# Patent

## Title
Cold menthol receptor antagonists

## 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 A, B, L, Q, R1, R2, and R3 are defined herein.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This Application is a divisional of application Ser. No. 12/539,267, filed Aug. 11, 2009 now U.S. Pat. No. 8,143,259, which in turn claims priority to U.S. Provisional Patent Application No. 61/089,928, filed Aug. 19, 2008, now abandoned, which are hereby incorporated by reference in their entirety.


STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
The research and development of the invention described below was not federally sponsored.
BACKGROUND OF THE INVENTION
Transient receptor potential (TRP) channels are non-selective cation channels that are activated by a variety of stimuli. Numerous members of the ion channel family have been identified to date, including the cold-menthol receptor, also called TRPM8 (McKemy D. D., et al., Nature 2002, 416(6876), 52-58). Collectively, the TRP channels and related TRP-like receptors connote sensory responsivity to the entire continuum of thermal exposure, selectively responding to threshold temperatures ranging from noxious hot through noxious cold as well as to certain chemicals that mimic these sensations. Specifically, TRPM8 is known to be stimulated by cool to cold temperatures as well as by chemical agents such as menthol and icilin, which may be responsible for the therapeutic cooling sensation that these agents provoke.
TRPM8 is located on primary nociceptive neurons (A-delta and C-fibers) and is also modulated by inflammation-mediated second messenger signals (Abe, J., et al., Neurosci Lett 2006, 397(1-2), 140-144; Premkumar, L. S., et al., J. Neurosci, 2005, 25(49), 11322-11329). The localization of TRPM8 on both A-delta and C-fibers may provide a basis for abnormal cold sensitivity in pathologic conditions wherein these neurons are altered, resulting in pain, often of a burning nature (Kobayashi, K., et al., J Comp Neurol, 2005, 493(4), 596-606; Roza, C., et al., Pain, 2006, 120(1-2), 24-35; and Xing, H., et al., J Neurophysiol, 2006, 95(2), 1221-30). Cold intolerance and paradoxical burning sensations induced by chemical or thermal cooling closely parallel symptoms seen in a wide range of clinical disorders and thus provide a strong rationale for the development of TRPM8 modulators as novel antihyperalgesic or antiallodynic agents. TRPM8 is also known to be expressed in the brain, lung, bladder, gastrointestinal tract, blood vessels, prostate and immune cells, thereby providing the possibility for therapeutic modulation in a wide range of maladies.
International patent application WO 2006/040136 A1 from Bayer Healthcare AG purportedly describes substituted 4-benzyloxy-phenylmethylamide derivatives as cold menthol receptor-1 (CMR-1) antagonists for the treatment of urological disorders. International patent application WO 2006/040103 A1, from Bayer Healthcare AG purportedly describes methods and pharmaceutical compositions for treatment and/or prophylaxis of respiratory diseases or disorders.
International patent applications WO 2007/017092A1, WO 2007/017093A1 and WO 2007/017094A1, from Bayer Healthcare AG, purportedly describe benzyloxyphenylmethyl carbamate, substituted 2-benzyloxybenzoic acid amide and substituted 4-benzyloxybenzoic acid amide derivatives for the treatment of diseases associated with the cold menthol receptor (CMR), a.k.a. TRPM8.
There is a need in the art for TRPM8 antagonists that can be used to treat a disease, syndrome, or condition in a mammal in which the disease, syndrome or condition is affected by the modulation of TRPM8 receptors, such as pain, the diseases that lead to such pain, and pulmonary or vascular dysfunction.
SUMMARY OF THE INVENTION
The present invention is directed to compounds of Formula (I)




wherein

A is phenyl, thienyl, or C5-7cycloalkyl;
or, when A is phenyl, L is —(CH2)mN(R4)(CH2)n—, and R1 and L are attached at adjacent carbon atoms of phenyl, R1 and R4 are optionally taken with the atoms to which they are attached to form a 9 to 11-membered benzofused heterocyclyl;
R1 is one to three substituents independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, hydroxy(C1-4)alkyl, C1-4-alkoxycarbonyl, fluoro, chloro, bromo, and cyano;
B is selected from the group consisting of C6-10aryl, benzothiophenyl, indolyl, furanyl, thiazolyl, isoquinolinyl, quinolinyl, pyrimidinyl, dihydrobenzofuranyl, benzothiazolyl, azabenzothiophenyl, and pyridinyl;
R2 is one to two substituents independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluoro, chloro, bromo, and cyano;
and R2 is optionally one additional substituent selected from the group consisting of C1-4alkoxycarbonyl, C1-4alkylsulfonyl, C1-4alkoxycarbonylamino, C1-4-alkylaminocarbonyl, di(C1-4)alkylaminocarbonyl, trifluoromethyl, trifluoromethanesulfonyl, trifluoromethoxy, phenyl, pyrimidinyl, N-morpholinyl, piperidinyl, piperazinyl, N-methyl-piperazinyl, pyridinyl, pyrrolidinyl, imidazolyl, 1,2,3,6-tetrahydro-pyridinyl, 4-(3,6-dihydro-2H-pyridin-4-yl) optionally substituted at nitrogen with t-butoxycarbonyl, and hydroxy(C1-4)alkyl;
wherein the phenyl of R2 is optionally substituted with carboxy, C1-4alkyl, C1-4alkoxycarbonyl, halogen, tetrazole, or trifluoromethyl;
L is —(CH2)m—Z—(CH2)n— or —CH2—;
m and n are independently 0 or 1, such that the sum of m+n is no greater than 1;
and Z is O, S, or NR4; provided that when Z is O or S, A is phenyl;
R3 is hydrogen or C1-2alkyl; or, when A is phenyl and Z is NR4, R3 is optionally taken with R1 to form a tetrahydroquinolinyl;
R4 is hydrogen, C1-3alkyl, or C1-3alkylcarbonyl;
Q is




wherein
X is a direct bond or NH;
s is 1 or 2;
p is 1 or 2;
D, E, H, and J are benzo or pyrido;
W is phenyl, phenylmethyl, phenylaminomethyl, or a heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, thienyl, thiazolyl, pyrimidinyl, and pyrazinyl;
wherein phenyl, phenyl of the phenylmethyl and phenylaminomethyl, and heteroaryl of W are optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, hydroxy(C1-4)alkyl, fluoro, chloro, bromo, amino, C1-4alkylamino, di(C1-4-alkyl)amino, C1-4alkoxycarbonyl, C1-4alkylcarbonylamino, carboxy, and trifluoromethyl;
or, W is hydrogen, and one of R5a and R5b is phenyl;
V is hydrogen, C1-4alkyl, C1-4alkoxycarbonyl, aminocarbonyl, C1-4-alkylaminocarbonyl, di(C1-4alkyl)aminocarbonyl, or hydroxymethyl;
R5a and R5b are independently hydrogen, C1-4alkyl, C1-4alkoxy, fluoro, chloro, bromo, cyano, hydroxy, C1-4alkylthio, trifluoromethyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, carboxy, C1-4alkoxycarbonyl, C1-4alkylsulfonyl, C1-4alkoxycarbonylamino, trifluoromethanesulfonyl, trifluoromethoxy, or hydroxy(C1-4)alkyl; provided that one of R5a and R5b is hydrogen;
R6 is C1-4alkyl or phenylmethyl;
R7 is phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, fluoro, chloro, bromo, amino, C1-4alkylamino, di(C1-4alkyl)amino, C1-4alkoxycarbonyl, carboxy, and trifluoromethyl;
R8 is hydrogen, phenyl, or phenylmethyl; wherein phenyl is optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, fluoro, chloro, bromo, amino, C1-4alkylamino, di(C1-4alkyl)amino, C1-4alkoxycarbonyl, carboxy, and trifluoromethyl;
R10 is hydrogen; or, when R8 is hydrogen, R10 is phenyl or pyridinyl;
R11 is hydrogen or hydroxyl;
R9, R12, R13, and R14 are independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, fluoro, chloro, bromo, cyano, hydroxy, C1-4alkylthio, and trifluoromethyl; wherein R9, R12, R13, and R14 are optionally one additional substituent independently selected from the group consisting of C1-4alkyl, phenyl, carboxy, C1-4alkoxycarbonyl, aminocarbonyl, C1-4alkylaminocarbonyl, di(C1-4alkyl)aminocarbonyl, hydroxy(C1-4)alkyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, C1-4alkylsulfonyl, C1-4alkoxycarbonylamino, trifluoromethanesulfonyl, trifluoromethoxy, and hydroxy(C1-4)alkyl;
provided that a compound of Formula (I) is other than


    a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-trifluoromethyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is NH, W is phenyl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-t-butyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-4, X is a direct bond, D is benzo, and R9 is 5-chloro;
    a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-trifluoromethyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-2, s is 1, R6 is methyl, and R7 is phenyl;
    a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-t-butyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-2, s is 1, R6 is methyl, and R7 is phenyl;
    a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-t-butyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is NH, W is phenyl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-trifluoromethyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-3, X is NH, p is 1, R8 is phenyl, and R10 and R11 are hydrogen;
    a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-trifluoromethyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is NH, W is 2-methoxy-phenyl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 2-cyano, B is phenyl, R2 is 2-chloro, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-bromo, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-chloro, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 2-fluoro, B is quinolin-3-yl, R2 is hydrogen, L is —(CH2)n, —Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 3,4-difluoro, B is benzothiophen-2-yl, R2 is 3-methyl, L is —CH2—, R3 is hydrogen, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is hydrogen, and R5 is hydrogen;
    a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-trifluoromethyl, L is —(CH2)n, —Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is NH, W is 3-chloro-phenyl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-trifluoromethyl, L is —(CH2)n, —Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is NH, W is thien-2-yl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-chloro, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen; and
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-(2-carboxy)-phenyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is hydrogen, and R5a and R5b are hydrogen;

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



Illustrative of the invention is a pharmaceutical composition comprising, consisting of and/or consisting essentially of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable diluent and a compound of Formula (I). Also illustrative of the invention is a process for making a pharmaceutical composition comprising, consisting of, and/or consisting essentially of admixing a compound of Formula (I) and a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable diluent.
The present invention is further directed to methods for treating or ameliorating a disease or condition in a subject, including a mammal, and/or a human in which the disease or condition is affected by the modulation of TRPM8 receptors, such as pain, the diseases that lead to such pain, and pulmonary or vascular dysfunction using a compound of Formula (I). In particular, the method of the present invention is directed to treating or ameliorating a TRPM8 receptor-modulated disorders including, inflammatory pain, cold-intolerance or cold allodynia, peripheral vascular pain, itch, urinary incontinence, chronic obstructive pulmonary disease, pulmonary hypertension, and anxiety, including other stress-related disorders using a compound of Formula (I).
The present invention is also directed to methods for producing the instant compounds and pharmaceutical compositions and medicaments thereof.


DETAILED DESCRIPTION OF THE INVENTION
As used herein, 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.
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. Therefore, designated numbers of carbon atoms (e.g. C1-8) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent. In substituent groups with multiple alkyl groups such as (C1-6alkyl)2-amino- the C1-8alkyl groups of the dialkylamino may be the same or different.
As used herein, unless otherwise noted, the term “alkoxy” refers to an —Oalkyl substituent group, wherein alkyl is as defined supra. To the extent substituted, an alkyl and alkoxy chain may be substituted on a carbon atom.
As used herein, the terms “alkenyl” and “alkynyl” refer to straight and branched carbon chains having 2 or more carbon atoms, 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.
As used herein, “cycloalkyl” refers to saturated or partially unsaturated, monocyclic or polycyclic hydrocarbon rings of from 3 to 14 carbon atom members. Examples of such rings include, and are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl. Similarly, “cycloalkenyl” refers to a cycloalkyl that contains at least one double bond in the ring. Additionally, a “benzofused cycloalkyl” is a cycloalkyl ring that is fused to a benzene ring. A “heteroaryl-fused cycloalkyl” is a cycloalkyl ring that is fused to a 5 or 6 membered heteroaryl ring (containing one of O, S or N and, optionally, one additional nitrogen).
As used herein, “heterocyclyl” refers to a nonaromatic cyclic ring of 5 to 7 members in which 1 to 2 members are nitrogen, or a nonaromatic cyclic ring of 5 to 7 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 to one unsaturated bonds, and, optionally, when the ring is of 6 or 7 members, it contains up to two unsaturated bonds. As used herein, “benzofused heterocyclyl” includes a 5 to 7 membered monocyclic heterocyclic ring fused to a benzene ring. As used herein, “heteroaryl-fused heterocyclyl” refers to 5 to 7 membered monocyclic heterocyclic ring fused to a 5 or 6 membered heteroaryl ring (containing one of O, S or N and, optionally, one additional nitrogen). As used herein, “cycloalkyl-fused heterocyclyl” refers to a 5 to 7 membered monocyclic heterocyclic ring fused to a 5 to 7 membered cycloalkyl or cycloalkenyl ring. Furthermore, As used herein, “heterocyclyl-fused heterocycyl” refers to a 5 to 7 membered monocyclic heterocyclic ring fused to a 5 to 7 membered heterocyclyl ring (of the same definition as above but absent the option of a further fused ring). 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. As used herein, “heterocyclyl” also includes a 5 to 7 membered monocyclic heterocycle bridged to form bicyclic rings. 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.
As used herein, “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.
As used herein, “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.
Optionally, the heteroaryl ring is fused to a benzene ring to form a “benzo fused heteroaryl”; similarly, the heteroaryl ring is optionally fused to a 5 or 6 membered heteroaryl ring (containing one of O, S or N and, optionally, one additional nitrogen) to form a “heteroaryl-fused heteroaryl”; similarly, the heteroaryl ring is optionally fused to a 5 to 7 membered cycloalkyl ring or a 5 to 7 membered heterocyclo ring (as defined supra but absent the option of a further fused ring) to form a “cycloalkyl-fused heteroaryl”. 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; examples of heteroaryl groups with the optionally fused benzene rings include indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl, benzotriazolyl, quinolizinyl, quinolinyl, isoquinolinyl or quinazolinyl.
As used herein, “arylalkyl” means an alkyl group substituted with an aryl group (e.g., benzyl, phenethyl). Similarly, “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 that are stable.
As used herein, the term “R” at a stereocenter designates that the stereocenter is purely of the R-configuration as defined in the art; likewise, the term “S” means that the stereocenter is purely of the S-configuration. As used herein, the terms “*R” or “*S” at a stereocenter are used to designate that the stereocenter is of pure but unknown configuration. As used herein, the term “RS” refers to a stereocenter that exists as a mixture of the R- and S-configurations. Similarly, the terms “*RS” or “*SR” refer to a stereocenter that exists as a mixture of the R- and S-configurations and is of unknown configuration relative to another stereocenter within the molecule.
Compounds containing one stereocenter drawn without a stereo bond designation are a mixture of two enantiomers. Compounds containing two stereocenters both drawn without stereo bond designations are a mixture of four diastereomers. Compounds with two stereocenters both labeled “RS” and drawn with stereo bond designations are a two-component mixture with relative stereochemistry as drawn. Compounds with two stereocenters both labeled “*RS” and drawn with stereo bond designations are a two-component mixture with relative stereochemistry unknown. Unlabeled stereocenters drawn without stereo bond designations are a mixture of the R- and S-configurations. For unlabeled stereocenters drawn with stereo bond designations, the absolute stereochemistry is as depicted.
Whenever the term “alkyl” or “aryl” or either of their prefix roots appear in a name of a substituent (e.g., arylalkyl, alkylamino) the name is to be interpreted as including those limitations given above for “alkyl” and “aryl.” Designated numbers of carbon atoms (e.g., C1-C6) refer independently to the number of carbon atoms in an alkyl moiety, an aryl moiety, or in 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 members included within a given 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.).
In general, under standard nomenclature rules used 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 “phenylC1-C6 alkylamidoC1-C6alkyl” 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 this invention 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.
As used herein, “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.
As used herein, “therapeutically effective amount” 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 or partial alleviation of the symptoms of the disease, syndrome, condition or disorder being treated.
As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in therapeutically effective amounts, as well as any product that results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
As used herein, “antagonist” is used to refer to a compound capable of producing, depending on the circumstance, a functional antagonism of the TRPM8 ion channel, including, but not limited to, competitive antagonists, non-competitive antagonists, desensitizing agonists, and partial agonists.
As used herein, “inflammatory hypersensitivity” is used to refer to a condition that is characterized by one or more hallmarks of inflammation, including edema, erythema, hyperthermia and pain, and/or by an exaggerated physiologic or pathophysiologic response to one or more than one type of stimulation, including thermal, mechanical, and/or chemical stimulation.
As used herein, “TRPM8-modulated” is used to refer to the condition of being affected by the modulation of the TRPM8 receptor, including the state of being mediated by the TRPM8 receptor.
An embodiment of the invention is a method of treating or preventing at least one of the following diseases, syndromes, and conditions selected from the group consisting of migraine, post herpetic neuralgia, post traumatic neuralgia, post chemotherapy neuralgia, complex regional pain syndrome land II (CRPS I/II), fibromyalgia, inflammatory bowel disease, pruritis, asthma, chronic obstructive pulmonary disease, toothache, bone pain and pyresis in a mammal, which method comprises, consists of and/or consists essentially of administering to a subject, including an animal, a mammal, and a human in need of such treatment or prevention a therapeutically effective amount of a TRPM8 antagonist that is a compound of Formula (I).
Another embodiment of the invention is a method of treating or preventing at least one of the following diseases, syndromes, and conditions selected from hypertension, peripheral vascular disease, Raynaud's disease, reperfusion injury or frostbite in a mammal, which method comprises administering to a subject, including an animal, a mammal, and a human in need of such treatment or prevention a therapeutically effective amount of a TRPM8 antagonist that is a compound of Formula (I).
A further embodiment of the invention is a method of accelerating post-anesthetic recovery or post hypothermia recovery in a subject, including an animal, a mammal, and a human, which method comprises administering to a subject, including an animal, a mammal, and a human in need of such accelerated recovery a therapeutically effective amount of a TRPM8 antagonist that is a compound of Formula (I).
An embodiment of the present invention is directed to compounds of Formula (I)




wherein

    
    
        a) A is phenyl, thienyl, or cyclohexyl; or, when A is phenyl, L is —(CH2)mN(R4)(CH2)n—, and R1 and L are attached to adjacent carbon atoms of phenyl, R1 and R4 are optionally taken with the atoms to which they are attached to form dihydroindolyl or 3,4-dihydro-2H-quinolin-1-yl;
        b) A is phenyl; or, when A is phenyl, L is —(CH2)mN(R4)(CH2)n—, and R1 and L are attached to adjacent carbon atoms of phenyl, R1 and R4 are optionally taken with the atoms to which they are attached to form dihydroindolyl;
        c) R1 is one to three substituents independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, hydroxy(C1-4)alkyl, methoxycarbonyl, fluoro, chloro, and cyano;
        d) R1 is one to two substituents independently selected from the group consisting of hydrogen, C1-2alkyl, C1-2alkoxy, methoxycarbonyl, and fluoro;
        e) R1 is one to two substituents independently selected from the group consisting of hydrogen, methoxycarbonyl, methoxy, and fluoro;
        f) R1 is selected from the group consisting of hydrogen, methoxycarbonyl, 2-methoxy, fluoro, and di-fluoro;
        g) B is selected from the group consisting of C6-10aryl, benzothiophenyl, azabenzothiophenyl, benzothiazolyl, quinolinyl, dihydrobenzofuranyl, and pyridinyl;
        h) B is selected from the group consisting of phenyl, benzothiophenyl, azabenzothiophenyl, benzothiazolyl, unsubstituted quinolinyl, dihydrobenzofuranyl, and substituted pyridinyl;
        i) B is selected from the group consisting of phenyl, benzothiophenyl, azabenzothiophenyl, benzothiazolyl, unsubstituted quinolinyl, dihydrobenzofuranyl, and substituted pyridinyl;
        j) R2 is one to two substituents independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, chloro, bromo, and cyano;
        
            and R2 is optionally one additional substituent selected from the group consisting of C1-4alkoxycarbonyl, C1-4alkylcarbonylamino, C1-4-alkylaminocarbonyl, trifluoromethyl, phenyl, pyrimidin-5-yl, N-morpholinyl, piperidinyl, pyridinyl, imidazolyl, 4-(3,6-dihydro-2H-pyridin-4-yl) optionally substituted at nitrogen with t-butoxycarbonyl, and hydroxy(C1-4)alkyl;
            
                wherein said phenyl of R2 is optionally substituted with carboxy or tetrazolyl;
            
            
        
        
        k) R2 is a substituent independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, chloro, bromo, and cyano;
        
            and R2 is optionally one additional substituent selected from the group consisting of C1-4alkoxycarbonyl, methylcarbonylamino, trifluoromethyl, phenyl optionally substituted with 4-carboxy, pyrimidin-5-yl, N-morpholinyl, piperidinyl, pyridinyl, imidazolyl, 4-(3,6-dihydro-2H-pyridin-4-yl) optionally substituted at nitrogen with t-butoxycarbonyl, and hydroxymethyl;
        
        
        l) R2 is a substituent selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, chloro, bromo, cyano, C1-4alkoxycarbonyl, methylcarbonylamino, trifluoromethyl, phenyl optionally substituted with 4-carboxy, pyrimidin-5-yl, N-morpholinyl, piperidinyl, pyridinyl, imidazolyl, 4-(3,6-dihydro-2H-pyridin-4-yl) substituted at nitrogen with t-butoxycarbonyl, and hydroxymethyl;
        m) L is —(CH2)m—Z—(CH2)n— or —CH2—; wherein m and n are independently 0 or 1, such that the sum of m+n is no greater than 1; and wherein Z is O or NR4; provided that when Z is O, A is phenyl;
        n) L is —(CH2)m—Z—(CH2)n— or —CH2—; wherein m and n are independently 0 or 1, such that the sum of m+n is no greater than 1; and Z is NR4;
        o) L is —(CH2)m—Z—(CH2)n— or —CH2—; wherein m and n are 0, and Z is NR4;
        p) R3 is hydrogen or methyl; or, when A is phenyl and Z is NR4, R3 is optionally taken with R1 to form tetrahydroquinolinyl;
        q) R3 is hydrogen;
        r) R4 is hydrogen, methyl, or methylcarbonyl;
        s) R4 is hydrogen or methyl;
        t) Q is
    
    






wherein s is 1, R6 is C1-4alkyl, and R7 is unsubstituted phenyl,





wherein
X is a direct bond;
p is 1;
and D, E, H, and J are benzo or pyrido;
u) Q is




wherein
X is a direct bond;
p is 1;
and D, E, H, and J are benzo or pyrido;
v) Q is




wherein
X is a direct bond;
p is 1;
and D, E, and J are benzo;
w) Q is




wherein X is a direct bond and E and H are benzo;

    
    
        x) W is phenyl, phenylmethyl, phenylaminomethyl, or a heteroaryl selected from the group consisting of pyridinyl, thiazolyl, furanyl, indolyl, and thienyl; wherein phenyl of W is optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, hydroxy(C1-4)alkyl, fluoro, chloro, bromo, amino, di(C1-4alkyl)amino, C1-4alkoxycarbonyl, C1-4-alkylcarbonylamino, carboxy, and trifluoromethyl; and wherein pyridinyl of W is optionally substituted with bromo;
        or, W is hydrogen, and one of R5a and R5b is phenyl;
        
            V is hydrogen, C1-4alkoxycarbonyl or hydroxy(C1-4)alkyl;
            and R5a and R5b are hydrogen;
        
        
        y) W is phenyl or a heteroaryl selected from the group consisting of pyridinyl, thiazolyl, furanyl, and thienyl; wherein phenyl of W is optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, hydroxymethyl, fluoro, chloro, bromo, amino, di(C1-4alkyl)amino, C1-4alkoxycarbonyl, C1-4alkylcarbonylamino, carboxy, and trifluoromethyl; and wherein pyridinyl of W is optionally substituted with bromo;
        
            V is hydrogen, C1-2alkoxycarbonyl or hydroxymethyl; and
            R5a and R5b are hydrogen;
        
        
        z) W is phenyl or a heteroaryl selected from the group consisting of pyridinyl, thiazolyl, furanyl, and thienyl; wherein phenyl of W is optionally substituted with a substituent selected from the group consisting of C1-2alkyl, C1-2alkoxy, hydroxymethyl, fluoro, chloro, bromo, amino, di(C1-4alkyl)amino, C1-2alkoxycarbonyl, C1-4alkylcarbonylamino, carboxy, and trifluoromethyl; and wherein pyridinyl of W is optionally substituted with bromo;
        
            V is hydrogen, C1-2alkoxycarbonyl or hydroxymethyl; and
            R5a and R5b are hydrogen;
        
        
        aa) R6 is methyl;
        bb) R7 is phenyl;
        cc) R5 is hydrogen, phenyl, or phenylmethyl;
        dd) R5 is hydrogen and R10 is phenyl or pyridinyl; or, R5 is phenyl and R10 is hydrogen;
        ee) R5 is hydrogen and R10 is pyridinyl; or, R5 is phenyl and R10 is hydrogen;
        ff) R11 is hydrogen or hydroxy;
        gg) R8 is phenyl; and R10 and R11 are hydrogen;
        hh) R9, R12, R13, and R14 are independently selected from the group consisting of hydrogen, methyl, and fluoro;
        ii) R9, R12, R13, and R14 are independently selected from the group consisting of hydrogen or methyl;
        jj) R9, R12, R13, and R14 are independently hydrogen;

and enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof;

and any combination of embodiments a) through jj) above, provided that it is understood that combinations in which different embodiments of the same substituent would be combined are excluded;

provided that a compound of Formula (I) is other than

    
    
    a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-trifluoromethyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is NH, W is phenyl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-t-butyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-4, X is a direct bond, D is benzo, and R9 is 5-chloro;
    a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-trifluoromethyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-2, s is 1, R6 is methyl, and R7 is phenyl;
    a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-t-butyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-2, s is 1, R6 is methyl, and R7 is phenyl;
    a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-t-butyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is NH, W is phenyl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-trifluoromethyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-3, X is NH, p is 1, R5 is phenyl, and R10 and R11 are hydrogen;
    a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-trifluoromethyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is NH, W is 2-methoxy-phenyl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 2-cyano, B is phenyl, R2 is 2-chloro, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-bromo, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-chloro, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 2-fluoro, B is quinolin-3-yl, R2 is hydrogen, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 3,4-difluoro, B is benzothiophen-2-yl, R2 is 3-methyl, L is —CH2—, R3 is hydrogen, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is hydrogen, and R5 is hydrogen;
    a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-trifluoromethyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is NH, W is 3-chloro-phenyl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-trifluoromethyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is NH, W is thien-2-yl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-chloro, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen; and
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-(2-carboxy)-phenyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is hydrogen, and R5a and R5b are hydrogen.


An embodiment of the present invention is directed to compounds of Formula (I)




wherein

    A is phenyl, thienyl, or cyclohexyl; or, when A is phenyl, L is —(CH2)mN(R4)(CH2)n—, and R1 and L are attached to adjacent carbon atoms of phenyl, R1 and R4 are optionally taken with the atoms to which they are attached to form dihydroindolyl or 3,4-dihydro-2H-quinolin-1-yl;
    R1 is one to three substituents independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, hydroxy(C1-4)alkyl, methoxycarbonyl, fluoro, chloro, and cyano;
    B is selected from the group consisting of C6-10aryl, benzothiophenyl, azabenzothiophenyl, benzothiazolyl, quinolinyl, dihydrobenzofuranyl, and pyridinyl;
    R2 is one to two substituents independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, chloro, bromo, and cyano;
    and R2 is optionally one additional substituent selected from the group consisting of C1-4alkoxycarbonyl, C1-4alkylcarbonylamino, C1-4alkylaminocarbonyl, trifluoromethyl, phenyl, pyrimidin-5-yl, N-morpholinyl, piperidinyl, pyridinyl, imidazolyl, 4-(3,6-dihydro-2H-pyridin-4-yl) optionally substituted at nitrogen with t-butoxycarbonyl, and hydroxy(C1-4)alkyl;
    wherein said phenyl of R2 is optionally substituted with carboxy or tetrazolyl;
    L is —(CH2)m—Z—(CH2)n— or —CH2—; wherein m and n are independently 0 or 1, such that the sum of m+n is no greater than 1; and wherein Z is O or NR4; provided that when Z is O, A is phenyl;
    R3 is hydrogen or methyl; or, when A is phenyl and Z is NR4, R3 is optionally taken with R1 to form a tetrahydroquinolinyl;
    R4 is hydrogen, methyl, or methylcarbonyl;
    Q is






wherein s is 1, R6 is C1-4alkyl, and R7 is unsubstituted phenyl,





wherein
X is a direct bond;
p is 1;
and D, E, H, and J are benzo or pyrido;


    W is phenyl, phenylmethyl, phenylaminomethyl, or a heteroaryl selected from the group consisting of pyridinyl, thiazolyl, furanyl, indolyl, and thienyl; wherein phenyl of W is optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, hydroxy(C1-4)alkyl, fluoro, chloro, bromo, amino, di(C1-4alkyl)amino, C1-4-alkoxycarbonyl, C1-4alkylcarbonylamino, carboxy, and trifluoromethyl; and wherein pyridinyl of W is optionally substituted with bromo;
    or, W is hydrogen, and one of R5a and R5b is phenyl;
    V is hydrogen, C1-4alkoxycarbonyl or hydroxy(C1-4)alkyl; and
    R5a and R5b are hydrogen;
    R8 is hydrogen, phenyl, or phenylmethyl; and R10 is hydrogen; or R10 is phenyl or pyridinyl when R8 is hydrogen;
    R11 is hydrogen or hydroxy;
    R9, R12, R13, and R14 are independently selected from the group consisting of hydrogen, methyl, and fluoro;
    provided that a compound of Formula (I) is other than
    a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-trifluoromethyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-2, s is 1, R6 is methyl, and R7 is phenyl;
    a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-t-butyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-2, s is 1, R6 is methyl, and R7 is phenyl;
    a compound wherein A is phenyl, R1 is 2-cyano, B is phenyl, R2 is 2-chloro, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-bromo, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-chloro, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 2-fluoro, B is quinolin-3-yl, R2 is hydrogen, L is —(CH2)n, —Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 3,4-difluoro, B is benzothiophen-2-yl, R2 is 3-methyl, L is —CH2—, R3 is hydrogen, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is hydrogen, and R5 is hydrogen;
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-chloro, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen; and
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-(2-carboxy)-phenyl, L is —(CH2)n, —Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is hydrogen, and R5a and R5b are hydrogen;

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



An embodiment of the present invention is directed to compounds of Formula (I)




wherein

    A is phenyl; or, when A is phenyl, L is —(CH2)mN(R4)(CH2)n—, and R1 and L are attached to adjacent carbon atoms of phenyl, R1 and R4 are optionally taken with the atoms to which they are attached to form dihydroindolyl;
    R1 is one to two substituents independently selected from the group consisting of hydrogen, C1-2alkyl, C1-2alkoxy, methoxycarbonyl, and fluoro;
    B is selected from the group consisting of phenyl, benzothiophenyl, azabenzothiophenyl, benzothiazolyl, unsubstituted quinolinyl, dihydrobenzofuranyl, and substituted pyridinyl;
    R2 is a substituent independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, chloro, bromo, and cyano;
    and R2 is optionally one additional substituent selected from the group consisting of C1-4alkoxycarbonyl, methylcarbonylamino, trifluoromethyl, phenyl optionally substituted with 4-carboxy, pyrimidin-5-yl, N-morpholinyl, piperidinyl, pyridinyl, imidazolyl, 4-(3,6-dihydro-2H-pyridin-4-yl) optionally substituted at nitrogen with t-butoxycarbonyl, and hydroxymethyl;
    L is —(CH2)m—Z—(CH2)n— or —CH2—; wherein m and n are independently 0 or 1, such that the sum of m+n is no greater than 1; and Z is NR4;
    R3 is hydrogen;
    R4 is hydrogen or methyl;


Q is




wherein
X is a direct bond;
p is 1;
and D, E, H, and J are benzo or pyrido;


    W is phenyl or a heteroaryl selected from the group consisting of pyridinyl, thiazolyl, furanyl, and thienyl; wherein phenyl of W is optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, hydroxymethyl, fluoro, chloro, bromo, amino, di(C1-4alkyl)amino, C1-4alkoxycarbonyl, C1-4alkylcarbonylamino, carboxy, and trifluoromethyl; and wherein pyridinyl of W is optionally substituted with bromo;
    V is hydrogen, C1-2alkoxycarbonyl or hydroxymethyl; and
    R5a and R5b are hydrogen;
    R5 is hydrogen and R10 is phenyl or pyridinyl; or R5 is phenyl and R10 is hydrogen;
    R11 is hydrogen or hydroxy;
    R9, R12, R13, and R14 are independently selected from the group consisting of hydrogen or methyl;
    provided that a compound of Formula (I) is other than
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-bromo, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-chloro, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 2-fluoro, B is quinolin-3-yl, R2 is hydrogen, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 3,4-difluoro, B is benzothiophen-2-yl, R2 is 3-methyl, L is —CH2—, R3 is hydrogen, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is hydrogen, and R5a and R5b are hydrogen; and
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-chloro, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;

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



An embodiment of the present invention is directed to compounds of Formula (I)




wherein

    A is phenyl;
    R1 is one to two substituents independently selected from the group consisting of hydrogen, methoxycarbonyl, methoxy, and fluoro; or, when L is —(CH2)mN(R4)(CH2)n—, and R1 and L are attached to adjacent carbon atoms of phenyl, R1 and R4 are optionally taken with the atoms to which they are attached to form dihydroindolyl;
    B is selected from the group consisting of phenyl, benzothiophenyl, azabenzothiophenyl, benzothiazolyl, unsubstituted quinolinyl, dihydrobenzofuranyl, and substituted pyridinyl;
    R2 is a substituent selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, chloro, bromo, cyano, C1-4alkoxycarbonyl, methylcarbonylamino, trifluoromethyl, phenyl optionally substituted with 4-carboxy, pyrimidin-5-yl, N-morpholinyl, piperidinyl, pyridinyl, imidazolyl, 4-(3,6-dihydro-2H-pyridin-4-yl) substituted at nitrogen with t-butoxycarbonyl, and hydroxymethyl;
    L is —(CH2)m—Z—(CH2)n— or —CH2—; wherein m and n are 0, and Z is NR4;
    R3 is hydrogen;
    R4 is hydrogen or methyl;


Q is




wherein
X is a direct bond;
p is 1;
and D, E, and J are benzo;


    W is phenyl or a heteroaryl selected from the group consisting of pyridinyl, thiazolyl, furanyl, and thienyl; wherein phenyl of W is optionally substituted with a substituent selected from the group consisting of C1-2alkyl, C1-2alkoxy, hydroxymethyl, fluoro, chloro, bromo, amino, di(C1-4alkyl)amino, C1-2alkoxycarbonyl, C1-4alkylcarbonylamino, carboxy, and trifluoromethyl; and wherein pyridinyl of W is optionally substituted with bromo;
    V is hydrogen, C1-2alkoxycarbonyl or hydroxymethyl; and
    R5a and R5b are hydrogen;
    R5 is hydrogen and R10 is pyridinyl; or, R5 is phenyl and R10 is hydrogen;
    R11 is hydrogen or hydroxy;
    R9, R12, R13, and R14 are independently hydrogen;
    provided that a compound of Formula (I) is other than
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-bromo, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-chloro, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 2-fluoro, B is quinolin-3-yl, R2 is hydrogen, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 3,4-difluoro, B is benzothiophen-2-yl, R2 is 3-methyl, L is —CH2—, R3 is hydrogen, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is hydrogen, and R5a and R5b are hydrogen; and
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-chloro, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;

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



Another embodiment of the present invention is directed to compounds of Formula (I)




wherein

    A is phenyl;
    R1 is selected from the group consisting of hydrogen, methoxycarbonyl, 2-methoxy, fluoro, and di-fluoro; or, when L is —(CH2)mN(R4)(CH2)n—, and R1 and L are attached to adjacent carbon atoms of phenyl, R1 and R4 are optionally taken with the atoms to which they are attached to form dihydroindolyl;
    B is selected from the group consisting of phenyl, benzothiophenyl, azabenzothiophenyl, benzothiazolyl, unsubstituted quinolinyl, dihydrobenzofuranyl, and substituted pyridinyl;
    R2 is a substituent selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, chloro, bromo, C1-4alkoxycarbonyl, methylcarbonylamino, trifluoromethyl, phenyl optionally substituted with 4-carboxy, pyrimidin-5-yl, N-morpholinyl, piperidinyl, pyridinyl, imidazolyl, 4-(3,6-dihydro-2H-pyridin-4-yl) substituted at nitrogen with t-butoxycarbonyl, and hydroxymethyl;
    L is —(CH2)m—Z—(CH2)n— or —CH2—; wherein m and n are 0, and Z is NR4;
    R3 is hydrogen;
    R4 is hydrogen or methyl;
    Q is






wherein X is a direct bond and E and H are benzo;

    W is phenyl or a heteroaryl selected from the group consisting of pyridinyl, thiazolyl, furanyl, and thienyl; wherein phenyl of W is optionally substituted with a substituent selected from the group consisting of C1-2alkyl, C1-2alkoxy, hydroxymethyl, fluoro, chloro, bromo, amino, di(C1-4alkyl)amino, C1-2alkoxycarbonyl, C1-4alkylcarbonylamino, carboxy, and trifluoromethyl; and wherein pyridinyl of W is optionally substituted with bromo;
    V is hydrogen, C1-2alkoxycarbonyl or hydroxymethyl; and
    R5a and R5b are hydrogen;
    R12 and R13 are independently hydrogen;
    provided that a compound of Formula (I) is other than
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-bromo, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-chloro, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 2-fluoro, B is quinolin-3-yl, R2 is hydrogen, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
    a compound wherein A is phenyl, R1 is 3,4-difluoro, B is benzothiophen-2-yl, R2 is 3-methyl, L is —CH2—, R3 is hydrogen, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is hydrogen, and R5a and R5b are hydrogen; and
    a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-chloro, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;

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



A further embodiment of the present invention is directed to compounds of Formula (Ia) wherein L is —(CH2)m—Z—(CH2)n—, X is a direct bond, R3 and R4 are each hydrogen, and stereocenters 1 and 2 are as defined in Formula (Ia), herein:




selected from the group consisting of



















TABLE 1





Cpd










Center


No.
R1
A
R2
B
Z
m
n
W
V
R5a/5b
(1,2)


























1
H
phenyl
4-t-butyl
phenyl
NR4
0
0
2-chloro-
H
H/H
*RS,*SR










phenyl


2
H
phenyl
4-t-butyl
phenyl
NR4
0
0
2-chloro-
H
H/H
*RS,*RS










phenyl


5
H
phenyl
4-t-butyl
phenyl
NR4
0
0
pyridin-3-yl
H
H/H
RS,RS


6
H
phenyl
4-t-butyl
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS










phenyl










methyl


7
H
phenyl
4-t-butyl
phenyl
NR4
0
0
4-chloro-
H
H/H
*SR,*SR










phenyl


8
H
phenyl
4-t-butyl
phenyl
NR4
0
0
3-chloro-
H
H/H
*RS,*SR










phenyl


9
H
phenyl
4-t-butyl
phenyl
NR4
0
0
3-chloro-
H
H/H
*RS,*RS










phenyl


10
H
phenyl
4-t-butyl
phenyl
NR4
0
0
phenyl
H
H/H
*R,S










amino-










methyl


12
H
phenyl
4-t-butyl
phenyl
NR4
0
0
phenyl
H
H/H
RS,RS


13
H
phenyl
4-t-butyl
phenyl
NR4
0
0
H
H
phenyl/H
RS,RS


16
H
phenyl
4-
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS





trifluoro




phenyl





methyl


17
H
phenyl
4-
phenyl
NR4
0
0
phenyl
H
H/H
RS,RS





trifluoro





methyl


19
H
phenyl
4-
phenyl
NR4
0
0
pyridin-3-yl
H
H/H
RS,RS





trifluoro





methyl


20
H
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS





trifluoro




phenyl





methyl


21
H
phenyl
4-
phenyl
NR4
0
0
2-chloro-
H
H/H
*R,*R





trifluoro




phenyl





methyl


22
H
phenyl
4-
phenyl
NR4
0
0
2-chloro-
H
H/H
*S,*S





trifluoro




phenyl





methyl


23
H
phenyl
4-
phenyl
NR4
0
0
2-chloro-
H
H/H
*S,*R





trifluoro




phenyl





methyl


24
H
phenyl
4-
phenyl
NR4
0
0
thien-2-yl
H
H/H
RS,RS





trifluoro





methyl


25
H
phenyl
4-
phenyl
NR4
0
0
indol-2-yl
H
H/H
*RS,*RS





trifluoro





methyl


26
H
phenyl
4-
phenyl
NR4
0
0
indol-2-yl
H
H/H
*RS,*SR





trifluoro





methyl


28
H
phenyl
4-
phenyl
NR4
0
0
pyridin-4-yl
H
H/H
RS,RS





trifluoro





methyl


29
H
phenyl
4-
phenyl
NR4
0
0
2-bromo-
H
H/H
RS,RS





trifluoro




phenyl





methyl


30
H
phenyl
4-
phenyl
NR4
0
0
2-trifluoro
H
H/H
*RS,*RS





trifluoro




methyl-





methyl




phenyl


31
H
phenyl
4-
phenyl
NR4
0
0
2-trifluoro
H
H/H
*RS,*SR





trifluoro




methyl-





methyl




phenyl


32
H
phenyl
4-
phenyl
NR4
0
0
2-methyl-
H
H/H
RS,RS





trifluoro




phenyl





methyl


43
H
phenyl
4-
phenyl
NR4
0
0
2-methoxy-
H
H/H
RS,RS





trifluoro




phenyl





methyl


45
H
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
*R,*R





trifluoro




phenyl





methyl


46
H
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
*R,*S





trifluoro




phenyl





methyl


47
H
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
*S,*S





trifluoro




phenyl





methyl


48
H
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
*S,*R





trifluoro




phenyl





methyl


49
H
phenyl
4-
phenyl
NR4
0
0
thiazol-2-yl
H
H/H
RS,RS





trifluoro





methyl


50
H
phenyl
4-
phenyl
NR4
0
0
pyridin-2-yl
H
H/H
*RS,*RS





trifluoro





methyl


51
H
phenyl
4-
phenyl
NR4
0
0
pyridin-2-yl
H
H/H
*RS,*SR





trifluoro





methyl


52
H
phenyl
4-
phenyl
NR4
0
0
furan-2-yl
H
H/H
RS,RS





trifluoro





methyl


53
H
phenyl
4-t-butyl
phenyl
NR4
0
0
pyridin-4-yl
H
H/H
RS,RS


54
H
phenyl
4-t-butyl
phenyl
NR4
0
0
pyridin-2-yl
H
H/H
*RS,*RS


55
H
phenyl
4-t-butyl
phenyl
NR4
0
0
pyridin-2-yl
H
H/H
*RS,*SR


57
2-fluoro
phenyl
2-chloro
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS










phenyl


58
H
phenyl
4-cyano
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS










phenyl


60
H
phenyl
4-
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,*S





trifluoro




phenyl





methyl


61
H
phenyl
4-
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,*R





trifluoro




phenyl





methyl


62
2-fluoro
phenyl
4-cyano
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS










phenyl


66
H
phenyl
4-
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS





methoxy




phenyl


67
H
phenyl
4-bromo
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS










phenyl


68
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS





trifluoro




phenyl





methyl


69
2-fluoro
phenyl
4-
phenyl
NR4
0
0
phenyl
H
H/H
RS,RS





trifluoro





methyl


70
H
phenyl
4-bromo
phenyl
NR4
0
0
phenyl
H
H/H
RS,RS


72
H
phenyl
4-
phenyl
NR4
0
0
phenyl
H
H/H
RS,RS





methoxy


74
4-fluoro
phenyl
4-
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS





trifluoro




phenyl





methyl


75
4-fluoro
phenyl
4-
phenyl
NR4
0
0
phenyl
H
H/H
*RS,*RS





trifluoro





methyl


76
4-fluoro
phenyl
4-
phenyl
NR4
0
0
phenyl
H
H/H
*RS,*SR





trifluoro





methyl


78
3-fluoro
phenyl
4-
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS





trifluoro




phenyl





methyl


79
3-fluoro
phenyl
4-
phenyl
NR4
0
0
2-methoxy-
H
H/H
RS,RS





trifluoro




phenyl





methyl


81
H
phenyl
4-
phenyl
NR4
0
1
2-chloro-
H
H/H
RS,RS





trifluoro




phenyl





methyl


82
H
phenyl
4-
phenyl
NR4
1
0
2-chloro-
H
H/H
RS,RS





trifluoro




phenyl





methyl


83
H
phenyl
4-
phenyl
NR4
1
0
phenyl
H
H/H
*SR,*RS





trifluoro





methyl


84
H
phenyl
4-chloro
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS










phenyl


85
H
phenyl
4-chloro
phenyl
NR4
0
0
2-methoxy-
H
H/H
RS,RS










phenyl


86
H
phenyl
4-chloro
phenyl
NR4
0
0
phenyl
H
H/H
RS,RS


89
2-fluoro
phenyl
4-bromo
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS










phenyl


90
2-fluoro
phenyl
4-bromo
phenyl
NR4
0
0
2-methoxy-
H
H/H
RS,RS










phenyl


91
2-fluoro
phenyl
4-bromo
phenyl
NR4
0
0
phenyl
H
H/H
RS,RS


94
H
phenyl
4-
phenyl
NR4
0
1
phenyl
H
H/H
RS,*R





trifluoro





methyl


95
H
phenyl
4-
phenyl
NR4
0
1
phenyl
H
H/H
RS,*S





trifluoro





methyl


96
H
phenyl
4-
phenyl
NR4
0
1
2-methoxy-
H
H/H
RS,RS





trifluoro




phenyl





methyl


97
H
phenyl
3-
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS





trifluoro




phenyl





methyl


98
H
phenyl
3-
phenyl
NR4
0
0
2-methoxy-
H
H/H
RS,RS





trifluoro




phenyl





methyl


101
H
phenyl
4-
phenyl
NR4
1
0
2-methoxy-
H
H/H
RS,RS





trifluoro




phenyl





methyl


103
H
phenyl
4-
phenyl
NR4
1
0
2-fluoro-
H
H/H
RS,RS





trifluoro




phenyl





methyl


105
3-cyano
thien-2-
4-
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS




yl
methoxy




phenyl


107
2-fluoro
phenyl
4-
phenyl
NR4
1
0
2-chloro-
H
H/H
RS,RS





trifluoro




phenyl





methyl


108
2-fluoro
phenyl
4-
phenyl
NR4
1
0
phenyl
H
H/H
RS,RS





trifluoro





methyl


109
2-fluoro
phenyl
4-
phenyl
NR4
1
0
2-methoxy-
H
H/H
RS,RS





trifluoro




phenyl





methyl


110
2-fluoro
phenyl
4-chloro
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS










phenyl


111
2-fluoro
phenyl
4-chloro
phenyl
NR4
0
0
2-methoxy-
H
H/H
RS,RS










phenyl


112
2-fluoro
phenyl
4-chloro
phenyl
NR4
0
0
phenyl
H
H/H
RS,RS


115
2-fluoro
phenyl
4-chloro
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS










phenyl


116
4-fluoro
phenyl
4-chloro
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS










phenyl


117
4-fluoro
phenyl
4-chloro
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS










phenyl


118
4-fluoro
phenyl
4-chloro
phenyl
NR4
0
0
2-methoxy-
H
H/H
RS,RS










phenyl


119
4-fluoro
phenyl
4-chloro
phenyl
NR4
0
0
phenyl
H
H/H
RS,RS


122
2,4-
phenyl
4-chloro
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS



difluoro






phenyl


123
2,4-
phenyl
4-chloro
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS



difluoro






phenyl


124
2,4-
phenyl
4-chloro
phenyl
NR4
0
0
2-methoxy-
H
H/H
RS,RS



difluoro






phenyl


125
2,4-
phenyl
4-chloro
phenyl
NR4
0
0
phenyl
H
H/H
RS,RS



difluoro


128
2-fluoro
phenyl
4-
phenyl
NR4
0
0
phenyl
H
H/H
RS,S





trifluoro





methyl


129
2-fluoro
phenyl
4-
phenyl
NR4
0
0
phenyl
H
H/H
RS,R





trifluoro





methyl


130
2,4-
phenyl
4-
phenyl
NR4
0
0
phenyl
H
H/H
RS,RS



difluoro

trifluoro





methyl


131
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS





trifluoro




phenyl





methyl


132
2-fluoro
phenyl
4-
phenyl
NR4
0
0
3-fluoro-
H
H/H
RS,RS





trifluoro




phenyl





methyl


133
2-fluoro
phenyl
4-
phenyl
NR4
0
0
3-fluoro-
H
H/H
*RS,*SR





trifluoro




phenyl





methyl


134
2-fluoro
phenyl
4-
phenyl
NR4
0
0
3-fluoro-
H
H/H
*RS,*RS





trifluoro




phenyl





methyl


135
2-fluoro
phenyl
4-
phenyl
NR4
0
0
4-fluoro-
H
H/H
RS,RS





trifluoro




phenyl





methyl


136
4-
phenyl
4-chloro
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS



methoxy






phenyl


137
4-
phenyl
4-chloro
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS



methoxy






phenyl


138
4-
phenyl
4-chloro
phenyl
NR4
0
0
2-methoxy-
H
H/H
RS,RS



methoxy






phenyl


139
4-
phenyl
4-chloro
phenyl
NR4
0
0
phenyl
H
H/H
RS,RS



methoxy


142
H
phenyl
4-chloro
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS










phenyl


143
2,6-
phenyl
4-chloro
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS



difluoro






phenyl


144
2,6-
phenyl
4-chloro
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS



difluoro






phenyl


145
2,6-
phenyl
4-chloro
phenyl
NR4
0
0
2-methoxy-
H
H/H
RS,RS



difluoro






phenyl


146
2,6-
phenyl
4-chloro
phenyl
NR4
0
0
phenyl
H
H/H
RS,RS



difluoro


148
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-methoxy-
H
H/H
RS,RS





trifluoro




phenyl





methyl


149
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
*R,*S





trifluoro




phenyl





methyl


150
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,*S





trifluoro




phenyl





methyl


151
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
*S,*S





trifluoro




phenyl





methyl


152
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
*R,*R





trifluoro




phenyl





methyl


153
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,*R





trifluoro




phenyl





methyl


154
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
*S,*R





trifluoro




phenyl





methyl


155
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,*S





trifluoro




phenyl





methyl


156
2-fluoro
phenyl
4-chloro
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,S










phenyl


157
2-fluoro
phenyl
4-chloro
phenyl
NR4
0
0
2-fluoro-
H
H/H
*R,S










phenyl


158
2-fluoro
phenyl
4-chloro
phenyl
NR4
0
0
2-fluoro-
H
H/H
*S,S










phenyl


159
2-fluoro
phenyl
4-bromo
phenyl
NR4
0
0
2-fluoro-
H
H/H
*R,S










phenyl


160
2-fluoro
phenyl
4-bromo
phenyl
NR4
0
0
2-fluoro-
H
H/H
*S,S










phenyl


161
2,6-
phenyl
4-bromo
phenyl
NR4
0
0
2-fluoro-
H
H/H
*R,S



difluoro






phenyl


162
2,6-
phenyl
4-bromo
phenyl
NR4
0
0
2-fluoro-
H
H/H
*S,S



difluoro






phenyl


163
2,3-
phenyl
4-chloro
phenyl
NR4
0
0
2-fluoro-
H
H/H
*SR,*SR



difluoro






phenyl


164
2,3-
phenyl
4-chloro
phenyl
NR4
0
0
2-fluoro-
H
H/H
*SR,*RS



difluoro






phenyl


165
2,3-
phenyl
4-chloro
phenyl
NR4
0
0
2-chloro-
H
H/H
*SR,*SR



difluoro






phenyl


166
2,3-
phenyl
4-chloro
phenyl
NR4
0
0
2-chloro-
H
H/H
*SR,*RS



difluoro






phenyl


167
2,3-
phenyl
4-chloro
phenyl
NR4
0
0
2-methoxy-
H
H/H
RS,RS



difluoro






phenyl


168
2,3-
phenyl
4-chloro
phenyl
NR4
0
0
phenyl
H
H/H
RS,RS



difluoro


170
2,5-
phenyl
4-chloro
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS



difluoro






phenyl


171
2,5-
phenyl
4-chloro
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS



difluoro






phenyl


172
2,5-
phenyl
4-chloro
phenyl
NR4
0
0
2-methoxy-
H
H/H
RS,RS



difluoro






phenyl


173
2,5-
phenyl
4-chloro
phenyl
NR4
0
0
phenyl
H
H/H
RS,RS



difluoro


175
2-fluoro
phenyl
4-bromo
phenyl
NR4
0
0
2-methoxy-
H
H/H
RS,S










phenyl


176
2-fluoro
phenyl
4-bromo
phenyl
NR4
0
0
2-methoxy-
H
H/H
RS,R










phenyl


178
2-fluoro
phenyl
4-
phenyl
NR4
0
0
4-dimethyl
H
H/H
RS,RS





trifluoro




amino-





methyl




phenyl


180
2-fluoro
phenyl
4-bromo
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,S










phenyl


181
2,6-
phenyl
4-bromo
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,S



difluoro






phenyl


182
2-fluoro
phenyl
4-ethoxy
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,S





carbonyl




phenyl


183
2,6-
phenyl
4-ethoxy
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,S



difluoro

carbonyl




phenyl


184
H
phenyl
4-
phenyl
NR4
1
0
phenyl
H
H/H
*S,*S





trifluoro





methyl


185
2-fluoro
phenyl
4-
phenyl
NR4
0
0
3-fluoro-
H
H/H
*R,S





trifluoro




phenyl





methyl


186
2-fluoro
phenyl
4-
phenyl
NR4
0
0
3-fluoro-
H
H/H
RS,S





trifluoro




phenyl





methyl


187
2-fluoro
phenyl
4-
phenyl
NR4
0
0
3-fluoro-
H
H/H
*S,S





trifluoro




phenyl





methyl


188
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-chloro-
H
H/H
*R,*S





trifluoro




phenyl





methyl


189
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-chloro-
H
H/H
*S,*S





trifluoro




phenyl





methyl


190
2-fluoro
phenyl
4-
phenyl
NR4
0
0
phenyl
H
H/H
*R,S





trifluoro





methyl


191
2-fluoro
phenyl
4-
phenyl
NR4
0
0
phenyl
H
H/H
*S,S





trifluoro





methyl


195
2-fluoro
phenyl
4-bromo
phenyl
NR4
0
0
phenyl
S-
H/H
*R,R











methoxy











carbonyl


196
2-fluoro
phenyl
4-bromo
phenyl
NR4
0
0
phenyl
S-
H/H
*S,R











methoxy











carbonyl


197
2-fluoro
phenyl
4-
phenyl
NR4
0
0
pyridin-4-yl
H
H/H
RS,RS





trifluoro





methyl


198
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,*R





trifluoro




phenyl





methyl


199
2-(1-
phenyl
4-
phenyl
O
0
0
2-fluoro-
H
H/H
RS,RS



hydroxy-

trifluoro




phenyl



1-methyl-

methyl



ethyl


202
2-fluoro
phenyl
4-
phenyl
NR4
0
0
pyridin-2-yl
H
H/H
RS,RS





trifluoro





methyl


203
2-fluoro
phenyl
4-
phenyl
NR4
0
0
pyridin-3-yl
H
H/H
RS,RS





trifluoro





methyl


204
2,6-
phenyl
4-bromo
phenyl
NR4
0
0
phenyl
S-
H/H
*R,R



difluoro







methoxy











carbonyl


205
2,6-
phenyl
4-bromo
phenyl
NR4
0
0
phenyl
S-
H/H
*S,R



difluoro







methoxy











carbonyl


206
H
phenyl
4-chloro
phenyl
NR4
0
0
phenyl
S-
H/H
*R,R











methoxy











carbonyl


207
H
phenyl
4-chloro
phenyl
NR4
0
0
phenyl
S-
H/H
*S,R











methoxy











carbonyl


208
2-fluoro
phenyl
4-bromo
phenyl
NR4
0
0
phenyl
R-
H/H
*R,S











methoxy











carbonyl


209
2-fluoro
phenyl
4-bromo
phenyl
NR4
0
0
phenyl
R-
H/H
*S,S











methoxy











carbonyl


210
2,6-
phenyl
4-bromo
phenyl
NR4
0
0
phenyl
R-
H/H
*R,S



difluoro







methoxy











carbonyl


211
2,6-
phenyl
4-bromo
phenyl
NR4
0
0
phenyl
R-
H/H
*S,S



difluoro







methoxy











carbonyl


212
H
phenyl
4-chloro
phenyl
NR4
0
0
phenyl
R-
H/H
*R,S











methoxy











carbonyl


213
H
phenyl
4-chloro
phenyl
NR4
0
0
phenyl
R-
H/H
*S,S











methoxy











carbonyl


214
H
phenyl
H
pyridin-3-
NR4
0
0
2-fluoro-
H
H/H
RS,RS






yl



phenyl


217
H
phenyl
H
pyridin-2-
NR4
0
0
2-fluoro-
H
H/H
*SR,*RS






yl



phenyl


218
H
phenyl
H
pyridin-2-
NR4
0
0
2-fluoro-
H
H/H
*RS,*RS






yl



phenyl


219
2,6-
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,S



difluoro

hydroxy




phenyl





methyl


220
2-fluoro
phenyl
4-
phenyl
NR4
0
0
4-methoxy
H
H/H
RS,RS





trifluoro




carbonyl-





methyl




phenyl


221
2-fluoro
phenyl
4-
phenyl
NR4
0
0
3-methoxy
H
H/H
RS,RS





trifluoro




carbonyl-





methyl




phenyl


222
2-fluoro
phenyl
4-
phenyl
NR4
0
0
4-carboxy-
H
H/H
RS,RS





trifluoro




phenyl





methyl


223
2-fluoro
phenyl
4-
phenyl
NR4
0
0
3-carboxy-
H
H/H
RS,RS





trifluoro




phenyl





methyl


224
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS





methane




phenyl





sulfonyl


225
2-fluoro
phenyl
H
benzothiophen-
NR4
0
0
2-fluoro-
H
H/H
RS,RS






2-yl



phenyl


226
H
phenyl
H
quinolin-3-
NR4
0
0
2-fluoro-
H
H/H
RS,RS






yl



phenyl


235
H
phenyl
4-chloro
phenyl
NR4
0
0
phenyl
S-
H/H
*R,R











hydroxy











methyl


236
2,6-
phenyl
4-bromo
phenyl
NR4
0
0
phenyl
S-
H/H
*S,R



difluoro







hydroxy











methyl


237
2-fluoro
phenyl
4-bromo
phenyl
NR4
0
0
phenyl
S-
H/H
*R,R











hydroxy











methyl


238
2-fluoro
phenyl
4-bromo
phenyl
NR4
0
0
phenyl
S-
H/H
RS,R











hydroxy











methyl


239
2-fluoro
phenyl
4-bromo
phenyl
NR4
0
0
phenyl
S-
H/H
*S,R











hydroxy











methyl


240
H
phenyl
4-chloro
phenyl
NR4
0
0
phenyl
S-
H/H
*S,R











hydroxy











methyl


241
2-fluoro
phenyl
4-bromo
phenyl
NR4
0
0
phenyl
R-
H/H
*S,S











hydroxy











methyl


242
2-fluoro
phenyl
4-bromo
phenyl
NR4
0
0
phenyl
R-
H/H
*R,S











hydroxy











methyl


243
2,6-
phenyl
4-bromo
phenyl
NR4
0
0
phenyl
S-
H/H
*R,R



difluoro







hydroxy











methyl


245
2-fluoro
phenyl
H
benzothiophen-
NR4
0
0
2-fluoro-
H
H/H
RS,S






2-yl



phenyl


246
2-fluoro
phenyl
N-methyl
indol-3-yl
NR4
0
0
2-fluoro-
H
H/H
*RS,*SR










phenyl


247
2-fluoro
phenyl
H
quinolin-6-
NR4
0
0
2-fluoro-
H
H/H
*R,S






yl



phenyl


248
2-fluoro
phenyl
H
quinolin-6-
NR4
0
0
2-fluoro-
H
H/H
RS,S






yl



phenyl


250
2-fluoro
phenyl
N-methyl
indol-3-yl
NR4
0
0
2-fluoro-
H
H/H
*SR,*SR










phenyl


251
2-fluoro
phenyl
H
quinolin-6-
NR4
0
0
2-fluoro-
H
H/H
*S,S






yl



phenyl


254
2-fluoro
phenyl
H
2,3-
NR4
0
0
2-fluoro-
H
H/H
RS,RS






dihydro-



phenyl






benzo






furan-5-yl


255
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS





(pyridin-




phenyl





2-yl)


257
2-fluoro
phenyl
4-
phenyl
NR4
0
0
3-dimethyl
H
H/H
RS,RS





trifluoro




amino-





methyl




phenyl


258
2-fluoro
phenyl
4-
phenyl
NR4
0
0
pyridin-3-yl
H
H/H
*S,S





trifluoro





methyl


259
2-fluoro
phenyl
4-
phenyl
NR4
0
0
pyridin-3-yl
H
H/H
RS,S





trifluoro





methyl


260
2-fluoro
phenyl
4-
phenyl
NR4
0
0
pyridin-3-yl
H
H/H
*R,S





trifluoro





methyl


261
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,S





isopropyl




phenyl





amino





carbonyl


262
2,6-
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,S



difluoro

isopropyl




phenyl





amino





carbonyl


263
2-fluoro
phenyl
4-
phenyl
O
0
0
2-fluoro-
H
H/H
RS,RS





trifluoro




phenyl





methyl


264
H
phenyl
H
quinolin-3-
NR4
0
0
2-fluoro-
H
H/H
RS,RS






yl



phenyl


265
2,6-
phenyl
4-methyl
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,S



difluoro

amino




phenyl





carbonyl


266
2-fluoro
phenyl
4-
phenyl
NR4
0
0
4-amino-
H
H/H
RS,RS





trifluoro




phenyl





methyl


269
2-fluoro
phenyl
4-bromo
phenyl
NR4
0
0
pyridin-3-yl
H
H/H
*SR,*SR


270
2,6-
phenyl
4-chloro
phenyl
NR4
0
0
pyridin-3-yl
H
H/H
RS,RS



difluoro


271
2-fluoro
phenyl
4-bromo
phenyl
NR4
0
0
4-dimethyl
H
H/H
RS,RS










amino-










phenyl


272
2-fluoro
phenyl
4-chloro
phenyl
NR4
0
0
4-dimethyl
H
H/H
RS,RS










amino-










phenyl


273
2,6-
phenyl
4-chloro
phenyl
NR4
0
0
4-dimethyl
H
H/H
RS,RS



difluoro






amino-










phenyl


277
2-fluoro
phenyl
H
quinolin-3-
NR4
0
0
2-methoxy-
H
H/H
*R,S






yl



phenyl


278
2-fluoro
phenyl
H
quinolin-3-
NR4
0
0
2-methoxy-
H
H/H
*S,S






yl



phenyl


279
2-fluoro
phenyl
H
quinolin-3-
NR4
0
0
2-fluoro-
H
H/H
RS,S






yl



phenyl


280
2-fluoro
phenyl
H
quinolin-3-
NR4
0
0
2-fluoro-
H
H/H
*S,S






yl



phenyl


281
2-fluoro
phenyl
H
quinolin-3-
NR4
0
0
2-fluoro-
H
H/H
*R,S






yl



phenyl


282
2-fluoro
phenyl
H
2,3-
NR4
0
0
pyridin-3-yl
H
H/H
RS,RS






dihydro-






benzo






furan-5-yl


284
2-fluoro
phenyl
H
quinolin-7-
NR4
0
0
2-fluoro-
H
H/H
RS,RS






yl



phenyl


285
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS





(pyridin-




phenyl





3-yl)


286
2-fluoro
phenyl
H
2,3-
NR4
0
0
2-fluoro-
H
H/H
RS,S






dihydro-



phenyl






benzo






furan-5-yl


287
2-fluoro
phenyl
4-ethoxy
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS





carbonyl




phenyl


288
2-fluoro
phenyl
4-pyrimidin-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS





5-yl




phenyl


289
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,S





pyridin-




phenyl





2-yl


290
2-fluoro
phenyl
4-chloro
phenyl
NR4
0
0
4-amino-
H
H/H
RS,RS










phenyl


293
2-fluoro
phenyl
4-N-morpholino
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS










phenyl


294
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS





pyridin-




phenyl





4-yl


295
2-fluoro
phenyl
4-(4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS





carboxy)-




phenyl





phenyl


296
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
*R,S





pyridin-




phenyl





2-yl


297
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
*S,S





pyridin-




phenyl





2-yl


298
2-fluoro
phenyl
H
quinolin-3-
NR4
0
0
pyridin-3-yl
H
H/H
*R,S






yl


299
2-fluoro
phenyl
4-(N-t-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS





butoxy




phenyl





carbonyl-





3,6-





dihydro-





2H-





pyridin-





4-yl)


300
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,S





pyridin-




phenyl





3-yl


301
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS





imidazol-




phenyl





1-yl


302
2-fluoro
phenyl
4-(3,6-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS





dihydro-




phenyl





2H-





pyridin-





4-yl)


303
2-fluoro
phenyl
H
quinolin-6-
NR4
0
0
2-chloro-
H
H/H
*RS,*SR






yl



phenyl


304
2-fluoro
phenyl
H
quinolin-6-
NR4
0
0
2-chloro-
H
H/H
*SR,*SR






yl



phenyl


305
2-fluoro
phenyl
4-
phenyl
NR4
0
0
3-amino-
H
H/H
RS,RS





trifluoro




phenyl





methyl


306
2-fluoro
phenyl
2-phenyl
pyridin-5-
NR4
0
0
2-fluoro-
H
H/H
RS,S






yl



phenyl


307
2-fluoro
phenyl
2-phenyl
pyridin-5-
NR4
0
0
2-fluoro-
H
H/H
*S,S






yl



phenyl


308
2-fluoro
phenyl
2-phenyl
pyridin-5-
NR4
0
0
2-fluoro-
H
H/H
*R,S






yl



phenyl


309
2-fluoro
phenyl
4-chloro-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS





3-




phenyl





methoxy





carbonyl


310
2-fluoro
phenyl
4-(3-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,RS





carboxy)-




phenyl





phenyl


311
3-
phenyl
H
2,3-
NR4
0
0
2-fluoro-
H
H/H
RS,RS



methoxy


dihydro-



phenyl



carbonyl


benzo






furan-5-yl


312
2-fluoro
phenyl
H
quinolin-6-
NR4
0
0
2-chloro-
H
H/H
*R,S






yl



phenyl


313
2-fluoro
phenyl
H
quinolin-6-
NR4
0
0
2-chloro-
H
H/H
*S,S






yl



phenyl


314
2-fluoro
phenyl
H
quinolin-6-
NR4
0
0
2-chloro-
H
H/H
*S,R






yl



phenyl


315
2-fluoro
phenyl
H
quinolin-6-
NR4
0
0
2-chloro-
H
H/H
*R,R






yl



phenyl


316
2-fluoro
phenyl
4-
phenyl
NR4
0
0
3-methyl
H
H/H
RS,RS





trifluoro




carbonyl





methyl




amino-










phenyl


317
2-fluoro
phenyl
4-
phenyl
NR4
0
0
4-methyl
H
H/H
RS,RS





trifluoro




carbonyl





methyl




amino-










phenyl


319
2-fluoro
phenyl
H
benzothiophen-
NR4
0
0
pyridin-3-yl
H
H/H
RS,RS






2-yl


320
2-fluoro
phenyl
H
2-thieno
NR4
0
0
2-fluoro-
H
H/H
RS,RS






[2,3-b]pyridin-



phenyl






2-






yl


321
2-fluoro
phenyl
H
benzothiophen-
NR4
0
0
pyridin-2-yl
H
H/H
RS,RS






2-yl


322
2-fluoro
phenyl
H
benzothiophen-
NR4
0
0
pyridin-4-yl
H
H/H
*SR,*SR






2-yl


323
2-fluoro
phenyl
H
benzothiophen-
NR4
0
0
pyridin-4-yl
H
H/H
*RS,*SR






2-yl


324
2-fluoro
phenyl
H
benzothiophen-
NR4
0
0
3-methoxy
H
H/H
RS,RS






2-yl



carbonyl-










phenyl


325
2-fluoro
phenyl
H
benzothiophen-
NR4
0
0
4-methoxy
H
H/H
RS,RS






2-yl



carbonyl-










phenyl


326
2-fluoro
phenyl
H
benzothiophen-
NR4
0
0
3-carboxy-
H
H/H
RS,RS






2-yl



phenyl


327
2-fluoro
phenyl
H
benzothiophen-
NR4
0
0
4-carboxy-
H
H/H
RS,RS






2-yl



phenyl


328
2-fluoro
phenyl
H
2-thieno
NR4
0
0
2-fluoro-
H
H/H
*SR,*SR






[2,3-b]pyridin-



phenyl






2-






yl


329
2-fluoro
phenyl
H
2-thieno
NR4
0
0
2-fluoro-
H
H/H
*RS,*SR






[2,3-b]pyridin-



phenyl






2-






yl


330
2-fluoro
phenyl
H
benzothiophen-
NR4
0
0
pyridin-2-yl
H
H/H
*SR,*SR






2-yl


331
2-fluoro
phenyl
H
benzothiophen-
NR4
0
0
pyridin-2-yl
H
H/H
*RS,*SR






2-yl


332
2-fluoro
phenyl
H
2-iso
NR4
0
0
2-fluoro-
H
H/H
*S,S






quinolin-4-



phenyl






yl


333
2-fluoro
phenyl
H
2-iso
NR4
0
0
2-fluoro-
H
H/H
*R,S






quinolin-4-



phenyl






yl


334
2-fluoro
phenyl
2-N-
pyridin-5-
NR4
0
0
2-fluoro-
H
H/H
RS,S





piperidin
yl



phenyl





yl


335
2-fluoro
phenyl
2-N-
pyridin-5-
NR4
0
0
2-methoxy-
H
H/H
RS,S





piperidin
yl



phenyl





yl


337
2-fluoro
phenyl
4-(4-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,S





carboxy)-




phenyl





phenyl


338
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-chloro-
H
H/H
*R,S





pyridin-




phenyl





2-yl


339
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-chloro-
H
H/H
*S,S





pyridin-




phenyl





2-yl


340
2-fluoro
phenyl
2-methyl
benzothiazol-
NR4
0
0
2-fluoro-
H
H/H
*R,S






6-



phenyl






yl


341
2-fluoro
phenyl
2-methyl
benzothiazol-
NR4
0
0
2-fluoro-
H
H/H
*S,S






6-yl



phenyl


342
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS





imidazol-




phenyl





1-yl


343
2-fluoro
phenyl
4-
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS





pyridin-




phenyl





3-yl


344
2-fluoro
phenyl
4-
phenyl
NR4
0
0
5-bromo-
H
H/H
RS,RS





trifluoro




pyridin-3-yl





methyl


345
2-fluoro
phenyl
4-
phenyl
NR4
0
0
5-bromo-
H
H/H
*SR,*SR





trifluoro




pyridin-3-yl





methyl


346
2-fluoro
phenyl
4-
phenyl
NR4
0
0
5-bromo-
H
H/H
*RS,*SR





trifluoro




pyridin-3-yl





methyl


347
2-fluoro
phenyl
4-
phenyl
NR4
0
0
3-methoxy
H
H/H
RS,S





trifluoro




carbonyl-





methyl




phenyl


348
2-fluoro
phenyl
4-
phenyl
NR4
0
0
3-dimethyl
H
H/H
RS,R





trifluoro




amino-





methyl




phenyl


349
2-fluoro
phenyl
4-
phenyl
NR4
0
0
3-carboxy-
H
H/H
RS,S





trifluoro




phenyl





methyl


350
2-fluoro
phenyl
4-(4-
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS





carboxy)-




phenyl





phenyl


351
2-fluoro
phenyl
H
2,3-
NR4
0
0
4-methoxy
H
H/H
RS,RS






dihydro-



carbonyl-






benzo



phenyl






furan-5-yl


352
2-fluoro
phenyl
4-
phenyl
NR4
0
0
4-methoxy
H
H/H
RS,RS





pyridin-




carbonyl-





2-yl




phenyl


353
2-fluoro
phenyl
4-
phenyl
NR4
0
0
4-carboxy-
H
H/H
RS,RS





pyridin-




phenyl





2-yl


354
2-fluoro
phenyl
4-(4-1H-
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,S





tetrazol-




phenyl





5-yl-





phenyl)


355
2-fluoro
phenyl
6-t-butyl
pyridin-3-

0
0
2-fluoro-
H
H/H
RS,S






yl



phenyl


356
2-fluoro
phenyl
6-t-butyl
pyridin-3-
NR4
0
0
2-fluoro-
H
H/H
*S,S






yl



phenyl


357
2-fluoro
phenyl
6-t-butyl
pyridin-3-
NR4
0
0
2-fluoro-
H
H/H
*R,S






yl



phenyl


358
2-fluoro
phenyl
2-N-
pyridin-5-
NR4
0
0
2-fluoro-
H
H/H
RS,S





morpholinyl
yl



phenyl


359
2-fluoro
phenyl
2-N-
pyridin-5-
NR4
0
0
2-fluoro-
H
H/H
S,S





morpholinyl
yl



phenyl


360
2-fluoro
phenyl
2-N-
pyridin-5-
NR4
0
0
2-fluoro-
H
H/H
*R,S





morpholinyl
yl



phenyl


361
2,6-
phenyl
H
benzothiophen-
NR4
0
0
2-fluoro-
H
H/H
RS,RS



difluoro


2-yl



phenyl


362
H
phenyl
2-chloro
phenyl
NR4
0
0
2-chloro-
H
H/H
RS,RS










phenyl


367
H
phenyl
4-t-butyl
phenyl
NR4
0
0
4-chloro-
H
H/H
RS,RS










phenyl


368
H
phenyl
4-t-butyl
phenyl
NR4
0
0
phenyl
H
H/H
*S,S










amino










methyl


369
H
phenyl
4-
phenyl
NR4
0
0
2-chloro-
H
H/H
*R,*S





trifluoro




phenyl





methyl


372
2-fluoro
phenyl
H
quinolin-3-
NR4
0
0
2-chloro-
H
H/H
RS,S






yl



phenyl


373
2-fluoro
phenyl
H
quinolin-3-
NR4
0
0
2-chloro-
H
H/H
*S,S






yl



phenyl


374
2-fluoro
phenyl
H
quinolin-3-
NR4
0
0
2-chloro-
H
H/H
*R,S






yl



phenyl


375
2-fluoro
phenyl
4-methyl
phenyl
NR4
0
0
2-fluoro-
H
H/H
RS,S





amino




phenyl





carbonyl









Another embodiment of the present invention is directed to compounds of Formula (Ia) wherein L is —(CH2)m—Z—(CH2)n—, R5a, R5b, and V are each hydrogen, and stereocenters 1 and 2 are as defined in Formula (Ia), herein:




selected from the group consisting of



















TABLE 2





Cpd










Center


No.
R1
A
R2
B
Z
m
n
R3
R4
W
(1, 2)


























80
H
phenyl
4-
phenyl
NR4
0
0
methyl
H
2-chloro-
RS, RS





trifluoro






phenyl





methyl


193
n/a
phenyl
4-
phenyl
NR4
0
0
taken with R1
H
2-chloro-
RS, RS





trifluoro




to form

phenyl





methyl




tetrahydro










quinolin-2-yl


194
n/a
phenyl
4-
phenyl
NR4
0
0
taken with R1
H
phenyl
RS, RS





trifluoro




to form





methyl




tetrahydro










quinolin-2-yl;


227
n/a
phenyl
4-
phenyl
NR4
0
0
H
taken with
phenyl
RS, RS





trifluoro





R1 to form





methyl





2,3-dihydro











indol-1-yl


228
n/a
phenyl
4-
phenyl
NR4
0
0
H
taken with
2-fluoro-
RS, RS





trifluoro





R1 to form
phenyl





methyl





2,3-dihydro











indol-1-yl


231
2-
phenyl
4-
phenyl
NR4
0
0
H
methyl
phenyl
RS, RS



fluoro

trifluoro





methyl


232
2-
phenyl
4-
phenyl
NR4
0
0
H
methyl
2-fluoro-
RS, RS



fluoro

trifluoro






phenyl





methyl


233
2-
phenyl
4-
phenyl
NR4
0
0
H
methyl
2-fluoro-
*RS, *SR



fluoro

trifluoro






phenyl





methyl


234
2-
phenyl
4-
phenyl
NR4
0
0
H
methyl
2-fluoro-
*RS, *RS



fluoro

trifluoro






phenyl





methyl


274
n/a
phenyl
4-
phenyl
NR4
0
0
H
R4 taken
pyridin-
*S, S





trifluoro





with R1 to
3-yl





methyl





form 2,3-











dihydro-











indol-1-yl


275
n/a
phenyl
4-
phenyl
NR4
0
0
H
R4 taken
pyridin-
RS, S





trifluoro





with R1 to
3-yl





methyl





form 2,3-











dihydro-











indol-1-yl


277
n/a
phenyl
4-
phenyl
NR4
0
0
H
R4 taken
pyridin-
*R, S





trifluoro





with R1 to
3-yl





methyl





form 2,3-











dihydro-











indol-1-yl


291
n/a
phenyl
4-
phenyl
NR4
0
0
H
R4 taken
phenyl
RS, RS





trifluoro





with R1 to





methyl





form 3,4-











dihydro-











2H-











quinolin-1-











yl


292
n/a
phenyl
4-
phenyl
NR4
0
0
H
R4 taken
2-fluoro-
RS, RS





trifluoro





with R1 to
phenyl





methyl





form 3,4-











dihydro-











2H-











quinolin-1-











yl


318
2-
phenyl
4-
phenyl
NR4
0
0

methyl
2-fluoro-
S, S



fluoro

trifluoro





carbonyl
phenyl





methyl


336
n/a
phenyl
4-
phenyl

NR4
0
0
R4 taken
pyridin-
RS, RS





trifluoro





with R1 to
3-yl





methyl





form 3,4-











dihydro-











2H-











quinolin-1-











yl









Another embodiment of the present invention is directed to a compound 63 of Formula (Ib) wherein L is —(CH2)m—Z—(CH2)n—, Q is q-1, X is NH, R3, R4, R5a, R5b, and V are each hydrogen, and stereocenters 1 and 2 are as defined in Formula (Ib), herein:




















TABLE 3





Cpd








Center


No.
R1
A
R2
B
Z
m
n
W
(1, 2)







63
H
phenyl
4-trifluoro
phenyl
NR4
0
0
2-chloro-phenyl
RS, RS





methyl









Another embodiment of the present invention is directed to compounds of Formula (Ic) wherein L is —CH2—, Q is q-1, X is a direct bond, R3, R5a, R5b, and V are each hydrogen, and stereocenters 1 and 2 are as defined in Formula (Ic), herein:




selected from the group consisting of














TABLE 4





Cpd





Center


No.
R1
A
R2
B
W
(1, 2)







177
2-
phenyl
3-
benzothiophen-
2-fluoro-
RS, RS



fluoro

methyl
2-yl
phenyl


201
2-
phenyl
4-
phenyl
2-fluoro-
RS, RS



fluoro

trifluoro

phenyl





methyl


244
2,6-
phenyl
4-
phenyl
2-fluoro-
RS, RS



difluoro

trifluoro

phenyl





methyl


249
2-
phenyl
4-
phenyl
2-
RS, S



fluoro

trifluoro

methoxy-





methyl

phenyl


252
2-
phenyl
4-
phenyl
2-fluoro-
RS, S



fluoro

trifluoro

phenyl





methyl


253
2,3-
phenyl
4-
phenyl
2-fluoro-
RS, RS



difluoro

trifluoro

phenyl





methyl


267
2,6-
phenyl
4-
phenyl
2-chloro-
RS, RS



difluoro

trifluoro

phenyl





methyl


268
2,6-
phenyl
4-
phenyl
pyridin-
RS, RS



difluoro
3-yl
trifluoro





methyl


283
2,6-
phenyl
H
phenyl
2-fluoro-
RS, S



difluoro



phenyl









Another embodiment of the present invention is directed to compound 56 of Formula (Id) wherein L is —(CH2)m—Z—(CH2)n—, R3 and R4 are each hydrogen, and stereocenters 1 and 2 are as defined in Formula (Id), herein:






















TABLE 5





Cpd










Center


No.
R1
A
R2
B
Z
m
n
s
R6
R7
(1, 2)







56
H
phenyl
4-t-butyl
phenyl
NR4
0
0
1
methyl
phenyl
*RS, *SR









Another embodiment of the present invention is directed to compounds of Formula (Ie) wherein L is —(CH2)m—Z—(CH2)n—, Z is NR4, m and n are each 0, R3 and R4 are each hydrogen, and stereocenters 1 and 2 are as defined in Formula (Ie), herein:




selected from the group consisting of


















TABLE 6





Cpd









Center


No.
R1
A
R2
B
X
p
R8
R10
R11
(1, 2)

























3
H
phenyl
4-t-butyl
phenyl
direct
1
H
phenyl
hydroxy
RS







bond


4
H
phenyl
4-t-butyl
phenyl
direct
1
H
pyridin-2-
hydroxy
RS







bond


yl


11
H
phenyl
4-t-butyl
phenyl
direct
1
phenyl
H
H
RS, RS







bond


14
H
phenyl
4-t-butyl
phenyl
direct
1
phenyl
H
H
RS, RS







bond

methyl


18
H
phenyl
4-t-butyl
phenyl
direct
2
phenyl
H
H
RS, RS







bond


44
H
phenyl
4-trifluoro
phenyl
direct
1
phenyl
H
H
RS, RS





methyl

bond


59
H
phenyl
4-trifluoro
phenyl
NH
2
phenyl
H
H
RS, RS





methyl









Another embodiment of the present invention is directed to compounds of Formula (If) wherein L is —(CH2)m—Z—(CH2)n—, Z is NR4, and stereocenter 1 is as defined in Formula (If), herein:




selected from the group consisting of


















TABLE 7





Cpd No.
R1
A
R2
B
R3
R4
m
n
D
R9







15
H
phenyl
4-t-butyl
phenyl
H
H
0
0
benzo
H


27
H
phenyl
4-
phenyl
H
H
0
0
benzo
7-





trifluoro






methyl





methyl


33
H
phenyl
4-
phenyl
H
H
0
0
benzo
H





trifluoro





methyl


34
2-
phenyl
4-
phenyl
H
H
0
0
benzo
H



methyl

trifluoro





methyl


35
2,6-di
phenyl
4-
phenyl
H
H
0
0
benzo
H



methyl

trifluoro





methyl


36
2-fluoro
phenyl
4-
phenyl
H
H
0
0
benzo
H





trifluoro





methyl


37
2-
phenyl
4-
phenyl
H
H
0
0
benzo
H



chloro

trifluoro





methyl


38
3-
phenyl
4-
phenyl
H
H
0
0
benzo
H



chloro

trifluoro





methyl


39
4-
phenyl
4-
phenyl
H
H
0
0
benzo
H



chloro

trifluoro





methyl


40
H
phenyl
4-
phenyl
H
H
0
1
benzo
H





trifluoro





methyl


41
H
cyclo
4-
phenyl
H
H
0
0
benzo
H




hexyl
trifluoro





methyl


42
n/a
phenyl
4-
phenyl
H
taken with R1
0
0
benzo
H





trifluoro


to form 2,3-





methyl


dihydroindol-








1-yl









Another embodiment of the present invention is directed to compounds of Formula (Ig) wherein L is —(CH2)m—Z—(CH2)n—, Z is NR4, and stereocenter 1 is designated as RS:




selected from the group consisting of


















TABLE 8





Cpd No.
R1
A
R2
B
R3
R4
m
n
E
R12

























64
2-fluoro
phenyl
4-
phenyl
H
H
0
0
benzo
H





trifluoro





methyl


71
H
phenyl
4-bromo
phenyl
H
H
0
0
benzo
H


73
H
phenyl
4-
phenyl
H
H
0
0
benzo
H





methoxy


77
4-fluoro
phenyl
4-
phenyl
H
H
0
0
benzo
H





trifluoro





methyl


87
H
phenyl
4-chloro
phenyl
H
H
0
0
benzo
H


92
2-fluoro
phenyl
4-bromo
phenyl
H
H
0
0
benzo
H


99
H
phenyl
3-
phenyl
H
H
0
0
benzo
H





trifluoro





methyl


100
H
phenyl
4-
phenyl
H
H
1
0
benzo
H





trifluoro





methyl


104
H
phenyl
4-
phenyl
H
H
1
0
benzo
4-fluoro





trifluoro





methyl


106
2-fluoro
phenyl
4-
phenyl
H
H
1
0
benzo
H





trifluoro





methyl


113
2-fluoro
phenyl
4-chloro
phenyl
H
H
0
0
benzo
H


114
2-fluoro
phenyl
4-chloro
phenyl
H
H
0
0
benzo
4-fluoro


120
4-fluoro
phenyl
4-chloro
phenyl
H
H
0
0
benzo
H


121
4-fluoro
phenyl
4-chloro
phenyl
H
H
0
0
benzo
4-fluoro


126
2,4-
phenyl
4-chloro
phenyl
H
H
0
0
benzo
H



difluoro


127
2,4-
phenyl
4-chloro
phenyl
H
H
0
0
benzo
4-fluoro



difluoro


140
4-
phenyl
4-chloro
phenyl
H
H
0
0
benzo
H



methoxy


141
4-
phenyl
4-chloro
phenyl
H
H
0
0
benzo
4-fluoro



methoxy


147
2,6-
phenyl
4-chloro
phenyl
H
H
0
0
benzo
H



difluoro


169
2,3-
phenyl
4-chloro
phenyl
H
H
0
0
benzo
H



difluoro


174
2,5-
phenyl
4-chloro
phenyl
H
H
0
0
benzo
H



difluoro


192
n/a
phenyl
4-
phenyl
taken with
H
0
0
benzo
H





trifluoro

R1 to form





methyl

tetrahydro







quinolin-2-yl


215
H
phenyl
H
pyridin-3-
H
H
0
0
benzo
H






yl


216
H
phenyl
H
pyridin-2-
H
H
0
0
benzo
H






yl


229
2-fluoro
phenyl
4-
phenyl
H
methyl
0
0
benzo
H





trifluoro





methyl


230
n/a
phenyl
4-
phenyl
H
taken with
0
0
benzo
H





trifluoro


R1 to form





methyl


2,3-








dihydro








indol-1-yl


256
2-fluoro
phenyl
H
benzothiophen-
H
H
0
0
benzo
H






2-yl


363
n/a
phenyl
4-
phenyl
H
taken with
0
0
benzo
H





trifluoro


R1 to form





methyl


3,4-








dihydro-








2H-








quinolin-1-








yl


370
2-fluoro
phenyl
H
benzothiophen-
H
H
0
0
pyrido to
H






2-yl




form











5,7-











dihydro-











pyrrolo[3,











4-b]pyridin-











6-yl as Q


371
2-fluoro
phenyl
H
quinolin-3-
H
H
0
0
benzo
H






yl









Another embodiment of the present invention is directed to compounds of Formula (Ih) wherein and stereocenter 1 is designated as RS:




selected from the group consisting of















TABLE 9





Cpd 









No.
R1
A
R2
B
R3
E
R12







179
2-fluoro
phenyl
3-methyl
benzothiophen-
H
benzo
H






2-yl


200
2-fluoro
phenyl
4-
phenyl
H
benzo
H





trifluoro





methyl









Another embodiment of the present invention is directed to compounds of Formula (Ii) wherein L is —(CH2)m—Z—(CH2)n—, Z is NR4, R3 and R4 are hydrogen, and stereocenter 1 is designated as RS:




selected from the group consisting of
















TABLE 10





Cpd No.
R1
A
R2
B
m
n
E
R12







364
2-fluoro
phenyl
4-
phenyl
0
0
benzo
H





chloro


365
2-fluoro
phenyl
4-
phenyl
0
0
benzo
H





bromo


366
2,6-
phenyl
4-
phenyl
0
0
benzo
H



difluoro

chloro









Another embodiment of the present invention is directed to compounds of Formula (ID wherein L is —(CH2)m—Z—(CH2)n—, Z is NR4, and R3 and R4 are each hydrogen, and stereocenter 1 is designated as RS:




selected from the group consisting of
















TABLE 11





Cpd










No.
R1
A
R2
B
m
n
J
R14























65
2-fluoro
phenyl
4-
phenyl
0
0
benzo
H





trifluoro





methyl


88
H
phenyl
4-chloro
phenyl
0
0
benzo
H


93
2-fluoro
phenyl
4-bromo
phenyl
0
0
benzo
H


102
H
phenyl
4-
phenyl
1
0
benzo
H





trifluoro





methyl









In the descriptions that follow, stereochemical assignments are presented in parentheses after each compound, wherein stereocenter 1 is that which bears R3, and stereocenter 2 (where applicable) is that which is present in ring Q and bears W (Q is q-1), R7 (Q is q-2), or R8 (Q is q-3).
The present invention is further directed to compounds of Formula (I)




selected from the group consisting of

    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (*RS,*SR);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are (*RS,*RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenylmethyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 4-chloro-phenyl, V is H, and R5a and R5b are H (*SR,*SR);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 3-chloro-phenyl, V is H, and R5a and R5b are H (*RS,*SR);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 3-chloro-phenyl, V is H, and R5a and R5b are H (*RS,*RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenylamino-methyl, V is H, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is H, V is H, and R5a is phenyl, and R5b is H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (*R,*R);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (*S,*S);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (*S,*R);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is thien-2-yl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is indol-2-yl, V is H, and R5a and R5b are H (*RS,*RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is indol-2-yl, V is H, and R5a and R5b are H (*RS,*SR);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-4-yl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-bromo-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-trifluoromethyl-phenyl, V is H, and R5a and R5b are H (*RS,*RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-trifluoromethyl-phenyl, V is H, and R5a and R5b are H (*RS,*SR);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methyl-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*R,*R);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*R,*S);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*S,*S);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*S,*R);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is thiazol-2-yl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-2-yl, V is H, and R5a and R5b are H (*RS,*RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-2-yl, V is H, and R5a and R5b are H (*RS,*SR);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is furan-2-yl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-4-yl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-2-yl, V is H, and R5a and R5b are H (*RS,*RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-2-yl, V is H, and R5a and R5b are H (*RS,*SR);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 2-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-cyano, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,*S);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,*R);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-cyano, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is NH, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-methoxy, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-methoxy, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 4-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 4-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (*RS,*RS);
    a compound of Formula (I) wherein R1 is 4-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (*RS,*SR);
    a compound of Formula (I) wherein R1 is 3-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 3-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is methyl, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 1, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 1, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 1, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (*SR,*RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 1, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,*R);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 1, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,*S);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 1, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 3-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 3-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 1, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 1, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 3-cyano, A is thien-2-yl, R2 is 4-methoxy, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 1, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 1, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 1, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5 is H (RS,RS);
    a compound of Formula (I) wherein R1 is 4-fluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 4-fluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 4-fluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 4-fluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2,4-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2,4-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2,4-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2,4-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,R);
    a compound of Formula (I) wherein R1 is 2,4-difluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 3-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 3-fluoro-phenyl, V is H, and R5a and R5b are H (*RS,*SR);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 3-fluoro-phenyl, V is H, and R5a and R5b are H (*RS,*RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 4-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 4-methoxy, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 4-methoxy, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 4-methoxy, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 4-methoxy, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*R,*S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5 is H (RS,*S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*S,*S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*R,*R);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,*R);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*S,*R);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,*S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is 2,3-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*SR,*SR);
    a compound of Formula (I) wherein R1 is 2,3-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*SR,*RS);
    a compound of Formula (I) wherein R1 is 2,3-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (*SR,*SR);
    a compound of Formula (I) wherein R1 is 2,3-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (*SR,*RS);
    a compound of Formula (I) wherein R1 is 2,3-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2,3-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2,5-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2,5-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2,5-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2,5-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (RS,R);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 3-methyl, B is benzothiophen-2-yl, L is —CH2—, R3 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 4-dimethylamino-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-ethoxycarbonyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-ethoxycarbonyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 1, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (*S*S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 3-fluoro-phenyl, V is H, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 3-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 3-fluoro-phenyl, V is H, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (*R,*S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (*S,*S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is n/a, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is taken with R1 to form a tetrahydroquinolin-2-yl, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is n/a, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is taken with R1 to form a tetrahydroquinolin-2-yl, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is methoxycarbonyl, and R5a and R5b are H (*R,R);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is methoxycarbonyl, and R5a and R5b are H (*S,R);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-4-yl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,*R);
    a compound of Formula (I) wherein R1 is 2-(1-hydroxy-1-methyl-ethyl, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is O, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, L is —CH2—, R3 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-2-yl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is methoxycarbonyl, and R5a and R5b are H (*R,R);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is methoxycarbonyl, and R5a and R5b are H (*S,R);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is methoxycarbonyl, and R5a and R5b are H (*R,R);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is methoxycarbonyl, and R5a and R5b are H (*S,R);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is methoxycarbonyl, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is methoxycarbonyl, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is methoxycarbonyl, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is methoxycarbonyl, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is methoxycarbonyl, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is methoxycarbonyl, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is H, B is pyridin-3-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is H, B is pyridin-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*SR,*RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is H, B is pyridin-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*RS,*RS);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-hydroxymethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 4-methoxycarbonyl-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 3-methoxycarbonyl-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 4-carboxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 3-carboxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-methanesulfonyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is benzothiophen-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is H, B is quinolin-3-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is n/a, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is taken with R1 to form 2,3-dihydroindol-1-yl, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is n/a, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is taken with R1 to form 2,3-dihydroindol-1-yl, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is methyl, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is methyl, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is methyl, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*RS,*SR);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is methyl, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*RS,*RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is S-hydroxymethyl, and R5a and R5b are H (*R,R);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is S-hydroxymethyl, and R5a and R5b are H (*S,R);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is S-hydroxymethyl, and R5a and R5b are H (*R,R);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is S-hydroxymethyl, and R5a and R5b are H (RS,R);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is S-hydroxymethyl, and R5a and R5b are H (*S,R);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is S-hydroxymethyl, and R5a and R5b are H (*S,R);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is R-hydroxymethyl, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is R-hydroxymethyl, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenyl, V is S-hydroxymethyl, and R5a and R5b are H (*R,R);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —CH2—, R3 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is benzothiophen-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is N-methyl, B is indol-3-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*RS,*SR);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is quinolin-6-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is quinolin-6-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, L is —CH2—, R3 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is N-methyl, B is indol-3-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*SR,*SR);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is quinolin-6-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, L is —CH2—, R3 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2,3-difluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, L is —CH2—, R3 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is 2,3-dihydro-benzofuran-5-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-(pyridin-2-yl), B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS)
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 3-dimethylamino-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is H, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is H, and R5 is H (*R,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-isopropylaminocarbonyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-isopropylaminocarbonyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is O, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is H, B is quinolin-3-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-methylaminocarbonyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 4-amino-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, L is —CH2—, R3 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, L is —CH2—, R3 is H, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is H, and R5a and R5b are H (*SR,*SR);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 4-dimethylamino-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 4-dimethylamino-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 4-dimethylamino-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is n/a, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is taken with R1 to form a 2,3-dihydro-indol-1-yl, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is H, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is n/a, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is taken with R1 to form a 2,3-dihydro-indol-1-yl, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is n/a, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is taken with R1 to form a 2,3-dihydro-indol-1-yl, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is H, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is quinolin-3-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is quinolin-3-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is quinolin-3-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is quinolin-3-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is quinolin-3-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is 2,3-dihydro-benzofuran-5-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is H, B is phenyl, L is —CH2—, R3 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is quinolin-7-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-(pyridin-3-yl), B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is 2,3-dihydro-benzofuran-5-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-ethoxycarbonyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-pyrimidin-5-yl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-pyridin-2-yl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 4-amino-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is n/a, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is taken with R1 to form 3,4-dihydro-2H-quinolin-1-yl, Q is q-1, X is a direct bond, W is phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is n/a, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is taken with R1 to form 3,4-dihydro-2H-quinolin-1-yl, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-N-morpholino, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-pyridin-4-yl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-(4-carboxy)-phenyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-pyridin-2-yl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-pyridin-2-yl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is quinolin-3-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is H, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-(N-t-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl), B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-pyridin-3-yl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-imidazol-1-yl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-(3,6-dihydro-2H-pyridin-4-yl), B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is quinolin-6-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (*RS,*SR);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is quinolin-6-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (*SR,*SR);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 3-amino-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 2-phenyl, B is pyridin-5-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 2-phenyl, B is pyridin-5-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5 is H (*S,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 2-phenyl, B is pyridin-5-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-chloro-3-methoxycarbonyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-(3-carboxy)-phenyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 3-methoxycarbonyl, A is phenyl, R2 is H, B is 2,3-dihydro-benzofuran-5-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is quinolin-6-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is quinolin-6-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is quinolin-6-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (*S,R);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is quinolin-6-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (*R,R);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 3-methylcarbonylamino-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 4-methylcarbonylamino-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is methylcarbonyl, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (S,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is benzothiophen-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is 2-thieno[2,3-b]pyridin-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is benzothiophen-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-2-yl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is benzothiophen-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-4-yl, V is H, and R5a and R5b are H (*SR,*SR);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is benzothiophen-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-4-yl, V is H, and R5a and R5b are H (*RS,*SR);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is benzothiophen-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 3-methoxycarbonyl-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is benzothiophen-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 4-methoxycarbonyl-phenyl, V is H, and R5 is H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is benzothiophen-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 3-carboxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is benzothiophen-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 4-carboxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is 2-thieno[2,3-b]pyridin-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*SR,*SR);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is 2-thieno[2,3-b]pyridin-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*RS,*SR);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is benzothiophen-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-2-yl, V is H, and R5a and R5b are H (*SR,*SR);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is benzothiophen-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is pyridin-2-yl, V is H, and R5a and R5b are H (*RS,*SR);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is 2-isoquinolin-4-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is 2-isoquinolin-4-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 2-N-piperidinyl, B is pyridin-5-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 2-N-piperidinyl, B is pyridin-5-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-methoxy-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is n/a, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is taken with R1 to form 3,4-dihydro-2H-quinolin-1-yl, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-(4-carboxy)-phenyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-pyridin-2-yl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-pyridin-2-yl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 2-methyl, B is benzothiazol-6-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 2-methyl, B is benzothiazol-6-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-imidazol-1-yl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-pyridin-3-yl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 5-bromo-pyridin-3-yl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 5-bromo-pyridin-3-yl, V is H, and R5a and R5b are H (*SR,*SR);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 5-bromo-pyridin-3-yl, V is H, and R5a and R5b are H (*RS,*SR);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 3-methoxycarbonyl-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 3-dimethylamino-phenyl, V is H, and R5a and R5b are H (RS,R);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 3-carboxy-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-(4-carboxy)-phenyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is 2,3-dihydro-benzofuran-5-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 4-methoxycarbonyl-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-pyridin-2-yl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 4-methoxycarbonyl-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-pyridin-2-yl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 4-carboxy-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-(4-1H-tetrazol-5-yl-phenyl), B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 6-t-butyl, B is pyridin-3-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 6-t-butyl, B is pyridin-3-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 6-t-butyl, B is pyridin-3-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 2-N-morpholinyl, B is pyridin-5-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 2-N-morpholinyl, B is pyridin-5-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (S,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 2-N-morpholinyl, B is pyridin-5-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is H, B is benzothiophen-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 2-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 4-chloro-phenyl, V is H, and R5a and R5b are H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is phenylaminomethyl, V is H, and R5a and R5b are is H (*S,S);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (*R,*S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is quinolin-3-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is quinolin-3-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (*S,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is quinolin-3-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is H, and R5a and R5b are H (*R,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-methylaminocarbonyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is H, and R5a and R5b are H (RS,S);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-2, X is a direct bond, R7 is phenyl, s is 1, and R6 is methyl (*RS,*SR);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-3, X is a direct bond, p is 1, R8 is H, R10 is phenyl, and R11 is hydroxy (RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-3, X is a direct bond, p is 1, R8 is H, R10 is pyridin-2-yl, and R11 is hydroxy (RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-3, X is a direct bond, p is 1, R8 is phenyl, R10 is H, and R11 is H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-3, X is a direct bond, p is 1, R8 is phenylmethyl, R10 is H, and R11 is H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-3, X is a direct bond, p is 2, R8 is phenyl, R10 is H, and R11 is H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-3, X is a direct bond, p is 1, R8 is phenyl, R10 is H, and R11 is H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-3, X is NH, p is 2, R8 is phenyl, R10 is H, and R11 is H (RS,RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-t-butyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-4, X is a direct bond, D is benzo, and R9 is H (RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-4, X is a direct bond, D is benzo, and R9 is 7-methyl (RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-4, X is a direct bond, D is benzo, and R9 is H (RS);
    a compound of Formula (I) wherein R1 is 2-methyl, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-4, X is a direct bond, D is benzo, and R9 is H (RS);
    a compound of Formula (I) wherein R1 is 2,6-dimethyl, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-4, X is a direct bond, D is benzo, and R9 is H (RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-4, X is a direct bond, D is benzo, and R9 is H (RS);
    a compound of Formula (I) wherein R1 is 2-chloro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-4, X is a direct bond, D is benzo, and R9 is H (RS);
    a compound of Formula (I) wherein R1 is 3-chloro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-4, X is a direct bond, D is benzo, and R9 is H (RS);
    a compound of Formula (I) wherein R1 is 4-chloro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-4, X is a direct bond, D is benzo, and R9 is H (RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 1, R3 is H, R4 is H, Q is q-4, X is a direct bond, D is benzo, and R9 is H (RS);
    a compound of Formula (I) wherein R1 is H, A is cyclohexyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-4, X is a direct bond, D is benzo, and R9 is H (RS);
    a compound of Formula (I) wherein R1 is n/a, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is taken with R1 to form 2,3-dihydroindol-1-yl, Q is q-4, X is a direct bond, D is benzo, and R9 is H (RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-methoxy, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is 4-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 3-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 1, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 1, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is 4-fluoro (RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 1, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is 4-fluoro (RS);
    a compound of Formula (I) wherein R1 is 4-fluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is 4-fluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is 4-fluoro (RS);
    a compound of Formula (I) wherein R1 is 2,4-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is 2,4-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is 4-fluoro (RS);
    a compound of Formula (I) wherein R1 is 4-methoxy, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is 4-methoxy, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is 4-fluoro (RS);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is 2,3-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is 2,5-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 3-methyl, B is benzothiophen-2-yl, L is —CH2—, R3 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is n/a, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is taken with R1 to form tetrahydroquinolin-2-yl, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, L is —CH2—, R3 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is H, B is pyridin-3-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is H, B is pyridin-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is methyl, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is n/a, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is taken with R1 to form 2,3-dihydroindol-1-yl, Q is q-5, X is a direct bond, D is benzo, and R9 is H;
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is benzothiophen-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is n/a, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is taken with R1 to form 3,4-dihydro-2H-quinolin-1-yl, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is hydrogen, Q is q-6, X is a direct bond, H is benzo, and R13 is H (RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is hydrogen, Q is q-6, X is a direct bond, H is benzo, and R13 is H (RS);
    a compound of Formula (I) wherein R1 is 2,6-difluoro, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is hydrogen, Q is q-6, X is a direct bond, H is benzo, and R13 is H (RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is benzothiophen-2-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is pyrido to form 5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl as Q, and R12 is H (RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is H, B is quinolin-3-yl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-5, X is a direct bond, E is benzo, and R12 is H (RS,S);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-7, X is a direct bond, J is benzo, and R14 is H (RS);
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-chloro, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-7, X is a direct bond, J is benzo, and R14 is H (RS);
    a compound of Formula (I) wherein R1 is 2-fluoro, A is phenyl, R2 is 4-bromo, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 0, n is 0, R3 is H, R4 is H, Q is q-7, X is a direct bond, J is benzo, and R14 is H (RS); and
    a compound of Formula (I) wherein R1 is H, A is phenyl, R2 is 4-trifluoromethyl, B is phenyl, Z is NR4, L is —(CH2)m—Z—(CH2)n—, m is 1, n is 0, R3 is H, R4 is H, Q is q-7, X is a direct bond, J is benzo, and R14 is H (RS).


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, such as, sodium or potassium salts; alkaline earth metal salts, such as, calcium or magnesium salts; and salts formed with suitable organic ligands, such as, quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include 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 that may be used in the preparation of pharmaceutically acceptable salts include acids, including acetic acid, 2,2-dichloroactic 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)-morpholin, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, 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 treating or preventing embodiments of the present invention, the term “administering” encompasses the treatment or prevention of the various diseases, conditions, syndromes and disorders described with the compound specifically disclosed or with a compound that 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 a 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, including a pharmaceutical composition, comprising, consisting of, and/or consisting essentially of 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 about 25%, preferably less than about 10%, more preferably less than about 5%, even more preferably less than about 2%, and even more preferably less than about 1% of the (−)-isomer calculated as.




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




Another embodiment of the present invention is a composition, including a pharmaceutical composition, comprising, consisting of, and consisting essentially of 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 about 25%, preferably less than about 10%, more preferably less than about 5%, even more preferably less than about 2% and even more preferably less than about 1% of the (+)-isomer calculated as




  
    
      %
      ⁢
      
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        -
        )
      
    
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    enantiomer
  
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            mass
            ⁡
            
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              -
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                (
                
                  
                    mass
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    ×
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During any of the processes for preparation of the compounds of the various 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 pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient and/or or a pharmaceutically acceptable 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, consisting of, and consisting essentially of compounds of formula (I) and at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, and/or pharmaceutically acceptable diluent.
By way of example, in the pharmaceutical 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), solubilizing agent(s), and combinations thereof.
Solid oral dosage forms, such tablets or capsules, containing the compounds of the present invention may be administered at least one dosage form at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.
Additional oral forms in which the present inventive compounds may be administered include elixirs, solutions, syrups, and suspensions; each optionally containing flavoring agents and coloring agents.
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 comprising, consisting of, and/or consisting essentially of an aqueous emulsion of polyethylene glycols or liquid paraffin. They can also be incorporated, at a concentration of between about 1% and about 10% by weight of the cream, into an ointment comprising, consisting of, and/or consisting essentially of a white wax or white soft paraffin base together with any stabilizers and preservatives as may be required. An alternative means of administration include transdermal administration by using a skin or transdermal patch.
The pharmaceutical compositions of the present invention (as well as the compounds of the present invention alone) can also be injected parenterally, for example, intracavernosally, intravenously, intramuscularly, subcutaneously, intradermally or intrathecally. In this case, the compositions will also include at least one of a suitable carrier, a suitable excipient, and a suitable diluent.
For parenteral administration, the pharmaceutical compositions of the present invention are best used in the form of a sterile aqueous solution that may contain other substances, for example, enough salts and monosaccharides to make the solution isotonic with blood.
For buccal or sublingual administration, the pharmaceutical compositions of the present invention may be administered in the form of tablets or lozenges, which can be formulated in a conventional manner.
By way of further example, pharmaceutical compositions containing at least one of the compounds of formula (I) as the active ingredient can be prepared by mixing the compound(s) with a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, and/or a pharmaceutically acceptable excipient according to conventional pharmaceutical compounding techniques.
The carrier, excipient, and diluent 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, syrups, elixirs and solutions, suitable carriers, excipients, and diluents 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, excipients, and diluents include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations also may be optionally coated with substances, such as, sugars, or be enterically-coated so as to modulate the major site of absorption and disintegration. For parenteral administration, the carrier, excipient, and diluent will usually include sterile water, and other ingredients may be added to increase solubility and preservation of the composition. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives, such as solubilizers and preservatives.
A therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof includes 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 diseases, syndromes, conditions, and disorders being treated.
For oral administration, a pharmaceutical composition is preferably provided in the form of tablets containing about 0.01, about 10, about 50, about 100, about 150, about 200, about 250, and about 500 milligrams of the inventive compound as the active ingredient.
Advantageously, a compound 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 and four times daily.
Optimal dosages a compound of formula (I) 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, syndrome, condition, or disorder. 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 a compound of formula (I) is required for a subject including an animal, a mammal, and a human, in need thereof.
As antagonists of the TRPM8 ion channel, the compounds of formula (I) are useful in methods for treating and preventing a disease, a syndrome, a condition, or a disorder in a subject, including an animal, a mammal and a human in which the disease, the syndrome, thecondition, or disorder is affected by the modulation of TRPM8 receptors. Such methods comprise, consist of, and consist essentially of administering to a subject, including a in need of such treatment or prevention a therapeutically effective amount of a compound, salt or solvate of formula (I). In particular, the compounds of formula (I) are useful for preventing or treating-pain, or diseases, syndromes, conditions, or disorders causing such pain, or pulmonary or vascular dysfunction. More particularly, the compounds of formula (I) are useful for preventing or treating inflammatory pain, inflammatory hypersensitivity conditions, neuropathic pain, anxiety, depression, and cardiovascular disease aggravated by cold, including peripheral vascular disease, vascular hypertension, pulmonary hypertension, Raynaud's disease, and coronary artery disease, by administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).
Examples of inflammatory pain include pain due to a disease, condition syndrome, disorder or a pain state, including inflammatory bowel disease, visceral pain, migraine, post operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor, musculoskeletal diseases, skin diseases, toothache, pyresis, burn, sunburn, snake bite, venomous snake bite, spider bite, insect sting, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome, menstrual pain, endometriosis, sinus headache, tension headache, or arachnoiditis.
One type of inflammatory pain is inflammatory hyperalgesia, which can be further distinguished as inflammatory somatic hyperalgesia or inflammatory visceral hyperalgesia. Inflammatory somatic hyperalgesia can be characterized by the presence of an inflammatory hyperalgesic state in which a hypersensitivity to thermal, mechanical and/or chemical stimuli exists. Inflammatory visceral hyperalgesia can also be characterized by the presence of an inflammatory hyperalgesic state, in which an enhanced visceral irritability exists.
Examples of inflammatory hyperalgesia include a disease, syndrome, condition, disorder or pain state including inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal pain, musculoskeletal diseases, skin diseases, post operative pain, headaches, toothache, burn, sunburn, insect sting, neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, enteritis, irritable bowel syndrome, and inflammatory bowel diseases including Crohn's Disease, and or ulcerative colitis.
One embodiment of the present invention is directed to a method for treating inflammatory somatic hyperalgesia in which a hypersensitivity to thermal, mechanical and/or chemical stimuli exists, comprising, consisting of, and/or consisting essentially of the step of administering to a subject, including an animal, a mammal, and a human, in need of such treatment a therapeutically effective amount of a compound, salt or solvate of formula (I).
A further embodiment of the present invention is directed to a method for treating inflammatory visceral hyperalgesia in which a enhanced visceral irritability exists, comprising, consisting of, and/or consisting essentially of the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound, salt or solvate of formula (I).
A further embodiment of the present invention is directed to a method for treating neuropathic cold allodynia in which a hypersensitivity to a cooling stimuli exists, comprising, consisting of, and/or consisting essentially of the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound, salt or solvate of formula (I).
Examples of an inflammatory hypersensitivity condition include urinary incontinence, benign prostatic hypertrophy, cough, asthma, rhinitis and nasal hypersensitivity, itch, contact dermatitis and/or dermal allergy, and chronic obstructive pulmonary disease.
Examples of a neuropathic pain include pain due to a disease, syndrome, condition, disorder, or pain state including cancer, neurological disorders, spine and peripheral nerve surgery, brain tumor, traumatic brain injury (TBI), spinal cord trauma, chronic pain syndrome, fibromyalgia, chronic fatigue syndrome, neuralgias (trigeminal neuralgia, glossopharyngeal neuralgia, postherpetic neuralgia and causalgia), lupus, sarcoidosis, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, central pain, neuropathies associated with spinal cord injury, stroke, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, bony fractures, oral neuropathic pain, Charcot's pain, complex regional pain syndrome I and II (CRPS I/II), radiculopathy, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome, 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, vulvodynia, or vidian neuralgia.
One type of neuropathic pain is neuropathic cold allodynia, which can be characterized by the presence of a neuropathy-associated allodynic state in which a hypersensitivity to cooling stimuli exists. Examples of neuropathic cold allodynia include allodynia due to a disease, condition, syndrome, disorder, or pain state including neuropathic pain (neuralgia), pain arising from spine and peripheral nerve surgery or trauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpetic neuralgia, causalgia, peripheral neuropathy, diabetic neuropathy, central pain, stroke, peripheral neuritis, polyneuritis, complex regional pain syndrome I and II (CRPS I/II) and radiculopathy.
Examples of anxiety include social anxiety, post traumatic stress disorder, phobias, social phobia, special phobias, panic disorder, obsessive compulsive disorder, acute stress, disorder, separation anxiety disorder, and generalized anxiety disorder.
Examples of depression include major depression, bipolar disorder, seasonal affective disorder, post natal depression, manic depression, and bipolar depression.
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 specific chemical reactions and specific conditions described in the schemes and examples. 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 and within the skill of persons versed in the art.
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
        DCE 1,2-dichloroethane
        DCM dichloromethane
        DEAD diethyl azodicarboxylate
        DIAD diisopropyl azodicarboxylate
        DIEA diisopropyl-ethyl amine
        DMAP 4-(dimethylamino)pyridine
        DMF N,N-dimethylformamide
        DMSO dimethylsulfoxide
        DPPA diphenylphosphoryl azide
        ESI electron-spray ionization
        EtOAc ethyl acetate
        EtOH ethanol
        h hour
        HATU 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate
        H BTU O-benzotriazol-1-yl-N,N,N′,N′ tetramethyluronium hexafluorophosphate
        HEK human embryonic kidney
        HOBt 1-hydroxybenzotriazole
        HPLC high performance liquid chromatography
        LDA lithium diisopropylamide
        LHMDS lithium bis(trimethylsilyl)amide
        Me methyl
        MeOH methanol
        MHz megahertz
        min minutes
        MPLC medium pressure liquid chromatography
        MS mass spectroscopy
        NaHMDS sodium bis(trimethylsilyl)amide
        NBS N-bromosuccinimide
        NCS N-chlorosuccinimide
        NMR nuclear magnetic resonance
        NT not tested
        PCC pyridinium chlorochromate
        Ph phenyl
        Pd/C palladium on activated carbon
        Ph3P triphenylphosphine
        PPA polyphosphoric acid
        rt room temperature
        TEN Et3N triethylamine
        TFA trifluoroacetic acid
        THF tetrahydrofuran
        TLC thin layer chromatography
        TMS tetramethylsilane
        TMSCN trimethylsilyl cyanide
    
    


Scheme A illustrates a route for the synthesis of compounds of formula (I)-A wherein L is —(CH2)m—Z—(CH2)n—, R3 is hydrogen, Z is NR4, R4 is hydrogen or C1-3alkyl, m is 0, and B is other than indolyl and benzothiazolyl.




A compound of formula A1 is either commercially available or may be prepared by known methods including those described in the scientific literature. A compound of formula A1 may be converted to a compound of formula A2 using concentrated hydrochloric acid in a C1-4alkyl alcoholic solvent. A compound of formula A2 may be converted to its corresponding bromide of formula A3 by the action of NBS in hydrobromic acid in carbon tetrachloride, or by another brominating agent, such as, bromine in acetic acid or by carbon tetrabromide with DBU. Treatment of a compound of formula A3 with an appropriately substituted amine of formula A4 affords a compound of formula A5. Saponification of a compound of formula A5 by the action of an alkali metal hydroxide affords a compound of formula A6. The carboxylic acid of formula A6 may be coupled with an appropriately substituted amine of formula A7, Q-H, in the presence of a peptide coupling agent, such as, HATU, DCC, HBTU, and the like, and optionally in the presence of a tertiary amine, to afford a compound of formula (I)-A. Compounds of formula A7 are either commercially available or may be prepared by known methods including those described in the scientific literature.
An alternate route to compounds of Formula (I)-A is presented in Scheme B.




A compound of formula A1 may be converted to its corresponding acid chloride by the action of a chlorinating agent, such as, thionyl chloride, oxalyl chloride, and the like. Subsequent treatment of the acid chloride with a conventional brominating agent affords a compound of formula B1. Conversion to a compound of formula (I)-A may be accomplished by reaction of the acid chloride of formula B1 with a compound of formula A7, followed by nucleophilic displacement of the bromide by a compound of formula A4.
Scheme C illustrates a route for the synthesis of compounds of formula (I)-C wherein ring A is phenyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, and R1 and R4 are taken with the atoms to which they are attached to form a 9 to 11-membered benzofused heterocyclyl.




A compound of formula A3 may undergo a nucleophilic displacement with an appropriately substituted amine of formula C1 to form a compound of formula C2. Saponification of a compound of formula C2 to its corresponding carboxylic acid, followed by coupling of the carboxylic acid with a compound of formula A7, as described herein, affords a compound of formula (I)-C.
Scheme D illustrates a route for the synthesis of compounds of formula (I)-D wherein L is —(CH2)m—Z—(CH2)n—, Z is NR4, and R4 is C1-3alkylcarbonyl.




A compound of formula D1 may converted to a compound of formula (I)-D by the action of an acylating agent of formula D2 in the presence of an appropriate organic base, such as, pyridine and other tertiary amine. Compounds of formula D2 are either commercially available or may be prepared by known methods including those described in the scientific literature. The LG group of formula D2 is an appropriate leaving group, such as chloride, acyloxy, and the like.
Scheme E illustrates a route for the synthesis of compounds of formula (I)-E wherein L is —(CH2)m—Z—(CH2)n—, Z is NR4, m is 0, and, specifically, R3 is C1-2alkyl.




A compound of formula E1 is either commercially available or may be prepared by known methods including those described in the scientific literature. A compound of formula E1 may be treated with an R3-substituted organolithium or organomagnesium bromide in an aprotic solvent at about −78° C. to afford a carbinol of formula E2. The alcohol of formula E2 may be treated with mesyl chloride to afford the mesylated compound of formula E3. Nucleophilic addition of an amine of formula A4, followed by saponification and coupling with a compound of formula A7 affords a compound of formula (I)-E.
Scheme F illustrates a route for the synthesis of compounds of formula (I)-F wherein L is —(CH2)m—Z—(CH2)n—, Z is NR4, and, specifically, Q is q-1, X is a direct bond, and V is C1-4alkoxycarbonyl.




A compound of formula F1 is either commercially available or may be prepared by known methods including those described in the scientific literature. Removal of the PG from an amine protected compound of formula F1 (wherein PG is a conventional amine protecting group) may achieved under appropriate conventional deprotection conditions known to one skilled in the art. For example, a Boc amine protecting group may be removed in the presence of HCl in an alcoholic solvent (ROH).
The aforementioned acidic reaction conditions also facilitates the conversion of the carboxy group of F1 to its corresponding ester of formula F2. Carboxylic acid intermediates of formula F3 that are useful for the preparation of certain compounds of Formula (I) may be synthesized according to the methods illustrated herein. In particular, Scheme A describes the preparation of compounds of formula F3 wherein m is 0 and n is 0 or 1. Furthermore, compounds of formula F3 wherein m is 1 and n is 0 may be prepared according to known methods including those described in the scientific literature (for example, Bioorg Med Chem Lett, 2001, 11, 2691). The amine of formula F2 may be coupled with a compound of formula F3 using the reagents and methods taught herein to afford a compound of formula (I)-F.
Scheme G illustrates a route for the synthesis of compounds of formula (I)-G wherein L is —(CH2)m—Z—(CH2)n—, Z is NR4 and, specifically, Q is q-1, X is a direct bond, and V is hydroxymethyl.




The ester of a compound of formula (I)-F may be converted to the corresponding primary alcohol of formula (I)-G by the action of a reducing agent such as a lithium borohydride, sodium borohydride, DIBAL, or the like.
Scheme H illustrates a route for the synthesis of compounds of formula (I)-H wherein L is —(CH2)m—Z—(CH2)n—, Z is NR4, and specifically, R2 is hydroxy(C1-4)alkyl.




A compound of formula H1 (wherein R2 is bromo) may be prepared using appropriate reagents and the methods taught herein. Alkoxy-carbonylation of a compound of formula H1 may be achieved using a palladium source, including trans-di-m-acetatobis[2-(di-o-tolylphosphino)benzyl]di-palladium(II), a carbon monoxide source, a trialkylphosphine, and a suitable alcoholic solvent (C1-6alkyl-OH), such as, ethanol, in a microwave reactor to afford a compound of formula H2. Reduction of the ester of a compound of formula H2 to a primary alcohol using a hydride source including a lithium borohydride, sodium borohydride, DIBAL, and the like affords a hydroxymethyl-substituted compound of formula (I)-H.
Useful intermediates of formula H3 may be prepared by a palladium catalyzed cross-coupling reaction of an appropriate vinyl and alkynyl boronic acid with a compound of formula H1. The boronic acid would necessitate a terminal protected alcohol or alcohol surrogate (herein defined as G) that could be converted to a hydroxy group subsequent to the cross-coupling reaction. Conversion of substituent G to a hydroxy(C2-4)alkyl may be achieved by conventional synthetic methods: for example, a protected alcohol may be deprotected under acidic conditions; or, when G is an alcohol surrogate, such as, an ester, or carboxylic acid treatment with conventional reduction reagents would afford the desired alcohol. The final reduction of the vinyl or alkynyl group in the presence of a conventional hydride source affords compounds of formula (I)-H wherein R2 is hydroxy(C2-4)alkyl. One skilled in the art will recognize that the order in which the chemical steps are performed may be dependent upon the properties of G. For example, in certain conditions it may be beneficial to perform the reduction of the vinyl or alkynyl group prior to generating the hydroxy group of formula (I)-H.
Scheme I illustrates a route for the synthesis of compounds of formula (I)-I wherein L is —(CH2)m—Z—(CH2)n—, Z is NR4, and specifically, R2 is C1-4alkylaminocarbonyl or di(C1-4)alkylaminocarbonyl.




A compound of formula H1 may be treated with an appropriately substituted amine of the formula HNRaRb (wherein Ra is hydrogen or C1-4alkyl and Rb is C1-4alkyl) in the presence of a palladium source such as trans-di-m-acetatobis[2-(di-o-tolylphosphino)benzyl]di-palladium(II), a carbon monoxide source, and a trialkylphosphine in a microwave reactor to afford an amide of formula (I)-I. Alternatively, an amide may be installed via a carboxy-substituted B ring. The conversion of the carboxy function to an amide of R2 may be carried out using peptide coupling agents and an amine; or, the carboxy function may be converted to its corresponding acid chloride using conventional chlorinating agents, followed by addition of an amine to yield the desired amide.
Scheme J illustrates a route for the synthesis of compounds of formula (I)-J wherein A is phenyl, L is —(CH2)m—Z—(CH2)n—, Z is NR4, m and n are 0, R4 is H, and R1 and R3 are taken together to form a tetrahydroquinolinyl.




A compound of formula J1 may be prepared by an adaptation of the procedures described in literature reference: Hino et al., J. Med. Chem. 1988, 31, 107. Chlorination of a compound of formula J1 may be accomplished by the action of a chlorinating agent including phosphorus pentachloride, N-chlorosuccinimide, and the like, followed by treatment with concentrated HCl to afford a compound of formula J2. A compound of formula J2 may be treated with an amine (X=direct bond) or hydrazine (X═NH) of formula A7, which upon rearrangement, affords a spiro compound of formula (I)-J.
Scheme K illustrates a route for the synthesis of compounds of formula (I)-K wherein L is —(CH2)m—Z—(CH2)n—, Z is NR4, and specifically, R2K is an R2 substituent other than cyano, C1-4alkoxycarbonyl, or carboxy.




A compound of formula K1 is either commercially available or may be prepared by known methods including those described in the scientific literature. A compound of formula K1 may be treated with a compound of formula A4 in the presence of trimethylsilyl cyanide and iodine to install ring A and linker L. Subsequent treatment with a suitable alcohol (ROH, wherein R is C1-4alkyl) in concentrated HCl affords a compound of formula K2. A compound of formula K2 may be saponified and subsequently coupled with a compound of formula A7 as taught in Scheme A to afford a compound of formula (I)-K.
Scheme L illustrates a route for the synthesis of compounds of formula (I)-L wherein L is —(CH2)m—Z—(CH2)n—, Z is NR4, and m is 0. Ring B is phenyl, benzothiophenyl, or dihydrobenzofuranyl, and R2L is an R2-substituent other than 4-alkoxycarbonyl, 4-cyano, and 4-trifluoromethyl.




A compound of formula L1 is either commercially available or may be prepared by known methods including those described in the scientific literature. A compound of formula L1 may be converted to a compound of formula L2 by the action of a compound of formula A4 in the presence of glyoxalic acid monohydrate. A compound of formula L2 may be coupled with a compound of formula A7 as described herein to yield a compound of formula (I)-L1.
Furthermore, when R2L is bromo as shown in a compound of formula (I)-L1, the bromo group may participate in a palladium cross-coupling reaction with a boronic acid of formula L3, in the presence of a palladium catalyst, potassium carbonate, and in alcoholic solvent to afford a compound of formula (I)-L2.
The R-ring of L3 may also bear a substituent selected from carboxy or tetrazolyl. The preparation of compounds wherein the R-ring is substituted would require R of formula L3 to be a phenyl ring substituted with a protected carboxy group, a carboxy precursor, or a tetrazolyl precursor. Carboxy and tetrazolyl precursors are those that are readily convertible to the desired substituent, including a bromide, C1-3alkoxycarbonyl, and cyano. For example, a bromide substituent may be alkoxy-carbonylated and subsequently hydrolyzed to form a carboxy function; alternatively, a C1-3alkoxycarbonyl or cyano group may be hydrolyzed in the presence of an alkali metal hydroxide to produce the aforementioned carboxy-substituted phenyl substituent of Ra. A cyano functionality may also serve as a tetrazolyl precursor. In this instance, reaction of the cyano-substituted compound of formula (I)-L2 with trimethylsilylazide in the presence of tributyltin oxide affords a tetrazolyl-substituted R-ring.
Scheme M illustrates a route for the synthesis of compounds of formula (I)-M wherein L is —(CH2)m—Z—(CH2)n—, Z is NR4, and specifically, m is 1, and therefore, by definition, n is 0.




A compound of formula M1 is either commercially available or may be prepared by known methods including those described in the scientific literature. A compound of formula M1 may be converted to a compound of formula M2 by the action of an aniline of formula A4 in the presence of catalyst Yb(OTf)3. A compound of formula M2 may be saponified and subsequently coupled with a compound of formula A7 as described herein to yield a compound of formula (I)-M.
Scheme N illustrates a route for the preparation of certain Q-intermediates of formula N3 wherein, specifically, X is NH.




A compound of formula N1 of formula Q-X—H, (wherein QN is the heterocyclic portion of Q) is either commercially available or may be prepared by known methods including those described in the scientific literature. A compound of formula N1 may be treated with isoamyl nitrite in an aprotic solvent to afford a nitroso-substituted compound of formula N2, which may then be reduced in the presence of a hydride source, such as, lithium aluminum hydride, to afford a hydrazine of formula N3 which may be used in coupling reactions as described for compounds of formula A7.
An alternate synthetic route entails treating a compound of formula N1 with potassium isocyanate to form the corresponding urea intermediate, which, upon treatment with sodium or potassium hypochlorite, is converted to a compound of formula N3.
Scheme P illustrates a route for the preparation of compounds of formula (I)-P wherein L is —(CH2)m—Z—(CH2)n— and specifically, A is phenyl, and Z is O.




A compound of formula P1 is either commercially available or may be prepared by known methods including those described in the scientific literature. A compound of formula P1 may be converted to a compound of formula P2 via a coupling reaction between the carboxy group of P1 and the amino group of a compound of formula A7 using appropriate coupling conditions as described herein. The hydroxy function of a compound of formula P2 may be coupled with a compound of formula P3 under conventional Mitsunobu coupling conditions to afford a compound of formula (I)-P1, wherein n is 0. Compounds of formula P3 are either commercially available or may be prepared by known methods including those described in the scientific literature.
Compounds of formula (I)-P2 wherein n is 1 may be prepared by the alkylation of a compound of formula P1 (wherein m=0 by definition) with a compound of formula P4 to afford a compound of formula P5. Subsequent coupling with a compound of formula A7 under the conditions described herein affords a compound of formula (I)-P2.
Scheme Q illustrates a route for the synthesis of compounds of formula (I)-Q wherein L is —CH2—.




A compound of formula A2 may be deprotonated with an organic base such as lithium diisopropylamide (LDA) and alkylated with a compound of formula Q1. Compounds of formula Q1 are either commercially available or may be prepared by known methods including those described in the scientific literature. The ester of formula Q2 may be saponified and subsequently coupled with a compound of formula A7 as described herein to yield a compound of formula (I)-Q. One skilled in the art will recognize that compounds of formula (I)-Q may similarly be prepared by altering the synthetic sequence such that the coupling reaction is performed prior to the installation of ring A.
Scheme R illustrates a route for the preparation of compounds of formula (I)-R wherein L is —(CH2)m—Z—(CH2)n—, and specifically, A is an R1-substituted phenyl, and Z is S.




Compounds of the present invention wherein m is 1 and n is 0 may be prepared from a compound of formula P2 wherein m is 1. A compound of formula P2 may be coupled with a compound of formula R1 under conventional Mitsunobu coupling conditions to afford a compound of formula (I)-R1, wherein n is 0. Compounds of formula R1 are either commercially available or may be prepared by known methods including those described in the scientific literature.
Furthermore, Scheme R illustrates the preparation of compounds of formula (I)-R2 wherein m is 0 and n is 1. Compounds of formula R2 are either commercially available or readily synthesized by known methods including those described in the scientific literature. A compound of formula R2 may be converted to its corresponding acid chloride by the action of a chlorinating agent such as thionyl chloride, oxalyl chloride, or the like. Subsequent treatment of the acid chloride of formula R3 with a compound of formula A7 may afford a compound of formula R4. Conversion to a compound of formula (I)-R2 may be accomplished by treating the alcohol functionality of a compound of formula R4 with a chlorinating agent, such as, thionyl chloride and the like, to afford a compound of formula R5, followed by nucleophilic displacement of the chloride with a compound of formula R6.
Compounds of Formula (I) that are chiral may be separated into their enantiomers by chromatography on a chiral stationary phase. Alternatively, basic or acidic compounds and intermediates to compounds of the present invention may be converted to diastereomeric salts by mixture with a chiral acid or base, respectively, and resolved into their enantiomers by fractional crystallization.
It is generally preferred that the respective product of each process step be separated from other components of the reaction mixture and subjected to purification before its use as a starting material in a subsequent step. Separation techniques typically include evaporation, extraction, precipitation and filtration. Purification techniques typically include column chromatography (Still, W. C. et. al., J. Org. Chem. 1978, 43, 2921), thin-layer chromatography, crystallization and distillation. The structures of the final products, intermediates and starting materials are confirmed by spectroscopic, spectrometric and analytical methods including nuclear magnetic resonance (NMR), mass spectrometry (MS) and liquid chromatography (HPLC). In the descriptions for the preparation of compounds of this invention, ethyl ether, tetrahydrofuran and dioxane are common examples of an ethereal solvent; benzene, toluene, hexanes and heptanes are typical hydrocarbon solvents and dichloromethane and dichloroethane are representative halogenated hydrocarbon solvents. In those cases where the product is isolated as the acid addition salt the free base may be obtained by techniques known to those skilled in the art. In those cases in which the product is isolated as an acid addition salt, the salt may contain one or more equivalents of the acid. Enantiomers of the compounds of the present invention may be separated using chiral HPLC.
SPECIFIC EXAMPLES
Reagents were purchased from commercial sources. Microanalyses were performed at Quantitative Technologies, Inc., Whitehouse, N.J. and are expressed in percentage by weight of each element per total molecular weight. Nuclear magnetic resonance (NMR) spectra for hydrogen atoms were measured in the indicated solvent with (TMS) as the internal standard on a Bruker Avance or Varian (300 or 400, or 500 MHz) spectrometer. The values are expressed in parts per million downfield from TMS. The mass spectra (MS) were determined on an Agilent spectrometer as (ESI) m/z (M+H+) using an electrospray technique. Optical rotations were obtained on a Perkin-Elmer polarimeter using the sodium D line as wavelength of light. 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. Where reactions were carried out in a microwave reactor, a Biotage InitiatorTM was used.
Example 1




A. (4-Trifluoromethyl-phenyl)-acetic acid methyl ester. To a solution of 4-(trifluoromethyl)phenylacetic acid (5 g, 24.5 mmol) in MeOH (25 mL) at room temperature was added conc. HCl (0.25 mL). The reaction was stirred overnight at room temperature. The solution was concentrated. The residue was dissolved in CH2Cl2 and washed with aq. 1N NaOH, H2O and brine. The organic layer was dried over Na2SO4 and concentrated to give Compound 1a (5 g, 94%) as a colorless oil.
B. Bromo-(4-trifluoromethyl-phenyl)-acetic acid methyl ester. To a solution of Compound 1a (4.98 g, 22.8 mmol) in CCl4 (23 mL) was added NBS (4.47 g, 25.4 mmol), followed by 2 drops of aq. 48% HBr. The reaction was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and filtered. The solid was washed with CCl4. The solutions were combined and concentrated to give Compound 1b (6.7 g, 99%) as a light yellow oil.
C. (2-Fluoro-phenylamino)-(4-trifluoromethyl-phenyl)-acetic acid methyl ester. A solution of Compound 1b (6.0 g, 20.2 mmol) and 2-fluoroaniline (4.9 mL) in CH3CN (50 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in CH2Cl2 and washed with aq. 10% HCl and sat. aq. NaHCO3. The organic layer was dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 10% EtOAc/heptane) gave Compound 1c (5.6 g, 85%) as a yellow oil.
D. (2-Fluoro-phenylamino)-(4-trifluoromethyl-phenyl)-acetic acid. To Compound 1c (2.0 g, 6.11 mmol) in THF (25 mL)/MeOH (25 mL)/H2O (25 mL) at room temperature was added LiOH.H2O (0.77 g, 18.3 mmol). The reaction was stirred at room temperature for 3 hours. It was acidified using aq. 10% HCl to pH=4. The mixture was concentrated to remove most of the organic solvent. The residue was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give Compound 1d (1.9 g, 99%) as a yellow solid.
E. 2-(2-Fluoro-phenylamino)-1-[(2S)-2-(2-fluoro-phenyl)-pyrrolidin-1-yl]-2-(4-trifluoromethyl-phenyl)-ethanone. A mixture of Compound 1d (2.0 g, 6.39 mmol), (S)-2-(2-fluorophenyl)pyrrolidine HCl salt (1.3 g, 6.47 mmol), Et3N (5.3 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (HATU, 2.43 g, 6.39 mmol) in CH2Cl2 (70 mL) was stirred at room temperature overnight. The mixture was washed with aq. 10% HCl and sat. aq. NaHCO3. The organic layer was dried over Na2SO4 and concentrated. Purification of the crude product with column chromatography (silica gel, 20% ethyl acetate/hexane) gave Compound 150 (2.17 g, 74%). MS 461 (M+1)+.
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 + 1)+



















27
411.1



52
415.2



53
414.3



57
443



58
416



61
459.1



62
434



64
415



65
429



66
421



67
469



68
477



69
443



70
435



71
407



72
387



73
359



74
477



77
415



78
477



79
473



81
473



84
425



85
421



86
391



87
363



88
377



89
487



90
483



91
453



92
425



93
439



94
439



95
439



96
469



97
459



98
455



99
397



110
443



111
439



112
409



113
381



114
399



115
427



116
443



117
427



118
439



119
409



120
381



121
399



122
461



123
445



124
457



125
427



126
399



127
417



128
443



129
443



130
461



131
461



132
461



135
461



136
455



137
439



138
451



139
421



140
393



141
411



142
409



143
461



144
445



145
457



146
427



147
399



148
473



153
461



155
477



156
427



167
457



168
427



169
399



170
445



171
461



172
457



173
427



174
399



175
483



176
483



178
486



180
471



181
489



186
461



197
444



198
477



202
444



203
444



220
501



221
501



227
451



228
469



229
429



230
423



231
457



232
475



257
486



259
444



266
458



270
428



271
496



272
452



273
470



275
452



290
424



291
465



292
483



305
458



316
500



317
500



336
466



344
522



347
501



348
486



362
425



363
437



364
395



365
439



366
413










Cpd 3: MS (M+1)+443.3; 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.48-1.19 (m, 1H) 1.20-1.29 (m, 9H) 1.30-2.03 (m, 3H) 2.85-3.47 (m, 2H) 3.95-4.40 (m, 2H) 5.60-5.68 (m, 1H) 6.53-6.65 (m, 1H) 6.80 (t, J=7.06 Hz, 2H) 7.00-7.54 (m, 11H).
Cpd 4: MS (M+1)+444.0; 1H-NMR (300 MHz, CDCl3) δ ppm 1.27 (s, 9 H) 1.44-2.58 (m, 4H) 3.16 (t, J=13.00 Hz, 1H) 3.30-3.69 (m, 1H) 3.70-4.01 (m, 1H) 4.46-4.72 (m, 1H) 5.28-5.58 (m, 1H) 6.19-6.69 (m, 6H) 6.70-7.03 (m, 2H) 7.04-7.25 (m, 4H) 7.28-7.51 (m, 3H) 7.55-7.83 (m, 1H) 8.01-8.78 (m, 3H).
Cpd 5: MS (M+1)+414.0; 1H-NMR (300 MHz, CDCl3) δ ppm 1.25-1.34 (m, 9H) 1.69-2.53 (m, 4H) 3.39-4.04 (m, 2H) 5.15-5.38 (m, 2H) 6.62-7.08 (m, 8H) 7.14 (t, J=7.91 Hz, 2H) 7.19-7.25 (m, 1H) 7.29 (s, 1H) 7.38 (t, J=8.85 Hz, 2H) 7.53-7.73 (m, 1H) 8.05-8.83 (m, 2H).
Cpd 6: MS (M+1)+460.8; 1H-NMR (300 MHz, CDCl3) δ ppm 1.19-1.34 (m, 9H) 1.42-2.12 (m, 2H) 2.34-2.97 (m, 3H) 3.03-3.44 (m, 2H) 3.44-3.89 (m, 2H) 5.13-5.34 (m, 1H) 6.73-7.13 (m, 4H) 7.15-7.42 (m, 9H).
Cpd 11: MS (M+1)+426.9; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.00-2.44 (m, 15H) 2.54 (s, 0H) 3.97-4.47 (m, 1H) 5.43-5.82 (m, 2H) 6.52-7.56 (m, 14H).
Cpd 12: MS (M+1)+413.2; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.20-1.37 (m, 9H) 1.47-2.34 (m, 4H) 3.29-4.25 (m, 2H) 4.67-5.51 (m, 2H) 6.02-6.88 (m, 4H) 6.93-7.52 (m, 10H).
Cpd 13: MS (M+1)+413.2; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.14-1.33 (m, 9H) 1.73-2.39 (m, 2H) 3.07-3.52 (m, 3H) 3.60-4.42 (m, 2H) 5.27-5.43 (m, 1H) 6.49-6.62 (m, 1H) 6.74 (dd, J=7.91, 3.39 Hz, 2H) 6.97-7.52 (m, 11H).
Cpd 14: MS (M+1)+441.2; 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.96-1.88 (m, 15H) 2.20-3.33 (m, 3H) 3.85-5.60 (m, 3H) 6.12-7.46 (m, 14H).
Cpd 15: MS (M+1)+384.9; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.25 (s, 9H) 2.98-3.31 (m, 2H) 3.86 (d, J=7.54 Hz, 1H) 4.44-4.64 (m, 1H) 5.48 (s, 1H) 6.56 (t, J=7.16 Hz, 1H) 6.76 (d, J=8.29 Hz, 2H) 6.96-7.10 (m, 3H) 7.15 (t, J=7.54 Hz, 1H) 7.22 (d, J=7.16 Hz, 1H) 7.36-7.45 (m, 2H) 7.49 (d, 2 H) 8.10 (d, J=7.91 Hz, 1H).
Cpd 16: MS (M+1)+459.8; 1H-NMR (300 MHz, CDCl3) δ ppm 1.68-2.51 (m, 4H) 3.25-4.13 (m, 2H) 4.68-5.39 (m, 1H) 5.40-5.68 (m, 1H) 6.09-7.25 (m, 11H) 7.27-7.68 (m, 4H).
Cpd 17: MS (M+1)+425.2; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.57-1.95 (m, 3H) 2.06-2.41 (m, 1H) 3.50-3.66 (m, 1H) 4.95-5.10 (m, 1H) 5.55-5.88 (m, 1H) 6.28-6.63 (m, 1H) 6.63-6.91 (m, 3H) 6.97-7.22 (m, 5H) 7.24-7.43 (m, 2H) 7.62-7.87 (m, 4H).
Cpd 18: MS (M+1)+441.1; 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.95-2.45 (m, 17H) 2.59-3.44 (m, 1H) 3.91-4.39 (m, 1H) 4.74-5.73 (m, 2H) 6.19-7.55 (m, 14H).
Cpd 19: MS (M+1)+426.1; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.64-2.43 (m, 4H) 3.42-4.26 (m, 2H) 5.05-5.19 (m, 1H) 5.57-5.84 (m, 1H) 6.12-7.81 (m, 11H) 8.14-8.78 (m, 2H).
Cpd 20: MS (M+1)+443.2; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.55-2.37 (m, 4H) 3.38-4.25 (m, 2H) 4.89-5.72 (m, 2H) 6.15-7.81 (m, 13H).
Cpd 24: MS (M+1)+431.1; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.78-2.29 (m, 4H) 3.29-4.14 (m, 2H) 5.18-5.76 (m, 2H) 6.23-7.79 (m, 12H).
Cpd 28: MS (M+1)+426.2; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.58-2.45 (m, 4H) 3.45-3.71 (m, 1H) 4.01-4.25 (m, 1H) 5.06-5.18 (m, 1H) 5.66 (s, 1H) 6.48-6.88 (m, 3H) 6.96-7.13 (m, 2H) 7.22-7.39 (m, 1H) 7.60-7.80 (m, 5H) 8.42-8.77 (m, 2H).
Cpd 29: MS (M+1)+505.0; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.51-2.42 (m, 4H) 3.37-4.76 (m, 2H) 5.06-5.29 (m, 1H) 5.53-6.17 (m, 1H) 6.27-7.81 (m, 13H).
Cpd 32: MS (M+1)+439.2; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.39-2.43 (m, 7H) 3.36-4.29 (m, 2H) 4.68-5.70 (m, 2H) 6.05-7.83 (m, 13H).
Cpd 43: MS (M+1)+455.2; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.43-2.42 (m, 4H) 3.33-4.23 (m, 5H) 4.76-5.29 (m, 1H) 5.50-5.68 (m, 1H) 6.09-6.60 (m, 2H) 6.67-7.40 (m, 8H) 7.54-7.82 (m, 3H).
Cpd 44: MS (M+1)+439.2; 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.56-2.45 (m, 6H) 2.58-3.04 (m, 1H) 4.03-4.48 (m, 1H) 5.55-6.03 (m, 2H) 6.55 (t, J=7.16 Hz, 1H) 6.65-6.89 (m, 3H) 6.93-7.68 (m, 7H) 7.70-7.88 (m, 3 H).
Cpd 60: MS (M+1)+459.2; 1H-NMR (300 MHz, CDCl3) δ ppm 1.69-2.09 (m, 3H) 2.28-4.12 (m, 1H) 4.65-5.22 (m, 1H) 5.31-5.67 (m, 4H) 6.06-6.41 (m, 1H) 6.61-7.24 (m, 8H) 7.28-7.69 (m, 4H).
The following compounds were prepared by the methods described in Example 1 as racemic mixtures which were separated further into their corresponding diastereomers or single stereoisomers using purification methods known to those skilled in the art.
Cpds 1 and 2: Separated on C-18, using CH3CN—H2O with 0.1% TFA as eluant. Cpd 1: first peak off column; MS (M+1)+446.9; 1H-NMR (300 MHz, CDCl3) δ ppm 1.09-1.34 (m, 9H) 1.66-2.48 (m, 4H) 3.30-4.08 (m, 2H) 4.09-4.42 (m, 3H) 5.08-5.68 (m, 2H) 6.32-6.90 (m, 5H) 6.92-7.24 (m, 5H) 7.27-7.37 (m, 3H).
Cpd 2: second peak off column; MS (M+1)+446.9; 1H-NMR (300 MHz, CDCl3) δ ppm 1.31 (d, J=5.27 Hz, 9H) 1.68-2.42 (m, 4H) 3.45-3.98 (m, 2H) 5.36 (s, 1H) 5.47 (dd, J=7.91, 2.26 Hz, 1H) 6.13-7.25 (m, 8H) 7.27-7.48 (m, 5H).
Cpds 367 and 7: Separated on C-18, using CH3CN—H2O with 0.1% TFA as eluant. Cpd 367: first peak off column; MS (M+1)+446.9; 1H-NMR (300 MHz, CDCl3) δ ppm 1.16-1.30 (m, 9H) 1.68-2.49 (m, 4H) 3.28-3.68 (m, 1 H) 3.69-4.04 (m, 1H) 5.00-5.52 (m, 2H) 6.59-7.07 (m, 7H) 7.14 (q, J=7.79 Hz, 2H) 7.21-7.25 (m, 2H) 7.28-7.36 (m, 2H).
Cpd 7: second peak off column; MS (M+1)+446.9; 1H-NMR (300 MHz, CDCl3) δ ppm 1.28-1.34 (m, 9H) 1.63-2.36 (m, 4H) 3.35-3.91 (m, 2H) 4.63-4.75 (m, 1H) 5.15-5.36 (m, 1H) 6.49-6.67 (m, 2H) 6.81-6.98 (m, 2H) 7.01-7.25 (m, 6H) 7.26-7.41 (m, 3H).
Cpds 8 and 9: Separated on C-18, using CH3CN—H2O with 0.1% TFA as eluant. Cpd 8: first peak off column; MS (M+1)+446.9; 1H-NMR (300 MHz, CDCl3) δ ppm 1.11-1.30 (m, 9H) 1.71-2.48 (m, 4H) 3.30-4.03 (m, 2H) 5.01-5.49 (m, 5H) 6.66-6.81 (m, 2H) 6.82-7.06 (m, 5H) 7.09-7.24 (m, 3H) 7.26-7.35 (m, 3H). Cpd 9: second peak off column; MS (M+1)+446.9; 1H-NMR (300 MHz, CDCl3) δ ppm (300 MHz, CDCl3) δ ppm 1.27-1.34 (m, 9H) 1.68-2.35 (m, 4H) 3.39-3.93 (m, 2H) 4.14 (br. s., 6H) 4.66-5.36 (m, 2H) 6.43-7.25 (m, 9H) 7.26-7.45 (m, 4H).
Cpds 10 and 368: Separated on C-18, using CH3CN—H2O with 0.1% TFA as eluant. Cpd 368: first peak off column; MS (M+1)+442.0; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.25 (s, 9H) 1.58-2.07 (m, 4H) 2.84 (dd, J=13.19, 9.80 Hz, 1H) 3.20 (d, J=7.54 Hz, 1H) 3.39 (dd, J=13.19, 3.39 Hz, 1H) 3.92 (t, J=8.67 Hz, 1H) 4.04-4.16 (m, 1H) 5.30 (s, 1H) 6.53 (q, J=7.16 Hz, 2H) 6.74 (dd, J=7.91, 2.64 Hz, 4H) 6.94-7.11 (m, 4H) 7.32-7.49 (m, 4H).
Cpd 10: second peak off column; MS (M+1)+441.9; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.22-1.27 (m, 9H) 1.75-1.96 (m, 4H) 2.68 (dd, J=13.19, 9.42 Hz, 1H) 3.20-3.45 (m, 2H) 3.68-3.84 (m, 1H) 4.20 (d, J=4.90 Hz, 1H) 5.25-5.34 (m, 1H) 6.47-6.66 (m, 3H) 6.71 (t, J=7.72 Hz, 3H) 6.93-7.15 (m, 4H) 7.24-7.48 (m, 4H).
Cpds 21 and 23: A mixture of stereoisomers were separated on a chiral ADH column (15 cm) with 100% EtOH at 0.7 mL/min as eluant to afford two sets of peaks. The first set was further separated using a chiral ODH column (15 cm) with 100% EtOH at 0.7 mL/min as eluant. Elution of the first set of peaks resulted in Compounds 21 and 23; Cpd 21: first peak off column; MS (M+1)+459.2; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.56-2.29 (m, 4H) 3.37-4.29 (m, 2H) 5.16-5.71 (m, 2H) 6.48-7.45 (m, 10H) 7.75 (s, 3H); [α]D+166.4 (c=0.007, MeOH). Cpd 23: second peak off column; MS (M+1)+459.2; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.38-2.44 (m, 4H) 3.46-4.14 (m, 2H) 4.68-5.72 (m, 2H) 6.08-7.88 (m, 13H); [α]D+65.4 (c=0.007, MeOH).
Cpds 22 and 369: The second set of peaks, peaks 3 and 4, were further separated on a chiral ADH column (15 cm) with 95% heptane/5% EtOH at 1 mL/min as eluant to afford Compounds 22 and 369; Cpd 369: first peak off column; MS (M+1)+459.2; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.48-2.43 (m, 4H) 3.47-4.16 (m, 2H) 4.69-5.72 (m, 2H) 6.06-7.86 (m, 13H); [c]p-63.4 (c=0.007, MeOH). Cpd 22: second peak off column; MS (M+1)+459.2; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.57-2.30 (m, 4H) 3.36-4.30 (m, 2H) 5.15-5.72 (m, 2H) 6.49-7.48 (m, 10H) 7.75 (s, 3H); [α]D−161.4 (c=0.007, MeOH).
Cpds 25 and 26: Separated on C-18, using CH3CN—H2O with 0.1% TFA as eluant. Cpd 25: first peak off column; MS (M+1)+ 464.2; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.69-2.35 (m, 4H) 3.43-4.00 (m, 2H) 4.98-5.45 (m, 2H) 5.54-6.80 (m, 5H) 6.84-7.56 (m, 5H) 7.66-7.83 (m, 4H). Cpd 26: second peak off column; MS (M+1)+464.2; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.82-2.41 (m, 4H) 3.34-4.22 (m, 2H) 5.16-5.63 (m, 2H) 6.14 (s, 1H) 6.48-7.47 (m, 11H) 7.70-7.84 (m, 3H) 10.79-11.05 (m, 1H).
Cpds 30 and 31: Separated on C-18, using CH3CN—H2O with 0.1% TFA as eluant. Cpd 30: first peak off column; MS (M+1)+493.1; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.51-2.32 (m, 4H) 3.40-3.70 (m, 1H) 3.70-4.33 (m, 1H) 4.99-5.69 (m, 2H) 6.46-6.77 (m, 3H) 6.79-7.52 (m, 5H) 7.54-7.80 (m, 5H). Cpd 31: second peak off column; MS (M+1)+493.1; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.54 (dd, J=12.62, 6.22 Hz, 1H) 1.85-2.02 (m, 2H) 2.26-2.41 (m, 1H) 3.64 (dt, J=10.08, 7.02 Hz, 1H) 4.06-4.17 (m, 1H) 4.80-5.65 (m, 2H) 6.49-6.58 (m, 2H) 6.71 (d, J=7.91 Hz, 2H) 7.02 (t, J=7.91 Hz, 2 H) 7.25 (t, J=7.54 Hz, 1H) 7.36 (t, J=7.72 Hz, 1H) 7.62-7.68 (m, 3H) 7.71-7.76 (m, 2H).
Cpds 45-48: Separated on a chiral ADH column (15 cm) with 100% EtOH at 0.7 mL/min as eluant. Cpd 45: first peak off column; MS (M+1)+ 443.2; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.57-2.46 (m, 4H) 3.34-4.27 (m, 2H) 5.13-5.37 (m, 1H) 5.60-5.74 (m, 1H) 6.47-7.39 (m, 10H) 7.67-7.83 (m, 3H); [α]D+159.3 (c=0.007, MeOH). Cpd 46: second peak off column; MS (M+1)+443.2; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.54-2.37 (m, 4H) 3.49-3.64 (m, 1H) 3.68-4.11 (m, 1H) 5.13-5.26 (m, 1H) 5.64 (s, 1H) 6.36-6.48 (m, 1H) 6.57 (t, J=7.16 Hz, 1H) 6.74 (d, J=7.91 Hz, 2H) 6.84 (t, J=7.72 Hz, 1H) 6.95-7.42 (m, 4H) 7.57-7.81 (m, 4H); [α]D+68.8 (c=0.007, MeOH). Cpd 47: third peak off column; MS (M+1)+443.2; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.59-2.42 (m, 4H) 3.37-4.22 (m, 2H) 5.15-5.36 (m, 1H) 5.63-5.72 (m, 1H) 6.54-7.34 (m, 10H) 7.71-7.79 (m, 3H); [α]D−170.9 (c=0.007, MeOH). Cpd 48: fourth peak off column; MS (M+1)+443.2; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.55-2.37 (m, 4H) 3.49-4.10 (m, 2H) 5.12-5.26 (m, 1H) 5.59-5.68 (m, 1H) 6.37-6.49 (m, 1H) 6.57 (t, J=7.35 Hz, 1H) 6.75 (d, J=7.54 Hz, 2H) 6.85 (t, J=7.54 Hz, 1H) 6.97-7.42 (m, 4H) 7.58-7.80 (m, 4H); [c]p-71.2 (c=0.007, MeOH).
Cpds 50 and 51: Separated on C-18, using CH3CN—H2O with 0.1% TFA as eluant. Cpd 50: first peak off column; MS (M+1)+426.2; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.74-2.78 (m, 4H) 3.27-4.38 (m, 2H) 4.97-5.37 (m, 1H) 5.50-5.68 (m, 1H) 6.46-8.68 (m, 13H). Cpd 51: second peak off column; MS (M+1)+493.1; 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.71-2.42 (m, 4H) 3.44-4.15 (m, 2H) 5.03-5.19 (m, 1H) 5.56-5.68 (m, 1H) 6.08-7.55 (m, 7H) 7.61-7.94 (m, 5H) 8.47-8.63 (m, 1H).
Cpds 54 and 55: Separated on C-18, using CH3CN—H2O with 0.1% TFA as eluant. Cpd 54: first peak off column; MS (M+1)+414.3. Cpd 55: second peak off column; MS (M+1)+414.3.
Cpds 75 and 76: Separated on SiO2 using EtOAc-hexane as eluant; Cpd 75: first peak off column; MS (M+1)+443.0; Cpd 76: second peak off column; MS (M+1)+443.0.
Cpds 149 and 151: Separated on SiO2 using EtOAc-hexanes as eluant.
Cpd 149: first peak off column; MS (M+1)+461. Cpd 151: second peak off column; MS (M+1)+461; 1H-NMR (400 MHz, CDCl3) mixture of rotomers: δ ppm 7.50-7.70 (m, 4H), 7.15 (m, 2H), 6.75-7.00/7.30 (m, 3H), 6.45-6.70 (m, 2H), 6.35/5.95 (m, 1H), 5.40/5.15 (m, 1H), 5.25/4.8 (s, 1H), 3.85 (m, 1H), 3.45-3.60 (m, 1H), 2.28 (m, 1H), 1.75-2.05 (m, 3H).
Cpds 152 and 154: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 152: first peak off column; MS (M+1)+461. Cpd 154: second peak off column; MS (M+1)+461.
Cpds 157 and 158: Separated on CHIRALPAK® ADTM using 5% IPA in hexane at 14 mL/min as eluant. Cpd 157: first peak off column; MS (M+1)+ 427. Cpd 158: second peak off column; MS (M+1)+427; 1H-NMR (400 MHz, CDCl3) mixture of rotomers: δ ppm 7.40-7.28 (m, 4H), 7.18-7.12 (m, 2H), 6.98-6.81 (m, 3H), 6.67-6.51 (m, 2H), 6.34/5.97 (td, 1H), 5.71-5.14 (m, 2H), 5.17/4.71 (d, 1H), 3.91-3.80 (m, 1H), 3.66/3.53 (m, 1H), 2.37-2.19 (m, 1H), 2.03-1.77 (m, 3H).
Cpds 159 and 160: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 159: first peak off column; MS (M+1)+471. Cpd 160: second peak off column; MS (M+1)+471; 1H-NMR (400 MHz, CDCl3) mixture of rotomers: δ ppm 7.52-7.40 (m, 2H), 7.34-7.28 (m, 2H), 7.19-7.13 (m, 2H), 7.04-6.81 (m, 3H), 6.67-6.49 (m, 2H), 6.34/5.97 (td, 1H), 5.71-5.14 (m, 2H), 5.15/4.70 (d, 1H), 3.93-3.79 (m, 1H), 3.66/3.53 (m, 1H), 2.37-2.19 (m, 1H), 2.05-1.77 (m, 3H).
Cpds 161 and 162: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 161: first peak off column; MS (M+1)+489. Cpd 162: second peak off column; MS (M+1)+489; 1H-NMR (400 MHz, CDCl3) mixture of rotomers: δ ppm 7.45-6.29 (m, 11H), 5.47-4.91 (m, 3H), 3.92-3.77 (m, 1H), 3.64/3.46 (m, 1H), 2.33-2.17 (m, 1H), 2.03-1.78 (m, 3H).
Cpds 163 and 164: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 163: first peak off column; MS (M+1)+445. Cpd 164: second peak off column; MS (M+1)+445.
Cpds 165 and 166: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 165: first peak off column; MS (M+1)+461. Cpd 166: second peak off column; MS (M+1)+461.
Cpds 185 and 187: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 185: first peak off column; MS (M+1)+461. Cpd 187: second peak off column; MS (M+1)+461; 1H-NMR (400 MHz, CDCl3) mixture of rotomers: δ ppm 7.36-7.68 (m, 4H), 6.53-7.19/6.30/5.98 (m, 8H), 5.75/5.20/4.80 (m, 3H), 3.50-3.85 (m, 2H), 2.25 (m, 1H), 1.72-1.98 (m, 3H).
Cpds 188 and 189: Separated on ADH with 50% MeOH in EtOH as eluant. Cpd 189: first peak off column; MS (M+1)+477; 1H-NMR (400 MHz, CDCl3) mixture of rotomers: δ ppm 7.47-7.65 (m, 4H), 6.80-7.38 (m, 5H), 6.55 (m, 2H), 4.68/5.26/5.52/5.78/5.95/6.07 (m, 4H), 3.90 (m, 1H), 3.65 (m, 1H), 2.30 (m, 1H), 1.75-2.05 (m, 3H). Cpd 188: second peak off column; MS (M+1)+477.
Cpds 190 and 191: Separated on ADH with 100% in MeOH as eluant. Cpd 191: first peak off column; MS (M+1)+443; 1H-NMR (400 MHz, CDCl3) mixture of rotomers: δ ppm 7.52-7.65 (m, 4H), 7.32-7.45 (m, 2H), 6.50-7.25 (m, 7H), 5.88/5.76/5.20/4.85/4.75 (m, 3H), 3.51-3.90 (m, 2H), 2.28 (m, 1H), 1.72-1.95 (m, 3H). Cpd 190: second peak off column; MS (M+1)+443.
Cpds 233 and 234: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 233: first peak off column; MS (M+1)+475. Cpd 234: second peak off column; MS (M+1)+475.
Cpds 258 and 260: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 258: first peak off column; MS (M+1)+444; 1H-NMR (400 MHz, CDCl3) mixture of rotomers: δ ppm 8.58/8.45/8.2 (m, 2H), 7.28-7.65 (m, 5H), 6.5-7.1 (m, 5H), 5.96/5.65/5.21/4.81 (m, 3H), 3.51-3.91 (m, 2H), 1.89-2.38 (m, 4H). Cpd 260: second peak off column; MS (M+1)+444.
Cpds 274 and 276: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 274: first peak off column; MS (M+1)+452. Cpd 276: second peak off column; MS (M+1)+452.
Cpds 345 and 346: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 345: first peak off column; MS (M+1)+522. Cpd 346: second peak off column; MS (M+1)+522.
Cpds 185 and 187: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 185: first peak off column; MS (M+1)+461. Cpd 187: second peak off column; MS (M+1)+461.
Cpds 133 and 134: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 133: first peak off column; MS (M+1)+461. Cpd 134: second peak off column; MS (M+1)+461.
Example 2




A. 2-Bromo-2-(4-(trifluoromethyl)phenyl)acetyl chloride. To a slurry of 2-(4-(trifluoromethyl)phenyl)acetic acid (10.21 g, 50.0 mmol) in CCl4 (5 mL) was added SOCl2 (14.6 mL, 200.6 mmol). The reaction was heated at 65° C. for 45 minutes then diluted with CCl4 (25 mL). N-Bromosuccinimide (10.70 g, 60.1 mmol) was added followed by 1 drop of 48% HBr. The temperature was then increased to 85° C. for an additional 2 hours. The reaction mixture was then cooled to room temperature and diluted with hexanes (250 mL). The solids were filtered off and the filtrate was evaporated in vacuo. The resulting residue was dissolved in hexanes (25 mL), filtered again and concentrated in vacuo to give Compound 2a in quantitative yield as a peach-colored liquid (15.29 g). 1H-NMR (CDCl3): δ 7.73-7.58 (m, 4H), 5.69 (s, 1H).
B. 1-(Indolin-1-yl)-2-(o-tolylamino)-2-(4-(trifluoromethyl)phenyl)-ethanone. A solution of Compound 2a (1.18 mL, 6.30 mmol) in DCM (30 mL) was added dropwise over a period of 13 minutes to a solution of indoline (0.67 mL, 5.98 mmol) in DCM (30 mL). The reaction mixture was stirred at room temperature for an additional 30 minutes and then quenched with 30 mL saturated NaHCO3 solution. The organics were isolated, dried over Na2SO4 and diluted with DCM to a volume of 60 mL. A 1/12 fraction of this solution by volume (0.50 mmol) was put into a vial. To this was added 2-methyl aniline (0.134 mL, 1.26 mmol). After stirring at ambient temperature for 2 days the reaction mixture was diluted with dichloroethane (5 mL) and heated at 50° C. overnight then 65° C. for 4 hours. Methanol was then added to quench the reaction. Trifluoroacetic acid was added and the mixture was evaporated in vacuo. The residue was purified by reverse-phase chromatography (25-95% acetonitrile/water+0.1% TFA) to give Compound 34 as a tan powder (0.068 g). 1H-NMR (DMSO-d6): δ 8.10 (d, 1H), 7.83 (d, 2H), 7.73 (d, 2H), 7.24 (d, 1H), 7.17 (t, 1H), 7.06-6.91 (m, 3H), 6.66 (d, 1H), 6.54 (t, 1H), 5.76 (d, 1H), 5.60 (d, 1H), 4.60-4.51 (m, 1H), 3.89 (q, 1H), 3.25-3.04 (m, 2H), 2.20 (s, 3H); MS: m/z 411.2 (M+1)+.
Following the procedure described above for Example 2 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 + 1)+



















33
397.2



35
425.2



36
415.2



37
431.1



38
431.1



39
431.2



40
411.2



41
403.2



42
423.2










Example 3




A. N-(2-Fluoro-phenyl)-N-[2-[(2S)-2-(2-fluoro-phenyl)-pyrrolidin-1-yl]-2-oxo-(1S)-1-(4-trifluoromethyl-phenyl)-ethyl]acetamide. To the solution of Compound 152 (prepared by the procedure described in Example 1) (0.23 g, 0.5 mmol) in methylene chloride (10 mL) was added acetyl chloride (0.1 g, 1.27 mmol), followed by triethylamine (0.5 mL). The mixture was stirred for 2 h and quenched with 1N HCl. The crude product was purified by column chromatography (SiO2, 0-30% ethyl acetate/hexanes) to give Compound 318 (0.1 g, 40%).
Example 4




A. 3-{(1S)-1-[2-(2-Fluoro-phenylamino)-2-(4-trifluoromethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-benzoic acid. The solution of Compound 347 (prepared by the procedure described in Example 1) (0.2 g, 0.4 mmol) in THF (6 mL) and methanol (2 mL) was added to the solution of LiOH—H2O (0.084 g, 2 mmol) in water (2 mL). The mixture was stirred overnight and quenched with 2N HCl, extracted with methylene chloride (10 ml), and the organic layer was dried over Na2SO4. The mixture was filtered and the filtrate was concentrated to give Compound 349 (0.2 g, 96%). MS 487 (M+1)+.
Following the procedure described for Example 4 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 + 1)+



















222
487



223
487










Example 5




A. 2-Hydroxy-2-(4-trifluoromethyl-phenyl)-propionic acid ethyl ester. A solution of CH3MgCl in THF (1.4 mL, 3.0 M, 4.2 mmol) was added to a solution of Compound 5a (1.0 g, 4.06 mmol) in THF (10 mL) dropwise at −78° C. The mixture was stirred at 78° C. for 2 h, warmed up to room temperature, and quenched with 1N HCl to pH 7. Methylene chloride was added, the organic layer separated, dried over Na2SO4, filtered, and concentrated to afford Compound 5b (0.9 g, 85%).
B. 2-Methanesulfonyloxy-2-(4-trifluoromethyl-phenyl)-propionic acid ethyl ester. Methanesulfonyl chloride (0.3 mL, 3.88 mmol) was slowly added to a solution of Compound 5b (0.52 g, 1.98 mmol) in methylene chloride (10 mL), followed by addition of triethylamine (1 mL, 7.2 mmol). The mixture was stirred overnight, washed with 1N HCl, and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to Compound 5c (0.6 g, 89%).
C. 2-Phenylamino-2-(4-trifluoromethyl-phenyl)-propionic acid ethyl ester. A solution of Compound 5c (0.2 g, 0.59 mmol) and aniline (0.1 g, 1.07 mmol) in acetonitrile (10 mL) was refluxed for 8 h and concentrated in vacuo. The resultant mixture was dissolved in methylene chloride (20 mL) and washed with 1N HCl (5 mL) and brine (5 mL). The crude residue was purified by preparative TLC (15% ethyl acetate/hexanes) to give Compound 5d (40 mg, 20%).
D. 2-Phenylamino-2-(4-trifluoromethyl-phenyl)-propionic acid. A solution of Compound 5d (17 mg, 0.05 mmol) in THF (6 mL) was added to a solution of LiOH—H2O (5 mg, 0.12 mmol) in water (2 mL). The mixture was stirred overnight and then neutralized with 2N HCl. Methylene chloride was added, the organic layer separated, dried over Na2SO4, and concentrated to afford Compound 5e (15 mg, 96%).
E. 1-[2-(2-Chloro-phenyl)-pyrrolidin-1-yl]-2-phenylamino-2-(4-trifluoromethyl-phenyl)-propan-1-one. To a solution of Compound 5e (15 mg, 0.05 mmol) and HATU (30 mg, 0.08 mmol) in methylene chloride (5 mL) was added 2-(2-chloro-phenyl)-pyrrolidine (15 mg, 0.08 mmol). The mixture was stirred overnight, concentrated in vacuo, and subjected to preparative TLC (30% ethyl acetate/hexanes) to give Compound 80 (15.2 mg, 66%). MS 473 (M+1)+.
Example 6




A. (2S,5R)-5-Phenyl-pyrrolidine-2-carboxylic acid methyl ester hydrochloride salt. To a solution of Compound 6a (500 mg; 1.72 mmol) in MeOH (5 mL) was added conc. HCl (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo to afford Compound 6b.
B. (2S,5R)-1-[2-(4-Bromo-phenyl)-2-(2,6-difluoro-phenylamino)-acetyl]-5-phenyl-pyrrolidine-2-carboxylic acid methyl ester. To a solution of Compound 6c (prepared by the procedures A-D described in Example 1, substituting the appropriate reagents, starting materials) (80 mg; 0.23 mmol) in CH2Cl2 (3 mL) was added Compound 6b (57 mg; 0.24 mmol), HATU (178 mg; 0.47 mmol) and triethylamine (0.32 mL; 2.23 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated in vacuo.
The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to afford Compound 204 (first peak off column), MS 529 (M+H) and Compound 205 (second peak off column), MS 529 (M+1)+.
Following the procedure described above for Example 6 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:
Cpds 195 and 196: Cpd 195: first peak off column; MS (M+1)+511. Cpd 196: second peak off column; MS (M+1)+511.
Cpds 206 and 207: Cpd 206: first peak off column; MS (M+1)+449. Cpd 207: second peak off column; MS (M+1)+449.
Cpds 208 and 209: Cpd 208: first peak off column; MS (M+1)+511; Cpd 209: second peak off column; MS (M+1)+511; 1H-NMR (400 MHz, CDCl3) δ ppm 7.72 (d, 2H), 7.53-7.46 (m, 4H), 7.39-7.35 (m, 1H), 7.27-7.22 (m, 2H), 6.88-6.82 (m, 1H), 6.74-6.70 (t, 1H), 6.57-6.51 (m, 1H), 5.98-5.93 (td, 1H), 5.02 (br, 1H), 4.77 (s, 1H), 4.71-4.68 (q, 1H), 4.61-4.58 (t, 1H), 3.84 (s, 3H), 2.34-2.22 (m, 1H), 2.18-1.98 (m, 3H).
Cpds 210 and 211: Cpd 210: first peak off column; MS (M+1)+529; 1H-NMR (400 MHz, CDCl3) δ ppm 7.57 (d, 2H), 7.39-7.27 (m, 5H), 7.09-7.07 (d, 2H), 6.52-6.43 (m, 3H), 5.09-5.05 (dt, 1H), 4.92-4.90 (d, 1H), 4.60-4.57 (q, 1H), 4.49-4.45 (t, 1H), 3.78 (s, 3H), 2.21-2.13 (m, 1H), 2.07-1.88 (m, 3H). Cpd 211: second peak off column; MS (M+1)+529.
Cpds 212 and 213: Cpd 212: first peak off column; MS (M+1)+449. Cpd 213: second peak off column; MS (M+1)+449.
Example 7




A. (2R)-2-(4-Bromo-phenyl)-2-(2,6-difluoro-phenylamino)-1-[(2S,5R)-2-hydroxymethyl-5-phenyl-pyrrolidin-1-yl]ethanone. To a solution of Compound 204 (31 mg; 0.06 mmol) in MeOH (1 mL) was added excess NaBH4. The reaction mixture was stirred at room temperature for 3 days and then H2O was added dropwise at 0° C. The resultant residue was diluted with EtOAc, washed with H2O and dried over Na2SO4. The mixture was then filtered and the filtrate was concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to afford Compound 243. MS 501 (M+1)+.
Following the procedure described above for Example 7 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 + 1)+



















67
421



235
421



236
501



237
483



238
483



239
483



241
483



242
483










Example 8




A. 4-{1-(2,6-Difluoro-phenylamino)-2-[(2S)-2-(2-fluoro-phenyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-benzoic acid ethyl ester. To a solution of Compound 181 (prepared by the procedures described in Example 1, substituting the appropriate reagents, starting materials) (140 mg; 0.29 mmol) in THF (0.6 mL) was added EtOH (0.1 mL), DBU (130 mg; 0.85 mmol), [Pd] (13.4 mg; 0.014 mmol), tri-t-butylphosphonium tetrafluoroborate (12.5 mg; 0.043 mmol) and molybdenum hexacarbonyl (151 mg; 0.57 mmol), sequentially. The reaction mixture was heated to 125° C. in a microwave reactor for 25 min and then the mixture was cooled and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to afford Compound 183. MS 483 (M+1)+.
B. 2-(2,6-Difluoro-phenylamino)-1-[(2S)-2-(2-fluoro-phenyl)-pyrrolidin-1-yl]-2-(4-hydroxymethyl-phenyl)-ethanone. To a solution of Compound 184 (30 mg; 0.062 mmol) in MeOH (1 mL) was added excess NaBH4. The reaction mixture was stirred at room temperature for 3 days and then was added H2O, dropwise at 0° C. The resultant residue was diluted with EtOAc, washed with H2O and dried over Na2SO4. The mixture was then filtered and the filtrate was concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to afford Compound 219. MS 441 (M+1)+.
Following Procedure A 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 + 1)+
Cpd
MS (M + 1)+









182
465
287
465










Example 9




A. 4-{1-(2,6-Difluoro-phenylamino)-2-[(2S)-2-(2-fluoro-phenyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-N-isopropyl-benzamide. To a solution of Compound 181 (52 mg; 0.11 mmol) in THF (0.2 mL) was added isopropylamine (62 mg; 1.1 mmol), DBU (48.5 mg; 0.32 mmol), [Pd] (5.0 mg; 0.005 mmol), tri-t-butylphosphonium tetrafluoroborate (4.6 mg; 0.016 mmol) and molybdenum hexacarbonyl (56 mg; 0.21 mmol), sequentially. The reaction mixture was heated to 125° C. in a microwave reactor for 20 min and then the mixture was cooled and evaporated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to afford Compound 262. MS 496 (M+1)+.
Following the procedure described above for Example 9 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 + 1)+
Cpd
MS (M + 1)+









261
478
265
468










Example 10




A. 3-Chloro-3-(4-trifluoromethyl-phenyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-one. To a solution of 3-(4-trifluoromethyl-phenyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (Compound 10a), prepared as described in Hino et al., J. Med. Chem. 1988, 31, 107 (290 mg, 0.95 mmol), in toluene (2 mL) was added phosphorous pentachloride (435 mg, 2.09 mmol). The reaction mixture was stirred at 110° C. for 1.5 h, concentrated in vacuo, partitioned between diethyl ether and water, the organic layer dried over Na2SO4, filtered, and the filtrate concentrated. To this crude reaction mixture in acetone (4 mL) was added concentrated HCl (0.85 mL) and the reaction mixture was stirred at rt for 2.5 h. The reaction mixture was partitioned between CH2Cl2 and water, the organic layer dried over Na2SO4, filtered, and concentrated in vacuo to give Compound 10b, which was used in the next step without further purification.
B. (2-Phenyl-pyrrolidin-1-yl)-[2-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-quinolin-2-yl]-methanone. To Compound 10b (37 mg, 0.11 mmol) was added racemic 2-phenyl-pyrrolidine (322 mg, 2.19 mmol), and the reaction mixture was stirred at 120° C. in a sealed culture tube for 4 h. The crude reaction mixture was purified directly by M PLC (SiO2, 0-40% gradient, eluting with EtOAc/hexanes) and then on preparative TLC (SiO2, 3:1, hexanes/EtOAc) to give 4 mg (8%) of Compound 194. MS 451.0 (M+1)+.
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 + 1)+



















192
423.1



193
485.1










Example 11




A. (2-Fluoro-phenylamino)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-acetic acid methyl ester. To a solution of 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5-carbaldehyde (500 mg, 2.63 mmol), in MeCN (2 mL) was added 2-fluoro-aniline (0.27 mL, 2.89 mmol), trimethylsilyl cyanide (0.52 mL, 4.16 mmol), and iodine (65 mg, 0.26 mmol). The reaction mixture was stirred at rt overnight, the crude reaction mixture was partitioned between EtOAc and water, the organic layer dried over Na2SO4, filtered, and concentrated in vacuo. To this crude reaction mixture in MeOH (5 mL) was added 4 N HCl in dioxane (5 mL) and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo, partitioned between saturated aqueous NaHCO3 and EtOAc, the organic layer dried over Na2SO4, filtered, and concentrated in vacuo. Purification by MPLC (SiO2, 0-30% gradient, eluting with EtOAc/hexanes) gave Compound 11a (319 mg, 31%). MS 344.1 (M+1)+.
B. (2-Fluoro-phenylamino)-(3,4,5,6-tetrahydro-2H-[1,2′]pyridinyl-5′-yl)-acetic acid. To compound 11a (319 mg, 0.93 mmol) in THF (2 mL) and water (1 mL) was added lithium hydroxide monohydrate (50 mg, 1.21 mmol) and the reaction mixture was stirred at rt overnight. The reaction mixture was acidified to pH 5 by the dropwise addition of 1 N HCl, extracted three times with EtOAc, the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to give Compound 11b (224 mg, 79%), which was used in the next step without further purification. MS 330.1 (M+1)+.
C. 2-(2-Fluoro-phenylamino)-1-[(2S)-2-(2-fluoro-phenyl)-pyrrolidin-1-yl]-2-(3,4,5,6-tetrahydro-2H-[1,2′]pyridinyl-5′-yl)-ethanone. To compound 11b (120 mg, 0.36 mmol) and Et3N (0.50 mL, 3.60 mmol) in CH2Cl2 (2.0 mL) was added (2S)-2-(2-fluoro-phenyl)-pyrrolidine (76 mg, 0.46 mmol) and HATU (273 mg, 0.72 mmol). The reaction mixture was stirred at rt overnight, the reaction mixture was partitioned between CH2Cl2 and saturated aqueous NaHCO3, the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by MPLC (SiO2, 0-30% gradient, eluting with EtOAc/hexanes) gave Compound 334 (81 mg, 47%) as a 1:1 mixture of diastereomers. MS 477.3 (M+1)+.
Following the procedure described above 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 as a racemic mixture.














Cpd
MS (M + 1)+



















224
471



250
444



255
470



264
426.1



279
441.1



284
444



289
470



293
478



301
459



306
470.1



320
450



335
489.2



342
475



355
450.1



358
479.3



371
398.1



372
479.3










Following the procedure described above 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 as mixtures that were separated further into their corresponding single stereoisomers using purification methods known to those skilled in the art.
Cpds 246 and 250: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 246: first peak off column; MS (M+1)+446. Cpd 250: second peak off column; MS (M+1)+446.
Cpds 247 and 251: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 247: first peak off column; MS (M+1)+444; 1H-NMR (400 MHz, CDCl3): δ ppm 8.94 (m, 1H), 8.19-8.11 (m, 2H), 7.88 (dd, 1H), 7.80 (m, 1H), 7.44 (m, 1H), 7.34-7.08 (m, 3H), 6.96-6.82 (m, 2H), 6.70-6.63 (m, 1H), 6.60-6.50 (m, 1H), 6.28/6.05 (m, 1H), 5.82/5.45 (m, 1H), 5.38/4.93 (d, 1H), 5.35/5.23 (m, 1H), 3.90 (m, 1H), 3.75-3.51 (m, 1H), 2.34-1.69 (m, 4H). Cpd 251: second peak off column; MS (M+1)+444.
Cpds 277 and 278: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 277: first peak off column; MS (M+1)+456.2; 1H-NMR (400 MHz, CDCl3) mixture of rotomers: δ ppm 9.07/8.94 (d, 1H), 8.21-4.98 (m, 16H), 3.97-3.49 (m, 5H), and 2.28-1.72 (m, 4H). Cpd 278: second peak off column; MS (M+1)+ 456.2.
Cpds 280 and 282: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 280: first peak off column; MS (M+1)+444.1; 1H-NMR (400 MHz, CDCl3) mixture of rotomers: δ ppm 9.06-8.98 (m, 1H), 8.22-6.50 (m, 12H), 6.37-6.01 (m, 1H), 5.78-4.97 (m, 3H), 3.96-3.49 (m, 2H), and 2.38-1.75 (m, 4H). Cpd 282: second peak off column; MS (M+1)+444.1.
Cpds 296 and 297: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 296: first peak off column; MS (M+1)+470; 1H-NMR (400 MHz, CDCl3): δ ppm 8.70 (m, 1H), 8.00 (q, 2H), 7.73 (m, 2H), 7.55 (q, 2H), 7.33-6.76 (m, 6H), 6.66 (m, 1H), 6.57-6.50 (m, 1H), 6.34/6.05 (m, 1H), 5.80/5.45 (m, 1H), 5.31/5.23 (m, 1H), 5.24/4.79 (d, 1H), 3.89-3.82 (m, 1H), 3.69-3.60 (m, 1H), 2.33-2.04 (m, 1H), 1.99-1.70 (m, 3H). Cpd 297: second peak off column; MS (M+1)+470.
Cpds 303 and 304: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 303: first peak off column; MS (M+1)+497. Cpd 304: second peak off column; MS (M+1)+497.
Cpds 307 and 309: Separated on CHIRALPAK® ADTM using 5% IPA in hexane at 14 mL/min as eluant. Cpd 307: first peak off column; MS (M+1)+ 470.1; 1H-NMR (400 MHz, CDCl3) mixture of rotomers: δ ppm 8.87/8.73 (m, 1H), 8.04-6.50 (m, 14H), 6.41-6.03 (m, 1H), 5.79-4.83 (m, 3H), 3.94-3.61 (m, 2H), and 2.39-1.79 (m, 4H). Cpd 309: second peak off column; MS (M+1)+ 470.1.
Cpds 312 and 313: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 312: first peak off column; MS (M+1)+497; 1H-NMR (400 MHz, CDCl3): δ ppm 8.94 (m, 1H), 8.19-8.11 (m, 2H), 7.90 (m, 1H), 7.81 (m, 1H), 7.52-6.48 (m, 8H), 6.08 (m, 1H), 5.87-4.82 (m, 3H), 3.94 (m, 1H), 3.72-3.58 (m, 1H), 2.38-1.71 (m, 4H). Cpd 313: second peak off column; MS (M+1)+497.
Cpds 314 and 316: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 314: first peak off column; MS (M+1)+497. Cpd 316: second peak off column; MS (M+1)+497.
Cpds 322 and 323: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 322: first peak off column; MS (M+1)+432; 1H-NMR (400 MHz, CDCl3): δ ppm 8.62/8.36 (m, 1H), 7.83-7.72 (m, 2H), 7.40-7.31 (m, 3H), 7.17-6.10 (m, 7H), 5.58 (s, 1H), 5.20 (m, 1H), 5.03 (m, 1H), 3.92-3.80 (m, 2H), 2.34 (m, 1H), 2.05-1.70 (m, 3H). Cpd 323: second peak off column; MS (M+1)+432.
Cpds 328 and 329: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 328: first peak off column; MS (M+1)+450; 1H-NMR (400 MHz, CDCl3): δ ppm 8.53 (m, 1H), 7.97 (m, 1H), 7.32-7.26 (m, 2H), 7.17-7.10 (m, 2H), 6.99-6.04 (m, 6H), 5.66-5.12 (m, 3H), 3.93-3.74 (m, 2H), 2.34 (m, 1H), 2.05-1.85 (m, 3H). Cpd 329: second peak off column; MS (M+1)+450.
Cpds 330 and 331: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 330: first peak off column; MS (M+1)+432; 1H-NMR (400 MHz, CDCl3): δ ppm 8.65-8.46 (m, 1H), 7.79-6.10 (m, 12H), 5.60-5.11 (m, 3H), 3.94-3.74 (m, 2H), 2.41-1.88 (m, 4H). Cpd 331: second peak off column; MS (M+1)+432.
Cpds 332 and 333: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 332: first peak off column; MS (M+1)+444.1. Cpd 333: second peak off column; MS (M+1)+444.1.
Cpds 338 and 339: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 338: first peak off column; MS (M+1)+486. Cpd 339: second peak off column; MS (M+1)+486.
Cpds 340 and 341: Separated on SiO2 using EtOAc-hexanes as eluant. Cpd 340: first peak off column; MS (M+1)+464; 1H-NMR (400 MHz, CDCl3): δ ppm 7.95 (t, 1H), 7.89 (dd, 1H), 7.58-7.48 (m, 1H), 7.35-6.48 (m, 7H), 6.26/6.02 (m, 1H), 5.78/5.43 (m, 1H), 5.29 (d, 1H), 5.20/4.85 (d, 1H), 3.87 (m, 1H), 3.71-3.50 (m, 1H), 2.85/2.83 (s, 3H), 2.36-2.18 (m, 1H), 2.05-1.73 (m, 3H). Cpd 341: second peak off column; MS (M+1)+464.
Cpds 356 and 357: Separated on CHIRALPAK® ADTM using 5% IPA in hexane at 14 mL/min as eluant. Cpd 356: first peak off column; MS (M+1)+ 450.1. Cpd 357: second peak off column; MS (M+1)+450.1; 1H-NMR (400 MHz, CDCl3) mixture of rotomers: δ ppm 8.73/8.59 (d, 1H), 7.71/7.60 (dd, 1H), 7.35-6.49 (m, 8H), 6.30-5.93 (m, 1H), 5.72-4.79 (m, 3H), 3.90-3.61 (m, 2H), 2.37-1.78 (m, 4H), and 1.38/1.35 (s, 9H).
Cpds 359 and 360: Separated on CHIRALPAK® ADTM using 5% IPA in hexane at 14 mL/min as eluant. Cpd 359: first peak off column; MS (M+1)+ 479.3; 1H-NMR (400 MHz, CDCl3) mixture of rotomers: δ ppm 8.36/8.21 (d, 1H), 7.58/7.48 (dd, 1H), 7.34-6.48 (m, 8H), 6.45-5.97 (m, 1H), 5.68-4.66 (m, 3H), 3.91-3.51 (m, 9H), and 2.36-1.78 (m, 5H). Cpd 360: second peak off column; MS (M+1)+479.3; 1H-NMR (400 MHz, CDCl3) mixture of rotomers: 6 ppm 8.73/8.59 (d, 1H), 7.71/7.60 (dd, 1H), 7.35-6.49 (m, 8H), 6.30-5.93 (m, 1H), 5.72-4.79 (m, 3H), 3.90-3.61 (m, 2H), 2.37-1.78 (m, 4H), and 1.38/1.35 (s, 9H).
Cpds 375 and 376: Separated on CHIRALPAK® ADTM using 5% IPA in hexane at 14 mL/min as eluant. Cpd 375: first peak off column; MS (M+1)+ 460.2; 1H-NMR (400 MHz, CDCl3) mixture of rotomers: δ ppm 9.08-9.00 (d, 1H), 8.24-4.86 (m, 16H), 4.06-3.56 (m, 2H), and 2.41-1.72 (m, 4H). Cpd 376: second peak off column; MS (M+1)+460.2.
Example 12




A. Benzo[b]thiophen-2-yl-(2-fluoro-phenylamino)-acetic acid. A mixture of thianaphthene-2-boronic acid (0.39 g, 2.19 mmol), 2-fluoroaniline (244 mg, 2.20 mmol) and glyoxylic acid monohydrate (202 mg, 2.20 mmol) in CH3CN (5 mL) was heated to reflux for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was washed with heptane, and the remaining solid was then dissolved in EtOAc and filtered. The EtOAc solution was dried over Na2SO4, filtered, and concentrated under reduced pressure to give intermediate 12a.
B. 2-Benzo[b]thiophen-2-yl-2-(2-fluoro-phenylamino)-1-[2-(2-fluoro-phenyl)-pyrrolidin-1-yl]-ethanone. To a solution of intermediate 12a (69 mg, 0.23 mmol) and 2-(2-fluorophenyl)pyrrolidine hydrochloride (92 mg, 0.46 mmol) in CH2Cl2 (3 mL) at room temperature was added Et3N (0.19 mL, 1.37 mmol) followed by HATU (170 mg, 0.45 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was then diluted with CH2Cl2, washed sequentially with aq. 10% HCl solution and aq. NaHCO3 solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 15% EtOAc/heptane) gave Compound 225 (60 mg, 58%). MS: 449 (M+1)+.
Following the procedure described above for Example 12 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 + 1)+



















105
452.1



245
449



254
435



256
403



282
418



286
435



309
485



311
475



319
432



321
432



361
467



370
404










Example 13




A. Phenylamino-pyridin-3-yl-acetic acid ethyl ester. To a solution of ethyl 3-pyridylacetate (1.83 g, 11.1 mmol), in THF (100 mL) at −78° C. was added DBU (1.66 mL, 11.1 mmol), and carbon tetrabromide (3.69 g, 11.1 mmol). The reaction mixture was stirred at −78° C. for 1.5 h and at 0° C. for 1 h, partitioned between EtOAc and saturated aqueous NH4Cl, the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. To this crude reaction mixture in THF (20 mL) was added aniline (1.51 mL, 16.7 mmol), and Et3N (3.1 mL, 22.2 mL) and the reaction mixture was stirred at 60° C. overnight. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3, the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by MPLC (SiO2, 0-50% gradient eluting with EtOAc/hexanes) gave Compound 13a (1.24 g, 29%). MS 257.1 (M+1)+.
B. Phenylamino-pyridin-3-yl-acetic acid. To Compound 13a (230 mg, 0.90 mmol) in THF (2 mL) and water (1 mL) was added lithium hydroxide monohydrate (56 mg, 1.35 mmol) and the reaction mixture was stirred at 60° C. for 4 h. The reaction mixture was neutralized with 1 N HCl, concentrated in vacuo, and purified by HPLC (C-18, 5-55% MeCN in water gradient) to give Compound 13b (60 mg, 44%). MS 229.1 (M+1)+.
C. 1-[2-(2-Fluoro-phenyl)-pyrrolidin-1-yl]-2-phenylamino-2-pyridin-3-yl-ethanone. To Compound 13b (25 mg, 0.11 mmol) and Et3N (0.15 mL, 1.10 mmol) in CH2Cl2 (0.5 mL) was added racemic 2-(2-fluoro-phenyl)-pyrrolidine hydrochloride (33 mg, 0.17 mmol) and HATU (84 mg, 0.22 mmol). The reaction mixture was stirred at rt overnight, partitioned between CH2Cl2 and saturated aqueous NaHCO3, the organic layer was dried over Na2SO4, and concentrated in vacuo. Purification by MPLC (SiO2, 0-60% gradient elution, EtOAc % in hexanes) gave Compound 214 (7 mg, 17%) as a mixture of four stereoisomers. MS 376.1 (M+1)+.
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 + 1)+









215
330.1



216
330.1










Using 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 additional compounds of the present invention were prepared as a mixture of four stereoisomers, and the diasteromeric pairs were separated using purification methods know to those skilled in the art.
Cods 217 and 218: Separated on C-18, using CH3CN—H2O as eluant. Cpd 217: first peak off column; MS (M+1)+376.1. Cpd 218: second peak off column; MS (M+1)+376.1.
Example 14




A. 3-Phenylamino-2-(4-trifluoromethyl-phenyl)-propionic acid ethyl ester. To a solution of 2-(4-trifluoromethyl-phenyl)-acrylic acid ethyl ester (prepared as described in WO2006/024611, 700 mg, 2.87 mmol) in THF (7.5 mL) was added aniline (1.30 mL, 14.34 mmol) and Yb(OTf)3 (173 mg, 0.28 mmol). The reaction mixture was stirred at 60° C. for 48 h, concentrated in vacuo, and purified by MPLC (SiO2, 33% EtOAc/hexanes) to give Compound 14a (721 mg, 75%). MS 338.1 (M+1)+.
B. 3-Phenylamino-2-(4-trifluoromethyl-phenyl)-propionic acid. To Compound 14a (700 mg, 2.08 mmol) in THF (2 mL) and water (1 mL) was added lithium hydroxide monohydrate (96 mg, 2.28 mmol) and the reaction mixture was stirred at rt for 48 h. The reaction mixture was neutralized with 1 N HCl, concentrated in vacuo, and purified by HPLC (C-18, 10-70% MeCN in water gradient) to give Compound 14b (441 mg, 69%). MS 310.1 (M+1)+.
C. 1-[2-(2-Chloro-phenyl)-pyrrolidin-1-yl]-3-phenylamino-2-(4-trifluoromethyl-phenyl)-propan-1-one. To compound 14b (90 mg, 0.29 mmol) and Et3N (0.32 mL, 2.32 mmol) in CH2Cl2 (1.2 mL) was added racemic 2-(2-chloro-phenyl)-pyrrolidine (68 mg, 0.37 mmol) and HATU (221 mg, 0.58 mmol). The reaction mixture was stirred at rt overnight, partitioned between CH2Cl2 and saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by HPLC (C-18, 50-100 MeCN in water gradient) gave Compound 83 (60 mg, 44%) as a mixture of four stereoisomers. MS 473.3 (M+1)+.
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 + 1)+









100
411.5



101
469.1



102
425.1



103
457.1



104
429.1



106
429.1



107
491.1



108
457.1










Example 15




A. 3-Phenylamino-1-[(2RS*)2-phenyl-pyrrolidin-1-yl]-(2RS*)-2-(4-trifluoromethyl-phenyl)-propan-1-one. To Compound 14b (90 mg, 0.29 mmol) and Et3N (0.32 mL, 2.32 mmol) in CH2Cl2 (1.2 mL) was added racemic 2-phenylpyrrolidine (67 mg, 0.37 mmol) and HATU (221 mg, 0.58 mmol) and the reaction mixture was stirred at rt overnight. The reaction mixture was partitioned between CH2Cl2 and saturated aqueous NaHCO3, the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give Compound 15a as a mixture of four stereoisomers. The mixture of four diastereomers was dissolved in DMF, and upon standing a precipitate formed. The precipitate was removed by filtration and the leftover supernatant was purified by HPLC (C-18, 10-100 MeCN in water gradient) to give Compound 130 as a mixture of two stereoisomers. MS 439.1 (M+1)+.
Example 16




A. 2-(2-Chloro-phenyl)-1-nitroso-pyrrolidine. To a solution of 2-(2-chloro-phenyl)pyrrolidine (1.0 g, 5.50 mmol) in THF (5.50 mL) was added isoamyl nitrite (0.95 mL, 7.16 mmol) and the reaction mixture was stirred at rt overnight. The crude reaction mixture was concentrated in vacuo and purified by MPLC (SiO2, 20% EtOAc/hexanes) to give 2-(2-chloro-phenyl)-1-nitroso-pyrrolidine (976 mg). MS 211.5 (M+1)+.
B. 2-(2-Chloro-phenyl)-pyrrolidin-1-ylamine. To a solution of 2-(2-chloro-phenyl)-1-nitroso-pyrrolidine (976 mg, 4.65 mmol) in THF (10 mL) at 0° C. was added lithium aluminum hydride (2 M in THF, 16.2 mL, 32.48 mmol) and the reaction mixture was stirred at 0° C. for 1 h and then at rt for 2 h. The reaction mixture was cooled to 0° C., quenched by the sequential dropwise addition of H2O (1.13 mL), 15% aqueous NaOH (1.13 mL), and water (3.41 mL), filtered, and concentrated in vacuo. Purification by MPLC (SiO2, 5% MeOH/CH2Cl2) gave Compound 16a (647 mg, 71%). MS 197.1 (M+1)+.
C. Phenylamino-(4-trifluoromethyl-phenyl)-acetic acid methyl ester. To a solution of Compound 1b (7.17 g, 24.22 mmol) in THF (25 mL) was added Et3N (6.73 mL, 48.44 mmol) and aniline (3.31 mL, 36.33 mmol). The reaction mixture was stirred at 80° C. for 6 h, partitioned between EtOAc and saturated aqueous NH4Cl, the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by MPLC (SiO2, 20% EtOAc/hexanes) gave Compound 16b (7.26 mg, 97%). MS 310.2 (M+1)+.
D. Phenylamino-(4-trifluoromethyl-phenyl)-acetic acid. To a solution of Compound 16b (7.26 g, 23.50 mmol) in THF (20 mL) and water (10 mL) was added lithium hydroxide monohydrate (1.04 g, 24.60 mmol) and the reaction mixture was stirred at 80° C. for 4 h. The reaction mixture was cooled to 0° C. and 1 N HCl was added dropwise until the solution reached pH 2. The resulting precipitate was removed by filtration and dried to give Compound 16c (5.40 g, 78%). MS 296.1 (M+1)+.
E. N-[2-(2-Chloro-phenyl)-pyrrolidin-1-yl]-2-phenylamino-2-(4-trifluoromethyl-phenyl)-acetamide. To Compound 16c (383 mg, 1.16 mol) in CH2Cl2 (6 mL) was added Compound 16a (300 mg, 1.53 mmol), EDC hydrochloride (323 mg, 1.69 mmol), and 1-hydroxybenzotriazole (228 mg, 1.69 mmol). The reaction mixture was stirred at rt overnight, partitioned between CH2Cl2 and saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by MPLC (SiO2, 5% MeOH/CH2Cl2) gave Compound 63 (351 mg, 64%) as a mixture of four stereoisomers. MS 474.1 (M+1)+.
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 compound of the present invention was prepared:
Cpd 58: Separated on SiO2 using 5% MeOH in CH2Cl2 as eluant. MS (M+1)+468.5.
Example 17




A. 4-Methyl-2-phenyl-piperazin-1-ylamine. To a solution of 1-methyl-3-phenyl-piperazine (2.50 g, 14.18 mmol) in 1N HCl (18 mL) was added dropwise 1N KOH until the solution reached pH 3. Potassium cyanate (1.38 g, 17.02 mmol) was added and the reaction mixture was stirred overnight. EtOH was added to the reaction mixture, the resulting precipitate was removed by filtration, and the supernatant was concentrated in vacuo to give a white powder. To this white powder in EtOH (15 mL) cooled to 0° C. was added dropwise a premixed solution of NaOCl (13-15% active chlorine, 11.43 mL) and 15% aqueous NaOH (20.58 mL), and the reaction mixture was allowed to warm to rt and stirred at rt for 1 h. 1N HCl was added dropwise until the reaction mixture reached pH 1, and stirring was continued for 15 min. The reaction mixture was made basic by the addition of solid K2CO3, extracted with CH2Cl2, dried over Na2SO4, filtered, and concentrated in vacuo to give Compound 17a (2.21 g, 81%). MS 192.2 (M+1)+.
B. (2RS*)-2-(4-tert-Butyl-phenyl)-N-[(2RS*)-4-methyl-2-phenyl-piperazin-1-yl]-2-phenylamino-acetamide. To compound 17a (150 mg, 0.45 mmol) in CH2Cl2 (1 mL) was added compound 17b (prepared by a procedure analogous to compound 1d in Example 1 and substituting 4-t-butylphenyl acetic acid for 4-trifluoromethylphenyl acetic acid and substituting aniline for 2-fluoro-aniline, 300 mg, 0.94 mmol), EDC hydrochloride (264 mg, 1.38 mmol), and 1-hydroxybenzotriazole (157 mg, 1.17 mmol). The reaction mixture was stirred at rt overnight, partitioned between CH2Cl2 and saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated in vacuo to give a mixture of four stereoisomers. Purification by MPLC (SiO2, 5% MeOH/CH2Cl2) gave two diastereomers, each as a mixture of two enantiomers. Compound 56 was the first diastereomer to elute from the column. MS 457.1 (M+1)+.
Example 18




A. 1-[2-(2-Fluoro-phenyl)-pyrrolidin-1-yl]-2-hydroxy-2-(4-trifluoromethyl-phenyl)-ethanone. To a solution of Compound 18a (1.0 g, 4.55 mmol) and 2-(2-fluorophenyl)pyrrolidine hydrochloride (0.92 g, 4.56 mmol) in CH2Cl2 (45 mL) at room temperature was added Et3N (3.80 mL, 27.3 mmol) followed by HATU (1.73 g, 4.55 mmol). The reaction was stirred at room temperature for 20 h. The reaction mixture was then diluted with CH2Cl2, washed sequentially with aq. 10% HCl solution and aq. NaHCO3 solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 30% EtOAc/heptane) gave Compound 18b (1.3 g, 78%). MS: 368 (M+1)+.
B. 2-(2-Fluoro-phenoxy)-1-[2-(2-fluoro-phenyl)-pyrrolidin-1-yl]-2-(4-trifluoromethyl-phenyl)-ethanone. To a solution of Compound 18b (0.5 g, 1.36 mmol), 2-fluorophenol (0.32 mL, 3.46 mmol) and PPh3 (0.89 g, 3.40 mmol) in THF (15 mL) at room temperature was added DIAD (0.34 mL, 1.76 mmol). The reaction was stirred at room temperature for 2.5 h, concentrated under reduced pressure, diluted with CH2Cl2, and washed sequentially with aq. 1N NaOH solution, aq. 1N HCl solution, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 20% EtOAc/heptane) gave Compound 263 (0.42 g, 67%). MS: 462 (M+1)+.
Example 19




A. 2-(2-Acetyl-phenoxy)-1-[2-(2-fluoro-phenyl)-pyrrolidin-1-yl]-2-(4-trifluoromethyl-phenyl)-ethanone. Intermediate 19a was prepared following the procedure described in step B of Example 18.
B. 1-[2-(2-Fluoro-phenyl)-pyrrolidin-1-yl]-2-[2-(1-hydroxy-1-methyl-ethyl)-phenoxy]-2-(4-trifluoromethyl-phenyl)-ethanone. To a solution of Compound 19a (80 mg, 0.16 mmol) in THF (2 mL) at 0° C. was added CH3MgBr (3.0 M in ethyl ether, 0.15 mL, 0.45 mmol). The reaction was stirred at 0° C. for 2 h. It was then diluted with ethyl ether, washed with aq. NH4Cl solution and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 30% EtOAc/heptane) gave Compound 199 (18 mg, 22%). MS: 502 (M+1)+.
Example 20




A. 3-(2-Fluoro-phenyl)-2-(4-trifluoromethyl-phenyl)-propionic acid methyl ester. To a solution of Compound 1a (0.5 g, 2.29 mmol) in THF (25 mL) at −78° C. was added LDA (2.0 M in heptane/THF/ethylbenzene, 1.4 mL, 2.8 mmol). The reaction mixture was stirred at −78° C. for 30 min before 2-fluorobenzyl bromide (0.42 ml, 3.48 mmol) was added. The reaction was kept at −78° C. for 2 h, warmed to 0° C. and stirred for another 2 h. To the reaction mixture was added aq. NH4Cl solution, and the resulting mixture was extracted with ethyl ether. The organic solution was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 10% EtOAc/heptane) gave Compound 20a (0.49 g, 66%).
C. 3-(2-Fluoro-phenyl)-2-(4-trifluoromethyl-phenyl)-propionic acid. A mixture of Compound 20a (0.22 g, 0.67 mmol) and LiOH H2O (113 mg, 2.69 mmol) in a mixed solution of THF (4 mL), MeOH (4 mL) and H2O (4 mL) was stirred at room temperature for 3 h. The reaction mixture was acidified with aq. 10% HCl, and extracted with EtOAc. The organic solution was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give Compound 20b (0.17 g, 81%).
D. 3-(2-Fluoro-phenyl)-1-[2-(2-fluoro-phenyl)-pyrrolidin-1-yl]-2-(4-trifluoromethyl-phenyl)-propan-1-one. To a solution of Compound 21b (85 mg, 0.27 mmol) and 2-(2-fluorophenyl)pyrrolidine hydrochloride (82 mg, 0.41 mmol) in CH2Cl2 (3 mL) at room temperature was added Et3N (0.23 mL, 1.65 mmol) followed by HATU (155 mg, 0.41 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was then diluted with CH2Cl2, washed sequentially with aq. 10% HCl and aq. NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 15% EtOAc/heptane) gave Compound 201 (100 mg, 80%). MS: 460 (M+1)+.
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 + 1)+









177
462



179
416



200
414



249
472



252
460



267
494



268
461



283
478










Example 21




A. 1-[2-(2-Fluoro-phenyl)-pyrrolidin-1-yl]-2-(4-trifluoromethyl-phenyl)-ethanone. To a solution of (4-trifluoromethyl-phenyl)-acetic acid (1.0 g, 4.90 mmol) and 2-(2-fluorophenyl)pyrrolidine hydrochloride (1.0 g, 4.96 mmol) in CH2Cl2 (50 mL) at room temperature was added Et3N (3.4 mL, 24.4 mmol) followed by HATU (1.90 g, 5.0 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was then diluted with CH2Cl2, washed sequentially with aq. 10% HCl and aq. NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 25% EtOAc/heptane) gave Compound 21a (1.2 g, 70%).
B. 3-(2,6-Difluoro-phenyl)-1-[2-(2-fluoro-phenyl)-pyrrolidin-1-yl]-2-(4-trifluoromethyl-phenyl)-propan-1-one. To a solution of Compound 21a (107 mg, 0.30 mmol) in THF (3 mL) at −78° C. was added LDA (2.0 M in heptane/THF/ethylbenzene, 0.2 mL, 0.4 mmol). The reaction mixture was stirred at −78° C. for 30 min before a solution of 2,6-difluorobenzyl bromide (107 mg, 0.55 mmol) in THF (1 mL) was added. The reaction was kept at −78° C. for 2 h, warmed to room temperature and stirred for another 16 h. To the reaction mixture was added aq. NH4Cl, and the resulting mixture was extracted with ethyl ether. The organic solution was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 15% EtOAc/heptane) gave Compound 244 (70 mg, 48%). MS: 478 (M+1)+.
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 + 1)+









253
478










Example 22




A. (4-Bromo-phenyl)-(2-fluoro-phenylamino)-acetic acid. A mixture of 4-bromophenylboronic acid (1.0 g, 4.98 mmol), 2-fluoroaniline (580 mg, 5.23 mmol) and glyoxylic acid monohydrate (480 mg, 5.52 mmol) in CH3CN (15 mL) was heated to reflux for 5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was washed with heptane, and the remaining solid was then dissolved in EtOAc and filtered. The EtOAc solution was washed with aq. 10% HCl and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give Compound 22a.
B. 2-(4-Bromo-phenyl)-2-(2-fluoro-phenylamino)-1-[2-(2-fluoro-phenyl)-pyrrolidin-1-yl]ethanone. To a solution of Compound 22a (1.0 g, 3.09 mmol) and 2-(2-fluorophenyl)pyrrolidine hydrochloride (630 mg, 3.13 mmol) in CH2Cl2 (30 mL) at room temperature was added Et3N (2.60 mL, 18.7 mmol) followed by HATU (1.2 g, 3.16 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was then diluted with CH2Cl2, washed sequentially with aq. 10% HCl and aq. NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 20% EtOAc/heptane) gave Compound 22b (600 mg, 41%). MS: 471 (M+1)+.
C. 2-(2-Fluoro-phenylamino)-1-[2-(2-fluoro-phenyl)-pyrrolidin-1-yl]-2-(4-pyridin-3-yl-phenyl)-ethanone. A mixture of Compound 22b (75 mg, 0.16 mmol), 3-pyridineboronic acid (39 mg, 0.32 mmol), K2CO3 (44 mg, 0.32 mmol) and Pd(dppf)Cl2CH2Cl2 (7 mg, 0.009 mmol) in a mixed solution of EtOH (1 mL) and H2O (0.2 mL) was irradiated in a microwave reactor at 130° C. for 30 min. The reaction mixture was diluted with CH2Cl2, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 40% EtOAc/heptane) gave Compound 285 (62 mg, 83%). MS: 470 (M+1)+.
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
MS (M + 1)+
Cpd
MS (M + 1)+









288
471
294
470



300
470
343
486










Example 23




A. 4-(4-{1-(2-Fluoro-phenylamino)-2-[2-(2-fluoro-phenyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester. A mixture of Compound 22b (75 mg, 0.16 mmol), 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-4-boronic acid pinacol ester (100 mg, 0.32 mmol), K2CO3 (44 mg, 0.32 mmol) and Pd(dppf)Cl2.CH2Cl2 (7 mg, 0.009 mmol) in a mixed solution of EtOH (1 mL) and H2O (0.2 mL) was irradiated in a microwave reactor at 130° C. for 30 min. The reaction mixture was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 20% EtOAc/heptane) gave Compound 299 (68 mg, 75%). MS: 574 (M+1)+.
B. 2-(2-Fluoro-phenylamino)-1-[2-(2-fluoro-phenyl)-pyrrolidin-1-yl]-2-[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-ethanone. To a solution of Compound 299 (58 mg, 0.10 mmol) in CH2Cl2 (4 mL) at room temperature was added CF3CO2H (1 mL). The reaction was stirred for 2 h before being concentrated under reduced pressure. The residue was dissolved in CH2Cl2, washed with aq. NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure to give Compound 302 (45 mg, 94%). MS: 474 (M+1)+.
Example 24




A. Compound 24a mixture. A mixture of intermediate 22b (75 mg, 0.16 mmol), 4-methoxycarbonylphenylboronic acid (57 mg, 0.32 mmol), K2CO3 (44 mg, 0.32 mmol) and Pd(dppf)Cl2 (7 mg, 0.009 mmol) in a mixed solution of EtOH (1 mL) and H2O (0.2 mL) was heated in a microwave reactor at 130° C. for 30 min. The reaction mixture was diluted with EtOAc, washed with aq. 10% HCl and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give Compound 24a as a mixture of three compounds.
B. 4′-{1-(2-Fluoro-phenylamino)-2-[2-(2-fluoro-phenyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-biphenyl-4-carboxylic acid. Compound 24a and LiOH H2O (50 mg, 1.19 mmol) in a mixed solution of THF (2 mL), MeOH (2 mL) and H2O (2 mL) was stirred at room temperature for 2.5 h. To the reaction mixture was added aq. 10% HCl to adjust to pH 2. The resulting mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 40% EtOAc/heptane) gave Compound 295 (60 mg, 74%). MS: 513 (M+1)+.
Following the procedure described above for Example 24 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 + 1)+
Cpd
MS (M + 1)+









310
513
337
513



350
529










Example 25




A. 3-Pyrrolidin-2-yl-benzoic acid methyl ester. To a solution of N-Boc-2-(3-carboxyphenyl)pyrrolidine (125 mg, 0.43 mmol) in MeOH (3 mL) at room temperature was added conc HCl (0.1 mL). The reaction was stirred for 4 days. It was then concentrated, diluted with CH2Cl2, washed with aq. NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure to give Compound 25a (68 mg, 77%).
B. 3-{1-[2-Benzo[b]thiophen-2-yl-2-(2-fluoro-phenylamino)-acetyl]-pyrrolidin-2-yl}-benzoic acid methyl ester. To a solution of Compound 12a (77 mg, 0.26 mmol) and Compound 26a (68 mg, 0.33 mmol) in CH2Cl2 (3 mL) at room temperature was added Et3N (0.21 mL, 1.51 mmol) followed by HATU (130 mg, 0.34 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was then diluted with ethyl ether, washed sequentially with aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 20% EtOAc/heptane) gave Compound 324 (74 mg, 59%). MS: 489 (M+1)+.
C. 3-{1-[2-Benzo[b]thiophen-2-yl-2-(2-fluoro-phenylamino)-acetyl]-pyrrolidin-2-yl}-benzoic acid. A mixture of Compound 324 (63 mg, 0.13 mmol) and LiOH H2O (42 mg, 1.0 mmol) in a mixed solution of THF (2 mL), MeOH (2 mL) and H2O (2 mL) was stirred at room temperature for 5 h. To the reaction mixture was added aq. 10% HCl to adjust to pH 2. The resulting mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give Compound 326 (60 mg, 98%). MS: 475 (M+1)+.
Following the procedure described above for Example 25 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 + 1)+
Cpd
MS (M + 1)+









327
489
329
475



353
475
354
510



355
496










Example 26




A. 4′-{1-(2-Fluoro-phenylamino)-2-[(2S)-2-(2-fluoro-phenyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-biphenyl-4-carbonitrile. A mixture of Compound 26a (prepared following a similar procedure as that of 22b) (80 mg, 0.17 mmol), 4-cyanophenylboronic acid (50 mg, 0.34 mmol), K2CO3 (47 mg, 0.34 mmol) and Pd(dppf)Cl2.CH2Cl2 (7 mg, 0.009 mmol) in a mixed solution of EtOH (1 mL) and H2O (0.2 mL) was irradiated in a microwave reactor at 130° C. for 30 min. The reaction mixture was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. Purification of the resultant residue by flash column chromatography (SiO2, 20% EtOAc/heptane) afforded Compound 26b (70 mg, 84%). MS: 494 (M+1)+.
B. 2-(2-Fluoro-phenylamino)-1-[(2S)-2-(2-fluoro-phenyl)-pyrrolidin-1-yl]-2-[4′-(1H-tetrazol-5-yl)-biphenyl-4-yl]-ethanone. A mixture of Compound 26b (68 mg, 0.14 mmol), TMSN3 (0.072 mL, 0.55 mmol) and Bu2SnO (10 mg, 0.04 mmol) in toluene (2 mL) was heated to reflux for 7.5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 3% MeOH/CH2Cl2) afforded Compound 354 (60 mg, 81%). MS: 537 (M+1)+.
Example 27




A. 2-Hydroxy-2-(4-(trifluoromethyl)phenyl)acetyl chloride. A suspension of Compound 18a (2.12 g, 10.0 mmol) in thionyl chloride (10 mL, 137 mmol) may be heated at reflux overnight and then may be evaporated in vacuo to afford Compound 27a which may be used without further purification.
B. 2-Hydroxy-1-(2-phenyl-pyrrolidin-1-yl)-2-(4-trifluoromethyl-phenyl)-ethanone. To a solution of 2-phenyl-pyrrolidine HCl salt (1.47 g, 8.00 mmol) and triethylamine (2 mL) in CH3CN (80 mL) may be added Compound 27a (2.09 g, 8.76 mmol) dropwise. Upon completion of the reaction, the reaction mixture may be diluted with water (100 mL) and extracted three times with EtOAc (100 mL). The combined organics may be washed once with brine (50 mL), dried with Na2SO4, filtered, and evaporated in vacuo. The material may be purified by column chromatography to afford Compound 27b.
C. 2-Chloro-1-(2-phenyl-pyrrolidin-1-yl)-2-(4-trifluoromethyl-phenyl)-ethanone. To a suspension of Compound 27b (0.349 g, 1.00 mmol) in CHCl3 (25 mL) may be added thionyl chloride (1 mL, 14 mmol). The reaction may be stirred at ambient temperature for approximately 2 d, diluted with additional CHCl3 (25 mL), washed twice with saturated NaHCO3 (25 mL) then once with brine (25 mL). The organic phase may be dried over Na2SO4 and filtered to give a solution of Compound 27c in approximately CHCl3 (50 mL) to make and approximately 0.02 M solution.
D. 1-(2-Phenyl-pyrrolidin-1-yl)-2-phenylsulfanyl-2-(4-trifluoromethyl-phenyl)-ethanone. To a 0.02 M solution of Compound 27c (37-38 mL, 0.75 mmol) may be added thiophenol (0.09 mL, 0.88 mmol) and after approximately 1 h additional thiophenol (0.29 mL, 2.84 mmol), CH3CN (10 mL) and K2CO3 (0.211, 1.53 mmol) may be added to any remaining Compound 27c. After stirring overnight the reaction mixture may be diluted with DCM (60 mL) and washed sequentially with 10% Na2CO3 solution (50 mL) and brine (50 mL). The organic phase may be dried with MgSO4, filtered and evaporated in vacuo. The residue may be purified by column chromatography to give Compound 27d.
Example 28
As a specific embodiment of an oral composition, 100 mg of Compound 1 is formulated with a sufficiently finely divided lactose to provide a total amount of about 580 to about 590 mg to fill a size 0 hard gel capsule.
Biological Examples
Example 1
In Vitro Canine TRPM8 Functional Assay
The functional activity of compounds of the formula (I) was determined by measuring changes in intracellular calcium concentration using a Ca2+-sensitive fluorescent dye. The changes in fluorescent signal were monitored by a fluorescence plate reader, either a FLIPRTM (Molecular Devices) or FDSS (Hamamatsu). Increases in intracellular Ca2+ concentration were readily detected upon activation with icilin.
HEK293 cells stably expressing canine TRPM8 were routinely grown as monolayers in Dulbecco's minimum essential medium supplemented with 10% FBS, 2 mM L-glutamine, 100 units/mL penicillin, 100 ug/mL streptomycin and 400 μg/mL G418. Cells were maintained in 5% CO2 at 37° C. At 24 hrs prior to assay, cells were seeded in black wall, clear-base poly-D-lysine coated 384-well plates (BD Biosciences, NJ, USA) at a density of 5,000 cells per well in culture medium and grown overnight in 5% CO2 at 37° C. On assay day, growth media was removed and cells were loaded with Calcium 3 Dye (Molecular Devices) for 35 min at 37° C., under 5% CO2 and then for 25 min at room temperature and atmosphere. Subsequently, cells were tested for agonist-induced increases in intracellular Ca2+ levels using FLIPRTM or FDSS. Cells were challenged with compounds of the formula (I) (at varying concentrations) and intracellular Ca2+ was measured for 5 min prior to the addition of icilin to all wells to achieve a final concentration that produces approximately an 80% maximal response. EC50 or IC50 values for compounds of the present invention were determined from eight-point dose-response studies and represent the concentration of compound required to elicit or inhibit 50% of the maximal response, respectively.
Maximal fluorescence intensity (FI) achieved upon addition of icilin was exported from the FLIPR or FDSS software and further analyzed using GraphPad Prism 3.02 (Graph Pad Software Inc., CA, U.S.A.). Basal FI was subtracted prior to normalizing data to percent of maximal response. Curves were generated using the average of quadruplicate wells for each data point, were analyzed using nonlinear regression of either sigmoidal dose response or sigmoidal dose response (variable slope). Finally, the EC50 and IC50 values were calculated with the best-fit dose curve determined by GraphPad Prism The resultant data are displayed in Table 12.











TABLE 12







% Inh
% Inh
% Inh


Cpd No.
IC50 (μM)
@ 1 μM
@ 0.5 μM
@ 0.2 μM



















1
0.31325
101.2




2
0.07257
100.93


3
0.3512
100.57


4
0.2912
101.68


5
0.09955
101.59


6

45.171


7
0.636
89.12


8
0.7776
86.64


9
0.1614
102.98


10
0.5166
102.05


11
0.1716
103.01


12
0.06062
103.1


13
0.3227
103.27


14
0.4158
102.22


15
0.2573
94.83


16
0.02161
102.71


17
0.06032
98.217


18
0.3488
95.361


19
0.2824
100


20
0.02986
101.39


21
0.1752

103.38


22
0.3777

102.36


23
0.01723

103.39


24
0.01494

102.36


25
0.1413

102.09


26


56.872


27
0.3158

93.164


28
0.09172

102.95


29
0.04087

104.16


30
0.1097

103.21


31
0.0485

104.03


32
0.03124

104.25


33
0.2017

96.475


34
0.1606

101.75


35


72.417


36
0.4588

90.735


37


49.878


38


63.009


39


73.007


40
0.2331

90.495


41


70.995


42
0.2311

102.12


42

29


43
0.03329

101.44


44
0.0576

101.2


45
0.1051

100.98


46
0.00746

101.53


47
0.1998

99.791


48
0.2189

85.869


49
0.07828

101.77


50
0.3765

83.592


51
0.04489

102.19


52
0.01981

97.762


53
0.05381

98.985


54


69.055


55
0.2074

99.911


56


26


57


35


58
0.1004

100.88


59


49


60
0.04143

103.24


61
0.1684

103.2


62
0.078

103


63


36


64
0.022, 0.025

102
100


65
0.048

100


66
0.028

102


67
0.042

102


68
0.007, 0.012,

103
89



0.013


69
0.005

102


70
0.023

103


71
0.074

91


72
0.046

102


73


33


74
0.073

98


75
0.02

98


76
0.101

97


77
0.084

98


78
0.138

94


79
0.05

98


80


69


81


69


82


31


83
0.248

96


84
0.015

98


85
0.006

97


86
0.015

97


87
0.081

97


88
0.096

99


89
0.02

98


90
0.007

97


91
0.014

97


92
0.089

98


93
0.176

95


94
0.162

98


95


67


96
0.206

96


97
0.089

100


98
0.056

100


99
0.089

99


100
0.29

90


101


61


102
0.159

98


103
0.182

75


104


62


105
0.432

88


106
0.17

98


107


36


108
0.329

88


109
0.334

88


110
0.0554

98


111
0.013

96


112
0.0181

96


113
0.0617

98


113
0.0617

98


114
0.1256

98


115
0.0101

97


116
0.0803

98


117
0.0475

101


118
0.0317

100


119
0.0697

100


120
0.13

95


121
0.1253

97


122
0.1469

96


123
0.1006

97


124
0.0817

98


125
0.0623

96


126
0.111

100


127
0.0869

97


128
0.0046

100


129
0.043

101


130
0.0362

101


131
0.0069

103


132
0.009

99


133
0.0209

98


134
0.014

98



.0087


135
0.0374

100


136
0.193

90


137
0.101

81


138
0.119

95


139
0.116

81


140
0.131

97


141
0.188

79


142
0.018

97


143
0.025

101


144
0.011

102


145
0.016

99


146
0.012

99


147
0.132

93


148
0.012

99


149
0.045, 0.074

100.98
83


150
0.012, 0.004

100.24
89


151
0.0072,

100.72
103



0.005


151


152
0.0613

100.83


153
0.044

99.694


154
0.104

97.552


155
0.017

99


156
0.009

92


157
0.146

93


158
0.005

98


159
0.109, 0.038

94
97


160
0.039,

95
87



0.013


161
0.063, 0.036

93
98


162
0.00545

99
100


163
0.145

94


164
0.026

96


165
0.162

99


166
0.061

96


167
0.034

97


168
0.035

97


169
0.142

92


170
0.0265


100


171
0.0418


98


172
0.0296


102


173
0.0356


103


174
0.0452


98


175
0.069


85


176
0.03


94


177



63


178
0.010


100


179
0.038


96


180
0.009


97


181
0.005


181



96


182
0.013


102


183
0.010


99


185
0.150


82


186
0.018


98


187
0.004


98


188



30


189
0.009


98


190
0.085


89


191
0.005


100


192



51


193



33


194
0.160


70


195



32


196



41


197
0.019


97


198
0.019, 0.035


101


199



62


200
0.055


89


201
0.032


99


202
0.025


100


203
0.007


102


204



47


205



62


206
0.076


92


207



47


208
0.009


101


209
0.099


94


210
0.007


99


211



69


212
0.017


99


213



63


214



58


215



18


216



32


217



26


218



49


219
0.068


89


220
0.048


96


221
0.022


102


222
0.066


93


223
0.040


97


224



55


225
0.007


98


226
0.0425


227
0.0306


228
0.0254


229
0.0444


230
0.1054


231


232


233



10


234


235
0.0537


236


237
0.0861


238
0.1117


239
0.1359


240


241


242
0.0655


243
0.1334


88


244
0.0167


98


245
0.0026


98


247
0.0084


93


248
0.0123


94


249



34


250



25


251
0.0537


90


252
0.0214


95


253
0.0658


89


254


255


256


257


258


259


260


261


262


263
0.11


84


264
0.043


93


265



15


266
0.002


100


267
0.030


98


268



13, 15


269



47


270



58


271
0.089


90


272
0.110


96


273
0.104


98


274
0.017


98


275
0.021


94


276
0.051


82


277
0.008


101


278
0.031, 0.036


94, 101


279
0.011


90


280
0.004, 0.008


93, 101


281
0.094


89


282



17


283
0.011


92


284
0.020, 0.026


92, 95


285
0.012, 0.015


91, 96


286
0.014


96


287
0.027


92


288
0.009, 0.010


91, 95


289
0.012


84


290
0.002


98


291
0.422


72


292



45


293
0.011


86


294
0.022, 0.027


92, 102


295
0.047


90


296
0.004, 0.009


88, 96


297
0.065, 0.069


85, 87


298



22


299
0.065


99


300
0.006, 0.008


101, 102


301
0.035


99


302



57


303
0.014


101


304
0.044


98


305
0.002


101


306
0.007


101, 102


307
0.004


102


308



11


309
0.013


102


310



41


311
0.051


99


312
0.005


101


313
0.081


87


314
0.040


88


315



49


316
0.026


102


317
0.003


102


318



47


319
0.025


94


320
0.025


87


321
0.008


94


322
0.008


89


323
0.024


95


324
0.028


101


325
0.062


101


326
0.078


97


327
0.041


99


328
0.008


101


329
0.048


101


330
0.006


101


331
0.013


101


332



47


333



62


334
0.005


101


335
0.026


101


336



43


337
0.056


91


338
0.017


101


339
0.027


97


340
0.005


101


341
0.024


100


342
0.028


100


343
0.017


101


344
0.044


98


345
0.044


92


346
0.038


97


347
0.040


99


348
0.022


100


349
0.033


100


350
0.042


99


351
0.092


83


352
0.115


88


353



19


354



53


355
0.005


100


356



57


357
0.003


100


358
0.008


100


359
0.007


100


360



43


361
0.008


96


362


21.91


363
0.134


72


364
0.036


91


365
0.03


94


366
0.046


98


367
0.149 ± 0.051
5.8157


368

15.864


369


7.773, (48%





@ 3 μM)


370
0.120


371
0.1


372
0.01


373
0.006


374



61


375


33
2









In Vivo Models
Example 2
Inhibition of Icilin-Induced Behaviors in Rodents
Icilin was initially developed as a “super-cooling” compound by Delmar Chemicals Ltd. Subsequently it was shown to be one of the most potent known agonists of TRPM8 (McKemy D D, et al. Nature 2002, 416(6876): 52-8), having an EC50=0.2 μM in stimulating calcium ion influx into TRPM8 transfected cells (Behrendt H J et al. Brit J Pharmacol 2004, 141(4): 737-45). Initial in vivo testing of icilin showed it to cause “wet-dog” shakes in rats. Similar shaking or jumping behavior was also evident in mice, rabbits, cats, dogs and monkeys. In humans, icilin produced a sensation of coolness on contact with mucous membranes, cold prickling when 0.1 mg was dropped on the tongue and coldness in the mouth, pharynx and chest lasting 30-60 minutes when 5-10 mg was ingested orally (Wei E T, Seid D A, J Pharm Pharmacol. 1983, 35, 110). The inhibition or reversal of icilin-induced shaking behaviors in rodents provides evidence for the utility of TRPM8 antagonists of the formula (I) in treating or preventing a disease, syndrome, disorder or condition in a subject in which the disease, syndrome, disorder or condition is affected by the modulation of TRPM8 receptors.
Example 2a
Inhibition of Icilin-Induced “Wet-Dog” Shakes in Rats
Male Sprague Dawley rats (2200-450 g, Charles River Labs, n=6-9/treatment) were used to evaluate the ability of selected compounds of the formula (I) to block icilin-induced “wet-dog” shakes (WDS). Compounds of the formula (I) were administered in an appropriate vehicle, such as hydroxypropyl-β-cyclodextrin (HP β CD), methocellulose, 10% Solutol, or H2O, or the like, by the appropriate route, i.p. or p.o., 30-60 minutes before icilin. Icilin was administered in PEG-400 or 10% solutol/H2O, at 1.0 or 3.0 mg/kg, i.p. and spontaneous “wet-dog” shakes were counted 10-20 minutes post-icilin. Results are presented as a percent inhibition of shakes, which was calculated as [1-(test compound WDS count/vehicle WDS count)]×100. Results are shown in Table 13.












TABLE 13






Dose



%


Cpd
(mg/kg)
Vehicle
Route
Pre-icilin
Inh







151
30
10% solutol
p.o..
2 h
100









Example 2b
Reversal of Icilin-Induced Behaviors in Rats
Male Sprague Dawley rats (225-450 g, Charles River Labs, n=4-6/treatment) were used to evaluate the ability of selected compounds of the formula (I) to reverse icilin-induced “wet-dog” shakes. Icilin was administered in PEG-400 or 10% solutol/H2O, at 1.0 or 3.0 mg/kg, i.p. and spontaneous “wet-dog” shakes (WDS) were counted 10-20 minutes post-icilin. Animals that exhibited 10 or more shakes were randomized into treatment groups and immediately administered compounds of the formula (I) in an appropriate vehicle, such as hydroxypropyl-β-cyclodextrin (HP β CD), methocellulose, 10% Solutol, or H2O, or the like, and by the appropriate route, such as i.p. or p.o. Spontaneous “wet-dog” shakes were counted 60-70 minutes after compound administration. Results are presented as a percent inhibition of shakes, which was calculated as [1-(test compound WDS count/vehicle WDS count)]×100. Results are shown in Table 14.











TABLE 14





Cpd
Dose





No.
(mg/kg)
Route
Post-icilin
% Inh







128
30
P.O.
20′
56% ± 19%


129
30
P.O.
20′
50% ± 21%


134
30
P.O.
20′
75% ± 11%


155
30
P.O.
20′
79% ± 13%


149
30
P.O.
20′
61% ± 15%


150
30
P.O.
20′
63% ± 15%


151
30
P.O.
20′
99% ± 1% 


158
30
P.O.
20′
86% ± 7% 









Example 3
In Vivo Model for of Chronic Inflammatory Pain
Complete Freund's Adjuvant (CFA)-Induced Hyperalgesia
Intraplantar injection of complete Freund's adjuvant (CFA) in rodents results in a long-lasting inflammatory reaction, characterized by a pronounced hypersensitivity to both thermal and mechanical stimuli. This hypersensitivity peaks between 24-72 hours following injection and can last for several weeks. To assess whether test compounds of the formula (I) reverse established hypersensitivity, a 100 μL intraplantar injection of CFA (suspended in a 1:1 emulsion of saline and heat-killed Mycobacterium tuberculosis in mineral oil) can be injected into a single hind paw of Sprague-Dawley rats (typically males ranging from 150-350 g). This paradigm also may be conducted with a multiple dosing or a prophylactic dosing regime designed to alter the course of hyperalgesia development. This test predicts the analgesic, anti-allodynic and antihyperalgesic effect of numerous effective clinical agents, including acetaminophen, NSAIDS, such as, aspirin and ibuprofen, and opioids, such as, morphine.
Example 3a
CFA-Induced Paw Radiant Heat Hypersensitivity
Each rat is placed in a test chamber on a warm glass surface and allowed to acclimate for approximately 10 minutes. A radiant thermal stimulus (beam of light) is then focused through the glass onto the plantar surface of each hind paw in turn. The thermal stimulus is automatically shut off by a photoelectric relay when the paw is moved or when the cut-off time is reached (20 seconds for radiant heat at  ̃5 Amps). An initial (baseline) response latency to the thermal stimulus is recorded for each animal prior to the injection of CFA. Twenty-four hours following intraplantar CFA injection, the response latency of the animal to the thermal stimulus is then re-evaluated and compared to the animal's baseline response time. Only rats that exhibit at least a 25% reduction in response latency (i.e., hyperalgesia) are included in further analysis. Immediately following the post-CFA latency assessment, test compound or vehicle (usually Solutol, hydroxypropyl methylcellulose, hydroxypropyl beta-cyclodextrin or PEG-400) is administered i.p. or p.o. to rats. Post-compound treatment withdrawal latencies are assessed at fixed time intervals, typically 30, 60 and 120 minutes. The percent reversal (% R) of hypersenstivitiy is calculated according to the following formula:

% Reversal=(Treatment Response−CFA Response)/(Baseline Response−CFA Response)×100.

Example 3b
CFA-Induced Paw Cold Hypersensitivity
Prior to intraplantar CFA injection, mice or rats are placed individually in elevated observation chambers having wire mesh floors. Through the mesh floor a series of three applications of acetone (0.04-0.10 mL/application) is sprayed onto the bottom of the paw using a multidose syringe device. A positive response takes the form of an abrupt withdrawal and licking of the paw. The cumulative duration of licking is recorded for each of the three trials which are then averaged to give the individual's response. Twenty-four hours following CFA injection acetone licking durations are markedly elevated implying a hypersensitivity to cooling. Test compounds of the formula (I) can be assessed for its ability to return acetone-evoked paw licking durations to pre-CFA levels (typically near zero) following systemic administration. Percent inhibition is calculated as follows

% Inhibition=[1−(treatment licking duration/vehicle licking duration)]×100.

Example 4
Chemically-Induced Abdominal Irritant Models of Visceral Pain
A chemical irritant (such as acetic acid, kaolin, bradykinin, phenyl-p-(benzo) quinine, bromo-acetylcholine, or zymosan) is injected in mice intraperitoneally, causing a contraction of the abdominal musculature, which is characterized by an elongation of the body extending through to the hind limbs. The number of such responses is quantitated and is reduced by pretreatment of analgesic agents, thus forming the basis for a screening test (Collier H O et al. Br J Pharmacol Chemother 1968, 32(2): 295-310). This type of abdominal irritant test has been used to predict the analgesic effect of numerous clinically effective agents, the potency of which in the abdominal irritant test parallels the magnitude of the dose needed in the relief of clinical pain. Such agents include acetaminophen; NSAIDS, such as aspirin and ibuprofen; opioids, such as morphine and codeine, and other centrally acting analgesics, such as, tramadol.
One modification of the chemically-induced abdmonial irritant model of visceral pain is to pretreat animals with agents known to induce inflammatory responses following intraperitoneal injection (such as zymosan, or thioglycolate). A small intraperitoneal dose of such an inflammogen, administered hours or days before the acute chemical irritant challenge, has been shown to increase the number of abdominal contractions observed (Ribeiro R A, et al. Eur J Pharmacol 2000, 387(1): 111-8). While some analgesic agents are effective at mitigating acute viscerochemical nociception, others, particularly those dependent upon receptor induction are more effective at preventing or reversing the enhancement of behavioral responses caused by a preconditioning inflammatory stimulus. Because of the up-regulation of the TRPM8 receptor in inflammation, TRPM8 antagonists that are effective at reducing the mean number of contractions are predicted to provide analgesic action in human clinical use.
The ability of compounds of the formula (I) to mitigate chemical irritant-induced abdominal contractions following a pre-conditioning inflammatory stimulus can be studied as follows. Thioglycolate (3%, w/v, 2-3 mL i.p.) is injected into male CD1 mice (20-40 g, Charles River Labs), at a maximum dosage volume of 80 mL/kg, to induce peritoneal inflammation. Following a twenty-four hour pre-inflammation period these mice are dosed orally with compounds of the formula (I) (30 mg/kg; n=10) or vehicle (HPMC with 2% Tween80; n=9) and then one hour later subjected to an abdominal irritant challenge of acetic acid (1%, 10 mL/kg, i.p.). Immediately following injection of acetic acid, mice are placed individually in glass bell jars (approximately 15 cm in diameter) for counting of abdominal contractions over the next 15 minutes. The total number of abdominal contractions is summed for each treatment group and employed in the following formula to calculate Percent Inhibition (% I):

% I=[1−(test compound contractions/vehicle contractions)]×100.

Example 5
In Vivo Models of Neuropathic Pain
The sciatic nerve is the major sensorimotor innervation of the (hind) leg and foot. Injury to the sciatic nerve or its constituent spinal nerves often results in pain-related behaviors. In rats and mice, tight ligation of the L5 spinal nerve with silk suture, partial tight ligation of the sciatic nerve with silk suture or loose ligation of the sciatic nerve with chromic gut suture each result in behaviors reminiscent of neuropathic pain in humans. These lesions (one per animal) are performed surgically in anesthetized rodents. Both the spinal nerve and sciatic nerve lesions result in allodynia, a painful response to normally innocuous stimuli, and hyperalgesia, an exaggerated response to normally noxious stimuli. It is important to note that both of these pain-related behaviors are evoked by the testing procedures and that normal use of the paw (e.g., walking) is relatively uncompromised, apart from occasional “guarding” of the paw. Subsequent to the surgery, the subjects' behaviors, such as grooming, feeding, and weight gain, are normal, except for hypersensitivity (as defined above) of the affected paw.
In addition to induction by nerve damage resulting from accidental trauma or surgical procedures, neuropathic pain can also be induced by diabetes (Fox, A., et al., Pain 81:307-316, 1999) or by treatment with chemotherapeutic agents, such as paclitaxel or vincristine (Yaksh, T L, et al., Pain 93:69-76, 2001).
Agents that attenuate neuropathic pain in the clinic also are effective in rodent neuropathic pain models. These agents include the recently approved Cymbalta (Duloxetine, lyengar, S., et al., JPET 2004 311:576-584), morphine (Suzuki, R., et al., Pain 1999 80:215-228) and gabapentin (Hunter, J C, et al., Eur J. Pharmacol. 1997 324:153-160). The dual TRPV1/TRPM8 receptor antagonist BCTC reduced mechanical hyperalgesia and tactile allodynia in the chronic constriction injury rodent neuropathic pain model (Pomonis, J D, et al., JPET. 2003 306:387-393; Behrendt, H., et al., Brit J. Pharm. 2004 141:737). Cold allodynia is a particularly debilitating symptom of neuropathic pain conditions (Jorum E., et al. Pain 2003 101:229-235). The antiallodynic effect of compounds of the formula (I) in this rodent model is predictive of clinical effect for these novel agents.
Example 5a
Chronic Constriction Injury (CCL)-Induced Model of Neuropathic Pain
Acetone-Induced Hypersensitivity
Male Sprague Dawley rats (225-450 g; n=5-8/treatment) were used to evaluate the ability of selected compounds of the formula (I) to reverse CCl-induced cold hypersensitivity. Four loose ligatures of 4-0 chromic gut were surgically placed around the left sciatic nerve under inhalation anesthesia as described by Bennett et al (Bennett G J, Xie Y K. Pain, 1988, 33(1): 87-107). 14 to 35 days following CCl surgery, subjects were placed in elevated observation chambers containing wire mesh floors and five applications of acetone (0.05 mL/application separated by approximately 5 minutes) were spritzed onto the plantar surface of the paw using a multidose syringe. An abrupt withdrawal or lifting of the paw was considered a positive response. The number of positive responses was recorded for each rat over the five trials. Following baseline withdrawal determinations, compounds of formula (I) are administered in an appropriate vehicle, such as hydroxypropyl-β-cyclodextrin (HP β CD), methylcellulose, Methocel, 10% Solutol, or H2O, or the like, by the appropriate route, i.p. or p.o. The number of withdrawals were redetermined 1 to 3 h after compound administration. Results are presented as a percent inhibition of shakes, which was calculated for each subject as [1-(test compound withdrawals/pre-test withdrawals)]×100 and then averaged by treatment.
Example 5b
Chronic Constriction Injury (CCl)-Induced Model of Neuropathic Pain
Cold Plate-Induced Hypersensitivity
In male SD rats (175-325 g), four loose ligatures of 4-0 chromic gut are surgically placed around the left sciatic nerve under inhalation anesthesia as described by Bennet et al (Bennett G J, Xie Y K., Pain 1988, 33(1): 87-107). Seven to 21 days following sciatic chronic constriction injury (CCl) surgery, the subjects can be placed onto a commercial cold plate device cooled by peltier elements such that the surface temperature is held at 1° C. Each subject can undergo a 6 minute conditioning period followed by a 3 minute assessment period during which the total duration of hind paw lifting is recorded. This procedure is repeated at several intervals prior to and following systemic drug administration. Compounds of the formula (I) can be assessed for their ability to return duration of paw lifting back to pre-lesion levels. The duration of paw lifting during the 3 minute test period following administration of test compound is taken as a percentage of the duration of paw lifting during the 3 minute test period prior to test compound treatment.
Example 6
Inflammatory Agent-Induced Models of Pyresis/Antipyresis
Compounds of the formula (I) can be tested in animal models of pyresis, according to previously documented and validated methods, such as those described by Kozak et al (Kozak W, Fraifeld V., Front Biosci 2004, 9: 3339-55). Fever is a frequent accompaniment of inflammatory disease. Animal models make use of the pyretic properties of yeast and other inflammatory agents, injecting a yeast suspension or other agent subcutaneously (Tomazetti J., et al. J Neurosci Methods 2005, 147(1): 29-35); Van Miert A S, Van Duin C T., Eur J Pharmacol 1977, 44(3): 197-204). For example, Male Wistar rats (75-100 g) can be housed in groups of four to a cage at controlled temperature (23±1° C.) with a 12 h light:12 h dark cycle (lights on at 07:00 h) and with standard lab chow and tap water ad libitum. All measured temperatures can be taken between 08:00 and 19:00 h. Each animal can be used in only one study. Rectal temperature (TR) can be measured by inserting a lubricated thermistor probe (external diameter: 3 mm) 2.8 cm into the rectum of the animal. The probe can be linked to a digital device, which displayed the temperature at the tip of the probe with a 0.1° C. precision and logs the values over time. Immediately after measuring the initial basal rectal temperature, the animals can be injected with commercially available dried baker yeast (Saccharomyces cerevisiae) suspended in pyrogen-free 0.9% NaCl (0.05-0.25 g/kg, i.p.) or 0.9% NaCl (10 ml/kg). TR changes can be recorded every hour up to 12 h, and expressed as the difference from the basal value. Since it has been previously reported that handling and temperature measuring-related stress alter rectal temperature, these animals can be habituated to the injection and measuring procedure for 2 days before experiments are carried out. In these sessions, the animals can be subjected to the same temperature measuring procedure described above, and can be injected intraperitoneally (i.p.) with 0.9% NaCl (10 ml/kg).
To assess the effect of potential antipyretic compounds on basal rectal temperature study animals can have their TR measured for 4 h, and after the fourth TR measurement they can be subcutaneously (s.c.) injected with vehicle (such as 10% Solutol in sterile water 5 ml/kg) or compounds of the formula (I) prepared in vehicle. TR can then be recorded every hour up to 8 h after the compound injections. To assess the effect of compounds of the formula (I) on baker yeast-induced hyperthermia, study animals can have their basal TR measured and then be injected with a pyrogenic dose of baker yeast (for example, 0.135 g/kg). TR changes can be recorded every hour up to 4 h, when potential antipyretics agents such as those compounds of the formula (I) are administered. Rectal temperature can then be monitored over the following 8 h. Basal rectal temperature and changes in rectal temperature can be expressed as means±S.E.M. of the differences from TR at 07:00 h. Data can be analyzed by two-way analysis of variance (ANOVA), with time of measures treated as within subject factor, depending on the experimental design. Post hoc analysis can be carried out by the F-test for simple effect and the Student-Newman-Keuls test, when appropriate. A value of P<0.05 would be considered statistically significant.
The modification of the subsequent pyretic response by therapeutic agents can also be monitored by rectal telemetry or other measurements of body temperature. Several clinically relevant agents such as acetaminophen, aspirin and ibuprofen, reduce fever in these models. The antipyretic effect of TRPM8 antagonists, such as the compounds of the formula (I), in these tests would also be predictive of their clinical effect.
Example 7
CFA-Induced Model of Rheumatoid Arthritis
Compounds of the formula (I) can be tested in animal models of rheumatoid arthritis, according to previously documented and validated methods, such as those described by Nagakura et al (Nagakura Y, et al., J Pharmacol Exp Ther 2003, 306(2): 490-7). For example, arthritis can be induced by the CFA inoculation in the rats (Male Lewis rats 150-225 g; Charles River). Briefly, 100 mg of Mycobacterium butyricum (Difco, Detroit, Mich.) can be thoroughly mixed with 20 mL of paraffin oil. Then mixture can be autoclaved for 20 min at 120° C. Each rat can be injected in the right footpad (hind paw) with the mixture in a 0.1-mL volume under inhalation anesthesia. The rats serving as controls can be injected with 0.1 mL of saline. Pain and other disease development parameters can be measured in the CFA- or saline-treated rats just before inoculation and up to 28 days post-inoculation. The measurement for pain parameters can be conducted for both mechanical and thermal (hot or cold) endpoints. The measurement of mechanical allodynia can be performed using the von Frey hairs (Semmes-Weinstein Monofilaments, Stoelting Co., IL) wherein the rats can be habituated to wire mesh bottom cages before the start of the experiment. Static allodynia can be tested in the unrestrained rats by touching the plantar surface of the hind paw with von Frey hairs in ascending order of force (1.2, 1.5, 2.0, 3.6, 5.5, 8.5, 12, 15, 29, and 76 g) for up to 6 s or until a paw withdrawal response can be elicited. The lowest amount of force required to elicit a response can be recorded as the withdrawal threshold in log g. Thermal hyperalgesia can be assessed using the radiant heat test wherein a mobile radiant heat source can be located under a glass surface upon which the rat is placed. The beam of light can be focused on the hind paw, and the paw withdrawal latencies are defined as the time taken by the rat to remove its hind paw from the heat source. The measurement of joint hyperalgesia can be performed by a modification of the previously reported method (Rupniak N M J, et al. Pain 1997, 71: 89-97). The torso of each rat can be held from the back with the left palm, and the bending and extension (one after the other and five times in each direction) of the ankle within its limits of range of motion can be performed with the right fingers. The total number of vocalizations emitted after the manipulation (the bending and extension, five times in each direction) can be recorded for each paw (the maximum score is 10 for each paw).
The scoring of mobility can be performed by modifying the evaluation scale reported by Butler et al. (Butler S H, et al. Pain 1992 48: 73-81): score 6, walks normally; score 5, walks being protective toward the ipsilateral hind paw (touches the ipsilateral hind paw fully on the floor); score 4, walks being protective toward the ipsilateral hind paw (touches only the toe of the ipsilateral hind paw on the floor); score 3, walks being protective toward both hind paws (touches the contralateral hind paw fully on the floor); score 2, walks being protective toward both hind paws (touches only the toe of the contralateral hind paw on the floor); scorel, crawls only using the fore paws; and score 0, does not move. Paw volumes can be measured by volume displacement of electrolyte solution in a commercially available plethysmometer device. The hind paw can be immersed to the junction of the hairy skin, and the volumes can be read on a digital display. The scoring of joint stiffness can be performed as follows: the body of rats can be held from the back with the left palm, and the bending and extension (once in each direction) of the ankle within its limits of range of motion can be performed with the right fingers. It can be confirmed beforehand that there is no restriction of ankle joint movement in the bending and extension manipulations in naive rats, and the scoring can be performed according to the evaluation scale reported by Butler et al. (1992): score 2, there are restrictions of full range of movement of the ankle in both bending and extension; score 1, there is a restriction of full range of movement of the ankle in bending or extension; and score 0, no restriction. The measurements for paw volume and joint stiffness can be conducted for both hind paws.
Compounds of the formula (I) can be assessed for antihyperalgesic efficacy as follows: thirty-two rats (eight rats per dose and four doses per compound) that are be treated with the CFA and another eight rats as naive controls can be used for each drug evaluation. The analgesic effects can be evaluated on post-inoculation day 9, when mechanical allodynia, thermal hyperalgesia, joint hyperalgesia, and joint stiffness in the ipsilateral paw reach almost the maximum, although those parameters in the contralateral paw changed only slightly and the systemic disturbance shown by the change of mobility score is small. On the day before evaluation, body weight, mechanical allodynia, thermal hyperalgesia, and joint hyperalgesia can be measured for the 32 rats that are to be used for compound evaluation. The rats are allocated to four groups (8 rats per group) such that the differences in the averages of those parameters among the groups became small. All the analgesic effect evaluations and behavioral observations can be carried out by the observer who is blind to the drug treatment.
Data can be expressed as the mean+/−S.E.M. The time-course curves for mechanical allodynia, thermal hyperalgesia, joint hyperalgesia, body weight, and paw volume can be subjected to two-way repeated measures analysis of variance with post hoc t test. In experiments for evaluation of compounds of formula (I), the difference in scores between the vehicle-treated and naive control groups can be analyzed by Student's t test to confirm significant changes in the pain parameters in the ipsilateral paw. The analgesic effects can be analyzed by Dunnett's t test, and in each case the drug-treated groups can be compared with the vehicle-treated group. In each statistical analysis, the comparison can be conducted for paws on the corresponding side. P<0.05 is considered statistically significant. In this model, the centrally acting analgesics morphine and tramadol fully relieved pain, whereas the NSAIDs, indomethacin and diclofenac are partially effective, evidencing the model's clinical predictability. The analgesic effect of compounds of the formula (I) in this test would predict their clinical usefulness in treating arthritis.
Example 8
In Vivo Model for Arthritis
Inflammogen-Induced Hyperalgesia of the Knee Joint
Compounds of the formula (I) can be tested in animal models of osteoarthritis, according to previously documented and validated methods, such as those described by Sluka, et al. (Sluka K A, Westlund K N., Pain 1993, 55(3): 367-77). For example, male Sprague-Dawley rats (Harlan, Indianapolis, Ind.) weighing 225 to 350 g can be briefly anesthetized with vaporized halothane and then injected with a mixture of 3% carrageenan and 3% kaolin (100 μL in 0.9% sterile saline) into the joint cavity of one knee. After the injection, the animals can be returned to their cages until the time of testing. For behavioral testing animals can be placed in individual clear plastic cages on top of an elevated wire mesh surface that restricted movement. The animals should be allowed to acclimate for approximately 1 hour before testing. Von Frey filaments, as described above, can then be used to test for enhanced responses to mechanical stimuli. The filaments can be successively applied through the wire mesh perpendicularly to the plantar surface in between the pads of the third and fourth phalanges. The response threshold to mechanical stimuli can be determined before inflammation of the knee joint; 4 hours after inflammation to confirm the development of hyperalgesia; immediately after the administration of test compound such as those of Formula (I), i.e., 5 hours after inflammation; and at 8, 12, and 24 hours after inflammation.
The Kruskal-Wallis test, a nonparametric test, can be used to analyze the effects for frequency, intensity, and group for response to mechanical stimuli at baseline, 4 hours after inflammation, and after compound treatment (5 hours, 8 hours, 12 hours, and 24 hours after inflammation). Further post hoc testing between groups can be executed by using the Mann-Whitney signed rank test. The data can be presented as median with 25th and 75th percentiles. Significance is P≧0.05.
Additionally, the gait of the animal or other pain-related behavior can be scored as the dependent measure of the painful effect of the arthritis on the animal's activity (Hallas B, Lehman S, Bosak A, et al., J Am Osteopath Assoc 1997, 97(4): 207-14). The effect of test drug on the animal's normal behavior can be quantified from zero, meaning no response, to three for incapacitating impairment. Effective analgesic treatment includes the clinically used indomethacin (Motta A F, et al., Life Sci 2003, 73(15): 1995-2004). Thus the benefit of compounds of the formula (I) in this model would predict their clinical relevance.
Example 9
Sarcoma Cell-Induced Models of Bone Cancer Pain
Compounds of the formula (I) can be tested in animal models of bone cancer pain, according to previously documented and validated methods, such as those described in the scientific literature (E1 Mouedden M, Meert T F., Pharmacol Biochem Behav, 2005, 82(1): 109-19; Ghilardi J R, et al., J Neurosci 2005, 25(12): 3126-31). In preparation for cell inoculation and tumor induction, osteolytic murine sarcoma cells (NCTC 2472, American Type Culture Collection (ATCC), Rockville, Md., USA) can be cultured in NCTC 135 medium (Invitrogen) containing 10% horse serum (Gibco) and passaged 2 times weekly according to ATCC guidelines. For their administration, cells can be detached by scraping and then centrifuged at 1000×g. The pellet can be suspended in fresh NCTC 135 medium (2.5×106 cells/20 μL) and then used for intramedullary femur inoculation. Male C3H/HeNCrI mice (25-30 g, Charles River Labs) can be used in such experiments. After induction of general anesthesia with xylazine (10 mg/kg i.p.) and ketamine (100 mg/kg i.p.) the left hind paw can be shaved and disinfected with povidone—iodine followed by 70% ethanol. A superficial incision of 1 cm can then be made over the knee overlaying the patella. The patellar ligament can then be cut, exposing the condyles of the distal femur. A 23-gauge needle can be inserted at the level of the intercondylar notch and the intramedullary canal of the femur to create a cavity for injection of the cells. Twenty microliters of media (sham animals) or media containing tumor cells (approximately 2.5×106 cells) can then be injected into the bone cavity using a syringe. To prevent leakage of cells outside the bone, the injection site can be sealed with dental acrylic and the wound closed with skin stitches.
Pain behaviors can be evaluated in separate groups (n=6) of sham and bone tumor mice with confirmed hyperalgesia as assessed by spontaneous lifting behavior. Animals can be behaviorally tested during a 3-week period prior to and after tumor inoculation. Body weight of the mice can be recorded throughout the experimental period to help monitor general health status. To measure the spontaneous lifting, the animals can be habituated in a transparent acrylic cylinder of 20 cm diameter put on an horizontal surface and thereafter observed during 4 min for spontaneous lifting behavior of the left hind paw. After spontaneous lifting behavior assessment, animals can be immediately placed on a mouse rotarod (e.g. ENV-575M Med Associates Inc., GA, USA) at a speed of 16 rpm for 2 min wherein limb-use during forced ambulation is scored: 4=normal; 3=limping; 2=partial non-use of left hind paw; 1=substantial non-use of left hind paw; 0=non-use of left hind paw. Assessment of cold allodynia may be made by exposing the ipsilateral hind paw of the mouse to 5 repeated applications of acetone (20 μL) and quantifying the lift/licking frequency and/or duration. Post-mortem evaluation of bone destruction can be assessed by ACT processing followed by scanning using a system such as the Skyscan 1076 microtomograph system for small animal imaging (Skyscan 1076\, Skyscan, Aartselaar, Belgium). Measured histomorphometry parameters of bone destruction can be subsequently correlated with behavioral endpoints.
The antihyperalgesic, antiallodynic and disease modifying effects of compounds of the formula (I) can be tested in this murine model of bone cancer pain in separate groups (n=6 per dose group). Animals with confirmed hyperalgesia, as assessed by spontaneous or acetone-evoked lifting, can be behaviorally tested, for example, on days 15 and 22 after distal femur tumor inoculation before and 1 h after systemic administration of vehicle (e.g. 10% Solutol in sterile water) or compounds of the formula (I). The statistical analysis can be performed by one-way ANOVA to compare behavioral measurements and bone parameters among the experimental groups. To compare behavioral measurements and bone parameters between sham and tumor-bearing animals, a Mann-Whitney U test can be used. Results are considered statistically significant at P<0.05 (two-tailed). Data are expressed as mean+/−S.E.M.
Bone cancer causes intense pain in humans, mimicked in animal models of bone cancer pain in rodents such as that described above. Analgesic treatments that are effective in this model include COX-2 inhibitors (Sabino Mass., Ghilardi J R, Jongen J L, et al., Cancer Res 2002, 62(24): 7343-9) and high doses of morphine (Luger N M, et al., Pain. 2002, 99(3): 397-406), agents used clinically for pain relief in patients experiencing bone cancer pain. Because this model so closely mimics the human disease state, the finding that cold allodynia is a prominent symptom (Lee, Seong, et al., Yonsei Med J 2005, 46(2): 252-9) strongly supports the concept that TRPM8 antagonists of the present invention will provide relief of pain associated with human bone cancer.
Example 10
Respiratory Irritant-Induced Models of Cough
Compounds of the formula (I) can be tested in animal models of antitussive activity, according to previously documented and validated methods, such as those described by: Tanaka, M. and Maruyama, K. J. Pharmacol. Sci. 2005, 99(1), 77-82; Trevisani, M., et al., Throax 2004, 59(9), 769-72; and Hall, E., et al., J. Med. Microbiol. 1999, 48: 95-98. Testing is conducted in transparent ventilated chambers with a constant airflow of 400 mL/min. The tussive agent (citric acid 0.25 M or capsaicin 30 mM) can be nebulised via a miniultrasonic nebuliser with an output of 0.4 mL/min. The appearance of cough can be detected by means of a tie clip microphone and confirmed by the characteristic posture of the animal. The cough sounds can be recorded and digitally stored. A blinded observer subsequently counts the number of elicited cough efforts. In some cases, animals can be sensitized by pre-exposure to certain agents such as ovalbumin. A test compound can be administered to at the peak of irritant-induced cough to evaluate the antitussive effects of the compound. In addition, prophylactic or multiple dosing regimes can be utilized to evaluate the test compound for modulation of the onset and duration of irritant-induced cough. Variations of these tests predict the antitussive effects of effective clinical agents, including NMDA antagonists such as dextrorphan and dextromethorphan, opioids such as codeine, beta 2 agonists such as salbutamol and antimuscarinics such as ipratropium (Bolser, D. C., et al., Eur. J. Pharmacol. 1995, 277(2-3), 159-64; Braga, P. C. Drugs Exper. Clin. Res. 1994, 20, 199-203). The antitussive action of menthol in both guinea pig and humans Eccles R., Curr Allergy Asthma Rep 2003, 3(3): 210-4; Laude E A, et al. Pulm Pharmacol. 1994, 7(3): 179-84; Morice A H, et al., Thorax 1994, 49(10): 1024-6) is predictive of the clinical utility of compounds of the formula (I) as antitussive agents.
Example 11
Chemical Irritant-Induced Models of Itch, Contact Dermatitis, Eczema and Other Manifestations of Dermal Allergy, Hypersensitivity and/or Inflammation
Compounds of the formula (I) can be tested in animal models of contact dermatitis or itch, according to previously documented and validated methods, such as those described in the scientific literature (Saint-Mezard, P., et al., Eur J. Dermatol. 2004, 14(5): 284-95; Thomsen, J. S., et al., J. Exp Dermatol. 2002, 11(4): 370-5; Weisshaar, E., et al., Arch Dermatol Res 1998, 290(6): 306-11; Wille J J, et al. Skin Pharmacol Appl Skin Physiol. 1999, 12(1-2): 18-27). Mice (or species such as guinea pig or rat) can be sensitized with 25 mL of 0.5% dinitrofluorobenzene solution (DNFB diluted 4:1 in acetone:olive oil immediately before application or other haptens, such as 12-myristate-13 acetate, picryl chloride, oxazolone, capsaicin, arachidonic acid, lactic acid, trans-retinoic acid or sodium lauryl sulfate) painted to the shaved dorsal skin or untreated (controls). Five days later, 10 mL of 0.2% DNFB a nonirritant dose) can be applied onto both sides of the right ear and the same amount of solvent alone onto the left ear. Ear thickness can be monitored daily using a caliper. Compounds of the formula (I) can be administered at the peak of inflammation to evaluate the anti-allergy activity of compounds. In addition, prophylactic or multiple dosing regimes can be utilized to evaluate the test compound for modulation of the onset and duration of anti-allergy activity. Variations of these tests can predict the anti-allergy and itch activity of effective clinical agents. The ability of these models to predict the therapeutic effect of compounds in human dermal conditions is supported by the cross-species ability of serotonin to induce itch (Weisshaar E, Gollnick H., Skin Therapy Lett 2000, 5(5): 1-2,5). Additionally, the contact sensitizing property of commercially important drugs and the ability of ion channel modulators to prevent and treat skin sensitization in these models (Kydonieus A, et al., Proceedings of the International Symposium on Controlled Release of Bioactive Materials 24th:23-24, 1997) demonstrate the therapeutic utility of compounds of the formula (I) in dermal sensitization.
Example 12
Chemical Irritant-Induced Models of Rhinitis and Other Manifestations of Nasal Hypersensitivity and/or Inflammation
Compounds of the formula (I) can be tested in animal models of rhinitis, according to previously documented and validated methods, such as those described in the scientific literature (Hirayama Y, et al., Eur J. Pharmacol. 2003, 467(1-3): 197-203; Magyar T, et al. Vaccine 2002, 20(13-14): 1797-802; Tiniakov R L, et al., J Appl Physiol 2003, 94(5): 1821-8). Testing can be conducted in mouse, guinea pig, dog or human in response to intranasal challenge with one or more irritants such as cold air, capsaicin, bradykinin, histamine, pollens, dextran sulfate, 2,4-tolylene diisocyanate, Bordetella bronchiseptica, Pasteurella multodica or acetic acid. In some cases, animals can be sensitized by pre-exposure to certain agents including, but not limited to, ragweed or ovalbumin. Prior to or following irritant administration, the test subject can receive, respectively, the prophylactic or therapeutic administration one or more times of compounds of the formula (I), or vehicle control, by the enteral or parenteral route. Significant differences indicative of nasal rhinitis or sensitization for the test compound-treated subjects compared with vehicle-treated subjects can be taken as evidence of anti-rhinitis activity. Independent variables include dose, frequency and route of administration, time interval between prophylactic or therapeutic test compound administration and irritant challenge as well as sex and non-sex genotype of the test subject. The intimate role of neurogenic inflammation in these hypersensitivity states demonstrates that compounds of the formula (I) desensitize or block the sensitization underlying these disease states.
Example 13
Conflict-Induced Models of Anxiety, Panic Disorder and Other Non-Adaptive Stressful or Phobic Responses
Compounds of the formula (I) can be tested in animal models of anxiety, panic disorders and other non-adaptive responses, according to previously documented and validated methods, such as those described by Cryan and Holmes (Cryan J F, Holmes A., Nat Rev Drug Discov 2005, 4(9): 775-90) or Braw et. al. (Y. Braw, et al., Behavioural Brain Research 2006, 167: 261-269). Specifically, for studies in rats, the following apparati may be utilized: an open-field arena (62 cm×62 cm) enclosed by opaque walls (30 cm high) and plus-maze consists of two open arms, 50 cm×10 cm, and two enclosed arms, 50 cm×10 cm×40 cm with an open roof, arranged such that the two arms of each type are opposite each other. The maze is elevated to a height of 70 cm. The walls of the enclosed arms are made from black Plexiglas, while the floors from white Plexiglas. Videotape recordings can be analyzed using the ‘Observer’ system (Noldus Information Technology). A subject rat can be removed from its home cage, weighed and placed gently in the center of the open-field arena. The rat can be allowed to explore the open-field freely while its behavior is videotaped for 5 min. Afterwards, it can be transferred to the plus-maze and placed at the center, facing a closed arm. The rat's behavior can again be videotaped for 5 min, after which it can be returned to its home cage. The apparatus can cleaned using a 70% ethanol solution between rats.
Open-field and plus-maze measures can be grouped into two behavioral classes, namely ‘anxiety-like behaviors’ and ‘activity’. Open-field behavioral measures may include 1) Anxiety measures: % time in center square, % number of entries to center square (from total squares entered), % time freezing, latency to first freezing (freezing is scored when the subject is in an immobile state for at least 3 seconds; and 2) Activity measures: Total squares entered, number of rearings (standing on two hind legs), latency for first rearing. Plus-maze measures may include 1) Anxiety: % time in open arms, % number of entries to open arms (from total entries), number of unprotected head dips, latency to enter open arm; and 2) Activity: Total entries to all arms. Anxiety-like behaviors and activity can be analyzed by one-way ANOVA's on each of the measures, for each the between-subject comparisons. Plus-maze analyses can be conducted in a similar fashion.
Testing may also be conducted in mouse or rat in this fashion in order to measure avoidance of other aversive environmental stimuli such as Geller or Vogel anticonflict tests, the light/dark test and the hole-board test (see Cryan J F, Holmes A., Nat Rev Drug Discov 2005, 4(9): 775-90). Prior to environmental exposure, the test subject can receive the prophylactic administration one or more times of compounds of the formula (I), or vehicle control (e.g. 10% Solutol in sterile water), by the enteral or parenteral route. The cumulative time or number of times spent engaged in the aversive behavior can be measured. Significant differences in one or more of these measures for the test compound-treated subjects compared with vehicle-treated subjects can be taken as evidence of anxiolytic activity. Because these models are pharmacologically validated by the effectiveness of clinically useful anxiolytics (Cryan J F, Holmes A., Nat Rev Drug Discov 2005, 4(9): 775-90), they will be useful for the detection of anxiolytic compounds of the formula (I).
Example 14
Bladder Pressure- and Hypertrophy-Induced Models of Urinary Incontinence
Compounds of the formula (I) can be tested in animal models of urinary incontinence according to previously documented and validated methods, such as those described by in the scientific literature (Kaiser S, Plath T, (Metagen Pharmaceuticals GmbH, Germany). 2003 DE patent no. 10215321; McMurray G, et al., Br J Pharmacol 2006, 147 Suppl 2: S62-79). TRPM8 is expressed in human prostate, testicle, seminiferous tubules, scrotal skin and inflamed bladder (Stein R J, et al., J Urol., 2004, 172(3): 1175-8); (Stein R J, et al., J Urol., 2004, 172(3): 1175-8; Mukerji, et al., BMC Urology 2006, 6:6). Excitation of TRPM8 receptors through cooling or application of menthol causes contraction in the bladder and a decrease in micturation threshold volume (Tsukimi Y, Mizuyachi K, et al., Urology. 2005, 65(2): 406-10). To assess compounds of the formula (I) for potential urinary incontinence activity, Sprague-Dawley rats are surgically implanted with bladder catheters allowing for the delivery of fluid (typically saline) and the monitoring of pressure (using a pressure transducer). Cystometry recordings can be monitored with a polygraph to evaluate voiding interval, threshold pressure, bladder capacity, bladder compliance, and the number of spontaneous bladder contractions. For example, the bladder catheter can be connected to a Harvard infusion pump, and bladders perfused overnight with saline at 2 mL/h. The next morning the bladder catheter can be attached (using a “T” connector) to a Statham pressure transducer (Model P23 Db) and to a Harvard infusion pump. A plastic beaker attached to a force displacement transducer (Grass FTO3) can be placed under the rat's cage to collect and record urine volume. The cystometric evaluation of bladder function can be started by infusing saline (20 mL/h) and after the first micturition the infusion is maintained for 20 min. Two hours after the first cystometry period, the rats can be dosed orally with compounds of the formula (I) and a second cystometry is performed between 30 min and 4 h after administration of test compound. The appropriate vehicle (e.g. 10% Solutol in sterile water) can be similarly administered to groups of rats that served as controls and the cystometry can be performed at the same respective time points.
Compounds of the formula (I) can also be evaluated under conditions of bladder hypertrophy and instability. Under anesthesia, a silk ligature is tied around the proximal urethra of rodents producing a partial outlet obstruction and subsequent hypertrophied bladder development within 6-9 weeks (Woods M. et al., J. Urology. 2001, 166:1142-47). Cystometry recordings can then be evaluated as described above. Such preclinical procedures are sensitive to compounds having clinical utility for the treatment of urinary incontinence (Soulard C, et al., J Pharmacol Exp Ther 1992, 260(3): 1152-8), and the activity of compounds of the formula (I) in this model would be predictive of clinical utility.
Example 15
In Vivo Model for Cold-Enhanced Central Pain States
Injury to the brain or spinal cord, such as that caused by trauma, interrupted blood flow and neurodegenerative diseases, often precipitates a central pain condition. Examples of such injuries characterized, in part by, a hypersensitivity to cold stimuli include multiple sclerosis (Morin C, et al., Clin J Pain, 2002, 18(3): 191-5; Svendsen K B, et al., Pain. 2005, 114(3): 473-81), stroke or cerebral ischemia (Greenspan J D, et al., Pain. 2004, 109(3): 357-66) and spinal cord injury (Defrin R, Ohry A, Blumen N, Urca G., Pain 2001, 89(2-3): 253-63; Defrin R, et al., Brain 2002, 125(Pt 3): 501-10; Finnerup N B, et al., Anesthesiology 2005, 102(5): 1023-30). Each of these conditions may be readily modeled in animals for assessment of the ability of compounds of the formula (I) to mollify the hypersensitive state. For example, a spinal cord injury (SCI) can be performed in adult Sprague-Dawley rats having a body weight of 150-200 g at time of surgery (Erichsen, et al., Pain 2005, 116: 347-358). The rats can be anaesthetized with chloral hydrate (300 mg/kg, i.p., Sigma, USA) and a catheter can be inserted into the jugular vein. A midline skin incision can then be made along the back to expose the T11-L2 vertebrae. The animals can be positioned beneath a tunable argon ion laser (Innova model 70, Coherent Laser Products Division, CA, USA) operating at a wavelength of 514 nm with an average power of 0.17 W. The laser light can be focused into a thin beam covering the single T13 vertebra, which can be irradiated for 10 min. Immediately before the irradiation, erythrosin B (Aldrich, 32.5 mg/kg dissolved in 0.9% saline) can be injected intravenously via the jugular catheter. Due to rapid metabolism of erythrosin B, the injection can be repeated after 5 min in order to maintain adequate blood concentrations. During irradiation, the body core temperature can be maintained at 37-38° C. by a heating pad. After irradiation the wound can be closed in layers and the skin sutured together.
SCI rats can be routinely tested for the presence of pain-like behaviors from 3-4 weeks after surgery. The fur of the animals can be shaved at least a day prior to examination of the cutaneous pain threshold to avoid sensitization of the skin receptors. During testing, the rats can be gently held in a standing position by the experimenter and the flank area and hindlimbs can be examined for hypersensitivity to sensory stimulation. On the day of drug testing, SCI rats can be administered drug according to the experimental schedule and the time course of pain-like behaviors can be measured. To test for the presence of cold allodynia, ethyl chloride or acetone can be sprayed onto the skin of the animals, often that which has been previously determined to be sensitive to mechanical stimulation by von Fry filament testing. The subsequent response to cold stimulation can be observed and classified according to the following scale: 0, no visible response; 1, localized response (skin twitch) without vocalization; 2, transient vocalization; 3, sustained vocalization. Kruskal Wallis ANOVA on ranks can be used to analyze the overall effects of non-parametric data obtained in response to cold stimulation following pretreatment with either compounds of the formula (I) or vehicle.
Example 16
In Vivo Model for Post-Anesthetic Shivering
Spontaneous post-anesthetic tremor that resembles shivering is common during recovery from anesthesia. Risks to postoperative patients include an increase in metabolic rate of up to 400%, hypoxemia, wound dehiscence, dental damage, and disruption of delicate surgical repairs. The etiology of spontaneous post-anesthetic tremor is most commonly attributed to normal thermoregulatory shivering in response to intraoperative hypothermia. In most operating and recovery rooms, shivering is controlled by the use of humidifiers, warming blankets, and inhalation of humidified heated oxygen. However, pharmacological control is an effective alternate treatment modality (Bhatnagar S, et al., Anaesth Intensive Care 2001, 29(2):149-54; Tsai Y C, Chu K S. Anesth Analg 2001, 93(5):1288-92). Compounds of the formula (I) may be assessed for their ability to mitigate post-ansethetic induced-shaking by using animal models such as that described by Nikki et al (Nikki P, Tammisto T. Acta Anaesthesiol Scand 1968, 12(3):125-34 and Grahn (Grahn, D A, et al. J Applied Physiology 1996, 81:2547-2554). For example, Wistar rats (males, weighing 250-450 g;) may be surgically implanted with an EEG/EMG recording array to assess post anesthetic tremor activity. The EEG electrodes are located bilaterally 2 mm off midline and adjacent to bregma and lamda. Following a one-week recovery period, frontal-occipital EEG, raw EMG, and integrated EMG activities, as well as three temperatures (skin, rectal, and water blanket temperatures during anesthesia), and ambient temperature post-anesthesia can be monitored throughout the experiment using copper-constantin thermocouples. The EEG and EMG signals can be recorded on polygraph paper (5 mm/s, Grass model 7E polygraph) and, during recovery from anesthesia, the EEG is computer scored in 10 second epochs as either synchronized: high amplitude (0.100 pV), low frequency (1-4 Hz dominated) activity characteristic of slow-wave sleep (SWS-like) or desynchronized: low amplitude (75 pV), high frequency (5-15 Hz dominated), characteristic of waking and rapid-eye-movement sleep (W-like). The EMG activity can be quantified as the averaged summed voltage/time interval by processing the raw EMG signal through an integrator (Grass model 7P3, 0.5 s time constant). On the day of an experiment, the animal can be placed in a small acrylic box (15×15×15 cm) and exposed to a halothane vapor-air mixture (4% halothane). Immediately after the induction of anesthesia, the animal can be removed from the enclosure and subsequently anesthetized through a nose cone. Following cessation of anesthesia, two stages of recovery can be judged: emergence from anesthesia and restoration of behavioral activity (behavioral recovery). Emergence from anesthesia may be defined as an increase in tonic EMG activity and a change in the EEG from a SWS-like pattern to a W-like pattern. Behaviorally, recovery has occurred when the animal rises from a prone position and initiated coordinated movements. The time intervals from termination of anesthesia to emergence and behavioral recovery can be measured in all animals. Time interval data can be subjected to a repeated measure analysis of variance, and the Scheffe's method can be employed for testing differences between pairs of means.
Example 17
TRPM8 Patch Clamp Assays
For patch clamp experiments, HEK293 cells are stably transfected with canine TRPM8 and cultured in DMEM supplemented with 10% fetal bovine serum, 100 units/ml penicillin, 100 μg/ml streptomycin and 1 mg/ml G418. Cells are maintained at 37° C. and in 5% CO2.
The extracellular solution contains (in mM): NaCl, 132; EGTA, 1; KCl, 5.4; MgCl2, 0.8; HEPES, 10; glucose, 10; pH=7.4. Recordings are performed using the conventional whole-cell patch clamp technique, 1-2 days after plating cells onto glass coverslips at densities appropriate for single cell recording. Currents are amplified by a patch clamp amplifier and filtered at 2 kHz (Axopatch 200B, Molecular Devices, Union City, Calif.). Menthol (100 μM) is applied to the cell at 0.5 ml/min via a gravity-fed perfusion system. Recordings involving menthol activation are performed at 22° C.
In experiments where temperatures are varied, temperature ramps are generated by cooling the perfusate in an in-line cooler (Model SC-20, Warner Instruments, Hamden, Conn.) controlled by a temperature controller (Model CL-100, Warner Instruments). The temperature in the vicinity of the recorded cell is measured with a custom-made miniature thermo-microprobe connected to a monitoring thermometer (Model TH-8, Physitemp, Clifton, N.J.), and sampled using Digidata 1322A and pClamp 9.0 (Molecular Devices), as are the currents concurrently measured in the whole-cell patch clamp mode. The current is continuously sampled (at 100 Hz) at a holding potential of −60 mV.
Compounds of the formula (I) are diluted from 10 mM DMSO stocks (stored at −20° C.) into an extracellular solution either containing 100 μM menthol or subjected to cooling. Increasing concentrations of a compound are applied to a cell in a cumulative manner and concentration-dependent responses are measured after steady-state activation is achieved by either 100 μM menthol or cooling to 10° C. A saturating concentration of a reference antagonist is applied at the end of an experiment (either in the presence of 100 μM menthol or 10° C. temperature) to establish the baseline from which all the other measurements are subtracted.
Percentage inhibition by a compound is calculated as follows: 100×(1−Icomp/I0); where Icomp and I0 are steady-state current amplitudes in either the presence or absence of a concentration of compounds of the formula (I). Concentration-response data are fitted to a logistic function as follows: R=100/(1+c/IC50)p; where, R is the percentage inhibition, p is the Hill coefficient and c is the concentration of compounds of the formula (I).
Example 18
In Vitro Rat and Human TRPM8 Functional Assay
For functional expression of TRPM8, the full-length cDNAs encoding human and rat TRPM8 are subcloned into pCI-NEO mammalian expression vectors. The expression constructs are transiently transfected into HEK293 cells according to the FuGENE 6 transfection Reagent® (ROCHE) instructions. HEK293 cells are routinely grown as monolayers in Dulbecco's minimum essential medium supplemented with 10% FBS, 1 mM L-glutamine, 100 units/mL penicillin and 100 ug/mL streptomycin. Cells are maintained in 5% CO2 at 37° C. Within twenty-four hours, transiently transfected human and rat TRPM8 are seeded into clear-base poly-D-lysine coated 384-well plates (BD Biosciences, NJ, USA) at a density of 10,000 cells per well in culture medium and grown overnight. The following day, all medium is removed and the cells are incubated with 524 of 0.5× calcium 3 dye (Molecular Devices) prepared in complete assay buffer containing 20 mM HEPES, 0.1% BSA, and 2.5 mM probenecid at 37° C. for thirty five minutes. The cells are then incubated for an additional fifteen minutes at room temperature before initiating experiments. Following incubation, plates are inserted into a FDSS instrument, where cells were challenged with compounds of the formula (I) (at varying concentrations) and intracellular Ca2+ are measured for 5 min prior to the addition of 100 nM icilin. IC50 values for compounds of compounds of the formula (I) are determined from eight-point dose-response studies
Maximal fluorescence intensity (FI) achieved upon addition of icilin is exported from the FDSS and further analyzed using GraphPad Prism 3.02 (Graph Pad Software Inc., CA, U.S.A.). Basal FI is subtracted prior to normalizing data to percent of maximal response. The dose response curves from the average of quadruplicate wells for each data point are analyzed by using nonlinear regression of either sigmoidal dose response or sigmoidal dose response (variable slope). Finally, the IC50 values are calculated with the best-fit dose curve determined by Prism.
Example 19
Cold-Evoked Cardiovascular Pressor Responses
Compounds of the formula (I) can be tested in animals and humans for their ability to mitigate cardiovascular pressor responses evoked by cold exposure. Seasonal environmental cooling is directly associated with elevated blood pressure and an increased incidence of coronary events in human populations worldwide (Barnett, A G et al. J Epidemiol Community Heath. 2005, 59:551-557). The clinical cold pressor test assesses changes in blood pressure (BP) and cold pain perception during a 2-3 minute immersion of one hand into ice water. This test may be utilized to characterize analgesic compounds (Koltzenberg Metal Pain. 2006, 126(1-3): 165-74) and to assess cold hypersensitivity (Desmeules J A et al., Arthritis Rheum. 2003, 48(5):1420-9). Compounds of the formula (I) can be studied in an anesthetized rat cold pressor paradigm to determine whether TRPM8 antagonism would interfere with the blood pressure pressor response to cold stimulation of the forepaws. Male Sprague-Dawley rats (300-450 g) anesthetized with sodium pentobarbital are instrumented with a jugular catheter and an indwelling carotid artery pressure transducer. Vehicle (10% Solutol in water) or test compound is infused (1 mL/kg) over one minute through the intravenous catheter. Ten minutes later both forelimbs are packed in crushed ice for 5 minutes. Percent changes in mean arterial pressure in response to this cold stimulus are calculated for vehicle and test compound pretreatments. Percent inhibition attributed to treatment with test compound is then determined using the following formula: % Inhibition=[1−(cold evoked % change in BP post-test compound/cold evoked % change in BP post-vehicle)]×100.
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

## Claims

1. A method for treating inflammatory pain, inflammatory hypersensitivity condition, neuropathic pain or anxiety in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of Formula (I)



wherein
A is phenyl, thienyl, or C5-7cycloalkyl; or, when A is phenyl, L is —(CH2)mN(R4)(CH2)n—, and R1 and L are attached at adjacent carbon atoms of phenyl, R1 and R4 are optionally taken with the atoms to which they are attached to form a 9 to 11-membered benzofused heterocyclyl;
R1 is one to three substituents independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, hydroxy(C1-4)alkyl, C1-4alkoxycarbonyl, fluoro, chloro, bromo, and cyano;
B is selected from the group consisting of C6-10aryl, benzothiophenyl, indolyl, furanyl, thiazolyl, isoquinolinyl, quinolinyl, pyrimidinyl, dihydrobenzofuranyl, benzothiazolyl, azabenzothiophenyl, and pyridinyl;
R2 is one to two substituents independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluoro, chloro, bromo, and cyano;
and R2 is optionally one additional substituent selected from the group consisting of C1-4alkoxycarbonyl, C1-4alkylsulfonyl, C1-4alkoxycarbonylamino, C1-4alkylaminocarbonyl, di(C1-4)alkylaminocarbonyl, trifluoromethyl, trifluoromethanesulfonyl, trifluoromethoxy, phenyl, pyrimidinyl, N-morpholinyl, piperidinyl, piperazinyl, N-methyl-piperazinyl, pyridinyl, pyrrolidinyl, imidazolyl, 1,2,3,6-tetrahydro-pyridinyl, 4-(3,6-dihydro-2H-pyridin-4-yl) optionally substituted at nitrogen with t-butoxycarbonyl, and hydroxy(C1-4)alkyl;
wherein the phenyl of R2 is optionally substituted with carboxy, C1-4alkyl, C1-4alkoxycarbonyl, halogen, tetrazole, or trifluoromethyl;
L is —(CH2)m—Z—(CH2)n— or —CH2—;
m and n are independently 0 or 1, such that the sum of m+n is no greater than 1;
and Z is O, S, or NR4; provided that when Z is O or S, A is phenyl;
R3 is hydrogen or C1-2alkyl; or, when A is phenyl and Z is NR4, R3 is optionally taken with R1 to form a tetrahydroquinolinyl;
R4 is hydrogen, C1-3alkyl, or C1-3alkylcarbonyl;
Q is




wherein
X is a direct bond or NH;
s is 1 or 2;

p is 1 or 2;
D, E, H, and J are benzo or pyrido;
W is phenyl, phenylmethyl, phenylaminomethyl, or a heteroaryl selected from the group consisting of pyridinyl, quinolinyl, isoquinolinyl, thienyl, thiazolyl, pyrimidinyl, and pyrazinyl;
wherein phenyl, phenyl of the phenylmethyl and phenylaminomethyl, and heteroaryl of W are optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, hydroxy(C1-4)alkyl, fluoro, chloro, bromo, amino, C1-4alkylamino, di(C1-4alkyl)amino, C1-4alkoxycarbonyl, C1-4alkylcarbonylamino, carboxy, and trifluoromethyl;
or, W is hydrogen, and one of R5a and R5b is phenyl;
V is hydrogen, C1-4alkyl, C1-4alkoxycarbonyl, aminocarbonyl, C1-4alkylaminocarbonyl, di(C1-4alkyl)aminocarbonyl, or hydroxymethyl;
R5a and R5b are independently hydrogen, C1-4alkyl, C1-4alkoxy, fluoro, chloro, bromo, cyano, hydroxy, C1-4alkylthio, trifluoromethylamino, C1-4alkylamino, di(C1-4alkyl)amino, carboxy, C1-4alkoxycarbonyl, C1-4alkylsulfonyl, C1-4alkoxycarbonylamino, trifluoromethanesulfonyl, trifluoromethoxy, or hydroxy(C1-4)alkyl; provided that one of R5a and R5b is hydrogen;
R6 is C1-4alkyl or phenylmethyl;
R7 is phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, fluoro, chloro, bromo, amino, C1-4alkylamino, di(C1-4alkyl)amino, C1-4alkoxycarbonyl, carboxy, and trifluoromethyl;
R8 is hydrogen, phenyl, or phenylmethyl; wherein phenyl is optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, fluoro, chloro, bromo, amino, C1-4alkylamino, di(C1-4alkyl)amino, C1-4alkoxycarbonyl, carboxy, and trifluoromethyl;
R10 is hydrogen; or, when R8 is hydrogen, R10 is phenyl or pyridinyl;
R11 is hydrogen or hydroxy;
R9, R12, R13, and R14 are independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, fluoro, chloro, bromo, cyano, hydroxy, C1-4alkylthio, and trifluoromethyl; wherein R9, R12, R13, and R14 are optionally one additional substituent independently selected from the group consisting of C1-4alkyl, phenyl, carboxy, C1-4alkoxycarbonyl, aminocarbonyl, C1-4alkylaminocarbonyl, di(C1-4alkyl)aminocarbonyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, C1-4alkylsulfonyl, C1-4alkoxycarbonylamino, trifluoromethanesulfonyl, trifluoromethoxy, and hydroxy(C1-4)alkyl;
provided that a compound of Formula (I) is other than
a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-trifluoromethyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is NH, W is phenyl, V is hydrogen, and R5a and R5b are hydrogen;
a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-t-butyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-4, X is a direct bond, D is benzo, and R9 is 5-chloro;
a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-trifluoromethyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-2, s is 1, R6 is methyl, and R7 is phenyl;
a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-t-butyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-2, s is 1, R6 is methyl, and R7 is phenyl;
a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-t-butyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is NH, W is phenyl, V is hydrogen, and R5a and R5b are hydrogen;
a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-trifluoromethyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-3, X is NH, p is 1, R8 is phenyl, and R10 and R11 are hydrogen;
a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-trifluoromethyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is NH, W is 2-methoxy-phenyl, V is hydrogen, and R5a and R5b are hydrogen;
a compound wherein A is phenyl, R1 is 2-cyano, B is phenyl, R2 is 2-chloro, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is hydrogen, and R5a and R5b are hydrogen;
a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-bromo, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-chloro, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
a compound wherein A is phenyl, R1 is 2-fluoro, B is quinolin-3-yl, R2 is hydrogen, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen;
a compound wherein A is phenyl, R1 is 3,4-difluoro, B is benzothiophen-2-yl, R2 is 3-methyl, L is —CH2—, R3 is hydrogen, Q is q-1, X is a direct bond, W is 2-chloro-phenyl, V is hydrogen, and R5 is hydrogen;
a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-trifluoromethyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is NH, W is 3-chloro-phenyl, V is hydrogen, and R5a and R5b are hydrogen;
a compound wherein A is phenyl, R1 is hydrogen, B is phenyl, R2 is 4-trifluoromethyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is NH, W is thien-2-yl, V is hydrogen, and R5a and R5b are hydrogen;
a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-chloro, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is pyridin-3-yl, V is hydrogen, and R5a and R5b are hydrogen; and
a compound wherein A is phenyl, R1 is 2-fluoro, B is phenyl, R2 is 4-(2-carboxy)-phenyl, L is —(CH2)m—Z—(CH2)n—, m and n are 0, Z is NR4, R3 is hydrogen, R4 is hydrogen, Q is q-1, X is a direct bond, W is 2-fluoro-phenyl, V is hydrogen, and R5a and R5b are hydrogen;
and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

2. The method of claim 1 wherein the inflammatory pain is due to inflammatory bowel disease, visceral pain, migraine, post operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor, musculoskeletal diseases, skin diseases, toothache, pyresis, burn, sunburn, snake bite, venomous snake bite, spider bite, insect sting, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome, menstrual pain, endometriosis, sinus headache, tension headache, or arachnoiditis.

3. The method of claim 1 wherein the inflammatory pain is inflammatory hyperalgesia.

4. The method of claim 3 wherein the inflammatory hyperalgesia is inflammatory somatic hyperalgesia or inflammatory visceral hyperalgesia.

5. The method of claim 4 wherein the inflammatory hyperalgesia is due to inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal pain, musculoskeletal diseases, skin diseases, post operative pain, headaches, fibromyalgia, toothache, burn, sunburn, insect sting, neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, enteritis, irritable bowel syndrome, Crohn's Disease, or ulcerative colitis.

6. The method of claim 1 wherein the inflammatory hypersensitivity condition is urinary incontinence, benign prostatic hypertrophy, cough, asthma, rhinitis, nasal hypersensitivity, itch, contact dermatitis, dermal allergy, or chronic obstructive pulmonary disease.

7. The method of claim 1 wherein the neuropathic pain is due to cancer, a neurological disorder, spine or peripheral nerve surgery, a brain tumor, traumatic brain injury (TBI), spinal cord trauma, a chronic pain syndrome, fibromyalgia, chronic fatigue syndrome, a neuralgia, lupus, sarcoidosis, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, central pain, neuropathies associated with spinal cord injury, stroke, ALS, Parkinson's disease, multiple sclerosis, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, a bony fracture, oral neuropathic pain, Charcot's pain, complex regional pain syndrome I and II (CRPS I/II), radiculopathy, Guillain-barre syndrome, meralgia paresthetica, burning-mouth syndrome, 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, vulvodynia or vidian neuralgia.

8. The method of claim 7 wherein the neuralgia is trigeminal neuralgia, glossopharyngeal neuralgia, postherpetic neuralgia, or causalgia.

9. The method of claim 1 wherein the neuropathic pain is neuropathic cold allodynia.

10. The method of claim 9 wherein the neuropathic cold allodynia is pain arising from spine and peripheral nerve surgery or trauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpetic neuralgia, causalgia, peripheral neuropathy, diabetic neuropathy, central pain, stroke, peripheral neuritis, polyneuritis, complex regional pain syndrome I and II (CRPS I/II), or radiculopathy.

11. The method of claim 1 wherein the anxiety is social anxiety, post traumatic stress disorder, phobias, social phobia, special phobias, panic disorder, obsessive compulsive disorder, acute stress disorder, separation anxiety disorder, or generalized anxiety disorder.