Title of Invention	"PYRROLO-TRIAZENE ANILINE COMPOUNDS"
Abstract	Compounds having the formula (I), and pharmaceutically acceptable salts, prodrugs, and solvates thereof, are useful as kinase inhibitors, wherein R1, R2, r3 R4, R5, r6, X and Z are as described in the specification.

Full Text

PYRROLO-TRIAZINE ANILINE COMPOUNDS USEFUL AS KINASE INHIBITORS Field of the Invention This invention relates to pyrrolotriazine compounds, more particularly, to cycloalkyl, heterocyclo and heteroaryl pyrrolotriazine aniline compounds useful for treating p38 kinase-associated conditions. The invention further pertains to pharmaceutical compositions containing at least one compound according to the invention useful for treating p38 kinase-associated conditions and methods of inhibiting the activity of p38 kinase in a mammal. Background of the Invention '••,, - ' ' ',;'•*,' A large number of cytokines participate in the inflammatory response, including IL-1, BL-6, IL-8 and TNF-a. Overproduction of cytokines such as 1L-1 and TNF-a are implicated in a wide variety of diseases, including inflammatory bowel disease, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, and congestive heart failure, among others [Henry et al, Drugs Put., 24:1345-1354 (1999); Salituro et al, Curr. Med. Chem.. 6:807-823 (1999)]. Evidence in human patients indicates that protein antagonists of cytokines are effective in treating chronic inflammatory diseases, such as, for example, monoclonal antibody to TNF-a (Enbrel) [Rankin et al, Br. J. Rheumatol.. 34:334-342 (1995)], and soluble TNF-a receptor-Fc fusion protein (Etanercept) [Moreland et al., Ann. Intern. Med., 130:478-486 (1999)1. The biosynthesis of TNF-a occurs in many cell types in response to an external stimulus, such as, for example, a mitogen, an infectious organism, or trauma. Important mediators of TNF-a production are the mitogen-activated protein (MAP) kinases, and in particular, p38 kinase. These kinases are activated in response to various stress stimuli, including but not limited to proinflammatory cytokines, endotoxin, ultraviolet light, and osmotic shock. Activation of p38 requires dual phosphorylation by upstream MAP kinase kinases (MKK3 and MKK6) on threonine and tyrosine within a Thr-Gly-Tyr motif characteristic of p38 isozymes. There are four known isoforms of p38, i.e., p38-oc, p38{3, p38y, and p385. The a and (3 isoforms are expressed in inflammatory cells and are key mediators of TNF-a production. Inhibiting the p38a and |3 enzymes in cells results in reduced levels of TNF-a expression. Also, administering p38a and J3 inhibitors in animal models of inflammatory disease has proven that such inhibitors are effective in treating those diseases. Accordingly, the p38 enzymes serve an important role in inflammatory processes mediated by IL-1 and TNF-a. Compounds that reportedly inhibit p38 kinase and cytokines such as IL-1 and TNF-a for use in treating inflammatory diseases are disclosed in US Pats. Nos. 6,277,989 and 6,130,235 to Scios, Inc; US Pats. Nos. 6,147,080 and 5,945,418 to Vertex Pharmaceuticals Inc; US Pats Nos. 6,251,914,5,977,103 and 5,658,903 to Smith-Kline Beecham Corp.; US Pats. Nos. 5,932,576 and 6,087,496 to G.D. Searle & Co.; WO 00/56738 and WO 01/27089 tc Astra Zeneca; WO 01/34605 to Johnson & Johnson; WO 00/12497 (quinazoline derivatives as p38 kinase inhibitors); WO 00/56738 (pyridine and pyrimidine derivatives for the same purpose); WO 00/12497 (discusses the relationship betweei p38 kinase inhibitors); and WO 00/12074 (piperazine and piperidine compounds useful as p38 inhibitors). The present invention provides certain pyrrolotriazine compounds, particularly, pyrrolotriazine aniline compounds useful as kinase inhibitors, particulai kinases p38a and p\ Pyrrolotriazine compounds useful as tyrosine kinase inhibitors are disclosed in US patent application Serial No. 09/573,829, filed May 18, 2000, assigned to the present assignee. Methods of treating p38 kinase-associated conditions as well as pyrrolotriazine compounds useful for that purpose are describee in US patent application Serial No. 10/036,293, assigned to the present assignee and having common inventors herewith, which claims the benefit of U.S. Provisional Application No. 60/249,877, filed November 17,2000, and U.S. Provisional Application No. 60/310,561, filed August 7,2001. Pyrrolotriazine compounds substituted with an acidic group reportedly having sPLAa-inhibitory activity are disclosed in WO 01/14378 Al to Shionogi & Co., Ltd, published March 1, 2001 in Japanese. Each of the patent applications, patents, and publications referred to herein is incorporated herein by reference. Summary of the Invention The instant invention pertains to compounds of formula (I), (Figure Remove) enantiomers, diastereomers, salts, and solvates thereof, wherein: X is selected from-O- -OC(=O)-, -S-, -S(=O)-, -SO2-, -C(=O)-, -CO2--NRr-, -NR8C(=0)- -NR8C(=O)NR9-, -NR8CO2-, -NR8SO2-, -NR8SO2NR9-, -SO2NR8-, -C(=O)NR8-, halogen, nitro, and cyano, or X is absent; Z is -C(=0)NR1(r-Bb, -(CH2)-C(=O)NR,o-Bc, -NRi0a C(=O)-Ba, -(CH2)-NR,0aC(=0)-Bc, -NRioaC(=0)NR10-B, -NRi0SO2-B, -SO2NRi0-B, -C(=O)-Ba, -CO2-Be, -OC(=O)-Ba, -C(=O)NRio-NR10a-Bd, -NR10CO2-Ba or -C(=0)NR10-(CH2)C(=0)Ba; Bis (a) optionally-substituted cycloalkyl, optionally-substituted heterocyclo, or optionally substituted heteroaryl; or (b) aryl substituted with one rh and zero to two Ri2; Ba is optionally substituted alkyl, optionally-substituted cycloalkyl, optionally-substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl; Bbis (a) optionally-substituted cycloalkyl, optionally-substituted heterocyclo, or optionally substituted heteroaryl; aryl substituted with one Rn and zero to two Ri2; or -C(=0)R13, -C02R13, -C(=0)NRi3Ri3a; B° is optionally substituted alkyl, optionally substituted alkoxy, optionally-substitutei cycloalkyl, optionally-substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl; Bd is hydrogen, -C(=O)Ri3, or -CO2Ri3; Be is hydrogen, optionally substituted alkyl, optionally-substituted cycloalkyl, optionally-substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl; ri and rs are independently selected from hydrogen, alkyl, substituted alkyl, -ORu, -SR14, -OC(=0)R]4, -C02RU, -C(=O)NRi4Ri4a, -NRi4Ri4a,-S(=O)R14, -SO2Ri4, -SO2NR14Ri4a, -NRi4SO2NR14aRi4b, -NR14aSO2Ri4, ~NRi4C(=O)Ri4a, -NRi4CO2Ri4a, ~NRi4C(=O)NR]4aRi4b, halogen, nitro, and cyano; R2 is hydrogen or Ci^alkyl; R3 is hydrogen, methyl, perfluoromethyl, methoxy, halogen, cyano, NH2, or NH(CH3] R* is selected from: a) hydrogen, provided that Rt is not hydrogen if X is — S(=O)-, -SO2-, -NR8CO2- or-NRgSO2-; b) alkyl, alkenyl, and alkynyl optionally independently substituted with keto and/or one to four Rn; aryl and heteroaryl either of which may be optionally independently substituted with one to three Rig; and heterocyclo and cycloalkyl either of which may be optionally independently substituted with keto and/or one to three Rie; or R» is absent if X is halogen, nitro, or cyano; R6 is attached to any available carbon atom of phenyl ring A and at each occurrence is independently selected from alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamine, alkylsulfonylamine, sulfonic acid, alkysulfonyl, sulfonamido, phenyl, benzyl, aryloxy, and benzyloxy, wherein each Re group in turn may be further substituted by one to two R^; Rg and Rg are independently selected from hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, heterocyclo, and heterbaryl; rio and Rioa are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, and aryl; rh is selected from alkyl, haloalkyl, alkoxy, haloalkoxy, -SO2alkyl, cycloalkyl, heterocyclo, and heteroaryl any of which may be optionally subsituted; or halo, cyano, ammo, alkylamino, and dialkylamino; Ri2 is selected from alkyl, Rn, and Ci^alkyl substituted with keto (=O) and/or one to three Rn; ris and Ri3a are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl and optionally subsituted aryl; rh, Ri4a and Ri4b are independently selected from hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, heterocyclo, and heteroaryl, except when R^ is joined to a sulphonyl group as in -S(=O)Ri4, -SO2Ri4, and -NRi4aSO2Ri4, then rh is not hydrogen; Rie is selected from alkyl, Rn, and Ci^alkyl substituted with keto (=O) and/or one to three Rn; Rn is selected from halogen, haloalkyl, haloalkoxy, nitro, cyano, -SR23, -ORB, -NR23R24, -NR23SO2R25, -SO2R25, -SO2NR23R24, -CO2R23, -C(=O)R23, -C(=0)NR23R24, -OC(=0)R23, -OC(=0)NR23R24, -NR23C(=0)R24, -NR23C02R24; aryl or heteroaryl either of which may be optionally substituted with one to three R2s; or (c) cycloalkyl or heterocyclo optionally substituted with keto(=O) and/or one to three R2e; and R2e are independently selected from Ci^alkyl, Co-ealkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, Ci.4alkylamino, aminoCi^alkyl, hydroxy, hydroxyCi^alkyl, alkoxy, Ci^alkylthio, aryl, heterocyclo, (aryl)alkyl, aryloxy, and (aryl)alkoxy; and Ra4 are each independently selected from hydrogen, alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, cycloalkyl, heteroaryl, and heterocyclo; R25 is selected from alkyl, substituted alkyl, aryl, heteroaryl, cycloalkyl and heterocyclo; and misO, 1,2 or 3. The invention further pertains to pharmaceutical compositions containing compounds of formula (I), and to methods of treating conditions associated with the activity of p38 kinase (a and |3), comprising administering to a mammal a pharmaceutically-acceptable amount of a compound of formula (T). Description of the Invention Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group. The term "alkyl" refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. The expression "lower alkyl" refers to unsubstituted alkyl groups of 1 to 4 carbon atoms. When a subscript is used with reference to an alkyl or other group, the subscript refers to the number of carbon atoms that the group may contain. For example, the term "CfMalkyl" includes a bond and alkyl groups of 1 to 4 carbon atoms. The term "substituted alkyl" refers to an alkyl group substituted by one to four substituents selected from halogen, hydroxy, alkoxy, keto (=O), alkanoyl, aryloxy, alkanoyloxy, NRaRb, alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, -SO2NRaRb, nitro, cyano, ~CO2H, -CONRaRb, alkoxycarbonyl, aryl, guanidino and heteroaryls or heterocyclos (such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like), wherehi Ra and Rb are selected from hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycle, and heterocyclealkyl. The substituent on the alkyl optionally in turn may be further substituted, in which case it will be with substituted one or more of Ci^alkyl, Ci^alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, Ci^alkylamino, aminoCi^alkyl, hydroxy, hydroxyCi^alkyl, alkoxy, alkylthio, phenyl, benzyl, phenyloxy, and/or benzyloxy. The term "alkenyl" refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms, having at least one double bond, and depending on the number of carbon atoms, up to four double bonds. The term "substituted alkenyl" refers to an alkenyl group substituted by one to two substituents selected from those recited above for substituted alkyl groups. The term "alkynyl" refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms, having at least one triple bond, and depending on the number of carbon atoms, up to four triple bonds. The term "substituted alkynyl" refers to an alkynyl group substituted by one to two substituents selected from those recited above for alkyl groups. When the term alkyl is used in connection with another group, as in heterocycloalkyl or cycloalkylalkyl, this means the identified (first named) group is bonded directly through an alkyl group which may be branched or straight chain (e.g., cyclopropylCi_4alkyl means a cyclopropyl group bonded through a straight or branched chain alkyl group having one to four carbon atoms.). In the case of substituents, as in "substituted cycloalkylalkyl," the alkyl portion of the group, besides being branched or straight chain, may be substituted as recited above for substituted alkyl groups and/or the first named group (e.g., cycloalkyl) may be substituted as recited herein for that group. The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine. The term "aryl" refers to monocyclic or bicyclic aromatic substituted or unsubstituted hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, and biphenyl groups.) Aryl groups may optionally include one to three additional rings (either cycloalkyl, heterocyclo or heteroaryl) fused thereto. Examples include: and the like. Each ring of the aryl may be optionally substituted with one to three rc (Figure Remove) groups, wherein rc at each occurrence is selected from alkyl, substituted alkyl, halogen, trifluoromethoxy, trifluoromethyl, -SR, -OR, -NRR', -NRSO2R', -SO2R, -S02NRR', -C02R', -C(=0)R', -C(=O)NRR', -OC(=O)R', -OC(=O)NRR', -NRC(=O)R', -NRCO2R', phenyl, C3.7 cycloalkyl, and five-to-six membered heterocyclo or heteroaryl, wherein each R and R' is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, phenyl, Cs-vcycloalkyl, and five-to-six membered heterocyclo or heteroaryl, except hi the case of a sulfonyl group, then R is not going to be hydrogen. Each substituent Rc optionally in turn may be further substituted by one or more (preferably 0 to 2) Rd groups, wherein Rd is selected from Ci-ealkyl, C2-6alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, ammo, Ci. 4alkylamino, aminoCi^alkyl, hydroxy, hydroxyCiwtalkyl, alkoxy, alkylthio, phenyl, benzyl, phenylethyl, phenyloxy, and benzyloxy. The term "aralkyl" refers to an aryl group bonded directly through an alkyl group, such as benzyl, wherein the alkyl group may be branched or straight chain. In the case of a "substituted aralkyl," the alkyl portion of the group besides being branched or straight chain, may be substituted as recited above for substituted alkyl groups and/or the aryl portion may be substituted as recited herein for aryl. Thus, the , wherein each R group may be hydrogen or may also be selected from Rc as defined above, in turn optionally substituted with one or more Rd- At least two of these "R" groups should be hydrogen and preferably at least five of the "R" groups is hydrogen. A preferred benzyl group involves the alkyl-portion being branched to define The term "heteroaryl" refers to a substituted or unsubstituted aromatic group for example, which is a 4 to 7 membered monocyclic, 7 to 1 1 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom and at least one carbon atom-containing ring. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. It may optionally be substituted with one to three (preferably 0 to 2) Rc groups, as defined above for aryl, which in turn may be substituted with one or more (preferably o to 2) Rd groups, also as recited above. Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl (i.e., N ), thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like. Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxaxolyl, benzothienyl, quinolinyl, terrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, dihydroisoindolyl, tetrahydroquinolinyl and the like. Exemplary tricyclic heteroaryl groups include carbazolyl, benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like. The term "cycloalkyl" refers to a saturated or partially unsaturated non-aromatic cyclic hydrocarbon ring system, preferably containing 1 to 3 rings and 3 to 7 carbon atoms per ring, which may be substituted or unsubstituted and/or which may be fused with a CyCi carbocylic ring, a heterocyclic ring, or which may have a bridge of 3 to 4 carbon atoms. The cycloalkyl groups including any available carbon or nitrogen atoms on any fused or bridged rings optionally may have 0 to 3 (preferably 0-2) substituents selected from rc groups, as recited above, and/or from keto (where appropriate) which in turn may be substituted with one to three Ra groups, also as recited above. Thus, when it is stated that a carbon-carbon bridge may be optionally substituted, it is meant that the carbon atoms in the bridged ring optionally may be substituted with an rc group, which preferably is seleted from CMalkyl, C2-4alkenyl, halogen, haloalkyl, haloalkoxy, cyano, amino, Ci^alkylamino, aminoCi^alkyl, hydroxy, hydroxyCi-4alkyl, and Ci^alkoxy. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicycloheptane, cycloctyl, cyclodecyl, cyclododecyl, and adamantyl. The terms "heterocycle", "heterocyclic" and "heterocyclo" each refer to a fully saturated or partially unsaturated nonaromatic cyclic group, which may be substituted or unsubstituted, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1,2 or 3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, where the nitrogen and sulfur heteroatoms also optionally may be oxidized and the nitrogen heteroatoms also optionally may be quaternized. Preferably two adjacent heteroatoms are not simultaneously selected from oxygen and nitrogen. The heterocyclic group may be attached at any nitrogen or carbon atom. The heterocyclo groups optionally may have 0 to 3 (preferably 0-2) substituents selected from keto (=O), and/or one or more rc groups, as recited above, which in turn may be substituted with one to three Rj groups, also as recited above. Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, and triazolyl, and the like. Exemplary bicyclic hetrocyclic groups include 2,3-dihydro-2-oxo-lH-indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,l-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzoraryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinoh'nyl, thienofuryl, thienopyridyl, thienothienyl, and the like. Also included are smaller heterocyclos, such as epoxides and aziridines. Unless otherwise indicated, when reference is made to a specifically-named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), heterocyclo (e.g., pyrrolidinyl) or heteroaryl (e.g., indolyl), the reference is intended to include rings having 0 to 3, preferably 0-2, substituents selected from those recited above for the the aryl, cycloalkyl, heterocyclo and/or heteroaryl groups, as appropriate. Additionally, when reference is made to a specific heteroaryl or heterocyclo group, the reference is intended to include those systems having the maximum number of non-cumulative double bonds or less than the maximum number of double bonds. Thus, for example, the term "isoquinoline" refers to isoquinoline and tetrahydroisoquinoline. Additionally, it should be understood that one skilled in the field may make appropriate selections for the substituents for the aryl, cycloalkyl, heterocyclo, and heteroaryl groups to provide stable compounds and compounds useful as pharmaceutically-acceptable compounds and/or intermediate compounds useful in making pharmaceutically-acceptable compounds. Thus, for example, in compounds of formula (I), when B is a cyclopropyl ring, preferably the ring has no more than two substituents, and preferably said substituents do not comprise nitro (NOa), more than one cyano group, or three halogen groups. Similarly, when m is 3, preferably Re, the substituents on the phenyl ring A, are not all nitro, and so forth. The term "heteroatoms" shall include oxygen, sulfur and nitrogen. The term "haloalkyl" means an alkyl having one or more halo substituents. The term "perfluoromethyl" means a methyl group substituted by one, two, or three fluoro atoms, i.e., CI^F, CHF2 and CFa. The term "perfluoroalkyl" means an alkyl group having from one to five fluoro atoms, such as pentafluoroethyl. The term "haloalkoxy" means an alkoxy group having one or more halo substituents. For example, "haloalkoxy" includes -OCFs. The term "carbocyclic" means a saturated or unsaturated monocyclic or bicyclic ring in which all atoms of all rings are carbon. Thus, the term includes cycloalkyl and aryl rings. The carbocyclic ring may be substituted in which case the substituents are selected from those recited above for cycloalkyl and aryl groups. When the term "unsaturated" is used herein to refer to a ring or group, the ring or group may be fully unsaturated or partially unsaturated. Definitions for the various other groups that are recited above in connection with substituted alkyl, substituted alkenyl, aryl, cycloalkyl, and so forth, are as follows: alkoxy is -ORC, alkanoyl is -C(=O)Re, aryloxy is -OAr, alkanoyloxy is -OC(=O)Re, amino is -NH2, alkylamino is -NHRe or -N(Re)2, arylamino is -NHAr or -NReAr, aralkylamino is —NH-Rf-Ar, alkanoylamino is -NH-C(=O)Re, aroylamino is -NH-C(=O)Ar, aralkanoylamino is -NH-C(=O)Rf-Ar, thiol is -SH, alkylthio is -SRe, arylthio is -SAr, aralkylthio is -S-Rf-Ar, alkylthiono is -S(=O)Re, arylthiono is -S(=O)Ar, aralkylthiono is -S(=O)Rf-Ar, alkylsulfonyl is -SO(q)Re, arylsulfonyl is -SO(q)Ar, arylsulfonylamine is -NHSO(q)Ar, alkylsulfonylamine is -NHSO2Re, aralkylsulfonyl is -SO(q)RfAr, sulfonamido is -SO2NH2, substituted sulfonamide is-SO2NHRe or -SO2N(Re)2, nitro is -NO2, carboxy is -CO2H, carbamyl is -CONH2, substituted carbamyl is -C(=O)NHRg or-C(=O)NRgRh, alkoxycarbonyl is ~-C(=O)ORe, carboxyalkyl is -Rf-CO2H,, sulfonic acid is -SOsH, arylsulfonylamine NH O —N—C—NH2 —N— C—NH2 is -NHSO(q)Ar, guanidino is H ' and ureido is H ( wherein Reis alkyl or substituted alkyl as defined above, Rf is alkylene or substituted alkylene as defined above, Rg and Rh are selected from alkyl, substituted alkyl, aryl, aralkyl, cycloalkyl, heterocyclo, and heteraryl; at is an aryl as defined above, and q is 2 or 3. Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds. The compounds of the present invention may form salts which are also within the scope of this invention. Pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, ?.g., in isolating or purifying the compounds of this invention. The compounds of the present invention may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine, lysine and the like. Such salts can be formed as known to those skilled in the art. The compounds of the present invention may form salts with a variety of organic and inorganic acids. Such salts include those formed with hydrogen chloride, hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid and various others (e.g., nitrates, phosphates, borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates and the like). Such salts can be formed as known to those skilled in the art. Salt forms of the compounds may be advantageous for improving the compound dissolution rate and oral bioavailability. In addition, zwitterions ("inner salts") may be formed. All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The definition of compounds according to the invention embraces all the possible stereoisomers and their mixtures. It embraces the racemic forms and the isolated optical isomers having the specified activity. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates from the conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization. Compounds of the present invention may also have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound for formula I) is a prodrug within the scope and spirit of the invention. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see: Design of Prodrugs. edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzvmology. Vol.42, p. 309-396, edited by K. Widder, et al. (Acamedic Press, 1985); A Textbook of Drug Design and Development edited by Krosgaard- Larsen and H. Bundgaard, Chapter 5, "Design and Application of Prodrugs," by H. Bundgaard, p. 113-191 (1991); and H. Bundgaard, Advanced Prog Delivery Reviews. 8,1-38 (1992), each of which is incorporated herein by reference. It should further be understood that solvates (e.g., hydrates) of the compounds of Formula (I) are also with the scope of the present invention. Methods of solvation are generally known in the art. Preferred compounds of formula (I) include compounds having the structure: Preferred compounds include those having the struture of formula (I*), nd solvates thereof, wherein: X is selected from -O-, -OC(=O)-, -S-, -S(=O)-, -SO2-, -C(=O)-, -CO2-, -NR8-, ~NR8C(=O)- -NR8C(=O)NR9- -NR8CO2-, -NR8SO2-, -NR8SO2NR9~, -SO2NR8-, -C(=0)NR8-, halogen, nitro, and cyano, orX is absent; Y is -C(=O)NRio- -NRi0aC(=O)NRicr-, ~NR]0SO2-, -SO2NRi0-, -C(=O)-, -CQz or -OC(=0)-; B is optionally-substituted cycloalkyl, heterocyclo, or heteroaryl; or aryl substituted with one rh and zero to two Ri2; or when Y is ~C(=O)NRio-, B also may be selected from-C(=O)Ri3, -CO2Ri3, -C(=O)NRi3R13a; ri and rs are independently selected from hydrogen, alkyl, substituted alkyl, -ORu, -SR14, -OC(=0)R14, -C02R14, -C(=0)NRi4Ri4a, -NR14R14a,-S(=O)R14, -SO2Ri4, -SO2NR14RMa, -NRi4SO2NRi4aRi4b, -NRi4aSO2R14, -NR14C(=O)Ri4a, -NRi4CO2Ri4a, -NRi4C(=O)NRi4aRi4b, halogen, nitro, and cyano; Rois hydrogen or Ci rs is hydrogen, methyl, perfluoromethyl, methoxy, halogen, cyano, NHa, or NH(CHs); R4 is selected from: b) hydrogen, provided that R} is not hydrogen if X is -S(=O)-, -SOj-, -NR8CO2-, or-NR8SO2-; b) alkyl, alkenyl, and alkynyl optionally substituted with keto and/or one to four Rn; f) aryl and heteroaryl optionally substituted with one to three Rie; and g) heterocyclo and cycloalkyl optionally substituted with keto and/or one to three R\6', or h) R4 is absent if X is halogen, nitro, or cyano; rs is attached to any available carbon atom of phenyl ring A and at each occurrence is independently selected from alkyl, halogen, trifiuoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamine, alkylsulfonylamine, sulfonic acid, alkysulfonyl, sulfonamido, phenyl, benzyl, aryloxy, and benzyloxy, wherein each Rg group in turn may be further substituted by one to two Rig; R8 and R9 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, heterocyclo, and heteroaryl; rio and Rioa are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, and aryl; rh is selected from optionally-substituted cycloalkyl, heterocyclo, and heteroaryl; Ri2 is selected from alkyl, Rn, and Ci^alkyl substituted with keto (=O) and/or one to three Rn; rb and Risa are selected from hydrogen, alkyl, and substituted alkyl; Ri4, Rua and Ri4b are independently selected from hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, heterocyclo, and heteroaryl, except when ru is joined to a sulphonyl group as in -S(=O)Ri4, -SO2Ri4, and -NRi4aSO2Ri4, then RJ4 is not hydrogen; Rie is selected from alkyl, Rn, and Chalky! substituted with keto (=O) and/or one to three RJ7; Rn is selected from halogen, haloalkyl, haloalkoxy, nitro, cyano, -SR23, ~OR23, -NR23R24, -NR23SO2R25, -SO2R25, -SO2NR23R24, -CO2R23) -C(=O)R23, -C(=0)NR23R24, -OC(=0)R23, -OC(=0)NR23R24, -NR23C(=O)R24, -NR23CO2R24, aryl or heteroaryl optionally substituted with one to three or cycloalkyl or heterocyclo optionally substituted with keto(=O) and/or one to three R2e; Rig and R2e are independently selected from C^alkyl, Cj-ealkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, Ci-4alkylamino, aminoCi^alkyl, hydroxy, hydroxyCi^alkyl, alkoxy, Ci^alkylthio, phenyl, benzyl, phenyloxy, and benzyloxy; R23 and R24 are each independently selected from hydrogen, alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, cycloalkyl, heteroaryl, and heterocyclo; R2s is selected from alkyl, substituted alkyl, aryl, heteroaryl, cycloalkyl and heterocyclo; and misO, 1,2 or 3. Preferred compounds of formula (I*) are those having formula (la). and pharmaceutically-acceptable salts, prodrugs, and solvates thereof, wherein: R3 is methyl, -CF3, or -OCF3; X is -C(=O)-, -NR8C(=O)-, or -C(=O)NR8-, wherein R8 is hydrogen or C^alkyl; Y is -C(=O)NH- -NHC(=O)NH-, -NHC(=O)- or -NHSO2-; B is an optionally-substituted monocyclic or bicyclic cycloalkyl, heteroaryl, or heterocycle, aryl substituted with at least one rh and zero to two Ri2, or when Y is -C(=O)NH- B also may be selected from -C(=O)R13) -CO2Ri3, and -C(=0)NK13R13a; Rt is hydrogen, C2.6alkyl, Ci^alkyl optionally substituted with one to three Rn, aryl or heteroaryl optionally substituted with one to three Rie, or cycloalkyl or heterocycle optionally-substituted with keto (=O) and/or one to three Reaand Reb are independently selected from hydrogen, Ci^alkyl, substituted halogen, trifluoroniethoxy, trifluoromethyl, —OR27, -C(=O)alkyl, -OC(=0)alkyl, -NR27R28, -SR27, -NO2> -CN, -CO2R27, -CONH2, -SO3H, -S(=O)allcyl, -S(=O)aryl, -NHSO2-aryl-R27, -SO2NHR27, -CONHR27, and -NHC(=O)NHR27; rh is cycloalkyl, heterocyclo, or heteroaryl optionally substituted with one to two R^; ris and Ri3a are hydrogen, alkyl or substituted alkyl; Ri2 and Rig are independently selected from Ci^alkyl, Rn, and Q^alkyl substituted with keto and/or one to two RJ7; R17 is selected from halogen, hydroxy, Cj^alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, phenyl, benzyl, phenyloxy, benzyloxy, NH2, NH(Ci^alkyl), N(Ci_ 4alkyl)2, C3_7cycloalkyl, and five or six membered heteroaryl or heterocycle; and R27 and R2s are selected from hydrogen, Chalky!, phenyl, Cs-vcycloalkyl, and five-to-six membered heterocyclo or heteroaryl. More preferred are compounds having the formula (la), as recited above, wherein: R3 is methyl, -CF3, or -OCF3; X is -C(=0)-, -C(=O)NH- or -C(=O)N(C^alkyl)-; Yis-C(=0)NH-; B is a C3-7cycloalkyl optionally substituted with one to two R7, a five membered heteroaryl optionally substituted with one to two R7, a five or six membered heterocyclo optionally substituted with one to two R7, aryl substituted with at least one Rn and optionally substituted with zero to two Ri2, or when Y is — C(=O)NH-> B may also be selected from -C(=O)(alkyl), -CO2(alkyl), and -C(=O)NH(alkyl); 14 is hydrogen, C2.6alkyl, Ci^alkyl optionally substituted with one to three Rn, aryl or heteroaryl optionally substituted with one to three Ri6, or cycloalkyi or heterocycle optionally-substituted with keto (=O), and/or one to three Rea and Reb are independently selected from hydrogen, Ci^alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, Ci^alkoxy, cyano, NH2, NH(Ci. 4alkyl), andN(CMalkyl)2; R7is selected from Ci^alkyl, substituted Ci^alkyl, halogen, trifluoromethoxy, trifluoromethyl, cyano, -SR20, -OR20, -NR20R2i, -NR20SO2R2i, -SO2R,9, -S02NR20R2i, -C02R20, -C(=0)R20, -C(=O)NR2oR2i, -OC(=O)R20, -OC(=O)NR20R2i, -NR20C(=O)R2i, -NR20CO2R21, phenyl, benzyl, C3.7 cycloalkyi, and five-to-six membered heterocyclo or heteroaryl; rh is cycloalkyi, heterocyclo, or heteroaryl optionally substituted with one to two R]g ris and Ri3a are hydrogen, alkyl or substituted alkyl; Ri2 and Rie are independently selected from Ci-4alkyl, Rn, and Ci-4alkyl substituted with keto and/or one to two Rn; Rn is selected from halogen, hydroxy, Q^alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, phenyl, benzyl, phenyloxy, benzyloxy, NH2, NH(Ci-4alkyl), N(Ci 4alkyl)2, cyclopentyl, cyclohexyl, or five or six membered heteroaryl or heterocycle; Ri9 is Ci^alkyl, phenyl, C3.7cycloalkyl, or five-to-six membered heterocyclo or heteroaryl; R20 and R2i are selected from hydrogen, Chalky!, phenyl, C3.7cycloalkyl, and five-to-six membered heterocyclo or heteroaryl; and R27 and R2g are selected from hydrogen, Ci^alkyl, phenyl, C3.7cycloalkyl, and five-to-six membered heterocyclo or heteroaryl. In compounds of formula (I), preferably R3 is methyl, -CF3, or -OCF3, more preferably methyl; X preferably is -C(=O)- or -C(=O)NH-; and Y is preferably -C(=O)NH-. Preferably when X is -C(=O)NH-, R4 is C2-6alkyl or substituted Q. ' 4alkyl, more preferably Ci^alkyl or optionally-substituted benzyl. When X is -C(=O)-, preferably R4 is an optionally-substituted aryl or heteroaryl. When R4 is a heterocyclo, advantageously it is selected from diazepinyl, morpholinyl, piperidinyl, and pyrrolidinyl, said heterocycle being optionally substituted with one to two of Ci_4alkyl, hydroxy, Ci-4alkoxy, phenyl, and/or benzyl. When X is -C(=O)- and Rj is aryl or heteroaryl, preferably R* is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl, optionally-substituted with C^alkyl; halogen, hydroxy, Ci. 4alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, phenyl, benzyl, phenyloxy, benzyloxy, NH2, NH(Ci^alkyl), N(Ci_4alkyl)2, cyclopentyl, cyclohexyl, or five or six membered heteroaryl or heterocycle. In compounds of formula (I), preferably phenyl ring A is unsubstituted or has one substituent. Said optional substituent Rea or Ret is preferably selected from Ci_ 4alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, C^alkoxy, nitro, and cyano, more preferably the substituent is Rea and is methyl or ethyl. In compounds of formula (I), preferably ring B is a cycloalkyl, heteroaryl, or heterocyclo ring selected from: wherein E, G, J and K are selected from O, S, NH and CH2, provided that when q is 0, then J and K are not simultaneously selected from O and S; and M is N or CH; wherein each hydrogen atom of E, G, J, K and M may optionally be replaced with an r.j group; R7 is selected from Ci-ealkyl, substituted Ciwtalkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, -CMalkoxy, -C(=O)alkyl, -OC(=O)alkyl, NH2, NH(Ci^alkyl), N(Cwalkyl)2, -CN, -CO2alkyl, -CONH2, -CONH(CH3), -CON(CH3)2, phenyl, benzyl, C3.7 cycloalkyl, and five-to-six membered heterocyclo or heteroaryl; n is 0, 1 or 2; and p and q are selected from 0, 1, 2, 3 or 4, provided that/? and q taken together are not greater than 4. In compounds of formula (I), also preferred are compounds where ring B is cyclopropyl, oxazolyl, or isoxazolyl which is unsubstituted or has one substituent R7. Said substituent R7 preferably is selected from Chalky!, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, -Ci_4alkoxy, -C(=O)alkyl, -OC(=O)alkyl, NH2, NH(Ci. 4alkyl), N(Cwalkyl)2, -CN, -CO2alkyl, -CONH2, phenyl, benzyl, C3.7 cycloalkyl, and five-to-six membered heterocyclo or heteroaryl, or a Chalky! substituted with hydroxy, amino, alkylamino, halogen, trifluoromethyl, trifluoromethoxy, or cyano. More preferably R7 is not present or is - (Figure Remove) Also preferred compounds are those of formula (2a) and (2b), and pharmaceutically acceptable salts, prodrugs, and solvates thereof, wherein: R3 is methyl or CFs; B is phenyl having at least one rh substituent and zero to two ru substituents, or B may be selected from: wherein E, G, J and K are selected from O, S, NH and CHk, provided that when q is 0, then J and K are not simultaneously selected from O and S; and M is N or CH; wherein each hydrogen atom of E, G, J, K and M optionally may be replaced with an R7 group; is phenyl or five or six membered heteraryl optionally substituted with up to two Ri6; is straight or branched Ca-ealkyl; cycloalkyl optionally substituted with keto and/or up to two Rie; heterocycle optionally substituted with keto and/or up to two Rie; or Ci^alkyl substituted with up to three of halogen, trifluoromethyl, cyano, hydroxy, alkoxy, haloalkyl, haloalkoxy, nitro, phenyl, phenyloxy or benzyloxy, wherein said phenyl group in turn is optionally substituted with one to two R2e; Rea is lower alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, C^alkoxy, nitro, amino, Ci_4alkylalmino, or cyano; Rj is Ci^alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, nitro, amino, Q. 4alkylalmino, hydroxy, Ci^alkoxy, phenyl, benzyl, phenyloxy, or benzyloxy; rh is cycloalkyl, heterocyclo, or heteroaryl optionally substituted with one to two R^; Ri2 and Rie at each occurrence are independently selected from hydrogen, alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, nitro, amino, Q. 4alkylalmino, hydroxy, alkoxy, phenyl, benzyl, phenyloxy, and benzyloxy; R26 is selected from Chalky!, trifluoromethyl, trifluoromethoxy, halogen, cyano, amino, Ci-4alkylalmino, hydroxy, alkoxy, phenyl, benzyl, phenyloxy, and benzyloxy; n is 0, 1 or 2; and p and q are 0, 1, 2, 3, or 4, provided that;? and q taken together are not greater than 4. Most preferred are compounds of formula (2a) or (2b), referenced abov cyclopropyl or cyclobutyl optionally substituted with one to two R7; phenyl substituted with five or six membered heterocyclo and zero to tw Ri2, orc) B is selected from one of: and is phenyl or pyridyl optionally substituted with up to two Rie, as defned above; is straight or branched Ca-ealkyl or optionally-substituted benzyl; R^a is methyl, ethyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, methoxy, ethoxy, or cyano; R7, Rn and Rie are selected from Q^alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, nitro, amino, CMalkylamino, aminoCi.4alkyl, hydroxy, hydroxyCi^alkyl, haloC^alkyl, Ci.4alkoxy, phenyl, benzyl, phenyloxy, and benzyloxy; and n is 0 or 1. Utility The compounds of the invention are selective inhibitors of p38 kinase activity, and in particular, isoforms p38a and p38{3. Accordingly, compounds of formula (I) have utility in treating conditions associated with p38 kinase activity. Such conditions include diseases in which cytokine levels are modulated as a consequence of intracellular signaling via p38, and in particular, diseases that are associated with an overproduction of cytokines IL-1, IL-4, IL-8, and TNF-a. As used herein, the terms "treating" or "treatment" encompass either or both responsive and prophylaxis measures, e.g., measures designed to inhibit or delay the onset of the disease or disorder, achieve a full or partial reduction of the symptoms or disease state, and/or to alleviate, ameliorate, lessen, or cure the disease or disorder and/or its symptoms. When reference is made herein to inhibition of "p-38on$ kinase," this means that either p38a and/or p38|3 kinase are inhibited. Thus, reference to an ICso value for inhibiting p-38o&'p kinase means that the compound has such effectiveness for inhibiting at least one of, or both of, p38a and p380 kinases. Li view of their activity as inhibitors ofp-38a/$ kinase, compounds of Formula (I) are useful in treating p-38 associated conditions including, but not limited to, inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, angiogenic disorders, infectious diseases, neurodegenerative diseases, and viral diseases. More particularly, the specific conditions or diseases that may be treated with the inventive compounds include, without limitation, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosis, scleroderma, chronic thyroiditis, Grave's disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease, inflammatory reaction induced by endotoxin, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic (3-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption disease, allograft rejections, fever and myalgias due to infection, cachexia secondary to infection, meloid formation, scar tissue formation, ulcerative colitis, pyresis, influenza, osteoporosis, osteoarthritis and multiple myeloma-related bone disorder, icute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, fCaposi's sarcoma, multiple myeloma, sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson's disease, cerebral ischemias or neurodegenerative disease caused by traumatic injury; angiogenic disorders including solid tumors, ocular neovasculization, and infantile haemangiomas; viral diseases including acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy, and herpes; stroke, myocardial ischemia, ischemia in stroke heart attacks, organ hyposia, vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, and conditions associated with prostaglandin endoperoxidase syndase-2. In addition, p38 inhibitors of this invention inhibit the expression of inducible pro-inflammatory proteins such as prostaglandin endoperoxide synthase-2 (PGHS-2), also referred to as cyclooxygenase-2 (COX-2). Accordingly, additional p38-associated conditions include edema, analgesia, fever and pain, such as neuromuscular pain, headache, pain caused by cancer, dental pain and arthritis pain. The inventive compounds also may be used to treat veterinary viral infections, such as lentivirus infections, including, but not limited to equine infectious anemia virus; or retro virus infections, including feline immunodeficiency virus, bovine immunodeficiency virus, and canine immunodeficiency virus. When the terms "p38 associated condition" or "p38 associated disease or disorder" are used herein, each is intended to encompass all of the conditions identified above as if repeated at length, as well as any other condition that is affected by p38 kinase activity. The present invention thus provides methods for treating such conditions, comprising administering to a subject in need thereof an effective amount of at least one compound of Formula (I) or a salt thereof. The methods of treating p38 kinase-associated conditions may comprise administering compounds of Formula (I) alone or in combination with each other and/or other suitable therapeutic agents useful in treating such conditions. Exemplary of such other therapeutic agents include corticosteroids, rolipram, calphostin, CSAIDs, 4-substituted imidazo [1,2-AJquinoxalines as disclosed in US Pat. No. 4,200,750; Interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors, such as deoxyspergualin (DSG); non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antiviral agents such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf); cytotoxic drags such as azathiprine and cyclophosphamide; TNF-a inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and raparriycin (sirolimus or Rapamune) or derivatives thereof. The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. In the methods of the present invention, such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the inventive compounds. The present invention also provides pharmaceutical compositions capable of treating p38-kinase associated conditions, including TNF-a, EL-1, and/or IL-8 mediated conditions, as described above. The inventive compositions may contain other therapeutic agents as described above and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (e.g., excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation. The compounds of Formula (I) may be administered by any means suitable for the condition to be treated, which may depend on the need for site-specific treatment or quantity of drug to be delivered. Topical administration is generally preferred for skin-related diseases, and systematic treatment preferred for cancerous or pre-cancerous conditions, although other modes of delivery are contemplated. For example, the compounds maybe delivered orally, such as in the form of tablets, capsules, granules, powders, or liquid formulations including syrups; topically, such as in the form of solutions, suspensions, gels or ointments; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g., as sterile injectable aq. or non-aq. solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; rectally such as in the form of suppositories; or liposomally. Dosage unit formulations containing non-toxic, pnarmaceutically acceptable vehicles or diluents may be administered. The compounds may be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved with suitable pharmaceutical compositions or, particularly in the case of extended release, with devices such as subcutaneous implants or osmotic pumps. Exemplary compositions for topical administration include a topical carrier such as PLASTBASE® (mineral oil gelled with polyethylene). Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The inventive compounds may also be orally delivered by sublingual and/or buccal administration, e.g., with molded, compressed, or freeze-dried tablets. Exemplary compositions may include fast-dissolving diluents such as mannitol, lactose, sucrose, and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (AVICEL®) or polyethylene glycols (PEG); an excipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g., GANTREZ®); and agents to control release such as polyacrylic copolymer (e.g., CARBOPOL 934®). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use. Exemplary compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and/or bioavailability, and/or other solubilizing or dispersing agents such as those known in the art. Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid. Exemplary compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures but liquefy and/or dissolve in the rectal cavity to release the drug. The effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for a mammal of from about 0.05 to 100 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats, horses, and the like. Thus, when the term "patient" is used herein, this term is intended to include all subjects, most preferably mammalian species, that are affected by mediation of p38 enzyme levels. Compounds of formula (I), including the compounds described in the examples hereof, have been tested in one or more of the assays described below and have shown activity as inhibitors of p38o/|3 enzymes and TNF-a. Biological Assays Generation of p38 Kinases cDNAs of human p38cc, (3 and yisozymes were cloned by PCR. These cDNAs were subcloned in the pGEX expression vector (Pharmacia). GST-p38 fusion protein was expressed in E. Coli and purified from bacterial pellets by affinity chromatography using glutathione agarose. p38 fusion protein was activated by incubating with constitutivery active MKK6. Active p38 was separated from MKK6 by affinity chromatography. Constitutivery active MKK6 was generated according to Raingeaud etal. [Mol. Cell. Biol., 1247-1255 (1996)]. TNF-q Production by LPS-StimuIated PBMCs Heparinized human whole blood was obtained from healthy volunteers. Peripheral blood mononuclear cells (PBMCs) were purified from human whole blood by Ficoll-Hypaque density gradient centrifugation and resuspended at a concentration of 5 x 106/ml in assay medium (RPMI medium containing 10% fetal bovine serum). 50 ul of cell suspension was incubated with 50 ul of test compound (4X concentration in assay medium containing 0.2% DMSO) in 96-well tissue culture plates for 5 minutes at RT. 100 ul of LPS (200 ng/ml stock) was then added to the cell suspension and the plate was incubated for 6 hours at 37°C. Following incubation, the culture medium was collected and stored at -20°C. TNF-a concentration in the medium was quantified using a standard ELISA kit (Pharmingen-San Diego, CA). Concentrations of TNF-a and ICso values for test compounds (concentration of compound that inhibited LPS-stimulated TNF-a production by 50%) were calculated by linear regression analysis. p38 Assay The assays were performed in V-bottomed 96-well plates. The final assay volume was 60 //I prepared from three 20 //I additions of enzyme, substrates (MBP and ATP) and test compounds in assay buffer (50 mM Tris pH 7.5, 10 mM MgCl2,50 mM NaCl and 1 mM DTT). Bacterially expressed, activated p38 was pre-incubated with test compounds for 10 min. prior to initiation of reaction with substrates. The reaction was incubated at 25°C for 45 min. and terminated by adding 5 fA of 0.5 M EDTA to each sample. The reaction mixture was aspirated onto a pre-wet filtermat using a Skatron Micro96 Cell Harvester (Skatron, Inc.), then washed with PBS. The filtermat was then dried in a microwave oven for 1 min., treated with MeltilLex A scintillation wax (Wallac), and counted on a Microbeta scintillation counter Model 1450 (Wallac). Inhibition data were analyzed by nonlinear least-squares regression using Prizm (GraphPadSoftware). The final concentration of reagents in the assays are ATP, 1 /M; [y-33P]ATP, 3 nM,; MBP (Sigma, #M1891), 2//g/well; p38, 10 nM; and DMSO, 0.3%. TNF-q Production by LPS-Stimulated Mice Mice (Balb/c female, 6-8 weeks of age, Harlan Labs; n=8/treatment group) were injected intraperitoneally with 50ug/kg lipopolysaccharide (LPS; E coli strain 0111:B4, Sigma) suspended in sterile saline. Ninety minutes later, mice were sedated by CC^Oa inhalation and a blood sample was obtained. Serum was separated and analyzed for TNF-alpha concentrations by commercial ELISA assay per the manufacturer's instructions (R&D Systems, Minneapolis, MN). Test compounds were administered orally at various times before LPS injection. The compounds were dosed either as suspensions or as solutions in various vehicles or solubilizing agents. Abbreviations For ease of reference, the following abbreviations are employed herein, including the methods of preparation and Examples that follow: Ph =phenyl Bz = benzyl t-Bu = tertiary butyl Me = methyl Et = ethyl Pr = propyl Iso-P = isopropyl MeOH = methanol EtOH = ethanol EtOAc = ethyl acetate Boc = tert-butyloxycarbonyl DCM = dichloromethane DCE = 1,2-dichloroethane DMF = dimethyl formamide DMSO = dimethyl sulfoxide TFA = trifluoroacetic acid THF = tetrahydrofuran HATU = O-(7~AzabenzoMazol-l-yl-^A^//^//'-tetramethyluronim hexafluorophosphate KOH = potassium hydroxide KaCOs = potassium carbonate POCls =phosphorous oxychloride EDC or EDCI = l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride DIPEA = diisopropylethylamine HOBt= 1-hydroxybenzotriazole hydrate m-CPBA = m-chloroperbenzoic acid NaH = sodium hydride NaOH = sodium hydroxide Pd = palladium Pd/C = palladium on carbon min = minute(s) L = liter mL = milliliter uL = microliter g = grarn(s) mg = milligram(s) mol = moles mmol = millimole(s) meq = milliequivalent RT or it = room temperature ret. t. = HPLC retention time (minutes) sat or sat'd = saturated aq. = aqueous TLC = thin layer chromatography HPLC = high performance liquid chromatography RP HPLC = reverse phase HPLC LC/MS = high performance liquid chromatography/mass spectrometry MS = mass spectrometry NMR = nuclear magnetic resonance mp = melting point In the Examples, designations associated with HPLC data reflect the following conditions: , a. Column: YMC ODSA S-5 5u Cl 8 4.6 x 50 mm; Solvent: solvent A = 10% MeOH/90% water/0.1% THF, and solvent B = 90% MeOH/10%water/0.1% THF; Method: 4 min gradient; b. Column: YMC s5 ODS 4.6 x 50 mm; Solvent: solvent A = 10% MeOH/90% water/0.2% H3PO4, and solvent B = 90% MeOH/10% water/0.2% H3P04; Method: 4 min gradient. Methods of Preparation Compounds of formula I may generally be prepared according to the following schemes and the knowledge of one skilled in the art. and/or the methods described in US patent applications Serial Nos. 10/036,293 and/or 09/573,829, incorporated herein by reference. In the schemes, the groups Ri-R?, X, Y, m, n and;? are as described herein for compounds of Formula (I). The reference to "B" is intended to encompass an optionally-substituted cycloalkyl, heterocyclo, or heteroaryl ring in formula (I), including without limitation the rings shown as: (Figure Remove) Commercially-available compound (1) can be reacted with oxalyl chloride with heating and then concentrated in vacuo and reacted with an amine B-NHa in the presence of a base, such as diisopropylamine, in an organic solvent, such as DCM to yield compound (2). Compound (2) can be reacted with hydrogen in the presence of a catalyst, such as Pd, in an alcoholic solvent, such as EtOH, at it to afford compound (3). Compound (3) can then be used as in Scheme 2 to produce compounds (8) of Scheme (Figure Remove) "Cl+iN R4gNH 3-methyl-l-pyrrole-2,4-diethyl ester can be reacted with chloramine in ether to produce compound (4). Reacting compound (4) in formamide with acetic acid produces compound (5). Compound (5) can be reacted with DIPEA and POC13 in toluene to produce compound (6). Compound (6) can be reacted with DIPEA and compound (3) in DMF to produce compound (7). Compound (7) can be reacted in THF with NaOH to produce an acid intermediate which upon treatment with HOBt, EDCI and the appropriate arnine (NRaRio) in DMF produces compounds (8). Compound (3) can be prepared by 1) reacting commercially-available 4-amino-3-methylbenzoic acid and N-(terf-butoxycarbonyl)anhydride in THF to produce a Boc-protected aniline intermediate; 2) reacting the aniline intermediate with -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlonde, HOBt, and DMF, followed by addition of methoxyamine hydrochloride and DIPEA to produce a BOC-protected N-methoxyamide intermediate; and 3) reacting that methoxyamide intermediate in a solution of HC1 in dioxane to produce compound (3) as a hydrochloride salt. Alternatively, compound (3) can be prepared as shown in Scheme 1. Scheme 3 A substituted hydroxamate (9) can be reacted with acid, such as HC1, in anhydrous MeOH, to afford compound (10). Compound (10) can be reacted with an aq. base such KOH with heating to form compound (11). Compound (11) is reacted with an amine B-NHa hi the presence of a coupling reagent, such as HATU, and a base such as diisopropylamine, in an organic solvent, such as N-methylpyrrolidinone to afford compounds (12). Hydroxamate (9) can be prepared as outlined in Schemes 1 and 2 and/or as shown in US patent application Serial No. 10/036,293. (Figure Remove) Commercially-available compound (13) can be reacted with a sulfonyl :hloride in the presence of a base, such as TEA, in an organic solvent, such as DCM o yield compound (14). Reaction of compound (14) with hydrogen in the presence of a catalyst, such as Pd in a solvent, such as MeOH, yields compound (15). Reaction of compound (15) with chloride (6) (see scheme 2) in an organic solvent, such as DMF, at it affords compound (16). Reaction of compound (16) with aq. KOH with heating affords compound (17). Compound (17) can be reacted with an amine RaNHi in the presence of a coupling reagent, such as EDCI, and a base such as diisopropylamine, in an organic solvent, such as DMF to afford compound (18). Chloropyrrolotriazine (6) (see Scheme 2) can be reacted with an aniline (13) (e.g., see Scheme 4) in anhydrous DMF at it to afford compound (19). Reaction of compound (19) with an aq. base such as NaOH with heating affords compound (20). Compound (20) can be reacted with an amine R4NH2 in the presence of a coupling reagent, such as HOBt, with or without a base such as diisopropylamine, in an organic solvent, such as DMF to afford compound (21). Compound (21) can be reacted with hydrogen in the presence of a catalyst, such as Pd/C, in an organic solvent, such as MeOH to afford compound (22). Reaction of compound (22) with an isocyanate in an organic solvent, such as DCE affords compound (23). (Figure Remove) Commercially-available compound (13), can be reacted with carbonyl lidazole and an amine B-NH2 in an organic solvent, such as DCE, to yield compound (24). Reaction of compound (24) with hydrogen in the presence of a catalyst, such as Pd, in an alcoholic solvent such as EtOH affords compound (25). Reaction of (25) with chloride (6) in an organic solvent, such as DMF, affords compound (26). Reaction of (26) with aq. NaOH with heating affords product (27). Product (27) can be reacted with an amine R4NH2 in the presence of a coupling reagent, such as EDCI, and a base such as diisopropylamine, in an organic solvent, such as DMF to afford compound (28). (Figure Remove) Scheme 7 shows methods for making compounds (4a) (see scheme 2), wherein rs is amino (4b), halogen (4c), or cyano (4d). Glycine ethyl ester (29) can be added to an alkyl alkoxy methylene cyanoacetate at from it to 80°C to obtain compound (30). Compound (30) is cyclized to form pyrrole (4b) upon treatment with a strong base, such as lithium hexamethyldisilazane, at from —78°C to rt in an organic solvent such as THF. Pyrrole (4b) can be converted to a halide using sodium nitrite in an organic solvent, such as DMF, and a halide source, such as CuBr to yield compound (4c). Compound (4c) can be converted to compound (4d) using CuCN in an organic solvent such as NMP at elevated temperatures. Alternatively, compound (4b) can be directly converted to compound (4d) using sodium nitrite hi an organic solvent, such as DMF, and a cyanide source such as CuCN. Compounds (4a)-(4d) can be used as described in previous schemes (e.g., Scheme 2), to form compounds of Formula (I) herein. Reduction of the ester group of pyrrolotriazine 5 {see Scheme 2) with a suitable reducing agent such as LAH in an aprotic organic solvent such as THF produces the alcohol (31). Alcohol (31) is oxidized to the aldehyde (32) with a suitable oxidant, such as Jones Reagent. Aldehyde (32) is reacted with a suitable organometallic reagent (such as phenylmagnesium bromide) to afford an intermediate secondary alcohol product that is subsequently oxidized to ketone (33) with a suitable oxidant, such as Jones Reagent. A chlorinating agent, such as POCls, is used to convert (33) to chloride (34). Chloride (34) is reacted with an aniline in a suitable solvent, such as DMF, at rt or elevated temperature to provide product (35), a compound of formula (I). nd (6) (see Scheme 2), with the appropriate amino benzoic acid in DMF affords compound (36). Reduction of the ester group of compound (36), with a suitable reducing agent such as DIBAL-H in an aprotic organic solvent such as THF produces the alcohol (37). Alcohol (37) can be reacted with an amine RNHa in the presence of a coupling reagent, such as BOP, in an organic solvent, such as DMF, to afford the product (38). Product (38) is oxidized to aldehyde (39) with a suitable oxidant, such as MnOa, in an organic solvent such as THF. Aldehyde (39) is reacted with a suitable organometallic reagent (such as phenylmagnesium bromide) to afford an intermediate secondary alcohol product that is subsequently oxidized to the ketone (40) with a suitable oxidant, such as PCC. In addition, other compounds of formula I may be prepared using procedures generally known to those skilled in the art. In particular, the following examples provide additional methods for the preparation of the compounds of this invention. The invention will now be further described by the following working examples, which are preferred embodiments of the invention. HPLC purifications were done on CIS reverse phase (RP) columns using water MeOH mixtures and TFA as buffer solution. These examples are illustrative rather than limiting. There may be other embodiments that fall within the spirit and scope of the invention as defined by the appended claims. Example 1 (Figure Remove) : To a solution of 3-amino-4-methylbenzoic acid (5.12 g, 33.9 mmol, 1.0 eq.), EDC (9.97 g, 52.0 mol, 1.5 eq.) and 4-(dimethylamino)pyridine (0.89 g, 7.3 mol, 0.2 eq.) hi DMF (100 mL) at 0°C was added cyclopropylamine (4.0 mL, 57.7 mol, 1.7 eq.) dropwise. After stirring for 15 min., the cold bath was removed, and the reaction mixture was stirred at rt overnight. Volatiles were removed at 50°C under reduced pressure. The residue was diluted with water and extracted with DCM (3x). The organic layers were combined, dried over sodium sulfate, and concentrated in vacua to give an oil. Silica gel chromatography using DCMrMeOH (20:1) afforded compound 1A as a yellow oil (6.98 g, 108 % yield). HPLC Ret. t. = 0.637 min.; LC/MS (M+H)+ = 191.09+. To a suspension of the starting oxopyrrolotriazine (3.00 g, 13.6 mmol) in toluene (45 mL) was added dropwise phosphorus oxychloride (1.90 mL, 20.4 mmol) and N,N~DIPEA (2.37 mL, 13.6 mmol) successively at it. The resulting mixture was heated at reflux for 36h, allowed to cool to it, and then poured into an ice-cold mixture of sat'd sodium bicarbonate solution (150 mL) and toluene (60 mL). The organic layer was separated and the aqueous layer extracted with toluene (3 x 50 mL). The combined extract was washed with sat'd sodium bicarbonate solution and brine and dried over anhydrous MgSCV Evaporation of solvent in vacua afforded compound IB (3.26 g, 100% yield) as a yellow solid. Step C: Example 1 A solution of products 1A (1.60 g, 8.40 mmol, 1.6 eq.) and IB (1.30 g, 5.40 mmol, 1.0 eq.) in DMF (13 mL) was stirred at it overnight. Water was added and the precipitate collected by filtration, washed with water, and dried. Trituration with diethyl ether afforded Example 1 (1.70 g, 80% yield) as an off-white solid. HPLC Ret. t. = 3.190 min.; LC/MS (M+H) + = 394.31+. (Figure Remove) A solution of Example 1 (0.86 g, 2.20 mmol, 1.0 eq.) in THF (4.0 mL) and 1 N aqueous NaOH (9.0 mL, 4.1 eq.) was stirred at 60°C overnight. After cooling to rt, the reaction mixture was concentrated in vacuo but not to dryness. To the solution at 0°C was added 1 N aqueous hydrochloric acid until it was acidic and the precipitate was collected and dried to afford crude Example 2 (0.51 g, 64.0 % yield). HPLC Ret. t. = 2.400 min.; LC/MS (M+H)+ = 366.06+. The filtrate was then extracted with EtOAc (3x) and the organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give Example 2 (0.035 g, 4.4 % yield). Examples (Figure Remove) A solution of Example 2 (0.026 g, 0.071 mmol, 1.0 eq.), EDC (0.021 g, 0.11 mmol, 1.5 eq.), HOBt (0.015 g, 0.11 mmol, 1.5 eq), n-butylamine (0.015 mL, 0.15 mmol, 2.1 eq.) and D1PEA (0.040 mL, 0.23 mmol, 3.2 eq.) in DMF (0.20 mL) was shaken at rt overnight. Water (1 mL) was added and the precipitate collected by filtration, washed with water, and dried to give Example 3 (0.021 g, 70% yield); HPLC Ret. t. = 2.883 rain.; LC/MS (M+H) + = 421.18+. Examples 4-22 Compounds having the formula (Id), above, wherein R4 has the values listed in the following Table, were prepared following the same procedure described for Example 3, using the appropriate amine in place of n-butylamine. Compounds having the formula (le), above, wherein Rt has the values listed in the following Table, were prepared following the same procedure described for Example 3, using piperizinylamine and morpholinylamine in place of n-butylamine. Compounds having the formula (If), wherein R Step A: To a well stirred mixture of ethyl vinyl ether (47.9 mL, 0.500 moL) and Rhodium (IT) acetate dimer (0.221 g, 0.500 mmol) in diethyl ether (10 mL) was slowly introduced ethyl diazoacetate (10.5 mL, 0.100 mol) in diethyl ether (30 mL) via a syringe pump at it over 8 hours. The insoluble material was removed by filtration through Celite, and the excess ethyl vinyl ether and solvent were evaporated in vacuo. The residue was distilled in vacua to give product 25A (10.3 g, 65% yield) as a colorless oil which was a mixture of cis and trans isomers in a ratio of approximately 1:1. Step B: To a solution of product 25A (10.3 g, 65.4 mmol) in MeOH (200 mL) was added a solution of NaOH (7.85 g, 196.2 mmol) in one portion, and the resulting solution was heated at reflux for 5 h. The mixture was concentrated under vacuum. The residue was acidified with 6 N HC1 to pH = 2 and extracted with EtOAc (5x). The combined organic phase was dried over MgSO,*. Evaporation of solvent in vacua gave product 25B (8.46 g, 99% yield) as a colorless oil which was a mixture of cis and trans isomers in a ratio of approximately 1:1. A mixture of product 25B (1.00 g, 7.68 mmol), diphenylphosphoryl azide (1.82 mL, 8.44 mmol), and TEA (1.18 mL, 8.47 mmol) in anhydrous f-BuOH (30 mL) was heated at 90°C for 27 h. The volatiles were evaporated in vacuo. The residue was diluted with 10% Na2CO3 solution (30 mL) and extracted with diethyl ether (4 x 30 mL). The combined organic phase was washed with brine, dried over MgSC>4, and the solution was concentrated in vacuo. Silica gel chromatography (40% Et2O/hexane) of the residue afforded product 25C (0.901 g, 58% yield) as a colorless oil which was a mixture of cis and trans isomers in a ratio of approximately 15:85 in favor of trans isomer. Step D: A mixture of product 25C (0.881 g, 4.38 mmol) and 1 N HC1 (20 mL) was heated at reflux for 5 h. After it was allowed to cool to rt, the mixture was extracted with diethyl ether. The aqueous layer was adjusted to pH = 11 with 1 N NaOH solution, and then extracted with diethyl ether (4x). The combined organic phase was dried over MgSC>4 and evaporation of the solvent gave (±)-franj-ethoxycyclopropylamine (0.224 g, 50% yield) as a slightly yellow oil. Example 28 (Figure Remove) To a solution of Example 27 (30.0 mg, 0.0585 mmol) in DCE (6 mL) was added BBr3 at 0°C. The resulting mixture was stirred at rt for 20 mm.., then quenched with water. The mixture was adjusted to pH = 9 with sat'd NaaCOs solution and extracted with EtOAc (3x). The combined organic phase was washed with brine and dried over MgSC>4. The solution was concentrated under vacuum and silica gel chromatography (6% MeOH/CHCla) of the residue afforded Example 28 (3.2 mg) as a white solid. HPLC Ret. t. = 3.09 min. (b); Compounds having the formula (Ig), wherein B has the values listed in the Table provided below, were prepared following the same procedures described for Examples 1 and 3, using an appropriately-substituted cyclopropyl amine in Step 1A and ethylam Compound 31A was prepared following the procedures described in US patent application Serial No. 10/036,293, assigned to the present assignee, which is incorporated herein by reference. Step B: A mixture of compound 31 A, 3-aminoisoxazole (0.30 mL, 4.06 mmol), benzotriazol-l-yloxytris(dimethylammo)phosphomum hexafluorophosphate (0.720 g, 1.63 mmol), and N-methylmorpholine (0.54 mL, 4.91 mmol) in DMF (4 mL) was heated at 65°C for two days. The mixture was diluted with EtOAc and washed with water (2x), 10% NaaCOs solution, and brine. The solution was concentrated in vacua and the product isolated by preparative HPLC. HPLC Ret. t. = 2.48 min. (a); LC/MS (M+H) + = 434.11*. Examples 32-38 Compounds having the formula (Ig), above, wherein B has the values listed in the Table provied below, were prepared following the same procedures described for Example 31, using ethylamine in place of propylamine to make the starting compound and in Step B, an appropriate aminoheteroaryl in place of aminoisooxazole.g, 362 mmol) in THF (800 mL) was added ester having the formula Et° N (8 g, 36.2 mmol) in several portions at rt. The reaction mixture was heated to reflux for 30 min., then cooled to rt, carefully quenched by being poured into ice water (1 L), and stirred rapidly for 1 h. The mixture was extracted with EtOAc and the combined extracts were washed with brine, dried over MgSC>4, filtered, and concentrated to give compound 39A (5.60 g, 86%). Step B: (39B) To a suspension of compound 39A (1.0 g, 5.58 mmol) in acetone (80 mL) at 0°C was added Jones Reagent (1.9 mL) dropwise. The reaction was stirred at 0°C for Ih, then carefully quenched with 2-propanol. Sat'd aq. sodium bicarbonate (100 mL) was added, and the mixture was extracted with EtOAc (5x100 mL). The combined extracts were washed with sat'd aq. sodium bicarbonate (1x100 mL), water (Ix 100 mL), and brine (Ix 100 mL), then dried over MgSC>4, filtered, and concentrated to afford compound 39B (647 mg, 65%). HPLC ret. t. (min): 1.50, MW: 177.16, LCMS[M+H]+= 178. Step C: To a solution of compound 39B (600 nig, 3.39 mmol) in THF (80 mL) at 0°C was added phenylmagnesium bromide (3M, 2.94 mL, 8.8 mL) dropwise over 5 min. After stirring for 30 min at 0°C, the reaction was warmed to rt over 1 h and quenched with sat'd aq. ammonium chloride. The mixture was extracted with EtOAc and the extracts were dried, filtered, and concentrated to afford the benzylic alcohol intermediate. The crude benzylic alcohol was dissolved in acetone (50 mL) and cooled to 0°C. Jones Reagent (LmL) was added dropwise and the reaction was stirred at 0°C for Ih, then carefully quenched with 2-propanol. Sat'd aq. sodium bicarbonate (50 mL) was added and the mixture was extracted with EtOAc (4x50 mL). The combined extracts were washed with sat'd aq. sodium bicarbonate (1x50 mL), water (1x50 mL), and brine (Ix 50 mL) before being dried over MgSC>4, filtered, and concentrated to afford compound 39C (563 mg, 66% over 2 steps). HPLC ret .t. (min): 2.82, MW: 253.26, LCMS[M+H]+= 254. Step D: (Figure Remove) Ketone 39C (152 mg, 0.6 mmol) was placed in POC13 (5 mL) and heated to 100°C for 1.75 h. The reaction was cooled to it and the excess POCla was evaporated under vacuum. The residue was dissolved in anhydrous DCM (10 mL) and added dropwise to a rapidly stirred solution of sat'd aq. sodium bicarbonate (50 ml) and DCM (50 mL) at 0°C. The mixture was stirred for 1 h, then the aqueous phase was extracted with DCM (3x50 mL). The organic phases were washed with sat'd aq. sodium bicarbonate (1x50 mL), water (1x50 mL), and brine (Ix 50 mL), then dried over MgSC>4, filtered, and concentrated to afford the chloride 39D (163 mg, 100%). Step E: To a solution of the chloride 39D (31.5 mg, 0.116 mmol) in DMF (1 mL) was added 3-amino-N-cyclopropyl-4-methyl-benzamide (compound 1 A) (44 mg, 0.23 mmol) and the solution was heated to 60°C for 3 h. Water (5 mL) was added to precipitate the product, which was collected by filtration, washed with water, and allowed to air dry to give Example 39. HPLC ret. t. (min): 3.34, MW: 425.49, LCMS[M+H]+=426. Examples 40 - 42 (Figure Remove) (Hi) Compounds having the formula (Ih), wherein Y and B have the values listed in the Table provided below, were prepared following the same or similar procedure as described above for Example 39, using the appropriate amine in step E. To a solution of compound 39D (60 mg, 0.221 mmol) in DMF (1 mL) was added 3-amino-4-methyl-benzoic acid (66.8 mg, 0.442 mmol) and the solution was heated to 60°C for 3 h. Water (5 mL) was added to precipitate the product, which was collected by filtration, washed with water, and allowed to air dry to give compound 43A (75 mg, 88%). HPLC ret. t (mm): 3.38, MW: 386.41, LCMS[M+H]+= 387. tep B: To a solution of the acid 43 A (30 rag, 0.078 mmol) and HATU (44 mg, 0.117 mmol) and DIPEA(17 uL, 0.1 mmol) in DMF (0.5 mL) at rt was added 3-amino-isoxazole. The reaction was stirred at rt for 1 h, and water (5 mL) was added to precipitate the product, which was collected by filtration, and purified by preparative HPLC to afford Example 43. HPLC ret. t. (min): 3.39, MW: 452.48, LCMS[M+H]+= 453. Example 44 To a solution of the compound 39B (160 mg, 0.90mmol) in THF (10 mL) at 0°C was added 6-methyl-2-pyridyhnagnesium bromide (0.25M, 14.4 mL, 3.6 mM) dropwise over 5 min. After stirring for 30 min at 0°C, the reaction was warmed to rt and stirred for 16 h. Additional aliquots of 6-memyl-2-pyridylmagnesium bromide were added to complete the conversion of the starting material and the reaction was quenched with sat'd aq. ammonium chloride. The mixture was extracted with EtOAc and the extracts were dried, filtered, and concentrated to afford a reddish brown semi-solid material. This material was dissolved in acetone (10 mL) and cooled to 0°C. Jones Reagent (0.4 mL) was added dropwise and the reaction was stirred at 0°C for Ih, then carefully quenched with 2-propanol. Sat'd aq. sodium bicarbonate (15 mL) was added and the mixture was extracted with EtOAc (4x20 mL). The combined extracts were washed with sat'd aq. sodium bicarbonate (1x20 mL), water (1x20 mL), and brine (Ix 20 mL), then dried over MgSO4, filtered, and concentrated to afford compound 44A (145 nig, 60% over 2 steps). Step B: 4 mL) and heated to 100°C overnight. The reaction was cooled to rt and the excess POC^ was evaporated under vacuum. The residue was dissolved in anhydrous DCM (10 mL) and added dropwise to a rapidly stirred solution of sat'd aq. sodium bicarbonate (50 ml) and DCM (50 mL) at 0°C. The mixture was stirred for 1 h, then the aqueous phase was extracted with DCM (3x50 mL). The organic phases were washed with sat'd aq. sodium bicarbonate (1x50 mL), water (1x50 mL), and brine (Ix 50 mL), then dried over MgSO4, filtered, and concentrated to afford the chloride 44B (64 mg, 79%). Step C: Example 44 To a solution of compound 44B (53 mg, 0.18 mmol) in DMF (0.5 mL) was idded compound 1A (84 mg, 0.44 mmol) and the solution was heated to 60°C for 2 h. Abater (5 mL) was added to precipitate the product, which was collected by filtration, washed with water, and allowed to ak dry to afford Example 44 (34.2 mg, 41%). HPLC ret. t. (min):3.39, MW: 452.48, LCMS[M+H]+= 453. Example 45 Example 45 was prepared following the same procedure as in Example 44, using a different benzamide in Step C. HPLC ret. t. (min):3.22, MW: 467.49, LCMS[M+Hf=468. To a solution of the chloride having the formula Eto 41.8 mmol) in DMF (60 mL) was added 3-amino-4-methyl-benzoic acid (6.3 g, 41.8 mmol) at rt. The reaction mixture was stirred for 16 h, poured into water (500 mL) and stirred rapidly for 1 h. The solids were filtered, washed with water (500 mL), and air dried to give the compound 46A (13.6 g, 92%) as a light pink solid. MS[M+H]+= 355. StepB: To a solution of the compound 46A (1 g, 2.8 mmol) in DCM (6 mL) at -78°C was added DIBAL-H (1M, 8.5 mL, 8.5 mmol) dropwise. The reaction was stirred for 2 h at -78°C, wanned to rt over 1.5 h, quenched with sat'd aq. NVUCl, then HC1 (1 N) was added to adjust the pH to 4 and the solution was extracted with EtOAc. After drying of the organic phases and concentration, compound 46B was obtained as a pink solid (874 mg, 100%). HPLC ret. t. (min): 1.74, MW: 312.33, and LCMS[M+H]+= 313. Step C: Example 46 To a solution of compound 46B (1.8 g, 5.9 mmol) in DMF (10 mL) was added BOP (2.9 g, 615 mmol), cyclopropylamine (2 mL, 29.8 mmol). The reaction was stirred overnight at rt, then poured into water (60 mL) to precipitate the product. The solids were collected by filtration and purified by preparative HPLC to give Example 46 (1.5g, 74%). HPLC ret. t. (min): 1.64, MW: 351.41, LCMS[M+H]+= 352. Example 47 To a solution of Example 46 (1.5g, 4.3 mmol) in THF (30 mL) at rt was added klnOa (5.4g, 64 mmol). After stirring for 40 min., the reaction was completed. The product was collected by filtration and the precipitate was washed with acetonitrile. After drying of the filtrate and concentration, Example 47 was obtained as a yellow oil (1.5g, quantitative). HPLC ret. t. (min): 2.52, MW: 349.40, LCMStM+H]+= 350. Example 48 To a solution of 2-bromopyridine (54 pi, 0.57 mmol) and TMEDA (85 \il, 0.57 mmol) in THF (10 mL) at -78°C was added nBuLi (1.6 M, 356 pi, 0.57 mmol) dropwise. To this solution was added Example 47 (50 mg, 0.14 mmol). The reaction was stirred for 0.5 h at -78°C, then warmed to rt and quenched with water. The mixture was extracted with EtOAc and the extracts were dried, filtered, and concentrated to afford the crude intermediate alcohol. To a solution of the crude alcohol in DCM (5 mL) at rt was added pyridinium chlorochromate (24.1 mg, 0.11 mmol). After stirring 1 h, the reaction was quenched with water (2 mL). The desired product was extracted with EtOAc and dried. After purification by preparative HPLC, Example 48 was obtained as yellow solid (24.6 mg, 40%). HPLC ret. t. (rnin): 2.95, MW: 426.48, LCMS[M+H]+= 427. Examples 49-68 Compounds having the structure R4- were prepared according to the procedure described for example 3 using the appropriate amine in place of n-butylamine. 1, Intermediate A:To a rt solution of 3-fluoropyridine (5.0 g) in dichloromethane (25 mL) and 30% aqueous hydrogen peroxide (10 mL) was added methyltrioxorhenium (25 nag) and the resulting mixture was stirred overnight. Manganese oxide (25 mg) was added and the solution was stirred at it for an additional hour. Sodium chloride was added to saturate the aqueous portion and the layers were separated. The aqueous portion was extracted with additional dichloromethane (3 x 100 mL) and the combined organic xtracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacua to provided a light yellow oil which solidified upon standing to afford product A as a tight yellow solid (4.92 g, 84%). HPLC Ret. Time: 0.30 min. Step 2, Intermediate B: CN B To solution of intermediate A (2.85 g, 25.2 mmol) in dichloromethane (25 ml) at rt was added trimethylsilylcyanide (10.0 mL, 75.6 mmol) and the mixture was refluxed for lOh. After cooling to rt, saturated aqueous sodium bicarbonate solution (30 mL) was added and the reulting mixture was extracted with dichloromethane (3 x 150 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provided a light brown oil (4.60 g) as the crude product. This material was purified by flash column chromatography on silicas gel eluting with 30% ethyl acetate in hexane to provide a light tan oil which solidified upon standing to give product B as a light tan solid (2.48 g, 84). HPLC Ret. Time: 1.03 min. Step 3, Intermediate C: r- To intermediate B (1.40 g) in ethanol (50 ml) were successively added 10% palladium on carbon (500 mg) and concentrated hydrogen chloride (2.9 ml) and the resulting mixture was shaken under hydrogen (40 psi) for 20 h. The solution was filtered through a bed of celite and the filtrate was concentrated in vacua to give 1.80 g of product C as a white solid. HPLC Ret. Time: 0.19 min. Step 4, Title compound: A mixture of intermediate D (40 mg, 0.11 rnmol), ED AC (25 mg, 0.13 mmol), and HOBt (16 mg, 0.12 mmol) in 0.3 mL of anhydrous DMF was stirred at rt for 2 hr then the amine hydrochloride C (0.13 mmol) and Hunig's base (38 pL, 0.22 mmol) were successively added. After stirring overnight at rt, the crude reaction mixture was subjected to purification by reverse-phase preparative HPLC to give the title compound. Example 70 and 71 Example 70 and 71 were prepared in the same manner as described for Example 23-24. E Step 1, Intermediate F: To intermediate E (lO.Og, 45.2 mmol) in POC13 (30 mL) at rt under argon was slowly added anhydrous DMF (7.0 mL, 90.4 mmol) and the resulting mixture was heated at 95°C for 15 hours. After cooling to rt, the contents were slowly poured into a well-stirred mixture of 1 L of saturated aq. sodium bicarbonate solution and 200 mL of crushed ice. After allowing the heterogeneous slurry to stir at rt for 2.5 h, the resulting solid was collected by vacuum filtration and the solid was washed with two 150 mL portions of water then allowed to partially dry in the funnel. The solid was finally washed with two portions of dichloromethane (100 mL each) and the resulting organic filtrate was dried over anhydrous sodium sulfate and concentrated in vacuo to provide product F as a yellow solid (5.35 g, 47%) which was used directly without further purification. HPLC Ret. Time: 2.96 min. Intermediate F (3.19 g, 11.9 mmol) and the corresponding aniline Step 2, Intermediate G: hydrochloride (3.52g, 15.5 mmol) in 40 mL of anhydrous DMF were stirred at it overnight then diluted with 200 mL of water and 30 mL of saturated aqueous sodium bicarbonate solution. After stirring at rt for Ih, the resulting solid was collected by vacuum filtration, washed with water, and dried in vacua to afford product G as an orange solid (4.2 g, 84%) which was used directly without further purification. HPLC Ret. Time: 2.97 min. MHT = 422.1 (m/z). StepS, Title Compound: To intermediate G (0.8 g, 1.90 mmol) in anhydrous THF (lOmL) at rt under argon were successively added 1-methylpiperazine (0.24 g, 2.47 mmol) and NaBH(OAc)3 (1.21 g, 5.70 mmol) followed by stirring at rt for 3 hour. The reaction mixture was quenched by addition of 50 mL of methanol followed by stirring for an additional hour at rt then concentrated and partitioned between 50 mL of saturated aqueous sodium bicarbonate solution and 200 ml of ethyl acetate. The layers were separated and the aqueous portion was saturated with sodium chloride and extracted with additional ethyl acetate (4 x lOOmL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacua to give the title compound as a light yellow solid (1.02 g, yield 89%). HPLC Ret. Time: 2.25 min. MH+(m/z) 506.2. Examples 73-80 The following compounds were prepared in the same manner as described for Example 72. Example Structure retention time MH+ added 6N aqueous sodium hydroxide solution (1.8 mL, 10.8 mmol) and the mixture was refluxed for 20h. After cooling to it, the methanol was removed in vacuo and the mixture was brought to pH 6 with IN HCI and freeze dried to give 1.02 g of the crude product H as a pale yellow solid containing residual sodium chloride. This material was used without further purification in the subsequent reaction. HPLC Ret. Time: 1.65min. MhT(m/z) 478.14. Step 2, Title Compounds: Intermediate H (40 mg, 0.083 mmol), ED AC (25 mg, O.lSmmol), and HOBt (16 mg, 0.12 mmol) were stirred at rt for 2 hr then the corresponding amine RNEb (0.13 mmol) and Hunig's base (38 uL, 0.22 mmol) were succesively added followed by stirring overnight at rt. The resulting mixture was subjected to reverse-phase preparative HPLC to obtain the title compounds. Ex. Structure retention time MH+ 1 82 83 Examples 84-86 were prepared from intermediate H as follows: Intermediate H (40 mg, 0.083 mmol), ED AC (25 mg, O.lSmmol), and HOBt (16 mg, 0.12 mmol) were stored at rt for 2 hr then the corresponding alcohol ROH (1 mL) and Hunig's base (38 jjL, 0.22 mmol) were succesively added followed by stirring overnight at rt. The resulting mixture was subjected to reverse-phase preparative HPLC to obtain the title compounds. Example To a solution of aldehyde [Example 47] (0.040 g, 0.114 mmol) in DMF (1 mL) at rt was added 2-chloroquinoxaline (0.0188 g, 0.114 mmol), sodium hydride (0.0054 mg, 0.138 mmol), N,N'-dimethylimadizolium iodide (0.084 mg, 0.038 mmol), and p-toluenesulfinic acid, sodium salt (0.008 mg, 0.044 mmol). After stirring overnight at rt, the solution was heated to 80°C and additional portions of N,N'-dimethylimadizolium iodide and sodium hydride were added. After 1 h the reaction was cooled to rt and water was added. The resulting precipitate was collected and further purified by preparative reverse phase HPLC to afford the title compound (0.003 g).). HPLC ret. t. (min): 3.61, MW: 477.5, LCMS[M+H]+= 478. Example 88 Step A: (8 8 A) To Example 2 (500 nig) was added thionyl chloride (6 mL) at rt. After stirring for 30 min at rt, the thionyl chloride was evaporated under reduced pressure affording 88A as a white solid (HC1 Salt, 580 mg) Step B: To a solution of acid chloride 88A (0.020 g, 0.048 rnmol) and anisole (0.026 mL, 0.238 mmol) in 1,2-dichloroethane (1 mL) at 0°C was added aluminum trichloride (0.0095 g, 0.071 mmol). After 2 hr at 0°C the solution was warmed to rt and additional aluminum trichloride (0.140 g) was added. After stirring at rt overnight, the reaction was quenched with water (0.2 mL) and the solvent was evaporated. The residue was recrystallized from a minimum of methanol/water and collected by filtration to afford the title compound (0.0065 g). ). HPLC ret. t. (min): 3.29, MW: 455.5, LCMS[M+H]+= 456. Examples 89-96 The following compounds were obtained in a manner similar to Example 88. 02N' (97A) A mixture of 3-fluoronitrobenzene (10.0 g, 71 mmol), morpholine (27 mL), and DMSO (118 mL) was stirred at 1 10°C for 36 h then cooled to rt and poured into 800 mL of water. The resulting mixture was stirred for 20 min and the solid was collected by vacuum filtration and dried in vacua to afford 13.6 g (92%) of 97A as a bright yellow solid. ). LCMS (M+H*) = 209.1. HPLC Ret. time: 1.48 min. Step B: (97B) To a slurry of 97A (13.6 g, 65 mmol) in methanol (225 mL) at rt were successively added ammonium formate (20.5 g, 326 mmol) and 10% palladium on charcoal (2.0 g) and the mixture was stirred at rt for 48 h. The resulting mixture was filtered through a pad of celite and the clear filtrate was concentrated in vacuo and the resulting residue was partitioned between water (50 mL) and ethyl acetate (150 mL). The layers were separated and the aqueous portion was extracted with additional ethyl acetate (2 x 50 mL). The combined extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 10.8 g (93%) of 97B as a tan solid. LCMS (M+H4) = 179.2. Step C: HN' ~' " '°H "l (97C) To a slurry of 2.0 g (4.2 mmol) of the compound H HN"^~YN'OCH3 o \^A,, o /-H' "VN-N^ x h N (97C*) (synthesized as described in WO 02/40486) in 12 mL of anhydrous methanol was added 18 mL of a 4 N solution of anhydrous hydrochloric acid in dioxane at room temperature. The resulting clear solution was stirred at room temperature for 16 h and the reaction mixture was concentrated in vacua. The resulting oil was dissolved in 16 mL of 1.5 N aqueous potassium hydroxide solution and heated to 50°C for 3 h. After cooling to room temperature, the mixture was diluted with 50 mL of water and 10% aqueous hydrochloric acid was added until pH was approximately 3 or 4. The resulting precipitated product was collected by vacuum filtration and washed with 50 mL of water and dried in vacua to afford 1.47 g (9%) of 97C as a white solid. An analytical sample of 97C was prepared by recrystallization from 10% aqueous acetonitrile. 1E NMR (CD3OD): 5 8.21 (br s, 1H), 8.11 (br s, 1H), 7.89-7.91 (m, 2H), 7.67 (br s, 1H), 7.44 (d, 1H), 3.40 (q, 2H), 2.86 (s, 3H), 2.36 (s, 3H), 1.25 (s, 3H). LCMS (M+Ef) = 354.2. HPLC: 2.24 min. StepD: Title Compound A mixture of 97C (40 mg, 0.11 mmol), HATU (65 mg, 0.17 mmol), diisopropylamine (20 JJL, 0.11 mmol), and 97B (39 mg, 0.22 mmol) in 0.3 mL of N-methylpyrrolidinone was heated at 80°C for 16 h and the reaction mixture was purified by reverse-phase preparative HPLC to afford 41 mg (74%) of the title compound as a light tan solid. !H NMR (CD3OD w/ TFA): 5 8.28 (s, IH), 8.19 (s, IH), 8.16 (d, IH), 8.11 (d, IH), 7.84 (s, IH), 7.71 (d, IH), 7.58 (t, 2H), 7.47 (d, IH), 3.44 (q, 2H), 2.94 (s, 3H), 2.47 (s, 3H), 1.26 (t, 3H). LCMS (M+H4) = 497.5. HPLC Ret. time: 3.30 min. Example 98 HN The tide compound was prepared as described for the preparation of Example 97 by substituting 97C* hi Step C with Example compound 70 in WO 02/40486. LCMS (M+H4) = 590.2. HPLC Ret. time: 3.26 min. The title compound was prepared as described for the preparation of Example 97 by substituting 97C* in Step C with Example compound 70 in WO 02/40486 and by substituting 97B with 4-aminopyridine in Step D. LCMS (M+H4) = 506.4. HPLC Ret. time: 2.95 min. Example 100 [Tie title compound was prepared as described for the preparation of Example 97 by ubstituting 97C* in Step C with Example compound 70 in WO 02/40486 and by substituting 97B with 2-aminopyridine in Step D. LCMS (M+H4) = 590.2. HPLC Ret. Time: 3.01 min. Examples 101-104 The following compounds were prepared in a similar manner that described for Example 100. E3.64 3.19 Example 105 A solution of 3-nitro-4-methyl benzoyl chloride (215 mg, 1.08 mmol) and N-tolyl-3-tert-butyl-5-aminopyrazole hydrochloride (287 mg, 1.08 mmol) in dichloromethane (5 mL) was added DEPEA (0.38 mL, 2.2 mmol) and the reaction mixture stirred for 2h. The reaction was concentrated to an oil which was dissolved in EtOAc (50 mL) and washed consecutively with aq NaHCO3, water, IN HC1, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to an oil which was purified via column chromatography (10% then 30% EtOAc/hexane) to give the nitro amide (420mg,99%). The above solids was dissolved in EtOH (156 mL) and added 5% Pd-C (wet, 10035 mg) and evacuated and back filled under a hydrogen balloon. The reaction was stirred for 32h, filtered and concentrated to a white solid which was used without further purification (403 mg, 99%), LRMS 363.6 (M+H).' Step B: Title Compound The title compound was prepared from the intermediate obtained in Step A following the procedure described for Example 1 and 2. Step A: (106A) A mixture of 3,5-difluoronitrobenzene (4.1 g, 26 mmol) and morpholine (11 mL) was heated to 100°C for 16 h then cooled to rt overnight. The resulting solid was collected by vacuum filtration and dissolved into methylene chloride (250 mL) and the solution was successively washed with IN aqueous HC1 (2 x 100 mL) and brine (100 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated in vacua to afford 4.0 g (69%) of 106A as a yellow solid. LCMS (M+H4) = 227.2. HPLC Ret. time: 2.85 min. Step B: H2N (106B) A mixture of 106A (4.0 g, 18 mmol) and 10% palladium on charcoal (0.4 g) in 150 mL of ethanol was stirred under an atmosphere of hydrogen at rt for 16 h. The resulting mixture was filtered through a pad of celite and the filtrate was concentrated in vacua to afford 3.4 g (96%) of 106B as an off-white solid. LCMS (M+H+) = 197.1. HPLC Ret. time: 0.92 min. StepC: Title Compound The title compound was prepared as described for the preparation of Example 97 by substituting 97B with 106B hi Step D. LCMS (M+H*) = 532.0. HPLC Ret. time: 3.04 min. Example 107 H \ N O The title compound was prepared as described for the preparation of Example 97 by substituting 97C* in Step C with Example compound 70 in WO 02/40486 and by substituting 97B with 106B in Step D. LCMS (M+H4) = 608.5. HPLC Ret time: 3.52 mm. Example 108 Step A: (108A) A mixture of 3-fluoronitrobenzene (1.0 g, 7.1 mmol) and 1-methylpiperizine (5 mL) was heated to 130°C for 3 days. After cooling to rt, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (4 x 40 mL). Concentration of the combined extracts yielded a dark red oil which was dissolved in dichloromethane (75 mL) and washed with 1 N aqueous HC1 (3 x 25 mL). The combined acidic aqueous extracts were neutralized to pH ~ 7 by addition of 3 N aqueous potassium hydroxide solution and extracted with dichloromethane (3 x 40 mL). The combined extracts were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacua to afford 0.92 g (59%) of 108A as a dark brown oil. LCMS (M+H*) = 222.1. HPLC Ret time: 0.97 min. Step B: (108B) 108B was prepared as described for the preparation of of 106B. LCMS (M+H*) = 192.3. HPLC Ret. time: 0.17 min. * StepC: Title Compound The title compound was prepared as described for the preparation of Example 97 by substituting 97B with 108B in Step D. LCMS (M+H+) = 527.3. HPLC Ret. time: 2.14 min. Example 109 Phe title compound was prepared as described for the preparation of Example 97. LCMS (M+H4) = 571.4. HPLC Ret. time: 2.22 min. Example 110 N Step A: O2N lisa/ (110A) A mixture of 3-fluoronitrobenzene (1.0 g, 7.1 rnrnol), pyrazole (0.58 g, 8.5 mmol), and cesium carbonate (2.8 g, 8.5 mmol) in 4 mL of N-methylpyrrolidinone was heated to 100°C for 17 h. After cooling to rt, the mixture was diluted with water (75 mL) and extracted with ethyl acetate (3 x 75 mL) and the combined extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 1.7 g (71 %) of 110A as a dark red oil. LCMS (M+H+) = 190.1. HPLC Ret. time: 2.42 min. StepB: H2N (HOB) A mixture of 110A (0.95 g, 5.0 mmol) and 10% palladium on charcoal (0.27 g) in 10 mL of ethyl acetate was stirred at rt under an atmosphere of hydrogen for 17 h. The resulting mixture was filtered through a pad of celite and the resulting filtrate was concentrated in vacuo to afford 0.73 g (91%) of 110B as a pale yellow oil. LCMS (M+H+) = 160.1. HPLC Ret time: 0.74 min. StepC: Title Compound The title compound was prepared as described for the preparation of Example 97 by substituting 97B with HOB in Step D. LCMS (M+H*) = 495.3. HPLC Ret. time: 2.91 mm. Example 111 The title compound was prepared as described for the preparation of Example 97. LCMS (M+H4) = 539.3. HPLC Ret. time: 2.97 min. Example 112 Step A: 02N' (112A) A mixture of 3-bromonitrobenzene (1.0 g, 5.0 mmol), imidazole (0.51 g, 7.5 mmol), 1,10-phenanthroline (0.89g, 5.0 mmol), dibenzylideneacetone (0.06 g, 0.25 mmol), cesium carbonate (1.8 g, 5.5 mmol), and copper(II) triflate benzene adduct (0.12 g, 0.25 mmol) in 1 mL of xylenes was heated at 120°C for 36 h. After cooling to rt, the mixture was diluted with dichloromethane (100 mL) and washed with saturated aqueous ammonium chloride solution (2 x 50 mL) and 1 N aqueous HCI (2 x 75 ml,). The combined acidic aqueous portions were neutralized to pH ~ 7 by adding 3N aqueous KOH and then extracted with dichloromethane (3 x 40 mL). The organic extracts were washed with brine (30 ml), dried over anhyd. sodium sulfate, filtered, and concentrated in vacua to afford 0.55g (58%) of 112A as a dark red semi-solid. LCMS (M+H+) = 190.1. HPLC Ret. time: 0.44 min. Step B: (112B) A mixture of 112A (0.55 g, 2.9 mmol) and 10% palladium on charcoal (0.15 g) in 15 mL of methanol was stirred at rt under an atmosphere of hydrogen for 17 h. The resulting mixture was filtered through a pad of celite and the resulting filtrate was concentrated in vacua to afford 0.36 g (77%) of 112B as a pale yellow solid. LCMS (M+H*) = 160.1. HPLC Ret. time: 0.19 min. StepC: Title Compound The title compound was prepared as described for the preparation of Example 97 by substituting 97B with 112B in Step D. LCMS (M+H4) = 495.2. HPLC Ret. time: 2.12 min. Example 113 The title compound was prepared as described for the preparation of Example 9' LCMS (M+H+) = 539.3. HPLC Ret. time: 2.32 min. Example 114 H HN" "" " '" N ° N O Step A: (114A) To a mixture of 3-bromonitrobenzene (1.0 g, 5.0 mmol), 2-pyrrolidinone (0.50 g, 5.9 mmol), potassium carbonate (1.37 g, 9.9 mmol), and fra/w-l,2-cyclohexanediamhie (0.06 mL, 0.50 mmol) were successively added 2.5 mL of anhydrous 1,4-dioxane and copper (I) iodide (94 mg, 0.50 mmol) and the contents were heated to 110°C for 24 h. After cooling to rt, the mixture was partitioned between water (50 mL) and ethyl acetate (75 mL). The aqueous layer was extracted with additional ethyl acetate (2 x 50 mL) and the combined extracts were washed with brine (30 ml), dried over anhyd. sodium sulfate, filtered, and concentrated in vacua to afford the crude product as a dark brown solid. Purification by flash chromatography on silica gel using a gradient elution from 70% ethyl acqtate in hexanes to 100% ethyl acetate gave 0.68 g (68%) of 114A as a pale yellow solid after concentration in vacua. LCMS (M+H*) = 208.1. HPLC Ret. time: 2.11 min. Step B: (114B) A mixture of 114A (0.68 g, 3.3 mmol) and 10% palladium on charcoal (0.35 g) in 10 mL of methanol was stirred at rt under an atmosphere of hydrogen for 17 h. The resulting mixture was filtered through a pad of celite and the resulting filtrate was concentrated in vacua to afford 0.55 g (95 %) of 114B as an off-white solid. LCMS (M+H+) = 177.1. HPLC Ret. time: 0.34 min. StepC: Title Compound The title compound was prepared as described for the preparation of Example 97 by substituting 97B with 114B in Step D. LCMS (M+H+) = 512.2. HPLC Ret. time: 2.68 min. Example 115 The title compound was prepared as described for the preparation of Example 97. LCMS (M+HT") = 556.3. HPLC Ret. time: 2.77 min. Example 116 Step A: (116A) To a solution of 4-methyl-3-nitroaniUne (3.93 g, 25.8 mmol) hi 200 mL of dichloromethane at rt under argon was added 2-chloropyridine-4-carbonyl chloride (5.00 g, 28.4 mmol) followed by triethylamine (8.0 mL, 56.7 mmol) via syringe and the resulting mixture was stirred for 2 h. The solvent removed in vacuo and the residue was triturated with 20 mL of dichloromethane and the solid was collected by filtration to yield 7.50 g (99.6%) of 116A as a yeUow solid. HPLC Ret. Time: 3.13 min. MH+(m/z) 292.3. Step B: To 1 16A (1.50 g) was added 50 ml of morpholine and the mixture was heated to 100°C under argon for 20 h then cooled to rt and slowly poured into ice- water (600 mL) with stirring. This mixture was stirred at rt for 15 min and the resulting solid was collected by filtration and dried in vacuo to afford 5.50 g (62.5%) of 1 16B as a light yellow solid. HPLC Ret. Time: 2.39 min. MET1" (m/z) 343.4. Step C: (116C) To compound 1 16B (1 .50 g) in absolute ethanol (100 mL) was added 10% palladium on carbon (200 mg) and and the mixture was shaken under hydrogen (30 psi) for 6 h. The solution was filtered through a pad of celite and the solvent was removed in vacuo to give 1.33 g of 1 16C as a light yellow solid. HPLC Ret. Time: 0.94 min. MIT (m/z) 3 13.3. Step D: /- o J»^ JL Hrolotriazine-6-ethylcarboxylate (0.14 g, 0.58 mmol) in anhydrous DMF was stirred at it for 20h. The reaction was diluted with ice-cold water and saturated aqueous sodium bicarbonate and the resulting precipitated solid was collected and washed with water to give 0.30 g of 1 16D as a light yellow solid. HPLC Ret. Time: 2.96 min. MH+ (m/z) 516.2. Step E: 116E 116D (0.30 g, 0.58 mmol) in 3 mL of IN sodium hydroxide and 2 mL of methanol was heated at 60°C for 4 h. Methanol was removed in vacua and the aqueous mixture was acidified with IN aqueous HC1 to pH ~ 2. The resulting solid was collected and washed with water to give 0.24 g of 116E as a pale yellow solid. HPLC Ret. time: 2.26 min. MH* (m/z) 488.2. Step F: HN Title Compound 116E (40 mg, 0.082 mmol), EDAC (19 mg, 0.098 mmol), HOBt (13 mg, 0.098 mmol), and Hunig's base (43 jiL, 0.25 mmol) were stirred at rt for 0.5 h and ethylamine hydrochloride (13 mg, 0.16 mmol) was added followed by stirring overnight. The crude reaction mixture was purified by reverse-phase preparative HPLC to give 28 mg of the title compound as a white solid. HPLC Ret. time: 2.^ min. MH*(m/z) 515.1. Example 117 The title compound was prepared from 116E as described in step F for the preparation of Example 116. HPLC Ret. Time: 2.82 min. MH* (m/z) 591.2. Example 118 \ , V-NH ^ "N The title compound was prepared from 1 16E as described in step F for the preparation of Example 116. HPLC Ret. Time: 1.82 min. MH"(m/z) 592.2. Example 119 3-Huorobenzonitrile (10.0 g, 82.6 mmol) and morpholhie (40 mL, 0.45mol) in DMSO (70 mL) was heated at 100°C for 3 days, The mixture was cooled to rt and poured into 500 mL of cold water. The resulting solid was collected by filtration to give 9.52 g of 119A as a pink solid. HPLC Ret. Time: 2.30 min. MH+ (m/z) 189.2. Step B: o HO (119B) A mixture of 119A (9.50 g) in 6N aqueous sulfuric acid (80 mL) was refiuxed for 20 h. After cooling to to 0°C, the mixture was brought to a pH of 2 by the slow addition of aqueous sodium hydroxide solution (50% w/w). After stirring for 15 min, the resulting solid was collected by filtration and washed with water then triturated with ethyl acetate (600 ml). The aqueous filtrate was extracted with additional ethyl acetate (450 ml) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacua to afford 9.50 g of 119B as a light pink solid. HPLC Ret. Time: 1.94 min. MH^m/z) 208.1. Step C: (119C) To 119B (10.3 g, 50.0 mmol) in anhydrous dichloromethane (SOOmL) at rt was slowly added oxalyl chloride (5.2 mL, 60.0 mmol) followed by 1 drop of anhydrous DMF. The reaction was stirred at room temperature for 3 h and the solvent was removed in vacua to afford an oil which was dissolved in anhydrous dichloromethane (200 mL). To this solution was added 4-methyl-3-nitroanih'ne (50 mmol) followed by a slow addition of triethylamine (20 mL, 140 mmol) and the mixture was stirred at rt overnight. The reaction was diluted with dichloromethane (400mL) and washed with water (150 mL x 2), saturated aqueous sodium bicarbonate (150mL x 2), then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacua to afford the crude product which was recrystallized from ethyl acetate to give 9.57 g (56%) of 119C as a yellow solid. HPLC Ret. Time: 3.07min. MH* (m/z) 342.1. Step D: (119D) Compound 119D was prepared as described for compound 116C. Step E: II ° (119E) 119E was prepared from 4-chloro-5-methylpyrrolotriazine-6-ethylcarboxylate as described for 116D by substituting compound 119D for compound 116C. HPLC Ret. Time: 3.39 min. MH*(m/z) 515.1. Step F: HN O HO (119F) 119F was prepared from 119E as described for 116E. HPLC R'et. Time: 2.78 min. MET (m/z) 487.2. StepG: Title Compound The title compound was prepared from 119F as described in Step F for the preparation of Example 116. HPLC Ret. Time: 2.68 min. MH+On/z) 514.1. Examples 120-123 Examples 120-123 were prepared as described for Example 119. Ex.# Structure HPLC retention time (min) 121 2.32 591.4 558.1 h HN Step A: 02N' (124A) Compound 124A was prepared from 4-methyl-3-nitroaniline utilizing the same procedure used for compound 114A by substituting 3,5-difluorobenzoyl chloride for 2-chloropyridine-4-carbonyl chloride. Step B: OjN' (124B) Compound 124A (12.2 g) in 80 mL of morpholine was refluxed under argon for 3days. The resulting mixture was cooled to it and poured into ice-water (1000 mL) with stirring. The mixture was stirred at rt for 15 min and the resulting solid was collected by filtration and dried in vacuo to afford 14.6 g of 124B as a light yellow solid. HPLC Ret. Tune: 3.35 min. MH+Om/z) 360.1. Step C: Compound 124C was prepared from by hydrogenation using Pd/C catalyst and hydrogen. Step D: ) 124D was prepared from 4-chloro-5-methylpyrrolotriazine-6-ethylcarboxylate as described for 116D by substituting compound 124C for compound 119D. HPLC Ret. Time: 3.59 min. MH^m/z) 533.3. step n: 124E was prepared from 124D as described for 116E. HPLC Ret. Time: 3.06 min. MH+Cm/z) 505.0. StepF: Title Compound The title compound was prepared from 124E as described in Step F for the preparation of Example 116. HPLC Ret. Time: 2.93 min. MBTCm/z) 532.1. Examples 125-147 Examples 125-147 were prepared as described for Example 124. Ex.# Structure HPLC retention time (min) 12(148B) 1486 was prepared from 148A as described for 116E. HPLC Ret. Time: 2.89 min. MET" (m/z) 328.1. Step 3.93 641.2 WO 2003/090912 PCT/US2003/012426 2.95 509.2 513.3 206 2.03 543.3 Example 207 A suspension of chloropyrrolotriazine (2.03 g, 8.47 mmol) and 3-nitro-5-methyl aniline (1.41 g, 9.3 mmol) in DMF (25 mL) was stirred at rt for 24 h. Water (125 mL) was added over 30 min and the solution stirred for 1 h upon which the pH was adjusted to neutral with sat. aq. NaHCOs. The solids were filtered, washed with water, and dried to give compound A (2.589 g, 85% yield) as a pale tan solid. StepB: To a solution of Compound A (825 mg, 2.32 mmol) in THF (2 mL) and MeOH (1 mL) was added IN NaOH (6 mL) and the reaction heated at 60°C for 24 h. The reaction mixture was cooled, concentrated to remove the organic solvents, and the pH was adjusted to neutral with 1N HC1. The solids were filtered, washed with water, and dried to give compound B. LCMS (M+H*) =328.1. HPLC (Condition A): 3.40 min. Step C: A solution of compound B (2.32 mmol), EDCI (489 mg, 2.55 mmol), and [OBt (345 mg, 2.55 mmol) in DMF (6 mL) was stirred at rt for 1 h, and then n-propyl mine (0.38 mL, 6.4 mmol) was added. The reaction was stirred for 4 h and water /as added to precipitate the product. The solids were filtered and purified via column chromatography on silica (33% ethyl acetate\hexanes) to give compound C (0.79 g, 93% yield) as a white solid. ]H NMR (CDC13): 5 9.11 (s, 1H), 7.92 (m, 2H), 7.71 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 5.82 (br m, 1H), 3.34 (q, J=6.7 Hz, 2H), 2.86 (s, 3H), 2.41 (s, 3H), 1.58 (m, 2H), 1.16 (t, J=7.5 Hz, 3H). LCMS (M+H4) = 369.3. HPLC (Condition A): 3.42 min. Step D: A solution of compound C (794 mg, 2.16 mmol) and 10% Pd/C (250 mg, wet) in MeOH (20 mL) was degassed and backfilled with hydrogen three times and stirred for 2 h. The solution was filtered and concentrated to give compound D (691 mg, 95% yield). JH NMR (CDC13): 5 7.94 (s, 1H), 7.73 (s, 1H), 7.53 (s, 1H), 7.23 (m, 1H), 7.06 (d, J=8.1 Hz, 1H), 6.53 (dd, J=8.1,2.2 Hz, 1H) 5.86 (br m, 1H), 3.43 (q, J=6.6 Hz, 2H), 2.91 (s, 3H), 2.27 (s, 3H), 1.68 (m, 2H), 1.02 (t, J=7.3 Hz, 3H). LCMS (M+H+) - 339.2. HPLC (Condition A): 2.39 min. Step E: Title Compound To a suspension of 2.5 g (7.4 mmol) of compound D in 50 mL of CHzQb was added 1.42 jjL of DIPEA at rt. The reaction mixture was cooled to 0°C and added ethylchloroformate (0.77 mL). The reaction was stirred for 2 h at room temperature and then quenched with MeoH. The solvents were removed and the product precipitated with water (40 mL). The product was collected by vacuum filtration and washed with water (2x) then dissolved in hot MeOH, decolorized with charcoal and recrystallized from EtOH to give 2.10 g (70%) of the titled compound as a pure product. Examples 208-233 Compounds having the formula below, wherein W and Ba have the values listed in the Table provided below, were prepared following the same procedure described for Example 1, using the appropriate acid chloride, chloroformate or isocyanate. o 3-Amino p-tolylacetic acid (131 mg, 0.8 mmol) and IB (220 mg, 0.92 mmol) were stirred for 18h in DMF (2 mL). Water was added to precipitate the product and the pH was adjusted to 6 with aq NaHCOs. The solids were filtered, washed with water and dried to afford the above ester (62%). Step C: Title Compound To the above acid (86 mg, 0.23 mmol) in DMF (2 mL) was added EDC (49 mg, 0.26 mmol) and HOBt (35 mg, 0.26 mmol). The mixture was stirred for 1 h followed by addition of methylamine (0.25 ml, 2M in THF). The reaction was stirred for 18h then added water (12mL). The solids were filtered to obtain the title compound (75mg, 84%). (M + H)+: 395.2, HPLC retention time: 2.85 min. Example 235 and 236 owing the procedure described in Example 2 and 3. H,C Step A: Compound IB was hydrolyzed under standard saponification methods and coupled with n-propylamine using the EDC/HOBt method to furnish the C-6 n-propylamido oxopyrrolotriazine. A solution of this compound (1.65g, 7 mmol) in toluene (50 mL) was added POC13 (0.8 mL, 8.45 mmol) and DIPEA (1 mL, 5.6 mmol) and the solution heated at reflux for lOh. The reaction was cooled and poured into ice cold aqueous NaHCO3. The solution was extracted with EtOAc (3x), dried over Na2SO4, filtered and concentrated to give the chloride as a yellow solid (1.65g, 93%) which was used without further purification. Step B: A solution of 3-nitro-4-methyl benzamide (402 mg, 2.2 mmol) in dichloroethane (15 mL) was added propionic anhydride (2.45 mmol) and DMAP (381 mg, 3.1 mmol) and the reaction mixture heated at 55 °C. Additional propionic anhydride (2.45 mmol) and DMAP (1.4 eq) was added and the reaction temperature increased to 85 °C for 2h. The reaction vessel was cooled and poured into CHzCb (50 mL) and water (25 mL). The organic layer was washed with IN HC1 and brine, dried over Na2SO4, filtered and concentrated in vacuo to an oil which was purified via column chromatography (15% then 30% EtOAc/hexane) to give the nitro imide (333 mg, 63%). The above compound (152 mg, 0.6 mmol) was dissolved in EtOH (6 mL) and added 5% Pd-C (wet, 35 mg) and evacuated and back filled under a hydrogen balloon. The reaction was stirred for 2h, filtered and concentrated to a white solid which was used without further purification (132 mg, 99%). The above aniline (20 mg) and chloride (20 mg) were combined hi DMF (0.25 mL) and stirred for 18h. The solution was added water (1 mL) drop wise and neutralized with dilute aq. NaHCOs. The solids were stirred rapidly for 2 h then filtered and washed with water to give 33.6 mg, 98% yield. Example 238 H,C Step A: H, 3-nitro-4-methyl benzamide (0.2g, 1.1 mmol) was suspended in dichloroethane (6 mL) and added oxalyl chloride (0.12 mL, 1.3 mmol) at 0 °C. The solution was allowed to warm to room temperature and stir for 1 h followed by heating at reflux for 18h. The reaction was cooled, concentrated to remove volatiles and dried under vacuum to give the desired product which was used without further purification. StepB: To the crude acyl isocyanate was added CEkCk (5 mL) and dry EtOH (1 mL) and the reaction stirred for 1 h. The solvents were removed in yacuo and the solids filtered with EtOAc and washed with ether to give a white solid (203 mg, 73%). The crude solids were dissolved in MeOH (25 mL) and hydrogenated under hydrogen balloon in the presence of 5% Pd-C for 2 h to give a white solid after filtration (174 mg, 97%). StepC: Title Compound This solid from the previous step was coupled with the above pyrrolotriazine chloride under standard conditions to afford the title compound hi 55% yield. Examples 239-267 Examples 239-267 were prepared as described in Example 238 by reacting the acyl isocyanate with an appropriate amine. 247 -NHCH, -OCH3 397.2 2.47 248 -NHCH3 -OCH2CH3 411.2 2.67 H,N H,c The amine (0.38g, 2.3 mmol) was dissolved in CKfeCk (10 mL) and cooled to 0 °C and added DIPEA (0.44 mL, 2.5 mmol). Ethyl chloroformate (0.22 mL, 2.3 mmol) was added and the reaction stirred for 5 minutes followed by the addition of MeOH (0.1 mL). The mixture was concentrated to an oil and dissolved in EtOAc (30 mL) followed by washing with water, dilute aq NaHCOa and brine. The organic layer was dried over Na2SC>4, filtered and concentrated to an oil. Purification via column chromatography (25%EtOAc/hexane) afforded the nitro product (500 mg, 92%). The above product was dissolved in EtOH (5 mL) and EtOAc (5 mL) and added 5% Pd-C (wet) followed by evacuation and backfilling with hydrogen (3x). The mixture was stirred for Ih and filtered to give the product (177 mg, 99%). This amine was then coupled and elaborated in a similar fashion as outlined in Example 1 to give the examples in the Table provided below. H,C Step A: HUC 02N H3CO OCH3 A solution of 3-nitro-4-methylacetophenone (O.lg, 0.53 mmol) in MeOH (5 mL) was added Accufluor and the solution heated at reflux for 18h. The reaction was cooled, concentrated and suspended in CEfeCla. The solution was filtered and the organic filtrates were washed with sat. NaHCOa and water. The organic layer was dried over NaaSO^ filtered and concentrated to an oil which was purified via column chromatography (10% the 25% EtOAc/hexane) to furnish the above product (70 mg, 54%). Step B: Title Compound This product was reduced to the amine in an identical fashion as the above examples to furnish 60 mg (98%) which was coupled directly with the intermediate obtained in Step A in the preparation of Example 237, to afford 73 mg of the crude ketal which was treated with 3N HCI (0.1 mL) hi acetone (3 mL) for 2 d. The reaction was neutralized with sat aq. NaHCOs and diluted with water (3 mL). The solids were filtered to give 55.3 mg of the title compoung. Example 295 Step A: X A solution of 3-nitro-4-methylbenzoyl chloride (1.6g) in THF (50 mL) and MeCN (50 mL) was added trimethylsilyldiazomethane (5 mL, 2M in hexanes) and TEA (1.4 mL) at 0 °C. The reaction mixture was stirred at 0°C for 24 h. The volatiles were removed in vacuo to give 3.3 g of a crude yellow solid. A portion was purified via column chromatography (25% EtOAc/hexane). The above diazoketone (44 mg, 0.22 mmol) was dissolved in CHaCli (1 mL) and EtOH (0.09 mL) and added BF3OEt2 (0.006 mL) was added. The mixture was stirred for 90 min and a second addition of BFaOEta (0.005 mL) was made. The reaction mixture was stirred for 16h and purified directly through a silica gel plug to afford the ketone (42.1 mg, 88%). Step B: The ketone was reduced to the amino-alcohol in an identical fashion as the above examples and coupled to the chloropyrrolotriazine as in Example 1 to give the alcohol (58mg). Step C: Title Compound The alcohol (56 nag, 0.14 mmol) was dissolved in OBfeCla and added PCC (36.3 mg, 0.17 mmol). The reaction was stirred at rt for 24 h, filtered through celite and purified via column chroamtography (25% EtOAc/hexane) to give the ketone (44mg, 79%). Examples 296-305 Examples 296-305 were prepared according to the procedure outlined in Example 31 (Claims) -, -NRg-, -NR8C(=0}-, -NR8C(=0)NR9-, -NRgCOr-, -NR8SO2-, -NR8SO2NR9-, -g-, -NR8C(=0}-, -NR8C(=0)NR9-, -NRgCOr-, -NR8SO2-, --, -NRg-, -NR8C(=0}-, -NR8C(=0)NR9-, -NRgCOr-, -NR8SO2-, -NR8SO2NR9-,NR8SO2NR9-,-, -C(=O)NRs-, halogen, nitro, and cyano, or X is absent; Z is -C(=0)NRi -(CH2)-NR10aC(=0)-Bc, -NR10aC(=0)NR10-B, -NRioSOr-B,-SO2NRio-B, -C(=0)-Ba, -COz-B6, -OC(=0)-Ba, -C(=0)NR10-NRioa-Bd, -NRi0CO2-Ba or -C(=0)NRio-(CH2)C(=0)Ba; Bis (a) optionally-substituted cycloalkyl, optionally-substituted heterocyclo, or optionally substituted heteroaryl; or (b) aryl substituted with one rh and zero to two Ri2; Ba is optionally substituted alkyl, optionally-substituted cycloalkyl, optionally-substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl; Bbis (a) optionally-substituted cycloalkyl, optionally-substituted heterocyclo, or optionally substituted heteroaryl; aryl substituted with one rh and zero to two Ri2; or -C(=0)Ri3, -C02Ri3, -C(=0)NR13R13a; Bc is optionally substituted alkyl, optionally substituted alkoxy, optionally-substituted cycloalkyl, optionally-substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl; Bd is hydrogen, -C(=O)Ri3, or-CO2Ri3; Be is hydrogen, optionally substituted alkyl, optionally-substituted cycloalkyl, optionally-substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl; ri and rs are independently selected from hydrogen, alkyl, substituted alkyl, -ORi4, -SRw, -OC(=O)Ri4, -CO2Ru, -C(=O)NRi4Ri4a, -NRi^ua, -S(=O)R14, -SO2Ri4, -SO2NRi4Ri4a, -NR14SO2NRi4aRi4b, -NRi4aSO2R14, -NRi4C(=O)RMa, -NRi4CO2Ri4a, -NRi4C(=O)NRMaRi4b, halogen, nitro, and cyano; R2 is hydrogen or Ci^alkyl; R3 is hydrogen, methyl, perfluoromethyl, methoxy, halogen, cyano, NH2, or NHfCHs); R4 is selected from: hydrogen, provided that R4 is not hydrogen if X is -S(=O)-, -SO2-, -NR8CO2-, or -NR8SO2-; alkyl, alkenyl, and alkynyl optionally independently substituted with keto and/or one to four Rn; (c) aryl and heteroaryl either of which may be optionally independently substituted with one to three Rie; and heterocyclo and cycloalkyl either of which may be optionally independently substituted with keto and/or one to three Rie; or R4 is absent if X is halogen, nitro, or cyano; / rs is attached to any available carbon atom of phenyl ring A and at each occurrence is independently selected from alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkyltbiono, arylthiono, arylsulfonylamine, alkylsulfonylamine, sulfonic acid, alkysulfonyl, sulfonamido, phenyl, benzyl, aryloxy, and benzyloxy, wherein each Rg group in turn may be further substituted by one to two Rig; Rg and Rg are independently selected from hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, heterocyclo, and heteroaryl; rio and Rioa are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, and aryl; rh is selected from alkyl, haloalkyl, alkoxy, haloalkoxy, -SO2alkyl, cycloalkyl, heterocyclo, and heteroaryl any of which may be optionally subsituted; or halo, cyano, ammo, alkylamino, and dialkylamino; Ri2 is selected from alkyl, Rn, and Ci^alkyl substituted with keto (=O) and/or one to three Rn; rb and Rna are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl and optionally subsituted aryl; ru, Ri4a and R^b are independently selected from hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, heterocyclo, and heteroaryl, except when Ri4 is joined to a sulphonyl group as in — S(=O)Ri4, -SO2Ri4, and — NRuaSC^Ru, then rh is not hydrogen; Rie is selected from alkyl, Rn, and Ci^alkyl substituted with keto (=O) and/or one to three Rn; Rn is selected from (a) halogen, haloalkyl, haloalkoxy, nitro, cyano, -SR^, -OR^, -NR23R24, -NR23SO2R25, -SO2R25, -SO2NR23R24, -CO2R23, -C(=O)R23, -C(=0)NR23R24, -OC(=0)R23 , -OC(=0)NR23R24, - (b) aryl or heteroaryl either of which may be optionally substituted with one to three R2s; or (c) cycloalkyl or heterocyclo optionally substituted with keto(=O) and/or one to three R2e; Rig and R2e are independently selected from Ci^alkyl, Ci-ealkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, Ci-4alkylamino, aminoCi-4alkyl, hydroxy, hydroxyCi-4alkyl, alkoxy, Ci^alkylthio, aryl, heterocyclo, (aryl)alkyl, aryloxy, and (aryl)alkoxy; R2s and R24 are each independently selected from hydrogen, alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, cycloalkyl, heteroaryl, and heterocyclo; Rasis selected from alkyl, substituted alkyl, aryl, heteroaryl, cycloalkyl and heterocyclo; and misO, 1,2 or 3. 2. A compound of claim 1 having the formula (I*): enantiomers, diastereomers, salts and solvates thereof wherein X is selected from -O-, -OC(=O)~, -S-, -S(=O)-, -SO2- -C(=O)-, -CO2-, -NR8-, ~NR8C(=O)~, -NR8C(=0)NR9- -NR8CO2-, -NR8SO2-, -NR8SO2NR9-, -SO2NRs-, -C(=O)NR8-, halogen, nitro, and cyano, or X is absent; Y is -C(=O)NR10~, -NRioaC(=O)NRio-, -NRioSO2-, -SO2NRi0-, -C^O)-, -CCV or-OC(=0)-; B is optionally-substituted cycloalkyl, heterocyclo, or heteroaryl; or aryl substituted with one Rn and zero to two Ri2; or when Y is -C(=O)NRi(r-, B also may be selected from -C(=O)Ri3, ~CO2Ri3, and -C(=O)NRi3Ri3a; ri and Rs are independently selected from hydrogen, alkyl, substituted alkyl, -ORj4, -SRw, ~OC(=0)RM, -CC^Ru, -C(=0)NRi4Rua, -NR14Ri4a,-S(=O)R14, -SO2Ri4, -SO2NRi4Ri4a, -NRi4SO2NRi4aRi4b, -NRi4aSO2Ru, -NRuC(=O)Ri4a, -NRi4CO2Ri4a, -NRi4C(=O)NRi4aRi4b, halogen, nitro, and cyano; R2 is hydrogen or R3 is hydrogen, methyl, perfluoromethyl, methoxy, halogen, cyano, NH2, or NH(CH3); R4 is selected from: a) hydrogen, provided that R$ is not hydrogen if X is — S(=O)-, -SOa—, -NR8CO2-, or -NR8SO2-; alkyl, alkenyl, and alfcynyl optionally substituted with keto and/or one to four Rn; aryl and heteroaryl optionally substituted with one to three Rie; and heterocyclo and cycloalkyl optionally substituted with keto and/or one to three Rie; or e) Rt is absent if X is halogen, nitro, or cyano; Re is attached to any available carbon atom of phenyl ring A and at each occurrence is independently selected from alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamine, alkylsulfonylamine, sulfonic acid, alkysulfonyl, sulfonamido, phenyl, benzyl, aryloxy, and benzyloxy, wherein each Re group in turn may be further substituted by one to two Rig; Rg and Rg are independently selected from hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, heterocyclo, and heteroaryl; rio and Rioa are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, and aryl; Rn is selected from optionally-substituted cycloalkyl, heterocyclo, and heteroaryl; RJ2 is selected from alkyl, Rn, and Ci^alkyl substituted with keto (=O) and/or one to three Rn; and Ri3a are selected from hydrogen, alkyl, and substituted alkyl; , Ri4a and R]4b are independently selected from hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, heterocyclo, and heteroaryl, except when ru is joined to a sulphonyl group as in -S(=O)Ru, —SOaRu, and -NRwaSC^Ru, then ru is not hydrogen; is selected from alkyl, Rn, and Ci^alkyl substituted with keto (=0) and/or one to three is selected from halogen, haloalkyl, haloalkoxy, nitro, cyano, -SR23, -NR23R24, -NR23SO2R25, -SO2R25, -SOiNTR^R^, -CO2R23, -C(=O)Ra3, -C(=0)NR23R24, -OC(=0)R23, -OC(=O)NR23R24, -NR23C(=O)R24, —NR23CO2R24, aryl or heteroaryl optionally substituted with one to three or cycloalkyl or heterocyclo optionally substituted with keto(=O) and/or one to three R26; and R2e are independently selected from Chalky!, C2-6alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, Ci^alkylamino, aminoCi-4alkyl, hydroxy, hydroxyCi^alkyl, alkoxy, Giwjalkylthio, phenyl, benzyl, phenyloxy, and benzyloxy; R23 and R24 are each independently selected from hydrogen, alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, cycloalkyl, heteroaryl, and heterocyclo; R2sis selected from alkyl, substituted alkyl, aryl, heteroaryl, cyclo alkyl and heterocyclo; and mis0,1,2 or 3. 3. A compound according to claim 2, or a pharmaceutically-acceptable salt, or an hydrate thereof, in which: B is a C3-7cycloalkyl optionally substituted with one to two R?, a five membered heteroaryl optionally substituted with one to two R/, a five or six membered heterocyclo optionally substituted with one to two R7, aryl substituted with one rh and zero to two R^; or when Y is -C(=O)NRio-, B also may be selected from -C(=O)R13, -CQjRia, and -C(=O)NRi3Ri3a; R7 is attached to any available carbon or nitrogen atom of ring B and at each occurrence is independently selected from keto (=O), alkyl, substituted alkyl, halogen, haloalkoxy, ureido, cyano, -SR2o, -OR^, -NR20R2i, -NR2oSO2R2i, -SO2R19, -SO2NR2oR2i, -CO2R20, -C(=O)Rao, -C(=O)NR20R2i, -OC(=O)R20, -OC(=O)NR2oR2i, -NR2oC(=O)R2i, -NR20CO2R2i, aryl, cycloalkyl, heterocycle, and heteroaryl; and/or when B is cycloalkyl, two R? groups may join to form an optionally-substituted carbon-carbon bridge of three to four carbon atoms, or two R? groups may join to form a fused carbocyclic, heterocyclic or heteroaryl ring, said fused ring being in turn optionally substituted with one to three R^.; Rao and R2i are selected from hydrogen, alkyl, alkenyl, substituted alkyl, substituted alkenyl, phenyl, C3.7cycloalkyl, and five-to-six membered heterocyclo or heteroaryl; and Ri2 and R22 are independently selected from Ci-ealkyl, C2.6alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, Ci^alkylamino, aminoCi^alkyl, hydroxy, hydroxyCwalkyl, alkoxy, alkylthio, phenyl, benzyl, phenyloxy, and benzyloxy. 4. A compound according to claim 2, having the formula (la), ar a pharmaceutically-acceptable salt, prodrug, or solvate thereof, wherein: R3 is methyl, -CF3, or -OCF3; X is -C(=O)-, -NR8C(=O)-, or -C(=O)NRg-, wherein R8 is hydrogen or CMalkyl; Y is -C(=O)NH-, -NHC(=O)NH-, or -NHSCV; R4 is hydrogen, C2-6alkyl, C^alkyl optionally substituted with one to three Rn, cycloalkyl or heterocycle optionally-substituted with keto (=O) and/or one to three Rie; or aryl or heteroaryl optionally substituted with one to three R]g; R§a and rq, are independently selected from hydrogen, Ci^alkyl, substituted Ci^alkyl halogen, trifluoromethoxy, trifluoromethyl, -OR2?, -C(=O)alkyl, -OC(=0)alkyl, -NR27R28, -SR27, -NO2, -CN, -CO2R27, -CONH2, -SO3H, -S(=O)aJlcyl, -S(=O)aryl, -NHSO2-aryl-R27, -SO2NHR27, -CONHR27, and -NHC(=O)NHR27; is selected from Ci^alkyl, Rn, and Ci^alkyl substituted with keto (=O) and/or one to two Rn; Rn is selected from halogen, hydroxy, C^alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, phenyl, benzyl, phenyloxy, benzyloxy, NEfe. NH(Ci-4alkyl), N(Ci_ 4alkyl)2, C3-7cycloalkyl, or five or six membered heteroaryl or heterocycle; and R27 and R2g are selected from hydrogen, Ci^alkyl, phenyl, C^cycloalkyl, and five-to- six membered heterocyclo or heteroaryl. 5. A compound according to claim 2, or a pharmaceutieally-acceptable salt, or solvate thereof, wherein: ring B is phenyl substituted with heterocycle and zero to one Ri2, or is a cycloalkyl, heteroaryl, or heterocyclo ring selected from: (R7)n and CEfe, provided that when q is 0, then J and K are not simultaneously selected from O and S; and M is N or CH; wherein each hydrogen atom of E, G, J, K and M may optionally be replaced with an R? group; ri and Ri2 are independently selected from Ci-ealkyl, substituted Ci^alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, -Ci^alkoxy, -C(=O)alkyl, -OC(=0)alkyl, NH2, NH(Cwalkyl), N(Ci.4alkyl)2, -CN, -CO2alkyl, -CONHo, -CONH(CH3), -CON(CH3)2, phenyl, benzyl, C3.7 cycloalkyl, and five-to-six membered heterocyclo or heteroaryl; n is 0, 1 or 2; and p and q are selected from 0, 1, 2, 3 and 4, provided that/? and q taken together are not greater than 4. 6. A compound according to claim 5, or a pharmaceutically acceptable salt, or solvate thereof, in which: Xis -C(=0)- -C(=0)NH-or -C(=O)N(CMalkyl)-; Yis-C(=O)NH~; R4 is hydrogen, C2-6alkyl, Ci-4alkyl optionally substituted with one to three Ri7, aryl or heteroaryl optionally substituted with one to three Rie, or cycloalkyl or heterocycle optionally-substituted with keto (=O), and/or one to three ris; is selected from Ci^alkyl, Rn, and Chalky! substituted with keto and/or one to two Rn; and is selected from halogen, hydroxy, C^alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, phenyl, benzyl, phenyloxy, benzyloxy, NHa, NH(Ci-4alkyl), and 7. A compound according to claim 2 or a pharmaceutically acceptable salt, or solvate thereof, in which ri and rs are independently hydrogen or A compound according to claim 2, or a pharmaceutically acceptable salt, or solvate thereof, in which R2 is hydrogen. A compound according to claim 2, or a pharmaceutically acceptable salt, or solvate thereof, in which rs is methyl, -CFs, or -OCFs. A compound according to claim 2, or a pharmaceutically acceptable salt, or solvate thereof, in which X is -C(=O)- or -C(=O)NH-. A compound according to claim 2, or a pharmaceutically acceptable salt, prodrug or solvate thereof, in which Y is -C(=O)NH-. 12. A compound according to claim 2, or a pharmaceutically acceptable salt, or solvate thereof, in which X is -C(=O)NH- and R4 is Ca-ealkyl, optionally-substituted benzyl, or a heterocyclic or heteroaryl ring selected from diazepinyl, morpholinyl, piperidinyl, and pyrrolidinyl, said heterocycle being optionally substituted with one to two of Ci^alkyl, hydroxy, Ci^alkoxy, phenyl, and/or benzyl. 13. A compound according to claim 2, or a pharmaceutically acceptable salt, prodrug or solvate thereof, in which X is -C(=O)— and R* is phenyl, pyridyl, pyrimidinyl, or pyrazinyl optionally-substituted with one to two of Ci^alkyl, halogen, hydroxy, Q^alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, phenyl, benzyl, phenyloxy, benzyloxy, NHa, NH(Ci_4alkyl), N(Ci^alkyl)2 and/or a Ci^alkyl substituted with one to two of halogen, hydroxy, Ci^alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, phenyl, benzyl, phenyloxy, benzyloxy, NH2, NH(Ci_ 4alkyl), and/or N(Ci-4alkyl)2. 14. A compound according to claim 2, or a pharmaceutically acceptable salt, or solvate thereof, in which B is cyclopropyl or cyclobutyl optionally substituted with one to two R.7, phenyl substituted with a five or six membered heterocycle and zero to two Rn, or B is selected from one of: m Ci^alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, amino, Ci^alkylahuino, hydroxy, C\. 4alkoxy, phenyl, benzyl, phenyloxy, and benzyloxy; and n is 0, 1 or 2. 15. A compound having the formula, enantiomers, diastereomers, salts, and solvates thereof, wherein rs is methyl or CF3; X is -C(=0)~ or ~C(=O)NH-; R4 is straight or branched Ca-ealkyl; cycloalkyl optionally substituted with keto and/or up to two Rig; heterocycle or heteroaryl optionally substituted with keto and/or up to two Rie; Ci^alkyl substituted with up to three of halogen, trifluoromethyl, cyano, hydroxy, alkoxy, haloalkyl, haloalkoxy, nitro, phenyl, phenyloxy or benzyloxy, wherein said phenyl group is optionally substituted with one to two R2e; or phenyl optionally substituted with zero to two ri$; Rea and R hydroxy, Ci^alkoxy, nitro, amino, CMalkylamino, and cyano; B is a C3.7cycloalkyl optionally substituted with one to two Ry, a five membered heteroaryl optionally substituted with one to two Ry, a five or six membered heterocyclo optionally substituted with one to two R;, phenyl substituted with rh and zero to two R12, -C(=O)Ri3, -CO2Ri3, and -C(=O)NRi3Ri3a; R7 is attached to any available carbon or nitrogen atom of ring B and at each occurrence is independently selected from alkyl, substituted alkyl, halogen, haloalkoxy, ureido, cyano, trifluoromethoxy, trifluoromethyl, hydroxy, -C\. 4alkoxy, -C(=O)alkyl, -OC(=O)alkyl, NH2, NH(Cwalkyl), N(Cwalkyl)2, -CN, -CO2alkyl, -CONH2, -CONH(CH3), -CONCCH^, phenyl, benzyl, €3.7 cycloalkyl, and five-to-six membered heterocyclo or heteroaryl; and/or when B is cycloalkyl, two R? groups may join to form an optionally-substituted carbon-carbon bridge of three to four carbon atoms, or two R? groups may join to form a fused carbocyclic, heterocyclic or heteroaryl ring, said fused ring being in turn optionally substituted with one to three R22; rh is cycloalkyl, heterocycio, or heteroaryl optionally substituted with one to two Ri3 and Risa are selected from hydrogen and Chalky!; R]2» ris, and Rig at each occurrence are independently selected from hydrogen, alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, nitro, ammo, Ci_ 4alkylamino, aminoCi^alkyl, haloCi^alkyl, hydroxy, hydroxyCi^alkyl, alkoxy, phenyl, benzyl, phenyloxy, and benzyloxy; Rao and Rai are selected from hydrogen, alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, cycloalkyl, heteroaryl, and heterocycio; and R22 and R26 are selected from Ci^alkyl, Ca-ealkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, Ci-4alkylamino, aminoCi-4alkyl, hydroxy, hydroxyCi. 4alkyl, alkoxy, alkylthio, phenyl, benzyl, phenyloxy, and benzyloxy. 16. A compound according to claim 15, or a pharmaceutically acceptable salt, or solvate thereof, in which B is phenyl substituted with heterocycio and one to two Ria; cyclopropyl or cyclobutyl optionally substituted with one to two R?; or B is selected from one of: (Figure Remove) l, trifluoromethyl, trifluoromethoxy, halogen, cyano, amino, Q. 4alkylalmino, hydroxy, C^alkoxy, phenyl, benzyl, phenyloxy, or benzyloxy, and n is 0, 1 or 2. 17. A compound having the formula (2a) or (2b), HN—B (Figure Remove)enantiomers diastereomers, salts and solvates thereof, wherein: R3 is methyl or CFs; R4a is phenyl or five or six membered heteroaryl optionally substituted with up to two or R4b is straight or branched Ca-ealkyl; cycloalkyl optionally substituted with keto and/or up to two Rie; heterocycle optionally substituted with keto and/or up to two ris; or C]-4alkyl substituted with up to three of halogen, trifluoromethyl, cyano, hydroxy, alkoxy, haloalkyl, haloalkoxy, nitro, phenyl, phenyloxy benzyloxy, wherein said phenyl or benzyl group in turn is optionally substituted with one to two R26; Rea is lower alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, Ci amino, Ci^alkylalmino, or cyano; B is selected from phenyl substituted with heterocyclo or heteroaryl and up to two R^, cyclopropyl or cyclobutyl either of which may be optionally substituted with one to two R/, or B is selected from one of: (Figure Remove)N a 4 -148- ? is Ci-4alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, nitro, amino, Ci. 4alkylalmino, hydroxy, C^alkoxy, phenyl, benzyl, phenyloxy, or benzyloxy; n, Rie and Rn at each occurrence are independently selected from hydrogen, alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, nitro, amino, Q. 4alkylalmino, hydroxy, alkoxy, phenyl, benzyl, phenyloxy, and benzyloxy; is selected from Ci-4alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, amino, Ci_4alkylalmino, hydroxy, alkoxy, phenyl, benzyl, phenyloxy, and benzyloxy; nisOor 1. 18. A compound according to claim 17 or a pharmaceutically acceptable salt, prodrug or solvate thereof, in which B is cyclopropyl optionally substituted with one to two R?, or B is selected from: (Figure Remove) A pharmaceutical composition comprising at least one compound according to claim 1 and a pharmaceutically-acceptable carrier or diluent. A pharmaceutical composition comprising at least one compound according to claim 15 and a pharmaceutically-acceptable carrier or diluent. A method of treating an inflammatory disorder comprising administering to a patient in need of such treatment a pharmaceutical composition according to claim 19. 22. The method of claim 21 in which the inflammatory disorder is selected from asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, diabetes, inflammatory bowel disease, osteoporosis, psoriasis, graft vs. host rejection, atherosclerosis, and arthritis including rhematoid arthritis, psoriatic arthritis, traumatic arthritis, rubella arthritis, gouty arthritis and osteoarthritis. 23. A compound having the formula, (Figure Remove) mantiomers, diastereomers, salts, and solvates thereof, wherein R.3 is methyl or CFs; X is -C(=0)- or -C(=0)NH-; R4 is straight or branched Ca-salkyl; cycloalkyl optionally substituted with keto and/or up to two Rie; heterocycle or heteroaryl optionally substituted with keto and/or up to two Rie; Ci-4alkyl substituted with up to three of halogen, trifluoromethyl, cyano, hydroxy, alkoxy, haloalkyl, haloalkoxy, nitro, phenyl, phenyloxy or benzyloxy, wherein said phenyl group is optionally substituted with one to two Rze; or phenyl optionally substituted with zero to two Rie; R6a and Rsb are selected from lower alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, Ci^alkoxy, nitro, amino, Ci^alkylamino, and cyano; B is a C^cycloalkyl optionally substituted with one to two R?, a five membered heteroaryl optionally substituted with one to two R?, a five or six membered heterocyclo optionally substituted with one to two rv, phenyl substituted with rh and zero to two R12, -C(=O)Ri3, -CO2Ri3, and -C(=O)NRi3Ri3a; R? is attached to any available carbon or nitrogen atom of ring B and at each occurrence is independently selected from alkyl, substituted alkyl, halogen, haloalkoxy, ureido, cyano, trifluoromethoxy, trifluoromethyl, hydroxy, -Q-4alkoxy, -C(=O)alkyl, -OC(=O)alkyl, NH2, NH(CMalkyl), N(d.4alkyl)2, -CN, -C02alkyl, -CONH2, -CONH(CH3), -CON(CH3)2, phenyl, benzyl, C3.7 cycloalkyl, and five-to-six membered heterocyclo or heteroaryl; and/or when B is cycloalkyl, two R? groups may join to form an optionally-substituted carbon-carbon bridge of three to four carbon atoms, or two Ry groups may join to form a fused carbocyclic, heterocyclic or heteroaryl ring, said fused ring being in turn optionally substituted with one to three R^; rh is cycloalkyl, heterocyclo, or heteroaryl optionally substituted with one to two ris; Ri3 and Ri3a are selected from hydrogen and Chalky!; Ri2, ris, and Rieat each occurrence are independently selected from hydrogen, alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, nitro, amino, Ci_ 4alkylamino, aminoCi^alkyl, haloCi^alkyl, hydroxy, hydroxyCi^alkyl, alkoxy, phenyl, benzyl, phenyloxy, and benzyloxy; R2o and R2i are selected from hydrogen, alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, cycloalkyl, heteroaryl, and heterocyclo; and R22 and R2e are selected from Ci^alkyl, C2.6alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, CMalkylamino, aminoCi-4alkyl, hydroxy, hydroxyCi. 4alkyl, alkoxy, alkylthio, phenyl, benzyl, phenyloxy, and benzyloxy. 24. A compound according to claim 23, or a pharmaceutically acceptable salt, or solvate thereof, in which B is phenyl substituted with heterocyclo and one to two Ri2; cyclopropyl or cyclobutyl optionally substituted with one to two R?; or B is selected from one of: 4alkylahnino, hydroxy, Ciwtalkoxy, phenyl, benzyl, phenyloxy, or benzyloxy; and n is 0, 1 or 2. 25. A compound having the formula, (Figure Remove) enantiomers, diastereomers, salts, and solvates thereof, wherein Ra is methyl or CF3; X is -C(=0)- or -C(=0)NH-; R4 is straight or branched Ca-eaLkyJ- ^vr.loalkvl ootionallv substituted with keto and/o up to two Rie; heterocycle or heteroaryl optionally substituted with keto and/or up to two Rie; Chalky! substituted with up to three of halogen, trifluoromethyl, cyano, hydroxy, alkoxy, haloalkyl, haloalkoxy, nitro, phenyl, phenyloxy or benzyloxy, 'wherein said phenyl group is optionally substituted with one to two Rag; or phenyl optionally substituted with zero to two Rie; Rea and Ra, are selected from lower alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, Ci-4alkoxy, nitro, amino, Ci^alkylamino, and cyano; B is a C3.7cyclo alkyl optionally substituted with one to two Ry, a five membered heteroaryl optionally substituted with one to two Rj, a five or six membered heterocyclo optionally substituted with one to two Ry, phenyl substituted with Rn and zero to two R]2, -C(=O)Ri3, -CO2Ri3, and -C(=O)NRi3Ri3a; rv is attached to any available carbon or nitrogen atom of ring B and at each occurrence is independently selected from alkyl, substituted alkyl, halogen, haloalkoxy, ureido, cyano, trifluoromethoxy, trifluoromethyl, hydroxy, -C\. 4alkoxy, -C(=O)alkyl, -OC(=O)alkyl, NH2, NH(CMalkyl), N(Ci.4alkyl)2, -CN, -CO2alkyl, -CONH2, -CONH(CH3), -CON(CH3)2, phenyl, benzyl, C3.7 cycloalkyl, and five-to-six membered heterocyclo or heteroaryl; and/or when B is cycloalkyl, two R? groups may join to form an optionally-substituted carbon-carbon bridge of three to four carbon atoms, or two R? groups may join to form a fused carbocyclic, heterocyclic or heteroaryl ring, said fused ring being in turn optionally substituted with one to three R22; rh is cycloalkyl, heterocyclo, or heteroaryl optionally substituted with one to two ris; and Rna are selected from hydrogen and Cj^alkyl; a, ris, and Rie at each occurrence are independently selected from hydrogen, alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, nitro, amino, Ci_ 4alkylamino, aminoCMalkyl, haloCi^alkyl, hydroxy, hydroxyCMalkyl, alkoxy, phenyl, benzyl, phenyloxy, and benzyloxy; R20 and R2i are selected from hydrogen, alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, cycloalkyl, heteroaryl, and heterocyclo; and R22 and R26 are selected from Chalky!, C2.6alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, Ci-4alkylamino, aminoCMalkyl, hydroxy, hydroxyCi. 4alkyl, alkoxy, alkylthio, phenyl, benzyl, phenyloxy, and benzyloxy. 26. A compound according to claim 25, or a pharmaceuticalry acceptable salt, or solvate thereof, in which B is phenyl substituted with heterocyclo and one to two cyclopropyl or cyclobutyl optionally substituted with one to two R?; or B is selected from one of: (Figure Remove) (Figure Remove) (Figure Remove) (Figure Remove) R7is Ci^alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, amino, Ci. 4atkylalmino, hydroxy, C^alkoxy, phenyl, benzyl, phenyloxy, or benzyloxy and n is 0,1 or 2. 27. A compound of claim 1 selected from (Figure Remove)salts and solvates thereof. snantiomers, diasteriomers, salts and solvates thereof.

Documents:

3189-DELNP-2004-Abstract-31-03-2008.pdf

3189-delnp-2004-abstract.pdf

3189-delnp-2004-assignments.pdf

3189-DELNP-2004-Claims-31-03-2008.pdf

3189-delnp-2004-claims.pdf

3189-delnp-2004-correspondence-others-02-05-2008.pdf

3189-DELNP-2004-Correspondence-Others-09-04-2008.pdf

3189-DELNP-2004-Correspondence-Others-31-03-2008.pdf

3189-delnp-2004-correspondence-others.pdf

3189-delnp-2004-description (complete).pdf

3189-DELNP-2004-Description (Complete)31-03-2008.pdf

3189-DELNP-2004-Form-1-31-03-2008.pdf

3189-delnp-2004-form-1.pdf

3189-delnp-2004-form-18.pdf

3189-DELNP-2004-Form-2-31-03-2008.pdf

3189-delnp-2004-form-2.pdf

3189-DELNP-2004-Form-3-09-04-2008.pdf

3189-delnp-2004-form-3.pdf

3189-delnp-2004-form-5.pdf

3189-DELNP-2004-GPA-31-03-2008.pdf

3189-delnp-2004-gpa.pdf

3189-delnp-2004-other-docoment-02-05-2008.pdf

3189-DELNP-2004-Others Docoment-09-04-2008.pdf

3189-delnp-2004-pct-220.pdf

3189-delnp-2004-pct-401.pdf

3189-delnp-2004-pct-409.pdf

3189-delnp-2004-pct-416.pdf

3189-delnp-2004-pct-notificatian.pdf

3189-delnp-2004-pct-request form.pdf

3189-delnp-2004-pct-search report.pdf

3189-DELNP-2004-Petition-137-09-04-2008.pdf