Background of the Invention Multiple sclerosis (MS) is a disease in which there are patches of demyelination throughout the white matter of the central nervous system, sometimes extending into the gray matter. Typically the symptoms of lesions of the white matter are weakness, incoordination, paresthesias, speech disturbances, and visual complaints. The course of the disease is usually prolonged, with remissions and relapses over a period of many years. It is also called disseminated sclerosis and insular sclerosis.

The etiology of MS is unknown. Some work implicates an immunologic abnormality. Postulated causes include infection by a slow or latent virus, and myelinolysis by enzymes. IgG is usually elevated in the CSF, and elevated titers have been associated with a variety of viruses, including measles. The significance of these findings and of reported associations with HLA allotypes and altered number of T cells has not been clarified. Women are somewhat more often affected than men. The disease is more common in temperate climates that in the tropics.

And while age of onset is usually between 20 and 40, MS has been linked to the geographic area where the patient spend his or hers first 15 years; it appears that relocation after the 15th birthday does not alter risk.

The pathology of MS can be summarized as follows: Plaques or islands of demyelination with destruction of oligodendroglia and perivascular inflammation are disseminated through the CNS, primarily in the white matter, with a predilection for the lateral and posterior columns, the optic nerve and periventricular areas.

Tracts in the midbrain, pons, and cerebellum also are affected, and gray matter in both cerebrum and cord may be affected. Cell bodies and axons usually are preserved, especially in early lesions. Later, axons may be destroyed, especially in the long tracts, and a fibrous gliosis gives the tracts their"sclerotic"appearance.

Both early and late lesions may be found simultaneously. Chemical changes in lipid and protein constituents of myelin have been demonstrated in and around plaques.

The cellular pathophysiology of the disease is not clearly understood.

However the weight of evidence suggests that it is an autoimmune disorder. As such, activation of immune and inflammatory cells, e. g. T cells, macrophages, and the generation of cytokines are likely to be involved.

There exists a need for new forms of intervention in MS. The compounds detailed below provide one new form to meet this need.

Summary of the Invention This invention covers a method for treating MS by administering an effective amount of a compound of Formula (I) alone or in admixture with a pharmaceutically acceptable excipient wherein Formula (I) comprises: wherein: Rl is- (CR4R5) nC (O) O (CR4R5) mR6,- (CR4R5) nC (O) NR4 (CR4R5) mR6, ~ (CR4R5) nO (CR4R5) mR6, or- (CR4R5) rR6 wherein the alkyl moieties may be optionally substituted with one or more halogens; <BR> <BR> m is 0 to 2;<BR> <BR> <BR> n is 1 to 4; risOto6; R4 and R5 are independently selected from hydrogen or a C1-2 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCl-3 alkyl, halo substituted aryloxyC1-3 alkyl, indanyl, indenyl, C7 11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3_6 cycloalkyl, or a C4_6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by OH, 1 to 3 methyl groups or one ethyl group; provided that: a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, then R6 is other than H in -(CR4R5) nO (CR4R5) mR6 ; X is YR2, halogen, nitro, NR4R5, or formyl amine; Y is O or S (O) m ; m'is 0,1, or 2; OorNR8;X2is X3 is hydrogen or X; X4is

X5 is H, R9, ORg, CN, C (O) Rg, C (O) OR8, C (O) NR8R8, or NR8R8 ; R2 is independently selected from the group consisting of-CH3 and- CH2CH3 optionally substituted by 1 or more halogens; s is 0 to 4; R3 is hydrogen, halogen, C1-4 alkyl, CH2NHC (O) C (O) NH2, halo- substituted C1-4 alkyl,-CH=CRgRg, cyclopropyl optionally substituted by Rg', CN, ORg, CH20Rg, NRgRlo, CH2NRgRlo, C (Z) H,C (0)ORg, C (O) NR8R10, or C#CR8'; Z'is 0, NR9, NORg, NCN, C (-CN) 2, CR8CN, CR8NO2, CR8C (O) OR8, CRgC (O) NRgRg, C (-CN) N02, C (-CN) C (O) OR9, or C (-CN) C (O) NRgRg; Z is C (Y')R14, C (O) OR14, C(Y')NR10R14, C(NR10)NR10R14, CN, C (NOR8) R14, C (O) NR8NR8C (O) Rg, C (O) NR8NR10R14, C (NOR14) R8, C (NR8) NRlORl4, C (NR14) NRgRg, C (NCN) NR10R14, C (NCN) SR9, (2-, 4-or 5-imidazolyl), (3-, 4-or 5-pyrazolyl), (4-or 5-triazolyl [1,2,3]), (3-or 5-triazolyl [1,2,4]), (5-tetrazolyl), (2-, 4-or 5-oxazolyl), (3-, 4-or 5-isoxazolyl), (3- or 5-oxadiazolyl [1,2,4]), (2-oxadiazolyl [1,3,4]), (2-thiadiazolyl [1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl); wherein all of the heterocylic ring systems may be optionally substituted one or more times by R14; the dotted line in formula (a) represents a single or double bond; Y'isOorS; R7 is- (CR4R5) qR 12 or C1-6 alkyl wherein the R 12 or C1-6 alkyl group is optionally substituted one or more times by C 1-2 alkyl optionally substituted by one to three fluorines,-F,-Br,-Cl,-N02,-NRloRI 1,-C (O) Rg,-C (O) ORg,-ORg,-CN, -OC(O)R8,-NR10C(O)NR10R11,-C(O)NR10R11,-OC(O)NR10R11, -NR10C(O)R13,-C(NR10)NR10R11,-NR10C(O)R11,-NR10C(O)OR9, -NR10C(NCN)SR9,-NR10C(NCN)NR10R11,-C(NCN)NR10R11,-C(NCN)SR9, -NR10C(O)C(O)NR10R11,-NR10C(O)C(O)R10,-NR10S(O)2R9,-S(O)m'R9 , thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl; qis0, 1, or2;

R 12 is C3-7 cycloalkyl, (2-, 3-or 4-pyridyl), pyrimidyl, pyrazolyl, (1-or 2- imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2-or 3-thienyl), (4-or 5-thiazolyl), quinolinyl, naphthyl, or phenyl; R8 is independently selected from hydrogen or Rg; Rg'is Rg or fluorine; Rg is C1 4 alkyl optionally substituted by one to three fluorines; Rlo is OR8 or R11; R11 is hydrogen, or C 1-4 alkyl optionally substituted by one to three fluorines; or when Rlo and R 1 are as NR1oRl 1 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from 0, N, or S; R13 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two Ci. 2 alkyi groups; R14 is hydrogen or R7; or when Rlo and R 14 are as NR1oRl4 they may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from 0, N, or S; provided that: f) when R12 is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N- piperazinyl, N-piperidinyl, or N-morpholinyl, then q is not 1; or g) when X2R1 is OCF2H or OCF3, X is F, OCF2H or OCF3, X3 is H, s is zero, X5 is H, Z is C (O) OR14 and R14 is CI-7 unsubstituted alkyl, then R3 is other than H; or the pharmaceutically acceptable salts thereof.

In addition, this invention relates to a method for treating MS by administering an effective amount of a compound of Formula (in to a mammal in need thereof, wherein Formula (II) is: wherein:

RI is- (CR4R5) nC (O) O (CR4R5) mR6,- (CR4R5) nC (O) NR4 (CR4R5) mR6, - (CR4R5) nO (CR4R5) mR6, or- (CR4R5) rR6 wherein the alkyl moieties unsubstituted or substituted with one or more halogens; m is 0 to 2; 0to4;nis risOto6; R4 and R5 are independently selected hydrogen or C 1-2 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC 1-3 alkyl, halo substituted aryloxyC 13 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3_6 cycloalkyl, or a C4_6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl or heterocyclic moiety is unsubstituted or substituted by 1 to 3 methyl groups, one ethyl group, or an hydroxyl group; provided that: a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, then R6 is other than H in - (CR4R5) nO (CR4R5) mR6 ; X is YR2, fluorine, NR4R5, or formyl amine; Y is O or S (O) m'; m'is 0, 1, or 2; X2 is O or NR8; X3 is hydrogen or X; X4 is H, R9, OR8, CN, C (O) Rg, C (O) oR8 C (O) NR8R8, or NR8R8; R2 is independently selected from-CH3 or-CH2CH3 optionally substituted by 1 or more halogens; 0to4;sis W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; R3 is COOR14, C (O) NR4R14 or R7; Z is OR14, S(O)m'R7,S(O)2NR10R14,NR10R14,SR14, NR14C (O) R9, NR10C (Y) R14, NRloC (O) OR7, NRloC (Y) NRloRl4

NRloS (O) 2NRl0Rl4 NRIOC (NCN) NR10R14, NR10S(O) 2R7, NR10C(CR4NO2)SR9,NR10C(CR4NO2)NR10R14,NR10C(NCN)SR9, orNR10C(O)C(O)OR14;NR10C(NR10)NR10R14,NR10C(O)C(O)NR10R14, Y'isOorS; R7 is- (CR4R5) qR 12 or C1-6 alkyl wherein the R 12 or C1-6 alkyl group is unsubstituted or substituted one or more times by methyl or ethyl unsubstituted or substituted by 1-3 fluorines,-F,-Br,-Cl,-N02,-NR1oR11,-C (O) Rg,-C02R8, -O (CH2) 2-4OR8, -O (CH2) qRg,-CN,-C (O) NR10R11, -O (CH2) qC (O) NR 1 OR 11,- O (CH2) qC (O) R9, -NR10C(O)NR10R11, -NR10C(O)R11, -NR10C(O)OR9, -C(NCN)NR10R11,-C(NCN)SR9,-NR10C(O)R13,-C(NR10)NR10R11, -NR10S(O)2R9,-S(O)m'R9,-NR10C(NCN)SR9,-NR10C(NCN)NR10R11, -NR10C(O)C(O)NR10R11, -NR10C(O) C (O) R10, or R13; q is 0, 1, or 2; R12 is R13, C3-C7 cycloalkyl, or an unsubstituted or substituted aryl or heteroaryl group selected from the group consisting of (2-, 3-or 4-pyridyl), pyrimidyl, pyrazolyl, (1-or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2-or 3-thienyl), quinolinyl, naphthyl, and phenyl; R8 is independently selected from hydrogen or Rg; Rg is C1-4 alkyl optionally substituted by one to three fluorines; OR8orR11;R10is Rl 11 is hydrogen, or C 1. 4 alkyi unsubstituted or substituted by one to three fluorines; or when R1o and R i are as NR10R11 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from 0, N, or S; R13 is a substituted or unsubstituted heteroaryl group selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, and thiadiazolyl, and where R13 is substituted on R12 or R13 the rings are connected through a carbon atom and each second R13 ring may be unsubstituted or substituted by one or two C1-2 alkyl groups unsubstituted or substituted on the methyl with 1 to 3 fluoro atoms; R14 is hydrogen or R7; or when R8 and R 14 are as NRgRl4 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from 0, N, or S; R15 is C (O) R14, C (O) NR8RI4, S (O) qNR8Rl4 or S (O) qR7 where q is 0,1 or 2; provided that:

(f) R7 is not C alkyi unsubstituted or substituted by one to three fluorines; or the pharmaceutically acceptable salts thereof.

Detailed Description of the Invention This invention relates to the use of compounds of Formulas (I) and (II), and to pharmaceutical compositions comprising a compound of Formulas (I) and (II) and a pharmaceutically acceptable carrier or diluent, for treating MS.

Without being limited in any fashion, it is believed the mechanism of action may be one of the action of cells such as macrophages and lymphocytes and supressing the production of IL-2, TNF- (x, TNF2, and other pro-inflammatory cytokines and mediators. Some reports indicate that rolipram, another regulator of TNF-is effective in treating experimental autoimmune encephalomyelitis (EAE) in animals. See for example Raine, C. S., Nature Medicine, Vol 1, No 3, pp211-214, 1995; Sommer, N. et al, Nature Medicine, Vol. 1, No. 3, pp. 244-248,1995; Genin, C. P., et al, Proc. Natl. Acad. Sci., Vol. 92, pp. 3601-3605, April 1995; and Takusuka, N., et al, The J. of Immunology, 1995,154: 4803-4812,1995.

Accordingly the compounds of Formulas (I) and (II) are useful in treating MS.

The preferred compounds for use in this invention are defined as follows: For compounds of Formula (I): When Rl for the compounds of the Formula (I) is an alkyl substituted by 1 or more halogens, the halogens are preferably fluorine and chlorine, more preferably a Ci-4 alkyls substituted by 1 or more fluorines. The preferred halo-substituted alkyl chain length is one or two carbons, and most preferred are the moieties-CF3,- CH2F,-CHF2,-CF2CHF2,-CH2CF3, and-CH2CHF2. Preferred RI substitutents for the compounds of the Formula (I) are CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl optionally substituted by OH, C7-11 polycycloalkyl, (3-or 4- cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C1-2 alkyl optionally substituted by 1 or more fluorines,- (CH2) 1-3C (O) O (CH2) 0-2CH3, - (CH2) 1-30 (CH2) 0-2CH3, and- (CH2) 2-40H.

When the RI term contains the moiety (CR4R5), the R4 and R5 terms are independently hydrogen or alkyl. This allows for branching of the individual methylene units as (CR4R5) n or (CR4R5) m; each repeating methylene unit is independent of the other, e. g., (CR4R5) n wherein n is 2 can be-CH2CH (-CH3)-, for instance. The individual hydrogen atoms of the repeating methylene unit or the branching hydrocarbon can optionally be substituted by fluorine independent of each other to yield, for instance, the preferred Ri substitutions, as noted above.

When Ri is a C7-1 l polycycloalkyl, examples are bicyclo [2.2.1]-heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, tricyclo [5.2.1.02, 6] decyl, etc. additional examples of which are described in Saccamano et al., WO 87/06576, published 5 November 1987, which disclosure is incorporated herein by reference in its entirety.

Z is preferably C (O) R8, C (O) ORg, C (O) NRgRg, C (NRg) NR8R8, CN, C (NOR8) R8, C (O) NR8NR8C (O) R8, C (NR8) NR8R8, C (NCN) NR8R8, C (NCN) SR9, (1-, 4-or 5- {Rg}-2-imidazolyl), (1-, 4-or 5- {Rg}-3-pyrazolyl), (1-, 2- or 5- {Rg}-4-triazolyl [1, 2,3]), (1-, 2-, 4-or 5- {Rg}-3-triazolyl [1, 2,4]), (1-or 2- {Rg}-5-tetrazolyl), (4-or 5- {R8}-2-oxazolyl), (3-or 4- {Rg}-5-isoxazolyl), (3- {R8}-5-oxadiazolyl [1,2,4]), (5- {R8}-3-oxadiazolyl [1,2,4]), (5- {Rg}-2-oxadiazolyl [1,3,4]), (5-{Rg}-2-thiadiazolyl [1,3,4]), (4-or 5-{R8}-2-thiazolyl),{R8}-2-thiazolyl), (4-or 5-{R8}-2-oxazolidinyl), (4-or 5-{K8}-2-thiazolidinyl), (1-,{K8}-2-thiazolidinyl), (1-, 4-or 5- {R8}-2-imidazolidinyl) ; most preferred are those compounds wherein the R8 group of Z is R4.

X5 is preferably hydrogen, C1-2 alkyl optionally substituted by one to three fluorines, OR8, CN, C (O) R8, C (O) OR8, C (O) NR8R8, or NR8R8.

Preferred X groups for Formula (I) are those wherein X is YR2 and Y is oxygen. The preferred X2 group for Formula (I) is that wherein X2 is oxygen. The preferred X3 group for Formula (I) is that wherein X3 is hydrogen. Preferred R2 groups, where applicable, are C1-2 alkyl optionally substituted by 1 or more halogens. The halogen atoms are preferably fluorine and chlorine, more preferably fluorine. More preferred R2 groups are those wherein R2 is methyl, or the fluoro- substituted alkyls, specifically a C1-2 alkyl, such as a-CF3,-CHF2, or-CH2CHF2 moiety. Most preferred are the-CHF2 and-CH3 moieties.

Preferred R3 moieties are C (O) NH2, C#CR8, CN, C (Z')H, CH2OH, CH2F, CF2H, and CF3. More preferred are -C#CH and CN. Z'is preferably O or NOR8.

Preferred R7 moieties include optionally substituted- (CH2) 1-2 (cyclopropyl), - (CH2) 0-2 (cyclobutyl),- (CH2) 0-2 (cyclopentyl),- (CH2) 0-2 (cyclohexyl), - (CH2) 0-2 (2-, 3-or 4-pyridyl),- (CH2) 1-2 (2-imidazolyl),- (CH2) 2 (4-morpholinyl), - (CH2) 2 (4-piperazinyl),- (CH2) 1-2 (2-thienyl),- (CH2) 1-2 (4-thiazolyl), and - (CH2) 0-2phenyl; Preferred rings when R1o and R l in the moiety-NR1oRl l together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from 0, N, or S include, but are not limited to 1-imidazolyl, 2-(R8)-1-imidazolyl, 1-pyrazolyl, 3-(R8)-1-pyrazolyl, 1-triazolyl, 2-triazolyl, 5- (R8)-l-triazolyl, 5- (R8)-2-triazolyl,

5- (Rg)-1-tetrazolyl, 5- (Rg)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl, morpholinyl, piperazinyl, 4- (Rg)-l-piperazinyl, or pyrrolyl ring.

Preferred rings when R1o and R 14 in the moiety-NR1oRl4 together with the nitrogen to which they are attached may form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from 0, N, or S include, but are not limited to 1-imidazolyl, 1-pyrazolyl, 1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl, piperazinyl, and pyrrolyl. The respective rings may be additionally substituted, where applicable, on an available nitrogen or carbon by the moiety R7 as described herein for Formula (I). Illustrations of such carbon substitutions includes, but are not limited to, 2- (R7)-1-imidazolyl, <BR> <BR> <BR> 4- (R7)-1-imidazolyl, 5- (R7)-1-imidazolyl, 3- (R7)-1-pyrazolyl, 4- (R7)-1-pyrazolyl,<BR> <BR> <BR> <BR> <BR> <BR> <BR> 5-(R7)-1-pyrazolyl, 4-(R7)-2-triazolyl, 5-(R7)-2-triazolyl, 4-(R7)-1-triazolyl, 5-(R7)-1-triazolyl, 5-(R7)-1-tetrazolyl,(R7)-1-triazolyl, 5-(R7)-1-tetrazolyl, and 5- (R7)-2-tetrazolyl. Applicable nitrogen substitution by R7 includes, but is not limited to, 1- (R7)-2-tetrazolyl, 2- (R7)-1-tetrazolyl, 4- (R7)-1-piperazinyl. Where applicable, the ring may be substituted one or more times by R7.

Preferred groups for NRioRl4 which contain a heterocyclic ring are 5- (R14)-l-tetrazolyl, 2-(R14)-l-imidazolyl, 5-(R14)-2-tetrazolyl, or 4-(R14)-l- piperazinyl.

Preferred rings for R13 include (2-, 4-or 5-imidazolyl), (3-, 4-or 5-pyrazolyl), (4-or 5-triazolyl [1,2,3]), (3-or 5-triazolyl [1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4-or 5-isoxazolyl), (3-or 5-oxadiazolyl [1,2,4]), (2-oxadiazolyl [1,3,4]), (2-thiadiazolyl [1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl).

When the R7 group is optionally substituted by a heterocyclic ring such as imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, the heterocyclic ring itself may be optionally substituted by R8 either on an available nitrogen or carbon atom, such as 1-(Rg)-2-imidazolyl, 1-(Rg)-4-imidazolyl, 1-(Rg)-5-imidazolyl, 1-(Rg)-3-pyrazolyl, 1-(Rg)-4-pyrazolyl, 1-(Rg)-5-pyrazolyl, 1-(Rg)-4-triazolyl,(Rg)-3-pyrazolyl, 1-(Rg)-4-pyrazolyl, 1-(Rg)-5-pyrazolyl, 1-(Rg)-4-triazolyl, or 1-(Rg)-5-triazolyl.(Rg)-5-triazolyl. Where applicable, the ring may be substituted one or more times by R8.

Preferred are those compounds of the Formula (I) wherein R 1 is-CH2- cyclopropyl,-CH2-C5-6 cycloalkyl,-C4-6 cycloalkyl optionally substituted by OH, tetrahydrofuran-3-yl, (3-or 4-cyclopentenyl), benzyl or-Cl-2 alkyl optionally substituted by 1 or more fluorines, and- (CH2) 2-4 OH; R2 is methyl or fluoro- substituted alkyl, R3 is CN or C_CRg; and X is YR2.

Most preferred are those compounds wherein R1 is -CH2-cyclopropyl, cyclopentyl, methyl or CF2H; R3 is CN or C=-CH; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; and R2 is CF2H or methyl.

A preferred subgenus of the compounds of Formula (I) are the compounds of Formula (Ia) wherein: R1 is CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl optionally substituted by OH, C7-11 polycycloalkyl, (3-or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C 1-2 alkyl optionally substituted by 1 or more fluorines,- (CH2) 1-3C (O) O (CH2) 0-2CH3,- (CH2) 1-30 (CH2) 0-2CH3, and -(CH2)2-4OH; X is YR2, halogen, nitro, NR4R5, or formyl amine; X4is X5 is H, R9, OR8, CN, C (O) Rg, C (O) OR8, C (O) NR8R8, or NR8R8; Y is S(O)m';or m'is 0,1, or 2; R2 is-CH3 or-CH2CH3 optionally substituted by 1 or more halogens; R3 is hydrogen, C1-4 alkyl, CH2NHC (O) C (O) NH2, halo-substituted C1-4 alkyl, CN, CH20Rg, C (Z) C(O)OR8, C (O) NR8R10, or C#CR8 ; OorNOR8;Z'is Z is C (O) R14, C (O) OR14, C (o) NR10R14, C(NR10)NR10R14, CN, C (NOR8) R14, C (O) NRgNRgC (O) Rg, C (O) NR8NR10R14, C (NOR14) R8, C (NR8) NRlORl4, C (NR14) NRgRg, C (NCN) NR10R14, C (NCN) SR9, (1-, 4-or 5- 4-or5-{R14}-3-pyrazolyl),(1-,2-or5-{R14}-2-imidazolyl),(1-, {R14}-4-triazolyl [1,2,3]), (1-, 2-, 4-or 5-{R14}-3-triazolyl[1, 2,4]), (1-or 2- or5-{R14}-2-oxazolyl),(3-or4-{R14}-5-isoxazolyl),{R14}-5-tet razolyl),(4- (3- {R14}-5-oxadiazolyl [1,2,4]), (5- {R14}-3-oxadiazolyl[1, 2,4]), (4-or(5-{R14}-2-oxadiazolyl[1,3,4]),(5-{R14}-2-thiadiazolyl[ 1,3,4]),

5-{R14}-2-thiazolyl),{R14}-2-thiazolyl), (4-or 5-{R14}-2-oxazolidinyl), (4-or 5-{R14}-2-thiazolidinyl), (l-,{R14}-2-thiazolidinyl), (l-, 4-or 5-{R14}-2-imidazolidinyl) ; R7 is- (CR4R5) qR 12 or C1-6 alkyl wherein the R 12 or C1-6 alkyl group is optionally substituted one or more times by C1-2 alkyl optionally substituted by one to three fluorines,-F,-Br,-Cl,-N02,-NRIoRl 1,-C (O) Rg,-C (O) ORg,-ORg,-CN, -C(O)NR10R11,-NR10C(O)NR10R11,-OC(O)R8, -NR10C(O)R13,-C(NR10)NR10R11,-NR10C(O)R11,-NR10C(O)OR9, -C (NCN) NR 1 oR 11,-C (NCN) SR9,-NR I OC (NCN) SRg,-NR 1 OC (NCN) NR10R11, -NRIOS (0) 2R9,-S (O) mRg,-NRIOC (O) C (O) NRIOR1 1,-NRIOC (O) C (O) R 10, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl; q is 0,1, or 2; R l2 is C3-C7 cycloalkyl, (2-, 3-or 4-pyridyl), (1-or 2-imidazolyl), piperazinyl, morpholinyl, (2-or 3-thienyl), (4-or 5-thiazolyl), or phenyl; the dotted line formula (a) represents a single or double bond; R8 is independently selected from hydrogen or Rg; Rg is C1-4 alkyl optionally substituted by one to three fluorines; OR8orR11;R10is R 11 is hydrogen or C1-4 alkyl optionally substituted by one to three fluorines; or when Rio and Rl i are as NR10R11 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from 0, N, or S; R13 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two C1-2 alkyl groups; Rl4 is hydrogen or R7; or when R1o and R 14 are as NR10R14 they may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from 0, N, or S; provided that: a) when R12 is N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, or N- morpholinyl, then q is not 1; or b) when Rl is CF2H or CF3, X is F, OCF2H, or OCF3, X5 is H, Z is C (O) OR14 and R14 is Ci-7 unsubstituted alkyl, then R3 is other than H; or the pharmaceutically acceptable salts thereof.

The most perferred compounds of Formula (I) are: methyl 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohex-1-ene-1- carboxylate;

4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohex-1-ene-1-carboxylic acid; methyl cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1- carboxylate]; methyl trans- [4-cyano-4- (3-cyclopentyloxy-4- methoxyphenyl) cyclohexane-1-carboxylate]; methyl cis- [4- (3, 4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1- carboxylate]; methyl trans- [4- (3,4-bisdifluoromethoxyphenyl)-4- cyanocyclohexane-1-carboxylate]; cis- [4-cyano-4- (3-cyclopentyloxy-4- methoxyphenyl) cyclohexane-1-carboxylic acid]; cis- [4-cyano-4- (3- cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylate], tris (hydroxymethyl) ammonium methane salt; cis- [4- (3,4- bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylic acid]; trans- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1- carboxylic acid]; cis- [4-cyano-4- (3-cyclopropylmethoxy-4- methoxyphenyl) cyclohexane-1-carboxylic acid]; trans- [4-cyano-4- (3- cyclopropylmethoxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid]; methyl cis- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexane-1- carboxylate]; methyl trans- [4-cyano-4- (3-cyclopropylmethoxy-4- methoxyphenyl) cyclohexane-1-carboxylate]; methyl cis- [4-cyano-4- (3-cyclopropylmethoxy-4- <BR> <BR> <BR> <BR> difluoromethoxyphenyl) cyclohexane-1-carboxylate]; methyl trans- [4-cyano-<BR> <BR> <BR> <BR> <BR> <BR> <BR> 4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-cyclohexane-1 -carboxylate]; cis-[4-cyano-4- (3-cyclopropylmethoxy-4- difluoromethoxyphenyl) cyclohexane-1-carboxylic acid]; trans- [4-cyano-4- (3- cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1-carboxylic acid]; cis-[4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1- carboxamide]; cis- [4-cyano-4- (3,4-bisdifluoromethoxyphenyl) cyclohexane-1- carboxamide]; trans- [4-cyano-4- (3,4-bisdifluoromethoxyphenyl) cyclohexane-1- carboxamide]; cis- [4-cyano-4- (3,4-bisdifluoromethoxyphenyl) cyclohexane-1- carbohydrazide]; cis- [4-cyano-4- (3,4-bisdifluoromethoxyphenyl) cyclohexane- 1- (2-acetylcarbohydrazide)]; cis- {4- (3,4-bisdifluoromethoxyphenyl)-4-cyano-1- (3- methyl [1,2,4] oxadiazol-5-yl) cyclohexane}; cis- {4- (3,4-bisdifluoromethoxyphenyl)- 4-cyano-1- (2-methyl [1,3,4] oxadiazol-5-yl) cyclohexane}; cis- {4- (3,4- bisdifluoromethoxyphenyl)-4-cyano-1- (2-methyl [1,3,4] thiadiazol-5- yl) cyclohexane}; cis- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl)-1-

hydroxy-1-tris (methylthio) methylcyclohexane]; methyl cis- [4-cyano-4- (3- <BR> <BR> cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-cyclohexane-1- carboxylate];<BR> <BR> <BR> cis- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl)-1- hydroxycyclohexane-1-carboxylic acid]; cis- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl)-1- hydroxycyclohexane-1-carboxamide]; methyl cis- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl)-1- <BR> <BR> methoxy-cyclohexane-1-carboxylate];<BR> <BR> <BR> cis- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl)-1- methoxycyclohexane-1-carboxylic acid]; cis- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl)-1- <BR> <BR> methoxycyclohexane-1-carboxamide];<BR> <BR> <BR> trans- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-<BR> <BR> <BR> cyclohexane-1-carboxaldehyde]; methyl trans- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl)-1- hydroxycyclohexane-1-carboxylate]; trans- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl)-1- hydroxycyclohexane-1-carboxylic acid]; methyl trans- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl)-1- methoxycyclohexane-1-carboxylate]; trans- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl)-1- methoxycyclohexane-1-carboxylic acid]; trans- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl)-1- methoxycyclohexane-1-carboxamide]; cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1- carboxamic acid]; N-methyl-cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane- 1-carboxamic acid]; cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-N- (2- cyanoethyl)carboxamide]; cis- [1- (2-cyanoethyl)-5- {4-cyano-4- (3-cyclopentyloxy-4- methoxyphenyl) cyclohexyl} tetrazole]; and cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl)-1- (tetrazol-5- yl) cyclohexane].

As regards the compounds of Formula (II), the preferred compounds are as follows:

When Rl is an alkyl substituted by 1 or more halogens, the halogens are preferably fluorine and chlorine, more preferably a C1 4 alkyl substituted by 1 or more fluorines. The preferred halo-substituted alkyl chain length is one or two carbons, and most preferred are the moieties-CF3,-CH2F,-CHF2,-CF2CHF2,- CH2CF3, and-CH2CHF2. Preferred R1 substitutents for the compounds of Formula (I) are CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl unsubstituted or substituted with OHC7-11 polycycloalkyl, (3-or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C1-2 alkyl unsubstituted or substituted by 1 or more fluorines,- (CH2) 1-3C (O) O (CH2) 0-2CH3,- (CH2) 1-30 (CH2) 0-2CH3, and - (CH2) 2-40H.

When R1 term contains the moiety (CR4R5), the R4 and R5 terms are independently hydrogen or alkyl. This allows for branching of the individual methylene units as (CR4R5) n or (CR4R5) m; each repeating methylene unit is independent of the other, e. g., (CR4R5) n wherein n is 2 can be-CH2CH (-CH3)-, for instance. The individual hydrogen atoms of the repeating methylene unit or the branching hydrocarbon can unsubstituted or be substituted by fluorine independent of each other to yield, for instance, the preferred R 1 substitutions, as noted above.

When Ri is a C7 1 l polycycloalkyl, examples are bicyclo [2.2.1]-heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, tricyclo [5.2.1.0296] decyl, etc. additional examples of which are described in Saccamano et al., WO 87/06576, published 5 November 1987.

W is preferably alkyl, alkenyl or alkynyl of 3 to 5 carbon atoms, and where it is alkenyl or alkynyl, that one or two double or triple bonds be present. It is most preferred that W is ethynyl or 1,3-butadiynyl.

Z is preferably OR14, OR15, SR14, S (O) m'R7. S (0) 2NRlORl4 NRlOR14, NR14C (O) R9, NR10C(O)R14, NR10C(O)OR7, NR10C(O)NR10R14, NRlpS (0) 2NRlORl4, NRlOC (NCN) NRlpRl4, NRIOS (0) 2R7, NR10C(CR4NO2)SR9,NR10C(CR4NO2)NR10R14,NR10C(NCN)SR9, NR10C(NR10)NR10R14, NR10C(O) C (O) NRIOR14, or NRIOC (O) C (O) OR14.

Preferred X groups for Formula (I) are those wherein X is YR2 and Y is oxygen. The preferred X2 group for Formula (I) is that wherein X2 is oxygen. The preferred X3 group for Formula (I) is that wherein X3 is hydrogen. Preferred R2 groups, where applicable, is a C1-2 alkyl unsubstituted or substituted by 1 or more halogens. The halogen atoms are preferably fluorine and chlorine, more preferably fluorine. More preferred R2 groups are those wherein R2 is methyl, or the fluoro- substituted alkyls, specifically a Cl-2 alkyl, such as a-CF3,-CHF2, or-CH2CHF2 moiety. Most preferred are the-CHF2 and-CH3 moieties.

Preferred R7 moieties include unsubstituted or substituted- (CH2) 0-2 (2-, 3- or 4-pyridyl), (CH2) 1-2 (2-imidazolyl), (CH2) 2 (4-morpholinyl), (CH2) 2 (4- piperazinyl), (CH2) 1-2 (2-thienyl), (CH2) 1-2 (4-thiazolyl), unsubstituted or substituted pyrimidinyl, and substituted or unsubstituted (CH2) 0-2phenyl.

Preferred rings when R1o and R 11 in the moiety-NR1oRl l together with the nitrogen to which they are attached form a 5 to 7 membered ring comprised of carbon or carbon and at least one heteroatom selected from 0, N, or S include, but are not limited to 1-imidazolyl, 2- (Rg)-1-imidazolyl, 1-pyrazolyl, 3- (R8)-l-pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(Rg)-1-triazolyl, 5-(Rg)-2-triazolyl, 5- (Rg)-1-tetrazolyl, 5- (Rg)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl, morpholinyl, piperazinyl, 4- (Rg)-1-piperazinyl, or pyrrolyl ring.

Preferred rings when R1o and R 14 in the moiety -NR10R14 together with the nitrogen to which they are attached may form a 5 to 7 membered ring comprised of carbon or carbon and at least one heteroatom selected from 0, N, or S include, but are not limited to 1-imidazolyl, 1-pyrazolyl, 1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl, piperazinyl, and pyrrolyl. The respective rings may be additionally substituted, where applicable, on an available nitrogen or carbon by the moiety R7 as described herein for Formula (I). Illustrations of such carbon substitutions includes, but is not limited to, 2- (R7)-1-imidazolyl, <BR> <BR> <BR> 4-(R7)-1-imidazolyl, 5-(R7)-1-imidazolyl, 3-(R7)-1-pyrazolyl, 4-(R7)-1-pyrazolyl,<BR> <BR> <BR> <BR> <BR> <BR> 5-(R7)-1-pyrazolyl, 4-(R7)-2-triazolyl, 5-(R7)-2-triazolyl, 4-(R7)-1-triazolyl, 5-(R7)-1-triazolyl, 5-(R7)-1-tetrazolyl,(R7)-1-triazolyl, 5-(R7)-1-tetrazolyl, and 5- (R7)-2-tetrazolyl. Applicable nitrogen substitution by R7 includes, but is not limited to, 1- (R7)-2-tetrazolyl, 2- (R7)-1-tetrazolyl, 4- (R7)-1-piperazinyl. Where applicable, the ring may be substituted one or more times by R7.

Preferred groups for NR 1 pR 14 which contain a heterocyclic ring are 5- (R14)-1-tetrazolyl, 2- (R14)-1-imidazolyl, 5- (R14)-2-tetrazolyl, 4- (R14)-1- piperazinyl, or 4- (R 15)-1-piperazinyl.

Preferred rings for R 13 include (2-, 4-or 5-imidazolyl), (3-, 4-or 5-pyrazolyl), (4-or 5-triazolyl [1,2,3]), (3-or 5-triazolyl [1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4-or 5-isoxazolyl), (3-or 5-oxadiazolyl [1,2,4]), (2-oxadiazolyl [1,3,4]), (2-thiadiazolyl [1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl).

When the R7 group is unsubstituted or substituted by a heterocyclic ring such as imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, the heterocyclic ring itself may be unsubstituted or substituted by R8 on an available nitrogen or carbon atom, such as 1-(R8)-2-imidazolyl, 1-(R8)-4-imidazolyl, 1-(R8)-5-imidazolyl,

1-(Rg)-3-pyrazolyl, 1-(Rg)-4-pyrazolyl, 1-(Rg)-5-pyrazolyl, 1-(Rg)-4-triazolyl,(Rg)-3-pyrazolyl, 1-(Rg)-4-pyrazolyl, 1-(Rg)-5-pyrazolyl, 1-(Rg)-4-triazolyl, or 1-(Rg)-5-triazolyl.(Rg)-5-triazolyl. Where applicable, the ring may be substituted one or more times by R8.

Preferred are those compounds of Formula (II) wherein R1 is-CH2- cyclopropyl,-CH2-C5-6 cycloalkyl,-C4-6 cycloalkyl unsubstituted or substituted by OH, tetrahydrofuran-3-yl, (3-or 4-cyclopentenyl), benzyl or-C1 2 alkyl unsubstituted or substituted by 1 or more fluorines, and- (CH2) 2-4 OH; R2 is methyl or fluoro-substituted alkyl, W is ethynyl or 1,3-butadiynyl; R3 is R7 where R7 is an unsubstituted or substituted aryl or heteroaryl ring, X is YR2, and Z is OR14, OR15, NR1oRl4, or NR14C (O) Rg.

Most preferred are those compounds of Formula (II) wherein Rl is -CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; and R2 is CF2H or methyl, W is ethynyl or 1,3-butadiynyl, and R3 is a substituted or unsubstituted pyrimidinyl ring.

The most preferred compounds of Formula (II) are: cis- [4- (2-aminopyrimidin-5-ylethynyl)-4- (3-cyclopentyloxy-4- methoxyphenyl) cyclohexan-1-ol], cis- [4- (2-aminopyrimidin-4-ylethynyl)-4- (3-cyclopentyloxy-4- methoxyphenyl)-cyclohexan-1-ol], trans- [4- (2-acetamidopyrimidin-5-ylethynyl)-4- (3-cyclopentyloy-4- methoxyphenyl) cyclohexan-1-ol], trans- [4- (2-aminopyrimidin-5-yl-ethynyl)-4- (3-cyclopentyloxy-4- <BR> <BR> <BR> methoxyphenyl)-cyclohexan-1-ol,<BR> <BR> <BR> <BR> cis- [4- (2-methylaminopyrimidin-5-ylethynyl)-4- (3-cyclopentyloxy-4- methoxyphenyl) cyclohexan-1-ol], cis- [4- (3-cyclopentyloxy-4-methoxyphenyl)-4- (pyrid-4- ylethynyl) cyclohexan-1-ol], cis- [4- (3-cyclopentyloxy-4-methoxyphenyl)-4- (pyrid-2- ylethynyl) cyclohexan-1-ol], cis- [4- (4-cyanothien-2-ylethynyl)-4- (3-cyclopentyloxy-4-methoxyphenyl)- cyclohexan-1-ol], cis- [4- (thiazol-2-ylethynyl)-4- (3-cyclopentyloxy-4- methoxyphenyl) cyclohexan-1-ol], cis- [4- (3-cyclopentyloxy-4-methoxyphenyl)-4- [4- (5-methyl- [1,2,4] oxadiazol-2-yl) thien-2-ylethynyl] cyclohexan-1-ol], cis- [4- (3-cyclopentyloxy-4-methoxyphenyl)-4- (2- [3- (3- methyl [1,2,4] oxadiazol-5-yl) phenyl] ethynyl) cyclohexan-1-ol],

cis- [4- (3-cyclopentyloxy-4-methoxyphenyl)-4- (2- [3- (5- methyl [1,3,4] oxadiazol-2-yl) phenyl] ethynyl) cyclohexan-1-ol], cis- [4- (3-cyclopentyloxy-4-methoxyphenyl)-4- (2- [3- (5- methyl [1,2,4] oxadiazol-3-yl) phenyl] ethynyl) cyclohexan-1-ol], cis-4- (3-cyclopentyloxy-4-methoxyphenyl)-4- [3- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl) phenylethynyl) cyclohexan-1-ol, cis-4- (3-cyclopentyloxy-4-methoxyphenyl)-4- [3- (5-methyl- [ 1,3,4] thiadiazol- 2-yl) phenylethynyl] cyclohexan-1-ol, trans- [4- (3-cyclopentyloxy-4-methoxyphenyl)-4- (pyrid-2- ylethynyl) cyclohexyl-1-amine], trans- [4- (3-cyclopentyloxy-4-methoxyphenyl)-4- (pyrid-2- ylethynyl) cyclohexyl-1-formamide], trans- [4- (3-cyclopentyloxy-4-methoxyphenyl)-4- [5- (5-methyl- [1,2,4] oxadiazol-2-yl) thien-2-ylethynyl] cyclohexyl-l-amine], cyclohexylsulfamate salt cis-[4- (3-cyclopentyloxy-4-methoxyphenyl)-4- (pyrid-2- ylethynyl) cyclohexyl-1-amine], cis- [4- (3-cyclopentyloxy-4-methoxyphenyl)-4- (pyrid-2- ylethynyl) cyclohexyl-1-formamide], cis-[4- (3-cyclopentyloxy-4-methoxyphenyl)-4- [5- (5-methyl- [1,2,4] oxadiazol-2-yl) thien-2-ylethynyl] cyclohexyl-1-amine], cyclohexylsulfamate salt, trans- [4- (2-aminopyrimidin-5-ylethynyl)-4- (3-cyclopentyloxy-4- methoxyphenyl) cyclohexyl-1-amine], cyclohexylsulfamate salt, or cis- [4- (2-aminopyrimidin-5-ylethynyl)-4- (3-cyclopentyloxy-4- methoxyphenyl) cyclohexyl-1-amine], cyclohexylsulfamate salt.

Some compounds of Formula (I) and Formula (II) may exist in both racemic and optically active forms; some may also exist in distinct diastereomeric forms possessing distinct physical and biological properties. All of these compounds are considered to be within the scope of the present invention. Therefore another aspect of the present invention is the administration of either a racemate, a single enantiomeric form, a single diastereomeric form, or mixtures thereof.

The terms cis and trans denote stereochemistry at the C-1 position of the cyclohexane ring relative to the R3 group at the C-4 position.

The terms"Cl-3 alkyl","Cl-4 alkyl","Cl-6 alkyl"or"alkyl"include both straight or branched chain radicals of 1 to 10, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-

butyl, isobutyl, tert-butyl, and the like."Alkenyl"includes both straight or branched chain radicals of 1 to 6 carbon lengths, unless the chain length is limited thereto, including but not limited to vinyl, 1-propenyl, 2-propenyl, 2-propynyl, or 3-methyl- 2-propenyl."Cycloalkyl"or"cycloalkyl alkyl"includes groups of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, or cyclohexyl."Aryl"or "aralkyl", unless specified otherwise, means an aromatic ring or ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl, or naphthyl. Preferably the aryl is monocyclic, i. e, phenyl. The alkyl chain includes both straight or branched chain radicals of 1 to 4 carbon atoms."Heteroaryl"as used herein, is meant an aromatic ring system containing one or more heteroatoms, such as imidazolyl, triazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, furanyl, or thienyl."Halo"as used herein is meant all halogens, i. e., chloro, fluoro, bromo, or iodo.

The phrase"down regulating or inhibiting the production of TNF"means: a) a decrease of excessive in vivo TNF levels, respectively, in a human to normal levels or below normal levels by inhibition of the in vivo release of IL-1 by all cells, including but not limited to monocytes or macrophages; b) a down regulation, at the translational or transcriptional level, of excessive in vivo TNF levels, respectively, in a human to normal levels or below normal levels; or c) a down regulation, by inhibition of the direct synthesis of TNF levels as a postranslational event.

All of the compounds of Formula (I) are useful in the method of treating MS; the mechanism of which may be that of inhibiting or down regulating the production of TNF, preferably by macrophages, monocytes or macrophages and monocytes, in a mammal. Mammals includes humans.

No unacceptable toxic effects are expected when these compounds are administered in accordance with the present invention.

METHODS OF PREPARATION: The preparation of compounds of Formula (I) is fully set forth in U. S. patent 5,552,438 issued 3 September 1996. This patent is incorporated herein in its entirety by reference as if fully set out herein. The compounds of Formula (II) are known compound and can be prepared by the methods set out in published PCT application PCT/US95/16711 published as W096/19988 on 4 July 1996. The whole contents of this published PCT application is incorporated herein by reference as if fully set forth herein.

METHODS OF TREATMENT In order to use a compound of Formula (I) and (II) or a pharmaceutically acceptable salt thereof for the treatment of MS, it will be formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. The compounds of Formula (I) and (II) or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylatic or therapeutic treatment of MS.

The pharmaceutical composition of the present invention will comprise an effective, non-toxic amount of a compound of Formula (I) or (II) and a pharmaceutically acceptable carrier or diluent. The compounds of Formula (I) and (II) are administered in conventional dosage forms prepared by combining a compound of Formula (I) and (II) in an amount sufficient to produce TNF production inhibiting activity, respectively, with standard pharmaceutical carriers according to conventional procedures. These procedures may involve mixing, granulating, and compressing or dissolving the ingredients as appropriate to the desired preparation.

Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge.

The amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1 gram. When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates, or oils and are incorporated in a soft gelatin capsule shell. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, glycerine, or water with a flavoring or coloring agent.

The daily dosage regimen for oral administration is suitably about. 001 mg/kg to lOOmg/kg, preferably 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) and (II) or a pharmaceutically acceptable salt thereof calculated as the free base. The active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit activity.

While it is possible for an active ingredient to be administered neat, it is preferable to present it as a pharmaceutical formulation. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e. g., from 1% to 2% by weight of formulation, although it may comprise as much as 10% w/w but

preferably not in excess of 5% w/w and more preferably from 0.1% to 1% w/w of Formulation.

Formulations of the present invention comprise an active ingredient together with one or more acceptable carrier (s) thereof and optionally any other therapeutic ingredient (s). The carrier (s) must be'acceptable'in the sense of being compatible with the other ingredients of Formulation and not deleterious to the recipient thereof.

It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration, and other well-known variables.