What is claimed is:
1. A compound of the formula:
47
or a pharmaceutically acceptable form thereof, wherein:
R represents:
(i) hydrogen, halogen, cyano or C1-C2 haloalkyl, or
(ii) C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C2alkanoyl, C3-C7cycloalkyl, C3-C7cycloalkenyl or heterocycloalkyl, each of which is optionally substituted;
R1 represents:
(i) hydrogen, hydroxy, halogen, amino, cyano, nitro, C1-C2haloalkyl or C1-C2 haloalkoxy;
(ii) C1-C4alkyl, C2-C4alkenyl, C1-C4alkoxy, C3-C7cycloalkyl, (C3-C 7cycloalkyl)C1-C2alkyl, or mono- or di-C1-C6alkylamino, or
(iii) phenylC0-C4carbhydryl or (5- or 6-membered heteroaryl)C0-C4carbhydryl, each of which is optionally substituted;
R2 is optionally substituted C1-C7 alkyl or optionally substituted C2-C7 alkenyl;
R3 is hydrogen or C1-C6alkyl;
R4 represents:
(i) C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is optionally substituted;
(ii) optionally substituted arylC0-C2alkyl having 1 ring or 2 fused rings;
(iii) optionally substituted arylC1-C2alkyl, wherein the aryl portion is fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1 or 2 ring atoms independently chosen from N, O and S, with remaining ring atoms being carbon; or
(iv) optionally substituted (4- to 12-membered heterocycle)C0-C4alkyl;
R5 and R6 are independently chosen from hydrogen and C1-C6alkyl; and
Ar represents:
(i) optionally substituted aryl having 1 ring or 2 fused or pendant rings;
(ii) optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1 or 2 ring atoms independently chosen from N, O and S, with remaining ring atoms being carbon; or
(iii) optionally substituted heteroaryl having 1 ring or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O and S.
2. A compound or pharmaceutically acceptable form thereof according to claim 1, wherein:
R represents:
(i) hydrogen, halogen, cyano or C1-C2haloalkyl; or
(ii) C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C2alkanoyl, C3-C7cycloalkyl, C3-C7 cycloalkenyl or 5- to 7-membered heterocycloalkyl, each of which is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, oxo, C1-C4alkyl, C1-C4alkoxy and C1-C2alkoxycarbonyl;
R1 represents:
(i) hydrogen, hydroxy, halogen, amino, cyano, nitro, C1-C2haloalkyl or C1-C2 haloalkoxy;
(ii) C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C3-C7cycloalkyl, (C3-C7cycloalkyl)C1-C2alkyl, or mono- or di-C1-C4alkylamino, each of which is substituted with from 0 to 3 substituents independently chosen from hydrogen, hydroxy, halogen, amino, cyano, oxo, C1-C4alkyl, C1-C4alkoxy and C1-C2alkoxycarbonyl; or
(iii) phenylC0-C4carbhydryl or (5- or 6-membered heteroaryl)C0-C4carbhydryl, wherein each 5- or 6-membered heteroaryl is independently chosen from imidazolyl, pyridyl, thiazolyl, pyrimidinyl and thienyl, and wherein each phenylC0-C4carbhydryl or (5- or 6-membered heteroaryl)C0-C4carbhydryl is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, COOH, CONH2, SO2NH2, C1-C2 haloalkyl, C1-C2 haloalkoxy, C1-C4 alkyl, C1-C4alkoxy, C2-C4alkanoyl, C1-C2alkylsulfonyl, C1-C2alkylsulfinyl and C1-C2alkylthio;
R2 is C1-C7alkyl or C2-C7alkenyl, each of which is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, oxo, C1-C2alkoxy, C1-C2 mono- and di-alkylamino, C3-C7cycloalkyl and phenyl;
R3 is hydrogen or C1-C6alkyl;
R4 represents:
(i) C1-C6alkyl, C2-C6 alkenyl or C2-C6 alkynyl, each of which is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, C1-C2alkyl, C1-C2alkoxy, or C1-C2alkoxycarbonyl;
(ii) arylC0-C2alkyl having 1 ring or 2 fused rings;
(iii) benzyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1 or 2 ring atoms independently chosen from N, O and S with remaining ring atoms being carbon; or
(iv) (4- to 12-membered heterocycle)C0-C2alkyl;
wherein each of (ii)(iv) is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, COOH, CONH2, SO2NH2, oxo, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C4alkyl, C1-C4alkoxy, mono- and di(C1-C6)alkylamino, C1-C4alkanoyl, C1-C2sulfonate, C1-C2alkylsulfonyl, C1-C2alkylsulfinyl, C1-C4alkylthio, C2-C4alkanone, C1-C4alkyl ester; C1-C4alkanoyloxy, C1-C2alkoxycarbonyl and C1-C2alkylcarboxamido; and
Ar represents:
(i) an aryl group having 1 ring or 2 fused or pendant rings;
(ii) phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1 or 2 ring atoms independently chosen from N, O and S with remaining ring atoms being carbon; or
(iii) a heteroaryl group having 1 ring or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms selected from N, O, and S;
each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, COOH, CONH2, SO2NH2, oxo, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C4alkyl, C1-C4alkoxy, mono- and di-(C1-C6)alkylamino, C1-C4alkanoyl, C1-C2sulfonate, C1-C2alkylsulfonyl, C1-C2alkylsulfinyl, C1-C4alkylthio, C2-C4alkanone, C1-C4alkyl ester, C1-C4alkanoyloxy, C1-C2alkoxycarbonyl and C1-C2alkylcarboxamido.
3. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein R5 is hydrogen, and R6 is hydrogen, methyl or ethyl.
4. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein R1 is phenyl substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, COOH, CONH2, SO2NH2, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C4alkyl, C1-C4alkoxy, C2-C4alkanoyl, C1-C2alkylsulfonyl, C1-C2alkylsulfinyl and C1-C2alkylthio.
5. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein R1 is phenyl substituted with 1 or 2 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, COOH, CONH2, SO2NH2, C1-C2 haloalkyl, C1-C2 haloalkoxy, C1-C2alkyl and C1-C2alkoxy.
6. A compound or pharmaceutically acceptable form thereof according to claim 2 wherein R1 is unsubstituted phenyl.
7. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein R1 is hydrogen, hydroxy, halogen, amino, cyano, tri-fluoromethyl, pentafluoroethyl, difluoromethyl, trifluoromethoxy or difluoromethoxy.
8. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein R1 is halogen.
9. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein R2 is propyl, butyl, pentyl or 3-methylbutyl.
10. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein R3 is hydrogen.
11. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein R4 is C1-C6alkyl.
12. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein R4 is benzyl substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, COOH, CONH2, SO2NH2, oxo, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C4alkyl, C1-C4alkoxy, mono- and di-(C1-C6)alkylamino, C1-C4alkanoyl, C1-C2sulfonate, C1-C2alkylsulfonyl, C1-C2alkylsulfinyl, C1-C4alkylthio, C2-C4alkanone, C1-C4alkyl ester, C1-C4alkanoyloxy, C1-C2alkoxycarbonyl and C1-C2alkylcarboxamido.
13. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein R4 is benzyl substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, amino, cyano, COOH, CONH2, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C2alkyl, mono- and di-(C1-C2)alkylamino, C1-C2alkoxy, C1-C2alkanoyl and C1-C2alkoxycarbonyl.
14. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein R4 is benzyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1 or 2 ring atoms chosen from N, O, and S with remaining ring atoms being carbon, wherein the benzyl fused to a 5- to 7-membered ring is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, COOH, CONH2, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C2alkyl, mono- and di-(C1-C2)alkylamino, C1-C2alkoxy, C1-C2alkanoyl and C1-C2alkoxycarbonyl.
15. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein R4 is benzo1,3dioxol-5-ylmethyl, 2,3-dihydro-1-benzofuran-6-ylmethyl, 2,3-dihydro-1-benzofuran-5-ylmethyl, chroman-6-ylmethyl, chroman-7-ylmethyl, 1H-indol-5-yl, 1H-indazol-5-yl, 1,2,3,4-tetrahydro-quinolin-6-yl or 2,3-dihydro-benzo1,4dioxin-6-ylmethyl, each of which is substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, C1-C2 alkyl and C1-C2alkoxy.
16. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein R4 is benzo1,3dioxol-5-ylmethyl or 2,3-dihydro-benzo1,4dioxin-6-ylmethyl.
17. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein Ar represents phenyl substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, COOH, CONH2, SO2NH2, oxo, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C4alkyl, C1-C4alkoxy, mono- and di-(C1-C6)alkylamino, C1-C4alkanoyl, C1-C2sulfonate, C1-C2alkylsulfonyl, C1-C2alkylsulfinyl, C1-C4alkylthio, C2-C4alkanone, C1-C4alkylester, C1-C4alkanoyloxy; C1-C2alkoxycarbonyl and C1-C2alkylcarboxamido.
18. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein Ar represents phenyl substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, amino, cyano, COOH, CONH2, C1-C2 haloalkyl, C1-C2haloalkoxy, C1-C2alkyl, mono- and di-(C1-C2alkyl)amino, C1-C2alkoxy, C1-C2alkanoyl and C1-C2alkoxycarbonyl.
19. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein Ar represents phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1 or 2 ring atoms independently chosen from N, O and S with remaining ring atoms being carbon, and wherein the phenyl fused to a 5- to 7-membered ring is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, COOH, CONH2, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C2alkyl, mono- and di-(C1-C2)alkylamino, C1-C2alkoxy, C1-C2alkanoyl and C1-C2alkoxycarbonyl.
20. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein Ar represents benzo1,3dioxol-5-yl, 2,3-dihydro-1-benzofuran-6-yl, 2,3-dihydro-1-benzofuran-5-yl, chroman-6-yl, chroman-7-yl, 1H-indol-5-yl, 1H-indazol-5-yl, 1,2,3,4-tetrahydro-quinolin-6-yl or 2,3-dihydro-benzo1,4dioxin-6-yl, each of which is substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, C1-C2 alkyl and C1-C2alkoxy.
21. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein Ar represents benzo1,3dioxol-5-yl or 2,3-dihydro-benzo1,4dioxin-6-yl.
22. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein R is halogen, cyano or acetyl.
23. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein R is C1-C4 alkyl, C2-C4 alkenyl, C3-C7cycloalkyl or C3-C7 cycloalkenyl each of which is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, C1-C3alkyl and C1-C3alkoxy.
24. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein R is morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, azetidinyl, homopiperidinyl, homomorpholinyl, homopiperazinyl or thiomorpholinyl, each of which substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, COOH, C1-C3alkyl and C1-C3alkoxy.
25. A compound or pharmaceutically acceptable form thereof according to claim 2, wherein:
R2 is propyl, butyl, pentyl or 3-methylbutyl;
R3 is hydrogen;
R5 is hydrogen;
R6 is hydrogen, methyl or ethyl; and
Ar represents phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1 or 2 ring atoms independently chosen from N, O and S with remaining ring atoms being carbon, and wherein the phenyl fused to a 5- to 7-membered ring is substituted with substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, C1-C2 alkyl and C1-C2alkoxy.
26. A compound or pharmaceutically acceptable form thereof according to claim 25, wherein
R1 is hydrogen or phenyl substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, COOH, CONH2, SO2NH2, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C4alkyl, C1-C4alkoxy, C2-C4alkanoyl, C1-C2alkylsulfonyl, C1-C2alkylsulfinyl and C1-C2alkylthio; and
R is:
(i) halogen, cyano or acetyl; or
(ii) C1-C4alkyl, C2-C4alkenyl, C3-C7cycloalkyl or C3-C7cycloalkenyl, each of which is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, C1-C3alkyl and C1-C3alkoxy.
27. A compound or pharmaceutically acceptable form thereof according to claim 26, wherein R4 is C1-C6alkyl.
28. A compound or pharmaceutically acceptable form thereof according to claim 26, wherein R4 is:
(i) benzyl substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, amino, cyano, COOH, CONH2, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C2alkyl, mono- and di-(C1-C2)alkylamino, C1-C2alkoxy, C1-C2alkanoyl, and C1-C2alkoxycarbonyl; or
(ii) benzyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1 or 2 ring atoms chosen from N, O, and S with remaining ring atoms being carbon, wherein the benzyl fused to a 5- to 7-membered ring is substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, C1-C2alkyl and C1-C2alkoxy.
29. A compound or pharmaceutically acceptable form thereof according to claim 25, wherein:
R1 is hydrogen, hydroxy, halogen, amino, cyano, tri-fluoromethyl, pentafluoroethyl, difluoromethyl, trifluoromethoxy or difluoromethoxy; and
R is morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, azetidinyl, homopiperidinyl, homomorpholinyl, homopiperazinyl or thiomorpholinyl, each of which substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, COOH, C1-C3alkyl and C1-C3alkoxy.
30. A compound or pharmaceutically acceptable form thereof according to claim 29, wherein R4 is C1-C6alkyl.
31. A compound or pharmaceutically acceptable form thereof according to claim 29, wherein R4 is
(i) benzyl substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, amino, cyano, COOH, CONH2, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C2alkyl, mono- and di-(C1-C2)alkylamino, C1-C2alkoxy, C1-C2alkanoyl and C1-C2alkoxycarbonyl; or
(ii) benzyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1 or 2 ring atoms chosen from N, O, and S with remaining ring atoms being carbon, wherein the benzyl fused to a 5- to 7-membered ring is substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, C1-C2alkyl and C1-C2alkoxy.
32. A compound or pharmaceutically acceptable form thereof according to claim 1, wherein the compound exhibits an IC50 of 500 nM or less in a standard in vitro C5a receptor-mediated chemotaxis or calcium mobilization assay.
33. A compound or pharmaceutically acceptable form thereof according to claim 1, wherein the compound exhibits an IC50 of 25 nM or less in a standard in vitro C5a receptor-mediated chemotaxis or calcium mobilization assay.
34. A compound or pharmaceutically acceptable form thereof according to claim 1, wherein the compound exhibits less than 5% agonist activity in a GTP binding assay.
35. A pharmaceutical composition comprising at least one compound or pharmaceutically acceptable form thereof according to claim 1, in combination with a physiologically acceptable carrier or excipient.
36. A method for inhibiting signal-transducing activity of a cellular C5a receptor, comprising contacting a cell expressing C5a receptor with at least one compound or pharmaceutically acceptable form thereof according to claim 1, and thereby reducing signal transduction by the C5a receptor.
37. A method according to claim 36, wherein the cell is contacted in vivo in an animal.
38. A method according to claim 37, wherein the animal is a human.
39. A method of inhibiting binding of C5a to C5a receptor in vitro, the method comprising contacting C5a receptor with at least one compound or pharmaceutically acceptable form thereof according to claim 1, under conditions and in an amount sufficient to detectably inhibit C5a binding to C5a receptor.
40. A method of inhibiting binding of C5a to C5a receptor in a human patient, comprising contacting cells expressing C5a receptor with at least one compound or pharmaceutically acceptable form thereof according to claim 1, in an amount sufficient to detectably inhibit C5a binding to cells expressing a cloned C5a receptor in vitro, and thereby inhibiting binding of C5a to the C5a receptor in the patient.
41. A method for treating a patient suffering from rheumatoid arthritis, psoriasis, cardiovascular disease, reperfusion injury, or bronchial asthma comprising administering to the patient a C5a receptor modulatory amount of a compound or pharmaceutically acceptable form thereof according to claim 1.
42. A method for treating a patient suffering from stroke, myocardial infarction, atherosclerosis, ischemic heart disease, or ischemia-reperfusion injury comprising administering to the patient a C5a receptor modulatory amount of a compound or pharmaceutically acceptable form thereof according to claim 1.
43. A method for inhibiting C5a receptor-mediated cellular chemotaxis, comprising contacting mammalian white blood cells with a C5a receptor modulatory amount of a compound or pharmaceutically acceptable form thereof according to claim 1.
44. A method for localizing C5a receptor in a tissue sample, comprising:
(a) contacting the tissue sample containing C5a receptor with a detectably labeled compound according to claim 1 under conditions that permit binding of the compound to C5a receptors; and
(b) detecting the bound compound.
45. A packaged pharmaceutical preparation, comprising:
(a) a pharmaceutical composition according to claim 35 in a container; and
(b) instructions for using the composition to treat a patient suffering from rheumatoid arthritis, psoriasis, cardiovascular disease, reperfusion injury, or bronchial asthma.
46. A packaged pharmaceutical preparation
(a) a pharmaceutical composition according to claim 35 in a container; and
(b) instructions for using the composition to treat stroke, myocardial infarction, atherosclerosis, ischemic heart disease, or ischemia-reperfusion injury.
47. A pharmaceutical composition according to claim 35, wherein the pharmaceutical composition is formulated as an injectible fluid, an aerosol, a cream, a gel, a pill, a capsule, a syrup, or a transdermal patch.
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 head-up display apparatus for a vehicle, the head-up display apparatus being configured to output an image whose shape is convex upwardly as a whole such that a width of the image in a leftright direction, when the image is viewed from a predetermined view point, indicates a width of the vehicle.
2. The head-up display apparatus for the vehicle of claim 1, wherein the image includes a meter that indicates an amount of a predetermined parameter that is related to a state of the vehicle or a traveling state.
3. The head-up display apparatus for the vehicle of claim 1, wherein the head-up display apparatus is configured to vary an output position of the image in the leftright direction based on sensor information, the sensor information representing at least one of a direction of the vehicle, and a position of the vehicle with respect to a lane maker.
4. The head-up display apparatus for the vehicle of claim 3, wherein the head-up display apparatus is configured to determine the output position of the image in the leftright direction such that a center of the image in the leftright direction is on a center line of the vehicle in a frontback direction.
5. The head-up display apparatus for the vehicle of claim 3, wherein the head-up display apparatus is configured to vary the output position of the image in the leftright direction based on steering angle information that represents the direction of the vehicle.
6. The head-up display apparatus for the vehicle of claim 5, wherein the head-up display apparatus is configured to vary the output position of the image in the leftright direction such that the image is between the predicted trajectories of left and right of the vehicle and equally away from the predicted trajectories in the leftright direction, the predicted trajectories being varied according to the steering angle.
7. The head-up display apparatus for the vehicle of claim 1, wherein the head-up display apparatus is configured to vary the output position of the image in an updown direction according to a vehicle speed.
8. The head-up display apparatus for the vehicle of claim 1, wherein the shape of the image includes an arc and convex shape in an upward direction, or a shape obtained by removing a lower base from a trapezoid shape whose lower base is longer than an upper base.
9. The head-up display apparatus for the vehicle of claim 1, wherein the output position of the image in the leftright direction is varied without an orientation with respect to a horizontal direction being varied.
10. The head-up display apparatus for the vehicle of claim 1, wherein the shape of the image is substantially symmetric with respect to the center thereof in the leftright direction.
11. (canceled)