Pyrrolo [1,2-d] [1,2-4] triazine as inhibitors of c-Jun N terminal kinases (JNK) and p-38 kinases

1. A compound, or a pharmaceutically-acceptable acid addition salt thereof, wherein the compound has the formula (V):

where

R 1 is hydrogen, alkyl or halo;

R 2 is hydrogen or alkyl;

R 3 is chloro, methyl, amino, carboxy, ethylaminocarbonyl, isopropylaminocarbonyl, cyclopropylaminocarbonyl, benzylaminocarbonyl, morpholinocarbonyl, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, ethoxycarbonylamino, isopropyloxycarbonylamino, isobutyloxycarbonylamino, phenylaminocarbonyl, oxazolyl, triazinyl or ethylaminocarbonylamino;

R 4 is selected from the group consisting of hydrogen, halo, alkyl, alkoxy and hydroxy;

R 6 is selected from the group consisting of hydrogen, halo, alkyl and alkoxy; and

Q 1 is alkyl, alkoxy, aralkylamino, alkylamino or cycloalkylamino;

wherein

“alkyl” means a straight- or branched-chain unsubstituted hydrocarbon group of 1-to-20 carbon atoms;

“alkoxy” means a radical —OR, where R is alkyl, as defined above;

“halo” means fluoro, chloro, bromo or iodo;

“cycloalkyl” means a saturated or partially-unsaturated nonaromatic cyclic hydrocarbon ring system containing 1-to-3 rings with 3-to-7 carbons per ring, which may be further fused with an unsaturated C 3 -C 7 -carbocyclic ring; and

“aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6-to-10 ring atoms, where the aryl ring may optionally be fused to a 5-, 6- or 7-membered monocyclic saturated ring optionally containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, with the remaining ring atoms being carbons, wherein one or two carbon atoms may be optionally replaced by a carbonyl group.

2. The compound according to claim 1 , or a pharmaceutically-acceptable acid addition salt thereof, wherein the compound has the formula (VI):

where the variables and included terms are as defined in claim 5 .

3. The compound according to claim 1 , or a pharmaceutically-acceptable acid addition salt thereof, wherein the compound has the formula (VII):

where R 3′ is carboxy, ethylaminocarbonyl, isopropylaminocarbonyl, cyclopropylaminocarbonyl, benzylaminocarbonyl, morpholinocarbonyl, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl or phenylaminocarbonyl, and the other variables and included terms are as defined in claim 1 .

4. The compound according to claim 1 , or a pharmaceutically-acceptable acid addition salt thereof, wherein the compound has the formula (VIII):

where Q 2 -C(═O)—NH— is ethoxycarbonylamino, isopropyloxycarbonylamino, isobutyloxycarbonylamno or ethylaminocarbonylamino and the other variables and included terms are as defined in claim 1 .

5. The compound according to claim 1 selected from:

or a pharmaceutically-acceptable acid addition salt thereof.

6. A method of treating or ameliorating one or more symptoms of cyclokine-mediated diseases or disorders, selected from the group consisting of rheumatoid arthritis and inflammatory bowel disease, comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of the formula (V):

wherein

R 1 is hydrogen, alkyl or halo;

R 2 is hydrogen or alkyl;

R 3 is chloro, methyl, amino, carboxy, ethylaminocarbonyl, isopropylaminocarbonyl, cyclopropylaminocarbonyl, benzylaminocarbonyl, morpholinocarbonyl, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, ethoxycarbonylamino, isopropyloxycarbonylamino, isobutyloxycarbonylamino, phenylaminocarbonyl, oxazolyl, triazinyl or ethylaminocarbonylamino;

R 4 is selected from the group consisting of hydrogen, halo, alkyl, alkoxy and hydroxy;

R 6 is selected from the group consisting of hydrogen, halo, alkyl and alkoxy; and

Q 1 is alkyl, alkoxy, aralkylamino, alkylamino or cycloalkylamino,

where

“alkyl” means a straight- or branched-chain unsubstituted hydrocarbon group of 1-to-20 carbon atoms;

“alkoxy” means a radical —OR, where R is alkyl, as defined above;

“halo” means fluoro, chloro, bromo or iodo;

“cycloalkyl” means a saturated or partially-unsaturated nonaromatic cyclic hydrocarbon ring system containing 1-to-3 rings with 3-to-7 carbons per ring, which may be further fused with an unsaturated C 3 -C 7 -carbocyclic ring; and

“aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6-to-10 ring atoms, where the aryl ring may optionally be fused to a 5-, 6- or 7-membered monocylic saturated ring optionally containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, with the remaining ring atoms being carbons, wherein one or two carbon atoms may be optionally replaced by a carbonyl group.

7. The method of claim 6 , further comprising administering a corticosteroid, a CSAID, a 4-substituted imidazo[1,2-A]quinoxaline, interleukin-10, a glucocorticoid, a salicylate, nitric oxide, an immunosuppressant, a nuclear translocation inhibitor, a non-steroidal anti-inflammatory drug, a steroid, an antiviral agent, an antiproliferative agent, a cytotoxic drug, a TNF-α inhibitor, a soluble TNF receptor, and/or rapamycin.

8. A pharmaceutical composition comprising a compound of the formula (V):

wherein

R 1 is hydrogen, alkyl or halo;

R 2 is hydrogen or alkyl;

R 3 is chloro, methyl, amino, carboxy, ethylaminocarbonyl, isopropylaminocarbonyl, cyclopropylaminocarbonyl, benzylaminocarbonyl, morpholinocarbonyl, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, ethoxycarbonylamino, isopropyloxycarbonylamino, isobutyloxycarbonylamino, phenylaminocarbonyl, oxazolyl, triazinyl or ethylaminocarbonylamino;

R 4 is selected from the group consisting of hydrogen, halo, alkyl, alkoxy and hydroxy;

R 6 is selected from the group consisting of hydrogen, halo, alkyl and alkoxy; and

Q 1 is alkyl, alkoxy, aralkylamino, alkylamino or cycloalkylamino,

where

“alkyl” means a straight- or branched-chain unsubstituted hydrocarbon group of 1-to-20 carbon atoms;

“alkoxy” means a radical —OR, where R is alkyl, as defined above;

“halo” means fluoro, chloro, bromo or iodo;

“cycloalkyl” means a saturated or partially-unsaturated nonaromatic cyclic hydrocarbon ring system containing 1-to-3 rings with 3-to-7 carbons per ring, which may be further fused with an unsaturated C 3 -C 7 -carbocyclic ring; and

“aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6-to-10 ring atoms, where the aryl ring may optionally be fused to a 5-, 6- or 7-membered monocylic saturated ring optionally containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, with the remaining ring atoms being carbons, wherein one or two carbon atoms may be optionally replaced by a carbonyl group,

or a pharmaceutically-acceptable acid addition salt thereof and a pharmaceutically-acceptable carrier therefor.

9. The pharmaceutical composition of claim 8 , further comprising one or more of the following: a corticosteroid, rolipram, calphostin, a CSAID, a 4-substituted imidazo[1,2-A]quinoxaline, interleukin-10, a glucocorticoid, a salicylate, nitric oxide, an immunosuppressant, a nuclear translocation inhibitor, deoxyspergualin, ibuprofen, celecoxib, rofecoxib, prednisone, dexamethasone, abacavir, methotrexate, leflunomide, FK506, azathioprine, cyclophosphamide, tenidap, an anti-TNF antibody, a soluble TNF receptor, and rapamycin.

10. The compound according to claim 1 , wherein “alkyl” means a straight- or branched-chain unsubstituted hydrocarbon group of 1-to-7 carbon atoms; and “halo” means fluoro or chloro.

11. A compound selected from