1. A compound having a structure represented by a formula:
wherein m is an integer selected from 2, 3, and 4;
wherein n is an integer selected from 0 and 1;
wherein p is an integer selected 0, 1, 2, 3, and 4;
wherein Q is selected from NR6, O, and S;
wherein R6 is selected from hydrogen and C1-C4 alkyl;
wherein R1 is selected from hydrogen and C1-C4 alkyl;
wherein each of R2 and R3 is independently selected from hydrogen and C1-C4 alkyl;
wherein each occurrence of R4a and R4b is independently selected from hydrogen, halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, and C1-C4 alkyl, or wherein each of R4a and R4b are optionally covalently bonded and, together with the intermediate atoms, comprise a 3- to 5-membered cycle;
wherein R5 is selected from Cy2 and Ar2;
wherein Cy2, when present, is selected from cycloalkyl and heterocycloalkyl, and Cy2 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that when m is 2 then Cy2 is not cycloalkyl;
wherein Ar2, when present, is selected from aryl and heteroaryl, and Ar2 is substituted with 0, 1, 2, or 3 substituents independently selected from halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4 dialkylamino, Cy3, Ar3, and \u2014NH(C\u2550O)(C1-C4 alkyl)Cy3, provided that when m is 2 then Ar2 is not substituted or unsubstituted phenyl, substituted or unsubstituted furanyl, or substituted or unsubstituted pyridinyl;
wherein Cy3, when present, is selected from cycloalkyl and heterocycloalkyl, and Cy3 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino;
wherein Ar3, when present, is selected from aryl and heteroaryl, and Ar3 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino;
provided that when m is 3, n is 0, and p is 0, that Ar2, when present, is not a structure represented by a formula:
and
wherein Ar1 is selected from aryl and heteroaryl, and Ar1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino,
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein Ar2 is aryl, and Ar2 is substituted with 0, 1, 2, or 3 substituents independently selected from halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, C1-C3 alkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4 dialkylamino, Cy3, and Ar3.
3. The compound of claim 1, wherein Ar2 is heteroaryl, and Ar2 is substituted with 0, 1, 2, or 3 substituents independently selected from halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, C1-C3 alkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4 dialkylamino, Cy3, and Ar3.
4. The compound of claim 1, wherein Ar1 is aryl, and Ar1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino.
5. The compound of claim 1, wherein Ar1 is phenyl, and Ar1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino.
6. The compound of claim 1, wherein Ar1 is heteroaryl, and Ar1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino.
7. The compound of claim 1, wherein Ar1 is thiophenyl, and Ar1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino.
8. The compound of claim 1, wherein the compound has a structure represented by a formula:
9. The compound of claim 1, wherein the compound has a structure represented by a formula:
10. The compound of claim 1, wherein the compound has a structure represented by a formula:
wherein each of R20a, R20b, R20c, R20d, and R20e are independently selected from hydrogen, halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R20a, R20b, R20c, R20d, and R20e are hydrogen.
11. The compound of claim 1, wherein the compound has a structure represented by a formula:
wherein each of R20b, R20c, and R20d are hydrogen and each of R20a and R20e are independently selected from hydrogen, halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino.
12. The compound of claim 1, wherein the compound has a structure represented by a formula:
13. The compound of claim 1, wherein the compound has a structure represented by a formula:
wherein each of R30a, R30b, and R30c are independently selected from hydrogen, halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino.
14. The compound of claim 1, wherein the compound has a structure represented by a formula:
15. A compound having a structure selected from:
or a pharmaceutically acceptable salt thereof.
16. A method for treating a disorder associated with E-cadherin activity in a subject, the method comprising administering to the subject an effective amount of at least one compound having a structure represented by a formula:
wherein m is an integer selected from 2, 3, and 4;
wherein n is an integer selected from 0 and 1;
wherein p is an integer selected 0, 1, 2, 3, and 4;
wherein Q is selected from NR6, O, and S;
wherein R6 is selected from hydrogen and C1-C4 alkyl;
wherein R1 is selected from hydrogen and C1-C4 alkyl;
wherein each of R2 and R3 is independently selected from hydrogen and C1-C4 alkyl;
wherein each occurrence of R4a and R4b is independently selected from hydrogen, halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, and C1-C4 alkyl, or wherein each of R4a and R4b are optionally covalently bonded and, together with the intermediate atoms, comprise a 3- to 5-membered cycle;
wherein R5 is selected from Cy2 and Ar2;
wherein Cy2, when present, is selected from cycloalkyl and heterocycloalkyl, and Cy2 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino;
wherein Ar2, when present, is selected from aryl and heteroaryl, and Ar2 is substituted with 0, 1, 2, or 3 substituents independently selected from halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, C1-C3 alkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4 dialkylamino, Cy3, Ar3, and \u2014NH(C\u2550O)(C1-C4 alkyl)Cy3;
wherein Cy3, when present, is selected from cycloalkyl and heterocycloalkyl, and Cy3 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino;
wherein Ar3, when present, is selected from aryl and heteroaryl, and Ar3 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino; and
wherein Ar1, when present, is selected from aryl and heteroaryl, and Ar1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, \u2014OH, \u2014CN, \u2014N3, \u2014NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino,
or a pharmaceutically acceptable salt thereof, thereby treating the disorder in the subject.
17. The method of claim 16, wherein the disorder associated with E-cadherin activity is a disorder of uncontrolled cellular proliferation.
18. The method of claim 17, wherein the disorder of uncontrolled cellular proliferation is cancer.
19. The method of claim 17, wherein the disorder of uncontrolled cellular proliferation is selected from breast cancer, renal cancer, gastric cancer, and colorectal cancer.
20. The method of claim 17, wherein the disorder of uncontrolled cellular proliferation is selected from lymphoma, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer, and malignant melanoma.
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 method for uphilllow pressure casting a liquid melt in a device which comprises a casting furnace lying below a casting table, the casting furnace having a riser pipe with a mouth opening, a mould having an underlying pouring-in hole, and a displaceable slide valve closure having a displaceable overlying opening section and a displaceable underlying opening section, said slide valve closure, when inserted between said casting furnace and said casting table, forming a flow-through channel comprising a substantially straight, longitudinal course during casting of the liquid melt, the flow-through channel being formed from the overlying opening section and the underlying opening section which are directly adjacent to one another, said method comprising:
casting the liquid melt in the pouring-in hole of the mould;
shutting off the slide valve closure;
displacing the overlying and underlying opening sections of the flow through channel with respect to one another and transversely to the longitudinal course of the flow-through channel directly after casting the liquid melt in the pouring-in hole of the mould, so that the overlying opening section remains in open communication with the pouring-in hole of the mould and the underlying opening section remains in open communication with the mouth opening of the riser, and the overlying and underlying sections are completely offset with respect to one another; and
actively cooling the liquid melt located inside the overlying opening section of the flow-through channel beginning at the latest from the time the two opening sections of the flow-through channel are displaced with respect to one another.
2. The method of claim 1, further comprising lowering the liquid melt in the riser pipe after the slide valve closure is shut-off until at least the underlying opening section of the flow-through channel is emptied of liquid melt.
3. The method of claim 2, further comprising lowering the liquid melt in the riser pipe as far as slightly below the mouth opening of the riser pipe after the slide valve closure is shut off.
4. The method of claim 2, further comprising introducing a protective gas at the mouth opening of the riser pipe during the lowering of the liquid melt.
5. The method of claim 1, further comprising displacing the overlying opening section of the flow-through channel jointly with the pouring-in hole of the mould with respect to the underlying opening section of the flow-through channel, said underlying opening section being held in a fixed position at the mouth opening of the riser pipe.
6. The method of claim 5, further comprising displacing the mould together with the overlying opening section of the flow-through channel.
7. The method of claim 1, further comprising actively cooling the liquid melt inside the pouring-in hole of the mould at the latest from the time the two opening sections of the flow-through channel are displaced with respect to each other.
8. The method of claim 1, further comprising removing the mould from the slide valve closure immediately after solidification of the liquid melt in the overlying opening section of the flow-through channel and in the pouring-in hole of the mould.
9. The method of claim 1, wherein said liquid melt comprises light metal alloys.
10. An apparatus for uphilllow-pressure casting a liquid melt, said apparatus comprising:
a casting furnace lying below a casting table, the casting furnace having a riser pipe with a mouth opening;
a mould having an underlying pouring-in hole; and
a displaceable slide valve closure constituting a flow-through channel comprising a substantially straight, longitudinal course during casting of the liquid melt, when said slide valve closure is slide valve closure is inserted between said casting furnace and said casting table, wherein the slide valve closure comprises two individually displaceable plates, an upper plate and a lower plate, each of said plates having a flow-through opening, wherein the two plates overlap with their flow-through openings during the casting of the liquid melt and are displaceable towards each other for shut-off directly after casting so that the flow-through opening in the upper plate is in open communication with the pouring-in hole free from undercut and the flow-through opening in the lower plate is in open communication with the mouth opening of the riser pipe while the flow-through openings are completely offset with respect to each other, and wherein a connecting-piece projection of a displaceable holder is surrounded by a coolant ring in the holder, said holder being connected to a coolant line.
11. The apparatus of claim 10, wherein the plates are held in a cassette secured to the casting table, and wherein the upper plate is held in the displaceable holder in the cassette on which the mould is placed.
12. The apparatus of claim 10, wherein the mould comprises a lower cylindrical sprue connecting piece, said sprue connecting piece forming the pouring-in hole which fits into a connecting-piece projection of the displaceable holder, said connecting piece projection being aligned towards the flow-through opening in the upper plate.
13. The apparatus of claim 12, wherein the front face of the cylindrical sprue connecting piece is placed on the upper plate.
14. The apparatus of claim 10, further comprising a coolant chamber below or inside the lower plate, said coolant chamber being connected to a coolant line.
15. The apparatus of claim 10, further comprising an actuating device for the holder, wherein said actuating device is arranged on the cassette.
16. The apparatus of claim 10, further comprising spring means acting on the holder, said spring means being supported in the cassette, and holding the upper plate and the lower plate braced against each other.
17. The apparatus of claim 10, wherein the riser pipe is suspended elastically flexibly in the casting furnace being adjustable in height with respect to the casting table.
18. The apparatus of claim 10, wherein the flow-through opening in the upper plate and the pouring-in hole continuously expand upwards, said flow-through opening and said pouring-in hole exhibiting an upwardly expanding conicity.
19. The apparatus of claim 10, wherein the flow-through opening in the lower plate and parts adjacent thereto in the downward direction as far as the mouth of the riser pipe, forming the flow-through channel, continuously expand downwards, exhibiting a downwardly expanding conicity.
20. The apparatus of claim 10, wherein the liquid melt further comprises light metal alloys.
21. The apparatus of claim 13, wherein the front face of the cylindrical sprue is braceable against the upper plate.