1. A compound of formula I
or a pharmaceutically acceptable salt thereof, wherein:
Y is \u2014C(O)\u2014 or a bond;
R1is a C1-6 aliphatic, wherein up to three methylene units are replaced by \u2014NH\u2014, \u2014NR11\u2014, \u2014O\u2014, \u2014S\u2014, \u2014CO2\u2014, \u2014OC(O)\u2014, \u2014C(O)CO\u2014, \u2014C(O)\u2014, \u2014C(O)O\u2014, \u2014C(O)NH\u2014, \u2014C(O)NR11\u2014, \u2014NC(\u2550N\u2014CN)N, \u2014NHCO\u2014, \u2014NR11CO\u2014, \u2014NHC(O)O\u2014, \u2014NR11C(O)O\u2014, \u2014SO2NH\u2014, \u2014SO2NR11\u2014, \u2014NHSO2\u2014, \u2014NR11SO2\u2014, SO2\u2014, \u2014NHC(O)NH\u2014, \u2014NR11C(O)NH\u2014, \u2014NHC(O)NR11\u2014, \u2014NR11C(O)NR11, \u2014OC(O)NH\u2014, \u2014OC(O)NR11\u2014, \u2014NHSO2NH\u2014, \u2014NR11SO2NH\u2014, \u2014NHSO2NR11\u2014, \u2014NR11SO2NR11\u2014, \u2014SO\u2014, or \u2014SO2\u2014; a C3-10 monocyclic or bicyclic cycloaliphatic; a C6-10 monocyclic or bicyclic aryl; a 5-10 membered monocyclic or bicyclic heteroaryl; or a 5-10 membered monocyclic or bicyclic heterocyclyl; wherein R1 is optionally substituted with 1-6 occurrences of JR1;
each R11 is independently selected from C1-6 aliphatic, C3-10 monocyclic or bicyclic cycloaliphatic, C6-10 monocyclic or bicyclic aryl, 5-10 membered monocyclic or bicyclic heteroaryl, or 5-10 membered monocyclic or bicyclic heterocyclyl; or two R11 groups, on the same substituent or different substituents, together with the atom(s) to which each R11 group is bound, form a 3-8 membered heterocyclyl;
each JR1 is independently selected from halogen, OH, OR, NO2, NH2, NHR, NR2, SH, SR, CN, C(O)NH2, C(O)NHR, C(O)NR2, C(O)OH, C(O)OR, NHC(O)H, NHC(O)R, NRC(O)H, NRC(O)R, NHC(O)OH, NHC(O)OR, NRC(O)OH, NRC(O)OR, or R; or two JR1, together with the carbon(s) to which they are attached, form a cyclopropyl ring or C\u2550O;
each R is independently selected from a C1-4 aliphatic or C3-4 cycloaliphatic optionally substituted with 1-4 occurrences of halogen, OH, NO2, NH2, SH or CN;
R2 is H, a C1-6 aliphatic, C3-6 cycloaliphatic, halogen, OH, OR, NO2, NH2, NHR, NR2, SH, SR, CN, C(O)NH2, C(O)NHR, C(O)NR2, C(O)OH, C(O)OR, NHC(O)H, NHC(O)R, NRC(O)H, NRC(O)R, NHC(O)OH, NHC(O)OR, NRC(O)OH, NRC(O)OR, or R; wherein said C1-6 aliphatic or C3-6 cycloaliphatic is optionally substituted with 1-4 occurrences of JR2;
each JR2 is independently selected from halogen, OH, OR, NO2, NH2, NHR, NR2, SH, SR, CN, C(O)NH2, C(O)NHR, C(O)NR2, C(O)OH, C(O)OR, NHC(O)H, NHC(O)R, NRC(O)H, NRC(O)R, NHC(O)OH, NHC(O)OR, NRC(O)OH, NRC(O)OR, or R; or two JR2, together with the carbon(s) to which they are attached, form a cyclopropyl ring or C\u2550O;
T is \u2014SO2NR4\u2014, \u2014CONR4\u2014 or \u2014C(O)O\u2014;
R4 is H or a C1-6 aliphatic or C3-7 cycloaliphatic optionally substituted with 1-6 occurrences of JR4;
each JR4 is independently selected from halogen, OH, OR\u2032, NO2, NH2, NHR\u2032, NR\u20322, SH, SR\u2032, CN, 5-6 membered aryl or heteroaryl, or R\u2032; or two JR4, together with the carbon(s) to which they are attached, form a cyclopropyl ring or C\u2550O;
each R\u2032 is independently selected from a C1-6 aliphatic or C3-7 cycloaliphatic optionally substituted with 1-6 occurrences of halogen, OH, NO2, NH2, SH or CN;
b is 0 or 1;
L is a C1-6 aliphatic wherein up to three methylene units are replaced by \u2014NH\u2014, \u2014NR5\u2014, \u2014O\u2014, \u2014S\u2014, \u2014CO2\u2014, \u2014OC(O)\u2014, \u2014C(O)CO\u2014, \u2014C(O)\u2014, \u2014C(O)NH\u2014, \u2014C(O)NR5\u2014, \u2014NC(\u2550N\u2014CN)N, \u2014NHCO\u2014, \u2014NR5CO\u2014, \u2014NHC(O)O\u2014, \u2014NR5C(O)O\u2014, \u2014SO2NH\u2014, \u2014SO2NR5\u2014, \u2014NHSO2\u2014, \u2014NR5SO2\u2014, \u2014NHC(O)NH\u2014, \u2014NR5C(O)NH\u2014, \u2014NHC(O)NR5\u2014, \u2014NR5C(O)NR5, \u2014OC(O)NH\u2014, \u2014OC(O)NR5\u2014, \u2014NHSO2NH\u2014, \u2014NR5SO2NH\u2014, \u2014NHSO2NR5\u2014, \u2014NR5SO2NR5\u2014, \u2014SO\u2014, or \u2014SO2\u2014, wherein L is optionally substituted with 1-4 occurrences of R6;
each R5 is independently selected from C1-6 aliphatic, C3-10 monocyclic or bicyclic cycloaliphatic, C6-10 monocyclic or bicyclic aryl, 5-10 membered monocyclic or bicyclic heteroaryl, or 5-10 membered monocyclic or bicyclic heterocyclyl; or two R5 groups, on the same substituent or different substituents, together with the atom(s) to which each R5 group is bound, form a 3-8 membered heterocyclyl;
each R6 is independently selected from halogen, OH, OR\u2032, NO2, NH2, NHR\u2032, NR\u20322, SH, SR\u2032, CN, or R\u2032; or two R6, together with the carbon(s) to which they are attached, form a cyclopropyl ring or C\u2550O;
n is 0 or 1;
R3 is H or an optionally substituted group selected from a C1-6 aliphatic, a C3-10 monocyclic or bicyclic cycloaliphatic, a C6-10 monocyclic or bicyclic aryl, a 5-10 membered monocyclic or bicyclic heteroaryl, or a 5-10 membered monocyclic or bicyclic heterocyclyl, wherein R3 is optionally substituted with 1-6 occurrences of JR3; or R3 and R4, together with the nitrogen to which R4 is attached, form a 5-10 membered monocyclic or bicyclic heterocyclyl or heteroaryl, wherein n is 0 and said heterocyclyl or heteroaryl is optionally substituted with 1-6 occurrences of JR3;
each JR3 is independently selected from \u2014(U)m\u2014X;
U is a C1 aliphatic, wherein up to two methylene units are optionally and independently replaced by GU and wherein U is optionally substituted with 1-4 Ju;
GU is \u2014NH\u2014, \u2014NR7\u2014, \u2014O\u2014, \u2014S\u2014, \u2014CO2\u2014, \u2014O C(O)\u2014, \u2014C(O)CO\u2014, \u2014C(O)\u2014, \u2014C(O)NH\u2014, \u2014C(O)NR7\u2014, \u2014NC(\u2550N\u2014CN)N\u2014, \u2014NHCO\u2014, \u2014NR7CO\u2014, \u2014NHC(O)O\u2014, \u2014NR7C(O )O\u2014, \u2014SO2NH\u2014, \u2014SO2NR7\u2014, \u2014NHSO2\u2014, \u2014NR7SO2\u2014, \u2014NHC(O)NH\u2014, \u2014NR7C(O)NH\u2014, \u2014NHC(O)NR7\u2014, \u2014NR7C(O)NR7, \u2014OC(O)NH\u2014, \u2014OC(O)NR7\u2014, \u2014NHSO2NH\u2014, \u2014NR7SO2NH\u2014, \u2014NHSO2NR7\u2014, \u2014NR7SO2NR7\u2014, \u2014SO\u2014, or \u2014SO2\u2014;
R7 is C1-6 aliphatic or C3-7 cycloaliphatic optionally substituted with 1-6 occurrences of halogen, OH, NO2, NH2, SH or CN;
m is 0 or 1;
each JU is independently selected from halogen, OH, OR\u2032, NO2, NH2, NHR\u2032, NR\u20322, SH, SR\u2032, CN, or R\u2032; or two JU, together with the carbon(s) to which they are attached, form a cyclopropyl ring or C\u2550O;
X is H, halogen, OH, OR, NO2, NH2, NHR, NR2, SH, SR, CN, C(O)NH2, C(O)NHR, C(O)NR2, C(O)OH, C(O)OR, NHC(O)H, NHC(O)R, NRC(O)H, NRC(O)R, NHC(O)OH, NHC(O)OR, NRC(O)OH, NRC(O)OR, or a group selected from a C1-6 aliphatic, a C3-10 monocyclic or bicyclic cycloaliphatic, a C6-10 monocyclic or bicyclic aryl, a 5-10 membered monocyclic or bicyclic heteroaryl, or a 5-10 membered monocyclic or bicyclic heterocyclyl, wherein said group is optionally substituted with 1-4 JX, or two X, together with the carbon(s) to which they are attached, form a cyclopropyl ring or C\u2550O; wherein X is not H when m is 0;
each JX is independently selected from halogen, OH, OR, NO2, NH2, NHR, NR2, SH, SR, CN, C(O)NH2, C(O)NHR, C(O)NR2, C(O)OH, C(O)OR, NHC(O)H, NHC(O)R, NRC(O)H, NRC(O)R, NHC(O)OH, NHC(O)OR, NRC(O)OH, NRC(O)OR; and
R9 is selected from H; halogen; OH; NO2; NH2; SH; CN; or a group selected from a C1-6 aliphatic or a C3-7 cycloaliphatic, wherein said group is optionally substituted with 1-6 occurrences of halogen, OH, NO2, NH2, SH or CN.
2. The compound or salt thereof according to claim 1, wherein Y is C(O) and the compound is of formula II:
3. The compound or salt thereof according to claim 2, wherein R\u2032 is a C1-3 aliphatic.
4. The compound or salt thereof according to claim 1, wherein R2 is CH3.
5. The compound or salt thereof according to claim 1, wherein said compound is of formula IIIa, IIIb or IIIc:
6. The compound or salt thereof according to claim 1, wherein R3 and R4, together with the nitrogen to which R4 is attached, form a monocyclic or bicyclic heterocyclyl or bicyclic heteroaryl selected from the following:
wherein Z is CH2, NH, O or S, and wherein the hydrogens of said CH2 of Z is optionally substituted by 1-2 occurrences of JR3 and the hydrogen of said NH of Z is optionally substituted by JR3.
7. The compound or salt thereof according to claim 1, wherein L is \u2014CH2\u2014.
8. The compound or salt thereof according to claim 1, wherein n is 0.
9. The compound or salt thereof according to claim 1, wherein R3 is a C1-4 aliphatic, a C3-6 monocyclic cycloaliphatic, phenyl, a 5-6 membered monocyclic heteroaryl, or a 5-10 membered monocyclic or bicyclic heterocyclyl, wherein R3 is optionally substituted with 1-4 occurrences of JR3.
10. The compound or salt thereof according to claim 9, wherein R3 is a C1-4 aliphatic, a C3-6 monocyclic cycloaliphatic, phenyl, a 5-6 membered monocyclic heteroaryl, or a 5-6 membered monocyclic heterocyclyl, wherein R3 is optionally substituted with 1-4 occurrences of JR3.
11. The compound or salt thereof according to claim 10, wherein each occurrence of JR3 is selected from halogen; OH; OR; CN; NH2; NHR; NR2; C(O)NH2; C(O)NHR; C(O)NR2; NHCOR; C(O)OR; C(O)OH; oxo; (CH2)0-3phenyl optionally substituted with halogen, OH, OR, NO2, NH2, SH or CN; or C1-4 aliphatic optionally substituted with halogen, OH, OR, NO2, NH2, SH or CN.
12. The compound or salt thereof according to claim 1, wherein R8 is selected from H, halogen, cyclopropyl, or a C1-3 aliphatic optionally substituted with 1-3 occurrences of halogen or OH.
13. The compound or salt thereof according to claim 1, wherein R9 is selected from H, OH, halogen, cyclopropyl, or a C1-3 aliphatic optionally substituted with 1-3 occurrences of halogen or OH.
14. A compound selected from
15. A compound selected from
16. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
17. A method of inhibiting phosphatidylinositol 3-kinase (PI3K) activity in a biological sample, comprising contacting said biological sample with a compound or salt thereof according to claim 1.
18. A method of treating or lessening the severity of a disease or condition selected from rheumatoid arthritis, systemic lupus erythematosus, atherosclerosis, lacrimal parotid gland syndrome, chronic obstructive pulmonary disease, pancreatitis, myocardial infarction, diabetes, multiple sclerosis or cancer comprising administering a compound according to claim 1 or a composition comprising said compound to a patient in need thereof.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1-19. Cancelled
20. A cleaning station for cleaning of a compression unit detached from a rotary tablet press, the compression unit comprising a number of dies arranged circumferentially in a rotary die table, each die being associated with at least a first punch having a first end receivable in the die through an opening of the die, a feeding device for the supply of material to be compressed into the dies, and a tablet discharge device for removal of compressed material in the form of tablets, wherein the cleaning station comprises at least two separate cleaning fluid devices each having a connection piece for detachable connection with a corresponding connection piece provided on the compression unit and communicating with an enclosure of the compression unit, the cleaning fluid devices being arranged for the supply of cleaning fluid to the compression unit and for the drainage of cleaning fluid from the compression unit.
21. A cleaning station according to claim 20, wherein at least one of the cleaning fluid devices is provided with a cleaning fluid spray nozzle arranged for automatic introduction through the corresponding connection piece on the compression unit.
22. A cleaning station for automated cleaning of a compression unit detached from a rotary tablet press, the compression unit comprising a number of dies arranged circumferentially in a rotary die ta-ble, each die being associated with at least a first punch having a first end receivable in the die through an opening of the die, a feeding device for the supply of material to be compressed into the dies, and a tablet discharge device for removal of compressed material in the form of tablets, the cleaning station comprising a cleaning chamber for accommodation of the compression unit during clean-ing, and the cleaning chamber being provided with at least a cleaning fluid spray nozzle, wherein the cleaning station comprises an automatic manipulator for opening at least partially a chamber which is comprised by the compression unit and which before opening encloses at least a die opening and its corresponding first punch end.
23. A cleaning station according to claim 22, wherein the cleaning chamber is adapted so that the second punch ends are accessible for actuation from outside the cleaning chamber.
24. A cleaning station according to claim 20, wherein it comprises a drive shaft for detachable connection to the rotary die table of the compression unit for rotation of the die table during cleaning in order to effect axial displacement of the punches.
25. A cleaning station according to claim 24, wherein it comprises an automatic manipulator for adjustment of a cam of the compression unit.
26. A cleaning station according to claim 24, wherein it comprises at least a cam for cooperation with a second end of the punches in order to effect axial displacement of the punches by rotation of the die table.
27. A cleaning station according to claim 20, wherein it comprises an automatic manipulator for opening andor moving a powder feeding device andor a tablet discharge device of the compression unit.
28. (cancelled).
29. A method of cleaning a compression unit detached from a rotary tablet press, the compression unit comprising a number of dies arranged circumferentially in a rotary die table, each die being associated with at least a first punch having a first end receivable in the die through an opening of the die, a feeding device for the supply of material to be compressed into the dies, and a tablet discharge de-vice for removal of compressed material in the form of tablets, wherein at least one separate cleaning fluid device by means of a connection piece is connected with a corresponding connection piece provided on the compression unit and communicating with an enclosure of the compression unit, and subsequently cleaning fluid is supplied to the enclosure of the compression unit from the at least one cleaning fluid device.
30. A method of cleaning according to claim 29, wherein at least two cleaning fluid devices are employed, and cleaning fluid is drained from the enclosure to one of the cleaning fluid devices.
31. A method of cleaning according to claim 30, wherein cleaning fluid is circulated through the en-closure of the compression unit in alternating directions.
32. A method of cleaning a compression unit detached from a rotary tablet press, the compression unit comprising a number of dies arranged circumferentially in a rotary die table, each die being associated with at least a first punch having a first end receivable in the die through an opening of the die, a feeding device for the supply of material to be compressed into the dies, and a tablet discharge de-vice for removal of compressed material in the form of tablets, whereby the compression unit is placed in a closed cleaning chamber, wherein, in the closed cleaning chamber, a chamber comprised by the compression unit and enclosing a die opening and its corresponding first punch end is opened, whereupon the compression unit is cleaned by means of cleaning fluid.
33. A method of cleaning according to claim 32, wherein, in the closed cleaning chamber, the punches are removed from the compression unit.
Please add the following new claims:
34. A cleaning station according to claim 22, wherein it comprises a drive shaft for detachable connection to the rotary die table of the compression unit for rotation of the die table during cleaning in order to effect axial displacement of the punches.
35. A cleaning station according to claim 22, wherein it comprises an automatic manipulator for opening andor moving a powder feeding device andor a tablet discharge device of the compression unit.