1. A compound selected from a compound of Formula I:
and pharmaceutically acceptable salts thereof, wherein in Formula I:
R1 is C1-8 alkyl, C1-8 haloalkyl, C1-8 alkoxy, C3-12 cycloalkyl, C-linked C2-11 heterocycloalkyl, heteroaryl, or \u2014NR1AR1B, wherein R1A and R1B are each independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkoxy, (6-10 membered aryl)-(XR1)0-1\u2014, (5-10 membered heteroaryl)-(XR1)0-1\u2014, and wherein R1A and R1B are optionally combined to form a 3 to 8 membered heterocyclic ring optionally comprising 1 additional heteroatom selected from N, O and S as ring vertex and optionally fused thereto is a benzene or pyridine ring; XR1 is selected from the group consisting of C1-4 alkylene, C1-4 heteroalkylene, C2-4 alkenylene, C2-4 alkynylene; and wherein the aliphatic and aromatic portions of R1 are optionally substituted with from 1 to 5 RR1 substituents selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, F, Cl, Br, I, \u2014OH, \u2014CN, \u2014NO2, \u2550O, \u2014(X1R)0-1NRR1aRR1b, \u2014(X1R)0-1ORR1a, \u2014(X1R)0-1SRR1a, \u2014(X1R)0-1N(RR1a)C(\u2550O)ORR1c, \u2014(X1R)0-1OC(\u2550O)N(RR1a)(RR1b), \u2014(X1R)0-1N(RR1a)C(\u2550O)N(RR1a)(RR1b), \u2014(X1R)0-1C(\u2550O)N(RR1a)(RR1b), \u2014(X1R)0-1N(RR1a)C(\u2550O)RR1b, \u2014(X1R)0-1C(\u2550O)ORR1a, \u2014(X1R)0-1OC(\u2550O)RR1a, \u2014(X1R)0-1\u2014P(\u2550O)(ORR1a)(ORR1b), \u2014(X1R)0-1S(O)1-2RR1c, \u2014(X1R)0-1S(O)1-2N(RR1a)(RR1b), \u2014(X1R)0-1N(RR1a)S(O)1-2N(RR1a)(RR1b) and \u2014(X1R)0-1N(RR1a)S(O)1-2(RR1c), wherein X1R is selected from the group consisting of C1-4 alkylene, C1-4 heteroalkylene, C2-4 alkenylene and C2-4 alkynylene; wherein RR1a and RR1b are independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-8 cycloalkyl, phenyl, benzyl, heteroaryl, and C2-7 heterocycloalkyl; RR1c is selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-8 cycloalkyl, phenyl, benzyl, heteroaryl, and C2-7 heterocycloalkyl;
RN is hydrogen, C1-4 alkyl or C1-4 haloalkyl;
B is C or N;
R2, R3 and R4 are each independently selected from the group consisting of H, F, Cl, Br, I, \u2014CN, C1-8 alkyl, C1-8 haloalkyl and C1-8 alkoxy, and R3 is absent when B is nitrogen;
R5 is selected from the group consisting of H, F, Cl, Br, I, \u2014CN, C1-8 alkyl, C1-8 haloalkyl, C1-8 alkoxy, C3-8 cycloalkyl, C2-7 heterocycloalkyl, phenyl and 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl is further optionally substituted with from 1 to 3 R5 substituents selected from F, Cl, Br, I, \u2014CN, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkoxy;
L is a linker selected from the group consisting of C1-4 alkylene, C2-4 alkenylene, C2-4 alkynylene, and C1-4 heteroalkylene, wherein L is optionally substituted with from 1 to 3 RL substituents selected from the group consisting of \u2550O, C1-4 alkyl, C1-4 haloalkyl and C1-4 acyl;
the subscript m represents the integer 0 or 1;
X1 and X2 are each independently selected from the group consisting of absent, \u2014O\u2014, \u2014S(O)\u2014, \u2014S(O)2\u2014 and \u2014N(RX)\u2014 wherein Rx is H, C1-8 alkyl, C1-8 acyl or \u2014S(O)2(C1-8 alkyl), and wherein if the subscript m is 0 then one of X1 or X2 is absent;
the subscript n is an integer from 0 to 5;
A is selected from the group consisting of hydrogen, C3-12 cycloalkyl, C2-11 heterocycloalkyl, phenyl having a 3-8 membered carbocyclic or heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and S fused thereto or a 5 to 6 membered heteroaryl having a 3-8 membered carbocyclic or heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and S fused thereto, and wherein if A is hydrogen then the subscript n is 0; and
RA is selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, F, Cl, Br, I, \u2014OH, \u2014CN, \u2014NO2, \u2550O, heteroaryl, \u2014(XRA)0-1NRA1RA2, \u2014(XRA)0-1ORA1, \u2014(XRA)0-1SRA1, \u2014(XRA)0-1N(RA1)C(\u2550O)ORA3, \u2014(XRA)0-1OC(\u2550O)N(RA1)(RA2), \u2014(XRA)0-1N(RA1)C(\u2550O)N(RA1)(RA2), \u2014(XRA)0-1C(\u2550O)N(RA1)(RA2), \u2014(XRA)0-1N(RA1)C(\u2550O)RA2, \u2014(XRA)0-1C(\u2550O)ORA1, \u2014(XRA)0-1OC(\u2550O)RA1, \u2014P(\u2550O)(ORA1)(ORA2), \u2014(XRA)0-1S(O)1-2RA3, \u2014(XRA)0-1S(O)1-2N(RA1)(RA2), \u2014(XRA)0-1N(RA1)S(O)1-2N(RA1)(RA2) and \u2014(XRA)0-1N(RA1)S(O)1-2(RA3), wherein XRA is selected from the group consisting of C1-4 alkylene, C1-4 heteroalkylene, C2-4 alkenylene and C2-4 alkynylene; wherein RA1 and RA2 are independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-8 cycloalkyl, tetrahydronapthalene, phenyl, benzyl, heteroaryl, and C2-7 heterocycloalkyl; RA3 is selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-8 cycloalkyl, tetrahydronapthalene, phenyl, benzyl, heteroaryl, and C2-7 heterocycloalkyl; wherein if A is a monocyclic C3-12 carbocycloalkyl or monocyclic C2-11 heterocycloalkyl, then any two RA substituents attached to adjacent atoms on the A ring are optionally combined to form a benzene or a 5 to 6 membered heteroaryl ring; and wherein the aliphatic and aromatic portions of a RA substitutent is optionally substituted with from 1 to 5 RRA substitutents selected from, F, Cl, Br, I, \u2014NH2, \u2014OH, \u2014CN, \u2014NO2, \u2550O, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 (halo)alkyl-C(\u2550O)\u2014, C1-4 (halo)alkyl-S(O)0-2\u2014, C1-4 (halo)alkyl-C(\u2550O)N(H)\u2014, C1-4 (halo)alkyl-N(H)\u2014C(\u2550O)\u2014, ((halo)alkyl)2N\u2014C(\u2550O)\u2014, C1-4 (halo)alkyl-OC(\u2550O)N(H)\u2014, C1-4 (halo)alkyl-OC(\u2550O)N(H)\u2014, (halo)alkyl-N(H)\u2014C(\u2550O)O\u2014, ((halo)alkyl)2N\u2014C(\u2550O)O\u2014, C1-4 alkylamino, C1-4 dialkylamino, C3-6 cycloalkyl, C3-6 cycloalkoxy, C2-5 heterocycloalkoxy and tetrahydronaphthalene;
with the proviso that a compound of Formula I is not
4-(cyclohexylmethoxy)-N-(methylsulfonyl)benzamide;
4-(cyclopentylmethoxy)-N-(methylsulfonyl)benzamide or
4-(cyclobutylmethoxy)-2,5-difluoro-N-(methylsulfonyl)benzamide.
2. The compound of claim 1 wherein:
R1 is C1-8 alkyl, C1-8 haloalkyl, C1-8 alkoxy, C3-12 cycloalkyl, C-linked C2-11 heterocycloalkyl or \u2014NR1AR1B, wherein R1A and R1B are each independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkoxy, (6-10 membered aryl)-(XR1)0-1\u2014, (5-10 membered heteroaryl)-(XR1)0-1\u2014, and wherein R1A and R1B are optionally combined to form a 3 to 8 membered heterocyclic ring optionally comprising 1 additional heteroatoms selected from N, O and S as ring vertex and optionally fused thereto is a benzene or pyridine ring; XR1 is selected from the group consisting of C1-4 alkylene, C1-4 heteroalkylene, C2-4 alkenylene, C2-4 alkynylene; and wherein the aliphatic and aromatic portions of R1 are optionally substituted with from 1 to 5 RR1 substituents selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, F, Cl, Br, I, \u2014OH, \u2014CN, \u2014NO2, \u2550O, \u2014(X1R)0-1NRR1aRR1b, \u2014(X1R)0-1ORR1a, \u2014(X1R)0-1SRR1a, \u2014(X1R)0-1N(RR1a)C(\u2550O)ORR1c, \u2014(X1R)0-1OC(\u2550O)N(RR1a)(RR1b), \u2014(X1R)0-1N(RR1a)C(\u2550O)N(RR1a)(RR1b), \u2014(X1R)0-1C(\u2550O)N(RR1a)(RR1b), \u2014(X1R)0-1N(RR1a)C(\u2550O)RR1b, \u2014(X1R)0-1C(\u2550O)ORR1a, \u2014(X1R)0-1OC(\u2550O)RR1a, \u2014(X1R)0-1\u2014P(\u2550O)(ORR1a)(ORR1b), \u2014(X1R)0-1S(O)1-2RR1c, \u2014(X1R)0-1S(O)1-2N(RR1a)(RR1b), \u2014(X1R)0-1N(RR1a)S(O)1-2N(RR1a)(RR1b) and \u2014(X1R)0-1N(RR1a)S(O)1-2(RR1c), wherein X1R is selected from the group consisting of C1-4 alkylene, C1-4 heteroalkylene, C2-4 alkenylene and C2-4 alkynylene; wherein RR1a and RR1b are independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-8 cycloalkyl, phenyl, benzyl, C5-6 heteroaryl and C2-7 heterocycloalkyl; RR1c is selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-8 cycloalkyl, phenyl, benzyl, C5-6 heteroaryl and C2-7 heterocycloalkyl;
RN is hydrogen, C1-4 alkyl or C1-4 haloalkyl;
B is C or N;
R2, R3 and R4 are each independently selected from the group consisting of H, F, Cl, Br, I, \u2014CN, C1-8 alkyl, C1-8 haloalkyl and C1-8 alkoxy, and R3 is absent when B is nitrogen;
R5 is selected from the group consisting of H, F, Cl, Br, I, \u2014CN, C1-8 alkyl, C1-8 haloalkyl, C1-8 alkoxy, C3-8 cycloalkyl, C2-7 heterocycloalkyl, phenyl and 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl is further optionally substituted with from 1 to 3 R5 substituents selected from F, Cl, Br, I, \u2014CN, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkoxy;
L is a linker selected from the group consisting of C1-4 alkylene, C2-4 alkenylene, C2-4 alkynylene, and C1-4 heteroalkylene, wherein L is optionally substituted with from 1 to 3 RL substituents selected from the group consisting of \u2550O, C1-4 alkyl, C1-4 haloalkyl and C1-4 acyl;
the subscript m represents the integer 0 or 1;
X1 and X2 are each independently selected from the group consisting of absent, \u2014O\u2014, \u2014S(O)\u2014, \u2014S(O)2\u2014 and \u2014N(RX)\u2014 wherein Rx is C1-8 alkyl, C1-8 acyl or \u2014S(O)2(C1-8 alkyl), and wherein if the subscript m is 0 then one of X1 or X2 is absent;
the subscript n is an integer from 0 to 5;
A is selected from the group consisting of hydrogen, C3-12 cycloalkyl, C2-11 heterocycloalkyl, phenyl having a 3-8 membered carbocyclic or heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and S fused thereto or a 5 to 6 membered heteroaryl having a 3-8 membered carbocyclic or heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and S fused thereto, and wherein if A is hydrogen then the subscript n is 0; and
RA is selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, F, Cl, Br, I, \u2014OH, \u2014CN, \u2014NO2, \u2014(XRA)0-1NRA1RA2, \u2014(XRA)0-1ORA1, \u2014(XRA)0-1SRA1, \u2014(XRA)0-1N(RA1)C(\u2550O)ORA3, \u2014(XRA)0-1OC(\u2550O)N(RA1)(RA2), \u2014(XRA)0-1N(RA1)C(\u2550O)N(RA1)(RA2), \u2014(XRA)0-1C(\u2550O)N(RA1)(RA2), \u2014(XRA)0-1N(RA1)C(\u2550O)RA2, \u2014(XRA)0-1C(\u2550O)ORA1, \u2014(XRA)0-1OC(\u2550O)RA1, \u2014P(\u2550O)(ORA1)(ORA2), \u2014(XRA)0-1S(O)1-2RA3, \u2014(XRA)0-1S(O)1-2N(RA1)(RA2), \u2014(XRA)0-1N(RA1)S(O)1-2N(RA1)(RA2) and \u2014(XRA)0-1N(RA1)S(O)1-2(RA3), wherein XRA is selected from the group consisting of C1-4 alkylene, C1-4 heteroalkylene, C2-4 alkenylene and C2-4 alkynylene; wherein RA1 and RA2 are independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-8 cycloalkyl, tetrahydronapthalene, phenyl, benzyl, C5-6 heteroaryl and C2-7 heterocycloalkyl; RA3 is selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-8 cycloalkyl, tetrahydronapthalene, phenyl, benzyl, C5-6 heteroaryl and C2-7 heterocycloalkyl; wherein if A is a monocyclic C3-12 carbocycloalkyl or monocyclic C2-11 heterocycloalkyl, then any two RA substituents attached to adjacent atoms on the A ring are optionally combined to form a benzene or a 5 to 6 membered heteroaryl ring; and wherein the aliphatic and aromatic portions of a RA substitutent is optionally substituted with from 1 to 5 RRA substitutents selected from, F, Cl, Br, I, \u2014NH2, \u2014OH, \u2014CN, \u2014NO2, \u2550O, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 (halo)alkyl-C(\u2550O)\u2014, C1-4 (halo)alkyl-S(O)0-2\u2014, C1-4 (halo)alkyl-C(\u2550O)N(H)\u2014, C1-4 (halo)alkyl-N(H)\u2014C(\u2550O)\u2014, ((halo)alkyl)2N\u2014C(\u2550O)\u2014, C1-4 (halo)alkyl-OC(\u2550O)N(H)\u2014, C1-4 (halo)alkyl-OC(\u2550O)N(H)\u2014, (halo)alkyl-N(H)\u2014C(\u2550O)O\u2014, ((halo)alkyl)2N\u2014C(\u2550O)O\u2014, C1-4 alkylamino, C1-4 dialkylamino, C3-6 cycloalkyl, C3-6 cycloalkoxy, C2-5 heterocycloalkoxy and tetrahydronaphthalene.
3. The compound of claim 1, wherein the compound has the formula
4. The compound of claim 1 wherein B is N and R3 is absent.
5. The compound of claim 1 wherein B is C.
6. The compound of claim 1 wherein R2, R3 and R4 are each independently selected from H, F, or Cl.
7. The compound of claim 1 wherein R2 is H, F or Cl; R3 and R4 are each H; and R5 is an optionally substituted group selected from the group consisting of H, F, Cl, Br, I, \u2014CN, C1-8 alkyl, C1-8 haloalkyl and C1-8 alkoxy.
8. The compound of claim 1 wherein R1 is C1-8 alkyl, C1-8 haloalkyl, C3-10 cycloalkyl or \u2014NR1AR1B.
9. The compound of claim 8, wherein R1 is selected from the group consisting of methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, monofluoromethyl, isopropyl and cyclopropyl.
10. The compound of claim 8, wherein R1 is selected from the group consisting of:
11. The compound of claim 1 wherein R1 is selected from the group consisting of: methyl, ethyl, tert-butyl, dimethylamino, methylamino, amino, morpholino, azetidino, imidazolyl, 3-hydroxyazetidino, 3-fluoroazetidino, cyclopropyl, pyrrolidinyl, 3,3-difluoroazetidino, tert-butyl, ethyl, 2-methoxyethyl, 3-methoxyazetidino, 2-hydroxyethyl, 3-hydroxypyrrolidinyl, and N-methylimidazolyl.
12. The compound of claim 1 wherein X1 is \u2014O\u2014 or \u2014N(H)\u2014; X2 is absent; the subscript m is 1; and -(L)- is an optionally substituted group selected from the group consisting of C1-4 alkylene, C2-4 alkenylene or C2-4 alkynylene.
13. The compound of claim 1, wherein X1 is \u2014O\u2014 or \u2014N(H)\u2014; X2 is absent; the subscript m is 1; and -(L)- is selected from the group consisting of \u2014CH2\u2014, \u2014C(\u2550O)\u2014, \u2014C(H)(CH3)\u2014, \u2014CH2\u2014CH2\u2014, \u2014CH2\u2014C(H)(CH3)\u2014, \u2014C(H)(CH3)\u2014C(H2)\u2014, \u2014CH2CH2CH2\u2014, \u2014CH2\u2014C(H)(CH3)\u2014CH2\u2014 or \u2014CH2CH2CH2CH2\u2014.
14. The compound of claim 13, wherein X1 is \u2014O\u2014; the subscript m is 1 and -(L)- is \u2014CH2\u2014 or \u2014CH2\u2014CH2\u2014.
15. The compound of claim 1 wherein X1 is absent; X2 is \u2014O\u2014 or \u2014N(H)\u2014; the subscript m is 1; and -(L)- is selected from the group consisting of \u2014C(H)2\u2014, \u2014C(\u2550O)\u2014, \u2014C(H)(CH3)\u2014, \u2014CH2\u2014CH2\u2014, \u2014CH2\u2014C(H)(CH3)\u2014, \u2014C(H)(CH3)\u2014C(H2)\u2014, \u2014CH2CH2CH2\u2014, \u2014CH2\u2014C(H)(CH3)\u2014CH2\u2014 or \u2014CH2CH2CH2CH2\u2014.
16. The compound of claim 1 wherein X1 and X2 is absent; the subscript m is 1; and -(L)- is selected from the group consisting of \u2014C(H)2\u2014, \u2014C(\u2550O)\u2014, \u2014C(H)(CH3)\u2014, \u2014CH2\u2014CH2\u2014, \u2014CH2\u2014C(H)(CH3)\u2014, \u2014C(H)(CH3)\u2014C(H2)\u2014, \u2014CH2CH2CH2\u2014, \u2014CH2\u2014C(H)(CH3)\u2014CH2\u2014 or \u2014CH2CH2CH2CH2\u2014.
17. The compound of claim 1 wherein X1 and X2 is absent; the subscript m is 1; and -(L)- is an optionally substituted C1-4 heteroalkylene.
18. The compound of claim 1 wherein m is 0; X1 is selected from \u2014O\u2014, and \u2014N(H)\u2014; and X2 is absent.
19. The compound of claim 1 wherein A is an optionally substituted ring selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, adamantane, bicyclo2.1.1hexane, bicyclo2.2.2octane, bicyclo2.2.1heptane, bicyclo3.1.1heptane, bicyclo3.2.1octane, bicyclo4.1.1octane, bicyclo3.3.1nonane and 1,2,3,4-tetrahydro-1,4-methanonaphthalene, 1,2,3,4-tetrahydroisoquinoline and chroman.
20. The compound of claim 19, wherein ring A is an optionally substituted ring selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, adamantane, cubane, bicyclo2.2.2octane, bicyclo3.1.1heptane, bicyclo2.2.1heptane, piperidinyl, tetrahydrofuranyl, tetrahydronaphthyl, spiro2,5octanyl, norpinanyl, spiro3.5nonanyl, 8-azabicyclo3.2.1octanyl, norbornanyl, spiro4.5decanyl, bicyclo4.1.0heptane and spiro5.5undecanyl.
21. The compound of claim 19, wherein ring A-(RA)n is selected from the group consisting of
22. The compound of claim 1 wherein ring A is an optionally substituted ring selected from the group consisting of azetidine, pyrrolidine, piperidine, homopiperidine, (1R,5S)-8-azabicyclo3.2.1octane, 3-oxa-9-azabicyclo3.3.1nonane, (1s,4s)-7-azabicyclo2.2.1heptane, (1R,4S)-5-azabicyclo2.1.1hexane, 7-(trifluoromethyl)-1,2,3,4-tetrahydropyrrolo1,2-apyrazine and quinuclidine.
23. The compound of claim 18, wherein A is selected from the group consisting of
24. The compound of claim 1 wherein RA is selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C3-5 cycloalkyl, C2-4 heterocycloalkyl, F, Cl, Br, I, \u2014OH, \u2014NH2, \u2014CN, \u2014NO2, C1-4 alkoxy, \u2014C(\u2550O)\u2014N(RA1)(RA2) and \u2014N(RA1)(RA2).
25. The compound of claim 24, wherein RA is methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, ethyl, pentafluoroethyl, cyclopropyl, \u2014F, Cl, \u2014OH, \u2014NH2 or \u2014CN.
26. A pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as described in claim 1 and a pharmaceutically acceptable excipient.
27. A method of treating a disease or condition in a mammal selected from the group consisting of pain, depression, cardiovascular diseases, respiratory diseases, and psychiatric diseases, and combinations thereof, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof as described in claim 1.
28. The method of claim 27, wherein said disease or condition is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, childbirth pain, labor pain, neurogenic bladder, ulcerative colitis, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache, sinus headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury or a combination thereof.
29. The method of claim 27, wherein said disease or condition is selected from the group consisting of pain associated with HIV, HIV treatment induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, eudynia, heat sensitivity, tosarcoidosis, irritable bowel syndrome, Crohns disease, pain associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxi related illnesses, familial erythromelalgia, primary erythromelalgia, familial rectal pain, cancer, epilepsy, partial and general tonic seizures, restless leg syndrome, arrhythmias, fibromyalgia, neuroprotection under ischaemic conditions cause by stroke or neural trauma, tach-arrhythmias, atrial fibrillation and ventricular fibrillation.
30. A method of treating pain in a mammal by the inhibition of ion flux through a voltage-dependent sodium channel in the mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof as described in claim 1.
31. A method of decreasing ion flux through a voltage-dependent sodium channel in a cell in a mammal, wherein the method comprises contacting the cell with a compound of Formula I or a pharmaceutically acceptable salt thereof as described in claim 1.
32. A method of treating pruritus in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof as described in claim 1.
33. A method of treating cancer in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof as described in claim 1.
34. A method of treating, but not preventing, pain in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof as described in claim 1.
35. The method of claim 34, wherein the pain is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, childbirth pain, labor pain, neurogenic bladder, ulcerative colitis, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache, sinus headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury or a combination thereof.
36. The method of claim 34, wherein the pain is associated with a disease or condition selected from the group consisting of HIV, HIV treatment induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, eudynia, heat sensitivity, tosarcoidosis, irritable bowel syndrome, Crohns disease, pain associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxi related illnesses, familial erythromelalgia, primary erythromelalgia, familial rectal pain, cancer, epilepsy, partial and general tonic seizures, restless leg syndrome, arrhythmias, fibromyalgia, neuroprotection under ischaemic conditions cause by stroke or neural trauma, tach-arrhythmias, atrial fibrillation and ventricular fibrillation.
37. A method for the treatment or prophylaxis of pain, depression, cardiovascular diseases, respiratory diseases, and psychiatric diseases, and combinations thereof, which method comprises administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof as described in claim 1.
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 hardware accelerator for assisting in processing queries from a host system to a database, wherein the hardware accelerator executes machine code for database query tasks in hardware processing elements from a database management system, said hardware accelerator comprising:
a scanning processing element to perform at least one of parallel field extraction and comparison of database columns;
an indexing processing element to perform at least one of a database projection operation; and
an associative processing element to perform at least one of groupingaggregating, sieving, sorting, and an associative join.
2. The hardware accelerator according to claim 1, further comprising a dedicated memory that is capable of storing gigabyte portions of the database.
3. The hardware accelerator according to claim 1, wherein the hardware accelerator is coupled to the host system over a Peripheral Component Interconnect Express connection.
4. The hardware accelerator according to claim 1, wherein the hardware accelerator is coupled to the host system over a HyperTransport connection.
5. The hardware accelerator according to claim 1, wherein the hardware accelerator comprises field programmable gate array (FPGA) logic that reconfigures operations of at least one of the scanning processing element, the indexing processing element, and the associative processing element.
6. The hardware accelerator according to claim 1, wherein comprises Application Specific Integrated Circuit (ASIC) logic that reconfigures operations of at least one of the scanning processing element, the indexing processing element, and the associative processing element.
7. A database hardware accelerator module configured to be coupled with a host system running a database management system via an interconnect bus, said module comprising:
a set of processing elements configured to receive database machine code instructions and execute them in their respective hardware without software and return results back to the host system upon completion, wherein the processing elements are configured with a dataflow architecture;
a self-routing fabric coupling the processing elements, wherein the processing elements communicate with each other based on Inter Macro-Op Communication (IMC) data structures in a pipelined parallel fashion; and
a memory capable of storing gigabyte portions of the database in compressed, column-store format.
8. The module of claim 7, wherein the IMC is a physical data structure in the processing elements.
9. The module of claim 7, wherein the set of processing elements are configured to support task pipelining.
10. The module of claim 7, wherein the set of processing elements are configured to process data fetched from storage while data is being fetched from storage.
11. The module of claim 7, wherein the processing elements access data in the memory based on a physical address that is arithmetically derived from a global database virtual address space.
12. The module of claim 7, wherein the processing elements access data in the memory based on a physical address that is arithmetically derived from a global database virtual address space and an implicit row identifier of the data in the database.
13. A database hardware accelerator node coupled to a host system, wherein the hardware accelerator executes machine code for database query tasks in hardware processing elements from a database management system running on the host system, said hardware accelerator comprising:
a set of processing cores comprising combined logic for a scanning processing element to perform at least one of parallel field extraction and comparison of database columns and an indexing processing element to perform at least one of a database projection operation and a hardware-accelerated index content addressable memory processing element to perform at least one of groupingaggregating, sieving, sorting, and an associative join;
a self routing switching fabric that couples the processing cores together; and
a memory capable of storing gigabyte portions of the database.
14. The hardware accelerator according to claim 13, further comprising a Peripheral Component Interconnect Express interface.
15. The hardware accelerator according to claim 13, further comprising a HyperTransport interface.
16. The hardware accelerator according to claim 13, wherein the set of processing cores are implemented based on field programmable gate arrays.
17. The hardware accelerator according to claim 13, wherein the set of processing cores are implemented based on Application Specific Integrated Circuits.
18. The hardware accelerator according claim 13, wherein the hardware accelerator comprises a set of four identical processing cores.
19. The hardware accelerator according claim 13, wherein the hardware accelerator comprises pairs of identical processing cores.
20. The hardware accelerator according to claim 13, wherein the memory is at least 256 Gigabytes.
21. The hardware accelerator according to claim 13, wherein the memory is about 32 Gigabytes.
22. The hardware accelerator according to claim 13, wherein the memory is about 16 Gigabytes.
23. The hardware accelerator according to claim 13, wherein the set of processing cores are programmable by machine code database instructions.
24. The hardware accelerator according to claim 13, wherein the set of processing cores are reconfigurable in the manner in which they execute machine code database instructions.
25. The hardware accelerator of claim 1, further comprising a task processor configured to assign the database query tasks from the host database system to at least one of the scanning processing element, the indexing processing element, and the associative processing element.
26. The hardware accelerator of claim 2, wherein the dedicated memory is about 32 Gigabytes.
27. The hardware accelerator of claim 2, wherein the dedicated memory is at least 256 Gigabytes.
28. The hardware accelerator of claim 2, wherein the hardware accelerator is configured as a memory module package.
29. The hardware accelerator of claim 2, wherein the hardware accelerator is configured as a rack-mountable unit.
30. The database hardware accelerator module of claim 7, wherein the hardware accelerator module is configured as a memory module package.
31. The database hardware accelerator module of claim 7, wherein the hardware accelerator module is configured as a rack-mountable unit.
32. A hardware accelerator for assisting in processing queries from a host system to a database, wherein the hardware accelerator is configured to execute database machine code instructions for at least a portion of the queries, said hardware accelerator comprising:
an input for receiving database machine code instructions for tasks of a query offloaded to the hardware accelerator;
a set of processing elements configured to execute the database machine code instructions on data from the database for the tasks; and
an output for providing a result for the tasks based on the execution of the database machine code instructions.
33. The hardware accelerator of claim 31, further comprising a memory configured to store portions of the database in column-store format.
34. The hardware accelerator of claim 32, wherein the processing elements are configured to process data from the memory in a dataflow based on the database machine code instructions.
35. The hardware accelerator of claim 32, wherein processing elements comprise logic configured to scan a set of pointers and data from the portion of the database in memory against a predicate specified in the database machine code instructions.
36. The hardware accelerator of claim 32, wherein the processing elements can be configured to perform a fetch database operation based on the database machine code instructions.
37. The hardware accelerator of claim 32, wherein the processing elements can be configured to perform a format database operation based on the database machine code instructions.
38. The hardware accelerator of claim 32, wherein the processing elements can be configured to perform a join database operation based on the database machine code instructions.
39. The hardware accelerator of claim 32, wherein the processing elements can be configured to emit a dataflow of a scan of contiguous rows in a portion of the database in the memory based on the database machine code instructions.
40. The hardware accelerator of claim 32, wherein the processing elements can be configured to emit a dataflow of a nested-loop cross-product join of two columns in the portion of the database in the memory based on the database machine code instructions.
41. The hardware accelerator of claim 32, wherein the processing elements can be configured to emit a dataflow of an index-based nested join of columns in the portion of the database in the memory based on the database machine code instructions.
42. The hardware accelerator of claim 32, wherein the processing elements can be configured to emit a dataflow of scans of a dispersed subset of rows in a column of the portion of the database in the memory based on the database machine code instructions.
43. The hardware accelerator of claim 38, wherein the processing elements are configured to communicate via numbered communications channels specified in the database machine code instructions.
44. The hardware accelerator of claim 32, wherein the processing elements are configured to traverse an index of data from the portion of the database in the memory against a set of predicates specified in the database machine code instructions.
45. The hardware accelerator of claim 32, wherein the processing elements are configured to scan a group index source column and emit a dataflow of pointers to a target table that have been joined through the index based on the database machine code instructions.
46. The hardware accelerator of claim 32, wherein the processing elements are configured to emit a dataflow of results for database list operations based on a database machine code instructions.
47. The hardware accelerator of claim 32, wherein the processing elements are configured to collect items from a dataflow of data from the portion of the database in memory against at least one predicate specified in the database machine code instructions.
48. The hardware accelerator of claim 32, wherein the processing elements can be configured to emit a dataflow for a two dimensional list composed of a set of input lists that are horizontally correlated based on the database machine code instructions
49. The hardware accelerator of claim 32, wherein the processing elements are configured to emit a dataflow for an inner-loop cross-product nested join of lists against a predicate specifying one or more columns based on the database machine code instructions.
50. The hardware accelerator of claim 32, wherein the processing elements are configured to emit a vertical merger of two lists from the portion of the database in the memory based on the database machine code instructions.
51. The hardware accelerator of claim 32, wherein the processing elements are configured to emit a dataflow of tuples from the portion of the database selected from the memory against at least one column predicate based on the database machine code instructions.
52. The hardware accelerator of claim 32, wherein the processing elements are configured to emit a dataflow of arithmetic results performed on at least one list based on the database machine code instructions.
53. The hardware accelerator of claim 32, wherein the processing elements are configured to emit a dataflow of results for operations that are based on an associative key based on the database machine code instructions.
54. The hardware accelerator of claim 32, wherein the processing elements are configured to emit results mapped to locations in memory for operations that are based on an associative key based on the database machine code instructions.
55. The hardware accelerator of claim 32, wherein the processing elements are configured to perform value-based database operations on the dataflow of data from the portion of the database in the memory based on the database machine code instructions.
56. The hardware accelerator of claim 32, wherein the processing elements are configured to emit a dataflow of results for a histogram of like keys found in an input list of a dataflow from the memory using a specified mapping based on the database machine code instructions.
57. The hardware accelerator of claim 32, wherein the processing elements are configured to emit a dataflow of reordered tuples in a 2-dimensional input list of two columns from a dataflow from the memory such that extreme N keys occur in the final N tuple rows, contiguously based on the database machine code instructions.
58. The hardware accelerator of claim 32, wherein the processing elements are configured to emit a dataflow of an aggregation function performed on the dataflow based on the database machine code instructions.
59. The hardware accelerator of claim 32, wherein the processing elements are configured to emit results to locations in memory for an aggregation function performed on the dataflow based on the database machine code instructions.