1-22. (canceled)
23. A compound of the Formula I:
wherein:
R1 is (C6-C14) aryl, or -(5-14 membered) heteroaryl, wherein said aryl and heteroaryl are each optionally substituted with one or more (C0-C4 alkylene)-R13;
R2 and R3 are independently selected from the group consisting of: \u2014H, a straight or branched C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8 cycloalkyl, C6-C14 aryl and (5-14 membered) heteroaryl, wherein said alkyl, alkenyl and alkynyl are each optionally substituted with one or more substituents selected from the group consisting of \u2014F, \u2014Cl, \u2014Br, \u2014OH, C1-C4 alkoxy, and \u2014S\u2014(C1-C4)alkyl, and wherein said aryl and heteroaryl are each optionally substituted with one or more (C0-C4 alkylene)-R13; or R2 and R3 taken together form a C3-C8 cycloalkyl;
R4 is C6-C14 aryl or (5-14 membered) heteroaryl substituted with one or more (C0-C4 alkylene)-R13;
R5 and R6 are independently selected from the group consisting of: \u2014H, \u2014F, \u2014Cl, \u2014Br, \u2014CN, \u2014CHO, \u2014NO2, \u2014C(\u2550O)NR9R10, \u2014C(\u2550O)OR10, \u2014NR9R10, \u2014NR9C(\u2550O)R10, \u2014NR9C(\u2550O)OR1, and NR9C(\u2550O)NR9R10;
or R5 and R6 are independently a straight or branched C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, (C0-C6 alkylene)-(C3-C12 cycloalkyl), or (C0-C6 alkylene)-(C3-C12 heterocycloalkyl), wherein said alkyl, alkenyl, alkynyl, alkylene, cycloalkyl and heteroalkyl are each optionally substituted with one or more (C0-C6 alkylene)-R7; or R5 and R6 are independently (C0-C6 alkylene)-(C6-C14 aryl) or (C0-C6 alkylene)-(5-14 membered heteroaryl), wherein said aryl and heteroaryl are each optionally substituted with one or more R7 and wherein said alkylene is optionally substituted with one or more (C0-C6 alkylene)-R8; or R5 and R6, when attached to the adjacent carbon atoms of the thiazole ring, together form a (4-8 membered) cycloalkyl, (4-8 membered)-heterocycloalkyl, or C6-C10 aryl wherein said cycloalkyl and heteroalkyl are each substituted with one or more (C0-C6 alkylene)-R8, (C0-C6 alkylene)-(C6-C14 aryl), and (C0-C6-alkylene)-(5-14 membered heteroaryl), wherein said aryl or heteroaryl are each optionally substituted with one or more R7;
Z is a bond or a straight or branched C1-C6 alkylene, wherein each hydrogen atom of said alkylene is optionally independently replaced with a fluorine;
X is O or S;
R7 is \u2014F, \u2014Cl, \u2014Br, \u2014OH, \u2014CN, \u2014CHO, \u2014NO2, \u2014NR9R10, \u2014NR9C(\u2550O)R10, \u2014NR9C(\u2550O)NR9R10, \u2014NR9C(\u2550O)OR10, \u2014OC(\u2550O)\u2014R9, \u2014OC(\u2550O)NR9R10, \u2014C(\u2550O)NR9R10, \u2014C(\u2550O)OR10, \u2014SO2NR9R10, \u2014C1-C6 alkyl, \u2014C2-C6 alkenyl, \u2014C2-C6 alkynyl-C3-C8cycloalkyl, \u2014C3-C8 heterocycloalkyl, \u2014C1-C6 alkoxy, \u2014(C6-C14) aryloxy, -(5-14 membered) heteroaryloxy, \u2014(C0-C4 alkylene)-(C6-C14) aryl, or \u2014(C0-C4 alkylene)-(5-14 membered) heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are each optionally substituted with one or more R8, and wherein each hydrogen atom of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl and alkoxy is optionally independently replaced with a fluorine;
R8 is \u2014F, \u2014Cl, \u2014Br, \u2014CN, \u2014CHO, \u2014OR9, \u2014OC(\u2550O)\u2014R9, \u2014OC(\u2550O)NR9R10, \u2014NO2, \u2014NR9R10, \u2014NR9C(\u2550O)R10\u2014NR9C(\u2550O)NR9R10, \u2014NR9C(\u2550O)OR10\u2014C(\u2550O)NR9R10, \u2014SO2NR9R10, \u2014C(\u2550O)R10 or \u2014C(\u2550O)OR10;
R9 and R10 are \u2014H, \u2014C1-C6 alkyl, \u2014C2-C6 alkenyl, \u2014C2-C6 alkynyl, \u2014(C0-C4 alkylene)-(C3-C8 cycloalkyl), \u2014(C0-C4alkylene)-(C6-C14 aryl), \u2014(C0-C4 alkylene)-(3-8 membered heterocycloalkyl), or \u2014(C0-C4 alkylene)-(5-14 membered heteroaryl), wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl are each optionally independently substituted with one or more substituents independently selected from the group consisting of \u2014F, \u2014Cl, \u2014Br, \u2014CN, \u2014CHO, \u2014OH, \u2014NO2, \u2014NR11R12, \u2014C(\u2550)ONR11R12, \u2014C(\u2550O)R11, \u2014C(\u2550O)OR12, \u2014SO2NR11R12, \u2014C1-C6 alkyl, \u2014C1-C6 alkoxy, \u2014C1-C6 hydroxyalkyl, \u2014(C0-C4)\u2014(C6-C14) aryl), and \u2014(C0-C4)-(5-14 membered heteroaryl);
or R9 and R10 with nitrogen forms a 4-8 membered heterocycloalkyl moiety, wherein said heterocycloalkyl is optionally substituted with one or more substitutents selected from the group consisting of \u2014F, \u2014Cl, \u2014Br, \u2014CN, \u2014CHO, \u2014OH, \u2014NO2, \u2014NR11R12, \u2014C(\u2550)ONR11R12, \u2014C(\u2550O)R11\u2014C(\u2550O)OR12\u2014SO2NR11R12, \u2014C1-C6 alkyl, \u2014C2-C6 alkenyl, \u2014C2-C6 alkynyl, \u2014C1-C6 alkoxy, \u2014C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C10 aryl, and 5-14 membered heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are each optionally substituted with F, \u2014Cl, \u2014Br, \u2014CN, \u2014OR11, \u2014OC(\u2550O)\u2014R11, \u2014OC(\u2550O)NR11R12, \u2014NO2, \u2014NR11R12, \u2014NR11C(\u2550O)R12\u2014NR11C(\u2550O)NR11R12, \u2014NR11C(\u2550O)OR12, \u2014C(\u2550O)NR11R12, \u2014SO2NR11R12, \u2014C(\u2550O)R11, or \u2014C(\u2550O)OR11;
R11 and R12 are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, C6-C14 aryl or 5-14 membered heteroaryl, wherein said alkyl, alkenyl, alkynyl, aryl and heteroaryl are each optionally independently substituted with from one to three substituents independently selected from the group consisting of \u2014OH, \u2014C1-C6 alkyl, \u2014C2-C6 alkenyl, \u2014C2-C6 alkynyl, \u2014C1-C6 alkoxy, \u2014C2-C6 alkenoxy, \u2014C2-C6 alkynoxy, \u2014C1-C6 hydroxyalkyl, \u2014F, \u2014Cl, \u2014Br, \u2014I, \u2014CN, \u2014NO2, \u2014CF3, \u2014NH2, \u2014NH(C1-C6 alkyl), \u2014N(C1-C6 alkyl)2, \u2014C(\u2550O)NH2, \u2014C(\u2550O)NH(C1-C6 alkyl), \u2014C(\u2550O)N(C1-C6 alkyl)2, \u2014SO2NH2, \u2014SO2NH(C1-C6 alkyl), \u2014SO2N(C1-C6 alkyl)2, \u2014C(\u2550O)H, \u2014C(\u2550O)OH and \u2014C(\u2550O)O(C1-C6 alkyl), wherein said alkyl, alkenyl and alkynyl substituents are each optionally independently further substituted with from one to six fluorine atoms;
or R11 and R12 with nitrogen taken together form a 4-8 membered heterocycloalkyl, wherein said heterocycloalkyl is optionally independently substituted with from one to three substituents independently selected from the group consisting of \u2014OH, \u2014C1-C6 alkyl, \u2014C2-C6 alkenyl, \u2014C2-C6 alkynyl, \u2014C1-C6 alkoxy, \u2014C2-C6 alkenoxy, \u2014C2-C6 alkynoxy, \u2014C1-C6 hydroxyalkyl, \u2014F, \u2014Cl, \u2014Br, \u2014I, \u2014CN, \u2014NO2, \u2014CF3, \u2014NH2, \u2014NH(C1-C6 alkyl), \u2014N(C1-C6 alkyl)2, \u2014C(\u2550O)NH2, \u2014C(\u2550O)NH(C1-C6 alkyl), \u2014C(\u2550O)N(C1-C6 alkyl)2, \u2014SO2NH2, \u2014SO2NH(C1-C6 alkyl), \u2014SO2N(C1-C6 alkyl)2, \u2014C(\u2550O)H, \u2014C(\u2550O)OH and \u2014C(\u2550O)O(C1-C6 alkyl), wherein said alkyl, alkenyl and alkynyl substituents are each optionally independently further substituted with from one to six fluorine atoms; and
R13 is \u2014F, \u2014Cl, \u2014Br, \u2014CN, \u2014CHO, \u2014OH, \u2014NO2, \u2014NR11R12, \u2014C(\u2550)ONR11R12, \u2014C(\u2550O)R11\u2014C(\u2550O)OR12\u2014SO2NR11R12, \u2014C1-C6 alkyl, \u2014C1-C6 alkoxy, \u2014C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, C6-C10 aryl or 5-14 membered heteroaryl, wherein each hydrogen atom of said alkyl, alkoxy, cycloalkyl and heterocycloalkyl is optionally independently replaced with a fluorine; or
a pharmaceutically acceptable salt thereof.
24. A compound according to claim 23, wherein Z is a bond, or a pharmaceutically acceptable salt thereof.
25. A compound according to claim 23, wherein Z is methylene, or a pharmaceutically acceptable salt thereof.
26. A compound according to claim 23, wherein R2 is hydrogen and R3 is independently selected from the group consisting of \u2014H, a straight or branched C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C6-C14 aryl and (5-14 membered) heteroaryl, or a pharmaceutically acceptable salt thereof.
27. A compound according to claim 23, wherein X is S or a pharmaceutically acceptable salt thereof.
28. A compound according to claim 27, wherein
or a pharmaceutically acceptable salt thereof.
29. A compound according to claim 27, wherein
or a pharmaceutically acceptable salt thereof.
30. A pharmaceutical composition for treating a disease or condition associated with the modulation of the Notch signaling pathway, comprising a compound according to claim 23, or a pharmaceutically acceptable salt thereof.
31. The composition of claim 30, wherein the disease or condition is cancer.
32. A method of treating a disease or condition selected from the group consisting of cancer, arteriosclerosis, diabetic retinopathy, rheumatoid arthritis, psoriasis, inflammatory bowel disease, inflammation, asthma, graft rejection, graft versus host disease, autoimmune disease and transplant rejection, comprising administering to said mammal an amount of a compound according to claim 23 that is effective in modulating Notch signaling pathway to treat such disease or condition.
33. A method according to claim 32, wherein said disease or condition 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. A downhole non-return valve, comprising:
a housing defining a valve inlet and a valve outlet;
a plug moveable between an open position and a fully sealed position; and
a biasing member urging the plug towards the fully sealed position wherein the urging force of the biasing member is sufficient to move the plug to a partially sealed position but is selected to be insufficient to move the plug to a fully sealed position.
2. The non-return valve of claim 1, wherein in the partially sealed position an outlet side of the plug is exposed to well pressure that aids in moving the plug to the fully sealed position
3. The non-return valve of claim 1, further comprising:
a shield to redirect fluid flow from the outlet of the valve.
4. The non-return valve of claim 3, wherein the shield circumferentially surrounds the outlet.
5. The non-return valve of claim 1, wherein the biasing member is a spring.
6. The non-return valve of claim 1, further comprising:
a seal surface at the plug engagable with a seal seat at the housing.
7. The non-return valve of claim 6, wherein the seal surface and seal seat are metal.
8. The non-return valve of claim 1, further comprising:
a first additional seal that engages a housing bore in the partially sealed position.
9. The non-return valve of claim 8, wherein the first additional seal is a wiper seal.
10. The non-return valve of claim 8, further comprising:
a second additional seal that engages the housing bore in the fully sealed position.
11. The non-return valve of claim 10, wherein the second additional seal is a V-packing seal.
12. The non-return valve of claim 1, further comprising:
run-in-configuration retainers that lock the plug in the fully sealed position during shipping, installation into the downhole environment, and initial pressure testing before releasing the plug from the run-in-configuration.
13. The non-return valve of claim 12, wherein the run-in-configuration retainers are releasable at a selected pressure.
14. The non-return valve of claim 12, wherein the run-in-configuration retainers are shear screws.
15. The non-return valve of claim 12, further comprising:
a collar receptive of the run-in-configuration retainers and movable relative to the plug, the collar configured to position the plug in the fully sealed position prior to release of the run-in-configuration retainers and to not restrict travel of the plug after release of the run-in-configuration retainers.
16. A downhole non-return valve, comprising:
a housing defining a valve inlet and valve outlet;
a plug moveable between an open position and a fully closed position; and
a sacrificial member adapted to divert fluid injected through the valve axially along an external surface of the valve housing.
17. A method of injecting fluid into a well bore through a non-return valve, comprising:
injecting fluid into a non-return valve the valve being in a fully sealed configuration;
pressurizing the fluid sufficiently to overcome a closing force comprising a combination of a biasing force and well pressure to open a valve outlet;
injecting fluid through the valve outlet into a well; and
ceasing injection of the fluid thereby permitting the closing force to fully seal the valve outlet.
18. The method of claim 17, further comprising:
partially sealing the plug to a housing bore with an additional first seal with the biasing force prior to fully sealing the valve outlet with the closing force.
19. The method of claim 18, further comprising:
cleaning the housing bore with the first additional seal prior to a second additional seal engaging the housing bore.
20. The method of claim 19, wherein the first additional seal is a wiper seal and the second additional seal is a V-packing seal.
21. The method of claim 17, further comprising:
shielding well bore components from fluid erosion with a sacrificial shield.
22. The method of claim 17, wherein the biasing force is provided by a biasing member.
23. A non-return valve, comprising:
a valve seat;
a valve piston in operable communication with the valve seat;
a first seal disposed at the piston to interact with the valve seat; and
a second seal positioned at the piston to interact with the valve seat temporally after the first seal.