Claims
- 1. A compound of Formula(I) wherein:R1 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; n is 1 to 4; r is 0 to 6; R4 and R5 are independently selected hydrogen or C1-2 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC1-3 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 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; X4 is H, R9, OR8, CN, C(O)R8, C(O)OR8, C(O)NR8R8, or NR8R8; R2 is independently selected from —CH3 or —CH2CH3 optionally substituted by 1 or more halogens; s is 0 to 4; Ar is phenyl unsubstituted or substitued by R7; Z is OR14, OR15, SR14, S(O)m′R7, S(O)2NR10R14, NR10R14, NR14C(O)R9, NR10C(Y′)R14, NR10C(O)OR7, NR10C(Y′)NR10R14, NR10S(O)2NR10R14, NR10C(NCN)NR10R14, NR10S(O)2R7, NR10C(CR4NO2)NR10R14, NR10C(NCN)SR9, NR10C(CR4NO2(SR9, NR10C(NR10)NR10R14, NR10C(O)C(O)NR10R14, or NR10C(O)C(O)OR14; Y′ is O or S; R7 is —(CR4R5)qR12 or C1-6 alkyl wherein: the R12 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; —NO2; —NR10R11; —C(O)R8; —CO2R8; —O(CH2)2-4OR8; —O(CH2)qR8; —CN; —C(O)NR10R11; —O(CH2)qC(O)NR10R11; —O(CH2)qC(O)9; —NR10C(O)NR10R11; —NR10C(O)R11; —NR10C(O)OR9; —NR10C(O)R13; —C(NR10)NR10R11; —C(NCN)NR10R11; —C(NCN)SR9; —NR10C(NCN)SR9; —NR10C(NCN)NR10R11; —NR10S(O)2R9; —S(O)m′R9; —NR10C(O)C(O)NR10R11; —NR10C(O)C(O)R10; or R13; q is 0, 1, or 2; R12 is R13, OR14, OR15, SR14, S(O)m′R7, S(O)2NR10R14, NR10R14, NR14C(O)R9, NR10C(Y′)R14, NR10C(O)OR7, NR10C(Y′)NR10R14, NR10S(O)2NR10R14, NR10C(NCN)NR10R14, NR10S(O)2R7, NR10C(CR4NO2)NR10R14, NR10C(NCN)SR9, NR10C(CR4NO2)SR9, NR10C(NR10)NR10R14, NR10C(O)C(O)NR10R14, or NR10C(O)C(O)OR14; or C3-C7 cycloalkyl, or (2-, 3- or 4-pyridyl), pyrimidinyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, or phenyl, wherein each of (2-, 3- or 4-pyridyl), pyrimidinyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, or phenyl may be substituted by OR14, OR15, SR14, S(O)m′R7, S(O)2NR10R14, NR10R14, NR14C(O)R9, NR10C(Y′)R14, NR10C(O)OR7, NR10C(Y′)NR10R14, NR10S(O)2NR10R14, NR10C(NCN)NR10R14, NR10S(O)2R7, NR10C(CR4NO2)NR10R14, NR10C(NCN)SR9, NR10C(CR4NO2)SR9, NR10C(NR10)NR10R14, NR10C(O)C(O)NR10R14, or NR10C(O)C(O)OR14; R8 is independently selected from hydrogen or R9; R9 is C1-4 alkyl optionally substituted by one to three fluorines; R10 is OR8 or R11; R11 is hydrogen, or C1-4 alkyl unsubstituted or substituted by one to three fluorines; or when R10 and R11 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 O, 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 unsubstituted or substituted on the methyl with 1 to 3 fluoro atoms; R14 is hydrogen or R7; or when R8 and R14 are as NR8R14 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 O, N, or S; R15 is C(O)R14, C(O)NR8R14, S(O)qNR8R14 or S(O)qR7 where q is 0, 1 or 2; provided that: (f) R7 is not C1-4 alkyl unsubstituted or substituted by one to three fluorines; or the pharmaceutically acceptable salts thereof.
- 2. A compound according to claim 1 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, and X is YR2.
- 3. A compound according to claim 1 wherein R1 is —CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; and R2 is CF2H or methyl.
- 4. A compound according to claim 1 which is cis-4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexanol;trans-4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexyl-1-amine; cis-4-[4-(2-Aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexyl-1-amine; and trans-4-[4-(2-Aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexyl-1-amine.
- 5. A compound of Formula (II) wherein:R1 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; n is 1 to 4; r is 0 to 6; R4 and R5 are independently selected hydrogen or C1-2 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC1-3 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 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; X4 is H, R9, OR8, CN, C(O)R8, C(O)OR8, C(O)NR8R8, or NR8R8; R2 is independently selected from —CH3 or —CH2CH3 optionally substituted by 1 or more halogens; s is 0 to 4; Ar is phenyl unsubstituted or substitued by R7; R7 is —(CR4R5)qR12 or C1-6 alkyl wherein: the R12 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; —NO2; —NR10R11; —C(O)R8; —CO2R8; —O(CH2)2-4OR8; —O(CH2)qR8; —CN; —C(O)NR10R11; —O(CH2)qC(O)NR10R11; —O(CH2)qC(O)R9; —NR10C(O)NR10R11; —NR10C(O)R11; —NR10C(O)OR9; —NR10C(O)R13; —C(NR10)NR10R11; —C(NCN)NR10R11; —C(NCN)SR9; —NR10C(NCN)SR9; —NR10C(NCN)NR10R11; —NR10S(O)2R9; —S(O)m′R9; —NR10C(O)C(O)NR10R11; —NR10C(O)C(O)R10; or R13; q is 0, 1, or 2; R12 is R13, OR14, OR15, SR14, S(O)m′R7, S(O)2NR10R14, NR10R14, NR14C(O)R9, NR10C(Y′)R14, NR10C(O)OR7, NR10C(Y′)NR10R14, NR10S(O)2NR10R14, NR10C(NCN)NR10R14, NR10S(O)2R7, NR10C(CR4NO2)NR10R14, NR10C(NCN)SR9, NR10C(CR4NO2)SR9, NR10C(NR10)NR10R14, NR10C(O)C(O)NR10R14, or NR10C(O)C(O)OR14; or C3-C7 cycloalkyl, or (2-, 3- or 4-pyridyl), pyrimidinyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, or phenyl, wherein each of (2-, 3- or 4-pyridyl), pyrimidinyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, or phenyl may be substituted by OR14, OR15, SR14, S(O)m′R7, S(O)2NR10R14, NR10R14, NR14C(O)R9, NR10C(Y′)R14, NR10C(O)OR7, NR10C(Y′)NR10R14, NR10S(O)2NR10R14, NR10C(NCN)NR10R14, NR10S(O)2R7, NR10C(CR4NO2)NR10R14, NR10C(NCN)SR9, NR10C(CR4NO2)SR9, NR10C(NR10)NR10R14, NR10C(O)C(O)NR10R14,or NR10C(O)C(O)OR14; R8 is independently selected from hydrogen or R9; R9 is C1-4 alkyl optionally substituted by one to three fluorines; R10 is OR8 or R11; R11 is hydrogen, or C1-4 alkyl unsubstituted or substituted by one to three fluorines; or when R10 and R11 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 O, 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 unsubstituted or substituted on the methyl with 1 to 3 fluoro atoms; R14 is hydrogen or R7; or when R8 and R14 are as NR8R14 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 O, N, or S; R15 is C(O)R14, C(O)NR8R14, S(O)qNR8R14 or S(O)qR7 where q is 0, 1 or 2; provided that: (f) R7 is not C1-4 alkyl unsubstituted or substituted by one to three fluorines; or the pharmaceutically acceptable salts thereof.
- 6. A compound according to claim 5 wherein A compound according to claim 1 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, and X is YR2.
- 7. A compound according to claim 5 wherein A compound according to claim 1 or 2 wherein R1 is —CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; and R2 is CF2H or methyl.
- 8. A compound according to claim 5 which is 4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexanone.
- 9. A pharamceutical composition comprising a compound of claim 1 and a pharamceutically acceptable excipient.
- 10. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable excipient.
- 11. A method for treating an inflammatory disease which method comprises administering a compound according to claim 1 in combination with a pharamceutically acceptable excipient to a patient in need thereof.
Parent Case Info
This application is a 371 of PCT/US00/21867 filed Aug. 10, 2000 which claims benefit of Provisional Serial No. 60/148,034 filed Aug. 10, 1999.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
PCT/US00/21867 |
|
WO |
00 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO01/10385 |
2/15/2001 |
WO |
A |
Foreign Referenced Citations (1)
Number |
Date |
Country |
407278038 |
Aug 1998 |
WO |
Provisional Applications (1)
|
Number |
Date |
Country |
|
60/148034 |
Aug 1999 |
US |