Tetrasubstituted Benzenes

Tetrasubstituted benzenes that act as modulators of gamma secretase and their use in the treatment of one or more symptoms of treating neurodegenerative disorders, e.g., Alzheimer's disease, are described.

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Description
RELATED APPLICATION INFORMATION

This application claims priority to U.S. provisional application Ser. No. 61/015,605, filed Dec. 20, 2007, and to U.S. provisional application Ser. No. 61/109,665, filed Oct. 30, 2008, both of which are herein incorporated by reference.

BACKGROUND

Alzheimer's disease (AD) is the most prevalent form of dementia. It is a neurodegenerative disorder that is associated (though not exclusively) with aging. The disorder is clinically characterized by a progressive loss of memory, cognition, reasoning and judgment that leads to an extreme mental deterioration and ultimately death. The disorder is pathologically characterized by the deposition of extracellular plaques and the presence of neurofibrillary tangles. These plaques are considered to play an important role in the pathogenesis of the disease.

These plaques mainly comprise of fibrillar aggregates of β-amyloid peptide (Aβ), which are products of the amyloid precursor protein (APP), a 695 amino-acid protein. APP is initially processed by β-secretase forming a secreted peptide and a membrane bound C99 fragment. The C99 fragment is subsequently processed by the proteolytic activity of γ-secretase. Multiple sites of proteolysis on the C99 fragment lead to the production of a range of smaller peptides (Aβ 37-42 amino acids). N-terminal truncations can also be found e.g. Aβ (4-42, 11-42) for convenience Aβ40 and Aβ42 as used herein incorporates these N-terminal truncated peptides. Upon secretion, the Aβ peptides initially form soluble aggregates which ultimately lead to the formation of insoluble deposits and plaques. Aβ42 is believed to be the most neurotoxic, the shorter peptides have less propensity to aggregate and form plaques. The Aβ plaques in the brain are also associated with cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, multi infarct dementia, dementia pugilistisca, inclusion body myositis and Down's Syndrome.

γ-secretase is an association of four proteins: Aph1, Nicastrin, Presenillin and Pen-2 (review De Strooper 2003, Neuron 38, 9). Aβ42 is selectively increased in patients carrying particular mutations in one of these components, presenilin. These mutations are correlated with early onset a familial AD. Inhibition of γ-secretase resulting in the lowering of Aβ42 is a desirable activity for the pharmaceutical community and numerous inhibitors have been found, e.g., Thompson et at (Bio. Org. and Med. Chem. Letters 2006, 16, 2357-63), Shaw et al (Bio. Org. and Med. Chem. Letters 2006, 17, 511-16) and Asberom et al (Bio. Org. and Med. Chem. Letters 2007, 15, 2219-2223). Inhibition of γ-secretase though is not without side-effects, some of which are due to the γ-secretase complex processing substrates other than C99, for e.g. Notch. A more desirable approach is to modulate the proteolytic activity of the γ-secretase complex in a manner that lowers Aβ42 in favor of shorter peptides without significantly affecting the activity of γ-secretase on substrates such as Notch.

Compounds that have shown modulation of γ-secretase include certain non-steroidal, anti-inflammatory drugs (NSAIDs), for example Flurbiprofen, (Stock et al Bio. Org. and Med. Chem. Letters 2006, 16, 2219-2223). Other publications that disclose agents said to reduce Aβ42 through the modulation of γ-secretase include: WO 04/074232, WO 05/054193, Perreto et al Journal of Medicinal Chemistry 2005, 48 5705-20, WO05/108362, WO 06/008558, WO 06/021441, WO 06/041874, WO 06/045554, WO04110350, WO 06/043964, WO 05/115990, EP1847524, WO 07/116,228, WO 07/110,667, WO 07/124,394, EP184752, EP 01849762, WO 07/125,364.

SUMMARY

Described herein are tetrasubstituted benzene compounds of formulas (I) and (II) and pharmaceutically acceptable salts thereof

Wherein:

A is CO2H or tetrazole;
R1 and R2 are independently selected from: (a) H, (b) F, (c) OH, (d) OR6, (e) SR6, (f) NHR7, (g) N(R7)2 (h) NHC(O)R6, (i) NHCO2R6, (j) (C2-C6)alkyl, (k) (C0-C3)alkyl-(C3-C7)cycloalkyl, (l) C1-C6 alkyl that is independently interrupted by one or more —O—, —S—, —S(O)—, or —S(O)2— groups, (m) (C3-C7)cycloalkyl, (n) (C0-C3)alkyl-(C3-C7)cycloalkyl, (o) heterocycloalkylalky and (p) (CH2)nQ wherein n=0-2 and wherein Q is a mono- or bicyclic aromatic or heteroaromatic ring system having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, and wherein Q is optionally independently substituted with up to 3 groups selected from alkyl, halogen, CF3, OH, OCF3, alkoxy, OCH2CH2OCH3, NH2, alkylamino, dialkylamino, morpholino, CN, NO2, alkylthio and alkylsulfonyl,

and wherein each alkyl or cycloalkyl of R1 and R2 is optionally independently substituted with one or more halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl,

provided that both R1 and R2 are not H,

or
R1 and R2 are taken together to form a 3-7 membered cycloalkyl or heterocycloalkyl ring which is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl
or
R1 and R2 are taken together to form a 3-7 membered cycloalkyl ring substituted with R20 and R21 where R20 and R21 are taken together to form a 3-7 membered cycloalkyl ring wherein each cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl
R6 is selected from:

(a) C1-C6 alkyl optionally and independently interrupted by one or more —O—, —S—, —S(O), or —S(O)2— groups,

(b) (C3-C7)cycloalkyl,

(c) (C0-C3)alkyl-(C3-C7)cycloalkyl, (d) heterocycloalkylalky and

(e) (CH2)nQ wherein n=0-2 and wherein Q is a mono- or bicyclic aromatic or heteroaromatic ring system having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, and wherein Q is optionally independently substituted with up to 3 groups selected from alkyl, halogen, CF3, OH, OCF3, alkoxy, OCH2CH2OCH3, NH2, alkylamino, dialkylamino, morpholino, CN, NO2, alkylthio and alkylsulfonyl;

R7 is independently chosen from alkyl, alkoxyethyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl or (CH2)nQ, wherein n=0-2 and wherein Q is a mono or bicyclic aromatic or heteroaromatic ring system having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C and wherein Q is optionally substituted with up to 3 groups independently selected from alkyl, halogen, CF3, OH, OCF3, alkoxy, OCH2CH2OCH3, NH2, alkylamino, dialkylamino, morpholino, CN, NO2, alkylthio, alkylsulfonyl; or in the case when two R7 are attached to the same N and are both alkyl, they can be taken together to form a 5-membered or 6-membered ring optionally containing O, S, N(H) or N-alkyl;
X is a bond or a divalent linking group selected from —O—, —OCH2—, —OCH(R7)—, —OCH2CH2—, —CH2—, —C(O)—, —CH═CH—, —CH2CH2—, —CH2O—, —CH2OCH2—, —CH2CH2O—, —S—, —SCH2—, CH2S—, —CH2SCH2—, —C(O)NH—, —C(O)N(R7)—, —NHC(O)—, —N(R7)C(O)—, —S(O)—, —S(O2)—, —S(O)2N(H)—, —S(O)2N(R7)—, —N(H)S(O)2—, —N(R7)S(O)2— wherein the point of attachment of divalent linking groups, X, to R3 in the Formulas I and II is to the right;
Y is a bond or a divalent linking group selected from —O—, —OCH2—, —OCH(R7), —OCH2CH2—, —CH2—, —C(O)—, —CH═CH—, —CH2CH2—, —CH2O—, —CH2OCH2—, —CH2CH2O—, —S—, —SCH2—, CH2S—, —CH2SCH2—, —C(O)NH—, —C(O)N(R7)—, —NHC(O)—, —N(R7)C(O)—, —S(O)—, —S(O2)—, —S(O)2N(H)—, —S(O)2N(R7)—, —N(H)S(O)2—, —N(R7)S(O)2— wherein the point of attachment of divalent linking groups, Y, to R4 in the Formulas I and II is to the right;
R3 is (a) C1-C7 alkyl optionally and independently interrupted by one or more —O—, —S—, —S(O)—, and —S(O)2— groups,

(b) (C0-C3)alkyl-(C3-C7)cycloalkyl,

(c) heterocycloalkylalkyl, or

(d) a group Z, wherein Z is a mono- or bi-cyclic ring system having 3 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from halogen, R6, CF3, CN, NO2, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(O)R6, OC(O)OR6, OC(O)NHR7, OC(O)N(R7)2, SR6, S(O)R6, S(O)2R6, S(O)2NHR7, S(O)2N(R7)2, NHR7, N(R7)2, NHC(O)R6, N(R7)C(O)R6, NHC(O)OR6, N(R7)C(O)OR6, N(R7)C(O)NH(R7), N(R7)C(O)NH(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, CO2H, CO2R6, COR6. In the case where R3 is a mono- or bi-cyclic ring system having 5 to 10 ring atoms, the attachment site may be either at a carbon atom or a nitrogen atom of the mono- or bi-cyclic ring system provided that only three bonds are made to nitrogen;

R4 is a (a) C1-C7 alkyl group optionally and independently interrupted by one or more —O—, —S—, —S(O)—, or —S(O)2— groups,

(b) (C0-C3)alkyl-(C3-C7)cycloalkyl,

(c) heterocycloalkylalkyl or

(d) a group Z, wherein Z is a mono- or bi-cyclic ring system having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from halogen, R6, CF3, CN, NO2, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(O)R6, OC(O)OR6, OC(O)NHR7, OC(O)N(R7)2, SR6, S(O)R6, S(O)2R6, S(O)2NHR7, S(O)2N(R7)2, NHR7, N(R7)2, NHC(O)R6, N(R7)C(O)R6, NHC(O)OR6, N(R7)C(O)OR6, N(R7)C(O)NH(R7), N(R7)C(O)NH(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, CO2H, CO2R6, COR6. In the case where R4 is a mono- or bi-cyclic ring system having 5 to 10 ring atoms, the attachment site may be either at a carbon atom or a nitrogen atom of the mono- or bi-cyclic ring system provided that only three bonds are made to nitrogen; and

R5 is selected from: NO2, NH2, aryl, heteroaryl, F, Cl, Br, CN, OH, C1-C4 alkoxy, SR6, S(O)2R6, S(O)2N(R7)2, (C1-C4) alkyl, (C0-C3)alkyl-(C3-C7) cycloalkyl, —O—(C0-C3)alkyl-(C3-C7)cycloalkyl, and (C2-C4) alkynyl, wherein each alkyl or cycloalkyl is optionally independently substituted with one or more halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl
provided that one or both of R3 and R4 is Z.

In one embodiment R1 and R2 are taken together form a 3-7 membered cycloalkyl or heterocycloalkyl ring. In another embodiment R1 is hydrogen and R2 is F, R6, OH, OR6, SR6, NHR7, N(R7)2 NHC(O)R6, NHCO2R6 wherein R6 and R7 are as defined previously. In a further embodiment R1 is hydrogen and R2 is R6, OR6 or SR6. In an additional embodiment R1 is hydrogen and R2 is alkyl, alkoxy or thioalkyl. In another embodiment R1 is hydrogen and R2 is R6. In a further embodiment R1 is hydrogen and R2 is C1-C4 alkyl.

In one embodiment X is a bond. In another embodiment X is a divalent linking group selected from —O—, —OCH2—, —OCH(R7)—, —OCH2CH2—, —CH2—, —C(O)—, —CH═CH—, —CH2CH2—, —CH2O—, —CH2OCH2—, —CH2CH2O—, —S—, —SCH2—, CH2S—, —CH2SCH2—, —C(O)NH—, —C(O)N(R7)—, —NHC(O)—, —N(R7)C(O)—, —S(O)—, —S(O2)—, —S(O)2N(H)—, —S(O)2N(R7)—, —N(H)S(O)2—, —N(R7)S(O)2— wherein the point of attachment of divalent linking groups, X, to R3 in the Formulas I and II is to the right. In another embodiment X is —O—, —OCH2—, —OCH(R7)—, CH2O—, —S—, —S(O)2—, —S(O)2N(H)—, —S(O)2N(R7)—, —C(O)NH— or —C(O)N(R7)—. In a further embodiment X is —O—, —S(O)2—, —S(O)2N(H)— or —S(O)2N(R7)—. In another embodiment X is —O— or —S(O)2—.

In one embodiment Y is a bond. In another embodiment Y is a divalent linking group selected from —O—, —OCH2—, —OCH(R7)—, —OCH2CH2—, —CH2—, —C(O)—, —CH═CH—, —CH2CH2—, —CH2O—, —CH2OCH2—, —CH2CH2O—, —S—, —SCH2—, CH2S—, —CH2SCH2, —C(O)NH—, —C(O)N(R7)—, —NHC(O)—, —N(R7)C(O)—, —S(O)—, —S(O2)—, —S(O)2N(H)—, —S(O)2N(R7)—, —N(H)S(O)2—, —N(R7)S(O)2— wherein the point of attachment of divalent linking groups, X, to R3 in the Formulas I and II is to the right. In another embodiment Y is —O—, —OCH2—, —OCH(R7)—CH2O—, —S—, —S(O)2—, —S(O)2N(H)—, —S(O)2N(R7)—, —C(O)NH— or —C(O)N(R7)—. In a further embodiment Y is —O—, —S(O)2—, —S(O)2N(H)— or —S(O)2N(R7)—. In another embodiment Y is —O— or —S(O)2—.

In one embodiment R3 is a C1-C7 alkyl group optionally interrupted by —O—, —S—, —S(O)—, or —S(O)2— groups. In another embodiment R3 is a C1-C7 alkyl group. In a further embodiment R3 is a C1-C4 alkyl group examples include but are not limited to methyl, ethyl, cyclopropylmethyl, trifluoroethyl. In another embodiment R3 is a cycloalkylalkyl group with examples including but not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl. In another embodiment R3 is heterocycloalkylalkyl. In another embodiment R3 is a group Z as defined above wherein Z is a mono- or bi-cyclic ring system having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from halogen, R6, CF3, CN, NO2, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(O)R6, OC(O)OR6, OC(O)NHR7, OC(O)N(R7)2, SR6, S(O)R6, S(O)2R6, S(O)2NHR7, S(O)2N(R7)2, NHR7, N(R7)2, NHC(O)R6, N(R7)C(O)R6, NHC(O)OR6, N(R7)C(O)OR6, N(R7)C(O)NH(R7), N(R7)C(O)NH(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, CO2H, CO2R6, COR6. In the latter embodiment Z comprises mono- or bi-cyclic ring system ring systems that furthermore may be fully saturated, partially saturated or aromatic. Examples of monocyclic ring systems that are fully saturated include but are not limited to 5-6 membered ring systems such as cyclohexyl, cyclopentanyl, piperazinyl, tetrahydrofuranyl and piperidinyl. Examples of monocyclic ring systems that are partially saturated include but are not limited to 5-6 membered ring systems such as cyclohexenyl, cyclopentenyl, dihydrofuranyl and tetrahydropyridinyl. piperidinyl. Examples of monocyclic ring systems that are aromatic include but are not limited to 5-6 membered ring systems such as phenyl, pyridyl, pyrimidyl, pyrrazolyl, thiophene-yl, furanyl, oxadiazolyl, thiadizolyl, triazolyl, oxazolyl and thiazolyl. Examples of bicyclic ring systems that are fully saturated include but are not limited to 9-10 membered bicyclic ring systems such as decalinyl, decahydroquinolinyl and decahydroisoquinolinyl. Examples of bicyclic ring systems that are partially saturated include but are not limited to 9-10 membered bicyclic ring systems such as tetrahydronapthyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl. Examples of bicyclic ring systems that are aromatic include but are not limited to 9-10 membered bicyclic ring systems such as napthyl, indolyl, indazolyl, benzimidazolyl, benzthiadiazolyl and imidazopyridinyl. In one further embodiment the mono- or bi-cyclic ring system ring system comprises up to 2 nitrogen atoms and up to 1 sulfur or oxygen atoms.

In one embodiment R4 is a C1-C7 alkyl group optionally interrupted by —O—, —S—, —S(O)—, or —S(O)2— groups. In another embodiment R4 is a C1-C7 alkyl group. In a further embodiment R4 is a C1-C4 alkyl group examples include but are not limited to methyl, ethyl, cyclopropylmethyl, trifluoroethyl. In another embodiment R4 is a cycloalkylalkyl group with examples including but not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl. In another embodiment R4 is heterocycloalkylalkyl. In another embodiment R4 is a group Z as defined above wherein Z is a mono- or bi-cyclic ring system having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from halogen, R6, CF3, CN, NO2, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(O)R6, OC(O)OR6, OC(O)NHR7, OC(O)N(R7)2, SR6, S(O)R6, S(O)2R6, S(O)2NHR7, S(O)2N(R7)2, NHR7, N(R7)2, NHC(O)R6, N(R7)C(O)R6, NHC(O)OR6, N(R7)C(O)OR6, N(R7)C(O)NH(R7), N(R7)C(O)NH(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, CO2H, CO2R6, COR6. In the latter embodiment Z comprises mono- or bi-cyclic ring system ring systems that furthermore may be fully saturated, partially saturated or aromatic. Examples of monocyclic ring systems that are fully saturated include but are not limited to 5-6 membered ring systems such as cyclohexyl, cyclopentanyl, piperazinyl, tetrahydrofuranyl and piperidinyl. Examples of monocyclic ring systems that are partially saturated include but are not limited to 5-6 membered ring systems such as cyclohexenyl, cyclopentenyl, dihydrofuranyl and tetrahydropyridinyl. piperidinyl. Examples of monocyclic ring systems that are aromatic include but are not limited to 5-6 membered ring systems such as phenyl, pyridyl, pyrimidyl, pyrrazolyl, thiophene-yl, furanyl, oxadiazolyl, thiadizolyl, triazolyl, oxazolyl and thiazolyl. Examples of bicyclic ring systems that are fully saturated include but are not limited to 9-10 membered bicyclic ring systems such as decalinyl, decahydroquinolinyl and decahydroisoquinolinyl. Examples of bicyclic ring systems that are partially saturated include but are not limited to 9-10 membered bicyclic ring systems such as tetrahydronapthyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl. Examples of bicyclic ring systems that are aromatic include but are not limited to 9-10 membered bicyclic ring systems such as napthyl, indolyl, indazolyl, benzimidazolyl, benzthiadiazolyl and imidazopyridinyl. In one further embodiment the mono- or bi-cyclic ring system ring system comprises up to 2 nitrogen atoms and up to 1 sulfur or oxygen atoms.

Other embodiments include compounds of Formulas III, IV, V, and VI and pharmaceutically acceptable salts thereof wherein R1, R2, R3, R4, R5, X, Y and Z are as defined above.

Other embodiments include compounds of Formulas VII, VIII, IX, and X and pharmaceutically acceptable salts thereof wherein R1, R2, R3, R4, R5, X, Y and Z are as defined above.

Other embodiments include compounds of Formulas III, IV, V, and VI wherein R2, R3, R4, R5, X, Y and Z are as defined above and R1 is hydrogen. Other embodiments include compounds of Formulas III, IV, V, and VI wherein R3, R4, R5 and Z are as defined above; R1 is hydrogen and R2 is C1-C4 alkyl.

Other embodiments include compounds of Formulas III, IV, V, and VI wherein R1, R2, R3, R4 and R5, and Z are as defined above and X and Y are independently chosen from a bond, —O—, —OCH2—, —C(O)—, —S—, —S(O)2—, —S(O)2N(R7)— and —N(R7)S(O)2—. Other embodiments include compounds of Formulas III, IV, V, and VI wherein R1, R2, R3, R4 and R5, and Z are as defined above and X and Y are independently chosen from a bond, —O—, —S(O)2— and —S(O)2N(R7). Another embodiment comprises compounds of Formulas III, IV, V, and VI wherein R1, R2, R3, R4 and R5, and Z are as defined above and X and Y are independently chosen from a bond, —O— and S(O)2N(R7). A further embodiment comprises compounds of Formulas III, IV, V, and VI wherein R1, R2, R3, R4, R5, and Z are as defined above and X and Y are independently chosen from a bond and —O—.

Other embodiments include compounds of Formulas III, IV, V, and VI wherein R1, R2, R5, X, Y and Z are as defined above and R3 and R4 and are independently chosen from a C1-C7 alkyl optionally and independently interrupted by one or more —O—, —S—, —S(O)—, and —S(O)2— groups, cycloalkylalkyl and heterocycloalkylalkyl. Other embodiments include compounds of Formulas III, IV, V, and VI wherein R1, R2, R5, X, Y and Z are as defined above and R3 and R4 and are independently chosen from C1-C4 alkyl and cyclopropylmethyl. Other embodiments include compounds of Formulas III, IV, V, and VI wherein R1, R2, R5, Z are as defined above and X, Y and are independently chosen from a bond, —S—, —SO2- and —O— and R3 and R4 and are independently chosen from C1-C4 alkyl and cyclopropylmethyl. Other embodiments include compounds of Formulas III, IV, V, and VI wherein R1, R2, R5, X, Y and Z are as defined above and R3 and R4 and are independently chosen from a group Z wherein Z is as defined above.

Other embodiments include compounds of Formulas III, IV, V, and VI wherein R1, R2, R3, R4 and R5, X and Y are as defined above and Z is a phenyl ring bearing up to 3 substituents independently selected from halogen, R6, CF3, CN, NO2, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(O)R6, OC(O)OR6, OC(O)NHR7, OC(O)N(R7)2, SR6, S(O)R6, S(O)2R6, S(O)2NHR7, S(O)2N(R7)2, NHR7, N(R7)2, NHC(O)R6, N(R7)C(O)R6, NHC(O)OR6, N(R7)C(O)OR6, N(R7)C(O)NH(R7), N(R7)C(O)NH(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, CO2H, CO2R6, COR6. Other embodiments include compounds of Formulas III, IV, V, and VI wherein R1, R2, R3, R4 and R5, X and Y are as defined above, and Z is a mono- or bi-cyclic ring system having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing up to 3 substituents independently selected from halogen, R6, CF3, CN, NO2, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(O)R6, OC(O)OR6, OC(O)NHR7, OC(O)N(R7)2, SR6, S(O)R6, S(O)2R6, S(O)2NHR7, S(O)2N(R7)2, NHR7, N(R7)2, NHC(O)R6, N(R7)C(O)R6, NHC(O)OR6, N(R7)C(O)OR6, N(R7)C(O)NH(R7), N(R7)C(O)NH(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, CO2H, CO2R6, COR6.

Other embodiments include compounds of Formulas III, IV, V, and VI wherein R1, R2, R3, R4 X, Y and Z are as defined above and R5 is NO2, NH2, F, Cl, Br, CN, OH, C1-C4 alkoxy, SR6, S(O)2R6 or S(O)2N(R7)2. Other embodiments include compounds of Formulas III, IV, V, and VI wherein R1, R2, R3, R4 X, Y and Z are as defined above and R5 is aryl or heteroaryl. Other embodiments include compounds of Formulas III, IV, V, and VI wherein R1, R2, R3, R4 X, Y and Z are as defined above and R5 is chlorine or fluorine.

Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R2, R3, R4, R5, X, Y and Z are as defined above and R1 is hydrogen. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R3, R4, R5 and Z are as defined above; R1 is hydrogen and R2 is C1-C4 alkyl.

Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R1, R2, R3, R4 and R5, and Z are as defined above and X and Y are independently chosen from a bond, —O—, —OCH2—, —C(O)—, —S—, —S(O)2—, —S(O)2N(R7)— and —N(R7)S(O)2—. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R1, R2, R3, R4 and R5, and Z are as defined above and X and Y are independently chosen from a bond, —O—, —S(O)2— and —S(O)2N(R7). Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R1, R2, R3, R4 and R5, and Z are as defined above and X and Y are independently chosen from a bond, —O— and S(O)2N(R7). Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R1, R2, R3, R4 and R5, and Z are as defined above and X and Y are independently chosen from a bond and —O—. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R1, R2, R5, X, Y and Z are as defined above and R3 and R4 and are independently chosen from a C1-C7 alkyl optionally and independently interrupted by one or more —O—, —S—, —S(O)—, and —S(O)2— groups, cycloalkylalkyl and heterocycloalkylalkyl. Other embodiments include compounds of Formulas III, IV, V, and VI wherein R1, R2, R5, X, Y and Z are as defined above and R3 and R4 and are independently chosen from C1-C4 alkyl and cyclopropylmethyl. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R1, R2, R5, Z are as defined above and X, Y and are independently chosen from a bond, —S—, —SO2— and —O— and R3 and R4 and are independently chosen from C1-C4 alkyl and cyclopropylmethyl. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R1, R2, R5, X, Y and Z are as defined above and R3 and R4 and are independently chosen from a group Z wherein Z is as defined above.

Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R1, R2, R3, R4 and R5, X and Y are as defined above and Z is a phenyl ring bearing up to 3 substituents independently selected from halogen, R6, CF3, CN, NO2, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(O)R6, OC(O)OR6, OC(O)NHR7, OC(O)N(R7)2, SR6, S(O)R6, S(O)2R6, S(O)2NHR7, S(O)2N(R7)2, NHR7, N(R7)2, NHC(O)R6, N(R7)C(O)R6, NHC(O)OR6, N(R7)C(O)OR6, N(R7)C(O)NH(R7), N(R7)C(O)NH(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, CO2H, CO2R6, COR6. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R1, R2, R3, R4 and R5, X and Y are as defined above, and Z is a mono- or bi-cyclic ring system having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C, said ring system optionally bearing ring bearing up to 3 substituents independently selected from halogen, R6, CF3, CN, NO2, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(O)R6, OC(O)OR6, OC(O)NHR7, OC(O)N(R7)2, SR6, S(O)R6, S(O)2R6, S(O)2NHR7, S(O)2N(R7)2, NHR7, N(R7)2, NHC(O)R6, N(R7)C(O)R6, NHC(O)OR6, N(R7)C(O)OR6, N(R7)C(O)NH(R7), N(R7)C(O)NH(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, CO2H, CO2R6, COR6.

Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R1, R2, R4 X, Y and Z are as defined above and R5 is NO2, NH2, F, Cl, Br, CN, OH, C1-C4 alkoxy, SR6, S(O)2R6 or S(O)2N(R7)2. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R1, R2, R4 X, Y and Z are as defined above and R5 is aryl or heteroaryl. Other embodiments include compounds of Formulas VII, VIII, IX, and X wherein R1, R2, R4 X, Y and Z are as defined above and R5 is chlorine or fluorine.

The compounds of formulas I-IX are expected to alter the activity of γ-secretase and are expected to be useful for the treatment of Alzheimer's disease and other neurodegenerative disorders.

In another embodiment A is CO2H.

In another embodiment a compound of formula (I) is selected.

In another embodiment a compound of formula (II) is selected.

In another embodiment a compound of formula (III) is selected.

In another embodiment a compound of formula (IV) is selected.

In another embodiment a compound of formula (V) is selected.

In another embodiment a compound of formula (VI) is selected.

In another embodiment a compound of formula (VII) is selected.

In another embodiment a compound of formula (VIII) is selected.

In another embodiment a compound of formula (IX) is selected.

In another embodiment R1 and R2 are independently selected from: H, (C1-C6)alkyl, (C0-C3)alkyl-(C3-C7)cycloalkyl, C1-C6 alkyl that is independently interrupted by one or more —O—, —S—, —S(O)—, or —S(O)2— groups or heterocycloalkylalkyl wherein each alkyl or cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, cyano, oxo, CF3, C1-C4 alkyl provided that R1 and R2 are not H simultaneously or

R1 and R2 are taken together to form a 3-7 membered cycloalkyl or heterocycloalkyl ring which are; optionally independently singly or multiply substituted with halo, hydroxy, cyano, CF3, C1-C4 alkyl
or
R1 and R2 are taken together to form a 3-7 membered cycloalkyl ring substituted with R20 and R21 where R20 and R21 are taken together to form a 3-7 membered cycloalkyl ring wherein each cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl.

In another embodiment R1 and R2 are independently selected from: H, (C1-C6)alkyl, (C0-C3)alkyl-(C3-C7)cycloalkyl wherein each alkyl or cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, cyano, CF3, C1-C4 alkyl provided that R1 and R2 are not H simultaneously.

In another embodiment R1 and R2 are independently selected from: H, (C1-C6)alkyl, wherein alkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl provided that R1 and R2 are not H simultaneously.

In another embodiment R1 and R2 are independently selected from: H, (C3-C6)alkyl, wherein alkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl provided that R1 and R2 are not H simultaneously.

In another embodiment R1 and R2 are independently selected from: H, n-propyl, iso-propyl, iso-butyl, n-butyl, iso-pentyl, and n-pentyl wherein alkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl provided that R1 and R2 are not H simultaneously.

In another embodiment R1 is H.

In another embodiment R1 is H and R2 is n-propyl.

In another embodiment R1 is H and R2 is iso-butyl.

In another embodiment R1 is H and R2 is n-butyl.

In another embodiment R1 is H and R2 is iso-pentyl.

In another embodiment R1 is H and R2 is n-pentyl.

In another embodiment R1 and R2 are independently selected from: H, (C0-C3)alkyl-(C3-C7)cycloalkyl wherein cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl provided that R1 and R2 are not H simultaneously.

In another embodiment R1 and R2 are independently selected from: H, (C0-C1)alkyl-(C3-C7)cycloalkyl wherein cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl provided that R1 and R2 are not H simultaneously.

In another embodiment R1 and R2 are independently selected from: H, (C0-C1)alkyl-(C3-C5)cycloalkyl wherein cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl provided that R1 and R2 are not H simultaneously.

In another embodiment R1 is H and R2 is selected from cyclopentyl, cyclopropylmethyl and cyclobutylmethyl.

In another embodiment R1 is H and R2 is cyclopentyl.

In another embodiment R1 is H and R2 is cyclopropylmethyl.

In another embodiment R1 is H and R2 is cyclobutylmethyl.

In another embodiment R1 and R2 are taken together to form a 3-7 membered cycloalkyl or heterocycloalkyl ring which are; optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl

or
R1 and R2 are taken together to form a 3-7 membered cycloalkyl ring substituted with R20 and R21 where R20 and R21 are taken together to form a 3-7 membered cycloalkyl ring wherein each cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl.

In another embodiment R1 and R2 are taken together to form a 3-7 membered cycloalkyl or heterocycloalkyl ring which are; optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl.

In another embodiment R1 and R2 are taken together to form a 3-7 membered cycloalkyl ring which are; optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl.

In another embodiment R1 and R2 are taken together to form a cyclopropyl ring.

In another embodiment R1 and R2 are taken together to form a cyclobutyl ring.

In another embodiment R1 and R2 are taken together to form a cyclopentyl ring.

In another embodiment R1 and R2 are taken together to form a cyclohexyl ring.

In another embodiment R1 and R2 are taken together to form a 3-7 membered cycloalkyl ring substituted with R20 and R21 where R20 and R21 are taken together to form a 3-7 membered cycloalkyl ring wherein each cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl.

In another embodiment R1 and R2 are taken together to form a 3-7 membered cycloalkyl ring substituted on the same carbon atom with R20 and R21 where R20 and R21 are taken together to form a 3-7 membered cycloalkyl ring wherein each cycloalkyl is optionally independently singly or multiply substituted with halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl.

In another embodiment R1 and R2 are taken together to form a spiro[2.3]hexane, a spiro[3.3]heptane or a spiro[3.4]octane ring system.

In another embodiment R1 and R2 are taken together to form a spiro[2.3]hexane ring system.

In another embodiment R1 and R2 are taken together to form a spiro[3.3]heptane ring system.

In another embodiment R1 and R2 are taken together to form a spiro[3.4]octane ring system.

In another embodiment R1 and R2 are taken together to form a 5,5-disubstituted spiro[2.3]hexane ring system.

In another embodiment R1 and R2 are taken together to form a 2,2-disubstituted spiro[3.3]heptane ring system.

In another embodiment R1 and R2 are taken together to form a 2,2-disubstituted spiro[3.4]octane ring system.

In another embodiment R1 and R2 are independently selected from: H, F, OH, OR6, SR6, NHR7, N(R7)2 NHC(O)R6 or NHCO2R6 provided that R1 and R2 are not H simultaneously.

In another embodiment R1 and R2 if not H are unsubstituted, except that when R1 and R2 are taken with the carbon to which they are attached form C3-C7 ring, the ring may be substituted with R20 and R21, which themselves are unsubstituted.

In another embodiment R1 and R2 if not H are optionally singly or multiply independently substituted with halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl

In another embodiment R1 and R2 if not H are singly or multiply independently substituted with halo, hydroxy, oxo, cyano, CF3, C1-C4 alkyl

In another embodiment R6 is C1-C6 alkyl optionally and independently interrupted by one or more —O—, —S—, —S(O)—, or —S(O)2— groups, (C3-C7)cycloalkyl, (C4-C8) cycloalkylalkyl, heterocycloalkylalkyl.

In another embodiment R6 is C1-C6 alkyl optionally and independently interrupted by one or more —O—, —S—, —S(O)—, or —S(O)2— groups.

In another embodiment R6 (C3-C7)cycloalkyl.

In another embodiment R6 is a (C0-C3)alkyl-(C3-C7)cycloalkyl

In another embodiment R6 heterocycloalkylalkyl.

In another embodiment R6 is (CH2)nQ.

In another embodiment R6 is —CH2-Q.

In another embodiment Q is aryl.

In another embodiment Q is heteroaryl.

In another embodiment Q is monocyclic heteroaryl.

In another embodiment Q is bicyclic heteroaryl.

In another embodiment X is a bond or a divalent linking group selected from —O—, —OCH2—, —OCH(R7)—, —OCH2CH2—, —CH2—, —C(O)—, —CH═CH—, —CH2CH2—, —CH2O—, —CH2OCH2, —CH2CH2O—, —S—, —SCH2—, CH2S— or —CH2SCH2—.

In another embodiment X is a bond or a divalent linking group selected from —O—, —OCH2—, —OCH(R7)—, —OCH2CH2—, —CH2O—, —CH2OCH2-5 or —CH2CH2O.

In another embodiment X is a bond or a divalent linking group selected from —CH2—, —C(O)—, —CH═CH— or —CH2CH2

In another embodiment X is a bond or a divalent linking group selected from —S—, —SCH2-5 CH2S— or —CH2SCH2—.

In another embodiment X is a bond or a divalent linking group selected from —O— or —S—.

In another embodiment X is a bond.

In another embodiment X is the divalent linking group —O—.

In another embodiment X is the divalent linking group —S—.

In another embodiment Y is a bond or a divalent linking group selected from —O—, —OCH2—, —OCH(R7)—, —OCH2CH2—, —CH2—, —C(O)—, —CH═CH—, —CH2CH2—, —CH2O—, —CH2OCH2—, —CH2CH2O—, —S—, —SCH2—, CH2S— or —CH2SCH2—.

In another embodiment Y is a bond or a divalent linking group selected from —O—, —OCH2—, —OCH(R7)—, —OCH2CH2—, —CH2O—, —CH2OCH2—, or —CH2CH2O

In another embodiment Y is a bond or a divalent linking group selected from —CH2—, —C(O)—, —CH═CH— or —CH2CH2—.

In another embodiment Y is a bond or a divalent linking group selected from —S—, —SCH2—, CH2S— or —CH2SCH2—.

In another embodiment Y is a bond or a divalent linking group selected from —O— or —S—.

In another embodiment Y is a bond.

In another embodiment Y is the divalent linking group —O—.

In another embodiment Y is the divalent linking group —S—.

In another embodiment R3 is a C1-C4 alkyl group.

In another embodiment R3 is a C1-C3 alkyl group.

In another embodiment R3 is a C2-C3 alkyl group.

In another embodiment R3 is selected from ethyl, n-propyl, iso-propyl, trifluoroethyl, or trifluoropropyl.

In another embodiment R3 is ethyl.

In another embodiment R3 is n-propyl.

In another embodiment R3 is iso-propyl.

In another embodiment R3 is trifluoroethyl.

In another embodiment R3 is trifluoropropyl.

In another embodiment R3 is a (C4-C10) cycloalkylalkyl group.

In another embodiment R3 is a (C0-C3)alkyl-(C3-C7) cycloalkyl group.

In another embodiment R3 is a (C3-C7) cycloalkyl group.

In another embodiment R3 is a (C1-C3)alkyl-(C3-C7) cycloalkyl group.

In another embodiment R3 is a (C1)alkyl-(C3-C7) cycloalkyl group.

In another embodiment R3 is a (C1)alkyl-(C3-C4) cycloalkyl group.

In another embodiment R3 is a cyclopropylmethyl group.

In another embodiment R3 is a cyclobutylmethyl group.

In another embodiment R3 is heterocycloalkylalkyl group.

In another embodiment R3 is represented by the group Z.

In another embodiment R3 is not cyclopropylmethyl

In another embodiment Z is monocyclic.

In another embodiment Z is bicyclic

In another embodiment Z is heteroaryl

In another embodiment Z is unsubstituted heteroaryl

In another embodiment Z is benzo[b]thiophenyl, benzo[c][1,2,5]oxadiazoyl, benzo[c][1,2,5]thiadiazolyl or benzo[d]thiazolyl

In another embodiment Z is benzo[b]thiophenyl or benzo[d]thiazolyl

In another embodiment Z is benzo[c][1,2,5]oxadiazoyl or benzo[c][1,2,5]thiadiazolyl

In another embodiment Z is benzo[b]thiophenyl

In another embodiment Z is benzo[c][1,2,5]oxadiazoyl

In another embodiment Z is benzo[c][1,2,5]thiadiazolyl

In another embodiment Z is benzo[d]thiazolyl

In another embodiment Z is aryl

In another embodiment Z is substituted phenyl

In another embodiment Z is 4-substituted phenyl

In another embodiment Z is optionally substituted with up to 3 substituents independently selected from halogen, R6, CF3, CN, NO2, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(O)R6, OC(O)OR6, OC(O)NHR7, OC(O)N(R7)2, SR6, S(O)R6, S(O)2R6, S(O)2NHR7, S(O)2N(R7)2, NHR7, N(R7)2, NHC(O)R6, N(R7)C(O)R6, NHC(O)OR6, N(R7)C(O)OR6, N(R7)C(O)NH(R7), N(R7)C(O)NH(R7)2, C(O)NH2, C(O)NHR7, C(O)N(R7)2, CO2H, CO2R6 or COR6

In another embodiment Z is optionally substituted with up to 3 substituents independently selected from halogen, R6, CF3, CN, NO2, C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH2CH2OCH3, OC(O)R6, OC(O)OR6, SR6, NHR7, N(R7)2CO2H, CO2R6 or COR6

In another embodiment Z is optionally substituted with up to 3 substituents independently selected from halogen, R6, CF3, CN, NO2, C1-C4 alkoxy, aryloxy, OCH2CH2OCH3, OC(O)R6, OC(O)OR6 or SR6

In another embodiment Z is optionally substituted with up to 3 substituents independently selected from halogen, R6, CF3, CN, NO2, C1-C4 alkoxy, OCH2CH2OCH3, OC(O)R6, OC(O)OR6 or SR6

In another embodiment Z is optionally substituted with up to 3 substituents independently selected from halogen, C1-C6 alkyl, (C0-C3)alkyl-(C3-C7)cycloalkyl, CF3, C1-C4 alkoxy, or SR6

In another embodiment Z is optionally substituted with up to 3 substituents independently selected from F, Cl, C1-C3 alkyl, (C3-C6)cycloalkyl, CF3, C1-C4 alkoxy, S—(C1-C4)alkyl or S—(C0-C3)alkyl-(C3-C7)cycloalkyl

In another embodiment Z is optionally substituted with up to 3 substituents independently selected from F, Cl, C1-C3 alkyl, (C3-C6)cycloalkyl, CF3, C1-C4 alkoxy, or S—(C1-C3)alkyl

In another embodiment Z is substituted CF3, OCF3, OCH2CF3, F, Cl, SMe, Me, Et, iPr

In another embodiment Z is substituted with F

In another embodiment Z is substituted with Cl

In another embodiment Z is substituted with C1-C3 alkyl

In another embodiment Z is substituted with (C3-C6)cycloalkyl

In another embodiment Z is substituted with CF3,

In another embodiment Z is substituted with C1-C4 alkoxy

In another embodiment Z is substituted with S—(C1-C3)alkyl

In another embodiment R4 is a C1-C7 alkyl group.

In another embodiment R4 is a C1-C4 alkyl group.

In another embodiment R4 is a C1-C3 alkyl group.

In another embodiment R4 is a C2-C3 alkyl group.

In another embodiment R4 is selected from ethyl, n-propyl, iso-propyl, trifluoroethyl, or trifluoropropyl.

In another embodiment R4 is ethyl.

In another embodiment R4 is n-propyl.

In another embodiment R4 is iso-propyl.

In another embodiment R4 is trifluoroethyl.

In another embodiment R4 is trifluoropropyl.

In another embodiment R4 is a (C4-C10) cycloalkylalkyl group.

In another embodiment R4 is a (C0-C3)alkyl-(C3-C7) cycloalkyl group.

In another embodiment R4 is a (C3-C7) cycloalkyl group.

In another embodiment R4 is a (C1-C3)alkyl-(C3-C7) cycloalkyl group.

In another embodiment R4 is a (C1)alkyl-(C3-C7) cycloalkyl group.

In another embodiment R4 is a (C1)alkyl-(C3-C4) cycloalkyl group.

In another embodiment R4 is a cyclopropylmethyl group.

In another embodiment R4 is a cyclobutylmethyl group.

In another embodiment R4 is heterocycloalkylalkyl group.

In another embodiment R4 is represented by the group Z.

In another embodiment R4 is not cyclopropylmethyl

In another embodiment R5 is, F, Cl, Br, CN, C1-C4 alkoxy, SR6, (C1-C4) alkyl, (C0-C3)alkyl-(C3-C7) cycloalkyl, —(C3-C7) cycloalkly or (C2-C4) alkynyl, where each alkyl or cycloalkly is optionally independently singly or multiply substituted with halo, hydroxy, cyano, CF3, C1-C4 alkyl.

In another embodiment R5 is, F, Cl, Br, CN, C1-C4 alkoxy, SR6, (C1-C4) alkyl, (C0-C3)alkyl-(C3-C7) cycloalkyl, —(C3-C7) cycloalkly or (C2-C4) alkynyl, where each alkyl or cycloalkly is optionally independently singly or multiply substituted with halo, hydroxy, cyano, CF3, C1-C4 alkyl.

In another embodiment R5 is F, Cl, Br, CN, C1-C4 alkoxy, —S—(C1-C4)alkyl or (C1-C4) alkyl, where each alkyl is optionally independently singly or multiply substituted with halo, hydroxy, cyano, CF3, C1-C4 alkyl.

In another embodiment R5 is F, Cl, Br, CN, C1-C3 alkoxy —S—(C1-C3)alkyl or (C1-C3) alkyl, where each alkyl is optionally independently singly or multiply substituted with halo, hydroxy, cyano, CF3, C1-C4 alkyl.

In another embodiment R5 is F, Cl, Br or CN.

In another embodiment R5 is F or Cl.

In another embodiment R5 is F.

In another embodiment R5 is Cl.

In another embodiment R5 is Br.

In another embodiment R5 is CN.

In another embodiment R5 is C1-C3 alkoxy —S—(C1-C3)alkyl or (C1-C3) alkyl.

In another embodiment R5 is C1-C3 alkoxy.

In another embodiment R5 is tri-fluoroethoxy or tri-fluoropropoxy.

In another embodiment R5 is (C1-C3) alkyl.

In another embodiment R5 is CF3.

In another embodiment R5 is —S—(C1-C3)alkyl.

In another embodiment R5 is —S-Me, —S-Et or —S—CH2CF3.

In another embodiment R5 is SR6.

In another embodiment R5 is (C0-C3)alkyl-(C3-C7) cycloalkyl, (C2-C4) alkynyl, or —(C3-C7) cycloalkyl.

In another embodiment R5 is (C0-C3)alkyl-(C3-C7) cycloalkyl.

In another embodiment R5 is (C2-C4) alkynyl.

In another embodiment R5 is trifluoroethynyl.

In another embodiment R5 is (C3-C7) cycloalkyl.

In another embodiment R5 is cyclopropyl.

In another embodiment R5 is NO2 or NH2.

In another embodiment R5 is aryl or heteroaryl.

In another embodiment the compound is a compound selected from examples 100-3217.

In another embodiment a racemic compound described in the disclosure is selected.

In another embodiment a single enantiomer of the previous embodiments is selected.

In another embodiment a single enantiomer of configuration (R) of the previous embodiments is selected.

In another embodiment a single enantiomer of configuration (S) of the previous embodiments is selected.

In another embodiment a solvate of a compound of formula (I-IX) is selected.

In another embodiment a polymorph of compound of formula (I-IX) is selected.

In a separate embodiment, a pharmaceutical composition comprising of the compound of the previous embodiments and a pharmaceutically acceptable carrier.

In a separate embodiment, a method for treating a neurodegenerative disorder comprising administering to a patient an effective amount of the pharmaceutical composition of the previous embodiments.

In another embodiment a method for treating Alzheimer's Disease comprising administering to a patient an effective amount of the pharmaceutical composition of the previous embodiments.

In the case compounds of Formula (I-IX) may contain asymmetric centers and exist as different enantiomers or diastereomers. All enantiomers or diastereomeric forms are embodied herein.

Compounds in the disclosure, e.g., compounds of Formulas I-IX, may be in the form of pharmaceutically acceptable salts. The phrase “pharmaceutically acceptable” refers to salts prepared from pharmaceutically acceptable non-toxic bases and acids, including inorganic and organic bases and inorganic and organic acids. Salts derived from inorganic bases include lithium, sodium, potassium, magnesium, calcium and zinc. Salts derived from organic bases include ammonia, primary (e.g. Tromethamine), secondary and tertiary amines, and amino acids (e.g. Lysine). Salts derived from inorganic acids include sulfuric, hydrochloric, phosphoric, methanesulphonic, hydrobromic. Salts derived from organic acids include C1-6 alkyl carboxylic acids, di-carboxylic acids and tricarboxylic acids such as acetic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, adipic acid and citric acid, and alkylsulfonic acids such as methanesulphonic, and aryl sulfonic acids such as para-tolouene sulfonic acid and benzene sulfonic acid. For detailed list of slats see P. H. Stahl and C. G. Wermuth (eds.) “Handbook of Pharmaceutical Salts, Properties, Selection and Use” Wiley-VCH (ISBN 3-906390-26-8)

Compounds and pharmaceutically acceptable salts thereof may be in the form of a solvates. This occurs when a compound of formula (I-IX)) crystallizes in a manner that it incorporates solvent molecules into the crystal lattice. Examples of solvents forming solvates are water (hydrates), MeOH, EtOH, iPrOH, and acetone. Formulas I-IX cover all solvates of the depicted compounds.

Compounds in the disclosure may exist in different crystal forms known as polymorphs.

Practitioners of the art will recognize that certain chemical groups may exist in multiple tautomeric forms. The scope of this disclosure is meant to include all such tautomeric forms. For example, a tetrazole may exist in two tautomeric forms, 1-H tetrazole and a 2-H tetrazole. This is depicted in figure below. This example is not meant to be limiting in the scope of tautomeric forms.

Practitioners of the art will recognize that certain electrophilic ketones, may exist in a hydrated form. The scope of this disclosure is to include all such hydrated forms. For example, a trifluoromethyl ketone may exist in a hydrated form via addition of water to the carbonyl group. This is depicted in figure below. This example is not meant to be limiting in the scope of hydrated forms.

Abbreviations used in the following examples and preparations include:

    • Aβ Amyloid-beta
    • ABL Aβ lowering
    • Ac acyl (Me-C(O)—)
    • AD Alzheimer's Disease
    • APP Amyloid Precursor Protein
    • Bn Benzyl
    • b/p brain/plasma
    • BSA Bovine serum Albumin
    • c Cyclo
    • calcd. Calculated
    • cBu Cyclobutyl
    • c-Bu Cyclobutyl
    • cmax Maximal concentration
    • cPr Cyclopropyl
    • c-Pr Cyclopropyl
    • CHAPS 3-[3-cholamidopropyl)-dimethyl-ammonio]-1-propane sulfonate
    • CTF Carboxy Terminal Fragment
    • CSF Cerebrospinal fluid
    • DAPT N-[(3,5-Difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine-1,1-dimethylethyl ester
    • DCC N,N′, Dicyclohexylcarbodiimide
    • DEA Di-ethylamine
    • DIEA Di-isopropylethyl amine
    • DMAP 4-Dimethylamino Pyridine
    • DMF Dimethylformamide
    • DMSO Dimethyl sulfoxide
    • Dppf 1,4-Bis(diphenylphosphino) ferrocene
    • EDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride
    • EDTA Ethylene Diamine Tetra-acetic Acid
    • ELISA Enzyme-Linked Immuno Sorbent Assay
    • Et3N Triethylamine
    • Eq. Equivalent
    • g gram(s)
    • HOBt 1-Hydroxybenzotriazole
    • HPLC High Pressure Liquid Chromatography
    • h Hour(s)
    • hr Hour(s)
    • i.v or IV. Intravenous
    • KHMDS Potassium Hexamethydisilazide
    • LC-MS Liquid Chromatography-Mass Spectrometry
    • LDA Lithium Di-isopropylamide
    • m Multiplet
    • MeOH Methyl Alcohol or Methanol
    • m meta
    • mcpba meta-chloro perbenzoic acid
    • min Minute(s)
    • mmol millimoles
    • mmole millimoles
    • ul Microliter
    • μl microliter
    • Ms Mesylate
    • MS Mass Spectrometry
    • MW Molecular Weight (all values are ±0.05)
    • n normal
    • NBS N-Bromosuccinimide
    • NCS N-Chlorosuccinimide
    • NIS N-Iodosuccinimide
    • NMR Nuclear Magnetic Resonance
    • NMM N-Methyl Morpholine
    • NSAIDS Non-Steroidal Anti-Inflammatory Drugs
    • o ortho
    • o/n overnight
    • p para
    • PBS Phosphate Buffered Saline
    • PEPPSI 1,3-Bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl) palladium(II) dichloride
    • PhNTf2 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide
    • POPd Dihydrogen dichlorobis(di-tert-butylphosphinito-kp) palladate (2-)
    • p.s.i. Pounds per square inch
    • PPAA 1-Propanephosphonic Acid Cyclic Anhydride
    • PyBOP® Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
    • PK Pharmacokinetics
    • RT (or rt) room temperature (about 20-25° C.)
    • s Singlet
    • sat. Saturated
    • sec secondary
    • t Triplet
    • tert tertiary
    • TBAF Tetra-butyl ammonium fluoride
    • TFA Trifluoroacetic Acid
    • THF Tetrahydrofuran
    • TMB 3,3′ 5,5′ Tetramethylbenzidine
    • TMS Trimethylsilyl
    • Tf Triflate
    • Ts Tosylate
    • v/v volume/volume
    • wt/v weight/volume

DESCRIPTION OF THE FIGURE

FIG. 1 demonstrates the desirable effect on Aβ after the administration of example 1301 (2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid) to in C57BL/6 mice when give one dose at 30 mg/kg in a Solutol HS 15: Ethanol:Water (15:10:75) formulation (measuring Aβ at 3 hours).

DETAILED DESCRIPTION

Described below are compounds within Formulas I and II as well as methods for preparing the compounds and using the compounds to treat one or more symptoms of Alzheimer's disease. The compounds of the disclosure are gamma secretase modulators (GSMs), i.e., compounds that act to shift the relative levels of Aβ peptides produced by γ-secretase. In some cases the compounds alter the relative levels of Aβ peptides produced by γ-secretase without significantly changing the total level of Aβ peptides produced.

General Reaction Schemes

The tetrasubstituted benzene compounds of Formulas I and II may be prepared by multistep organic synthetic routes from known fluoronitrobenzene and chloronitrobenzene starting materials e.g. 2,4-difluoronitrobenzene, 4-fluoro-2-cyano-nitrobenzene, 3-nitro-4-chlorobenzene, 2,4,5-trifluoronitrobenzene, 2,4,5-trichloronitrobenzene or alternatively from 4-hydroxyphenyl and 4-aminophenyl acetic acid starting materials by one skilled in the art of organic synthesis using established organic synthesis procedures.

The 1-position acetic acid moiety common to compounds of Formulas I and II, as the free acid itself or as an ester derivative thereof, is already present in the case of a 4-hydroxyphenyl acetic acid or 4-hydroxyphenyl acetic acid ester starting material. In the case of a 4-fluoronitrobenzene starting materials or intermediates, the acetic acid moiety can be introduced by standard nucleophilic aromatic substitution of the 4-fluoro group with an unsubstituted malonic ester (eg diethyl malonate) or a malonic ester derivative already bearing an R1 group (eg. diethyl 2-isobutylmalonate). Introduction of the X—R3 and Y—R4 groups or intermediate groups that are further elaborated to X—R3 and Y—R4 can be carried out by substitution or manipulation of suitable 3 or 4-position functional groups in appropriate starting materials or intermediates en route to Formulas I and II respectively. In cases where X or Y is a bond, a 3 or 4-position halogen or triflate group is replaced with an aryl or heteroaryl group by carbon-carbon bond forming reaction typically a Suzuki coupling reaction. In cases where X or Y is O, S or N, a 3 or 4-position halogen (eg the corresponding 2-fluoro group of a 2,4-difluoronitrobenzene starting material) substitution reaction is performed using HO—R3 or HS—R3 or H2N—R3 and a base (eg NaH, K2CO3) in a suitable solvent (eg DMF). Compounds where X or Y is —S(O)— or —S(O2)— are prepared by oxidation of compounds where X or Y is S. Compounds where X or Y is —S(O)2N(H)—, —S(O)2N(R5)— can be prepared by conversion of a 3 or 4-position nitro group (eg the nitro group of the nitrobenzene starting material) to a sulfonyl chloride via Sandmeyer reaction followed by addition of the corresponding amine. Compounds where X or Y is N(H)S(O)2— or —N(R5)S(O)2— can be prepared by reduction of a 3 or 4-position nitro group to the corresponding aniline followed by reaction with the corresponding sulfonylchloride. Compounds where X or Y is NHC(O)— or —N(R5)C(O)— can be prepared by reduction of a 3 or 4-position nitro group to the corresponding aniline followed by reaction with the corresponding carboxylic acid chloride. Compounds where X or Y is a —C(O)— can be prepared by addition of an organometallic reagent (e.g., a Grignard reagent or organolithium) to a 3 or 4-position cyano group directly or in a 2-step sequence by addition of an organometallic reagent to a 3 or 4-position carboxaldehyde group followed by oxidation. Compounds where X or Y is —C(O)NH— or C(O)N(R5)—)- can be prepared by addition of a corresponding amine to a 3 or 4-position carboxylic acid which in turn may be prepared by hydrolysis of a 3 or 4-position cyano group. Either aromatic nucleophilic substitution of a 2-fluoro-1-nitrobenzene intermediate or alkylation of a 3 or 4-hydroxybenzene intermediate with the corresponding alkyl bromide or triflate may be used to prepare compounds of Formulas I and II where the R4 group is OCH2CF3, C2-C4 alkoxy, or cyclopropyloxymethyl. Compounds wherein the R4 group is an alkyl, aryl or heteroaryl group attached by a carbon-carbon bond may be prepared by a Suzuki coupling reaction. In this process an aryl or heteroaryl boronic acid or borate ester is reacted with an intermediate compound having a 3 or 4-position halogen or triflate group. This method results in replacement of the halogen or triflate group with an aryl or heteroaryl group which is then bonded to the intermediate at the carbon atom previously bearing the boronic acid or ester group. Compounds wherein the R4 group is a heteroaryl group attached by a carbon-nitrogen bond may be prepared by reacting a 3 or 4-iodo intermediate with a heteroaromatic heterocycle having an acidic N—H group under Ulman reaction or copper catalyzed reaction conditions.

Compounds of Formulas I and II wherein A=tetrazole may be prepared from their corresponding nitriles A=CN which are available via dehydration of the corresponding primary amides A=CONH2 whose preparation is described above. Thus, treatment of the nitrile with an azide, such as sodium azide or tributylstanyl azide (Bu3SnN3) at a temperature of 20-100° C., optionally with a solvent such as DMF, THF or DMSO.

Compounds of the disclosure of Formula III in which R1 is R8 an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R2 is R9 a hydrogen, alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, Y is O, X is a bond, R3 is Z, R4 and R5 are as described previously and thus having general Formula XXIV may be prepared generally as depicted in Scheme 1.

Thus, as depicted in Scheme 1 an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl or arylalkyl R8 group is introduced in the first step by treating ethyl 4-benzyloxyphenylacetate one equivalent of a suitable deprotonating base such as sodium hydride in an appropriate organic solvent followed by the addition of the corresponding reactive alkyl bromide R8Br such as isobutylbromide to yield XX where R9 is hydrogen. In cases where a second alkyl or aralkyl group is present this alkylation step is repeated using R9Br as an alkylating agent. In cases where a spirocyclic ring is formed by R8 and R9 (e.g. cyclopropyl) then the appropriate dibromide is used (e.g. dibromoethane in the case of cyclopropyl). The benzyl group is then removed under standard catalytic hydrogenation conditions and the resulting phenol is treated with bromine in acetic acid to give the bromophenol intermediate XXI. Nitration of XXI then yields nitrophenol intermediate XXII which then us subjected to a standard base mediated aliphatic or aromatic nucleophilic substitution reaction with an alkyl or aryl halide R4—X to give intermediate XXIII where R4 is alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl. This is then followed by introduction of the Z group by standard reactions. Such reactions are exemplified by the well established Suzuki coupling of a substituted aryl or heteroaryl boronic acid derivative Z—B(OH)2 using a suitable palladium(0) catalyst typically bearing with phosphine ligands (e.g. Pd(PPh3)4 or tetrakistriphenylphosphine) in the case where Z is linked by a carbon-carbon bond and by copper (eg CuI) mediated Ulman type coupling of a heteroaryl ring bearing an active N—H group where Z is a heteroaryl ring linked by a nitrogen-carbon bond.

After introduction of the Z group, the nitro group is converted to the corresponding aniline by any number of standard reduction conditions (eg SnCl2 reduction). This is followed by conversion of the resulting aniline to the diazonium salt which is then converted “in situ” either directly to R5 either directly in the case where R5 is F, Cl, Br, CN, OH, C1-C4 alkoxy or SR6, by using the appropriate copper salt ie CuCl, CuBr, CuCN or nucleophile ie water, alcohol or thiol or in a subsequent step e.g. oxidation (eg with MCPBA) of the product of thiol coupling when R5 is S(O)2R6; e.g. Suzuki coupling of the bromide product when R5 is heteroaryl e.g. treatment of an intermediate sulfonylchloride obtained via CuCl/SO2 conditions with an amine HN(R7)2, when R5 is S(O)2N(R7)2, e.g. Burton trifluoromethylation reaction of the iodide product (Burton, D. J.; Wiemers, D. M. J. Am. Chem. Soc. 1985, 107, 5014 and 1986, 108, 832; Miller, J. A., Coleman, M. C.; Matthews, R. S. J. Org. Chem. 1993, 58, 2637) when R5 is CF3 Standard ester hydrolysis yields compounds of Formula XXIV.

Compounds of the disclosure of Formula III in which R1 is OH, OR6, SR6, NHR7, N(R7)2 NHC(O)R6 or NHCO2R6; R2 is H; Y is O, X is a bond, R3 is Z, R4 and R5 are as described previously and thus having general Formula XXVII may be prepared generally as depicted in Scheme 2. Thus, as depicted in Scheme 2 bromination of intermediates of general Formula XXV, prepared according to Scheme 1, e.g. with N-bromosuccinimide (NBS) yields intermediate XXVI. In a subsequent step the Br atom is replaced by a suitable alkoxide, thiolate or masked amine nucleophile (eg azide or N3). The product of the latter reaction is either directly subjected to ester hydrolysis or further processed in optional steps (eg by conversion the masked amine to an amino group followed by reductive amination to give mono or dialkylamine derivatives, and optionally acylation or carbamoylation of such amine derivatives) and then subjected to final ester hydrolysis to give compounds of Formula XXVII in which R10 is OH, OR6, SR6, NHR7, N(R7)2 NHC(O)R6 or NHCO2R6

Compounds of the disclosure of Formula III and IV in which R1 is R8 an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R2 is R9 a hydrogen, alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, X and Y are a bond, R3 and R4 are respectively Z1 and Z2 representing independently chosen Z groups as defined above and R5 is as described previously and thus having general Formula XXX may be prepared generally as depicted in Scheme 3 starting from compounds of general Formula XXII which can be prepared as described in Scheme 1.

Compounds of Formula V in which R1 is R8 an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R2 is R9 a hydrogen, alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl; X is Q=O, S, or SO2; R5 is F or Cl; R3 and Z are as described previously and thus having general Formula XXXIV may be prepared generally as depicted in Scheme 4. Accordingly, the 4-halo group of 2,4,5-trifluoronitrobenzene or 2,4,5-trichloronitrobenzene is selectively displaced by reaction with a 2-substituted diethylmalonate R8YCH(CO2Et)2 under basic conditions (eg NaH/DMF) followed by hydrolysis and esterification to give intermediate XXXI. Subsequently the 2-halo group undergoes nucleophilic aromatic substitution reaction by treatment with a R3-J-H compound (wherein J is O, S) under basic conditions (eg NaH/DMF) followed by reduction and Sandmeyer reaction to give iodide XXXII.

Suzuki coupling then gives intermediates of general formula XXXIII. Introduction of an R9 group may be conducted using alkylation conditions described above. Compounds wherein J is SO2 may be prepared by standard oxidation of intermediates XXXIII wherein J is S. Final products having general Formula XXXIV are then prepared by standard ester hydrolysis.

Compounds of Formula IV in which R1 is R8 an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R2 is R9 a hydrogen, alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl; X is O; R5 is Cl; R3 and Z are as described previously and thus having general Formula XXXVIII may be prepared generally as depicted in Scheme 5. Accordingly, the 4-fluoro group of 2,4-difluoronitrobenzene is selectively displaced by reaction with a 2-substituted diethylmalonate R8CH2(CO2Et)2 under basic conditions (eg NaH/DMF) followed by hydrolysis and esterification to give intermediate XXXV. Subsequently the 2-halo group undergoes nucleophilic aromatic substitution reaction by treatment with a R3—O—H compound under basic conditions (eg NaH/DMF) followed by reduction and chlorination reaction (eg with N-chlorosuccinimide) to give chloroaniline intermediates of general formula XXXVI. Sandmeyer iodination reaction to followed by Suzuki coupling then gives intermediates of general formula XXXVII. Introduction of an R9 group may be conducted using alkylation conditions described above. Final products having general Formula XXXVIII are then prepared by standard ester hydrolysis.

Compounds of Formula IV in which R1 is R8 an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R2 is R9 a hydrogen, alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl; X is J=O, S; R5 is NO2, NH2, CN, SR6, SO2R6, SO2N(R7)2 F, Cl, Br; R3 and Z are as described previously and thus having general Formula XLII may be prepared generally as depicted in Scheme 6. Accordingly, the 2-fluoro group of 2,4-difluoronitrobenzene is selectively displaced by reaction with a an alcohol or thiol of formula R3-J-H under basic conditions (eg NaH/DMF). The 4-fluoro group of the resulting product is substituted with diethylmalonate under basic conditions (eg NaH/DMF) followed by hydrolysis and esterification to give intermediates of Formula XXXIX. Reduction of the nitro group of XXXIX followed by nitration of the resulting aniline give nitroaniline intermediates of Formula XL. Sandmeyer iodination reaction, followed by Suzuki coupling and finally alkylation reaction to introduce R8 then gives intermediates of general Formula XLI. The nitro group of XLI may be optionally reduced via any number of standard reduction conditions (eg SnCl2) to an aniline which may in turn optionally be converted to diverse other R5 groups either directly or in multistep procedures. Thus, in the case where R5 is F, Cl, Br, CN, OH, C1-C4 alkoxy or SR6, diazotization of the aniline is followed by direct “in situ” conversion to R5 using the appropriate copper salt ie CuCl, CuBr, CuCN or nucleophile ie water, alcohol or thiol. Intermediates where R5 is S(O)2R6 may be prepared by subsequent step oxidation (eg with MCPBA) of the above products of thiol coupling wherein R5 is SR6. Intermediates where R5 is eg heteroaryl, C2-C4 alkynyl or cyclopropyl may be prepared by subsequent Suzuki coupling of the above products wherein R5 is Br or I. Intermediates where R5 is CF3 may be prepared by Burton reaction of the above products wherein R5 is I. Intermediates where R5 is S(O)2N(R7)2, may be prepared by subsequent reaction of above direct sulfonylchloride products (obtained via CuCl/SO2 conditions) with an amine HN(R7)2, Final products having general Formula XLII are then prepared by optional alkylation reaction to introduce R9 followed by standard ester hydrolysis.

ll

Compounds of Formula VII in which R1 is R8 an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R2 is R9 a hydrogen, alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl; X is J=O, S; R5 is NO2, NH2, CN, SR6, SO2R6, SO2N(R7)2 F, Cl, Br; R3 and Z are as described previously and thus having general Formula XLV may be prepared generally as depicted in Scheme 7. Reduction of the nitro group of XXXIX followed by bromination (eg with NBS) of the resulting aniline and prepared by 1 alkylation reaction to introduce R9 gives bromoaniline intermediates of Formula XLIII Suzuki coupling reaction substitutes Z groups for the Br group to give intermediates of general Formula XLIV. The aniline group in intermediates of Formula XLIV may in turn optionally be converted to diverse other R5 groups either directly or in multistep procedures. Thus, in the case where R5 is F, Cl, Br, CN, OH, C1-C4 alkoxy or SR6, diazotization of the aniline is followed by direct “in situ” conversion to R5 using the appropriate copper salt ie CuCl, CuBr, CuCN or nucleophile ie water, alcohol or thiol. Intermediates where R5 is S(O)2R6 may be prepared by subsequent step oxidation (eg with MCPBA) of the above products of thiol coupling wherein R5 is SR6. Intermediates where R5 is eg heteroaryl, C2-C4 alkynyl or cyclopropyl may be prepared by subsequent Suzuki coupling of the above products wherein R5 is Br or I. Intermediates where R5 is CF3 may be prepared by Burton reaction of the above products wherein R5 is I. Intermediates where R5 is S(O)2N(R7)2, may be prepared by subsequent reaction of above direct sulfonylchloride products (obtained via CuCl/SO2 conditions) with an amine HN(R7)2, Final products having general Formula XLII are then prepared by optional alkylation reaction to introduce R9 followed by standard ester hydrolysis.

Compounds of Formula IV in which R1 is R8 an alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R2 is R9 a hydrogen, alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl; X—R3 and R5 are identical (J-R3 in Scheme 8) and are either C1-C4 alkoxy or SR6 groups; and Z is as described previously and thus having general Formula L may be prepared generally as depicted in Scheme 8. Accordingly, the 2 and 6-fluoro groups of 2,4,6-trifluoronitrobenzene are selectively displaced by reaction with a an alcohol or thiol of formula R3-J-H under basic conditions (eg NaH/DMF). The 4-fluoro group of the resulting product is substituted with diethylmalonate under basic conditions (eg NaH/DMF) followed by hydrolysis and esterification to give intermediates of Formula XLVIII. Reduction of the nitro group of followed by Sandmeyer iodination reaction of the resulting aniline gives intermediates of Formula XLVIII. Suzuki coupling and followed by alkylation reaction to introduce R8 then gives intermediates of general Formula XLIX. Final products having general Formula L are then prepared by optional alkylation reaction to introduce R9 followed by standard ester hydrolysis.

Enantioselective Methods

Compounds of formulas I-IX may be prepared in an enantioselectively, this can be accomplished via resolution via chiral HPLC (CHIRALPAK-AD H (250×4.6 mm, 5 μm). Mobile phase: Hexane (0.1% TFA):IPA (93:7), Flow rate 0.8 mL/min., Diluent Hexane:IPA (90:10); Column temperature 40° C.) or via asymmetric synthesis. The phenyl acetic acids of formula (XXXV) are converted into the corresponding acid chlorides, via treatment with SOCl2 or oxalyl chloride with a catalytic amount of DMF. The reaction is performed in an inert solvent such as CH2Cl2, CHCl3, THF, or toluene at a temperature of 0-80° C. The acid chloride is treated with either (R)- or (S)-4-benzyloxazolidin-2-one to (R isomer depicted-XXXXVI) give the oxazolidinone (XXXVII). The oxazolidinone ( ) is then subjected to a base such as NaHMDs, LiHMDS, KHMDS, BuLi or KOtBu in an inert solvent such as THF, Me-THF or Et2O at a temperature of −78 to 0° C. The subsequent enolate is then treated with the appropriate electrophile to give the alkylated oxazolidinone (XXXVIII). The chiral auxillary is removed under conditions such as LiOH/H2O2 followed by a reductive work up with a reagent such as sodium bi-sulfite to give the desired products of formulas (I-IX).

Alternatively the racemic compound of formula (I-IX) may be coupled to the Evans chiral oxazolidinone via an intermediate such as the corresponding acid chloride. Upon completion of the coupling, the reaction produces a mixture of diastereoisomers which may be separated by methods such as flash chromatography or crystallization to give single diastereoisomers or enriched mixtures favouring one diastereoisomer over the other (see scheme 10). The auxillary may be removed as described previously.

Examples of enantiomers include but are not limited to;

  • (R)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic acid
  • (S)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic acid
  • (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetic acid compound (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid
  • (R)-2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid
  • (S)-2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid
  • (R)-4-methyl-2-(5-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-3-yl)pentanoic acid
  • (S)-4-methyl-2-(5-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-3-yl)pentanoic acid
  • (R)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic acid
  • (S)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic acid
  • (R)-4-methyl-2-(6-(2,2,2-trifluoroethoxy)-4′,5-bis(trifluoromethyl)biphenyl-3-yl)pentanoic acid
  • (S)-4-methyl-2-(6-(2,2,2-trifluoroethoxy)-4′,5-bis(trifluoromethyl)biphenyl-3-yl)pentanoic acid
  • (R)-3-cyclopropyl-2-(6-(2,2,2-trifluoroethoxy)-4′,5-bis(trifluoromethyl)biphenyl-3-yl)propanoic acid
  • (S)-3-cyclopropyl-2-(6-(2,2,2-trifluoroethoxy)-4′,5-bis(trifluoromethyl)biphenyl-3-yl)propanoic acid
  • (R)-3-cyclopropyl-2-(5-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-3-yl)propanoic acid
  • (S)-3-cyclopropyl-2-(5-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-3-yl)propanoic acid
  • (R)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic acid
  • (S)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic acid
  • (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid
  • (S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid
  • (R)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-4-methylpentanoic acid
  • (S)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-4-methylpentanoic acid
  • (R)-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoic acid
  • (S)-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoic acid
  • (R)-3-cyclopropyl-2-(2-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-4-yl)propanoic acid compound
  • (S)-3-cyclopropyl-2-(2-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-4-yl)propanoic acid compound
  • (R)-2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic acid
  • (S)-2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic acid
  • (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid
  • (S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid
  • (R)-2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic acid
  • (S)-2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic acid
  • (S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetic acid
  • (S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid
  • (R)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-2-cyclopentylacetic acid
  • (S)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-2-cyclopentylacetic acid
  • (R)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclobutylpropanoic acid
  • (S)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclobutylpropanoic acid
  • (R)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid
  • (S)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid
  • (R)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-4-methylpentanoic acid
  • (S)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-4-methylpentanoic acid
  • (R)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-2-cyclopentylacetic acid
  • (S)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-2-cyclopentylacetic acid
  • (R)-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoic acid
  • (S)-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoic acid
  • (R)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclobutylpropanoic acid
  • (S)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclobutylpropanoic acid
  • (R)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid
  • (S)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid
  • (R)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-4-methylpentanoic acid
  • (S)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-4-methylpentanoic acid
  • (R)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic acid
  • (S)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic acid
  • (R)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic acid
  • (S)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic acid
  • (R)-2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid
  • (S)-2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid
  • (R)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic acid
  • (S)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic acid
  • (R)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-4-methylpentanoic acid
  • (S)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-4-methylpentanoic acid
  • (R)-2-(4-(benzo[c][1,2,5]thiadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic acid
  • (S)-2-(4-(benzo[c][1,2,5]thiadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic acid
  • (R)-2-(4-(benzo[c][1,2,5]thiadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic acid
  • (S)-2-(4-(benzo[c][1,2,5]thiadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic acid
  • (R)-4-methyl-2-(2-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-4-yl)pentanoic acid
  • (S)-4-methyl-2-(2-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-4-yl)pentanoic acid

In a further aspect the compounds of the disclosure are embodied in with distinct examples listed in Tables below.

TABLE 1 Formula III Ex R1 R2 Y R4 R5 Z 100 CH3 H O CH2CH3 F 4-fluorophenyl 101 CH2CH3 H O CH2CH3 F 4-fluorophenyl 102 CH2CF3 H O CH2CH3 F 4-fluorophenyl 103 CH2CH2CH3 H O CH2CH3 F 4-fluorophenyl 104 CH2CH(CH3)2 H O CH2CH3 F 4-fluorophenyl 105 cyclopropylmethyl H O CH2CH3 F 4-fluorophenyl 106 SCH(CH3)2 H O CH2CH3 F 4-fluorophenyl 107 OCH2CH3 H O CH2CH3 F 4-fluorophenyl 108 (CH2)2 O CH2CH3 F 4-fluorophenyl 109 (CH2)4 O CH2CH3 F 4-fluorophenyl 110 CH3 H O CH2CH3 F 4-chlorophenyl 111 CH2CH3 H O CH2CH3 F 4-chlorophenyl 112 CH2CF3 H O CH2CH3 F 4-chlorophenyl 113 CH2CH2CH3 H O CH2CH3 F 4-chlorophenyl 114 CH2CH(CH3)2 H O CH2CH3 F 4-chlorophenyl 115 cyclopropylmethyl H O CH2CH3 F 4-chlorophenyl 116 SCH(CH3)2 H O CH2CH3 F 4-chlorophenyl 117 OCH2CH3 H O CH2CH3 F 4-chlorophenyl 118 (CH2)2 O CH2CH3 F 4-chlorophenyl 119 (CH2)4 O CH2CH3 F 4-chlorophenyl 120 CH3 H O CH2CH3 F 4-trifluoromethylphenyl 121 CH2CH3 H O CH2CH3 F 4-trifluoromethylphenyl 122 CH2CF3 H O CH2CH3 F 4-trifluoromethylphenyl 123 CH2CH2CH3 H O CH2CH3 F 4-trifluoromethylphenyl 124 CH2CH(CH3)2 H O CH2CH3 F 4-trifluoromethylphenyl 125 cyclopropylmethyl H O CH2CH3 F 4-trifluoromethylphenyl 126 SCH(CH3)2 H O CH2CH3 F 4-trifluoromethylphenyl 127 OCH2CH3 H O CH2CH3 F 4-trifluoromethylphenyl 128 (CH2)2 O CH2CH3 F 4-trifluoromethylphenyl 129 (CH2)4 O CH2CH3 F 4-trifluoromethylphenyl 130 CH3 H O CH2CH3 F 4-methoxyphenyl 131 CH2CH3 H O CH2CH3 F 4-methoxyphenyl 132 CH2CF3 H O CH2CH3 F 4-methoxyphenyl 133 CH2CH2CH3 H O CH2CH3 F 4-methoxyphenyl 134 CH2CH(CH3)2 H O CH2CH3 F 4-methoxyphenyl 135 cyclopropylmethyl H O CH2CH3 F 4-methoxyphenyl 136 SCH(CH3)2 H O CH2CH3 F 4-methoxyphenyl 137 OCH2CH3 H O CH2CH3 F 4-methoxyphenyl 138 (CH2)2 O CH2CH3 F 4-methoxyphenyl 139 (CH2)4 O CH2CH3 F 4-methoxyphenyl 140 CH3 H O CH2CH3 F 3,4 dichloro phenyl 141 CH2CH3 H O CH2CH3 F 3,4 dichloro phenyl 142 CH2CF3 H O CH2CH3 F 3,4 dichloro phenyl 143 CH2CH2CH3 H O CH2CH3 F 3,4 dichloro phenyl 144 CH2CH(CH3)2 H O CH2CH3 F 3,4 dichloro phenyl 145 cyclopropylmethyl H O CH2CH3 F 3,4 dichloro phenyl 146 SCH(CH3)2 H O CH2CH3 F 3,4 dichloro phenyl 147 OCH2CH3 H O CH2CH3 F 3,4 dichloro phenyl 148 (CH2)2 O CH2CH3 F 3,4 dichloro phenyl 149 (CH2)4 O CH2CH3 F 3,4 dichloro phenyl 150 CH3 H O CH2CH3 F 5-benzo[c][1,2,5]- oxadiazolyl 151 CH2CH3 H O CH2CH3 F 5-benzo[c][1,2,5]- oxadiazolyl 152 CH2CF3 H O CH2CH3 F 5-benzo[c][1,2,5]- oxadiazolyl 153 CH2CH2CH3 H O CH2CH3 F 5-benzo[c][1,2,5]- oxadiazolyl 154 CH2CH(CH3)2 H O CH2CH3 F 5-benzo[c][1,2,5]- oxadiazolyl 155 cyclopropylmethyl H O CH2CH3 F 5-benzo[c][1,2,5]- oxadiazolyl 156 SCH(CH3)2 H O CH2CH3 F 5-benzo[c][1,2,5]- oxadiazolyl 157 OCH2CH3 H O CH2CH3 F 5-benzo[c][1,2,5]- oxadiazolyl 158 (CH2)2 O CH2CH3 F 5-benzo[c][1,2,5]- oxadiazolyl 159 (CH2)4 O CH2CH3 F 5-benzo[c][1,2,5]- oxadiazolyl 160 CH3 H O CH2CH3 F 5-benzo[c][1,2,5]- thiadiazolyl 161 CH2CH3 H O CH2CH3 F 5-benzo[c][1,2,5]- thiadiazolyl 162 CH2CF3 H O CH2CH3 F 5-benzo[c][1,2,5]- thiadiazolyl 163 CH2CH2CH3 H O CH2CH3 F 5-benzo[c][1,2,5]- thiadiazolyl 164 CH2CH(CH3)2 H O CH2CH3 F 5-benzo[c][1,2,5]- thiadiazolyl 165 cyclopropylmethyl H O CH2CH3 F 5-benzo[c][1,2,5]- thiadiazolyl 166 SCH(CH3)2 H O CH2CH3 F 5-benzo[c][1,2,5]- thiadiazolyl 167 OCH2CH3 H O CH2CH3 F 5-benzo[c][1,2,5]- thiadiazolyl 168 (CH2)2 O CH2CH3 F 5-benzo[c][1,2,5]- thiadiazolyl 169 (CH2)4 O CH2CH3 F 5-benzo[c][1,2,5]- thiadiazolyl 170 CH3 H O CH2CF3 F 4-fluorophenyl 171 CH2CH3 H O CH2CF3 F 4-fluorophenyl 172 CH2CF3 H O CH2CF3 F 4-fluorophenyl 173 CH2CH2CH3 H O CH2CF3 F 4-fluorophenyl 174 CH2CH(CH3)2 H O CH2CF3 F 4-fluorophenyl 175 cyclopropylmethyl H O CH2CF3 F 4-fluorophenyl 176 SCH(CH3)2 H O CH2CF3 F 4-fluorophenyl 177 OCH2CH3 H O CH2CF3 F 4-fluorophenyl 178 (CH2)2 O CH2CF3 F 4-fluorophenyl 179 (CH2)4 O CH2CF3 F 4-fluorophenyl 180 CH3 H O CH2CF3 F 4-chlorophenyl 181 CH2CH3 H O CH2CF3 F 4-chlorophenyl 182 CH2CF3 H O CH2CF3 F 4-chlorophenyl 183 CH2CH2CH3 H O CH2CF3 F 4-chlorophenyl 184 CH2CH(CH3)2 H O CH2CF3 F 4-chlorophenyl 185 cyclopropylmethyl H O CH2CF3 F 4-chlorophenyl 186 SCH(CH3)2 H O CH2CF3 F 4-chlorophenyl 187 OCH2CH3 H O CH2CF3 F 4-chlorophenyl 188 (CH2)2 O CH2CF3 F 4-chlorophenyl 189 (CH2)4 O CH2CF3 F 4-chlorophenyl 190 CH3 H O CH2CF3 F 4-trifluoromethylphenyl 191 CH2CH3 H O CH2CF3 F 4-trifluoromethylphenyl 192 CH2CF3 H O CH2CF3 F 4-trifluoromethylphenyl 193 CH2CH2CH3 H O CH2CF3 F 4-trifluoromethylphenyl 194 CH2CH(CH3)2 H O CH2CF3 F 4-trifluoromethylphenyl 195 cyclopropylmethyl H O CH2CF3 F 4-trifluoromethylphenyl 196 SCH(CH3)2 H O CH2CF3 F 4-trifluoromethylphenyl 197 OCH2CH3 H O CH2CF3 F 4-trifluoromethylphenyl 198 (CH2)2 O CH2CF3 F 4-trifluoromethylphenyl 199 (CH2)4 O CH2CF3 F 4-trifluoromethylphenyl 200 CH3 H O CH2CF3 F 4-methoxyphenyl 201 CH2CH3 H O CH2CF3 F 4-methoxyphenyl 202 CH2CF3 H O CH2CF3 F 4-methoxyphenyl 203 CH2CH2CH3 H O CH2CF3 F 4-methoxyphenyl 204 CH2CH(CH3)2 H O CH2CF3 F 4-methoxyphenyl 205 cyclopropylmethyl H O CH2CF3 F 4-methoxyphenyl 206 SCH(CH3)2 H O CH2CF3 F 4-methoxyphenyl 207 OCH2CH3 H O CH2CF3 F 4-methoxyphenyl 208 (CH2)2 O CH2CF3 F 4-methoxyphenyl 209 (CH2)4 O CH2CF3 F 4-methoxyphenyl 210 CH3 H O CH2CF3 F 3,4 dichloro phenyl 211 CH2CH3 H O CH2CF3 F 3,4 dichloro phenyl 212 CH2CF3 H O CH2CF3 F 3,4 dichloro phenyl 213 CH2CH2CH3 H O CH2CF3 F 3,4 dichloro phenyl 214 CH2CH(CH3)2 H O CH2CF3 F 3,4 dichloro phenyl 215 cyclopropylmethyl H O CH2CF3 F 3,4 dichloro phenyl 216 SCH(CH3)2 H O CH2CF3 F 3,4 dichloro phenyl 217 OCH2CH3 H O CH2CF3 F 3,4 dichloro phenyl 218 (CH2)2 O CH2CF3 F 3,4 dichloro phenyl 219 (CH2)4 O CH2CF3 F 3,4 dichloro phenyl 220 CH3 H O CH2CF3 F 5-benzo[c][1,2,5]- oxadiazolyl 221 CH2CH3 H O CH2CF3 F 5-benzo[c][1,2,5]- oxadiazolyl 222 CH2CF3 H O CH2CF3 F 5-benzo[c][1,2,5]- oxadiazolyl 223 CH2CH2CH3 H O CH2CF3 F 5-benzo[c][1,2,5]- oxadiazolyl 224 CH2CH(CH3)2 H O CH2CF3 F 5-benzo[c][1,2,5]- oxadiazolyl 225 cyclopropylmethyl H O CH2CF3 F 5-benzo[c][1,2,5]- oxadiazolyl 226 SCH(CH3)2 H O CH2CF3 F 5-benzo[c][1,2,5]- oxadiazolyl 227 OCH2CH3 H O CH2CF3 F 5-benzo[c][1,2,5]- oxadiazolyl 228 (CH2)2 O CH2CF3 F 5-benzo[c][1,2,5]- oxadiazolyl 229 (CH2)4 O CH2CF3 F 5-benzo[c][1,2,5]- oxadiazolyl 230 CH3 H O CH2CF3 F 5-benzo[c][1,2,5]- thiadiazolyl 231 CH2CH3 H O CH2CF3 F 5-benzo[c][1,2,5]- thiadiazolyl 232 CH2CF3 H O CH2CF3 F 5-benzo[c][1,2,5]- thiadiazolyl 233 CH2CH2CH3 H O CH2CF3 F 5-benzo[c][1,2,5]- thiadiazolyl 234 CH2CH(CH3)2 H O CH2CF3 F 5-benzo[c][1,2,5]- thiadiazolyl 235 cyclopropylmethyl H O CH2CF3 F 5-benzo[c][1,2,5]- thiadiazolyl 236 SCH(CH3)2 H O CH2CF3 F 5-benzo[c][1,2,5]- thiadiazolyl 237 OCH2CH3 H O CH2CF3 F 5-benzo[c][1,2,5]- thiadiazolyl 238 (CH2)2 O CH2CF3 F 5-benzo[c][1,2,5]- thiadiazolyl 239 (CH2)4 O CH2CF3 F 5-benzo[c][1,2,5]- thiadiazolyl 240 CH3 H O CH2-c-Pr F 4-fluorophenyl 241 CH2CH3 H O CH2-c-Pr F 4-fluorophenyl 242 CH2CF3 H O CH2-c-Pr F 4-fluorophenyl 243 CH2CH2CH3 H O CH2-c-Pr F 4-fluorophenyl 244 CH2CH(CH3)2 H O CH2-c-Pr F 4-fluorophenyl 245 cyclopropylmethyl H O CH2-c-Pr F 4-fluorophenyl 246 SCH(CH3)2 H O CH2-c-Pr F 4-fluorophenyl 247 OCH2CH3 H O CH2-c-Pr F 4-fluorophenyl 248 (CH2)2 0 CH2-c-Pr F 4-fluorophenyl 249 (CH2)4 0 CH2-c-Pr F 4-fluorophenyl 250 CH3 H O CH2-c-Pr F 4-chlorophenyl 251 CH2CH3 H O CH2-c-Pr F 4-chlorophenyl 252 CH2CF3 H O CH2-c-Pr F 4-chlorophenyl 253 CH2CH2CH3 H O CH2-c-Pr F 4-chlorophenyl 254 CH2CH(CH3)2 H O CH2-c-Pr F 4-chlorophenyl 255 cyclopropylmethyl H O CH2-c-Pr F 4-chlorophenyl 256 SCH(CH3)2 H O CH2-c-Pr F 4-chlorophenyl 257 OCH2CH3 H O CH2-c-Pr F 4-chlorophenyl 258 (CH2)2 O CH2-c-Pr F 4-chlorophenyl 259 (CH2)4 O CH2-c-Pr F 4-chlorophenyl 260 CH3 H O CH2-c-Pr F 4-trifluoromethylphenyl 261 CH2CH3 H O CH2-c-Pr F 4-trifluoromethylphenyl 262 CH2CF3 H O CH2-c-Pr F 4-trifluoromethylphenyl 263 CH2CH2CH3 H O CH2-c-Pr F 4-trifluoromethylphenyl 264 CH2CH(CH3)2 H O CH2-c-Pr F 4-trifluoromethylphenyl 265 cyclopropylmethyl H O CH2-c-Pr F 4-trifluoromethylphenyl 266 SCH(CH3)2 H O CH2-c-Pr F 4-trifluoromethylphenyl 267 OCH2CH3 H O CH2-c-Pr F 4-trifluoromethylphenyl 268 (CH2)2 0 CH2-c-Pr F 4-trifluoromethylphenyl 269 (CH2)4 0 CH2-c-Pr F 4-trifluoromethylphenyl 270 CH3 H O CH2-c-Pr F 4-methoxyphenyl 271 CH2CH3 H O CH2-c-Pr F 4-methoxyphenyl 272 CH2CF3 H O CH2-c-Pr F 4-methoxyphenyl 273 CH2CH2CH3 H O CH2-c-Pr F 4-methoxyphenyl 274 CH2CH(CH3)2 H O CH2-c-Pr F 4-methoxyphenyl 275 cyclopropylmethyl H O CH2-c-Pr F 4-methoxyphenyl 276 SCH(CH3)2 H O CH2-c-Pr F 4-methoxyphenyl 277 OCH2CH3 H O CH2-c-Pr F 4-methoxyphenyl 278 (CH2)2 O CH2-c-Pr F 4-methoxyphenyl 279 (CH2)4 O CH2-c-Pr F 4-methoxyphenyl 280 CH3 H O CH2-c-Pr F 3,4 dichloro phenyl 281 CH2CH3 H O CH2-c-Pr F 3,4 dichloro phenyl 282 CH2CF3 H O CH2-c-Pr F 3,4 dichloro phenyl 283 CH2CH2CH3 H O CH2-c-Pr F 3,4 dichloro phenyl 284 CH2CH(CH3)2 H O CH2-c-Pr F 3,4 dichloro phenyl 285 cyclopropylmethyl H O CH2-c-Pr F 3,4 dichloro phenyl 286 SCH(CH3)2 H O CH2-c-Pr F 3,4 dichloro phenyl 287 OCH2CH3 H O CH2-c-Pr F 3,4 dichloro phenyl 288 (CH2)2 O CH2-c-Pr F 3,4 dichloro phenyl 289 (CH2)4 O CH2-c-Pr F 3,4 dichloro phenyl 290 CH3 H O CH2-c-Pr F 5-benzo[c][1,2,5]- oxadiazolyl 291 CH2CH3 H O CH2-c-Pr F 5-benzo[c][1,2,5]- oxadiazolyl 292 CH2CF3 H O CH2-c-Pr F 5-benzo[c][1,2,5]- oxadiazolyl 293 CH2CH2CH3 H O CH2-c-Pr F 5-benzo[c][1,2,5]- oxadiazolyl 294 CH2CH(CH3)2 H O CH2-c-Pr F 5-benzo[c][1,2,5]- oxadiazolyl 295 cyclopropylmethyl H O CH2-c-Pr F 5-benzo[c][1,2,5]- oxadiazolyl 296 SCH(CH3)2 H O CH2-c-Pr F 5-benzo[c][1,2,5]- oxadiazolyl 297 OCH2CH3 H O CH2-c-Pr F 5-benzo[c][1,2,5]- oxadiazolyl 298 (CH2)2 O CH2-c-Pr F 5-benzo[c][1,2,5]- oxadiazolyl 299 (CH2)4 O CH2-c-Pr F 5-benzo[c][1,2,5]- oxadiazolyl 300 CH3 H O CH2-c-Pr F 5-benzo[c][1,2,5]- thiadiazolyl 301 CH2CH3 H O CH2-c-Pr F 5-benzo[c][1,2,5]- thiadiazolyl 302 CH2CF3 H O CH2-c-Pr F 5-benzo[c][1,2,5]- thiadiazolyl 303 CH2CH2CH3 H O CH2-c-Pr F 5-benzo[c][1,2,5]- thiadiazolyl 304 CH2CH(CH3)2 H O CH2-c-Pr F 5-benzo[c][1,2,5]- thiadiazolyl 305 cyclopropylmethyl H O CH2-c-Pr F 5-benzo[c][1,2,5]- thiadiazolyl 306 SCH(CH3)2 H O CH2-c-Pr F 5-benzo[c][1,2,5]- thiadiazolyl 307 OCH2CH3 H O CH2-c-Pr F 5-benzo[c][1,2,5]- thiadiazolyl 308 (CH2)2 O CH2-c-Pr F 5-benzo[c][1,2,5]- thiadiazolyl 309 (CH2)4 O CH2-c-Pr F 5-benzo[c][1,2,5]- thiadiazolyl 310 CH3 H O CH2CH3 Cl 4-fluorophenyl 311 CH2CH3 H O CH2CH3 Cl 4-fluorophenyl 312 CH2CF3 H O CH2CH3 Cl 4-fluorophenyl 313 CH2CH2CH3 H O CH2CH3 Cl 4-fluorophenyl 314 CH2CH(CH3)2 H O CH2CH3 Cl 4-fluorophenyl 315 cyclopropylmethyl H O CH2CH3 Cl 4-fluorophenyl 316 SCH(CH3)2 H O CH2CH3 Cl 4-fluorophenyl 317 OCH2CH3 H O CH2CH3 Cl 4-fluorophenyl 318 (CH2)2 O CH2CH3 Cl 4-fluorophenyl 319 (CH2)4 O CH2CH3 Cl 4-fluorophenyl 320 CH3 H O CH2CH3 Cl 4-chlorophenyl 321 CH2CH3 H O CH2CH3 Cl 4-chlorophenyl 322 CH2CF3 H O CH2CH3 Cl 4-chlorophenyl 323 CH2CH2CH3 H O CH2CH3 Cl 4-chlorophenyl 324 CH2CH(CH3)2 H O CH2CH3 Cl 4-chlorophenyl 325 cyclopropylmethyl H O CH2CH3 Cl 4-chlorophenyl 326 SCH(CH3)2 H O CH2CH3 Cl 4-chlorophenyl 327 OCH2CH3 H O CH2CH3 Cl 4-chlorophenyl 328 (CH2)2 O CH2CH3 Cl 4-chlorophenyl 329 (CH2)4 O CH2CH3 Cl 4-chlorophenyl 330 CH3 H O CH2CH3 Cl 4-trifluoromethylphenyl 331 CH2CH3 H O CH2CH3 Cl 4-trifluoromethylphenyl 332 CH2CF3 H O CH2CH3 Cl 4-trifluoromethylphenyl 333 CH2CH2CH3 H O CH2CH3 Cl 4-trifluoromethylphenyl 334 CH2CH(CH3)2 H O CH2CH3 Cl 4-trifluoromethylphenyl 335 cyclopropylmethyl H O CH2CH3 Cl 4-trifluoromethylphenyl 336 SCH(CH3)2 H O CH2CH3 Cl 4-trifluoromethylphenyl 337 OCH2CH3 H O CH2CH3 Cl 4-trifluoromethylphenyl 338 (CH2)2 O CH2CH3 Cl 4-trifluoromethylphenyl 339 (CH2)4 O CH2CH3 Cl 4-trifluoromethylphenyl 340 CH3 H O CH2CH3 Cl 4-methoxyphenyl 341 CH2CH3 H O CH2CH3 Cl 4-methoxyphenyl 342 CH2CF3 H O CH2CH3 Cl 4-methoxyphenyl 343 CH2CH2CH3 H O CH2CH3 Cl 4-methoxyphenyl 344 CH2CH(CH3)2 H O CH2CH3 Cl 4-methoxyphenyl 345 cyclopropylmethyl H O CH2CH3 Cl 4-methoxyphenyl 346 SCH(CH3)2 H O CH2CH3 Cl 4-methoxyphenyl 347 OCH2CH3 H O CH2CH3 Cl 4-methoxyphenyl 348 (CH2)2 O CH2CH3 Cl 4-methoxyphenyl 349 (CH2)4 O CH2CH3 Cl 4-methoxyphenyl 350 CH3 H O CH2CH3 Cl 3,4 dichloro phenyl 351 CH2CH3 H O CH2CH3 Cl 3,4 dichloro phenyl 352 CH2CF3 H O CH2CH3 Cl 3,4 dichloro phenyl 353 CH2CH2CH3 H O CH2CH3 Cl 3,4 dichloro phenyl 354 CH2CH(CH3)2 H O CH2CH3 Cl 3,4 dichloro phenyl 355 cyclopropylmethyl H O CH2CH3 Cl 3,4 dichloro phenyl 356 SCH(CH3)2 H O CH2CH3 Cl 3,4 dichloro phenyl 357 OCH2CH3 H O CH2CH3 Cl 3,4 dichloro phenyl 358 (CH2)2 O CH2CH3 Cl 3,4 dichloro phenyl 359 (CH2)4 O CH2CH3 Cl 3,4 dichloro phenyl 360 CH3 H O CH2CH3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 361 CH2CH3 H O CH2CH3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 362 CH2CF3 H O CH2CH3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 363 CH2CH2CH3 H O CH2CH3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 364 CH2CH(CH3)2 H O CH2CH3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 365 cyclopropylmethyl H O CH2CH3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 366 SCH(CH3)2 H O CH2CH3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 367 OCH2CH3 H O CH2CH3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 368 (CH2)2 O CH2CH3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 369 (CH2)4 O CH2CH3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 370 CH3 H O CH2CH3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 371 CH2CH3 H O CH2CH3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 372 CH2CF3 H O CH2CH3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 373 CH2CH2CH3 H O CH2CH3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 374 CH2CH(CH3)2 H O CH2CH3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 375 cyclopropylmethyl H O CH2CH3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 376 SCH(CH3)2 H O CH2CH3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 377 OCH2CH3 H O CH2CH3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 378 (CH2)2 O CH2CH3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 379 (CH2)4 O CH2CH3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 380 CH3 H O CH2CF3 Cl 4-fluorophenyl 381 CH2CH3 H O CH2CF3 Cl 4-fluorophenyl 382 CH2CF3 H O CH2CF3 Cl 4-fluorophenyl 383 CH2CH2CH3 H O CH2CF3 Cl 4-fluorophenyl 384 CH2CH(CH3)2 H O CH2CF3 Cl 4-fluorophenyl 385 cyclopropylmethyl H O CH2CF3 Cl 4-fluorophenyl 386 SCH(CH3)2 H O CH2CF3 Cl 4-fluorophenyl 387 OCH2CH3 H O CH2CF3 Cl 4-fluorophenyl 388 (CH2)2 0 O CH2CF3 Cl 4-fluorophenyl 389 (CH2)4 0 O CH2CF3 Cl 4-fluorophenyl 400 CH3 H O CH2CF3 Cl 4-chlorophenyl 401 CH2CH3 H O CH2CF3 Cl 4-chlorophenyl 402 CH2CF3 H O CH2CF3 Cl 4-chlorophenyl 403 CH2CH2CH3 H O CH2CF3 Cl 4-chlorophenyl 404 CH2CH(CH3)2 H O CH2CF3 Cl 4-chlorophenyl 405 cyclopropylmethyl H O CH2CF3 Cl 4-chlorophenyl 406 SCH(CH3)2 H O CH2CF3 Cl 4-chlorophenyl 407 OCH2CH3 H O CH2CF3 Cl 4-chlorophenyl 408 (CH2)2 O CH2CF3 Cl 4-chlorophenyl 409 (CH2)4 O CH2CF3 Cl 4-chlorophenyl 410 CH3 H O CH2CF3 Cl 4-trifluoromethylphenyl 411 CH2CH3 H O CH2CF3 Cl 4-trifluoromethylphenyl 412 CH2CF3 H O CH2CF3 Cl 4-trifluoromethylphenyl 413 CH2CH2CH3 H O CH2CF3 Cl 4-trifluoromethylphenyl 414 CH2CH(CH3)2 H O CH2CF3 Cl 4-trifluoromethylphenyl 415 cyclopropylmethyl H O CH2CF3 Cl 4-trifluoromethylphenyl 416 SCH(CH3)2 H O CH2CF3 Cl 4-trifluoromethylphenyl 417 OCH2CH3 H O CH2CF3 Cl 4-trifluoromethylphenyl 418 (CH2)2 O CH2CF3 Cl 4-trifluoromethylphenyl 419 (CH2)4 O CH2CF3 Cl 4-trifluoromethylphenyl 420 CH3 H O CH2CF3 Cl 4-methoxyphenyl 421 CH2CH3 H O CH2CF3 Cl 4-methoxyphenyl 422 CH2CF3 H O CH2CF3 Cl 4-methoxyphenyl 423 CH2CH2CH3 H O CH2CF3 Cl 4-methoxyphenyl 424 CH2CH(CH3)2 H O CH2CF3 Cl 4-methoxyphenyl 425 cyclopropylmethyl H O CH2CF3 Cl 4-methoxyphenyl 426 SCH(CH3)2 H O CH2CF3 Cl 4-methoxyphenyl 427 OCH2CH3 H O CH2CF3 Cl 4-methoxyphenyl 428 (CH2)2 O CH2CF3 Cl 4-methoxyphenyl 429 (CH2)4 O CH2CF3 Cl 4-methoxyphenyl 430 CH3 H O CH2CF3 Cl 3,4 dichloro phenyl 431 CH2CH3 H O CH2CF3 Cl 3,4 dichloro phenyl 432 CH2CF3 H O CH2CF3 Cl 3,4 dichloro phenyl 433 CH2CH2CH3 H O CH2CF3 Cl 3,4 dichloro phenyl 434 CH2CH(CH3)2 H O CH2CF3 Cl 3,4 dichloro phenyl 435 cyclopropylmethyl H O CH2CF3 Cl 3,4 dichloro phenyl 436 SCH(CH3)2 H O CH2CF3 Cl 3,4 dichloro phenyl 437 OCH2CH3 H O CH2CF3 Cl 3,4 dichloro phenyl 438 (CH2)2 O CH2CF3 Cl 3,4 dichloro phenyl 439 (CH2)4 O CH2CF3 Cl 3,4 dichloro phenyl 440 CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 441 CH2CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 442 CH2CF3 H O CH2CF3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 443 CH2CH2CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 444 CH2CH(CH3)2 H O CH2CF3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 445 cyclopropylmethyl H O CH2CF3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 446 SCH(CH3)2 H O CH2CF3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 447 OCH2CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 448 (CH2)2 O CH2CF3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 449 (CH2)4 O CH2CF3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 450 CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 451 CH2CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 452 CH2CF3 H O CH2CF3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 453 CH2CH2CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 454 CH2CH(CH3)2 H O CH2CF3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 455 cyclopropylmethyl H O CH2CF3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 456 SCH(CH3)2 H O CH2CF3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 457 OCH2CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 458 (CH2)2 O CH2CF3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 459 (CH2)4 O CH2CF3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 460 CH3 H O CH2-c-Pr Cl 4-fluorophenyl 461 CH2CH3 H O CH2-c-Pr Cl 4-fluorophenyl 462 CH2CF3 H O CH2-c-Pr Cl 4-fluorophenyl 463 CH2CH2CH3 H O CH2-c-Pr Cl 4-fluorophenyl 464 CH2CH(CH3)2 H O CH2-c-Pr Cl 4-fluorophenyl 465 cyclopropylmethyl H O CH2-c-Pr Cl 4-fluorophenyl 466 SCH(CH3)2 H O CH2-c-Pr Cl 4-fluorophenyl 467 OCH2CH3 H O CH2-c-Pr Cl 4-fluorophenyl 468 (CH2)2 O CH2-c-Pr Cl 4-fluorophenyl 469 (CH2)4 O CH2-c-Pr Cl 4-fluorophenyl 470 CH3 H O CH2-c-Pr Cl 4-chlorophenyl 471 CH2CH3 H O CH2-c-Pr Cl 4-chlorophenyl 472 CH2CF3 H O CH2-c-Pr Cl 4-chlorophenyl 473 CH2CH2CH3 H O CH2-c-Pr Cl 4-chlorophenyl 474 CH2CH(CH3)2 H O CH2-c-Pr Cl 4-chlorophenyl 475 cyclopropylmethyl H O CH2-c-Pr Cl 4-chlorophenyl 476 SCH(CH3)2 H O CH2-c-Pr Cl 4-chlorophenyl 477 OCH2CH3 H O CH2-c-Pr Cl 4-chlorophenyl 478 (CH2)2 O CH2-c-Pr Cl 4-chlorophenyl 479 (CH2)4 O CH2-c-Pr Cl 4-chlorophenyl 480 CH3 H O CH2-c-Pr Cl 4-trifluoromethylphenyl 481 CH2CH3 H O CH2-c-Pr Cl 4-trifluoromethylphenyl 482 CH2CF3 H O CH2-c-Pr Cl 4-trifluoromethylphenyl 483 CH2CH2CH3 H O CH2-c-Pr Cl 4-trifluoromethylphenyl 484 CH2CH(CH3)2 H O CH2-c-Pr Cl 4-trifluoromethylphenyl 485 cyclopropylmethyl H O CH2-c-Pr Cl 4-trifluoromethylphenyl 486 SCH(CH3)2 H O CH2-c-Pr Cl 4-trifluoromethylphenyl 487 OCH2CH3 H O CH2-c-Pr Cl 4-trifluoromethylphenyl 488 (CH2)2 O CH2-c-Pr Cl 4-trifluoromethylphenyl 489 (CH2)4 O CH2-c-Pr Cl 4-trifluoromethylphenyl 490 CH3 H O CH2-c-Pr Cl 4-methoxyphenyl 491 CH2CH3 H O CH2-c-Pr Cl 4-methoxyphenyl 492 CH2CF3 H O CH2-c-Pr Cl 4-methoxyphenyl 493 CH2CH2CH3 H O CH2-c-Pr Cl 4-methoxyphenyl 494 CH2CH(CH3)2 H O CH2-c-Pr Cl 4-methoxyphenyl 495 cyclopropylmethyl H O CH2-c-Pr Cl 4-methoxyphenyl 496 SCH(CH3)2 H O CH2-c-Pr Cl 4-methoxyphenyl 497 OCH2CH3 H O CH2-c-Pr Cl 4-methoxyphenyl 498 (CH2)2 O CH2-c-Pr Cl 4-methoxyphenyl 499 (CH2)4 O CH2-c-Pr Cl 4-methoxyphenyl 500 CH3 H O CH2-c-Pr Cl 3,4 dichloro phenyl 501 CH2CH3 H O CH2-c-Pr Cl 3,4 dichloro phenyl 502 CH2CF3 H O CH2-c-Pr Cl 3,4 dichloro phenyl 503 CH2CH2CH3 H O CH2-c-Pr Cl 3,4 dichloro phenyl 504 CH2CH(CH3)2 H O CH2-c-Pr Cl 3,4 dichloro phenyl 505 cyclopropylmethyl H O CH2-c-Pr Cl 3,4 dichloro phenyl 506 SCH(CH3)2 H O CH2-c-Pr Cl 3,4 dichloro phenyl 507 OCH2CH3 H O CH2-c-Pr Cl 3,4 dichloro phenyl 508 (CH2)2 O CH2-c-Pr Cl 3,4 dichloro phenyl 509 (CH2)4 O CH2-c-Pr Cl 3,4 dichloro phenyl 510 CH3 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]- oxadiazolyl 511 CH2CH3 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]- oxadiazolyl 512 CH2CF3 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]- oxadiazolyl 513 CH2CH2CH3 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]- oxadiazolyl 514 CH2CH(CH3)2 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]- oxadiazolyl 515 cyclopropylmethyl H O CH2-c-Pr Cl 5-benzo[c][1,2,5]- oxadiazolyl 516 SCH(CH3)2 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]- oxadiazolyl 517 OCH2CH3 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]- oxadiazolyl 518 (CH2)2 O CH2-c-Pr Cl 5-benzo[c][1,2,5]- oxadiazolyl 519 (CH2)4 O CH2-c-Pr Cl 5-benzo[c][1,2,5]- oxadiazolyl 520 CH3 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]- thiadiazolyl 521 CH2CH3 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]- thiadiazolyl 522 CH2CF3 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]- thiadiazolyl 523 CH2CH2CH3 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]- thiadiazolyl 524 CH2CH(CH3)2 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]- thiadiazolyl 525 cyclopropylmethyl H O CH2-c-Pr Cl 5-benzo[c][1,2,5]- thiadiazolyl 526 SCH(CH3)2 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]- thiadiazolyl 527 OCH2CH3 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]- thiadiazolyl 528 (CH2)2 O CH2-c-Pr Cl 5-benzo[c][1,2,5]- thiadiazolyl 529 (CH2)4 O CH2-c-Pr Cl 5-benzo[c][1,2,5]- thiadiazolyl 530 CH3 H O CH2-c-Pr NO2 4-trifluoromethylphenyl 531 CH2CH3 H O CH2-c-Pr NO2 4-trifluoromethylphenyl 532 CH2CF3 H O CH2-c-Pr NO2 4-trifluoromethylphenyl 533 CH2CH2CH3 H O CH2-c-Pr NO2 4-trifluoromethylphenyl 534 CH2CH(CH3)2 H O CH2-c-Pr NO2 4-trifluoromethylphenyl 535 cyclopropylmethyl H O CH2-c-Pr NO2 4-trifluoromethylphenyl 536 SCH(CH3)2 H O CH2-c-Pr NO2 4-trifluoromethylphenyl 537 OCH2CH3 H O CH2-c-Pr NO2 4-trifluoromethylphenyl 538 (CH2)2 O CH2-c-Pr NO2 4-trifluoromethylphenyl 539 (CH2)4 O CH2-c-Pr NO2 4-trifluoromethylphenyl 540 CH3 H O CH2-c-Pr NO2 5-benzo[c][1,2,5]- oxadiazolyl 541 CH2CH3 H O CH2-c-Pr NO2 5-benzo[c][1,2,5]- oxadiazolyl 542 CH2CF3 H O CH2-c-Pr NO2 5-benzo[c][1,2,5]- oxadiazolyl 543 CH2CH2CH3 H O CH2-c-Pr NO2 5-benzo[c][1,2,5]- oxadiazolyl 544 CH2CH(CH3)2 H O CH2-c-Pr NO2 5-benzo[c][1,2,5]- oxadiazolyl 545 cyclopropylmethyl H O CH2-c-Pr NO2 5-benzo[c][1,2,5]- oxadiazolyl 546 SCH(CH3)2 H O CH2-c-Pr NO2 5-benzo[c][1,2,5]- oxadiazolyl 547 OCH2CH3 H O CH2-c-Pr NO2 5-benzo[c][1,2,5]- oxadiazolyl 548 (CH2)2 O CH2-c-Pr NO2 5-benzo[c][1,2,5]- oxadiazolyl 549 (CH2)4 O CH2-c-Pr NO2 5-benzo[c][1,2,5]- oxadiazolyl 550 CH3 H O CH2-c-Pr NH2 4-trifluoromethylphenyl 551 CH2CH3 H O CH2-c-Pr NH2 4-trifluoromethylphenyl 552 CH2CF3 H O CH2-c-Pr NH2 4-trifluoromethylphenyl 553 CH2CH2CH3 H O CH2-c-Pr NH2 4-trifluoromethylphenyl 554 CH2CH(CH3)2 H O CH2-c-Pr NH2 4-trifluoromethylphenyl 555 cyclopropylmethyl H O CH2-c-Pr NH2 4-trifluoromethylphenyl 556 SCH(CH3)2 H O CH2-c-Pr NH2 4-trifluoromethylphenyl 557 OCH2CH3 H O CH2-c-Pr NH2 4-trifluoromethylphenyl 558 (CH2)2 O CH2-c-Pr NH2 4-trifluoromethylphenyl 559 (CH2)4 O CH2-c-Pr NH2 4-trifluoromethylphenyl

TABLE 2 Formula V EX R1 R2 X R3 R5 Z 560 CH3 H O CH2CH3 F 4-fluorophenyl 561 CH2CH3 H O CH2CH3 F 4-fluorophenyl 562 CH2CF3 H O CH2CH3 F 4-fluorophenyl 563 CH2CH2CH3 H O CH2CH3 F 4-fluorophenyl 564 CH2CH(CH3)2 H O CH2CH3 F 4-fluorophenyl 565 cyclopropyl- H O CH2CH3 F 4-fluorophenyl methyl 566 SCH(CH3)2 H O CH2CH3 F 4-fluorophenyl 567 OCH2CH3 H O CH2CH3 F 4-fluorophenyl 568 (CH2)2 O CH2CH3 F 4-fluorophenyl 569 (CH2)4 O CH2CH3 F 4-fluorophenyl 570 CH3 H O CH2CH3 F 4-chlorophenyl 571 CH2CH3 H O CH2CH3 F 4-chlorophenyl 572 CH2CF3 H O CH2CH3 F 4-chlorophenyl 573 CH2CH2CH3 H O CH2CH3 F 4-chlorophenyl 574 CH2CH(CH3)2 H O CH2CH3 F 4-chlorophenyl 575 cyclopropyl- H O CH2CH3 F 4-chlorophenyl methyl 576 SCH(CH3)2 H O CH2CH3 F 4-chlorophenyl 577 OCH2CH3 H O CH2CH3 F 4-chlorophenyl 578 (CH2)2 O CH2CH3 F 4-chlorophenyl 579 (CH2)4 O CH2CH3 F 4-chlorophenyl 580 CH3 H O CH2CH3 F 4-trifluoromethylphenyl 581 CH2CH3 H O CH2CH3 F 4-trifluoromethylphenyl 582 CH2CF3 H O CH2CH3 F 4-trifluoromethylphenyl 583 CH2CH2CH3 H O CH2CH3 F 4-trifluoromethylphenyl 584 CH2CH(CH3)2 H O CH2CH3 F 4-trifluoromethylphenyl 585 cyclopropyl- H O CH2CH3 F 4-trifluoromethylphenyl methyl 586 SCH(CH3)2 H O CH2CH3 F 4-trifluoromethylphenyl 587 OCH2CH3 H O CH2CH3 F 4-trifluoromethylphenyl 588 (CH2)2 O CH2CH3 F 4-trifluoromethylphenyl 589 (CH2)4 O CH2CH3 F 4-trifluoromethylphenyl 590 CH3 H O CH2CH3 F 4-methoxyphenyl 591 CH2CH3 H O CH2CH3 F 4-methoxyphenyl 592 CH2CF3 H O CH2CH3 F 4-methoxyphenyl 593 CH2CH2CH3 H O CH2CH3 F 4-methoxyphenyl 594 CH2CH(CH3)2 H O CH2CH3 F 4-methoxyphenyl 595 cyclopropyl- H O CH2CH3 F 4-methoxyphenyl methyl 596 SCH(CH3)2 H O CH2CH3 F 4-methoxyphenyl 597 OCH2CH3 H O CH2CH3 F 4-methoxyphenyl 598 (CH2)2 O CH2CH3 F 4-methoxyphenyl 599 (CH2)4 O CH2CH3 F 4-methoxyphenyl 600 CH3 H O CH2CH3 F 3,4 dichloro phenyl 601 CH2CH3 H O CH2CH3 F 3,4 dichloro phenyl 602 CH2CF3 H O CH2CH3 F 3,4 dichloro phenyl 603 CH2CH2CH3 H O CH2CH3 F 3,4 dichloro phenyl 604 CH2CH(CH3)2 H O CH2CH3 F 3,4 dichloro phenyl 605 cyclopropyl- H O CH2CH3 F 3,4 dichloro phenyl methyl 606 SCH(CH3)2 H O CH2CH3 F 3,4 dichloro phenyl 607 OCH2CH3 H O CH2CH3 F 3,4 dichloro phenyl 608 (CH2)2 O CH2CH3 F 3,4 dichloro phenyl 609 (CH2)4 O CH2CH3 F 3,4 dichloro phenyl 610 CH3 H O CH2CH3 F 5-benzo[c][1,2,5]oxadiazolyl 611 CH2CH3 H O CH2CH3 F 5-benzo[c][1,2,5]oxadiazolyl 612 CH2CF3 H O CH2CH3 F 5-benzo[c][1,2,5]oxadiazolyl 613 CH2CH2CH3 H O CH2CH3 F 5-benzo[c][1,2,5]oxadiazolyl 614 CH2CH(CH3)2 H O CH2CH3 F 5-benzo[c][1,2,5]oxadiazolyl 615 cyclopropyl- H O CH2CH3 F 5-benzo[c][1,2,5]oxadiazolyl methyl 616 SCH(CH3)2 H O CH2CH3 F 5-benzo[c][1,2,5]oxadiazolyl 617 OCH2CH3 H O CH2CH3 F 5-benzo[c][1,2,5]oxadiazolyl 618 (CH2)2 O CH2CH3 F 5-benzo[c][1,2,5]oxadiazolyl 619 (CH2)4 O CH2CH3 F 5-benzo[c][1,2,5]oxadiazolyl 620 CH3 H O CH2CH3 F 5-benzo[c][1,2,5]thiadiazolyl 621 CH2CH3 H O CH2CH3 F 5-benzo[c][1,2,5]thiadiazolyl 622 CH2CF3 H O CH2CH3 F 5-benzo[c][1,2,5]thiadiazolyl 623 CH2CH2CH3 H O CH2CH3 F 5-benzo[c][1,2,5]thiadiazolyl 624 CH2CH(CH3)2 H O CH2CH3 F 5-benzo[c][1,2,5]thiadiazolyl 625 cyclopropyl- H O CH2CH3 F 5-benzo[c][1,2,5]thiadiazolyl methyl 626 SCH(CH3)2 H O CH2CH3 F 5-benzo[c][1,2,5]thiadiazolyl 627 OCH2CH3 H O CH2CH3 F 5-benzo[c][1,2,5]thiadiazolyl 628 (CH2)2 O CH2CH3 F 5-benzo[c][1,2,5]thiadiazolyl 629 (CH2)4 O CH2CH3 F 5-benzo[c][1,2,5]thiadiazolyl 630 CH3 H O CH2CF3 F 4-fluorophenyl 631 CH2CH3 H O CH2CF3 F 4-fluorophenyl 632 CH2CF3 H O CH2CF3 F 4-fluorophenyl 633 CH2CH2CH3 H O CH2CF3 F 4-fluorophenyl 634 CH2CH(CH3)2 H O CH2CF3 F 4-fluorophenyl 635 cyclopropyl- H O CH2CF3 F 4-fluorophenyl methyl 636 SCH(CH3)2 H O CH2CF3 F 4-fluorophenyl 637 OCH2CH3 H O CH2CF3 F 4-fluorophenyl 638 (CH2)2 O CH2CF3 F 4-fluorophenyl 639 (CH2)4 O CH2CF3 F 4-fluorophenyl 640 CH3 H O CH2CF3 F 4-chlorophenyl 641 CH2CH3 H O CH2CF3 F 4-chlorophenyl 642 CH2CF3 H O CH2CF3 F 4-chlorophenyl 643 CH2CH2CH3 H O CH2CF3 F 4-chlorophenyl 644 CH2CH(CH3)2 H O CH2CF3 F 4-chlorophenyl 645 cyclopropyl- H O CH2CF3 F 4-chlorophenyl methyl 646 SCH(CH3)2 H O CH2CF3 F 4-chlorophenyl 647 OCH2CH3 H O CH2CF3 F 4-chlorophenyl 648 (CH2)2 O CH2CF3 F 4-chlorophenyl 649 (CH2)4 O CH2CF3 F 4-chlorophenyl 650 CH3 H O CH2CF3 F 4-trifluoromethylphenyl 651 CH2CH3 H O CH2CF3 F 4-trifluoromethylphenyl 652 CH2CF3 H O CH2CF3 F 4-trifluoromethylphenyl 653 CH2CH2CH3 H O CH2CF3 F 4-trifluoromethylphenyl 654 CH2CH(CH3)2 H O CH2CF3 F 4-trifluoromethylphenyl 655 cyclopropyl- H O CH2CF3 F 4-trifluoromethylphenyl methyl 656 SCH(CH3)2 H O CH2CF3 F 4-trifluoromethylphenyl 657 OCH2CH3 H O CH2CF3 F 4-trifluoromethylphenyl 658 (CH2)2 O CH2CF3 F 4-trifluoromethylphenyl 659 (CH2)4 O CH2CF3 F 4-trifluoromethylphenyl 660 CH3 H O CH2CF3 F 4-methoxyphenyl 661 CH2CH3 H O CH2CF3 F 4-methoxyphenyl 662 CH2CF3 H O CH2CF3 F 4-methoxyphenyl 663 CH2CH2CH3 H O CH2CF3 F 4-methoxyphenyl 664 CH2CH(CH3)2 H O CH2CF3 F 4-methoxyphenyl 665 cyclopropyl- H O CH2CF3 F 4-methoxyphenyl methyl 666 SCH(CH3)2 H O CH2CF3 F 4-methoxyphenyl 667 OCH2CH3 H O CH2CF3 F 4-methoxyphenyl 668 (CH2)2 O CH2CF3 F 4-methoxyphenyl 669 (CH2)4 O CH2CF3 F 4-methoxyphenyl 670 CH3 H O CH2CF3 F 3,4 dichloro phenyl 671 CH2CH3 H O CH2CF3 F 3,4 dichloro phenyl 672 CH2CF3 H O CH2CF3 F 3,4 dichloro phenyl 673 CH2CH2CH3 H O CH2CF3 F 3,4 dichloro phenyl 674 CH2CH(CH3)2 H O CH2CF3 F 3,4 dichloro phenyl 675 cyclopropyl- H O CH2CF3 F 3,4 dichloro phenyl methyl 676 SCH(CH3)2 H O CH2CF3 F 3,4 dichloro phenyl 677 OCH2CH3 H O CH2CF3 F 3,4 dichloro phenyl 678 (CH2)2 O CH2CF3 F 3,4 dichloro phenyl 679 (CH2)4 O CH2CF3 F 3,4 dichloro phenyl 680 CH3 H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazolyl 681 CH2CH3 H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazolyl 682 CH2CF3 H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazolyl 683 CH2CH2CH3 H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazolyl 684 CH2CH(CH3)2 H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazolyl 685 cyclopropyl- H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazolyl methyl 686 SCH(CH3)2 H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazolyl 687 OCH2CH3 H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazolyl 688 (CH2)2 O CH2CF3 F 5-benzo[c][1,2,5]oxadiazolyl 689 (CH2)4 O CH2CF3 F 5-benzo[c][1,2,5]oxadiazolyl 690 CH3 H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazolyl 691 CH2CH3 H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazolyl 692 CH2CF3 H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazolyl 693 CH2CH2CH3 H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazolyl 694 CH2CH(CH3)2 H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazolyl 695 cyclopropyl- H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazolyl methyl 696 SCH(CH3)2 H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazolyl 697 OCH2CH3 H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazolyl 698 (CH2)2 O CH2CF3 F 5-benzo[c][1,2,5]thiadiazolyl 699 (CH2)4 O CH2CF3 F 5-benzo[c][1,2,5]thiadiazolyl 700 CH3 H O CH2-c-Pr F 4-fluorophenyl 701 CH2CH3 H O CH2-c-Pr F 4-fluorophenyl 702 CH2CF3 H O CH2-c-Pr F 4-fluorophenyl 703 CH2CH2CH3 H O CH2-c-Pr F 4-fluorophenyl 704 CH2CH(CH3)2 H O CH2-c-Pr F 4-fluorophenyl 705 cyclopropyl- H O CH2-c-Pr F 4-fluorophenyl methyl 706 SCH(CH3)2 H O CH2-c-Pr F 4-fluorophenyl 707 OCH2CH3 H O CH2-c-Pr F 4-fluorophenyl 708 (CH2)2 O CH2-c-Pr F 4-fluorophenyl 709 (CH2)4 O CH2-c-Pr F 4-fluorophenyl 710 CH3 H O CH2-c-Pr F 4-chlorophenyl 711 CH2CH3 H O CH2-c-Pr F 4-chlorophenyl 712 CH2CF3 H O CH2-c-Pr F 4-chlorophenyl 713 CH2CH2CH3 H O CH2-c-Pr F 4-chlorophenyl 714 CH2CH(CH3)2 H O CH2-c-Pr F 4-chlorophenyl 715 cyclopropyl- H O CH2-c-Pr F 4-chlorophenyl methyl 716 SCH(CH3)2 H O CH2-c-Pr F 4-chlorophenyl 717 OCH2CH3 H O CH2-c-Pr F 4-chlorophenyl 718 (CH2)2 O CH2-c-Pr F 4-chlorophenyl 719 (CH2)4 O CH2-c-Pr F 4-chlorophenyl 720 CH3 H O CH2-c-Pr F 4-trifluoromethylphenyl 721 CH2CH3 H O CH2-c-Pr F 4-trifluoromethylphenyl 722 CH2CF3 H O CH2-c-Pr F 4-trifluoromethylphenyl 723 CH2CH2CH3 H O CH2-c-Pr F 4-trifluoromethylphenyl 724 CH2CH(CH3)2 H O CH2-c-Pr F 4-trifluoromethylphenyl 725 cyclopropyl- H O CH2-c-Pr F 4-trifluoromethylphenyl methyl 726 SCH(CH3)2 H O CH2-c-Pr F 4-trifluoromethylphenyl 727 OCH2CH3 H O CH2-c-Pr F 4-trifluoromethylphenyl 728 (CH2)2 O CH2-c-Pr F 4-trifluoromethylphenyl 729 (CH2)4 O CH2-c-Pr F 4-trifluoromethylphenyl 730 CH3 H O CH2-c-Pr F 4-methoxyphenyl 731 CH2CH3 H O CH2-c-Pr F 4-methoxyphenyl 732 CH2CF3 H O CH2-c-Pr F 4-methoxyphenyl 733 CH2CH2CH3 H O CH2-c-Pr F 4-methoxyphenyl 734 CH2CH(CH3)2 H O CH2-c-Pr F 4-methoxyphenyl 735 cyclopropyl- H O CH2-c-Pr F 4-methoxyphenyl methyl 736 SCH(CH3)2 H O CH2-c-Pr F 4-methoxyphenyl 737 OCH2CH3 H O CH2-c-Pr F 4-methoxyphenyl 738 (CH2)2 O CH2-c-Pr F 4-methoxyphenyl 739 (CH2)4 O CH2-c-Pr F 4-methoxyphenyl 740 CH3 H O CH2-c-Pr F 3,4 dichloro phenyl 741 CH2CH3 H O CH2-c-Pr F 3,4 dichloro phenyl 742 CH2CF3 H O CH2-c-Pr F 3,4 dichloro phenyl 743 CH2CH2CH3 H O CH2-c-Pr F 3,4 dichloro phenyl 744 CH2CH(CH3)2 H O CH2-c-Pr F 3,4 dichloro phenyl 745 cyclopropyl- H O CH2-c-Pr F 3,4 dichloro phenyl methyl 746 SCH(CH3)2 H O CH2-c-Pr F 3,4 dichloro phenyl 747 OCH2CH3 H O CH2-c-Pr F 3,4 dichloro phenyl 748 (CH2)2 O CH2-c-Pr F 3,4 dichloro phenyl 749 (CH2)4 O CH2-c-Pr F 3,4 dichloro phenyl 750 CH3 H O CH2-c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 751 CH2CH3 H O CH2-c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 752 CH2CF3 H O CH2-c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 753 CH2CH2CH3 H O CH2-c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 754 CH2CH(CH3)2 H O CH2-c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 755 cyclopropyl- H O CH2-c-Pr F 5-benzo[c][1,2,5]oxadiazolyl methyl 756 SCH(CH3)2 H O CH2-c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 757 OCH2CH3 H O CH2-c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 758 (CH2)2 O CH2-c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 759 (CH2)4 O CH2-c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 760 CH3 H O CH2-c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 761 CH2CH3 H O CH2-c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 762 CH2CF3 H O CH2-c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 763 CH2CH2CH3 H O CH2-c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 764 CH2CH(CH3)2 H O CH2-c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 765 cyclopropyl- H O CH2-c-Pr F 5-benzo[c][1,2,5]thiadiazolyl methyl 766 SCH(CH3)2 H O CH2-c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 767 OCH2CH3 H O CH2-c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 768 (CH2)2 O CH2-c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 769 (CH2)4 O CH2-c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 770 CH3 H O CH2CH3 Cl 4-fluorophenyl 771 CH2CH3 H O CH2CH3 Cl 4-fluorophenyl 772 CH2CF3 H O CH2CH3 Cl 4-fluorophenyl 773 CH2CH2CH3 H O CH2CH3 Cl 4-fluorophenyl 774 CH2CH(CH3)2 H O CH2CH3 Cl 4-fluorophenyl 775 cyclopropyl- H O CH2CH3 Cl 4-fluorophenyl methyl 776 SCH(CH3)2 H O CH2CH3 Cl 4-fluorophenyl 777 OCH2CH3 H O CH2CH3 Cl 4-fluorophenyl 778 (CH2)2 O CH2CH3 Cl 4-fluorophenyl 779 (CH2)4 O CH2CH3 Cl 4-fluorophenyl 780 CH3 H O CH2CH3 Cl 4-chlorophenyl 781 CH2CH3 H O CH2CH3 Cl 4-chlorophenyl 782 CH2CF3 H O CH2CH3 Cl 4-chlorophenyl 783 CH2CH2CH3 H O CH2CH3 Cl 4-chlorophenyl 784 CH2CH(CH3)2 H O CH2CH3 Cl 4-chlorophenyl 785 cyclopropyl- H O CH2CH3 Cl 4-chlorophenyl methyl 786 SCH(CH3)2 H O CH2CH3 Cl 4-chlorophenyl 787 OCH2CH3 H O CH2CH3 Cl 4-chlorophenyl 788 (CH2)2 O CH2CH3 Cl 4-chlorophenyl 789 (CH2)4 O CH2CH3 Cl 4-chlorophenyl 790 CH3 H O CH2CH3 Cl 4-trifluoromethylphenyl 791 CH2CH3 H O CH2CH3 Cl 4-trifluoromethylphenyl 792 CH2CF3 H O CH2CH3 Cl 4-trifluoromethylphenyl 793 CH2CH2CH3 H O CH2CH3 Cl 4-trifluoromethylphenyl 794 CH2CH(CH3)2 H O CH2CH3 Cl 4-trifluoromethylphenyl 795 cyclopropyl- H O CH2CH3 Cl 4-trifluoromethylphenyl methyl 796 SCH(CH3)2 H O CH2CH3 Cl 4-trifluoromethylphenyl 797 OCH2CH3 H O CH2CH3 Cl 4-trifluoromethylphenyl 798 (CH2)2 O CH2CH3 Cl 4-trifluoromethylphenyl 799 (CH2)4 O CH2CH3 Cl 4-trifluoromethylphenyl 800 CH3 H O CH2CH3 Cl 4-methoxyphenyl 801 CH2CH3 H O CH2CH3 Cl 4-methoxyphenyl 802 CH2CF3 H O CH2CH3 Cl 4-methoxyphenyl 803 CH2CH2CH3 H O CH2CH3 Cl 4-methoxyphenyl 804 CH2CH(CH3)2 H O CH2CH3 Cl 4-methoxyphenyl 805 cyclopropyl- H O CH2CH3 Cl 4-methoxyphenyl methyl 806 SCH(CH3)2 H O CH2CH3 Cl 4-methoxyphenyl 807 OCH2CH3 H O CH2CH3 Cl 4-methoxyphenyl 808 (CH2)2 O CH2CH3 Cl 4-methoxyphenyl 809 (CH2)4 O CH2CH3 Cl 4-methoxyphenyl 810 CH3 H O CH2CH3 Cl 3,4 dichloro phenyl 811 CH2CH3 H O CH2CH3 Cl 3,4 dichloro phenyl 812 CH2CF3 H O CH2CH3 Cl 3,4 dichloro phenyl 813 CH2CH2CH3 H O CH2CH3 Cl 3,4 dichloro phenyl 814 CH2CH(CH3)2 H O CH2CH3 Cl 3,4 dichloro phenyl 815 cyclopropyl- H O CH2CH3 Cl 3,4 dichloro phenyl methyl 816 SCH(CH3)2 H O CH2CH3 Cl 3,4 dichloro phenyl 817 OCH2CH3 H O CH2CH3 Cl 3,4 dichloro phenyl 818 (CH2)2 O CH2CH3 Cl 3,4 dichloro phenyl 819 (CH2)4 O CH2CH3 Cl 3,4 dichloro phenyl 820 CH3 H O CH2CH3 Cl 5-benzo[c][1,2,5]oxadiazolyl 821 CH2CH3 H O CH2CH3 Cl 5-benzo[c][1,2,5]oxadiazolyl 822 CH2CF3 H O CH2CH3 Cl 5-benzo[c][1,2,5]oxadiazolyl 823 CH2CH2CH3 H O CH2CH3 Cl 5-benzo[c][1,2,5]oxadiazolyl 824 CH2CH(CH3)2 H O CH2CH3 Cl 5-benzo[c][1,2,5]oxadiazolyl 825 cyclopropyl- H O CH2CH3 Cl 5-benzo[c][1,2,5]oxadiazolyl methyl 826 SCH(CH3)2 H O CH2CH3 Cl 5-benzo[c][1,2,5]oxadiazolyl 827 OCH2CH3 H O CH2CH3 Cl 5-benzo[c][1,2,5]oxadiazolyl 828 (CH2)2 O CH2CH3 Cl 5-benzo[c][1,2,5]oxadiazolyl 829 (CH2)4 O CH2CH3 Cl 5-benzo[c][1,2,5]oxadiazolyl 830 CH3 H O CH2CH3 Cl 5-benzo[c][1,2,5]thiadiazolyl 831 CH2CH3 H O CH2CH3 Cl 5-benzo[c][1,2,5]thiadiazolyl 832 CH2CF3 H O CH2CH3 Cl 5-benzo[c][1,2,5]thiadiazolyl 833 CH2CH2CH3 H O CH2CH3 Cl 5-benzo[c][1,2,5]thiadiazolyl 834 CH2CH(CH3)2 H O CH2CH3 Cl 5-benzo[c][1,2,5]thiadiazolyl 835 cyclopropyl- H O CH2CH3 Cl 5-benzo[c][1,2,5]thiadiazolyl methyl 836 SCH(CH3)2 H O CH2CH3 Cl 5-benzo[c][1,2,5]thiadiazolyl 837 OCH2CH3 H O CH2CH3 Cl 5-benzo[c][1,2,5]thiadiazolyl 838 (CH2)2 O CH2CH3 Cl 5-benzo[c][1,2,5]thiadiazolyl 839 (CH2)4 O CH2CH3 Cl 5-benzo[c][1,2,5]thiadiazolyl 840 CH3 H O CH2CF3 Cl 4-fluorophenyl 841 CH2CH3 H O CH2CF3 Cl 4-fluorophenyl 842 CH2CF3 H O CH2CF3 Cl 4-fluorophenyl 843 CH2CH2CH3 H O CH2CF3 Cl 4-fluorophenyl 844 CH2CH(CH3)2 H O CH2CF3 Cl 4-fluorophenyl 845 cyclopropyl- H O CH2CF3 Cl 4-fluorophenyl methyl 846 SCH(CH3)2 H O CH2CF3 Cl 4-fluorophenyl 847 OCH2CH3 H O CH2CF3 Cl 4-fluorophenyl 848 (CH2)2 0 O CH2CF3 Cl 4-fluorophenyl 849 (CH2)4 0 O CH2CF3 Cl 4-fluorophenyl 850 CH3 H O CH2CF3 Cl 4-chlorophenyl 851 CH2CH3 H O CH2CF3 Cl 4-chlorophenyl 852 CH2CF3 H O CH2CF3 Cl 4-chlorophenyl 853 CH2CH2CH3 H O CH2CF3 Cl 4-chlorophenyl 854 CH2CH(CH3)2 H O CH2CF3 Cl 4-chlorophenyl 855 cyclopropyl- H O CH2CF3 Cl 4-chlorophenyl methyl 856 SCH(CH3)2 H O CH2CF3 Cl 4-chlorophenyl 857 OCH2CH3 H O CH2CF3 Cl 4-chlorophenyl 858 (CH2)2 O CH2CF3 Cl 4-chlorophenyl 859 (CH2)4 O CH2CF3 Cl 4-chlorophenyl 860 CH3 H O CH2CF3 Cl 4-trifluoromethylphenyl 861 CH2CH3 H O CH2CF3 Cl 4-trifluoromethylphenyl 862 CH2CF3 H O CH2CF3 Cl 4-trifluoromethylphenyl 863 CH2CH2CH3 H O CH2CF3 Cl 4-trifluoromethylphenyl 864 CH2CH(CH3)2 H O CH2CF3 Cl 4-trifluoromethylphenyl 865 cyclopropyl- H O CH2CF3 Cl 4-trifluoromethylphenyl methyl 866 SCH(CH3)2 H O CH2CF3 Cl 4-trifluoromethylphenyl 867 OCH2CH3 H O CH2CF3 Cl 4-trifluoromethylphenyl 868 (CH2)2 O CH2CF3 Cl 4-trifluoromethylphenyl 869 (CH2)4 O CH2CF3 Cl 4-trifluoromethylphenyl 870 CH3 H O CH2CF3 Cl 4-methoxyphenyl 871 CH2CH3 H O CH2CF3 Cl 4-methoxyphenyl 872 CH2CF3 H O CH2CF3 Cl 4-methoxyphenyl 873 CH2CH2CH3 H O CH2CF3 Cl 4-methoxyphenyl 874 CH2CH(CH3)2 H O CH2CF3 Cl 4-methoxyphenyl 875 cyclopropyl- H O CH2CF3 Cl 4-methoxyphenyl methyl 876 SCH(CH3)2 H O CH2CF3 Cl 4-methoxyphenyl 877 OCH2CH3 H O CH2CF3 Cl 4-methoxyphenyl 878 (CH2)2 O CH2CF3 Cl 4-methoxyphenyl 879 (CH2)4 O CH2CF3 Cl 4-methoxyphenyl 880 CH3 H O CH2CF3 Cl 3,4 dichloro phenyl 881 CH2CH3 H O CH2CF3 Cl 3,4 dichloro phenyl 882 CH2CF3 H O CH2CF3 Cl 3,4 dichloro phenyl 883 CH2CH2CH3 H O CH2CF3 Cl 3,4 dichloro phenyl 884 CH2CH(CH3)2 H O CH2CF3 Cl 3,4 dichloro phenyl 885 cyclopropyl- H O CH2CF3 Cl 3,4 dichloro phenyl methyl 886 SCH(CH3)2 H O CH2CF3 Cl 3,4 dichloro phenyl 887 OCH2CH3 H O CH2CF3 Cl 3,4 dichloro phenyl 888 (CH2)2 O CH2CF3 Cl 3,4 dichloro phenyl 889 (CH2)4 O CH2CF3 Cl 3,4 dichloro phenyl 890 CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazolyl 891 CH2CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazolyl 892 CH2CF3 H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazolyl 893 CH2CH2CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazolyl 894 CH2CH(CH3)2 H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazolyl 895 cyclopropyl- H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazolyl methyl 896 SCH(CH3)2 H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazolyl 897 OCH2CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazolyl 898 (CH2)2 O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazolyl 899 (CH2)4 O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazolyl 900 CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazolyl 901 CH2CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazolyl 902 CH2CF3 H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazolyl 903 CH2CH2CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazolyl 904 CH2CH(CH3)2 H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazolyl 905 cyclopropyl- H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazolyl methyl 906 SCH(CH3)2 H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazolyl 907 OCH2CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazolyl 908 (CH2)2 O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazolyl 909 (CH2)4 O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazolyl 910 CH3 H O CH2-c-Pr Cl 4-fluorophenyl 911 CH2CH3 H O CH2-c-Pr Cl 4-fluorophenyl 912 CH2CF3 H O CH2-c-Pr Cl 4-fluorophenyl 913 CH2CH2CH3 H O CH2-c-Pr Cl 4-fluorophenyl 914 CH2CH(CH3)2 H O CH2-c-Pr Cl 4-fluorophenyl 915 cyclopropyl- H O CH2-c-Pr Cl 4-fluorophenyl methyl 916 SCH(CH3)2 H O CH2-c-Pr Cl 4-fluorophenyl 917 OCH2CH3 H O CH2-c-Pr Cl 4-fluorophenyl 918 (CH2)2 O CH2-c-Pr Cl 4-fluorophenyl 919 (CH2)4 O CH2-c-Pr Cl 4-fluorophenyl 920 CH3 H O CH2-c-Pr Cl 4-chlorophenyl 921 CH2CH3 H O CH2-c-Pr Cl 4-chlorophenyl 922 CH2CF3 H O CH2-c-Pr Cl 4-chlorophenyl 923 CH2CH2CH3 H O CH2-c-Pr Cl 4-chlorophenyl 924 CH2CH(CH3)2 H O CH2-c-Pr Cl 4-chlorophenyl 925 cyclopropyl- H O CH2-c-Pr Cl 4-chlorophenyl methyl 926 SCH(CH3)2 H O CH2-c-Pr Cl 4-chlorophenyl 927 OCH2CH3 H O CH2-c-Pr Cl 4-chlorophenyl 928 (CH2)2 O CH2-c-Pr Cl 4-chlorophenyl 929 (CH2)4 O CH2-c-Pr Cl 4-chlorophenyl 930 CH3 H O CH2-c-Pr Cl 4-trifluoromethylphenyl 931 CH2CH3 H O CH2-c-Pr Cl 4-trifluoromethylphenyl 932 CH2CF3 H O CH2-c-Pr Cl 4-trifluoromethylphenyl 933 CH2CH2CH3 H O CH2-c-Pr Cl 4-trifluoromethylphenyl 934 CH2CH(CH3)2 H O CH2-c-Pr Cl 4-trifluoromethylphenyl 935 cyclopropyl- H O CH2-c-Pr Cl 4-trifluoromethylphenyl methyl 936 SCH(CH3)2 H O CH2-c-Pr Cl 4-trifluoromethylphenyl 937 OCH2CH3 H O CH2-c-Pr Cl 4-trifluoromethylphenyl 938 (CH2)2 O CH2-c-Pr Cl 4-trifluoromethylphenyl 939 (CH2)4 O CH2-c-Pr Cl 4-trifluoromethylphenyl 940 CH3 H O CH2-c-Pr Cl 4-methoxyphenyl 941 CH2CH3 H O CH2-c-Pr Cl 4-methoxyphenyl 942 CH2CF3 H O CH2-c-Pr Cl 4-methoxyphenyl 943 CH2CH2CH3 H O CH2-c-Pr Cl 4-methoxyphenyl 944 CH2CH(CH3)2 H O CH2-c-Pr Cl 4-methoxyphenyl 945 cyclopropyl- H O CH2-c-Pr Cl 4-methoxyphenyl methyl 946 SCH(CH3)2 H O CH2-c-Pr Cl 4-methoxyphenyl 947 OCH2CH3 H O CH2-c-Pr Cl 4-methoxyphenyl 948 (CH2)2 O CH2-c-Pr Cl 4-methoxyphenyl 949 (CH2)4 O CH2-c-Pr Cl 4-methoxyphenyl 950 CH3 H O CH2-c-Pr Cl 3,4 dichloro phenyl 951 CH2CH3 H O CH2-c-Pr Cl 3,4 dichloro phenyl 952 CH2CF3 H O CH2-c-Pr Cl 3,4 dichloro phenyl 953 CH2CH2CH3 H O CH2-c-Pr Cl 3,4 dichloro phenyl 954 CH2CH(CH3)2 H O CH2-c-Pr Cl 3,4 dichloro phenyl 955 cyclopropyl- H O CH2-c-Pr Cl 3,4 dichloro phenyl methyl 956 SCH(CH3)2 H O CH2-c-Pr Cl 3,4 dichloro phenyl 957 OCH2CH3 H O CH2-c-Pr Cl 3,4 dichloro phenyl 958 (CH2)2 O CH2-c-Pr Cl 3,4 dichloro phenyl 959 (CH2)4 O CH2-c-Pr Cl 3,4 dichloro phenyl 960 CH3 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 961 CH2CH3 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 962 CH2CF3 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 963 CH2CH2CH3 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 964 CH2CH(CH3)2 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 965 cyclopropyl- H O CH2-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl methyl 966 SCH(CH3)2 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 967 OCH2CH3 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 968 (CH2)2 O CH2-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 969 (CH2)4 O CH2-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 970 CH3 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 971 CH2CH3 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 972 CH2CF3 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 973 CH2CH2CH3 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 974 CH2CH(CH3)2 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 975 cyclopropyl- H O CH2-c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl methyl 976 SCH(CH3)2 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 977 OCH2CH3 H O CH2-c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 978 (CH2)2 O CH2-c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 979 (CH2)4 O CH2-c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl

TABLE 3 Formula III Compounds of Formula III Ex R1 R2 Y R4 R5 Z  980 CH2CH3 H O CH2 CF3 CF3 4-trifluoromethyl- phenyl  981 CH2CF3 H O CH2 CF3 CF3 4-trifluoromethyl- phenyl  982 CH2CH2CH3 H O CH2 CF3 CF3 4-trifluoromethyl- phenyl  983 CH2CH(CH3)2 H O CH2 CF3 CF3 4-trifluoromethyl- phenyl  984 cyclopropyl- H O CH2 CF3 CF3 4-trifluoromethyl- methyl phenyl  985 cyclobutyl- H O CH2 CF3 CF3 4-trifluoromethyl- methyl phenyl  986 (CH2)2 O CH2 CF3 CF3 4-trifluoromethyl- phenyl  987 (CH2)3 O CH2 CF3 CF3 4-trifluoromethyl- phenyl  988 (CH2)4 O CH2 CF3 CF3 4-trifluoromethyl- phenyl  989 (CH2)5 O CH2 CF3 CF3 4-trifluoromethyl- phenyl  990 5,5-spiro[2.3]- O CH2 CF3 CF3 4-trifluoromethyl- hexane phenyl  991 Cyclopentyl H O CH2 CF3 CF3 4-trifluoromethyl- phenyl  992 CH2CH3 H O CH2 CF3 CF3 4-tolyl  993 CH2CF3 H O CH2 CF3 CF3 4-tolyl  994 CH2CH2CH3 H O CH2 CF3 CF3 4-tolyl  995 CH2CH(CH3)2 H O CH2 CF3 CF3 4-tolyl  996 cyclopropyl- H O CH2 CF3 CF3 4-tolyl methyl  997 cyclobutyl- H O CH2 CF3 CF3 4-tolyl methyl  998 (CH2)2 O CH2 CF3 CF3 4-tolyl  999 (CH2)3 O CH2 CF3 CF3 4-tolyl 1000 (CH2)4 O CH2 CF3 CF3 4-tolyl 1001 (CH2)5 O CH2 CF3 CF3 4-tolyl 1002 5,5-spiro[2.3]- O CH2 CF3 CF3 4-tolyl hexane 1003 Cyclopentyl H O CH2 CF3 CF3 4-tolyl 1004 CH2CH3 H O CH2 CF3 CF3 4-ethyl phenyl 1005 CH2CF3 H O CH2 CF3 CF3 4-ethyl phenyl 1006 CH2CH2CH3 H O CH2 CF3 CF3 4-ethyl phenyl 1007 CH2CH(CH3)2 H O CH2 CF3 CF3 4-ethyl phenyl 1008 cyclopropyl- H O CH2 CF3 CF3 4-ethyl phenyl methyl 1009 cyclobutyl- H O CH2 CF3 CF3 4-ethyl phenyl methyl 1010 (CH2)2 O CH2 CF3 CF3 4-ethyl phenyl 1011 (CH2)3 O CH2 CF3 CF3 4-ethyl phenyl 1012 (CH2)4 O CH2 CF3 CF3 4-ethyl phenyl 1013 (CH2)5 O CH2 CF3 CF3 4-ethyl phenyl 1014 5,5-spiro[2.3]- O CH2 CF3 CF3 4-ethyl phenyl hexane 1015 Cyclopentyl H O CH2 CF3 CF3 4-ethyl phenyl 1016 CH2CH3 H O CH2 CF3 CF3 4-isopropyl phenyl 1017 CH2CF3 H O CH2 CF3 CF3 4-isopropyl phenyl 1018 CH2CH2CH3 H O CH2 CF3 CF3 4-isopropyl phenyl 1019 CH2CH(CH3)2 H O CH2 CF3 CF3 4-isopropyl phenyl 1020 cyclopropyl- H O CH2 CF3 CF3 4-isopropyl phenyl methyl 1021 cyclobutyl- H O CH2 CF3 CF3 4-isopropyl phenyl methyl 1022 (CH2)2 O CH2 CF3 CF3 4-isopropyl phenyl 1023 (CH2)3 O CH2 CF3 CF3 4-isopropyl phenyl 1024 (CH2)4 O CH2 CF3 CF3 4-isopropyl phenyl 1025 (CH2)5 O CH2 CF3 CF3 4-isopropyl phenyl 1026 5,5-spiro[2.3]- O CH2 CF3 CF3 4-isopropyl phenyl hexane 1027 Cyclopentyl H O CH2 CF3 CF3 4-isopropyl phenyl 1028 CH2CH3 H O CH2 CF3 CF3 4-thiomethylphenyl 1029 CH2CF3 H O CH2 CF3 CF3 4-thiomethylphenyl 1030 CH2CH2CH3 H O CH2 CF3 CF3 4-thiomethylphenyl 1031 CH2CH(CH3)2 H O CH2 CF3 CF3 4-thiomethylphenyl 1032 cyclopropyl- H O CH2 CF3 CF3 4-thiomethylphenyl methyl 1033 cyclobutyl- H O CH2 CF3 CF3 4-thiomethylphenyl methyl 1034 (CH2)2 O CH2 CF3 CF3 4-thiomethylphenyl 1035 (CH2)3 O CH2 CF3 CF3 4-thiomethylphenyl 1036 (CH2)4 O CH2 CF3 CF3 4-thiomethylphenyl 1037 (CH2)5 O CH2 CF3 CF3 4-thiomethylphenyl 1038 5,5-spiro[2.3]- O CH2 CF3 CF3 4-thiomethylphenyl hexane 1039 Cyclopentyl H O CH2 CF3 CF3 4-thiomethylphenyl 1040 CH2CH3 H O CH2 CF3 CF3 4-trifluoromethoxy- phenyl 1041 CH2CF3 H O CH2 CF3 CF3 4-trifluoromethoxy- phenyl 1042 CH2CH2CH3 H O CH2 CF3 CF3 4-trifluoromethoxy- phenyl 1043 CH2CH(CH3)2 H O CH2 CF3 CF3 4-trifluoromethoxy- phenyl 1044 cyclopropyl- H O CH2 CF3 CF3 4-trifluoromethoxy- methyl phenyl 1045 cyclobutyl- H O CH2 CF3 CF3 4-trifluoromethoxy- methyl phenyl 1046 (CH2)2 O CH2 CF3 CF3 4-trifluoromethoxy- phenyl 1047 (CH2)3 O CH2 CF3 CF3 4-trifluoromethoxy- phenyl 1048 (CH2)4 O CH2 CF3 CF3 4-trifluoromethoxy- phenyl 1049 (CH2)5 O CH2 CF3 CF3 4-trifluoromethoxy- phenyl 1050 5,5-spiro[2.3]- O CH2 CF3 CF3 4-trifluoromethoxy- hexane phenyl 1051 Cyclopentyl H O CH2 CF3 CF3 4-trifluoromethoxy- phenyl 1052 CH2CH3 H O CH2-c-Pr CF3 4-trifluoromethyl- phenyl 1053 CH2CF3 H O CH2-c-Pr CF3 4-trifluoromethyl- phenyl 1054 CH2CH2CH3 H O CH2-c-Pr CF3 4-trifluoromethyl- phenyl 1055 CH2CH(CH3)2 H O CH2-c-Pr CF3 4-trifluoromethyl- phenyl 1056 cyclopropyl- H O CH2-c-Pr CF3 4-trifluoromethyl- methyl phenyl 1057 cyclobutyl- H O CH2-c-Pr CF3 4-trifluoromethyl- methyl phenyl 1058 (CH2)2 O CH2-c-Pr CF3 4-trifluoromethyl- phenyl 1059 (CH2)3 O CH2-c-Pr CF3 4-trifluoromethyl- phenyl 1060 (CH2)4 O CH2-c-Pr CF3 4-trifluoromethyl- phenyl 1061 (CH2)5 O CH2-c-Pr CF3 4-trifluoromethyl- phenyl 1062 5,5-spiro[2.3]- O CH2-c-Pr CF3 4-trifluoromethyl- hexane phenyl 1063 Cyclopentyl H O CH2-c-Pr CF3 4-trifluoromethyl- phenyl 1064 CH2CH3 H O CH2-c-Pr CF3 4-tolyl 1065 CH2CF3 H O CH2-c-Pr CF3 4-tolyl 1066 CH2CH2CH3 H O CH2-c-Pr CF3 4-tolyl 1067 CH2CH(CH3)2 H O CH2-c-Pr CF3 4-tolyl 1068 cyclopropyl- H O CH2-c-Pr CF3 4-tolyl methyl 1069 cyclobutyl- H O CH2-c-Pr CF3 4-tolyl methyl 1070 (CH2)2 O CH2-c-Pr CF3 4-tolyl 1071 (CH2)3 O CH2-c-Pr CF3 4-tolyl 1072 (CH2)4 O CH2-c-Pr CF3 4-tolyl 1073 (CH2)5 O CH2-c-Pr CF3 4-tolyl 1074 5,5-spiro[2.3]- O CH2-c-Pr CF3 4-tolyl hexane 1075 Cyclopentyl H O CH2-c-Pr CF3 4-tolyl 1076 CH2CH3 H O CH2-c-Pr CF3 4-ethyl phenyl 1077 CH2CF3 H O CH2-c-Pr CF3 4-ethyl phenyl 1078 CH2CH2CH3 H O CH2-c-Pr CF3 4-ethyl phenyl 1079 CH2CH(CH3)2 H O CH2-c-Pr CF3 4-ethyl phenyl 1080 cyclopropyl- H O CH2-c-Pr CF3 4-ethyl phenyl methyl 1081 cyclobutyl- H O CH2-c-Pr CF3 4-ethyl phenyl methyl 1082 (CH2)2 O CH2-c-Pr CF3 4-ethyl phenyl 1083 (CH2)3 O CH2-c-Pr CF3 4-ethyl phenyl 1084 (CH2)4 O CH2-c-Pr CF3 4-ethyl phenyl 1085 (CH2)5 O CH2-c-Pr CF3 4-ethyl phenyl 1086 5,5-spiro[2.3]- O CH2-c-Pr CF3 4-ethyl phenyl hexane 1087 Cyclopentyl H O CH2-c-Pr CF3 4-ethyl phenyl 1088 CH2CH3 H O CH2-c-Pr CF3 4-isopropyl phenyl 1089 CH2CF3 H O CH2-c-Pr CF3 4-isopropyl phenyl 1090 CH2CH2CH3 H O CH2-c-Pr CF3 4-isopropyl phenyl 1091 CH2CH(CH3)2 H O CH2-c-Pr CF3 4-isopropyl phenyl 1092 cyclopropyl- H O CH2-c-Pr CF3 4-isopropyl phenyl methyl 1093 cyclobutyl- H O CH2-c-Pr CF3 4-isopropyl phenyl methyl 1094 (CH2)2 O CH2-c-Pr CF3 4-isopropyl phenyl 1095 (CH2)3 O CH2-c-Pr CF3 4-isopropyl phenyl 1096 (CH2)4 O CH2-c-Pr CF3 4-isopropyl phenyl 1097 (CH2)5 O CH2-c-Pr CF3 4-isopropyl phenyl 1098 5,5-spiro[2.3]- O CH2-c-Pr CF3 4-isopropyl phenyl hexane 1099 Cyclopentyl H O CH2-c-Pr CF3 4-isopropyl phenyl 1100 CH2CH3 H O CH2-c-Pr CF3 4-thiomethylphenyl 1101 CH2CF3 H O CH2-c-Pr CF3 4-thiomethylphenyl 1102 CH2CH2CH3 H O CH2-c-Pr CF3 4-thiomethylphenyl 1103 CH2CH(CH3)2 H O CH2-c-Pr CF3 4-thiomethylphenyl 1104 cyclopropyl- H O CH2-c-Pr CF3 4-thiomethylphenyl methyl 1105 cyclobutyl- H O CH2-c-Pr CF3 4-thiomethylphenyl methyl 1106 (CH2)2 O CH2-c-Pr CF3 4-thiomethylphenyl 1107 (CH2)3 O CH2-c-Pr CF3 4-thiomethylphenyl 1108 (CH2)4 O CH2-c-Pr CF3 4-thiomethylphenyl 1109 (CH2)5 O CH2-c-Pr CF3 4-thiomethylphenyl 1110 5,5-spiro[2.3]- O CH2-c-Pr CF3 4-thiomethylphenyl hexane 1111 Cyclopentyl H O CH2-c-Pr CF3 4-thiomethylphenyl 1112 CH2CH3 H O CH2-c-Pr CF3 4-trifluoromethoxy- phenyl 1113 CH2CF3 H O CH2-c-Pr CF3 4-trifluoromethoxy- phenyl 1114 CH2CH2CH3 H O CH2-c-Pr CF3 4-trifluoromethoxy- phenyl 1115 CH2CH(CH3)2 H O CH2-c-Pr CF3 4-trifluoromethoxy- phenyl 1116 cyclopropyl- H O CH2-c-Pr CF3 4-trifluoromethoxy- methyl phenyl 1117 cyclobutyl- H O CH2-c-Pr CF3 4-trifluoromethoxy- methyl phenyl 1118 (CH2)2 O CH2-c-Pr CF3 4-trifluoromethoxy- phenyl 1119 (CH2)3 O CH2-c-Pr CF3 4-trifluoromethoxy- phenyl 1120 (CH2)4 O CH2-c-Pr CF3 4-trifluoromethoxy- phenyl 1121 (CH2)5 O CH2-c-Pr CF3 4-trifluoromethoxy- phenyl 1122 5,5-spiro[2.3]- O CH2-c-Pr CF3 4-trifluoromethoxy- hexane phenyl 1123 Cyclopentyl H O CH2-c-Pr CF3 4-trifluoromethoxy- phenyl 1124 CH2CH3 H O CH2 CF3 OCH2 4-trifluoromethyl- CF3 phenyl 1125 CH2CF3 H O CH2 CF3 OCH2 4-trifluoromethyl- CF3 phenyl 1126 CH2CH2CH3 H O CH2 CF3 OCH2 4-trifluoromethyl- CF3 phenyl 1127 CH2CH(CH3)2 H O CH2 CF3 OCH2 4-trifluoromethyl- CF3 phenyl 1128 cyclopropyl- H O CH2 CF3 OCH2 4-trifluoromethyl- methyl CF3 phenyl 1129 cyclobutyl- H O CH2 CF3 OCH2 4-trifluoromethyl- methyl CF3 phenyl 1130 (CH2)2 O CH2 CF3 OCH2 4-trifluoromethyl- CF3 phenyl 1131 (CH2)3 O CH2 CF3 OCH2 4-trifluoromethyl- CF3 phenyl 1132 (CH2)4 O CH2 CF3 OCH2 4-trifluoromethyl- CF3 phenyl 1133 (CH2)5 O CH2 CF3 OCH2 4-trifluoromethyl- CF3 phenyl 1134 5,5-spiro[2.3]- O CH2 CF3 OCH2 4-trifluoromethyl- hexane CF3 phenyl 1135 Cyclopentyl H O CH2 CF3 OCH2 4-trifluoromethyl- CF3 phenyl 1136 CH2CH3 H O CH2 CF3 OCH2 4-tolyl CF3 1137 CH2CF3 H O CH2 CF3 OCH2 4-tolyl CF3 1138 CH2CH2CH3 H O CH2 CF3 OCH2 4-tolyl CF3 1139 CH2CH(CH3)2 H O CH2 CF3 OCH2 4-tolyl CF3 1140 cyclopropyl- H O CH2 CF3 OCH2 4-tolyl methyl CF3 1141 cyclobutyl- H O CH2 CF3 OCH2 4-tolyl methyl CF3 1142 (CH2)2 O CH2 CF3 OCH2 4-tolyl CF3 1143 (CH2)3 O CH2 CF3 OCH2 4-tolyl CF3 1144 (CH2)4 O CH2 CF3 OCH2 4-tolyl CF3 1145 (CH2)5 O CH2 CF3 OCH2 4-tolyl CF3 1146 5,5-spiro[2.3]- O CH2 CF3 OCH2 4-tolyl hexane CF3 1147 Cyclopentyl H O CH2 CF3 OCH2 4-tolyl CF3 1148 CH2CH3 H O CH2 CF3 OCH2 4-ethyl phenyl CF3 1149 CH2CF3 H O CH2 CF3 OCH2 4-ethyl phenyl CF3 1150 CH2CH2CH3 H O CH2 CF3 OCH2 4-ethyl phenyl CF3 1151 CH2CH(CH3)2 H O CH2 CF3 OCH2 4-ethyl phenyl CF3 1152 cyclopropyl- H O CH2 CF3 OCH2 4-ethyl phenyl methyl CF3 1153 cyclobutyl- H O CH2 CF3 OCH2 4-ethyl phenyl methyl CF3 1154 (CH2)2 O CH2 CF3 OCH2 4-ethyl phenyl CF3 1155 (CH2)3 O CH2 CF3 OCH2 4-ethyl phenyl CF3 1156 (CH2)4 O CH2 CF3 OCH2 4-ethyl phenyl CF3 1157 (CH2)5 O CH2 CF3 OCH2 4-ethyl phenyl CF3 1158 5,5-spiro[2.3]- O CH2 CF3 OCH2 4-ethyl phenyl hexane CF3 1159 Cyclopentyl H O CH2 CF3 OCH2 4-ethyl phenyl CF3 1160 CH2CH3 H O CH2 CF3 OCH2 4-isopropyl phenyl CF3 1161 CH2CF3 H O CH2 CF3 OCH2 4-isopropyl phenyl CF3 1162 CH2CH2CH3 H O CH2 CF3 OCH2 4-isopropyl phenyl CF3 1163 CH2CH(CH3)2 H O CH2 CF3 OCH2 4-isopropyl phenyl CF3 1164 cyclopropyl- H O CH2 CF3 OCH2 4-isopropyl phenyl methyl CF3 1165 cyclobutyl- H O CH2 CF3 OCH2 4-isopropyl phenyl methyl CF3 1166 (CH2)2 O CH2 CF3 OCH2 4-isopropyl phenyl CF3 1167 (CH2)3 O CH2 CF3 OCH2 4-isopropyl phenyl CF3 1168 (CH2)4 O CH2 CF3 OCH2 4-isopropyl phenyl CF3 1169 (CH2)5 O CH2 CF3 OCH2 4-isopropyl phenyl CF3 1170 5,5-spiro[2.3]- O CH2 CF3 OCH2 4-isopropyl phenyl hexane CF3 1171 Cyclopentyl H O CH2 CF3 OCH2 4-isopropyl phenyl CF3 1172 CH2CH3 H O CH2 CF3 OCH2 4-thiomethylphenyl CF3 1173 CH2CF3 H O CH2 CF3 OCH2 4-thiomethylphenyl CF3 1174 CH2CH2CH3 H O CH2 CF3 OCH2 4-thiomethylphenyl CF3 1175 CH2CH(CH3)2 H O CH2 CF3 OCH2 4-thiomethylphenyl CF3 1176 cyclopropyl- H O CH2 CF3 OCH2 4-thiomethylphenyl methyl CF3 1177 cyclobutyl- H O CH2 CF3 OCH2 4-thiomethylphenyl methyl CF3 1178 (CH2)2 O CH2 CF3 OCH2 4-thiomethylphenyl CF3 1179 (CH2)3 O CH2 CF3 OCH2 4-thiomethylphenyl CF3 1180 (CH2)4 O CH2 CF3 OCH2 4-thiomethylphenyl CF3 1181 (CH2)5 O CH2 CF3 OCH2 4-thiomethylphenyl CF3 1182 5,5-spiro[2.3]- O CH2 CF3 OCH2 4-thiomethylphenyl hexane CF3 1183 Cyclopentyl H O CH2 CF3 OCH2 4-thiomethylphenyl CF3 1184 CH2CH3 H O CH2 CF3 OCH2 4-trifluoromethoxy- CF3 phenyl 1185 CH2CF3 H O CH2 CF3 OCH2 4-trifluoromethoxy- CF3 phenyl 1186 CH2CH2CH3 H O CH2 CF3 OCH2 4-trifluoromethoxy- CF3 phenyl 1187 CH2CH(CH3)2 H O CH2 CF3 OCH2 4-trifluoromethoxy- CF3 phenyl 1188 cyclopropyl- H O CH2 CF3 OCH2 4-trifluoromethoxy- methyl CF3 phenyl 1189 cyclobutyl- H O CH2 CF3 OCH2 4-trifluoromethoxy- methyl CF3 phenyl 1190 (CH2)2 O CH2 CF3 OCH2 4-trifluoromethoxy- CF3 phenyl 1191 (CH2)3 O CH2 CF3 OCH2 4-trifluoromethoxy- CF3 phenyl 1192 (CH2)4 O CH2 CF3 OCH2 4-trifluoromethoxy- CF3 phenyl 1193 (CH2)5 O CH2 CF3 OCH2 4-trifluoromethoxy- CF3 phenyl 1194 5,5-spiro[2.3]- O CH2 CF3 OCH2 4-trifluoromethoxy- hexane CF3 phenyl 1195 Cyclopentyl H O CH2 CF3 OCH2 4-trifluoromethoxy- CF3 phenyl 1196 CH2CH3 H O CH2-c-Pr OCH2 4-trifluoromethyl- CF3 phenyl 1197 CH2CF3 H O CH2-c-Pr OCH2 4-trifluoromethyl- CF3 phenyl 1198 CH2CH2CH3 H O CH2-c-Pr OCH2 4-trifluoromethyl- CF3 phenyl 1199 CH2CH(CH3)2 H O CH2-c-Pr OCH2 4-trifluoromethyl- CF3 phenyl 1200 cyclopropyl- H O CH2-c-Pr OCH2 4-trifluoromethyl- methyl CF3 phenyl 1201 cyclobutyl- H O CH2-c-Pr OCH2 4-trifluoromethyl- methyl CF3 phenyl 1202 (CH2)2 O CH2-c-Pr OCH2 4-trifluoromethyl- CF3 phenyl 1203 (CH2)3 O CH2-c-Pr OCH2 4-trifluoromethyl- CF3 phenyl 1204 (CH2)4 O CH2-c-Pr OCH2 4-trifluoromethyl- CF3 phenyl 1205 (CH2)5 O CH2-c-Pr OCH2 4-trifluoromethyl- CF3 phenyl 1206 5,5-spiro[2.3]- O CH2-c-Pr OCH2 4-trifluoromethyl- hexane CF3 phenyl 1207 Cyclopentyl H O CH2-c-Pr OCH2 4-trifluoromethyl- CF3 phenyl 1208 CH2CH3 H O CH2-c-Pr OCH2 4-tolyl CF3 1209 CH2CF3 H O CH2-c-Pr OCH2 4-tolyl CF3 1210 CH2CH2CH3 H O CH2-c-Pr OCH2 4-tolyl CF3 1211 CH2CH(CH3)2 H O CH2-c-Pr OCH2 4-tolyl CF3 1212 cyclopropyl- H O CH2-c-Pr OCH2 4-tolyl methyl CF3 1213 cyclobutyl- H O CH2-c-Pr OCH2 4-tolyl methyl CF3 1214 (CH2)2 O CH2-c-Pr OCH2 4-tolyl CF3 1215 (CH2)3 O CH2-c-Pr OCH2 4-tolyl CF3 1216 (CH2)4 O CH2-c-Pr OCH2 4-tolyl CF3 1217 (CH2)5 O CH2-c-Pr OCH2 4-tolyl CF3 1218 5,5-spiro[2.3]- O CH2-c-Pr OCH2 4-tolyl hexane CF3 1219 Cyclopentyl H O CH2-c-Pr OCH2 4-tolyl CF3 1220 CH2CH3 H O CH2-c-Pr OCH2 4-ethyl phenyl CF3 1221 CH2CF3 H O CH2-c-Pr OCH2 4-ethyl phenyl CF3 1222 CH2CH2CH3 H O CH2-c-Pr OCH2 4-ethyl phenyl CF3 1223 CH2CH(CH3)2 H O CH2-c-Pr OCH2 4-ethyl phenyl CF3 1224 cyclopropyl- H O CH2-c-Pr OCH2 4-ethyl phenyl methyl CF3 1225 cyclobutyl- H O CH2-c-Pr OCH2 4-ethyl phenyl methyl CF3 1226 (CH2)2 O CH2-c-Pr OCH2 4-ethyl phenyl CF3 1227 (CH2)3 O CH2-c-Pr OCH2 4-ethyl phenyl CF3 1228 (CH2)4 O CH2-c-Pr OCH2 4-ethyl phenyl CF3 1229 (CH2)5 O CH2-c-Pr OCH2 4-ethyl phenyl CF3 1230 5,5-spiro[2.3]- O CH2-c-Pr OCH2 4-ethyl phenyl hexane CF3 1231 Cyclopentyl H O CH2-c-Pr OCH2 4-ethyl phenyl CF3 1232 CH2CH3 H O CH2-c-Pr OCH2 4-isopropyl phenyl CF3 1233 CH2CF3 H O CH2-c-Pr OCH2 4-isopropyl phenyl CF3 1234 CH2CH2CH3 H O CH2-c-Pr OCH2 4-isopropyl phenyl CF3 1235 CH2CH(CH3)2 H O CH2-c-Pr OCH2 4-isopropyl phenyl CF3 1236 cyclopropyl- H O CH2-c-Pr OCH2 4-isopropyl phenyl methyl CF3 1237 cyclobutyl- H O CH2-c-Pr OCH2 4-isopropyl phenyl methyl CF3 1238 (CH2)2 O CH2-c-Pr OCH2 4-isopropyl phenyl CF3 1239 (CH2)3 O CH2-c-Pr OCH2 4-isopropyl phenyl CF3 1240 (CH2)4 O CH2-c-Pr OCH2 4-isopropyl phenyl CF3 1241 (CH2)5 O CH2-c-Pr OCH2 4-isopropyl phenyl CF3 1242 5,5-spiro[2.3]- O CH2-c-Pr OCH2 4-isopropyl phenyl hexane CF3 1243 Cyclopentyl H O CH2-c-Pr OCH2 4-isopropyl phenyl CF3 1244 CH2CH3 H O CH2-c-Pr OCH2 4-thiomethylphenyl CF3 1245 CH2CF3 H O CH2-c-Pr OCH2 4-thiomethylphenyl CF3 1246 CH2CH2CH3 H O CH2-c-Pr OCH2 4-thiomethylphenyl CF3 1247 CH2CH(CH3)2 H O CH2-c-Pr OCH2 4-thiomethylphenyl CF3 1248 cyclopropyl- H O CH2-c-Pr OCH2 4-thiomethylphenyl methyl CF3 1249 cyclobutyl- H O CH2-c-Pr OCH2 4-thiomethylphenyl methyl CF3 1250 (CH2)2 O CH2-c-Pr OCH2 4-thiomethylphenyl CF3 1251 (CH2)3 O CH2-c-Pr OCH2 4-thiomethylphenyl CF3 1252 (CH2)4 O CH2-c-Pr OCH2 4-thiomethylphenyl CF3 1253 (CH2)5 O CH2-c-Pr OCH2 4-thiomethylphenyl CF3 1254 5,5-spiro[2.3]- O CH2-c-Pr OCH2 4-thiomethylphenyl hexane CF3 1255 Cyclopentyl H O CH2-c-Pr OCH2 4-thiomethylphenyl CF3 1256 CH2CH3 H O CH2-c-Pr OCH2 4-trifluoromethoxy- CF3 phenyl 1257 CH2CF3 H O CH2-c-Pr OCH2 4-trifluoromethoxy- CF3 phenyl 1258 CH2CH2CH3 H O CH2-c-Pr OCH2 4-trifluoromethoxy- CF3 phenyl 1259 CH2CH(CH3)2 H O CH2-c-Pr OCH2 4-trifluoromethoxy- CF3 phenyl 1260 cyclopropyl- H O CH2-c-Pr OCH2 4-trifluoromethoxy- methyl CF3 phenyl 1261 cyclobutyl- H O CH2-c-Pr OCH2 4-trifluoromethoxy- methyl CF3 phenyl 1262 (CH2)2 O CH2-c-Pr OCH2 4-trifluoromethoxy- CF3 phenyl 1263 (CH2)3 O CH2-c-Pr OCH2 4-trifluoromethoxy- CF3 phenyl 1264 (CH2)4 O CH2-c-Pr OCH2 4-trifluoromethoxy- CF3 phenyl 1265 (CH2)5 O CH2-c-Pr OCH2 4-trifluoromethoxy- CF3 phenyl 1266 5,5-spiro[2.3]- O CH2-c-Pr OCH2 4-trifluoromethoxy- hexane CF3 phenyl 1267 Cyclopentyl H O CH2-c-Pr OCH2 4-trifluoromethoxy- CF3 phenyl

TABLE 4 Compounds of Formula III Formula III Ex R1 R2 Y R4 R5 Z 1268 cyclobutyl- H O CH2 CF3 Cl 4-trifluoro- methyl methylphenyl 1269 (CH2)3 O CH2 CF3 Cl 4-trifluoro- methylphenyl 1270 (CH2)5 O CH2 CF3 Cl 4-trifluoro- methylphenyl 1271 5,5-spiro[2.3] O CH2 CF3 Cl 4-trifluoro- hexane methylphenyl 1272 Cyclopentyl H O CH2 CF3 Cl 4-trifluoro- methylphenyl 1273 CH2CH3 H O CH2 CF3 Cl 4-tolyl 1274 CH2CF3 H O CH2 CF3 Cl 4-tolyl 1275 CH2CH2CH3 H O CH2 CF3 Cl 4-tolyl 1276 CH2CH(CH3)2 H O CH2 CF3 Cl 4-tolyl 1277 cyclopropyl- H O CH2 CF3 Cl 4-tolyl methyl 1278 cyclobutyl- H O CH2 CF3 Cl 4-tolyl methyl 1279 (CH2)2 O CH2 CF3 Cl 4-tolyl 1280 (CH2)3 O CH2 CF3 Cl 4-tolyl 1281 (CH2)4 O CH2 CF3 Cl 4-tolyl 1282 (CH2)5 O CH2 CF3 Cl 4-tolyl 1283 5,5-spiro[2.3] O CH2 CF3 Cl 4-tolyl hexane 1284 Cyclopentyl H O CH2 CF3 Cl 4-tolyl 1285 CH2CH3 H O CH2 CF3 Cl 4-ethyl phenyl 1286 CH2CF3 H O CH2 CF3 Cl 4-ethyl phenyl 1287 CH2CH2CH3 H O CH2 CF3 Cl 4-ethyl phenyl 1288 CH2CH(CH3)2 H O CH2 CF3 Cl 4-ethyl phenyl 1289 cyclopropyl- H O CH2 CF3 Cl 4-ethyl phenyl methyl 1290 cyclobutyl- H O CH2 CF3 Cl 4-ethyl phenyl methyl 1291 (CH2)2 O CH2 CF3 Cl 4-ethyl phenyl 1292 (CH2)3 O CH2 CF3 Cl 4-ethyl phenyl 1293 (CH2)4 O CH2 CF3 Cl 4-ethyl phenyl 1294 (CH2)5 O CH2 CF3 Cl 4-ethyl phenyl 1295 5,5-spiro[2.3] O CH2 CF3 Cl 4-ethyl phenyl hexane 1296 Cyclopentyl H O CH2 CF3 Cl 4-ethyl phenyl 1297 CH2CH3 H O CH2 CF3 Cl 4-isopropyl phenyl 1298 CH2CF3 H O CH2 CF3 Cl 4-isopropyl phenyl 1299 CH2CH2CH3 H O CH2 CF3 Cl 4-isopropyl phenyl 1300 CH2CH(CH3)2 H O CH2 CF3 Cl 4-isopropyl phenyl 1301 cyclopropyl- H O CH2 CF3 Cl 4-isopropyl methyl phenyl 1302 cyclobutyl- H O CH2 CF3 Cl 4-isopropyl methyl phenyl 1303 (CH2)2 O CH2 CF3 Cl 4-isopropyl phenyl 1304 (CH2)3 O CH2 CF3 Cl 4-isopropyl phenyl 1305 (CH2)4 O CH2 CF3 Cl 4-isopropyl phenyl 1306 (CH2)5 O CH2 CF3 Cl 4-isopropyl phenyl 1307 5,5-spiro[2.3] O CH2 CF3 Cl 4-isopropyl hexane phenyl 1308 Cyclopentyl H O CH2 CF3 Cl 4-isopropyl phenyl 1309 CH2CH3 H O CH2 CF3 Cl 4-thiomethyl- phenyl 1310 CH2CF3 H O CH2 CF3 Cl 4-thiomethyl- phenyl 1311 CH2CH2CH3 H O CH2 CF3 Cl 4-thiomethyl- phenyl 1312 CH2CH(CH3)2 H O CH2 CF3 Cl 4-thiomethyl- phenyl 1313 cyclopropyl- H O CH2 CF3 Cl 4-thiomethyl- methyl phenyl 1314 cyclobutyl- H O CH2 CF3 Cl 4-thiomethyl- methyl phenyl 1315 (CH2)2 O CH2 CF3 Cl 4-thiomethyl- phenyl 1316 (CH2)3 O CH2 CF3 Cl 4-thiomethyl- phenyl 1317 (CH2)4 O CH2 CF3 Cl 4-thiomethyl- phenyl 1318 (CH2)5 O CH2 CF3 Cl 4-thiomethyl- phenyl 1319 5,5-spiro[2.3] O CH2 CF3 Cl 4-thiomethyl- hexane phenyl 1320 Cyclopentyl H O CH2 CF3 Cl 4-thiomethyl- phenyl 1321 CH2CH3 H O CH2 CF3 Cl 4-trifluoro- methoxyphenyl 1322 CH2CF3 H O CH2 CF3 Cl 4-trifluoro- methoxyphenyl 1323 CH2CH2CH3 H O CH2 CF3 Cl 4-trifluoro- methoxyphenyl 1324 CH2CH(CH3)2 H O CH2 CF3 Cl 4-trifluoro- methoxyphenyl 1325 cyclopropyl- H O CH2 CF3 Cl 4-trifluoro- methyl methoxyphenyl 1326 cyclobutyl- H O CH2 CF3 Cl 4-trifluoro- methyl methoxyphenyl 1327 (CH2)2 O CH2 CF3 Cl 4-trifluoro- methoxyphenyl 1328 (CH2)3 O CH2 CF3 Cl 4-trifluoro- methoxyphenyl 1329 (CH2)4 O CH2 CF3 Cl 4-trifluoro- methoxyphenyl 1330 (CH2)5 O CH2 CF3 Cl 4-trifluoro- methoxyphenyl 1331 5,5-spiro[2.3] O CH2 CF3 Cl 4-trifluoro- hexane methoxyphenyl 1332 Cyclopentyl H O CH2 CF3 Cl 4-trifluoro- methoxyphenyl 1333 cyclobutyl- H O CH2-c-Pr Cl 4-trifluoro- methyl methylphenyl 1334 (CH2)3 O CH2-c-Pr Cl 4-trifluoro- methylphenyl 1335 (CH2)5 O CH2-c-Pr Cl 4-trifluoro- methylphenyl 1336 5,5-spiro[2.3] O CH2-c-Pr Cl 4-trifluoro- hexane methylphenyl 1337 Cyclopentyl H O CH2-c-Pr Cl 4-trifluoro- methylphenyl 1338 CH2CH3 H O CH2-c-Pr Cl 4-tolyl 1339 CH2CF3 H O CH2-c-Pr Cl 4-tolyl 1340 CH2CH2CH3 H O CH2-c-Pr Cl 4-tolyl 1341 CH2CH(CH3)2 H O CH2-c-Pr Cl 4-tolyl 1342 cyclopropyl- H O CH2-c-Pr Cl 4-tolyl methyl 1343 cyclobutyl- H O CH2-c-Pr Cl 4-tolyl methyl 1344 (CH2)2 O CH2-c-Pr Cl 4-tolyl 1345 (CH2)3 O CH2-c-Pr Cl 4-tolyl 1346 (CH2)4 O CH2-c-Pr Cl 4-tolyl 1347 (CH2)5 O CH2-c-Pr Cl 4-tolyl 1348 5,5-spiro[2.3] O CH2-c-Pr Cl 4-tolyl hexane 1349 Cyclopentyl H O CH2-c-Pr Cl 4-tolyl 1350 CH2CH3 H O CH2-c-Pr Cl 4-ethyl phenyl 1351 CH2CF3 H O CH2-c-Pr Cl 4-ethyl phenyl 1352 CH2CH2CH3 H O CH2-c-Pr Cl 4-ethyl phenyl 1353 CH2CH(CH3)2 H O CH2-c-Pr Cl 4-ethyl phenyl 1354 cyclopropyl- H O CH2-c-Pr Cl 4-ethyl phenyl methyl 1355 cyclobutyl- H O CH2-c-Pr Cl 4-ethyl phenyl methyl 1356 (CH2)2 O CH2-c-Pr Cl 4-ethyl phenyl 1357 (CH2)3 O CH2-c-Pr Cl 4-ethyl phenyl 1358 (CH2)4 O CH2-c-Pr Cl 4-ethyl phenyl 1359 (CH2)5 O CH2-c-Pr Cl 4-ethyl phenyl 1360 5,5-spiro[2.3] O CH2-c-Pr Cl 4-ethyl phenyl hexane 1361 Cyclopentyl H O CH2-c-Pr Cl 4-ethyl phenyl 1362 CH2CH3 H O CH2-c-Pr Cl 4-isopropyl phenyl 1363 CH2CF3 H O CH2-c-Pr Cl 4-isopropyl phenyl 1364 CH2CH2CH3 H O CH2-c-Pr Cl 4-isopropyl phenyl 1365 CH2CH(CH3)2 H O CH2-c-Pr Cl 4-isopropyl phenyl 1366 cyclopropyl- H O CH2-c-Pr Cl 4-isopropyl methyl phenyl 1367 cyclobutyl- H O CH2-c-Pr Cl 4-isopropyl methyl phenyl 1368 (CH2)2 O CH2-c-Pr Cl 4-isopropyl phenyl 1369 (CH2)3 O CH2-c-Pr Cl 4-isopropyl phenyl 1370 (CH2)4 O CH2-c-Pr Cl 4-isopropyl phenyl 1371 (CH2)5 O CH2-c-Pr Cl 4-isopropyl phenyl 1372 5,5-spiro[2.3] O CH2-c-Pr Cl 4-isopropyl hexane phenyl 1373 Cyclopentyl H O CH2-c-Pr Cl 4-isopropyl phenyl 1374 CH2CH3 H O CH2-c-Pr Cl 4-thiomethyl- phenyl 1375 CH2CF3 H O CH2-c-Pr Cl 4-thiomethyl- phenyl 1376 CH2CH2CH3 H O CH2-c-Pr Cl 4-thiomethyl- phenyl 1377 CH2CH(CH3)2 H O CH2-c-Pr Cl 4-thiomethyl- phenyl 1378 cyclopropyl- H O CH2-c-Pr Cl 4-thiomethyl- methyl phenyl 1379 cyclobutyl- H O CH2-c-Pr Cl 4-thiomethyl- methyl phenyl 1380 (CH2)2 O CH2-c-Pr Cl 4-thiomethyl- phenyl 1381 (CH2)3 O CH2-c-Pr Cl 4-thiomethyl- phenyl 1382 (CH2)4 O CH2-c-Pr Cl 4-thiomethyl- phenyl 1383 (CH2)5 O CH2-c-Pr Cl 4-thiomethyl- phenyl 1384 5,5-spiro[2.3] O CH2-c-Pr Cl 4-thiomethyl- hexane phenyl 1385 Cyclopentyl H O CH2-c-Pr Cl 4-thiomethyl- phenyl 1386 CH2CH3 H O CH2-c-Pr Cl 4-trifluoro- methoxyphenyl 1387 CH2CF3 H O CH2-c-Pr Cl 4-trifluoro- methoxyphenyl 1388 CH2CH2CH3 H O CH2-c-Pr Cl 4-trifluoro- methoxyphenyl 1389 CH2CH(CH3)2 H O CH2-c-Pr Cl 4-trifluoro- methoxyphenyl 1390 cyclopropyl- H O CH2-c-Pr Cl 4-trifluoro- methyl methoxyphenyl 1391 cyclobutyl- H O CH2-c-Pr Cl 4-trifluoro- methyl methoxyphenyl 1392 (CH2)2 O CH2-c-Pr Cl 4-trifluoro- methoxyphenyl 1393 (CH2)3 O CH2-c-Pr Cl 4-trifluoro- methoxyphenyl 1394 (CH2)4 O CH2-c-Pr Cl 4-trifluoro- methoxyphenyl 1395 (CH2)5 O CH2-c-Pr Cl 4-trifluoro- methoxyphenyl 1396 5,5-spiro[2.3] O CH2-c-Pr Cl 4-trifluoro- hexane methoxyphenyl 1397 Cyclopentyl H O CH2-c-Pr Cl 4-trifluoro- methoxyphenyl 1398 CH2CH3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1399 CH2CF3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1400 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1401 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1402 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-trifluoro- methyl methylphenyl 1403 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-trifluoro- methyl methylphenyl 1404 (CH2)2 O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1405 (CH2)3 O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1406 (CH2)4 O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1407 (CH2)5 O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1408 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-trifluoro- hexane methylphenyl 1409 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1410 CH2CH3 H O CH2 CF3 OCH2 CF3 4-tolyl 1411 CH2CF3 H O CH2 CF3 OCH2 CF3 4-tolyl 1412 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-tolyl 1413 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-tolyl 1414 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-tolyl methyl 1415 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-tolyl methyl 1416 (CH2)2 O CH2 CF3 OCH2 CF3 4-tolyl 1417 (CH2)3 O CH2 CF3 OCH2 CF3 4-tolyl 1418 (CH2)4 O CH2 CF3 OCH2 CF3 4-tolyl 1419 (CH2)5 O CH2 CF3 OCH2 CF3 4-tolyl 1420 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-tolyl hexane 1421 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-tolyl 1422 CH2CH3 H O CH2 CF3 OCH2 CF3 4-ethyl phenyl 1423 CH2CF3 H O CH2 CF3 OCH2 CF3 4-ethyl phenyl 1424 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-ethyl phenyl 1425 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-ethyl phenyl 1426 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-ethyl phenyl methyl 1427 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-ethyl phenyl methyl 1428 (CH2)2 O CH2 CF3 OCH2 CF3 4-ethyl phenyl 1429 (CH2)3 O CH2 CF3 OCH2 CF3 4-ethyl phenyl 1430 (CH2)4 O CH2 CF3 OCH2 CF3 4-ethyl phenyl 1431 (CH2)5 O CH2 CF3 OCH2 CF3 4-ethyl phenyl 1432 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-ethyl phenyl hexane 1433 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-ethyl phenyl 1434 CH2CH3 H O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 1435 CH2CF3 H O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 1436 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 1437 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 1438 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-isopropyl methyl phenyl 1439 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-isopropyl methyl phenyl 1440 (CH2)2 O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 1441 (CH2)3 O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 1442 (CH2)4 O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 1443 (CH2)5 O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 1444 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-isopropyl hexane phenyl 1445 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 1446 CH2CH3 H O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 1447 CH2CF3 H O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 1448 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 1449 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 1450 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-thiomethyl- methyl phenyl 1451 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-thiomethyl- methyl phenyl 1452 (CH2)2 O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 1453 (CH2)3 O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 1454 (CH2)4 O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 1455 (CH2)5 O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 1456 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-thiomethyl- hexane phenyl 1457 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 1458 CH2CH3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 1459 CH2CF3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 1460 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 1461 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 1462 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-trifluoro- methyl methoxyphenyl 1463 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-trifluoro- methyl methoxyphenyl 1464 (CH2)2 O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 1465 (CH2)3 O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 1466 (CH2)4 O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 1467 (CH2)5 O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 1468 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-trifluoro- hexane methoxyphenyl 1469 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 1470 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 1471 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 1472 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 1473 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 1474 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-trifluoro- methyl methylphenyl 1475 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-trifluoro- methyl methylphenyl 1476 (CH2)2 O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 1477 (CH2)3 O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 1478 (CH2)4 O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 1479 (CH2)5 O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 1480 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-trifluoro- hexane methylphenyl 1481 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 1482 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-tolyl 1483 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-tolyl 1484 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-tolyl 1485 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-tolyl 1486 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-tolyl methyl 1487 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-tolyl methyl 1488 (CH2)2 O CH2-c-Pr OCH2 CF3 4-tolyl 1489 (CH2)3 O CH2-c-Pr OCH2 CF3 4-tolyl 1490 (CH2)4 O CH2-c-Pr OCH2 CF3 4-tolyl 1491 (CH2)5 O CH2-c-Pr OCH2 CF3 4-tolyl 1492 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-tolyl hexane 1493 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-tolyl 1494 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 1495 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 1496 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 1497 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 1498 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl methyl 1499 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl methyl 1500 (CH2)2 O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 1501 (CH2)3 O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 1502 (CH2)4 O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 1503 (CH2)5 O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 1504 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-ethyl phenyl hexane 1505 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 1506 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 1507 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 1508 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 1509 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 1510 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-isopropyl methyl phenyl 1511 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-isopropyl methyl phenyl 1512 (CH2)2 O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 1513 (CH2)3 O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 1514 (CH2)4 O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 1515 (CH2)5 O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 1516 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-isopropyl hexane phenyl 1517 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 1518 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 1519 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 1520 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 1521 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 1522 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-thiomethyl- methyl phenyl 1523 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-thiomethyl- methyl phenyl 1524 (CH2)2 O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 1525 (CH2)3 O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 1526 (CH2)4 O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 1527 (CH2)5 O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 1528 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-thiomethyl- hexane phenyl 1529 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl CH2CH3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 1530 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 1531 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 1532 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 1533 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-trifluoro- methyl methoxyphenyl 1534 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-trifluoro- methyl methoxyphenyl 1535 (CH2)2 O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 1536 (CH2)3 O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 1537 (CH2)4 O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 1538 (CH2)5 O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 1539 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-trifluoro- hexane methoxyphenyl 1540 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl

TABLE 5 Compounds of Formula IV Formula IV Ex R1 R2 X R3 R5 Z 1541 CH2CH3 H O CH2 CF3 CF3 4-trifluoro- methylphenyl 1542 CH2CF3 H O CH2 CF3 CF3 4-trifluoro- methylphenyl 1543 CH2CH2CH3 H O CH2 CF3 CF3 4-trifluoro- methylphenyl 1544 CH2CH(CH3)2 H O CH2 CF3 CF3 4-trifluoro- methylphenyl 1545 cyclopropyl- H O CH2 CF3 CF3 4-trifluoro- methyl methylphenyl 1546 cyclobutyl- H O CH2 CF3 CF3 4-trifluoro- methyl methylphenyl 1547 (CH2)2 O CH2 CF3 CF3 4-trifluoro- methylphenyl 1548 (CH2)3 O CH2 CF3 CF3 4-trifluoro- methylphenyl 1549 (CH2)4 O CH2 CF3 CF3 4-trifluoro- methylphenyl 1550 (CH2)5 O CH2 CF3 CF3 4-trifluoro- methylphenyl 1551 5,5-spiro[2.3]- O CH2 CF3 CF3 4-trifluoro- hexane methylphenyl 1552 Cyclopentyl H O CH2 CF3 CF3 4-trifluoro- methylphenyl 1553 CH2CH3 H O CH2 CF3 CF3 4-tolyl 1554 CH2CF3 H O CH2 CF3 CF3 4-tolyl 1555 CH2CH2CH3 H O CH2 CF3 CF3 4-tolyl 1556 CH2CH(CH3)2 H O CH2 CF3 CF3 4-tolyl 1557 cyclopropyl- H O CH2 CF3 CF3 4-tolyl methyl 1558 cyclobutyl- H O CH2 CF3 CF3 4-tolyl methyl 1559 (CH2)2 O CH2 CF3 CF3 4-tolyl 1560 (CH2)3 O CH2 CF3 CF3 4-tolyl 1561 (CH2)4 O CH2 CF3 CF3 4-tolyl 1562 (CH2)5 O CH2 CF3 CF3 4-tolyl 1563 5,5-spiro[2.3] O CH2 CF3 CF3 4-tolyl hexane 1564 Cyclopentyl H O CH2 CF3 CF3 4-tolyl 1565 CH2CH3 H O CH2 CF3 CF3 4-ethyl phenyl 1566 CH2CF3 H O CH2 CF3 CF3 4-ethyl phenyl 1567 CH2CH2CH3 H O CH2 CF3 CF3 4-ethyl phenyl 1568 CH2CH(CH3)2 H O CH2 CF3 CF3 4-ethyl phenyl 1569 cyclopropyl- H O CH2 CF3 CF3 4-ethyl phenyl methyl 1570 cyclobutyl- H O CH2 CF3 CF3 4-ethyl phenyl methyl 1571 (CH2)2 O CH2 CF3 CF3 4-ethyl phenyl 1572 (CH2)3 O CH2 CF3 CF3 4-ethyl phenyl 1573 (CH2)4 O CH2 CF3 CF3 4-ethyl phenyl 1574 (CH2)5 O CH2 CF3 CF3 4-ethyl phenyl 1575 5,5-spiro[2.3] O CH2 CF3 CF3 4-ethyl phenyl hexane 1576 Cyclopentyl H O CH2 CF3 CF3 4-ethyl phenyl 1577 CH2CH3 H O CH2 CF3 CF3 4-isopropyl phenyl 1578 CH2CF3 H O CH2 CF3 CF3 4-isopropyl phenyl 1579 CH2CH2CH3 H O CH2 CF3 CF3 4-isopropyl phenyl 1580 CH2CH(CH3)2 H O CH2 CF3 CF3 4-isopropyl phenyl 1581 cyclopropyl- H O CH2 CF3 CF3 4-isopropyl methyl phenyl 1582 cyclobutyl- H O CH2 CF3 CF3 4-isopropyl methyl phenyl 1583 (CH2)2 O CH2 CF3 CF3 4-isopropyl phenyl 1584 (CH2)3 O CH2 CF3 CF3 4-isopropyl phenyl 1585 (CH2)4 O CH2 CF3 CF3 4-isopropyl phenyl 1586 (CH2)5 O CH2 CF3 CF3 4-isopropyl phenyl 1587 5,5-spiro[2.3] O CH2 CF3 CF3 4-isopropyl hexane phenyl 1588 Cyclopentyl H O CH2 CF3 CF3 4-isopropyl phenyl 1589 CH2CH3 H O CH2 CF3 CF3 4-thiomethyl- phenyl 1590 CH2CF3 H O CH2 CF3 CF3 4-thiomethyl- phenyl 1591 CH2CH2CH3 H O CH2 CF3 CF3 4-thiomethyl- phenyl 1592 CH2CH(CH3)2 H O CH2 CF3 CF3 4-thiomethyl- phenyl 1593 cyclopropyl- H O CH2 CF3 CF3 4-thiomethyl- methyl phenyl 1594 cyclobutyl- H O CH2 CF3 CF3 4-thiomethyl- methyl phenyl 1595 (CH2)2 O CH2 CF3 CF3 4-thiomethyl- phenyl 1596 (CH2)3 O CH2 CF3 CF3 4-thiomethyl- phenyl 1597 (CH2)4 O CH2 CF3 CF3 4-thiomethyl- phenyl 1598 (CH2)5 O CH2 CF3 CF3 4-thiomethyl- phenyl 1599 5,5-spiro[2.3] O CH2 CF3 CF3 4-thiomethyl- hexane phenyl 1600 Cyclopentyl H O CH2 CF3 CF3 4-thiomethyl- phenyl 1601 CH2CH3 H O CH2 CF3 CF3 4-trifluoro- methoxyphenyl 1602 CH2CF3 H O CH2 CF3 CF3 4-trifluoro- methoxyphenyl 1603 CH2CH2CH3 H O CH2 CF3 CF3 4-trifluoro- methoxyphenyl 1604 CH2CH(CH3)2 H O CH2 CF3 CF3 4-trifluoro- methoxyphenyl 1605 cyclopropyl- H O CH2 CF3 CF3 4-trifluoro- methyl methoxyphenyl 1606 cyclobutyl- H O CH2 CF3 CF3 4-trifluoro- methyl methoxyphenyl 1607 (CH2)2 O CH2 CF3 CF3 4-trifluoro- methoxyphenyl 1608 (CH2)3 O CH2 CF3 CF3 4-trifluoro- methoxyphenyl 1609 (CH2)4 O CH2 CF3 CF3 4-trifluoro- methoxyphenyl 1610 (CH2)5 O CH2 CF3 CF3 4-trifluoro- methoxyphenyl 1611 5,5-spiro[2.3] O CH2 CF3 CF3 4-trifluoro- hexane methoxyphenyl 1612 Cyclopentyl H O CH2 CF3 CF3 4-trifluoro- methoxyphenyl 1613 CH2CH3 H O CH2-c-Pr CF3 4-trifluoro- methylphenyl 1614 CH2CF3 H O CH2-c-Pr CF3 4-trifluoro- methylphenyl 1615 CH2CH2CH3 H O CH2-c-Pr CF3 4-trifluoro- methylphenyl 1616 CH2CH(CH3)2 H O CH2-c-Pr CF3 4-trifluoro- methylphenyl 1617 cyclopropyl- H O CH2-c-Pr CF3 4-trifluoro- methyl methylphenyl 1618 cyclobutyl- H O CH2-c-Pr CF3 4-trifluoro- methyl methylphenyl 1619 (CH2)2 O CH2-c-Pr CF3 4-trifluoro- methylphenyl 1620 (CH2)3 O CH2-c-Pr CF3 4-trifluoro- methylphenyl 1621 (CH2)4 O CH2-c-Pr CF3 4-trifluoro- methylphenyl 1622 (CH2)5 O CH2-c-Pr CF3 4-trifluoro- methylphenyl 1623 5,5-spiro[2.3] O CH2-c-Pr CF3 4-trifluoro- hexane methylphenyl 1624 Cyclopentyl H O CH2-c-Pr CF3 4-trifluoro- methylphenyl 1625 CH2CH3 H O CH2-c-Pr CF3 4-tolyl 1626 CH2CF3 H O CH2-c-Pr CF3 4-tolyl 1627 CH2CH2CH3 H O CH2-c-Pr CF3 4-tolyl 1628 CH2CH(CH3)2 H O CH2-c-Pr CF3 4-tolyl 1629 cyclopropyl- H O CH2-c-Pr CF3 4-tolyl methyl 1630 cyclobutyl- H O CH2-c-Pr CF3 4-tolyl methyl 1631 (CH2)2 O CH2-c-Pr CF3 4-tolyl 1632 (CH2)3 O CH2-c-Pr CF3 4-tolyl 1633 (CH2)4 O CH2-c-Pr CF3 4-tolyl 1634 (CH2)5 O CH2-c-Pr CF3 4-tolyl 1635 5,5-spiro[2.3] O CH2-c-Pr CF3 4-tolyl hexane 1636 Cyclopentyl H O CH2-c-Pr CF3 4-tolyl 1637 CH2CH3 H O CH2-c-Pr CF3 4-ethyl phenyl 1638 CH2CF3 H O CH2-c-Pr CF3 4-ethyl phenyl 1639 CH2CH2CH3 H O CH2-c-Pr CF3 4-ethyl phenyl 1640 CH2CH(CH3)2 H O CH2-c-Pr CF3 4-ethyl phenyl 1641 cyclopropyl- H O CH2-c-Pr CF3 4-ethyl phenyl methyl 1642 cyclobutyl- H O CH2-c-Pr CF3 4-ethyl phenyl methyl 1643 (CH2)2 O CH2-c-Pr CF3 4-ethyl phenyl 1644 (CH2)3 O CH2-c-Pr CF3 4-ethyl phenyl 1645 (CH2)4 O CH2-c-Pr CF3 4-ethyl phenyl 1646 (CH2)5 O CH2-c-Pr CF3 4-ethyl phenyl 1647 5,5-spiro[2.3] O CH2-c-Pr CF3 4-ethyl phenyl hexane 1648 Cyclopentyl H O CH2-c-Pr CF3 4-ethyl phenyl 1649 CH2CH3 H O CH2-c-Pr CF3 4-isopropyl phenyl 1650 CH2CF3 H O CH2-c-Pr CF3 4-isopropyl phenyl 1651 CH2CH2CH3 H O CH2-c-Pr CF3 4-isopropyl phenyl 1652 CH2CH(CH3)2 H O CH2-c-Pr CF3 4-isopropyl phenyl 1653 cyclopropyl- H O CH2-c-Pr CF3 4-isopropyl methyl phenyl 1654 cyclobutyl- H O CH2-c-Pr CF3 4-isopropyl methyl phenyl 1655 (CH2)2 O CH2-c-Pr CF3 4-isopropyl phenyl 1656 (CH2)3 O CH2-c-Pr CF3 4-isopropyl phenyl 1657 (CH2)4 O CH2-c-Pr CF3 4-isopropyl phenyl 1658 (CH2)5 O CH2-c-Pr CF3 4-isopropyl phenyl 1659 5,5-spiro[2.3] O CH2-c-Pr CF3 4-isopropyl hexane phenyl 1660 Cyclopentyl H O CH2-c-Pr CF3 4-isopropyl phenyl 1661 CH2CH3 H O CH2-c-Pr CF3 4-thiomethyl- phenyl 1662 CH2CF3 H O CH2-c-Pr CF3 4-thiomethyl- phenyl 1663 CH2CH2CH3 H O CH2-c-Pr CF3 4-thiomethyl- phenyl 1664 CH2CH(CH3)2 H O CH2-c-Pr CF3 4-thiomethyl- phenyl 1665 cyclopropyl- H O CH2-c-Pr CF3 4-thiomethyl- methyl phenyl 1666 cyclobutyl- H O CH2-c-Pr CF3 4-thiomethyl- methyl phenyl 1667 (CH2)2 O CH2-c-Pr CF3 4-thiomethyl- phenyl 1668 (CH2)3 O CH2-c-Pr CF3 4-thiomethyl- phenyl 1669 (CH2)4 O CH2-c-Pr CF3 4-thiomethyl- phenyl 1670 (CH2)5 O CH2-c-Pr CF3 4-thiomethyl- phenyl 1671 5,5-spiro[2.3] O CH2-c-Pr CF3 4-thiomethyl- hexane phenyl 1672 Cyclopentyl H O CH2-c-Pr CF3 4-thiomethyl- phenyl 1673 CH2CH3 H O CH2-c-Pr CF3 4-trifluoro- methoxyphenyl 1674 CH2CF3 H O CH2-c-Pr CF3 4-trifluoro- methoxyphenyl 1675 CH2CH2CH3 H O CH2-c-Pr CF3 4-trifluoro- methoxyphenyl 1676 CH2CH(CH3)2 H O CH2-c-Pr CF3 4-trifluoro- methoxyphenyl 1677 cyclopropyl- H O CH2-c-Pr CF3 4-trifluoro- methyl methoxyphenyl 1678 cyclobutyl- H O CH2-c-Pr CF3 4-trifluoro- methyl methoxyphenyl 1679 (CH2)2 O CH2-c-Pr CF3 4-trifluoro- methoxyphenyl 1680 (CH2)3 O CH2-c-Pr CF3 4-trifluoro- methoxyphenyl 1681 (CH2)4 O CH2-c-Pr CF3 4-trifluoro- methoxyphenyl 1682 (CH2)5 O CH2-c-Pr CF3 4-trifluoro- methoxyphenyl 1683 5,5-spiro[2.3] O CH2-c-Pr CF3 4-trifluoro- hexane methoxyphenyl 1684 Cyclopentyl H O CH2-c-Pr CF3 4-trifluoro- methoxyphenyl 1685 CH2CH3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1686 CH2CF3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1687 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1688 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1689 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-trifluoro- methyl methylphenyl 1690 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-trifluoro- methyl methylphenyl 1691 (CH2)2 O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1692 (CH2)3 O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1693 (CH2)4 O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1694 (CH2)5 O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1695 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-trifluoro- hexane methylphenyl 1696 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1697 CH2CH3 H O CH2 CF3 OCH2 CF3 4-tolyl 1698 CH2CF3 H O CH2 CF3 OCH2 CF3 4-tolyl 1699 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-tolyl 1700 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-tolyl 1701 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-tolyl methyl 1702 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-tolyl methyl 1703 (CH2)2 O CH2 CF3 OCH2 CF3 4-tolyl 1704 (CH2)3 O CH2 CF3 OCH2 CF3 4-tolyl 1705 (CH2)4 O CH2 CF3 OCH2 CF3 4-tolyl 1706 (CH2)5 O CH2 CF3 OCH2 CF3 4-tolyl 1707 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-tolyl hexane 1708 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-tolyl 1709 CH2CH3 H O CH2 CF3 OCH2 CF3 4-ethyl phenyl 1710 CH2CF3 H O CH2 CF3 OCH2 CF3 4-ethyl phenyl 1711 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-ethyl phenyl 1712 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-ethyl phenyl 1713 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-ethyl phenyl methyl 1714 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-ethyl phenyl methyl 1715 (CH2)2 O CH2 CF3 OCH2 CF3 4-ethyl phenyl 1716 (CH2)3 O CH2 CF3 OCH2 CF3 4-ethyl phenyl 1717 (CH2)4 O CH2 CF3 OCH2 CF3 4-ethyl phenyl 1718 (CH2)5 O CH2 CF3 OCH2 CF3 4-ethyl phenyl 1719 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-ethyl phenyl hexane 1720 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-ethyl phenyl 1721 CH2CH3 H O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 1722 CH2CF3 H O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 1723 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 1724 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 1725 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-isopropyl methyl phenyl 1726 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-isopropyl methyl phenyl 1727 (CH2)2 O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 1728 (CH2)3 O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 1729 (CH2)4 O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 1730 (CH2)5 O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 1731 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-isopropyl hexane phenyl 1732 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 1733 CH2CH3 H O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 1734 CH2CF3 H O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 1735 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 1736 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 1737 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-thiomethyl- methyl phenyl 1738 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-thiomethyl- methyl phenyl 1739 (CH2)2 O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 1740 (CH2)3 O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 1741 (CH2)4 O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 1742 (CH2)5 O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 1743 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-thiomethyl- hexane phenyl 1744 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 1745 CH2CH3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 1746 CH2CF3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 1747 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 1748 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 1749 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-trifluoro- methyl methoxyphenyl 1750 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-trifluoro- methyl methoxyphenyl 1751 (CH2)2 O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 1752 (CH2)3 O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 1753 (CH2)4 O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 1754 (CH2)5 O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 1755 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-trifluoro- hexane methoxyphenyl 1756 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 1757 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 1758 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 1759 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 1760 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 1761 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-trifluoro- methyl methylphenyl 1762 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-trifluoro- methyl methylphenyl 1763 (CH2)2 O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 1764 (CH2)3 O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 1765 (CH2)4 O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 1766 (CH2)5 O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 1767 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-trifluoro- hexane methylphenyl 1768 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 1769 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-tolyl 1770 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-tolyl 1771 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-tolyl 1772 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-tolyl 1773 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-tolyl methyl 1774 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-tolyl methyl 1775 (CH2)2 O CH2-c-Pr OCH2 CF3 4-tolyl 1776 (CH2)3 O CH2-c-Pr OCH2 CF3 4-tolyl 1777 (CH2)4 O CH2-c-Pr OCH2 CF3 4-tolyl 1778 (CH2)5 O CH2-c-Pr OCH2 CF3 4-tolyl 1779 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-tolyl hexane 1780 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-tolyl 1781 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 1782 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 1783 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 1784 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 1785 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl methyl 1786 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl methyl 1787 (CH2)2 O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 1788 (CH2)3 O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 1789 (CH2)4 O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 1790 (CH2)5 O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 1791 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-ethyl phenyl hexane 1792 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 1793 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 1794 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 1795 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 1796 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 1797 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-isopropyl methyl phenyl 1798 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-isopropyl methyl phenyl 1799 (CH2)2 O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 1800 (CH2)3 O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 1801 (CH2)4 O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 1802 (CH2)5 O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 1803 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-isopropyl hexane phenyl 1804 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 1805 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 1806 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 1807 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 1808 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 1809 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-thiomethyl- methyl phenyl 1810 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-thiomethyl- methyl phenyl 1811 (CH2)2 O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 1812 (CH2)3 O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 1813 (CH2)4 O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 1814 (CH2)5 O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 1815 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-thiomethyl- hexane phenyl 1816 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 1817 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 1818 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 1819 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 1820 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 1821 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-trifluoro- methyl methoxyphenyl 1822 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-trifluoro- methyl methoxyphenyl 1823 (CH2)2 O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 1824 (CH2)3 O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 1825 (CH2)4 O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 1826 (CH2)5 O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 1827 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-trifluoro- hexane methoxyphenyl 1828 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl

TABLE 6 Compounds of Formula IV Formula IV Ex R1 R2 X R3 R5 Z 1829 CH2CH3 H O CH2 CF3 Cl 4-trifluoro- methylphenyl 1830 CH2CF3 H O CH2 CF3 Cl 4-trifluoro- methylphenyl 1831 CH2CH2CH3 H O CH2 CF3 Cl 4-trifluoro- methylphenyl 1832 CH2CH(CH3)2 H O CH2 CF3 Cl 4-trifluoro- methylphenyl 1833 cyclopropyl- H O CH2 CF3 Cl 4-trifluoro- methyl methylphenyl 1834 cyclobutyl- H O CH2 CF3 Cl 4-trifluoro- methyl methylphenyl 1835 (CH2)2 O CH2 CF3 Cl 4-trifluoro- methylphenyl 1836 (CH2)3 O CH2 CF3 Cl 4-trifluoro- methylphenyl 1837 (CH2)4 O CH2 CF3 Cl 4-trifluoro- methylphenyl 1838 (CH2)5 O CH2 CF3 Cl 4-trifluoro- methylphenyl 1839 5,5-spiro[2.3] O CH2 CF3 Cl 4-trifluoro- hexane methylphenyl 1840 Cyclopentyl H O CH2 CF3 Cl 4-trifluoro- methylphenyl 1841 CH2CH3 H O CH2 CF3 Cl 4-tolyl 1842 CH2CF3 H O CH2 CF3 Cl 4-tolyl 1843 CH2CH2CH3 H O CH2 CF3 Cl 4-tolyl 1844 CH2CH(CH3)2 H O CH2 CF3 Cl 4-tolyl 1845 cyclopropyl- H O CH2 CF3 Cl 4-tolyl methyl 1846 cyclobutyl- H O CH2 CF3 Cl 4-tolyl methyl 1847 (CH2)2 O CH2 CF3 Cl 4-tolyl 1848 (CH2)3 O CH2 CF3 Cl 4-tolyl 1849 (CH2)4 O CH2 CF3 Cl 4-tolyl 1850 (CH2)5 O CH2 CF3 Cl 4-tolyl 1851 5,5-spiro[2.3] O CH2 CF3 Cl 4-tolyl hexane 1852 Cyclopentyl H O CH2 CF3 Cl 4-tolyl 1853 CH2CH3 H O CH2 CF3 Cl 4-ethyl phenyl 1854 CH2CF3 H O CH2 CF3 Cl 4-ethyl phenyl 1855 CH2CH2CH3 H O CH2 CF3 Cl 4-ethyl phenyl 1856 CH2CH(CH3)2 H O CH2 CF3 Cl 4-ethyl phenyl 1857 cyclopropyl- H O CH2 CF3 Cl 4-ethyl phenyl methyl 1858 cyclobutyl- H O CH2 CF3 Cl 4-ethyl phenyl methyl 1859 (CH2)2 O CH2 CF3 Cl 4-ethyl phenyl 1860 (CH2)3 O CH2 CF3 Cl 4-ethyl phenyl 1861 (CH2)4 O CH2 CF3 Cl 4-ethyl phenyl 1862 (CH2)5 O CH2 CF3 Cl 4-ethyl phenyl 1863 5,5-spiro[2.3] O CH2 CF3 Cl 4-ethyl phenyl hexane 1864 Cyclopentyl H O CH2 CF3 Cl 4-ethyl phenyl 1865 CH2CH3 H O CH2 CF3 Cl 4-isopropyl phenyl 1866 CH2CF3 H O CH2 CF3 Cl 4-isopropyl phenyl 1867 CH2CH2CH3 H O CH2 CF3 Cl 4-isopropyl phenyl 1868 CH2CH(CH3)2 H O CH2 CF3 Cl 4-isopropyl phenyl 1869 cyclopropyl- H O CH2 CF3 Cl 4-isopropyl methyl phenyl 1870 cyclobutyl- H O CH2 CF3 Cl 4-isopropyl methyl phenyl 1871 (CH2)2 O CH2 CF3 Cl 4-isopropyl phenyl 1872 (CH2)3 O CH2 CF3 Cl 4-isopropyl phenyl 1873 (CH2)4 O CH2 CF3 Cl 4-isopropyl phenyl 1874 (CH2)5 O CH2 CF3 Cl 4-isopropyl phenyl 1875 5,5-spiro[2.3] O CH2 CF3 Cl 4-isopropyl hexane phenyl 1876 Cyclopentyl H O CH2 CF3 Cl 4-isopropyl phenyl 1877 CH2CH3 H O CH2 CF3 Cl 4-thiomethyl- phenyl 1878 CH2CF3 H O CH2 CF3 Cl 4-thiomethyl- phenyl 1879 CH2CH2CH3 H O CH2 CF3 Cl 4-thiomethyl- phenyl 1880 CH2CH(CH3)2 H O CH2 CF3 Cl 4-thiomethyl- phenyl 1881 cyclopropyl- H O CH2 CF3 Cl 4-thiomethyl- methyl phenyl 1882 cyclobutyl- H O CH2 CF3 Cl 4-thiomethyl- methyl phenyl 1883 (CH2)2 O CH2 CF3 Cl 4-thiomethyl- phenyl 1884 (CH2)3 O CH2 CF3 Cl 4-thiomethyl- phenyl 1885 (CH2)4 O CH2 CF3 Cl 4-thiomethyl- phenyl 1886 (CH2)5 O CH2 CF3 Cl 4-thiomethyl- phenyl 1887 5,5-spiro[2.3] O CH2 CF3 Cl 4-thiomethyl- hexane phenyl 1888 Cyclopentyl H O CH2 CF3 Cl 4-thiomethyl- phenyl 1889 CH2CH3 H O CH2 CF3 Cl 4-trifluoro- methoxyphenyl 1890 CH2CF3 H O CH2 CF3 Cl 4-trifluoro- methoxyphenyl 1891 CH2CH2CH3 H O CH2 CF3 Cl 4-trifluoro- methoxyphenyl 1892 CH2CH(CH3)2 H O CH2 CF3 Cl 4-trifluoro- methoxyphenyl 1893 cyclopropyl- H O CH2 CF3 Cl 4-trifluoro- methyl methoxyphenyl 1894 cyclobutyl- H O CH2 CF3 Cl 4-trifluoro- methyl methoxyphenyl 1895 (CH2)2 O CH2 CF3 Cl 4-trifluoro- methoxyphenyl 1896 (CH2)3 O CH2 CF3 Cl 4-trifluoro- methoxyphenyl 1897 (CH2)4 O CH2 CF3 Cl 4-trifluoro- methoxyphenyl 1898 (CH2)5 O CH2 CF3 Cl 4-trifluoro- methoxyphenyl 1899 5,5-spiro[2.3] O CH2 CF3 Cl 4-trifluoro- hexane methoxyphenyl 1900 Cyclopentyl H O CH2 CF3 Cl 4-trifluoro- methoxyphenyl 1901 CH2CH3 H O CH2-c-Pr Cl 4-trifluoro- methylphenyl 1902 CH2CF3 H O CH2-c-Pr Cl 4-trifluoro- methylphenyl 1903 CH2CH2CH3 H O CH2-c-Pr Cl 4-trifluoro- methylphenyl 1904 CH2CH(CH3)2 H O CH2-c-Pr Cl 4-trifluoro- methylphenyl 1905 cyclopropyl- H O CH2-c-Pr Cl 4-trifluoro- methyl methylphenyl 1906 cyclobutyl- H O CH2-c-Pr Cl 4-trifluoro- methyl methylphenyl 1907 (CH2)2 O CH2-c-Pr Cl 4-trifluoro- methylphenyl 1908 (CH2)3 O CH2-c-Pr Cl 4-trifluoro- methylphenyl 1909 (CH2)4 O CH2-c-Pr Cl 4-trifluoro- methylphenyl 1910 (CH2)5 O CH2-c-Pr Cl 4-trifluoro- methylphenyl 1911 5,5-spiro[2.3] O CH2-c-Pr Cl 4-trifluoro- hexane methylphenyl 1912 Cyclopentyl H O CH2-c-Pr Cl 4-trifluoro- methylphenyl 1913 CH2CH3 H O CH2-c-Pr Cl 4-tolyl 1914 CH2CF3 H O CH2-c-Pr Cl 4-tolyl 1915 CH2CH2CH3 H O CH2-c-Pr Cl 4-tolyl 1916 CH2CH(CH3)2 H O CH2-c-Pr Cl 4-tolyl 1917 cyclopropyl- H O CH2-c-Pr Cl 4-tolyl methyl 1918 cyclobutyl- H O CH2-c-Pr Cl 4-tolyl methyl 1919 (CH2)2 O CH2-c-Pr Cl 4-tolyl 1920 (CH2)3 O CH2-c-Pr Cl 4-tolyl 1921 (CH2)4 O CH2-c-Pr Cl 4-tolyl 1922 (CH2)5 O CH2-c-Pr Cl 4-tolyl 1923 5,5-spiro[2.3] O CH2-c-Pr Cl 4-tolyl hexane 1924 Cyclopentyl H O CH2-c-Pr Cl 4-tolyl 1925 CH2CH3 H O CH2-c-Pr Cl 4-ethyl phenyl 1926 CH2CF3 H O CH2-c-Pr Cl 4-ethyl phenyl 1927 CH2CH2CH3 H O CH2-c-Pr Cl 4-ethyl phenyl 1928 CH2CH(CH3)2 H O CH2-c-Pr Cl 4-ethyl phenyl 1929 cyclopropyl- H O CH2-c-Pr Cl 4-ethyl phenyl methyl 1930 cyclobutyl- H O CH2-c-Pr Cl 4-ethyl phenyl methyl 1931 (CH2)2 O CH2-c-Pr Cl 4-ethyl phenyl 1932 (CH2)3 O CH2-c-Pr Cl 4-ethyl phenyl 1933 (CH2)4 O CH2-c-Pr Cl 4-ethyl phenyl 1934 (CH2)5 O CH2-c-Pr Cl 4-ethyl phenyl 1935 5,5-spiro[2.3] O CH2-c-Pr Cl 4-ethyl phenyl hexane 1936 Cyclopentyl H O CH2-c-Pr Cl 4-ethyl phenyl 1937 CH2CH3 H O CH2-c-Pr Cl 4-isopropyl phenyl 1938 CH2CF3 H O CH2-c-Pr Cl 4-isopropyl phenyl 1939 CH2CH2CH3 H O CH2-c-Pr Cl 4-isopropyl phenyl 1940 CH2CH(CH3)2 H O CH2-c-Pr Cl 4-isopropyl phenyl 1941 cyclopropyl- H O CH2-c-Pr Cl 4-isopropyl methyl phenyl 1942 cyclobutyl- H O CH2-c-Pr Cl 4-isopropyl methyl phenyl 1943 (CH2)2 O CH2-c-Pr Cl 4-isopropyl phenyl 1944 (CH2)3 O CH2-c-Pr Cl 4-isopropyl phenyl 1945 (CH2)4 O CH2-c-Pr Cl 4-isopropyl phenyl 1946 (CH2)5 O CH2-c-Pr Cl 4-isopropyl phenyl 1947 5,5-spiro[2.3] O CH2-c-Pr Cl 4-isopropyl hexane phenyl 1948 Cyclopentyl H O CH2-c-Pr Cl 4-isopropyl phenyl 1949 CH2CH3 H O CH2-c-Pr Cl 4-thiomethyl- phenyl 1950 CH2CF3 H O CH2-c-Pr Cl 4-thiomethyl- phenyl 1951 CH2CH2CH3 H O CH2-c-Pr Cl 4-thiomethyl- phenyl 1952 CH2CH(CH3)2 H O CH2-c-Pr Cl 4-thiomethyl- phenyl 1953 cyclopropyl- H O CH2-c-Pr Cl 4-thiomethyl- methyl phenyl 1954 cyclobutyl- H O CH2-c-Pr Cl 4-thiomethyl- phenyl 1955 (CH2)2 O CH2-c-Pr Cl 4-thiomethyl- phenyl 1956 (CH2)3 O CH2-c-Pr Cl 4-thiomethyl- phenyl 1957 (CH2)4 O CH2-c-Pr Cl 4-thiomethyl- phenyl 1958 (CH2)5 O CH2-c-Pr Cl 4-thiomethyl- phenyl 1959 5,5-spiro[2.3] O CH2-c-Pr Cl 4-thiomethyl- hexane phenyl 1960 Cyclopentyl H O CH2-c-Pr Cl 4-thiomethyl- phenyl 1961 CH2CH3 H O CH2-c-Pr Cl 4-trifluoro- methoxyphenyl 1962 CH2CF3 H O CH2-c-Pr Cl 4-trifluoro- methoxyphenyl 1963 CH2CH2CH3 H O CH2-c-Pr Cl 4-trifluoro- methoxyphenyl 1964 CH2CH(CH3)2 H O CH2-c-Pr Cl 4-trifluoro- methoxyphenyl 1965 cyclopropyl- H O CH2-c-Pr Cl 4-trifluoro- methyl methoxyphenyl 1966 cyclobutyl- H O CH2-c-Pr Cl 4-trifluoro- methyl methoxyphenyl 1967 (CH2)2 O CH2-c-Pr Cl 4-trifluoro- methoxyphenyl 1968 (CH2)3 O CH2-c-Pr Cl 4-trifluoro- methoxyphenyl 1969 (CH2)4 O CH2-c-Pr Cl 4-trifluoro- methoxyphenyl 1970 (CH2)5 O CH2-c-Pr Cl 4-trifluoro- methoxyphenyl 1971 5,5-spiro[2.3] O CH2-c-Pr Cl 4-trifluoro- hexane methoxyphenyl 1972 Cyclopentyl H O CH2-c-Pr Cl 4-trifluoro- methoxyphenyl 1973 CH2CH3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1974 CH2CF3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1975 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1976 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1977 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-trifluoro- methyl methylphenyl 1978 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-trifluoro- methyl methylphenyl 1979 (CH2)2 O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1980 (CH2)3 O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1981 (CH2)4 O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1982 (CH2)5 O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1983 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-trifluoro- hexane methylphenyl 1984 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 1985 CH2CH3 H O CH2 CF3 OCH2 CF3 4-tolyl 1986 CH2CF3 H O CH2 CF3 OCH2 CF3 4-tolyl 1987 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-tolyl 1988 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-tolyl 1989 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-tolyl methyl 1990 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-tolyl methyl 1991 (CH2)2 O CH2 CF3 OCH2 CF3 4-tolyl 1992 (CH2)3 O CH2 CF3 OCH2 CF3 4-tolyl 1993 (CH2)4 O CH2 CF3 OCH2 CF3 4-tolyl 1994 (CH2)5 O CH2 CF3 OCH2 CF3 4-tolyl 1995 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-tolyl hexane 1996 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-tolyl 1997 CH2CH3 H O CH2 CF3 OCH2 CF3 4-ethyl phenyl 1998 CH2CF3 H O CH2 CF3 OCH2 CF3 4-ethyl phenyl 1999 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-ethyl phenyl 2000 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-ethyl phenyl 2001 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-ethyl phenyl methyl 2002 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-ethyl phenyl methyl 2003 (CH2)2 O CH2 CF3 OCH2 CF3 4-ethyl phenyl 2004 (CH2)3 O CH2 CF3 OCH2 CF3 4-ethyl phenyl 2005 (CH2)4 O CH2 CF3 OCH2 CF3 4-ethyl phenyl 2006 (CH2)5 O CH2 CF3 OCH2 CF3 4-ethyl phenyl 2007 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-ethyl phenyl hexane 2008 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-ethyl phenyl 2009 CH2CH3 H O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 2010 CH2CF3 H O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 2011 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 2012 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 2013 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-isopropyl methyl phenyl 2014 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-isopropyl methyl phenyl 2015 (CH2)2 O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 2016 (CH2)3 O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 2017 (CH2)4 O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 2018 (CH2)5 O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 2019 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-isopropyl hexane phenyl 2020 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 2031 CH2CH3 H O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 2032 CH2CF3 H O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 2033 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 2034 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 2035 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-thiomethyl- methyl phenyl 2036 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-thiomethyl- methyl phenyl 2037 (CH2)2 O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 2038 (CH2)3 O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 2039 (CH2)4 O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 2040 (CH2)5 O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 2041 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-thiomethyl- hexane phenyl 2042 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 2043 CH2CH3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 2044 CH2CF3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 2045 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 2046 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 2047 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-trifluoro- methyl methoxyphenyl 2048 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-trifluoro- methyl methoxyphenyl 2049 (CH2)2 O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 2050 (CH2)3 O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 2051 (CH2)4 O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 2052 (CH2)5 O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 2053 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-trifluoro- hexane methoxyphenyl 2054 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 2055 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 2056 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 2057 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 2058 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 2059 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-trifluoro- methyl methylphenyl 2060 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-trifluoro- methyl methylphenyl 2061 (CH2)2 O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 2062 (CH2)3 O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 2063 (CH2)4 O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 2064 (CH2)5 O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 2065 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-trifluoro- hexane methylphenyl 2066 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 2067 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-tolyl 2068 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-tolyl 2069 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-tolyl 2070 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-tolyl 2071 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-tolyl methyl 2072 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-tolyl methyl 2073 (CH2)2 O CH2-c-Pr OCH2 CF3 4-tolyl 2074 (CH2)3 O CH2-c-Pr OCH2 CF3 4-tolyl 2075 (CH2)4 O CH2-c-Pr OCH2 CF3 4-tolyl 2076 (CH2)5 O CH2-c-Pr OCH2 CF3 4-tolyl 2077 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-tolyl hexane 2078 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-tolyl 2079 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 2080 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 2081 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 2082 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 2083 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl methyl 2084 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl methyl 2085 (CH2)2 O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 2086 (CH2)3 O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 2087 (CH2)4 O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 2088 (CH2)5 O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 2089 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-ethyl phenyl hexane 2090 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 2091 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 2092 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 2093 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 2094 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 2095 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-isopropyl methyl phenyl 2096 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-isopropyl methyl phenyl 2097 (CH2)2 O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 2098 (CH2)3 O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 2099 (CH2)4 O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 2100 (CH2)5 O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 2101 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-isopropyl hexane phenyl 2102 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 2103 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 2104 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 2105 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 2106 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 2107 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-thiomethyl- methyl phenyl 2108 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-thiomethyl- methyl phenyl 2109 (CH2)2 O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 2110 (CH2)3 O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 2111 (CH2)4 O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 2112 (CH2)5 O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 2113 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-thiomethyl- hexane phenyl 2114 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 2115 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 2116 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 2117 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 2118 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 2119 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-trifluoro- methyl methoxyphenyl 2120 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-trifluoro- methyl methoxyphenyl 2121 (CH2)2 O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 2122 (CH2)3 O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 2123 (CH2)4 O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 2124 (CH2)5 O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 2125 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-trifluoro- hexane methoxyphenyl 2126 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl

TABLE 7 Compounds of Formula VII Formula VII Ex R1 R2 Y R4 R5 Z 2127 CH2CH3 H O CH2 CF3 CF3 4-trifluoro- methylphenyl 2128 CH2CF3 H O CH2 CF3 CF3 4-trifluoro- methylphenyl 2129 CH2CH2CH3 H O CH2 CF3 CF3 4-trifluoro- methylphenyl 2130 CH2CH(CH3)2 H O CH2 CF3 CF3 4-trifluoro- methylphenyl 2131 cyclopropyl- H O CH2 CF3 CF3 4-trifluoro- methyl methylphenyl 2132 cyclobutyl- H O CH2 CF3 CF3 4-trifluoro- methyl methylphenyl 2133 (CH2)2 O CH2 CF3 CF3 4-trifluoro- methylphenyl 2134 (CH2)3 O CH2 CF3 CF3 4-trifluoro- methylphenyl 2135 (CH2)4 O CH2 CF3 CF3 4-trifluoro- methylphenyl 2136 (CH2)5 O CH2 CF3 CF3 4-trifluoro- methylphenyl 2137 5,5-spiro[2.3] O CH2 CF3 CF3 4-trifluoro- hexane methylphenyl 2138 Cyclopentyl H O CH2 CF3 CF3 4-trifluoro- methylphenyl 2139 CH2CH3 H O CH2 CF3 CF3 4-tolyl 2140 CH2CF3 H O CH2 CF3 CF3 4-tolyl 2141 CH2CH2CH3 H O CH2 CF3 CF3 4-tolyl 2142 CH2CH(CH3)2 H O CH2 CF3 CF3 4-tolyl 2143 cyclopropyl- H O CH2 CF3 CF3 4-tolyl methyl 2144 cyclobutyl- H O CH2 CF3 CF3 4-tolyl methyl 2145 (CH2)2 O CH2 CF3 CF3 4-tolyl 2146 (CH2)3 O CH2 CF3 CF3 4-tolyl 2147 (CH2)4 O CH2 CF3 CF3 4-tolyl 2148 (CH2)5 O CH2 CF3 CF3 4-tolyl 2149 5,5-spiro[2.3] O CH2 CF3 CF3 4-tolyl hexane 2150 Cyclopentyl H O CH2 CF3 CF3 4-tolyl 2151 CH2CH3 H O CH2 CF3 CF3 4-ethyl phenyl 2152 CH2CF3 H O CH2 CF3 CF3 4-ethyl phenyl 2153 CH2CH2CH3 H O CH2 CF3 CF3 4-ethyl phenyl 2154 CH2CH(CH3)2 H O CH2 CF3 CF3 4-ethyl phenyl 2155 cyclopropyl- H O CH2 CF3 CF3 4-ethyl phenyl methyl 2156 cyclobutyl- H O CH2 CF3 CF3 4-ethyl phenyl methyl 2157 (CH2)2 O CH2 CF3 CF3 4-ethyl phenyl 2158 (CH2)3 O CH2 CF3 CF3 4-ethyl phenyl 2159 (CH2)4 O CH2 CF3 CF3 4-ethyl phenyl 2160 (CH2)5 O CH2 CF3 CF3 4-ethyl phenyl 2161 5,5-spiro[2.3] O CH2 CF3 CF3 4-ethyl phenyl hexane 2162 Cyclopentyl H O CH2 CF3 CF3 4-ethyl phenyl 2163 CH2CH3 H O CH2 CF3 CF3 4-isopropyl phenyl 2164 CH2CF3 H O CH2 CF3 CF3 4-isopropyl phenyl 2165 CH2CH2CH3 H O CH2 CF3 CF3 4-isopropyl phenyl 2166 CH2CH(CH3)2 H O CH2 CF3 CF3 4-isopropyl phenyl 2167 cyclopropyl- H O CH2 CF3 CF3 4-isopropyl methyl phenyl 2168 cyclobutyl- H O CH2 CF3 CF3 4-isopropyl methyl phenyl 2169 (CH2)2 O CH2 CF3 CF3 4-isopropyl phenyl 2170 (CH2)3 O CH2 CF3 CF3 4-isopropyl phenyl 2171 (CH2)4 O CH2 CF3 CF3 4-isopropyl phenyl 2172 (CH2)5 O CH2 CF3 CF3 4-isopropyl phenyl 2173 5,5-spiro[2.3] O CH2 CF3 CF3 4-isopropyl hexane phenyl 2174 Cyclopentyl H O CH2 CF3 CF3 4-isopropyl phenyl 2175 CH2CH3 H O CH2 CF3 CF3 4-thiomethyl- phenyl 2176 CH2CF3 H O CH2 CF3 CF3 4-thiomethyl- phenyl 2177 CH2CH2CH3 H O CH2 CF3 CF3 4-thiomethyl- phenyl 2178 CH2CH(CH3)2 H O CH2 CF3 CF3 4-thiomethyl- phenyl 2179 cyclopropyl- H O CH2 CF3 CF3 4-thiomethyl- methyl phenyl 2180 cyclobutyl- H O CH2 CF3 CF3 4-thiomethyl- methyl phenyl 2181 (CH2)2 O CH2 CF3 CF3 4-thiomethyl- phenyl 2182 (CH2)3 O CH2 CF3 CF3 4-thiomethyl- phenyl 2183 (CH2)4 O CH2 CF3 CF3 4-thiomethyl- phenyl 2184 (CH2)5 O CH2 CF3 CF3 4-thiomethyl- phenyl 2185 5,5-spiro[2.3] O CH2 CF3 CF3 4-thiomethyl- hexane phenyl 2186 Cyclopentyl H O CH2 CF3 CF3 4-thiomethyl- phenyl 2187 CH2CH3 H O CH2 CF3 CF3 4-trifluoro- methoxyphenyl 2188 CH2CF3 H O CH2 CF3 CF3 4-trifluoro- methoxyphenyl 2189 CH2CH2CH3 H O CH2 CF3 CF3 4-trifluoro- methoxyphenyl 2190 CH2CH(CH3)2 H O CH2 CF3 CF3 4-trifluoro- methoxyphenyl 2191 cyclopropyl- H O CH2 CF3 CF3 4-trifluoro- methyl methoxyphenyl 2192 cyclobutyl- H O CH2 CF3 CF3 4-trifluoro- methyl methoxyphenyl 2193 (CH2)2 O CH2 CF3 CF3 4-trifluoro- methoxyphenyl 2194 (CH2)3 O CH2 CF3 CF3 4-trifluoro- methoxyphenyl 2195 (CH2)4 O CH2 CF3 CF3 4-trifluoro- methoxyphenyl 2196 (CH2)5 O CH2 CF3 CF3 4-trifluoro- methoxyphenyl 2197 5,5-spiro[2.3] O CH2 CF3 CF3 4-trifluoro- hexane methoxyphenyl 2198 Cyclopentyl H O CH2 CF3 CF3 4-trifluoro- methoxyphenyl 2199 CH2CH3 H O CH2-c-Pr CF3 4-trifluoro- methylphenyl 2200 CH2CF3 H O CH2-c-Pr CF3 4-trifluoro- methylphenyl 2201 CH2CH2CH3 H O CH2-c-Pr CF3 4-trifluoro- methylphenyl 2202 CH2CH(CH3)2 H O CH2-c-Pr CF3 4-trifluoro- methylphenyl 2203 cyclopropyl- H O CH2-c-Pr CF3 4-trifluoro- methyl methylphenyl 2204 cyclobutyl- H O CH2-c-Pr CF3 4-trifluoro- methyl methylphenyl 2205 (CH2)2 O CH2-c-Pr CF3 4-trifluoro- methylphenyl 2206 (CH2)3 O CH2-c-Pr CF3 4-trifluoro- methylphenyl 2207 (CH2)4 O CH2-c-Pr CF3 4-trifluoro- methylphenyl 2208 (CH2)5 O CH2-c-Pr CF3 4-trifluoro- methylphenyl 2209 5,5-spiro[2.3] O CH2-c-Pr CF3 4-trifluoro- hexane methylphenyl 2210 Cyclopentyl H O CH2-c-Pr CF3 4-trifluoro- methylphenyl 2211 CH2CH3 H O CH2-c-Pr CF3 4-tolyl 2212 CH2CF3 H O CH2-c-Pr CF3 4-tolyl 2213 CH2CH2CH3 H O CH2-c-Pr CF3 4-tolyl 2214 CH2CH(CH3)2 H O CH2-c-Pr CF3 4-tolyl 2215 cyclopropyl- H O CH2-c-Pr CF3 4-tolyl methyl 2216 cyclobutyl- H O CH2-c-Pr CF3 4-tolyl methyl 2217 (CH2)2 O CH2-c-Pr CF3 4-tolyl 2218 (CH2)3 O CH2-c-Pr CF3 4-tolyl 2219 (CH2)4 O CH2-c-Pr CF3 4-tolyl 2220 (CH2)5 O CH2-c-Pr CF3 4-tolyl 2221 5,5-spiro[2.3] O CH2-c-Pr CF3 4-tolyl hexane 2222 Cyclopentyl H O CH2-c-Pr CF3 4-tolyl 2223 CH2CH3 H O CH2-c-Pr CF3 4-ethyl phenyl 2224 CH2CF3 H O CH2-c-Pr CF3 4-ethyl phenyl 2225 CH2CH2CH3 H O CH2-c-Pr CF3 4-ethyl phenyl 2226 CH2CH(CH3)2 H O CH2-c-Pr CF3 4-ethyl phenyl 2227 cyclopropyl- H O CH2-c-Pr CF3 4-ethyl phenyl methyl 2228 cyclobutyl- H O CH2-c-Pr CF3 4-ethyl phenyl methyl 2229 (CH2)2 O CH2-c-Pr CF3 4-ethyl phenyl 2230 (CH2)3 O CH2-c-Pr CF3 4-ethyl phenyl 2231 (CH2)4 O CH2-c-Pr CF3 4-ethyl phenyl 2232 (CH2)5 O CH2-c-Pr CF3 4-ethyl phenyl 2233 5,5-spiro[2.3] O CH2-c-Pr CF3 4-ethyl phenyl hexane 2234 Cyclopentyl H O CH2-c-Pr CF3 4-ethyl phenyl 2235 CH2CH3 H O CH2-c-Pr CF3 4-isopropyl phenyl 2236 CH2CF3 H O CH2-c-Pr CF3 4-isopropyl phenyl 2237 CH2CH2CH3 H O CH2-c-Pr CF3 4-isopropyl phenyl 2238 CH2CH(CH3)2 H O CH2-c-Pr CF3 4-isopropyl phenyl 2239 cyclopropyl- H O CH2-c-Pr CF3 4-isopropyl methyl phenyl 2240 cyclobutyl- H O CH2-c-Pr CF3 4-isopropyl methyl phenyl 2241 (CH2)2 O CH2-c-Pr CF3 4-isopropyl phenyl 2242 (CH2)3 O CH2-c-Pr CF3 4-isopropyl phenyl 2243 (CH2)4 O CH2-c-Pr CF3 4-isopropyl phenyl 2244 (CH2)5 O CH2-c-Pr CF3 4-isopropyl phenyl 2245 5,5-spiro[2.3] O CH2-c-Pr CF3 4-isopropyl hexane phenyl 2246 Cyclopentyl H O CH2-c-Pr CF3 4-isopropyl phenyl 2247 CH2CH3 H O CH2-c-Pr CF3 4-thiomethyl- phenyl 2248 CH2CF3 H O CH2-c-Pr CF3 4-thiomethyl- phenyl 2249 CH2CH2CH3 H O CH2-c-Pr CF3 4-thiomethyl- phenyl 2250 CH2CH(CH3)2 H O CH2-c-Pr CF3 4-thiomethyl- phenyl 2251 cyclopropyl- H O CH2-c-Pr CF3 4-thiomethyl- methyl phenyl 2252 cyclobutyl- H O CH2-c-Pr CF3 4-thiomethyl- methyl phenyl 2253 (CH2)2 O CH2-c-Pr CF3 4-thiomethyl- phenyl 2254 (CH2)3 O CH2-c-Pr CF3 4-thiomethyl- phenyl 2255 (CH2)4 O CH2-c-Pr CF3 4-thiomethyl- phenyl 2256 (CH2)5 O CH2-c-Pr CF3 4-thiomethyl- phenyl 2257 5,5-spiro[2.3] O CH2-c-Pr CF3 4-thiomethyl- hexane phenyl 2258 Cyclopentyl H O CH2-c-Pr CF3 4-thiomethyl- phenyl 2259 CH2CH3 H O CH2-c-Pr CF3 4-trifluoro- methoxyphenyl 2260 CH2CF3 H O CH2-c-Pr CF3 4-trifluoro- methoxyphenyl 2261 CH2CH2CH3 H O CH2-c-Pr CF3 4-trifluoro- methoxyphenyl 2262 CH2CH(CH3)2 H O CH2-c-Pr CF3 4-trifluoro- methoxyphenyl 2263 cyclopropyl- H O CH2-c-Pr CF3 4-trifluoro- methyl methoxyphenyl 2264 cyclobutyl- H O CH2-c-Pr CF3 4-trifluoro- methyl methoxyphenyl 2265 (CH2)2 O CH2-c-Pr CF3 4-trifluoro- methoxyphenyl 2266 (CH2)3 O CH2-c-Pr CF3 4-trifluoro- methoxyphenyl 2267 (CH2)4 O CH2-c-Pr CF3 4-trifluoro- methoxyphenyl 2268 (CH2)5 O CH2-c-Pr CF3 4-trifluoro- methoxyphenyl 2269 5,5-spiro[2.3] O CH2-c-Pr CF3 4-trifluoro- hexane methoxyphenyl 2270 Cyclopentyl H O CH2-c-Pr CF3 4-trifluoro- methoxyphenyl 2271 CH2CH3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 2272 CH2CF3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 2273 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 2274 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 2275 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-trifluoro- methyl methylphenyl 2276 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-trifluoro- methyl methylphenyl 2277 (CH2)2 O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 2278 (CH2)3 O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 2279 (CH2)4 O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 2280 (CH2)5 O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 2281 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-trifluoro- hexane methylphenyl 2282 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-trifluoro- methylphenyl 2283 CH2CH3 H O CH2 CF3 OCH2 CF3 4-tolyl 2284 CH2CF3 H O CH2 CF3 OCH2 CF3 4-tolyl 2285 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-tolyl 2286 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-tolyl 2287 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-tolyl methyl 2288 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-tolyl methyl 2289 (CH2)2 O CH2 CF3 OCH2 CF3 4-tolyl 2290 (CH2)3 O CH2 CF3 OCH2 CF3 4-tolyl 2291 (CH2)4 O CH2 CF3 OCH2 CF3 4-tolyl 2292 (CH2)5 O CH2 CF3 OCH2 CF3 4-tolyl 2293 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-tolyl hexane 2294 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-tolyl 2295 CH2CH3 H O CH2 CF3 OCH2 CF3 4-ethyl phenyl 2296 CH2CF3 H O CH2 CF3 OCH2 CF3 4-ethyl phenyl 2297 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-ethyl phenyl 2298 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-ethyl phenyl 2299 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-ethyl phenyl methyl 2300 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-ethyl phenyl methyl 2301 (CH2)2 O CH2 CF3 OCH2 CF3 4-ethyl phenyl 2302 (CH2)3 O CH2 CF3 OCH2 CF3 4-ethyl phenyl 2303 (CH2)4 O CH2 CF3 OCH2 CF3 4-ethyl phenyl 2304 (CH2)5 O CH2 CF3 OCH2 CF3 4-ethyl phenyl 2305 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-ethyl phenyl hexane 2306 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-ethyl phenyl 2307 CH2CH3 H O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 2308 CH2CF3 H O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 2309 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 2310 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 2311 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-isopropyl methyl phenyl 2312 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-isopropyl methyl phenyl 2313 (CH2)2 O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 2314 (CH2)3 O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 2315 (CH2)4 O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 2316 (CH2)5 O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 2317 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-isopropyl hexane phenyl 2318 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-isopropyl phenyl 2319 CH2CH3 H O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 2320 CH2CF3 H O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 2321 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 2322 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 2323 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-thiomethyl- methyl phenyl 2324 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-thiomethyl- methyl phenyl 2325 (CH2)2 O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 2326 (CH2)3 O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 2327 (CH2)4 O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 2328 (CH2)5 O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 2329 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-thiomethyl- hexane phenyl 2330 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-thiomethyl- phenyl 2331 CH2CH3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 2332 CH2CF3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 2333 CH2CH2CH3 H O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 2334 CH2CH(CH3)2 H O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 2335 cyclopropyl- H O CH2 CF3 OCH2 CF3 4-trifluoro- methyl methoxyphenyl 2336 cyclobutyl- H O CH2 CF3 OCH2 CF3 4-trifluoro- methyl methoxyphenyl 2337 (CH2)2 O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 2338 (CH2)3 O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 2339 (CH2)4 O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 2340 (CH2)5 O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 2341 5,5-spiro[2.3] O CH2 CF3 OCH2 CF3 4-trifluoro- hexane methoxyphenyl 2342 Cyclopentyl H O CH2 CF3 OCH2 CF3 4-trifluoro- methoxyphenyl 2343 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 2344 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 2345 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 2346 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 2347 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-trifluoro- methyl methylphenyl 2348 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-trifluoro- methyl methylphenyl 2349 (CH2)2 O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 2350 (CH2)3 O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 2351 (CH2)4 O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 2352 (CH2)5 O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 2353 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-trifluoro- hexane methylphenyl 2354 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-trifluoro- methylphenyl 2355 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-tolyl 2356 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-tolyl 2357 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-tolyl 2358 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-tolyl 2359 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-tolyl methyl 2360 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-tolyl methyl 2361 (CH2)2 O CH2-c-Pr OCH2 CF3 4-tolyl 2362 (CH2)3 O CH2-c-Pr OCH2 CF3 4-tolyl 2363 (CH2)4 O CH2-c-Pr OCH2 CF3 4-tolyl 2364 (CH2)5 O CH2-c-Pr OCH2 CF3 4-tolyl 2365 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-tolyl hexane 2366 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-tolyl 2367 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 2368 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 2369 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 2370 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 2371 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl methyl 2372 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl methyl 2373 (CH2)2 O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 2374 (CH2)3 O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 2375 (CH2)4 O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 2376 (CH2)5 O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 2377 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-ethyl phenyl hexane 2378 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-ethyl phenyl 2379 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 2380 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 2381 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 2382 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 2383 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-isopropyl methyl phenyl 2384 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-isopropyl methyl phenyl 2385 (CH2)2 O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 2386 (CH2)3 O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 2387 (CH2)4 O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 2388 (CH2)5 O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 2389 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-isopropyl hexane phenyl 2390 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-isopropyl phenyl 2391 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 2392 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 2393 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 2394 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 2395 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-thiomethyl- methyl phenyl 2396 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-thiomethyl- methyl phenyl 2397 (CH2)2 O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 2398 (CH2)3 O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 2399 (CH2)4 O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 2400 (CH2)5 O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 2401 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-thiomethyl- hexane phenyl 2402 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-thiomethyl- phenyl 2403 CH2CH3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 2404 CH2CF3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 2405 CH2CH2CH3 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 2406 CH2CH(CH3)2 H O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 2407 cyclopropyl- H O CH2-c-Pr OCH2 CF3 4-trifluoro- methyl methoxyphenyl 2408 cyclobutyl- H O CH2-c-Pr OCH2 CF3 4-trifluoro- methyl methoxyphenyl 2409 (CH2)2 O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 2410 (CH2)3 O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 2411 (CH2)4 O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 2412 (CH2)5 O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl 2413 5,5-spiro[2.3] O CH2-c-Pr OCH2 CF3 4-trifluoro- hexane methoxyphenyl 2414 Cyclopentyl H O CH2-c-Pr OCH2 CF3 4-trifluoro- methoxyphenyl

TABLE 8 Compounds of Formula VII Formula VII Ex R1 R2 Y R4 R5 Z 2415 CH2CH3 H O CH2CF3 Cl 4-trifluoromethylphenyl 2416 CH2CF3 H O CH2CF3 Cl 4-trifluoromethylphenyl 2417 CH2CH2CH3 H O CH2CF3 Cl 4-trifluoromethylphenyl 2418 CH2CH(CH3)2 H O CH2CF3 Cl 4-trifluoromethylphenyl 2419 cyclopropylmethyl H O CH2CF3 Cl 4-trifluoromethylphenyl 2420 cyclobutylmethyl H O CH2CF3 Cl 4-trifluoromethylphenyl 2421 (CH2)2 O CH2CF3 Cl 4-trifluoromethylphenyl 2422 (CH2)3 O CH2CF3 Cl 4-trifluoromethylphenyl 2423 (CH2)4 O CH2CF3 Cl 4-trifluoromethylphenyl 2424 (CH2)5 O CH2CF3 Cl 4-trifluoromethylphenyl 2425 5,5-spiro[2.3]hexane O CH2CF3 Cl 4-trifluoromethylphenyl 2426 Cyclopentyl H O CH2CF3 Cl 4-trifluoromethylphenyl 2427 CH2CH3 H O CH2CF3 Cl 4-tolyl 2428 CH2CF3 H O CH2CF3 Cl 4-tolyl 2429 CH2CH2CH3 H O CH2CF3 Cl 4-tolyl 2430 CH2CH(CH3)2 H O CH2CF3 Cl 4-tolyl 2431 cyclopropylmethyl H O CH2CF3 Cl 4-tolyl 2432 cyclobutylmethyl H O CH2CF3 Cl 4-tolyl 2433 (CH2)2 O CH2CF3 Cl 4-tolyl 2434 (CH2)3 O CH2CF3 Cl 4-tolyl 2435 (CH2)4 O CH2CF3 Cl 4-tolyl 2436 (CH2)5 O CH2CF3 Cl 4-tolyl 2437 5,5-spiro[2.3]hexane O CH2CF3 Cl 4-tolyl 2438 Cyclopentyl H O CH2CF3 Cl 4-tolyl 2439 CH2CH3 H O CH2CF3 Cl 4-ethyl phenyl 2440 CH2CF3 H O CH2CF3 Cl 4-ethyl phenyl 2441 CH2CH2CH3 H O CH2CF3 Cl 4-ethyl phenyl 2442 CH2CH(CH3)2 H O CH2CF3 Cl 4-ethyl phenyl 2443 cyclopropylmethyl H O CH2CF3 Cl 4-ethyl phenyl 2444 cyclobutylmethyl H O CH2CF3 Cl 4-ethyl phenyl 2445 (CH2)2 O CH2CF3 Cl 4-ethyl phenyl 2446 (CH2)3 O CH2CF3 Cl 4-ethyl phenyl 2447 (CH2)4 O CH2CF3 Cl 4-ethyl phenyl 2448 (CH2)5 O CH2CF3 Cl 4-ethyl phenyl 2449 5,5-spiro[2.3]hexane O CH2CF3 Cl 4-ethyl phenyl 2450 Cyclopentyl H O CH2CF3 Cl 4-ethyl phenyl 2451 CH2CH3 H O CH2CF3 Cl 4-isopropyl phenyl 2452 CH2CF3 H O CH2CF3 Cl 4-isopropyl phenyl 2453 CH2CH2CH3 H O CH2CF3 Cl 4-isopropyl phenyl 2454 CH2CH(CH3)2 H O CH2CF3 Cl 4-isopropyl phenyl 2455 cyclopropylmethyl H O CH2CF3 Cl 4-isopropyl phenyl 2456 cyclobutylmethyl H O CH2CF3 Cl 4-isopropyl phenyl 2457 (CH2)2 O CH2CF3 Cl 4-isopropyl phenyl 2458 (CH2)3 O CH2CF3 Cl 4-isopropyl phenyl 2459 (CH2)4 O CH2CF3 Cl 4-isopropyl phenyl 2460 (CH2)5 O CH2CF3 Cl 4-isopropyl phenyl 2461 5,5-spiro[2.3]hexane O CH2CF3 Cl 4-isopropyl phenyl 2462 Cyclopentyl H O CH2CF3 Cl 4-isopropyl phenyl 2463 CH2CH3 H O CH2CF3 Cl 4-thiomethylphenyl 2464 CH2CF3 H O CH2CF3 Cl 4-thiomethylphenyl 2465 CH2CH2CH3 H O CH2CF3 Cl 4-thiomethylphenyl 2466 CH2CH(CH3)2 H O CH2CF3 Cl 4-thiomethylphenyl 2467 cyclopropylmethyl H O CH2CF3 Cl 4-thiomethylphenyl 2468 cyclobutylmethyl H O CH2CF3 Cl 4-thiomethylphenyl 2469 (CH2)2 O CH2CF3 Cl 4-thiomethylphenyl 2470 (CH2)3 O CH2CF3 Cl 4-thiomethylphenyl 2471 (CH2)4 O CH2CF3 Cl 4-thiomethylphenyl 2472 (CH2)5 O CH2CF3 Cl 4-thiomethylphenyl 2473 5,5-spiro[2.3]hexane O CH2CF3 Cl 4-thiomethylphenyl 2474 Cyclopentyl H O CH2CF3 Cl 4-thiomethylphenyl 2475 CH2CH3 H O CH2CF3 Cl 4-trifluoromethoxyphenyl 2476 CH2CF3 H O CH2CF3 Cl 4-trifluoromethoxyphenyl 2477 CH2CH2CH3 H O CH2CF3 Cl 4-trifluoromethoxyphenyl 2478 CH2CH(CH3)2 H O CH2CF3 Cl 4-trifluoromethoxyphenyl 2479 cyclopropylmethyl H O CH2CF3 Cl 4-trifluoromethoxyphenyl 2480 cyclobutylmethyl H O CH2CF3 Cl 4-trifluoromethoxyphenyl 2481 (CH2)2 O CH2CF3 Cl 4-trifluoromethoxyphenyl 2482 (CH2)3 O CH2CF3 Cl 4-trifluoromethoxyphenyl 2483 (CH2)4 O CH2CF3 Cl 4-trifluoromethoxyphenyl 2484 (CH2)5 O CH2CF3 Cl 4-trifluoromethoxyphenyl 2485 5,5-spiro[2.3]hexane O CH2CF3 Cl 4-trifluoromethoxyphenyl 2486 Cyclopentyl H O CH2CF3 Cl 4-trifluoromethoxyphenyl 2487 CH2CH3 H O CH2—c-Pr Cl 4-trifluoromethylphenyl 2488 CH2CF3 H O CH2—c-Pr Cl 4-trifluoromethylphenyl 2489 CH2CH2CH3 H O CH2—c-Pr Cl 4-trifluoromethylphenyl 2490 CH2CH(CH3)2 H O CH2—c-Pr Cl 4-trifluoromethylphenyl 2491 cyclopropylmethyl H O CH2—c-Pr Cl 4-trifluoromethylphenyl 2492 cyclobutylmethyl H O CH2—c-Pr Cl 4-trifluoromethylphenyl 2493 (CH2)2 O CH2—c-Pr Cl 4-trifluoromethylphenyl 2494 (CH2)3 O CH2—c-Pr Cl 4-trifluoromethylphenyl 2495 (CH2)4 O CH2—c-Pr Cl 4-trifluoromethylphenyl 2496 (CH2)5 O CH2—c-Pr Cl 4-trifluoromethylphenyl 2497 5,5-spiro[2.3]hexane O CH2—c-Pr Cl 4-trifluoromethylphenyl 2498 Cyclopentyl H O CH2—c-Pr Cl 4-trifluoromethylphenyl 2499 CH2CH3 H O CH2—c-Pr Cl 4-tolyl 2500 CH2CF3 H O CH2—c-Pr Cl 4-tolyl 2501 CH2CH2CH3 H O CH2—c-Pr Cl 4-tolyl 2502 CH2CH(CH3)2 H O CH2—c-Pr Cl 4-tolyl 2503 cyclopropylmethyl H O CH2—c-Pr Cl 4-tolyl 2504 cyclobutylmethyl H O CH2—c-Pr Cl 4-tolyl 2505 (CH2)2 O CH2—c-Pr Cl 4-tolyl 2506 (CH2)3 O CH2—c-Pr Cl 4-tolyl 2507 (CH2)4 O CH2—c-Pr Cl 4-tolyl 2508 (CH2)5 O CH2—c-Pr Cl 4-tolyl 2509 5,5-spiro[2.3]hexane O CH2—c-Pr Cl 4-tolyl 2510 Cyclopentyl H O CH2—c-Pr Cl 4-tolyl 2511 CH2CH3 H O CH2—c-Pr Cl 4-ethyl phenyl 2512 CH2CF3 H O CH2—c-Pr Cl 4-ethyl phenyl 2513 CH2CH2CH3 H O CH2—c-Pr Cl 4-ethyl phenyl 2514 CH2CH(CH3)2 H O CH2—c-Pr Cl 4-ethyl phenyl 2515 cyclopropylmethyl H O CH2—c-Pr Cl 4-ethyl phenyl 2516 cyclobutylmethyl H O CH2—c-Pr Cl 4-ethyl phenyl 2517 (CH2)2 O CH2—c-Pr Cl 4-ethyl phenyl 2518 (CH2)3 O CH2—c-Pr Cl 4-ethyl phenyl 2519 (CH2)4 O CH2—c-Pr Cl 4-ethyl phenyl 2520 (CH2)5 O CH2—c-Pr Cl 4-ethyl phenyl 2521 5,5-spiro[2.3]hexane O CH2—c-Pr Cl 4-ethyl phenyl 2522 Cyclopentyl H O CH2—c-Pr Cl 4-ethyl phenyl 2523 CH2CH3 H O CH2—c-Pr Cl 4-isopropyl phenyl 2524 CH2CF3 H O CH2—c-Pr Cl 4-isopropyl phenyl 2525 CH2CH2CH3 H O CH2—c-Pr Cl 4-isopropyl phenyl 2526 CH2CH(CH3)2 H O CH2—c-Pr Cl 4-isopropyl phenyl 2527 cyclopropylmethyl H O CH2—c-Pr Cl 4-isopropyl phenyl 2528 cyclobutylmethyl H O CH2—c-Pr Cl 4-isopropyl phenyl 2529 (CH2)2 O CH2—c-Pr Cl 4-isopropyl phenyl 2530 (CH2)3 O CH2—c-Pr Cl 4-isopropyl phenyl 2531 (CH2)4 O CH2—c-Pr Cl 4-isopropyl phenyl 2532 (CH2)5 O CH2—c-Pr Cl 4-isopropyl phenyl 2533 5,5-spiro[2.3]hexane O CH2—c-Pr Cl 4-isopropyl phenyl 2534 Cyclopentyl H O CH2—c-Pr Cl 4-isopropyl phenyl 2535 CH2CH3 H O CH2—c-Pr Cl 4-thiomethylphenyl 2536 CH2CF3 H O CH2—c-Pr Cl 4-thiomethylphenyl 2537 CH2CH2CH3 H O CH2—c-Pr Cl 4-thiomethylphenyl 2538 CH2CH(CH3)2 H O CH2—c-Pr Cl 4-thiomethylphenyl 2539 cyclopropylmethyl H O CH2—c-Pr Cl 4-thiomethylphenyl 2540 cyclobutylmethyl H O CH2—c-Pr Cl 4-thiomethylphenyl 2541 (CH2)2 O CH2—c-Pr Cl 4-thiomethylphenyl 2542 (CH2)3 O CH2—c-Pr Cl 4-thiomethylphenyl 2543 (CH2)4 O CH2—c-Pr Cl 4-thiomethylphenyl 2544 (CH2)5 O CH2—c-Pr Cl 4-thiomethylphenyl 2545 5,5-spiro[2.3]hexane O CH2—c-Pr Cl 4-thiomethylphenyl 2546 Cyclopentyl H O CH2—c-Pr Cl 4-thiomethylphenyl 2547 CH2CH3 H O CH2—c-Pr Cl 4-trifluoromethoxyphenyl 2548 CH2CF3 H O CH2—c-Pr Cl 4-trifluoromethoxyphenyl 2549 CH2CH2CH3 H O CH2—c-Pr Cl 4-trifluoromethoxyphenyl 2550 CH2CH(CH3)2 H O CH2—c-Pr Cl 4-trifluoromethoxyphenyl 2551 cyclopropylmethyl H O CH2—c-Pr Cl 4-trifluoromethoxyphenyl 2552 cyclobutylmethyl H O CH2—c-Pr Cl 4-trifluoromethoxyphenyl 2553 (CH2)2 O CH2—c-Pr Cl 4-trifluoromethoxyphenyl 2554 (CH2)3 O CH2—c-Pr Cl 4-trifluoromethoxyphenyl 2555 (CH2)4 O CH2—c-Pr Cl 4-trifluoromethoxyphenyl 2556 (CH2)5 O CH2—c-Pr Cl 4-trifluoromethoxyphenyl 2557 5,5-spiro[2.3]hexane O CH2—c-Pr Cl 4-trifluoromethoxyphenyl 2558 Cyclopentyl H O CH2—c-Pr Cl 4-trifluoromethoxyphenyl 2559 CH2CH3 H O CH2CF3 OCH2CF3 4-trifluoromethylphenyl 2560 CH2CF3 H O CH2CF3 OCH2CF3 4-trifluoromethylphenyl 2561 CH2CH2CH3 H O CH2CF3 OCH2CF3 4-trifluoromethylphenyl 2562 CH2CH(CH3)2 H O CH2CF3 OCH2CF3 4-trifluoromethylphenyl 2563 cyclopropylmethyl H O CH2CF3 OCH2CF3 4-trifluoromethylphenyl 2564 cyclobutylmethyl H O CH2CF3 OCH2CF3 4-trifluoromethylphenyl 2565 (CH2)2 O CH2CF3 OCH2CF3 4-trifluoromethylphenyl 2566 (CH2)3 O CH2CF3 OCH2CF3 4-trifluoromethylphenyl 2567 (CH2)4 O CH2CF3 OCH2CF3 4-trifluoromethylphenyl 2568 (CH2)5 O CH2CF3 OCH2CF3 4-trifluoromethylphenyl 2569 5,5-spiro[2.3]hexane O CH2CF3 OCH2CF3 4-trifluoromethylphenyl 2570 Cyclopentyl H O CH2CF3 OCH2CF3 4-trifluoromethylphenyl 2571 CH2CH3 H O CH2CF3 OCH2CF3 4-tolyl 2572 CH2CF3 H O CH2CF3 OCH2CF3 4-tolyl 2573 CH2CH2CH3 H O CH2CF3 OCH2CF3 4-tolyl 2574 CH2CH(CH3)2 H O CH2CF3 OCH2CF3 4-tolyl 2575 cyclopropylmethyl H O CH2CF3 OCH2CF3 4-tolyl 2576 cyclobutylmethyl H O CH2CF3 OCH2CF3 4-tolyl 2577 (CH2)2 O CH2CF3 OCH2CF3 4-tolyl 2578 (CH2)3 O CH2CF3 OCH2CF3 4-tolyl 2579 (CH2)4 O CH2CF3 OCH2CF3 4-tolyl 2580 (CH2)5 O CH2CF3 OCH2CF3 4-tolyl 2581 5,5-spiro[2.3]hexane O CH2CF3 OCH2CF3 4-tolyl 2582 Cyclopentyl H O CH2CF3 OCH2CF3 4-tolyl 2583 CH2CH3 H O CH2CF3 OCH2CF3 4-ethyl phenyl 2584 CH2CF3 H O CH2CF3 OCH2CF3 4-ethyl phenyl 2585 CH2CH2CH3 H O CH2CF3 OCH2CF3 4-ethyl phenyl 2586 CH2CH(CH3)2 H O CH2CF3 OCH2CF3 4-ethyl phenyl 2587 cyclopropylmethyl H O CH2CF3 OCH2CF3 4-ethyl phenyl 2588 cyclobutylmethyl H O CH2CF3 OCH2CF3 4-ethyl phenyl 2589 (CH2)2 O CH2CF3 OCH2CF3 4-ethyl phenyl 2590 (CH2)3 O CH2CF3 OCH2CF3 4-ethyl phenyl 2591 (CH2)4 O CH2CF3 OCH2CF3 4-ethyl phenyl 2592 (CH2)5 O CH2CF3 OCH2CF3 4-ethyl phenyl 2593 5,5-spiro[2.3]hexane O CH2CF3 OCH2CF3 4-ethyl phenyl 2594 Cyclopentyl H O CH2CF3 OCH2CF3 4-ethyl phenyl 2595 CH2CH3 H O CH2CF3 OCH2CF3 4-isopropyl phenyl 2596 CH2CF3 H O CH2CF3 OCH2CF3 4-isopropyl phenyl 2597 CH2CH2CH3 H O CH2CF3 OCH2CF3 4-isopropyl phenyl 2598 CH2CH(CH3)2 H O CH2CF3 OCH2CF3 4-isopropyl phenyl 2599 cyclopropylmethyl H O CH2CF3 OCH2CF3 4-isopropyl phenyl 2600 cyclobutylmethyl H O CH2CF3 OCH2CF3 4-isopropyl phenyl 2601 (CH2)2 O CH2CF3 OCH2CF3 4-isopropyl phenyl 2602 (CH2)3 O CH2CF3 OCH2CF3 4-isopropyl phenyl 2603 (CH2)4 O CH2CF3 OCH2CF3 4-isopropyl phenyl 2604 (CH2)5 O CH2CF3 OCH2CF3 4-isopropyl phenyl 2605 5,5-spiro[2.3]hexane O CH2CF3 OCH2CF3 4-isopropyl phenyl 2606 Cyclopentyl H O CH2CF3 OCH2CF3 4-isopropyl phenyl 2607 CH2CH3 H O CH2CF3 OCH2CF3 4-thiomethylphenyl 2608 CH2CF3 H O CH2CF3 OCH2CF3 4-thiomethylphenyl 2609 CH2CH2CH3 H O CH2CF3 OCH2CF3 4-thiomethylphenyl 2610 CH2CH(CH3)2 H O CH2CF3 OCH2CF3 4-thiomethylphenyl 2611 cyclopropylmethyl H O CH2CF3 OCH2CF3 4-thiomethylphenyl 2612 cyclobutylmethyl H O CH2CF3 OCH2CF3 4-thiomethylphenyl 2613 (CH2)2 O CH2CF3 OCH2CF3 4-thiomethylphenyl 2614 (CH2)3 O CH2CF3 OCH2CF3 4-thiomethylphenyl 2615 (CH2)4 O CH2CF3 OCH2CF3 4-thiomethylphenyl 2616 (CH2)5 O CH2CF3 OCH2CF3 4-thiomethylphenyl 2617 5,5-spiro[2.3]hexane O CH2CF3 OCH2CF3 4-thiomethylphenyl 2618 Cyclopentyl H O CH2CF3 OCH2CF3 4-thiomethylphenyl 2619 CH2CH3 H O CH2CF3 OCH2CF3 4-trifluoromethoxyphenyl 2620 CH2CF3 H O CH2CF3 OCH2CF3 4-trifluoromethoxyphenyl 2621 CH2CH2CH3 H O CH2CF3 OCH2CF3 4-trifluoromethoxyphenyl 2622 CH2CH(CH3)2 H O CH2CF3 OCH2CF3 4-trifluoromethoxyphenyl 2623 cyclopropylmethyl H O CH2CF3 OCH2CF3 4-trifluoromethoxyphenyl 2624 cyclobutylmethyl H O CH2CF3 OCH2CF3 4-trifluoromethoxyphenyl 2625 (CH2)2 O CH2CF3 OCH2CF3 4-trifluoromethoxyphenyl 2626 (CH2)3 O CH2CF3 OCH2CF3 4-trifluoromethoxyphenyl 2627 (CH2)4 O CH2CF3 OCH2CF3 4-trifluoromethoxyphenyl 2628 (CH2)5 O CH2CF3 OCH2CF3 4-trifluoromethoxyphenyl 2629 5,5-spiro[2.3]hexane O CH2CF3 OCH2CF3 4-trifluoromethoxyphenyl 2630 Cyclopentyl H O CH2CF3 OCH2CF3 4-trifluoromethoxyphenyl 2632 CH2CH3 H O CH2—c-Pr OCH2CF3 4-trifluoromethylphenyl 2633 CH2CF3 H O CH2—c-Pr OCH2CF3 4-trifluoromethylphenyl 2634 CH2CH2CH3 H O CH2—c-Pr OCH2CF3 4-trifluoromethylphenyl 2635 CH2CH(CH3)2 H O CH2—c-Pr OCH2CF3 4-trifluoromethylphenyl 2636 cyclopropylmethyl H O CH2—c-Pr OCH2CF3 4-trifluoromethylphenyl 2637 cyclobutylmethyl H O CH2—c-Pr OCH2CF3 4-trifluoromethylphenyl 2638 (CH2)2 O CH2—c-Pr OCH2CF3 4-trifluoromethylphenyl 2639 (CH2)3 O CH2—c-Pr OCH2CF3 4-trifluoromethylphenyl 2640 (CH2)4 O CH2—c-Pr OCH2CF3 4-trifluoromethylphenyl 2641 (CH2)5 O CH2—c-Pr OCH2CF3 4-trifluoromethylphenyl 2642 5,5-spiro[2.3]hexane O CH2—c-Pr OCH2CF3 4-trifluoromethylphenyl 2643 Cyclopentyl H O CH2—c-Pr OCH2CF3 4-trifluoromethylphenyl 2644 CH2CH3 H O CH2—c-Pr OCH2CF3 4-tolyl 2645 CH2CF3 H O CH2—c-Pr OCH2CF3 4-tolyl 2646 CH2CH2CH3 H O CH2—c-Pr OCH2CF3 4-tolyl 2647 CH2CH(CH3)2 H O CH2—c-Pr OCH2CF3 4-tolyl 2648 cyclopropylmethyl H O CH2—c-Pr OCH2CF3 4-tolyl 2649 cyclobutylmethyl H O CH2—c-Pr OCH2CF3 4-tolyl 2650 (CH2)2 O CH2—c-Pr OCH2CF3 4-tolyl 2651 (CH2)3 O CH2—c-Pr OCH2CF3 4-tolyl 2652 (CH2)4 O CH2—c-Pr OCH2CF3 4-tolyl 2653 (CH2)5 O CH2—c-Pr OCH2CF3 4-tolyl 2654 5,5-spiro[2.3]hexane O CH2—c-Pr OCH2CF3 4-tolyl 2655 Cyclopentyl H O CH2—c-Pr OCH2CF3 4-tolyl 2656 CH2CH3 H O CH2—c-Pr OCH2CF3 4-ethyl phenyl 2657 CH2CF3 H O CH2—c-Pr OCH2CF3 4-ethyl phenyl 2658 CH2CH2CH3 H O CH2—c-Pr OCH2CF3 4-ethyl phenyl 2659 CH2CH(CH3)2 H O CH2—c-Pr OCH2CF3 4-ethyl phenyl 2660 cyclopropylmethyl H O CH2—c-Pr OCH2CF3 4-ethyl phenyl 2661 cyclobutylmethyl H O CH2—c-Pr OCH2CF3 4-ethyl phenyl 2662 (CH2)2 O CH2—c-Pr OCH2CF3 4-ethyl phenyl 2663 (CH2)3 O CH2—c-Pr OCH2CF3 4-ethyl phenyl 2664 (CH2)4 O CH2—c-Pr OCH2CF3 4-ethyl phenyl 2665 (CH2)5 O CH2—c-Pr OCH2CF3 4-ethyl phenyl 2666 5,5-spiro[2.3]hexane O CH2—c-Pr OCH2CF3 4-ethyl phenyl 2667 Cyclopentyl H O CH2—c-Pr OCH2CF3 4-ethyl phenyl 2668 CH2CH3 H O CH2—c-Pr OCH2CF3 4-isopropyl phenyl 2669 CH2CF3 H O CH2—c-Pr OCH2CF3 4-isopropyl phenyl 2670 CH2CH2CH3 H O CH2—c-Pr OCH2CF3 4-isopropyl phenyl 2671 CH2CH(CH3)2 H O CH2—c-Pr OCH2CF3 4-isopropyl phenyl 2672 cyclopropylmethyl H O CH2—c-Pr OCH2CF3 4-isopropyl phenyl 2673 cyclobutylmethyl H O CH2—c-Pr OCH2CF3 4-isopropyl phenyl 2674 (CH2)2 O CH2—c-Pr OCH2CF3 4-isopropyl phenyl 2675 (CH2)3 O CH2—c-Pr OCH2CF3 4-isopropyl phenyl 2676 (CH2)4 O CH2—c-Pr OCH2CF3 4-isopropyl phenyl 2677 (CH2)5 O CH2—c-Pr OCH2CF3 4-isopropyl phenyl 2678 5,5-spiro[2.3]hexane O CH2—c-Pr OCH2CF3 4-isopropyl phenyl 2679 Cyclopentyl H O CH2—c-Pr OCH2CF3 4-isopropyl phenyl 2680 CH2CH3 H O CH2—c-Pr OCH2CF3 4-thiomethylphenyl 2681 CH2CF3 H O CH2—c-Pr OCH2CF3 4-thiomethylphenyl 2682 CH2CH2CH3 H O CH2—c-Pr OCH2CF3 4-thiomethylphenyl 2683 CH2CH(CH3)2 H O CH2—c-Pr OCH2CF3 4-thiomethylphenyl 2684 cyclopropylmethyl H O CH2—c-Pr OCH2CF3 4-thiomethylphenyl 2685 cyclobutylmethyl H O CH2—c-Pr OCH2CF3 4-thiomethylphenyl 2686 (CH2)2 O CH2—c-Pr OCH2CF3 4-thiomethylphenyl 2687 (CH2)3 O CH2—c-Pr OCH2CF3 4-thiomethylphenyl 2688 (CH2)4 O CH2—c-Pr OCH2CF3 4-thiomethylphenyl 2689 (CH2)5 O CH2—c-Pr OCH2CF3 4-thiomethylphenyl 2690 5,5-spiro[2.3]hexane O CH2—c-Pr OCH2CF3 4-thiomethylphenyl 2691 Cyclopentyl H O CH2—c-Pr OCH2CF3 4-thiomethylphenyl 2692 CH2CH3 H O CH2—c-Pr OCH2CF3 4-trifluoromethoxyphenyl 2693 CH2CF3 H O CH2—c-Pr OCH2CF3 4-trifluoromethoxyphenyl 2694 CH2CH2CH3 H O CH2—c-Pr OCH2CF3 4-trifluoromethoxyphenyl 2695 CH2CH(CH3)2 H O CH2—c-Pr OCH2CF3 4-trifluoromethoxyphenyl 2696 cyclopropylmethyl H O CH2—c-Pr OCH2CF3 4-trifluoromethoxyphenyl 2697 cyclobutylmethyl H O CH2—c-Pr OCH2CF3 4-trifluoromethoxyphenyl 2698 (CH2)2 O CH2—c-Pr OCH2CF3 4-trifluoromethoxyphenyl 2699 (CH2)3 O CH2—c-Pr OCH2CF3 4-trifluoromethoxyphenyl 2700 (CH2)4 O CH2—c-Pr OCH2CF3 4-trifluoromethoxyphenyl 2701 (CH2)5 O CH2—c-Pr OCH2CF3 4-trifluoromethoxyphenyl 2702 5,5-spiro[2.3]hexane O CH2—c-Pr OCH2CF3 4-trifluoromethoxyphenyl 2703 Cyclopentyl H O CH2—c-Pr OCH2CF3 4-trifluoromethoxyphenyl

TABLE 9 Compounds of Formula III Formula III Ex R1 R2 Y R4 R5 Z 2704 CH2CH3 H O CH2CH2CF3 Cl 4-trifluoromethylphenyl 2705 CH2CF3 H O CH2CH2CF3 Cl 4-trifluoromethylphenyl 2706 CH2CH2CH3 H O CH2CH2CF3 Cl 4-trifluoromethylphenyl 2707 CH2CH(CH3)2 H O CH2CH2CF3 Cl 4-trifluoromethylphenyl 2708 cyclopropylmethyl H O CH2CH2CF3 Cl 4-trifluoromethylphenyl 2709 cyclobutylmethyl H O CH2CH2CF3 Cl 4-trifluoromethylphenyl 2710 (CH2)2 O CH2CH2CF3 Cl 4-trifluoromethylphenyl 2711 (CH2)3 O CH2CH2CF3 Cl 4-trifluoromethylphenyl 2712 (CH2)4 O CH2CH2CF3 Cl 4-trifluoromethylphenyl 2713 (CH2)5 O CH2CH2CF3 Cl 4-trifluoromethylphenyl 2714 5,5-spiro[2.3]hexane O CH2CH2CF3 Cl 4-trifluoromethylphenyl 2715 Cyclopentyl H O CH2CH2CF3 Cl 4-trifluoromethylphenyl

TABLE 10 Compounds of Formula III Formula III Ex R1 R2 Y R4 R5 Z 2716 CH2CH3 H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2717 CH2CF3 H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2718 CH2CH2CH3 H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2719 CH2CH(CH3)2 H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2720 cyclopropylmethyl H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2721 cyclobutylmethyl H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2722 (CH2)2 O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2723 (CH2)3 O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2724 (CH2)4 O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2725 (CH2)5 O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2726 5,5-spiro[2.3]hexane O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2727 Cyclopentyl H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2733 cyclobutylmethyl H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 2735 (CH2)3 O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 2737 (CH2)5 O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 2738 5,5-spiro[2.3]hexane O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 2739 Cyclopentyl H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 2745 cyclobutylmethyl H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 2747 (CH2)3 O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 2749 (CH2)5 O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 2750 5,5-spiro[2.3]hexane O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 2751 Cyclopentyl H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 2752 CH2CH3 H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2753 CH2CF3 H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2754 CH2CH2CH3 H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2755 CH2CH(CH3)2 H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2756 cyclopropylmethyl H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2757 cyclobutylmethyl H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2758 (CH2)2 O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2759 (CH2)3 O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2760 (CH2)4 O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2761 (CH2)5 O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2762 5,5-spiro[2.3]hexane O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2763 Cyclopentyl H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2769 cyclobutylmethyl H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 2771 (CH2)3 O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 2773 (CH2)5 O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 2774 5,5-spiro[2.3]hexane O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 2775 Cyclopentyl H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 2781 cyclobutylmethyl H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 2783 (CH2)3 O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 2785 (CH2)5 O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 2786 5,5-spiro[2.3]hexane O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 2787 Cyclopentyl H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 2788 CH2CH3 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2789 CH2CF3 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2790 CH2CH2CH3 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2791 CH2CH(CH3)2 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2792 cyclopropylmethyl H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2793 cyclobutylmethyl H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2794 (CH2)2 O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2795 (CH2)3 O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2796 (CH2)4 O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2797 (CH2)5 O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2798 5,5-spiro[2.3]hexane O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2799 Cyclopentyl H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2805 cyclobutylmethyl H O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 2807 (CH2)3 O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 2809 (CH2)5 O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 2810 5,5-spiro[2.3]hexane O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 2811 Cyclopentyl H O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 2817 cyclobutylmethyl H O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2819 (CH2)3 O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2821 (CH2)5 O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2822 5,5-spiro[2.3]hexane O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2823 Cyclopentyl H O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2824 CH2CH3 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2825 CH2CF3 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2826 CH2CH2CH3 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2827 CH2CH(CH3)2 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2828 cyclopropylmethyl H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2829 cyclobutylmethyl H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2830 (CH2)2 O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2831 (CH2)3 O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2832 (CH2)4 O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2833 (CH2)5 O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2834 5,5-spiro[2.3]hexane O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2835 Cyclopentyl H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2841 cyclobutylmethyl H O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 2843 (CH2)3 O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 2845 (CH2)5 O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 2846 5,5-spiro[2.3]hexane O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 2847 Cyclopentyl H O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 2853 cyclobutylmethyl H O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 2855 (CH2)3 O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 2857 (CH2)5 O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 2858 5,5-spiro[2.3]hexane O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 2859 Cyclopentyl H O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole

TABLE 11 Compounds of Formula IV Formula IV Ex R1 R2 X R3 R5 Z 2860 CH2CH3 H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2861 CH2CF3 H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2862 CH2CH2CH3 H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2863 CH2CH(CH3)2 H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2864 cyclopropylmethyl H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2865 cyclobutylmethyl H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2866 (CH2)2 O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2867 (CH2)3 O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2868 (CH2)4 O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2869 (CH2)5 O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2870 5,5-spiro[2.3]hexane O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2871 Cyclopentyl H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 2872 CH2CH3 H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 2873 CH2CF3 H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 2874 CH2CH2CH3 H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 2875 CH2CH(CH3)2 H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 2876 cyclopropylmethyl H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 2877 cyclobutylmethyl H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 2878 (CH2)2 O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 2879 (CH2)3 O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 2880 (CH2)4 O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 2881 (CH2)5 O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 2882 5,5-spiro[2.3]hexane O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 2883 Cyclopentyl H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 2884 CH2CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 2885 CH2CF3 H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 2886 CH2CH2CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 2887 CH2CH(CH3)2 H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 2888 cyclopropylmethyl H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 2889 cyclobutylmethyl H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 2890 (CH2)2 O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 2891 (CH2)3 O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 2892 (CH2)4 O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 2893 (CH2)5 O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 2894 5,5-spiro[2.3]hexane O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 2895 Cyclopentyl H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 2896 CH2CH3 H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2897 CH2CF3 H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2898 CH2CH2CH3 H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2899 CH2CH(CH3)2 H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2900 cyclopropylmethyl H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2901 cyclobutylmethyl H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2902 (CH2)2 O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2903 (CH2)3 O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2904 (CH2)4 O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2905 (CH2)5 O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2906 5,5-spiro[2.3]hexane O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2907 Cyclopentyl H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 2908 CH2CH3 H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 2909 CH2CF3 H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 2910 CH2CH2CH3 H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 2911 CH2CH(CH3)2 H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 2912 cyclopropylmethyl H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 2913 cyclobutylmethyl H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 2914 (CH2)2 O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 2915 (CH2)3 O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 2916 (CH2)4 O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 2917 (CH2)5 O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 2918 5,5-spiro[2.3]hexane O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 2919 Cyclopentyl H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 2920 CH2CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 2921 CH2CF3 H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 2922 CH2CH2CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 2923 CH2CH(CH3)2 H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 2924 cyclopropylmethyl H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 2925 cyclobutylmethyl H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 2926 (CH2)2 O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 2927 (CH2)3 O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 2928 (CH2)4 O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 2929 (CH2)5 O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 2930 5,5-spiro[2.3]hexane O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 2931 Cyclopentyl H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 2932 CH2CH3 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2933 CH2CF3 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2934 CH2CH2CH3 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2935 CH2(CH3)2 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2936 cyclopropylmethyl H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2937 cyclobutylmethyl H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2938 (CH2)2 O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2939 (CH2)3 O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2940 (CH2)4 O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2941 (CH2)5 O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2942 5,5-spiro[2.3]hexane O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2943 Cyclopentyl H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 2944 CH2CH3 H O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 2945 CH2CF3 H O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 2946 CH2CH2CH3 H O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 2947 CH2(CH3)2 H O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 2948 cyclopropylmethyl H O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 2949 cyclobutylmethyl H O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 2950 (CH2)2 O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 2951 (CH2)3 O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 2952 (CH2)4 O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 2953 (CH2)5 O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 2954 5,5-spiro[2.3]hexane O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 2955 Cyclopentyl H O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 2956 CH2CH3 H O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2957 CH2CF3 H O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2958 CH2CH2CH3 H O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2959 CH2(CH3)2 H O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2960 cyclopropylmethyl H O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2961 cyclobutylmethyl H O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2962 (CH2)2 O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2963 (CH2)3 O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2964 (CH2)4 O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2965 (CH2)5 O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2966 5,5-spiro[2.3]hexane O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2967 Cyclopentyl H O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2968 CH2CH3 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2969 CH2CF3 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2970 CH2CH2CH3 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2971 CH2(CH3)2 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2972 cyclopropylmethyl H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2973 cyclobutylmethyl H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2974 (CH2)2 O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2975 (CH2)3 O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2976 (CH2)4 O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2977 (CH2)5 O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2978 5,5-spiro[2.3]hexane O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2979 Cyclopentyl H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 2980 CH2CH3 H O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 2981 CH2CF3 H O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 2982 CH2CH2CH3 H O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 2983 CH2(CH3)2 H O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 2984 cyclopropylmethyl H O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 2985 cyclobutylmethyl H O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 2986 (CH2)2 O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 2987 (CH2)3 O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 2988 (CH2)4 O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 2989 (CH2)5 O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 2990 5,5-spiro[2.3]hexane O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 2991 Cyclopentyl H O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 2992 CH2CH3 H O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 2993 CH2CF3 H O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 2994 CH2CH2CH3 H O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 2995 CH2(CH3)2 H O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 2996 cyclopropylmethyl H O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 2997 cyclobutylmethyl H O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 2998 (CH2)2 O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 2999 (CH2)3 O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 3000 (CH2)4 O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 3001 (CH2)5 O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 3002 5,5-spiro[2.3]hexane O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 3003 Cyclopentyl H O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole

TABLE 12 Compounds of Formula VII Formula VII Ex R1 R2 Y R4 R5 Z 3004 CH2CH3 H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 3005 CH2CF3 H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 3006 CH2CH2CH3 H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 3007 CH2(CH3)2 H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 3008 cyclopropylmethyl H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 3009 cyclobutylmethyl H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 3010 (CH2)2 O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 3011 (CH2)3 O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 3012 (CH2)4 O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 3013 (CH2)5 O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 3014 5,5-spiro[2.3]hexane O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 3015 Cyclopentyl H O CH2CF3 CF3 5-benzo[c][1,2,5]oxadiazole 3016 CH2CH3 H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 3017 CH2CF3 H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 3018 CH2CH2CH3 H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 3019 CH2(CH3)2 H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 3020 cyclopropylmethyl H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 3021 cyclobutylmethyl H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 3022 (CH2)2 O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 3023 (CH2)3 O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 3024 (CH2)4 O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 3025 (CH2)5 O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 3026 5,5-spiro[2.3]hexane O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 3027 Cyclopentyl H O CH2CF3 F 5-benzo[c][1,2,5]oxadiazole 3028 CH2CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 3029 CH2CF3 H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 3030 CH2CH2CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 3031 CH2(CH3)2 H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 3032 cyclopropylmethyl H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 3033 cyclobutylmethyl H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 3034 (CH2)2 O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 3035 (CH2)3 O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 3036 (CH2)4 O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 3037 (CH2)5 O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 3038 5,5-spiro[2.3]hexane O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 3039 Cyclopentyl H O CH2CF3 Cl 5-benzo[c][1,2,5]oxadiazole 3040 CH2CH3 H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 3041 CH2CF3 H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 3042 CH2CH2CH3 H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 3043 CH2(CH3)2 H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 3044 cyclopropylmethyl H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 3045 cyclobutylmethyl H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 3046 (CH2)2 O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 3047 (CH2)3 O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 3048 (CH2)4 O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 3049 (CH2)5 O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 3050 5,5-spiro[2.3]hexane O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 3051 Cyclopentyl H O CH2CF3 CF3 5-benzo[c][1,2,5]thiadiazole 3052 CH2CH3 H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 3053 CH2CF3 H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 3054 CH2CH2CH3 H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 3055 CH2(CH3)2 H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 3056 cyclopropylmethyl H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 3057 cyclobutylmethyl H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 3058 (CH2)2 O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 3059 (CH2)3 O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 3060 (CH2)4 O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 3061 (CH2)5 O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 3062 5,5-spiro[2.3]hexane O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 3063 Cyclopentyl H O CH2CF3 F 5-benzo[c][1,2,5]thiadiazole 3064 CH2CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 3065 CH2CF3 H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 3066 CH2CH2CH3 H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 3067 CH2(CH3)2 H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 3068 cyclopropylmethyl H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 3069 cyclobutylmethyl H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 3070 (CH2)2 O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 3071 (CH2)3 O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 3072 (CH2)4 O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 3073 (CH2)5 O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 3074 5,5-spiro[2.3]hexane O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 3075 Cyclopentyl H O CH2CF3 Cl 5-benzo[c][1,2,5]thiadiazole 3076 CH2CH3 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 3077 CH2CF3 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 3078 CH2CH2CH3 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 3079 CH2(CH3)2 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 3080 cyclopropylmethyl H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 3081 cyclobutylmethyl H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 3082 (CH2)2 O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 3083 (CH2)3 O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 3084 (CH2)4 O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 3085 (CH2)5 O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 3086 5,5-spiro[2.3]hexane O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 3087 Cyclopentyl H O CH2—c-Pr CF3 5-benzo[c][1,2,5]oxadiazole 3088 CH2CH3 H O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 3089 CH2CF3 H O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 3090 CH2CH2CH3 H O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 3091 CH2(CH3)2 H O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 3092 cyclopropylmethyl H O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 3093 cyclobutylmethyl H O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 3094 (CH2)2 O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 3095 (CH2)3 O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 3096 (CH2)4 O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 3097 (CH2)5 O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 3098 5,5-spiro[2.3]hexane O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 3099 Cyclopentyl H O CH2—c-Pr F 5-benzo[c][1,2,5]oxadiazole 310O CH2CH3 H O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 3101 CH2CF3 H O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 3102 CH2CH2CH3 H O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 3103 CH2(CH3)2 H O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 3104 cyclopropylmethyl H O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 3105 cyclobutylmethyl H O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 3106 (CH2)2 O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 3107 (CH2)3 O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 3108 (CH2)4 O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 3109 (CH2)5 O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 3110 5,5-spiro[2.3]hexane O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 3111 Cyclopentyl H O CH2—c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 3112 CH2CH3 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 3113 CH2CF3 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 3114 CH2CH2CH3 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 3115 CH2(CH3)2 H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 3116 cyclopropylmethyl H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 3117 cyclobutylmethyl H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 3118 (CH2)2 O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 3119 (CH2)3 O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 3120 (CH2)4 O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 3121 (CH2)5 O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 3122 5,5-spiro[2.3]hexane O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 3123 Cyclopentyl H O CH2—c-Pr CF3 5-benzo[c][1,2,5]thiadiazole 3124 CH2CH3 H O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 3125 CH2CF3 H O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 3126 CH2CH2CH3 H O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 3127 CH2(CH3)2 H O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 3128 cyclopropylmethyl H O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 3129 cyclobutylmethyl H O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 3130 (CH2)2 O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 3131 (CH2)3 O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 3132 (CH2)4 O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 3133 (CH2)5 O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 3134 5,5-spiro[2.3]hexane O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 3135 Cyclopentyl H O CH2—c-Pr F 5-benzo[c][1,2,5]thiadiazole 3136 CH2CH3 H O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 3137 CH2CF3 H O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 3138 CH2CH2CH3 H O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 3139 CH2(CH3)2 H O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 3140 cyclopropylmethyl H O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 3141 cyclobutylmethyl H O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 3142 (CH2)2 O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 3143 (CH2)3 O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 3144 (CH2)4 O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 3145 (CH2)5 O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 3146 5,5-spiro[2.3]hexane O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 3147 Cyclopentyl H O CH2—c-Pr Cl 5-benzo[c][1,2,5]thiadiazole

EXPERIMENTAL PROCEDURES Example 534 2-(6-cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

Step-1 2-(3-Bromo-4-hydroxyphenyl)-4-methylpentanoate

To a stirred solution of ethyl 2-(4-hydroxyphenyl)-4-methylpentanoate E-9 (15 g, 63.55 mmol) in 100 ml of glacial acetic acid at 0° C., slowly added bromine (20.26 g, 64.14 mol) and stirred at same temperature for 2.5 h. After completion the reaction, the reaction mixture was poured into water and neutralized with saturated sodium carbonate solution and extracted with ethyl acetate (300 ml×3). The organic layer was washed with water, saturated sodium bicarbonate solution and brine. The organic layer was then distilled off to yield product ethyl 2-(3-bromo-4-hydroxyphenyl)-4-methylpentanoate. Yield: (16 g, 80%). 1H NMR (CDCl3): δ 7.20 (m 2H), 6.80 (d, J=7.9 Hz, 1H), 4.90 (bs, 1H), 4.15 (q, 2H), 3.60 (t, 1H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m, 6H). Mass: (315, M+1, 100%).

Step-2 2-(3-Bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoic acid

Ethyl 2-(3-bromo-4-hydroxyphenyl)-4-methylpentanoate (16 g) was taken in acetic acid (100 ml) and to it added drop wise 70% nitric acid (10 ml) below 15° C. The reaction mixture was stirred for 2 h. After completion of the reaction; it was poured into 300 ml of ice water and extracted with ethyl acetate (300 ml×3). The ethyl acetate layer was washed with bicarbonate solution, water and finally brine solution. The organic layer was then distilled off and the crude residue was purified by column chromatography using Ethyl acetate:hexane (2:3) as eluent provided 12 g of 2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoic acid. The acid was taken in 50 ml of absolute ethanol and 2 ml of concentrated sulfuric acid and refluxed for 1 h. The ethanol layer was distilled off, washed it with water and dried gave 13 g of ethyl 2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoate intermediate. 1H NMR (CDCl3): δ 8.20 (s 1H), 7.20 (s, 1H), 4.90 (bs, 1H), 4.15 (q, 2H), 3.60 (t, 1H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m, 6H). Mass: (360, M+1, 100%).

Step 3 Ethyl 2-(3-bromo-4-(cyclopropylmethoxy)-5-nitrophenyl)-4-methylpentanoate

A solution of ethyl 2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoate (4.1 g, 11.26 mmol) was taken in 50 ml of DMSO and to it added Cs2CO3 (3.02 g, 12.39 mmol). The reaction mixture was stirred at room temperature for 15 minutes and then added cyclopropylmethyl bromide (1.67 g, 12.39 mmol) dropwise. After completion of addition, the reaction mixture was stirred at 70° C. for 4 h. After completion of the reaction, it was poured into water (200 ml) and extracted with ethyl acetate (100 ml×3). The ethyl acetate layer was washed with 1N HCl, water and finally brine solution. The organic layer was then distilled off and the crude residue was purified by column chromatography using Ethyl acetate:hexane (1:3) as eluent provided 3 g of ethyl 2-(3-bromo-4-(cyclopropylmethoxy)-5-nitrophenyl)-4-methylpentanoate. 1H NMR (CDCl3): δ 8.20 (s 1H), 7.20 (s, 1H), 4.15 (q, 2H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (414, M+1, 100%).

Step 4 Ethyl 2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

To a solution of ethyl 2-(3-bromo-4-(cyclopropylmethoxy)-5-nitrophenyl)-4-methylpentanoate (2 g, 4.83 mmol) in 30 ml of DMF/Water (25:5 ml) was added Pd(PPh3)4 (558 mg, 0.483 mmol), Cs2CO3 (5.5 g, 16.9 mmol) and 4-CF3-PhB(OH)2 (1.01 g, 5.31 mmol) and the reaction mixture was stirred at 90° C. for 12 h. After completion of the reaction, it was poured into water (100 ml) and extracted with ethyl acetate (100 ml×3). The ethyl acetate layer was washed with 1N HCl, water and finally brine solution. The organic layer was then distilled off and the crude residue was purified by column chromatography using Ethyl acetate:hexane (2:3) as eluent provided 1.3 g of ethyl 2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate. 1H NMR (CDCl3): δ 8.20 (s 1H), 7.40-7.20 (m, 5H), 4.15 (q, 2H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (480, M+1, 100%).

Step 5 2-(6-(Cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

Ethyl 2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (100 mg, 0.208 mmol) was taken in a mixture of MeOH; THF:Water (30 ml, 10:10:2) and to it added LiOH (30 mg, 0.7 mmol). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, it was poured into water (50 ml) and extracted with ethyl acetate (100 ml×2). The ethyl acetate layer was washed with 1N HCl, water and finally brine solution. The organic layer was then distilled off and the crude residue was purified by column chromatography using Ethyl acetate:hexane (1:1) as eluent provided 70 mg of 2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid. 1H NMR (CDCl3): δ 8.20 (s 1H), 7.40-7.20 (m, 5H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (452, M+1, 100%).

Example 554 2-(6-cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

Step 1 Ethyl 2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

Ethyl 2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (300 mg, 0.626 mmol) was taken in 30 ml of Toluene:Water (1:1) and to it added Fe powder (203 mg, 3.62 mmol), Ammonium formate (228 mg, 3.62 mmol). The reaction mixture was refluxed for 3 h and then filtered through celite. The toluene was distilled off under reduced pressure and the crude residue was purified by column chromatography using Ethyl acetate:hexane (2:3) as eluent provided 220 mg of ethyl 2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate. 1H NMR (CDCl3): δ 7.40-7.20 (m, 5H), 6.90 (s 1H), 4.50 (bs, 2H), 4.15 (q, 2H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (450, M+1, 100%).

Step 3 2-(5-Amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

Ethyl 2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate. (120 mg, 0.267 mmol) was taken in a mixture of MeOH; THF:Water (30 ml, 10:10:2) and to it added LiOH (30 mg, 0.7 mmol). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, it was poured into water (50 ml) and extracted with ethyl acetate (100 ml×2). The ethyl acetate layer was washed with 1N HCl, water and finally brine solution. The organic layer was then distilled off and the crude residue was purified by column chromatography using Ethyl acetate:hexane (1:1) as eluent provided 80 mg of 2-(6-cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid 2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid. 1H NMR (CDCl3): δ 7.40-7.20 (m, 5H), 7.00 (s, 1H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (422, M+1, 100%).

Example 484 2-(6-cyclopropylmethoxy)-5-chloro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

Step 1 Ethyl 2-(6-cyclopropylmethoxy)-5-chloro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

2-(6-Cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (150 mg, 0.33 mmol) was taken up in 10 ml of 6N HCl and a solution of sodium nitrite (30 mg, 0.40 mmol, 5 ml in water) was added at 0° C. The reaction mixture was stirred for 15 minutes at 0° C. and then poured into a saturated solution of copper (II) chloride in water (25 ml) The reaction mixture was then heated at 70° C. for 3 hours. The mixture was cooled to room temperature and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography using ethyl acetate:hexane (2:3) as eluent to yield 120 mg of ethyl 2-(6-cyclopropylmethoxy)-5-chloro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate. 1H NMR (CDCl3): δ 7.60-7.45 (m, 5H), 7.20 (s 1H), 4.15 (q, 2H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (470, M+1, 100%).

Step 2 2-(6-Cyclopropylmethoxy)-5-chloro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

The ethyl 2-(6-cyclopropylmethoxy)-5-chloro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate above (120 mg, 0.207 mmol) was taken up in a mixture of MeOH; THF:Water (30 ml, 10:10:2) and LiOH (42 mg, 0.7 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, it was poured into water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined extracts were washed with 1N HCl, water and finally brine solution. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography using ethyl acetate:hexane (1:1) as eluent to yield 105 mg of 2-(6-cyclopropylmethoxy)-5-chloro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid product. 1H NMR (CDCl3): δ 7.65-7.40 (m, 5H), 7.20 (s, 1H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (442, M+1, 100%). HPLC Purity (99%).

Example 264 2-(6-cyclopropylmethoxy)-5-fluoro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

Step 1 Ethyl 2-(6-cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

2-(6-cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (200 mg, 0.53 mmol) was taken up in 5 ml of 1,2-dichlorobenzene and a solution of BF3-etherate (1.5M, 5 ml) was added at 0° C. The reaction mixture was stirred for 15 minutes at 0° C. and t-butyl nitrite (1.5M, 3 ml) was added in a dropwise manner. The reaction mixture was then heated at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography using ethyl acetate:hexane (2:3) as eluent to provide 120 mg of ethyl 2-(6-cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate. 1H NMR (CDCl3): δ 7.60-7.35 (m, 5H), 7.20 (s 1H), 4.15 (q, 2H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (453, M+1, 100%).

Step 2 2-(6-cyclopropylmethoxy)-5-fluoro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

The above ethyl 2-(6-cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (120 mg, 0.267 mmol) was taken up in MeOH; THF:Water (20 ml, 10:10:2) and LiOH (42 mg, 0.7 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. After completion, the reaction was poured into water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined ethyl acetate layers were washed with 1N HCl, water and finally brine solution. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography using ethyl acetate:hexane (1:1) as eluent to yield 85 mg of 2-(6-cyclopropylmethoxy)-5-fluoro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid product. 1H NMR (CDCl3): δ 7.55-7.30 (m, 5H), 7.10 (s, 1H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (425, M+1, 100%). HPLC Purity (97%).

Example 724 2-(2-cyclopropylmethoxy-5-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid

Step 1 Diethyl 2-(2,5-difluoro-4-nitrophenyl)-2-isobutylmalonate

2-Isobutylmalonic acid diethyl ester (40.0 g, 0.185 mol) in DMF (50 mL) was added dropwise to a stirred suspension of sodium hydride (60% in mineral oil, 8.0 g, 0.33 mol) in 200 mL DMF (200 mL) over 20 min. at 0° C. under nitrogen. The mixture was stirred for 0.5 h at room temperature, cooled to 0° C. and 1,2,4-trifluoro-5-nitro-benzene (30.0 g, 169.5 mmol) in DMF (150 mL) was added dropwise. The resulting reaction mixture was stirred at room temperature for 16 h, poured into ice water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed with water (3×100 mL), brine (100 mL) and dried (MgSO4). Evaporation of solvent under reduced pressure gave a brown oil which was purified by column chromatography over silica gel (Heptane-EtOAc, gradient) to give 57.0 g (90%) of 2-(2,5-difluoro-4-nitrophenyl)-2-isobutylmalonic acid diethyl ester as yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.87 (dd, J=12.3, 6.0 Hz, 1H), 7.79 (dd, J=10.1, 6.4 Hz, 1H), 4.30-4.18 (m, 4H), 2.27 (d, J=5.8 Hz, 2H), 1.60-1.50 (m, 1H), 1.26 (t, J=7.1 Hz, 6H), 0.82 (d, J=7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 168.2, 155.1 (d, 1JCF=252.3 Hz), 150.9 (d, 1JCF=263.2 Hz), 135.7, 135.1, 120.0 (dd, 2JCF=26.0, 3JCF=4.0 Hz), 113.0 (d, 2JCF=29.0 Hz), 62.3, 43.1, 24.9, 23.8, 13.8.

Step 2 2-(2,5-Difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid

The above 2-(2,5-difluoro-4-nitrophenyl)-2-isobutylmalonic acid diethyl ester (57.0 g, 152.8 mmol) was dissolved in AcOH/H2O/EtOH (400 mL/120 mL/50 mL) and the reaction mixture was heated under reflux for 96 h. After cooling the solvent was evaporated under reduced pressure and water (200 mL) was added. The reaction mixture was extracted with EtOAc (3×100 mL), and the combined extracts were washed with water (3×100 mL), brine (100 mL) and dried (MgSO4). Evaporation of solvent under reduced pressure gave a yellow oil which crystallized on standing to yield 27 g of 2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid. Chromatography of the residual oil (Heptane-EtOAc gradient) gave an additional 3 g of product (72% combined yield). 1H NMR (300 MHz, CDCl3/TMS): δ 9.63 (br s, 1H), 7.82 (dd, J=8.8, 6.0 Hz, 1H), 7.38 (dd, J=11.0, 5.8 Hz, 1H), 4.14-4.08 (m, 1H), 2.05-1.95 (m, 1H), 1.76-1.66 (m, 1H), 1.52-1.43 (m, 1H), 0.95-0.92 (m, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 177.6, 158.2 (d, 1JCF=232.5 Hz), 150.9 (d, 1JCF=262.5 Hz), 136.0, 134.7, 119.0 (d, 2JCF=20.0, Hz), 113.1 (d, 2JCF=29.4 Hz), 41.7, 41.3, 26.0, 22.6, 21.9.

Step 3 2-(2,5-Difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester

2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid (29.0 g, 0.11 mol) was dissolved in EtOH (200 mL) and H2SO4 (96%) 10 mL added. The reaction mixture was refluxed for 3 h and the solvent evaporated to an oil which was dissolved in EtOAc. Water (150 mL) added and the reaction mixture was extracted with EtOAc (3×100 mL). Organic phases washed with saturated NaHCO3 (50 mL), water (100 mL) and brine (100 mL) then dried under MgSO4. The evaporation of solvent under reduced pressure gave 2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester as yellow oil 32.0 g, (97%), which was used for the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 7.81 (dd, J=8.8, 6.2 Hz, 1H), 7.41 (dd, J=11.1, 5.6 Hz, 1H), 4.23-4.05 (m, 3H), 2.04-1.94 (m, 1H), 1.71-1.62 (m, 1H), 1.51-1.42 (m, 1H), 1.25 (t, J=7.1 Hz, 3H), 0.95-0.92 (m, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 171.6, 155.0 (d, 1JCF=246.0 Hz), 151.5 (d, 1JCF=261.3 Hz), 145.5, 135.7, 118.8 (dd, 2JCF=24.0, 3JCF=4.0 Hz), 113.0 (d, 2JCF=20.0 Hz), 61.6, 41.8, 26.1, 22.5, 22.0, 14.1.

Step 4 2-(5-cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester

Cyclopropylmethanol (10.0 g, 138.8 mmol) was treated with n-BuLi (2.5M in hexane 7.4 g, 46 mL, 115.6 mmol) at −15° C. under nitrogen, and the reaction mixture was stirred 1 h at 25° C. To the mixture was added 2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester (29 g, 96 mmol) in Cyclopropylmethanol (30 mL) dropwise at 25° C. and the reaction mixture stirred for an additional 16 h. Water (100 mL) was added and the reaction mixture was extracted with EtOAc (3×100 mL). The combined organic phases washed with water (3×100 mL), brine (100 mL) and dried (MgSO4). Evaporation of the solvent under reduced pressure gave a brown oil which was purified by column chromatography over silica gel (Heptane-EtOAc gradient) to give 29.5 g, (81%) of 2-(5-cyclopropylmethoxy-2-fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.60 (d, J=9.0 Hz, 1H), 7.15 (d, J=5.7 Hz, 1H), 4.07 (t, J=7.7 Hz, 1H), 4.00-3.80 (m, 4H), 2.01-1.92 (m, 1H), 1.68-1.60 (m, 1H), 1.52-1.43 (m, 1H), 1.34-1.20 (m, 1H), 1.19-1.00 (m, 1H), 0.94 (d, J=6.3 Hz, 6H), 0.65 (d, J=7.7 Hz, 2H), 0.54 (d, J=7.7 Hz, 2H), 0.39 (d, J=4.4 Hz, 2H), 0.25 (d, J=4.4 Hz, 2H); 13C NMR (75 MHz, CDCl3/TMS): δ 172.6, 152.7 (d, 1JCF=243.4 Hz), 148.8, 138.1, 133.3 (d, 2JCF=15.7 Hz), 115.8, 112.6 (d, 2JCF=29.5 Hz), 75.1, 70.0, 42.1, 41.7, 26.1, 22.5, 22.2, 10.0, 9.8, 3.4.

Step 5 2-(5-Cyclopropylmethoxy-2-fluoro-4-amino-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester

2-(5-cyclopropylmethoxy-2-fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (10.0 g, 26.4 mmol) was dissolved in EtOH (200 mL) and hydrogenated at 50 psi, 25° C. for 24 h over 10% Pd—C (1 g). The mixture was filtered and the solvent evaporated to give crude a brown oi, which was purified by column chromatography over silica gel (Heptane-EtOAc gradient) to give 6.7 g, (72%) of 2-(5-cyclopropylmethoxy-2-fluoro-4-amino-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ 6.73 (d, J=6.9 Hz, 1H), 6.40 (d, J=11.0 Hz, 1H), 4.00-3.70 (m, 5H), 1.91-1.81 (m, 1H), 1.65-1.56 (m, 1H), 1.51-1.39 (m, 1H), 1.28-1.18 (m, 1H), 1.12-1.00 (m, 1H), 0.90 (d, J=6.6 Hz, 6H), 0.63-0.57 (m, 2H), 0.53-047 (m, 2H), 0.35-0.28 (m, 2H), 0.25-0.18 (m, 2H); 13C NMR (75 MHz, CDCl3/TMS): δ 174.2, 154.8 (d, 1JCF=236.0 Hz), 142.6, 136.6 (d, 3JCF=11.5 Hz), 114.1 (d, 2JCF=16.8 Hz), 111.6 (d, 3JCF=4.8 Hz), 101.6 (d, 2JCF=28.2 Hz), 73.8, 69.2, 42.1, 40.8, 25.9, 22.7, 22.2, 10.5, 9.8, 3.2.

Step 6 2-(5-Cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester

2-(5-cyclopropylmethoxy-2-fluoro-4-amino-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (2.9 g, 8.3 mmol) was dissolved in a mixture of EtOH/H2O/H2SO4 (96%) 50 mL/100 mL/2.5 mL at 0° C. A solution of NaNO2 (0.63 g, 9.1 mmol) in water (20 mL) was added dropwise at 0° C. and the reaction mixture was stirred for 20 min. A solution of KI (4.0 g, 24.1 mmol) in water (20 mL) was added dropwise at 0° C. and the reaction mixture was heated 50-60° C. for 2.5 h. The reaction mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with 10% sodium thiosulfate (30 mL) followed by brine (30 mL) and then dried over MgSO4. and solvent evaporated to give crude brown oil, which was purified by column chromatography over silica gel (Heptane-EtOAc gradient) to give 2.2 g, (57%) of 2-(5-cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.46 (d, J=8.8 Hz, 1H), 6.83 (d, J=6.3 Hz, 1H), 4.01-3.83 (m, 5H), 1.96-1.86 (m, 1H), 1.69-1.58 (m, 1H), 1.51-1.39 (m, 1H), 1.28-1.18 (m, 1H), 1.12-1.00 (m, 1H), 0.91 (d, J=6.3 Hz, 6H), 0.66-0.60 (m, 2H), 0.55-047 (m, 2H), 0.42-0.34 (m, 2H), 0.26-0.18 (m, 2H); 13C NMR (75 MHz, CDCl3/TMS): δ 173.2, 154.3 (d, 1JCF=243.4 Hz), 154.1, 127.1 (d, 2JCF=16.2 Hz), 125.5 (d, 2JCF=26.4 Hz), 112.3 (d, 3JCF=3.6 Hz), 84.6 (d, 3JCF=8.4 Hz), 74.5, 69.6, 41.9, 41.5, 26.0, 22.7, 22.2, 10.2, 9.8, 3.3.

Step 7 2-(2-Cyclopropylmethoxy-5-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester

To a solution of 2-(5-cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.2 g, 0.43 mmol) in anhydrous DME (10 mL) under argon was added 4-trifluoromethylphenylboronic acid (0.1 g, 0.53 mmol), CsF (0.16 g, 1.05 mmol), and Pd(PPh3)4 (0.015 g, 0.013 mmol). The reaction mixture was refluxed for 18 h, a water/EtOAc 15/15 mL mixture was added and the organic phase was separated and dried over MgSO4. The solvent was then evaporated to give a yellow oil which was purified by column chromatography over silica gel (Heptane-EtOAc gradient) to give 0.18 of 2-(2-cyclopropylmethoxy-5-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a light yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.70-7.64 (m, 4H), 7.05 (d, J=10.4 Hz, 1H), 7.01 (d, J=6.1 Hz, 1H), 4.09 (t, J=7.7 Hz, 1H), 4.02-3.87 (m, 2H), 3.78 (d, J=6.6 Hz, 2H), 2.04-1.90 (m, 1H), 1.74-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.25-1.05 (m, 2H), 0.95 (d, J=6.3 Hz, 6H), 0.60-0.40 (m, 4H), 0.30-0.10 (m, 4H). 13C NMR (75 MHz, CDCl3/TMS): δ 173.5, 154.3 (d, 1JCF=239.7 Hz), 151.9, 140.7, 132.0, 129.5, 126.6 (d, 2JCF=16.9 Hz), 124.8 (q, 3JCF=3.7 Hz), 124.0 (q, 1JCF=271.6 Hz), 117.0 (d, 2JCF=24.6 Hz), 113.6, 74.1, 69.6, 41.1, 41.5, 26.1, 22.7, 22.2, 10.2, 9.8, 3.2.

Step 8 2-(2-Cyclopropylmethoxy-5-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid

2-(2-cyclopropylmethoxy-5-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.14 g, 0.29 mmol) was dissolved in a mixture of EtOH/H2O (9 ml/1 ml) and KOH 0.3 g added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic extracts were dried over MgSO4 and evaporated under reduced pressure to an oil which was purified by column chromatography over silica gel (Heptane-EtOAc gradient) to give 0.12 g of a white solid. A second chromatography of the solid gave 0.03 g (25%) of pure 2-(2-cyclopropylmethoxy-5-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid product as a crystalline white solid. M.P.=110-111° C., 1H NMR (300 MHz, CDCl3/TMS): δ 8.99 (br s 1H), 7.66 (br s, 4H), 7.05 (d, J=9.9 Hz, 1H), 6.94 (d, J=5.2 Hz, 1H), 4.08 (t, J=7.7 Hz, 1H), 3.76 (d, J=6.6 Hz, 2H), 2.04-1.90 (m, 1H), 1.81-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.32-1.05 (m, 2H), 0.94 (d, J=6.0 Hz, 6H), 0.54 (d, J=7.4 Hz, 2H), 0.24 (d, J=3.9 Hz, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.2, 154.7 (d, 1JCF=239.8 Hz), 152.0, 140.6, 132.0, 129.9, 129.6, 125.7 (d, 2JCF=16.2 Hz), 124.8 (q, 3JCF=3.6 Hz), 124.0 (q, 1JCF=270 Hz), 117.2 (d, 2JCF=25.2 Hz), 113.9, 74.2, 41.3, 29.8, 25.9, 22.8, 22.1, 10.3, 3.2.

Example 485 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid

Step 1 Ethyl 2-(3-bromo-4-hydroxyphenyl)acetate

To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (20 g, 0.11 mol) in 200 ml of CCl4, was slowly added bromine (18.8 g, 0.11 mol) dissolved in 10 ml of CCl4 at 0° C. for 30 min. The reaction mass was stirred for another 30 min at 0° C. After completion of the reaction, the mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layers were washed with water, and 10% sodium bi-sulfite solution, dried over Na2SO4, filtered and concentrated in vacuo to give ethyl 2-(3-bromo-4-hydroxyphenyl)acetate in 78% yield. (22.4 g). 1HNMR (CDCl3): 7.42 (s, 1H); 7.14 (d, 1H); 6.97 (d, 1H); 5.53 (bs, 1H); 4.13 (q, 2H); 3.52 (s, 2H); 1.16 (t, 3H).

Step 2 Ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate

To a stirred solution of ethyl 2-(3-bromo-4-hydroxyphenyl)acetate (20 g, 0.076 mol) in 200 ml of DCM was added MeOH (3.4 ml, 0.84 mol) and the mixture was refluxed. Sulfuryl chloride (6.8 ml 0.846 mol) was slowly added under over a period of 10 min. The reaction mixture was refluxed for a further 5 h. Upon completion of reaction, the mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layer were washed with 10% NaHCO3 solution and water, dried over Na2SO4, filtered and evaporated under vacuum to give ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate in 60% yield. (13.6 g). 1HNMR (CDCl3): 7.37 (s, 1H); 7.27 (s, 1H); 5.68 (bs, 1H); 4.16 (q, 2H); 3.48 (s, 2H); 1.29 (t, 3H).

Step 3 Ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate

To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (4 g, 0.011 mol) and K2CO3 (2.8 g, 0.02 mol) in 100 ml of DMSO was slowly added cyclopropyl methylbromide (1.46 ml, 0.017 mol) at room temperature. Upon completion of the addition, the reaction mixture was heated at 60° C. for 4 h. Upon completion of the reaction, the mixture was poured onto water and extracted with EtOAc (×2). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated in vacuo to give ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate in 72% yield. (93.4 g). 1HNMR (CDCl3): 7.38 (bs, 1H); 7.28 (s, 1H); 4.16 (q, 2H); 3.87 (d, 2H); 3.58 (s, 2H); 1.38 (m, 1H); 1.28 (t, 3H); 0.63 (m, 2H); 0.38 (m, 2H).

Step 4 Ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate

A mixture of ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate (4 g, 0.011 mol), 4-Trifluoromethyl phenylboronic acid (2.6 g, 0.012 mol), Palladium Tetrakis(triphenylphosphine) (1.3 g, 0.001 mol), Cesium carbonate (13.1 g, 0.04 mol) in DMF/water mixture (100 ml/5 ml) was stirred overnight at 100° C. Upon completion of reaction, the precipitate were removed by filtration. The filtrate was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by Flash Column Chromatography to give ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate in 57% yield. (2.7 g). 1HNMR (CDCl3): 7.69 (bs, 4H); 7.36 (s, 1H); 7.17 (s, 1H); 4.18 (q, 2H); 3.59 (s, 2H); 3.39 (d, 2H); 1.28 (t, 3H); 0.96 (m, 1H); 0.41 (m, 2H); 0.01 (m, 2H).

Step 5 Ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate

To a suspension of NaH (37 mg, 50% suspension, 0.79 mmol) in 25 ml of DMF was slowly added a mixture of ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (300 mg, 0.719 mmol) and cyclopropylmethyl bromide (108 mg, 0.782 mmol) in 20 ml of DMF at 0° C. for 15 min under nitrogen atmosphere. Upon completion of the addition, the mixture was stirred for 15 min at 0° C. The reaction mixture was poured onto crushed ice and extracted with EtOAc (×2). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by Flash column Chromatography to give ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate in 62% yield. (0.210 g). 1HNMR (CDCl3): 7.69 (s, 4H); 7.41 (s, 1H); 7.21 (s, 1H); 4.19 (q, 2H); 3.63 (t, 1H); 3.41 (d, 2H); 1.94 (m, 1H); 1.78 (m, 1H); 1.27 (t, 3H); 0.97 (bs, 1H); 0.72 (bs, 1H); 0.42 (m, 4H); 0.13 (m, 2H); 0.1 (m, 2H).

Step 6 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid

A mixture of ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (100 mg, 0.214 mmol) and lithium hydroxide monohydrate (27 mg, 0.642 mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml 5/ml) was stirred for 3 h at room temperature. Upon completion of reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with EtOAc (×2). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid in 56% yield. (52.6 mg). 1HNMR (CDCl3): 7.71 (s, 4H); 7.42 (s, 1H); 7.23 (s, 1H); 3.68 (t, 1H); 3.41 (d, 2H); 1.93 (m, 1H); 1.77 (m, 1H); 0.97 (bs, 1H); 0.71 (bs, 1H); 0.42 (m, 4H); 0.12 (m, 2H); 0.1 (m, 2H).

Example 414 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

Step 1 Ethyl 2-(3-amino-5-bromo-4-hydroxyphenyl)-4-methylpentanoate

To a stirred solution compound ethyl 2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoate (6 g), in dry methanol (100 mL) was added Pd(OH)2 under an atmosphere of nitrogen. The reaction mixture was stirred for 5 h under an atmosphere of hydrogen. The reaction mixture was filtered through Celite™, washed with methanol and concentrated to dryness under reduced pressure. The crude material was purified by column chromatography to yield ethyl 2-(3-amino-5-bromo-4-hydroxyphenyl)-4-methylpentanoate (4 g, 72%). 1HNMR (CDCl3, 200 MHz): 6.80 (s, 1H); 6.62 (s, 1H); 5.35 (bs, 1H); 4.13 (q, 2H); 3.41 (t, 1H); 1.93-1.56 (m, 2H); 1.51 (m, 1H); 1.21 (t, 3H), 0.97 (d, 6H).

Step 2 Ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoate

Ethyl 2-(3-amino-5-bromo-4-hydroxyphenyl)-4-methylpentanoate 1 (4 g, 0.012 mol) was dissolved in a mixture of ACN/H2O/HCl 60 mL/30 mL/8 mL at 0° C. A solution of NaNO2 (0.919 g, 1.1 eq) in water (10 mL) was added dropwise at 0° C. and the reaction mixture was stirred for 1 h at 0° C. A solution of CuCl (5.99 g, 0.060 mol) in water (10 mL) was added dropwise to the reaction mixture at 0° C. The reaction mixture was then heated to 50° C. for 2.5 h. upon which the mixture was poured into ice water, extracted with ethyl acetate (3×100 mL) The combined organic layers were washed with water (200 mL) and brine (100 mL), dried over NaSO4 and concentrated in vacuo to give crude black oil which was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoate as yellow oil 2.2 g, (47.3%). 1HNMR (CDCl3, 200 MHz): 7.38 (s, 1H); 7.4 (s, 1H); 5.80 (bs, 1H); 4.13 (q, 2H); 3.51 (t, 1H); 1.93-1.56 (m, 2H); 1.51 (m, 1H); 1.21 (t, 3H), 0.97 (d, 6H);

Step 3 Ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4-methyl pentanoate

To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoate (2 g, 0.57 mmol) and K2CO3 (1.58 g, 0.011 mol) in dry DMF (20 mL), slowly added trifluoroethyl iodide (7.2 g, 3.39 ml, 0.034 mol) at room temperature. Upon completion of the addition, the reaction mixture was slowly heated to 100° C. for 4 h. Upon completion, the reaction mixture was poured into water and extracted with ethyl acetate (2×50 mL). The combined organic layer were washed with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (1.4 g, 60% yield). 1HNMR (CDCl3, 400 MHz): 7.43 (s, 1H); 7.34 (s, 1H); 4.4 (q, 2H), 4.13 (q, 2H); 3.55 (t, 1H); 1.93 (m, 1H), 1.58 (m, 1H); 1.45 (m, 1H); 1.24 (t, 3H), 0.92 (d, 6H);

Step 4 Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

A mixture of ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (1 g, 1 eq), 4-Trifluoromethyl phenylboronic acid (2.6 g, 1.4 eq), Pd(PPh3)4 (1.3 g, 0.1 eq) and Cesium Fluoride (13.1 g, 2 eq) in DME (30 ml) was stirred for overnight at 100° C. Upon completion, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water followed by brine, dried over Na2SO4 and concentrated under vacuo. The residue was purified by Flash Column Chromatography to give ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate in 74% yield (1.08 g). 1HNMR (CDCl3, 400 MHz): 7.68 (m, 5H), 7.43 (s, 1H); 7.24 (s, 1H); 4.4 (q, 2H), 4.13 (q, 2H); 3.55 (t, 1H); 1.93 (m, 1H), 1.58 (m, 1H); 1.45 (m, 1H); 1.24 (t, 3H), 0.92 (d, 6H);

Step 5 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (800 mg, mmol) and lithium hydroxide monohydrate (27 mg, 0.642 mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml 5/ml) was stirred for 3 h at room temperature. Upon completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid in 88% yield (670 mg).

Or alternatively example 414 may be synthesized via the following procedures:

Step 1 Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.75 g, 1.70 mmol) was dissolved in anhydrous DMF (20 mL), NaH (60% wt. in paraffin oil, 0.049 g, 2.04 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature, upon which isobutyl bromide (0.2 mL, 1.87 mmol), was added in a drop wise manner at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and then saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic layers were washed with water (2×10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a colorless oil, witch was purified by flash column chromatography to give ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (0.5 g, 59% yield) as a thick liquid.

Step 2 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methyl pentanoic acid

A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (0.6 g, 1.21 mmol) and lithium hydroxide monohydrate (0.509 g, 12.1 mmol) in MeOH/THF/Water a solvent mixture (10 mL/10 mL/10 mL) was stirred for 4 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×20 mL). The combined organic layers washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methyl pentanoic acid (0.4 g, 72% yield) as a white solid.

Example 1055 2-(6-Cyclopropylmethoxy-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic Acid Step 1 Diethyl 2-isobutyl-2-(4-nitro-3-(trifluoromethyl)phenyl)malonate

To a solution of diethyl isobutylmalonate (50.0 g, 231 mmol) in anhydrous DMF (200 mL) cooled in an ice bath was added NaH (60%, 11.1 g, 277 mmol) in small portions. After the addition, the reaction mixture was stirred at 0° C. for 10 min and then at room temperature for 30 min. 5-Chloro-2-nitrobenzotrifluoride (47.3 g, 210 mmol) in anhydrous DMF (50 mL) was added dropwise and the mixture was stirred at room temperature for two days. The DMF was removed under high vacuum and the residue was diluted with ethyl acetate (400 mL). Water (400 mL) was added dropwise; ammonium chloride (25 g) was added and the layers were separated. The organic layer was washed with brine (400 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a red-brown oil, which was purified by silica-gel flash chromatography eluting with heptane/ethyl acetate (12:1) to give the desired product diethyl 2-isobutyl-2-(4-nitro-3-(trifluoromethyl)phenyl)malonate (74.4 g, 87%) as a yellow oil: 1H NMR (300 MHz, CDCl3): δ 8.07 (s, 1H), 7.94 (d, 2H, J=8.7 Hz), 7.88 (d, 2H, J=8.7 Hz), 4.25 (m, 4H), 2.33 (d, 2H, J=6.6 Hz), 1.51 (m, 1H), 1.26 (t, 6H, J=7.2 Hz), 0.84 (d, 6H, J=6.6 Hz); 13C NMR (75 MHz, CDCl3): δ 169.23, 146.71, 142.86, 132.94, 127.94 (q, J=5 Hz), 124.55, 123.12 (q, J=33 Hz), 121.79 (q, J=272 Hz), 62.19, 61.59, 44.16, 24.66, 23.66, 13.89.

Step 2 4-Methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid

To a solution of diethyl 2-isobutyl-2-(4-nitro-3-(trifluoromethyl)phenyl)malonate (74.4 g, 184 mmol) in acetic acid (500 mL) were added water (157 mL) and concentrated H2SO4 (55 mL) carefully. The reaction mixture was refluxed for three days and then concentrated under reduced pressure. The residue was diluted with water (400 mL) and extracted with ethyl acetate (6×100 mL). The combined organic extracts were washed with water (400 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a brown oil. The residue was purified by silica-gel flash chromatography eluting with heptane/EtOAc (5:1 and then 2:1) to give 4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid (42.5 g, 76%) as a yellowish oil: 1H NMR (300 MHz, CDCl3): δ 11.51 (s, 1H, br), 7.87 (d, 1H, J=8.4 Hz), 7.78 (s, 1H), 7.71 (d, 1H, J=8.4 Hz), 3.84 (t, 1H, J=7.8 Hz), 2.06 (m, 1H), 1.72 (m, 1H), 1.49 (m, 1H), 0.95 (d, 3H, J=6.6. Hz), 0.94 (d, 3H, J=6.3 Hz); 13C NMR (75 MHz, CDCl3): δ 178.76, 147.09, 143.94, 132.66, 127.70 (q, J=5 Hz), 125.40, 123.95 (q, J=34 Hz), 121.74 (q, J=271 Hz), 42.16, 25.96, 22.44, 22.09.

Step 3 4-Methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid ethyl ester

To a solution of 4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid (42.3 g, 139 mmol) in absolute ethanol (300 mL) was added concentrated sulfuric acid (95-98%, 9.0 mL) and the solution was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure; the residue was treated with a solution of sodium carbonate (5%, 300 mL) and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with brine (300 mL), dried over sodium sulfate, and concentrated under reduced pressure. Purification by silica-gel flash chromatography eluting with heptane/EtOAc (10:1) gave 4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid ethyl ester (38.4 g, 83%) as a yellowish oil: 1H NMR (300 MHz, CDCl3): δ 7.90 (d, 1H, J=8.4 Hz), 7.82 (s, 1H), 7.74 (dd, 1H, J=8.4, 1.5 Hz), 4.18 (m, 2H), 3.83 (t, 1H, J=7.5 Hz), 2.06 (m, 1H), 1.70 (m, 1H), 1.50 (m, 1H), 1.27 (t, 3H, J=7.2 Hz), 0.97 (d, 3H, J=6.6 Hz), 0.96 (d, 3H, J=6.3 Hz); 13C NMR (75 MHz, CDCl3): δ 172.24, 146.83, 145.04, 132.40, 127.51 (q, J=5 Hz), 125.28, 123.80 (q, J=32 Hz), 121.78 (q, J=272 Hz), 61.45, 49.45, 42.65, 26.03, 22.41, 22.17, 14.10.

Step 4 2-(4-Amino-3-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester

A suspension of 4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid ethyl ester (38.3 g, 115 mmol), tin (II) chloride (87.2 g, 460 mmol) and water (16.6 g, 920 mmol) in ethanol (500 mL) was heated at reflux for four hours. The reaction mixture was concentrated under reduced pressure; the residue was treated with ethyl acetate (300 mL) and aqueous NaOH solution (1 N, 2.5 L). The aqueous layer was extracted with ethyl acetate (3×600 mL). The combined organic layers were washed with brine (1 L), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel flash chromatography eluting with heptane/ethyl acetate (10:1) to give 2-(4-amino-3-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (31.1 g, 89%) as a yellow oil: 1H NMR (300 MHz, CDCl3): δ 7.35 (d, 1H, J=2.1 Hz), 7.27 (dd, 1H, J=8.4, 2.1 Hz), 6.69 (d, 1H, J=8.4 Hz), 4.10 (m, 4H), 3.54 (t, 1H, J=7.8 Hz), 1.91 (m, 1H), 1.58 (m, 1H), 1.44 (m, 1H), 1.21 (t, 3H, J=6.9 Hz), 0.90 (d, 3H, J=6.6 Hz), 0.89 (d, 3H, J=6.6 Hz); 13C NMR (75 MHz, CDCl3): δ 174.14, 143.45, 132.22, 128.58, 125.91 (q, J=4 Hz), 124.80 (q, J=271 Hz), 117.35, 113.60 (q, J=29 Hz), 60.60, 48.54, 42.35, 25.77, 22.46, 22.18, 14.04.

Step 5 2-(4-Hydroxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester

To sulfuric acid (95-98%, 20.0 mL) was added 2-(4-amino-3-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (6.06 g, 20.0 mmol). The mixture was cooled to 0° C. and water (30.0 mL) was added dropwise. A solution of NaNO2 (1.66 g, 24.0 mmol) in water (12 mL) was added dropwise and the mixture was stirred for additional 20 min. A few crystals of urea were added to decompose any excess NaNO2. A solution of cupric nitrate (466 g, 2.00 mol) in water (880 mL) was added, followed by addition of Cu2O (2.86 g, 20.0 mmol). The mixture was stirred for 5 min and diethyl ether (1 L) was added. The organic extract was washed with brine (500 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel flash chromatography eluting with heptane/ethyl acetate (20:1) to give 2-(4-hydroxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (2.20 g, 31%) as a yellow oil: HRMS (DIP-CI-MS): calcd for C15H19NO5F3 (M+H)+: 350.1215. found 350.1240; 1H NMR (300 MHz, CDCl3): δ 11.13 (s, 1H), 8.29 (s, 1H), 7.90 (s, 1H), 4.15 (m, 2H), 3.69 (t, 1H, J=7.8 Hz), 2.00 (m, 1H), 1.62 (m, 1H), 1.47 (m, 1H), 1.25 (t, 3H, J=7.2 Hz), 0.94 (d, 3H, J=6.3 Hz), 0.93 (d, 3H, J=6.6 Hz); 13C NMR (75 MHz, CDCl3): δ 172.75, 152.45, 134.67 (q, J=5 Hz), 134.29, 131.40, 127.90, 122.35, (q, J=271 Hz), 121.42 (q, J=32 Hz), 61.51, 48.76, 42.76, 26.23, 22.60, 22.42, 14.32.

Step 6 2-(4-Cyclopropylmethoxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester

To a solution of 2-(4-hydroxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (2.66 g, 7.62 mmol), cyclopropanemethanol (0.60 g, 8.38 mmol) and triphenylphosphine (2.40 g, 9.14 mmol) in anhydrous THF (32 mL) was added diethyl azodicarboxylate (40 wt % solution in toluene, 3.98 g, 9.14 mmol) dropwise. The reaction mixture was stirred at room temperature for two days and then concentrated under reduced pressure. The residue was triturated with THF/hexane (1:5, 3×15 mL). The combined extracts were concentrated under reduced pressure to give a yellow solid, which was purified by silica-gel flash chromatography eluting with heptane/ethyl acetate (60:1 and then 10:1) to give 2-(4-cyclopropylmethoxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (1.89 g, 61%) as a colorless oil: 1H NMR (300 MHz, CDCl3): δ 7.92 (s, 1H), 7.73 (s, 1H), 4.06 (m, 2H), 3.79 (d, 2H, J=7.2 Hz), 3.64 (t, 1H, J=7.5 Hz), 1.93 (m, 1H), 1.55 (m, 1H), 1.40 (m, 1H), 1.24 (m, 1H), 1.17 (t, 3H, J=6.9 Hz), 0.86 (m, 6H), 0.56 (d, 2H, J=6.6 Hz), 0.27 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 172.49, 149.98, 144.40, 135.55, 130.96 (q, J=5 Hz), 128.29, 126.77, (q, J=31 Hz), 122.37 (q, J=272 Hz), 82.03, 61.37, 48.74, 42.66, 26.04, 22.36, 22.32, 14.14, 10.66, 3.39.

Step 7 2-(3-Amino-4-cyclopropylmethoxy-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester

A mixture of 2-(4-cyclopropylmethoxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (1.85 g, 4.59 mmol) and Pd/C (1.85 g) in ethanol and 1 N HCl (4.60 mL) was hydrogenated under 36 psi H2 in a Parr apparatus. After 4 h, the reaction mixture was filtered through Celite 521®. The filtrate was concentrated under reduced pressure to give a yellow oil. The residue was treated with an aqueous solution of sodium carbonate (3 g in 100 mL of water) and the resulting solution was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a brown oil, which was purified by silica-gel flash chromatography eluting with a gradient of heptane/ethyl acetate (from 10:1 to 2:1) to give 2-(3-amino-4-cyclopropylmethoxy-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (0.88 g, 51%) as a light pink oil: 1H NMR (300 MHz, CDCl3): δ 6.83 (s, 1H), 6.80 (s, 1H), 4.04 (m, 2H), 3.85 (s, 2H), 3.66 (d, 2H, J=6.9 Hz), 3.45 (t, 1H, J=7.8 Hz), 1.84 (m, 1H), 1.49 (m, 1H), 1.39 (m, 1H), 1.22 (m, 1H), 1.14 (t, 3H, J=7.2 Hz), 0.82 (m, 6H), 0.56 (d, 2H, J=7.5 Hz), 0.27 (d, 2H, J=4.5 Hz); 13C NMR (75 MHz, CDCl3): δ 173.61, 142.71, 141.25, 135.51, 123.75 (q, J=30 Hz), 123.52 (q, J=271 Hz), 118.46, 115.52 (q, J=5 Hz), 77.88, 60.70, 49.03, 42.53, 25.86, 22.40, 22.31, 14.07, 10.98, 3.19.

Step 8 2-(4-Cyclopropylmethoxy-3-iodo-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester

To a solution of p-toluenesulfonic acid monohydrate (0.308 g, 1.62 mmol) in acetonitrile (2.3 mL) was added 2-(3-amino-4-cyclopropylmethoxy-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (0.20 g, 0.54 mmol). The resulting suspension of the amine salt was cooled in an ice bath. A solution of sodium nitrite (0.0745 g, 1.08 mmol) in water (0.32 mL) was added dropwise, followed by addition of a solution of KI (1.79 g, 10.8 mmol) in water (2.0 mL). The reaction mixture was stirred in the ice bath for one hour and then at room temperature for one hour. TLC showed that the reaction was completed. Water (20 mL) was added and then an aqueous solution of sodium bicarbonate (1 M) to adjust the pH to 8. Ethyl acetate (20 mL) was added for extraction. The organic layer was washed with aqueous Na2S2O4 solution (10%, 20 mL) and brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to give a brown oil, which was purified by silica-gel flash chromatography eluting with heptane/ethyl acetate (30:1) to give 2-(4-cyclopropylmethoxy-3-iodo-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (0.15 g, 57%) as a yellowish oil: 1H NMR (300 MHz, CDCl3): δ 7.93 (s, 1H), 7.52 (s, 1H), 4.11 (m, 2H), 3.83 (d, 2H, J=7.2 Hz), 3.59 (t, 1H, J=7.5 Hz), 1.95 (m, 1H), 1.50 (m, 3H), 1.22 (t, 3H, J=6.9 Hz), 0.91 (d, 3H, J=6.3 Hz), 0.90 (d, 3H, J=6.3 Hz), 0.64 (m, 2H), 0.43 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 172.96, 155.55, 142.66, 136.98, 126.94 (q, J=5 Hz), 124.87 (q, J=30 Hz), 122.64 (q, J=272 Hz), 93.73, 79.79, 61.06, 48.53, 42.65, 26.01, 22.39, 14.16, 10.75, 3.36.

Step 9 2-(6-Cyclopropylmethoxy-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid ethyl ester

A mixture of 2-(4-cyclopropylmethoxy-3-iodo-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (0.14 g, 0.29 mmol), 4-(trifluoromethyl)benzeneboronic acid (0.089 g, 0.47 mmol), Pd(dppf)Cl2 (0.023 g, 0.031 mmol) and a solution of aqueous sodium carbonate (2 M, 0.31 mL, 0.62 mmol) in 1,4-dioxane (4 mL) was degassed and heated at 100° C. for ten days. The reaction mixture was concentrated under reduced pressure; the residue was treated with water (30 mL) and ethyl acetate (30 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with heptane/ethyl acetate (100:1) to give a colorless oil (0.11 g), which was further purified by flash chromatography on silica gel 100 C18-reversed phase eluting with MeOH/H2O (5:1 to 20:3) to give 2-(6-cyclopropylmethoxy-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid ethyl ester (0.05 g, 34%) as a white solid: 1H NMR (300 MHz, CDCl3/TMS): δ 7.73 (m, 4H), 7.58 (s, 1H), 7.48 (s, 1H), 4.13 (m, 2H), 3.70 (t, 1H, J=7.5 Hz), 3.27 (d, 2H, J=7.2 Hz), 2.00 (m, 1H), 1.67 (m, 2H), 1.51 (m, 1H), 1.25 (t, 3H, J=7.2 Hz), 0.93 (m, 8H), 0.45 (d, 2H, J=7.5 Hz); 13C NMR (75 MHz, CDCl3/TMS): δ 173.35, 153.80, 140.99, 135.48, 135.40, 134.05, 130.05 (q, J=32 Hz), 129.88 (q, J=32 Hz), 129.42, 126.41 (q, J=5 Hz), 125.33 (q, J=4 Hz), 124.06 (q, J=270 Hz), 123.48 (q, J=270 Hz), 79.47, 60.98, 49.21, 42.87, 26.19, 22.46, 14.22, 10.56, 3.13.

Step 10 2-(6-Cyclopropylmethoxy-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid

A mixture of 2-(6-cyclopropylmethoxy-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid ethyl ester (0.04 g, 0.08 mmol) and aqueous KOH (1.4 M, 0.4 mL) in ethanol (5 mL) was stirred at room temperature for two days. After the solvent was removed under reduced pressure, the residue was diluted with water (30 mL), acidified with 1 N HCl to pH 1, and then extracted with ethyl acetate (30 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and freeze-dried overnight to give the desired carboxylic acid 2-(6-cyclopropylmethoxy-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid (0.04 g, 100%) as a white solid: mp 148-149° C.; HRMS (ESI-TOF): calcd for C24H23O3F6Na2 (M−H+2 Na)+: 519.1341. found 519.1366; 1H NMR (300 MHz, CDCl3/TMS): δ 7.72 (m, 4H), 7.59 (s, 1H), 7.48 (s, 1H), 3.73 (m, 1H), 3.27 (d, 2H, J=6.9 Hz), 2.02 (m, 1H), 1.69 (m, 1H), 1.56 (m, 1H), 1.28 (m, 1H), 0.94 (m, 8H), 0.46 (m, 2H); the proton of COOH was not observed; 13C NMR (75 MHz, CDCl3/TMS): δ 178.95, 154.12, 140.82, 135.61, 134.49, 134.24, 130.18 (q, J=32 Hz), 129.44 (q, J=32 Hz), 129.40, 126.50 (q, J=5 Hz), 125.39 (q, J=4 Hz), 124.04 (q, J=270 Hz), 123.40 (q, J=271 Hz), 79.55, 48.91, 42.35, 26.07, 22.49, 22.35, 10.58, 3.15; HPLC purity: 95.2%, retention time=11.78 min.

Example 754 2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluorophenyl)-4-methylpentanoic acid

Step 1 Cyclopropylmethyl 2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluorophenyl)-4-methylpentanoate

To a solution of 2-(5-cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.2 g, 0.43 mmol) in DME (anhydrous, 10 mL) under argon atmosphere was added 4-trifluoromethylphenylboronic acid (0.1 g, 0.53 mmol), CsF (0.16 g, 1.05 mmol), and Pd(PPh3)4 (0.015 g, 0.013 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). A mixture of water and EtOAc (15 mL/15 mL) was added and the layers were separated. The organic phase was dried over MgSO4 and evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatograph using Heptane-EtOAc (60:1-9:1) to give cyclopropylmethyl 2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluorophenyl)-4-methylpentanoate as a yellowish oil (0.18 g, 90%). 1H NMR (300 MHz, CDCl3/TMS): δ 7.70-7.64 (m, 4H), 7.05 (d, J=10.4 Hz, 1H), 7.01 (d, J=6.1 Hz, 1H), 4.09 (t, J=7.7 Hz, 1H), 4.02-3.87 (m, 2H), 3.78 (d, J=6.6 Hz, 2H), 2.04-1.90 (m, 1H), 1.74-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.25-1.05 (m, 2H), 0.95 (d, J=6.3 Hz, 6H), 0.60-0.40 (m, 4H), 0.30-0.10 (m, 4H). 13C NMR (75 MHz, CDCl3/TMS): δ 173.5, 154.3 (d, 1JCF=239.7 Hz), 151.9, 140.7, 132.0, 129.5, 126.6 (d, 2JCF=16.9 Hz), 124.8 (q, 3JCF=3.7 Hz), 124.0 (q, 1JCF=271.6 Hz), 117.0 (d, 2JCF=24.6 Hz), 113.6, 74.1, 69.6, 41.1, 41.5, 26.1, 22.7, 22.2, 10.2, 9.8, 3.2.

Step 2 2-(4-benzo[1,2,5]oxadiazol-5-yl-5-cyclopropylmethoxy-2-fluoro-phenyl)-4-methylpentanoic acid

Cyclopropylmethyl 2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluorophenyl)-4-methylpentanoate (0.14 g, 0.29 mmol) was dissolved in a mixture of EtOH/H2O (9 mL/1 mL) and KOH (0.3 g) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5, and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4 and evaporated under reduced pressure to give a colorless oil. Purification by gradient column chromatography on silica gel Heptane-EtOAc (50:1-9:1) gave 2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluorophenyl)-4-methylpentanoic acid as a white solid (0.12 g, quantitative); pure portion (0.03 g, 25%); white microcrystals, M.P.=110-111° C., 1H NMR (300 MHz, CDCl3/TMS): δ 8.99 (br s, 1H), 7.66 (br s, 4H), 7.05 (d, J=9.9 Hz, 1H), 6.94 (d, J=5.2 Hz, 1H), 4.08 (t, J=7.7 Hz, 1H), 3.76 (d, J=6.6 Hz, 2H), 2.04-1.90 (m, 1H), 1.81-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.32-1.05 (m, 2H), 0.94 (d, J=6.0 Hz, 6H), 0.54 (d, J=7.4 Hz, 2H), 0.24 (d, J=3.9 Hz, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.2, 154.7 (d, 1JCF=239.8 Hz), 152.0, 140.6, 132.0, 129.9, 129.6, 125.7 (d, 2JCF=16.2 Hz), 124.8 (q, 3JCF=3.6 Hz), 124.0 (q, 1JCF=270 Hz), 117.2 (d, 2JCF=25.2 Hz), 113.9, 74.2, 41.3, 29.8, 25.9, 22.8, 22.1, 10.3, 3.2.

Example 2959 2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid

Step 1 2-(3-Fluoro-4-nitro-phenyl)-2-isobutyl-malonic acid diethyl ester

To a solution of 2-isobutylmalonic acid diethyl ester (75.0 g, 0.35 mol) in DMF (200 mL) was added sodium hydride (60% in mineral oil, 13.0 g, 0.57 mol) over 20 min. at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h, then warmed to 25° C. The reaction mixture was cooled down to 0° C. again and a solution of 2,4-difluoronitro-benzene (50.0 g, 0.31 mol) in DMF (150 mL) was added dropwise at 0° C. The reaction mixture was stirred at 25° C. for 16 h. After cooling, the reaction mixture was poured into ice water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic phases washed with water (3×100 mL), brine (100 mL), and dried (MgSO4). Evaporation of the solvent under reduced pressure gave a brown oil. The crude product (92.0 g, 82%) was used for the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 8.03 (t, J=8.4 Hz, 1H), 7.70 (dd, J=12.9, 1.7 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 4.25-4.18 (m, 4H), 2.28 (d, J=6.3 Hz, 2H), 1.54-1.45 (m, 1H), 1.25 (t, J=7.0 Hz, 6H), 0.82 (d, J=7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 169.2, 154.5 (d, 1JCF=263.1 Hz), 146.9 (d, unresolved), 125.3, 124.1 (d, 3JCF=3.6 Hz), 118.6 (d, 2JCF=23.3 Hz), 62.0, 60.3, 44.1, 24.7, 23.6, 13.9.

Step 2 2-(3-fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid

2-(3-Fluoro-4-nitro-phenyl)-2-isobutyl-malonic acid diethyl ester (92.0 g, 0.26 mol) was dissolved in AcOH/H2O/H2SO4 (96%) (500 mL/200 mL/70 mL) and the reaction mixture was refluxed for 24 h. After cooling and evaporation, water (300 mL) was added. The reaction mixture was extracted with EtOAc (3×100 mL). The combined organic phases were washed with water (3×100 mL), brine (100 mL) and dried (MgSO4). The evaporation of solvent under reduced pressure gave a brown oil (61 g, quantitative), which was used for the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 8.07-8.01 (m, 1H), 7.33-7.26 (m, 2H), 3.79-3.73 (m, 1H), 2.05-1.95 (m, 1H), 1.76-1.66 (m, 1H), 1.52-1.43 (m, 1H), 0.95-0.92 (m, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 178.3, 156.0 (d, 1JCF=232.5 Hz), 147.0, 136.0, 126.2, 124.3, 118.1 (d, 2JCF=30 Hz), 49.3, 42.0, 25.8, 22.4, 22.0.

Step 3 2-(3-Fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester

2-(3-Fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid (29.0 g, 0.12 mmol) was dissolved in EtOH (100 mL) and H2SO4 (96%, 5 mL) was added. The reaction mixture was refluxed for 3 h and the solvent evaporated. Water (100 mL) was added and the reaction mixture was extracted with EtOAc (3×100 mL). The combined organic phases were washed with saturated NaHCO3 solution (50 mL), water (100 mL) and brine (100 mL), and then dried over MgSO4. Evaporation of the solvent under reduced pressure gave a brown oil (31.0 g, 97%), which was used for the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 8.03 (t, J=8.4 Hz, 1H), 7.33-7.26 (m, 2H), 4.17-4.11 (m, 2H), 3.73 (t, J=7.6 Hz, 1H), 2.10-1.94 (m, 1H), 1.71-1.62 (m, 1H), 1.51-1.42 (m, 1H), 1.25 (t, J=7.0 Hz, 3H), 0.95-0.92 (m, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 172.2, 155.3 (d, 1JCF=265.0 Hz), 148.3 (d, 3JCF=8.4 Hz), 136.5, 126.1, 124.1 (d, 3JCF=3.6 Hz), 117.8 (d, 2JCF=21.6 Hz), 61.3, 49.4, 42.3, 25.9, 22.5, 22.1, 14.1.

Step 4 2-(3-Cyclopropylmethoxy-4-nitro-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester

Cyclopropylmethanol (80.0 g, 1.11 mol) was treated with n-BuLi (2.5 M in hexane, 9.1 g, 57 mL, 0.14 mol) at a temperature ranging from −15 to 0° C. The reaction mixture was stirred for 1 h at 25° C. Then, a solution of 2-(3-fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester in cyclopropylmethanol (30 mL) was added at 25° C. and the reaction mixture was stirred for 16 h. Water (100 mL) was added and the reaction mixture was extracted with EtOAc (3×100 mL). The combined organic phases were washed with water (3×100 mL), brine (100 mL), and dried (MgSO4). Evaporation of the solvent under reduced pressure gave a brown oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc (9:1-4:1) to give 2-(3-cyclopropylmethoxy-4-nitro-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil (34.0 g, 93%). 1H NMR (300 MHz, CDCl3/TMS): δ 7.78 (d, J=8.4 Hz, 1H), 7.06 (s, 1H), 6.97 (d, J=8.4 Hz, 1H), 4.00-3.83 (m, 4H), 3.69 (t, J=8.0 Hz, 1H), 2.07-1.92 (m, 1H), 1.69-1.60 (m, 1H), 1.52-1.42 (m, 1H), 1.32-1.20 (m, 1H), 1.19-1.00 (m, 1H), 0.92 (d, J=6.3 Hz, 6H), 0.68-0.62 (m, 2H), 0.56-0.48 (m, 2H), 0.42-0.38 (m, 2H), 0.26-0.21 (m, 2H); 13C NMR (75 MHz, CDCl3/TMS): δ 172.9, 152.3, 146.2, 138.8, 125.6, 119.8, 114.4, 74.2, 69.8, 49.8, 42.6, 26.0, 22.5, 22.2, 10.0, 9.7, 3.3.

Step 5 2-(4-Amino-3-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester

2-(3-Cyclopropylmethoxy-4-nitro-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (34.0 g, 94.2 mmol) was dissolved in AcOH (300 mL) and water (20 mL). Then, Zn powder (60.0 g, 923 mmol) was added in portions. The reaction mixture was refluxed for 1 h and after cooling the precipitate was filtered. The solvent was evaporated and water (150 mL) was added. The reaction mixture was extracted with EtOAc (3×100 mL) and the combined organic phases were washed with water (3×100 mL) and brine (100 mL). Drying of the organic phase was performed with magnesium sulfate. The evaporation of the solvent gave crude product as a brown oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc to give 2-(4-amino-3-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil (23 g, 75%). 1H NMR (300 MHz, CDCl3/TMS): δ 6.73-6.61 (m, 3H), 3.94-3.78 (m, 6H), 3.53 (t, J=7.7 Hz, 1H), 1.94-1.85 (m, 1H), 1.65-1.56 (m, 1H), 1.52-1.43 (m, 1H), 1.28-1.18 (m, 1H), 1.11-1.03 (m, 1H), 0.90 (d, J=6.6 Hz, 6H), 0.64-0.58 (m, 2H), 0.53-0.47 (m, 2H), 0.36-0.33 (m, 2H), 0.24-0.21 (m, 2H); 13C NMR (75 MHz, CDCl3/TMS): δ 174.6, 146.4, 135.3, 129.3, 120.5, 114.6, 111.2, 73.1, 69.0, 49.2, 42.7, 25.8, 22.6, 22.4, 10.4, 9.8, 3.2.

Step 6 2-(4-Amino-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester

2-(4-Amino-3-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (16.3 g, 49.1 mmol) was dissolved in chloroform (200 mL) and N-chlorosuccinimide (5.3 g, 0.75 equiv, 39.6 mmol) was added. The reaction mixture was refluxed for 1 h and after cooling treated with 10% potassium carbonate solution (100 mL). The reaction mixture was extracted with EtOAc (3×50 mL) and the combined organic phases were dried over magnesium sulfate. Evaporation of the solvent gave the crude product as a brown oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc to give 2-(4-amino-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil (5 g, 36%). 1H NMR (300 MHz, CDCl3/TMS): δ 6.85 (s, 1H), 6.66 (s, 1H), 3.95-3.80 (m, 4H), 3.49 (t, J=7.7 Hz, 1H), 1.94-1.82 (m, 1H), 1.63-1.52 (m, 1H), 1.50-1.40 (m, 1H), 1.28-1.18 (m, 1H), 1.11-1.03 (m, 1H), 0.90 (d, J=6.6 Hz, 6H), 0.66-0.58 (m, 2H), 0.53-0.47 (m, 2H), 0.37-0.32 (m, 2H), 0.25-0.20 (m, 2H); 13C NMR (75 MHz, CDCl3/TMS): δ 174.2, 146.8, 132.6, 128.7, 120.6, 118.3, 109.4, 73.6, 69.3, 49.0, 42.6, 25.9, 22.6, 22.4, 10.4, 9.8, 3.3.

Step 7 2-(3-Chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester

2-(4-Amino-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (5.0 g, 13.7 mmol) was dissolved in a mixture of EtOH/H2O/H2SO4 (96%) (65 mL/100 mL/2.5 mL) and the reaction mixture was cooled down to 0° C. A solution of NaNO2 (0.95 g, 13.7 mmol) in water (5 mL) was added dropwise at 0° C. and the reaction mixture was stirred for 30 min. A solution of KI (7.0 g, 42.2 mmol) in water (20 mL) was added dropwise at 0° C. The reaction mixture was heated to 50-60° C. for 2.5 h. The reaction mixture was extracted with EtOAc (3×50 mL). The organic layers were combined and washed with 10% sodium thiosulfate solution (30 mL) followed by brine (30 mL). The organic phase was dried over MgSO4 and the solvent evaporated to give a crude brown oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc (20:1-9:1) to give 2-(3-Chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil (4.0 g, 62%). 1H NMR (300 MHz, CDCl3/TMS): δ 7.07 (s, 1H), 6.66 (s, 1H), 3.95-3.80 (m, 4H), 3.58 (t, J=7.7 Hz, 1H), 1.96-1.89 (m, 1H), 1.66-1.52 (m, 1H), 1.50-1.40 (m, 1H), 1.28-1.18 (m, 1H), 1.11-1.03 (m, 1H), 0.91 (d, J=6.6 Hz, 6H), 0.67-0.61 (m, 2H), 0.56-0.50 (m, 2H), 0.45-0.40 (m, 2H), 0.26-0.21 (m, 2H); 13C NMR (75 MHz, CDCl3/TMS): δ 173.2, 159.2, 141.6, 139.4, 121.4, 109.8, 90.4, 74.0, 69.7, 49.4, 42.5, 26.0, 22.6, 22.3, 10.2, 9.8, 3.3.

Step 8 2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester

To a solution of 2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.27 g, 0.57 mmol) in DME (anhydrous, 10 mL) under argon atmosphere were added 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,2,5]oxadiazole (0.15 g, 0.61 mmol), CsF (0.2 g, 1.32 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.021 g, 0.029 mmol, need 0.06 mmol to complete the reaction!). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). A mixture water/EtOAc (15 mL/15 mL) was added and the layers were separated. The organic phase was dried over MgSO4, then evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography using Heptane-EtOAc (20:1-9:1) to give 2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.11 g, 41%) of as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.83 (d, J=9.3 Hz, 1H), 7.77 (s, 1H), 7.36-7.33 (m, 1H), 7.11 (s, 1H), 6.91 (s, 1H), 4.02-3.81 (m, 4H), 3.67 (t, J=7.7 Hz, 1H), 2.03-1.96 (m, 1H), 1.74-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.20-1.05 (m, 2H), 0.96 (d, J=6.3 Hz, 6H), 0.57-0.47 (m, 4H), 0.28 (br s, 2H), 0.19 (br s, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 173.4, 157.0, 149.2, 148.3, 142.0, 138.7, 135.4, 133.5, 126.4, 121.6, 117.4, 114.9, 110.6, 73.4, 69.8, 49.8, 42.8, 26.1, 22.5, 22.4, 10.0, 9.8, 3.3, 3.1

Step 9 2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid

2-(4-Benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.11 g, 0.23 mmol) was dissolved in a mixture of EtOH/H2O (9 mL/1 mL) and KOH (0.1 g, 1.76 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5, and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4 and evaporated under reduced pressure to give 2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid as a yellow oil (0.068 g, 70%). 1H NMR (300 MHz, CDCl3/TMS): δ 8.40 (br s, 1H), 7.70 (d, J=9.3 Hz, 1H), 7.62 (s, 1H), 7.19 (d, J=9.3 Hz, 1H), 6.97 (s, 1H), 6.73 (s, 1H), 3.67 (d, J=6.6 Hz, 2H), 3.52 (t, J=7.7 Hz, 1H), 1.90-1.81 (m, 1H), 1.62-1.53 (m, 1H), 1.50-1.39 (m, 1H), 0.98-0.68 (m, 1H), 0.81 (d, J=6.1 Hz, 6H), 0.37-0.31 (m, 2H), 0.15-0.10 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.1, 157.1, 149.1, 148.3, 141.0, 138.6, 135.3, 133.7, 126.8, 121.6, 117.4, 115.0, 110.9, 73.4, 49.4, 41.9, 25.9, 22.6, 22.3, 10.0, 3.1.

Example 2995 2-(4-Benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid

Step 1 2-(4-Benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester

To a solution of 2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.18 g, 0.38 mmol) in DME (anhydrous, 10 mL) under argon atmosphere were added 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,2,5]thiodiazole (0.15 g, 0.57 mmol), CsF (0.14 g, 0.92 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.02 g, 0.027 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). A mixture of water and EtOAc (15 mL/15 mL) was added and the layers were separated. The combined organic phases were dried over MgSO4 and evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc (20:1-9:1) to give 2-(4-benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.08 g, 50%) as a yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.83 (d, J=9.3 Hz, 1H), 7.77 (s, 1H), 7.36-7.33 (m, 1H), 7.11 (s, 1H), 6.91 (s, 1H), 4.02-3.81 (m, 4H), 3.67 (t, J=7.7 Hz, 1H), 2.03-1.96 (m, 1H), 1.74-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.20-1.05 (m, 2H), 0.96 (d, J=6.3 Hz, 6H), 0.57-0.47 (m, 4H), 0.28 (br s, 2H), 0.19 (br s, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 173.5, 157.1, 154.7, 154.0, 141.4, 136.8, 133.7, 132.9, 126.9, 122.8, 121.6, 120.0, 110.8, 73.3, 69.7, 49.7, 42.7, 26.1, 22.5, 22.5, 10.0, 9.8, 3.3, 3.1.

Step 2 2-(4-Benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid

2-(4-Benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.08 g, 0.19 mmol) was dissolved in a mixture of EtOH and H2O (9 mL/1 mL) and KOH (0.1 g, 1.76 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5, and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4 and evaporated under reduced pressure to give 2-(4-benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid as a yellow oil (0.038 g, 55%). 1H NMR (300 MHz, CDCl3/TMS): δ 8.02 (d, J=9.0 Hz, 1H), 7.96 (s, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.13 (s, 1H), 6.89 (s, 1H), 3.81 (d, J=6.4 Hz, 2H), 3.68 (t, J=7.6 Hz, 1H), 2.04-1.96 (m, 1H), 1.78-1.69 (m, 1H), 1.63-1.55 (m, 1H), 1.10-1.00 (m, 1H), 0.97 (d, J=6.4 Hz, 6H), 0.50-0.39 (m, 2H), 0.22-0.12 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.1, 157.2, 154.6, 154.0, 140.5, 136.7, 134.0, 132.9, 127.8, 122.9, 121.6, 120.1, 111.0, 73.4, 49.4, 42.0, 25.9, 22.6, 22.3, 10.0, 3.1.

Example 1904 2-(2-Chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid

Step 1 2-(2-Chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester

To a solution of 2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.09 g, 0.19 mmol) in DME (anhydrous, 10 mL) under argon atmosphere were added 4-trifluoromethylphenylboronic acid (0.04 g, 0.2 mmol), CsF (0.07 g, 0.46 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.06 g, 0.08 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). A mixture of water and EtOAc (15 mL/15 mL) was added and the layers were separated. The organic phase was dried over MgSO4, then evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc (20:1-9:1) to give 2-(2-chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.063 g, 70%) as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.66 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.08 (s, 1H), 6.88 (s, 1H), 4.01-3.86 (m, 2H), 3.77 (d, J=6.6 Hz, 2H), 3.65 (t, J=7.9 Hz, 1H), 2.04-1.95 (m, 1H), 1.71-1.62 (m, 1H), 1.59-1.48 (m, 1H), 1.20-1.02 (m, 2H), 0.96-0.94 (m, 6H), 0.56-0.46 (m, 4H), 0.27-0.25 (m, 2H), 0.16-0.15 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 173.5, 157.0, 141.2, 138.9, 133.6, 130.8 (two signals), 127.8, 124.5 (q), 124.3 (q, 1JCF=271.0 Hz), 121.6, 111.0, 73.3, 69.7, 49.6, 42.7, 26.1, 22.6, 22.4, 10.0, 9.8, 3.3, 3.1.

Step 2 2-(2-Chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid

2-(2-Chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.06 g, 0.12 mmol) was dissolved in a mixture of EtOH and H2O (9 mL/1 mL) and KOH (0.1 g, 1.76 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5 and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4 and evaporated under reduced pressure to give 2-(2-chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid as a yellowish solid (0.046 g, 85%). M.p.=115-116° C. 1H NMR (300 MHz, CDCl3/TMS): δ 7.67 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.08 (s, 1H), 6.85 (s, 1H), 3.77 (d, J=6.4 Hz, 2H), 3.65 (t, J=7.7 Hz, 1H), 2.04-1.94 (m, 1H), 1.75-1.66 (m, 1H), 1.60-1.52 (m, 1H), 1.15-0.89 (m, 1H), 0.95 (d, J=6.4 Hz, 6H), 0.54-0.40 (m, 2H), 0.20-0.10 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.0, 157.1, 140.3, 138.8, 133.8, 130.8, 129.3 (q), 128.2, 124.6, 124.3 (q, 1JCF=271.0 Hz), 121.6, 111.2, 73.4, 49.4, 42.0, 25.9, 22.6, 22.3, 10.0, 3.0.

Example 3200 2-(2,4′-Dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic acid

Step 1 2-(2,4′-Dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester

To a solution of 2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.32 g, 0.67 mmol) in DME (anhydrous, 20 mL) under argon atmosphere were added 4-chlorophenylboronic acid (0.13 g, 0.83 mmol), CsF (0.24 g, 1.58 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.05 g, 0.07 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). A mixture of water and EtOAc (15 mL/15 mL) was added and the layers were separated. The organic phase was dried over MgSO4 and evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc (20:1-9:1) to give 2-(2,4′-dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.26 g, 87%) as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.37 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.2 Hz, 2H), 7.07 (s, 1H), 6.86 (s, 1H), 3.96-3.89 (m, 2H), 3.76 (d, J=6.3 Hz, 2H), 3.63 (t, J=7.7 Hz, 1H), 2.04-1.95 (m, 1H), 1.71-1.48 (m, 2H), 1.21-1.00 (m, 2H), 0.94 (d, J=6.3 Hz, 6H), 0.55-0.48 (m, 4H), 0.27-0.15 (m, 4H). 13C NMR (75 MHz, CDCl3/TMS): δ 173.5, 157.1, 140.8, 133.7, 133.5, 133.0, 131.8, 128.1, 127.8, 121.5, 111.1, 73.2, 69.6, 49.6, 42.6, 26.1, 22.6, 22.5, 10.0, 9.8, 3.3, 3.0.

Step 2 2-(2,4′-Dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic acid

2-(2,4′-Dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.18 g, 0.36 mmol) was dissolved in a mixture of EtOH and H2O (9 mL/1 mL) and KOH (0.2 g, 3.6 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5 and the reaction mixture was extracted with EtOAc (3×10 mL). The organic phase was dried over MgSO4 and evaporated under reduced pressure to give 2-(2,4′-dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic acid as a yellowish solid (0.15 g, 93%). M.p.=52-53° C. 1H NMR (300 MHz, CDCl3/TMS): δ 10.60 (br s, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.07 (s, 1H), 6.83 (s, 1H), 3.75 (d, J=6.3 Hz, 2H), 3.63 (t, J=7.3 Hz, 1H), 1.99-1.93 (m, 1H), 1.74-1.65 (m, 1H), 1.59-1.51 (m, 1H), 1.11-1.00 (m, 1H), 0.94 (d, J=6.3 Hz, 6H), 0.54-0.40 (m, 2H), 0.22-0.12 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.7, 157.2, 139.7, 134.0, 133.4, 133.1, 131.8, 128.5, 127.9, 121.6, 111.3, 73.3, 49.4, 42.0, 25.9, 22.6, 22.3, 10.0, 3.0.

Example 3201 4-Methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoic acid

Step 1 4-Methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoic acid cyclopropylmethyl ester

To a solution of 2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.53 g, 1.11 mmol) in DME (anhydrous, 20 mL) under argon atmosphere were added 4-chlorophenylboronic acid (0.25 g, 1.30 mmol), CsF (0.41 g, 2.70 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.24 g, 0.33 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). A mixture water and EtOAc (15 mL/15 mL) was added and the layers were separated. The organic phase was dried over MgSO4 and evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc (20:1-9:1) to give 4-methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoic acid cyclopropylmethyl ester (0.37 g, 70%) as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.48-7.42 (m, 2H), 7.17-7.14 (m, 2H), 7.07 (s, 1H), 6.86 (s, 1H), 4.07-3.87 (m, 2H), 3.78 (d, J=6.3 Hz, 2H), 3.64 (t, J=7.7 Hz, 1H), 2.03-1.93 (m, 1H), 1.70-1.49 (m, 2H), 1.21-1.00 (m, 2H), 0.95-0.93 (m, 6H), 0.56-0.49 (m, 4H), 0.27-0.19 (m, 4H). 13C NMR (75 MHz, CDCl3/TMS): δ 173.4, 156.9, 141.3, 134.9, 133.6, 132.5, 131.6, 131.2, 129.9, 129.5, 126.6, 121.5, 110.8, 73.2, 69.6, 49.6, 42.6, 26.1, 22.6, 22.4, 10.0, 9.8, 3.3, 3.1.

Step 2 4-Methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoic acid

4-Methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoic acid cyclopropylmethyl ester (0.37 g, 0.75 mmol) was dissolved in a mixture of EtOH and H2O (9 mL/1 mL) and KOH (0.2 g, 3.6 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5, and the reaction mixture was extracted with EtOAc (3×10 mL). The organic phase was dried over MgSO4 and evaporated under reduced pressure to give 4-methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoic acid as a white solid (0.30 g, 90%). M.p.=118-119° C. 1H NMR (300 MHz, CDCl3/TMS): δ 9.70 (br s, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.42 (d, J=1.6 Hz, 1H), 7.53 (dd, J=8.2, 1.4 Hz, 1H), 7.07 (s, 1H), 6.83 (s, 1H), 3.78 (d, J=6.3 Hz, 2H), 3.63 (t, J=7.3 Hz, 1H), 2.02-1.93 (m, 1H), 1.74-1.65 (m, 1H), 1.59-1.51 (m, 1H), 1.11-1.00 (m, 1H), 0.94 (d, J=6.3 Hz, 6H), 0.54-0.47 (m, 2H), 0.24-0.16 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.4, 157.0, 140.3, 134.8, 133.9, 132.5, 131.6, 131.3, 129.9, 129.6, 127.0, 121.5, 111.1, 73.3, 49.4, 42.0, 25.9, 22.6, 22.3, 10.0, 3.1.

Example 1976 2-[2,6-Bis-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-4-yl]-4-methyl-pentanoic acid

Step 1 5-Fluoro-2-nitro-1,3-bis-(2,2,2-trifluoro-ethoxy)-benzene

To a solution of 2,2,2-trifluoroethanol (28.2 g, 282.0 mmol) in toluene (120 mL) n-BuLi (1.6 M in hexane, 8.0 g, 80 mL, 125.0 mmol) was added at 0° C. and the reaction mixture warmed up to 25° C. A solution of 1,3,5-trifluoronitrobenzene (10.0 g, 56.5 mmol) in toluene (50 mL) was added dropwise. The reaction mixture was refluxed for 30 h and then poured into water (100 mL). The reaction mixture was extracted with EtOAc (3×100 mL). The organic layers were combined and dried over MgSO4. The solvent was evaporated under reduced pressure to give 5-fluoro-2-nitro-1,3-bis-(2,2,2-trifluoro-ethoxy)-benzene as a brown oil (18.0 g, 95%). The product was used for the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 6.47 (d, J=9.4 Hz, 2H), 4.40 (q, J=8.0 Hz, 4H).

Step 2 2-[4-Nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-malonic acid diethyl ester

To a solution of diethyl malonate (18.0 g, 114.9 mmol) in DMF (50 mL) was added sodium hydride (60% in mineral oil, 3.0 g, 125.0 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 0.5 h and a solution of 5-fluoro-2-nitro-1,3-bis-(2,2,2-trifluoro-ethoxy)-benzene (18.0 g, 53.4 mmol) in DMF (30 mL) was added dropwise. The reaction mixture was heated 100° C. for 24 h. After cooling the reaction mixture was poured into water (300 mL) and extracted with EtOAc (3×50 mL). The combined organic phases were washed with water (3×100 mL), brine (100 mL) and dried (MgSO4). Evaporation of the solvent under reduced pressure gave 2-[4-nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-malonic acid diethyl ester as a brown oil (20.8 g, 80%). The crude product was used for the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 6.91 (s, 2H), 4.62 (s, 1H), 4.48 (q, J=8.0 Hz, 4H), 4.28-4.16 (m, 4H), 1.31-1.25 (m, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ 166.4, 149.2, 136.7, 132.3, 122.3 (q, 1JCF=276.6 Hz), 109.5 (two signals), 67.0 (q, 2JCF=36.7 Hz), 61.4, 41.6, 14.0.

Step 3 [4-Nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]acetic acid ethyl ester

Crude 2-[4-nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-malonic acid diethyl ester (20.8 g, 43.6 mmol) was dissolved in a mixture of AcOH/12 N HCl (150 mL/150 mL) and the reaction mixture was refluxed for 16 h. The solvent was evaporated and water (100 mL) was added. The reaction mixture was extracted with EtOAc (3×100 mL). The organic layers were combined, washed with water (3×100 mL), and dried over MgSO4. The solvent was evaporated under reduced pressure to give a brown solid, which was washed with a mixture of Heptane/Et2O (100 mL/100 mL) to give [4-nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl ester as a solid (10.0 g, 57%). 1H NMR (300 MHz, CDCl3/TMS): δ 6.71 (s, 2H), 4.45 (q, J=7.7 Hz, 4H), 4.18 (q, J=7.2 Hz, 2H), 3.63 (s, 2H), 1.28 (t, J=7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ 169.7, 149.6, 138.5, 132.4, 122.4 (q, 1JCF=277.6 Hz), 109.4 (two signals), 67.0 (q, 2JCF=37.2 Hz), 61.6, 41.4, 14.2.

Step 4 [4-Amino-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]acetic acid ethyl ester

[4-Nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl ester (10.0 g, 24.7 mmol) was dissolved in EtOH (200 mL) and hydrogenated at 50 psi, 25° C. for 16 h in the presence of Pd—C catalyst (10%, 1 g). The catalyst was filtered off and the solvent evaporated to give a crude brown oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc to give [4-amino-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl ester as a yellow oil (8.3 g, 90%). 1H NMR (300 MHz, CDCl3/TMS): δ 6.52 (s, 2H), 4.37 (q, J=8.0 Hz, 4H), 4.14 (q, J=7.2 Hz, 2H), 3.90 (br s, 2H), 3.48 (s, 2H), 1.25 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3/TMS): δ 171.4, 145.0, 126.3, 123.2, (q, 1JCF=277.6 Hz), 122.6, 110.0, 109.8 (two signals), 66.8 (q, 2JCF=35.5 Hz), 61.0, 41.0, 14.2.

Step 5 [4-Iodo-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]acetic acid ethyl ester

[4-Amino-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl ester (7.1 g, 18.9 mmol) was dissolved in MeCN (50 mL) and p-TsOH×H2O (11.0 g, 57.9 mmol) was added. The reaction mixture was cooled down to −15° C. and NaNO2 (1.6 g, 23.2 mmol) in water (1 mL) was added. The reaction mixture was stirred at −15° C. for 0.5 h; then a solution of KI (15.0 g, 93.8 mmol) in water (10 mL) was added. The reaction mixture was stirred at −15° C. for additional 0.5 h and quenched with 1 N NaHCO3 solution to pH 9-10. After addition of 10% NaHSO3 solution (20 mL), the reaction mixture was extracted with EtOAc (3×50 mL). The combined organic phases were washed with saturated NaCl solution, dried (MgSO4) and evaporated to give crude a brown oil (9.0 g), which was purified by gradient column chromatography on silica gel eluting with Heptane-EtOAc (9:1-3:1) to give [4-iodo-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl ester as a white solid (3.8 g, 41%). 1H NMR (300 MHz, CDCl3/TMS): δ 6.53 (s, 2H), 4.40 (q, J=8.0 Hz, 4H), 4.16 (q, J=7.1 Hz, 2H), 3.56 (s, 2H), 1.26 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3/TMS): δ 170.3, 157.7, 136.7, 122.8 (q, 1JCF=277.6 Hz), 108.9 (two signals), 78.3, 67.0 (q, 2JCF=36.0 Hz), 61.3, 41.2, 14.2.

Step 6 [2,6-Bis-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-4-yl]-acetic acid ethyl ester

To a solution of [4-iodo-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl ester (0.8 g, 1.65 mmol) in DME (anhydrous, 15 mL) under argon atmosphere were added 4-trifluoromethylphenylboronic acid (0.4 g, 2.10 mmol), CsF (0.6 g, 3.95 mmol), and Pd(PPh3)4 (0.3 g, 0.26 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). A mixture of water and EtOAc (15 mL/15 mL) was added and the layers were separated. The organic phase was dried over MgSO4 and evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc (20:1-9:1) to give [2,6-bis-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-4-yl]-acetic acid ethyl ester (0.54 g, 70%) as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.64 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 6.68 (s, 2H), 4.28-4.16 (6H), 3.63 (s, 2H), 1.29 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3/TMS): δ 170.6, 155.3, 136.1, 135.5, 131.0, 129.4, 129.0, 124.4 (q, 3JCF=3.9 Hz), 124.2, 122.9, 119.0, 109.2 (two signals), 66.5 (q, 2JCF=35.5 Hz), 61.3, 41.5, 14.2.

Step 7 2-[2,6-Bis-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-4-yl]-4-methyl-pentanoic acid

[2,6-Bis-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-4-yl]-acetic acid ethyl ester (0.52 g, 1.03 mmol) was dissolved in anhydrous DMF (5 mL) and sodium hydride (60% in oil, 0.05 g, 2.08 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 20 min and isobutyl bromide (0.15 g, 1.09 mmol) was added. The reaction mixture was stirred for 1 h at the same temperature and at 25° C. for 15 min., followed by addition of saturated ammonium chloride solution (10 mL). The reaction mixture was extracted with ethyl acetate (2×20 mL) and the combined organic phases were washed with water (3×20 mL), saturated sodium chloride solution (10 mL) and dried over magnesium sulfate. Evaporation gave the crude yellow oil (0.56 g), which was purified by silica gel column chromatography with Heptane/EtOAc to give a white solid (0.24 g). The resulting solid was dissolved in EtOH (10 mL), and H2O (1 mL) and potassium hydroxide (0.2 g) were added. The reaction mixture was refluxed for 2 h and solvent evaporated. Then, 6 N HCl was added to adjust the pH to 3-5 and the mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4 and evaporated to give 2-[2,6-Bis-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-4-yl]-4-methyl-pentanoic acid as a white solid (0.2 g, 40%). 1H NMR (300 MHz, CDCl3/TMS): δ 7.65 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 6.72 (s, 2H), 4.24 (q, J=8.0 Hz, 4H), 3.69 (t, J=7.7 Hz, 1H), 2.03-1.96 (m, 1H), 1.76-1.67 (m, 1H), 1.60-1.52 (m, 1H), 0.96 (d, J=6.3 Hz, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.3, 155.4, 140.6, 135.3, 130.9, 129.6, 129.1, 124.5 (q, 3JCF=4 Hz), 124.2 (q, 1JCF=272 Hz), 122.9 (q, 1JCF=278 Hz), 119.8, 107.9, 66.5 (q, 2JCF=36 Hz), 49.7, 42.2, 25.9, 22.6, 22.3.

Example 2420 2-[6-Chloro-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid

Step 1 4-Fluoro-1-nitro-2-(2,2,2-trifluoro-ethoxy)-benzene

To a solution of 2,4-difluoronitrobenzene (300.0 g, 1.89 mol) and 2,2,2-trifluoroethanol (245.0 g, 2.45 mol) in toluene (600 mL) was added sodium hydroxide (90.5 g, 2.26 mol) in portions over 30 min to keep the temperature between 30 and 40° C. After the temperature had dropped to 30° C., the reaction mixture was heated to 45-50° C. using an oil bath for additional 16 h. After cooling, water (500 mL) and 2.5 N H2SO4 (200-300 mL, for adjustment of pH to 5) were added and the organic layer was separated. The water layer was extracted with EtOAc (2×300 mL). The combined organic layers were washed with saturated sodium chloride solution (100 mL) and dried over magnesium sulfate. The solvent was evaporated to give a yellow oil, which solidified after 30 min to give a yellowish solid (450.0 g, quantitative). The crude product was used in the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 8.03-7.98 (m, 1H), 6.93-6.82 (m, 2H), 4.49 (q, J=7.7 Hz, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 165.0 (d, 1JCF=259.6 Hz), 152.3 (d, 3JCF=13.1 Hz), 128.2 (d, 3JCF=11.9 Hz), 122.4 (d, 1JCF=273.4 Hz), 110.1 (d, 2JCF=22.5 Hz), 105.9 (q, 1JCF=242.6 Hz), 104.3 (d, 2JCF=26.1 Hz), 67.6 (q, 1JCF=36.7 Hz).

Step 2 [4-Nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]acetic acid

Potassium hydroxide (≧85%, 176 g, ≧2.67 mmol) was added to a solution of 4-fluoro-1-nitro-2-(2,2,2-trifluoro-ethoxy)-benzene (412 g, ˜90% purity, 1.56 mmol) and diethyl malonate (503.0 g, 3.14 mmol) in DMSO (700 mL) in portions to keep the temperature at ˜40° C. The reaction mixture became deep red in color. The reaction mixture was stirred at 40° C. overnight. Monitoring was performed by TLC (EtOAc:Hept., 1:3).

Acetic acid (1 L) was added to the warm reaction mixture followed by a mixture of concentrated sulfuric acid (325 mL) in water (1 L) in one portion. A precipitate, which was formed initially, dissolved at the end of the addition. Effective stirring was required for this reaction. The reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and EtOAc (1000 mL) and water (1000 mL) were added. The organic layer (bottom layer!) was separated. The aqueous solution was extracted with EtOAc (500 mL), the organic phases were combined, washed with water (3×2000 mL), brine (500 mL), and dried over MgSO4 with charcoal. The solvent was evaporated and the solid residue was washed by stirring with heptane/EtOAc (20:1, 500 mL). The solid was filtered and dried in vacuum. The yield of 2-(4-nitro-3-(2,2,2-trifluoro-ethoxy)phenyl)acetic acid was 256 g (65%). 1H NMR (300 MHz, CDCl3/TMS): δ 7.80 (d, J=8.3 Hz, 1H), 7.25 (s, 1H), 7.10 (d, J=8.3 Hz, 1H), 5.07 (s, 1H), 4.67 (q, J=8.2 Hz, 2H), 3.70 (s, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 175.0, 151.5, 144.0, 140.3, 126.4, 125.0, 122.2 (d, 1JCF=273.0 Hz), 118.0, 67.6 (q, 1JCF=36.0 Hz), 42.5.

Step 3 [4-Nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]acetic acid methyl ester

Concentrated sulfuric acid (50 mL) was added slowly to a solution of 2-(4-nitro-3-(2,2,2-trifluoro-ethoxy)phenyl)acetic acid (180 g, 0.64 mol) in MeOH (500 mL). The reaction mixture was stirred at room temperature overnight. The methanol was evaporated and EtOAc (500 mL) was added. The solution was washed with water (2×200 mL) and brine and dried over MgSO4. The solvent was evaporated, the solid residue was stirred with heptane (200 mL), and the solid was filtered. Yield 182.2 g (96%). 1H NMR (300 MHz, CDCl3/TMS): δ 7.82 (d, J=8.7 Hz, 1H), 7.07-7.05 (m, 2H), 4.47 (q, J=8.0 Hz, 2H), 3.68 (s, 3H), 3.67 (s, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 170.1, 150.4, 141.2, 139.4, 125.9, 123.9, 122.6 (d, 1JCF=277.6 Hz), 117.5, 67.6 (q, 1JCF=36.7 Hz), 52.4, 41.0.

Step 4 3-Cyclobutyl-2-[4-nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-propionic acid methyl ester

[4-Nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid methyl ester (33 g, 94.5 mmol) and (bromomethyl)cyclobutane (17 g, 114.1 mmol) were mixed in DMSO (50 mL) and KOH (6.4 g, 114.1 mmol) was added in portions over 15 min. The reaction mixture was stirred for 16 h and water (100 mL) was added. The reaction mixture was extracted with EtOAc (3×50 mL). The combined organic phases were dried over MgSO4 and evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography using Heptane-EtOAc (9:1-4:1) to give 15 g (40%) of the product as a yellow oil. (The synthesis was repeated with temperature kept at 40° C. over 16 h to give the product in quantitative yield). 1H NMR (300 MHz, CDCl3/TMS): δ 7.86 (d, J=8.0 Hz, 1H), 7.12-7.09 (m, 2H), 4.50 (q, J=7.7 Hz, 2H), 3.68 (s, 3H), 3.55 (t, J=7.3 Hz, 1H), 2.22-2.10 (m, 2H), 2.03-1.75 (m, 5H), 1.70-1.55 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 172.9, 150.5, 146.4, 139.4, 126.0, 122.7, 122.6 (d, 1JCF=277.6 Hz), 116.0, 67.5 (q, 1JCF=36.7 Hz), 52.3, 49.6, 40.7, 33.9, 28.2, 27.9, 18.4.

Step 5 2-[4-Amino-3-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propionic acid methyl ester

A solution of the 3-cyclobutyl-2-[4-nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-propionic acid methyl ester (15 g, 36.0 mmol) in EtOH (150 mL) was hydrogenated at 50 psi and 25° C. for 16 h in the presence of Pd—C catalyst (10%, 1.5 g). On the next day, the catalyst was filtered off and the solvent evaporated to give the crude product (12.3 g, 88%) as a yellow oil, which was used without purification for the next step. 1H NMR (300 MHz, CDCl3/TMS): δ 6.79-6.73 (m, 2H), 6.66 (d, J=8.0 Hz, 1H), 4.36 (q, J=8.3 Hz, 2H), 3.80 (br s, 2H), 3.63 (s, 3H), 3.35 (t, J=7.7 Hz, 1H), 2.20-1.86 (m, 4H), 1.85-1.70 (m, 3H), 1.67-1.51 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 174.7, 146.7, 135.7, 129.1, 123.3 (d, 1JCF=277.6 Hz), 122.7, 115.4, 112.2, 66.4 (q, 1JCF=35.4 Hz), 51.9, 48.9, 40.8, 34.0, 28.3, 28.1, 18.5.

Step 6 2-[4-Amino-3-bromo-5-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propionic acid methyl ester

To a solution of the 2-[4-amino-3-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propionic acid methyl ester (12.3 g, 31.8 mmol) in chloroform (150 mL) was added N-bromosuccinimide (7 g, 39.3 mmol). The reaction mixture was stirred at 25° C. for 16 h and a mixture of water and methylene chloride (100 mL/100 mL) was added. The reaction mixture was extracted with methylene chloride (2×50 mL) and the organic phases were separated. The combined organic phases were dried over MgSO4 and evaporated to give a crude yellow oil, which was purified by a short silica gel column chromatography eluting with heptane-EtOAc (4:1) to give the product (13.9 g, 94%) as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.06 (d, J=1.1 Hz, 1H), 6.70 (d, J=1.2 Hz, 1H), 4.37 (q, J=8.0 Hz, 2H), 4.21 (br s, 2H), 3.64 (s, 3H), 3.31 (t, J=7.7 Hz, 1H), 2.20-1.89 (m, 4H), 1.81-1.75 (m, 3H), 1.67-1.51 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 174.2, 144.6, 134.4, 128.9, 125.7, 123.0 (d, 1JCF=277.6 Hz), 110.9, 108.7, 66.5 (q, 1JCF=36.0 Hz), 52.0, 48.6, 40.7, 33.9, 28.3, 28.0, 18.5.

Step 7 2-[6-Amino-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid methyl ester

To a solution of 2-[4-amino-3-bromo-5-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propionic acid methyl ester (13.8 g, 29.6 mmol) in DME (anhydrous, 100 mL) under argon atmosphere were added 4-trifluoromethylphenylboronic acid (6.8 g, 35.8 mmol), CsF (11 g, 72.3 mmol), and Pd(PPh3)4 (3.4 g, 2.94 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). On the next day, a mixture water and EtOAc (100 mL/100 mL) was added and the layers were separated. The organic phase was dried over MgSO4 and evaporated to give a crude yellow oil, which was purified by a short silica gel column chromatography by use of Heptane-EtOAc (4:1) to give the product (14.7 g, 94%) as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.70 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H), 6.78 (dd, J=9.6, 1.4 Hz, 2H), 4.43 (q, J=8.0 Hz, 2H), 3.95 (br s, 2H), 3.66 (s, 3H), 3.39 (t, J=7.7 Hz, 1H), 2.25-2.07 (m, 2H), 2.03-1.91 (m, 2H), 1.88-1.75 (m, 3H), 1.69-1.52 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 174.6, 144.8, 133.1, 129.2, 128.6, 126.3, 125.7 (q, 3JCF=3.6 Hz), 123.8, 123.3 (q, 1JCF=277.6 Hz), 111.4, 66.5 (q, 1JCF=35.4 Hz), 52.0, 49.0, 40.9, 34.1, 28.3, 28.1, 18.5.

Step 8 2-[6-Chloro-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid methyl ester

To a solution of 2-[6-amino-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid methyl ester (14.7 g, 27.7 mmol) in a mixture of MeCN and H2O (120 mL/120 mL), concentrated HCl (25 mL) was added. The reaction mixture was cooled down to 0-5° C. and a solution of NaNO2 (2.9 g, 42.0 mmol) in water (3 mL) was added dropwise. The reaction mixture was stirred at 0-5° C. for 40 min and CuCl (I) (27 g, 272.7 mmol) was added at once. The reaction mixture was heated at 50° C. for additional 3 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL) and the combined organic phases were washed with water (200 mL) and brine (100 mL). The organic phase was dried over MgSO4 and evaporated to give the product (14.5 g, 95%) as a yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.70 (d, J=8.2 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 6.98 (dd, J=6.1, 1.6 Hz, 2H), 4.47 (q, J=8.0 Hz, 2H), 3.68 (s, 3H), 3.48 (t, J=7.7 Hz, 1H), 2.20-2.10 (m, 2H), 2.03-1.75 (m, 5H), 1.70-1.52 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 173.6, 153.5, 142.2, 141.0, 138.9, 129.7, 125.0 (q, 3JCF=3.6 Hz), 124.8, 124.0 (q, 1JCF=271.6 Hz), 126.6 (q, 1JCF=278.8 Hz), 121.4, 114.0, 67.3 (q, 1JCF=35.4 Hz), 52.2, 49.3, 40.8, 34.0, 28.3, 28.0, 18.5.

Step 9 2-[6-Chloro-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid

To a solution of the 2-[6-chloro-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid methyl ester (8.0 g, 14.5 mmol) in a mixture of the EtOH (100 mL) and H2O (15 mL) was added potassium hydroxide (10 g, 178.5 mmol). The reaction mixture was refluxed for 3 h and the solvent evaporated. Then, 6 N HCl was added to adjust the pH to 3-5 and the mixture was extracted with EtOAc (3×50 mL). The combined organic phases were dried over MgSO4 and evaporated to give 2-[6-chloro-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid as a white solid (7.0 g, 90%). 1H NMR (300 MHz, CDCl3/TMS): δ 7.70 (d, J=8.2 Hz, 2H), 7.53 (d, J=8.2 Hz, 2H), 6.98 (s, 2H), 4.47 (q, J=8.0 Hz, 2H), 3.49 (t, J=7.7 Hz, 1H), 2.27-2.13 (m, 2H), 2.06-1.73 (m, 5H), 1.71-1.52 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.1, 153.6, 142.1, 141.2, 138.0, 129.7, 125.0 (q, 3JCF=3.6 Hz), 124.9, 124.0 (q, 1JCF=262.5 Hz), 123.0 (q, 1JCF=277.6 Hz), 121.8, 114.3, 67.3 (q, 1JCF=36.0 Hz), 49.3, 40.3, 33.9, 28.3, 28.0, 18.5.

Example 415 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid

Step 1 Ethyl 2-(3-chloro-4-hydroxyphenyl)acetate

To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (20 g, 0.076 mol) in 200 ml of DCM was added MeOH (3.4 ml, 0.84 mol). The mixture was brought to reflux and sulfuryl chloride (6.8 ml 0.846 mol) dissolved in DCM (50 mL) was slowly added under over 10 min. The reaction mixture was refluxed further for 5 h, upon which the reaction mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layers were washed with 10% NaHCO3 solution and water. The organic layer was dried over Na2SO4, filtered and evaporated under vacuum to give compound ethyl 2-(3-chloro-4-hydroxyphenyl)acetate in 60% yield. (13.6 g).

Step 2 Ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate

To a stirred solution of compound ethyl 2-(3-chloro-4-hydroxyphenyl)acetate (11 g, 51 mmol) in 200 ml of CCl4, was slowly added bromine (8.22 g, 51 mmol) as a solution CCl4 (100 ml) at 0° C. over a period of 30 min. The reaction mixture was stirred for a further 30 min at 0° C. Upon which the reaction mixture was poured onto crushed ice and extracted with DCM (2×100 mL). The combined organic layers were washed with water followed by 10% sodium bisulfite solution, dried over Na2SO4 filtered and evaporated under reduced pressure to give ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (12.2 g) as a white solid in 80% yield. 1HNMR (CDCl3): 7.37 (s, 1H); 7.27 (s, 1H); 5.68 (bs, 1H); 4.16 (q, 2H); 3.48 (s, 2H); 1.29 (t, 3H).

Step 3 Ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-acetate

To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (2 g, 6.8 mmol), potassium carbonate (2.35 g, 17.0 mmol) in dry DMF (20 mL), was slowly added trifluoro ethyl iodide (8.58 g, 4.0 mL, 40.8 mmol) at room temperature, the reaction mixture was slowly heated to 100° C. and heating was continued for 4 h. Upon which the reaction mixture was poured onto water and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4 and evaporated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc) to gave compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-acetate (0.750 g, 30% yield). 1HNMR (CDCl3, 400 MHz): 7.43 (s, 1H); 7.34 (s, 1H); 4.4 (q, 2H), 4.13 (q, 2H); 3.55 (t, 1H); 1.93 (m, 1H), 1.58 (m, 1H); 1.45 (m, 1H); 1.24 (t, 3H), 0.92 (d, 6H);

Step 4 Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate

A mixture of 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-acetate (0.750 g, 2.0 mmol), 4-trifluoromethyl phenylboronic acid (0.567 g, 3.0 mmol), Pd (PPh3)4 (0.231 g, 0.2 mmol), cesium fluoride (0.604 g, 4.0 mmol) in DME (10 ml) was stirred overnight at 100° C., upon which the precipitates were removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water followed by brine and dried over Na2SO4. The crude residue was purified by flash column chromatography to give ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.525 g, 73.6%) as an off white solid.

Step 5 Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (1.0 g, 2.27 mmol) was dissolved in anhydrous DMF (80 mL), NaH (60% wt. in paraffin oil, 0.109 g, 2.72 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature, upon which cyclopropyl methyl bromide (0.24 mL, 2.5 mmol) was added in a dropwise manner at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. upon which saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×50 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to give colorless oil, which was purified by flash column chromatography to yield compound ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (0.68 g).

Step 6 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid

A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (0.68 g, 0.4 mmol) and lithium hydroxide monohydrate (100 mg, 4.6 mmol) in a MeOH/THF/Water solvent mixture (15 ml/15 ml/15/ml) was stirred for 3 h at room temperature. After completion of reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid in 88% yield (0.4 g). 1H-NMR (CDCl3, 500 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.43 (s, 1H); 7.24 (s, 1H); 3.98 (q, 2H); 3.72 (t, 1H); 1.94 (m, 1H), 1.78 (m, 1H); 0.71 (m, 1H), 0.46 (m, 2H), 0.02-0.19 (m, 2H).

Example 1269 1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclobutane carboxylic acid Step 1 Ethyl-1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(Trifluoromethyl)biphenyl-3-yl)-cyclo butane carboxylate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (1.5 g, 3.4 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.163 g, 6.8 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 1,3-dibromopropane (0.757 g, 3.7 mmol) was added drop wise at 0° C. The reaction mixture was stirred for an additional 1 h at 0° C. and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield compound ethyl-1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclo butane carboxylate (400 mg).

Step 2 1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclobutane carboxylic acid

A mixture of ethyl-1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclo butane carboxylate (400 mg, 0.83 mmol) and lithium hydroxide monohydrate (0.2 g, 8.3 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. Upon completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography to give 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclobutane carboxylic acid in 88% yield (0.21 g). 1H-NMR (CDCl3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.39 (s, 1H); 7.26 (s, 1H); 3.98 (q, 2H); 2.86 (m, 2H); 2.52 (m, 2H); 2.16 (m, 1H), 1.91 (m, 1H).

Example 419 1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclopentane carboxylic acid Step 1 Ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclo pentane carboxylate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.8 g, 1.81 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.109 g, 4.5 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 1,4-dibromobutane (0.432 g, 1.99 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. upon which saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield compound ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclo pentane carboxylate (400 mg) as a thick liquid.

Step 2 1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclopentane carboxylic acid

A mixture of compound ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclo pentane carboxylate (100 mg, 0.21 mmol) and lithium hydroxide monohydrate (96 mg, 2.1 mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml 5/ml) was stirred for 3 h at room temperature. After completion of reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclopentane carboxylic acid (0.05 g). 1H-NMR (CDCl3, 500 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.56 (s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 2.68 (m, 2H); 1.94 (m, 2H); 1.78 (m, 4H).

Example 3202 445-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylic acid Step 1 Ethyl 4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.4 g, 3.4 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.163 g, 6.8 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 1-iodo-2-(2-iodoethoxy)ethane (1.2 g, 3.7 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield ethyl 4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylate (400 mg).

Step 2 4-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylic acid

A mixture of ethyl 4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylate (400 mg, 0.78 mmol) and lithium hydroxide monohydrate (0.188 g, 7.8 mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml 5/ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. Residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). Combined organic layer was washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylic acid (100 mg). 1H-NMR (CDCl3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.56 (s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 3.61 (t, 2H); 2.53 (dd, 2H); 1.99 (m, 2H).

Example 3203 1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylic acid Step 1 Ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.5 g, 1.13 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.113 g, 2.8 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 3,3-dimethyl-1,5-dibromopentane (0.322 g, 1.25 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield compound ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylate (230 mg).

Step 2 1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylic acid

A mixture of compound ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylate (200 mg, 0.37 mmol) and lithium hydroxide monohydrate (88 mg, 3.7 mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml 5/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylic acid in 67% yield (150 mg). 1H-NMR (CDCl3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.56 (s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 2.48 (dd, 2H); 1.88 (m, 2H); 1.41 (m, 4H), 0.98 (s, 3H), 0.91 (s, 3H).

Example 1270 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexane carboxylic acid Step 1 Ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexanecarboxylate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.5 g, 1.13 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.113 g, 2.8 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 1,5-dibromopentane (0.19 g, 1.24 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield compound ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexanecarboxylate (0.37 g) as a thick liquid.

Step 2 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexane carboxylic acid

A mixture of ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexanecarboxylate (0.37 g, 0.72 mmol) and lithium hydroxide monohydrate (0.174 g, 7.28 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexane carboxylic acid (0.25 g) as a white solid. 1H-NMR (CDCl3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.55 (s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 2.48 (dd, 2H); 1.52-1.81 (m, 6H); 1.33 (m, 2H).

Example 1271 5-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylic acid Step 1 Ethyl 5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-Spiro[2,3]hexane-5-carboxylate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.6 g, 1.36 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.136 g, 3.4 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 1,1-bis(bromomethyl)cyclopropane (0.482 g, 1.4 mmol, for preparation see J. Org. Chem 1993, 58, 4122-26) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield compound ethyl 5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylate (150 mg) as a low melting solid.

Step 2 5-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylic acid

A mixture of ethyl 5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylate (0.5 g, 0.9 mmol) and lithium hydroxide monohydrate (0.415 g, 9.88 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. Residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylic acid (0.29 g). 1H-NMR (CDCl3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.41 (s, 1H); 7.21 (s, 1H); 3.98 (q, 2H); 2.95 (d, 2H); 2.75 (d, 2H), 0.58 (t, 2H), 0.48 (t, 2H).

Example 1268 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid Step 1 Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.6 g, 0.49 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.039 g, 1.69 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and cyclobutylmethyl bromide (0.223 g, 1.49 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4 The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate (0.25 g) as a colorless liquid.

Step 2 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid

A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate (0.25 g, 0.49 mmol) and lithium hydroxide monohydrate (0.206 g, 4.9 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. Residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid (0.106 g) as a white solid. 1H-NMR (CDCl3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.41 (s, 1H); 7.18 (s, 1H); 3.98 (q, 2H); 3.51 (t, 1H); 2.15-2.28 (m, 2H); 1.55-2.15 (m, 7H).

Example 1272 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetic acid Step 1 Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.8 g, 1.8 mmol) was dissolved in anhydrous DMF (40 mL), NaH (60% wt. in paraffin oil, 0.052 g, 2.18 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and cyclopentyl bromide (0.298 g, 1.99 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×50 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield compound ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetate (0.4 mg) as a thick liquid.

Step 2 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetic acid

A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetate (400 mg, 0.78 mmol) and lithium hydroxide monohydrate (0.330 g, 7.87 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetic acid (0.08 g). 1H-NMR (CDCl3, 400 MHz): 12.5 (s, 1H), 7.84 (d, 2H); 7.70 (d, 2H), 7.55 (s, 1H); 7.35 (s, 1H); 4.22 (q, 2H); 3.3.35 (d, 1H); 1.82 (m, 1H); 1.18-1.68 (m, 7H); 1.08 (m, 1H).

Example 3204 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoic acid Step 1 Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoate

Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.6 g, 1.36 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.039 g, 1.36 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and cyclopentyl bromide (0.283 g, 1.49 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield compound ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoate (0.29 g) as a colorless liquid.

Step 2 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoic acid

A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoate (400 mg, 0.719 mmol) and lithium hydroxide monohydrate (0.306 g, 7.29 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoic acid (0.1 g). 1H-NMR (CDCl3, 400 MHz): 7.55-7.78 (m, 4H); 7.42 (s, 1H), 7.18 (s, 1H); 6.92-7.16 (m, 4H); 3.98 (q, 2H); 3.84 (t, 1H); 3.41 (dd, 1H), 3.02 (dd, 1H).

Example 1905 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoic acid

Step 1 2-(Cyclopropylmethoxy)-4-fluoro-1-nitrobenzene

Cyclopropyl methanol (15 g, 207 mmol) was added to a stirred suspension of NaH (60% in mineral oil, 8.37 g) in 200 mL THF over a period of 15 min at 0° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 1 h at RT. The mixture was cooled to 0° C. and a solution of 2,4-difluoro-1-nitrobenzene (30 g, 187 mmol) in 200 mL THF was added in a drop wise manner. The reaction mixture was stirred at 0° C. for 2 h and then poured onto ice water. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give 22.0 g of 2-(cyclopropylmethoxy)-4-fluoro-1-nitrobenzene as an orange oil (86%).

Step 2 Diethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)malonate

Diethyl malonate (9.8 g, 1.1 eq) was added to a stirred suspension of sodium hydride

(60% in mineral oil, 2.09 g) in DMF (88 mL) over 15 min. at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. A solution of 2-cyclopropylmethoxy-4-fluoro-1-nitrobenzene (10 g, 1 eq) in DMF (88 mL) was added drop wise at 0° C., and the reaction mixture was heated to 100° C. for 3 h. The reaction mixture was allowed to cool to room temperature, poured into ice water and extracted with EtOAc (3×100 mL). The combined organic phases were washed with water (3×100 mL) and brine (100 mL), dried (MgSO4) and filtered. Evaporation of the volatiles under reduced pressure gave 10.0 g of crude product which was purified by chromatography over silica gel (hexane/EtOAc) gave of diethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)malonate (7.0 g). 1H-NMR (CDCl3, 200 MHz): 0.4 (m, 2H), 0.71 (m, 2H), 1.3 (m, 1H), 1.3 (t, 6H), 3.96 (d, 2H), 4.25 (q, 4H), 4.5 (s, 1H), 7.02 (d, 1H), 7.18 (s, 1H), 7.81 (d, 2H).

Step 3 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetic acid

Compound diethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)malonate (10 g) was dissolved in 100 mL ethanol and cooled to 0° C., NaOH solution (4 eq) was added slowly to the reaction mixture for about 15 min. The reaction mixture was heated gently up to 60° C. for 5 h. Progress of the reaction was monitored by TLC analysis. After complete conversion of starting material solvent was evaporated under reduced pressure, residue dissolved in H2O, acidified with 6N HCl to pH-2. Filtered the solid material washed with water, dried under reduced pressure to give 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetic acid (6.5 g) as a yellow solid. 1H-NMR (CDCl3, 200 MHz): 0.36 (m, 2H), 0.58 (m, 2H), 1.28 (m, 1H), 3.71 (s, 2H), 4.01 (d, 2H), 7.02 (d, 1H), 7.23 (s, 1H), 7.81 (d, 1H).

Step 4 Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate

2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetic acid (40 g, 143 mmol) was dissolved in 20% EtOH-HCl solution (200 ml) and refluxed for 3 h to convert the starting material to ester. The volatiles were removed under reduced pressure and the residue was extracted with ethyl acetate (×2). The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by re crystallization to ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (38 g) as pale yellow solid.

Step 5 Ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate

To a stirred solution of compound ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (10 g), in dry MeOH (100 mL), Pd(OH)2 (2 g) was added and the mixture was reduced under an H2 atmosphere for 6 h at room temperature. The mixture was filtered a pad of Celite™ washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate (7.5 g) as a thick liquid. 1H-NMR (CDCl3, 200 MHz): 0.38 (m, 2H), 0.61 (m, 2H), 1.23 (m, 1H), 1.23 (t, 3H), 3.51 (s, 2H), 3.80 (d, 2H), 4.16 (q, 2H), 6.72 (m, 3H).

Step 6 Ethyl 2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)acetate

To a stirred solution of ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate (1.2 g, 4.0 mmol) in dry CCl4 (60 mL), NCS (0.427 g, 3.2 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was diluted with water and extracted with DCM (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and the volatiles removed in vacuo. The crude reaction mixture was purified by column chromatography to give ethyl 2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)acetate (920 mg) as a yellow solid.

Step 7 Ethyl 2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate

Ethyl-2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)-acetate (2.5 g, 10.0 mmol) was dissolved in a mixture of EtOH/H2O/H2SO4 (96%) 200 mL/400 mL/10 mL at 0° C. A solution of NaNO2 (3.2 g, 1.16 eq) in water (40 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min at the same temperature. A solution of KI (30 g, 30.1 mmol) in water (80 mL) was added drop wise at 0° C. The reaction mixture was heated to 50° C. for 2.5 h upon which the volatiles were removed under reduced pressure. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with 10% sodium thiosulfate (2×50 mL), water (300 mL) and brine (300 mL). The organic solution was dried over Na2SO4 and concentrated under reduced pressure to give a crude black oil which was purified by chromatography over silica gel (hexane/EtOAc) to give the product ethyl 2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate as a yellow oil (8.7 g).

Step 8 Ethyl 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate

A mixture of compound ethyl 2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate (5.1 g, 14 mmol), 4-trifluoromethylphenylboronic acid (3.36 g, 17 mmol), CsF (0.28 g, 1.84 mmol) and Pd (PPh3)4 (0.410 g, 0.4 mmol) in 75 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled to RT and 75 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over NaSO4, filtered and concentrated under reduced pressure to give a yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate (4.6 g) as a yellow oil. 1H-NMR (CDCl3, 200 MHz): 0.41 (m, 2H), 0.62 (m, 2H), 1.22 (t, 3H), 1.23 (m, 1H), 3.58 (s, 2H), 3.89 (d, 2H), 4.17 (q, 2H), 6.96 (m, 2H), 7.31 (s, 1H), 7.64 (m, 4H).

Step 9 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoic acid

Ethyl 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate (1.1 g, 2.4 mmol) was dissolved in 10 mL anhydrous DMF and NaH (60% wt. in oil, 0.9 g) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and cyclopropyl methyl bromide (1.25 mL) was added drop wise at 0° C. The reaction mixture was stirred for an additional 1 h at 0° C. upon which saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4, filtered and the volatiles removed under reduced pressure to give 0.85 g of a colorless oil. The oil was dissolved in 10 mL of EtOH/H2O (9:1, v/v) and (1.0 g) LiOH added. The reaction mixture was refluxed for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4 and evaporated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3 cyclopropylpropanoic acid (0.42 g) as a white solid, L-21-1 (56%). 1H NMR (300 MHz, CDCl3): δ 7.65 (d, 2H), 7.38 (d, 2H), 7.08 (s, 1H), 6.83 (s, 1H), 3.75 (d, 2H), 3.62 (t, 1H), 1.96 (m, 1H), 1.08 (m, 1H), 0.84 (m, 1H), 0.44 (m, 4H), 0.16 (m, 4H).

Example 1908 1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-cyclobutanecarboxylic acid

Ethyl 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate (0.5 g,) was dissolved in 10 mL anhydrous DMF and NaH (60% wt. in oil, 0.13 g, mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and 1,3-dibromopropane (1.5 mL) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and upon which saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4, filtered and concentrated under reduced pressure to give 240 mg of a colorless oil. The oil was dissolved in 10 mL of EtOH/H2O (9:1, v/v) and 0.42 g LiOH added. The reaction mixture was refluxed for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified via column chromatography over silica gel (hexane/EtOAc 9:1) to give 1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-cyclobutanecarboxylic acid (0.210 g) as a white solid (52% yield). 1H NMR (300 MHz, CDCl3): δ 7.68 (d, 2H), 7.41 (d, 2H), 7.06 (s, 1H), 6.89 (s, 1H), 3.78 (d, 2H), 2.88 (m, 2H), 2.58 (m, 2H), 2.16 (m, 1H), 1.97 (m, 1H), 1.03 (m, 1H), 0.46 (m, 2H), 0.18 (m, 2H).

Example 1909 1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-cyclopentanecarboxylic acid

Ethyl 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate (0.5 g) was dissolved in 10 mL anhydrous DMF and NaH (60% wt. in oil, 0.13 g, mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and 1,4-dibromobutane (0.24 g) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4, filtered and concentrated under reduced pressure to give 380 mg of colorless oil. The oil was dissolved in 10 mL of EtOH/H2O (9:1, vvl) and 1.0 g LiOH added. The reaction mixture was refluxed for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4 filtered and concentrated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave 1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-cyclopentanecarboxylic acid (0.210 g) as a white solid (60%). 1H NMR (500 MHz, CDCl3): δ 7.68 (d, 2H), 7.41 (d, 2H), 7.16 (s, 1H), 6.91 (s, 1H), 3.78 (d, 2H), 2.66 (m, 2H), 1.97 (m, 2H), 1.79 (m, 4H), 1.03 (m, 1H), 0.46 (d, 2H), 0.18 (d, 2H).

Example 2491 2-(6-Chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid

Step 1 Ethyl 3-cyclopropyl-2-(3(cyclopropylmethoxy)-4-nitrophenyl)propanoate

Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (5 g, 17.9 mmol) was dissolved in 50 mL anhydrous DMF, NaH (60% wt. in oil, 0.475 g, 19.7 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and cyclopropylmethyl bromide (2.67 g, 19.7 mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give ethyl 3-cyclopropyl-2-(3(cyclopropylmethoxy)-4-nitrophenyl)propanoate (4 g) as a colorless oil.

Step 2 Ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)-3-cyclopropylpropanoate

To a stirred solution of ethyl 3-cyclopropyl-2-(3(cyclopropylmethoxy)-4-nitrophenyl)propanoate (4.0 g), in dry MeOH (100 mL), Pd(OH)2 (2 g) was added and the mixture was reduced under an atmosphere of H2 for 6 h at room temperature. The reaction mixture was filtered through a pad of Celite™ washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)-3-cyclopropylpropanoate (3.5 g) as a thick liquid.

Step 3 Ethyl 2-(4-amino-3-bromo-5-(Cyclopropylmethoxy)phenyl)-3-cyclopropyl propanoate

To a stirred solution of ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)-3-cyclopropylpropanoate (3.0 g, 9.8 mmol) in dry CHCl3 (50 mL), NBS (1.4 g, 7.8 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was diluted with water and extracted with DCM (2×50 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to yield the ethyl 2-(4-amino-3-bromo-5-(Cyclopropylmethoxy)phenyl)-3-cyclopropyl propanoate (1.5 g) as a yellow solid.

Step 4 Ethyl 2-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate

A mixture of ethyl 2-(4-amino-3-bromo-5-(Cyclopropylmethoxy)phenyl)-3-cyclopropyl propanoate (2.8 g, 7.2 mmol), 4-trifluoromethylphenylboronic acid (2.05 g, 18.8 mmol), CsF (2.19 g, 14.5 mmol) and Pd (PPh3)4 (0.837 g, 0.72 mmol) in 30 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled to RT, and 75 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over NaSO4, filtered and concentrated under reduced pressure to give a yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (2.5 g) as a yellow oil.

Step 5 Ethyl 2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate

Ethyl 2-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (1 g, 2.2 mmol) was dissolved in a mixture of MeCN/H2O/HCl 30 mL/30 mL/2 mL at 0° C. A solution of NaNO2 (0.200 g, 2.9 mmol) in water (10 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (1.1 g, 11.1 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 90° C. for 2.0 h and the mixture was concentrated under reduced pressure. The reaction mixture was extracted with EtOAc (3×50 mL), the combined organic layers were washed with water (50 mL) followed by brine (50 mL), was dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude black oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (1.1 g) as a yellow oil.

Step 6 2-(6-Chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid

2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (80 mg) was dissolved in 10 mL of MeOH/THF/H2O (10 mL/10 mL/5 mL) and 57 mg LiOH added. The reaction mixture was stirred at room temperature for 5 h and then concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave compound 2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid (45 mg) as a white solid. 1H-NMR (500 MHz, CDCl3): 7.71 (d, 2H), 7.54 (d, 2H), 6.95 (d, 1H), 6.87 (s, 1H), 3.97 (d, 2H), 3.64 (t, 1H), 2.55 (m, 2H), 1.96 (m, 1H), 1.08 (m, 1H), 0.84 (m, 1H), 0.44 (m, 4H), 0.16 (m, 4H).

Example 2494 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylic acid

Step 1 Ethyl 1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclobutanecarboxylate

Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (5 g, 17.9 mmol) was dissolved in 50 mL anhydrous DMF, NaH (60% wt. in oil, 1.43 g, 35.9 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and 1,3-dibromopropane (1.91 mL, 17.9 mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give ethyl 1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclobutanecarboxylate (2.8 g) as a colorless oil.

Step 2 Ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate

To a stirred solution of ethyl 1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclobutanecarboxylate (2.8 g), in dry MeOH (100 mL), Pd(OH)2 (1.2 g) was added and the reaction mixture was reduced under an atmosphere of H2 for 6 h at room temperature. The reaction mixture was filtered through a pad of Celite™ washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (2.4 g) as a thick liquid.

Step 3 Ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate

To a stirred solution of ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (2.4 g, 8.3 mmol) in dry CHCl3 (50 mL), NBS (1.4 g, 7.8 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at r