1. A method of treatment of a disease or condition mediated by ABL1 T315I (SEQ ID NO 1), ALK2 (SEQ ID NO 2), ARKS (SEQ ID NO 64), Aurora A (SEQ ID NO 3), Aurora B (SEQ ID NO 4), Aurora C (SEQ ID NO 5), BRAF (SEQ ID NO 6), BRAF V599E (SEQ ID NO 7), CHK1 (SEQ ID NO 8), CHK2 (SEQ ID NO 9), C-KIT (SEQ ID NO 10), CLK1 (SEQ ID NO 11), CLK2 (SEQ ID NO 12), CLK3 (SEQ ID NO 13), CLK4 (SEQ ID NO 14), CSF1R (SEQ ID NO 15), DYRK1A (SEQ ID NO 16), DYRK1B (SEQ ID NO 17), DYRK2 (SEQ ID NO 18), DYRK3 (SEQ ID NO 19), DYRK4 (SEQ ID NO 20), FLT3 (SEQ ID NO 21), GSK3\u03b2 (SEQ ID NO 22), JAK1 (SEQ ID NO 23), JAK2 (SEQ ID NO 24), JAK3 (SEQ ID NO 25), KDR (SEQ ID NO 26), LCK (SEQ ID NO 27), LRRK2 (SEQ ID NO 62), LRRK2 G2019S (SEQ ID NO 28), LRRK2 T1602S R1628P T2352M (SEQ ID NO 29), MAP4K4 (SEQ ID NO 30), MELK (SEQ ID NO 31), MLK (SEQ ID NO 32), PDGFR (SEQ ID NO 41), PKA (SEQ ID NO 63), PKC\u03b1 (SEQ ID NO 42), PKC\u03c4 (SEQ ID NO 43), PIM1 (SEQ ID NO 44), RET (SEQ ID NO 45), ROCK1 (SEQ ID NO 46), ROCK2 (SEQ ID NO 47), RSK1 (SEQ ID NO 48), RSK2 (SEQ ID NO 49), p70S6K (SEQ ID NO 50), SGK1 (SEQ ID NO 51), SNF1LK (SEQ ID NO 52), SIK2 (SEQ ID NO 53), SYK (SEQ ID NO 54), TNIK (SEQ ID NO 55), TRKA (SEQ ID NO 56), TRKB (SEQ ID NO 57) or TRKC (SEQ ID NO 58) and mutations thereof comprising administering to a mammal a compound having the structure of Formula I:
wherein:
X is \u2014N;
L1 is independently a substituted or unsubstituted 6-membered aryl, heteroaryl, substituted or unsubstituted 5-membered aryl or heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, \u2014C(O)\u2014, S(O)n, \u2014O, \u2014NH, substituted or unsubstituted C1-C5 alkylene, substituted or unsubstituted 2 to 5 membered heteroalkylene groups; where \u201cn\u201d is from 0 to 2, \u2014CH3, halo, \u2014OCH3, \u2014CF3, OCF3, \u2014CN, \u2014NH2, \u2014CH2OCF2, \u2014COOH, \u2014OR4 \u2014SR4, \u2014NHR4, \u2014C(O)R4\u2014, \u2014C(S)R4, \u2014C(O)NR4, and \u2014S(O)2R4, \u2014S(O)2NHR4, \u2014NHCOR4, \u2014CONHR4, CONR4, \u2014CH\u2550CHR4, \u2014NCH3R4,
R4 is optionally substituted at each occurrence and is selected from alkyl, heteroaryl, cycloalkyl, heterocycloalkyl, \u2014C1-6 alkyl, \u2014C1-4 haloaliphatic, \u2014C2-6 alkenyl, monodialkylamino, aryl C4-7 heterocycloakyl, \u2014C5-6 aryl and, wherein the functional groups are each optionally substituted with one or more of fluoro, \u2014NH2, hydroxyl, fluoro substituted lower alkyl, alkoxy, alkylthio, monodialkylamino and cycloalkylamino functional groups or additional substituents selected from \u2014NR5R6 and \u2014CR5R6 respectively, and wherein
R4 together with the carbon to which it is attached may form a 3-7 member monocyclic cycloalkyl, 5-6 membered monocyclic heterocycloalkyl, heterocycloalkyl, heteroaryl; wherein the monocyclic cycloalkyl or heterocycloalkyl are each independently optionally substituted with one or more of fluoro, \u2014NH2, hydroxyl, fluoro substituted lower alkyl, alkoxy, alkylthio, monodialkylamino and cycloalkylamino;
R5 and R6 are each independently \u2014H, cycloalkyl, alkyl, heterocycloalkyl, aryl, heteroaryl, \u2014C1-6 alkyl, \u2014C3-7 cycloalkyl, \u2014C3-6 heterocyclocycloalkyl, each optionally substituted with one or more of fluoro, \u2014NH2, hydroxyl, fluoro substituted C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkoxy, alkylthio, monodialkylamino and cycloalkylamino;
wherein L1 is optionally substituted with \u2014R7 or Y9;
wherein R7 is independently a bond, substituted or unsubstituted \u2014C\u2550S, C\u2550O, \u2014C1-6 alkyl, each optionally further substituted by C1-6 alkyl, (for example, (\u2014CH2)n, wherein n is an integer from 0-3), \u2014O, \u2014S, \u2014SO, SO2, \u2014NH or \u2014CH\u2550CH groups; and
R7 may be cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are each optionally substituted with one or more of fluoro, \u2014OH, \u2014NH2, OCH3, CH2OCH3, methylthio, ethylthio, butylthio, isobutylthio, monodialkylamino, and alkyl carbon bound to the N of \u2014C(O)NHR8, \u2014C(S)NHR8 or \u2014S(O)2NHR8; wherein the alkyl chain(s) of OCH3, CH2OCH3, methylthio, ethylthio, butylthio, isobutylthio, and monodialkylamino are each optionally independently substituted with one or more of fluoro, \u2014OH, \u2014NH2, wherein any substitution of the alkyl chain carbon bound to O of alkoxy, S of thioalkyl or N of monodialkylamino is fluoro;
R8 combines with the nitrogen to which it is attached to form a 5-7 member heterocycloalkyl optionally substituted with one or more of fluoro, \u2014OH, \u2014NH2, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoro substituted C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, OCH3, CH2OCH3, fluoro substituted OCH3, CH2OCH3, methylthio, ethylthio, butylthio, isobutylthio, and fluoro-substituted methylthio, ethylthio, butylthio, isobutylthio;
Y9 is \u2014C1-6 alkyl, C3-7 cycloalkyl, \u2014C1-6-alkyl \u2014C3-7-cycloalkyl, \u2014C1-6 alkyl heteroaryl, \u2014C4-7 heterocycloalkyl, aryl or heteroaryl, each optionally independently substituted with one or more substituents selected from R4; and
R1, R2 and R3 are each independently halo, \u2014CN, \u2014NH2, \u2014C1-6 aliphatic, \u2014OC1-6 aliphatic, \u2014C3-6 cycloaliphatic, \u2014OC3-6 cycloaliphatic, \u2014NH2, \u2014NHCOC1-6 alkyl, \u2014NHCO1-6 cycloalkyl, \u2014NHCO1-6 heterocycloalkyl, \u2014CONHC1-6 alkyl, \u2014CONH1-6 cycloalkyl, \u2014CONH1-6 heterocycloalkyl, \u2014NHC1-6 aliphatic, \u2014NHC3-6 cycloaliphatic, \u2014NHS(O)2C1-6 aliphatic, \u2014NHS(O)2C3-6 cycloaliphatic, \u2014NHS(O)2 phenyl, \u2014NHS(O)2 benzyl, \u2014NHS(O)2 heteroaryl, \u2014S(O)2C1-6 aliphatic, \u2014S(O)2C3-6 cycloaliphatic, \u2014S(O)2 phenyl, \u2014S(O)2 benzyl, \u2014S(O)2 heteroaryl, \u2014S(O)2NHC1-6 aliphatic, \u2014S(O)2NHC3-6 cycloaliphatic, \u2014S(O)2NHphenyl, \u2014S(O)2NHbenzyl, or \u2014S(O)2NHheteroaryl, wherein each of said heteroaryl of R1, R2 and R3 is independently a 5- or 6-member ring having 1, 2, or 3 atoms selected from N, O, or S, and wherein said aliphatic, cycloaliphatic, phenyl, benzyl, or heteroaryl of R1, R2 and R3 is each optionally substituted with 1, 2, or 3 ZR10 groups;
wherein one or two of R1, R2 and R3 may be hydrogen when one or two of R1, R2 and R3 are halo, \u2014CN, \u2014NH2, \u2014C1-6 aliphatic, \u2014OC1-6 aliphatic, \u2014C3-6 cycloaliphatic, \u2014OC3-6 cycloaliphatic, \u2014NH2, \u2014NHCOC1-6 alkyl, \u2014NHCO1-6 cycloalkyl, \u2014NHCO1-6 heterocycloalkyl, \u2014CONHC1-6 alkyl, \u2014CONH1-6 cycloalkyl, \u2014CONH1-6 heterocycloalkyl, \u2014NHC1-6 aliphatic, \u2014NHC3-6 cycloaliphatic, \u2014NHS(O)2C1-6 aliphatic, \u2014NHS(O)2C3-6 cycloaliphatic, \u2014NHS(O)2 phenyl, \u2014NHS(O)2 benzyl, \u2014NHS(O)2 heteroaryl, \u2014S(O)2C1-6 aliphatic, \u2014S(O)2C3-6 cycloaliphatic, \u2014S(O)2 phenyl, \u2014S(O)2 benzyl, \u2014S(O)2 heteroaryl, \u2014S(O)2NHC1-6 aliphatic, \u2014S(O)2NHC3-6 cycloaliphatic, \u2014S(O)2NHphenyl, \u2014S(O)2NHbenzyl, or \u2014S(O)2NHheteroaryl, wherein each of said heteroaryl of R1, R2 and R3 is independently a 5- or 6-member ring having 1, 2, or 3 atoms selected from N, O, or S, and wherein said aliphatic, cycloaliphatic, phenyl, benzyl, or heteroaryl of R1, R2 and R3 is each optionally substituted with 1, 2, or 3 ZR10 groups;
wherein ZR10 is halo, oxo, \u2014C1-2 alkyl, substituted C1-2 alkyl with 1-3 \u2014F or \u2014Cl atoms, \u2014C3-6 cycloalkyl, \u2014OH, \u2014OC1-2 alkyl, \u2014OC1-2 alkyl substituted with 1-3 \u2014F or \u2014Cl atoms, \u2014C(O)C1-2 alkyl, or \u2014SC1-2 alkyl,
and the pharmaceutically acceptable salts, isomers and tautomers thereof.
2. A method of treatment according to claim 1 wherein the disease or condition is selected from the group consisting of Parkinson’s disease, Alzheimer’s disease, Down’s syndrome, Huntington’s disease, neurodegenerative disease, central nervous system disease, cancer, metabolic disorder, inflammatory disease, pain of neuropathic origin, pain of inflammatory origin, cardiovascular disease, rheumatoid arthritis, osteoarthritis, type 2 diabetes, metabolic syndrome and obesity.
3. A method of treatment according to claim 1 wherein the disease or condition is mediated by one of LRRK2 T1602S T2352M and R1628P (SEQ ID NO 29) variants.
4. A method of treatment according to claim 1 wherein the disease is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease and Down’s syndrome.
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 comprising:
detecting a communication fault between a first node and a second node, wherein
the first node is configured to communicate one or more first inputoutput (IO) requests to the second node as remote IO requests, and
the second node is configured to communicate one or more second IO requests and the remote IO requests to one or more storage devices; and
in response to a detection of the communication fault, performing a fencing operation,
wherein
the fencing operation is performed with a fenced IO operation,
the fenced IO operation comprises performing an arbitration process to determine whether the first node or the second node is part of a winner node group or a loser node group, and
the performing the fencing operation comprises:
completing one or more received remote IO requests, wherein
the received remote IO request(s) comprise one or more of the remote IO requests received by the second node,
the arbitration process determines that the second node is part of the winner node group, and
the received remote IO requests are issued by a proxy node on behalf of the first node, and
avoiding processing of additional remote IO requests from the first node, wherein
the arbitration process determines that the first node is part of the loser node group.
2. The method of claim 1, wherein the communication fault indicates one or more of
a network partition condition between the first node and the second node, or
a fault in a network coupling the first node and the second node.
3. The method of claim 1, wherein the performing the fencing operation further comprises
instructing one of the one or more storage devices to delete one or more keys associated with the first node, wherein the instructing comprises using a second node to perform the instructing.
4. The method of claim 3, wherein the instructing the one or more storage devices comprises
determining whether the second node is configured to communicate with each of the one or more storage devices, and
in response to a determination that the second node is not configured to communicate with the each of the storage devices,
using a third node to perform the instructing.
5. The method of claim 1, wherein the performing the fencing operation further comprises
determining existence of a device communication error, wherein
the device communication error indicates a device fault, and
in response to a determination of a device fault, discontinuing use of the first storage device.
6. The method of claim 1, further comprising:
in response to a determination of the communication fault,
determining whether to perform the fencing operation with respect to one or more of
the first node, or
the second node.
7. The method of claim 1, wherein the completing the remote IO request(s) comprise
communicating the remote IO request(s) to the one or more storage devices.
8. The method of claim 1, wherein the performing the fencing operation comprises
instructing a third node to
complete one or more IO requests received from the first node, and
avoid processing of additional IO requests from the first node.
9. The method of claim 1, wherein
the one or more second IO requests comprise IO requests that are originated by the second node.
10. The method of claim 1, wherein
the completing the remote IO requests comprises
the second node completing the remote IO requests, and
avoiding processing of the additional remote IO requests from the first node comprises
the second node avoiding processing of the additional remote IO requests from the first node.
11. The method of claim 1, wherein
the received remote IO request(s) comprise the one or more of the remote IO requests received by the second node prior to performance of the fencing operation, and
the additional remote IO requests from the first node comprise one or more of the remote IO requests received by the second node after the performance of the fencing operation.
12. A system comprising:
one or more processors,
a control module, wherein
the control module is configured to
detect a communication fault between a first node and a second node, wherein
the first node is configured to communicate the first inputoutput (IO) requests to the second node as remote IO requests, and
the second node is configured to communicate one or more second IO requests and the remote IO requests to one or more storage devices; and
in response to a detection of the communication fault, perform a fencing operation, wherein
the fencing operation is performed with a fenced IO operation,
the fenced IO operation comprises performing an arbitration process to determine whether the first node or the second node is part of a winner node group or a loser node group, and
the control module performing the fencing operation comprises:
the control module instructing the second node to complete one or more received remote IO requests, wherein
the received remote IO request(s) comprise one or more of the remote IO requests received by the second node,
the arbitration process determines that the second node is part of the winner node group, and
the received remote IO requests are issued by a proxy node on behalf of the first node, and
the control module instructing the second node to avoid processing of additional remote IO requests from the first node, wherein
the arbitration process determines that the first node is part of the loser node group;
wherein the control module is configured to be executed using the one or more processors.
13. The system of claim 12, wherein the communication fault indicates one or more of
a network partition condition between the first node and the second node, or
a fault in a network coupling the first node and the second node.
14. The system of claim 12, wherein the control module performing the fencing operation comprises
the control module instructing one of the one or more storage devices to delete one or more keys associated with the first node, wherein the instructing comprises
using another node to perform the instructing.
15. The system of claim 12, wherein
the received remote IO request(s) comprise the one or more of the remote IO requests received by the second node prior to performance of the fencing operation, and
the additional remote IO requests from the first node comprise one or more of the remote IO requests received by the second node after the performance of the fencing operation.
16. The system of claim 12, wherein
the control module instructing the second node to complete the remote IO request(s) comprises
the control module instructing the second node to communicate the remote IO request(s) to the one or more storage devices.
17. A computer program product comprising:
a plurality of instructions, comprising
a first set of instructions, executable on a computer system, configured to detect a communication fault between a first node and a second node, wherein
the first node is configured to communicate one or more first inputoutput (IO) requests to the second node as remote IO requests, and
the second node is configured to communicate one or more second IO requests and the remote IO requests to one or more storage devices, and
a second set of instructions, executable on the computer system, configured to in response to a detection of the communication fault, perform a fencing operation, wherein
the fencing operation is performed with a fenced IO operation,
the fenced IO operation comprises performing an arbitration process to determine whether the first node or the second node is part of a winner node group or a loser node group, and
the performing the fencing operation comprises:
completing one or more received remote IO requests, wherein
the received remote IO request(s) comprise one or more of the remote IO requests received by the second node,
the arbitration process determines that the second node is part of the winner node group, and
the received remote IO requests are issued by a proxy node on behalf of the first node, and
avoiding processing of additional remote IO requests from the first node, wherein
the arbitration process determines that the first node is part of the loser node group; and
a computer-readable storage medium, wherein the instructions are encoded in the computer-readable storage medium.
18. The computer program product of claim 17, wherein the communication fault indicates one or more of
a network partition condition between the first node and the second node, or
a fault in a network coupling the first node and the second node.
19. The computer program product of claim 17, wherein the plurality of instructions further comprise:
a third set of instructions, executable on a computer system, configured to communicate with another node to instruct one of the one or more storage devices to delete one or more keys associated with the first node.
20. The computer program product of claim 17, wherein
the received remote IO request(s) comprise the one or more of the remote IO requests received by the second node prior to performance of the fencing operation, and
the additional remote IO requests from the first node comprise one or more of the remote IO requests received by the second node after the performance of the fencing operation.