Inhibitors of NF-κB

1. A compound of formula (1) or formula (2):

or a pharmaceutical salt thereof,

wherein:

HET is a saturated or unsaturated mono- or multi-ring carbocycle in which one or more of the ring carbon atoms is replaced by N, S, P or O;

each R 1 is independently hydrogen; CF 3 ; phenyl optionally substituted with cyano, halo, nitro, hydroxyl, (C1-C6)alkyl, (C1-C6)alkyl-OH, (C1-C6)alkoxy, COR 3 , NR 4 R 5 or NHCO(C1-C6) alkyl; cyano; halo; nitro; hydroxyl; (C1-C6)alkyl; (C1-C6)alkyl-OH; (C1-C6)alkoxy; (C1-C6)thioalkoxy; phenoxy; COR 3 ; NR 4 R 5 ; NHCO(C1-C6) alkyl; SO 2 (C1-C6) alkyl; or SO 2 NR 4 R 5 ;

R 2 is H, R 6 , COR 6 , CONHR 6 , COOR 6 , CH 2 OCOR 6 , P(O)(OH) 2 , P(O)(O(C1-C6)alkyl) 2 , P(O)(OCH 2 OCO(C1-C6)alkyl) 2 , P(O)(OH)(OCH 2 OCO(C1-C6)alkyl), P(O)(OH)(O(C1-C6)alkyl), P(O)(OH)(C1-C6)alkyl, glycosyl or an inorganic salt of P(O)(OH) 2 , P(O)(O(C1-C6)alkyl) 2 , P(O)(OCH 2 OCO(C1-C6)alkyl) 2 , P(O)(OH)(OCH 2 OCO(C1-C6)alkyl), P(O)(OH)(OC1-C6)alkyl or P(O)(OH)(C1-C6)alkyl;

R 6 is C1-C6 alkyl, trifluoromethyl, (C3-C6)cycloalkyl, cyclohexylmethyl or phenyl, wherein the phenyl is substituted with 0 to 4 groups selected from the group consisting of fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, (C1-C4)alkyl, (C1-C4)alkoxy and phenylmethyl, wherein the phenylmethyl is substituted on the phenyl ring with 0-4 groups selected from the group consisting of fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, (C1-C4)alkyl, (C1-C4)alkoxy, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, and 5-pyrimidinyl;

R 3 is independently hydroxyl, (C1-C6)alkoxy, phenoxy or -NR 4 R 5 ;

each R 4 and R 5 are independently hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl; and

n is 0-3,

wherein on HET, there exists an ortho relationship between the OR 2 group and the amide moiety.

2. The compound of claim 1 , wherein R 2 is H.

3. The compound of claim 1 , wherein HET is pyridyl and n is 0.

4. The compound of claim 1 , having the structure of formula (3):

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 , wherein R 2 is H.

6. A pharmaceutical composition comprising a compound of formula (1) or formula (2) according to claim 1 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically effective diluent or carrier.

7. A pharmaceutical composition comprising a compound of formula (3) according to claim 4 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically effective diluent or carrier.

8. The compound of claim 2 , wherein HET is pyridyl and n is 0.

9. The compound of claim 1 or pharmaceutical salt thereof, which is selected from the group consisting of:

(±)-2-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)nicotinamide;

(±)-2-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)quinoline-3-carboxamide;

(±)-3-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)picolinamide;

(±)-4-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-nicotinamide;

(±)-6-chloro-4-hydroxy-quinoline-3-carboxylic acid-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-amide;

(±)-4-hydroxy-8-trifluoromethyl-quinoline-3-carboxylic acid-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-amide;

(±)-5-chloro-2-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-nicotinamide;

(±)-4-hydroxy-2-phenylpyrimidine-5-carboxylic acid (2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-amide;

(±)-3-hydroxy-quinoxaline-2-carboxylic acid (2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-amide;

(±)-2-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-6-methyl-nicotinamide;

(±)-4-hydroxy-2-piperidin-l-yl-pyrimidine-5-carboxylic acid (2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-amide;

(±)-3-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)picolinamide, mesylate;

(±)-3-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)picolinamide trifluoroacetate;

(±)-3-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)picolinamide tosylate;

(±)-3-hydroxy-quinoline-2-carboxylic acid-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-amide;

(±)-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-2-methoxy-nicotinamide;

(±)-3-hydroxy-quinoline-2-carboxylic acid-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-amide mesylate;

(±)-3-hydroxy-quinoline-2-carboxylic acid-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-amide trifluoroacetate;

(±)-3-hydroxy-quinoline-2-carboxylic acid-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-amide tosylate;

(±)-3-methoxy-pyridine-2-carboxylic acid (2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-amide;

(±)-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-2-methoxy-nicotinamide trifluoroacetate;

(±)-3-methoxy-pyridine-2-carboxylic acid (2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-amide trifluoroacetate;

(±)-2-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-6-trifluoromethyl-nicotinamide;

(±)-4-hydroxy-2-methyl-pyrimidine-5-carboxylic acid (2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-amide;

(±)-2-methoxy-quinoline-3-carboxylic acid (2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-amide;

(±)-3-methoxy-pyrazine-2-carboxylic acid (2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-amide;

(±)-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid (2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-amide;

(±)-N-(2,5-dioxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-2-hydroxyquinoline-3-carboxamide;

(±)-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-8-methoxyquinoline-7-carboxamide;

(±)-N-(2,5-Dioxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-2-methoxy-nicotinamide (±)-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-3-methoxyquinoline-2-carboxamide;

(±)-N-(2,5-dioxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-8-methoxyquinoline-7-carboxamide;

(±)-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-8-methoxyquinoline-7-carboxamide trifluoroacetate;

(±)-N-(2,5-dioxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-3-hydroxyisonicotinamide (±)- N-(2,5-dioxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-2-methoxyquinoline-3-carboxamide;

(±)-2-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-6-methoxyquinoline-3-carboxamide;

(±)-6-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)benzo[d]oxazole-5-carboxamide;

(±)-6-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)benzo[d]thiazole-5-carboxamide;

(±)-3-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)piperidine-2-carboxamide;

(±)-3-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)pyrazine-2-carboxamide;

(±)-5-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo [4.1.0]hept-3-en-3-yl)pyrimidine-4-carboxamide;

(±)-2-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3; -yl)-1,8-naphthyridine-3-carboxamide;

(±)-7-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)pyrido[2,3-d]pyrimidine- 6 -carboxamide;

(±)-4-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)pyridazine-3-carboxamide;

(±)-4-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-1H-pyrazole-3-carboxamide;

4-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)furan-3-carboxamide;

(±)-4-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)thiophene-3-carboxamide;

(±)-3-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)isothiazole-4-carboxamide;

(±)-3-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)isoxazole-4-carboxamide;

(±)-6-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)-1H-indole-5-carboxamide;

(±)-6-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3 -en-3 -yl)-1H-benzo[d]imidazole-5-carboxamide; and

(±)-2-hydroxy-N-(2-hydroxy-5-oxo-7-oxa-bicyclo[4.1.0]hept-3-en-3-yl)morpholine-3-carboxamide.