1. A method for preparing a sample, the method comprises:
receiving, by a manipulator, a mask and an initial sample;
positioning, by the manipulator, the mask and the initial sample in front of an imaging device so that the mask and a first side of an edge area of the initial sample face the imaging device;
aligning, by the manipulator, the mask and the initial sample so that the mask masks a masked portion of the edge area of the initial sample while maintaining an exposed portion of the edge area of the initial sample unmasked; wherein the aligning comprises obtaining images of the mask and the initial sample by the imaging device;
positioning, by the manipulator, the mask and the initial sample in front of an ion miller so that the mask and the first side of the edge area of the initial sample face the ion miller; while unchanging a spatial relationship between the mask and the initial sample;
milling, by the ion miller, the exposed portion of the edge area of the initial sample while masking the masked portion by the mask, to provide a partially milled sample;
positioning, by the manipulator, the mask and the initial sample in front of the imaging device so that the mask and a second side of the edge area of the initial sample face the imaging device; wherein the second side differs from the first side;
aligning, by the manipulator, the mask and the initial sample so that the mask masks a masked portion of the edge area of the partially milled sample while maintaining an exposed portion of the edge area of the partially milled sample unmasked; wherein the aligning comprises obtaining images of the mask and the partially milled sample by the imaging device;
positioning, by the manipulator, the mask and the partially milled sample in front of the ion miller so that the mask and the second side of the edge area of the partially milled sample face the ion miller, while unchanging a spatial relationship between the mask and the partially milled sample; and
milling, by the ion miller, the exposed portion of the edge area of the partially milled sample while masking the masked portion by the mask, to provide a milled sample.
2. The method according to claim 1, wherein the positioning, by the manipulator of the mask and the initial sample in front of the ion miller comprises rotating the mask and the initial sample by the manipulator.
3. The method according to claim 1, wherein the milling by the ion miller the exposed portion of the edge area of the partially milled sample comprises monitoring a thickness of the edge area of the milled sample, during the milling, by a transmissive detector of the imaging device.
4. The method according to claim 1, comprising changing a spatial relationship between the mask and the partially milled based on thickness feedback information obtained during the milling of the edge area of the partially milled sample.
5. The method according to claim 1, comprising changing a spatial relationship between the mask and the partially milled based on thickness feedback information obtained after the milling of the partially milled sample.
6. The method according to claim 1, wherein an imaging device optical axis is normal to a milling tool optical axis; and wherein the positioning, by the manipulator of the mask and the initial sample in front of the ion miller comprises rotating the mask and the initial sample by the manipulator.
7. The method according to claim 1, wherein the method comprises:
positioning, by the manipulator, the mask and the initial sample so that the mask and a first side of the edge area of the initial sample are normal to an optical axis of the imaging device;
positioning, by the manipulator, the mask and the initial sample in front of an ion miller so that the mask and the first side of the edge area of the initial sample are normal to an optical axis of the ion miller;
positioning, by the manipulator, the mask and the initial sample in front of the imaging device so that the mask and a second side of the edge area of the initial sample are normal to an optical axis of the imaging device; and
positioning, by the manipulator, the mask and the partially milled sample in front of the ion miller so that the mask and the second side of the edge area of the partially milled sample are normal optical axis of the ion miller.
8. The method according to claim 1, wherein the edge area of the initial sample has a thickness of at least one micros and wherein thickness of the edge area of the milled sample does not exceed 50 nanometers.
9. The method according to claim 1, wherein the milling comprises milling while rotating a milling beam about the optical axis of the ion miller.
10. The method according to claim 1, comprising removing, by ion milling, the exposed portion of the edge area of the partially milled sample.
11. The method according to claim 1, comprising stopping the milling of the edge area of the partially milled sample based on a thickness of the edge area of the partially milled sample.
12. The method according to claim 11, comprising monitoring the thickness of the edge area of the partially milled sample by a transmissive detector of the imaging device.
13. The method according to claim 11, comprising comparing a current outputted to the transmissive detector of the imaging device to a predefined relationship between current values and thickness values.
14. The method according to claim 1, further comprising:
positioning, by the manipulator, the mask and the milled sample in front of the imaging device so that the mask and a first side of an edge area of the milled sample face the imaging device;
aligning, by the manipulator, the mask and the milled sample so that the mask masks a masked portion of the edge area of the milled sample while maintaining an exposed portion of the edge area of the milled sample unmasked; wherein the aligning comprises obtaining images of the mask and the milled sample by the imaging device;
positioning, by the manipulator, the mask and the milled sample in front of the ion miller so that the mask and the first side of the edge area of the milled sample face the ion miller; while unchanging a spatial relationship between the mask and the milled sample; and
milling, by the ion miller, the exposed portion of the edge area of the milled sample while masking the masked portion by the mask, to provide a further milled sample.
15. The method according to claim 1, wherein the imaging device is an optical device.
16. The method according to claim 1, wherein the imaging device is scanning electron microscope.
17. The method according to claim 1, comprising monitoring a progress of the milling of the initial sample by a backscattered electron detector; and monitoring a completion of a milling of the partially milled sample by a transmissive detector.
18. The method according to claim 1, comprising automatically stopping the milling of the partially milled sample when reaching a desired thickness of the edge area of the partially milled sample.
19. A sample preparation system, comprising:
a manipulator;
an imaging device; and
an ion miller;
wherein the manipulator is arranged to:
receive a mask and an initial sample;
position the mask and the initial sample in front of an imaging device so that the mask and a first side of an edge area of the initial sample face the imaging device;
participate in an alignment of the mask and the initial sample so that the mask masks a masked portion of the edge area of the initial sample while maintaining an exposed portion of the edge area of the initial sample unmasked;
position the mask and the initial sample in front of an ion miller so that the mask and the first side of the edge area of the initial sample face the ion miller; while unchanging a spatial relationship between the mask and the initial sample;
wherein the ion miller is arranged to mill the exposed portion of the edge area of the initial sample while masking the masked portion by the mask, to provide a partially milled sample;
wherein the manipulator is further arranged to:
position the mask and the initial sample in front of the imaging device so that the mask and a second side of the edge area of the initial sample face the imaging device; wherein the second side differs from the first side;
participate in an alignment of the mask and the partially milled sample so that the mask masks a masked portion of the edge area of the partially milled sample while maintaining an exposed portion of the edge area of the partially milled sample unmasked;
position the mask and the partially milled sample in front of the ion miller so that the mask and the second side of the edge area of the partially milled sample face the ion miller, while unchanging a spatial relationship between the mask and the partially milled sample;
wherein the ion miller is further adapted to mill the exposed portion of the edge area of the partially milled sample while masking the masked portion by the mask, to provide a milled sample; and
wherein the imaging device is arranged to:
obtain images of the mask and the initial sample during the alignment of the mask and the initial sample; and
obtain images of the mask and the partially milled sample during the alignment of the mask and the partially milled sample.
20. The system according to claim 19, manipulator is arranged to rotate the mask and the initial sample until the mask and the initial sample face the ion miller.
21. The system according to claim 19, wherein the imaging system comprises a transmissive detector that is arranged to provide detection signals indicative of a thickness of the exposed portion of the edge area of the partially milled sample, during a milling of the exposed portion of the edge area of the partially milled sample.
22. The system according to claim 19, wherein the manipulator is arranged to change a spatial relationship between the mask and the partially milled based on thickness feedback information obtained during a milling of the edge area of the partially milled sample.
23. The system according to claim 19, comprising wherein the manipulator is arranged to change a spatial relationship between the mask and the partially milled based on thickness feedback information obtained after a milling of the partially milled sample.
24. The system according to claim 19, wherein an imaging device optical axis is normal to a milling tool optical axis; and wherein the manipulator is arranged to rotate the mask and the initial sample until the mask and the initial sample face the ion miller.
25. The system according to claim 19, wherein the manipulator is arranged to:
position the mask and the initial sample so that the mask and a first side of the edge area of the initial sample are normal to an optical axis of the imaging device;
position the mask and the initial sample in front of an ion miller so that the mask and the first side of the edge area of the initial sample are normal to an optical axis of the ion miller;
position the mask and the initial sample in front of the imaging device so that the mask and a second side of the edge area of the initial sample are normal to an optical axis of the imaging device; and
position the mask and the partially milled sample in front of the ion miller so that the mask and the second side of the edge area of the partially milled sample are normal optical axis of the ion miller.
26. The system according to claim 19, wherein the edge area of the initial sample has a thickness of at least one micros and wherein the system is arranged to mill the edge area of the milled sample until a thickness of the edge area of the milled sample does not exceed 50 nanometers.
27. The system according to claim 19, wherein ion miller is arranged to mill while rotating a milling beam about the optical axis of the ion miller.
28. The system according to claim 19, wherein the ion miller is arranged to remove the exposed portion of the edge area of the partially milled sample.
29. The system according to claim 19, comprising a controller that is arranged to stop a milling of the edge area of the partially milled sample based on a thickness of the edge area of the partially milled sample.
30. The system according to claim 29, comprising a transmissive detector that is arranged to assist in a monitoring of a thickness of the edge area of the partially milled sample.
31. The system according to claim 29, comprising a controller that is arranged to compare a current outputted by the transmissive detector of the imaging device to a predefined relationship between current values and thickness values.
32. The system according to claim 19, wherein the manipulator is further arranged to:
position the mask and the milled sample in front of the imaging device so that the mask and a first side of an edge area of the milled sample face the imaging device;
participate in an alignment of the mask and the milled sample so that the mask masks a masked portion of the edge area of the milled sample while maintaining an exposed portion of the edge area of the milled sample unmasked;
position the mask and the milled sample in front of the ion miller so that the mask and the first side of the edge area of the milled sample face the ion miller; while unchanging a spatial relationship between the mask and the milled sample; and
wherein the ion miller is further arranged to mill the exposed portion of the edge area of the milled sample while the masked portion is being masked by the mask, to provide a further milled sample.
33. The system according to claim 19, wherein the imaging device is an optical device.
34. The system according to claim 19, wherein the imaging device is a scanning electron microscope.
35. The system according to claim 19, comprising a backscattered electron detector arranged to participate in a monitoring of a progress of a milling of the initial sample; and a transmissive detector that is arranged to assist in a monitoring of a completion of a milling of the partially milled sample.
36. The system according to claim 19, comprising a controller that is arranged to automatically stop a milling of the partially milled sample when reaching a desired thickness of the edge area of the partially milled sample.
37. The system according to claim 19, wherein the ion miller differs from the imaging device.
38. The system according to claim 19, wherein the ion miller is the imaging device.
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 compound of formula (2)
or a pharmaceutically acceptable salt thereof, wherein
Cy2 is aryl or heteroaryl, each of which is optionally substituted and wherein each of aryl and heteroaryl is optionally fused to one or more aryl or heteroaryl rings, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings is optionally substituted;
X is selected from the group consisting of: a covalent bond, C0-C4-hydrocarbyl, C0-C4-hydrocarbyl-(CO)\u2014C0-C4-hydrocarbyl, C0-C4-hydrocarbyl-(NR7)\u2014C0-C4-hydrocarbyl, C0-C4-hydrocarbyl-(S)\u2014C0-C4-hydrocarbyl, C0-C4-hydrocarbyl-(O)\u2014C0-C4-hydrocarbyl, C0-C4-hydrocarbyl-(SO)\u2014C0-C4-hydrocarbyl, C0-C4-hydrocarbyl-(SO2)\u2014C0-C4-hydrocarbyl, C0-C4-hydrocarbyl-(NH)\u2014(CO)\u2014C0-C4-hydrocarbyl, C0-C4-hydrocarbyl-(CO)\u2014(NH)\u2014C0-C4-hydrocarbyl, \u2014NH\u2014CO\u2014NH\u2014, \u2014NH\u2014CS\u2014NH\u2014, \u2014O\u2014CO\u2014O\u2014, \u2014O\u2014CS\u2014O\u2014, \u2014NH\u2014C(NH)\u2014NH\u2014, \u2014S(O)2\u2014N(R7)\u2014, \u2014N(R7)\u2014S(O)2\u2014, \u2014NH\u2014C(O)\u2014O\u2014, and \u2014O\u2014C(O)\u2014NH\u2014,
wherein R7 is selected from the group consisting of hydrogen, C1-C5-alkyl, aryl, aralkyl, acyl, heterocyclyl, heteroaryl, SO2-alkyl, SO2-aryl, CO-alkyl, CO-aryl, CO\u2014NH-alkyl, CO\u2014NH-aryl, CO\u2014O-alkyl and CO\u2014O-aryl, each of which is optionally substituted,
n is 0 to 4,
Y is N or CH, and
T is NH2 or OH.
2. A compound according to claim 1 having S stereochemistry at C-3 position of the ring
3. A compound according to claim 1 having R stereochemistry at C-3 position of the ring
4. A compound according to claim 1, selected from the group consisting of:
N-(2-Amino-phenyl)-4-3-(pyridin-3-ylamino)-pyrrolidin-1-yl-benzamide;
(S)-N-(2-Aminophenyl)-4-(3-(pyridin-3-ylamino)pyrrolidin-1-yl)benzamide;
(R)-N-(2-aminophenyl)-4-(3-(pyridin-3-ylamino)pyrrolidin-1-yl)benzamide;
(S)-N-(2-Aminophenyl)-4-(3-(pyridin-3-yloxy)pyrrolidin-1-yl)benzamide
(R)-N-(2-Aminophenyl)-4-(3-(pyridin-3-yloxy)pyrrolidin-1-yl)benzamide;
(S)-N-(1-(4-(2-Aminophenyl carbamoyl)phenyl)pyrrolidin-3-yl)nicotinamide;
(S)-N-(2-Aminophenyl)-4-(3-(pyridin-2-ylthio)pyrrolidin-1-yl)benzamide; and
N-(2-Aminophenyl)-4-((S)-3-((S)-pyridin-2-ylsulfinyl)pyrrolidin-1-yl)benzamide.
5. A composition comprising a mixture of enantiomers of compounds of claim 1.
6. The composition of claim 5 wherein the mixture is racemic.
7. The composition of claim 5 wherein the mixture is enantiomerically enriched.
8. A composition comprising one or more compounds according to any one of claims 1-4 and a pharmaceutically acceptable carrier.