1. A compound of Formula I
wherein:
Y is \u2014N(R4)R5 or \u2014OR5;
X is O, S, or N(R6);
R1 is an aryl or heteroaryl;
R2 and R3 are each independently selected from the group consisting of C1-C6 alkyl which may be interrupted by one or more hetero atoms, \u2014(CR7R8)t(aryl), \u2014(CR7R8)t(heteroaryl), \u2014(CR7R8)t(cycloalkyl), or \u2014(CR7R8)t(heterocyclyl),
or R1 is \u2014H;
or R2 and R3 together with the carbon atom to which they are attached join to form a C3-C10 heterocyclic or carbocyclic ring system,
or R3 and R6 join to form a heterocyclic ring;
R4 is \u2014H, C1-C8 alkyl, \u2014C(O)(CR7R8)t)N(R6)2, \u2014C(O)(CR7R8)t, \u2014C(O)2(CR7R8)t, \u2014(CR7R8)t(aryl), \u2014(CR7R8)t(heteroaryl), \u2014(CR7R8)t(cycloalkyl), or \u2014(CR7R8)t(heterocyclyl), or R4 and R3 join to form a heterocyclic ring;
R5 and R6 are independently selected from \u2014H and C1-C8 alkyl, or R5 and R6 together with the atoms to which they are linked join to form a 5 to 6-membered heterocyclic ring, or R4 and R5 together with the nitrogen atom to which they are linked join to form a 5 to 6-membered heterocylic or heteroaryl ring; and
R7 and R8 are independently selected from \u2014H, C1-C6 alkyl, and aryl;
wherein n is an integer from 1 to 6; m is an integer from 0 to 2; and each t is independently an integer from 0 to 3;
wherein each of the above alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl moieties and heterocyclic and carbocyclic rings are optionally and independently substituted by 1-3 substituents selected from
amino,
aryl, heteroaryl, cycloalkyl, or heterocyclyl optionally substituted by 1-5 substituents selected from
C1-C6 alkoxy,
C1-C6 alkyl optionally substituted by halo,
aryl,
halo,
heteroaryl,
C1-C6 hydroxyl, and
\u2014NHS(O)2\u2014C1-C6 alkyl);
C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C2-C6 alkenyl, or C2-C6 alkynyl, wherein each of which may be interrupted by one or more hetero atoms,
cyano,
halo,
hydroxy,
nitro, or
\u2014O-aryl;
or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof.
2. The compound of claim 1 or pharmaceutically acceptable salt, hydrate, or stereoisomer thereof, wherein m, n, and t are 1.
3. The compound of claim 1 or pharmaceutically acceptable salt, hydrate, or stereoisomer thereof, wherein X is \u2014N(R6) and Y is \u2014N(R4)(R5).
4. The compound of claim 1 or pharmaceutically acceptable salt, hydrate, or stereoisomer thereof, wherein X is \u2014N(R6), Y is \u2014N(4)(R5), R1 is heteroaryl, R2 is \u2014H, R3 is \u2014(CR7R8)t(aryl) or \u2014(CR7R8)t(heteroaryl), and m, n, and t are 1.
5. The compound of claim 4 or pharmaceutically acceptable salt, hydrate, or stereoisomer thereof, wherein X is \u2014N(R), Y is \u2014N(R4)(R5), R1 is heteroaryl, R2 is \u2014H, R3 is \u2014(CR7R8)t(aryl) or \u2014(CR7R8)t(heteroaryl), and m, n, and t are 1, wherein R4, R5, and R6 are \u2014H, and R7 and R8 are independently selected from H and C1-C3 alkyl.
6. The compound of claim 1 selected from
(S)-3-(3-Fluoro-phenyl)-N-5-(3-methyl-1H-indazol-5-yl)-1,3,4thiadiazol-2-yl-propane-1,2-diamine;
(S)-3-(3,4-Difluoro-phenyl)-N-5-(3-methyl-1H-indazol-5-yl)-1,3,4thiadiazol-2-yl-propane-1,2-diamine;
(S)-3-(3,4-Dichloro-phenyl)-N-5-(3-methyl-1H-indazol-5-yl)-1,3,4thiadiazol-2-yl-propane-1,2-diamine;
N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(3-methyl-1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(2-bromophenyl)propyl)-5-(3-methyl-1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(4-ethylphenyl)propyl)-5-(3-methyl-1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(3,5-difluorophenyl)propyl)-5-(3-methyl-1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(2-methoxyphenyl)propyl)-5-(3-methyl-1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
(S)-3-(4-Methoxy-phenyl)-N-5-(3-methyl-1H-indazol-5-yl)-1,3,4)thiadiazol-2-yl-propane-1,2-diamine;
(S)-3-(2-Chloro-phenyl)-N-5-(3-methyl-1H-indazol-5-yl)-1,3,4thiadiazol-2-yl-propane-1,2-diamine;
(S)-N-5-(3-Methyl-1H-indazol-5-yl)-1,3,4thiadiazol-2-yl-3-o-tolyl-propane-1,2-diamine;
(S)-N-5-(3-Methyl-1H-indazol-5-yl)-1,3,4thiadiazol-2-yl-3-(3-trifluoromethyl-phenyl)-propane-1,2-diamine;
(S)-3-(4-Fluoro-phenyl)-N-5-(3-methyl-1H-indazol-5-yl)-1,3,4thiadiazol-2-yl-propane-1,2-diamine;
(S)-3-(4-Chloro-phenyl)-N-5-(3-methyl-1H-indazol-5-yl)-1,3,4thiadiazol-2-yl-propane-1,2-diamine;
(S)-N-5-(3-Methyl-1H-indazol-5-yl)-1,3,4thiadiazol-2-yl-3-m-tolyl-propane-1,2-diamine;
N-((S)-2-amino-3-(3-bromophenyl)propyl)-5-(3-methyl-1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(3-chlorophenyl)propyl)-5-(3-methyl- 1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(4-isopropylphenyl)propyl)-5-(3-methyl-1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(2,4-dichlorophenyl)propyl)-5-(3-methyl-1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-p-tolylpropyl)-5-(3-methyl- 1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(naphthalen-2-yl)propyl)-5-(3-methyl-1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(benzobthiophen-3-yl)propyl)-5-(3-methyl-1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(4-chlorophenyl)propyl)-5-(1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(naphthalen-2-yl)propyl)-5-(1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(4-isopropylphenyl)propyl)-5-(1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(3,4-dichlorophenyl)propyl)-5-(1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(2,4-dichlorophenyl)propyl)-5-( 1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(4-methoxyphenyl)propyl)-5-(1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(4-bromophenyl)propyl)-5-( 1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(3-(trifluoromethyl)phenyl)propyl)-5-(1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(3-(trifluoromethyl)phenyl)propyl)-5-(3-methyl-1H-pyrazolo3,4-bpyridin-5-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-3-(4-chlorophenyl)-2-(methylamino)propyl)-5-(3-methyl-1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
5-(3-methyl-1H-indazol-5-yl)-N-((S)-2-(methylamino)-3-(3-(trifluoromethyl)phenyl)propyl)-1,3,4-thiadiazol-2-amine;
5-(1H-indazol-5-yl)-N-((S)-2-(methylamnino)-3-(4-(trifluoromethyl)phenyl)propyl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(4-methoxyphenyl)propyl)-5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(3-(trifluoromethyl)phenyl)propyl)-5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(3-methoxyphenyl)propyl)-5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(2,4-dichlorophenyl)propyl)-5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(4-dichlorophenyl)propyl)-5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(3,5-difluorophenyl)propyl)-5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-m-tolylpropyl)-5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(1 ,6-naphthyridin-2-yl)-1,3,4-thiadiazol-2-amine;
N-((S)-2-amino-3-(4-bromophenyl)propyl)-5-(3-methyl-1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine;
N-((2S,3S)-2-amino-3-(4-(trifluoromethyl)phenyl)butyl)-5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amine; and
N-((2S,3S)-2-amino-3-(4-(trifluoromethyl)phenyl)butyl)-5-(1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine.
7. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of claim 1.
8. The composition of claim 7, further comprising at least one additional therapeutic agent.
9. A method for treating a kinase-mediated disorder in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of claim 1.
10. The method of claim 9 wherein the disorder is mediated by PKA, PKB, PKC, FKHR, SGK, LCK, BTK, Tie2, KDR, Erk, MSK, MK2, MSK, p38, P70S6, ROCK2, GSK3, or a CDK complex.
11. The method of claim 9 wherein the disorder is mediated by PKB.
12. The method of claim 9 wherein the treatment comprises selective inhibition of PKB.
13. The method of claim 9 wherein the disorder is cancer.
14. A method of treating a proliferation-related disorder in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of claim 1.
15. The method of claim 14 wherein the disorder is abnormal cell growth.
16. The method of claim 14 wherein the disorder is inflammation or an inflammation-related disorder.
17. The method of claim 14 wherein the disorder is a metabolic disease.
18. The method of claim 17 wherein the metabolic disease is diabetes.
19. The method of claim 15 wherein the disorder is cancer.
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. An image-forming device comprising:
a casing within which an accommodating area is formed;
a process cartridge that is detachably accommodated in the accommodating area;
a conveying roller that conveys a recording medium along a conveying path, wherein the process cartridge is accommodated along a section of the conveying path; and
a driving member enabling manual driving of the conveying roller,
wherein the process cartridge mounted in the accommodating area covers the driving member, thereby preventing operation on the driving member.
2. The image-forming device according to claim 1, wherein the driving member includes an operating part exposed in the accommodating area, the operating part being operated to manually drive the conveying roller.
3. The image-forming device according to claim 2, wherein the operating part of the driving member is partially exposed in the accommodating area.
4. The image-forming device according to claim 2, wherein the operating part is a disk-shaped dial having a rotational axis extending parallel to a rotational axis of the conveying roller.
5. The image-forming device according to claim 1, wherein a portion of the conveying path is revealed when the process cartridge is removed from the accommodating area.
6. The image-forming device according to claim 1, further comprising a drive motor that generates a driving force for driving the conveying roller, a driving force communicating mechanism that switches between a communicating state in which the driving force is transmitted from the drive motor to the conveying roller and a non-communicating state in which the driving force is not transmitted from the drive motor to the conveying roller.
7. The image-forming device according to claim 6, wherein the driving force communicating mechanism is switched from the communicating state to the non-communicating state when the driving member is operated.
8. The image-forming device according to claim 6, wherein the drive motor is driven to rotate in a first direction for conveying the recording medium, and the driving force communicating mechanism is switched from the communicating state to the non-communicating state when the drive motor is driven in a second direction opposite the first direction.
9. The image-forming device according to claim 6, wherein the driving force communicating mechanism includes a planetary gear.
10. The image-forming device according to claim 6, further comprising a first gear provided on a rotational shaft of the drive motor, and a second gear provided on a rotational shaft of the conveying roller, wherein the first gear and the second gear are engaged with each other at one side surface of the casing, and the driving member is disposed on the one side surface of the casing.
11. The image-forming device according to claim 1, further comprising:
a recording-medium supply cassette that is detachably mounted in a bottom section of the casing;
a feeding roller that feeds a recording medium from the recording-medium supply cassette in a back-to-front direction in the casing;
a guide that defines the conveying path in a U-shape through which the recording medium is conveyed and that guides the recording medium supplied by the feeding roller in a front-to-back direction in the casing; and
a cover that is disposed on a front surface of the casing and swung open in a direction toward the front of the casing, wherein
the accommodating area is disposed above the conveying path; and
the driving member is disposed near a downstream end of the guide with respect to a direction in which the recording medium is conveyed.
12. The image-forming device according to claim 1, wherein the casing has a front side and a rear side opposite to the front side, wherein the conveying roller rotates in a direction for conveying the recording medium through the conveying path when the driving member is operated in a back-to-front direction with respect to the casing.
13. The image-forming device according to claim 1, further comprising:
a paper dust removing member that removes paper dust adhering to the recording medium;
an auger that has a shaft and a fin spiral about the shaft, the auger being driven to rotate in cooperation with the driving member, whereby paper dust removed by the paper dust removing member is transported along the shaft of the auger; and
a storage unit that stores the paper dust transported by the auger, wherein
the conveying roller rotates in a predetermined direction for conveying the recording medium; and
the auger is driven to rotate in a direction for transporting the paper dust to the storage unit when the driving member is operated to rotate the conveying roller in the predetermined direction.
14. The image-forming device according to claim 1, further comprising an image-carrying member onto which an electrostatic latent image is formed, wherein the process cartridge includes a developing member that develops a visible image by selectively supplying a developer onto the image carrying member.
15. The image-forming device according to claim 14, further comprising a transfer member that transfers the visible image developed on the image carrying member from the image carrying member to the recording medium.
16. The image-forming device according to claim 1, wherein the driving member is positioned below the process cartridge in a vertical direction and overlaps with the process cartridge in the vertical direction when the process cartridge is mounted in the accommodating area.
17. An image-forming device comprising:
a casing within which an accommodating area is formed;
a process cartridge that is detachably accommodated in the accommodating area;
a conveying roller that is rotatable about a shaft and conveys a recording medium along a conveying path, wherein the process cartridge is accommodated along a section of the conveying path, and the process cartridge is mounted on or removed from the accommodating area in a direction orthogonal to the shaft of the conveying roller; and
a driving member enabling manual driving of the conveying roller,
wherein the process cartridge mounted in the accommodating area covers the driving member, thereby preventing operation on the driving member.