy-phenoxy)-5-piperazin-1-yl-2-pyridin-3-yl-pyrimidine
Using an adaptation of the method described in Procedure E of Example 1, substituting Compound 20e for Compound 1g, the title Compound 327 was obtained as a HCl salt. Free base- 1H-NMR (400 MHz, CDCl3): δ 9.28 (d, 1H), 8.57 (dd, 1H), 8.34 (dt, 1H), 8.23 (s, 1H), 7.28 (td, 1H), 7.15 (dd, 2H), 6.97 (dd, 2H), 3.87 (s, 3H), 3.28 (t, 4H), 3.11 (t, 4H); MS: m/z 364.2 (M+H)+.
Following the procedure described above for Example 20 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:















Cpd
MS (M + H)+
Cpd
MS (M + H)+








324
363.2
325
389.2



326
389.2
199
403.2



328
389.2
329
403.2



207
403.2
208
403.2



329
403.2
331
389.2



215
389.2
332
403.2



333
403.2
334
403.2



336
378.0
224
364.0



225
392.0
226
350.0



305
392.0
236
378.0



338
401.0
237
364.0



339
364.0
341
410.0



340
350.0
342
394.0



245
408.0
344
403.0



343
403.0
246
408.0



345
403.0
252
424.2



346
408.0
347
424.0



254
424.0
255
410.0



348
410.0
256
394.0



349
394.0
257
378.0



258
392.2
259
392.0



350
438.0
351
378.0



352
378.0
261
378.0



354
378.0
355
392.2



356
378.0
358
392.2



296
352.0
267
392.2









Following the procedure described above for Example 20 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared as mixtures (contained 4 isomers).















Cpd
MS (M + H)+
Cpd
MS (M + H)+








306
392.0
312
438.0



309
422.2
315
406.2









Using purification methods known to those skilled in the art, the above mixtures of the present invention were further separated into their corresponding diastereoisomers and/or single stereoisomer.












Cpd
stationary phase/order of elution off the column
MS (M + H)+







307
C-18 (CH3CN—H2O)/first peak off column
392.0


308
C-18 (CH3CN—H2O)/first peak off column
392.0


311
CHIRALPAK ® AD TM (50% methanol with 0.5%
422.0



isopropylamine/50% Ethanol with 0.5%




isopropylamine; flow rate: 1.0 mL/min)/first peak off




column



312
CHIRALPAK ® AD TM (50% methanol with 0.5%
422.0



isopropylamine/50% Ethanol with 0.5%




isopropylamine; flow rate: 1.0 mL/min)/second peak




off column



313
CHIRALPAK ® AD TM (50% methanol with 0.5%
422.0



isopropylamine/50% Ethanol with 0.5%




isopropylamine; flow rate: 1.0 mL/min)/third peak off




column



314
CHIRALPAK ® AD TM (50% methanol with 0.5%
422.0



isopropylamine/50% Ethanol with 0.5%




isopropylamine; flow rate: 1.0 mL/min)/fourth peak off




column



316
CHIRALCEL ® OJ TM (85% heptane/7.5% ethanol/
438.2



7.5% ammonia sat. in methanol 7N, flow rate: 2.0 mL/min)/




third peak off column



317
CHIRALCEL ® OJ TM (85% heptane/7.5% ethanol/
438.2



7.5% ammonia sat. in methanol 7N, flow rate: 2.0 mL/min)/




fourth peak off column



318
CHIRALCEL ® OJ TM (85% heptane/7.5% ethanol/
438.2



7.5% ammonia sat. in methanol 7N, flow rate: 2.0 mL/min)/




first peak off column



319
CHIRALCEL ® OJ TM (85% heptane/7.5% ethanol/
438.2



7.5% ammonia sat. in methanol 7N, flow rate: 2.0 mL/min)/




second peak off column



321
CHIRALPAK ® AD TM (20% IPA in hexane at 15 mL/min)/
392.2



third peak off column



322
CHIRALPAK ® AD TM (20% IPA in hexane at 15 mL/min)/
392.2



fourth peak off column



323
CHIRALPAK ® AD TM (20% IPA in hexane at 15 mL/min)/
392.2



first peak off column





2Using Boc-protected mixtures, chiral separations were performed to obtain the Boc-protected single isomers, which were then deprotected to give the example compounds.






Example 21
An Alternative Route for Preparing Compounds Described in Example 20




A. 2,5-Dichloro-4-(4-methoxy-phenoxy)-pyrimidine (21b)
To a solution of Compound 21a (5 g; 27.26 mmol) in acetone (480 mL), cooled to 0° C., was added a solution of 4-methoxy-phenol (3.38 g; 27.26 mmol) in a mixture of 1 N NaHCO3 (aq) (27.3 mL) and H2O (120 mL), dropwise, by an additional funnel. Upon completion of the addition, the reaction mixture was allowed to warm to ambient temperature, and then stirred at room temperature for 3 h. The resultant mixture was concentrated in vacuo, and the resultant residue was diluted with EtOAc, then washed sequentially with 1 N NaOH (aq) and H2O. The organic phase was washed sequentially with H2O and brine, and dried over Na2SO4. The mixture was filtered and the filtrate concentrated under reduced pressure to give a crude material. The crude material was recrystallized from EtOAc-hexanes to afford Compound 21b (7.0 g; 94% yield).
1H-NMR (400 MHz, CDCl3): δ 8.46 (s, 1H), 7.09-7.27 (m, 2H), 6.94-6.98 (m, 2H), 3.85 (s, 3H); MS: m/z 271.0 (M+H)+.
B. 5-Chloro-4-(4-methoxy-phenoxy)-2-pyridin-3-yl-pyrimidine (21c)
Under argon pressure, a mixture of Compound 21b (2.43 g; 8.98 mmol), pyridin-3-yl boronic acid (1.43 g; 11.67 mmol), Na2CO3 (1.90 g; 17.96 mmol) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) (370 mg, 0.45 mmol) in dioxane (35 mL) was stirred at room temperature for 5 min, and then deionized water (7 mL) was added. The mixture was heated at 75° C. under an argon atmosphere for 20 h. The resultant mixture was diluted with EtOAc, washed with saturated NH4Cl (aq) and H2O. The organic phase was washed sequentially with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 23c (2.10 g; 75% yield). 1H-NMR (400 MHz, CDCl3): δ 9.34 (dd, 1H), 8.6 (s, 1H), 8.65 (dd, 1H), 8.42 (dt, 1H), 7.31-7.34 (m, 1H), 7.15-7.19 (m, 2H), 6.97-7.01 (m, 2H), 3.88 (s, 3H); MS: m/z 314.0 (M+H)+.
C. 4-[4-(4-Methoxy-phenoxy)-2-pyridin-3-yl-pyrimidin-5-yl]-2-(R)-methyl-piperazine-1-carboxylic acid tert-butyl ester (21d)
Using an adaptation of the method described in Procedure D of Example 22, substituting 2-(R)-methyl-piperazine-1-carboxylic acid tert-butyl ester for piperazine-1-carboxylic acid tert-butyl ester, the title Compound 23d was obtained. 1H-NMR (400 MHz, CDCl3): δ 9.30 (br. s, 1H), 8.58 (br. s, 1H), 8.36 (d, 1H), 8.20 (s, 1H), 7.25-7.32 (m, 1H), 7.13-7.18 (m, 2H), 6.96-7.00 (m, 2H), 4.40 (br. s, 1H), 4.02-4.05 (m, 1H), 3.88 (s, 3H), 3.59-3.62 (m, 1H), 3.30-3.51 (m, 1H), 2.89-2.96 (m, 2H), 1.50 (s, 9H), 1.40 (d, 3H); MS: m/z 478.0 (M+H)+.
D. Cpd 357
4-(4-Methoxy-phenoxy)-5-[3-(R)-methyl-piperazin-1-yl]-2-pyridin-3-yl-pyrimidine
Using an adaptation of the method described in Procedure E of Example 1, substituting Compound 21d for Compound 1g, the title Compound 357 was obtained as a HCl salt. Free base- 1H-NMR (400 MHz, CDCl3): δ 9.29 (d, 1H), 8.58 (dd, 1H), 8.36 (dt, 1H), 8.23 (s, 1H), 7.25-7.30 (m, 1H), 7.14-7.18 (m, 2H), 6.96-7.00 (m, 2H), 3.88 (s, 3H), 3.60-3.67 (m, 2H), 3.12-3.18 (m, 3H), 2.85-2.92 (m, 1H), 2.53-2.58 (m, 1H), 1.18 (d, 3H); MS: m/z 378.0 (M+H)+.
Following the procedure described above for Example 21 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:















Cpd
MS (M + H)+
Cpd
MS (M + H)+








320
374.2
360
422.2



361
422.0









CPD 320
The title compound was prepared in an analogous manner to Compound 21e of Example 21, substituting 4-cyclopropyl-phenol4 for 4-methoxy-phenol in Procedure A, and substituting piperazine-1-carboxylic acid tert-butyl ester for 2-(R)-methyl-piperazine-1-carboxylic acid tert-butyl ester in Procedure C. 1H-NMR (400 MHz, MeOH-d4): δ 9.11 (d, 1H), 8.49 (dd, 1H), 8.40 (dt, 1H), 8.29 (s, 1H), 7.42 (dd, 1H), 7.15-7.20 (m, 2H), 7.10-7.12 (m, 2H), 3.29-3.32 (m, 4H), 3.04-3.06 (m, 4H), 1.94-2.01 (m, 1H), 0.98-1.03 (m, 2H), 0.70-0.74 (m, 2H); MS: m/z 374.2 (M+H)+. 4 4-Cyclopropyl-phenol was prepared by the following synthetic scheme and procedure:




A. 4-Cyclopropyl-phenol
To a solution of diethylzinc (59 mL, 65.9 mmol) in toluene (80 mL) was added acetic acid 4-vinyl-phenyl ester (5 mL, 32.7 mmol) and diiodomethane (6.86 mL, 85 mmol). The resultant mixture was stirred at room temperature for 5 h, and then heated to reflux for 12 h. The reaction mixture was quenched with 2N HCl solution, the organic layer separated, washed with brine, dried over Na2SO4, and concentrated to afford a brown oil (4.5 g). The brown oil (4.5 g) was dissolved in MeOH/THF (20/20 mL), then treated with Na2CO3 (5.41 g, 51.1 mmol) at room temperature for 2 h. The reaction mixture was diluted with EtOAc, washed sequentially with saturated NH4Cl (aq) and H2O, and extracted with EtOAc (3×). The organic extracts were combined, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (3.2 g; 94% yield), which was used directly without further purification.
Example 22




A. (3-Benzyloxycarbonylamino-cyclohexyl)-carbamic acid tert-butyl ester (22b, 22c)
To a mixture of (3-amino-cyclohexyl)-carbamic acid tert-butyl ester (22a) (1.5 g, 7 mmol) and benzyloxycarbonyl chloride (1.1 mL; 7.7 mmol) in CH2Cl2 (30 mL) at −20° C. was added diisopropylmethylamine (2.4 mL; 14 mmol) dropwise under argon atmosphere. The reaction mixture was stirred for 15 min at the same temperature, and it was allowed to warm to room temperature and stirred for an additional 2 h. The reaction mixture was diluted with CH2Cl2 and washed with brine. The organic phase was dried and concentrated to give a crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 22b (second fraction; 1,3-cis racemic mixture) (1.8 g; 74% yield) and Compound 22c (first fraction; 1,3-trans racemic mixture). Compound 22b: 1H-NMR (400 MHz, CDCl3): δ 7.30-7.40 (m, 5H), 5.09 (s, 2H), 4.59 (br. s, 1H), 4.37 (br. s, 1H), 3.54 (br. s, 2H), 2.29-2.31 (m, 1H), 1.99 (br. s, 2H), 1.76-1.81 (m, 1H), 1.44 (s, 9H), 1.34-1.44 (m, 1H), 0.90-1.05 (m, 3H); MS: m/z 249.0 (M+H-Boc)+. Compound 22c: 1H-NMR (400 MHz, CDCl3): δ 7.30-7.40 (m, 5H), 5.09 (s, 2H), 4.78 (br. s, 1H), 4.56 (br. s, 1H), 3.77-3.85 (m, 2H), 1.68-1.79 (m, 4H), 1.53-1.62 (m, 2H), 1.38-1.49 (m, 2H), 1.45 (s, 9H); MS: m/z 249.0 (M+H-Boc)+.
B. [3-(S)-Benzyloxycarbonylamino-cyclohexyl]-1-(R)-carbamic acid tert-butyl ester (27d) and [3-(R)-Benzyloxycarbonylamino-cyclohexyl]-1-(S)-carbamic acid tert-butyl ester (22e)
Compound 22b (850 mg) was separated into two enantiomeric pure compounds, Compound 22d (340 mg; the first fraction) and Compound 22e (365 mg; the second fraction), by using CHIRALPAK® ADTM column (mobile phase: 9% isopropanol in hexanes; flow rate: 60 mL/min). Compound 22d: 1H-NMR (400 MHz, CDCl3): δ 7.30-7.39 (m, 5H), 5.09 (s, 2H), 4.60 (br. s, 1H), 4.38 (br. s, 1H), 3.54 (br. s, 2H), 2.28-2.31 (m, 1H), 1.99 (br. s, 2H), 1.75-1.81 (m, 1H), 1.44 (s, 9H), 1.34-1.44 (m, 1H), 0.89-1.05 (m, 3H); MS: m/z 249.0 (M+H-Boc)+. Compound 22e: 1H-NMR (400 MHz, CDCl3): δ 7.30-7.39 (m, 5H), 5.09 (s, 2H), 4.60 (br. s, 1H), 4.39 (br. s, 1H), 3.54 (br. s, 2H), 2.28-2.32 (m, 1H), 1.99 (br. s, 2H), 1.75-1.81 (m, 1H), 1.44 (s, 9H), 1.34-1.44 (m, 1H), 0.91-1.05 (m, 3H); MS: m/z 249.0 (M+H-Boc)+; [α]D=−9.0 (c=1.2 in CHCl3). The absolute stereochemistry of Compound 22e was determined by comparing the optical rotation of the synthetic (3R-Amino-cyclohexyl)-1S-carbamic acid tert-butyl ester3 with the material from chiral HPLC separation. 3 An alternative approach of synthesizing enantiomeric pure [3-(R)-Amino-cyclohexyl]-1-(S)-carbamic acid tert-butyl ester was described in the following scheme and procedure:




B1. [3-(R)-Amino-cyclohexyl]-1-(S)-carbamic acid tert-butyl ester (22k)
To a solution of Compound 22j (prepared according to the literature procedure described in Bioorganic & Medicinal Chemistry 2005, 13, 2509) (294 mg, 1.21 mmol) and Et3N (0.185 mL, 1.33 mmol) in toluene (7 mL) was added (PhO)2P(O)N3 (0.29 mL, 1.34 mmol). The reaction mixture was heated to reflux for 1 h before BnOH (0.5 mL, 4.8 mmol) was added. The reaction was heated to reflux for another 7 h. The mixture was concentrated and purified by flash column chromatography (SiO2, 30% EtOAc/heptane) to give Compound 22k (0.1 g; 24% yield). 1H-NMR (400 MHz, CDCl3): δ 7.35 (m, 5H), 5.08 (s, 2H), 4.67 (d, 1H), 4.42 (s, 1H), 3.53 (m, 2H), 2.29 (d, 1H), 1.97 (s, 2H), 1.75 (m, 1H), 1.43 (s, 9H), 1.39 (m, 1H), 0.98 (m, 3H); MS: m/z 371 (M+Na)+; [α]D=−6.3 (c=1.1 in CHCl3).
C. [3-(S)-Amino-cyclohexyl]-1-(R)-carbamic acid tert-butyl ester (22f)
A portion of 10% Pd/C (42 mg), Compound 22d (214 mg; 0.61 mmol) and MeOH (35 mL) was added to a Parr bottle. The reaction mixture was shaken under a 40-psi H2 atmosphere for 2 h. The resultant mixture was passed through a bed of diatomaceous earth and the filtrate was evaporated in vacuo to afford Compound 22f (90 mg) as a white solid. The compound was used in the next reaction without further purification. 1H-NMR (400 MHz, CDCl3): δ 4.55-4.66 (m, 1H), 3.48-3.50 (m, 1H), 2.75-2.81 (m, 1H), 2.08-2.14 (m, 1H), 1.91-1.94 (m, 1H), 1.74-1.82 (m, 2H), 1.45 (s, 9H), 1.26-1.45 (m, 1H), 0.89-1.05 (m, 3H); MS: m/z 215.2 (M+H)+.
D. 5-Chloro-4-(4-methoxy-phenoxy)-2-(5-methoxy-pyridin-3-yl)-pyrimidine (22g)
Compound 22g was prepared in an analogous manner to that of Compound 21c in Example 21, substituting 3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine for pyridin-3-yl boronic acid in Procedure B of Example 23.
E. {3-(S)-[4-(4-Methoxy-phenoxy)-2-pyridin-3-yl-pyrimidin-5-ylamino]-cyclohexyl}-1-(R)-carbamic acid tert-butyl ester (22h)
To a dry Schlenk tube was added a mixture of Compound 22g (116 mg; 0.34 mmol)), Compound 22f (60 mg; 0.28 mmol), Cs2CO3 (182 mg; 0.56 mmol), (diphenylphosphino)ferrocene (54 mg; 0.10 mmol), and tris(dibenzylideneacetone)dipalladium(0) (26 mg; 0.028 mmol). The tube was sealed with a teflon-lined septum, evacuated, and refilled with argon. Dioxane (0.35 mL; reaction conc.>0.75M) was added to the mixture via syringe, and the mixture was heated at 95° C. for 3 h. The resultant mixture was diluted with EtOAc, washed with saturated NH4Cl (aq) and H2O. The organic phase was washed sequentially with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 22h (110 mg; 93% yield). 1H-NMR (400 MHz, CDCl3): δ 8.84 (d, 1H), 8.24 (d, 1H), 8.01 (s, 1H), 7.89-7.90 (m, 1H), 7.14-7.18 (m, 1H), 6.94-6.98 (m, 2H), 4.48-4.50 (m, 1H), 4.23-4.25 (m, 1H), 3.86 (s, 6H), 3.62 (br. s, 1H), 3.43-3.51 (m, 1H), 2.52-2.55 (m, 1H), 2.20-2.23 (m, 1H), 2.04-2.07 (m, 1H), 1.89-1.94 (m, 1H), 1.46 (s, 9H), 1.41-1.46 (m, 1H), 1.08-1.21 (m, 3H); MS: m/z 522.2 (M+H)+.
E. Cpd 312
N-[4-(4-Methoxy-phenoxy)-2-(5-methoxy-pyridin-3-yl)-pyrimidin-5-yl]-cyclohexane-(1R,3S)-1,3-diamine
Using an adaptation of the method described in Procedure E of Example 1, substituting Compound 22h for Compound 1g, the title Compound 312 was obtained as a HCl salt (92 mg). Free base-1H-NMR (400 MHz, CDCl3): δ 8.86 (s, 1H), 8.24 (d, 1H), 7.99 (s, 1H), 7.88-7.89 (m, 1H), 7.16-7.19 (m, 2H), 6.95-6.98 (m, 2H), 4.44-4.46 (m, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.43-3.51 (m, 1H), 2.89-2.95 (m, 1H), 2.34-2.37 (m, 1H), 2.15-2.19 (m, 1H), 1.88-1.95 (m, 2H), 1.41-1.51 (m, 3H), 1.10-1.26 (m, 3H); MS: m/z 422.0 (M+H)+.
Following the procedure described above for Example 22 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:
CPD 311
The title compound was prepared in an analogous manner to Compound 312 of Example 22, substituting Compound 22e for Compound 22d in Procedure C. Free base-1H-NMR (400 MHz, CDCl3): δ 8.86 (d, 1H), 8.24 (d, 1H), 7.99 (s, 1H), 7.88-7.89 (m, 1H), 7.15-7.20 (m, 2H), 6.94-6.98 (m, 2H), 4.44-4.46 (m, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.42-3.51 (m, 1H), 2.89-2.96 (m, 1H), 2.34-2.37 (m, 1H), 2.15-2.18 (m, 1H), 1.88-1.95 (m, 2H), 1.40-1.51 (m, 3H), 1.10-1.25 (m, 3H); MS: m/z 422.0 (M+H)+.
CPD 316
The title compound was prepared in an analogous manner to Compound 312 of Example 22, substituting 5-chloro-4-(4-methoxy-phenoxy)-2-(5-methylsulfanyl-pyridin-3-yl)-pyrimidine (prepared in a same manner to Compound 21c of Example 21, substituting 5-(methylthio)pyridine-3-boronic acid for pyridin-3-yl boronic acid in Procedure B) for Compound 22g in Procedure D. Free base-1H-NMR (400 MHz, CDCl3): δ 8.99 (d, 1H), 8.40 (d, 1H), 8.20-8.21 (m, 1H), 7.98 (s, 1H), 7.14-7.18 (m, 2H), 6.94-6.98 (m, 2H), 4.47-4.49 (m, 1H), 3.86 (s, 3H), 3.41-3.51 (m, 1H), 2.87-2.94 (m, 1H), 2.47 (s, 3H), 2.32-2.35 (m, 1H), 2.14-2.17 (m, 1H), 1.87-1.92 (m, 2H), 1.37-1.50 (m, 3H), 1.08-1.27 (m, 3H); MS: m/z 438.2 (M+H)+.
Example 23




A. Cpd 355
4-(4-Methoxy-phenoxy)-5-(4-methyl-piperazin-1-yl)-2-pyridin-3-yl-pyrimidine
Using an adaptation of the method described in Procedure D of Example 22 check to see if this method is present in examples, substituting 1-methyl-piperazine for piperazine-1-carboxylic acid tert-butyl ester, the title Compound 355 was obtained as a free base. HCl salt- 1H-NMR (400 MHz, DMSO-d6): δ 11.24 (br. s, 1H), 9.12 (d, 1H), 8.81 (dd, 1H), 8.64 (d, 1H), 8.54 (s, 1H), 7.87 (dd, 1H), 7.26-7.30 (m, 2H), 7.03-7.08 (m, 2H), 3.86-3.91 (m, 2H), 3.81 (s, 3H), 3.52-3.55 (m, 2H), 3.22-3.40 (m, 4H), 2.83 (d, 3H); MS: m/z 378.0 (M+H)+.
Following the procedure described above for Example 23 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:













Cpd
MS (M + H)+








297
352.0



359
392.3









Example 24




A. 5-Bromo-2-(5-cyano-pyridin-3-yl)-4-(4-methoxy-phenoxy)-pyrimidine (24a)
Using an adaptation of the method described in Procedure C of Example 22, substituting 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrile for pyridin-3-yl boronic acid, the title Compound 24a was obtained as white powder. 1H-NMR (400 MHz, CDCl3): δ 9.50 (d, 1H), 8.91 (d, 1H), 8.80 (s, 1H), 8.69 (t, 1H), 7.14 (d, 2H), 6.99 (d, 2H), 3.88 (s, 3H); MS: m/z 383.0 (M+H)+.
B. CPD 335
5-[4-(4-Methoxy-phenoxy)-5-(3-oxo-piperazin-1-O-pyrimidin-2-yl]-nicotinonitrile
Using an adaptation of the method described in Procedure D of Example 22, substituting Compound 24a for Compound 22d and substituting piperazin-2-one for piperazine-1-carboxylic acid tert-butyl ester, the title Compound 335 (10% yield) was obtained as a free base after purification by preparative TLC. 1H-NMR (400 MHz, CDCl3): δ 9.44 (d, 1H), 8.84 (d, 1H), 8.63 (t, 1H), 8.24 (s, 1H), 7.12 (d, 2H), 6.98 (d, 2H), 6.03 (br. s, 1H), 4.04 (s, 2H), 3.88 (s, 3H), 3.61-3.64 (m, 4H); MS: m/z 403.0 (M+H)+.
Example 25




A. 4-[2-(5-Cyano-pyridin-3-yl)-4-(4-methoxy-phenoxy)-pyrimidin-5-yl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (25a)
Using an adaptation of the method described in Procedure D of Example 22, substituting Compound 24a for Compound 22d, substituting 3-oxo-piperazine-1-carboxylic acid tert-butyl ester for piperazine-1-carboxylic acid tert-butyl ester and substituting Xantphos for (diphenylphosphino)ferrocene, the title Compound 25a (85% yield) was obtained. 1H-NMR (400 MHz, CDCl3): δ 9.51 (d, 1H), 8.90 (d, 1H), 8.71 (t, 1H), 8.65 (s, 1H), 7.11 (d, 2H), 6.97 (d, 2H), 4.34 (s, 2H), 3.88 (s, 3H), 3.87-3.90 (m, 2H), 3.82-3.85 (m, 2H); MS: m/z 503.0 (M+H)+.
B. CPD 337
5-[4-(4-Methoxy-phenoxy)-5-(2-oxo-piperazin-1-yl)-Pyrimidin-2-yl]-nicotinonitrile
To a solution of Compound 24a in CH2Cl2 (3 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 3 h and the solvent was evaporated in vacuo to give the crude material. The crude material was purified by preparative TLC to afford Compound 337 as a TFA salt. 1H-NMR (400 MHz, CDCl3): δ 9.52 (d, 1H), 8.93 (d, 1H), 8.74 (t, 1H), 8.68 (s, 1H), 7.09 (d, 2H), 6.98 (d, 2H), 4.11 (br. s, 4H), 3.87 (s, 3H), 3.72 (br. s, 2H); MS: m/z 403.0 (M+H)+.
Example 26




A. 2-(S)-{[2-(5-Formyl-pyridin-3-yl)-4-(4-methoxy-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (26a)
The title compound was prepared in an analogous manner to Compound 1g of Example 1, substituting 5-formylpyridin-3-yl boronic acid for Compound 1f in Procedure D.
B. 2-(S)-{[2-(5-Hydroxymethyl-pyridin-3-yl)-4-(4-methoxy-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (26b)
To a solution of Compound 26a (200 mg, 0.40 mmol) in THF (5 mL) at 0° C. was added LiBH4 solution (2.0 M in THF) (0.3 mL) dropwise. The reaction mixture was stirred at 0° C. for 0.5 h, then warmed to room temperature over 2 h. The resultant mixture was diluted with water. The mixture was extracted with EtOAc (3×), and the organic phases were combined, dried over Na2SO4, and concentrated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 26b (71.5 mg; 35% yield). 1H-NMR (400 MHz, CDCl3): δ 9.00 (s, 1H), 8.43 (s, 1H), 8.39 (s, 1H), 7.80-7.94 (m, 1H), 7.13-7.16 (m, 2H), 6.91-6.94 (m, 2H), 5.83 (br. s, 0.6H), 5.06 (br. s, 0.4H), 4.71 (s, 2H), 4.18-4.26 (m, 1H), 3.84 (s, 3H), 3.86 (br. s, 0.6H), 3.50 (br. s, 0.4H), 3.37-3.40 (m, 2H), 3.15-3.20 (m, 2H), 2.06-2.15 (m, 1H), 1.90-1.98 (m, 2H), 1.77-1.86 (m, 1H), 1.43-1.49 (m, 9H); MS: m/z 508.2 (M+H)+.
C. CPD 269
(5-{4-(4-Methoxy-phenoxy)-5-[(pyrrolidin-2-(S)-ylmethyl)-amino]-pyrimidin-2-yl}-pyridin-3-yl)-methanol
To a solution of Compound 26b (71.5 mg) in dichloromethane (2 mL) was treated with TFA (1 mL) at room temperature for 2 h. The reaction mixture was adjusted to pH 12 with 1 N NaOH (aq). The resultant mixture was extracted with CH2Cl2 (3×). The organic extracts were combined, dried over Na2SO4, and concentrated under reduced pressure to give the free base (52 mg). The free base was dissolved in CH2Cl2 (2 mL), and treated with 1.0 M HCl in Et2O (0.25 mL) at ambient temperature for 2 h. A solid was collected and dried by vacuum filtration to afford Compound 269 as a HCl salt. Free base-1H-NMR (400 MHz, MeOH-d4): δ 8.95-9.05 (m, 1H), 8.55-8.70 (m, 1H), 8.36-8.42 (m, 1H), 8.06-8.11 (m, 1H), 7.15-7.21 (m, 2H), 6.98-7.02 (m, 2H), 4.72 (s, 1H), 4.63 (s, 1H), 3.83 (d, 3H), 3.74-3.83 (m, 1H), 3.45-3.58 (m, 2H), 3.13-3.28 (m, 2H), 2.15-2.25 (m, 1H), 1.93-2.08 (m, 2H), 1.68-1.79 (m, 1H); MS: m/z 408.2 (M+H)+.
Example 27




A. 4-(R)-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-2-(S)-1,2 dicarboxylic acid 1-tert-butyl ester 2-methyl ester (27b)
A solution of Compound 27a (2.64 g; 10.8 mmol) in DMF (12 mL) was treated with t-butyl-dimethyl silylchloride (1.78 g; 11.84 mmol) and imidazole (1.2 g; 17.64 mmol) at room temperature for 2 h. The resultant mixture was concentrated in vacuuo and partitioned between EtOAc and H2O. The organic phase was washed sequentially with 0.1 N HCl (aq), saturated NaHCO3 (aq), and brine, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 27b. 1H-NMR (400 MHz, CDCl3): δ 4.32-4.45 (m, 2H), 3.74-3.75 (d, 3H), 3.58-3.64 (m, 1H), 3.32-3.43 (m, 1H), 2.16-2.19 (m, 1H), 2.00-2.06 (m, 1H), 1.42-1.47 (d, 9H), 0.88 (s, 9H), 0.07 (s, 6H). MS: m/z 360.2 (M+H)+.
B. 4-(R)-(tert-Butyl-dimethyl-silanyloxy)-2-(S)-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (27c)
To a solution of Compound 27b (392 mg; 1.09 mmol) in THF/MeOH (3/3 mL) at 0° C. was added NaBH4 (148 mg; 3.92 mmol) and LiCl (166 mg; 3.92 mmol). The reaction mixture was stirred at 0° C. for 0.5 h, then warmed to room temperature over 2 h. The resultant mixture was diluted with 0.5N HCl (aq). The mixture was extracted with EtOAc (3×), the organic extracts were combined, dried over Na2SO4, and concentrated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 27c (345 mg; 95% yield). 1H-NMR (400 MHz, CDCl3): δ 4.90 (br. s, 1H), 4.28 (m, 1H), 4.10-4.16 (m, 1H), 3.69-3.72 (m, 1H), 3.53-3.57 (m, 1H), 3.43-3.46 (m, 1H), 3.33-3.37 (m, 1H), 1.94-1.98 (m, 1H), 1.53-1.63 (m, 1H), 1.48 (s, 9H), 0.88 (s, 9H), 0.07 (s, 6H); MS: m/z 332.2 (M+H)+.
C. 4-(R)-(tert-Butyl-dimethyl-silanyloxy)-2-(S)-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (27d)
To a solution of oxalyl chloride (0.16 mL; 1.785 mmol) in CH2Cl2 (2 mL) at −78° C. was added DMSO (0.25 mL; 3.55 mmol) dropwise and the mixture was stirred for 10 min. The mixture was then treated with a solution of Compound 27c (395 mg; 1.19 mmol) in CH2Cl2 (3 mL) dropwise and continually stirred for 20 min. To the resultant mixture was added Et3N (0.5 mL; 3.55 mmol) dropwise and the mixture was stirred at −78° C. for 30 min. The mixture was allowed to warm to ambient temperature while continually stirring over 20 min. The reaction mixture was quenched with saturated NH4Cl (aq), extracted with EtOAc, washed with water and brine; and the combined organic extracts were dried over Na2SO4, and concentrated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 27d (250 mg; 64% yield). 1H-NMR (400 MHz, CDCl3): δ 9.44-9.57 (m, 1H), 4.20-4.39 (m, 1H), 3.35-3.57 (m, 1H), 1.89-2.09 (m, 1H), 1.44-1.49 (m, 9H), 0.88 (s, 9H), 0.08 (s, 6H); MS: m/z 330.2 (M+H)+.
D. 4-(R)-(tert-Butyl-dimethyl-silanyloxy)-2-(S)-{[2-chloro-4-(4-methoxy-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (27e)
To a solution of Compound 1c (191 mg, 0.759 mmol) in 1,2-dichloroethane (4 mL) was added Compound 27d (250 mg; 0.759 mmol) and acetic acid (0.2 mL) at ambient temperature, and the mixture was stirred at room temperature for 1.5 h. The mixture was then treated with NaB(OAc)3H (240 mg; 1.14 mmol) and continually stirred at room temperature for 4 h. The resultant mixture was diluted with CH2Cl2, then washed with saturated NaHCO3 (aq) and water. The organic phase was washed sequentially with water and brine, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 27e. 1H-NMR (400 MHz, CDCl3): δ 7.70-7.75 (m, 1H), 7.10-7.13 (m, 2H), 6.94-7.01 (m, 2H), 5.79 (br. s, 0.6H), 4.73 (br. s, 0.4H), 4.30-4.39 (m, 2H), 3.84 (s, 3H), 3.12-3.69 (m, 4H), 2.06-2.16 (m, 1H), 1.80-1.87 (m, 1H), 1.45-1.48 (m, 9H), 0.88 (s, 9H), 0.08 (s, 6H); MS: m/z 565.2 (M+H)+.
E. 4-(R)-(tert-Butyl-dimethyl-silanyloxy)-2-{[4-(4-methoxy-phenoxy)-2-(S)-(pyridin-3-O-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (27f)
To a teflon-lined septum sealed Schlenk tube, a mixture of Compound 27e (130 mg; 0.23 mmol), pyridin-3-yl boronic acid (56.5 mg; 0.46 mmol), K2CO3 (64 mg; 0.46 mmol) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(11) (11.3 mg, 0.014 mmol) in a mixture of ethanol (0.5 mL) and H2O (0.1 mL) was added. The reaction mixture was irradiated in a microwave instrument at 130° C. for 30 min. The resultant mixture was diluted with EtOAc, then washed with saturated NH4Cl (aq) and water. The organic phase was washed with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 27f (100 mg; 71% yield). 1H-NMR (400 MHz, CDCl3): δ 9.27 (s, 1H), 8.52-8.53 (m, 1H), 8.33-8.35 (m, 1H), 7.99-8.02 (m, 1H), 7.26-7.28 (m, 1H), 7.13-7.19 (m, 2H), 6.95-6.97 (m, 2H), 5.77 (br. s, 0.6H), 4.84 (br. s, 0.4H), 4.35-4.42 (m, 2H), 3.87 (s, 3H), 3.28-3.69 (m, 4H), 2.12-2.18 (m, 1H), 1.86-1.91 (m, 1H), 1.47-1.51 (m, 9H), 0.88 (s, 9H), 0.08 (s, 6H); MS: m/z 608.1 (M+H)+.
F. CPD 270
5-(S)-{[4-(4-Methoxy-phenoxy)-2-(pyridin-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidin-3-(R)-ol
Compound 27f (100 mg; 0.165 mmol) in trifluoroacetic acid (1 mL) was stirred at room temperature 20 h. The reaction mixture was adjusted to pH 12 by the addition of 1 N NaOH (aq). The resultant mixture was extracted with CH2Cl2 and H2O. The organic phase was washed with H2O and dried over Na2SO4. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (3 mL), treated with 1.0 M HCl in Et2O (0.33 mL; 0.33 mmol) at ambient temperature, and the reaction mixture was stirred for 20 h. The mixture was evaporated in vacuo, and the reside was triturated with Et2O. A solid was collected and dried by vacuum filtration to afford Compound 270 (63 mg; 81% yield) as a HCl salt. Cpd 270 (free base) 1H-NMR (400 MHz, CDCl3): δ 9.26 (d, 1H), 8.53 (dd, 1H), 8.32 (dt, 1H), 7.99 (s, 1H), 7.24-7.27 (m, 1H), 7.15-7.19 (m, 2H), 6.95-6.99 (m, 2H), 4.85-4.88 (m, 1H), 4.54-4.55 (m, 1H), 3.88 (s, 3H), 3.82-3.88 (m, 2H), 3.28-3.34 (m, 1H), 3.06-3.13 (m, 1H), 3.03-3.04 (m, 2H), 2.04-2.09 (m, 1H), 1.73-1.80 (m, 1H), 1.6 (br. s, 1H); MS: m/z 394.0 (M+H)+.
Following the procedure described above for Example 27 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:















Cpd
MS (M + H)+
Cpd
MS (M + H)+








271
394.0
272
394.0









Example 28




A. 4-(R)-(tert-Butyl-dimethyl-silanyloxy)-2-{[2-chloro-4-(4-methoxy-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (28b)
Using an adaptation of the method described in Procedure D of Example 27, substituting Compound 28a (commercially available) for Compound 27d, the title Compound 28b was obtained. 1H-NMR (400 MHz, CDCl3): δ 7.70-7.75 (m, 1H), 7.06-7.13 (m, 2H), 6.91-6.95 (m, 2H), 5.74-5.79 (m, 0.6H), 4.73-4.82 (m, 0.4H), 4.38-4.44 (m, 2H), 3.83 (s, 3H), 3.12-3.69 (m, 4H), 2.10-2.24 (m, 1H), 1.78-1.88 (m, 1H), 1.44-1.48 (m, 9H), 0.88-0.92 (m, 9H), 0.08-0.10 (m, 6H); MS: m/z 565.0 (M+H)+.
B. 4-(R)-(tert-Butyl-dimethyl-silanyloxy)-2-{[4-(4-methoxy-phenoxy)-2-(S)-(5-methoxy-pyridin-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (34c) and 4-(R)-(tert-Butyl-dimethyl-silanyloxy)-2-{[4-(4-methoxy-phenoxy)-2-(R)-(5-methoxy-pyridin-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (28d)
Using an adaptation of the method described in Procedure E of Example 27, substituting Compound 28b for Compound 27e and substituting 3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine for pyridin-3-yl boronic acid, the title Compound 28c and Compound 28d were obtained separately after flash column chromatography (SiO2). Compound 28c—1H-NM R (400 MHz, CDCl3): δ 8.87 (s, 1H), 8.24 (s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.13-7.20 (m, 2H), 6.94-6.96 (m, 2H), 5.78 (br. s, 0.6H), 4.86 (br. s, 0.4H), 4.34-4.42 (m, 2H), 3.86 (s, 6H), 3.29-3.51 (m, 4H), 2.12-2.18 (m, 1H), 1.86-1.94 (m, 1H), 1.47-1.51 (m, 9H), 0.87-0.89 (m, 9H), 0.08 (s, 6H); MS: m/z 638.2 (M+H)+. Compound 28d- 1H-NMR (400 MHz, CDCl3): δ 8.86 (br. s, 1H), 8.23 (br. s, 1H), 7.98-7.99 (m, 1H), 7.89 (s, 1H), 7.12-7.20 (m, 2H), 6.92-6.96 (m, 2H), 5.84 (br. s, 0.6H), 4.97 (br. s, 0.4H), 4.27-4.43 (m, 2H), 3.85 (s, 6H), 3.57-3.81 (m, 2H), 3.29-3.39 (m, 2H), 2.18-2.25 (m, 1H), 1.82-1.91 (m, 1H), 1.45-1.50 (m, 9H), 0.91-0.92 (m, 9H), 0.10-0.11 (m, 6H); MS: m/z 638.2 (M+H)+.
C. CPD 273
5-(S)-{[4-(4-Methoxy-phenoxy)-2-(5-methoxy-pyridin-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidin-3-(R)-ol
Using an adaptation of the method described in Procedure F of Example 27, substituting Compound 28c for Compound 27f, the title Compound 273 was obtained as a HCl salt. Cpd 273, free base- 1H-NMR (400 MHz, CDCl3): δ 8.87 (d, 1H), 8.25 (d, 1H), 8.00 (s, 1H), 7.89 (dd, 1H), 7.16-7.20 (m, 2H), 6.94-6.98 (m, 2H), 4.83-4.86 (m, 1H), 4.53-4.55 (m, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.79-3.87 (m, 1H), 3.26-3.32 (m, 1H), 3.04-3.11 (m, 1H), 3.01-3.02 (m, 2H), 2.02-2.08 (m, 1H), 1.72-1.79 (m, 1H), 1.25-1.27 (m, 1H); MS: m/z 424.0 (M+H)+.
D. CPD 274
5-(R)-{[4-(4-Methoxy-phenoxy)-2-(5-methoxy-pyridin-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidin-3-(R)-ol
Using an adaptation of the method described in Procedure F of Example 27, substituting Compound 28d for Compound 27f, the title Compound 274 was obtained as a HCl salt. Free base- 1H-NMR (400 MHz, CDCl3): δ 8.85 (d, 1H), 8.24 (d, 1H), 7.99 (s, 1H), 7.88 (dd, 1H), 7.16-7.20 (m, 2H), 6.93-6.97 (m, 2H), 5.08-5.10 (m, 1H), 4.46-4.50 (m, 1H), 3.86 (s, 3H), 3.86 (s, 3H), 3.62-3.69 (m, 1H), 3.42-3.49 (m, 1H), 3.31-3.38 (m, 1H), 3.01-3.14 (m, 2H), 2.28-2.37 (m, 1H), 1.66-1.73 (m, 1H), 1.25-1.27 (m, 1H); MS: m/z 424.0 (M+H)+.
Following the procedure described above for Example 28 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:
Compounds 1 through 319, and 321 through 323 of Formula (I) in the table below were synthesized using the procedures described above.







TABLE 1







Formula (I)








 














Cpd






Stereo


No
R1
R2
A—L—
a
L
Ra
Chem

















1
4-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methoxy-
phenyl








phenyl








2
phenyl
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S




phenyl







3
3-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methoxy-
phenyl








phenyl








4
2-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methoxy-
phenyl








phenyl








5
naphth-1-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







6
naphth-2-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







7
pyridin-4-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







8
pyridin-3-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







9
thien-3-yl
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S




phenyl







10
furan-3-yl
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S




phenyl







11
pyridin-3-
4-trifluoro
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
methoxy-









phenyl







12
pyridin-3-
4-amino
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
carbonyl-









phenyl







13
pyridin-3-
4-methyl
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
carbonyl









amino-phenyl







14
pyridin-3-
phenyl
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl








15
3-hydroxy-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



phenyl
phenyl







16
quinolin-5-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







17
quinolin-8-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







18
2-methyl-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



quinolin-5-
phenyl








yl








19
4-biphenyl
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S




phenyl







20
quinolin-3-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







21
dibenzo
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



thiophen-
phenyl








2-yl








22
6-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methoxy-
phenyl








pyridin-3-









yl








23
pyrimidin-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-yl
phenyl







24
2-fluoro-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








25
6-fluoro-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








26
2-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methoxy-
phenyl








pyridin-3-









yl








27
2,6-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



dihydroxy
phenyl








pyrimidin-









5-yl








28
3-cyano-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



phenyl
phenyl







29
3-nitro-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



phenyl
phenyl







30
3-amino
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



carbonyl-
phenyl








phenyl








31
3-N,N-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



diethyl
phenyl








amino









carbonyl-









phenyl








32
3-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methane-
phenyl








sulfonyl-









phenyl








33
4-hydroxy-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



phenyl
phenyl







34
indol-5-yl
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S




phenyl







35
4H-[1,2,4]
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



oxadiazol-
phenyl








5-on-3-yl








36
pyridin-3-
4-fluoro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







37
6-
4-fluoro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methoxy-
phenyl








pyridin-3-









yl








38
3-fluoro-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



phenyl
phenyl







39
6-
2-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methoxy-
phenyl








pyridin-3-









yl








40
pyridin-3-
2-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







41
3-diethyl
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



amino-
phenyl








phenyl








42
3-methyl
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



carbonyl
phenyl








amino-









phenyl








43
4-methyl
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



carbonyl
phenyl








amino-









phenyl








44
6-
4-amino-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methoxy-
phenyl








pyridin-3-









yl








45
3-amino-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



phenyl
phenyl







46
pyridin-3-
4-amino-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







47
benzo
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



thiazol-2-
phenyl








yl








48
thiazol-2-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







49
benzo-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



thiophen-2-
phenyl








yl








50
3-trifluoro
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methyl-
phenyl








phenyl








51
3-trifluoro
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methoxy-
phenyl








phenyl








52
2-methyl
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



thio-
phenyl








pyrimidin-









5-yl








53
2-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methoxy-
phenyl








pyrimidin-









5-yl








54
5-fluoro-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








55
3,5
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



difluoro-
phenyl








phenyl








56
3,4-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



difluoro-
phenyl








phenyl








57
3,4-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



difluoro-4-
phenyl








hydroxy









methyl-









phenyl








58
2,4-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



dimethoxy-
phenyl








pyrimidin-









5-yl








59
6-
4-hydroxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methoxy-
phenyl








pyridin-3-









yl








60
2-ethoxy-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyrimidin-
phenyl








5-yl








61
pyrazol-5-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







62
3,5-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



dimethyl-
phenyl








isoxazol-









4-yl








63
2,3-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



dihydro
phenyl








benzo









furan-5-yl








64
3-fluoro-4-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methoxy-
phenyl








phenyl








65
pyrazol-4-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







66
2-methyl
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



thio-
phenyl








pyrimidin-









4-yl








67
1-methyl-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyrazol-4-
phenyl








yl








68
5-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methoxy-
phenyl








pyridin-3-









yl








69
5-cyano-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








70
3-fluoro-5-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methoxy-
phenyl








phenyl








71
3-fluoro-5-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methyl-
phenyl








phenyl








72
6-amino-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








73
3-fluoro-6-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H




methoxy-
phenyl








pyridin-3-









yl








74
6-hydroxy-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








75
6-hydroxy-
4-hydroxy-
a1—L1
pyrrolidin-2-yl
methyl
H




pyridin-3-
phenyl








yl








76
quinoxalin-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



6-yl
phenyl







77
1H-pyrrolo
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



[2,3-b]
phenyl








pyridin-5-









yl








78
benzo[1,2,
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5]oxadiazol-
phenyl








5-yl








79
pyrimidin-
4-methoxy-
a1—L1
4,4-difluoro-
methyl
H
2S



5-yl
phenyl

pyrrolidin-2-yl





80
pyrimidin-
4-methoxy-
a1—L1
4-fluoro-
methyl
H
2S, 4R



5-yl
phenyl

pyrrolidin-2-yl





81
2-amino-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyrimidin-
phenyl








5-yl








82
2-dimethyl
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



amino-
phenyl








pyrimidin-









5-yl








83
2-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



(morpholin-
phenyl








4-yl)-









pyrimidin-









5-yl








84
2-(4-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methyl-
phenyl








pyrazin-1-









yl)-









pyrimidin-









5-yl








85
pyrimidin-
benzothiazol-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-yl
6-yl







86
5-cyano-
benzothiazol-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
6-yl








yl








87
pyrimidin-
2-methyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-yl
benzothiazol-









6-yl







88
5-cyano-
2-methyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
benzothiazol-








yl
6-yl







89
pyrimidin-
4-methoxy-
a1—L1
4-fluoro-
methyl
H
2S, 4S



5-yl
phenyl

pyrrolidin-2-yl





90
5-cyano-
2-methyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
benzothiazol-








yl
6-yl







91
pyrimidin-
2-methyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-yl
benzothiazol-









6-yl







92
3,5-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



dimethyl-
phenyl








phenyl








93
benzo[1,3]
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



dioxol-5-yl
phenyl







94
3,5-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



dichloro-
phenyl








phenyl








95
6-cyano-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








96
5-cyano-
3,5-difluoro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
4-methoxy-








yl
phenyl







97
pyrimidin-
3,5-difluoro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-yl
4-methoxy-









phenyl







98
5-cyano-
3-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








99
pyrimidin-
3-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-yl
phenyl







100
pyridin-3-
3-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







101
5-cyano-
2,3-difluoro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
4-methoxy-








yl
phenyl







102
5-fluoro-
2,3-difluoro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
4-methoxy-








yl
phenyl







103
pyrimidin-
2,3-difluoro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-yl
4-methoxy-









phenyl







104
5-cyano-
4-ethoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








105
pyrimidin-
4-ethoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-yl
phenyl







106
5-fluoro-
4-ethoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








107
5-methyl
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



thio-
phenyl








pyridin-3-









yl








108
5-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methane-
phenyl








sulfonyl-









pyridin-3-









yl








109
pyrimidin-
4-methoxy-
a1—L1
piperidin-3-yl
absent
H
racemic



5-yl
phenyl







110
5-cyano-
4-difluoro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
methoxy-








yl
phenyl







111
pyrimidin-
4-difluoro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-yl
methoxy-









phenyl







112
5-fluoro-
4-difluoro
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
methoxy-








yl
phenyl







113
5-cyano-
4-n-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
propyloxy-








yl
phenyl







114
pyrimidin-
4-n-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-yl
propyloxy-









phenyl







115
5-fluoro-
4-n-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
propyloxy-








yl
phenyl







117
indol-4-yl
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S




phenyl







118
indol-6-yl
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S




phenyl







119
indol-7-yl
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S




phenyl







120
pyrazin-2-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







121
2-cyano-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyrimidin-3-
phenyl








yl








122
5-cyano-
4-(2,2,2-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
trifluoro-








yl
ethoxy)-









phenyl







123
pyrimidin-
4-(2,2,2-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-yl
trifluoro-









ethoxy)-









phenyl







124
5-fluoro-
4-(2,2,2-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
trifluoro-








yl
ethoxy)-









phenyl







125
5-cyano-
4-n-butoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








126
pyrimidin-
4-n-butoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-yl
phenyl







127
5-fluoro-
4-n-butoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








128
5-fluoro-
4-chloro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








129
5-cyano-
4-chloro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








130
pyrimidin-
4-chloro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-yl
phenyl







131
5-fluoro-
3-fluoro-4-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
methoxy-








yl
phenyl







132
5-cyano-
3-fluoro-4-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
methoxy-








yl
phenyl







133
pyrimidin-
3-fluoro-4-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-yl
methoxy-









phenyl







134
5-cyano-
4-methoxy-
a1—L1
4-fluoro-
methyl
H
2S, 4R



pyridin-3-
phenyl

pyrrolidin-2-yl






yl








135
pyridin-3-
3-cyano-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







136
pyridin-3-
4-cyano-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







137
pyridin-3-
3-fluoro-4-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
cyano-phenyl







138
pyridin-3-
4-cyclopropyl
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
carbonyl









amino-phenyl







139
5-cyano-
4-isopropyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
oxy-phenyl








yl








140
pyrimidin-
4-isopropyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-yl
oxy-phenyl







141
pyridin-3-
4-isopropyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
oxy-phenyl







142
3-cyano-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-fluoro-
phenyl








phenyl








143
5-cyano-
4-hydroxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
methyl-








yl
phenyl







144
pyrimidin-
4-hydroxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-yl
methyl-









phenyl







145
pyridin-3-
4-hydroxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
methyl-









phenyl







146
5-cyano-
4-fluoro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








147
5-cyano-
4-methyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








148
pyrimidin-
4-methyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-yl
phenyl







149
pyridin-3-
4-methyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







150
5-cyano-
4-methyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
thio-phenyl








yl








151
pyrimidin-
4-methyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-yl
thio-phenyl







152
pyridin-3-
4-methyl
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
thio-phenyl







153
5-cyano-
4-(methoxy
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
methyl)-








yl
phenyl







154
pyrimidin-
4-(methoxy
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-yl
methyl)-









phenyl







155
pyridin-3-
4-(methoxy
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
methyl)-









phenyl







156
pyrimidin-
4-hydroxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-yl
phenyl







157
pyridin-3-
3-diethyl
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
amino









carbonyl-









phenyl







158
pyridin-3-
4-pyrrolidin-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
1-yl









carbonyl-









phenyl







159
pyridin-3-
4-carboxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







160
pyridin-3-
4-piperidin-1-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
yl









carbonyl-









phenyl







161
pyridin-3-
4-(morpholin-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
4-yl









carbonyl)-









phenyl







162
pyridin-3-
4-(4-methyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
piperazin-1-yl









carbonyl)-









phenyl







163
pyridin-3-
3-carboxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







164
5-fluoro-
3-carboxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








165
5-fluoro-
4-carboxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








166
pyridin-3-
3-(pyrrolidin-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
1-yl









carbonyl)-









phenyl







167
pyridin-3-
3-(piperidin-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
1-yl









carbonyl)-









phenyl







168
pyridin-3-
3-(morpholin-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
4-yl









carbonyl)-









phenyl







169
pyridin-3-
3-(4-methyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
piperazin-1-yl









carbonyl)-









phenyl







170
5-fluoro-
3-diethyl
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
amino








yl
carbonyl-









phenyl







171
5-fluoro-
3-(pyrrolidin-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
1-yl








yl
carbonyl)-









phenyl







172
5-fluoro-
3-(piperidin-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
1-yl








yl
carbonyl)-









phenyl







173
5-fluoro-
3-(morpholin-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
4-yl








yl
carbonyl)-









phenyl







174
5-fluoro-
3-(4-methyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
piperazin-1-yl








yl
carbonyl)-









phenyl







175
pyridin-3-
4-diethyl
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
amino









carbonyl-









phenyl







176
5-fluoro-
4-(pyrrolidin-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
1-yl








yl
carbonyl)-









phenyl







177
pyridin-3-
4-benzyloxy
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
carbonyl









amino-phenyl







178
5-fluoro-
4-methyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








179
5-cyano-
4-ethyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








180
5-chloro-
4-ethyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








181
pyrimidin-5-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
—C(O)Me
2S



yl
phenyl







182
5-fluoro-
4-ethyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








183
5-cyano-
3-fluoro-4-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
methyl-








yl
phenyl







184
pyridin-3-
4-ethyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







185
5-fluoro-
3-fluoro-4-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
methyl-








yl
phenyl







186
5-chloro-
3-fluoro-4-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
methyl-








yl
phenyl







187
pyridin-3-
3-fluoro-4-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
methyl-









phenyl







188
pyridin-3-
3-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
benzyloxy-









carbonyl









amino-phenyl







189
5-cyano-
2,3-difluoro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
4-methyl-








yl
phenyl







190
5-chloro-
2,3-difluoro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
4-methyl-








yl
phenyl







191
5-fluoro-
2,3-difluoro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
4-methyl-








yl
phenyl







192
pyridin-3-
2,3-difluoro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
4-methyl-









phenyl







193
5-fluoro-
4-methoxy-
a1—L1
4-fluoro-
methyl
H
2S, 4R



pyridin-3-
phenyl

pyrrolidin-2-yl






yl








194
5-chloro-
4-methoxy-
a1—L1
4-fluoro-
methyl
H
2S, 4R



pyridin-3-
phenyl

pyrrolidin-2-yl






yl








195
5-cyano-
4-ethyl-
a1—L1
4-fluoro-
methyl
H
2S, 4R



pyridin-3-
phenyl

pyrrolidin-2-yl






yl








196
pyridin-3-
4-methoxy-
a1—L1
4-fluoro-
methyl
H
2S, 4R



yl
phenyl

pyrrolidin-2-yl





197
5-fluoro-
4-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
benzyloxy-








yl
carbonyl









amino-phenyl







198
5-fluoro-
4-amino-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








199
5-cyano-
4-methoxy-
a1—L1
piperidin-3-yl
absent
H
3S



pyridin-3-
phenyl








yl








200
5-cyano-
3-methyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








201
5-chloro-
3-methyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








202
5-fluoro-
3-methyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








203
pyridin-3-
3-methyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







204
5-cyano-
3-methyl-4-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
methoxy-








yl
phenyl







205
5-fluoro-
3-methyl-4-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
methoxy-








yl
phenyl







206
5-cyano-
4-fluoro
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
methyl-








yl
phenyl







207
5-cyano-
4-methoxy-
a1—L1
piperidin-3-yl
absent
H
3S



pyridin-3-
phenyl








yl








208
5-cyano-
4-methoxy-
a1—L1
piperidin-4-yl
absent
H




pyridin-3-
phenyl








yl








209
pyridin-3-
4-(pyridin-3-yl
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
methyl)-









phenyl







210
5-chloro-
3-methyl-4-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
methoxy-








yl
phenyl







211
pyridin-3-
3-methyl-4-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
methoxy-









phenyl







212
5-fluoro-
4-(methyl
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
carbonyl








yl
amino)-









phenyl







213
5-fluoro-
4-methane
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
sulfonyl








yl
amino-phenyl







214
pyridin-3-
4-methane
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
sulfonyl









amino-phenyl







215
5-cyano-
4-methoxy-
a1—L1
azetidin-3-yl
methyl
H




pyridin-3-
phenyl








yl








216
pyridin-3-
4-formamido-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
phenyl







217
pyridin-3-
4-fluoro
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
methyl-









phenyl







218
5-cyano-
3-methyl-4-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
fluoro-phenyl








yl








219
5-fluoro-
3-methyl-4-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
fluoro-phenyl








yl








220
5-cyano-
4-trifluoro
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
methyl-








yl
phenyl







221
5-fluoro-
4-trifluoro
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
methyl-








yl
phenyl







222
5-fluoro-
4-methane
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
sulfonyl-








yl
phenyl







223
5-fluoro-
4-formamido-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








224
pyridin-3-
4-methoxy-
a1—L1
pyrrolidin-3-yl
absent
H
3R



yl
phenyl







225
pyridin-3-
4-methoxy-
a1—L1
piperidin-2-yl
methyl
H
2S



yl
phenyl







226
pyridin-3-
4-methoxy-
a1—L1
azetidin-3-yl
absent
H




yl
phenyl







227
5-chloro-
2-methyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








228
5-cyano-
3-methyl
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
carbonyl








yl
oxy-phenyl







229
5-chloro-
2-chloro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








230
5-cyano-
2-chloro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








231
5-cyano-
3-hydroxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








232
5-
2-chloro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methoxy-
phenyl








pyridin-3-









yl








233
5-methyl
2-chloro-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



thio-
phenyl








pyridin-3-y








234
5-methyl
4-methoxy-
a1—L1
4-fluoro-
methyl
H
2S, 4R



thio-
phenyl

pyrrolidin-2-yl






pyridin-3-y








235
5-
4-methoxy-
a1—L1
4-fluoro-
methyl
H
2S, 4R



methoxy-
phenyl

pyrrolidin-2-yl






pyridin-3-









yl








236
pyridin-3-
4-methoxy-
a1—L1
piperidin-3-yl
absent
H
3S



yl
phenyl







237
pyridin-3-
4-methoxy-
a1—L1
pyrrolidin-3-yl
absent
H
3S



yl
phenyl







238
5-methyl-
4-methoxy-
a1—L1
4-fluoro-
methyl
H
2S, 4R



pyridin-3-
phenyl

pyrrolidin-2-yl






yl








239
5-methyl-
4-methoxy-
a1—L1
4-fluoro-
methyl
H
2S, 4S



pyridin-3-
phenyl

pyrrolidin-2-yl






yl








240
5-
4-methoxy-
a1—L1
4-fluoro-
methyl
H
2S, 4S



methoxy-
phenyl

pyrrolidin-2-yl






pyridin-3-









yl








241
5-methyl
4-(2-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



thio-
methoxy-








pyridin-3-
ethoxy)-








yl
phenyl







242
5-methyl-
4-(2-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
methoxy-








yl
ethoxy)-









phenyl







243
5-
4-(2-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methoxy-
methoxy-








pyridin-3-
ethoxy)-








yl
phenyl







244
pyridin-3-
4-(2-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



yl
methoxy-









ethoxy)-









phenyl







245
5-
4-methoxy-
a1—L1
piperidin-3-yl
absent
H
3S



methoxy-
phenyl








pyridin-3-









yl








246
5-
4-methoxy-
a1—L1
piperidin-3-yl
absent
H
3R



methoxy-
phenyl








pyridin-3-









yl








247
5-
4-methoxy-
a1—L1
piperidin-3-yl
absent
H
3S



methoxy-
phenyl








pyridin-3-









yl








248
5-methyl
3-methyl-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



thio-
carbonyl








pyridin-3-
oxy-phenyl








yl








249
5-
3-hydroxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methoxy-
phenyl








pyridin-3-









yl








250
5-
3-methyl
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methoxy-
carbonyl








pyridin-3-
oxy-phenyl








yl








251
5-methyl-
3-methyl
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
carbonyl








yl
oxy-phenyl







252
5-methyl
4-methoxy-
a1—L1
piperidin-3-yl
absent
H
3S



thio-
phenyl








pyridin-3-









yl








253
5-methyl-
4-methoxy-
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
phenyl








yl








254
5-methyl
4-methoxy
a1—L1
piperidin-3-yl
absent
H
3R



thio
phenyl








pyridin-3-









yl








255
5-methyl
4-methoxy
a1—L1
pyrrolidin-3-yl
absent
H
3S



thio-
phenyl








pyridin-3-









yl








256
5-
4-methoxy
a1—L1
pyrrolidin-3-yl
absent
H
3S



methoxy
phenyl








pyridin-3-









yl








257
5-methyl-
4-methoxy
a1—L1
pyrrolidin-3-yl
absent
H
3S



pyridin-3-
phenyl








yl








258
5-methyl-
4-methoxy
a1—L1
piperidin-3-yl
absent
H
3R



pyridin-3-
phenyl








yl








259
5-methyl-
4-methoxy
a1—L1
piperidin-3-yl
absent
H
3S



pyridin-3-
phenyl








yl








260
5-methyl-
4-fluoro
a1—L1
pyrrolidin-2-yl
methyl
H
2S



pyridin-3-
methoxy








yl
phenyl







261
pyridin-3-
4-methoxy
a1—L1
piperidin-3-yl
absent
H
3R



yl
phenyl







262
6-fluoro-5-
4-methoxy
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methyl
phenyl








pyridin-3-









yl








263
2,5-
4-methoxy
a1—L1
pyrrolidin-2-yl
methyl
H
2S



dimethyl-
phenyl








pyridin-3-









yl








264
6′-chloro
4-methoxy
a1—L1
pyrrolidin-2-yl
methyl
H
2S



3,5′-
phenyl








dimethyl-









[2,3′]bi









pyridinyl-









5-yl








265
6-chloro-
4-methoxy
a1—L1
pyrrolidin-2-yl
methyl
H
2S



4-methyl
phenyl








pyridin-3-









yl








266
6-chloro-
4-methoxy
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-methyl-
phenyl








pyridin-3-









yl








267
pyridin-3-
4-methoxy
a1—L1
piperdin-2-yl
methyl
H
2R



yl
phenyl







268
2-chloro-
4-methoxy
a1—L1
pyrrolidin-2-yl
methyl
H
2S



5-methyl
phenyl








pyridin-3-









yl








269
5-hydroxy
4-methoxy
a1—L1
pyrrolidin-2-yl
methyl
H
2S



methyl-
phenyl








pyridin-3-









yl








270
pyridin-3-
4-methoxy
a1—L1
4-hydroxy-
methyl
H
trans



yl
phenyl

pyrrolidin-2-yl


2S, 4R


271
pyridin-3-
4-methoxy
a1—L1
4-hydroxy-
methyl
H
cis



yl
phenyl

pyrrolidin-2-yl


2R, 4R


272
pyridin-3-
4-methoxy
a1—L1
4-hydroxy-
methyl
H
cis



yl
phenyl

pyrrolidin-2-yl


2S, 4S


273
5-methoxy
4-methoxy
a1—L1
4-hydroxy-
methyl
H
trans



pyridin-3-
phenyl

pyrrolidin-2-yl


2S, 4R



yl








274
5-methoxy
4-methoxy
a1—L1
4-hydroxy-
methyl
H
cis



pyridin-3-
phenyl

pyrrolidin-2-yl


2R, 4R



yl








275
5-cyano-
4-methoxy-
a1—L1
morpholin-2-yl
methyl
H
racemic



pyridin-3-
phenyl








yl








276
5-fluoro-
4-methoxy-
a2—L2
morpholin-2-yl
methyl
H




pyridin-3-
phenyl








yl








277
pyrimidin-5-
4-methoxy-
a2—L2
morpholin-2-yl
methyl
H




yl
phenyl







278
pyrimidin-5-
4-methoxy-
a2—L2
morpholin-3-yl
methyl
H
racemic



yl
phenyl







279
5-cyano-
4-methoxy-
a2—L2
morpholin-3-yl
methyl
H
racemic



pyridin-3-
phenyl








yl








280
5-cyano-
4-methoxy-
a2—L2
morpholin-3-yl
methyl
H
3S



pyridin-3-
phenyl








yl








281
5-fluoro-
4-methoxy-
a2—L2
morpholin-3-yl
methyl
H
3S



pyridin-3-
phenyl








yl








282
pyridin-3-
4-methoxy-
a2—L2
morpholin-3-yl
methyl
H
3S



yl
phenyl







283
5-cyano-
4-methoxy-
a3—L3
imidazol-2-yl
methylene
H




pyridin-3-
phenyl








yl








284
5-cyano-
4-methoxy-
a3—L3
3H-imidazol-2-yl
methylene
H




pyridin-3-
phenyl








yl








285
5-cyano-
4-methoxy-
a3—L3
5-methyl-
methyl
H
0



pyridin-3-
phenyl

3H-imidazol-4-yl






yl








286
5-cyano-
4-methoxy-
a3—L3
3-methyl-
methyl
H
0



pyridin-3-
phenyl

3H-imidazol-4-yl






yl








287
5-cyano-
4-methoxy-
a3—L3
2-ethyl-5-
methyl
H




pyridin-3-
phenyl

methyl-3H-






yl


imidazol-4-yl





288
pyridin-3-
4-methoxy-
a3—L3
3H-imidazol-4-yl
methyl
H




yl
phenyl







289
5-methyl
4-methoxy-
a3—L3
3H-imidazol-4-yl
methyl
H




thio-
phenyl








pyridin-3-









yl








290
5-methoxy-
4-methoxy-
a3—L3
3H-imidazol-4-yl
methyl
H




pyridin-3-
phenyl








yl








291
5-methyl-
4-methoxy-
a3—L3
3H-imidazol-4-yl
methyl
H




pyridin-3-
phenyl








yl








292
5-cyano-
4-methoxy-
a4—L4
2-amino
propyl
H
2S



pyridin-3-
phenyl








yl








293
5-cyano-
4-methoxy-
a4—L4
2-amino
ethyl
H




pyridin-3-
phenyl








yl








294
5-cyano-
4-methoxy-
a4—L4
2-amino
4-
H
2S



pyridin-3-
phenyl


methyl-





yl



pentyl




295
pyrimidin-
4-methoxy-
a4—L4
2-amino
4-
H
2S



5-yl
phenyl


methyl-









pentyl




296
5-methyl-
4-methoxy
a4—L4
2-amino
ethyl
H




pyridin-3-
phenyl








yl








297
pyridin-3-
4-methoxy
a4—L4
2-methylamino
ethyl
H




yl
phenyl







298
5-cyano-
4-methoxy-
a5—L5
4-amino
absent
H
cis/



pyridin-3-
phenyl

cyclohexyl


trans



yl





mixture


299
5-cyano-
4-methoxy-
a5—L5
2-amino
methyl
H
2S, 1R



pyridin-3-
phenyl

cyclohexyl






yl








300
pyrimidin-
4-methoxy-
a5—L5
2-amino
methyl
H
2S, 1R



5-yl
phenyl

cyclohexyl





301
5-cyano-
4-methoxy-
a5—L5
3-amino
methyl
H
trans



pyridin-3-
phenyl

cyclobutyl






yl








302
pyrimidin-
4-methoxy-
a5—L5
3-amino
methyl
H
trans



5-yl
phenyl

cyclobutyl





303
5-cyano-
4-methoxy-
a5—L5
3-amino
absent
H
cis/



pyridin-3-
phenyl

cyclobutyl


trans



yl





mixture


304
pyrimidin-
4-methoxy-
a5—L5
3-amino
absent
H
cis/



5-yl
phenyl

cyclobutyl


trans









mixture


305
pyridin-3-
4-methoxy-
a5—L5
4-amino
absent
H
cis



yl
phenyl

cyclohexyl





306
pyridin-3-
4-methoxy-
a5—L5
3-amino
absent
H
Racemic,



yl
phenyl

cyclohexyl


mixture









of cis/









trans


307
pyridin-3-
4-methoxy-
a5—L5
3-amino
absent
H
1RS,



yl
phenyl

cyclohexyl


3SR









(racemic









cis)


308
pyridin-3-
4-methoxy-
a5—L5
2-amino
absent
H
1RS,



yl
phenyl

cyclohexyl


2SR









(racemic









single









stereo









isomer,









unknown









cis/









trans)


309
5-methoxy-
4-methoxy-
a5—L5
3-amino
absent
H
Racemic,



pyridin-3-
phenyl

cyclohexyl


mixture



yl





of cis/









trans


310
5-methyl
4-methoxy
a5—L5
3-amino
absent
H
Racemic,



thio
phenyl

cyclohexyl


mixture



pyridin-3-





of cis/



yl





trans


311
5-methoxy
4-methoxy
a5—L5
3-amino
absent
H
cis



pyridin-3-
phenyl

cyclohexyl


1R, 3S



yl








312
5-methoxy
4-methoxy
a5—L5
3-amino
absent
H
cis



pyridin-3-
phenyl

cyclohexyl


1S, 3R



yl








313
5-methoxy
4-methoxy
a5—L5
3-amino
absent
H
trans,



pyridin-3-
phenyl

cyclohexyl


one



yl





enant.









Absolute









unknown


314
5-methoxy
4-methoxy
a5—L5
3-amino
absent
H
trans,



pyridin-3-
phenyl

cyclohexyl


one



yl





enant.,









absolute









unknown


315
5-methyl-
4-methoxy
a5—L5
3-amino
absent
H
Racemic,



pyridin-3-
phenyl

cyclohexyl


mixture



yl





of cis/









trans


316
5-methyl
4-methoxy
a5—L5
3-amino
absent
H
cis



thio
phenyl

cyclohexyl


1S, 3R



pyridin-3-









yl








317
5-methyl
4-methoxy
a5—L5
3-amino
absent
H
cis



thio
phenyl

cyclohexyl


1R, 3S



pyridin-3-









yl








318
5-methyl
4-methoxy
a5—L5
3-amino
absent
H
trans,



thio
phenyl

cyclohexyl


one



pyridin-3-





enant.,



yl





absolute









unknown


319
5-methyl
4-methoxy
a5—L5
3-amino
absent
H
trans,



thio
phenyl

cyclohexyl


one



pyridin-3-





enant.,



yl





absolute









unknown


321
pyridin-3-
4-methoxy-
a5—L5
3-amino
absent
H
cis



yl
phenyl

cyclohexyl


1S, 3R


322
pyridin-3-
4-methoxy-
a5—L5
3-amino
absent
H
cis



yl
phenyl

cyclohexyl


1R, 3S


323
pyridin-3-
4-methoxy-
a5—L5
3-amino
absent
H
trans,



yl
phenyl

cyclohexyl


one









enant.,









absolute









unknown









Compounds 320, and 324 through 361 of Formula (I), in the table below were synthesized using the procedures described above.

















 











Cpd


A—L— and Ra
Stereo


No
R1
R2
are taken to form
chem





320
pyridin- 3-yl
4- cyclopropyl- phenyl
piperazin-1-yl



324
phenyl
4- methoxy- phenyl
piperazin-1-yl



325
5-cyano- pyridin-3-yl
4- methoxy- phenyl
piperazin-1-yl



326
5-cyano- pyridin-3-yl
4- methoxy- phenyl
3-amino- pyrrolidin-1-yl
3R


327
pyridin-3-yl
4- methoxy- phenyl
piperazin-1-yl



328
5-cyano- pyridin-3-yl
4- methoxy- phenyl
3-amino  pyrrolidin-1-yl
3S


329
5-cyano- pyridin-3-yl
4- methoxy- phenyl
3-amino  piperidin-1-yl
3S


330
5-cyano- pyridin-3-yl
4- methoxy- phenyl
3-amino  piperidin-1-yl
3R


331
5-cyano- pyridin-3-yl
4- methoxy- phenyl
3-aminomethyl  azetidin-1-yl



332
5-cyano- pyridin-3-yl
4- methoxy- phenyl
2-aminomethyl  pyrrolidin-1-yl
2R


333
5-cyano- pyridin-3-yl
4- methoxy- phenyl
4-amino piperidin-1-yl



334
5-cyano- pyridin-3-yl
4- methoxy- phenyl
2-aminomethyl  pyrrolidin-1-yl
2R


335
5-cyano- pyridin-3-yl
4- methoxy- phenyl
3- oxopiperazin- 1-yl



336
pyridin-3-yl
4- methoxy- phenyl
[1,4]diazepan- 1-yl



337
5-cyano- pyridin-3-yl
4- methoxy- phenyl
2-oxopiperazin- 1-yl



338
5-cyano- pyridin-3-yl
4- methoxy- phenyl
3,6-diaza- bicyclo[3.1.1] hept-3-ylamino



339
pyridin-3-yl
4- methoxy- phenyl
3-amino  pyrrolidin-1-yl
3R


340
pyridin-3-yl
4- methoxy- phenyl
3-amino- azetidin-1-yl



341
5-methylthio- pyridin-3-y
4- methoxy- phenyl
piperazin-1-yl



342
5-methoxy- pyridin-3-yl
4- methoxy- phenyl
piperazin-1-yl



343
5-cyano- pyridin-3-yl
4- methoxy- phenyl
3-methyl- piperazin-1-yl
racemic


344
5-cyano- pyridin-3-yl
4- methoxy- phenyl
2-methyl- piperazin-1-yl
2R


345
5-cyano- pyridin-3-yl
4- methoxy- phenyl
2-methyl- piperazin-1-yl
2S


346
5-methoxy- pyridin-3-yl
4- methoxy- phenyl
[1,4]- diazepan-1-yl



347
5-methylthio  pyridin-3-yl
4- methoxy phenyl
[1,4]- diazepan-1-yl



348
5-methylthio  pyridin-3-yl
4- methoxy phenyl
3-amino- pyrrolidin-1-yl
3R


349
5-methoxy  pyridin-3-yl
4- methoxy phenyl
3-amino- pyrrolidin-1-yl
3R


350
5-methylthio  pyridin-3-yl
4- methoxy phenyl
3,3-dimethyl- piperazin-1-yl



351
5-methyl- pyridin-3-yl
4- methoxy phenyl
piperazin-1-yl



352
5-methyl- pyridin-3-yl
4- methoxy phenyl
3-amino- pyrrolidin-1-yl
3R


353
pyridin-3-yl
4- methoxy phenyl
4-methyl- piperazin-1-yl



354
pyridin-3-yl
4- methoxy phenyl
2-methyl- piperazin-1-yl
2S


355
pyridin-3-yl
4- methoxy phenyl
3,3-dimethyl- piperazin-1-yl



356
pyridin-3-yl
4- methoxy phenyl
3-methyl- piperazin-1-yl
3S


357
pyridin-3-yl
4- methoxy phenyl
3-methyl- piperazin-1-yl
3R


358
5-methyl- pyridin-3-yl
4- methoxy phenyl
[1,4]diazepan- 1-yl



359
pyridin-3-yl
4- methoxy phenyl
3,5-dimethyl- piperazin-1-yl
cis


360
5-methoxy pyridin-3-yl
4- methoxy phenyl
2-ethyl- piperazin-1-yl
2S


361
5-methoxy pyridin-3-yl
4- methoxy phenyl
3-ethyl- piperazin-1-yl
3R









BIOLOGICAL EXAMPLES
In Vitro Assays
Example 1
NG108-15, 24-Well Delta Opioid Receptor Binding Assay
Methods: NG108-15 cell membranes were purchased from Applied Cell Sciences (Rockville, Md.). 5 mg/mL of membrane protein was suspended in 10 mM TRIS-HCl pH 7.2, 2 mM EDTA, 10% sucrose. With several brief pulses from a Polytron homogenizer, each vial was homogenized in 5 mls of 50 mM Tris Buffer, pH 7.4. The homogenate was diluted in 50 mM Tris Buffer containing 5 mM MgCl2 to 330 ug/ml in the working solution for a final concentration of 133 ug/well. This particulate preparation was used for the 24-well delta opioid binding assay.
Following incubation with the delta selective peptide ligand  ̃0.2 nM [3H]Naltrindole at 25° C. for 2.5 h in a 24-well plate with total volume of 1 mL, the plate contents were filtered through a UniFilter24, GF/B. This plate was presoaked in 0.3% PEI and filtered through a 24-well Harvester. The UniFilter24 was rinsed three times with 2 mL of 10 mM HEPES (pH 7.4), and dried in an oven at 37° C. for 1.5 hours. To each well, was added 150 uL of Scint0 (PerkinElmer, Cat#6013611). The plates were then read on a TopCount.
Analysis: The data from the scintillation counter were used to calculate either the % inhibition compared to control binding (when only a single concentration of test compound was evaluated) or a Ki value (when a range of concentrations was tested). Non-specific binding (N.S.—1 mM Naloxone) is used as the negative control, while the Total Binding (T.B.—Membrane and ligand only) is used as the positive control. If one concentration is screened, the % inhibition is calculated as (cpms of total binding minus cpms of compound) divided by (cpms of T.B.minus cpms of N.S). The triplicate % Inhibitions are averaged and reported. If multiple concentrations are generated, the values are analyzed using the one-site binding non-linear regression program in Prism to determine Ki values. The bottom and top values are globally shared. The triplicate K is are then averaged and reported.
The data obtained are shown in Table 2, below.
Example 2
Rat Brain Delta Opioid Receptor Binding Assay
Procedure: Male, Wistar rats (150-250 g, VAF, Charles River, Kingston, N.Y.) were killed by CO2, and their brains were removed and placed immediately in ice cold Tris HCl buffer (50 mM, pH 7.4). The forebrains were separated from the remainder of the brain by a coronal transection, beginning dorsally at the colliculi and passing ventrally through the midbrain-pontine junction. After dissection, the forebrains were homogenized in Tris buffer in a Teflon®-glass homogenizer. The homogenate was diluted to a concentration of 1 g of forebrain tissue per 80 mL Tris and centrifuged at 39,000×g for 10 min. The pellet was resuspended in the same volume of Tris buffer containing 5 mM MgCl2 with several brief pulses from a Polytron homogenizer. This particulate preparation was used for the delta opioid binding assays. Following incubation with the delta selective peptide ligand  ̃4 nM [3H]DPDPE or 0.25 nM [3H]naltrindole at 25° C. for 2.5 h in a 96-well plate with total volume of 1 mL, the plate contents were filtered through Wallac filtermat B sheets on a Tomtec 96-well harvester. The filters were rinsed three times with 2 mL of 10 mM HEPES (pH 7.4), and dried in a 650 W microwave oven for 1.75 min twice. To each sample area 2×50 μL of Betaplate Scint scintillation fluid (LKB) was added and the radioactivity was quantified on a LKB (Wallac) 1205 BetaPlate liquid scintillation counter.
Analysis: The data from the scintillation counter were used to calculate either the % inhibition compared to control binding (when only a single concentration of test compound was evaluated) or a K, value (when a range of concentrations was tested). Percent inhibition was calculated as: [(total dpm-test compound dpm)/(total dpm-nonspecific dpm)]*100. Kd and Ki values were calculated using GraphPad PRISM data analysis program. The data obtained are shown in Table 2, below.
Example 3
Rat Brain Mu Opioid Receptor Binding Assay
Procedure: Male, Wistar rats (150-250 g, VAF, Charles River, Kingston, N.Y.) were killed by CO2, and their brains were removed and placed immediately in ice cold Tris HCl buffer (50 mM, pH 7.4). The forebrains were separated from the remainder of the brain by a coronal transection, beginning dorsally at the colliculi and passing ventrally through the midbrain-pontine junction. After dissection, the forebrains were homogenized in Tris buffer in a Teflon®-glass homogenizer. The homogenate was diluted to a concentration of 1 g of forebrain tissue per 80 mL Tris and centrifuged at 39,000×g for 10 min. The pellet was resuspended in the same volume of Tris buffer containing 5 mM MgCl2 with several brief pulses from a Polytron homogenizer. This particulate preparation was used for the mu opioid binding assays. Following incubation with the mu selective peptide ligand,  ̃0.8 nM [3H]DAMGO, at 25° C. for 2.5 h in a 96-well plate with total assay volume of 1 mL, the plate contents were filtered through Wallac filtermat B sheets on a Tomtec 96-well harvester. The filters were rinsed three times with 2 mL of 10 mM HEPES (pH 7.4), and dried in a 650 W microwave oven for 1.75 min twice. To each sample area 2×40 μL of Betaplate Scint scintillation fluid (LKB) was added and the radioactivity was quantifed on a LKB (Wallac) 1205 BetaPlate liquid scintillation counter.
Analysis: The data from the scintillation counter was used to calculate either the % inhibition compared to control binding (when only a single concentration of test compound was evaluated) or a Ki value (when a range of concentrations was tested). Percent inhibition was calculated as: [(total dpm-test compound dpm)/(total dpm-nonspecific dpm)]*100. Kd and Ki values were calculated using GraphPad PRISM data analysis program. The data obtained are shown in Table 2, below.







TABLE 2







Delta and Mu Opioid Receptor Binding Data












δ-binding
δ-binding
δ-binding




NG108 cell
(DPDPE
(Naltrindole



Cpd
membrane
ligand)
ligand)
μ-binding


No.
Ki (μm)
Ki (μM)
Ki (μM)
Ki (μM)














1

0.363

3.228


2

0.020
0.033
3.387,






3.139


3

0.142

2.345


4

2.217

>10


5


0.157
>10


6


0.116
9.007


7


0.013
2.169


8


0.00619
0.0428


9


0.001
2.968


10


0.034
2.000


11


0.005
3.083


12


0.018
4.516


13


0.002
5.568


14


0.001
1.731


15


0.0001
0.416


16


0.014
1.317


17


0.030
3.081


18


0.172
2.237


19


0.201
8.084


20


0.00493
0.146


21


0.201
2.387


22


0.000909
1.100


23


0.00125
0.214


24


0.001
1.064


25


0.000308
0.616


26


0.008
4.049


27


2.569
15.549


28


0.00610
0.295


29


0.086
2.663


30


0.003
1.087


31


0.031
0.837


32


0.0126
0.0641


33


0.029
0.029


34


0.015
0.015


35


0.184
0.184


36


0.003
4.769


37


0.010
>10


38


0.001
4.906


39


0.067
8.991


40


0.093
7.642


41


0.041
1.529


42


0.016
1.230


43


0.004
0.523


44


0.004
2.693


45


0.011
0.812


46


0.027
3.550


47


0.006
1.126


48


0.024
0.862


49


0.103
3.563


50


0.055
0.597


51


0.022
1.026


52


0.0004
0.539


53


0.0002
0.591


54
0.000188

0.00033
0.2172


55


0.021
2.046


56


0.015
1.944


57


0.011
0.113


58


0.004
0.640


59
0.00154

0.000954
1.610


60


0.014
1.523


61


0.259
3.988


62


0.544
1.915


63


0.037
0.633


64


0.008
0.466


65


0.003
0.555


66


0.010
0.390


67


0.001
1.561


68


0.002
0.465


69
0.000139

0.0041
0.196


70


0.047
2.253


72


0.002
0.732


73


0.003
1.102


74


0.026
1.062


75


0.036
5.117


76


0.111
0.333


77


0.154
0.313


78


0.075
1.878


79


0.095
>10


80


0.002
0.106


81


0.355
0.569


82


0.028
1.050


83


0.014
0.673


84


0.016
0.338


85


0.002
>10


86


0.002
1.176


87


0.072



88


0.014



89


0.010



90


0.009



91


0.022



92


0.035



93


0.008
0.554


94


0.143



95


0.011



96


0.035



97


0.039



98


0.003
0.102


99


0.059



100


0.033



101


0.007
0.058


102


0.003



103


0.011



104


0.008
0.190


105


0.003
0.421


106


0.006
0.042


107


0.001
0.039


108


0.107



109


0.001
0.522


110


0.033
1.071


111


0.009



112


0.006



113


0.045
1.433


114


0.008



115


0.052



117


0.157



118


0.155



119


4.018



120


0.104



121


0.020
0.379


122


0.122



123
0.0004





124
0.0003

0.126



125


0.078



126


0.565



127


0.224



128
0.0004





129
0.0003





130
0.002





131
0.0002





132
0.0004


0.061


133
0.0004





134
4.8084e−005


0.027


135
0.002





136
0.007





137
0.009





138
0.004





139
0.002





140
0.008





141
0.003





142
0.0002





143
0.001





144
0.007





145
0.005





146
0.0004





147
0.0004


0.438


148
0.001





149
0.001





150
0.0003





151
0.001





152
0.0004





153
0.001





154
0.009





155
0.005





156
0.001





157
0.040





158
1.604





159
4.452





160
0.338





161
0.795





162
0.852





163
6.386





164
2.283





165
3.765





166
0.027





167
0.021





168
0.050





169
0.033





275


0.046



276


0.227



277


0.032



278
0.00164

0.999



279


0.005



280


0.006



281
0.001





282
0.001





292


0.002



293


0.008



294
0.006





295
0.064





298


0.004



299


0.023
0.222


300


0.021



301
0.0005


0.658


302
0.001





304
0.002





* When compounds were tested more than once, the values have been reported as averages of their individual experiments.






Example 4
[35S]GTPγS Binding Assay in NG108-15 Cell Membranes (Delta Opioid Functional Assay)-200 nM Screen
Methods: NG108-15 cell membranes were purchased from Applied Cell Sciences (Rockville, Md.). 5 mg/mL of membrane protein was suspended in 10 mM TRIS-HCl pH 7.2, 2 mM EDTA, 10% sucrose. Membranes were maintained at 4-8° C. A 1 mL volume of membranes was added into 10 mL cold binding assay buffer. The assay buffer contained 50 mM Tris, pH 7.6, 5 mM MgCl2, 100 mM NaCl, 1 mM DTT and 1 mM EGTA. The membrane suspension was homogenized twice with a Polytron, and centrifuged at 3000 rpm for 10 min. The supernatant was then centrifuged at 18,000 rpm for 20 min. Ten mL assay buffer was added into the pellet containing tube. The pellet and buffer were mixed with a Polytron.
Incubation procedure: The pellet membranes (75 μg/mL) were preincubated with SPA (10 mg/mL) at 25° C. for 45 min in the assay buffer. The SPA (5 mg/mL) coupled with membranes (37.5 μg/mL) was then incubated with 0.1 nM [35S] GTPγS in the same Tris buffer containing 100 μM GDP in total volume of 200 μL. 200 nM of receptor agonists was used to stimulate [35S]-GTPγS binding. The basal binding was tested in the absence of agonists and non-specific binding was tested in the presence of 10 μM unlabeled GTPγS. The data were analyzed on a Packard Top Count and are shown in Table 3, below.
Data

% of Basal=(stimulated−non specific)*100/(basal−non specific). Relative Efficacy of a compound at 200 nM

=(% of Basal of test compound at 200 nM)/(Calculated Max of SNC80 dose response. Curve in prism).

Example 5
[35S]GTPγS Binding Assays in CHO-hMOR Cell Membranes (mu Opioid Functional Assay
Methods: CHO-hMOR cell membranes can be purchased from Receptor Biology, Inc. (Baltimore, Md.). About 10 mg/mL of membrane protein can be suspended in 10 mM TRIS-HCl pH 7.2, 2 mM EDTA, 10% sucrose, and the suspension kept on ice. A 1 mL volume of membranes can be added to 15 mL cold binding assay buffer containing 50 mM HEPES, pH 7.6, 5 mM MgCl2, 100 mM NaCl, 1 mM DTT and 1 mM EDTA. The membrane suspension can be homogenized with a Polytron and centrifuged at 3,000 rpm for 10 min. The supernatant can then be centrifuged at 18,000 rpm for 20 min. The pellet can be resuspended in 10 mL assay buffer with a Polytron. The membranes can be preincubated with wheat germ agglutinin coated SPA beads (Amersham) at 25° C. for 45 min in the assay buffer. The SPA bead (5 mg/mL) coupled membranes (10 μg/mL) can be then incubated with 0.5 nM [35S]GTPγS in the assay buffer. The basal binding can be that taking place in the absence of added test compound; this unmodulated binding can be considered as 100%, with agonist stimulated binding rising to levels significantly above this value. A range of concentrations of receptor agonist can be used to stimulate [35S]GTPγS binding. Both basal and non-specific binding can be tested in the absence of agonist; non-specific binding determination included 10 μM unlabeled GTPγS.
Compounds can be tested for function as antagonists by evaluating their potential to inhibit agonist-stimulated GTPγS binding. Radioactivity can be quantified on a Packard TopCount. The following parameters can be calculated:



  
    
      %
      ⁢
      
        
      
      ⁢
      stimulation
    
    =
    
      
        
          (
          
            
              test
              ⁢
              
                
              
              ⁢
              compound
              ⁢
              
                
              
              ⁢
              cpm
            
            -
            
              non
              ⁢
              
                -
              
              ⁢
              specific
              ⁢
              
                
              
              ⁢
              cpm
            
          
          )
        
        
          
            (
            
              
                basal
                ⁢
                
                  
                
                ⁢
                cpm
              
              -
              
                non
                ⁢
                
                  -
                
                ⁢
                specific
                ⁢
                
                  
                
                ⁢
                cpm
              
            
            )
          
          .
        
      
      ×
      100
    
  




  
    
      %
      ⁢
      
        
      
      ⁢
      inhibition
    
    =
    
      
        
          (
          
            
              %
              ⁢
              
                
              
              ⁢
              stimulation
              ⁢
              
                
              
              ⁢
              by
              ⁢
              
                
              
              ⁢
              1
              ⁢
              
                
              
              ⁢
              μM
              ⁢
              
                
              
              ⁢
              DAMGO
            
            -
            
              

            
            ⁢
            
              
            
            ⁢
            
              %
              ⁢
              
                
              
              ⁢
              stimulation
              ⁢
              
                
              
              ⁢
              by
              ⁢
              
                
              
              ⁢
              test
              ⁢
              
                
              
              ⁢
              compound
            
          
          )
        
        
          (
          
            
              %
              ⁢
              
                
              
              ⁢
              stimulation
              ⁢
              
                
              
              ⁢
              by
              ⁢
              
                
              
              ⁢
              1
              ⁢
              
                
              
              ⁢
              μM
              ⁢
              
                
              
              ⁢
              DAMGO
            
            -
            100
          
          )
        
      
      ×
      100
    
  



EC50 values can be calculated using GraphPad Prism and are shown in Table 3, below.








TABLE 3







Delta and Mu Opioid Receptor Functional Data

















GTPγS







GTPγS
δ-opioid
GTPγS
GTPγS



GTPγS
GTPγS
δ-opioid
receptor
μ-opioid
μ-opioid



δ-
δ-opioid
receptor
% Inh
receptor
receptor


Cpd
RelEfficacy
receptor
Rel
@10
EC50
% Inh


No.
@200 nM
EC50 (μM)
Efficacy
μM
(μM)
@10 μM
















2

0.430;
0.733
5.790






0.069


5

0.164
0.803
18.100


7

0.436
0.912
17.066


8

0.0681
0.848
23.626

2.480


56

0.536
0.909
26.261


57

0.032
0.828
9.212


58

1.514
0.823
12.772


59

0.433
1.0063
1.478


60

0.089
0.926
3.735


63

0.693
0.993


64

0.088
0.830
12.034


65

0.339
0.824


66

0.568
0.760
5.771


67

0.194
0.944


68

0.031
0.912


11.460


69

0.0085
1.004

>10
22.837


72

0.105
0.905
15.204


73

0.059
0.956


74

0.856
0.868
2.367


80

0.113
1.049


85

>10


86

0.386
0.633


88

0.478
0.538


89

1.315
0.963


90

0.923
1.045


91

>10


92

0.470
1.183


93

0.072
1.115


95

0.708
1.025


96

0.749
0.942


97

7.119
1.128


98

0.106
1.060


99

0.939
1.007


100

1.625
1.019


101

0.103
1.096

>10
16.560


102

0.255
0.989


103

0.311
1.066


104

0.018
0.921


105

0.146
1.099


106

0.027
1.019

>10
16.954


107
1.046
0.0213
0.957

5.100
4.050


109

0.057
1.102


110

0.081
0.986


111

0.491
1.031


112

0.330
1.082


113

0.075
1.104


114

0.306
1.088


115

2.710
1.039


120


121

0.019
1.010


122


123
0.653
0.057
1.124


128

0.453
1.144


129
0.633
0.0551
0.976


130
0.245


131
0.819
0.076
1.063


132

0.015
1.042

9.277
9.396


133
0.755
0.028
1.041


134

0.004
1.087

2.785
1.000


135

1.383
1.023


136

9.005
0.789


137

>10


138

1.340
0.882


139

2.266
1.118


140
0.137


141
0.149


142
0.931
0.029
1.006


143

0.690
1.066


144
0.191


145

4.024
1.180


146

0.387
1.197


147

0.051
1.077


148
0.411
0.158
1.052


149
0.403
0.236
1.026


150
0.801
0.033
1.093


151
0.704
0.119
1.121


152
0.607
0.070
1.083


153
0.454
0.193
1.120


154
0.164


155
0.170


156

0.177
0.967


157
0.213


166
0.169


167
0.328


168
0.300


170
0.176


171
0.257


172
0.246


173
0.249


174
0.205


175
0.005


176
0.112


177
0.511
0.255
1.389


178
0.578
0.300
1.239


179
0.601
0.119
1.182


180
0.250


181
0.139


182
0.470
0.377
1.065


183
0.723
0.091
1.091


184
0.497
0.418
1.271


185
0.447
0.101
1.014


186
0.466
0.331
1.113


187
0.497
0.160
1.104


188
0.779
0.219
1.950


189
0.375


190
0.222


191
0.410


192
0.135


193
0.801
0.032
1.090


194
0.665
0.022
1.034


195
0.477
0.194
1.119


196
0.800
0.0693
1.146


197
0.411
0.145
1.289


198
0.513
0.118
1.050


199
0.615
0.033
1.140


200
0.289


201
0.148


202
0.122


203
0.096


204
0.911
0.026
0.982


205
0.609
0.044
1.178


206
0.292


207
0.963
0.002
1.047


208
0.398


209
0.002


210
0.730
0.044
1.150


211
0.814
0.106
1.050


212
0.161


212
0.658
0.029
0.994


213
0.079


214
0.115


215
0.674
0.128
1.002


216
0.406
0.494
0.969


217
0.480
0.612
0.882


218
0.642
0.353
0.960


219
0.475
>1


220
0.457
0.454
0.890


221
0.324


222
0.284


223
0.802
0.152
0.986


224
0.460
0.214
1.104


225
0.260
0.483
0.718


226
0.320


227
0.480
0.246
1.093


228
1.039
0.006
1.082


229
0.715
0.061
0.890


230
0.847


231
1.159
0.005
1.113


232
0.679
0.143
1.021


233
0.549


234
0.847
0.034
0.987


7.287


235
0.962
0.00733
0.953


236
1.026
0.0170
1.042


6.203


237





3.524


238

0.008
0.966


239
0.348


240
0.376


241
0.381


242
0.413


243
0.433


244
0.354


245

0.0127
1.095


4.259


246

0.078
1.043


248
0.754
0.047
1.084


249
1.000
0.011
0.940


250
0.912
0.026
1.022


251
0.955
0.015
1.145


252

0.025
1.007


2.480


253

0.0168
0.997


254

0.151
0.928


255

0.0464
0.997


17.090


256

0.034
1.004


6.203


257

0.095
0.830


258

0.075
0.835


259

0.0749
1.030


260

0.300
0.937


261

0.241
0.979


262

0.037
0.957


263

0.027
0.869


264

0.120
1.036


265

0.053
1.024


266

0.018
1.041


267

0.121
0.920


268

0.081
1.023


269

0.053
0.984


270

0.197
0.820


271

0.185
0.745


272

>1


273

0.026
1.001


274

0.286
0.863


275

0.922
1.024


276


277

1.092
1.012


278
0.263


279

0.170
1.004


280

0.181
0.998


281
0.221


282
0.349


284
0.600
0.055
0.609


285
0.730
0.027
0.782


286
0.1


287
0.640


288
0.428


289
0.402


290
0.398


291
0.303


292

0.363
0.958


293

0.317
0.975


294

>10


296

0.429
0.938


297

0.424
0.820


298

0.087
1.012


299

0.129
0.840


300

1.052
0.968


301

0.087
1.085


302
0.393


303
0.622
0.114
1.047


304
0.228


305
0.780
0.090
1.081


306
0.910
0.031
1.127


307
0.880
0.011
1.191


308
0.140


309

0.035
1.162


310

0.031
1.042


311

0.0987
0.936


312

0.00435
1.007


313

0.131
1.033


314

0.206
0.840


315

0.042
1.019


316

0.00338
0.977


317

>1


318


0.539


319

0.112
0.871


320

0.191
0.918


321

0.005
1.022


322

0.196
0.960


323

0.060
0.988


324
0.519
0.428
1.045


325
0.866
0.011
1.042


326
0.744
0.032
1.104


327
0.471
0.0527
1.037


4.259


328
0.377


329
0.475
0.138
1.006


330
0.547
0.051
0.894


331
0.764
0.108
0.928


332
0.393


333
0.664
0.118
1.116


334
0.423


335
0.050


336
0.830
0.0502
1.009


17.090


338
0.723
0.197
0.956


339
0.641


341

0.041
0.788


0.000


342

0.0439
1.020


343
0.985
0.001
1.105

1.977
7.287


344
0.808
0.047
1.089


345
0.989
0.001
1.089

1.934
0.000


346

0.0470
1.031


347

0.069
0.898


−0.404


348

0.101
0.689


349

0.082
0.929


0.000


350

0.083
1.079


351

0.0249
1.036


351

0.034
1.056


352

0.079
0.967


353

0.270
0.651


354

0.026
1.050


355

0.022
1.002

0.243
0.000


356

0.031
1.030


357

0.005
0.929

1.831
11.460


358

0.0242
0.978


359

0.034
0.709


360

0.013
1.015


361

0.070
0.962





* When compounds were tested more than once, the values have been reported as averages of their individual experiments.






In Vivo Assays
Example 6
CFA-Induced Paw Radiant Heat Hypersensitivity
Each rat was placed in a test chamber on a warm glass surface and allowed to acclimate for approximately 10 min. A radiant thermal stimulus (beam of light) was then focused through the glass onto the plantar surface of each hind paw in turn. The thermal stimulus was automatically shut off by a photoelectric relay when the paw was moved or when the cut-off time was reached (20 sec for radiant heat at  ̃5 amps). An initial (baseline) response latency to the thermal stimulus was recorded for each animal prior to the injection of complete Freund's adjuvant (CFA). Twenty-four hours following intraplantar CFA injection, the response latency of the animal to the thermal stimulus was then re-evaluated and compared to the animal's baseline response time. Only rats that exhibited at least a 25% reduction in response latency (i.e., were hyperalgesic) were included in further analysis. Immediately following the post-CFA latency assessment, test compound or vehicle (usually Solutol, hydroxypropyl methylcellulose HPMC, hydroxypropyl beta-cyclodextrin HPRCD, or PEG-400) was administered i.p. or p.o. to rats. Post-compound treatment withdrawal latencies were assessed at fixed time intervals, typically 30, 60, 100, 120, 180, and 300 min. The percent reversal (% R) of hypersensitivity was calculated according to the following formula:

% reversal=[(treatment response−post CFA response)]/[(baseline response−post CFA response)]×100.

Results are expressed as an average of % reversal values for individual animals, +/−SEM (Standard Error of the Mean).
ED50 values and associated statistics were calculated with PharmTools Pro software (The McCary Group Inc., Schnecksville. Pa.).







TABLE 4







Time-course studies: The term “Algos” denotes a study run at a


contract lab under the same conditions as internal studies)




















maximum %




dose

route of
no. of
last time
reversal @ time
+/−


Cpd
(mg/kg)
vehicle
admin.
animals
point (min)
(min)
SEM

















8
30
0.5% HPMC
p.o.
6
100
49.0
16.4


8
100
0.5% HPMC
p.o.
6
100
64.8
10.0


8
100
0.5% HPMC
p.o.
7
180
12.5@ 30′
54.6








46.5@ 60′
34.0


8
100
0.5% HPMC
p.o.
9
180
27.7 @ 30′
17.6


8
100
0.5% HPMC
p.o.
10
180
 75.1 @ 180′
17.2


Algos


23
100
0.5% HPMC
p.o.
8
240
 75.8 @ 120′
17.6


23
100
0.5% HPMC
p.o.
8
120
 23.1 @ 120′
19.1


23
100
0.5% HPMC
p.o.
10
180
 76.8 @ 120′
21.3


54
100
0.5% HPMC
p.o.
8
120
17.8 @ 60′
14.1


54
100
0.5% HPMC
p.o.
8
180
 32.7 @ 180′
8.9


69
100
0.5% HPMC
p.o.
8
60
10.1 @ 60′
6.7


69
100
0.5% HPMC
p.o.
8
180
55.7 @ 60′
16.7


Algos


69
100
0.5% HPMC
p.o.
8
180
 65.4 @ 180′
15.8


Algos


107
100
0.5% HPMC
p.o.
9
240
 52.8 @ 120′
17.3


235
30
0.5% HPMC
p.o.
9
240
43.7 @ 60′
20.1


238
30
0.5% HPMC
p.o.
9
240
39.5 @ 60′
18.4


253
30
0.5% HPMC
p.o.
9
240
75.9 @ 60′
11.9


327
30
0.5% HPMC
p.o.
9
240
101.8 @ 60′ 
28.2


336
30
0.5% HPMC
p.o.
9
120
23.4 @ 30′
12.6


346
30
0.5% HPMC
p.o.
8
120
37.0 @ 30′
27.1


351
30
0.5% HPMC
p.o.
8
120
 9.8 @ 30′
10.3


354
30
0.5% HPMC
p.o.
9
120
24.7 @ 60′
5.4
















TABLE 5







Dose-response studies:



















time





doses

route of
no. of
point
ED50


Cpd
(mg/kg)
vehicle
admin.
animals
(min)
(mg/kg)
SEM

















23
10, 30, 100,
0.5%
p.o.
8
120
35.35
18.2



300
HPMC


107
10, 30, 100,
0.5%
p.o.
8
120
32.0
8.0



300
HPMC


327
 3, 10, 30
20%
p.o.
8
60
14.3
3.1




HPβCD









Example 7
Mouse Graded Abdominal Irritant Test (GrAIT)
Test compound or vehicle was administered s.c. to mice. Following the pretreatment time, an i.p. injection of 0.6% of acetic acid in 0.5 mL was administered. Five min after acetic acid administration, mice were placed into clear chambers and were continuously observed for 5 min. Behavioral responses including twisting and elongation of the body that extended through the hindlimbs were counted and averaged for the group of animals over the observation period.














TABLE 6











#








Pre-
abdominal
# abdominal



dose

route of
no. of
treatment
stretches
stretches


Cpd
(mg/kg)
vehicle
admin.
animals
(min)
(vehicle)
(compound)






















8
30
10% Solutol
s.c.
10
30
20.8
18.9


20
30
10% Solutol
s.c.
10
30
14.1
19.8


22
30
10% Solutol
s.c.
10
30
19.8
16.0


22
30
10% Solutol
s.c.
10
30
13.0
18.6


22
100
10% Solutol
s.c.
10
30
19.8
17.4


22
300
10% Solutol
s.c.
10
30
19.8
20.3


23
30
10% Solutol
s.c.
10
30
13.6
16.7


24
30
10% Solutol
s.c.
10
30
15.5
16.9


25
30
10% Solutol
s.c.
10
30
15.5
12.3


26
30
10% Solutol
s.c.
10
30
13.6
16.7

## Claims

1. A compound of Formula I



wherein
R1 is selected from the group consisting of
i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkyl, C2-4alkenyl, C2-4alkynyl, C1-4-alkoxy, C1-4alkylthio, hydroxy, chloro, and fluoro; in addition, phenyl is optionally substituted with a single amino, C1-4-alkylamino, di(C1-4-alkyl)amino, di(C1-4alkyl)aminocarbonyl, C1-4-alkylaminocarbonyl, hydroxy(C1-4alkyl, aminocarbonyl, C1-4-alkylcarbonylamino, C1-4alkoxycarbonylamino, ureido, C1-4alkylureido, di(C1-4-alkyl)ureido, cyano, trifluoromethoxy, C1-4-alkylsulfonyl, nitro, trifluoromethyl, bromo, piperazin-1-yl optionally substituted with 4-C1-4alkyl, morpholin-4-yl, phenyl, formamido, or pyridinyl substituent;
and wherein the phenyl and pyridinyl substituents of the R1-phenyl are each optionally substituted with one substituent selected from the group consisting of C1-4alkyl, C1-4-alkoxy, C1-4-alkylthio, fluoro, chloro, cyano, amino, and hydroxy;

ii) pyrimidinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, and hydroxy; in addition, pyrimidinyl is optionally substituted with a single amino, C1-4-alkylamino, di(C1-4-alkyl)amino, di(C1-4-alkyl)aminocarbonyl, C1-4alkylaminocarbonyl, hydroxy(C1-4alkyl, aminocarbonyl, C1-4alkylcarbonylamino, C1-4-alkoxycarbonylamino, ureido, C1-4-alkylureido, di(C1-4alkyl)ureido, cyano, trifluoromethoxy, C1-4-alkylsulfonyl, nitro, trifluoromethyl, bromo, piperazin-1-yl optionally substituted with 4-C1-4-alkyl, morpholin-4-yl, formamido, pyrrol-1-yl, phenyl, pyridinyl or piperidin-1-yl substituent;
and wherein the phenyl and pyridinyl substituents of the R1-pyrimidinyl are each optionally substituted with one substituent selected from the group consisting of C1-4alkyl, C1-4-alkoxy, C1-4-alkylthio, fluoro, chloro, cyano, amino, and hydroxy;

iii) pyridinyl optionally substituted with one to two substituents independently selected form the group consisting of C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, hydroxy, fluoro, chloro, and cyano; in addition, pyridinyl is optionally substituted with a single hydroxymethyl, amino, C1-4-alkylamino, di(C1-4-alkyl)amino, C1-4alkylsulfonyl, aminocarbonyl, C1-4-alkylaminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-4-alkylcarbonylamino, C1-4-alkoxyaminocarbonyl, ureido, C1-4-alkylureido, di(C1-4-alkyl)ureido, piperazin-1-yl, morpholin-4-yl, phenyl, or pyridinyl;
and, wherein the phenyl and pyridinyl substituents of the R1-pyridinyl are optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkyl, C1-4-alkoxy, C1-4-alkylthio, fluoro, chloro, cyano, amino, and hydroxy; and

iv) a G-substituent selected from the group consisting of naphthyl, pyrazolyl, thienyl, benzothiazolyl, benzimidazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, pyrazinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, isoxazolyl, oxazolyl, pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl, dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, benzothiophenyl, indazolyl, and 2,3-dihydrobenzo[1,4]dioxinyl;
wherein G is optionally independently substituted with one to two substituents selected from the group consisting of C1-4-alkyl, C1-4-alkoxy, fluoro, chloro, bromo, cyano, C1-4-alkylcarbonyl, amino, C1-4-alkylamino, and di(C1-4alkyl)amino;

R2 is
(i) phenyl optionally substituted with one to three substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluoro, chloro, and hydroxy; in addition, phenyl of R2 is optionally substituted with a single amino, C1-4alkylamino, di(C1-4alkyl)amino, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl, C1-4alkylaminocarbonyl, di(C1-4)alkylaminocarbonyl, C1-4-alkylcarbonylamino, 2,2,2-trifluoroethoxy, cyano, C3-7cycloalkylcarbonylamino, hydroxy(C1-4alkyl, C1-4alkoxy(C1-4)alkyl, C1-4-alkoxy-(C1-4)alkoxy, C1-4alkylcarbonyloxy, C1-4alkylsulfonylamino, C1-4alkylsulfonyl, pyridinyl(C1-4)alkyl, benzyloxycarbonylamino, 4-methyl-piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, carboxy, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, C3-7cycloalkyl, C3-7cycloalkyl-(C1-3)alkyl, or C3-7cycloalkyl-(C1-3)alkoxy substituent;
(ii) 1,2-dihydrobenzofuranyl; provided that 1,2-dihydrobenzofuranyl is bound to 0 of Formula (I) at the benzo portion of the ring; and wherein the benzo portion of 1,2-dihydrobenzofuranyl is optionally independently substituted with one to two substituents selected from the group consisting of C1-4-alkyl, fluoro, chloro, bromo, cyano, C1-4-alkylcarbonyl, amino, C1-4alkylamino, and di(C1-4alkylamino;
or
(iii) heteroaryl selected from the group consisting of benzothiazolyl, benzooxazolyl, pyridinyl, pyrimidinyl, indazolyl, quinolinyl, quinazolinyl, benzimidazolyl, pyrazinyl, triazinyl, benzothiophenyl, benzofuranyl, and isoquinolinyl;
wherein heteroaryl of R2 is optionally independently substituted with one to two substituents selected from the group consisting of C1-4-alkyl, fluoro, chloro, bromo, cyano, C1-4alkylcarbonyl, amino, C1-4alkylamino, and di(C1-4alkylamino;

A-L- is selected from the group consisting of a1-L1-; a2-L2-; a3-L3-; a4-L4-; and a5-L5-; wherein L1 is absent or C1-4-alkyl;
a1 is bound through a carbon atom to L1 and is selected from the group consisting of
i) pyrrolidinyl optionally substituted at carbon with C1-4-alkyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, aminomethyl, hydroxy, cyano, C1-4alkoxy, C1-4alkoxycarbonyl, or one to two fluoro substituents; and wherein pyrrolidinyl is optionally substituted at nitrogen with C1-4-alkyl, phenyl(C1-4)alkyl, C1-4alkylcarbonyl, C1-4-alkoxycarbonyl, or phenyl(C1-4)alkoxycarbonyl;
ii) piperidinyl optionally substituted with C1-4-alkyl, phenyl, amino, C1-4-alkylamino, di(C1-4-alkyl)amino, aminomethyl, hydroxy, cyano, C1-4-alkoxy, C1-4alkoxycarbonyl, phenyl(C1-4)alkyl, C1-4-alkylcarbonyl, or phenyl(C1-4)alkoxycarbonyl;
and
iii) azetidinyl optionally substituted with 3-amino, 3-hydroxy, 3-C1-4-alkoxy, C1-4alkyl, or aminomethyl;
provided that when L1 is absent, a1 is attached to N(Ra) via a carbon atom other than that which is alpha to a nitrogen atom of a1;
and provided that when a1 is substituted with a substituent containing an oxygen or nitrogen radical as a point of attachment to a1, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a1;
L2 is C1-4alkyl;
a2 is bound through a carbon atom to L2 and is selected from the group consisting of
i) piperazinyl optionally substituted at carbon with C1-4-alkyl, aminomethyl, cyano, or C1-4-alkoxycarbonyl; and wherein piperazinyl is optionally substituted at nitrogen with C1-4-alkyl, phenyl(C1-4)alkyl, C1-4-alkylcarbonyl, C1-4-alkoxycarbonyl, or phenyl(C1-4)alkoxycarbonyl;
and
iii) morpholinyl optionally independently substituted with phenyl(C1-4)alkyl or one to two C1-4alkyl substituents;
L3 is methylene;
a3 is imidazolyl optionally independently substituted with one to two C1-4alkyl substituents;
L4 is (C2-6)alkyl; and when L4 is C3-6alkyl, L4 is optionally substituted with chloro, hydroxy or C1-4-alkoxy; provided that the chloro, hydroxy, and C1-4-alkoxy substituents are not alpha to a nitrogen-bearing carbon atom;
a4 is selected from the group consisting of amino and C1-4-alkylamino;
provided that a4 is attached at a carbon atom other than that alpha to N(Ra);
L5 is absent or C1-4-alkyl;
a5 is C3-7cycloalkyl substituted with RB; wherein RB is selected from the group consisting of amino, C1-4alkylamino, di(C1-4alkyl)amino, aminomethyl, C1-4alkylamino-methyl, and di(C1-4alkyl)amino-methyl;
provided that when RB contains a nitrogen radical as the point of attachment to C3-7cycloalkyl, the attachment is at a carbon atom other than that alpha to N(Ra);
or,
A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of
i) pyrrolidinyl wherein pyrrolidinyl is optionally substituted with C1-4-alkyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, aminomethyl, cyano, C1-4alkoxy, C1-4alkoxycarbonyl, or phenyl;
ii) piperazinyl optionally substituted with 4-C1-4-alkyl; and wherein piperazinyl is optionally independently substituted at carbon with one to two C1-4-alkyl substituents, 2-oxo, 3-oxo, trifluoromethyl, aminomethyl, or hydroxymethyl
iii) piperidinyl optionally substituted with one to two C1-4alkyl substituents, amino, C1-4alkylamino, di(C1-4alkyl)amino, aminomethyl, hydroxy, cyano, C1-4alkoxy, C1-4-alkoxycarbonyl, phenyl, phenyl(C1-4)alkyl, or one to two fluoro substituents;
and, wherein the phenyl and the phenyl portion of phenyl(C1-4)alkyl are optionally substituted with C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluoro, chloro, cyano, amino, or hydroxy;
iv) azetidinyl optionally substituted with 3-amino or 3-aminomethyl;
v) [1,4]diazepan-1-yl optionally substituted with one to two C1-4alkyl substituents; and
vi) 3,6-diazoabicyclo[3.1.1]hept-3-yl optionally substituted with one to two C1-4-alkyl substituents;
Ra is hydrogen or C1-4-alkylcarbonyl;
provided that a compound of Formula (I) is other than a compound selected from the group consisting of
a compound wherein R1 is 4-fluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
a compound wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is (S)-morpholin-3-yl, L2 is methyl, Ra is H, and X is O; a compound wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-(piperidin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is (5)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
a compound wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
a compound wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2-methyl-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
a compound wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, RB is 2-amino, Ra is H, and X is O;
and
a compound wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-diethylaminocarbonyl-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein R1 is selected from the group consisting of
i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkyl, C1-4-alkoxy, hydroxy, chloro, and fluoro; in addition, phenyl is optionally substituted with a single amino, di(C1-4-alkyl)amino, di(C1-4alkyl)aminocarbonyl, hydroxy(C1-4alkyl, aminocarbonyl, C1-4alkylcarbonylamino, cyano, trifluoromethoxy, C1-4alkylsulfonyl, nitro, trifluoromethyl, or phenyl substituent;
ii) pyrimidinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkoxy, C1-4-alkylthio, and hydroxy; in addition, pyrimidinyl is optionally substituted with a single cyano, morpholin-4yl, amino, di(C1-4-alkyl)amino, or piperazin-1-yl optionally substituted with 4-C1-4alkyl substituent;
iii) pyridinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, hydroxy, fluoro, chloro, and cyano; in addition, pyridinyl is optionally substituted with a single hydroxymethyl, amino, aminocarbonyl, C1-4-alkylsulfonyl, or pyridinyl substituent;
wherein the pyridinyl substituent of the R1-pyridinyl is optionally independently substituted with one to two substituents selected from the group consisting of chloro and methyl;
and

iv) a G-substituent selected from the group consisting of naphthyl, pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, pyrazinyl, quinoxalinyl, oxazolyl, pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl, dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl;
wherein G is optionally independently substituted with one to two substituents selected from the group consisting of C1-4-alkyl, fluoro, and chloro.

3. The compound of claim 2 wherein R1 is selected from the group consisting of
i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkyl, C1-4-alkoxy, hydroxy, chloro, and fluoro; in addition, phenyl is optionally substituted with a single amino, di(C1-4-alkyl)amino, di(C1-4alkyl)aminocarbonyl, hydroxy(C1-4alkyl, aminocarbonyl, C1-4alkylcarbonylamino, cyano, trifluoromethoxy, C1-4alkylsulfonyl, nitro, trifluoromethyl, or phenyl substituent;
ii) pyrimidinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkoxy, C1-4-alkylthio, and hydroxy; in addition, pyrimidinyl is optionally substituted with a single cyano, morpholin-4-yl, amino, di(C1-4-alkyl)amino, or piperazin-1-yl optionally substituted with 4-C1-4alkyl substituent;
iv) pyridinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, hydroxy, fluoro, chloro, and cyano; in addition, pyridinyl is optionally substituted with a single hydroxymethyl, amino, C1-4-alkylsulfonyl, or pyridinyl substituent;
wherein the pyridinyl substituent of the R1-pyridinyl is optionally independently substituted with one to two substituents selected from chloro and methyl;
and

iv) a G-substituent selected from the group consisting of naphthyl, pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, pyrazinyl, quinoxalinyl, oxazolyl, pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl, dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl;
wherein G is optionally independently substituted with one to two C1-4-alkyl substituents.

4. The compound of claim 3 wherein R1 is selected from the group consisting of
i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkyl, C1-2alkoxy, hydroxy, chloro, and fluoro; in addition, phenyl is optionally substituted with a single amino, di(C1-4-alkyl)amino, di(C1-4alkyl)aminocarbonyl, hydroxy(C1-4alkyl, aminocarbonyl, C1-4alkylcarbonylamino, cyano, trifluoromethoxy, C1-4alkylsulfonyl, nitro, trifluoromethyl, or phenyl substituent;
ii) pyrimidinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkoxy and C1-4-alkylthio; in addition, pyrimidinyl is optionally substituted with a single cyano, morpholin-4-yl, di(C1-4alkyl)amino, or piperazin-1-yl optionally substituted with 4-C1-4alkyl substituent;
iii) pyridinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, hydroxy, fluoro, chloro, and cyano; in addition, pyridinyl is optionally substituted with a single hydroxymethyl, amino, C1-4-alkylsulfonyl, or pyridinyl substituent;
wherein the pyridinyl substituent of the R1-pyridinyl is optionally independently substituted with one to two substituents selected from chloro and methyl;

and
iv) a G-substituent selected from the group consisting of naphthyl, pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, pyrazinyl, quinoxalinyl, pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl, dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl;
wherein G is optionally substituted with one C1-4alkyl substituent.

5. The compound of claim 4 wherein R1 is selected from the group consisting of
i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkyl, C1-2alkoxy, hydroxy, and fluoro; in addition, phenyl is optionally substituted with a single amino, di(C1-4-alkyl)amino, di(C1-4-alkyl)aminocarbonyl, hydroxy(C1-4alkyl, aminocarbonyl, C1-4alkylcarbonylamino, cyano, trifluoromethoxy, C1-4-alkylsulfonyl, nitro, or trifluoromethyl substituent;
ii) pyrimidinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkoxy and C1-4-alkylthio; in addition, pyrimidinyl is optionally substituted with a single cyano, morpholin-4-yl, di(C1-4alkyl)amino, or piperazin-1-yl optionally substituted with 4-C1-4alkyl substituent;
iii) pyridinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, hydroxy, fluoro, chloro, and cyano; in addition, pyridinyl is optionally substituted with a single hydroxymethyl or amino substituent;
and

iv) a G-substituent selected from the group consisting of pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, and benzo[1,2,5]oxadiazolyl;
wherein G is optionally substituted with one C1-4alkyl substituent.

6. The compound of claim 5 wherein R1 is selected from the group consisting of
i) phenyl optionally substituted with a substituent selected from the group consisting of C1-2alkyl, C1-2alkoxy, hydroxy, and fluoro; or, phenyl is optionally substituted with one substituent selected from the group consisting of amino, di(C1-4alkyl)amino, di(C1-4-alkyl)aminocarbonyl, hydroxymethyl, aminocarbonyl, C1-4alkylcarbonylamino, cyano, trifluoromethoxy, C1-2alkylsulfonyl, nitro, and trifluoromethyl;
ii) pyrimidinyl optionally substituted with one to two substituents selected from the group consisting of C1-4-alkoxy and C1-4-alkylthio; or, pyrimidinyl is optionally substituted with one substituent selected from the group consisting of morpholin-4-yl, di(C1-4-alkyl)amino, and piperazin-1-y optionally substituted with 4-methyl;
iii) pyridinyl optionally substituted with one to two substituents selected from the group consisting of C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, hydroxy, fluoro, and chloro; or, pyridinyl optionally substituted with one substituent selected from the group consisting of cyano, hydroxymethyl, and amino;
iv) a G-substituent selected from the group consisting of pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, and benzo[1,2,5]oxadiazolyl;
wherein G is optionally substituted with one C1-4alkyl substituent.

7. The compound of claim 1 wherein R2 is
(i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, one to two fluoro substituents, chloro, and hydroxy; in addition, phenyl is optionally substituted with a single amino, fluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl, di(C1-4)alkylaminocarbonyl, C1-4-alkylcarbonylamino, 2,2,2-trifluoroethoxy, cyano, C3-7cycloalkylcarbonylamino, hydroxy(C1-4alkyl, C1-4-alkoxy(C1-4)alkyl, C1-4-alkoxy-(C1-4)alkoxy, C1-4-alkylcarbonyloxy, C1-4-alkylsulfonylamino, C1-4-alkylsulfonyl, pyridinyl(C1-4)alkyl, benzyloxycarbonylamino, 4-methyl-piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, carboxy, piperidin-1-ylcarbonyl, or morpholin-4-ylcarbonyl substituent;
or,

(ii) heteroaryl selected from the group consisting of benzothiazolyl, benzooxazolyl, and pyridinyl; wherein heteroaryl is optionally independently substituted with one to two C1-4alkyl substituents.

8. The compound of claim 7 wherein R2 is
(i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-2alkoxy, C1-4-alkylthio, one to two fluoro substituents, chloro, and hydroxy; in addition, phenyl is optionally substituted with a single amino, fluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl, C1-4alkylcarbonylamino, C1-4alkylcarbonyloxy, 2,2,2-trifluoroethoxy, benzyloxycarbonylamino, hydroxy(C1-4alkyl, or C1-4-alkoxy(C1-4alkyl substituent;
or,
(ii) heteroaryl selected from the group consisting of benzothiazolyl and benzooxazolyl; wherein heteroaryl is optionally independently substituted with one to two C1-4alkyl substituents.

9. The compound of claim 8 wherein R2 is
(i) phenyl optionally substituted with one to two substituents selected from the group consisting of C1-4alkyl, C1-2alkoxy, C1-4alkylthio, one to two fluoro substituents, chloro, and hydroxy; in addition, phenyl is optionally substituted with a single amino, fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl, C1-4-alkylcarbonylamino, C1-4-alkylcarbonyloxy, 2,2,2-trifluoroethoxy, or C1-4-alkoxy(C1-4alkyl substituent;
or,

(ii) heteroaryl selected from the group consisting of benzothiazolyl and benzooxazolyl; wherein heteroaryl is optionally independently substituted with one to two C1-4alkyl substituents.

10. The compound of claim 9 wherein R2 is phenyl optionally substituted with one to two substituents selected from the group consisting of C1-2alkyl, C1-2alkoxy, C1-2alkylthio, fluoro, 3-chloro, 4-chloro, and hydroxy; or phenyl is optionally substituted with one substituent selected from the group consisting of amino, difluoromethoxy, trifluoromethoxy, aminocarbonyl, C1-4-alkylcarbonylamino, C1-4-alkylcarbonyloxy, and 2,2,2-trifluoroethoxy;
or, R2 is a heteroaryl selected from the group consisting of benzothiazolyl and benzooxazolyl; wherein heteroaryl of R2 is optionally independently substituted with one to two C1-2alkyl substituents.

11. The compound of claim 10 wherein R2 is
(i) phenyl optionally substituted with one substituent selected from the group consisting of C1-2alkyl, C1-2alkoxy, C1-2alkylthio, one to two fluoro substituents, 3-chloro, 4-chloro, and hydroxy; or, phenyl is optionally substituted with one substituent selected from the group consisting of amino, difluoromethoxy, trifluoromethoxy, aminocarbonyl, C1-4-alkylcarbonylamino, C1-4alkylcarbonyloxy, and 2,2,2-trifluoroethoxy;
or,
(ii) heteroaryl selected from the group consisting of benzothiazolyl and benzooxazolyl; wherein heteroaryl of R2 is optionally independently substituted with one to two C1-2alkyl substituents.

12. A compound of claim 1 wherein A-L- is selected from the group consisting of a1-L1-; a2-L2; a3-L3-; a4-L4-; and a5-L5-; wherein
L1 is absent or C1-4-alkyl;
a1 is bound through a carbon atom to L1 and is selected from the group
consisting of
i) pyrrolidinyl optionally substituted at carbon with amino, hydroxy, or one to two fluoro substituents;
ii) piperidinyl;
and
iii) azetidinyl;
provided that when L1 is absent, a1 is attached to N(Ra) via a carbon atom other than that which is alpha to a nitrogen atom of a1;
and provided that when a1 is substituted with a substituent containing an oxygen or nitrogen radical as a point of attachment to a1, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a1;
L2 is C1-4-alkyl;
a2 is bound through a carbon atom to L2 and a2 is morpholinyl;
L3 is methylene;
a3 is imidazolyl optionally independently substituted with one to two C1-4-alkyl substituents;
L4 is (C2-6)alkyl;
a4 is selected from the group consisting of amino and C1-4alkylamino;
provided that a4 is attached at a carbon atom of (C2-6)alkyl other than that alpha to N(Ra);
L5 is absent or C1-4alkyl;
a5 is C3-7cycloalkyl substituted with RB; wherein RB is amino;
provided that when RB contains a nitrogen radical as a point of attachment to C3-7cycloalkyl, the attachment is at a carbon atom other than that alpha to N(Ra);
or,
A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of
i) pyrrolidin-1-yl wherein pyrrolidin-1-yl is optionally substituted with C1-4-alkyl, amino, or aminomethyl;
ii) piperazin-1-yl optionally substituted with 4-C1-4-alkyl; and wherein piperazin-1-yl is optionally independently substituted at carbon with one to two C1-4-alkyl substituents, 2-oxo, or 3-oxo;
iii) piperidin-1-yl optionally substituted with one to two C1-4alkyl substituents or amino;
iv) azetidin-1-yl optionally substituted with 3-amino or 3-aminomethyl;
v) [1,4]diazepan-1-yl;
and
vi) 3,6-diazoabicyclo[3.1.1]hept-3-yl.

13. The compound of claim 12 wherein A-L- is selected from the group
consisting of a1-L1-; a2-L2-; a3-L3-; a4-L4-; and a5-L5-; wherein
L1 is absent or C1-2alkyl;
a1 is bound through a carbon atom to L1 and is selected from the group consisting of
i) pyrrolidinyl optionally substituted at carbon with hydroxy or one to two fluoro substituents;
ii) piperidin-3-yl;
and
iii) azetidinyl;
provided that when L1 is absent, a1 is attached to N(Ra) via a carbon atom other than that which is alpha to a nitrogen atom of a1;
and provided that when a1 is substituted with a substituent containing an oxygen or nitrogen radical as a point of attachment to a1, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a1;
L2 is C1-2alkyl;
a2 is bound through a carbon atom to L2 and a2 is morpholinyl;
L3 is methylene;
a3 is imidazolyl optionally independently substituted with one to two C1-2alkyl substituents;
L4 is (C2-4)alkyl;
a4 is selected from the group consisting of amino and C1-4-alkylamino;
provided that a4 is attached at a carbon atom other than that alpha to N(Ra);

L5 is absent or C1-4-alkyl;
a5 is C4-6cycloalkyl substituted with RB; wherein RB is amino;
provided that when RB contains a nitrogen radical as the point of attachment to C5-6cycloalkyl, the attachment is at a carbon atom other than that alpha to N(Ra);
or,
A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of
i) pyrrolidin-1-yl optionally substituted with amino or aminomethyl;
ii) piperazin-1-yl optionally substituted with 4-C1-4alkyl; and wherein piperazin-1-yl is optionally independently substituted at carbon with one to two C1-4-alkyl substituents;
iii) piperidin-1-yl optionally substituted with amino;
iv) azetidin-1-yl optionally substituted with 3-aminomethyl;
and
v) [1,4]diazepan-1-yl;
provided that the position of a substituent containing a nitrogen radical as a point of attachment to the nitrogen-bound heterocyclyl is at a carbon atom other than that alpha to a heterocyclyl nitrogen atom.

14. The compound of claim 13 wherein A-L- is selected from the group consisting of a1-L1-; a2-L2-; a3-L3-, a4-L4-; and a5-L5-; wherein
L1 is absent or C1-2alkyl;
a1 is bound through a carbon atom to L1 and is selected from the group consisting of
i) pyrrolidinyl optionally substituted at carbon with hydroxy or one to two fluoro substituents;
and
ii) piperidin-3-yl
provided that when L1 is absent, a1 is attached to N(Ra) via a carbon atom other than that which is alpha to a nitrogen atom of a1;
and provided that when a1 is substituted with a substituent containing an oxygen or nitrogen radical as a point of attachment to a1, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a1;
L2 is methylene;
a2 is bound through a carbon atom to L2 and a2 is morpholinyl;
L3 is methylene;
a3 is imidazolyl optionally substituted with one to two methyl substituents;
L4 is (C2-3)alkyl;
a4 is amino, provided that a4 is attached at a carbon atom other than that alpha to N(Ra);
L5 is absent or C1-2alkyl;
a5 is C4-6cycloalkyl substituted with RB; wherein RB is amino;
provided that when RB contains a nitrogen radical as the point of attachment to C5-6cycloalkyl, the attachment is at a carbon atom other than that alpha to N(Ra);
or,
A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of
i) pyrrolidin-1-yl optionally substituted with amino;
ii) piperazin-1-yl optionally independently substituted at carbon with one to two C1-4alkyl substituents;
iii) piperidin-1-yl optionally substituted with amino;
and
iv) [1,4]diazepan-1-yl;
provided that the position of a substituent containing an nitrogen radical as a point of attachment to the nitrogen-bound heterocyclyl is at a carbon atom other than that alpha to the heterocyclyl nitrogen atom.

15. The compound of claim 14 wherein A-L- is selected from the group consisting of a1-L1-; a2-L2-; a3-L3-, a4-L4-; and a5-L5-; wherein
L1 is absent or C1-2alkyl;
a1 is bound through a carbon atom to L1 and is selected from the group consisting of
i) pyrrolidinyl optionally substituted at carbon with hydroxy or one to two fluoro substituents;
and
ii) piperidin-3-yl
provided that when L1 is absent, a1 is attached to N(Ra) via a carbon atom other than that which is alpha to a nitrogen atom of a1;
and provided that when a1 is substituted with a substituent containing an oxygen or nitrogen radical as a point of attachment to a1, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a1;
L2 is methylene;
a2 is bound through a carbon atom to L2 and a2 is morpholinyl;
L3 is methylene;
a3 is imidazolyl optionally substituted with one to two methyl substituents;
L4 is (C2-3)alkyl;
a4 is amino, provided that a4 is attached at a carbon atom other than that alpha to N(Ra);
L5 is absent or C1-2alkyl;
a5 is C4-6cycloalkyl substituted with RB; wherein RB is amino;
provided that when RB contains a nitrogen radical as the point of attachment to C5-6cycloalkyl, the attachment is at a carbon atom other than that alpha to N(Ra);
or,
A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of
i) pyrrolidin-1-yl optionally substituted with amino;
ii) piperazin-1-yl optionally independently substituted at carbon with one to two C1-2alkyl substituents;
iii) piperidin-1-yl optionally substituted with amino;
and
iv) [1,4]diazepan-1-yl;
provided that the position of a substituent containing an nitrogen radical as a point of attachment to the nitrogen-bound heterocyclyl is at a carbon atom other than that alpha to the heterocyclyl nitrogen atom.

16. The compound of claim 1 wherein Ra is hydrogen.

17. A compound of Formula (I)



wherein
R1 is selected from the group consisting of
i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkyl, C1-4-alkoxy, hydroxy, chloro, and fluoro; in addition, phenyl is optionally substituted with a single amino, di(C1-4-alkyl)amino, di(C1-4alkyl)aminocarbonyl, hydroxy(C1-4alkyl, aminocarbonyl, C1-4alkylcarbonylamino, cyano, trifluoromethoxy, C1-4alkylsulfonyl, nitro, trifluoromethyl, or phenyl substituent;
ii) pyrimidinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkoxy, C1-4-alkylthio, and hydroxy; in addition, pyrimidinyl is optionally substituted with a single cyano, morpholin-4-yl, amino, di(C1-4-alkyl)amino, or piperazin-1-yl optionally substituted with 4-C1-4alkyl substituent;
iii) pyridinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, hydroxy, fluoro, chloro, and cyano; in addition, pyridinyl is optionally substituted with a single hydroxymethyl, amino, aminocarbonyl, C1-4-alkylsulfonyl, or pyridinyl substituent;
wherein the pyridinyl substituent of the R1-pyridinyl is optionally independently substituted with one to two substituents selected from chloro and methyl; and

iv) a G-substituent selected from the group consisting of naphthyl, pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, pyrazinyl, quinoxalinyl, oxazolyl, pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl, dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl;
wherein G is optionally independently substituted with one to two substituents selected from the group consisting of C1-4-alkyl, fluoro, and chloro;

R2 is phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, one to two fluoro substituents, chloro, and hydroxy; in addition, phenyl is optionally substituted with amino, fluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl, di(C1-4alkylaminocarbonyl, C1-4alkylcarbonylamino, 2,2,2-trifluoroethoxy, cyano, C3-7cycloalkylcarbonylamino, hydroxy(C1-4alkyl, C1-4alkoxy(C1-4)alkyl, C1-4alkoxy-(C1-4)alkoxy, C1-4alkylcarbonyloxy, C1-4alkylsulfonylamino, C1-4alkylsulfonyl, pyridinyl(C1-4)alkyl, benzyloxycarbonylamino, 4-methyl-piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, carboxy, piperidin-1-ylcarbonyl, or morpholin-4-ylcarbonyl;
or, R2 is a heteroaryl selected from the group consisting of benzothiazolyl, benzooxazolyl, and pyridinyl; wherein heteroaryl is optionally independently substituted with one to two C1-4alkyl substituents;

A-L- is selected from the group consisting of a1-L1-; a2-L2-; a3-L3-;
a4-L4-; and a5-L5-; wherein

L1 is absent or C1-4-alkyl;
a1 is bound through a carbon atom to L1 and is selected from the group
consisting of
i) pyrrolidinyl optionally substituted at carbon with amino, hydroxy, or one to two fluoro substituents;
ii) piperidinyl;
and
iii) azetidinyl;
provided that when L1 is absent, a1 is attached to N(Ra) via a carbon atom other than that which is alpha to a nitrogen atom of a1;
and provided that when a1 is substituted with a substituent containing an oxygen or nitrogen radical as a point of attachment to a1, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a1;
L2 is C1-4-alkyl;
a2 is bound through a carbon atom to L2 and a2 is morpholinyl;
L3 is methylene;
a3 is imidazolyl optionally independently substituted with one to two
C1-4alkyl substituents;

L4 is (C2-6)alkyl;
a4 is selected from the group consisting of amino and C1-4alkylamino;
provided that a4 is attached at a carbon atom of (C2-6)alkyl other than that alpha to N(Ra);
L5 is absent or C1-4alkyl;
a5 is C3-7cycloalkyl substituted with RB; wherein RB is amino;
provided that when RB contains a nitrogen radical as a point of attachment to C3-7cycloalkyl, the attachment is at a carbon atom other than that alpha to N(Ra);
or,
A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of
i) pyrrolidin-1-yl wherein pyrrolidin-1-yl is optionally substituted with C1-4-alkyl, amino, or aminomethyl;
ii) piperazin-1-yl optionally substituted with 4-C1-4-alkyl; and wherein piperazin-1-yl is optionally independently substituted at carbon with one to two C1-4alkyl substituents, 2-oxo, or 3-oxo;
iii) piperidin-1-yl optionally substituted with one to two C1-4alkyl substituents or amino;
iv) azetidin-1-yl optionally substituted with 3-amino or 3-aminomethyl;
v) [1,4]diazepan-1-yl;
and
vi) 3,6-diazoabicyclo[3.1.1]hept-3-yl;
Ra is hydrogen or methylcarbonyl;
provided that a compound of Formula (I) is other than a compound selected from the group consisting of
a compound wherein R1 is 4-fluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
a compound wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is (S)-morpholin-3-yl, L2 is methyl, Ra is H, and X is O; a compound wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-(piperidin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
a compound wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
a compound wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2-methyl-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O; and
a compound wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, RB is 2-amino, Ra is H, and X is O;
and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

18. A compound of Formula (I)



wherein
R1 is selected from the group consisting of
i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkyl, C1-4-alkoxy, hydroxy, chloro, and fluoro; in addition, phenyl is optionally substituted with a single amino, di(C1-4-alkyl)amino, di(C1-4-alkyl)aminocarbonyl, hydroxy(C1-4alkyl, aminocarbonyl, C1-4alkylcarbonylamino, cyano, trifluoromethoxy, C1-4-alkylsulfonyl, nitro, trifluoromethyl, or phenyl substituent;
ii) pyrimidinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkoxy, C1-4-alkylthio, and hydroxy; in addition, pyrimidinyl is optionally substituted with a single cyano, morpholin-4-yl, amino, di(C1-4-alkyl)amino, or piperazin-1-yl optionally substituted with 4-C1-4alkyl substituent;
iii) pyridinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, hydroxy, fluoro, chloro, and cyano; in addition, pyridinyl is optionally substituted with a single hydroxymethyl, amino, C1-4-alkylsulfonyl, or pyridinyl substituent;
wherein the pyridinyl substituent of the R1-pyridinyl is optionally independently substituted with one to two substituents selected from chloro and methyl; and

v) a G-substituent selected from the group consisting of naphthyl, pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, pyrazinyl, quinoxalinyl, oxazolyl, pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl, dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl;
wherein G is optionally independently substituted with one to two C1-4-alkyl substituents;

R2 is
(i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkyl, C1-2alkoxy, C1-4-alkylthio, one to two fluoro substituents, chloro, and hydroxy; in addition, phenyl is optionally substituted with amino, fluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl, C1-4-alkylcarbonylamino, C1-4alkylcarbonyloxy, 2,2,2-trifluoroethoxy, benzyloxycarbonylamino, hydroxy(C1-4)alkyl, or C1-4-alkoxy(C1-4)alkyl;
or,
(ii) heteroaryl selected from the group consisting of benzothiazolyl and benzooxazolyl; wherein heteroaryl is optionally independently substituted with one to two C1-4alkyl substituents;
A-L- is selected from the group consisting of a1-L1-; a2-L2-; a3-L3-;
a4-L4-; and a5-L5-; wherein

L1 is absent or C1-2alkyl;
a1 is bound through a carbon atom to L1 and is selected from the group consisting of
i) pyrrolidinyl optionally substituted at carbon with hydroxy or one to two fluoro substituents;
ii) piperidin-3-yl;
and
iii) azetidinyl;
provided that when L1 is absent, a1 is attached to N(Ra) via a carbon atom other than that which is alpha to a nitrogen atom of a1;
and provided that when a1 is substituted with a substituent containing an oxygen or nitrogen radical as a point of attachment to a1, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a1;
L2 is C1-2alkyl;
a2 is bound through a carbon atom to L2 and a2 is morpholinyl;
L3 is methylene;
a3 is imidazolyl optionally independently substituted with one to two C1-2alkyl substituents;
L4 is (C2-4)alkyl;
a4 is selected from the group consisting of amino and C1-4-alkylamino;
provided that a4 is attached at a carbon atom other than that alpha to N(Ra);

L5 is absent or C1-4-alkyl;
a5 is C4-6cycloalkyl substituted with RB; wherein RB is amino;
provided that when RB contains a nitrogen radical as the point of attachment to C5-6cycloalkyl, the attachment is at a carbon atom other than that alpha to N(Ra);

or,
A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of
i) pyrrolidin-1-yl optionally substituted with amino or aminomethyl;
ii) piperazin-1-yl optionally substituted with 4-C1-4alkyl; and wherein piperazin-1-yl is optionally independently substituted at carbon with one to two C1-4-alkyl substituents;
iii) piperidin-1-yl optionally substituted with amino;
iv) azetidin-1-yl optionally substituted with 3-aminomethyl;
and
v) [1,4]diazepan-1-yl;
provided that the position of a substituent containing a nitrogen radical as a point of attachment to the nitrogen-bound heterocyclyl is at a carbon atom other than that alpha to a heterocyclyl nitrogen atom;

Ra is hydrogen;
provided that a compound of Formula (I) is other than a compound selected from the group consisting of

a compound wherein R1 is 4-fluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
a compound wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is (S)-morpholin-3-yl, L2 is methyl, Ra is H, and X is O;
a compound wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2-methyl-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
and
a compound wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, RB is 2-amino, Ra is H, and X is O;
and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

19. A compound of Formula (I)



wherein
R1 is selected from the group consisting of
i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkyl, C1-2alkoxy, hydroxy, chloro, and fluoro; in addition, phenyl is optionally substituted with a single amino, di(C1-4-alkyl)amino, di(C1-4alkyl)aminocarbonyl, hydroxy(C1-4alkyl, aminocarbonyl, C1-4alkylcarbonylamino, cyano, trifluoromethoxy, C1-4alkylsulfonyl, nitro, trifluoromethyl, or phenyl substituent;
ii) pyrimidinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkoxy and C1-4-alkylthio; in addition, pyrimidinyl is optionally substituted with a single cyano, morpholin-4-yl, di(C1-4alkyl)amino, or piperazin-1-yl optionally substituted with 4-C1-4alkyl substituent;
iii) pyridinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, hydroxy, fluoro, chloro, and cyano; in addition, pyridinyl is optionally substituted with a single hydroxymethyl, amino, C1-4-alkylsulfonyl, or pyridinyl substituent;
wherein the pyridinyl substituent of the R1-pyridinyl is optionally independently substituted with one to two substituents selected from chloro and methyl;

and
iv) a G-substituent selected from the group consisting of naphthyl, pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, pyrazinyl, quinoxalinyl, pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl, dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl;
wherein G is optionally substituted with one C1-4alkyl substituent;

R2 is
(i) phenyl optionally substituted with one to two substituents selected from the group consisting of C1-4-alkyl, C1-2alkoxy, C1-4-alkylthio, one to two fluoro substituents, chloro, and hydroxy; in addition, phenyl is optionally substituted with a single amino, fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl, C1-4-alkylcarbonylamino, C1-4-alkylcarbonyloxy, 2,2,2-trifluoroethoxy, or C1-4-alkoxy(C1-4)alkyl substituent;
(ii) or heteroaryl selected from the group consisting of benzothiazolyl and benzooxazolyl; wherein heteroaryl is optionally independently substituted with one to two C1-4alkyl substituents;
A-L- is selected from the group consisting of a1-L1-; a2-L2-; a3-L3-;
a4-L4-; and a5-L5-; wherein

L1 is absent or C1-2alkyl;
a1 is bound through a carbon atom to L1 and is
i) pyrrolidinyl optionally substituted at carbon with hydroxy or one to two fluoro substituents;
ii) piperidin-3-yl
or
iii) azetidinyl;
provided that when L1 is absent, a1 is attached to N(Ra) via a carbon atom other than that which is alpha to a nitrogen atom of a1;
and provided that when a1 is substituted with a substituent containing a nitrogen radical as a point of attachment to a1, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a1;
L2 is methylene;
a2 is bound through a carbon atom to L2 and a2 is morpholinyl;
L3 is methylene;
a3 is imidazolyl optionally independently substituted with one to two C1-4alkyl substituents;
L4 is (C2-3)alkyl;
a4 is amino, provided that a4 is attached at a carbon atom other than that alpha to N(Ra);
L5 is absent or C1-2alkyl;
a5 is C4-6cycloalkyl substituted with RB; wherein RB is amino;
provided that when RB contains a nitrogen radical as the point of attachment to C5-6cycloalkyl, the attachment is at a carbon atom other than that alpha to N(Ra);
or,
A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of
i) pyrrolidin-1-yl optionally substituted with amino or aminomethyl;
ii) piperazin-1-yl optionally independently substituted at carbon with one to two C1-4alkyl substituents;
iii) piperidin-1-yl optionally substituted with amino;
iv) azetidin-1-yl optionally substituted with 3-aminomethyl;
and
v) [1,4]diazepan-1-yl;
provided that the position of a substituent containing an nitrogen radical as a point of attachment to the nitrogen-bound heterocyclyl is at a carbon atom other than that alpha to the heterocyclyl nitrogen atom;

Ra is hydrogen;
provided that a compound of Formula (I) is other than a compound selected from the group consisting of

a compound wherein R1 is 4-fluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
a compound wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is (S)-morpholin-3-yl, L2 is methyl, Ra is H, and X is O;
a compound wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2-methyl-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
and
a compound wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, RB is 2-amino, Ra is H, and X is O;
and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

20. A compound of Formula (I)



wherein
R1 is selected from the group consisting of
i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkyl, C1-2alkoxy, hydroxy, and fluoro; in addition, phenyl is optionally substituted with a single amino, di(C1-4-alkyl)amino, di(C1-4-alkyl)aminocarbonyl, hydroxy(C1-4alkyl, aminocarbonyl, C1-4alkylcarbonylamino, cyano, trifluoromethoxy, C1-4-alkylsulfonyl, nitro, or trifluoromethyl substituent;
ii) pyrimidinyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4-alkoxy and C1-4-alkylthio; in addition, pyrimidinyl is optionally substituted with a single cyano, morpholin-4-yl, di(C1-4alkyl)amino, or piperazin-1-yl optionally substituted with 4-C1-4alkyl substituent;
iii) pyridinyl optionally substituted with one to two substituents independently selected form the group consisting of C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, hydroxy, fluoro, chloro, and cyano; in addition, pyridinyl is optionally substituted with hydroxymethyl or amino;
and
iv) a G-substituent selected from the group consisting of pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, and benzo[1,2,5]oxadiazolyl;
wherein G is optionally substituted with one C1-4alkyl substituent;
R2 is
(i) phenyl optionally substituted with one to two substituents selected from the group consisting of C1-2alkyl, C1-2alkoxy, C1-2alkylthio, fluoro, 3-chloro, 4-chloro, and hydroxy; or phenyl is optionally substituted with one substituent selected from the group consisting of amino, difluoromethoxy, trifluoromethoxy, aminocarbonyl, C1-4-alkylcarbonylamino, C1-4-alkylcarbonyloxy, and 2,2,2-trifluoroethoxy;
or,
(ii) heteroaryl selected from the group consisting of benzothiazolyl and benzooxazolyl; wherein heteroaryl of R2 is optionally independently substituted with one to two C1-2alkyl substituents;
A-L- is selected from the group consisting of a1-L1-; a2-L2-; a3-L3-, a4-L4-; and a5-L5-; wherein
L1 is absent or C1-2alkyl;
a1 is bound through a carbon atom to L1 and is
i) pyrrolidinyl optionally substituted at carbon with hydroxy or one to two fluoro substituents;
or
ii) piperidin-3-yl
provided that when L1 is absent, a1 is attached to N(Ra) via a carbon atom other than that which is alpha to a nitrogen atom of a1;
and provided that when a1 is substituted with a substituent containing an oxygen or nitrogen radical as a point of attachment to a1, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a1;
L2 is methylene;
a2 is bound through a carbon atom to L2 and a2 is morpholinyl;
L3 is methylene;
a3 is imidazolyl optionally substituted with one to two methyl substituents;
L4 is (C2-3)alkyl;
a4 is amino, provided that a4 is attached at a carbon atom other than that alpha to N(Ra);
L5 is absent or C1-2alkyl;
a5 is C4-6cycloalkyl substituted with RB; wherein RB is amino;
provided that when RB contains a nitrogen radical as the point of attachment to C5-6cycloalkyl, the attachment is at a carbon atom other than that alpha to N(Ra);
or,
A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of
i) pyrrolidin-1-yl optionally substituted with amino;
ii) piperazin-1-yl optionally independently substituted at carbon with one to two C1-4alkyl substituents;
iii) piperidin-1-yl optionally substituted with amino;
and
iv) [1,4]diazepan-1-yl;
provided that the position of a substituent containing an nitrogen radical as a point of attachment to the nitrogen-bound heterocyclyl is at a carbon atom other than that alpha to the heterocyclyl nitrogen atom;

Ra is hydrogen;
provided that a compound of Formula (I) is other than a compound selected from the group consisting of

a compound wherein R1 is 4-fluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
a compound wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is (S)-morpholin-3-yl, L2 is methyl, Ra is H, and X is O;
a compound wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2-methyl-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
and
a compound wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, RB is 2-amino, Ra is H, and X is O;
and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

21. A compound of Formula (I)



wherein
R1 is selected from the group consisting of
i) phenyl optionally substituted with a substituent selected from the group consisting of C1-2alkyl, C1-2alkoxy, hydroxy, and fluoro; or, phenyl is optionally substituted with one substituent selected from the group consisting of amino, di(C1-4alkyl)amino, di(C1-4alkyl)aminocarbonyl, hydroxymethyl, aminocarbonyl, C1-4alkylcarbonylamino, cyano, trifluoromethoxy, C1-2alkylsulfonyl, nitro, and trifluoromethyl;
ii) pyrimidinyl optionally substituted with one to two substituents selected from the group consisting of C1-4-alkoxy and C1-4-alkylthio; or, pyrimidinyl is optionally substituted with one substituent selected from the group consisting of morpholin-4-yl, di(C1-4-alkyl)amino, and piperazin-1-yl optionally substituted with 4-methyl;
iii) pyridinyl optionally substituted with one to two substituents selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, fluoro, and chloro; or, pyridinyl optionally substituted with one substituent selected from the group consisting of cyano, hydroxymethyl, and amino;
and
iv) a G-substituent selected from the group consisting of pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, and benzo[1,2,5]oxadiazolyl;
wherein G is optionally substituted with one C1-4alkyl substituent;

R2 is
(i) phenyl optionally substituted with one to two substituents selected from the group consisting of C1-2alkyl, C1-2alkoxy, C1-2alkylthio, one to two fluoro substituents, 3-chloro, 4-chloro, and hydroxy; or, phenyl is optionally substituted with one substituent selected from the group consisting of amino, difluoromethoxy, trifluoromethoxy, aminocarbonyl, C1-4-alkylcarbonylamino, C1-4-alkylcarbonyloxy, and 2,2,2-trifluoroethoxy;
or
(ii) heteroaryl selected from the group consisting of benzothiazolyl and benzooxazolyl; wherein heteroaryl of R2 is optionally independently substituted with one to two C1-2alkyl substituents;
A-L- is selected from the group consisting of a1-L1-; a2-L2-; a3-L3-, a4-L4-; and a5-L5-; wherein
L1 is absent or C1-2alkyl;
a1 is bound through a carbon atom to L1 and is
i) pyrrolidinyl optionally substituted at carbon with hydroxy or one to two fluoro substituents;
or
ii) piperidin-3-yl
provided that when L1 is absent, a1 is attached to N(Ra) via a carbon atom other than that which is alpha to a nitrogen atom of a1;
and provided that when a1 is substituted with a substituent containing an oxygen or nitrogen radical as a point of attachment to a1, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a1;
L2 is methylene;
a2 is bound through a carbon atom to L2 and a2 is morpholinyl;
L3 is methylene;
a3 is imidazolyl optionally substituted with one to two methyl substituents;
L4 is (C2-3)alkyl;
a4 is amino, provided that a4 is attached at a carbon atom other than that alpha to N(Ra);
L5 is absent or C1-2alkyl;
a5 is C4-6cycloalkyl substituted with RB; wherein RB is amino;
provided that when RB contains a nitrogen radical as the point of attachment to C5-6cycloalkyl, the attachment is at a carbon atom other than that alpha to N(Ra);
or,
A-L- is taken with Ra and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of
i) pyrrolidin-1-yl optionally substituted with amino;
ii) piperazin-1-yl optionally independently substituted at carbon with one to two C1-2alkyl substituents;
iii) piperidin-1-yl optionally substituted with amino;
and
iv) [1,4]diazepan-1-yl;
provided that the position of a substituent containing an nitrogen radical as a point of attachment to the nitrogen-bound heterocyclyl is at a carbon atom other than that alpha to the heterocyclyl nitrogen atom;
Ra is hydrogen;
provided that a compound of Formula (I) is other than a compound selected from the group consisting of

a compound wherein R1 is 4-fluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
a compound wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is (S)-morpholin-3-yl, L2 is methyl, Ra is H, and X is O;
a compound wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2-methyl-phenyl, A-L- is a1-L1, a1 is (S)-pyrrolidin-2-yl, L1 is methyl, Ra is H, and X is O;
and
a compound wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, RB is 2-amino, Ra is H, and X is O;
and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

22. A compound of Formula (I)



selected from the group consisting of:
a compound of Formula (I) wherein R1 is 4-methoxy-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3-methoxy-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 2-methoxy-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is naphth-1-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is naphth-2-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-4-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is thien-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is furan-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-trifluoromethoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methylcarbonylamino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3-hydroxy-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is quinolin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is quinolin-8-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 2-methyl-quinolin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 4-biphenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is quinolin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is dibenzothiophen-2-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 6-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 2-fluoro-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 6-fluoro-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 2-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 2,6-dihydroxy-pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3-cyano-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3-nitro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3-aminocarbonyl-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3-N,N-diethylaminocarbonyl-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3-methanesulfonyl-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 4-hydroxy-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is indol-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 4H-[1,2,4]oxadiazol-5-on-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-fluoro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 6-methoxy-pyridin-3-yl, R2 is 4-fluoro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3-fluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 6-methoxy-pyridin-3-yl, R2 is 2-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 2-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3-diethylamino-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3-methylcarbonylamino-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 4-methylcarbonylamino-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 6-methoxy-pyridin-3-yl, R2 is 4-amino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3-amino-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-amino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is benzothiazol-2-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is thiazol-2-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is benzothiophen-2-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3-trifluoromethyl-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3-trifluoromethoxy-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 2-methylthio-pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 2-methoxy-pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3,5-difluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3,4-difluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3,5-difluoro-4-hydroxymethyl-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 2,4-dimethoxy-pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 6-methoxy-pyridin-3-yl, R2 is 4-hydroxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 2-ethoxy-pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrazol-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3,5-dimethyl-isoxazol-4-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 2,3-dihydrobenzofuran5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3-fluoro-4-methoxy-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrazol-4-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 2-methylthio-pyrimidin-4-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 1-methyl-pyrazol-4-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3-fluoro-5-methoxy-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3-fluoro-5-methyl-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 6-amino-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-6-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 6-hydroxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 6-hydroxy-pyridin-3-yl, R2 is 4-hydroxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is quinoxalin-6-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 1H-pyrrolo[2,3-b]pyridin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is benzo[1,2,5]oxadiazol-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4,4-difluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4R)
a compound of Formula (I) wherein R1 is 2-amino-pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 2-dimethylamino-pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 2-(morpholin-4-yl)-pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 2-(4-methyl-pyrazin-1-yl)-pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is benzothiazol-6-yl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 2-methyl-benzoxazol-6-yl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2-methyl-benzoxazol-6-yl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4R)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2-methyl-benzothiazol-6-yl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3,5-dimethyl-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is benzo[1,3]dioxol-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3,5-dichloro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 6-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 3,5-difluoro-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 3,5-difluoro-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 3-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 3-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2,3-difluoro-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 2,3-difluoro-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 2,3-difluoro-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-ethoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-ethoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-ethoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-methylthio-pyridin-3-y, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-methanesulfonyl-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, and Ra is H; (racemic)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-difluoromethoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-difluoromethoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-difluoromethoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-n-propyloxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-n-propyloxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-n-propyloxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is indol-4-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is indol-6-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is indol-7-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrazin-2-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 2-cyano-pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-(2,2,2-trifluoro-ethoxy)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-(2,2,2-trifluoro-ethoxy)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-(2,2,2-trifluoro-ethoxy)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-n-butoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-n-butoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-n-butoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-chloro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-chloro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-chloro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is -fluoro-pyridin-3-yl, R2 is 3-fluoro-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 3-fluoro-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 3-fluoro-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4R)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-cyano-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-cyano-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-cyclopropylcarbonylamino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-isopropyloxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-isopropyloxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-isopropyloxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 3-cyano-5-fluoro-phenyl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-hydroxymethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-hydroxymethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-hydroxymethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-fluoro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methylthio-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methylthio-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methylthio-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxymethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxymethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxymethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-hydroxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-diethylaminocarbonyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-pyrrolidin-1-ylcarbonyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-carboxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-piperidin-1-ylcarbonyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-(morpholin-4-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-carboxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-carboxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-carboxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-(pyrrolidin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-(piperidin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-(morpholin-4-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-diethylaminocarbonyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-(pyrrolidin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-(piperidin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-(morpholin-4-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-diethylaminocarbonyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-(pyrrolidin-1-ylcarbonyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-benzyloxycarbonylamino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-ethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-chloro-pyridin-3-yl, R2 is 4-ethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-aminocarbonyl-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, Ra is methylcarbonyl; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-ethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 3-fluoro-4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-ethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-fluoro-4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-chloro-pyridin-3-yl, R2 is 3-fluoro-4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-fluoro-4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-benzyloxycarbonylamino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2,3-difluoro-4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-chloro-pyridin-3-yl, R2 is 2,3-difluoro-4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 2,3-difluoro-4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 2,3-difluoro-4-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4R)
a compound of Formula (I) wherein R1 is 5-chloro-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4R)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-ethyl-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4R)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4R)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-benzyloxycarbonylamino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-amino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, and Ra is H; (3S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 3-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-chloro-pyridin-3-yl, R2 is 3-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 3-methyl-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-methyl-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-fluoromethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, and Ra is H; (3S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is piperidin-4-yl, L1 is absent, and Ra is H;
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-(pyridin-3-ylmethyl)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-chloro-pyridin-3-yl, R2 is 3-methyl-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 3-methyl-4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-methylcarbonylamino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-methanesulfonylamino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methanesulfonylamino-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is azetidin-3-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-formamido-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-fluoromethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 3-methyl-4-fluoro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 3-methyl-4-fluoro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-trifluoromethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-trifluoromethyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-methanesulfonyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-formamido-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-3-yl, L1 is absent, and Ra is H; (3R)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is piperidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is azetidin-3-yl, L1 is absent, and Ra is H;
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-chloro-pyridin-3-yl, R2 is 2-methyl-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 3-methylcarbonyloxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-chloro-pyridin-3-yl, R2 is 2-chloro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 2-chloro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 3-hydroxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 2-chloro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-methylthio-pyridin-3-y, R2 is 2-chloro-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-methylthio-pyridin-3-y, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4R)
a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4R)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, and Ra is H; (3S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-3-yl, L1 is absent, and Ra is H; (3S)
a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4R)
a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4S)
a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is 4-fluoro-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S,4S)
a compound of Formula (I) wherein R1 is 5-methylthio-pyridin-3-y, R2 is 4-(2-methoxy-ethoxy)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-(2-methoxy-ethoxy)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-(2-methoxy-ethoxy)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-(2-methoxy-ethoxy)-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, and Ra is H; (3S)
a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, and Ra is H; (3R)
a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, Ra is H; (3S)
a compound of Formula (I) wherein R1 is 5-methylthio-pyridin-3-y, R2 is 3-methylcarbonyloxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 3-hydroxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 3-methylcarbonyloxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 3-methylcarbonyloxy-phenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-methylthio-pyridin-3-y, R2 is 4-methoxy-phenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, and Ra is H; (3S)
a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-methylthiopyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, Ra is H; (3R)
a compound of Formula (I) wherein R1 is 5-methylthiopyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-3-yl, L1 is absent, Ra is H; (3S)
a compound of Formula (I) wherein R1 is 5-methoxypyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-3-yl, L1 is absent, Ra is H; (3S)
a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-3-yl, L1 is absent, Ra is H; (3S)
a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, Ra is H; (3R)
a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, Ra is H; (3S)
a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-fluoromethoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H;
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is piperidin-3-yl, L1 is absent, Ra is H; (3R)
a compound of Formula (I) wherein R1 is 6-fluoro-5-methylpyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 2,5-dimethyl-pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 6′-chloro-3,5′-dimethyl-[2,3′]bipyridinyl-5-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 6-chloro-4-methylpyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 6-chloro-5-methyl-pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is piperidin-2-yl, L1 is methyl, and Ra is H; (2R)
a compound of Formula (I) wherein R1 is 2-chloro-5-methylpyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-hydroxymethyl-pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is pyrrolidin-2-yl, L1 is methyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is 4-hydroxy-pyrrolidin-2-yl, L1 is methyl, Ra is H; (trans 2S,4R)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is -hydroxypyrrolidin-2-yl, L1 is methyl, and Ra is H; (cis 2R,4R)
a compound of Formula (I) wherein R1 is 5-methoxypyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is 4-hydroxy-pyrrolidin-2-yl, L1 is methyl, Ra is H, (trans 2S,4R)
a compound of Formula (I) wherein R1 is 5-methoxypyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a1-L1, a1 is 4-hydroxy-pyrrolidin-2-yl, L1 is methyl, and Ra is H; (cis 2R,4R)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is morpholin-2-yl, L2 is methyl, and Ra is H; (racemic)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is morpholin-2-yl, L2 is methyl, and Ra is H;
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is morpholin-2-yl, L2 is methyl, and Ra is H;
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is morpholin-3-yl, L2 is methyl, and Ra is H; (racemic)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is morpholin-3-yl, L2 is methyl, and Ra is H; (racemic)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is morpholin-3-yl, L2 is methyl, and Ra is H; (3S)
a compound of Formula (I) wherein R1 is 5-fluoro-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is morpholin-3-yl, L2 is methyl, and Ra is H; (3S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a2-L2, a2 is morpholin-3-yl, L2 is methyl, and Ra is H; (3S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a3-L3, a3 is imidazol-2-yl, L3 is methyl, and Ra is H;
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a3-L3, a3 is 3H-imidazol-4-yl, L3 is methyl, and Ra is H;
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a3-L3, a3 is 5-methyl-3H-imidazol-4-yl, L3 is methyl, R and Ra is H;
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a3-L3, a3 is 3-methyl-3H-imidazol-4-yl, L3 is methyl, and Ra is H;
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a3-L3, a3 is 2-ethyl-5-methyl-3H-imidazol-4-yl, L3 is methyl, and Ra is H;
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a3-L3, a3 is 3H-imidazol-4-yl, L3 is methyl, and Ra is H;
a compound of Formula (I) wherein R1 is 5-methylthio-pyridin-3-y, R2 is 4-methoxy-phenyl, A-L- is a3-L3, a3 is 3H-imidazol-4-yl, L3 is methyl, and Ra is H;
a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a3-L3, a3 is 3H-imidazol-4-yl, L3 is methyl, and Ra is H;
a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a3-L3, a3 is 3H-imidazol-4-yl, L3 is methyl, and Ra is H;
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a4-L4, a4 is 2-amino, L4 is propyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a4-L4, a4 is 2-amino, L4 is ethyl, and Ra is H;
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a4-L4, a4 is 2-amino, L4 is 4-methyl-pentyl, and Ra is H; (2S)
a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a4-L4, a4 is 2-amino, L4 is ethyl, and Ra is H;
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a4-L4, a4 is 2-methylamino, L4 is ethyl, and Ra is H;
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (cis/trans mixture)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is methyl, and Ra is H; (2S,1R)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is methyl, and Ra is H; (2S,1R)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclobutyl, L5 is methyl, and Ra is H; (trans)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclobutyl, L5 is methyl, and Ra is H; (trans)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclobutyl, L5 is absent, and Ra is H; (cis/trans mixture)
a compound of Formula (I) wherein R1 is pyrimidin-5-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclobutyl, L5 is absent, and Ra is H; (cis/trans mixture)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (cis)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (racemic, cis/trans mixture)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (1RS,3SR racemic cis)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (1RS,2SR racemic single stereoisomer, unknown cis/trans)
a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; racemic, mixture of cis/trans)
a compound of Formula (I) wherein R1 is 5-methylthiopyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (racemic, mixture of cis and trans)
a compound of Formula (I) wherein R1 is 5-methoxypyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (cis 1R,3S)
a compound of Formula (I) wherein R1 is 5-methoxypyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, Ra is H; (cis 1S,3R)
a compound of Formula (I) wherein R1 is 5-methoxypyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (trans, one enantiomer, absolute unknown)
a compound of Formula (I) wherein R1 is 5-methoxypyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (trans, one enantiomer, absolute unknown)
a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (racemic, mixture of cis and trans)
a compound of Formula (I) wherein R1 is 5-methylthiopyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (cis 1S,3R)
a compound of Formula (I) wherein R1 is 5-methylthiopyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (trans, one enantiomer, absolute unknown)
a compound of Formula (I) wherein R1 is 5-methylthiopyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (trans, one enantiomer, absolute unknown)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-cyclopropylphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form piperazin-1-yl;
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (cis 1S,3R)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (cis 1R,3S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, A-L- is a5-L5, a5 is cyclohexyl, L5 is absent, and Ra is H; (trans, one enantiomer, absolute unknown)
a compound of Formula (I) wherein R1 is phenyl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form piperazin-1-yl;
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form piperazin-1-yl;
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-aminopyrrolidin-1-yl;
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form piperazin-1-yl;
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, A-L- is, A-L- and Ra are taken to form, 3-aminopyrrolidin-1-yl 3S
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-aminopiperidin-1-yl; (3S)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-aminopiperidin-1-yl; (3R)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-aminomethylazetidin-1-yl;
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 2-aminomethylpyrrolidin-1-yl; (2R)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 4-aminopiperidin-1-yl;
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 2-aminomethylpyrrolidin-1-yl; (2R)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-oxopiperazin-1-yl;
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form [1,4]diazepan-1-yl;
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 2-oxopiperazin-1-yl;
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3,6-diaza-bicyclo[3.1.1]hept-3-ylamino;
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, v 3-aminopyrrolidin-1-yl; (3R) a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-amino-azetidin-1-yl;
a compound of Formula (I) wherein R1 is 5-methylthio-pyridin-3-y, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form piperazin-1-yl;
a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form piperazin-1-yl;
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-methyl-piperazin-1-yl; (racemic)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 2-methyl-piperazin-1-yl; (2R)
a compound of Formula (I) wherein R1 is 5-cyano-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 2-methyl-piperazin-1-yl; (2S)
a compound of Formula (I) wherein R1 is 5-methoxy-pyridin-3-yl, R2 is 4-methoxy-phenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form [1,4]-diazepan-1-yl;
a compound of Formula (I) wherein R1 is 5-methylthiopyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form [1,4]-diazepan-1-yl;
a compound of Formula (I) wherein R1 is 5-methylthiopyridin-3-yl, R2 is 4-methoxyphenyl and A-L- and Ra are taken together with the atoms to which they are attached to form 3-amino-pyrrolidin-1-yl; (3R)
a compound of Formula (I) wherein R1 is 5-methoxypyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-amino-pyrrolidin-1-yl; (3R)
a compound of Formula (I) wherein R1 is 5-methylthiopyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3,3-dimethyl-piperazin-1-yl;
a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form piperazin-1-yl;
a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-amino-pyrrolidin-1-yl; (3R)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 4-methyl-piperazin-1-yl;
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 2-methyl-piperazin-1-yl; (2S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3,3-dimethyl-piperazin-1-yl;
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-methyl-piperazin-1-yl; (3S)
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-methyl-piperazin-1-yl; (3R)
a compound of Formula (I) wherein R1 is 5-methyl-pyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form [1,4]diazepan-1-yl;
a compound of Formula (I) wherein R1 is pyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3,5-dimethyl-piperazin-1-yl; (cis)
a compound of Formula (I) wherein R1 is 5-methoxypyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 2-ethyl-piperazin-1-yl; (2S)
a compound of Formula (I) wherein R1 is 5-methoxypyridin-3-yl, R2 is 4-methoxyphenyl, and A-L- and Ra are taken together with the atoms to which they are attached to form 3-ethyl-piperazin-1-yl; (3R);
and pharmaceutically acceptable salts thereof.

23. A pharmaceutical composition comprising a compound of claim 1 and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent.

24. The pharmaceutical composition of claim 23, wherein the composition is a solid, oral dosage form.

25. The pharmaceutical composition of claim 23, wherein the composition is a syrup, an elixir, or a suspension.