1. A method of treating a disorder associated with the N-Formyl peptide receptor 2 modulation, wherein the disorder is selected from: ocular inflammatory diseases, wet age-related macular degeneration, dry age-related macular degeneration, corneal wound healing, uveitis, dry eye, Keratitis, allergic eye diseases, conditions affecting the posterior part of the eye, maculopathies, retinal degeneration, non-exudative age related macular degeneration, exudative age related macular degeneration, choroidal neovascularization, diabetic retinopathy, retinopathy of prematurity acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, diabetic macular edema, infectious keratitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, post-surgical corneal inflammation, and blepharitis, which comprises administering to a mammal in need thereof, a pharmaceutical composition comprising a therapeutically effective amount of at least one compound represented by Formula I or a pharmaceutically acceptable salt thereof:
wherein:
\u201c\u201d is a single bond or a double bond;
\u201c\u201d is a single bond or a double bond;
R1 is H, halogen, \u2014S(O)R10, \u2014S(O)2R11, nitro, cyano, \u2014OC1-6 alkyl, \u2014SC1-6 alkyl, \u2014C1-6 alkyl, \u2014C2-6 alkenyl, \u2014C2-6 alkynyl, C(O)R12, NR13R14, C3-8 cycloalkyl, C3-8 cycloalkenyl or hydroxyl;
R2 is H, halogen, \u2014S(O)R10, \u2014S(O)2R11, nitro, cyano, \u2014OC1-6 alkyl, \u2014SC1-6 alkyl, \u2014C1-6 alkyl, \u2014C2-6 alkenyl, \u2014C2-6 alkynyl, C(O)R12, NR13R14, C3-8 cycloalkyl, C3-8 cycloalkenyl or hydroxyl;
R3 is H, halogen, \u2014S(O)R10, \u2014S(O)2R11, nitro, cyano, \u2014OC1-6 alkyl, \u2014SC1-6 alkyl, \u2014C1-6 alkyl, \u2014C2-6 alkenyl, \u2014C2-6 alkynyl, C(O)R12, NR13R14, C3-8 cycloalkyl, C3-8 cycloalkenyl, C6-10 aryl or hydroxyl;
R4 is H or C(O)R12;
R5 is H, \u2014OC1-6 alkyl, \u2014SC1-6 alkyl, \u2014C1-6 alkyl, \u2014C2-6 alkenyl or \u2014C2-6 alkynyl;
R6 is H, \u2014OC1-6 alkyl, \u2014SC1-6 alkyl, \u2014C1-6 alkyl, \u2014C2-6 alkenyl or \u2014C2-6 alkynyl;
Y is O or S;
X is O, NR, or CH2;
Ra is C6-10 aryl,
heteroaryl, C3-8 cycloalkyl, C3-8 cycloalkenyl or H;
Rb is halogen;
c is 0, 1 or 2;
R7 is H, halogen, \u2014S(O)R10, \u2014S(O)2R11, nitro, hydroxyl, cyano, \u2014OC1-6 alkyl, \u2014SC1-6 alkyl, \u2014C1-6 alkyl, \u2014C2-6 alkenyl, \u2014C2-6 alkynyl, C(O)R12, NR13R14, C3-8 cycloalkenyl or C3-8 cycloalkyl;
R8 is H, halogen, \u2014S(O)R10, \u2014S(O)2R11, cyano, \u2014OC1-6 alkyl, \u2014SC1-6 alkyl, \u2014C1-6 alkyl, \u2014C2-6 alkenyl, \u2014C2-6 alkynyl, C(O)R12, NR13R14, C3-8 cycloalkenyl or C3-8 cycloalkyl;
R9 is H, \u2014S(O)2R11, \u2014OC1-6 alkyl, \u2014SC1-6 alkyl, \u2014C1-6 alkyl, \u2014C2-6 alkenyl, \u2014C2-6 alkynyl, C(O)R12, C3-8 cycloalkenyl or C3-8 cycloalkyl;
R10 is \u2014C1-6 alkyl, C3-8 cycloalkyl, or C3-8 cycloalkenyl;
R11 is H, hydroxyl, \u2014C1-6 alkyl, C3-8 cycloalkyl or C3-8 cycloalkenyl;
R12 is H, hydroxyl, \u2014C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, NR13R14 or \u2014OC1-6 alkyl;
R13 is H, \u2014C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl SO2R11 or C(O)R15;
R14 is H, \u2014C1-6 alkyl, C3-8 cycloalkenyl, aryl, heterocycle or C3-8 cycloalkyl;
R15 is H, \u2014C1-6 alkyl, C3-8 cycloalkenyl or C3-8 cycloalkyl; and
R is H, \u2014C1-6 alkyl, C3-8 cycloalkenyl or C3-8 cycloalkyl;
with the provisos
when \u201c\u201d is a double bond then R5 and R6 are void; and
the compound is not of structures
2. The method according to claim 1, wherein said compound is represented by Formula I wherein:
\u201c\u201d is a single bond or a double bond;
\u201c\u201d is a single bond or a double bond;
R1 is H, halogen, nitro, cyano, \u2014OC1-6 alkyl, \u2014SC1-6 alkyl, \u2014C1-6 alkyl, C(O)R12, NR13R14, C3-8 cycloalkyl, C3-8 cycloalkenyl or hydroxyl;
R2 is H, halogen, nitro, cyano, \u2014OC1-6 alkyl, \u2014SC1-6 alkyl, \u2014C1-6 alkyl, C(O)R12, NR13R14, C3-8 cycloalkyl, C3-8 cycloalkenyl or hydroxyl;
R3 is H, halogen, nitro, cyano, \u2014OC1-6 alkyl, \u2014SC1-6 alkyl, \u2014C1-6 alkyl, C(O)R12, NR13R14, C3-8 cycloalkyl, C3-8 cycloalkenyl, C6-10 aryl or hydroxyl;
R4 is H or C(O)R12;
R5 is H, \u2014OC1-6 alkyl, \u2014SC1-6 alkyl or \u2014C1-6 alkyl;
R6 is H, \u2014OC1-6 alkyl, \u2014SC1-6 alkyl or \u2014C1-6 alkyl;
Y is O;
X is NR;
Ra is
Rb is bromine;
c is 0;
R7 is H, halogen, nitro, cyano, \u2014SC1-6 alkyl, \u2014C1-6 alkyl, C(O)R12, C3-8 cycloalkenyl or C3-8 cycloalkyl;
R8 is H, halogen, cyano, \u2014OC1-6 alkyl, \u2014SC1-6 alkyl, \u2014C1-6 alkyl, C(O)R12, NR13R14, C3-8 cycloalkenyl or C3-8 cycloalkyl;
R12 is H, hydroxyl, \u2014C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, NR13R14 or \u2014OC1-6 alkyl;
R13 is H, \u2014C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl or C(O)R15;
R14 is H, \u2014C1-6 alkyl, C3-8 cycloalkenyl, aryl, heterocycle or C3-8 cycloalkyl;
R15 is H, \u2014C1-6 alkyl, C3-8 cycloalkenyl or C3-8 cycloalkyl; and
R is H;
with the provisos:
when \u201c\u201d is a double bond then R5 and R6 are void; and
the compound is not of structures
3. The method according to claim 1, wherein said compound is represented by Formula I wherein:
\u201c\u201d is a double bond;
\u201c\u201d is a double bond;
R1 is H or \u2014C1-6 alkyl;
R2 is H, halogen or \u2014C1-6 alkyl;
R3 is H, C6-10 aryl or \u2014C1-6 alkyl;
R4 is C(O)R12;
Y is O;
X is NR;
Ra is
Rb is bromine;
c is 0;
R7 is H or C1-6 alkyl;
R8 is H or \u2014C1-6 alkyl;
R12 is hydroxyl; and
R is H.
4. The method according to claim 1, wherein said compound is represented by Formula I wherein:
\u201c\u201d is a double bond;
\u201c\u201d is a double bond;
R1 is H;
R2 is H;
R3 is H;
R4 is H or C(O)R12;
Y is O;
X is NR;
Ra is
Rb is bromine;
c is 0;
R7 is H or C(O)R12;
R12 is hydroxyl;
R is H; and
the compound is not of structure
5. The method according to claim 1, wherein said compound is represented by Formula I wherein:
\u201c\u201d is a double bond;
\u201c\u201d is a double bond;
R1 is H;
R2 is H;
R3 is H;
R4 is C(O)R12;
Y is O;
X is NR;
Ra is
Rb is bromine;
c is 0;
R7 is C1-6 alkyl;
R12 is hydroxyl; and
R is H.
6. The method according to claim 1, wherein said compound is represented by Formula I wherein:
\u201c\u201d is a single bond;
\u201c\u201d is a single bond;
R1 is \u2014C1-6 alkyl;
R2 is H;
R3 is \u2014C1-6 alkyl;
R4 is C(O)R12;
R5 is, \u2014C1-6 alkyl;
R6 is, \u2014C1-6 alkyl;
Y is O;
X is NR;
Ra is
Rb is bromine;
c is 0;
R7 is C(O)R12;
R12 is hydroxyl; and
R is H.
7. The method according to claim 1, wherein said compound represented by Formula I is selected from:
2-{(4-Bromophenyl)aminocarbonyl}-7-tert-butyl-3,4-dihydronaphthalene-1-carboxylic acid;
2-{(4-Bromophenyl)aminocarbonyl}-5-isopropyl-3,4-dihydronaphthalene-1-carboxylic acid;
2-{(4-Bromophenyl)aminocarbonyl}-4,4-dimethyl-3,4-dihydronaphthalene-1-carboxylic acid;
2-{(4-Bromophenyl)aminocarbonyl}-7-chloro-3,4-dihydronaphthalene-1-carboxylic acid;
2-{(4-Bromophenyl)aminocarbonyl}-3,4-dihydronaphthalene-1-carboxylic acid;
2-{(4-Bromophenyl)aminocarbonyl}-5,8-dimethyl-3,4-dihydronaphthalene-1-carboxylic acid;
2-{(4-Bromophenyl)aminocarbonyl}-5,7-dimethyl-3,4-dihydronaphthalene-1-carboxylic acid;
2-{(4-Bromophenyl)aminocarbonyl}-5-phenyl-3,4-dihydronaphthalene-1-carboxylic acid;
2-{(4-Bromophenyl)aminocarbonyl}-1-naphthoic acid;
2-{(4-Bromophenyl)aminocarbonyl}-4-ethyl-1-naphthoic acid;
3-{(4-Bromophenyl)aminocarbonyl}-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid; and
3-{(4-Bromophenyl)aminocarbonyl}-2-naphthoic acid.
8. The method according to claim 1, wherein said mammal is a human.
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 of verifying software operating nodes of a network using time-based verification, said method comprising the steps of:
(1) sending from a main verifier node to a plurality of nodes that are one network hop away from said main verifier node a time-based verification challenge;
(2) each of said first plurality of nodes executing said challenge to generate a result and returning said result to said main verifier node;
(3) said main verifier node determining time delays between issuing said challenges and receiving said responses for each of said plurality of first nodes;
(4) said main verifier node determining whether each of said first plurality of nodes is operating properly based on said result and said time delay;
(5) for each node in said first plurality of nodes that is verified to be operating properly, said main verifier node requesting said node to issue a challenge to a corresponding second plurality of nodes, said second plurality of nodes consisting of said network that are one hop away from said node;
(6) each verified node of said first plurality of nodes issuing said challenges to said corresponding second plurality of nodes without said challenge passing through another node of said network;
(7) each of said nodes of said second pluralities of nodes executing said challenge to generate a result and returning said result to said corresponding node of said first plurality of nodes;
(8) each verified node of said first plurality of nodes determining a time delay between issuing said challenge and receiving said response for each node of said second plurality of nodes corresponding to said node;
(9) each verified node of said first plurality of nodes sending said responses and recorded time delays to said main verifier node; and
(10) said main verifier node determining whether said nodes of said second pluralities of nodes are operating properly based on said results and said time delays.
2. The method of claim 1 wherein said challenges each comprise a cryptographic challenge that requires said second node to perform a calculation to render said result.
3. The method of claim 2 wherein step (10) comprises said main verifier determining if said result is an expected result and determining if said time delay is within an expected time window.
4. The method of claim 1 further comprising the steps of:
(11) for each node in said second pluralities of nodes that is verified to be operating properly, said main verifier node requesting said node to issue a challenge to a corresponding third plurality of nodes, said third plurality of nodes consisting of nodes of said network that are one hop away from said node;
(12) each verified node of said second pluralities of nodes issuing said challenges to said corresponding third plurality of nodes without said challenge passing through another node of said network;
(13) each of said nodes of said third pluralities of nodes executing said challenge to generate a result and returning said result to said corresponding node of said second plurality of nodes;
(14) each verified node of said second plurality of nodes determining a time delay between issuing said challenge and receiving said response for each node of said third plurality of nodes corresponding to said node;
(15) each verified node of said second pluralities of nodes sending said responses and recorded time delays to said main verifier node; and
(16) said main verifier node determining whether said nodes of said third plurality of nodes are operating properly based on said results and said time delays.
5. The method of claim 4 wherein if said main verifier determines a node to be operating improperly, the improperly operating node is removed from the network and said main verifier finds an alternate route to nodes one hop from said improperly operating node.
6. A computer program product embodied on a non-transitory computer-readable storage medium for verifying software operating within nodes of a network using time-based verification, said computer product comprising:
first executable instructions for sending from a main verifier node to a plurality of nodes that are one network hop away from said main verifier node a time-based verification challenge;
second executable instructions for executing said challenge at each of said first plurality of nodes to generate a result and returning said result to said main verifier node;
third executable instructions for determining at said main verifier node time delays between issuing said challenges and receiving said responses for each of said plurality of first nodes;
fourth executable instructions for determining at said main verifier nodes whether each of said first plurality of nodes is operating properly based on said result and said time delay;
for each node in said first plurality of nodes that is verified to be operating properly, fifth executable instructions for requesting by said main verifier node said node in said first plurality of nodes that is verified to be operating properly issue a challenge to a corresponding second plurality of nodes, said second plurality of nodes consisting of nodes of said network that are one hop away from said node;
sixth computer executable instructions for issuing said challenges from each verified node of said first plurality of nodes to said corresponding second plurality of nodes without said challenge passing through another node of said network;
seventh computer executable instructions for executing said challenge at each of said nodes of said second pluralities of nodes to generate a result and returning said result to said corresponding node of said first plurality of nodes;
eighth computer executable instructions for determining at each verified node of said first plurality of nodes a time delay between issuing said challenge and receiving said response for each node of said second plurality of nodes corresponding to said node;
ninth computer executable instructions for sending said responses and recorded time delays from each verified node of said first plurality of nodes to said main verifier node; and
tenth computer executable instructions for determining at said main verifier node whether said nodes of said second pluralities of nodes are operating properly based on said results and said time delays.
7. The computer product embodied on a non-transitory computer-readable storage medium of claim 6 wherein said challenges each comprise a cryptographic challenge that requires said second node to perform a calculation to render said result.
8. The computer product embodied on a non-transitory computer-readable storage medium of claim 7 wherein said tenth executable instructions comprise instructions for determining at said main verifier if said result is an expected result and determining if said time delay is within an expected time window.
9. The computer product embodied on a non-transitory computer-readable storage medium of claim 6 comprising:
for each node in said second pluralities of nodes that is verified to be operating properly, eleventh executable instructions for requesting by said main verifier node said node in said second pluralities of nodes that is verified to be operating properly issue a challenge to a corresponding third plurality of nodes, said third plurality of nodes consisting of nodes of said network that are one hop away from said node;
twelfth executable instructions for issuing by each verified node of said second pluralities of nodes said challenges to said corresponding third plurality of nodes without said challenge passing through another node of said network;
thirteenth executable instructions for executing said challenge at each of said nodes of said third pluralities of nodes to generate a result and returning said result to said corresponding node of said second plurality of nodes;
fourteenth executable instructions for determining at each verified node of said second plurality of nodes a time delay between issuing said challenge and receiving said response for each node of said third plurality of nodes corresponding to said node;
fifteenth executable instructions for sending said responses and recorded time delays from each verified node of said second pluralities of nodes to said main verifier node; and
sixteenth executable instructions for determining at said main verifier node whether said nodes of said third plurality of nodes are operating properly based on said results and said time delays.
10. The computer product embodied on a non-transitory computer-readable storage medium of claim 9 wherein if said main verifier determines a node to be operating improperly, the improperly operating node is removed from the network and said main verifier finds and alternate route to nodes one hop from said improperly operating node.