US 2008/0293732 A1Published application

Substituted pyrazoles

AssigneeOrtho-McNeil Pharmaceutical, Inc.

InventorsMary Pat Beavers, J. Guy Breitenbucher, Hui Cai, James P. Edwards, Cheryl A. Grice, Darin J. Gustin, Haripada Khatuya, Steven P. Meduna, Barbara A. Pio, Kevin L. Tays, Jianmei Wei

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Abstract

Substituted pyrazoles, methods of manufacturing them, compositions containing them, and methods of using them to treat, for example, autoimmune diseases mediated by cathepsin S.

Claims63

Dependent claims

A method for inhibiting the proteolytic activity of human cathepsin S comprising contacting human cathepsin S with a compound of formula (I) below:

wherein:
R1 is hydrogen, azido, halogen, C1-5 alkoxy, hydroxy, C1-5 alkyl, C2-5 alkenyl, cyano, nitro, R7R8N, C2-8 acyl, R9OC═O, R10R11NC═O, or R10R11NSO2;
or R1 is taken together with W as described below;
R2 is hydrogen, halogen, C1-5 alkoxy, C1-5 alkyl, C2-5 alkenyl, C1-5 haloalkyl, cyano, or R48R49N;
each of R3 and R4 is independently hydrogen or C1-5 alkyl;
R5 and R6 are taken together to form pyridinyl or a 5-membered carbocyclic ring or 7-membered carbocyclic ring, which ring is unsaturated or aromatic, and each of said pyridinyl, 5-membered ring and 7-membered ring is optionally substituted with between one and three substituents independently selected from halo, cyano, amino, nitro, R40, R40O—, R40S—, R40O(C1-5 alkylene)-, R40O(C═O)—R40(C═O), R40(C═S), R40(C═O)O—, R40O(C═O)—, (R40SO2, NHR62 (C═NH)—, NHR62 SO2—, and NHR62 (C═O)—;
R40 is H, C1-5 alkyl, C2-5 alkenyl, phenyl, benzyl, phenethyl, C1-5 heterocyclyl, (C1-5 heterocyclyl)C1-5 alkylene, amino, or mono- or di(C1-5 alkyl)amino, or R58OR59—, wherein R58 is H, C1-5 alkyl, C2-5 alkenyl, phenyl, benzyl, phenethyl, C1-5 heterocyclyl, or (C1-5 heterocyclyl)C1-6 alkylene and R59 is C1-5 alkylene, phenylene, or divalent C1-5 heterocyclyl;
and
R62 can be H in addition to the values for R40;
R7 is hydrogen, C1-5 alkyl, C3-5 alkenyl, phenyl, naphthyl, C1-5 heterocyclyl, C2-8 acyl, aroyl, R27OC═O, R28R29NC═O, R27SO, R27SO2, or R28R29NSO2;
R8 is hydrogen, C1-5 alkyl, C3-5 alkenyl, phenyl, or C1-5 heterocyclyl;
alternatively, R7 and R8 are taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring is saturated, unsaturated or aromatic;
R9 is C1-5 alkyl, phenyl, naphthyl, or C1-5 heterocyclyl;
R21 is hydrogen, C1-5 alkyl, C3-5 alkenyl, phenyl, naphthyl, C1-5 heterocyclyl, C2-8 acyl, aroyl, R30OC═O, R31R32NC═O, R30SO, R30SO2, or R31R32NSO2;
R22 is hydrogen, C1-5 alkyl, C3-5 alkenyl, phenyl, or C1-5 heterocyclyl;
alternatively, R21 and R22 are taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring is saturated, unsaturated or aromatic;
each of R23, R26, R27, R30, R33, R44, R45, and R50 is C1-5 alkyl, phenyl, naphthyl, or C1-5 heterocyclyl;
R24 is hydrogen, C1-5 alkyl, C3-5 alkenyl, phenyl, naphthyl, C1-5 heterocyclyl, C2-8 acyl, aroyl, R33OC═O, R34R35NC═O, R33SO, R33SO2, or R34R35NSO2;
R25 is hydrogen, C1-5 alkyl, C3-5 alkenyl, phenyl, or C1-5 heterocyclyl;
alternatively, R24 and R25 are taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring is saturated, unsaturated or aromatic;
each of R10 and R11 is independently hydrogen, C1-5 alkyl, C2-5 alkenyl, phenyl, or C1-5 heterocyclyl;
alternatively, R10 and R11 are taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring is saturated, unsaturated or aromatic;
each of R28, R29, R31, R32, R34, R35, R46, R47 and R52 is independently hydrogen, C1-5 alkyl, phenyl, or C1-5 heterocyclyl;
alternatively, R28 and R29, R31 and R32, R34 and R35, R46 and R47, or R51 and R52, independently, are taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring is saturated, unsaturated or aromatic;
n is 1;
G represents C3-6 alkenediyl or C3-6 alkanediyl, optionally substituted with hydroxy, halogen, C1-5 alkyl, C1-5 alkoxy, oxo, hydroximino, CO2R60, R60R61NCO2, (L)-C1-4 alkylene-, (L)-C1-5 alkoxy, N3, or [(L)-C1-5 alkylene]amino;
each of R60 and R61 is independently hydrogen, C1-5 alkyl, C3-5 alkenyl, phenyl, benzyl, phenethyl, or C1-5 heterocyclyl;
alternatively, R60 and R61 are taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring is saturated, unsaturated or aromatic;
L is amino, mono- or di-C1-5 alkylamino, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, or piperazinyl, where available ring nitrogens are optionally substituted with C1-5 alkyl, benzyl, C2-5 acyl, C1-5 alkylsulfonyl, or C1-5 alkyloxycarbonyl;
X is nitrogen or R12C;
Y is nitrogen or R13C;
Z is nitrogen or R14C;
with the following provisos:
1) when Z and Y are each N, then X is N, and
2) when X is R12C and Y is R13C, then Z is R14C;
R12 is hydrogen, halogen, C1-5 alkoxy, C1-5 alkyl, C2-5 alkenyl, cyano, nitro,
R21R22N, C2-8 acyl, C1-5 haloalkyl, C1-5 heterocyclyl, (C1-5 heterocyclyl)C1-5 alkylene, R23OC═O, R23O(C═O)NH—, R23SO, R22NHCO—, R22NH(C═O)NH—, R23(C1-4 alkylene)NHCO—, R23SO2, or R23SO2NH—;
R13 is hydrogen, halogen, C1-5 alkoxy, C1-5 alkyl, C2-5 alkenyl, cyano, nitro,
R42R43N, C2-8 acyl, C1-5 haloalkyl, C1-5 heterocyclyl, (C1-5 heterocyclyl)C1-5 alkylene, R44OC═O, R44O(C═O)NH—, R44SO, R43NHCO—, R43NH(C═O)NH—, R44(C1-4 alkylene)NHCO—, R44SO2, or R44SO2NH—;
R14 is hydrogen, halogen, C1-5 alkoxy, C1-5 alkyl, C2-5 alkenyl, cyano, nitro, R24R25N, C2-8 acyl, C1-5 haloalkyl, C1-5 heterocyclyl, (C1-5 heterocyclyl)C1-5 alkylene, R26OC═O, R26O(C═O)NH—, R26SO, R25NHCO—, R25NH(C═O)NH—, R26(C1-4 alkylene)NHCO—, R26SO2, or R26SO2NH—;
Ar represents a monocyclic or bicyclic aryl or heteroaryl ring, optionally substituted with between 1 and 3 substituents selected from halogen, C1-5 alkoxy, C1-5 alkyl, C2-5 alkenyl, cyano, azido, nitro, R15R16N, R17SO2, R17S, R17SO, R17OC═O, R15R16NC═O, C1-5 haloalkyl, C1-5 haloalkoxy, C1-5 haloalkylthio, and C1-5 alkylthio;
R15 is hydrogen, C1-5 alkyl, C3-5 alkenyl, phenyl, benzyl, C1-5 heterocyclyl, C2-8 acyl, aroyl, R53OC═O, R54R55NC═O, R53S, R53S, R53SO2, or R54R55NSO2;
R16 is hydrogen, C1-5 alkyl, C3-5 alkenyl, phenyl, benzyl, or C1-5 heterocyclyl;
alternatively, R15 and R16 are taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring is saturated, unsaturated or aromatic;
each of R17 and R53 is C1-5 alkyl, phenyl, or C1-5 heterocyclyl;
each of R54 and R55 is independently hydrogen, C1-5 alkyl, C2-5 alkenyl, phenyl, benzyl, or C1-5 heterocyclyl;
alternatively, R54 and R55 are taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring is saturated, unsaturated or aromatic;
W represents SO2, C═O, CHR20, or a covalent bond;
or W and R1, taken together with the 6-membered ring to which they are both attached, form one of the following two formulae:
wherein Xa is O, S, or N;
and Xb is O, S or SO2;
R20 is hydrogen, C1-5 alkyl, phenyl, benzyl, naphthyl, or C1-5 heterocyclyl;
R42 is hydrogen, C1-5 alkyl, C3-5 alkenyl, phenyl, naphthyl, C1-5 heterocyclyl, C2-8 acyl, aroyl, R45OC═, R46R47NC═O, R45SO, R45SO2, or R46R47NSO2;
R43 is hydrogen, C1-5 alkyl, C3-5 alkenyl, phenyl, or C1-5 heterocyclyl;
alternatively, R42 and R43 are taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring is saturated, unsaturated or aromatic;
R44 is C1-5 alkyl, C2-5 alkenyl, phenyl, naphthyl, or C1-5 heterocyclyl;
R48 is hydrogen, C1-5 alkyl, C3-5 alkenyl, phenyl, naphthyl, C1-5 heterocyclyl, C2-8 acyl, aroyl, R50OC═O, R51R52NC═O, R50SO, R50SO2, or R51R52NSO2;
R49 is hydrogen, C1-5 alkyl, C3-5 alkenyl, phenyl, or C1-5 heterocyclyl;
alternatively, R48 and R49 are taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring is saturated, unsaturated or aromatic;
and
wherein each of the above hydrocarbyl or heterocarbyl groups, unless otherwise indicated, and in addition to any specified substituents, is optionally and independently substituted with between 1 and 3 substituents selected from methyl, halomethyl, hydroxymethyl, halo, hydroxy, amino, nitro, cyano, C1-5 alkyl, C1-5 alkoxy, —COOH, C2-6 acyl, [di(C1-4 alkyl)amino]C2-5 alkylene, [di(C1-4 alkyl)amino]C2-5 alkyl-NH—CO—, and C1-5 haloalkoxy;
or a pharmaceutically acceptable salt, ester, or amide thereof.

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