NOVEL PIPERAZINES, PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE THEREOF

1 . (canceled)

2 . A method of treating an inflammatory condition in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt thereof:

wherein:

R 1 is selected from the group consisting of H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, C(═O)R 5 , C(═O)OR 5 and C(═O)NR 5 R 5 ;

V is selected from the group consisting of a bond, C(R 4 ) 2 , C(R 4 ) 2 C(R 4 ) 2 , C(R 4 ) 2 C(R 4 ) 2 R 6 , C(R 4 ) 2 C(R 4 ) 2 C(R 4 ) 2 R 6 , C(═O), C(═O)R 6 , C(═S), C(═S)R 6 , CH 2 C(═O), CH 2 C(═O)R 6 , CH 2 C(═S), CH 2 C(═S)R 6 , SO 2 , and SO 2 R 6 ;

A is a linking —C(R a ) 2 —X a —;

X a is selected from the group consisting of O, C(R 4 ) 2 O, OC(R 4 ) 2 , NR 5 , C(═O), C(R 4 ) 2 C(═O), C(═O)NR 5 , C(R 4 ) 2 NR 5 , NR 5 C(R 4 ) 2 , NR 5 C(═O), NR 5 C(═O)C(R 4 ) 2 , S, C(R 4 ) 2 S, and SC(R 4 ) 2 ;

when X a is C(R 4 ) 2 O, C(R 4 ) 2 NR 5 , C(═O), C(R 4 ) 2 C(═O), C(═O)NR 5 or C(R 4 ) 2 S, then each R a is independently selected from the group consisting of H, C1-C10 alkyl, C1-C10 alkyl substituted with one or more R 7 , C2-C10 alkenyl, C2-C10 alkenyl substituted with one or more R 7 , C2-C10 alkynyl, C2-C10 alkynyl substituted with one or more R 7 , C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or more R 8 , C4-C10 cycloalkenyl, C4-C10 cycloalkenyl substituted with one or more R 8 , halo, haloalkyl, OR 5 , SR 5 , NR 5 R 5 , C(═O)OR 5 , NO 2 , CN, C(═O)R 5 , C(═O)C(═O)R 5 , C(═O)NR 5 R 5 , N(R 5 )C(═O)R 5 , NR 5 S(═O) n R 5 , N(R 5 )C(═O)OR 5 , NR 5 C(═O)C(═O)R 5 , NR 5 C(═O)R 5 , NR 5 S(═O) n NR 5 R 5 , NR 5 S(═O) n R 5 , S(═O) n R 5 , S(═O) n NR 5 R 5 and OC(═O)R 5 , or both R a are taken together to form a 3 to 6 membered ring containing 0 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein said ring is substituted with one or more R 8 ;

and,

when X a is O, OC(R 4 ) 2 , NR 5 , NR 5 C(R 4 ) 2 NR 5 C(═O), NC(═O)R 5 C(R 4 ) 2 , S, or SC(R 4 ) 2 , then each R a is independently selected from the group consisting of H, C1-C10 alkyl, C1-C10 alkyl substituted with one or more R 7 , C2-C10 alkenyl, C2-C10 alkenyl substituted with one or more R 7 , C2-C10 alkynyl, C2-C10 alkynyl substituted with one or more R 7 , C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or more R 8 , C4-C10 cycloalkenyl, C4-C10 cycloalkenyl substituted with one or more R 8 , haloalkyl, C(═O)OR 5 , CN, C(═O)R 5 , C(═O)C(═O)R 5 and C(═O)NR 5 R 5 , or both R a are taken together to form a 3 to 6 membered ring containing 0 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein said ring is substituted with one or more R 8 ;

each R 4 is independently selected from the group consisting of H, C1-C10 alkyl, C1-C10 alkyl substituted with one or more R 7 , C2-C10 alkenyl, C2-C10 alkenyl substituted with one or more R 7 , C2-C10 alkynyl, C2-C10 alkynyl substituted with one or more R 7 , C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or more R 8 , C4-C10 cycloalkenyl, C4-C10 cycloalkenyl substituted with one or more R 8 , halo, haloalkyl, OR 5 , SR 5 , NR 5 R 5 , C(═O)OR 5 , NO 2 , CN, C(═O)R 5 , C(═O)C(═O)R 5 , C(═O)NR 5 R 5 , N(R 5 )C(═O)R 5 , NR 5 S(═O) n R 5 , NR 5 C(═O)OR 5 , NR 5 C(═O)C(═O)R 5 , NR 5 C(═O)R 5 , NR 5 S(═O) n NR 5 R 5 , NR 5 S(═O) n R 5 , S(═O) n R 5 , S(═O) n NR 5 R 5 and OC(═O)R 5 , or two R 4 are taken together to form a 3-6 membered ring comprising 0-3 heteroatoms, wherein said heteroatom is independently selected from the group consisting of N, O and S, and wherein said ring is substituted with one or more R 8 ;

each R 5 is independently selected from the group consisting of H, C1-C10 alkyl and C2-C10 alkenyl;

each R 6 is independently selected from the group consisting of C(R 4 ) 2 , C(R 4 ) 2 C(R 4 ) 2 , NR 5 , O, C(═O), C(═O)C(R4) 2 , C(═O)O, OC(R 4 ) 2 , C(R 4 ) 2 O, C(R 4 ) 2 S, C(R 4 ) 2 NR 5 , NR 5 CH 2 , S and SC(R 4 ) 2 ;

each R 7 is independently selected from the group consisting of halo, haloalkyl, OR 5 , SR 5 , C(═O)R 5 , OC(═O)R 5 , C(═O)OR 5 , NR 5 R 5 , NO 2 , CN, OC(═O)NR 5 R 5 , C(═O)NR 5 R 5 , N(R 5 )C(═O)R 5 , NR 5 C(═O)OR 5 , S(═O) n NR 5 R 5 , C3-C8 cycloalkyl, C4-C10 cycloalkenyl, 3-8 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C5-C11 bicycloalkyl, C5-C11 bicycloalkenyl, 5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkenyl, aryl, and heteroaryl, wherein said aryl and heteroaryl are each optionally substituted with one or more R 9 ;

each R 8 is independently selected from the group consisting of R 7 , C1-C10 alkyl, C1-C10 alkyl substituted with one or more R 7 , C2-C10 alkenyl, C2-C10 alkenyl substituted with one or more R 7 , C2-C10 alkynyl, and C2-C10 alkynyl substituted with one or more R 7 ;

each R 9 is independently selected from the group consisting of C1-C10 alkyl, C1-C10 alkyl substituted with one or more R 7 , C2-C10 alkenyl, C2-C10 alkenyl substituted with one or more R 7 , C2-C10 alkynyl, C2-C10 alkynyl substituted with one or more R 7 , C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or more R 8 , C4-C10 cycloalkenyl, C4-C10 cycloalkenyl substituted with one or more R 8 , 3-8 membered heterocycloalkyl, 3-8 membered eterocycloalkyl substituted with one or more R 8 , 4-10 membered heterocycloalkenyl, 4-10 membered heterocycloalkenyl substituted with one or more R 8 , C5-C11 bicycloalkyl, C5-C11 bicycloalkyl substituted with one or more R 8 , C5-C11 bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R 8 , 5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkyl substituted with one or more R 8 , 5-11 membered heterobicycloalkenyl, 5-11 membered heterobicycloalkenyl substituted with one or more R 8 , halo, OR 5 , SR 5 , NR 5 R 5 , C(═O)OR 5 , NO 2 , CN, C(═O)R 5 , C(═O)C(═O)R 5 , C(═O)NR 5 R 5 , NR 5 C(═O)R 5 , NR 5 S(═O) n R 5 , NR 5 C(═O)OR 5 , NR 5 C(═O)C(═O)R 5 , NR 5 C(═O)NR 5 R 5 , NR 5 S(═O) n NR 5 R 5 , NR 5 S(═O) n R 5 , S(═O) n R 5 , S(═O) n NR 5 R 5 , OC(═O)R 5 , optionally substituted aryl, and optionally substituted heteroaryl;

R 12 is selected from the group consisting of C1-C10 alkyl, C1-C10 alkyl substituted with one or more R 7 , C2-C10 alkenyl, C2-C10 alkenyl substituted with one or more R 7 , C2-C10 alkynyl, C2-C10 alkynyl substituted with one or more R 7 , C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with one or more R 8 , C4-C10 cycloalkenyl, C4-C10 cycloalkenyl substituted with one or more R 8 , 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one or more R 8 , 4-10 membered heterocycloalkenyl, 4-10 membered heterocycloalkenyl substituted with one or more R 8 , C5-C11 bicycloalkyl, C5-C11 bicycloalkyl substituted with one or more R 8 , C5-C11 bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R 8 , 5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkyl substituted with one or more R 8 , 5-11 membered heterobicycloalkenyl, 5-11 membered heterobicycloalkenyl substituted with one or more R 8 , aryl, and heteroaryl, wherein said aryl and heteroaryl are each optionally substituted with one or more R 9 ;

each R 13 independently selected from the group consisting of C1-C10 alkyl, C1-C10 alkyl substituted with one or more R 7 , C2-C10 alkenyl, C2-C10 alkenyl substituted with one or more R 7 , C2-C10 alkynyl, C2-C10 alkynyl substituted with one or more R 7 , C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or more R 8 , C4-C10 cycloalkenyl, C4-C10 cycloalkenyl substituted with one or more R 8 , 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one or more R 8 , 4-10 membered heterocycloalkenyl, 4-10 membered heterocycloalkenyl substituted with one or more R 8 , C5-C11 bicycloalkyl, C5-C11 bicycloalkyl substituted with one or more R 8 , C5-C11 bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R 8 , 5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkyl substituted with one or more R 8 , 5-11 membered heterobicycloalkenyl, 5-11 membered heterobicycloalkenyl, 5-11 membered heterobicycloalkenyl substituted with one or more R 8 , halo, OR 5 , SR 5 , NR 5 R 5 , C(═O)OR 5 , NO 2 , CN, C(═O)R 5 , C(═O)C(═O)R 5 , C(═O)NR 5 R 5 , NR 5 C(═O)R 5 , NR 5 S(═O) a R 5 , NR 5 C(═O)OR 5 , NR 5 C(═O)C(═O)R 5 , NR 5 C(═O)NR 5 R 5 , NR 5 S(═O) a NR 5 R 5 , NR 5 S(═O) a R 5 , S(═O) a R 5 , S(═O) a NR 5 R 5 , OC(═O)R 5 , optionally substituted aryl and optionally substituted heteroaryl;

n is 1 or 2; and

q is 0, 1, 2, 3 or 4.

3 . The method of claim 2 , wherein X a is selected from the group consisting of O, and wherein NR 5 and each R a is independently selected from the group consisting of H, C1-C10 alkyl, C2-C10 alkenyl, OR 5 , halo and haloalkyl.

4 . The method of claim 2 , wherein R 12 is selected from the group consisting of aryl and heteroaryl, wherein the aryl and heteroaryl are each optionally substituted with one or more R 9 .

5 . The method of claim 2 , wherein X a is O and V is a bond.

6 . The method of claim 4 , wherein R 12 is selected from the group consisting of:

wherein:

W is selected from the group consisting of NR 5 , O and S;

each m is an integer from 0 to 3;

each p is an integer from 0 to 5;

each q is an integer from 0 to 4;

each t is an integer from 0 to 2; and

each R 9 is independently selected from the group consisting of C1-C10 alkyl, C1-C10 alkyl substituted with one or more R 7 , halo, OR 5 , NR 5 R 5 , C(O)OR 5 , NO 2 , CN, S(O) n R 5 optionally substituted aryl and optionally substituted heteroaryl.

7 . The method of claim 4 , wherein R 12 is:

wherein:

W is O; and

m is 0.

8 . The method of claim 2 , wherein the compound is selected from the group consisting of

(R)-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridine,

(S)-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridine,

(R)-N-(4-methoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,

(S)-N-(4-methoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,

any pharmaceutical salts thereof, and any mixtures thereof.

9 . The method of claim 2 , wherein the compound is administered as a pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier.

10 . The method of claim 2 , wherein the compound is administered via a route selected from the group consisting of parenteral, oral, pulmonary, ophthalmic, nasal, rectal, vaginal, aural, topical, buccal, transdermal, mucosal, intravenous, intramuscular, subcutaneous, intradermal, intraocular, intracerebral, intracerbroventricular, intralymphatic, intraarticular, intrathecal and intraperitoneal.

11 . The method of claim 2 , wherein the subject is further administered at least one additional agent selected from the group consisting of antibiotic, anti-inflammatory agent, anti-fungal, steroid, decongestant, bronchodialator and anti-TNF agent.

12 . The method of claim 2 , wherein the inflammatory condition is selected from the group consisting of appendicitis, peptic, gastric or duodenal ulcers, peritonitis, pancreatitis, pseudomembranous colitis, acute colitis, ulcerative colitis, ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, Crohn's disease, enteritis, ileus, Whipple's disease, asthma, chronic obstructive pulmonary disease, acute lung injury, allergy, anaphylactic shock, immune complex disease, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhinitis, cystic fibrosis, pneumonitis, pneumoultramicroscopic silicovolcanoconiosis, alvealitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus, herpes, disseminated bacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns, dermatitis, dermatomyositis, sunburn, urticaria, warts, wheals, vasulitis, angiitis, endocarditis, arteritis, atherosclerosis, thrombophlebitis, pericarditis, myocarditis, myocardial ischemia, periarteritis nodosa, rheumatic fever, Alzheimer's disease, coeliac disease, congestive heart failure, adult respiratory distress syndrome, meningitis, encephalitis, multiple sclerosis, cerebral infarction, cerebral embolism, Guillame-Barre syndrome, neuritis, neuralgia, spinal cord injury, paralysis, uveitis, arthritides, arthralgias, osteomyelitis, fasciitis, Paget's disease, gout, periodontal disease, rheumatoid arthritis, synovitis, myasthenia gravis, thryoiditis, systemic lupus erythematosus, Goodpasture's syndrome, Behcet's syndrome, allograft rejection, graft-versus-host disease, interstitial cystitis, Type I diabetes, ankylosing spondylitis, Berger's disease, Type II diabetes, Retier's syndrome and Hodgkins disease.

13 . The method of claim 2 , wherein the inflammatory condition is selected from the group consisting of peritonitis, pancreatitis, ulcerative colitis, Crohn's disease, asthma, organ ischemia, reperfusion injury, sepsis, cachexia, burns, myocardial ischemia, adult respiratory distress syndrome, acute lung injury, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematous, chronic obstructive pulmonary disease, psoriasis, Behcet's syndrome, allograft rejection, graft-versus-host disease and ileus.

14 . The method of claim 2 , wherein the inflammatory condition is selected from the group consisting of peritonitis, pancreatitis, ulcerative colitis, Crohn's disease, asthma, sepsis, acute lung injury, adult respiratory distress syndrome, rheumatoid arthritis, systemic lupus erythematosus, chronic obstructive pulmonary disease, psoriasis and ileus.

15 . The method of claim 2 , wherein the subject is a mammal.

16 . The method of claim 2 , wherein the subject is human.