1. A compound of the structure:
or a pharmaceutically acceptable salt, crystal form, or hydrate, wherein:
A is
a) an aryl ring, wherein any stable aryl ring atom is independently unsubstituted or substituted with
1) halogen,
2) NO2,
3) CN,
4) CR46\u2550C(R47R48)2,
5) C\u2261C R46,
6) (CRiRj)rOR46,
7) (CRiRj)rN(R46R47),
8) (CRiRj)rC(O)R46,
9) (CRiRj)rC(O)OR46,
10) (CRiRj)rR46,
11) (CRiRj)rS(O)0-2R61,
12) (CRiRj)rS(O)0-2N(R46R47),
13) OS(O)0-2R61,
14) N(R46)C(O)R47,
15) N(R46)S(O)0-2R61,
16) (CRiRj)rN(R46)R61,
17) (CRiRj)rN(R46)R61OR47,
18) (CRiRj)rN(R46)(CRkRl)sC(O)N(R47R48),
19) N(R46)(CRiRj)rR61,
20) N(R46)(CRiRj)rN(R47R48),
21) (CRiRj)rC(O)N(R47R48), or
22) oxo, or
b) a heteroaryl ring selected from the group consisting of
a 5-membered unsaturated monocyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from the group consisting or N, O or S,
a 6-membered unsaturated monocyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from the group consisting N, O and S, and
a 9- or 10-membered unsaturated bicyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from the group consisting or N, O or S;
wherein any stable S heteroaryl ring atom is unsubstituted or mono- or di-substituted with oxo, and any stable C or N heteroaryl ring atom is independently unsubstituted or substituted with
1) halogen,
2) NO2,
3) CN,
4) CR46\u2550C(R47R48)2,
5) C\u2261CR46,
6) (CRiRj)rOR46,
7) (CRiRj)rN(R46R47),
8) (CRiRj)rC(O)R46,
9) (CRiRj)rC(O)OR46,
10) (CRiRj)rR46,
11) (CRiRj)rS(O)0-2R61,
12) (CRiRj)rS(O)0-2N(R46R47),
13) OS(O)0-2R61,
14) N(R46)C(O)R47,
15) N(R46)S(O)0-2R61,
16) (CRiRj)rN(R46)R61,
17) (CRiRj)rN(R46)R61OR47,
18) (CRiRj)rN(R46)(CRkRl)SC(O)N(R47R48),
19) N(R46)(CRiRj)rR61,
20) N(R46)(CRiRj)rN(R47R48),
21) (CRiRj)rC(O)N(R47R48), or
22) oxo;
R1 is selected from the group consisting of
1) hydrogen,
2) (CRaRb)nR40
3) (CRaRb)nOR40,
4) (CRaRb)nN(R40R41),
5) (CRaRb)nN(R40)C(O)OR41,
6) (CRaRb)nN(R40)(CRcRd)2N(R41)C(O)R49,
7) C3-8 cycloalkyl,
8) (CRaRb)nC(O)OR40,
9) (CRaRb)nN(R40)(CRcRd)1-3R41,
10) (CRaRb)nS(O)0-2R6,
11) (CRaRb)nS(O)0-2N(R40R41),
12) (CRaRb)nN(R40)R6OR41,
13) (CRaRb)nN(R40)(CRcRd)0-6C(O)N(R41R42);
R5 is selected from the group consisting of
1) C(O)N(R55R50),
2) C(O)OR55, and
3) C(O)R82;
R2, R8, R9 and R10 are independently selected from:
1) hydrogen,
2) halogen,
3) NO2,
4) CN,
5) CR43\u2550C(R44R45),
6) C\u2261CR43,
7) (CReRf)pOR43,
8) (CReRf)pN(R43R44),
9) (CReRf)pC(O)R43,
10) (CReRf)pC(O)OR43,
11) (CReRf)pR43,
12) (CReRf)pS(O)0-2R60,
13) (CReRf)pS(O)0-2N(R43R44),
14) OS(O)0-2R60,
15) N(R43)C(O)R44,
16) N(R43)S(O)0-2R60,
17) (CReRf)pN(R43)R60,
18) (CReRf)pN(R43)R60OR44,
19) (CReRf)pN(R43)(CRgRh)qC(O)N(R44R45),
20) N(R43)(CReRf)pR60,
21) N(R43)(CReRf)pN(R44R45), and
22) (CReRf)pC(O)N(R43R44),
or R2 and R8 are independently as defined above, and R9 and R10, together with the atoms to which they are attached, form the ring
where Rm is C1-6alkyl;
Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rk and Rl are independently selected from the group consisting of:
1) hydrogen,
2) C1-C6 alkyl,
3) halogen,
4) aryl,
5) R80,
6) C3-C10 cycloalkyl, and
7) OR4,
said alkyl, aryl, and cycloalkyl being unsubstituted, monosubstituted with R7, disubstituted with R7 and R15, trisubstituted with R7, R15 and R16, or tetrasubstituted with R7, R15, R16 and R17;
R4, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, and R55 are independently selected from the group consisting of
1) hydrogen,
2) C1-C6 alkyl,
3) C3-C10 cycloalkyl,
4) aryl,
5) R81,
6) CF3,
7) C2-C6 alkenyl, and
8) C2-C6 alkynyl,
said alkyl, aryl, and cycloalkyl is unsubstituted, mono-substituted with R18, di-substituted with R18 and R19, tri-substituted with R18, R19 and R20, or tetra-substituted with R18, R19, R20 and R21;
R6, R60, R61, and R62 are independently selected from the group consisting of
1) C1-C6 alkyl,
2) aryl,
3) R83, and
4) C3-C10 cycloalkyl;
said alkyl, aryl, and cycloalkyl is unsubstituted, mono-substituted with R26, di-substituted with R26 and R27, tri-substituted with R26, R27 and R28, or tetra-substituted with R26, R27, R28 and R29;
R7, R15, R16, R17, R18, R19, R20, R21, R26, R27, R28, and R29 are independently selected from the group consisting of
1) C1-C6 alkyl,
2) halogen,
3) OR51,
4) CF3,
5) aryl,
6) C3-C10 cycloalkyl,
7) R84,
8) S(O)0-2N(R51R52),
9) C(O)OR51,
10) C(O)R51,
11) CN,
12) C(O)N(R51R52),
13) N(R51)C(O)R52,
14) S(O)0-2R62,
15) NO2, and
16) N(R51R52);
R80, R81, R82, R83, and R84 are independently selected from a group of unsubstituted or substituted heterocyclic rings consisting of a 4-6 membered unsaturated or saturated monocyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from the group consisting N, O and S, and a 9- or 10-membered unsaturated or saturated bicyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from the group consisting or N, O or S; and
n, p, q, r, and s are independently 0, 1, 2, 3, 4, 5 or 6, and wherein said compound is selected from the group consisting of
4-(3-fluorophenyl)-6-methoxy-N,N,2-trimethyl-1-oxo-1,2-dihydroisoquinoline-3-carboxamide,
4-(3-fluorophenyl)-6-methoxy-2-methyl-3-(pyrrolidin-1-ylcarbonyl)isoquinolin-1(2H)-one,
2-allyl-6-methoxy-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxamide,
6-methoxy-2-methyl-4-phenyl-3-pyridin-2-ylisoquinolin-1(2h)-one,
2-cyclopropyl-6-methoxy-4-phenyl-3-(1,3-thiazol-2-yl)isoquinolin-1(2h)-one,
methyl 4-(3-fluorophenyl)-6-methoxy-2-methyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylate,
methyl 6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylate,
7-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid,
methyl 7-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylate, and
ethyl 2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylate.
2. A method of treating a condition in a mammal, the treatment of which is effected or facilitated by Kv1.5 inhibition, which comprises administering a compound of claim 1 in an amount that is effective at inhibiting Kv1.5 wherein the condition is cardiac arrhythmia.
3. A method of claim 2, wherein the cardiac arrhythmia is atrial fibrillation.
4. A method of claim 2, wherein the cardiac arrhythmia is selected from the group consisting of atrial flutter, atrial arrhythmia and supraventricular tachycardia.
5. A method of treating cardiac arrhythmia comprising administering a compound of claim 1 with a compound selected from one of the classes of compounds consisting of antiarrhythmic agents having Kv1.5 blocking activities, ACE inhibitors, angiotensin II antagonists, cardiac glycosides, L-type calcium channel blockers, T-type calcium channel blockers, selective and nonselective beta blockers, endothelin antagonists, thrombin inhibitors, aspirin, nonselective NSAIDs, warfarin, factor Xa inhibitors, low molecular weight heparin, unfractionated heparin, clopidogrel, ticlopidine, IIbIIIa receptor antagonists, 5HT receptor antagonists, integrin receptor antagonists, thromboxane receptor antagonists, TAFI inhibitors and P2T receptor antagonists.
6. A method for treating tachycardia in a patient which comprises treating the patient with an antitachycardia device in combination with a compound of claim 1.
7. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and the compound of claim 1 or a pharmaceutically acceptable crystal form or hydrate thereof.
8. A pharmaceutical composition made by combining the compound of claim 1 and a pharmaceutically acceptable carrier.
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 mobile hard disk drive, comprising:
an electrical module comprising a circuit board, a face panel connected to one end of said circuit board, said face panel comprising a plurality of transmission interfaces electrically connected to said circuit board and adapted for connecting to respective external mating interfaces and an insertion slot cut through opposing front and back walls thereof, and a holder box mounted at one side of said circuit board, said holder box defining therein a receiving chamber in communication with said insertion slot of said face panel; and
a hard disk tray detachably insertable through said insertion slot of said face panel into said receiving chamber of said holder box, said hard disk tray comprising an accommodation open chamber adapted for accommodating a hard disk, and a plurality of arched spring plates symmetrically disposed at two opposite lateral sides thereof and insertable with said hard disk tray through said insertion slot of said face panel into said receiving chamber of said holder box for friction engagement with two opposite inner lateral walls in said receiving chamber of said holder box.
2. The mobile hard disk drive as claimed in claim 1, wherein said circuit board further comprises a plurality of mounting screw holes respectively located in corners thereof; said holder box further comprises a plurality of spacer columns respectively perpendicularly extended from a back side thereof and respectively attached to the mounting screw holes of said circuit board, a plurality of screw holes respectively extended through said spacer columns in communication with the respective mounting screw holes of said circuit board, and a plurality of screws respectively threaded into the screw holes in said spacer columns and the respective mounting screw holes of said circuit board to affix said circuit board and said holder box together.
3. The mobile hard disk drive as claimed in claim 1, wherein said circuit board further comprises connection interface means for the connection of mating connection interface means of a hard disk being mounted in said accommodation open chamber of said hard disk tray.
4. The mobile hard disk drive as claimed in claim 1, wherein said face panel further comprises two locating screw holes respectively disposed at opposing top and bottom sides relative to said insertion slot; said hard disk tray further comprises an end plate located at one end relative to said accommodation open chamber, two hand screws respectively mounted near two distal ends of said end plate and adapted for threading into the locating screw holes of said face panel to lock said hard disk tray to said face panel, and a handle located at said end plate between said two hand screws.
5. The mobile hard disk drive as claimed in claim 1, wherein said hard disk tray further comprises a plurality of hook holes arranged in pairs and symmetrically disposed at two opposite lateral sides relative to said accommodation open chamber for securing said arched spring plates.
6. The mobile hard disk drive as claimed in claim 1, wherein said hard disk tray further comprises multiple pairs of hook holes symmetrically disposed at two opposite lateral sides relative to said accommodation open chamber for securing said arched spring plates; each said arched spring plate comprises two hooked end portions respectively hooked in the two hook holes of one of said pairs of hook holes.
7. The mobile hard disk drive as claimed in claim 1, wherein said hard disk tray further comprises a plurality of mounting screw holes located at the two opposite lateral sides thereof, and a plurality of screws respectively threaded into the mounting screw holes thereof and respective mounting screw holes at two opposite lateral sides of the hard disk being accommodated in said accommodation open chamber of said hard disk tray.