# Patent

## Title
Tetrasubstituted benzenes

## Abstract

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.

## Background
RELATED APPLICATION INFORMATION
This application is a continuation of U.S. patent application Ser. No. 12/341,201, filed Dec. 22, 2008, now U.S. Pat. No. 8,217,064, which 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, all 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 at (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 at 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 at 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)2NHC(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, R4X, 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, R4X, 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, R4X, 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, R4X, 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, R4X, 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, R4X, 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)2NHC(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—, 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—, 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)cycloalkyl or (C2-C4)alkynyl, where each alkyl or cycloalkyl 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)cycloalkyl or (C2-C4)alkynyl, where each alkyl or cycloalkyl 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
Cylcobutyl


c-Bu
Cylcobutyl


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 HS15: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)2NHC(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)2NHC(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)2F, 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.




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)2F, 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, BuL1 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 (1-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 seprated 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
CH2CH3
F
4-fluorophenyl


171
CH2CH3
H
O
CH2CH3
F
4-fluorophenyl


172
CH2CF3
H
O
CH2CH3
F
4-fluorophenyl


173
CH2CH2CH3
H
O
CH2CH3
F
4-fluorophenyl


174
CH2CH(CH3)2
H
O
CH2CH3
F
4-fluorophenyl


175
cyclopropylmethyl
H
O
CH2CH3
F
4-fluorophenyl


176
SCH(CH3)2
H
O
CH2CH3
F
4-fluorophenyl


177
OCH2CH3
H
O
CH2CH3
F
4-fluorophenyl


178
(CH2)2

O
CH2CH3
F
4-fluorophenyl


179
(CH2)4

O
CH2CH3
F
4-fluorophenyl


180
CH3
H
O
CH2CH3
F
4-chlorophenyl


181
CH2CH3
H
O
CH2CH3
F
4-chlorophenyl


182
CH2CF3
H
O
CH2CH3
F
4-chlorophenyl


183
CH2CH2CH3
H
O
CH2CH3
F
4-chlorophenyl


184
CH2CH(CH3)2
H
O
CH2CH3
F
4-chlorophenyl


185
cyclopropylmethyl
H
O
CH2CH3
F
4-chlorophenyl


186
SCH(CH3)2
H
O
CH2CH3
F
4-chlorophenyl


187
OCH2CH3
H
O
CH2CH3
F
4-chlorophenyl


188
(CH2)2

O
CH2CH3
F
4-chlorophenyl


189
(CH2)4

O
CH2CH3
F
4-chlorophenyl


190
CH3
H
O
CH2CH3
F
4-trifluoromethylphenyl


191
CH2CH3
H
O
CH2CH3
F
4-trifluoromethylphenyl


192
CH2CF3
H
O
CH2CH3
F
4-trifluoromethylphenyl


193
CH2CH2CH3
H
O
CH2CH3
F
4-trifluoromethylphenyl


194
CH2CH(CH3)2
H
O
CH2CH3
F
4-trifluoromethylphenyl


195
cyclopropylmethyl
H
O
CH2CH3
F
4-trifluoromethylphenyl


196
SCH(CH3)2
H
O
CH2CH3
F
4-trifluoromethylphenyl


197
OCH2CH3
H
O
CH2CH3
F
4-trifluoromethylphenyl


198
(CH2)2

O
CH2CH3
F
4-trifluoromethylphenyl


199
(CH2)4

O
CH2CH3
F
4-trifluoromethylphenyl


200
CH3
H
O
CH2CH3
F
4-methoxyphenyl


201
CH2CH3
H
O
CH2CH3
F
4-methoxyphenyl


202
CH2CF3
H
O
CH2CH3
F
4-methoxyphenyl


203
CH2CH2CH3
H
O
CH2CH3
F
4-methoxyphenyl


204
CH2CH(CH3)2
H
O
CH2CH3
F
4-methoxyphenyl


205
cyclopropylmethyl
H
O
CH2CH3
F
4-methoxyphenyl


206
SCH(CH3)2
H
O
CH2CH3
F
4-methoxyphenyl


207
OCH2CH3
H
O
CH2CH3
F
4-methoxyphenyl


208
(CH2)2

O
CH2CH3
F
4-methoxyphenyl


209
(CH2)4

O
CH2CH3
F
4-methoxyphenyl


210
CH3
H
O
CH2CH3
F
3,4 dichloro phenyl


211
CH2CH3
H
O
CH2CH3
F
3,4 dichloro phenyl


212
CH2CF3
H
O
CH2CH3
F
3,4 dichloro phenyl


213
CH2CH2CH3
H
O
CH2CH3
F
3,4 dichloro phenyl


214
CH2CH(CH3)2
H
O
CH2CH3
F
3,4 dichloro phenyl


215
cyclopropylmethyl
H
O
CH2CH3
F
3,4 dichloro phenyl


216
SCH(CH3)2
H
O
CH2CH3
F
3,4 dichloro phenyl


217
OCH2CH3
H
O
CH2CH3
F
3,4 dichloro phenyl


218
(CH2)2

O
CH2CH3
F
3,4 dichloro phenyl


219
(CH2)4

O
CH2CH3
F
3,4 dichloro phenyl


220
CH3
H
O
CH2CH3
F
5-benzo[c][1,2,5]oxadiazolyl


221
CH2CH3
H
O
CH2CH3
F
5-benzo[c][1,2,5]oxadiazolyl


222
CH2CF3
H
O
CH2CH3
F
5-benzo[c][1,2,5]oxadiazolyl


223
CH2CH2CH3
H
O
CH2CH3
F
5-benzo[c][1,2,5]oxadiazolyl


224
CH2CH(CH3)2
H
O
CH2CH3
F
5-benzo[c][1,2,5]oxadiazolyl


225
cyclopropylmethyl
H
O
CH2CH3
F
5-benzo[c][1,2,5]oxadiazolyl


226
SCH(CH3)2
H
O
CH2CH3
F
5-benzo[c][1,2,5]oxadiazolyl


227
OCH2CH3
H
O
CH2CH3
F
5-benzo[c][1,2,5]oxadiazolyl


228
(CH2)2

O
CH2CH3
F
5-benzo[c][1,2,5]oxadiazolyl


229
(CH2)4

O
CH2CH3
F
5-benzo[c][1,2,5]oxadiazolyl


230
CH3
H
O
CH2CH3
F
5-benzo[c][1,2,5]thiadiazolyl


231
CH2CH3
H
O
CH2CH3
F
5-benzo[c][1,2,5]thiadiazolyl


232
CH2CF3
H
O
CH2CH3
F
5-benzo[c][1,2,5]thiadiazolyl


233
CH2CH2CH3
H
O
CH2CH3
F
5-benzo[c][1,2,5]thiadiazolyl


234
CH2CH(CH3)2
H
O
CH2CH3
F
5-benzo[c][1,2,5]thiadiazolyl


235
cyclopropylmethyl
H
O
CH2CH3
F
5-benzo[c][1,2,5]thiadiazolyl


236
SCH(CH3)2
H
O
CH2CH3
F
5-benzo[c][1,2,5]thiadiazolyl


237
OCH2CH3
H
O
CH2CH3
F
5-benzo[c][1,2,5]thiadiazolyl


238
(CH2)2

O
CH2CH3
F
5-benzo[c][1,2,5]thiadiazolyl


239
(CH2)4

O
CH2CH3
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

O
CH2-c-Pr
F
4-fluorophenyl


249
(CH2)4

O
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

O
CH2-c-Pr
F
4-trifluoromethylphenyl


269
(CH2)4

O
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

O
CH2CF3
Cl
4-fluorophenyl


389
(CH2)4

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
cyclopropylmethyl
H
O
CH2CH3
F
4-fluorophenyl


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
cyclopropylmethyl
H
O
CH2CH3
F
4-chlorophenyl


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
cyclopropylmethyl
H
O
CH2CH3
F
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2CH3
F
4-methoxyphenyl


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
cyclopropylmethyl
H
O
CH2CH3
F
3,4 dichloro phenyl


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
cyclopropylmethyl
H
O
CH2CH3
F
5-benzo[c][1,2,5]oxadiazolyl


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
cyclopropylmethyl
H
O
CH2CH3
F
5-benzo[c][1,2,5]thiadiazolyl


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
cyclopropylmethyl
H
O
CH2CF3
F
4-fluorophenyl


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
cyclopropylmethyl
H
O
CH2CF3
F
4-chlorophenyl


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
cyclopropylmethyl
H
O
CH2CF3
F
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2CF3
F
4-methoxyphenyl


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
cyclopropylmethyl
H
O
CH2CF3
F
3,4 dichloro phenyl


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
cyclopropylmethyl
H
O
CH2CF3
F
5-benzo[c][1,2,5]oxadiazolyl


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
cyclopropylmethyl
H
O
CH2CF3
F
5-benzo[c][1,2,5]thiadiazolyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
F
4-fluorophenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
F
4-chlorophenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
F
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
F
4-methoxyphenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
F
3,4 dichloro phenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
F
5-benzo[c][1,2,5]oxadiazolyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
F
5-benzo[c][1,2,5]thiadiazolyl


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
cyclopropylmethyl
H
O
CH2CH3
Cl
4-fluorophenyl


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
cyclopropylmethyl
H
O
CH2CH3
Cl
4-chlorophenyl


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
cyclopropylmethyl
H
O
CH2CH3
Cl
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2CH3
Cl
4-methoxyphenyl


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
cyclopropylmethyl
H
O
CH2CH3
Cl
3,4 dichloro phenyl


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
cyclopropylmethyl
H
O
CH2CH3
Cl
5-benzo[c][1,2,5]oxadiazolyl


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
cyclopropylmethyl
H
O
CH2CH3
Cl
5-benzo[c][1,2,5]thiadiazolyl


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
cyclopropylmethyl
H
O
CH2CF3
Cl
4-fluorophenyl


846
SCH(CH3)2
H
O
CH2CF3
Cl
4-fluorophenyl


847
OCH2CH3
H
O
CH2CF3
Cl
4-fluorophenyl


848
(CH2)2

O
CH2CF3
Cl
4-fluorophenyl


849
(CH2)4

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
cyclopropylmethyl
H
O
CH2CF3
Cl
4-chlorophenyl


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
cyclopropylmethyl
H
O
CH2CF3
Cl
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2CF3
Cl
4-methoxyphenyl


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
cyclopropylmethyl
H
O
CH2CF3
Cl
3,4 dichloro phenyl


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
cyclopropylmethyl
H
O
CH2CF3
Cl
5-benzo[c][1,2,5]oxadiazolyl


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
cyclopropylmethyl
H
O
CH2CF3
Cl
5-benzo[c][1,2,5]thiadiazolyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
Cl
4-fluorophenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
Cl
4-chlorophenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
Cl
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
Cl
4-methoxyphenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
Cl
3,4 dichloro phenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
Cl
5-benzo[c][1,2,5]oxadiazolyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
Cl
5-benzo[c][1,2,5]thiadiazolyl


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







Compounds of Formula III













Ex
R1
R2
Y
R4
R5
Z





980
CH2CH3
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


981
CH2CF3
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


982
CH2CH2CH3
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


983
CH2CH(CH3)2
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


984
cyclopropylmethyl
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


985
cyclobutylmethyl
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


986
(CH2)2

O
CH2 CF3
CF3
4-trifluoromethylphenyl


987
(CH2)3

O
CH2 CF3
CF3
4-trifluoromethylphenyl


988
(CH2)4

O
CH2 CF3
CF3
4-trifluoromethylphenyl


989
(CH2)5

O
CH2 CF3
CF3
4-trifluoromethylphenyl


990
5,5-spiro[2.3]hexane

O
CH2 CF3
CF3
4-trifluoromethylphenyl


991
Cyclopentyl
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2 CF3
CF3
4-tolyl


997
cyclobutylmethyl
H
O
CH2 CF3
CF3
4-tolyl


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]hexane

O
CH2 CF3
CF3
4-tolyl


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
cyclopropylmethyl
H
O
CH2 CF3
CF3
4-ethyl phenyl


1009
cyclobutylmethyl
H
O
CH2 CF3
CF3
4-ethyl phenyl


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]hexane

O
CH2 CF3
CF3
4-ethyl phenyl


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
cyclopropylmethyl
H
O
CH2 CF3
CF3
4-isopropyl phenyl


1021
cyclobutylmethyl
H
O
CH2 CF3
CF3
4-isopropyl phenyl


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]hexane

O
CH2 CF3
CF3
4-isopropyl phenyl


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
cyclopropylmethyl
H
O
CH2 CF3
CF3
4-thiomethylphenyl


1033
cyclobutylmethyl 
H
O
CH2 CF3
CF3
4-thiomethylphenyl


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]hexane

O
CH2 CF3
CF3
4-thiomethylphenyl


1039
Cyclopentyl
H
O
CH2 CF3
CF3
4-thiomethylphenyl


1040
CH2CH3
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1041
CH2CF3
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1042
CH2CH2CH3
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1043
CH2CH(CH3)2
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1044
cyclopropylmethyl
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1045
cyclobutylmethyl
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1046
(CH2)2

O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1047
(CH2)3

O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1048
(CH2)4

O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1049
(CH2)5

O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1050
5,5-spiro[2.3]hexane

O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1051
Cyclopentyl
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1052
CH2CH3
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1053
CH2CF3
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1054
CH2CH2CH3
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1055
CH2CH(CH3)2
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1056
cyclopropylmethy
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1057
cyclobutylmethyl
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1058
(CH2)2

O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1059
(CH2)3

O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1060
(CH2)4

O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1061
(CH2)5

O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1062
5,5-spiro[2.3]hexane

O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1063
Cyclopentyl
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
CF3
4-tolyl


1069
cyclobutylmethyl 
H
O
CH2-c-Pr
CF3
4-tolyl


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]hexane

O
CH2-c-Pr
CF3
4-tolyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
CF3
4-ethyl phenyl


1081
cyclobutylmethyl
H
O
CH2-c-Pr
CF3
4-ethyl phenyl


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]hexane

O
CH2-c-Pr
CF3
4-ethyl phenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
CF3
4-isopropyl phenyl


1093
cyclobutylmethyl
H
O
CH2-c-Pr
CF3
4-isopropyl phenyl


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]hexane

O
CH2-c-Pr
CF3
4-isopropyl phenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
CF3
4-thiomethylphenyl


1105
cyclobutylmethyl
H
O
CH2-c-Pr
CF3
4-thiomethylphenyl


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]hexane

O
CH2-c-Pr
CF3
4-thiomethylphenyl


1111
Cyclopentyl
H
O
CH2-c-Pr
CF3
4-thiomethylphenyl


1112
CH2CH3
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1113
CH2CF3
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1114
CH2CH2CH3
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1115
CH2CH(CH3)2
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1116
cyclopropylmethyl
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1117
cyclobutylmethyl
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1118
(CH2)2

O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1119
(CH2)3

O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1120
(CH2)4

O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1121
(CH2)5

O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1122
5,5-spiro[2.3]hexane

O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1123
Cyclopentyl
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1124
CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1125
CH2CF3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1126
CH2CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1127
CH2CH(CH3)2
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1128
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1129
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1130
(CH2)2

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1131
(CH2)3

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1132
(CH2)4

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1133
(CH2)5

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1134
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1135
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1136
CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-tolyl


1137
CH2CF3
H
O
CH2 CF3
OCH2 CF3
4-tolyl


1138
CH2CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-tolyl


1139
CH2CH(CH3)2
H
O
CH2 CF3
OCH2 CF3
4-tolyl


1140
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-tolyl


1141
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-tolyl


1142
(CH2)2

O
CH2 CF3
OCH2 CF3
4-tolyl


1143
(CH2)3

O
CH2 CF3
OCH2 CF3
4-tolyl


1144
(CH2)4

O
CH2 CF3
OCH2 CF3
4-tolyl


1145
(CH2)5

O
CH2 CF3
OCH2 CF3
4-tolyl


1146
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2 CF3
4-tolyl


1147
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-tolyl


1148
CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


1149
CH2CF3
H
O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


1150
CH2CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


1151
CH2CH(CH3)2
H
O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


1152
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


1153
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


1154
(CH2)2

O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


1155
(CH2)3

O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


1156
(CH2)4

O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


1157
(CH2)5

O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


1158
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


1159
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


1160
CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


1161
CH2CF3
H
O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


1162
CH2CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


1163
CH2CH(CH3)2
H
O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


1164
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


1165
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


1166
(CH2)2

O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


1167
(CH2)3

O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


1168
(CH2)4

O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


1169
(CH2)5

O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


1170
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


1171
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


1172
CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1173
CH2CF3
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1174
CH2CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1175
CH2CH(CH3)2
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1176
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1177
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1178
(CH2)2

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1179
(CH2)3

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1180
(CH2)4

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1181
(CH2)5

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1182
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1183
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1184
CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1185
CH2CF3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1186
CH2CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1187
CH2CH(CH3)2
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1188
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1189
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1190
(CH2)2

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1191
(CH2)3

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1192
(CH2)4

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1193
(CH2)5

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1194
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1195
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1196
CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1197
CH2CF3
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1198
CH2CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1199
CH2CH(CH3)2
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1200
cyclopropylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1201
cyclobutylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1202
(CH2)2

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1203
(CH2)3

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1204
(CH2)4

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1205
(CH2)5

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1206
5,5-spiro[2.3]hexane

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1207
Cyclopentyl
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1208
CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-tolyl


1209
CH2CF3
H
O
CH2-c-Pr
OCH2 CF3
4-tolyl


1210
CH2CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-tolyl


1211
CH2CH(CH3)2
H
O
CH2-c-Pr
OCH2 CF3
4-tolyl


1212
cyclopropylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-tolyl


1213
cyclobutylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-tolyl


1214
(CH2)2

O
CH2-c-Pr
OCH2 CF3
4-tolyl


1215
(CH2)3

O
CH2-c-Pr
OCH2 CF3
4-tolyl


1216
(CH2)4

O
CH2-c-Pr
OCH2 CF3
4-tolyl


1217
(CH2)5

O
CH2-c-Pr
OCH2 CF3
4-tolyl


1218
5,5-spiro[2.3]hexane

O
CH2-c-Pr
OCH2 CF3
4-tolyl


1219
Cyclopentyl
H
O
CH2-c-Pr
OCH2 CF3
4-tolyl


1220
CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-ethyl phenyl


1221
CH2CF3
H
O
CH2-c-Pr
OCH2 CF3
4-ethyl phenyl


1222
CH2CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-ethyl phenyl


1223
CH2CH(CH3)2
H
O
CH2-c-Pr
OCH2 CF3
4-ethyl phenyl


1224
cyclopropylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-ethyl phenyl


1225
cyclobutylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-ethyl phenyl


1226
(CH2)2

O
CH2-c-Pr
OCH2 CF3
4-ethyl phenyl


1227
(CH2)3

O
CH2-c-Pr
OCH2 CF3
4-ethyl phenyl


1228
(CH2)4

O
CH2-c-Pr
OCH2 CF3
4-ethyl phenyl


1229
(CH2)5

O
CH2-c-Pr
OCH2 CF3
4-ethyl phenyl


1230
5,5-spiro[2.3]hexane

O
CH2-c-Pr
OCH2 CF3
4-ethyl phenyl


1231
Cyclopentyl
H
O
CH2-c-Pr
OCH2 CF3
4-ethyl phenyl


1232
CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-isopropyl phenyl


1233
CH2CF3
H
O
CH2-c-Pr
OCH2 CF3
4-isopropyl phenyl


1234
CH2CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-isopropyl phenyl


1235
CH2CH(CH3)2
H
O
CH2-c-Pr
OCH2 CF3
4-isopropyl phenyl


1236
cyclopropylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-isopropyl phenyl


1237
cyclobutylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-isopropyl phenyl


1238
(CH2)2

O
CH2-c-Pr
OCH2 CF3
4-isopropyl phenyl


1239
(CH2)3

O
CH2-c-Pr
OCH2 CF3
4-isopropyl phenyl


1240
(CH2)4

O
CH2-c-Pr
OCH2 CF3
4-isopropyl phenyl


1241
(CH2)5

O
CH2-c-Pr
OCH2 CF3
4-isopropyl phenyl


1242
5,5-spiro[2.3]hexane

O
CH2-c-Pr
OCH2 CF3
4-isopropyl phenyl


1243
Cyclopentyl
H
O
CH2-c-Pr
OCH2 CF3
4-isopropyl phenyl


1244
CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


1245
CH2CF3
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


1246
CH2CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


1247
CH2CH(CH3)2
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


1248
cyclopropylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


1249
cyclobutylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


1250
(CH2)2

O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


1251
(CH2)3

O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


1252
(CH2)4

O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


1253
(CH2)5

O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


1254
5,5-spiro[2.3]hexane

O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


1255
Cyclopentyl
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


1256
CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1257
CH2CF3
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1258
CH2CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1259
CH2CH(CH3)2
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1260
cyclopropylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1261
cyclobutylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1262
(CH2)2

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1263
(CH2)3

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1264
(CH2)4

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1265
(CH2)5

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1266
5,5-spiro[2.3]hexane

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1267
Cyclopentyl
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl




















TABLE 4







Compounds of Formula III













Ex
R1
R2
Y
R4
R5
Z





1268
cyclobutylmethyl 
H
O
CH2 CF3
Cl
4-trifluoromethylphenyl


1269
(CH2)3

O
CH2 CF3
Cl
4-trifluoromethylphenyl


1270
(CH2)5

O
CH2 CF3
Cl
4-trifluoromethylphenyl


1271
5,5-spiro[2.3]hexane

O
CH2 CF3
Cl
4-trifluoromethylphenyl


1272
Cyclopentyl
H
O
CH2 CF3
Cl
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2 CF3
Cl
4-tolyl


1278
cyclobutylmethyl
H
O
CH2 CF3
Cl
4-tolyl


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]hexane

O
CH2 CF3
Cl
4-tolyl


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
cyclopropylmethyl
H
O
CH2 CF3
Cl
4-ethyl phenyl


1290
cyclobutylmethyl
H
O
CH2 CF3
Cl
4-ethyl phenyl


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]hexane

O
CH2 CF3
Cl
4-ethyl phenyl


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
cyclopropylmethyl
H
O
CH2 CF3
Cl
4-isopropyl phenyl


1302
cyclobutylmethyl
H
O
CH2 CF3
Cl
4-isopropyl 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]hexane

O
CH2 CF3
Cl
4-isopropyl phenyl


1308
Cyclopentyl
H
O
CH2 CF3
Cl
4-isopropyl phenyl


1309
CH2CH3
H
O
CH2 CF3
Cl
4-thiomethylphenyl


1310
CH2CF3
H
O
CH2 CF3
Cl
4-thiomethylphenyl


1311
CH2CH2CH3
H
O
CH2 CF3
Cl
4-thiomethylphenyl


1312
CH2CH(CH3)2
H
O
CH2 CF3
Cl
4-thiomethylphenyl


1313
cyclopropylmethyl
H
O
CH2 CF3
Cl
4-thiomethylphenyl


1314
cyclobutylmethyl
H
O
CH2 CF3
Cl
4-thiomethylphenyl


1315
(CH2)2

O
CH2 CF3
Cl
4-thiomethylphenyl


1316
(CH2)3

O
CH2 CF3
Cl
4-thiomethylphenyl


1317
(CH2)4

O
CH2 CF3
Cl
4-thiomethylphenyl


1318
(CH2)5

O
CH2 CF3
Cl
4-thiomethylphenyl


1319
5,5-spiro[2.3]hexane

O
CH2 CF3
Cl
4-thiomethylphenyl


1320
Cyclopentyl
H
O
CH2 CF3
Cl
4-thiomethylphenyl


1321
CH2CH3
H
O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1322
CH2CF3
H
O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1323
CH2CH2CH3
H
O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1324
CH2CH(CH3)2
H
O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1325
cyclopropylmethyl
H
O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1326
cyclobutylmethyl
H
O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1327
(CH2)2

O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1328
(CH2)3

O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1329
(CH2)4

O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1330
(CH2)5

O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1331
5,5-spiro[2.3]hexane

O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1332
Cyclopentyl
H
O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1333
cyclobutylmethyl
H
O
CH2—c-Pr
Cl
4-trifluoromethylphenyl


1334
(CH2)3

O
CH2—c-Pr
Cl
4-trifluoromethylphenyl


1335
(CH2)5

O
CH2—c-Pr
Cl
4-trifluoromethylphenyl


1336
5,5-spiro[2.3]hexane

O
CH2—c-Pr
Cl
4-trifluoromethylphenyl


1337
Cyclopentyl
H
O
CH2—c-Pr
Cl
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2—c-Pr
Cl
4-tolyl


1343
cyclobutylmethyl
H
O
CH2—c-Pr
Cl
4-tolyl


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]hexane

O
CH2—c-Pr
CI
4-tolyl


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
cyclopropylmethyl
H
O
CH2—c-Pr
Cl
4-ethyl phenyl


1355
cyclobutylmethyl
H
O
CH2—c-Pr
Cl
4-ethyl phenyl


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]hexane

O
CH2—c-Pr
Cl
4-ethyl phenyl


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
cyclopropylmethyl
H
O
CH2—c-Pr
Cl
4-isopropyl phenyl


1367
cyclobutylmethyl
H
O
CH2—c-Pr
Cl
4-isopropyl 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]hexane

O
CH2—c-Pr
Cl
4-isopropyl phenyl


1373
Cyclopentyl
H
O
CH2—c-Pr
Cl
4-isopropyl phenyl


1374
CH2CH3
H
O
CH2—c-Pr
Cl
4-thiomethylphenyl


1375
CH2CF3
H
O
CH2—c-Pr
Cl
4-thiomethylphenyl


1376
CH2CH2CH3
H
O
CH2—c-Pr
Cl
4-thiomethylphenyl


1377
CH2CH(CH3)2
H
O
CH2—c-Pr
Cl
4-thiomethylphenyl


1378
cyclopropylmethyl
H
O
CH2—c-Pr
Cl
4-thiomethylphenyl


1379
cyclobutylmethyl
H
O
CH2—c-Pr
Cl
4-thiomethylphenyl


1380
(CH2)2

O
CH2—c-Pr
Cl
4-thiomethylphenyl


1381
(CH2)3

O
CH2—c-Pr
Cl
4-thiomethylphenyl


1382
(CH2)4

O
CH2—c-Pr
Cl
4-thiomethylphenyl


1383
(CH2)5

O
CH2—c-Pr
Cl
4-thiomethylphenyl


1384
5,5-spiro[2.3]hexane

O
CH2—c-Pr
Cl
4-thiomethylphenyl


1385
Cyclopentyl
H
O
CH2—c-Pr
Cl
4-thiomethylphenyl


1386
CH2CH3
H
O
CH2—c-Pr
Cl
4-trifluoromethoxyphenyl


1387
CH2CF3
H
O
CH2—c-Pr
Cl
4-trifluoromethoxyphenyl


1388
CH2CH2CH3
H
O
CH2—c-Pr
Cl
4-trifluoromethoxyphenyl


1389
CH2CH(CH3)2
H
O
CH2—c-Pr
Cl
4-trifluoromethoxyphenyl


1390
cyclopropylmethyl
H
O
CH2—c-Pr
Cl
4-trifluoromethoxyphenyl


1391
cyclobutylmethyl
H
O
CH2—c-Pr
Cl
4-trifluoromethoxyphenyl


1392
(CH2)2

O
CH2—c-Pr
Cl
4-trifluoromethoxyphenyl


1393
(CH2)3

O
CH2—c-Pr
Cl
4-trifluoromethoxyphenyl


1394
(CH2)4

O
CH2—c-Pr
Cl
4-trifluoromethoxyphenyl


1395
(CH2)5

O
CH2—c-Pr
Cl
4-trifluoromethoxyphenyl


1396
5,5-spiro[2.3]hexane

O
CH2—c-Pr
Cl
4-trifluoromethoxyphenyl


1397
Cyclopentyl
H
O
CH2—c-Pr
Cl
4-trifluoromethoxyphenyl


1398
CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1399
CH2CF3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1400
CH2CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1401
CH2CH(CH3)2
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1402
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1403
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1404
(CH2)2

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1405
(CH2)3

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1406
(CH2)4

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1407
(CH2)5

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1408
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1409
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-tolyl


1415
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-tolyl


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]hexane

O
CH2 CF3
OCH2 CF3
4-tolyl


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
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


1427
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


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]hexane

O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


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
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


1439
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-isopropyl 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]hexane

O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


1445
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


1446
CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1447
CH2CF3
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1448
CH2CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1449
CH2CH(CH3)2
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1450
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1451
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1452
(CH2)2

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1453
(CH2)3

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1454
(CH2)4

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1455
(CH2)5

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1456
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1457
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1458
CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1459
CH2CF3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1460
CH2CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1461
CH2CH(CH3)2
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1462
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1463
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1464
(CH2)2

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1465
(CH2)3

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1466
(CH2)4

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1467
(CH2)5

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1468
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1469
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1470
CH2CH3
H
O
CH2—c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1471
CH2CF3
H
O
CH2—c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1472
CH2CH2CH3
H
O
CH2—c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1473
CH2CH(CH3)2
H
O
CH2—c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1474
cyclopropylmethyl
H
O
CH2—c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1475
cyclobutylmethyl
H
O
CH2—c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1476
(CH2)2

O
CH2—c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1477
(CH2)3

O
CH2—c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1478
(CH2)4

O
CH2—c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1479
(CH2)5

O
CH2—c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1480
5,5-spiro[2.3]hexane

O
CH2—c-Pr
OCH2 CF3
4-trifluoromethylphenyl


1481
Cyclopentyl
H
O
CH2—c-Pr
OCH2 CF3
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2—c-Pr
OCH2 CF3
4-tolyl


1487
cyclobutylmethyl
H
O
CH2—c-Pr
OCH2 CF3
4-tolyl


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]hexane

O
CH2—c-Pr
OCH2 CF3
4-tolyl


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
cyclopropylmethyl
H
O
CH2—c-Pr
OCH2 CF3
4-ethyl phenyl


1499
cyclobutylmethyl
H
O
CH2—c-Pr
OCH2 CF3
4-ethyl phenyl


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]hexane

O
CH2—c-Pr
OCH2 CF3
4-ethyl phenyl


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
cyclopropylmethyl
H
O
CH2—c-Pr
OCH2 CF3
4-isopropyl phenyl


1511
cyclobutylmethyl
H
O
CH2—c-Pr
OCH2 CF3
4-isopropyl 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]hexane

O
CH2—c-Pr
OCH2 CF3
4-isopropyl phenyl


1517
Cyclopentyl
H
O
CH2—c-Pr
OCH2 CF3
4-isopropyl phenyl


1518
CH2CH3
H
O
CH2—c-Pr
OCH2 CF3
4-thiomethylphenyl


1519
CH2CF3
H
O
CH2—c-Pr
OCH2 CF3
4-thiomethylphenyl


1520
CH2CH2CH3
H
O
CH2—c-Pr
OCH2 CF3
4-thiomethylphenyl


1521
CH2CH(CH3)2
H
O
CH2—c-Pr
OCH2 CF3
4-thiomethylphenyl


1522
cyclopropylmethyl
H
O
CH2—c-Pr
OCH2 CF3
4-thiomethylphenyl


1523
cyclobutylmethyl
H
O
CH2—c-Pr
OCH2 CF3
4-thiomethylphenyl


1524
(CH2)2

O
CH2—c-Pr
OCH2 CF3
4-thiomethylphenyl


1525
(CH2)3

O
CH2—c-Pr
OCH2 CF3
4-thiomethylphenyl


1526
(CH2)4

O
CH2—c-Pr
OCH2 CF3
4-thiomethylphenyl


1527
(CH2)5

O
CH2—c-Pr
OCH2 CF3
4-thiomethylphenyl


1528
5,5-spiro[2.3]hexane

O
CH2—c-Pr
OCH2 CF3
4-thiomethylphenyl


1529
Cyclopentyl
H
O
CH2—c-Pr
OCH2 CF3
4-thiomethylphenyl



CH2CH3
H
O
CH2—c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1530
CH2CF3
H
O
CH2—c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1531
CH2CH2CH3
H
O
CH2—c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1532
CH2CH(CH3)2
H
O
CH2—c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1533
cyclopropylmethyl
H
O
CH2—c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1534
cyclobutylmethyl
H
O
CH2—c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1535
(CH2)2

O
CH2—c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1536
(CH2)3

O
CH2—c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1537
(CH2)4

O
CH2—c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1538
(CH2)5

O
CH2—c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1539
5,5-spiro[2.3]hexane

O
CH2—c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


1540
Cyclopentyl
H
O
CH2—c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl




















TABLE 5







Compounds of Formula IV













Ex
R1
R2
X
R3
R5
Z





1541
CH2CH3
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


1542
CH2CF3
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


1543
CH2CH2CH3
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


1544
CH2CH(CH3)2
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


1545
cyclopropylmethyl
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


1546
cyclobutylmethyl
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


1547
(CH2)2

O
CH2 CF3
CF3
4-trifluoromethylphenyl


1548
(CH2)3

O
CH2 CF3
CF3
4-trifluoromethylphenyl


1549
(CH2)4

O
CH2 CF3
CF3
4-trifluoromethylphenyl


1550
(CH2)5

O
CH2 CF3
CF3
4-trifluoromethylphenyl


1551
5,5-spiro[2.3]hexane

O
CH2 CF3
CF3
4-trifluoromethylphenyl


1552
Cyclopentyl
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2 CF3
CF3
4-tolyl


1558
cyclobutylmethyl 
H
O
CH2 CF3
CF3
4-tolyl


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]hexane

O
CH2 CF3
CF3
4-tolyl


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
cyclopropylmethyl
H
O
CH2 CF3
CF3
4-ethyl phenyl


1570
cyclobutylmethyl
H
O
CH2 CF3
CF3
4-ethyl phenyl


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]hexane

O
CH2 CF3
CF3
4-ethyl phenyl


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
cyclopropylmethyl
H
O
CH2 CF3
CF3
4-isopropyl phenyl


1582
cyclobutylmethyl
H
O
CH2 CF3
CF3
4-isopropyl 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]hexane

O
CH2 CF3
CF3
4-isopropyl phenyl


1588
Cyclopentyl
H
O
CH2 CF3
CF3
4-isopropyl phenyl


1589
CH2CH3
H
O
CH2 CF3
CF3
4-thiomethylphenyl


1590
CH2CF3
H
O
CH2 CF3
CF3
4-thiomethylphenyl


1591
CH2CH2CH3
H
O
CH2 CF3
CF3
4-thiomethylphenyl


1592
CH2CH(CH3)2
H
O
CH2 CF3
CF3
4-thiomethylphenyl


1593
cyclopropylmethyl
H
O
CH2 CF3
CF3
4-thiomethylphenyl


1594
cyclobutylmethyl
H
O
CH2 CF3
CF3
4-thiomethylphenyl


1595
(CH2)2

O
CH2 CF3
CF3
4-thiomethylphenyl


1596
(CH2)3

O
CH2 CF3
CF3
4-thiomethylphenyl


1597
(CH2)4

O
CH2 CF3
CF3
4-thiomethylphenyl


1598
(CH2)5

O
CH2 CF3
CF3
4-thiomethylphenyl


1599
5,5-spiro[2.3]hexane

O
CH2 CF3
CF3
4-thiomethylphenyl


1600
Cyclopentyl
H
O
CH2 CF3
CF3
4-thiomethylphenyl


1601
CH2CH3
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1602
CH2CF3
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1603
CH2CH2CH3
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1604
CH2CH(CH3)2
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1605
cyclopropylmethyl
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1606
cyclobutylmethyl
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1607
(CH2)2

O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1608
(CH2)3

O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1609
(CH2)4

O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1610
(CH2)5

O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1611
5,5-spiro[2.3]hexane

O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1612
Cyclopentyl
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


1613
CH2CH3
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1614
CH2CF3
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1615
CH2CH2CH3
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1616
CH2CH(CH3)2
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1617
cyclopropylmethyl
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1618
cyclobutylmethyl
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1619
(CH2)2

O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1620
(CH2)3

O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1621
(CH2)4

O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1622
(CH2)5

O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1623
5,5-spiro[2.3]hexane

O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


1624
Cyclopentyl
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
CF3
4-tolyl


1630
cyclobutylmethyl
H
O
CH2-c-Pr
CF3
4-tolyl


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]hexane

O
CH2-c-Pr
CF3
4-tolyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
CF3
4-ethyl phenyl


1642
cyclobutylmethyl
H
O
CH2-c-Pr
CF3
4-ethyl phenyl


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]hexane

O
CH2-c-Pr
CF3
4-ethyl phenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
CF3
4-isopropyl phenyl


1654
cyclobutylmethyl
H
O
CH2-c-Pr
CF3
4-isopropyl 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]hexane

O
CH2-c-Pr
CF3
4-isopropyl phenyl


1660
Cyclopentyl
H
O
CH2-c-Pr
CF3
4-isopropyl phenyl


1661
CH2CH3
H
O
CH2-c-Pr
CF3
4-thiomethylphenyl


1662
CH2CF3
H
O
CH2-c-Pr
CF3
4-thiomethylphenyl


1663
CH2CH2CH3
H
O
CH2-c-Pr
CF3
4-thiomethylphenyl


1664
CH2CH(CH3)2
H
O
CH2-c-Pr
CF3
4-thiomethylphenyl


1665
cyclopropylmethyl
H
O
CH2-c-Pr
CF3
4-thiomethylphenyl


1666
cyclobutylmethyl
H
O
CH2-c-Pr
CF3
4-thiomethylphenyl


1667
(CH2)2

O
CH2-c-Pr
CF3
4-thiomethylphenyl


1668
(CH2)3

O
CH2-c-Pr
CF3
4-thiomethylphenyl


1669
(CH2)4

O
CH2-c-Pr
CF3
4-thiomethylphenyl


1670
(CH2)5

O
CH2-c-Pr
CF3
4-thiomethylphenyl


1671
5,5-spiro[2.3]hexane

O
CH2-c-Pr
CF3
4-thiomethylphenyl


1672
Cyclopentyl
H
O
CH2-c-Pr
CF3
4-thiomethylphenyl


1673
CH2CF3
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1674
CH2CF3
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1675
CH2CH2CH3
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1676
CH2CH(CH3)2
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1677
cyclopropylmethyl
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1678
cyclobutylmethyl
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1679
(CH2)2

O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1680
(CH2)3

O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1681
(CH2)4

O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1682
(CH2)5

O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1683
5,5-spiro[2.3]hexane

O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1684
Cyclopentyl
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


1685
CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1686
CH2CF3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1687
CH2CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1688
CH2CH(CH3)2
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1689
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1690
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1691
(CH2)2

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1692
(CH2)3

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1693
(CH2)4

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1694
(CH2)5

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1695
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1696
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-tolyl


1702
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-tolyl


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]hexane

O
CH2 CF3
OCH2 CF3
4-tolyl


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
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


1714
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


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]hexane

O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


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
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


1726
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-isopropyl 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]hexane

O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


1732
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


1733
CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1734
CH2CF3
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1735
CH2CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1736
CH2CH(CH3)2
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1737
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1738
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1739
(CH2)2

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1740
(CH2)3

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1741
(CH2)4

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1742
(CH2)5

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1743
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1744
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


1745
CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1746
CH2CF3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1747
CH2CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1748
CH2CH(CH3)2
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1749
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1750
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1751
(CH2)2

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1752
(CH2)3

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1753
(CH2)4

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1754
(CH2)5

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1755
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1756
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


1757
CH2CH3
H
O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethylphenyl


1758
CH2CF3
H
O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethylphenyl


1759
CH2CH2CH3
H
O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethylphenyl


1760
CH2CH(CH3)2
H
O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethylphenyl


1761
cyclopropylmethyl
H
O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethylphenyl


1762
cyclobutylmethyl
H
O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethylphenyl


1763
(CH2)2

O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethylphenyl


1764
(CH2)3

O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethylphenyl


1765
(CH2)4

O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethylphenyl


1766
(CH2)5

O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethylphenyl


1767
5,5-spiro[2.3]hexane

O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethylphenyl


1768
Cyclopentyl
H
O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr 
OCH2 CF3
4-tolyl


1774
cyclobutylmethyl
H
O
CH2-c-Pr 
OCH2 CF3
4-tolyl


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]hexane

O
CH2-c-Pr 
OCH2 CF3
4-tolyl


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
cyclopropylmethyl
H
O
CH2-c-Pr 
OCH2 CF3
4-ethyl phenyl


1786
cyclobutylmethyl 
H
O
CH2-c-Pr 
OCH2 CF3
4-ethyl phenyl


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]hexane

O
CH2-c-Pr 
OCH2 CF3
4-ethyl phenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr 
OCH2 CF3
4-isopropyl phenyl


1798
cyclobutylmethyl
H
O
CH2-c-Pr 
OCH2 CF3
4-isopropyl 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]hexane

O
CH2-c-Pr 
OCH2 CF3
4-isopropyl phenyl


1804
Cyclopentyl
H
O
CH2-c-Pr 
OCH2 CF3
4-isopropyl phenyl


1805
CH2CH3
H
O
CH2-c-Pr 
OCH2 CF3
4-thiomethylphenyl


1806
CH2CF3
H
O
CH2-c-Pr 
OCH2 CF3
4-thiomethylphenyl


1807
CH2CH2CH3
H
O
CH2-c-Pr 
OCH2 CF3
4-thiomethylphenyl


1808
CH2CH(CH3)2
H
O
CH2-c-Pr 
OCH2 CF3
4-thiomethylphenyl


1809
cyclopropylmethyl
H
O
CH2-c-Pr 
OCH2 CF3
4-thiomethylphenyl


1810
cyclobutylmethyl
H
O
CH2-c-Pr 
OCH2 CF3
4-thiomethylphenyl


1811
(CH2)2

O
CH2-c-Pr 
OCH2 CF3
4-thiomethylphenyl


1812
(CH2)3

O
CH2-c-Pr 
OCH2 CF3
4-thiomethylphenyl


1813
(CH2)4

O
CH2-c-Pr 
OCH2 CF3
4-thiomethylphenyl


1814
(CH2)5

O
CH2-c-Pr 
OCH2 CF3
4-thiomethylphenyl


1815
5,5-spiro[2.3]hexane

O
CH2-c-Pr 
OCH2 CF3
4-thiomethylphenyl


1816
Cyclopentyl
H
O
CH2-c-Pr 
OCH2 CF3
4-thiomethylphenyl


1817
CH2CH3
H
O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethoxyphenyl


1818
CH2CF3
H
O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethoxyphenyl


1819
CH2CH2CH3
H
O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethoxyphenyl


1820
CH2CH(CH3)2
H
O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethoxyphenyl


1821
cyclopropylmethyl
H
O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethoxyphenyl


1822
cyclobutylmethyl
H
O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethoxyphenyl


1823
(CH2)2

O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethoxyphenyl


1824
(CH2)3

O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethoxyphenyl


1825
(CH2)4

O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethoxyphenyl


1826
(CH2)5

O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethoxyphenyl


1827
5,5-spiro[2.3]hexane

O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethoxyphenyl


1828
Cyclopentyl
H
O
CH2-c-Pr 
OCH2 CF3
4-trifluoromethoxyphenyl




















TABLE 6







Compounds of Formula IV













Ex
R1
R2
X
R3
R5
Z





1829
CH2CH3
H
O
CH2 CF3
Cl
4-trifluoromethylphenyl


1830
CH2CF3
H
O
CH2 CF3
Cl
4-trifluoromethylphenyl


1831
CH2CH2CH3
H
O
CH2 CF3
Cl
4-trifluoromethylphenyl


1832
CH2CH(CH3)2
H
O
CH2 CF3
Cl
4-trifluoromethylphenyl


1833
cyclopropylmethyl
H
O
CH2 CF3
Cl
4-trifluoromethylphenyl


1834
cyclobutylmethyl
H
O
CH2 CF3
Cl
4-trifluoromethylphenyl


1835
(CH2)2

O
CH2 CF3
Cl
4-trifluoromethylphenyl


1836
(CH2)3

O
CH2 CF3
Cl
4-trifluoromethylphenyl


1837
(CH2)4

O
CH2 CF3
Cl
4-trifluoromethylphenyl


1838
(CH2)5

O
CH2 CF3
Cl
4-trifluoromethylphenyl


1839
5,5-spiro[2.3]hexane

O
CH2 CF3
Cl
4-trifluoromethylphenyl


1840
Cyclopentyl
H
O
CH2 CF3
Cl
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2 CF3
Cl
4-tolyl


1846
cyclobutylmethyl
H
O
CH2 CF3
Cl
4-tolyl


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]hexane

O
CH2 CF3
Cl
4-tolyl


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
cyclopropylmethyl
H
O
CH2 CF3
Cl
4-ethyl phenyl


1858
cyclobutylmethyl
H
O
CH2 CF3
Cl
4-ethyl phenyl


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]hexane

O
CH2 CF3
Cl
4-ethyl phenyl


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
cyclopropylmethyl
H
O
CH2 CF3
Cl
4-isopropyl phenyl


1870
cyclobutylmethyl
H
O
CH2 CF3
Cl
4-isopropyl 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]hexane

O
CH2 CF3
Cl
4-isopropyl phenyl


1876
Cyclopentyl
H
O
CH2 CF3
Cl
4-isopropyl phenyl


1877
CH2CH3
H
O
CH2 CF3
Cl
4-thiomethylphenyl


1878
CH2CF3
H
O
CH2 CF3
Cl
4-thiomethylphenyl


1879
CH2CH2CH3
H
O
CH2 CF3
Cl
4-thiomethylphenyl


1880
CH2CH(CH3)2
H
O
CH2 CF3
Cl
4-thiomethylphenyl


1881
cyclopropylmethyl
H
O
CH2 CF3
Cl
4-thiomethylphenyl


1882
cyclobutylmethyl
H
O
CH2 CF3
Cl
4-thiomethylphenyl


1883
(CH2)2

O
CH2 CF3
Cl
4-thiomethylphenyl


1884
(CH2)3

O
CH2 CF3
Cl
4-thiomethylphenyl


1885
(CH2)4

O
CH2 CF3
Cl
4-thiomethylphenyl


1886
(CH2)5

O
CH2 CF3
Cl
4-thiomethylphenyl


1887
5,5-spiro[2.3]hexane

O
CH2 CF3
Cl
4-thiomethylphenyl


1888
Cyclopentyl
H
O
CH2 CF3
Cl
4-thiomethylphenyl


1889
CH2CH3
H
O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1890
CH2CF3
H
O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1891
CH2CH2CH3
H
O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1892
CH2CH(CH3)2
H
O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1893
cyclopropylmethyl
H
O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1894
cyclobutylmethyl
H
O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1895
(CH2)2

O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1896
(CH2)3

O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1897
(CH2)4

O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1898
(CH2)5

O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1899
5,5-spiro[2.3]hexane

O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1900
Cyclopentyl
H
O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


1901
CH2CH3
H
O
CH2-c-Pr
Cl
4-trifluoromethylphenyl


1902
CH2CF3
H
O
CH2-c-Pr
Cl
4-trifluoromethylphenyl


1903
CH2CH2CH3
H
O
CH2-c-Pr
Cl
4-trifluoromethylphenyl


1904
CH2CH(CH3)2
H
O
CH2-c-Pr
Cl
4-trifluoromethylphenyl


1905
cyclopropylmethyl
H
O
CH2-c-Pr
Cl
4-trifluoromethylphenyl


1906
cyclobutylmethyl
H
O
CH2-c-Pr
Cl
4-trifluoromethylphenyl


1907
(CH2)2

O
CH2-c-Pr
Cl
4-trifluoromethylphenyl


1908
(CH2)3

O
CH2-c-Pr
Cl
4-trifluoromethylphenyl


1909
(CH2)4

O
CH2-c-Pr
Cl
4-trifluoromethylphenyl


1910
(CH2)5

O
CH2-c-Pr
Cl
4-trifluoromethylphenyl


1911
5,5-spiro[2.3]hexane

O
CH2-c-Pr
Cl
4-trifluoromethylphenyl


1912
Cyclopentyl
H
O
CH2-c-Pr
Cl
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
Cl
4-tolyl


1918
cyclobutylmethyl
H
O
CH2-c-Pr
Cl
4-tolyl


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]hexane

O
CH2-c-Pr
Cl
4-tolyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
Cl
4-ethyl phenyl


1930
cyclobutylmethyl
H
O
CH2-c-Pr
Cl
4-ethyl phenyl


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]hexane

O
CH2-c-Pr
Cl
4-ethyl phenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
Cl
4-isopropyl phenyl


1942
cyclobutylmethyl
H
O
CH2-c-Pr
Cl
4-isopropyl 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]hexane

O
CH2-c-Pr
Cl
4-isopropyl phenyl


1948
Cyclopentyl
H
O
CH2-c-Pr
Cl
4-isopropyl phenyl


1949
CH2CH3
H
O
CH2-c-Pr
Cl
4-thiomethylphenyl


1950
CH2CF3
H
O
CH2-c-Pr
Cl
4-thiomethylphenyl


1951
CH2CH2CH3
H
O
CH2-c-Pr
Cl
4-thiomethylphenyl


1952
CH2CH(CH3)2
H
O
CH2-c-Pr
Cl
4-thiomethylphenyl


1953
cyclopropylmethyl
H
O
CH2-c-Pr
Cl
4-thiomethylphenyl


1954
cyclobutylmethyl
H
O
CH2-c-Pr
Cl
4-thiomethylphenyl


1955
(CH2)2

O
CH2-c-Pr
Cl
4-thiomethylphenyl


1956
(CH2)3

O
CH2-c-Pr
Cl
4-thiomethylphenyl


1957
(CH2)4

O
CH2-c-Pr
Cl
4-thiomethylphenyl


1958
(CH2)5

O
CH2-c-Pr
Cl
4-thiomethylphenyl


1959
5,5-spiro[2.3]hexane

O
CH2-c-Pr
Cl
4-thiomethylphenyl


1960
Cyclopentyl
H
O
CH2-c-Pr
Cl
4-thiomethylphenyl


1961
CH2CH3
H
O
CH2-c-Pr
Cl
4-trifluoromethoxyphenyl


1962
CH2CF3
H
O
CH2-c-Pr
Cl
4-trifluoromethoxyphenyl


1963
CH2CH2CH3
H
O
CH2-c-Pr
Cl
4-trifluoromethoxyphenyl


1964
CH2CH(CH3)2
H
O
CH2-c-Pr
Cl
4-trifluoromethoxyphenyl


1965
cyclopropylmethyl
H
O
CH2-c-Pr
Cl
4-trifluoromethoxyphenyl


1966
cyclobutylmethyl
H
O
CH2-c-Pr
Cl
4-trifluoromethoxyphenyl


1967
(CH2)2

O
CH2-c-Pr
Cl
4-trifluoromethoxyphenyl


1968
(CH2)3

O
CH2-c-Pr
Cl
4-trifluoromethoxyphenyl


1969
(CH2)4

O
CH2-c-Pr
Cl
4-trifluoromethoxyphenyl


1970
(CH2)5

O
CH2-c-Pr
Cl
4-trifluoromethoxyphenyl


1971
5,5-spiro[2.3]hexane

O
CH2-c-Pr
Cl
4-trifluoromethoxyphenyl


1972
Cyclopentyl
H
O
CH2-c-Pr
Cl
4-trifluoromethoxyphenyl


1973
CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1974
CH2CF3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1975
CH2CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1976
CH2CH(CH3)2
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1977
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1978
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1979
(CH2)2

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1980
(CH2)3

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1981
(CH2)4

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1982
(CH2)5

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1983
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


1984
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-tolyl


1990
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-tolyl


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]hexane

O
CH2 CF3
OCH2 CF3
4-tolyl


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
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


2002
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


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]hexane

O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


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
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


2014
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-isopropyl 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]hexane

O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


2020
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


2031
CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2032
CH2CF3
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2033
CH2CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2034
CH2CH(CH3)2
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2035
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2036
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2037
(CH2)2

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2038
(CH2)3

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2039
(CH2)4

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2040
(CH2)5

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2041
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2042
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2043
CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2044
CH2CF3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2045
CH2CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2046
CH2CH(CH3)2
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2047
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2048
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2049
(CH2)2

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2050
(CH2)3

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2051
(CH2)4

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2052
(CH2)5

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2053
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2054
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2055
CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2056
CH2CF3
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2057
CH2CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2058
CH2CH(CH3)2
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2059
cyclopropylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2060
cyclobutylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2061
(CH2)2

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2062
(CH2)3

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2063
(CH2)4

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2064
(CH2)5

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2065
5,5-spiro[2.3]hexane

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2066
Cyclopentyl
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-tolyl


2072
cyclobutylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-tolyl


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]hexane

O
CH2-c-Pr
OCH2 CF3
4-tolyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-ethyl phenyl


2084
cyclobutylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-ethyl phenyl


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]hexane

O
CH2-c-Pr
OCH2 CF3
4-ethyl phenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-isopropyl phenyl


2096
cyclobutylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-isopropyl 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]hexane

O
CH2-c-Pr
OCH2 CF3
4-isopropyl phenyl


2102
Cyclopentyl
H
O
CH2-c-Pr
OCH2 CF3
4-isopropyl phenyl


2103
CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2104
CH2CF3
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2105
CH2CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2106
CH2CH(CH3)2
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2107
cyclopropylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2108
cyclobutylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2109
(CH2)2

O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2110
(CH2)3

O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2111
(CH2)4

O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2112
(CH2)5

O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2113
5,5-spiro[2.3]hexane

O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2114
Cyclopentyl
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2115
CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2116
CH2CF3
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2117
CH2CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2118
CH2CH(CH3)2
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2119
cyclopropylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2120
cyclobutylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2121
(CH2)2

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2122
(CH2)3

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2123
(CH2)4

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2124
(CH2)5

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2125
5,5-spiro[2.3]hexane

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2126
Cyclopentyl
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl




















TABLE 7







Compounds of Formula VII













Ex
R1
R2
Y
R4
R5
Z





2127
CH2CH3
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


2128
CH2CF3
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


2129
CH2CH2CH3
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


2130
CH2CH(CH3)2
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


2131
cyclopropylmethyl
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


2132
cyclobutylmethyl
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


2133
(CH2)2

O
CH2 CF3
CF3
4-trifluoromethylphenyl


2134
(CH2)3

O
CH2 CF3
CF3
4-trifluoromethylphenyl


2135
(CH2)4

O
CH2 CF3
CF3
4-trifluoromethylphenyl


2136
(CH2)5

O
CH2 CF3
CF3
4-trifluoromethylphenyl


2137
5,5-spiro[2.3]hexane

O
CH2 CF3
CF3
4-trifluoromethylphenyl


2138
Cyclopentyl
H
O
CH2 CF3
CF3
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2 CF3
CF3
4-tolyl


2144
cyclobutylmethyl
H
O
CH2 CF3
CF3
4-tolyl


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]hexane

O
CH2 CF3
CF3
4-tolyl


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
cyclopropylmethyl
H
O
CH2 CF3
CF3
4-ethyl phenyl


2156
cyclobutylmethyl
H
O
CH2 CF3
CF3
4-ethyl phenyl


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]hexane

O
CH2 CF3
CF3
4-ethyl phenyl


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
cyclopropylmethyl
H
O
CH2 CF3
CF3
4-isopropyl phenyl


2168
cyclobutylmethyl
H
O
CH2 CF3
CF3
4-isopropyl 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]hexane

O
CH2 CF3
CF3
4-isopropyl phenyl


2174
Cyclopentyl
H
O
CH2 CF3
CF3
4-isopropyl phenyl


2175
CH2CH3
H
O
CH2 CF3
CF3
4-thiomethylphenyl


2176
CH2CF3
H
O
CH2 CF3
CF3
4-thiomethylphenyl


2177
CH2CH2CH3
H
O
CH2 CF3
CF3
4-thiomethylphenyl


2178
CH2CH(CH3)2
H
O
CH2 CF3
CF3
4-thiomethylphenyl


2179
cyclopropylmethyl
H
O
CH2 CF3
CF3
4-thiomethylphenyl


2180
cyclobutylmethyl
H
O
CH2 CF3
CF3
4-thiomethylphenyl


2181
(CH2)2

O
CH2 CF3
CF3
4-thiomethylphenyl


2182
(CH2)3

O
CH2 CF3
CF3
4-thiomethylphenyl


2183
(CH2)4

O
CH2 CF3
CF3
4-thiomethylphenyl


2184
(CH2)5

O
CH2 CF3
CF3
4-thiomethylphenyl


2185
5,5-spiro[2.3]hexane

O
CH2 CF3
CF3
4-thiomethylphenyl


2186
Cyclopentyl
H
O
CH2 CF3
CF3
4-thiomethylphenyl


2187
CH2CH3
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


2188
CH2CF3
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


2189
CH2CH2CH3
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


2190
CH2CH(CH3)2
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


2191
cyclopropylmethyl
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


2192
cyclobutylmethyl
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


2193
(CH2)2

O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


2194
(CH2)3

O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


2195
(CH2)4

O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


2196
(CH2)5

O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


2197
5,5-spiro[2.3]hexane

O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


2198
Cyclopentyl
H
O
CH2 CF3
CF3
4-trifluoromethoxyphenyl


2199
CH2CH3
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


2200
CH2CF3
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


2201
CH2CH2CH3
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


2202
CH2CH(CH3)2
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


2203
cyclopropylmethyl
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


2204
cyclobutylmethyl
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


2205
(CH2)2

O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


2206
(CH2)3

O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


2207
(CH2)4

O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


2208
(CH2)5

O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


2209
5,5-spiro[2.3]hexane

O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


2210
Cyclopentyl
H
O
CH2-c-Pr
CF3
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
CF3
4-tolyl


2216
cyclobutylmethyl
H
O
CH2-c-Pr
CF3
4-tolyl


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]hexane

O
CH2-c-Pr
CF3
4-tolyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
CF3
4-ethyl phenyl


2228
cyclobutylmethyl
H
O
CH2-c-Pr
CF3
4-ethyl phenyl


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]hexane

O
CH2-c-Pr
CF3
4-ethyl phenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
CF3
4-isopropyl phenyl


2240
cyclobutylmethyl
H
O
CH2-c-Pr
CF3
4-isopropyl 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]hexane

O
CH2-c-Pr
CF3
4-isopropyl phenyl


2246
Cyclopentyl
H
O
CH2-c-Pr
CF3
4-isopropyl phenyl


2247
CH2CH3
H
O
CH2-c-Pr
CF3
4-thiomethylphenyl


2248
CH2CF3
H
O
CH2-c-Pr
CF3
4-thiomethylphenyl


2249
CH2CH2CH3
H
O
CH2-c-Pr
CF3
4-thiomethylphenyl


2250
CH2CH(CH3)2
H
O
CH2-c-Pr
CF3
4-thiomethylphenyl


2251
cyclopropylmethyl
H
O
CH2-c-Pr
CF3
4-thiomethylphenyl


2252
cyclobutylmethyl
H
O
CH2-c-Pr
CF3
4-thiomethylphenyl


2253
(CH2)2

O
CH2-c-Pr
CF3
4-thiomethylphenyl


2254
(CH2)3

O
CH2-c-Pr
CF3
4-thiomethylphenyl


2255
(CH2)4

O
CH2-c-Pr
CF3
4-thiomethylphenyl


2256
(CH2)5

O
CH2-c-Pr
CF3
4-thiomethylphenyl


2257
5,5-spiro[2.3]hexane

O
CH2-c-Pr
CF3
4-thiomethylphenyl


2258
Cyclopentyl
H
O
CH2-c-Pr
CF3
4-thiomethylphenyl


2259
CH2CH3
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


2260
CH2CF3
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


2261
CH2CH2CH3
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


2262
CH2CH(CH3)2
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


2263
cyclopropylmethyl
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


2264
cyclobutylmethyl
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


2265
(CH2)2

O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


2266
(CH2)3

O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


2267
(CH2)4

O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


2268
(CH2)5

O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


2269
5,5-spiro[2.3]hexane

O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


2270
Cyclopentyl
H
O
CH2-c-Pr
CF3
4-trifluoromethoxyphenyl


2271
CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


2272
CH2CF3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


2273
CH2CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


2274
CH2CH(CH3)2
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


2275
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


2276
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


2277
(CH2)2

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


2278
(CH2)3

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


2279
(CH2)4

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


2280
(CH2)5

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


2281
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


2282
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-tolyl


2288
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-tolyl


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]hexane

O
CH2 CF3
OCH2 CF3
4-tolyl


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
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


2300
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


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]hexane

O
CH2 CF3
OCH2 CF3
4-ethyl phenyl


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
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


2312
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-isopropyl 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]hexane

O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


2318
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-isopropyl phenyl


2319
CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2320
CH2CF3
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2321
CH2CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2322
CH2CH(CH3)2
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2323
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2324
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2325
(CH2)2

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2326
(CH2)3

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2327
(CH2)4

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2328
(CH2)5

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2329
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2330
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-thiomethylphenyl


2331
CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2332
CH2CF3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2333
CH2CH2CH3
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2334
CH2CH(CH3)2
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2335
cyclopropylmethyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2336
cyclobutylmethyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2337
(CH2)2

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2338
(CH2)3

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2339
(CH2)4

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2340
(CH2)5

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2341
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2342
Cyclopentyl
H
O
CH2 CF3
OCH2 CF3
4-trifluoromethoxyphenyl


2343
CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2344
CH2CF3
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2345
CH2CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2346
CH2CH(CH3)2
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2347
cyclopropylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2348
cyclobutylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2349
(CH2)2

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2350
(CH2)3

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2351
(CH2)4

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2352
(CH2)5

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2353
5,5-spiro[2.3]hexane

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


2354
Cyclopentyl
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethylphenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-tolyl


2360
cyclobutylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-tolyl


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]hexane

O
CH2-c-Pr
OCH2 CF3
4-tolyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-ethyl phenyl


2372
cyclobutylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-ethyl phenyl


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]hexane

O
CH2-c-Pr
OCH2 CF3
4-ethyl phenyl


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
cyclopropylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-isopropyl phenyl


2384
cyclobutylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-isopropyl 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]hexane

O
CH2-c-Pr
OCH2 CF3
4-isopropyl phenyl


2390
Cyclopentyl
H
O
CH2-c-Pr
OCH2 CF3
4-isopropyl phenyl


2391
CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2392
CH2CF3
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2393
CH2CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2394
CH2CH(CH3)2
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2395
cyclopropylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2396
cyclobutylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2397
(CH2)2

O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2398
(CH2)3

O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2399
(CH2)4

O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2400
(CH2)5

O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2401
5,5-spiro[2.3]hexane

O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2402
Cyclopentyl
H
O
CH2-c-Pr
OCH2 CF3
4-thiomethylphenyl


2403
CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2404
CH2CF3
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2405
CH2CH2CH3
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2406
CH2CH(CH3)2
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2407
cyclopropylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2408
cyclobutylmethyl
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2409
(CH2)2

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2410
(CH2)3

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2411
(CH2)4

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2412
(CH2)5

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2413
5,5-spiro[2.3]hexane

O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl


2414
Cyclopentyl
H
O
CH2-c-Pr
OCH2 CF3
4-trifluoromethoxyphenyl




















TABLE 8







Compounds of Formula VII













Ex
R1
R2
Y
R4
R5
Z





2415
CH2CH3
H
O
CH2 CF3
Cl
4-trifluoromethylphenyl


2416
CH2CF3
H
O
CH2 CF3
Cl
4-trifluoromethylphenyl


2417
CH2CH2CH3
H
O
CH2 CF3
Cl
4-trifluoromethylphenyl


2418
CH2CH(CH3)2
H
O
CH2 CF3
Cl
4-trifluoromethylphenyl


2419
cyclopropylmethyl
H
O
CH2 CF3
Cl
4-trifluoromethylphenyl


2420
cyclobutylmethyl
H
O
CH2 CF3
Cl
4-trifluoromethylphenyl


2421
(CH2)2

O
CH2 CF3
Cl
4-trifluoromethylphenyl


2422
(CH2)3

O
CH2 CF3
Cl
4-trifluoromethylphenyl


2423
(CH2)4

O
CH2 CF3
Cl
4-trifluoromethylphenyl


2424
(CH2)5

O
CH2 CF3
Cl
4-trifluoromethylphenyl


2425
5,5-spiro[2.3]hexane

O
CH2 CF3
Cl
4-trifluoromethylphenyl


2426
Cyclopentyl
H
O
CH2 CF3
Cl
4-trifluoromethylphenyl


2427
CH2CH3
H
O
CH2 CF3
Cl
4-tolyl


2428
CH2CF3
H
O
CH2 CF3
Cl
4-tolyl


2429
CH2CH2CH3
H
O
CH2 CF3
Cl
4-tolyl


2430
CH2CH(CH3)2
H
O
CH2 CF3
Cl
4-tolyl


2431
cyclopropylmethyl
H
O
CH2 CF3
Cl
4-tolyl 


2432
cyclobutylmethyl
H
O
CH2 CF3
Cl
4-tolyl


2433
(CH2)2

O
CH2 CF3
Cl
4-tolyl


2434
(CH2)3

O
CH2 CF3
Cl
4-tolyl


2435
(CH2)4

O
CH2 CF3
Cl
4-tolyl


2436
(CH2)5

O
CH2 CF3
Cl
4-tolyl


2437
5,5-spiro[2.3]hexane

O
CH2 CF3
Cl
4-tolyl


2438
Cyclopentyl
H
O
CH2 CF3
Cl
4-tolyl


2439
CH2CH3
H
O
CH2 CF3
Cl
4-ethyl phenyl


2440
CH2CF3
H
O
CH2 CF3
Cl
4-ethyl phenyl


2441
CH2CH2CH3
H
O
CH2 CF3
Cl
4-ethyl phenyl


2442
CH2CH(CH3)2
H
O
CH2 CF3
Cl
4-ethyl phenyl


2443
cyclopropylmethyl
H
O
CH2 CF3
Cl
4-ethyl phenyl


2444
cyclobutylmethyl
H
O
CH2 CF3
Cl
4-ethyl phenyl


2445
(CH2)2

O
CH2 CF3
Cl
4-ethyl phenyl


2446
(CH2)3

O
CH2 CF3
Cl
4-ethyl phenyl


2447
(CH2)4

O
CH2 CF3
Cl
4-ethyl phenyl


2448
(CH2)5

O
CH2 CF3
Cl
4-ethyl phenyl


2449
5,5-spiro[2.3]hexane

O
CH2 CF3
Cl
4-ethyl phenyl


2450
Cyclopentyl
H
O
CH2 CF3
Cl
4-ethyl phenyl


2451
CH2CH3
H
O
CH2 CF3
Cl
4-isopropyl phenyl


2452
CH2CF3
H
O
CH2 CF3
Cl
4-isopropyl phenyl


2453
CH2CH2CH3
H
O
CH2 CF3
Cl
4-isopropyl phenyl


2454
CH2CH(CH3)2
H
O
CH2 CF3
Cl
4-isopropyl phenyl


2455
cyclopropylmethyl
H
O
CH2 CF3
Cl
4-isopropyl phenyl


2456
cyclobutylmethyl
H
O
CH2 CF3
Cl
4-isopropyl phenyl


2457
(CH2)2

O
CH2 CF3
Cl
4-isopropyl phenyl


2458
(CH2)3

O
CH2 CF3
Cl
4-isopropyl phenyl


2459
(CH2)4

O
CH2 CF3
Cl
4-isopropyl phenyl


2460
(CH2)5

O
CH2 CF3
Cl
4-isopropyl phenyl


2461
5,5-spiro[2.3]hexane

O
CH2 CF3
Cl
4-isopropyl phenyl


2462
Cyclopentyl
H
O
CH2 CF3
Cl
4-isopropyl phenyl


2463
CH2CH3
H
O
CH2 CF3
Cl
4-thiomethylphenyl


2464
CH2CF3
H
O
CH2 CF3
Cl
4-thiomethylphenyl


2465
CH2CH2CH3
H
O
CH2 CF3
Cl
4-thiomethylphenyl


2466
CH2CH(CH3)2
H
O
CH2 CF3
Cl
4-thiomethylphenyl


2467
cyclopropylmethyl
H
O
CH2 CF3
Cl
4-thiomethylphenyl


2468
cyclobutylmethyl
H
O
CH2 CF3
Cl
4-thiomethylphenyl


2469
(CH2)2

O
CH2 CF3
Cl
4-thiomethylphenyl


2470
(CH2)3

O
CH2 CF3
Cl
4-thiomethylphenyl


2471
(CH2)4

O
CH2 CF3
Cl
4-thiomethylphenyl


2472
(CH2)5

O
CH2 CF3
Cl
4-thiomethylphenyl


2473
5,5-spiro[2.3]hexane

O
CH2 CF3
Cl
4-thiomethylphenyl


2474
Cyclopentyl
H
O
CH2 CF3
Cl
4-thiomethylphenyl


2475
CH2CH3
H
O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


2476
CH2CF3
H
O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


2477
CH2CH2CH3
H
O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


2478
CH2CH(CH3)2
H
O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


2479
cyclopropylmethyl
H
O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


2480
cyclobutylmethyl
H
O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


2481
(CH2)2

O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


2482
(CH2)3

O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


2483
(CH2)4

O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


2484
(CH2)5

O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


2485
5,5-spiro[2.3]hexane

O
CH2 CF3
Cl
4-trifluoromethoxyphenyl


2486
Cyclopentyl
H
O
CH2 CF3
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
CH2 CF3
OCH2CF3
4-trifluoromethylphenyl


2560
CH2CF3
H
O
CH2 CF3
OCH2CF3
4-trifluoromethylphenyl


2561
CH2CH2CH3
H
O
CH2 CF3
OCH2CF3
4-trifluoromethylphenyl


2562
CH2CH(CH3)2
H
O
CH2 CF3
OCH2CF3
4-trifluoromethylphenyl


2563
cyclopropylmethyl
H
O
CH2 CF3
OCH2CF3
4-trifluoromethylphenyl


2564
cyclobutylmethyl
H
O
CH2 CF3
OCH2CF3
4-trifluoromethylphenyl


2565
(CH2)2

O
CH2 CF3
OCH2CF3
4-trifluoromethylphenyl


2566
(CH2)3

O
CH2 CF3
OCH2CF3
4-trifluoromethylphenyl


2567
(CH2)4

O
CH2 CF3
OCH2CF3
4-trifluoromethylphenyl


2568
(CH2)5

O
CH2 CF3
OCH2CF3
4-trifluoromethylphenyl


2569
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2CF3
4-trifluoromethylphenyl


2570
Cyclopentyl
H
O
CH2 CF3
OCH2CF3
4-trifluoromethylphenyl


2571
CH2CH3
H
O
CH2 CF3
OCH2CF3
4-tolyl


2572
CH2CF3
H
O
CH2 CF3
OCH2CF3
4-tolyl


2573
CH2CH2CH3
H
O
CH2 CF3
OCH2CF3
4-tolyl


2574
CH2CH(CH3)2
H
O
CH2 CF3
OCH2CF3
4-tolyl


2575
cyclopropylmethyl
H
O
CH2 CF3
OCH2CF3
4-tolyl


2576
cyclobutylmethyl
H
O
CH2 CF3
OCH2CF3
4-tolyl


2577
(CH2)2

O
CH2 CF3
OCH2CF3
4-tolyl


2578
(CH2)3

O
CH2 CF3
OCH2CF3
4-tolyl


2579
(CH2)4

O
CH2 CF3
OCH2CF3
4-tolyl


2580
(CH2)5

O
CH2 CF3
OCH2CF3
4-tolyl


2581
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2CF3
4-tolyl


2582
Cyclopentyl
H
O
CH2 CF3
OCH2CF3
4-tolyl


2583
CH2CH3
H
O
CH2 CF3
OCH2CF3
4-ethyl phenyl


2584
CH2CF3
H
O
CH2 CF3
OCH2CF3
4-ethyl phenyl


2585
CH2CH2CH3
H
O
CH2 CF3
OCH2CF3
4-ethyl phenyl


2586
CH2CH(CH3)2
H
O
CH2 CF3
OCH2CF3
4-ethyl phenyl


2587
cyclopropylmethyl
H
O
CH2 CF3
OCH2CF3
4-ethyl phenyl


2588
cyclobutylmethyl
H
O
CH2 CF3
OCH2CF3
4-ethyl phenyl


2589
(CH2)2

O
CH2 CF3
OCH2CF3
4-ethyl phenyl


2590
(CH2)3

O
CH2 CF3
OCH2CF3
4-ethyl phenyl


2591
(CH2)4

O
CH2 CF3
OCH2CF3
4-ethyl phenyl


2592
(CH2)5

O
CH2 CF3
OCH2CF3
4-ethyl phenyl


2593
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2CF3
4-ethyl phenyl


2594
Cyclopentyl
H
O
CH2 CF3
OCH2CF3
4-ethyl phenyl


2595
CH2CH3
H
O
CH2 CF3
OCH2CF3
4-isopropyl phenyl


2596
CH2CF3
H
O
CH2 CF3
OCH2CF3
4-isopropyl phenyl


2597
CH2CH2CH3
H
O
CH2 CF3
OCH2CF3
4-isopropyl phenyl


2598
CH2CH(CH3)2
H
O
CH2 CF3
OCH2CF3
4-isopropyl phenyl


2599
cyclopropylmethyl
H
O
CH2 CF3
OCH2CF3
4-isopropyl phenyl


2600
cyclobutylmethyl
H
O
CH2 CF3
OCH2CF3
4-isopropyl phenyl


2601
(CH2)2

O
CH2 CF3
OCH2CF3
4-isopropyl phenyl


2602
(CH2)3

O
CH2 CF3
OCH2CF3
4-isopropyl phenyl


2603
(CH2)4

O
CH2 CF3
OCH2CF3
4-isopropyl phenyl


2604
(CH2)5

O
CH2 CF3
OCH2CF3
4-isopropyl phenyl


2605
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2CF3
4-isopropyl phenyl


2606
Cyclopentyl
H
O
CH2 CF3
OCH2CF3
4-isopropyl phenyl


2607
CH2CH3
H
O
CH2 CF3
OCH2CF3
4-thiomethylphenyl


2608
CH2CF3
H
O
CH2 CF3
OCH2CF3
4-thiomethylphenyl


2609
CH2CH2CH3
H
O
CH2 CF3
OCH2CF3
4-thiomethylphenyl


2610
CH2CH(CH3)2
H
O
CH2 CF3
OCH2CF3
4-thiomethylphenyl


2611
cyclopropylmethyl
H
O
CH2 CF3
OCH2CF3
4-thiomethylphenyl


2612
cyclobutylmethyl
H
O
CH2 CF3
OCH2CF3
4-thiomethylphenyl


2613
(CH2)2

O
CH2 CF3
OCH2CF3
4-thiomethylphenyl


2614
(CH2)3

O
CH2 CF3
OCH2CF3
4-thiomethylphenyl


2615
(CH2)4

O
CH2 CF3
OCH2CF3
4-thiomethylphenyl


2616
(CH2)5

O
CH2 CF3
OCH2CF3
4-thiomethylphenyl


2617
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2CF3
4-thiomethylphenyl


2618
Cyclopentyl
H
O
CH2 CF3
OCH2CF3
4-thiomethylphenyl


2619
CH2CH3
H
O
CH2 CF3
OCH2CF3
4-trifluoromethoxyphenyl


2620
CH2CF3
H
O
CH2 CF3
OCH2CF3
4-trifluoromethoxyphenyl


2621
CH2CH2CH3
H
O
CH2 CF3
OCH2CF3
4-trifluoromethoxyphenyl


2622
CH2CH(CH3)2
H
O
CH2 CF3
OCH2CF3
4-trifluoromethoxyphenyl


2623
cyclopropylmethyl
H
O
CH2 CF3
OCH2CF3
4-trifluoromethoxyphenyl


2624
cyclobutylmethyl
H
O
CH2 CF3
OCH2CF3
4-trifluoromethoxyphenyl


2625
(CH2)2

O
CH2 CF3
OCH2CF3
4-trifluoromethoxyphenyl


2626
(CH2)3

O
CH2 CF3
OCH2CF3
4-trifluoromethoxyphenyl


2627
(CH2)4

O
CH2 CF3
OCH2CF3
4-trifluoromethoxyphenyl


2628
(CH2)5

O
CH2 CF3
OCH2CF3
4-trifluoromethoxyphenyl


2629
5,5-spiro[2.3]hexane

O
CH2 CF3
OCH2CF3
4-trifluoromethoxyphenyl


2630
Cyclopentyl
H
O
CH2 CF3
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













Ex
R1
R2
Y
R4
R5
Z





2704
CH2CH3
H
O
CH2 CH2 CF3
Cl
4-trifluoromethylphenyl


2705
CH2CF3
H
O
CH2 CH2 CF3
Cl
4-trifluoromethylphenyl


2706
CH2CH2CH3
H
O
CH2 CH2 CF3
Cl
4-trifluoromethylphenyl


2707
CH2CH(CH3)2
H
O
CH2 CH2 CF3
Cl
4-trifluoromethylphenyl


2708
cyclopropylmethyl 
H
O
CH2 CH2 CF3
Cl
4-trifluoromethylphenyl


2709
cyclobutylmethyl
H
O
CH2 CH2 CF3
Cl
4-trifluoromethylphenyl


2710
(CH2)2

O
CH2 CH2 CF3
Cl
4-trifluoromethylphenyl


2711
(CH2)3

O
CH2 CH2 CF3
Cl
4-trifluoromethylphenyl


2712
(CH2)4

O
CH2 CH2 CF3
Cl
4-trifluoromethylphenyl


2713
(CH2)5

O
CH2 CH2 CF3
Cl
4-trifluoromethylphenyl


2714
5,5-spiro[2.3]hexane

O
CH2 CH2 CF3
Cl
4-trifluoromethylphenyl


2715
Cyclopentyl
H
O
CH2 CH2 CF3
Cl
4-trifluoromethylphenyl




















TABLE 10







Compounds of Formula III













Ex
R1
R2
Y
R4
R5
Z





2716
CH2CH3
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2717
CH2CF3
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2718
CH2CH2CH3
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2719
CH2CH(CH3)2
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2720
cyclopropylmethyl 
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2721
cyclobutylmethyl
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2722
(CH2)2

O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2723
(CH2)3

O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2724
(CH2)4

O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2725
(CH2)5

O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2726
5,5-spiro[2.3]hexane

O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2727
Cyclopentyl
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2733
cyclobutylmethyl
H
O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


2735
(CH2)3

O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


2737
(CH2)5

O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


2738
5,5-spiro[2.3]hexane

O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


2739
Cyclopentyl
H
O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


2745
cyclobutylmethyl 
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


2747
(CH2)3

O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


2749
(CH2)5

O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


2750
5,5-spiro[2.3]hexane

O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


2751
Cyclopentyl
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


2752
CH2CH3
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2753
CH2CF3
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2754
CH2CH2CH3
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2755
CH2CH(CH3)2
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2756
cyclopropylmethyl
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2757
cyclobutylmethyl 
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2758
(CH2)2

O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2759
(CH2)3

O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2760
(CH2)4

O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2761
(CH2)5

O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2762
5,5-spiro[2.30]hexane

O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2763
Cyclopentyl
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2769
cyclobutylmethyl 
H
O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


2771
(CH2)3

O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


2773
(CH2)5

O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


2774
5,5-spiro[2.3]hexane

O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


2775
Cyclopentyl
H
O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


2781
cyclobutylmethyl 
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


2783
(CH2)3

O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


2785
(CH2)5

O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


2786
5,5-spiro[2.3]hexane

O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


2787
Cyclopentyl
H
O
CH2 CF3
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













Ex
R1
R2
X
R3
R5
Z





2860
CH2CH3
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2861
CH2CF3
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2862
CH2CH2CH3
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2863
CH2CH(CH3)2
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2864
cyclopropylmethyl
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2865
cyclobutylmethyl 
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2866
(CH2)2

O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2867
(CH2)3

O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2868
(CH2)4 

O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2869
(CH2)5

O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2870
5,5-spiro[2.3]hexane

O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2871
Cyclopentyl
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


2872
CH2CH3
H
O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


2873
CH2CF3
H
O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


2874
CH2CH2CH3
H
O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


2875
CH2CH(CH3)2
H
O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


2876
cyclopropylmethyl
H
O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


2877
cyclobutylmethyl
H
O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


2878
(CH2)2

O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


2879
(CH2)3

O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


2880
(CH2)4

O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


2881
(CH2)5

O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


2882
5,5-spiro[2.3]hexane

O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


2883
Cyclopentyl
H
O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


2884
CH2CH3
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


2885
CH2CF3
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


2886
CH2CH2CH3
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


2887
CH2CH(CH3)2
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


2888
cyclopropylmethyl
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


2889
cyclobutylmethyl
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


2890
(CH2)2

O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


2891
(CH2)3

O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


2892
(CH2)4

O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


2893
(CH2)5

O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


2894
5,5-spiro[2.3]hexane

O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


2895
Cyclopentyl
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


2896
CH2CH3
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2897
CH2CF3
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2898
CH2CH2CH3
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2899
CH2CH(CH3)2
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2900
cyclopropylmethyl
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2901
cyclobutylmethyl 
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2902
(CH2)2

O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2903
(CH2)3

O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2904
(CH2)4

O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2905
(CH2)5

O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2906
5,5-spiro[2.3]hexane

O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2907
Cyclopentyl
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


2908
CH2CH3
H
O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


2909
CH2CF3
H
O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


2910
CH2CH2CH3
H
O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


2911
CH2CH(CH3)2
H
O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


2912
cyclopropylmethyl
H
O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


2913
cyclobutylmethyl 
H
O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


2914
(CH2)2

O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


2915
(CH2)3

O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


2916
(CH2)4

O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


2917
(CH2)5

O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


2918
5,5-spiro[2.3]hexane

O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


2919
Cyclopentyl
H
O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


2920
CH2CH3
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


2921
CH2CF3
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


2922
CH2CH2CH3
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


2923
CH2CH(CH3)2
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


2924
cyclopropylmethyl
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


2925
cyclobutylmethyl 
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


2926
(CH2)2

O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


2927
(CH2)3

O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


2928
(CH2)4

O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


2929
(CH2)5

O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


2930
5,5-spiro[2.3]hexane

O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


2931
Cyclopentyl
H
O
CH2 CF3
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
CH2CH(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
CH2CH(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
CH2CH(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
CH2CH(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
CH2CH(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
CH2CH(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













Ex
R1
R2
Y
R4
R5
Z





3004
CH2CH3
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


3005
CH2CF3
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


3006
CH2CH2CH3
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


3007
CH2CH(CH3)2
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


3008
cyclopropylmethyl
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


3009
cyclobutylmethyl
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


3010
(CH2)2

O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


3011
(CH2)3

O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


3012
(CH2)4

O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


3013
(CH2)5

O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


3014
5,5-spiro[2.3]hexane

O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


3015
Cyclopentyl
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]oxadiazole


3016
CH2CH3
H
O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


3017
CH2CF3
H
O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


3018
CH2CH2CH3
H
O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


3019
CH2CH(CH3)2
H
O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


3020
cyclopropylmethyl
H
O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


3021
cyclobutylmethyl
H
O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


3022
(CH2)2

O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


3023
(CH2)3

O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


3024
(CH2)4

O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


3025
(CH2)5

O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


3026
5,5-spiro[2.3]hexane

O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


3027
Cyclopentyl
H
O
CH2 CF3
F
5-benzo[c][1,2,5]oxadiazole


3028
CH2CH3
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


3029
CH2CF3
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


3030
CH2CH2CH3
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


3031
CH2CH(CH3)2
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


3032
cyclopropylmethyl
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


3033
cyclobutylmethyl
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


3034
(CH2)2

O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


3035
(CH2)3

O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


3036
(CH2)4

O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


3037
(CH2)5

O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


3038
5,5-spiro[2.3]hexane

O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


3039
Cyclopentyl
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]oxadiazole


3040
CH2CH3
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


3041
CH2CF3
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


3042
CH2CH2CH3
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


3043
CH2CH(CH3)2
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


3044
cyclopropylmethyl
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


3045
cyclobutylmethyl 
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


3046
(CH2)2

O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


3047
(CH2)3

O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


3048
(CH2)4

O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


3049
(CH2)5

O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


3050
5,5-spiro[2.3]hexane

O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


3051
Cyclopentyl
H
O
CH2 CF3
CF3
5-benzo[c][1,2,5]thiadiazole


3052
CH2CH3
H
O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


3053
CH2CF3
H
O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


3054
CH2CH2CH3
H
O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


3055
CH2CH(CH3)2
H
O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


3056
cyclopropylmethyl
H
O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


3057
cyclobutylmethyl 
H
O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


3058
(CH2)2

O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


3059
(CH2)3

O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


3060
(CH2)4

O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


3061
(CH2)5

O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


3062
5,5-spiro[2.3]hexane

O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


3063
Cyclopentyl
H
O
CH2 CF3
F
5-benzo[c][1,2,5]thiadiazole


3064
CH2CH3
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


3065
CH2CF3
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


3066
CH2CH2CH3
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


3067
CH2CH(CH3)2
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


3068
cyclopropylmethyl
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


3069
cyclobutylmethyl 
H
O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


3070
(CH2)2

O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


3071
(CH2)3

O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


3072
(CH2)4

O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


3073
(CH2)5

O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


3074
5,5-spiro[2.3]hexane

O
CH2 CF3
Cl
5-benzo[c][1,2,5]thiadiazole


3075
Cyclopentyl
H
O
CH2 CF3
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
CH2CH(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
CH2CH(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


3100
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
CH2CH(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
CH2CH(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
CH2CH(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
CH2CH(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 mmo) 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 x2). 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 molo) 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 CeliteTM, 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: 1HNMR (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: 1HNMR (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: 1HNMR (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+2Na)+: 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 NH2SO4 (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 molo) 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
4-(5-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 CeliteTM 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). 1HNMR (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 CeliteTM 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 CeliteTM 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 room temperature. The reaction mixture was diluted with water, 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 ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (1.5 g) as a yellow solid.
Step 4
Ethyl 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate




A mixture of ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (0.32 g, 0.86 mmol), 4-trifluoromethylphenylboronic acid (0.246 g, 1.3 mmol), CsF (0.262 g, 1.7 mmol) and Pd (PPh3)4 (0.1 g, 0.08 mmol) in 10 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled to RT and 25 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over Na2SO4, 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 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.290 g) as a yellow oil.
Step 5
Ethyl 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate




Ethyl 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.280 g, 0.64 mmol) was dissolved in a mixture of MeCN/H2O/HCl 10 mL/10 mL/4 mL at 0° C. A solution of NaNO2 (0.066 g, 0.96 mmol) in water (2 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 (0.32 g, 3.2 mmol) in water (2 mL) was added drop wise at 0° C. The reaction mixture was heated to 70° C. for 1 h and the solvent was evaporated under reduced pressure. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na2SO4, filtered and concentrated to give crude black oil which was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.110 g) as yellow oil.
Step 6
1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylic acid




Ethyl 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.1 g) dissolved in MeOH/THF/H2O (10 mL/10 mL/5 mL) and 70 mg LiOH added. The reaction mixture was stirred at room temperature 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 extracts were dried over MgSO4, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylic acid (75 mg) as a white solid. 1H-NMR (500 MHz, CDCl3): 7.71 (d, 2H), 7.54 (d, 2H), 6.86 (s, 1H), 6.85 (s, 1H), 3.97 (d, 2H), 2.85 (m, 2H), 2.54 (m, 2H), 2.13 (m, 1H), 1.92 (m, 1H), 1.35 (t, 1H), 0.47 (m, 2H), 0.41 (m, 2H).
Example 2495
1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylic acid




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




Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)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, 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), and dried over MgSO4, filtered and concentrated under reduced pressure to give ethyl 1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclopentanecarboxylate (380 mg) as a colorless oil.
Step 2
Ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate




To a stirred solution of ethyl 1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclopentanecarboxylate (10 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 mixture was filtered through a pad of CeliteTM, washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate (7.5 g) as a thick liquid.
Step 3
Ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate




To a stirred solution of ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate (1.2 g, 4.0 mmol) in dry CCl4 (60 mL), NBS (0.427 g, 3.2 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, 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 ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate (920 mg) as a yellow solid.
Step 4
Ethyl 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate




A mixture of ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate (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, and 75 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (4.6 g) as a yellow oil.
Step 5
Ethyl 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate




Ethyl 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (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 solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution 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 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate as yellow oil (1.1 g).
Step 6
1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylic acid




Ethyl 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (80 mg) 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 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-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentane carboxylic acid (45 mg) as a white solid. 1H-NMR (500 MHz, CDCl3): 7.68 (d, 2H), 7.55 (d, 2H), 6.99 (s, 1H), 6.97 (s, 1H), 3.97 (d, 2H), 2.64 (m, 2H), 1.95 (m, 2H), 1.77 (m, 4H), 1.21 (m, 1H), 0.45 (m, 2H), 0.18 (m, 2H);
Example 2419
2-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid




Step 1
Ethyl 3-cyclopropyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)propanoate




Ethyl 2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)acetate (2 g, 6.5 mmol) was dissolved in 50 mL anhydrous DMF, NaH (60% wt. in oil, 0.171 g, 7.1 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and cyclopropylmethyl bromide (0.967 g, 7.16 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-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)propanoate (1.05 g) as a colorless oil.
Step 2
Ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate




To a stirred solution of ethyl 3-cyclopropyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)propanoate (1.0 g), in dry MeOH (100 mL) Pd(OH)2 (500 mg) was added and the mixture was reduced under an atmosphere of H2 for 6 h at room temperature. The mixture was filtered off through a pad of CeliteTM, washing with MeOH. The combined filtrates were concentrated under reduced pressure to give ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (0.9 g) as a thick liquid.
Step 3
Ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate




To a stirred solution of ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (0.9 g, 2.7 mmol) in dry CHCl3 (50 mL), NBS (0.412 g, 2.3 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to give ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (1.02 g) as a yellow solid.
Step 4
Ethyl 2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate




A mixture of ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (1.1, 3.3 mmol), 4-trifluoromethylphenylboronic acid (1.26 g, 6.7 mmol), CsF (1.26 g, 8.3 mmol) and Pd (PPh3)4 (0.38 g, 0.33 mmol) in 50 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 50 mL of EtOAc and 50 mL of water were added. The organic phase was separated, dried over Na2SO4, 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-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (0.85 g, 82% yield) as a white solid.
Step 5
Ethyl 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate




Ethyl 2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (0.85 g, 1.78 mmol) was dissolved in a mixture of MeCN/H2O/HCl 15 mL/15 mL/2 mL at 0° C. A solution of NaNO2 (0.185 g, 2.68 mmol) in water (2 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 (1.8 g, 17.8 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 90° C. for 2 h. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na2SO4, filtered and concentrated under reduced pressure to give an oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (0.528 g) as a yellow oil.
Step 6
2-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid




The ethyl 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (500 mg, 1.01 mmol) dissolved in 20 mL of MeOH/THF/H2O (10 mL/10 mL/5 mL) and LiOH (57 mg) was added. The reaction mixture was stirred at room temperature 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 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclopropylpropanoic acid (250 mg) as a white solid. 1H-NMR (500 MHz, CDCl3): 7.72 (d, 2H), 7.54 (d, 2H), 7.02 (d, 2H), 4.44 (q, 2H), 3.72 (t, 1H), 1.92 (m, 1H), 1.79 (m, 1H), 1.08 (m, 1H), 0.66 (m, 1H), 0.44 (m, 2H), 0.16 (m, 2H).
Example 2422
Ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate




Step 1
Ethyl 1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate




Ethyl 2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)acetate (3 g, 9.7 mmol) was dissolved in 50 mL anhydrous DMF, NaH (60% wt. in oil, 0.514 g, 10.7 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and 1,3-dibromopropane (1.03 mL, 9.7 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 1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (900 mg) as a colorless oil.
Step 2
Ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate




To a stirred solution of ethyl 1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (900 mg), in dry MeOH (50 mL), Pd(OH)2 (400 mg) was added and the mixture reduced under an atmosphere of H2 for 6 h at room temperature. The mixture was filtered through a pad of CeliteTM washing with MeOH, the combined filtrates were concentrated under reduced pressure to yield ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (800 mg) as a thick liquid.
Step 3
Ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate




To a stirred solution of ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)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 hat room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents were dried over Na2SO4, filtered and concentrated under educed pressure. The crude reaction mixture was purified by column chromatography to give ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (1.5 g) as a yellow solid.
Step 4
Ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate




A mixture of ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (0.32 g, 0.86 mmol), 4-trifluoromethylphenylboronic acid (0.246 g, 1.3 mmol), CsF (0.262 g, 1.7 mmol) and Pd (PPh3)4 (0.1 g, 0.08 mmol) in 10 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 25 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over Na2SO4, 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 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.290 g) as a yellow oil.
Step 5
Ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate




Ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.280 g, 0.64 mmol) was dissolved in a mixture of MeCN/H2O/HCl 10 mL/10 mL/4 mL at 0° C. A solution of NaNO2 (0.066 g, 0.96 mmol) in water (2 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 (0.32 g, 3.2 mmol) in water (2 mL) was added drop wise at 0° C. The reaction mixture was heated to 70° C. for 1 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na2SO4, filtered and concentrated to give oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate as a yellow oil (0.110 g).
Step 6
1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylic acid




Ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.1 g) dissolved in MeOH/THF/H2O (10 mL/10 mL/5 mL) and 70 mg LiOH added. The reaction mixture was stirred at room temperature 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 evaporated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylic acid (75 mg) of the product as a white solid. 1H-NMR (500 MHz, CDCl3): 7.74 (d, 2H), 7.53 (d, 2H), 6.99 (s, 1H), 6.97 (s, 1H), 4.43 (q, 2H), 2.88 (m, 2H), 2.54 (m, 2H), 2.15 (m, 1H), 1.93 (m, 1H)
Example 2423
1-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylic acid




Step 1
Ethyl 1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate




Ethyl 2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)acetate (0.5 g, mmol) 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, 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-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentane carboxylate (380 mg) as a colorless oil.
Step 2
Ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate




To a stirred solution of ethyl 1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentane carboxylate (10 g), in dry MeOH (100 mL) Pd(OH)2 (2 g) was added and reduced under an atmosphere of H2 for 6 h at room temperature. The mixture was filtered through a pad of CeliteTM washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (7.5 g) as a thick liquid.
Step 3
Ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate




To a stirred solution of ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (1.2 g, 4.0 mmol) in dry CCl4 (60 mL), NBS (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, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to give ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (920 mg) as a yellow solid.
Step 4
Ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate




A mixture of ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (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, and 75 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (4.6 g) as a yellow oil.
Step 5
Ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate




Ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (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 solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na2SO4, filtered and concentrated under reduced pressure to give an oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give the ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentane carboxylate (1.1 g) as yellow oil.
Step 6
1-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylic acid




The ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentane carboxylate (80 mg) 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 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-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentane carboxylic acid (45 mg) as a white solid. 1H-NMR (500 MHz, CDCl3): 7.74 (d, 2H), 7.55 (d, 2H), 7.08 (s, 1H), 4.44 (q, 2H), 2.66 (m, 2H), 1.98 (m, 2H), 1.78 (m, 4H).
Example 2418
2-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid




Step 1
Ethyl 4-methyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)pentanoate




Ethyl 2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)acetate (4 g, 16.2 mmol) was dissolved in 50 mL anhydrous DMF and NaH (60% wt. in oil, 0.846 g, 21.1 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and isobutyl bromide (2.12 mL, 19.5 mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH4Cl solution 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 4-methyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)pentanoate (1.5 g) as a colorless oil.
Step 2
Ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate




To a stirred solution of ethyl 4-methyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)pentanoate (1.5 g), in dry MeOH (100 mL), Pd(OH)2 (500 mg) was added and the mixture reduced under an atmosphere of H2 for 6 h at room temperature. The mixture was filtered through a pad of CeliteTM washing with MeOH. The combined filtrates were concentrated under reduced pressure to give ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (1.2 g) as a thick liquid.
Step 3
Ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate




To a stirred solution of ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.750 g, 2.2 mmol) in dry CHCl3 (100 mL), NBS (0.320 g, 1.8 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, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to give ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (700 mg) as a yellow solid.
Step 4
Ethyl 2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate




A mixture of ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.70 g, 1.6 mmol), 4-trifluoromethylphenylboronic acid (0.642 g, 3.39 mmol), CsF (0.641 g, 4.2 mmol) and Pd (PPh3)4 (0.196 g, 0.16 mmol) in 40 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 35 mL of EtOAc and 35 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (650 mg) as a colorless liquid.
Step 5
Ethyl 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate




Ethyl 2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (640 mg, 1.3 mmol) was dissolved in a mixture of MeCN/H2O/HCl 15 mL/15 mL/1 mL at 0° C. A solution of NaNO2 (0.138 g, 2.0 mmol) in water (2 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 (1.32 g, 13.4 mmol) in water (5 mL) was added drop wise at 0° C. The reaction mixture was heated to 80° C. for 2 h and the mixture was concentrated under reduced pressure. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na2SO4, filtered and concentrated to give crude black oil which was purified by chromatography over silica gel (hexane/EtOAc) to give the ethyl 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (380 mg) as a yellow solid.
Step 6
2-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid




Ethyl 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (320 mg, 0.647 mmol) was dissolved in a MeOH/THF/H2O (10 mL/10 mL/5 mL) mixture, LiOH (163 mg, 3.88 mmol) was 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 evaporated under reduced pressure. Purification was achived by re-crystallization in hexane/ether mixture to give 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (220 mg) as a white solid. 1H-NMR (500 MHz, CDCl3): 7.74 (d, 2H), 7.55 (d, 2H), 7.01 (s, 2H), 4.44 (q, 2H), 3.68 (t, 1H), 1.98 (m, 2H), 1.61 (m, 1H), 1.54 (m, 1H), 0.95 (d, 6H)
Example 1277
2-(5-Chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoic acid




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




To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (25 g, 138 mmol) in 375 ml of DCM, sulfuryl chloride (9.48 mL 118 mmol) was slowly added at 0° C. over a period of 30 min. Diethyl ether (19.6 mL) was slowly added reaction mixture at 0° C. and stirring was continued for 30 min at 0° C. The reaction mixture was slowly warmed to 15° C. for 1 h. After completion of reaction, the mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layers were washed with 10% NaHCO3 solution followed by water. The organic layer was dried over Na2SO4, filtered and evaporated under vacuum to give compound ethyl 2-(3-chloro-4-hydroxyphenyl)acetate (15 g) as a thick oil.
Step 2
Ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate




To a stirred solution of ethyl 2-(3-chloro-4-hydroxyphenyl)acetate (15 g, 69 mmol) in CCl4 (270 mL), bromine (11.1 g, 69 mmol) was added slowly (dissolved in 140 mL of CCl4) at −10° C. over a period of 30 min. The reaction mixture was stirred for another 1 h at −10° C. Upon completion of the reaction, the mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layers were washed with saturated Na2S2O3 solution, water, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by re-crystallization using hexane to yield compound ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (7 g, 7 g starting material recovered) as a white solid.
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 (6.5 g, 22 mmol), in DMF (100 mL), K2CO3 (7.67 g, 55.6 mmol) was added. Trifluoroethyl iodide (13.16 mL, 133 mmol) was added in a drop wise manner to the reaction mixture at RT. The mixture was then heated at 60° C. for 4 h. After completion of reaction, the mixture was poured into water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography to give compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (6.5 g) as a white solid.
Step 4
Ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate




To a suspension of NaH (0.327 g, 60% in paraffin oil, 8.1 mmol) in DMF (100 mL), slowly added a mixture of ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (3.0 g, 6.8 mmol) and cyclopropyl methylbromide (0.718 mL, 7.5 mmol) dissolved in DMF (20 mL) at 0° C. for 15 min under an atmosphere of nitrogen. The reaction mixture was allowed stir at 0° C. for 15 min, upon which the mixture was poured onto crushed ice and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, brine, dried over Na2SO4 and evaporated. The residue was purified by Flash column chromatography to give compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (2.35 g) as a thick syrup.
Step 5
Ethyl 2-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate




A mixture of compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (500 mg, 1.15 mmol), 4-methyl phenylboronic acid (0.237 g, 1.74 mmol), Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 2-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy) biphenyl-3-yl)-3-cyclopropylpropanoate (375 mg,) as a thick oil.
Step 7
2-(5-Chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid




A mixture of ethyl 2-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy) biphenyl-3-yl)-3-cyclopropylpropanoate (370 mg, 0.84 mmol) and lithium hydroxide monohydrate (282 mg, 6.7 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/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 (2×25 mL). The combined organic layers were washed with water, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid (200 mg) as a white solid. 1HNMR (CDCl3): 7.21-7.42 (m, 6H); 3.87 (q, 2H); 3.65 (t, 1H); 2.39 (s, 3H), 1.93 (m, 1H); 1.88 (m, 1H); 0.66 (m, 1H); 0.42 (m, 2H); 0.12 (m, 1H); 0.1 (m, 1H).
Example 1289
2-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid
Step 1
Ethyl 2-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate




A mixture of compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (500 mg, 1.15 mmol), 4-ethyl phenylboronic acid (225 mg, 1.74 mmol), Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 2-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate (400 mg) as a thick oil.
Step 2
2-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid




A mixture of ethyl 2-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate (400 mg, 0.88 mmol) and lithium hydroxide monohydrate (222 mg, 5.2 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/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 (2×25 mL). The combined organic layers were washed with water, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid (200 mg) as a white solid. 1HNMR (CDCl3): 7.42 (d, 2H), 7.38 (s, 1H), 7.22 (d, 2H) 7.20 (s, 1H), 3.85 (q, 2H); 3.66 (t, 1H); 2.73 (q, 2H), 1.93 (m, 1H); 1.88 (m, 1H); 1.29 (t, 3H), 0.66 (m, 1H); 0.42 (m, 2H); 0.12 (m, 1H); 0.05 (m, 1H).
Example 1313
2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoic acid
Step 1
Ethyl 2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate




A mixture of compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (500 mg, 1.15 mmol), 4-thiomethyl phenylboronic acid (293 mg, 1.7 mmol), Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate (360 mg) as a thick oil.
Step 2
2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoic acid




A mixture of ethyl 2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate (350 mg, 0.74 mmol) and lithium hydroxide monohydrate (186 mg, 4.44 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. Residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoic acid (310 mg) as a white solid. 1HNMR (CDCl3): 7.46 (d, 2H), 7.38 (s, 1H), 7.32 (d, 2H), 7.22 (s, 1H), 3.93 (q, 2H); 3.68 (t, 1H); 2.56 (s, 3H), 1.93 (m, 1H); 1.78 (m, 1H); 1.29 (t, 3H), 0.65 (m, 1H); 0.42 (m, 2H); 0.12 (m, 1H); 0.05 (m, 1H).
Example 1325
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethoxy)biphenyl-3-yl)-3-cyclopropyl propanoic acid
Step 1
Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate




A mixture of compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (500 mg, 1.15 mmol), 4-trifluormethoxy phenylboronic acid (310 mg, 1.65 mmol), Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate (260 mg) as a thick oil.
Step 2
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethoxy)biphenyl-3-yl)-3-cyclopropyl propanoic acid




A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate (260 mg, 0.50 mmol) and lithium hydroxide monohydrate (186 mg, 4.44 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 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 (2×25 mL). The combined organic layers were washed with water, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethoxy)biphenyl-3-yl)-3-cyclopropyl propanoic acid (180 mg) as white solid. 1HNMR (CDCl3): 7.56 (d, 2H), 7.40 (s, 1H), 7.25 (m, 3H), 3.98 (q, 2H); 3.68 (t, 1H); 2.56 (s, 3H), 1.913 (m, 1H); 1.76 (m, 1H); 1.29 (t, 3H), 0.62 (m, 1H); 0.41 (m, 2H); 0.12 (m, 1H); 0.05 (m, 1H).
Example 1301
2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoic acid
Step 1
Ethyl 2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate




A mixture of compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (500 mg, 1.15 mmol), 4-isopropyl phenylboronic acid (225 mg, 1.74 mmol), Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate (400 mg) as thick oil.
Step 2
2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoic acid




A mixture of ethyl 2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoate (400 mg, 0.85 mmol) and lithium hydroxide monohydrate (215 mg, 5.1 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/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 (2×25 mL). The combined organic layers were washed with water, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl propanoic acid (180 mg) as white solid. 1HNMR (CDCl3): 7.44 (d, 2H), 7.38 (s, 1H), 7.31 (d, 2H) 7.21 (s, 1H), 3.86 (q, 2H); 3.67 (t, 1H); 2.98 (m, 1H), 1.93 (m, 1H); 1.78 (m, 1H); 1.28 (d, 6H), 0.66 (m, 1H); 0.43 (m, 2H); 0.12 (m, 1H); 0.05 (m, 1H).
Example 1280
1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid




Step 1
Ethyl 1-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate




To a suspension of NaH (0.65 g, 60% in paraffin oil) in DMF (100 mL), slowly added a mixture of ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (3.0 g, 6.8 mmol) and 1,3-dibromo propane (1.61 g, 8.0 mmol) dissolved in DMF (20 mL) at 0° C. for 15 min under an atmosphere of nitrogen. The reaction mixture was allowed stir at 0° C. for 15 min, upon which the reaction mixture was poured onto crushed ice and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by Flash column chromatography to give ethyl 1-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (2.12 g) as a thick syrup.
Step 2
Ethyl 1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate




A mixture of compound ethyl 1-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (500 mg, 1.2 mmol), 4-methyl phenylboronic acid (0.237 g, 1.68 mmol), Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate (325 mg) as thick oil.
Step 3
1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid




A mixture of ethyl 1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate (300 mg, 0.70 mmol) and lithium hydroxide monohydrate (280 mg, 11.6 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 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 (2×25 mL). The combined organic layers were washed with water, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid (185 mg, 66%) as white solid. 1HNMR (CDCl3): 7.42 (m, 2H); 7.32 (s, 1H), 7.23 (d, 2H), 7.18 (s, 1H), 3.87 (q, 2H); 2.85 (m, 2H), 2.54 (m, 2H), 2.39 (s, 3H), 2.12 (m, 1H); 1.83 (m, 1H).
Step 4
Ethyl 1-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate




A mixture of compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (500 mg, 1.2 mmol), 4-ethyl phenylboronic acid (225 mg, 1.74 mmol), Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 1-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate (360 mg) as a thick oil.
Step 5
1-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid




A mixture of ethyl 1-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate (350 mg, 0.84 mmol) and lithium hydroxide monohydrate (222 mg, 9.2 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 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 (2×25 mL). The combined organic layers were washed with water, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid (260 mg) as white solid. 1HNMR (CDCl3, 500 MHz): 7.42 (d, 2H), 7.38 (s, 1H), 7.22 (d, 2H) 7.20 (s, 1H), 3.85 (q, 2H); 2.82 (m, 2H), 2.71 (q, 2H), 2.52 (m, 2H), 2.15 (m, 1H), 1.91 (m, 1H); 1.27 (t, 3H).
Example 1316
1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid
Step 1
Ethyl 1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate




A mixture of ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (500 mg, 1.2 mmol), 4-thiomethyl phenylboronic acid (293 mg, 1.7 mmol), Palladium Tetrakis (triphenylphosphine) (0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate (342 mg) as thick oil.
Step 2
1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid




A mixture of ethyl 1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate (325 mg, 0.70 mmol) and lithium hydroxide monohydrate (186 mg, 4.44 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/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 (2×25 mL). The combined organic layers were washed with water, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid (265 mg) as a white solid. 1HNMR (CDCl3): 7.46 (d, 2H), 7.38 (s, 1H), 7.32 (d, 2H), 7.19 (s, 1H), 3.93 (q, 2H); 2.83 (m, 2H), 2.53 (s, 3H), 2.32 (m, 2H), 2.13 (m, 1H), 1.93 (m, 1H).
Example 1304
1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl) cyclobutane carboxylic acid
Step 1
Ethyl 1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate




A mixture of ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (500 mg, 1.2 mmol), 4-isopropyl phenylboronic acid (245 mg, 1.68 mmol), Palladium Tetrakis (triphenylphosphine) (0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate (425 mg) as thick oil.
Step 2
1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid




A mixture of ethyl 1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate (400 mg, 0.88 mmol) and lithium hydroxide monohydrate (215 mg, 5.1 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/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 (2×25 mL). The combined organic layers were washed with water, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid (289 mg) as white solid. 1HNMR (CDCl3): 7.44 (d, 2H), 7.38 (s, 1H), 7.31 (d, 2H) 7.21 (s, 1H), 3.86 (q, 2H); 2.99 (m, 1H), 2.86 (m, 2H), 2.52 (m, 2H), 2.13 (m, 1H), 1.92 (m, 1H); 1.28 (d, 6H).
Example 1833
2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoic acid




Step 1
Ethyl-2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropyl propanoate




To a stirred solution of ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (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 to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by column chromatography to yield compound ethyl-2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropyl propanoate (0.920 g) as a yellow solid.
Step 2
Ethyl 2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate




Ethyl-2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropyl propanoate (0.9 g, 2.6 mmol) was dissolved in a mixture of AcCN/H2O/HCl (96%) 25 mL/25 mL/1 ml, at 0° C. A solution of NaNO2 (0.277 g, 4.02 mmol) in water (2 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 (4.5 g, 26.8 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 70° C. for 1 h. 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 (100 mL) followed by brine (100 mL). The solution was dried over Na2SO4, filtered and concentrated to give crude black oil which was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl 2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (1.1 g, 90.9%) as yellow oil.
Step 3
Ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropyl propanoate




A mixture of ethyl 2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (1.1 g, 2.4 mmol), 4-trifluoromethylphenylboronic acid (0.928 g, 4.9 mmol), CsF (0.926 g, 6.1 mmol) and Pd (PPh3)4 (0.283 g, 0.245 mmol) in 50 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 40 mL of EtOAc and 40 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil. The oil was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropyl propanoate (0.650 g) as a yellow oil.
Step 4
2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoic acid




Ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropyl propanoate (0.65 g, 1.31 mmol) was dissolved in 25 mL of MeOH/THF/H2O (10:10:5, vvl), LiOH (0.252 g, 10.5 mmol) was added. The reaction mixture was stirred for 5 h at room temperature 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 Na2SO4, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (DCM/MeOH, 95:5) gave the 2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoic acid (0.585 g) as a white solid. 1H NMR (500 MHz, CDCl3/TMS): δ 7.71 (d, 2H), 7.39 (d, 2H), 7.22 (s, 1H), 6.91 (s, 1H), 4.23 (q, 2H), 3.72 (t, 1H), 1.93 (m, 1H), 1.82 (m, 1H), 0.81 (m, 1H), 0.52 (m, 2H), 0.15 (m, 2H).
Example 1836
1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutane carboxylic acid




Step 1
Ethyl 1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate




To a stirred solution of ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (2.0 g, 6.3 mmol) in dry CHCl3 (30 mL), NCS (0.842 g, 6.3 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×100 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by Flash column chromatography to yield ethyl 1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (0.4 g) as thick syrup.
Step 2
Ethyl 1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate




Ethyl 1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (0.45 g, 1.27 mmol) was dissolved in a mixture of AcCN/H2O/HCl (96%) 15 mL/10 mL/3.1 mL at 0° C. A solution of NaNO2 (0.132 g, 1.91 mmol) in water (1 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 (2.11 g, 12.7 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 80° C. for 1 h. 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 (100 mL) followed by brine (100 mL). The solution was dried over Na2SO4, filtered and concentrated to give crude black oil which was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl 1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (0.350 g) as yellow oil.
Step 3
Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylate




A mixture of ethyl 1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (0.35, 7.35 mmol), 4-trifluoromethylphenylboronic acid (0.277 g, 1.47 mmol), CsF (0.277 g, 1.83 mmol) and Pd (PPh3)4 (0.084 g, 0.36 mmol) in 20 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 20 mL of EtOAc and 20 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylate (0.182 g) as a colorless oil.
Step 4
1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylic acid




Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylate (0.2 g, 0.41 mmol) was dissolved in 25 mL of MeOH/THF/H2O (10:10:5, vvl), LiOH (0.10 g, 4.1 mmol) was added. The reaction mixture was stirred for 5 h at room temperature 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 Na2SO4, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (DCM/MeOH, 95:5) gave the compound 1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylic acid (0.06 g) as a white solid. 1H NMR (500 MHz, CDCl3/TMS): δ 7.72 (d, 2H), 7.41 (d, 2H), 7.19 (s, 1H), 6.79 (s, 1H), 4.23 (q, 2H), 3.92 (m, 2H), 2.58 (m, 2H), 2.19 (m, 1H), 1.97 (m, 1H);
Example 1837
Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylate




Step 1
Ethyl 1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate




To a stirred solution of ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (1.2 g, 3.6 mmol) in dry CHCl3 (60 mL), NCS (0.411 g, 3.08 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×100 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by Flash column chromatography to yield ethyl 1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (0.860 g) as a thick syrup.
Step 2
Ethyl 1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate




Ethyl 1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (0.86 g, 2.3 mmol) was dissolved in a mixture of AcCN/H2O/HCl (96%) 10 mL/8 mL/2.1 mL at 0° C. A solution of NaNO2 (0.243 g, 3.5 mmol) in water (1 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 (3.9 g, 23.5 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 80° C. for 1 h. 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 (100 mL) followed by brine (100 mL). The solution was dried over Na2SO4, filtered and concentrated to give crude black oil which was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl 1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (0.580 g) as pale yellow oil.
Step 3
Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylate




A mixture of ethyl 1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (0.58, 1.2 mmol), 4-trifluoromethylphenylboronic acid (0.56 g, 2.4 mmol), CsF (0.46 g, 3.0 mmol) and Pd (PPh3)4 (0.14 g, 0.12 mmol) in 20 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 25 mL of EtOAc and 25 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylate (0.480 g) as a color less oil.
Step 4
1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylic acid




Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentane carboxylate (0.32 g, 0.64 mmol) was dissolved in 25 mL of MeOH/THF/H2O (10:10:5, vvl), LiOH (0.163 g, 3.88 mmol) was added. The reaction mixture was stirred for 5 h at room temperature 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 Na2SO4, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (DCM/MeOH, 95:5) gave the 1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (0.220 g, 73%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.69 (d, 2H), 7.41 (d, 2H), 7.26 (s, 1H), 6.92 (s, 1H), 4.22 (q, 2H), 3.71 (m, 2H), 1.98 (m, 2H), 1.81 (m, 4H).
Example 1832
2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoic acid




Step 1
Ethyl 2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate




To a stirred solution of ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.25 g, 0.75 mmol) in dry CHCl3 (20 mL), NCS (0.08 g, 0.6 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×100 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by Flash column chromatography to yield ethyl 2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.15 g) as thick syrup.
Step 2
Ethyl-2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate




Ethyl 2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.7 g, 1.9 mmol) was dissolved in a mixture of AcCN/H2O/HCl (96%) 20 mL/20 mL/1.3 mL at 0° C. A solution of NaNO2 (0.197 g, 2.8 mmol) in water (2 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 (3.16 g, 19.0 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 80° C. for 1 h. The reaction mixture was extracted with EtOAc (3×100 mL), and the combined organic layers were washed with 10% sodium thiosulfate (2×50 mL), water (100 mL) followed by brine (100 mL). The solution was dried over Na2SO4, filtered and concentrated to give crude black oil which was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl-2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.35 g) as pale yellow oil.
Step 3
Ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoate




A mixture of ethyl-2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.5, 1.04 mmol), 4-trifluoromethylphenylboronic acid (0.96 g, 2.09 mmol), CsF (0.395 g, 2.6 mmol) and Pd (PPh3)4 (0.121 g, 0.104 mmol) in 50 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 25 mL of EtOAc and 25 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoate (0.265 g,) as a colorless oil.
Step 4
2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoic acid




Ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoate (0.35 g, 0.733 mmol) was dissolved in 25 mL of MeOH/THF/H2O (10:10:5, vvl), LiOH (0.176 g, 7.33 mmol) was added. The reaction mixture was stirred for 5 h at room temperature 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 Na2SO4, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (DCM/MeOH, 95:5) gave the compound 2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoic acid (0.085 g) as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.69 (d, 2H), 7.41 (d, 2H), 7.20 (s, 1H), 6.86 (s, 1H), 4.23 (q, 2H), 3.71 (t, 1H), 2.01 (m, 1H), 1.73 (m, 1H), 1.58 (m, 1H), 0.98 (d, 6H).
Example 1908
1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutane carboxylic acid




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




Cyclopropylmethanol (15 g, 207 mmol) was added to a stirred suspension of NaH (60% in mineral oil, 8.37 g) in 200 mL THF 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 2,4-difluoro-1-nitrobenzene (30 g, 187 mmol) in 200 mL THF was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 2 h and then poured into ice water. The reaction 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 product as 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 88 mL DMF 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), brine (100 mL) and dried (MgSO4). Evaporation of solvent under reduced pressure gave 10.0 g of crude product which was purified by silica gel chromatography (hexane/EtOAc) gave 7.0 g of the desired product (42%)
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
Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate




i) 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, the residue dissolved in H2O, acidified with 6N HCl to pH-2. The solid material was collected via filtration, washed with water, dried under reduced pressure to yield 6.5 g (90%) of 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetic acid 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).
ii) 2-(3-(Cyclopropylmethoxy)-4-nitrophenyl)acetic acid (6.5 g) was taken up in an ethanolic HCl solution (50 mL, 25%) and refluxed for 4 h, monitored by TLC. The reaction mixture was concentrated in vacuo to dryness and dissolved in ethyl acetate. The mixture was washed with NaHCO3 solution, dried over NaSO4 and concentrated in vacuo to give crude yellow solid which was purified by recrystallization to give the desired product (4.2 g).
1H-NMR (CDCl3, 200 MHz): 0.36 (m, 2H), 0.58 (m, 2H), 1.12 (t, 3H), 1.28 (m, 1H), 3.71 (s, 2H), 4.01 (d, 2H), 4.21 (q, 2H), 7.02 (d, 1H), 7.23 (s, 1H), 7.81 (d, 1H).
Step 4
Ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate




To a stirred solution of ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (10 g), in dry MeOH (100 mL) was added Pd(OH)2 (2 g). The mixture was hydrogenated under a H2 atmosphere for 6 h at room temperature. The reaction mixture was filtered through a pad of CeliteTM, washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield 7.5 g of the desired product as an oil.
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 5
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 to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by column chromatography to yield Ethyl 2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)acetate (920 mg) as a yellow solid.
Step 6
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 AcCN/H2O/HCl (96%) 50 mL/50 mL/25 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 and the solvent was evaporated. 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) followed by brine (300 mL). The solution was dried over Na2SO4, filtered and concentrated in vacuo to give crude black oil which was purified by chromatography over silica gel (hexane/EtOAc) to give the ethyl 2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate (1.2 g)
Step 7
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, 12.9 mmol), 4-trifluoromethylphenylboronic acid (3.66 g, 19 mmol), CsF (3.9 g, 25.8 mmol) and Pd (PPh3)4 (1.5 g, 1.3 mmol) in 100 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 75 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by column chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate (3.2 g) as yellow oil.
Step 8
1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutane carboxylic acid




Ethyl 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate (0.5 g, 1.2 mmol) was dissolved in 10 mL anhydrous DMF, NaH (60% wt. in oil, 0.058 g, 2.4 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 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 a (320 mg) of colorless oil. The oil was dissolved in 10 mL of EtOH/H2O (9:1, vvl) and 0.163 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)cyclobutane carboxylic acid (0.210 g) as a white solid. 1HNMR (300 MHz, CDCl3): δ 7.68 (d, 2H), 7.41 (d, 2H), 7.06 (s, 1H), 6.78 (s, 1H), 3.78 (d, 2H), 2.86 (m, 2H), 2.58 (m, 2H), 2.16 (m, 1H), 1.95 (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)cyclopentane carboxylic acid
1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentane carboxylic 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, 0.058 g, 2.4 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 a (320 mg, 0.64 mmol) of colorless oil. The oil was dissolved in 10 mL of EtOH/H2O (9:1, vvl) and LiOH (0.163 g, 3.88 mmol) 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) to give 1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentane carboxylic acid (220 mg) as a white solid. 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 2418
2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid




Step 1
Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)-4-methylpentanoate




Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (2.2 g, 7.8 mmol) was dissolved in 20 mL anhydrous DMF and NaH (60% wt. in oil, 0.189 g, 7.8 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and isobutyl bromide (1.08 g, 7.8 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), and dried over MgSO4, filtered and concentrated under reduced pressure to give ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)-4-methylpentanoate (2.06 g) of colorless oil.
Step 2
Ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)-4-methylpentanoate




To a stirred solution of ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)-4-methylpentanoate (2.0 g, 5.9 mmol), in dry MeOH (50 mL) Pd(OH)2 (1.1 g) was added. The mixture was reduced under an atmosphere of H2 for 6 h at room temperature. The reaction mixture was filtered off through a pad of CeliteTM, washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (1.69 g) as a thick liquid.
Step 3
Ethyl 2-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)-4-methylpentanoate




To a stirred solution of ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (1.65 g, 5.4 mmol) in dry CCl4 (60 mL), NBS (0.96 g, 5.4 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by column chromatography to yield ethyl 2-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (1.5 g) as a yellow solid.
Step 4
Ethyl-2-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate




A mixture of ethyl 2-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (1.5 g, 3.9 mmol), 4-trifluoromethylphenylboronic acid (1.1 g, 5.8 mmol), CsF (1.47 g, 7.8 mmol) and Pd (PPh3)4 (0.45 g, 0.39 mmol) in 75 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 75 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to 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)-4-methyl pentanoate (1.2 g) as a yellow oil.
Step 5
Ethyl-2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate




Ethyl-2-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methyl pentanoate (0.2 g, 0.44 mmol) was dissolved in a mixture of AcCN/H2O/HCl 10 mL/10 mL/1 mL at 0° C. A solution of NaNO2 (0.039 g, 0.53 mmol) in water (1 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 (0.22 g, 2.2 mmol) in water (5 mL) was added drop wise at 0° C. The reaction mixture was heated to 40° C. for 2.0 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (30 mL) followed by brine (20 mL). The solution was dried over Na2SO4, filtered and concentrated in vacuo to give crude black oil which was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl-2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (0.12 g) as a thick oil.
Step 6
2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid




The ethyl-2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (120 mg, 0.255 mmol) dissolved in 10 mL of MeOH/THF/H2O (10 mL/10 mL/5 mL) and LiOH (30 mg, 1.2 mmol) was added. The reaction mixture was stirred at room temperature 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 evaporated under reduced pressure. Purification by column chromatography over silica gel (DCM:MeOH 9:1) gave 2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (89 mg) as a white solid. 1H-NMR (500 MHz, CDCl3): 7.68 (d, 2H), 7.55 (d, 2H), 6.92 (s, 1H), 6.85 (s, 1H), 3.96 (d, 2H), 3.64 (t, 1H), 1.98 (m, 1H), 1.68 (m, 1H), 1.55 (m, 1H), 1.32 (m, 1H), 0.91 (d, 6H), 0.64 (m, 2H), 0.42 (m, 2H);
Example 3205
2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoic acid




Step 1
Ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate




To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (12 g, 40.816 mmol) in DMSO (80 mL) were added K2CO3 (14.08 g, 102.020 mmol) and cyclopropylmethylbromide (5 mL, 4.880 mmol) at RT under inert atmosphere. The reaction mixture was stirred at 80° C. temperature over a period of 14 h. After completion of starting material (by TLC), the reaction mixture was cooled to RT and quenched with water and extracted with EtOAc (3×100 mL). Combined organic layers were washed with water (3×75 mL), brine and dried over Na2SO4. After filtration and concentration under reduced pressure, the crude material was purified by column chromatography to afford ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate (10 g) yellow solid.
Step 2
Ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methoxybutanoate




To a stirred solution of NaH (0.3 g, 12.5 mmol) in DMF (10 mL) was added ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate (2.0 g, 5.70 mmol) at 0° C. The reaction mixture was stirred at 0° C. over a period of 30 min. To the reaction mixture was added 2-bromo ethyl methyl ether (0.87 g, 6.25 mmol) and stirred at 0 oC for 30 min. After completion of starting material (by TLC), the reaction mixture was diluted with water (20 mL), acidified with 1N HCl (pH=5) and extracted with EtOAc (3×50 mL). Combined organic layers were washed with water (3×25 mL), brine and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude material was purified by column chromatography to afford ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methoxybutanoate (560 mg) as an off white solid.
Step 3
Ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoate




To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methoxybutanoate (2.3 g, 5.660 mmol) in a mixture of DMF (50 mL) and water (5 mL) were added Cs2CO3 (6.4 g, 19.815 mmol), Pd(TPP)4 (1.3 g, 1.120 mmol) and 4-(trifluoromethyl)phenyl boronic acid (1.29 g, 6.780 mmol) at RT under N2 atmosphere and the resulting mixture was stirred at 80° C. for 14 h. After completion of starting material (by TLC), filtered off the catalyst and celite bed was washed with EtOAc and extracted with EtOAc (3×100 mL). Combined organic layers were washed with water (3×50 mL), brine and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude material was purified by column chromatography to afford ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoate (1.2 g) as an off white solid.
Step 4
2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoic acid




To a stirred solution of ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoate (0.3 g, 0.638 mmol) in a mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H2O (53 mg, 12.030 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (20 mL), brine (30 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography to afford 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoic acid (100 mg) as an off white solid. 1HNMR (500 MHz) (CDCl3): δ ppm 7.68 (m, 4H), 7.40 (s, 1H), 7.20 (s, 1H), 3.80 (t, 1H), 3.41 (d, 2H), 3.25 (m, 5H), 2.39 (m, 1H), 1.99 (m, 1H), 0.95 (m, 1H), 0.4 (d, 2H), 0.0 (m, 2H).
Example 3206
2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid




Step 1
Ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methyl pentanoate




To a stirred solution of NaH (0.76 g, 15.82 mmol) in DMF (50 mL) was added compound 2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoic acid (5.0 g, 14.4 mmol) at 0° C. The reaction mixture was stirred at 0° C. over a period of 30 min. To the reaction mixture was added isobutyl bromide (2.93 g, 21.57 mmol) and stirred at 0° C. for 1 h. After completion of starting material (by TLC), diluted with water (40 mL), acidified with 1N HCl (pH=5) and extracted with EtOAc (3×100 mL). Combined organic layers were washed with water (3×50 mL), brine and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude material was purified by column chromatography to afford ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methyl pentanoate (5.0 g) as a liquid.
Step 2
Ethyl 2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate




To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methyl pentanoate (0.5 g, 1.239 mmol) in a mixture of DMF (10 mL) and water (5 mL) were added Cs2CO3 (1.4 g, 4.325 mmol), Pd (TPP)4 (286 mg, 2.475 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (355 mg, 1.363 mmol) at RT under N2 atmosphere and the resulting mixture was stirred at 80° C. for 14 h. After completion of starting material (by TLC), the solids were removed via filtration through a bed of CeliteTM was washing with EtOAc (3×100 mL). The combined organic layers were washed with water (3×50 mL), brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to afford ethyl 2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (100 mg) as an off white solid.
Step 3
2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid




To a stirred solution of ethyl 2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (0.1 g, 0.218 mmol) in a mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H2O (45 mg, 1.090 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography to afford 2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid (39 mg) as an off white solid. 1HNMR (500 MHz) (CDCl3): δ (ppm) 9.05 (s, 1H), 8.2 (m, 2H), 7.73 (m, 1H), 7.40 (s, 1H), 7.30 (s, 1H), 3.63 (t, 1H), 3.40 (d, 2H), 1.99 (m, 1H), 1.65 (m, 1H), 1.55 (m, 1H), 0.93 (m, 7H), 0.38 (d, 2H), −0.5 (d, 2H).
Example 514
2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid
Step 1
Ethyl 2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate




To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (0.5 g, 1.240 mmol) in a mixture of DMF (20 mL) and water (5 mL) were added Cs2CO3 (1.4 g, 4.342 mmol), Pd(TPP)4 (286 mg, 2.480 mmol) and 5-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole (355 mg, 1.364 mmol) at RT under N2 atmosphere and the resulting mixture was stirred at 80° C. for 14 h. After completion of starting material (by TLC), the solids were removed via filtration through a bed of CeliteTM was washing with EtOAc (3×100 mL). The combined organic layers were washed with water (3×50 mL), brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to afford ethyl 2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (250 mg) as an off white solid.
2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid




To a stirred solution of ethyl 2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (0.25 g, 0.565 mmol) in a mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H2O (118.7 mg, 2.828 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography to afford compound 2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid (152 mg) as an off white solid. 1HNMR (500 MHz) (CDCl3): δ (ppm) 7.92 (s, 1H), 7.85 (m, 1H), 7.72 (m, 1H), 7.46 (s, 1H), 7.25 (s, 1H), 3.65 (t, 1H), 3.48 (d, 2H), 1.95 (m, 1H), 1.65 (m, 1H), 1.55 (m, 1H), 1.22 (m, 1H0, 0.93 (d, 6H), 0.39 (d, 2H), 0.0 (m, 2H).
Example 524
2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid
Step 1
Ethyl 2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate




To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (0.5 g, 1.239 mmol) in a mixture of DMF (10 mL) and water (5 mL) were added Cs2CO3 (1.4 g, 4.325 mmol), Pd(TPP)4 (286 mg, 2.475 mmol) and 5-(4,4,5,5, -tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]thiazdiazole (355 mg, 1.363 mmol) at RT under N2 atmosphere and the resulting mixture was stirred at 80° C. for 14 h. After completion of starting material (by TLC), the solids were removed via filtration through a bed of CeliteTM was washing with EtOAc (3×100 mL). The combined organic layers were washed with water (3×50 mL), brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to afford ethyl 2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (222 mg) as an off white solid.
Step 2
2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid




To a stirred solution of ethyl 2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (0.22 g, 0.479 mmol) in a mixture of THF (5 mL), methanol (5 mL) and water (2 mL) was added LiOH.H2O (60.3 mg, 1.438 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography to afford 2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methyl pentanoic acid (105 mg, 50.0%) as an off white solid. 1HNMR (500 MHz) (CDCl3): δ (ppm) 8.18 (s, 1H), 8.03 (d, 1H), 7.96 (d, 1H), 7.42 (s, 1H), 7.18 (s, 1H), 3.68 (t, 1H), 3.43 (d, 2H), 2.00 (m, 1H), 1.70 (m, 1H), 1.58 (m, 1H), 0.98 (d, 6H), 0.88 (m, 1H), 0.38 (d, 2H), 0.0 (m, 2H).
Example 3207
2-(6-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid




Step 1
Ethyl 2-(3-bromo-5-(chlorosulfonyl)-4-hydroxyphenyl)-4-methyl pentanoate




To a stirred compound ethyl 2-(3-bromo-4-hydroxyphenyl)-4-methylpentanoate (1.0 g, 3.174 mmol) in DCM (15 ml) chlorosulfonic acid (2 mL, 28.571 mmol) was added. The reaction mixture was stirred for 14 h at 80° C. under N2 atmosphere. After completion of starting material (by TLC), the reaction mixture was quenched with NaHCO3 solution and extracted with DCM (3×100 mL). Combined organic layers were washed with water (3×75 mL), brine and dried over Na2SO4, filtered and concentrated in vacuo to give ethyl 2-(3-bromo-5-(chlorosulfonyl)-4-hydroxyphenyl)-4-methyl pentanoate (0.5 g) as a liquid.
Step 2
Ethyl 2-(3-bromo-5-(N,N-dimethylsulfamoyl)-4-hydroxyphenyl)-4-methylpentanoate




To a stirred solution of ethyl 2-(3-bromo-5-(chlorosulfonyl)-4-hydroxyphenyl)-4-methyl pentanoate (0.73 g, 1.765 mmol) in THF (20 mL) was added N,N-dimethylamine solution (5.2 mL, 10.592 mmol) at RT under inert atmosphere. The reaction mixture was stirred at RT over a period of 14 h. After completion of starting material (by TLC), the reaction mixture was quenched with water and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (3×75 mL), brine and dried over Na2SO4. After filtration and concentration under reduced pressure, the crude material was purified by column chromatography to afford ethyl 2-(3-bromo-5-(N,N-dimethylsulfamoyl)-4-hydroxyphenyl)-4-methylpentanoate (0.6 g) as a pale yellow liquid.
Step 3
Ethyl 2-(3-bromo-4-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)phenyl)-4-methylpentanoate




To a stirred solution of ethyl 2-(3-bromo-5-(N,N-dimethylsulfamoyl)-4-hydroxyphenyl)-4-methylpentanoate (0.75 g, 1.77 mmol) in DMSO (25 mL) were added K2CO3 (367 mg, 2.106 mmol) and cyclopropylmethylbromide (0.2 mL, 2.13 mmol) at RT under inert atmosphere. The reaction mixture was stirred at 80° C. temperature over a period of 14 h. After completion of starting material (by TLC), the reaction mixture was cooled to RT and quenched with water and extracted with EtOAc (3×100 mL). Combined organic layers were washed with water (3×75 mL), brine and dried over Na2SO4. After filtration and evaporation, the crude material was purified by column chromatography to afford ethyl 2-(3-bromo-4-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)phenyl)-4-methylpentanoate (350 mg) as a liquid.
Step 4
2-(6-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid




To a stirred solution of 2-(3-bromo-4-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)phenyl)-4-methylpentanoate (0.5 g, 1.049 mmol) in a mixture of DMF (10 mL) and water (5 mL) were added Cs2CO3 (1.19 g, 3.670 mmol), Pd(TPP)4 (243 mg, 0.209 mmol) and 4-(trifluoromethyl)phenylbornate (220 mg, 1.150 mmol) at RT under N2 atmosphere and the resulting mixture was stirred at 80° C. for 14 h. After completion of starting material (by TLC), filtered off the catalyst and celite bed was washed with EtOAc and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (3×50 mL), brine and dried over anhydrous Na2SO4. After filtration and concentration in vacuo, the crude material was purified by column chromatography to afford 2-(6-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (100 mg) as an off white solid. 1HNMR (500 MHz) (CDCl3): δ (ppm) 7.83 (s, 1H), 7.72 (m, 4H), 7.51 (s, 1H), 3.73 (m, 1H), 3.38 (d, 2H), 2.95 (s, 3H), 2.87 (s, 3H), 2.01 (m, 1H), 1.65 (m, 1H), 1.51 (m, 1H), 0.91 (m, 7H), 0.40 (d, 2H), 0.00 (m, 2H).
Step 5
Ethyl 2-(6-(cyclopropylmethoxy)-5-iodo-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate




To a stirred solution of ethyl 2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (1.0 g, 2.227 mmol) in a mixture of HCl:H2O (0.81 mL, 6.681 mmol) was added NaNO2 (0.180 g, 2.672 mmol). After being stirred for 1 h at 0° C. then added KI (3.69 g, 22.271 mmol) at 0° C. under inert atmosphere. The reaction mixture was stirred at 100° C. temperature over a period of 2 h. After completion of starting material (by TLC), the reaction mixture was cooled to RT and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (3×75 mL), brine and dried over Na2SO4. After filtration and concentration in vacuo, the crude material was purified by column chromatography to afford ethyl 2-(6-(cyclopropylmethoxy)-5-iodo-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (0.93 g) as a solid.
Example 3210
2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid
Step 1
Ethyl 2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate




To a stirred solution of ethyl 2-(6-(cyclopropylmethoxy)-5-iodo-4′-(trifluoromethyl) biphenyl-3-yl)-4-methylpentanoate (0.25 g, 0.447 mmol) in NMP (10 mL) was added CuCN (50 mg, 0.536 mmol) at RT under inert atmosphere. The reaction mixture was stirred at 200° C. temperature over a period of 2 h. After completion of starting material (by TLC), the reaction mixture was cooled to RT and extracted with EtOAc (3×20 mL). Combined organic layers were washed with water (3×15 mL), brine and dried over Na2SO4. After filtration and evaporation, the crude material was purified by column chromatography to afford ethyl 2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl) biphenyl-3-yl)-4-methylpentanoate (0.125 g) a solid.
Step 2
2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid




To a stirred solution of ethyl 2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl) biphenyl-3-yl)-4-methylpentanoate (0.125 g, 0.272 mmol) in a mixture of THF (5 mL), methanol (5 mL) and water (2 mL) was added LiOH.H2O (34 mg, 0.816 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography to afford 2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (50 mg) as an off white solid. 1HNMR (500 MHz) (CDCl3): δ (ppm) 7.70 (m, 4H), 7.61 (s, 1H), 7.51 (s, 1H), 3.71 (t, 1H), 3.55 (m, 2H), 2.00 (m, 1H), 1.67 (m, 1H), 1.51 (m, 1H), 1.02 (m, 1H), 0.91 (d, 6H), 0.45 (m, 2H), 0.05 (m, 2H).
Example 3208
2-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid




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




To a stirred solution of ethyl 2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (1.0 g, 2.604 mmol) in a mixture of HCl:H2O (0.86 mL, 10.4 mmol) and THF (10 mL) was added NaNO2 (0.215 g, 3.92 mmol). After being stirred for 1 h at 0° C. then added NaSMe (368 mg, 0.260 mmol) at 0° C. under an inert atmosphere. The reaction mixture was stirred at RT over a period of 14 h. After complete consumption of starting material (by TLC), the reaction mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (3×75 mL), brine and dried over Na2SO4. After filtration and concentration under vacuo, the crude material was purified by column chromatography to afford ethyl 2-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (0.93 g) as a solid.
Step 2
2-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid




To a stirred solution of ethyl 2-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (80 mg, 0.166 mmol) in a mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H2O (20 mg, 0.832 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuo. The crude material was purified by column chromatography to afford 2-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (38 mg) as an off white solid. 1HNMR (500 MHz) (CDCl3): δ (ppm) 7.75 (d, 2H), 7.65 (d, 2H), 7.31 (s, 1H), 7.23 (s, 1H), 3.65 (t, 1H), 3.60 (d, 2H), 2.82 (s, 3H), 1.98 (m, 1H), 1.65 (m, 1H), 1.5 (m, 1H), 1.22 (m, 1H), 0.9 (d, 6H), 0.38 (d, 2H), 0.01 (d, 2H).
Example 3209
2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-methylbutanoic acid
Step 1
Ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-3-methylbutanoate




To a stirred solution of NaH (40 mg, 0.830 mmol) in DMF (5 mL) was added compound ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (300 mg, 0.728 mmol) and stirred at 0° C. for 1 h. To the reaction mixture at 0° C. was added isopropyl bromide (0.08 mL, 0.880 mmol) and continued stirring at 0° C. over a period of 30 min. After complete consumption of the starting material (by TLC), the reaction mixture was diluted with water (20 mL), acidified with 1N Hcl (pH=5) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (3×15 mL), brine and dried over anhydrous Na2SO4. After filtration and concentration under educed pressure, the crude material was purified by column chromatography to afford ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-3-methylbutanoate (120 mg) as a liquid.
Step 2
2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-methylbutanoic acid




To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-3-methylbutanoate (0.12 g, 0.260 mmol) in a mixture of THF (5 mL), methanol (5 mL) and water (2 mL) was added LiOH.H2O (75 mg, 1.320 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of the starting material, as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography to afford ethyl2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-methylbutanoate (100 mg) as an off white solid. 1HNMR (500 MHz) (CDCl3): δ (ppm) 7.66 (m, 4H), 7.41 (s, 1H), 7.20 (s, 1H), 3.41 (d, 2H), 3.15 (d, 1H), 2.3 (m, 1H), 1.12 (d, 3H), 0.97 (m, 1H), 0.72 (d, 3H), 0.40 (d, 2H), 0.00 (d, 2H).
Example 482
2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoic acid
Step 1
Ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoate




To a stirred solution of NaH (64 mg, 0.13 mmol) in DMF (15 mL) was added ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (500 mg, 0.12 mmol) and 1,1,1-trifluoro-2-iodoethane (0.304 mL, 0.15 mmol) at 0° C. The reaction mixture was stirred at 0° C. over a period of 30 min. After completion of starting material (by TLC), diluted with water (20 mL), acidified with 1N HCl (pH=5) and extracted with EtOAc (3×30 mL). Combined organic layers were washed with water (3×15 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by column chromatography to afford ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoate (300 mg) as liquid.
Step 2
2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoic acid




To a stirred solution of ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl) biphenyl-3-yl)-4,4,4-trifluorobutanoate (0.1 g, 0.404 mmol) in a mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H2O (85 mg, 2.024 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of the starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL) the combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The crude material was purified by column chromatography to 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoic acid (38 mg) as sticky syrup. 1HNMR (500 MHz) (CDCl3): δ (ppm) 7.71 (m, 4H), 7.39 (s, 1H), 7.19 (s, 1H), 3.92 (m, 1H), 3.41 (d, 2H), 3.08 (m, 1H), 2.54 (m, 1H), 0.96 (m, 1H), 0.40 (d, 2H), 0.00 (m, 2H).
The following examples can also be made using analogous procedures as described previously, substituting the appropriate reagents known to those of ordinary skill in the art.
Example 3211


    2-(5-chloro-6-(cyclopropylmethoxy)biphenyl-3-yl)-4-methylpentanoic acid


Example 3212


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


Example 3213


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


Example 3214


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


Example 3215


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


Example 3216


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


Example 3217


    2-(3-(benzo[d]thiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid


The following examples can also be made using analogous procedures as described previously, substituting the appropriate reagents known to those of ordinary skill in the art.
Examples 464, 474, 480, 481, 483, 485, 488, 489, 494, 504, 1292, 1334, 2490, 2708, 3211, 3212, 3213, 3214, 3215, 3216 and 3217
Pharmacology Experimental
Measurement of AP In Vitro
The Aβ peptide is proteolytically derived from a larger integral membrane amyloid precursor protein (APP). The production of Aβ is derived from proteolytic cleavages at its N- and C-termini within β-APP by the β and γ-secretase activities, respectively. Transfected cells overexpressing β-APP or its equivalent producing the Aβ peptide can be used to monitor the effects of synthetic compounds on the production of Aβ.
To analyze a compound's effects on the concentrations of the various products of the γ-secretase cleavage activity, the Aβ peptides, various methods known to a person skilled in the art are available. Examples of such methods, but not limited to, include mass-spectrometric identification as described by Wang et al, 1996, J. Biol. Chem. 271:31894-31902) or detection by specific antibodies using, for example, ELISA's.
Examples of such assays for measuring the production of Aβtotal, Aβ40 and Aβ42 by ELISA include but are not limited to those described by Vassar et al., 1999, Science 286:735-741. Suitable kits containing the necessary antibodies and reagents for such an analysis are available, for example, but not limited to the Genetics Company, Wako, Covance, and Innogenetics. The kits are essentially used according to the manufacturers recommendations similar to the assay that is described by Citron et al., (1997) Nature Medicine 3:67-72 and the original assay described by Seubert et al., (1992) Nature 359:325-327.
Screening was carried out using the human embryonic kidney cell line HEK-293 overexpressing an amyloid precursor protein (APP) transgene grown in Pro-293a CDM media (BioWhittaker). Cells were grown to approximately 70-80% confluency subsequent to the addition of test compounds. The growth media was aspirated or removed, the cells washed, and replaced with 100 μl of compound, appropriately diluted in serum free media. The plates are then incubated for 16-18 hours at 37° C.
Conditioned Medium samples are removed for analysis/quantitation of the various Aβ peptide levels by differential ELISA's as described in accompanying instructions to the kits. Those compounds examined which do not demonstrate any overt toxicity or non-specific inhibitory properties are investigated further for their Aβ inhibitory effects and form the basis of medicinal chemistry efforts and to study the effect of the compounds in different experimental conditions and configurations.
Table 14 shows representative in vitro data (HEK 293) EC50 data for compounds of the disclosure where:
A indicates a compound has an EC50 for lowering Aβ42 of <1 μM
B indicates a compound has an EC50 for lowering Aβ42 of >1 μM but <5 μM
C indicates a compound has an EC50 for lowering Aβ42 of >5 μM









TABLE 14






Example #
Activity


















264
A



414
A



415
A



419
A



464
A



474
A



480
A



481
A



482
A



483
A



484
A



485
A



488
A



489
A



494
A



504
A



514
A



524
A



534
A



554
A



724
A



754
B



1055
A



1268
A



1269
A



1270
A



1271
A



1272
A



1277
A



1280
A



1289
A



1292
A



1301
A



1304
A



1313
A



1316
A



1325
A



1334
A



1832
A



1833
A



1836
A



1837
A



1904
A



1905
A



1908
A



1909
A



1976
A



2418
A



2419
A



2422
A



2423
A



2490
A



2491
A



2494
A



2495
A



2708
A



2959
A



2995
A



3200
A



3201
A



3202
B



3203
A



3204
A



3205
A



3206
A



3207
B



3208
A



3209
A



3210
A



3211
A



3212
A



3213
A



3214
A



3215
A



3216
A



3217
B









Table 15 shows individual EC50 values for representative compounds of the disclosure.









TABLE 15





Example 

EC50 (Aβ42) 


#
Compounds Name
HEK 293 (μM)

















484
2-(5-chloro-6-(cyclopropylmethoxy)-4′-
0.069



(trifluoromethyl)biphenyl-3-yl)-4-




methylpentanoic acid



514
2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-
0.274



chloro-4-(cyclopropylmethoxy)phenyl)-4-




methylpentanoic acid



2959
2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-3-
0.298



chloro-5-(2-cyclopropylethyl)phenyl)-4-




methylpentanoic acid



2995
2-(4-(benzo[c][1,2,5]thiadiazol-5-yl)-3-
0.220



chloro-5-(2-cyclopropylethyl)phenyl)-4-




methylpentanoic acid



3210
2-(5-cyano-6-(cyclopropylmethoxy)-4′-
0.275



(trifluoromethyl)biphenyl-3-yl)-4-




methylpentanoic acid









Experimental Procedures for Rat Primary Cortical Culture-Based Abeta1→42/1→x ELISAs
Rat primary neocortical cultures are established through the dissection of the neocortices from 10-12 E17 embryos harvested from time-pregnant SD (Sprague Dawley) rats (Charles River Laboratories). Following dissection, the combined neocortical tissue specimen volume is brought up to 5 mL with dissection medium (DM; 1×HBSS (Invitrogen Corp., cat#14185-052)/10 mM HEPES (Invitrogen Corp., cat#15630-080)/1 mM Sodium Pyruvate (Invitrogen Corp., cat#11360-070)) supplemented with 100 uL Trypsin (0.25%; Invitrogen Corp., cat#15090-046) and 100 uL DNase I (0.1% stock solution in DM, Roche Diagnostics Corp., cat#0104159), undergoing digestion via incubation at 37° C. for 10 minutes. Digested tissue is washed once in plating medium (PM; NeuroBasal (Invitrogen Corp., cat#21103-049)/10% Horse Serum (Sigma-Aldrich Co., cat#H1138)/0.5 mM L-Glutamine (Invitrogen Corp., cat#25030-081)), then resuspended in a fresh 10 mL PM volume for trituration. Trituration consists of 18 cycles with a 5 mL-serological pipet, followed by 18 cycles with a flame-polished glass Pasteur pipet. The volume is elevated to 50 mL with PM, the contents then passed over a 70 um cell-strainer (BD Biosciences, cat#352350) and transferred directly to a wet-ice bath. The cell-density is quantified using a hemacytometer, and diluted to allow for the plating of 50000 cells/well/100 uL in pre-coated 96-well PDL-coated plates (Corning, Inc., cat#3665). Cells are incubated for 4-5 hours at 37° C./5% CO2, after which time the entire volume is exchanged to feeding medium (FM; NeuroBasal/2% B-27 Serum-free supplement (Invitrogen Corp., cat#17504-044)/0.5 mM L-Glutamine/1% Penicillin-Streptomycin (Invitrogen Corp., cat#15140-122)). The cultures undergo two 50% fresh FM exchanges, after 3 days in vitro (DIV3), and again at DIV7.
Human C-terminal recognition-site Abeta1→42 and Rat N-terminal recognition-site Abeta1→x capture-antibodies, diluted 1:300 in 0.05M Carbonate-Bicarbonate buffer (Sigma-Aldrich Co., C-3041), are use to coat (100 uL/well) flat-bottomed F96 MicroWellTM (MaxiSorpTM surface) plates (Nalge Nunc International, cat#439454), and incubated overnight at 4° C. for eventual use in the ELISA assay. Compounds to be screened are solubilized in dimethyl sulphoxide (DMSO, Sigma-Aldrich Co., cat#15493-8), and further diluted in DMSO in an eight-point dose-response format. Into 96-well plates, dose-response compound dilutions (1000× the desired final concentration) are stamped out at 2 uL/well, in duplicate (up to 3 compounds/plate), as a daughter plate. In addition, DMSO and N—[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor (GSI), are incorporated as solvent and positive controls, respectively. With the assistance of liquid-handling automation, the compound daughter plate is diluted 1:500 with warmed FM, and two DIV8 culture plates are leveled to 60 uL/well, and immediately overlaid with 60 uL/well of the 2× diluted daughter plate. The plates are returned to the 37° C./5% CO2-incubator for 24 hours.
Each coated capture-antibody ELISA plate undergoes 4×250 uL/well Phosphate-buffered saline with 0.05% Tween®-20 SigmaUltra (PBS-T; Fluka, cat#79383/Sigma-Aldrich Co., cat#P7949) washes. The ELISA plates are then overlaid with 120 uL/well PBS-T supplemented with 1% Bovine Serum Albumin Diluent/Blocking solution (BSA; Kirkegaard & Perry Laboratories (KPL), Inc., cat#50-61-01) and incubate at room-temperature on an orbital shaker for a minimum of 2 hours.
Rat Abeta1→42 and rat Abeta1→40 peptide (American Peptide Co., cat#62-0-84/62-0-86A) DMSO stock solutions are serially-diluted 1:2 in FM yielding a final concentration range of 0-500 pg/mL, to be plated on the respective ELISA plates for determination of the corresponding standard curve, from which concentrations of specific or total Abeta peptides in the presence of a particular drug concentration can be calculated. The conditioned medium from the duplicate culture plates are collected and combined into one round-bottom 96-well transfer plate which is incubated on wet-ice. The culture plates are rinsed once with 120 ul/well FM, and replenished immediately with 100 uL/well FM, being returned to the incubator for 10 minutes. Cell-viability is evaluated by adding 20 uL/well of warmed CellTiter 96® Aqueous One Solution (MTS/PES; Promega Corp., cat#G3581), and returning the plates to the incubator for 30-90 minutes. Plate absorbance at 492 nm is read on a spectrophotometer, and from which, the ratio of absorbance of compound-treated cells to absorbance of solvent (DMSO)-treated control cells is calculated. The calculation of the corresponding EC50 values is performed following non-linear curve-fitting using GraphPad Prism® software.
For each ELISA plate, a corresponding transfer-plate is created containing 120 uL/well of either the rat Abeta1→42 or rat Abeta1→40 peptide standard solutions, in duplicate, and 110-115 uL/well of the collected conditioned-medium plate, half designated for the Abeta1→42 ELISA, and the other half for the Abeta1→x ELISA. The ELISA plates undergo a second set of 4×250 uL/well PBS-T washes, immediately followed by being overlaid with their designated transfer-plate. The ELISA plates incubate on an orbital-shaker for 16-18 hours at 4° C.
Detection antibody solution is prepared by diluting beta-Amyloid 17-24 (4G8) biotinylated monoclonal antibody (Covance, Inc., cat#SIG-39240-200) 1:1500 in PBS-T supplemented with 0.67% BSA. The ELISA plates undergo 4×250 uL/well PBS-T washes, and are overlaid with 100 uL/well of 4G8 diluted detection-antibody solution. The Abeta1→42 ELISA plates are incubated on an orbital-shaker at room-temperature for 90 minutes, the Abeta1→x ELISA plates for 60 minutes.
In order to conjugate the biotinylated monoclonal 4G8 antibody, following 4×250 uL/well PBS-T washes, the ELISA plates undergo a one-hour incubation at 100 ul/well with a 1:15000 dilution of Streptavidin-HRP conjugate (Jackson ImmunoResearch Laboratories, Inc., cat#016-030-0840) on an orbital-shaker at room temperature.
Following a final set of 4×250 uL/well PBS-T washes, the ELISA plates are overlaid with 100 ul/well SureBlue 3,3′,5,5′-Tetramethylbenzidine (TMB) Microwell Peroxidase substrate solution (Kirkegaard & Perry Laboratories, Inc., cat#52-00-02), protected from light, and incubate for 20-45 minutes at room temperature. At the point the desired level of development is attained, 100 ul/well of TMB Stop solution (Kirkegaard & Perry Laboratories, Inc., cat#50-85-05) is added, and the plate thoroughly shaken in preparation for reading on a spectrophotometer. SureBlue TMB Microwell Substrate develops a deep blue color in the presence of a peroxidase-labeled conjugate, and turns yellow when stopped by acidification, allowing for plate absorbance at 450 nm to be read. From the calculation of the standard curve, the compound dose-response curves, normalized to DAPT performance, are plotted as % DMSO using GraphPad Prism® software, and the corresponding EC50 values calculated.
Measurement of Aβ 42 In Vivo
Compounds of the invention can be used to treat AD in mammal such as a human or alternatively in a validated animal model such as the mouse, rat, or guinea pig. The mammal may not be diagnosed with AD, or may not have a genetic predisposition for AD, but may be transgenic such that it overproduces and eventually deposits Aβ in a manner similar to that seen in the human. Additionally, non-transgenic animals may also be used to determine the biochemical efficacy of the compound, with an appropriate assay.
Compounds can be administered in any standard form using any standard method. For example, but not limited to, compounds can be in the form of liquid, tablets or capsules that are taken orally or by injection. Compounds can be administered at any dose that is sufficient to significantly reduce, for example, levels of Aβtota or more specifically Aβ342 in the blood plasma, cerebrospinal fluid (CSF), or brain.
To determine whether acute administration of the compound would reduce Aβ42 levels in-vivo, two-three month old Tg2576 transgenic mice expressing APP695 containing the “Swedish” variant could be used or any other appropriately validated transgenic model. This transgenic mouse displays spontaneous, progressive accumulation of β-amyloid (Aβ) in brain, eventually resulting in amyloid plaques within the subiculum, hippocampus and cortex. Animals of this age have high levels of Aβ in the brain but no detectable Aβ deposition. Mice treated with the compound would be examined and compared to those untreated or treated with vehicle and brain levels of soluble Aβ42 and total Aβ would be quantitated by standard techniques, for example, using ELISA. Treatments may be acute or sub-chronic and treatment periods may vary from hours to days or longer and can be adjusted based on the results of the biochemical endpoint once a time course of onset of effect can be established.
A typical protocol for measuring Aβ or Aβ42 levels from in-vivo samples is shown but it is only one of many variations that could used to detect the levels of Aβ. For example, aliquots of compounds can be dissolved in DMSO (volume equal to 1/10th of the final formulation volume), vortexed and further diluted (1:10) with a 10% (w/v) hydroxypropyl β cyclodextrin (HBC, Aldrich, Ref No 33, 260-7) solution in PBS, where after they are sonicated for 20 seconds.

    
    
        Compounds may be administered as a single oral dose given three to four hours before sacrifice and subsequent analysis or alternatively could be given over a course of days and the animals sacrificed three to four hours after the administration of the final dose
        Tg2576 mice can be anesthetized with a mixture of ketamine/xylazine (80/16 mg/kg intraperitoneally). When a deep level of anesthesia is reached, the mouse's head is secured in a stereotaxic frame. The skin on the back of the neck is retracted and the muscles on the back of the neck are removed to expose the cisterna magna. CSF is collected from the cisterna magna using a pulled 10 μl micropipette taking care not to contaminate the CSF with blood. The CSF is immediately diluted 1:10 in 1% 3-[3-cholamidopropyl)-dimethyl-ammonio]-1-propane sulfonate (CHAPS) [weight per volume in phosphate buffered saline (w/v in PBS)] containing protease inhibitors (PI's) (Complete, Mini protease inhibitor cocktail tablets-Roche), quick frozen in liquid nitrogen and stored at −80° C. until ready for biochemical analysis.
    
    


Blood is collected via cardiac puncture using a 25 gauge needle attached to a 1 ml syringe and was dispensed into a 0.6 ml microtainer tube containing ethylenediaminetetraacetic acid (EDTA). The blood was centrifuged immediately at 4° C. for 5 minutes at 1500×G. The resulting plasma was aliquoted into 0.5 ml microcentrifuge tubes, the aliquots are quick frozen in liquid nitrogen and are stored at −80° C.
The brain is removed after removing the skull and is rinsed with PBS. The cerebellum/brain-stem is removed, frozen, and retained for drug exposure analysis; the remaining brain section was quartered. The rear right quarter, which contained cortex and hippocampus, is weighed, frozen in liquid nitrogen and stored at −80° C. until ELISA analysis. The remaining brain tissue is frozen in liquid nitrogen and stored at −80° C.
For total Aβ or Aβ40 analysis brain tissue is homogenized at a volume of 24 ml/g in cold 1% CHAPS containing protease inhibitors and the resulting homogenates are centrifuged for 1 hour at 100,000×g at 4° C. The supernatant is removed and transferred to a fresh tube and further diluted to 240 ml/g in CHAPS with protease inhibitors.
For Aβ42 analysis brain tissue is homogenized at a volume of 50 ml/g in cold 1% CHAPS containing PI's. Homogenates were spun for 1 hour at 100,000×g at 4° C. The supernatant is removed and transferred to a fresh tube and further to diluted to a final volume 66.7 ml/g in 1% CHAPS with protease inhibitors.
To quantify the amount of human Aβ42 in the soluble fraction of the brain homogenates, commercially available Enzyme-Linked-Immunosorbent-Assay (ELISA) kits can be used (h Amyloid Aβ42 ELISA high sensitive, The Genetics Company, Zurich, Switzerland is just one of many examples). The ELISA is performed according to the manufacturer's protocol. Briefly, the standard (a dilution of synthetic Aβ1-42) and samples are prepared in a 96-well polypropylene plate without protein binding capacity (Greiner bio-one, Frickenhausen, Germany). The standard dilutions with final concentrations of 1000, 500, 250, 125, 62.5, 31.3 and 15.6 pg/ml and the samples are prepared in the sample diluent, furnished with the ELISA kit, to a final volume of 60 μl. Samples, standards and blanks (50 μl) are added to the anti-Aβ-coated polystyrol plate (capture antibody selectively recognizes the C-terminal end of the antigen) in addition with a selective anti-Aβ-antibody conjugate (biotinylated detection antibody) and incubated overnight at 4° C. in order to allow formation of the antibody-Amyloid-antibody-complex. The following day, a Streptavidine-Peroxidase-Conjugate is added, followed 30 minutes later by an addition of TMB/peroxide mixture, resulting in the conversion of the substrate into a colored product. This reaction is stopped by the addition of sulfuric acid (1M) and the color intensity is measured by means of photometry with an ELISA-reader with a 450 nm filter. Quantification of the Aβ content of the samples is obtained by comparing absorbance to a standard curve made with synthetic Aβ1-42.
Similar analysis, with minor modification, can be carried out with CSF (Diluted 1:10 (for a final loading dilution of 1:100) in 1% CHAPS containing PI and plasma samples (Diluted 1:15 in 0.1% CHAPS [w/v in PBS]).
Certain compounds of the disclosure may lower Aβ42 by >15%, in some cases certain compounds may lower Aβ42>25% and in further cases certain compounds may lower Aβ42>40% relative to basal levels.
In Vivo Studies (Rats)
Male Sprague Dawley rats from Harlan, 230-350 g, were used for studies. Fasted rats were dosed via oral gavage, with vehicle (15% Solutol HS 15, 10% EtOH, 75% Water) or compound, at a volume of 10 ml/kg. For PK studies, at fixed time points after dosing, the rats were euthanized with an excess of CO2. Terminal blood was collected through cardiac puncture, mixed in EDTA tubes, immediately spun (3 min at 11,000 rpm at 4° C.), and snap frozen for plasma collection. A piece of frontal cortex was collected and snap frozen for compound level determination. For A-beta lowering studies, at a determined time point after dosing (Cmax if it is ≧3 hr), rats were euthanized as in the PK studies and plasma was collected as described above. Cerebellum was removed and saved for compound level determination, and the remaining brain was divided into 4 quadrants, snap frozen and saved to examine A-beta peptide levels. Solutol HS 15 was purchased from Mutchler Inc.
Practitioners will also know that similar methods can also be applied to other species such as mice (including transgenic strains such as Tg2576), guinea pig, dog and monkey.
Analysis of In Vivo Aβ Lowering Studies
Compounds of the invention can be used to treat AD in mammal such as a human or alternatively in a validated animal model such as the mouse, rat, or guinea pig. The mammal may not be diagnosed with AD, or may not have a genetic predisposition for AD, but may be transgenic such that it overproduces and eventually deposits Aβ in a manner similar to that seen in the human. Alternatively, non-transgenic animals may also be used to determine the biochemical efficacy of the compound, that is, the effect on the Aβ biomarker, with an appropriate assay.
Compounds can be administered in any standard form using any standard method. For example, but not limited to, compounds can be in the form of liquid, tablets or capsules that are taken orally or by injection. Compounds can be administered at any dose that is sufficient to significantly reduce, for example, levels of Aβtotal or more specifically Aβ42 in the blood plasma, cerebrospinal fluid (CSF), or brain.
To determine whether acute administration of the compound would reduce Aβ42 levels in-vivo, two-three month old non-transgenic Sprague-Dawley rats were used. Rats treated with the compound would be examined and compared to those untreated or treated with vehicle and brain levels of soluble Aβ42 and Aβtotal would be quantitated by standard techniques, for example, using an immunoassay such as an ELISA. Treatments may be acute or sub-chronic and treatment periods may vary from hours to days or longer and can be adjusted based on the results of the biochemical endpoint once a time course of onset of effect can be established.
A typical protocol for measuring Aβ or Aβ42 levels from in-vivo samples is shown but it is only one of many variations that could used to detect the levels of Aβ.

    
    
        Compounds may be administered as a single oral dose given three to four hours before sacrifice and subsequent analysis or alternatively could be given over a course of days and the animals sacrificed three to four hours after the administration of the final dose.
    
    


For total Aβ or Aβ42 analysis brain tissue is homogenized in ten volumes of ice cold 0.4% DEA/50 mM NaCl containing protease inhibitors, e.g., for 0.1 g of brain 1 ml of homogenization buffer is added. Homogenization is achieved either by sonciation for 30 seconds at 3-4W of power or with a polytron homogenizer at three-quarters speed for 10-15 seconds. Homogenates (1.2 ml) are transferred to pre-chilled centrifuge tubes (Beckman 343778 polycarbonate tubes) are placed into a Beckman TLA20.2 rotor. Homogenates are centrifuged for 1 hour at 100,000 rpm (355,040×g) at 4° C. The resulting supernatants are transferred to fresh sample tubes and placed on ice (the pellets are discarded).
The samples are further concentrated and purified by passage over Waters 60 mg HLB Oasis columns according to the methods described (Lanz and Schachter (2006) J. Neurosci Methods. 157(1):71-81; Lanz and Schachter (2008). J. Neurosci Methods. 169(1):16-22). Briefly, using a vacuum manifold (Waters#WAT200607) the columns are attached and conditioned with 1 ml of methanol at a flow rate of 1 ml/minute. Columns are then equilibrated with 1 ml of water. Samples are loaded (800 μl) into individual columns (the Aβ will attach to the column resin). The columns are washed sequentially with 1 ml of 5% methanol followed by 1 ml of 30% methanol. After the final wash the eluates are collected in 13×100 mm tubes by passing 800 μl of solution of 90% methanol/2% ammonium hydroxide) over the columns at 1 ml/minute. The samples are transferred to 1.5 ml non-siliconized sample tubes are dried in a speed-vac concentrator at medium heat for at least 2 hours or until dry.
The dried samples are either stored at −80° C. or are used immediately by resuspending the pellets in 80 μl of Ultra-Culture serum-free media (Lonza) supplemented with protease inhibitors by vortexing for 10 seconds. Sixty microliters of each sample is transferred to a pre-coated immunoassay plate coated with an affinity purified rabbit polyclonal antibody specific to Aβ42 (x-42). Sixty microliters of fresh supplemented ultraculture is added to the remaining sample and 60 microliters is transferred to a pre-coated and BSA blocked immunoassay plate coated with an affinity purified rabbit polyclonal antibody specific to total rodent Aβ (1-x). Additional standard samples of rodent Aβ/rodent Aβ42 are also added to the plates with final concentrations of 1000, 500, 250, 125, 62.5, 31.3 and 15.6 pg/ml. The samples are incubated overnight at 4° C. in order to allow formation of the antibody-Amyloid-antibody-complex. The following day the plates are washed 3-4 times with 150 microliters of phosphate buffered saline containing 0.05% Tween 20. After removal of the final wash 100 μl of the monoclonal antibody 4G8 conjugated to biotin (Covance) diluted 1:1000 in PBS-T containing 0.67% BSA was added and the plates incubated at room temperature for 1-2 hours. The plates are again washed 3-4 times with PBS-T and 100 μl of a Streptavidin-Peroxidase-Conjugate diluted 1:10,000 from a 0.5 mg/ml stock in PBS-T contained 0.67% BSA is added and the plates incubated for at least 30 minutes. Following a final set of washes in PBS-T, a TMB/peroxide mixture is added, resulting in the conversion of the substrate into a colored product. This reaction is stopped by the addition of sulfuric acid (1M) and the color intensity is measured by means of photometry with an microplate reader with a 450 nm filter. Quantification of the Aβ content of the samples is obtained by comparing absorbance to a standard curve made with synthetic Aβ. This is one example of a number of possible measurable endpoints for the immunoassay which would give similar results.
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 HS15:Ethanol:Water (15:10:75) formulation (measuring Aβ at 3 hours).
Pharmacokinetic Analysis
Sample Preparation
Plasma samples and standards were prepared for analysis by treating with a 3× volume of acetonitrile containing 500 ng/mL of internal standard (a selected aryl propionic acid). Typically 150 μL of acetonitrile with internal standard was added to 50 μL of plasma. Acetonitrile was added first to each well of a 96-well Phenomenex Strata Impact protein precipitation filter plate followed by the addition of the plasma sample or standard. The filter plate was allowed to sit for at least 15 minutes at room temperature before a vacuum was applied to filter the samples into a clean 96-well plate.
If sample concentrations were observed or predicted to be greater than 1000 ng/mL, plasma samples were diluted with blank plasma 10-150 fold depending on the anticipated concentration and upper limit of quantitation of the analytical method.
Samples of frontal cortex or cerebellum were homogenized then treated in similar manner. To each brain sample, a 4× volume of PBS (pH 7.4) buffer was added along with a 15× volume of acetonitrile (containing internal standard) in a 2 mL screw-cap plastic tube. The tubes were then filled one third of the way with 1 mm zirconia/silica beads (Biospec) and placed in a Mini Bead Beater for 3 minutes. The samples were inspected and if any visible pieces of brain remained, they were returned to the Bead Beater for another 2-3 minutes of shaking. The resulting suspension was considered to be a 5-fold dilution treated with a 3× volume of acetonitrile (with internal standard). Calibration standards were prepared in 5-fold diluted blank brain homogenate and precipitated with a 3× volume of acetonitrile immediately after the addition of the appropriate spiking solution (see below). All brain standards and samples were allowed to sit for at least 15 minutes prior to filtering them through a Phenomenex Strata Impact protein precipitation filter plate into a clean 96-well plate.
Spiking solutions for plasma and brain calibration standards were prepared at concentrations of 0.02, 0.1, 0.2, 1, 2, 10, 20, 100 and 200 μg/mL in 50:50 acetonitrile/water. Calibration standards were prepared by taking 190 μL of blank matrix (plasma or brain homogenate) and adding 10 μL of spiking solution resulting in final concentrations of 1, 5, 10, 50, 100, 500, 1000, 5000 and 10,000 ng/mL.
LC-MS/MS Analysis
Precipitated plasma and brain samples were analyzed by LC-MS/MS using a Shimadzu LC system consisting of two LC-10AD pumps and a SIL-HTc autosampler connected to an Applied Biosystems MDS/Sciex API 3200 QTRAP mass spectrometer.
For chromatographic separation, a Phenomenex Luna C-18 3 μM (2×20 mm) column was used with an acetonitrile-based gradient mobile phase. The two mobile phase components were:
Mobile phase A: water with 0.05% (v/v) formic acid and 0.05% (v/v) 5 N ammonium hydroxide.
Mobile phase B: 95:5 acetonitrile/water with 0.05% (v/v) formic acid and 0.05% (v/v) 5 N ammonium hydroxide.
The gradient for each analysis was optimized for the specific compound, but generally, the run started with between 0% and 40% of mobile phase B, ramped up to 100% of mobile phase B over 1-2 minutes, then held there for 2-3 minutes before returning to the initial conditions for 4 minutes to re-equilibrate.
The API 3200 QTRAP mass spectrometer was used in MRM mode with negative electrospray ionization. MRM transitions and mass spec settings were optimized for each compound.
Standard curves were created by quadratic or linear regression with 1/x*x weighting. Calibration standards were prepared 1-10,000 ng/mL, but the highest (and sometimes lowest) standards were often not acceptable for quantitation and only those standards with reasonable back-calculated accuracies were included in the calibration curve. Ideally, only standards with +/−15% of nominal concentration would be included in the fitted standard curve, but occasionally larger deviations were accepted after careful consideration. Sample concentrations below the quantitation range were reported as “BQL”. Concentrations above the curve were usually re-run with larger sample dilutions
Glucuronidation Protocols
Microsomal glucuronidation reactions were conducted using the UGT Reaction Mix solutions (A and B) from BD Biosciences and following the vendor's protocol. 10 μM of test article or control compound was incubated with 0.5 mg/mL of human or rat liver microsomes. Samples were taken at 0 and 60 minutes and acetonitrile was added to terminate the reactions. Samples were analyzed by LC/MS, monitoring for the loss of parent compound and the appearance of glucuronide. Control reactions were run for each compound substituting water for the glucuronic acid solution to monitor for any loss of parent compound due to degradation or unanticipated micro somal reactions.
Hepatocyte experiments were run using cryopreserved human hepatocytes (single donor) obtained from Celsis/In Vitro Technologies. Cells were thawed and counted according to the vendor's protocols using the trypan blue exclusion method to obtain the count of live cells. Test article and control compounds were incubated at a concentration of 5 uM in KHB buffer (Celsis/In Vitro Technologies) containing 1 million cells per mL. Samples were taken at 0, 60 and 120 minutes. The reactions were terminated with addition of acetonitrile. Samples were analyzed by LC/MS, monitoring for the loss of parent compound and the appearance of glucuronide.
Pharmacology
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. Certain compounds of the disclosure modulate γ-secretase activity with respect to APP proteolytic processing and in so doing lower the production of Aβ42 both in vitro in cells and in vivo in animals. In some cases this effect occurs at concentrations that do not significantly impair the viability of cells in vitro and at doses that are well tolerated in vivo. Certain compounds of the disclosure lower Aβ42 secretion in native neuronal and cellular construct assay systems with EC50 values that are below 1 micromolar (Class A compounds, Table 14) while others have EC50 values from 1-5 micromolar (Class B compounds, Table 14) and others have EC50 values greater than 5 micromolar (Class C compounds). Certain compounds of the disclosure do not appear to significantly interfere with γ-secretase related Notch processing activity. Compounds that significantly interfere with γ-secretase related Notch processing activity have been associated with toxic side-effects. Certain compounds of the disclosure have favorable pharmacokinetic (PK) properties in animals. Thus, certain of the compounds are orally bioavailable, penetrate into the brain and have favorable PK parameters including half-life and clearance supporting pharmaceutical application in humans. In turn, certain compounds of the disclosure significantly lower Aβ42 production in the brains of non-transgenic and transgenic animals after single dose and multi-dose oral administration with no overt side effects. For certain compounds of the disclosure single oral doses of <30 milligrams/kilogram are efficacious at lowering Aβ42 production in the brains of rats (e.g. Sprague-Dawley) and wild type mice (e.g. C57BL/6). Certain compounds of the disclosure which lower Aβ42 at doses of <30 milligrams/kilogram appear to be well tolerated and show no overt or clinical chemical toxicity after subchronic 14-day administration at doses >30 milligrams/kilogram/day. Certain compounds of the disclosure have favorable absorption-distribution-metabolism and excretion (ADME) properties. Moreover, certain compounds of the disclosure do not appear to significantly bio-accumulate in tissues especially in the brain. Compounds of Formulas I-IX wherein A=CO2H show favorable profiles with respect to acylglucoronide (A=CO2Glu) metabolite formation. The potential for acylglucoronide metabolites to cause of toxicity has been described particularly for non-steroidal anti-inflammatory drugs (NSAIDs) containing carboxylic acid groups (Ebner et at Drug Metabolism and Disposition 1999, 27(10),1143-49). Several such NSAIDs have been removed from the market due to idiosyncratic toxicity in humans and it has been speculated that NSAID idiosyncratic toxicity is related to the relative load and relative reactivity of acylglucoronide metabolites. Therefore, carboxylic acid compounds which are less prone to acylgluconoride formation are expected to be less toxic. As measured using established in vitro assay systems, certain desirable compounds of the disclosure are less prone to acylglucoronidation than NSAID compounds that remain on the market are regarded as safe (e.g., flurbiprofen).
Dosage and Administration
The present disclosure includes pharmaceutical composition for treating a subject having a neurological disorder comprising a therapeutically effective amount of a compound of Formulas I-IX, a derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent.
The pharmaceutical compositions can be administered in a variety of dosage forms including, but not limited to, a solid dosage form or in a liquid dosage form, an oral dosage form, a parenteral dosage form, an intranasal dosage form, a suppository, a lozenge, a troche, buccal, a controlled release dosage form, a pulsed release dosage form, an immediate release dosage form, an intravenous solution, a suspension or combinations thereof. The dosage can be an oral dosage form that is a controlled release dosage form. The oral dosage form can be a tablet or a caplet. The compounds can be administered, for example, by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration. In one embodiment, the compounds or pharmaceutical compositions comprising the compounds are delivered to a desired site, such as the brain, by continuous injection via a shunt.
In another embodiment, the compound can be administered parenterally, such as intravenous (i.v.) administration. The formulations for administration will commonly comprise a solution of the compound of the Formulas I-IX dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. These formulations may be sterilized by conventional, well known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of compound of Formulas I-IX in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For i.v. administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol.
In one embodiment, a compound of Formulas I-IX can be administered by introduction into the central nervous system of the subject, e.g., into the cerbrospinal fluid of the subject. The formulations for administration will commonly comprise a solution of the compound of Formulas I-IX dissolved in a pharmaceutically acceptable carrier. In certain aspects, the compound of Formulas I-IX is introduced intrathecally, e.g., into a cerebral ventricle, the lumbar area, or the cisterna magna. In another aspect, the compound of Formulas I-IX is introduced intraocullarly, to thereby contact retinal ganglion cells.
The pharmaceutically acceptable formulations can easily be suspended in aqueous vehicles and introduced through conventional hypodermic needles or using infusion pumps. Prior to introduction, the formulations can be sterilized with, preferably, gamma radiation or electron beam sterilization.
In one embodiment, the pharmaceutical composition comprising a compound of Formulas I-IX is administered into a subject intrathecally. As used herein, the term “intrathecal administration” is intended to include delivering a pharmaceutical composition comprising a compound of Formulas I-IX directly into the cerebrospinal fluid of a subject, by techniques including lateral cerebroventricular injection through a burrhole or cisternal or lumbar puncture or the like (described in Lazorthes et al. Advances in Drug Delivery Systems and Applications in Neurosurgery, 143-192 and Omaya et al., Cancer Drug Delivery, 1: 169-179, the contents of which are incorporated herein by reference). The term “lumbar region” is intended to include the area between the third and fourth lumbar (lower back) vertebrae. The term “cisterna magna” is intended to include the area where the skull ends and the spinal cord begins at the back of the head. The term “cerebral ventricle” is intended to include the cavities in the brain that are continuous with the central canal of the spinal cord. Administration of a compound of Formulas I-IX to any of the above mentioned sites can be achieved by direct injection of the pharmaceutical composition comprising the compound of Formulas I-IX or by the use of infusion pumps. For injection, the pharmaceutical compositions can be formulated in liquid solutions, preferably in physiologically compatible buffers such as Hank's solution or Ringer's solution. In addition, the pharmaceutical compositions may be formulated in solid form and re-dissolved or suspended immediately prior to use. Lyophilized forms are also included. The injection can be, for example, in the form of a bolus injection or continuous infusion (e.g., using infusion pumps) of pharmaceutical composition.
In one embodiment, the pharmaceutical composition comprising a compound of Formulas I-IX is administered by lateral cerebro ventricular injection into the brain of a subject. The injection can be made, for example, through a burr hole made in the subject's skull. In another embodiment, the encapsulated therapeutic agent is administered through a surgically inserted shunt into the cerebral ventricle of a subject. For example, the injection can be made into the lateral ventricles, which are larger, even though injection into the third and fourth smaller ventricles can also be made.
In yet another embodiment, the pharmaceutical composition is administered by injection into the cisterna magna, or lumbar area of a subject.
For oral administration, the compounds will generally be provided in unit dosage forms of a tablet, pill, dragee, lozenge or capsule; as a powder or granules; or as an aqueous solution, suspension, liquid, gels, syrup, slurry, etc. suitable for ingestion by the patient. Tablets for oral use may include the active ingredients mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
Pharmaceutical preparations for oral use can be obtained through combination of a compound of Formulas I-IX with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds, if desired, to obtain tablets or dragee cores. Suitable solid excipients in addition to those previously mentioned are carbohydrate or protein fillers that include, but are not limited to, sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.
Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredients is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
For transmucosal administration (e.g., buccal, rectal, nasal, ocular, etc.), penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
The suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperatures and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
The compounds can be delivered transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, or aerosols.
The compounds may also be presented as aqueous or liposome formulations. Aqueous suspensions can contain a compound of Formulas I-IX in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolarity.
Oil suspensions can be formulated by suspending a compound of Formulas I-IX in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulations can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.
In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or transcutaneous delivery (e.g., subcutaneously or intramuscularly), intramuscular injection or a transdermal patch. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
For administration by inhalation, the compounds are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
In general a suitable dose will be in the range of 0.01 to 100 mg per kilogram body weight of the recipient per day, preferably in the range of 0.2 to 10 mg per kilogram body weight per day. The desired dose is preferably presented once daily, but may be dosed as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day.
The compounds can be administered as the sole active agent, or in combination with other known therapeutics to be beneficial in the treatment of neurological disorders. In any event, the administering physician can provide a method of treatment that is prophylactic or therapeutic by adjusting the amount and timing of drug administration on the basis of observations of one or more symptoms (e.g., motor or cognitive function as measured by standard clinical scales or assessments) of the disorder being treated.
Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton Pa. (“Remington's After a pharmaceutical composition has been formulated in an acceptable carrier, it can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of the compounds of Formulas I-IX, such labeling would include, e.g., instructions concerning the amount, frequency and method of administration.

## Claims

1. A method for the therapeutic treatment of Alzheimer's disease comprising administering to a patient in need thereof an effective amount of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof.

2. A method for the therapeutic treatment of Alzheimer's disease comprising administering to a patient in need thereof an effective amount of (S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof.

3. A method for the therapeutic treatment of Alzheimer's disease comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising:
(R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable carrier or excipient.

4. The method of claim 3, wherein the pharmaceutical composition is in a solid dosage form.

5. The method of claim 3, wherein the pharmaceutical composition is in an oral dosage form.

6. The method of claim 5, wherein the oral dosage form is a tablet or a capsule.

7. The method of claim 6, wherein the oral dosage form is a tablet.

8. A method for the therapeutic treatment of Alzheimer's disease comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising:
(S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable carrier or excipient.

9. The method of claim 8, wherein the pharmaceutical composition is in a solid dosage form.

10. The method of claim 8, wherein the pharmaceutical composition is in an oral dosage form.

11. The method of claim 10, wherein the oral dosage form is a tablet or a capsule.

12. The method of claim 11, wherein the oral dosage form is a tablet.