1. A method for treating an autoimmune disease in a subject, said method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one compound selected from compounds of formula (I)
wherein:
R1 is hydrogen, azido, halogen, C1-5 alkoxy, hydroxy, C1-5 alkyl, C2-5 alkenyl, cyano, nitro, R7R8N, C2-8 acyl, R9OC\u2550O, R10R\u2033NC\u2550O, 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\u2014, R40S\u2014, R40O(C1-5 alkylene)-, R40O(C\u2550O)\u2014, R40(C\u2550O)\u2014, R40(C\u2550S)\u2014, R40(C\u2550O)O\u2014, R40O(C\u2550O)(C\u2550O)\u2014, R40SO2, NHR62(C\u2550NH)\u2014, NHR62SO2\u2014, and NHR62(C\u2550O)\u2014;
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(C1-15 alkyl)amino, or R58OR59\u2014, 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\u2550O, R28R29NC\u2550O, 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\u2550O R31R32NC\u2550O, 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, R2, 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\u2550O, R34R35NC\u2550O, 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, R51 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, hydroxyimino, CO2R60, R60R61NCO2, (L)-C1-4 alkylene-, (L)-C1-5 alkoxy, N3, or (L)-C1-5 alkyleneamino;
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 R12C;
Y is R13C;
Z is nitrogen;
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\u2550O, R23O(C\u2550O)NH\u2014, R23SO, R22NHCO\u2014, R22NH(C\u2550O)NH\u2014, R23(C1-4 alkylene)NHCO\u2014, R23SO2, or R23SO2NH\u2014;
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\u2550O, R44O(C\u2550O)NH\u2014, R44SO, R43NHCO\u2014, R43NH(C\u2550O)NH\u2014, R44(C1-4 alkylene)NHCO\u2014, R44SO2, or R44SO2NH\u2014;
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\u2550O, R26O(C\u2550O)NH\u2014, R26SO, R25NHCO\u2014, R25NH(C\u2550O)NH\u2014, R26(C1-4 alkylene)NHCO\u2014, R26SO2, or R26SO2NH\u2014;
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\u2550O, R15R16NC\u2550O, C1-5 haloalkyl, C1-5 haloalkoxy, C1-5haloalkylthio, and C1-5 alkylthio;
R15 is hydrogen, C1-5 alkyl, C3-5 alkenyl, phenyl, benzyl, C1-5 heterocyclyl, C2-8 acyl, aroyl, R53OC\u2550O, R54R55NC\u2550O, R53S, R53SO, R53SO2, or R54R55NSO2;
R16 is hydrogen, C1-5 alkyl, C3-5 alkenyl, phenyl, benzyl, or C1-5 heterocyclyl; alternatively, R15 and R1-5 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\u2550O, 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\u2550O, R46R47NC\u2550O, 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\u2550O, R51R52NC\u2550O, 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, \u2014COOH, C2-6 acyl, di(C1-4 alkyl)aminoC2-5 alkylene, di(C1-4 alkyl)aminoC2-5 alkyl-NH\u2014CO\u2014, and C1-5 haloalkoxy;
and pharmaceutically acceptable salts, esters, or amides thereof;
wherein the autoimmune disease is selected from lupus, rheumatoid arthritis, and asthma.
2. A method according to claim 1, wherein R1 is hydrogen, halogen, C1-5 alkoxy, hydroxy, C1-5 alkyl, cyano, nitro, R7R8N, C2-8 acyl, or R10R11NSO2.
3. A method according to claim 2, wherein R1 is halogen, cyano, nitro, R7R8N, or R10R11NSO2.
4. A method according to claim 1, wherein R2 is hydrogen.
5. A method according to claim 1, wherein each of R3 and R4 is independently hydrogen or C1-3 alkyl.
6. A method according to claim 5, wherein one of R3 and R4 is hydrogen.
7. A method according to claim 6, wherein each of R3 and R4 is hydrogen.
8. A method according to claim 1, wherein R3 is hydrogen and R4 is C1-3 alkyl.
9. A method according to claim 1, wherein R5 and R6 taken together form pyridinyl.
10. A method according to claim 9, wherein R5 and R6 taken together form pyridinyl, optionally N-substituted with R40O(C\u2550O)(C\u2550O)\u2014, R40SO2, R40NHCO2, R40(C\u2550O)\u2014, or R4ON(C\u2550O)\u2014.
11. A method according to claim 1, wherein each of R7, R8, R21, R22R24, and R25 is independently hydrogen or C1-5 alkyl; or, independently, each of R7 and R8, R21 and R22, and R24 and R25 are taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring is saturated, unsaturated or aromatic.
12. A method according to claim 11, wherein at least one of R7 and R8, R21 and R22, and R24 and R25, taken together, is morpholinyl, piperidinyl, or pyrrolidinyl.
13. A method according to claim 1, wherein R9, R23, R26, and R27 are each independently C1-5 alkyl.
14. A method according to claim 1, wherein G is C3-4 alkanediyl, optionally substituted with hydroxy, (L)-C1-5 alkyloxy-, or (L)-C1-5 alkyleneamino-.
15. A method according to claim 14, wherein G is C3 alkanediyl, optionally substituted with hydroxy, (L)-C1-5 alkyloxy-, or (L)-C1-5 alkyleneamino-.
16. A method according to claim 1, wherein X is CH.
17. A method according to claim 1, wherein R12 is hydrogen, R23O(C\u2550O)NH\u2014, R22NH(C\u2550O)NH\u2014, R23SO2NH, R23SO, or R23SO2, and R13 is hydrogen, R44O(C\u2550O)NH\u2014, R43NH(C\u2550O)NH\u2014, R44SO2NH, R44SO, or R44SO2.
18. A method according to claim 1, wherein R14 is hydrogen, halogen, C1-5 alkoxy, C1-5 alkyl, cyano, nitro, R26O(C\u2550O)NH\u2014, R25NH(C\u2550O)NH\u2014, R26SO2NH, or R24R25N.
19. A method according to claim 18, wherein R14 is halogen, R26O(C\u2550O)NH\u2014, R26NH(C\u2550O)NH\u2014, R26SO2NH, or R24R25N.
20. A method according to claim 1, wherein Ar represents a monocyclic ring, optionally substituted with between 1 and 2 substituents selected independently from halogen, C1-5 alkyl, cyano, nitro, R15R16N, CF3, and OCF3.
21. A method according to claim 20, wherein Ar is a six membered ring substituted with between 1 and 2 substituents selected from halo, CF3, and OCF3, said substitutent or substitutents being at the 4-position or at the 3- and 4-positions, respectively.
22. A method according to claim 1, wherein W is SO2, C\u2550O, or CHR20.
23. A method according to claim 1, wherein W is a covalent bond.
24. A method according to claim 1, wherein W and R1 taken together are formula (I)(a).
25. A method according to claim 1, wherein W and R1 taken together are formula (I)(b).
26. A method according to claim 1, wherein one of R3 and R4 is hydrogen; Ar represents a monocyclic ring, optionally substituted with between 1 and 2 substituents selected from halogen, C1-5 alkyl, cyano, nitro, R15R16N, CF3, and OCF3; R12 is hydrogen, R23SO, or R23SO2; R13 is hydrogen, R44SO, or R44SO2; R14 is hydrogen, halogen, C1-5 alkoxy, C1-5 alkyl, cyano, nitro, or R24R25N; and G is C3-4 alkanediyl, optionally substituted with hydroxy, C1-3 alkyl, (L)-C1-5 alkyloxy, or (L)-C1-5 alkyleneamino-.
27. A method according to claim 1, wherein each of R3 and R4 is hydrogen; Ar represents a six membered ring, optionally substituted with between 1 and 2 substituents selected from halogen, C1-5 alkyl, cyano, nitro, R15R16N, CF3, and OCF3; R12 is hydrogen, R23SO, or R23SO2; R13 is hydrogen, R44SO, or R44SO2; R14 is hydrogen, halogen, C1-5 alkoxy, C1-5 alkyl, cyano, nitro, or R24R25N; and G is C3 alkanediyl, optionally substituted with hydroxy, (L)-C1-5 alkyloxy-, or (L)-C1-5 alkylamino.
28. A method according to claim 27 wherein Ar is phenyl.
29. A method according to claim 28, wherein W and R1 taken together are formula (I)(b).
30. A method for treating an autoimmune disease in a subject, said method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one compound selected from:
1-{3-(4-Chloro-phenyl)-1-2-hydroxy-3-(4-pyridin-2-yl-piperazin-1-yl)-propyl-1,4,6,7-tetrahydro-pyrazolo4,3-cpyridin-5-yl}-ethanone;
1-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-4-(4-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl-propyl}-1,4,6,7-tetrahydro-pyrazolo4,3-cpyridin-5-yl)-ethanone;
1-(3-(4-Chloro-phenyl)-1-{3-4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo4,3-cpyridin-5-yl)-ethanone; and
pharmaceutically acceptable salts, esters, or amides thereof;
wherein the autoimmune disease is selected from lupus, rheumatoid arthritis, and asthma.
31. A method for inhibiting the proteolytic activity of human cathepsin S comprising contacting human cathepsin S with at least one compound selected from:
1-{3-(4-Chloro-phenyl)-1-2-hydroxy-3-(4-pyridin-2-yl-piperazin-1-yl)-propyl-1,4,6,7-tetrahydro-pyrazolo4,3-cpyridin-5-yl}-ethanone;
1-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-4-(4-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl-propyl}-1,4,6,7-tetrahydro-pyrazolo4,3-cpyridin-5-yl)-ethanone;
1-(3-(4-Chloro-phenyl)-1-{3-4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo4,3-cpyridin-5-yl)-ethanone;
and pharmaceutically acceptable salts, esters, or amides thereof.
32. A method of claim 31, wherein the human cathepsin S is in a human subject.
33. A method of claim 32, wherein the human subject is suffering from an autoimmune disease selected from lupus, rheumatoid arthritis, and asthma.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A luminous decoration assembly for automobile comprising:
a decorating member;
a stripped light shell connected with the decorating member;
a flexible guiding strap retained in the stripped light shell; and
at least one light-emitting element disposed on one end of the flexible guiding strap so as to project light to the one end of the flexible guiding strap, and cause the flexible guiding strap to emit light to the stripped light shell.
2. The luminous decoration assembly for the automobile as claimed in claim 1, wherein the decorating member includes a stripped groove defined thereon so as to retain with the stripped light shell.
3. The luminous decoration assembly for the automobile as claimed in claim 1, wherein the stripped light shell includes an extending portion coupled with the decorating member.
4. The luminous decoration assembly for the automobile as claimed in claim 3, wherein the extending portion adheres with the decorating member by ways of at least one adhesive piece.
5. The luminous decoration assembly for the automobile as claimed in claim 1, wherein the stripped light shell also includes a stripped slot for engaging with the flexible guiding strap.
6. The luminous decoration assembly for the automobile as claimed in claim 1, wherein the stripped light shell are provided with a plurality of light diffusion lines.
7. The luminous decoration assembly for the automobile as claimed in claim 1, wherein the stripped light shell further includes a light reflecting sheet.
8. The luminous decoration assembly for the automobile as claimed in claim 1, wherein the at least one light-emitting element are disposed on two ends of the flexible guiding strap so as to project the light to the one end of the flexible guiding strap.
9. The luminous decoration assembly for the automobile as claimed in claim 1, wherein the flexible guiding strap further includes a fitting sleeve disposed on the one end of the flexible guiding strap.
10. The luminous decoration assembly for the automobile as claimed in claim 8, wherein the flexible guiding strap further includes a fitting sleeve disposed on the one end of the flexible guiding strap.
11. The luminous decoration assembly for the automobile as claimed in claim 1, wherein the at least one light-emitting element is either a light-emitting diodes (LED) or a bulb.