US 2006/0223792 A1Published application

Phenyl and pyridyl LTA4H modulators

OwnerChristopher Butler, James Edwards +6inventors

InventorsChristopher Butler, James Edwards, Anne Fourie, Cheryl Grice, Lars Karlsson, Brad Savall, Kevin Tays, Jianmei Wei

Life of this patent

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Abstract

Leukotriene A4 hydrolase (LTA4H) inhibitors, compositions containing them, and methods of use for the inhibition of LTA4H enzyme activity and the treatment, prevention or inhibition of inflammation and inflammatory conditions.

Claims61

Dependent claims

A method for inhibiting LTA4H enzyme activity, comprising exposing LTA4H enzyme to an inhibitory amount of at least one compound of formula (I):

wherein
X is selected from the group consisting of CH and N;
Y is selected from the group consisting of R1(CH2)2-3O—, R7N(R8)CO2—, R7N(R8)C(O)N(R8)—, R7N(R8)CO2CH2—, R7N(R8)C(O)CH2—, R1OC(O)N(R8)—, R1OCO2—, R1CO2—, R1CH(R9)CO2—, R1C(O)CH(R10)O—, and R1CH(R9)CH(R10)O—, provided that when one of R9 and R10 in R1CH(R9)CH(R10)O— is —H, then the other is not —H;
R1 is a moiety selected from the group consisting of phenyl, thienyl, pyrrolyl, furanyl, oxazolyl, imidazolyl, thiazolyl, indolyl, indanyl, and tetrahydronaphthyl, wherein R1 is substituted with 0, 1, or 2 substituents R4;
R4 is selected from the group consisting of —H, —OCH3, —Cl, —F, —Br, —I, —OH, —NH2, —CN, —CF3, and —CH3;
R7 is —C14alkyl or is selected from the group consisting of phenyl, thienyl, pyrrolyl, furanyl, oxazolyl, imidazolyl, thiazolyl, indolyl, indanyl, and tetrahydronaphthyl, wherein R7 is substituted with 0, 1, or 2 substituents R4;
R8 is —H or —C1-4alkyl;
or, R and R8 are taken together with the nitrogen member to which they are attached to form pyrrolidinyl, piperidinyl, morpholinyl, or thiomorpholinyl;
R9 is —H, —C1-4alkyl, —Cl, or —OH;
R10 is —H, —C1-4alkyl or is taken together with one of R4 to form a 5- or 6-membered carbocyclic ring;
Z is selected from the group consisting of bond, —CH2—, —OCH2—, —OCH2CH(R11)—, and —CH2CH(R11)—;
R11 is —H or —OH;
provided that when Z is bond, then Y is one of R1(CH2)2-3O—, R1CO2—, R1CH(R9)CO2—, R1C(O)CH(R10)O—, and R1CH(OH)CH(R10)O—;
R6 is —H or —F;
and
R2 and R3 are each independently selected from the group consisting of
A) —H, —C1-7alkyl, —C3-7alkenyl, wherein the carbon in said alkenyl that is attached to the nitrogen member has only single bonds, —C3-7alkynyl, wherein the carbon in said alkynyl that is attached to the nitrogen member has only single bonds, —C3-7cycloalkyl optionally benzofused, —C5-7cycloalkenyl, —C3-7cycloalkylC1-7alkyl, —C1-7alkylC3-7cycloalkyl and phenyl, wherein each of the substituents A) is independently substituted with 0, 1, or 2 substituents RQ, and each of said RQ is a substituent at a carbon member that is at least one carbon member removed from the nitrogen member;
B) a 4-7 membered saturated heterocyclic ring HetRa, said 4-7 membered saturated heterocyclic ring HetRa, having 0 or 1 double bonds, having a carbon member point of attachment and containing a member >NRM as a heteroatom member, and said heteroatom member being separated from said carbon member point of attachment by at least one additional carbon member;
C) —C1-7alkylC(O)Rx, optionally substituted with CH2RAr or CH2RAr′;
D) —C2-5alkylC(O)Rx, wherein two valence allowed carbon members in the C2-5alkyl of said —C2-5alkylC(O)Rx are part of a saturated C3-6carbocycle;
E) —C2-5alkylOH wherein two valence allowed carbon members in the C2-5alkyl of said —C2-5alkylOH are part of a saturated C3-6carbocycle;
F) —C0-4alkylphenyl, wherein the phenyl in said —C0-4alkylphenyl is fused at two adjacent carbon members in said phenyl to Rf, or is benzofused;
G) —C0-4alkylAr6, where Ar6 is a 6-membered heteroaryl having a carbon member point of attachment and having 1 or 2 —N═ heteroatom members, and benzofused;
H) —C0-4alkylAr5, where Ar5 is a 5-membered heteroaryl, having one heteroatom member selected from the group consisting of O, S, and >NRY, and having 0 or 1 —N═ additional heteroatom member, optionally containing 1 or 2 carbonyl groups, and optionally benzofused;
I) —C1-4alkylAr5′, where Ar5′ is a 5-membered heteroaryl containing 3 or 4 nitrogen members, optionally substituted with RY, and having a valence allowed site as a point of attachment;
J) —C0-4alkylAr6-6, where Ar6-6 is a C0-4alkyl-attached phenyl fused at valence allowed sites to a 6-membered heteroaryl, wherein said 6-membered heteroaryl has 1 or 2 —N═ heteroatom members;
K) —C0-4alkylAr6-5, where Ar6-5 is a C0-4alkyl-attached phenyl fused at valence allowed sites to a 5-membered heteroaryl, said 5-membered heteroaryl having one heteroatom member selected from the group consisting of O, S, and >NRY, and said 5-membered heteroaryl having 0 or 1 additional heteroatom member which is —N═;
L) one of 2-(4-ethyl-phenoxy)-benzothiazole, 2-(4-ethyl-phenoxy)-benzooxazole, and 2-(4-ethyl-phenoxy)-1H-benzoimidazole;
and
M) —SO2C1-4alkyl;
alternatively R2 and R3 are taken together with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected from the group consisting of
i) a 4-7 membered saturated heterocyclic ring HetRb, said 4-7 membered saturated heterocyclic ring HetRb having one heteroatom member that is said attachment nitrogen, and being substituted with 0, 1, or 2 substituents at the same or at different ring members, said substituents being selected from the group consisting of —RY, —CN, —C(O)RY, —C0-4alkylCO2RY, —C0-4alkylC(O)CO2RY, —C0-4alkylORY,—C0-4alkylC(O)NRYRZ, —C0-4alkylNRYC(O)RZ, —C(O)NRZORY, —C0-4alkylNRYC(O)CH2ORY, —C0-4alkylNRYC(O)CH2C(O)RY, —C0-4alkylNRYCO2RY, —C0-4alkylNRYC(O)NRYRZ, —C0-4alkylNRYC(S)NRYRZ, —NRYC(O)CO2RY, —NRYRZ, —C0-4alkylNRWSO2RY, 1,3-dihydro-indol-2-one-1-yl, 1,3-dihydro-benzoimidazol-2-one-1-yl, tetrazol-5-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol-5-yl, pyrrolidine-2-thion-1-yl, piperidine-2-thion-1-yl, —C0-4alkylC(O)N(RY)(SO2RY), —C0-4alkylN(RY)(SO2)NRYRY, —C0-4alkylN(RY)(SO2)NRYCO2RY, halo,
ii) a 5-7 membered saturated heterocyclic ring HetRc, said 5-7 membered saturated heterocyclic ring HetRc having one additional heteroatom member separated from said attachment nitrogen by at least one carbon member, said additional heteroatom member being selected from the group consisting of O, S(═O)0-2, and >NRM, said 5-7 membered saturated heterocyclic ring HetRc having 0 or 1 carbonyl members, and being substituted with 0, 1, or 2 substituents at the same or at different carbon ring members, said substituents being selected from the group consisting of —C(O)RY, —CO2RY, —C3-4alkylCO2RY and RZ;
iii) one of imidazolidin-1-yl, 2-imidazolin-1-yl, pyrazol-1-yl, imidazol-1-yl, 2H-tetrazol-2-yl, 1H-tetrazol-1-yl, pyrrol-1-yl, 2-pyrrolin-1-yl, and 3-pyrrolin-1-yl, wherein each of said 2H-tetrazol-2-yl and 1H-tetrazol-1-yl is substituted at the carbon member with 0 or 1 of —C0-4alkylRZ, —C0-4alkylSRY, —C0-4alkylC0-2RY, and substituent HetRa;
and
iv) one of 1,2,3,4-tetrahydro-quinolin-1-yl, 1,2,3,4-tetrahydro-isoquinolin-2-yl, indol-1-yl, isoindol-2-yl, indolin-1-yl, benzimidazol-1-yl, 2,8-diaza-spiro[4.5]decan-1-one-8-yl, 4-{[(2-tert-butoxycarbonylamino-cyclobutanecarbonyl)-amino]-methyl}-piperidin-1-yl, 4-{[(2-amino-cyclobutanecarbonyl)-amino]-methyl}-piperidin-1-yl, 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid-9-yl tert-butyl ester, 4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-8-yl, and 4-oxo-1,3,8-triaza-spiro[4.5]dec-8-yl;
wherein
RK is selected from the group consisting of —H, —C1-4alkyl and —C0-4alkylRAr, each of said —C1-4alkyl and —C0-4alkylRAr being optionally substituted with 1, 2, or 3 substituents RN;
RL is selected from the group consisting of —CO2RS and —C(O)NRSRS′;
RM is selected from the group consisting of RZ, indol-7-yl, —SO2RY, —C3-4alkylC0-2RY, —CO2RY, —C(O)NRZORY, —C(O)RY, —C(O)C1-4alkylORY, —C0-4alkylC(O)NRSRS′, C0-4alkylC(O)CO2RY, 1,3-dihydro-indol-2-one-1-yl, 1,3-dihydro-benzoimidazol-2-one-1-yl, tetrazol-5-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol-5-yl and —C0-4alkylC(O)N(RY)(SO2RY), each of said RM that is not —H being optionally substituted with 1, 2, or 3 substituents RN;
RN is selected from the group consisting of —OCH3, —Cl, —F, —Br, —I, —OH, —NH2, —CN, —CF3, —CH3, —OC(O)CH3, and —NO2;
RQ is selected from the group consisting of —Cl, —F, —Br, —I, —CF3, —CCl3, —CN, —C1-4alkyl, —CO4alkylRAr, —C0-4alkylRAr′, —C0-4alkylORY, —C0-4alkylCO2RY, —C0-4alkylNRYRZ, —C0-4alkylNRYCORY, —C0-4alkylNRYCONRYRZ, —C0-4alkylNRYSO2RY, and —C0-4alkylSRY;
RS and RS′ are independently selected from the group consisting of —H, —C1-4alkyl, and —C0-4alkylphenyl;
alternatively, RS and RS′ are taken together with the nitrogen member to which said RS and RS′ are attached to form a 4-7 membered heterocyclic ring having 0 or 1 additional heteroatom member selected from the group consisting of O, S, and >NRY, provided that said additional heteroatom member is separated by at least two carbon members from said nitrogen member to which said RS and RS′ are attached, and provided that where RY is C0-4alkylRAr, then RAr is not substituted with RL;
RW is selected from the group consisting of RY, and —C3-7cycloalkyl;
RX is selected from the group consisting of —ORY, —NRYRZ, —C1-4alkyl, and —C0-4alkylRAr;
RY is selected from the group consisting of —H, —C1-4alkyl, —C0-4alkylRAr and —C0-4alkylRAr′, each of said RY that is not —H being optionally substituted with 1, 2, or 3 substituents RN;
RZ is selected from the group consisting of RY, —C2-4alkylORY, —C1-2alkylCO2RY, —C1-2alkylC(O)NRSRS′, and —C2-4alkylNRSRS′;
provided that when RY and RZ are attached to a nitrogen member, then RY and RZ are selected as defined above, or RY and RZ are taken together with the RY— and RZ— attached nitrogen member to form a 4-7 membered heterocyclic ring HetRd having 0 or 1 additional heteroatom members selected from the group consisting of O, S, and >NRM, said 4-7 membered heterocyclic ring HetRd having 0 or 1 carbonyl members, and said 4-7 membered heterocyclic ring HetRd having 0 or 1 valence allowed carbon members substituted with at least one of RM, —CO2H, and —C0-1alkylORY;
RAr is a moiety with a carbon member attachment point and said RAr is selected from the group consisting of phenyl, pyridyl, pyrimidyl, and pyrazinyl, wherein each valence allowed carbon member in each of said RAr is independently substituted with at least one of 0, 1, 2, or 3 substituents RN, and 0 or 1 substituent RL;
RAr′ is a 3-8 membered ring having 0, 1, or 2 heteroatom members selected from the group consisting of O, S, N, and >NRY, said RAr′ having 0, 1, or 2 unsaturated bonds and having 0 or 1 carbonyl members, wherein each valence allowed member in each of said RAr′ ring is independently substituted with 0, 1, or 2 substituents RK;
and
Rf is a linear 3- to 5-membered hydrocarbon moiety having 0 or 1 unsaturated carbon-carbon bonds and having 0 or 1 carbonyl members;
or an enantiomer, diasteromer, racemate, tautomer, hydrate, solvate, or a pharmaceutically acceptable salt, ester, or amide thereof.

51 more elements

A compound of formula (II):

wherein
X is selected from the group consisting of CH and N;
Y′ is selected from the group consisting of R1(CH2)2-3O—, R7N(R8)CO2—, R7N(R8)C(O)N(R8)—, R7N(R8)CO2CH2—, R7N(R8)C(O)CH2—, R1OC(O)N(R8)—, R1OCO2—, R1CO2—, R1CH(R9)CO2—, R1C(O)CH(R10)O—, and R1CH(R9)CH(R10)O—, provided that when one of R9 and R10 in R1CH(R9)CH(R10)O— is —H, then the other is not —H;
R1 is a moiety selected from the group consisting of phenyl, thienyl, pyrrolyl, furanyl, oxazolyl, imidazolyl, thiazolyl, indolyl, indanyl, and tetrahydronaphthyl, wherein R1 is substituted with 0, 1, or 2 substituents R4;
R4 is selected from the group consisting of —H, —OCH3, —Cl, —F, —Br, —I, —OH, —NH2, —CN, —CF3, and —CH3;
R7 is —C1-4alkyl or is selected from the group consisting of phenyl, thienyl, pyrrolyl, furanyl, oxazolyl, imidazolyl, thiazolyl, indolyl, indanyl, and tetrahydronaphthyl, wherein R7 is substituted with 0, 1, or 2 substituents R4;
R8 is —H or —C1-4alkyl;
or, R7 and R8 are taken together with the nitrogen member to which they are attached to form pyrrolidinyl, piperidinyl, morpholinyl, or thiomorpholinyl;
R9 is —H, —C1-4alkyl, —Cl, or —OH;
R10 is —H, —C1-4alkyl or is taken together with one of R4 to form a 5- or 6-membered carbocyclic ring;
R11 is —H or —OH;
Z is selected from the group consisting of bond, —CH2—, —OCH2—, —OCH2CH(R11)—, and —CH2CH(R11)—;
provided that when Z is bond, then Y′ is one of R1(CH2)2-3O—, R1CO2—, R1CH(R9)CO2—, R1C(O)CH(R10)O—, and R1CH(OH)CH(R10)O—;
R6 is —H or —F;
and
R2′ and R3′ are each independently selected from the group consisting of
A) H, C1-7alkyl, C3-7alkenyl, wherein the carbon in said alkenyl that is attached to the nitrogen member has only single bonds, C3-7alkynyl, wherein the carbon in said alkynyl that is attached to the nitrogen member has only single bonds, C3-7cycloalkyl optionally benzofused, C5-7cycloalkenyl, C3-7cycloalkylC1-7alkyl, C1-7alkylC3-7cycloalkyl and phenyl, wherein each of the substituents A) is independently substituted with 0, 1, or 2 substituents RQ, and each of said RQ is a substituent at a carbon member that is at least one carbon member removed from the nitrogen member;
B) a 4-7 membered saturated heterocyclic ring HetRa, said 4-7 membered saturated heterocyclic ring HetRa, having 0 or 1 double bonds, having a carbon member point of attachment and containing a member >NRM as a heteroatom member, and said heteroatom member being separated from said carbon member point of attachment by at least one additional carbon member;
C) —C1-7alkylC(O)Rx, optionally substituted with CH2RAr or CH2RAr′;
D) —C2-5alkylC(O)Rx, wherein two valence allowed carbon members in the C2-5alkyl of said —C2-5alkylC(O)Rx are part of a saturated C3-6carbocycle;
E) —C2-5alkylOH wherein two valence allowed carbon members in the C2-5alkyl of said —C2-5alkylOH are part of a saturated C3-6carbocycle;
F) —C0-4alkylphenyl, wherein the phenyl in said —C0-4alkylphenyl is fused at two adjacent carbon members in said phenyl to Rf, or is benzofused;
G) —C0-4alkylAr6, where Ar6 is a 6-membered heteroaryl having a carbon member point of attachment and having 1 or 2 —N═ heteroatom members, and benzofused;
H) —C0-4alkylAr5, where Ar5 is a 5-membered heteroaryl, having one heteroatom member selected from the group consisting of O, S, and >NRY, and having 0 or 1 —N═ additional heteroatom member, optionally containing 1 or 2 carbonyl groups, and optionally benzofused;
I) —C1-4alkylAr5′, where Ar5′ is a 5-membered heteroaryl containing 3 or 4 nitrogen members, optionally substituted with RY, and having a valence allowed site as a point of attachment;
J) —C0-4alkylAr6-6, where Ar6-6 is a C0-4alkyl-attached phenyl fused at valence allowed sites to a 6-membered heteroaryl, wherein said 6-membered heteroaryl has 1 or 2 —N═ heteroatom members;
K) —C0-4alkylAr6-5, where Ar6-5 is a C0-4alkyl-attached phenyl fused at valence allowed sites to a 5-membered heteroaryl, said 5-membered heteroaryl having one heteroatom member selected from the group consisting of O, S, and >NRY, and said 5-membered heteroaryl having 0 or 1 additional heteroatom member which is —N═;
L) one of 2-(4-ethyl-phenoxy)-benzothiazole, 2-(4-ethyl-phenoxy)-benzooxazole, and 2-(4-ethyl-phenoxy)-1H-benzoimidazole;
and
M) —SO2C1-4alkyl;
alternatively R2′ and R3′ are taken together with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected from the group consisting of
i) a 4-7 membered saturated heterocyclic ring HetRb, said 4-7 membered saturated heterocyclic ring HetRb having one heteroatom member that is said attachment nitrogen, and being substituted with 0, 1, or 2 substituents at the same or at different ring members, said substituents being selected from the group consisting of —RY, —CN, —C(O)RY, —C0-4alkylCO2RY, —C0-4alkylC(O)CO2RY, —C0-4alkylORY, —C0-4alkylC(O)NRYRZ, —C0-4alkylNRYC(O)RZ, —C(O)NRZORY, —C0-4alkylNRYC(O)CH2ORY, —C0-4alkylNRYC(O)CH2C(O)RY, —C0-4alkylNRYCO2RY, —C0-4alkylNRYC(O)NRYRZ, —C0-4alkylNRYC(S)NRYRZ, —NRYC(O)CO2RY, —NRYRZ, —C0-4alkylNRWSO2RY, 1,3-dihydro-indol-2-one-1-yl, 1,3-dihydro-benzoimidazol-2-one-1-yl, tetrazol-5-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol-5-yl, pyrrolidine-2-thion-1-yl, piperidine-2-thion-1-yl, —C0-4alkylC(O)N(RY)(SO2RY), —C0-4alkylN(RY)(SO2)NRYRY, —C0-4alkylN(RY)(SO2)NRYCO2RY, halo,
ii) a 5-7 membered saturated heterocyclic ring HetRc, said 5-7 membered saturated heterocyclic ring HetRc having one additional heteroatom member separated from said attachment nitrogen by at least one carbon member, said additional heteroatom member being selected from the group consisting of O, S(═O)0-2, and >NRM, said 5-7 membered saturated heterocyclic ring HetRc having 0 or 1 carbonyl members, and being substituted with 0, 1, or 2 substituents at the same or at different carbon ring members, said substituents being selected from the group consisting of —C(O)RY, —CO2RY, —C3-4alkylCO2RY and RZ;
iii) one of imidazolidin-1-yl, 2-imidazolin-1-yl, pyrazol-1-yl, imidazol-1-yl, 2H-tetrazol-2-yl, 1H-tetrazol-1-yl, pyrrol-1-yl, 2-pyrrolin-1-yl, and 3-pyrrolin-1-yl, wherein each of said 2H-tetrazol-2-yl and 1H-tetrazol-1-yl is substituted at the carbon member with 0 or 1 of —C0-4alkylRZ, —C0-4alkylSRY, —C0-4alkylC0-2RY, and substituent HetRa;
and
iv) one of 1,2,3,4-tetrahydro-quinolin-1-yl, 1,2,3,4-tetrahydro-isoquinolin-2-yl, indol-1-yl, isoindol-2-yl, indolin-1-yl, benzimidazol-1-yl, 2,8-diaza-spiro[4.5]decan-1-one-8-yl, 4-{[(2-tert-butoxycarbonylamino-cyclobutanecarbonyl)-amino]-methyl}-piperidin-1-yl, 4-{[(2-amino-cyclobutanecarbonyl)-amino]-methyl}-piperidin-1-yl, 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid-9-yl tert-butyl ester, 4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-8-yl, and 4-oxo-1,3,8-triaza-spiro[4.5]dec-8-yl;
wherein
RK is selected from the group consisting of —H, —C1-4alkyl and —C0-4alkylRAr, each of said —C1-4alkyl and —C0-4alkylRAr being optionally substituted with 1, 2, or 3 substituents RN;
RL is selected from the group consisting of —CO2RS and —C(O)NRSRS′;
RM is selected from the group consisting of RZ, indol-7-yl, —SO2RY, —C3-4alkylC0-2RY, —CO2RY, —C(O)NRZORY, —C(O)RY, —C(O)C1-4alkylORY, —C0-4alkylC(O)NRSRS′, C0-4alkylC(O)CO2RY, 1,3-dihydro-indol-2-one-1-yl, 1,3-dihydro-benzoimidazol-2-one-1-yl, tetrazol-5-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol-5-yl and —C0-4alkylC(O)N(RY)(SO2RY), each of said RM that is not —H being optionally substituted with 1, 2, or 3 substituents RN;
RN is selected from the group consisting of —OCH3, —Cl, —F, —Br, —I, —OH, —NH2, —CN, —CF3, —CH3, —OC(O)CH3, and —NO2;
RQ is selected from the group consisting of —Cl, —F, —Br, —I, —CF3, —CCl3, —CN, —C1-4alkyl, —C0-4alkylRAr, —C0-4alkylRAr′, —C0-4alkylORY, —C0-4alkylCO2RY, —C0-4alkylNRYRZ, —C0-4alkylNRYCORY, —C0-4alkylNRYCONRYRZ, —C0-4alkylNRYSO2RY, and —C0-4alkylSRY;
RS and RS′ are independently selected from the group consisting of —H, —C1-4alkyl, and —C0-4alkylphenyl;
alternatively, RS and RS′ are taken together with the nitrogen member to which said RS and RS′ are attached to form a 4-7 membered heterocyclic ring having 0 or 1 additional heteroatom member selected from the group consisting of O, S, and >NRY, provided that said additional heteroatom member is separated by at least two carbon members from said nitrogen member to which said RS and RS′ are attached, and provided that where RY is C0-4alkylRAr, then RAr is not substituted with RL;
RW is selected from the group consisting of RY, and —C3-7cycloalkyl;
RX is selected from the group consisting of —ORY, —NRYRZ, —C1-4alkyl, and —C0-4alkylRAr;
RY is selected from the group consisting of —H, —C1-4alkyl, —C0-4alkylRAr and —C0-4alkylRAr′, each of said RY that is not —H being optionally substituted with 1, 2, or 3 substituents RN;
RZ is selected from the group consisting of RY, —C2-4alkylORY, —C1-2alkylCO2RY, —C1-2alkylC(O)NRSRS′, and —C2-4alkylNRSRS′;
provided that when RY and RZ are attached to a nitrogen member, then RY and RZ are selected as defined above, or RY and RZ are taken together with the RY— and RZ— attached nitrogen member to form a 4-7 membered heterocyclic ring HetRd having 0 or 1 additional heteroatom members selected from the group consisting of O, S, and >NRM, said 4-7 membered heterocyclic ring HetRd having 0 or 1 carbonyl members, and said 4-7 membered heterocyclic ring HetRd having 0 or 1 valence allowed carbon members substituted with at least one of RM, —CO2H, and —C0-1alkylORY;
RAr is a moiety with a carbon member attachment point and said RAr is selected from the group consisting of phenyl, pyridyl, pyrimidyl, and pyrazinyl, wherein each valence allowed carbon member in each of said RAr is independently substituted with at least one of 0, 1, 2, or 3 substituents RN, and 0 or 1 substituent RL;
RAr′ is a 3-8 membered ring having 0, 1, or 2 heteroatom members selected from the group consisting of O, S, N, and >NRY, said RAr′ having 0, 1, or 2 unsaturated bonds and having 0 or 1 carbonyl members, wherein each valence allowed member in each of said RAr′ ring is independently substituted with 0, 1, or 2 substituents RK;
and
Rf is a linear 3- to 5-membered hydrocarbon moiety having 0 or 1 unsaturated carbon-carbon bonds and having 0 or 1 carbonyl members;
or an enantiomer, diasteromer, racemate, tautomer, hydrate, solvate, or a pharmaceutically acceptable salt, ester, or amide thereof.
provided that when
(c1) Y′ is R1(CH2)2-30—,
(c2) Z is CH2, and
(c3) X is CH,
then R2′ and R3′ independently are not —H, —C1-7alkyl, or unsubstituted —C1-7alkylC(O)Rx;
or R2′ and R3′ taken together with the nitrogen to which they are attached do not form HetRb or HetRc where RY or RM are phenyl, pyridyl, or pyrimidyl.

57 more elements

A compound selected from:

1-(2-{4-[(3-Hydroxy-phenyl)-methyl-carbamoyloxy]-phenoxy}-ethyl)-piperidine-4-carboxylic acid ethyl ester;
1-(2-{4-[(3-Hydroxy-phenyl)-methyl-carbamoyloxy]-phenoxy}-ethyl)-piperidine-4-carboxylic acid;
Dimethyl-carbamic acid 4-[2-(4-hydroxy-4-phenyl-piperidin-1-yl)-ethoxy]-phenyl ester;
(3-Hydroxy-phenyl)-carbamic acid 4-[2-(4-hydroxy-4-phenyl-piperidin-1-yl)-ethoxy]-phenyl ester;
N-(2-Hydroxy-phenyl)-2-{4-[2-(4-hydroxy-4-phenyl-piperidin-1-yl)-ethoxy]-phenyl}-acetamide;
[4-(2-Piperidin-1-yl-ethoxy)-phenyl]-carbamic acid phenyl ester hydrochloride;
Phenyl-carbamic acid 4-(2-piperidin-1-yl-ethoxy)-phenyl ester;
Phenyl-carbamic acid 4-(2-piperidin-1-yl-ethoxy)-benzyl ester;
(4-Hydroxy-phenyl)-carbamic acid 4-[2-(4-hydroxy-4-phenyl-piperidin-1-yl)-ethoxy]-phenyl ester;
Methyl-phenyl-carbamic acid 4-[2-(4-hydroxy-4-phenyl-piperidin-1-yl)-ethoxy]-phenyl ester;
Phenyl-carbamic acid 4-[2-(4-propyl-piperidin-1-yl)-ethoxy]-phenyl ester;
Phenyl-carbamic acid 4-[3-(4-hydroxy-4-phenyl-piperidin-1-yl)-propoxy]-phenyl ester;
(2-Fluoro-phenyl)-carbamic acid 4-(2-piperidin-1-yl-ethoxy)-phenyl ester;
N-(2-Hydroxy-phenyl)-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetamide;
(3-Chloro-phenyl)-carbamic acid 4-(2-piperidin-1-yl-ethoxy)-phenyl ester;
Phenyl-carbamic acid 4-(2-diethylamino-ethoxy)-phenyl ester;
Phenyl-carbamic acid 4-[2-(4-hydroxy-4-phenyl-piperidin-1-yl)-ethoxy]-phenyl ester;
Phenyl-carbamic acid 4-(2-dibutylamino-ethoxy)-phenyl ester;
Phenyl-carbamic acid 4-[2-(cyclopropylmethyl-propyl-amino)-ethoxy]-phenyl ester;
Phenyl-carbamic acid 4-[2-(4-benzyl-piperidin-1-yl)-ethoxy]-phenyl ester;
Phenyl-carbamic acid 4-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-phenyl ester;
Phenyl-carbamic acid 4-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-phenyl ester;
Phenyl-carbamic acid 4-{2-[4-(4-chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-ethoxy}-phenyl ester;
Phenyl-carbamic acid 4-(2-azepan-1-yl-ethoxy)-phenyl ester;
Phenyl-carbamic acid 4-{2-[4-(4-bromo-phenyl)-4-hydroxy-piperidin-1-yl]-ethoxy}-phenyl ester;
Phenyl-carbamic acid 4-{2-[4-(4-chloro-phenyl)-4-hydroxy-piperidin-1-yl]-ethoxy}-phenyl ester;
Thiophen-3-yl-carbamic acid 4-(2-piperidin-1-yl-ethoxy)-phenyl ester;
Thiophen-2-yl-carbamic acid 4-(2-piperidin-1-yl-ethoxy)-phenyl ester;
Phenyl-carbamic acid 4-{2-[4-(2-hydroxy-acetylamino)-piperidin-1-yl]-ethoxy}-phenyl ester;
Methyl-phenyl-carbamic acid 4-{2-[4-(2-hydroxy-acetylamino)-piperidin-1-yl]-ethoxy}-phenyl ester;
Phenyl-carbamic acid 4-[2-(4-methanesulfonylamino-piperidin-1-yl)-ethoxy]-phenyl ester;
Methyl-phenyl-carbamic acid 4-[2-(4-methanesulfonylamino-piperidin-1-yl )-ethoxy]-phenyl ester;
Phenyl-carbamic acid 5-{2-[4-(2-hydroxy-acetylamino)-piperidin-1-yl]-ethoxy}-pyridin-2-yl ester;
Phenyl-carbamic acid 5-[2-(4-acetylamino-piperidin-1-yl)-ethoxy]-pyridin-2-yl ester;
and mixtures thereof.

32 more elements

A compound selected from:

N-[1-(4-Phenethyloxy-benzyl)-piperidin-4-yl]methanesulfonamide;
1-(6-Phenethyloxy-pyridin-3-ylmethyl)-piperidine-4-carboxylic acid;
1-(4-Phenethyloxy-benzyl)-piperidine;
1-(4-Phenethyloxy-benzyl)-piperidine-4-carboxylic acid;
1-[4-(3-Phenyl-propoxy)-benzyl]-piperidine;
1-[4-(4-Phenyl-butoxy)-benzyl]-piperidine;
1-[1-(4-Phenethyloxy-benzyl )-piperidin-4-yl]-pyrrolidin-2-one;
8-(4-Phenethyloxy-benzyl)-2,8-diaza-spiro[4.5]decan-1-one;
1-(4-Phenethyloxy-benzyl)-piperidine-4-carboxylic acid amide;
1-(4-Phenethyloxy-benzyl)-piperidine-3-carboxylic acid amide;
1-(4-Phenethyloxy-benzyl)-piperidin-4-ol;
1-(4-Phenethyloxy-benzyl )-4-(1H-tetrazol-5-yl)-piperidine;
1-(4-Phenethyloxy-benzyl)-piperidin-4-ylamine;
1-[4-(3-Phenyl-propoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester;
1-{1-[4-(3-Phenyl-propoxy)-benzyl]-piperidin-4-yl}-pyrrolidin-2-one;
1-[4-(3-Phenyl-propoxy)-benzyl]-piperidin-4-ol;
1-[4-(3-Phenyl-propoxy)-benzyl]-piperidin-3-ol;
1-[4-(3-Phenyl-propoxy)-benzyl]-piperidine-4-carboxylic acid amide;
1-[4-(3-Phenyl-propoxy)-benzyl]-piperidine-3-carboxylic acid amide;
1-[4-(3-Phenyl-propoxy)-benzyl]-piperidine-4-carboxylic acid;
N-[1-(4-Phenethyloxy-benzyl)-piperidin-4-yl]-acetamide;
[1-(4-Phenethyloxy-benzyl )-piperidin-4-yl]-urea;
[1-(4-Phenethyloxy-benzyl )-piperidin-4-yl]-carbamic acid methyl ester;
1-[4-(3-Phenyl-propoxy)-benzyl]-piperidin-4-ylamine;
N-{1-[4-(3-Phenyl-propoxy)-benzyl]-piperidin-4-yl}-methanesulfonamide;
N-{1-[4-(3-Phenyl-propoxy)-benzyl]-piperidin-4-yl}-acetamide;
{1-[4-(3-Phenyl-propoxy)-benzyl]-piperidin-4-yl}-carbamic acid methyl ester;
{1-[4-(3-Phenyl-propoxy)-benzyl]-piperidin-4-yl}-urea;
2-Hydroxy-N-{1-[4-(3-phenyl-propoxy)-benzyl]-piperidin-4-yl}-acetamide;
2-Hydroxy-N-[1-(4-phenethyloxy-benzyl)-piperidin-4-yl]-acetamide;
N-{1-[6-(3-Phenyl-propoxy)-pyridin-3-ylmethyl]-piperidin-4-yl}-acetamide;
N-{1-[6-(3-Phenyl-propoxy)-pyridin-3-ylmethyl]-piperidin-4-yl}-methanesulfonamide;
1-{1-[6-(3-Phenyl-propoxy)-pyridin-3-ylmethyl]-piperidin-4-yl}-pyrrolidin-2-one;
N-[1-(3-Fluoro4-phenethyloxy-benzyl )-piperidin-4-yl]-acetamide;
and mixtures thereof.

32 more elements

A compound selected from:

1′-[2-(4-Phenethyloxy-phenyl)-ethyl]-[1,4′]bipiperidinyl-3-carboxylic acid ethyl ester;
1′-[2-(4-Phenethyloxy-phenyl)-ethyl]-[1,4′]bipiperidinyl-3-carboxylic acid;
1′-{2-[4-(2-Oxo-2-phenyl-ethoxy)-phenyl]-ethyl}-[1,4′]bipiperidinyl-2-one;
1′-{2-[4-(2-Hydroxy-2-phenyl-ethoxy)-phenyl]-ethyl}-[1,4′]bipiperidinyl-2-one
1-[2-(4-Phenethyloxy-phenyl)-ethyl]-piperidine-4-carbonitrile;
1-[2-(4-Phenethyloxy-phenyl)-ethyl]-4-(1H-tetrazol-5-yl )-piperidine;
1-[2-(4-Phenethyloxy-phenyl)-ethyl]4-(1H-[1,2,3]triazol-4-yl)-piperidine;
Cyclopropyl-[2-(4-phenethyloxy-phenyl)-ethyl]-amine;
4-{Cyclopropyl-[2-(4-phenethyloxy-phenyl)-ethyl]-amino}-butyronitrile;
3-{Cyclopropyl-[2-(4-phenethyloxy-phenyl)-ethyl]-amino}-propionic acid ethyl ester;
3-{Cyclopropyl-[2-(4-phenethyloxy-phenyl)-ethyl]-amino}-propionic acid trifluoroacetic acid salt;
1′-[2-(4-Phenethyloxy-phenyl)-ethyl]-[1,4′]bipiperidinyl-2-carboxylic acid ethyl ester;
1-[2-(4-Phenethyloxy-phenoxy)-ethyl]-piperidine;
2-{4-[2-(Cyclohexyl-ethyl-amino)-ethyl]-phenoxy}-1-phenyl-ethanone;
2-{4-[2-(Cyclohexyl-ethyl-amino)-ethyl]-phenoxy}-1-phenyl-ethanol;
1-{2-[4-(2-Oxo-2-phenyl-ethoxy)-phenyl]-ethyl}-piperidine-4-carboxylic acid methyl ester;
1-{2-[4-(2-Hydroxy-2-phenyl-ethoxy)-phenyl]-ethyl}-piperidine-4-carboxylic acid methyl ester;
1-[2-(4-Phenethyloxy-phenyl)-ethyl]-piperidine-4-carboxylic acid methyl ester;
1-{2-[4-(2-Hydroxy-2-phenyl-ethoxy)-phenyl]-ethyl}-piperidine-4-carboxylic acid amide;
1-[2-(4-Phenethyloxy-phenyl)-ethyl]-piperidine-4-carboxylic acid amide;
1′-[2-(4-Phenethyloxy-phenyl)-ethyl]-[1,4′]bipiperidinyl-2-one;
1-[2-(4-Phenethyloxy-phenyl)-ethyl]-piperidine-4-carboxylic acid;
4-[2-(4-Phenethyloxy-phenyl)-ethyl]-piperazin-2-one;
3-[2-(4-Phenethyloxy-phenyl)-ethylamino]-propionic acid ethyl ester;
3-{Methyl-[2-(4-phenethyloxy-phenyl)-ethyl]-amino}-propionic acid ethyl ester;
3-{Cyclohexyl-[2-(4-phenethyloxy-phenyl)-ethyl]-amino}-propionic acid ethyl ester;
3-{Methyl-[2-(4-phenethyloxy-phenyl)-ethyl]-amino}-propionic acid;
3-{Cyclohexyl-[2-(4-phenethyloxy-phenyl)-ethyl]-amino}-propionic acid;
3-{(1-Acetyl-piperidin-4-yl)-[2-(4-phenethyloxy-phenyl)-ethyl]-amino}-propionic acid ethyl ester;
3-{(1-Acetyl-piperidin-4-yl)-[2-(4-phenethyloxy-phenyl)-ethyl]-amino}-propionic acid;
1-{2-[4-(2-Hydroxy-2-phenyl-ethoxy)-phenyl]-ethyl}-piperidine-4-carboxylic acid;
2-[4-(2-Piperidin-1-yl-ethyl)-phenoxy]-indan-1-one;
Chloro-phenyl-acetic acid 4-(2-piperidin-1-yl-ethyl)-phenyl ester;
Indan-2-carboxylic acid 4-(2-piperidin-1-yl-ethyl)-phenyl ester;
2-[4-(2-Piperidin-1-yl-ethyl)-phenoxy]-indan-1-ol;
1-{2-[4-(3-Phenyl-propoxy)-phenyl]-ethyl}-piperidine-4-carboxylic acid;
2-Hydroxy-N-{1-[2-(4-phenethyloxy-phenoxy)-ethyl]-piperidin-4-yl}-acetamide;
2-Hydroxy-N-(1-{2-[4-(3-phenyl-propoxy)-phenyl]-ethyl}-piperidin-4-yl)-acetamide;
2-Hydroxy-N-{1-[2-(4-phenethyloxy-phenyl)-ethyl]-piperidin-4-yl}-acetamide;
N-{1-[2-(4-Phenethyloxy-phenoxy)-ethyl]-piperidin-4-yl}-methanesulfonamide;
N-(1-{2-[4-(3-Phenyl-propoxy)-phenyl]-ethyl}-piperidin-4-yl)-methanesulfonamide;
N-{1-[2-(4-Phenethyloxy-phenyl)-ethyl]-piperidin-4-yl}-methanesulfonamide;
N-{1-[2-(6-Phenethyloxy-pyridin-3-yl)-ethyl]-piperidin-4-yl}-methanesulfonamide;
2-Hydroxy-N-{1-[2-(6-phenethyloxy-pyridin-3-yl)-ethyl]-piperidin-4-yl}-acetamide;
1-{1-[2-(6-Phenethyloxy-pyridin-3-yl)-ethyl]-piperidin-4-yl}-pyrrolidin-2-one;
and mixtures thereof.

43 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/393,532Filed 30 Mar 2006
Priority: 31 Mar 2005
Published: 5 Oct 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification50 codes

C07D 295/088
With the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings: to…
A61K 31/135
Amines: having aromatic rings , e.g. ketamine, nortriptyline
A61K 31/445
Non condensed pyridines; Hydrogenated derivatives thereof: non condensed piperidines, e.g. piperocaine
A61K 31/454
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone

Family

Application60/667,199Us provisional application · filed 31 Mar 2005
US 2006/0223792 A1This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

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Abstract

A method for inhibiting LTA4H enzyme activity, comprising exposing LTA4H enzyme to an inhibitory amount of at least one compound of formula (I):

wherein
X is selected from the group consisting of CH and N;
Y is selected from the group consisting of R1(CH2)2-3O—, R7N(R8)CO2—, R7N(R8)C(O)N(R8)—, R7N(R8)CO2CH2—, R7N(R8)C(O)CH2—, R1OC(O)N(R8)—, R1OCO2—, R1CO2—, R1CH(R9)CO2—, R1C(O)CH(R10)O—, and R1CH(R9)CH(R10)O—, provided that when one of R9 and R10 in R1CH(R9)CH(R10)O— is —H, then the other is not —H;
R1 is a moiety selected from the group consisting of phenyl, thienyl, pyrrolyl, furanyl, oxazolyl, imidazolyl, thiazolyl, indolyl, indanyl, and tetrahydronaphthyl, wherein R1 is substituted with 0, 1, or 2 substituents R4;
R4 is selected from the group consisting of —H, —OCH3, —Cl, —F, —Br, —I, —OH, —NH2, —CN, —CF3, and —CH3;
R7 is —C14alkyl or is selected from the group consisting of phenyl, thienyl, pyrrolyl, furanyl, oxazolyl, imidazolyl, thiazolyl, indolyl, indanyl, and tetrahydronaphthyl, wherein R7 is substituted with 0, 1, or 2 substituents R4;
R8 is —H or —C1-4alkyl;
or, R and R8 are taken together with the nitrogen member to which they are attached to form pyrrolidinyl, piperidinyl, morpholinyl, or thiomorpholinyl;
R9 is —H, —C1-4alkyl, —Cl, or —OH;
R10 is —H, —C1-4alkyl or is taken together with one of R4 to form a 5- or 6-membered carbocyclic ring;
Z is selected from the group consisting of bond, —CH2—, —OCH2—, —OCH2CH(R11)—, and —CH2CH(R11)—;
R11 is —H or —OH;
provided that when Z is bond, then Y is one of R1(CH2)2-3O—, R1CO2—, R1CH(R9)CO2—, R1C(O)CH(R10)O—, and R1CH(OH)CH(R10)O—;
R6 is —H or —F;
and
R2 and R3 are each independently selected from the group consisting of
A) —H, —C1-7alkyl, —C3-7alkenyl, wherein the carbon in said alkenyl that is attached to the nitrogen member has only single bonds, —C3-7alkynyl, wherein the carbon in said alkynyl that is attached to the nitrogen member has only single bonds, —C3-7cycloalkyl optionally benzofused, —C5-7cycloalkenyl, —C3-7cycloalkylC1-7alkyl, —C1-7alkylC3-7cycloalkyl and phenyl, wherein each of the substituents A) is independently substituted with 0, 1, or 2 substituents RQ, and each of said RQ is a substituent at a carbon member that is at least one carbon member removed from the nitrogen member;
B) a 4-7 membered saturated heterocyclic ring HetRa, said 4-7 membered saturated heterocyclic ring HetRa, having 0 or 1 double bonds, having a carbon member point of attachment and containing a member >NRM as a heteroatom member, and said heteroatom member being separated from said carbon member point of attachment by at least one additional carbon member;
C) —C1-7alkylC(O)Rx, optionally substituted with CH2RAr or CH2RAr′;
D) —C2-5alkylC(O)Rx, wherein two valence allowed carbon members in the C2-5alkyl of said —C2-5alkylC(O)Rx are part of a saturated C3-6carbocycle;
E) —C2-5alkylOH wherein two valence allowed carbon members in the C2-5alkyl of said —C2-5alkylOH are part of a saturated C3-6carbocycle;
F) —C0-4alkylphenyl, wherein the phenyl in said —C0-4alkylphenyl is fused at two adjacent carbon members in said phenyl to Rf, or is benzofused;
G) —C0-4alkylAr6, where Ar6 is a 6-membered heteroaryl having a carbon member point of attachment and having 1 or 2 —N═ heteroatom members, and benzofused;
H) —C0-4alkylAr5, where Ar5 is a 5-membered heteroaryl, having one heteroatom member selected from the group consisting of O, S, and >NRY, and having 0 or 1 —N═ additional heteroatom member, optionally containing 1 or 2 carbonyl groups, and optionally benzofused;
I) —C1-4alkylAr5′, where Ar5′ is a 5-membered heteroaryl containing 3 or 4 nitrogen members, optionally substituted with RY, and having a valence allowed site as a point of attachment;
J) —C0-4alkylAr6-6, where Ar6-6 is a C0-4alkyl-attached phenyl fused at valence allowed sites to a 6-membered heteroaryl, wherein said 6-membered heteroaryl has 1 or 2 —N═ heteroatom members;
K) —C0-4alkylAr6-5, where Ar6-5 is a C0-4alkyl-attached phenyl fused at valence allowed sites to a 5-membered heteroaryl, said 5-membered heteroaryl having one heteroatom member selected from the group consisting of O, S, and >NRY, and said 5-membered heteroaryl having 0 or 1 additional heteroatom member which is —N═;
L) one of 2-(4-ethyl-phenoxy)-benzothiazole, 2-(4-ethyl-phenoxy)-benzooxazole, and 2-(4-ethyl-phenoxy)-1H-benzoimidazole;
and
M) —SO2C1-4alkyl;
alternatively R2 and R3 are taken together with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected from the group consisting of
i) a 4-7 membered saturated heterocyclic ring HetRb, said 4-7 membered saturated heterocyclic ring HetRb having one heteroatom member that is said attachment nitrogen, and being substituted with 0, 1, or 2 substituents at the same or at different ring members, said substituents being selected from the group consisting of —RY, —CN, —C(O)RY, —C0-4alkylCO2RY, —C0-4alkylC(O)CO2RY, —C0-4alkylORY,—C0-4alkylC(O)NRYRZ, —C0-4alkylNRYC(O)RZ, —C(O)NRZORY, —C0-4alkylNRYC(O)CH2ORY, —C0-4alkylNRYC(O)CH2C(O)RY, —C0-4alkylNRYCO2RY, —C0-4alkylNRYC(O)NRYRZ, —C0-4alkylNRYC(S)NRYRZ, —NRYC(O)CO2RY, —NRYRZ, —C0-4alkylNRWSO2RY, 1,3-dihydro-indol-2-one-1-yl, 1,3-dihydro-benzoimidazol-2-one-1-yl, tetrazol-5-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol-5-yl, pyrrolidine-2-thion-1-yl, piperidine-2-thion-1-yl, —C0-4alkylC(O)N(RY)(SO2RY), —C0-4alkylN(RY)(SO2)NRYRY, —C0-4alkylN(RY)(SO2)NRYCO2RY, halo,
ii) a 5-7 membered saturated heterocyclic ring HetRc, said 5-7 membered saturated heterocyclic ring HetRc having one additional heteroatom member separated from said attachment nitrogen by at least one carbon member, said additional heteroatom member being selected from the group consisting of O, S(═O)0-2, and >NRM, said 5-7 membered saturated heterocyclic ring HetRc having 0 or 1 carbonyl members, and being substituted with 0, 1, or 2 substituents at the same or at different carbon ring members, said substituents being selected from the group consisting of —C(O)RY, —CO2RY, —C3-4alkylCO2RY and RZ;
iii) one of imidazolidin-1-yl, 2-imidazolin-1-yl, pyrazol-1-yl, imidazol-1-yl, 2H-tetrazol-2-yl, 1H-tetrazol-1-yl, pyrrol-1-yl, 2-pyrrolin-1-yl, and 3-pyrrolin-1-yl, wherein each of said 2H-tetrazol-2-yl and 1H-tetrazol-1-yl is substituted at the carbon member with 0 or 1 of —C0-4alkylRZ, —C0-4alkylSRY, —C0-4alkylC0-2RY, and substituent HetRa;
and
iv) one of 1,2,3,4-tetrahydro-quinolin-1-yl, 1,2,3,4-tetrahydro-isoquinolin-2-yl, indol-1-yl, isoindol-2-yl, indolin-1-yl, benzimidazol-1-yl, 2,8-diaza-spiro[4.5]decan-1-one-8-yl, 4-{[(2-tert-butoxycarbonylamino-cyclobutanecarbonyl)-amino]-methyl}-piperidin-1-yl, 4-{[(2-amino-cyclobutanecarbonyl)-amino]-methyl}-piperidin-1-yl, 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid-9-yl tert-butyl ester, 4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-8-yl, and 4-oxo-1,3,8-triaza-spiro[4.5]dec-8-yl;
wherein
RK is selected from the group consisting of —H, —C1-4alkyl and —C0-4alkylRAr, each of said —C1-4alkyl and —C0-4alkylRAr being optionally substituted with 1, 2, or 3 substituents RN;
RL is selected from the group consisting of —CO2RS and —C(O)NRSRS′;
RM is selected from the group consisting of RZ, indol-7-yl, —SO2RY, —C3-4alkylC0-2RY, —CO2RY, —C(O)NRZORY, —C(O)RY, —C(O)C1-4alkylORY, —C0-4alkylC(O)NRSRS′, C0-4alkylC(O)CO2RY, 1,3-dihydro-indol-2-one-1-yl, 1,3-dihydro-benzoimidazol-2-one-1-yl, tetrazol-5-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol-5-yl and —C0-4alkylC(O)N(RY)(SO2RY), each of said RM that is not —H being optionally substituted with 1, 2, or 3 substituents RN;
RN is selected from the group consisting of —OCH3, —Cl, —F, —Br, —I, —OH, —NH2, —CN, —CF3, —CH3, —OC(O)CH3, and —NO2;
RQ is selected from the group consisting of —Cl, —F, —Br, —I, —CF3, —CCl3, —CN, —C1-4alkyl, —CO4alkylRAr, —C0-4alkylRAr′, —C0-4alkylORY, —C0-4alkylCO2RY, —C0-4alkylNRYRZ, —C0-4alkylNRYCORY, —C0-4alkylNRYCONRYRZ, —C0-4alkylNRYSO2RY, and —C0-4alkylSRY;
RS and RS′ are independently selected from the group consisting of —H, —C1-4alkyl, and —C0-4alkylphenyl;
alternatively, RS and RS′ are taken together with the nitrogen member to which said RS and RS′ are attached to form a 4-7 membered heterocyclic ring having 0 or 1 additional heteroatom member selected from the group consisting of O, S, and >NRY, provided that said additional heteroatom member is separated by at least two carbon members from said nitrogen member to which said RS and RS′ are attached, and provided that where RY is C0-4alkylRAr, then RAr is not substituted with RL;
RW is selected from the group consisting of RY, and —C3-7cycloalkyl;
RX is selected from the group consisting of —ORY, —NRYRZ, —C1-4alkyl, and —C0-4alkylRAr;
RY is selected from the group consisting of —H, —C1-4alkyl, —C0-4alkylRAr and —C0-4alkylRAr′, each of said RY that is not —H being optionally substituted with 1, 2, or 3 substituents RN;
RZ is selected from the group consisting of RY, —C2-4alkylORY, —C1-2alkylCO2RY, —C1-2alkylC(O)NRSRS′, and —C2-4alkylNRSRS′;
provided that when RY and RZ are attached to a nitrogen member, then RY and RZ are selected as defined above, or RY and RZ are taken together with the RY— and RZ— attached nitrogen member to form a 4-7 membered heterocyclic ring HetRd having 0 or 1 additional heteroatom members selected from the group consisting of O, S, and >NRM, said 4-7 membered heterocyclic ring HetRd having 0 or 1 carbonyl members, and said 4-7 membered heterocyclic ring HetRd having 0 or 1 valence allowed carbon members substituted with at least one of RM, —CO2H, and —C0-1alkylORY;
RAr is a moiety with a carbon member attachment point and said RAr is selected from the group consisting of phenyl, pyridyl, pyrimidyl, and pyrazinyl, wherein each valence allowed carbon member in each of said RAr is independently substituted with at least one of 0, 1, 2, or 3 substituents RN, and 0 or 1 substituent RL;
RAr′ is a 3-8 membered ring having 0, 1, or 2 heteroatom members selected from the group consisting of O, S, N, and >NRY, said RAr′ having 0, 1, or 2 unsaturated bonds and having 0 or 1 carbonyl members, wherein each valence allowed member in each of said RAr′ ring is independently substituted with 0, 1, or 2 substituents RK;
and
Rf is a linear 3- to 5-membered hydrocarbon moiety having 0 or 1 unsaturated carbon-carbon bonds and having 0 or 1 carbonyl members;
or an enantiomer, diasteromer, racemate, tautomer, hydrate, solvate, or a pharmaceutically acceptable salt, ester, or amide thereof.

51 more elements

Facts

Application

11/393,532Filed 30 Mar 2006

Priority

31 Mar 2005

Published

5 Oct 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification50 codes

C07D 295/088
With the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings: to…
A61K 31/135
Amines: having aromatic rings , e.g. ketamine, nortriptyline
A61K 31/445
Non condensed pyridines; Hydrogenated derivatives thereof: non condensed piperidines, e.g. piperocaine
A61K 31/454
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone