MXPA06007314A - Bicyclic heterocyclic p-38 kinase inhibitors - Google Patents

Abstract

Provided are bicyclic heterocycle-based p38 kinase, including p38alpha and p38beta kinase, inhibitors. Pharmaceutical compositions containing the compounds are also provided. Methods of use of the compounds and compositions are also provided, including methods of treatment, prevention, or amehoration of one or more symptoms of p38 kinase mediated diseases and disorders, including, but not limited to, inflammatory diseases and disorders.

Description

INHIBITORS OF CHINASE P-38 HETEROCICLICOS B1CICLICOS RELATED APPLICATIONS Priority here is claimed to United States of America Provisional Patent Applications Nos. 60 / 532,529 filed on December 23, 2003, and 60 / 575,113 filed on May 28, 2004. Where permitted by national laws , the disclosures of the provisionally referenced provisional applications are hereby incorporated in their entirety.

FIELD Bicyclic heterocyclic compounds having a cytokine inhibitory activity are provided herein. The uses of the bicyclic heterocyclic compounds are also provided for the treatment of conditions associated with p38a and β kinases, and for the treatment of conditions associated with the p38 kinase.

BACKGROUND A large number of cytokines participate in the inflammatory response, including IL-1, IL-6, IL-8, and TNF-a. The overproduction of cytokines, such as IL-1 and TNF-a is implicated in a wide variety of diseases, including inflammatory bowel disease, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, and heart failure. congestive, among others (Henry et al, Drugs Fut., 24: 1345-1354 (1999); Salituro et al., Curr. Med. Chem., 6: 807-823 (1999)). Evidence in human patients indicates that cytokine protein antagonists are effective in the treatment of chronic inflammatory diseases, such as, for example, the monoclonal antibody to TNF-a (Remicade) (Rankin et al., Br. J. Rheumatol 34: 334-342 (1995)), and the soluble fusion protein of the TNF-α-Fc receptor (Etanercept) (Moreland et al., 25 Ann. Intern. Med. 130: 478-486 (1999)). 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 a trauma. The important mediators of TNF-a production are mitogen-activated protein (MAP) kinases, and in particular, p38 kinases. These kinases are activated in response to different stress stimuli, including, but not limited to, pro-inflammatory cytokines, endotoxin, ultraviolet light, and osmotic shock. Activation of p38 requires double phosphorylation by upstream MAP kinase kinases (MKK3 and MAKK6) on threonine and tyrosine within a Thr-Gly-Tyr motif characteristic of p38 isozymes. There are four known isoforms of p38, ie, p38a, p38ß, p38 ?, and p38d. The isoforms a and β are expressed in inflammatory cells, and are key modulators of TNF-a production. Inhibition of the p38a and β enzymes in the cells results in reduced levels of TNF-α expression. Also, the administration of inhibitors of p38a and β in animal models of inflammatory disease, has proven that these inhibitors are effective in the treatment of these diseases. In accordance with the above, p38 enzymes serve an important role in inflammatory processes mediated by IL-1 and TNF-a. Compounds which, as reported, inhibit p38 kinase and cytokines such as IL-1 and TNF-α, for use in the treatment of inflammatory diseases, are disclosed in US Pat. Nos. 6,277,989 and 6,130,235 to Scios, Inc .; in Patents of the United States of North America Numbers 6,147,080 and 5,945,418 to Vértex Pharm aceuticals Inc .; in U.S. Patent Nos. 6,251,914, 5,977,103 and 5,658,903 to Smith-Kline Beecham Corp .; in Patents of the United States of North America Nos. 5,932,576 and 6,087,496 to G. D. Searle & Co.; in the International Publications Numbers WO 00/56738 and WO 01/27089 to Astra Zeneca; in International Publication Number WO 01/34605 to Johnson &; Johnson; in International Publication Number WO 00/12497 (quinazoline derivatives as inhibitors of p38 kinase); in International Publication Number WO 00/56738 (pyridine and pyrimidine derivatives for the same purpose); in International Publication Number WO 00/12497 (discusses the relationship between p38 kinase inhibitors); and in International Publication Number WO 00/12074 (piperazine and piperidine compounds useful as p38 inhibitors). Pyrrolotriazine compounds useful as tyrosine kinase inhibitors are disclosed in U.S. Patent Application Serial Number 09 / 573,829 filed May 18, 2000, assigned to Bristol-Myers Squibb. In addition, pyrrolotriazine kinase inhibitors are disclosed in International Publication Number WO 02/40486, assigned to Bristol-Myers Squibb. Recent requests: WO 03/032970, WO 03/033482, WO 03/032971, WO 03/032986, WO 03/032980, WO 03/032987, WO 03/033483, WO 03/033457, and WO 03/032972, which are incorporated into this application. A series of 5- and 6-membered ring heterocycles substituted by aminoaryl useful as inhibitors of IMPH is disclosed in International Publication Number WO 00/25780. U.S. Patent Nos. 6,005,109 and 6,103,900 disclose pyrazoles and pyrazolo-pyrimidines having a CRF antagonist activity. International Publications Nos. WO 03/090912 and WO 03/091229 disclose certain pyrrolo-triazines useful as kinase inhibitors. Each of the patent applications, patents, and publications referred to herein, are incorporated herein by reference. Compounds are provided for use in compositions and methods for modulating the activity of cytokines. In one embodiment, the compounds are used in compositions and methods to modulate the p38 kinase, including, but not limited to, the kinase activity p38a and p38β. In certain embodiments, the compounds are bicyclic heterocyclic compounds that are substituted with a cycloalkyl amide moiety. In certain embodiments, the compounds provided herein are substituted purines, pyrrolo-triazines, pyrazolo-pyrimidines, imidazolo-pyrimidines, and related compounds. In one embodiment, compounds of Formula I are provided herein: or pharmaceutically acceptable derivatives thereof, wherein: R is hydrogen, halogen, alkyl, cycloalkyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, pseudo-halogen, -NR4R5, or -OR4; R2, in each presentation, is independently selected from alkyl, substituted alkyl, lower cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, -OR4, -CN, -NR4R5, -S (= 0) alkyl, -S ( = 0) -aryl, -NHS02-aryieno-R4, -NHS02-alkyl, -C02R4, -CONH3, -S03H, -S (0) -alkyl, -S (0) -aryl, -S02NHR4, and -N HC (= 0) NH R4; n is 0, 1, or 2; R3 is selected from hydrogen, alkyl, -OR4, substituted alkyl, cycloalkyl, -CR4-cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; Y is an individual bond, -C (= 0) NH-, -NH (C = O) -, -NH (C = 0) NH-, -S02NH-, -NHS02-, or -C (= 0) -; X1 is an individual bond, alkylene, -O-, -S-, -S (O) -, -S02-, -C (O) -, -CO (O) - or -C (0) NH-; A is a bicyclic heterocyclic ring system with at least one heteroatom in each ring, wherein the heteroatoms are each independently selected from N, O, and S, and is optionally substituted with up to two R13; .

X2 is an individual bond: alkylene, -O-, -S-NH- -N (alkyl of 1 to 4 carbon atoms) -, -NH-alkylene of 1 to 4 carbon atoms-, -N (alkyl of 1) to 4 carbon atoms) -alkylene of 1 to 4 carbon atoms, -S (O) -, -S02-, -C (O) -, -CO (O) -, or -C (0) NH-; D is a monocyclic or bicyclic aromatic or non-aromatic ring system optionally containing up to four heteroatoms selected from N, O, and S, and wherein a CH2 adjacent to any of the N, O, or S heteroatoms is optionally substituted with oxo (= 0), or D is alkyl of 1 to 6 carbon atoms, wherein D is optionally substituted by one to four groups (CR9R10) WE; w is an integer from 0 to 4; R 0 is selected from H, alkyl of 1 to 4 carbon atoms-hydroxyl, alkyl of 1 to 4 carbon atoms-aryl, and alkyl of 1 to 4 carbon atoms-heteroaryl, wherein this aryl or heteroaryl group is unsubstituted or substituted with 1 to 3 groups independently selected from halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl, haloalkoxy, OH, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms-carbonyl, CN, NH2, NR6R7, SR6, S (0) R6, S02R6, S03R6, S02NR6, C02H, C02R6, and CONR6R7; E is selected from H, halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl, haloalkoxy, OH, OR6, CN, CHO, C02R6, CONR6R7, OCOR6, OC (= 0) OR6, OC (= 0) NR6R7, OCH2C02R6, C (= 0) R6, NH2, NHR6, NR6R7, NR7C (= 0) R6, NR7C (= 0) OR6, N R7C (= 0) C (= 0) 0 R6, NR7C (= 0) C (= 0) NR6R7, N R7C (= 0) C (= O) (alq u I or from 1 to 6 carbon atoms), NR7C (= NCN) OR6, NR7C (= 0) NR6R7, NR7C (= NCN) NR6R7, N R7C (= NR6) N R7R8, NR6S02NR6R7, NR7S02R6, SR6, S ( = 0) R6, S02R6, S03R7, S02NR6R7, NHOH, NHOR6, NR6NR7NR8, N (COR6) OH, N (C02R6) OH, CONR7 (CR9R10) rR6, CO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10) rR6 , CO (CR9R10) pO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10) rOR6, CO (CR9R10) pO (CR9R10) qR6, CO (CR6R1) rNR6R7, OC (O) O (CR9R10) mNR6R7, O ( CO) n (CR9R10) R6, O (CR9R10) mNR6R7, N R7C (O) (C R9R1 °) rO R6, NR7C (= NC) (CR9R10) rR6, NR7CO (CR9R10) rNR6R7, NR7 (CR9R10) mOR6, NR7 (CR9R10) rCO2R6, N R7 (C R9 R1) mN R6 R7, NR7, NR3 (CR9R10) nSO2 (CR9R10) rCO2R6, N R7 (C R9R °) mN R6R7, NR7 (CR9R10) nSO2 (CR9R10) qR6, CONR7 (CR9R10) nSO2 (CR9R 0) qR6, SO2NR7 (CR9R10) qR6, SO2NR6 (CR9R10) rnOR6, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms-methyl, aryl, heterocyclic optional- substituted with 1 or 2 alkyl groups, heteroaryl optionally substituted with 1 or 2 alkyl groups, and alkylaryl, wherein the aryl groups are unsubstituted or substituted with 1 or 2 substituents, each independently selected from R 12, or two groups E , which replace the adjacent atoms on D, and which together form alkylenedioxyl, thioalkyleneoxy or alkylenedithioxyl; m is an integer that has a value of 2 to 6; p is an integer that has a value of 1 to 3; q is an integer that has a value from 0 to 3; r is an integer that has a value from 0 to 6; R12, in each presentation, is independently selected from halogen, No2, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms carbon, haloalkyl, haloalkoxy, OH, oxo, alkoxy of 1 to 4 carbon atoms, OR6, O (CR9R10) CO2R6, O (CR9R10) mNR6R7, O (CR9R0) pCN, O (CR 9R 1 °) rC (= 0) N R6R7, C 1 -C 4 alkyl, CN, NH 2, NHR 6, NR 6 R 7, N R 7 (CR 9 R 10) CO2 R 6, NR 7 OR 6, N R 7 (CR 9 R 1) m O R 6, N R 7 CH ((CR 9 R 10) POR 6) 2, N R7C ((C R9R1 °) pO R6) 3, NR7C (= 0) R6, NR7 (CR9R10) mNR6R7, N R7 (CR9 R 1 °) R6, SR7, S (0) R7, S02R7, S02NR6, S03R7 , C02H, C02R6, and CONR6R7; R 4 is hydrogen, lower alkyl, and lower cycloalkyl; R5 is hydrogen, lower alkyl, and lower cycloalkyl; R6, R7, and R8 are independently selected as follows:) R7, R 'are independently selected from H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 atoms of carbon, alkynyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-carbonyl, cycloalkyl of 3 to 7 carbon atoms- (alkyl of 0 to 5 carbon atoms) -carbonyl, alkoxy of 1 to 6 carbon-carbonyl, aryl- (C 0 -C 5) -carbonyl, aryl- (C 1-5 alkoxy) -carbonyl, heterocyclic- (C 0 -C 5) -carbonyl atoms , heterocyclic- (alkoxy of 1 to 5 carbon atoms) -carbonyl, alkyl of 1 to 6 carbon atoms-sulfonyl, aryl-sulfonyl, heteroaryl-sulfyl, alkyl of 0 to 4 carbon atoms-aryl, alkyl of 0 to 4 carbon atoms-heterocyclic, wherein the cycloalkyl, aryl, or heterocyclic groups are unsubstituted or substituted with 1 or 2 substituents, each independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, hydroxyl, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, haloalkyl, N02, and CN; or i) R6 and R7, or R6 and R8, or R7 and R8, when both substituents are on the same nitrogen atom (as in (-NR6R7) or (NR7R8)), they can be taken together with the nitrogen atom with which they are attached, to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, 1-piperazinyl, 1-imidazolyl, 3-azabicyclo- (3,2,2) -nonan-3-yl, and 1-tetrazolyl, this heterocycle being optionally substituted with 1 to 3 groups, each independently selected from oxo, alkyl of 0 to 4 carbon atoms-OH, alkyl of 0 to 4 carbon atoms-O-alkyl of 1 to 4 carbon atoms, alkyl of 0 to 4 carbon atoms-CON H2, alkyl of 0 to 4 carbon atoms-C02-alkyio of 0 to 4 carbon atoms carbon, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkyl of 0 to 6 carbon atoms carbonyl, cycloalkyl 3 to 7 carbon atoms-carbonyl, C 1 -C 6 -alkoxycarbonyl, cycloalkoxyl of 3 to 7 carbon atoms, -NHCO-alkyl, aryl, heteroaryl, aryl-alkoxycarbonyl, heteroaryl- alkoxycarbonyl, alkyl of 1 to 6 carbon atoms-sulfonyl, aryl-sulfonyl, and heteroaryl-sulfonyl; R9 is hydrogen or alkyl of 1 to 4 carbon atoms; and R13 is hydrogen, alkyl, haloalkyl, aminocarbonyl, hydroxyl, hydroxycarbonyl, alkoxycarbonyl, cycloalkyl-aminocarbonyl, substituted alkyl, aryl, substituted aryl, heteroaryl, heterocyclyl, thioalkyl, alkyl-amino-carbonyl, or lower cycloalkyl; wherein the substituents on the alkyl group are selected from 1 to 4 substituents selected from halogen, hydroxyl, alkoxy, oxo (= 0), alkanoyl, aryloxy, alkanoyloxy, amino, alkyl-amino, arylamino, aralkyl -amino, disubstituted amines, wherein the two amino substituents are selected from alkyl, aryl, or aralkyl; alkanoyl-amino, aroyl-amino, aralkanoyl-amino, substituted alkanoyl-amino, substituted aryl-amino, substituted aralkanoyl-amino, thiol, thioalkyl, thioaryl, thioaralkyl, thionoalkyl, thionoaryl, thionoaralkyl, alkyl-sulfonyl, aryl-sulfonyl, aralkyl -sulfonyl, sulfonamido, for example S02NH2, substituted sulfonamido, nitro, cyano, carboxyl, carbamyl, for example CONH2, substituted carbamyl, for example CONH-alkyl, CONH-aryl, WITH H-aralkyl, or the cases wherein there are two substituents on the nitrogen selected from alkyl, aryl, or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino, and substituted or unsubstituted heterocycles, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, and the like, and substituents on the aryl group are selected from from 1 to 4 substituents selected from alkyl, substituted aryl, haloalkyl, halogen, trifluoro-methoxy, trifluoromethyl, hydroxyl, hydroxy-alkyl, amino-alkyl, alkoxy, alkanoyl, alkanoyloxy, amino, arylamino, aralkylamino , dialkylamino, alkanoylamino, thiol, thioalkyl, ureido, nitro, cyano, cyano-alkyl, heterocyclyl, carboxyl, carboxy-alkyl, carbamyl, alkoxy-carbonyl, amino-carbonyl, thionoalkyl, thionoaryl, aryl-sulfonyl-amine , sulfonic acid, alkylsulfonyl, sulfonamido, aryloxy, and CONRaR, wherein Ra and Rb are selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy-carbonyl-amino-alkylaryl, and alkylamino; or Ra and Rb, together with the nitrogen with which they are substituted, form a heterocyclic or heteroaryl ring of 3 to 6 members. The substituent may be further substituted by hydroxyl, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl, or aralkyl. In one embodiment, the groups A, Y, R1, R2, R3, X1, X2, and D are selected such that the resulting compound has an effect on the activity of the cytokine. Also of interest are any pharmaceutically acceptable derivatives, including salts, esters, enol-ethers, enol-esters, solvates, hydrates, and prodrugs of the compounds described herein. Pharmaceutically acceptable salts include, but are not limited to, salts of amines, such as, but not limited to, N, N'-dibenzyl-ethylene-diamine, chloro-procaine, choline, ammonia, diethanolamine, and other hydroxy -alkyl-amines, ethylene diamine, N-methyl-glucamine, procaine, N-benzyl-phenethyl-amine, para-chloro-benzyl-2-pyrrolidin-1'-ylmethyl-benzimidazole, diethylamine and other alkyl -amines, piperazine and tris- (hydroxy-methyl) -amino-methane; alkali metal salts, such as, but not limited to, lithium, potassium, and sodium; alkaline earth metal salts, such as, but not limited to, barium, calcium, and magnesium; transition metal salts, such as, but not limited to, zinc, aluminum, and other metal salts, such as, but not limited to, sodium acid phosphate and disodium phosphate; and also including but not limited to, salts of mineral acids such as, but not limited to, hydrochlorides and sulfates; and salts of organic acids, such as, but not limited to, acetates, lactates, maleates, tartrates, citrates, ascorbates, succinates, butyrates, valerate, and fumarates. Also provided are pharmaceutical compositions formulated for administration by an appropriate route, and means containing effective concentrations of one or more of the compounds provided herein, or pharmaceutically acceptable derivatives thereof, which provide effective amounts for treatment, prevention, or the decrease of one or more symptoms of diseases or disorders that are modulated or otherwise affected by the activity of the cytokine, in one embodiment the activity of the p38 kinase, or where the activity of the cytokine is involved, in a mode the activity of the p38 kinase. Effective amounts and concentrations are effective to decrease any of the symptoms of any of the diseases or disorders. Methods are provided for the treatment, prevention, or amelioration of one or more symptoms of diseases or disorders mediated by, or in which cytokine activity is involved, in one embodiment, the activity of p38 kinase. These methods include methods of treatment, prevention, and reduction of one or more symptoms of inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, angiogenic disorders, infectious diseases, neurodegenerative diseases, and viral diseases, using one or more of the compounds provided herein, or pharmaceutically acceptable derivatives thereof. Methods for modulating the activity of cytokines are also provided, in one embodiment the activity of the p38 kinases, using the compounds and compositions provided herein. Methods are also provided for reducing the expression of inducible pro-inflammatory proteins, including, but not limited to, prostaglandin-2 endoperoxide synthases (PGHS-2), also referred to as cyclo-oxygenase-2 (COX-2), in a subject in need thereof, by administration of one or more compounds or compositions provided herein. In the practice of the methods, effective amounts of the compounds or compositions containing therapeutically effective concentrations of the compounds are administered, which are formulated for systemic delivery, including parenteral, oral, or intravenous, or for local or topical application, for the treatment of diseases or disorders mediated by cytokine, in a p38 kinase modality, or diseases or disorders in which the activity of the cytokine is involved, in a modality the activity of the p38 kinase, including, but not limited to, inflammatory diseases, diseases autoimmune, destructive bone disorders, proliferative disorders, angiogenic disorders, infectious diseases, neurodegenerative diseases, and viral diseases, to an individual exhibiting the symptoms of these diseases or disorders. The amounts are effective to decrease or eliminate one or more symptoms of the diseases or disorders. Manufacturing articles are provided which contain a packaging material, a compound or composition, or a pharmaceutically acceptable derivative thereof, provided herein, which is effective to modulate the activity of the cytokines, in a form of p38 kinases, or for the treatment, prevention, or reduction of one or more symptoms of the diseases or disorders mediated by the cytokine, in a p38 kinase modality, or diseases or disorders where the activity of the cytokine is involved, in a modality the activity of the p38 kinase, within the packaging material, and a label indicating that the compound or composition, or the pharmaceutically acceptable derivative thereof, is used to modulate the activity of the cytokine, in one embodiment the activity of the kinases p38, or for the treatment, prevention, or reduction of one or more symptoms of cytokine-mediated diseases or disorders, in a modality d the p38 kinase, or of the diseases or disorders where the activity of the cytokine is involved, in one embodiment the activity of the p38 kinase.

DETAILED DESCRIPTION A. Definitions. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents, applications, published requests, and other publications are incorporated as a reference in their entirety. In the event that there is a plurality of definitions for a term in the present, those in this section prevail, unless otherwise reported. As used herein, p38a refers to the enzyme disclosed in Han J., Richter B., Li Z., Kravchenko V., Ulevitch R.J., Molecular cloning of human p38 MAP kinase. Bíochim Biophys Acta. 1995; 1265 (2-3): 224-7. As used herein, p38β refers to the enzyme disclosed in Jiang Y., Chen C, Li Z., Guo W., Gegner JA, Lin S., Han J., Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta). J. Biol. Chem., July 26, 1996; 271 (30): 17920-6. As used in the present, p38? refers to the enzyme disclosed in Li, Z .; Jiang, Y .; Ulevitch, R. J .; Han, J .: The primary structure of p38-gamma: a new member of p38 group of MAP kinases. Biochem. Biophys. Res. Commun. 228: 334-340, 1996. As used herein, p38d refers to the enzyme disclosed in Molecular Cloning and Characterization of a Novel p38 Mitogen-activated Protein Kinase; Xuhong Sunny Wang, Katrina Diener, Carl L. Manthey, Shen-wu Wang, Bradley Rosenzweig, Jeffrey Bray, John Delaney, Craig N. Cole, Po-Ying Chan-Hui, Nathan Mantlo, Henri S. Lichenstein, Mark Zukowski and Zhengbin Yao The term "condition associated with p38", as used herein, means any disease or condition where p38 is known to play a role. This includes conditions that are known to be caused by an overproduction of IL-1, TNF, IL-6, or IL-8. These conditions include, but are not limited to, inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, viral diseases, and neurodegenerative diseases. As used herein, inhibition of p-38a / β kinase means that p38a and / or p38ß kinase is inhibited. Accordingly, reference to an IC50 value for inhibiting the p-38a / β kinase means that the compound has that effectiveness to inhibit at least one of, or both of, the p38a and p38ß kinases. As used herein, pharmaceutically acceptable derivatives of a compound include salts, esters, enol-ethers, enol-esters, acetals, ketals, orfo-esters, henniacetals, hemicetales, acids, bases, solvates, hydrates, or pro-drugs thereof. These derivatives can easily be prepared by those skilled in the art, using the methods known for that derivation. The compounds produced can be administered to animals or humans without substantial toxic effects, and are pharmaceutically active or pro-drug. The pharmaceutically acceptable salts include, but are not limited to, amine salts, such as, but not limited to, N, N'-dibenzyl-ethylene-diamine, chloro-procaine, choline, ammonia, diethanolamine, and other hydroxy- alkyl-amines, ethylene diamine, N-methyl-glucamine, procaine, N-benzyl-phenethylamine, 1-para-chloro-benzyl-2-pyrrolidin-1'-ylmethyl-benzimidazole, diethylamine and others alkyl amines, piperazine, and tris- (hydroxy-methyl) -amino-methane; alkali metal salts, such as, but not limited to, lithium, potassium, and sodium; alkaline earth metal salts, such as, but not limited to, barium, calcium, and magnesium; salts of transition metals, such as, but not limited to, zinc; and other metal salts, such as, but not limited to, sodium acid phosphate and disodium phosphate; and also including but not limited to, nitrates, borates, methansulfonates, benzenesulfonates, toluenesulphonates, salts of mineral acids, such as, but not limited to, hydrochlorides, hydrobromides, iodides, and sulfates; and salts of organic acids, such as, but not limited to, acetates, trifluoroacetates, maleates, oxalates, lactates, maleates, tartrates, citrates, benzoates, salicylates, ascorbates, succinates, butyrates, valerate, and fumarates. Pharmaceutically acceptable esters include, but are not limited to, alkyl-, alkenyl-, alkynyl-, aryl-, heteroaryl-, aralkyl-, heteroaralkyl-, cycloalkyl-, and heterocyclyl-esters of the acid groups, including, but not limited to, limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids, and boronic acids. Pharmaceutically acceptable enol ethers include, but are not limited to, the derivatives of the formula C = C (OR), wherein R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, or heterocyclyl . The pharmaceutically acceptable enol esters include, but are not limited to, the derivatives of the formula C = C (OC (0) R), wherein R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, or heterocyclyl. The pharmaceutically acceptable solvates and hydrates are the complexes of a compound with one or more solvent molecules or water, or from 1 to about 100, or from 1 to about 10, or from 1 to about 2, 3, or 4 solvent molecules. or water. As used herein, "treatment" means any manner in which one or more of the symptoms of a disease or disorder is diminished or otherwise altered beneficially. The treatment also encompasses any pharmaceutical use of the compositions herein, such as use for the treatment of diseases or disorders mediated by the p38 kinase, or diseases or disorders in which the activity of the p38 kinase is involved, including the activity of p38a. As used herein, decreasing the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition, refers to any decrease, whether permanent or temporary, lasting or transient, that may be attributed or associated or the administration of the composition. As used herein, IC5o refers to an amount, concentration, or dosage of a particular test compound that achieves a 50 percent inhibition of a maximal response, such as modulation of p38 kinase activity, in an essay that measures this answer. As used herein, EC5o refers to a dosage, concentration, or amount of a particular test compound that elicits a dose-dependent response to 50 percent of the maximum expression of a particular response that is induced, provoked, or enhanced by the particular test compound. As used herein, a "prodrug" is a compound that, after its administration in vivo, is metabolized by one or more steps or processes, or is otherwise converted to biologically, pharmaceutically, or therapeutically active form of the compound.

To produce a pro-drug, the pharmaceutically active compound is modified so that the active compound is regenerated by the metabolic processes. The prodrug can be designed to alter the metabolic stability or transport characteristics of a drug, to mask side effects or toxicity, to improve the taste of a drug, or to alter other characteristics or properties of a drug. By virtue of the knowledge of the pharmacodynamic processes and the metabolism of the drug in vivo, those skilled in the art, once a pharmaceutically active compound is known, can design the prodrugs of the compound (see, for example, Nogrady (1985). Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392). It should be understood that the compounds provided herein may contain chiral centers. These chiral centers may be of the (R) or (S) configuration, or may be a mixture thereof. Accordingly, the compounds provided herein may be enantiomerically pure, or they may be stereoisomeric or diastereomeric mixtures. In the case of amino acid residues, these residues may be of the L or D form. The configuration for naturally occurring amino acid residues is in general L.

When not specified, the residue is of the form L. As used herein, the term "amino acid" refers to the a-amino acids that are racemic, or of the D or L configuration. The preceding "d" designation an amino acid designation (eg, dAla, dSer, dVal, etc.) refers to the D isomer of the amino acid. The designation "di" preceding an amino acid designation (e.g., dIPip) refers to a mixture of the L and D isomers of the amino acid. It should be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one skilled in the art will recognize that the administration of a compound in its (R) form is equivalent, for compounds undergoing epimerization in vivo, to the administration of the compound in its (S) form. As used herein, substantially pure means sufficiently homogeneous to appear free of easily detectable impurities, determined by conventional analytical methods, such as thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC). , and mass spectrometry (MS), used by those skilled in the art to evaluate this purity, or sufficiently pure so that further purification does not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance.

Methods for purifying the compounds to produce substantially chemically pure compounds are known to those skilled in the art. However, a chemically substantially pure compound can be a mixture of stereoisomers. In those cases, an additional purification could increase the specific activity of the compound. As used herein, the alkyl, alkenyl, and alkynyl carbon chains, if not specified, contain from 1 to 20 carbon atoms, or 1 or 2 to 16 carbon atoms, and are straight or branched. In certain embodiments, the alkenyl carbon chains of 2 to 20 carbon atoms contain from 1 to 8 double bonds, and in certain embodiments, the alkenyl carbon chains of 2 to 16 carbon atoms contain 1 to 5 double bonds. links In certain embodiments, the alkynyl carbon chains of 2 to 20 carbon atoms contain from 1 to 8 triple bonds, and in certain embodiments, the alkynyl carbon chains of 2 to 16 carbon atoms contain from 1 to 5 triple bonds . Exemplary alkyl, alkenyl, and alkynyl groups herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, normal butyl, secondary butyl, tertiary butyl, isopentyl, neopentyl, tertiary pentyl, isohexyl, allyl (propenyl), and propargyl (propynyl). As used herein, lower alkyl, lower alkenyl, and lower alkynyl refer to carbon chains having from about 1 or about 2 carbon atoms to about 6 carbon atoms. As used herein, "a I q u (e n) (i n) i I o" refers to an alkyl group containing at least one double bond and at least one triple bond. As used herein, "cycloalkyl" refers to a mono- or multi-cyclic saturated ring system, in certain embodiments of 3 to 10 carbon atoms, and in other embodiments of 3 to 6 carbon atoms; Cycloalkenyl and cycloalkynyl refer to mono- or multi-cyclic ring systems which include at least one. double bond and at least one triple bond. The cycloalkenyl and cycloalkynyl groups, in certain embodiments, may contain from 3 to 10 carbon atoms, the cycloalkenyl groups containing other embodiments of 4 to 7 carbon atoms, and containing the cycloalkynyl groups in other embodiments of 8 to 10 carbon atoms . The ring systems of the cycloalkyl, cycloalkenyl, and cycloalkynyl groups can be composed of a ring or of 2 or more rings that can be joined together in a fused, bridged, or spiro-connected manner. "Cycloalk (en) (in) yl" refers to a cycloalkyl group that contains at least one double bond and at least one triple bond. As used herein, "aryl" refers to monocyclic or multicyclic aromatic groups containing from 6 to 19 carbon atoms. Aryl groups include, but are not limited to, groups such as unsubstituted or substituted fluorenyl, unsubstituted or substituted phenyl, and unsubstituted or substituted naphthyl. As used herein, "heteroaryl" refers to a monocyclic or multicyclic aromatic ring system, in certain embodiments, of from about 5 to about 15 members, wherein one or more, in a 1 to 3 mode, of the Ring system atoms is a heteroatom, that is, a different element of carbon, including, but not limited to, nitrogen, oxygen, or sulfur. The heteroaryl group may be optionally fused to a benzene ring. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolinyl, and isoquinolinyl. As used herein, a "heteroaryl" group is a heteroaryl group that is positively charged on one or more of the heteroatoms. As used herein, "heterocyclyl" refers to a monocyclic or multicyclic non-aromatic ring system, in a 3 to 10 member modality, in another 4 to 7 member modali, in an additional 5 to 6 modality. members, wherein one or more, in certain embodiments 1 to 3, of the atoms in the ring system is a heteroatom, that is, a different element of carbon, including, but not limited to, nitrogen, oxygen, or sulfur. In the embodiments wherein the heteroatoms are nitrogen, the nitrogen is optionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkyl-alkyl, heterocyclyl-alkyl, acyl, guanidino, or the nitrogen may be quaternized to form an ammonium group, wherein the substituents are selected as above. As used herein, "aralkyl" refers to an alkyl group wherein one of the hydrogen atoms of the alkyl is replaced by an aryl group. As used herein, "heteroaralkyl" refers to an alkyl group wherein one of the hydrogen atoms of the alkyl is replaced by a heteroaryl group. As used herein, "halo," "halogen," or "halide," refers to F, Cl, Br, or I. As used herein, the pseudo-halide or pseudo-halogen groups are groups which behave in a manner substantially similar to halides. These compounds can be used in the same way, and can be treated in the same manner, as halides. The pseudo-halides include, but are not limited to, cyanide, cyanate, thiocyanate, selenocyanate, trifluoromethoxy, and azide. As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen. These groups include, but are not limited to, chloro-methyl, trifluoro-methyl, and 1-chloro-2-f-luoro-ethyl. As used herein, "haloalkoxy" refers to RO-, wherein R is a haloalkyl group. As used herein, "sulfinyl" or "thionyl" refers to -S (O) -. As used herein, "sulfonyl" or "sulfuryl" refers to -S (0) 2-. As used herein, "sulfo" refers to -S (0) 20-. As used herein, "carboxyl" refers to a divalent radical, -C (0) 0- As used herein, "amino-carbonyl" refers to -C (0) NH2. As used herein, "alkyl-amino-carbonyl" refers to -C (0) NHR, wherein R is alkyl, including lower alkyl. As used herein, "dialkyl amino-carbonyl" refers to -C (0) NR'R, wherein R 'and R are independently alkyl, including lower alkyl; "carboxamide" refers to the groups of the formula -NR'COR, wherein R 'and R are independently alkyl, including lower alkyl.

As used herein, "diaryl-aminocarbonyl" refers to -C (0) NRR ', wherein R and R' are independently selected from aryl, including lower aryl, such as phenyl. As used herein, "aryl-alkyl-amino-carbonyl" refers to -C (0) NRR ', wherein one of R and R' is aryl, including lower aryl, such as phenyl, and the other of R and R 'is alkyl, including lower alkyl. As used herein, "aryl-amino-carbonyl" refers to -C (0) NHR, wherein R is aryl, including lower aryl, such as phenyl. As used herein, "hydroxycarbonyl" refers to -COOH. As used herein, "alkoxycarbonyl" refers to -C (0) 0R, wherein R is alkyl, including lower alkyl. As used herein, "aryloxycarbonyl" refers to -C (0) OR, wherein R is aryl, including lower aryl, such as phenyl. As used herein, "alkoxy" and "thioalkyl" refer to RO- and RS-, wherein R is alkyl, including lower alkyl. As used herein, "aryloxy" and "thioaryl" refer to RO- and RS-, wherein R is aryl, including lower aryl, such as phenyl.

As used herein, "alkylene" refers to a straight-chain, branched or cyclic divalent aliphatic hydrocarbon group, in certain straight or branched embodiments, having in an embodiment of 1 to 20 carbon atoms, which it has in another modality of 1 to 12 carbon atoms. In a further embodiment, alkylene includes lower alkylene. Optionally, one or more oxygen and sulfur groups, including S (= 0) and S (= 0) 2, or substituted or unsubstituted nitrogen atoms, including the -NR- groups, can be optionally inserted throughout the alkylene group. -N + RR-, wherein the nitrogen substituents are alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or COR ', wherein R' is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OY, or -NYY, in where Y is hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl. Alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (- (CH2) 3-), methylenedioxyl (-0-CH2-0-), and ethylenedioxyl (- 0- (CH2) 2-0-). The term "lower alkylene" refers to alkylene groups having from 1 to 6 carbon atoms. In certain embodiments, the alkylene groups are lower alkylene, including alkylene of 1 to 3 carbon atoms. As used herein, "aza-alkylene" refers to - (CRR) n-NR- (CRR) m-, where n and m are each independently an integer from 0 to 4. As used herein, "oxa-alkylene" refers to - (CRR) p-0- (CRR) m-, where n and m are each independently an integer from 0 to 4. As used herein, "thia-alkylene" refers to a - (CRR) nS- (CRR) m-, - (CRR) nS (= 0) - (CR R) m-, y (CRR) nS (= 0) 2- (CRR) m-, where n and m Each is independently an integer from 0 to 4. As used herein, "alkenylene" refers to a straight-chain, branched or cyclic divalent aliphatic hydrocarbon group, in a straight or branched embodiment, having certain embodiments of the invention. at about 20 carbon atoms and at least one double bond, and in other embodiments from 1 to 12 carbon atoms. In the further embodiments, the alkenylene groups include lower alkenylene. Optionally, one or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms may be inserted throughout the alkenylene group, wherein the nitrogen substituent is alkyl. Alkenylene groups include, but are not limited to, -CH = CH-CH = CH- and -CH = CH-CH2-. The term "lower alkenylene" refers to alkenylene groups having from 2 to 6 carbon atoms. In certain embodiments, the alkenylene groups are lower alkenylene, including alkenylene of 3 to 4 carbon atoms. As used herein, "alkynylene" refers to a straight chain divalent aliphatic hydrocarbon group, branched or cyclic, in certain straight or branched embodiments, having in an embodiment of 2 to about 20 carbon atoms and at least one triple bond, and in another embodiment of 1 to 12 carbon atoms. In a further embodiment, alkynylene includes lower alkynylene. Optionally, one or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms may be inserted throughout the alkynylene group, wherein the nitrogen substituent is alkyl. Alkynylene groups include, but are not limited to, -C = C-C = C-, -C = C-, and -C = C-CH2-. The term "lower alkynylene" refers to alkynylene groups having from 2 to 6 carbon atoms. In certain embodiments, the alkynylene groups are lower alkynylene, including alkynylene of 3 to 4 carbon atoms. As used herein, alk (en) (in) ylene "refers to a straight-chain, branched or cyclic divalent aliphatic hydrocarbon group, in certain straight or branched embodiments, having in an embodiment from 2 to about 20 carbon atoms. carbon and at least one triple bond, and at least one double bond; and in another embodiment of 1 to 12 carbon atoms. In the additional embodiments, alkyl (en) (in) ilene includes alq (en) (in) lower ileum. Optionally, one or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms may be inserted throughout the alkynylene group, wherein the nitrogen substituent is alkyl. The groups alk (en) (in) ileno include, but are not limited to, -C = C- (CH2) nC = C-, where n is 1 or 2. The term "alqu (en) (in) ileno "lower" refers to the alk (en) (in) ylene groups having up to 6 carbon atoms. In certain embodiments, the alk (en) (in) ylene groups have about 4 carbon atoms. As used herein, "cycloalkylene" refers to a divalent saturated mono- or multi-cyclic ring system, in certain embodiments of 3 to 10 carbon atoms, and in other embodiments of 3 to 6 carbon atoms; Cycloalkenylene and cycloalkynylene refer to divalent mono- or multi-cyclic ring systems that include at least one double bond and at least one triple bond, respectively. The cycloalkenylene and cycloalkynylene groups, in certain embodiments, may contain from 3 to 10 carbon atoms, containing the cycloalkenylene groups in certain embodiments of 4 to 7 carbon atoms, and containing the cycloalkynylene groups in certain embodiments of 8 to 10 carbon atoms . The ring systems of the cycloalkylene, cycloalkenylene, and cycloalkynylene groups may be composed of a ring or of 2 or more rings, which may be joined together in a fused, bridged, or spiro-connected manner. "Cycloalk (en) (in) -ylene" refers to a cycloalkylene group containing at least one double bond and at least one triple bond. As used herein, "arylene" refers to a mono-cyclic or poly-cyclic divalent aromatic group, and in certain monocyclic embodiments, having in an embodiment of from 5 to about 20 carbon atoms and at least one ring aromatic, and in another form of 5 to 12 carbon atoms. In the additional embodiments, arylene includes lower arylene. Arylene groups include, but are not limited to, 1,2-, 1,3-, and 1,4-phenylene. The term "lower arylene" refers to arylene groups having 6 carbon atoms. As used herein, "heteroarylene" refers to a divalent monocyclic or multicyclic aromatic ring system, in an embodiment of about 5 to about 15 ring atoms, wherein one or more, in certain embodiments 1 to 3, of the atoms of the ring system is a heteroatom, that is, a different element of carbon, including, but not limited to, nitrogen, oxygen, or sulfur. The term "lower heteroarylene" refers to heteroarylene groups having 5 or 6 ring atoms. As used herein, "heterocyclylene" refers to a non-aromatic mono-cyclic or multi-cyclic divalent ring system, in certain 3 to 10 member modalities, in a 4 to 7 member modality, and in another embodiment from 5 to 6 members, wherein one or more, including 1 to 3, atoms of the ring system is a heteroatom, that is, a different element of carbon, including, but not limited to, nitrogen, oxygen, or sulfur . As used herein, "substituted alkyl", "substituted alkenyl", "substituted alkynyl", "substituted cycloalkyl", "substituted cycloalkenyl", "substituted cycloalkynyl", "substituted aryl", "substituted heteroaryl", "substituted heterocyclyl" "," substituted alkylene "," substituted alkenylene "," substituted alkynylene "," substituted cycloalkylene "," substituted cycloalkenylene "," substituted cycloalkynylene "," substituted arylene "," substituted heteroarylene ", and" substituted heterocyclylene ", refer to to the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene groups, cycloalkynylene, arylene, heteroarylene, and heterocyclylene, respectively, which are substituted with one or more substituents, in certain embodiments with 1, 2, 3, or 4 substituents, wherein the substituents are as defined herein, and in a modality are selected from Q1. As used herein, "alkylidene" refers to a divalent group, such as = CR'R ", which is attached to an atom of another group, forming a double bond.The alkylidene groups include, but are not limited to a, methylidene (= CH2), and ethylidene (= CHCH3) As used herein, "aryl-alkylidene" refers to an alkylidene group wherein R 'or R "is an aryl group. The "cycloalkylidene" groups are those in which R 'and R "are linked to form a carbocyclic ring The" heterocyclicidene "groups are those in which at least one of R' and R" contains a heteroatom in the chain, and R ' and R "are linked to form a heterocyclic ring As used herein," amido "refers to the divalent group -C (0) NH-" Thioamido "refers to the divalent group -C (S) NH-. "Oxyalido" refers to the divalent group OC (0) NH. "Tia-amido" refers to the divalent group -SC (0) NH- "Ditia-amido" refers to the divalent group -SC (S) NH-. "Ureido" refers to the divalent group -HNC (0) NH- "Tioureido" refers to the divalent group -HNC (S) NH- "As used herein," semicarbazide "refers to -N HC (0 ) NH NH- "Carbazate" refers to the divalent group -OC (0) NHNH- "Isothiocarbazate" refers to the divalent group -SC (0) NHNH- "Thiocarbazate" refers to the divalent group -OC (S) NHNH- "Sulfonyl hydrazide" refers to the divalent group - S02NHNH-. "Hydrazide" refers to the divalent group -C (0) NHNH-. "Azo" refers to the divalent group -N = N-. "Hydrazinyl" refers to the divalent group -NH-NH-. When the number of any given substituent (eg, haloalkyl) is not specified, there may be one or more substituents present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "1 to 3 carbon atom-phenyl" may include one or more of the same or different alkoxy groups, containing 1, 2, or 3 carbon atoms. As used herein, abbreviations for any protecting groups, amino acids, and other compounds, unless otherwise indicated, in accordance with their common usage, are recognized abbreviations, or those of the Commission Nomenclature. Biochemistry IUPAC-IUB (see, (1972) Biochem 11: 942-944). Some of the abbreviations used here are listed below: Ph = Phenyl. Bz = Benzyl. t-Bu = tertiary butyl. Me = Methyl. Et = Ethyl. Pr = Propyl. Iso-P or Pr = Isopropyl. MeOH = Methanol. EtOH - Ethanol.

EtOAc Ethyl acetate. Boc Terbutyloxycarbonyl. CBZ Carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl. DCM or < L »H 2 12 Dichloromethane. DCE 1,2-dichloroethane. DMF Dimethyl-formamide. DMSO Dimethyl sulfoxide. TFA Trifluoroacetic acid. THF Tetrahydrofuran. HATU 0- (7-Azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyl-uronium hexafluoro-phosphate. KOH Potassium hydroxide. K2C03 Potassium carbonate. POCL3 Phosphorus oxychloride. KOtBu Potassium Terbutoxide. EDC or EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.

DIPEA Di-isopropyl-ethyl-amine. HOBt 1-Hydroxy-benzotriazole Hydrate. -CPBA m-chloro-perbenzoic acid. NaH Sodium hydride. NaOH Sodium hydroxide. Na2S04 Sodium sulfate.

Na2S203 Sodium thiosulfate. PD Palladio. Pd / C Palladium on carbon. min minute (s). L Liter. L Mililiter. μL Microlitro. g Gram (s). mg Milligram (s). Mol Moles. mmol Millimole (en). meq Miliequivalent. RT or rt Ambient temperature. tr Retention time in HPLC (minutes). Sat Sat Sat Saturated B. Com posts. In one embodiment, the compounds provided herein for use in the compositions and methods provided herein, have Formula I, wherein the variables are as described below. All combinations of these modalities are within the scope of the present disclosure. In one embodiment, R1 is hydrogen, lower alkyl, lower cycloalkyl, alkenyl, or alkynyl. In another embodiment, R1 is methyl, halogen, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, -NH2, or -NR4R5. In another embodiment, R1 is methyl, halogen, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, -NH2, -NR4RS, or -OR4. In another embodiment, R1 is methyl, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, -NH2, -NR4RS, or -OR4. In one embodiment, R is hydrogen or lower alkyl. In another embodiment, R1 is hydrogen or methyl. In another embodiment, R1 is methyl. In another embodiment, R2 is alkyl or cycloalkyl. In one embodiment, R2 is hydrogen or alkyl. In one embodiment, R 2 is hydrogen or lower alkyl. In one embodiment, R2 is hydrogen. In another embodiment, R3 is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, heterocyclyl, and heteroaryl. In another embodiment, R3 is selected from alkyl, -OR4, substituted alkyl, cycloalkyl, -CR4-cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle. In one embodiment, R3 is cycloalkyl, cycloalkyl-alkyl, alkoxyalkyl, or heteroaryl. In one embodiment, R3 is methyl, isopropyl, ethyl, cyclopropyl, cyclopropyl-methyl, methoxy-methyl, oxazolyl, or thiazolyl. In another embodiment, R3 is cyclopropyl. In another embodiment, Y is -C (= 0) NH-, -NH (C = 0) -, -NH (C = 0) NH-, -S02NH-, -NHS02- or -C (= 0) -. In another embodiment, Y is an individual bond, -C (= 0) NH-, or -S02NH-. In another embodiment, Y is -C (= 0) NH-. In another embodiment, X1 is an individual bond or alkylene. In another mode, X1 is an individual link or -CH2-. In another modality, X1 is an individual link. In another embodiment, A is a bicyclic heterocyclic ring system, wherein each ring contains at least one N atom, and is optionally substituted with up to two R13. In another embodiment, A is a bicyclic heteroaryl ring system, wherein each ring contains at least one N atom, and is optionally substituted with up to two R13. In another embodiment, A is a bicyclic heteroaryl ring system, wherein each ring contains two N atoms, and is optionally substituted with up to two R13. In another modality, A is an imidazolo-pyrimidine, pyrazolo-pyrimidine, imidazolo-pyrimidinone, or pyrazolo-pyrimidinone group. In another embodiment, A is an imidazolo-pyrimidine or pyrazolo-pyrimidine group. In another embodiment, X2 is an individual bond, alkylene, or -NH-. In another embodiment, X2 is an individual link, -CH2-, or -NH-. In another modality, X2 is an individual link. In another embodiment, D is heterocyclyl, cycloalkyl, heteroaryl, or aryl, and is optionally substituted by 1 to 4, in one mode per 1 or 2 groups (CR9R10) WE. In another embodiment, D is cyclohexyl, cyclopentyl, pyridyl, pyrimidinyl, or phenyl, and is optionally substituted by 1 to 4, in one mode per 1 or 2 groups (CR9R10) WE. In another embodiment, D is phenyl and is optionally substituted by 1 to 4, in one embodiment by 1 or 2 groups (CR9R10) WE. In another embodiment, A is optionally substituted with a group R13. In another embodiment, R 13 is alkyl, OH, or NH 2. In another embodiment, R 13 is methyl, OH, or NH 2. In another embodiment, (CR9R10) WE is alkyl, alkoxy, halogen, -CH2-heterocyclyl, -CONH-cycloalkyl, alkyl-sulfonyl, thioalkyl, alkyl-su-Ifonyl-amide, haloalkyl, aminocarbonyl, pseudo-halogen, or heterocyclyl , or two groups (CR9R10) WE, which substitute the adjacent atoms on D, together form alkylenedioxyl. In another modality, (CR9R10) WE. is methoxy, methyl, 1,4-triazolyl, methylsulfonyl, ethoxy, 4-methyl-1-piperazinyl-methyl, fluorine, chlorine, cyclohexyl-amino-carbonyl, methane-sulfonyl-1-amino, thiomethyl, 4-morpholinyl, trifluoromethyl, amino-carbonyl, iodo, cyano, or cyclopropyl-amino-carbonyl, or two groups (CR9R10) WE, which substitute the adjacent atoms on D, together form methylenedioxyl or ethylenedioxyl.

In another embodiment, R1 is halogen, alkyl, cycloalkyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, pseudo-halogen, -NR4R5, or -OR4; and Y is -C (= 0) NH-, -NH (C = 0) -, -NH (C = 0) NH-, -S02NH-, -NHS02- or -C (= 0) -.

In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II: where k is an integer from 0 to 4; and the other variables are as defined above.

In another embodiment, the compounds for use in the compositions and methods provided herein have Formula III: wherein the variables are as defined above. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula IV: wherein the substituents are selected as above.

In another embodiment, the compounds for use in the compositions and methods provided herein have Formula V: wherein the substituents are selected as above.

In another embodiment, the compounds for use in the compositions and methods provided herein have Formula VI: wherein the substituents are selected as above. In another embodiment, the compounds for use in the compositions and methods provided herein have the Formula VII: where f is an integer from 0 to 3; and the remaining variables are selected as above.

In another embodiment, the compounds for use in the compositions and methods provided herein have Formula VIII: where the variables are as defined above.

In another embodiment, the compounds for use in the compositions and methods provided herein have Formula IX: wherein k is an integer from 0 to 4; and the other variables are as defined above. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula X: where the variables are as defined above.

In another embodiment, the compounds for use in the compositions and methods provided herein have Formula XI: wherein the substituents are selected as above.

In another embodiment, the compounds for use in the compositions and methods provided herein have Formula XII: wherein the substituents are selected as above. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula XIII: wherein the substituents are selected as above.

In another embodiment, the compounds for use in the compositions and methods provided herein have Formula XIV: where f is an integer from 0 to 3; and the remaining variables are selected as above.

In another embodiment, the compounds for use in the compositions and methods provided herein have Formula XV: where the variables are as defined above. In another embodiment, the compounds are selected from those shown in the Examples.

C. Preparation of the Compounds. The compounds provided herein may be prepared in general in accordance with the following schemes and the knowledge of one skilled in the art. In addition to the documents incorporated as reference, we present the following. Examples of the methods useful for the production of the compounds provided herein are illustrated in Schemes 1 to 5. Appropriately substituted 1 H-pyrazolo- [3,4-d] -pyrimidines of type (I), which are useful herein, can be made by various means, for example as shown in Scheme 1, the acid catalyzed cyclization of (5-amino-1 H -pyrazol-4-yl) -ketones with formamide.

Scheme 1 (I) Appropriately substituted 9H-purines of type (II), which are useful herein, can be made by various means, for example as shown in Scheme 2, the acid-catalyzed cyclization of the (5-amino) -1H-imidazol-4-yl) -ketones with formamide.

Scheme 2 JÍ "* _C? NH2) _ Ts? H N * / 180 ° C, Micropods (II) In an alternative way, the 9H-purines of the type (III) bearing a 6-aryl substituent, can be prepared by various means, for example as shown in Scheme 3. The microwave-mediated reaction between 4,6-dichloro-pyrimin-5-ylamine and an amine appropriately substituted in a solvent such as NMP, in the presence of a base, such as DIEA, at a temperature preferably between 60 ° C and 250 ° C, produces the mono-substituted pyrimidine. This intermediate is treated with orfo-triethyl formate and a catalytic acid, such as acetic acid, to provide the 6-chloro-purine intermediate. The 6-chloro-purine thus obtained can be treated in the microwave oven with an appropriately substituted organometallic reagent, such as a tributyl-stannane or an appropriately substituted boronic acid under palladium (O) catalysis, in a solvent, such as dimethyl. -formamide or dioxane, at a temperature preferably between 60 ° C and 150 ° C, to provide the desired substituted purine.

Alternatively, 9H-purines of the type (III) bearing a 6-aryl substituent can be prepared by various means, for example as shown in Scheme 4.

Alternatively, the 9H-purines of the type (III) bearing a 6-aryl substituent can be prepared by various means, for example as shown in Scheme 5.

Appropriately substituted 5-amino-4-acyl-pyrazoles of type (IV), which are useful herein as intermediates for the preparation of 1H-pyrazolo- [3,4-dj-pyrimidines of type (I), they can be made by various means, for example as shown in Scheme 4. An appropriately substituted 3-oxo-propionitrile is treated with diphenyl-formamidine, in a solvent such as toluene or xylene, at a temperature preferably between 60 ° C and 150 ° C. The intermediate thus obtained can be treated with an appropriately substituted hydrazine, in a solvent such as ethanol, at a temperature preferably between 50 ° C and 100 ° C, to give 4-acyl-5-amino-pyrazole. A base, such as triethylamine or di-isopropyl-ethyl-amine, can be added to the reaction mixture to neutralize in situ any hydrazine obtained as a hydrochloride or trifluoroacetate salt. The 3-oxo-propionitriles useful herein can be purchased commercially, or can be prepared by various means, for example from the esters, by reaction with the lithium salt of acetonitrile, as disclosed in the Publication International Number WO 99/57101, and as shown in Scheme 4a.

Scheme 4 Scheme 4a The appropriately substituted 5-amin-4-acyl-imidazoles of the type (V), useful as intermediates for the preparation of the 9H-purines of the type (II), can be made by various means, for example as shown in Scheme 5. Appropriately substituted amines can be treated with triethyl orfo-formate in the microwave oven, at a temperature preferably between 60 ° C and 150 ° C. The intermediate thus obtained can be treated with ammonium-m-alonitrile tosylate, and a catalyst, such as p-toluenesulfonic acid, in a solvent such as acetic acid, to provide 5-amino-1 H-imidazole-4. - carbonitrile. The reaction of the carbonitrile with an organometallic reagent, such as a Grignard reagent, in a solvent such as tetrahydrofuran, followed by hydrolysis with acid, yields 4-acyl-5-amino-im-idazole.

Scheme 5 R2-NH2 D. Formulation of Pharmaceutical Compositions. The pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more of the compounds provided herein that are useful in the prevention, treatment, or abatement of one or more of the symptoms of the diseases or disorders associated with the p38 kinase, including the activity of the p38a kinase, or where the p38 kinase is involved, in a pharmaceutically acceptable vehicle. Diseases or disorders associated with the p38 kinase include, but are not limited to, inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, angiogenic disorders, infectious diseases, neurodegenerative diseases, and viral diseases. Suitable pharmaceutical carriers for administration of the compounds provided herein include any of these vehicles known to those skilled in the art as suitable for the particular mode of administration. In addition, the compounds can be formulated as the sole pharmaceutically active ingredient in the composition, or they can be combined with other active ingredients. The compositions contain one or more compounds provided herein. In one embodiment, the compounds are formulated in suitable pharmaceutical preparations, such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained-release formulations, or elixirs, for oral administration, or in sterile solutions or suspensions for administration parenteral, as well as a transdermal patch preparation, or dry powder inhalers. In one embodiment, the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, for example, Ansel, Introduction to Pharmaceutical Dosage Forms, Fourth Edition, 1985, 126). In the compositions, effective concentrations of one or more pharmaceutically acceptable compounds or derivatives thereof are mixed with a suitable pharmaceutical carrier. The compounds can be derived as the salts, esters, enol-ethers, or esters, acetals, ketals, orfo-esters, hemiacetals, hemiketals, acids, bases, solvates, hydrates, or corresponding prodrugs prior to formulation, as described above . The concentrations of the compounds in the compositions are effective to deliver an amount, after administration, that treats, prevents, or decreases one or more of the symptoms of the diseases or disorders associated with the activity of the p38 kinase, or where the activity of p38 kinase is involved. In one embodiment, the compositions are formulated for single dose administration. In order to formulate a composition, the weight fraction of the compound is dissolved, suspended, dispersed, or otherwise mixed in a selected vehicle, at an effective concentration so that the treated condition is alleviated, prevented, or decrease one or more symptoms. The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects in the treated patient. The therapeutically effective concentration can be determined empirically by testing the compounds in in vitro and in vivo systems described herein (see, for example, Example 15), and then extrapolated therefrom for dosages for humans. The concentration of the active compound in the pharmaceutical composition will depend on the rates of absorption, inactivation, and excretion of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and the amount administered, as well as other known factors by those skilled in the art. For example, the amount that is supplied is sufficient to decrease one or more of the symptoms of the diseases or disorders associated with the activity of the p38 kinase, or where the activity of the p38 kinase is involved, as described herein . In one embodiment, a therapeutically effective dosage should produce a serum concentration of the active ingredient from about 0.1 nanog boules / ml per liter to about 50-100 micrograms / milliliter. In another modality, the pharmaceutical compositions should provide a dosage of about 0.001 milligrams to about 2,000 milligrams of the compound per kilogram of body weight per day. The pharmaceutical unit dosage forms are prepared to provide from about 0.01 milligrams, 0.1 milligrams, or 1 milligram to about 500 milligrams, 1,000 milligrams, or 2,000 milligrams, and in a form of about 10 milligrams to about 500 milligrams of the active ingredient or a combination of essential ingredients per unit dosage form. The active ingredient can be administered all at once, or it can be divided into a number of smaller doses to be administered in time intervals. It is understood that the precise dosage and duration of treatment is a function of the disease being treated, and can be determined empirically using known test protocols, or by extrapolation from in vivo or in vitro test data. It should be noted that the concentrations and dosage values may also vary with the severity of the condition to be alleviated. It should further be understood that, for any particular subject, the specific dosage regimens should be adjusted over time according to the individual need and professional judgment of the person administering or supervising the administration of the compositions, and that the intervals of The concentration stipulated herein are only an example and are not intended to limit the scope or practice of the claimed compositions. In cases where the compounds exhibit insufficient solubility, methods for the solubilization of the compounds can be employed. These methods are known to those skilled in the art, and include, but are not limited to, the use of co-solvents, such as dimethyl sulfoxide (DMSO), the use of surfactants, such as TWEEN®, or the dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as prodrugs of the compounds, can also be used in the formulation of the effective pharmaceutical compositions. When mixing or adding the compounds, the resulting mixture can be a solution, suspension, emulsion, or the like. The shape of the resulting mixture depends on a number of factors, including the intended mode of administration and the solubility of the compound in the carrier or vehicle selected. The effective concentration is sufficient to decrease the symptoms of the disease, disorder, or condition treated, and can be determined in an empirical manner. Pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable amounts of the compounds or their pharmaceutically acceptable derivatives. The pharmaceutically and therapeutically active compounds and their derivatives, in one embodiment, are formulated and administered in unit dosage forms or in multiple dosage forms. The unit dosage forms used herein refer to physically separate units suitable for human and animal subjects, and packaged individually as is known in the art. Each unit dose contains a predetermined amount of the therapeutically active compound, sufficient to produce the desired therapeutic effect, in association with the carrier, vehicle, or pharmaceutical diluent required. Examples of the unit dosage forms include ampoules and syringes, and individually packaged tablets or capsules. The unit dosage forms can be administered in fractions or multiples thereof. One form of multiple doses is a plurality of identical unit dosage forms packaged in a single container for administration in a segregated unit dose form. Examples of multiple dose forms include flasks, bottles of tablets or capsules, or bottles of liters. Therefore, the multiple dose form is a multiple of unit doses that do not segregate in the package. Liquid pharmaceutically administrable compositions, for example, can be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above, and optional pharmaceutical adjuvants in a vehicle, such as, for example, water, serum, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances, such as wetting agents, emulsifying agents, solubilizing agents, pH regulating agents and the like, for example, acetate, sodium citrate, derivatives of cyclodextrin, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents. The actual methods of preparation of these dosage forms are known, or will be apparent to those skilled in the art.; for example, see Remington's Pharmaceuticals Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975. Dosage forms or compositions containing the active ingredient in the range of 0.005 percent to 100 percent can be prepared, the rest being filled in with a non-toxic vehicle. The methods for the preparation of these compositions are known to those skilled in the art. The contemplated compositions can have from 0.001 percent to 100 percent active ingredient, in a 0.1 to 95 percent modality, and in another modality from 75 to 85 percent. 1. Compositions for Oral Administration. Oral pharmaceutical dosage forms are solid, gel, or liquid. The solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets include dragees and compressed chewable tablets, which may have an enteric coating, a sugar coating, or a film coating. The capsules can be hard or soft gelatin capsules, while the granules and powders can be provided in a non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art. to. Solid compositions for oral administration. In certain embodiments, the formulations are solid dosage forms, and in one embodiment, capsules or tablets. The tablets, pills, capsules, troches, and the like, may contain one or more of the following ingredients, or compounds of a similar nature: a binder; a lubricant; a diluent; a skid; a disintegrating agent; a coloring agent; a sweetening agent; a flavoring agent; a wetting agent; an emetic coating; and a film coating. Examples of the binders include microcrystalline cellulose, tragacanth gum, glucose solution, acacia mucilage, gelatin solution, melase, polyvinyl pyrrolidine, povidone, crospovidones, sucrose, and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium, and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol, and calcium diphosphate. Skimmers include, but are not limited to, colloidal silicon dioxide. Disintegrating agents include sodium croscarmellose, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methyl cellulose, agar, and carboxymethyl cellulose. Coloring agents include, for example, any of the certified and approved water soluble FD and C dyes, and mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate. Sweetening agents include sucrose, lactose, mannitol, and artificial sweetening agents, such as saccharin, and any number of spray-dried flavors. Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds that produce a pleasant sensation, such as, but not limited to, peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan mono-oleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Emetic coatings include fatty acids, fats, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Film coatings include hydroxyethyl cellulose, sodium carboxy methyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. The compound, or the pharmaceutically acceptable derivative thereof, could be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition can also be formulated in combination with an antacid or other ingredient. When the unit dosage form is a capsule, it may contain, in addition to the material of the above type, a liquid carrier, such as a fatty oil. In addition, the unit dosage forms may contain other different materials that modify the physical form of the dosage unit, for example sugar coatings and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, spray, chewing gum, or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent, and certain preservatives, dyes, colorants, and flavorings. The active materials can also be mixed with other active materials that do not impair the desired action, or with materials that complement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound or a pharmaceutically acceptable derivative thereof as described herein. Higher concentrations, up to about 98 weight percent of the active ingredient may be included. In all embodiments, the tablet and capsule formulations can be coated as is known to those skilled in the art, for the purpose of modifying or sustaining the dissolution of the active ingredient. Accordingly, for example, they can be coated with a conventional enterically digestible coating, such as phenyl salicylate, waxes, and cellulose acetate phthalate. b. Liquid compositions for oral administration. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. The emulsions are oil in water or water in oil. The elixirs are transparent sweetened hydroalcoholic preparations. The pharmaceutically acceptable vehicles used in the elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, for example sucrose, and may contain a preservative. An emulsion is a two-phase system, where a liquid is dispersed in the form of small globules through another liquid. The pharmaceutically acceptable vehicles used in the emulsions are non-aqueous liquids, emulsifying agents, and preservatives. The suspensions use pharmaceutically acceptable and conservative suspending agents. The pharmaceutically acceptable substances used in the non-effervescent granules, to be reconstituted in a liquid oral dosage form, include diluents, sweeteners, and wetting agents. The pharmaceutically acceptable substances used in the effervescent granules, to reconstitute in a liquid oral dosage form, include organic acids and a source of carbon dioxide. The coloring and flavoring agents are used in all the above dosage forms. Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of preservatives include glycerin, methyl- and propyl-paraben, benzoic acid, sodium benzoate, and alcohol. Examples of the non-aqueous liquids used in the emulsions include mineral oil and cottonseed oil. Examples of the emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan mono-oleate. Suspending agents include carboxymethylcellulose sodium, pectin, tragacanth, Veegum, and acacia. Sweetening agents include sucrose, syrups, glycerin, and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan mono-oleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. The coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds that produce a pleasant taste sensation. For a solid dosage form, the solution or suspension, for example in propylene carbonate, vegetable oils, or triglycerides, in one embodiment, is encapsulated in a gelatin capsule. These solutions, and their preparation and encapsulation, are disclosed in the Patents of the United States of North America Nos. 4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, for example, in a polyethylene glycol, can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, for example water, to be easily measured for administration. Alternatively, liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate), and other vehicles. , and these solutions or suspensions are encapsulated in caps of hard or soft gelatin capsules. Other useful formulations include those stipulated in the Patents of the United States of North America Numbers RE28, 819 and 4,358,603. Briefly stated, these formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or poly-alkylene glycol, including, but not limited to, 1,2-dimethoxy-methane, diglyme, triglyme, tetraglime, polyethylene glycol dimethyl ether-350, polyethylene glycol-550 dimethyl ether, polyethylene glycol-dimethyl ether-750, where 350, 550, and 750 refer to the approximate average molecular weight of polyethylene glycol, and one or more antioxidants, such as butylated hydroxy-toluene (BHT), butylated hydroxy-anisole (BHA), propyl gallate, vitamin E, hydroxyquinone, hydroxycoumarins, ethanol-amine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol , phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates. Other formulations include, but are not limited to, aqueous alcoholic solutions, including a pharmaceutically acceptable acetal. The alcohols used in these formulations are any pharmaceutically acceptable water miscible solvents having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acétals include, but are not limited to, d i - (a I q u i E or lower) -acetals of the lower alkyl aldehydes, such as acetaldehyde diethyl acetal. 2. Solutions and Injectable Emulsions. The parenteral administration is also contemplated herein, in a modality characterized by injection, either subcutaneous, intramuscular, or intravenous. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid before injection, or as emulsions. Injectable solutions and emulsions also contain one or more excipients. Suitable excipients are, for example, water, serum, dextrose, glycerol, or ethanol. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH regulating agents, stabilizers, solubility enhancers, and other agents, such as such as, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrins. The implantation of a slow release or sustained release system, in such a way that a constant level of dosage is maintained (see, for example, U.S. Patent Number 3,710,795), is also contemplated herein. Briefly, a compound provided herein is dispersed in a solid internal matrix, for example, methyl polymethacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, rubber. natural, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, poly-dimethyl-si-loxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, crosslinked polyvinyl alcohol, and partially hydrolyzed, crosslinked polyvinyl acetate, which is surrounded by an outer polymeric membrane, for example polyethylene, polypropylene, ethylene / propylene copolymers , ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubbers, poly-dimethylsiloxanes, neoprene rubber, chlorinated polyethylene, poly-cl vinyl chloride, copolymers of vinyl chloride with vinyl acetate, vinylidene chloride, ethylene and propylene, polyethylene terephthalate ionomer, butyl rubber, epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate terpolymer / vinyl alcohol, and ethylene / vinyl oxy-ethanol copolymer, which are insoluble in body fluids. The compound diffuses through the outer polymer membrane in a rate-of-release rate step. The percentage of the active compound contained in these parenteral compositions depends very much on their specific nature, as well as on the activity of the compound and the needs of the subject. Parenteral administration of the compositions includes intravenous, subcutaneous, and intramuscular administration. Preparations for parenteral administration include sterile ready-for-injection solutions, sterile dry soluble products, such as freeze-dried powders, ready to be combined with a solvent just before use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just before use, and sterile emulsions. The solutions can be aqueous or non-aqueous. If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing viscosifying and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof. Pharmaceutically acceptable vehicles used in parenteral preparations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, pH regulators, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents, and other pharmaceutically acceptable substances. Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose Injection and Lactated Ringers. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, and peanut oil. Antimicrobial agents at bacteriostatic or fungistatic concentrations should be added to parenteral preparations packaged in multi-dose containers, including phenols or cresols, mercurials, benzyl alcohol, chloro-butanol, methyl- and propyl-p-hydroxy-benzoic acid esters, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. PH regulators include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxy methyl cellulose, hydroxy propyl methyl cellulose, and polyvinyl pyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEN® 80). A metal ion chelating or sequestering agent includes EDTA. Pharmaceutical vehicles also include ethyl alcohol, polyethylene glycol, and propylene glycol, for vehicles miscible in water; and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment. The concentration of the pharmaceutically active compound is adjusted in such a way that an injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight, and condition of the patient or animal, as is known in the art. Parenteral unit dose preparations are packaged in an ampule, vial, or syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art. Illustratively, an intravenous or intra arterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an injected active material as necessary to produce the desired pharmacological effect. Injectables are designed for local and systemic administration. In one embodiment, a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1 weight percent / weight to about 90 weight percent / weight or more, in certain embodiments more than 1 weight percent / weight of the active compound, in the treated tissues. The compound can be suspended in a micronized form or in another suitable form, or it can be derivatized to produce a more soluble active product, or to produce a pro-drug. The shape of the resulting mixture depends on a number of factors, including the intended mode of administration and the solubility of the compound in the carrier or vehicle selected. The effective concentration is sufficient to decrease the symptoms of the condition, and can be determined in an empirical manner. 3. Liofed powders. Here also lyophilized powders are of interest, which can be reconstituted to be administered as solutions, emulsions, and other mixtures. They can also be reconstituted and formulated as solids or gels. The sterile lyophilized powder is prepared by dissolving a compound provided herein, or a pharmaceutically acceptable derivative thereof, in a suitable solvent. The solvent may contain an excipient that improves the stability or other pharmacological component of the powder or reconstituted solution prepared from the powder. The excipients that can be used include, but are not limited to, dextrose, sorbitan, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, or other suitable agent. The solvent may also contain a pH regulator, such as citrate, sodium or potassium phosphate, or another regulator known to those skilled in the art, in one embodiment, at an approximately neutral pH. Subsequent sterile filtration of the solution, followed by lyophilization under conventional conditions known to those skilled in the art, provides the desired formulation. In one embodiment, the resulting solution will be distributed in bottles for lyophilization. Each bottle will contain a single dosage or multiple dosages of the compound. The lyophilized powder can be stored under appropriate conditions, such as from about 4 ° C to room temperature. Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, lyophilized powder is added to sterile water or another suitable vehicle. The precise amount depends on the selected compound. This amount can be determined in an empirical way. 4. Topical Administration. Topical mixtures are prepared as described for local and systemic administration. The resulting mixture can be a solution, suspension, emulsion, or the like, and is formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, dyes, pastes, foams, sprays, irrigations, sprays, suppositories, patches , skin patches, or any other formulations suitable for topical administration. The compounds or pharmaceutically acceptable derivatives thereof can be formulated as aerosols for topical application, such as by inhalation (see, for example, US Pat. Nos. 4,044,126; 4,414,209; and 4,364,923, which describe aerosols. for the delivery of a steroid useful for the treatment of inflammatory diseases, in particular asthma). These formulations for administration to the respiratory tract may be in the form of an aerosol or a solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier, such as lactose. In such a case, the particles of the formulation, in one embodiment, will have diameters of less than 50 microns, and in one embodiment less than 10 microns. The compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions, and for application to the eye or for intracisternal application or intraspinal. Topical administration is contemplated for transdermal delivery, and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the active compound can also be administered alone or in combination with other pharmaceutically acceptable excipients. These solutions, in particular those intended for ophthalmic use, can be formulated as isotonic solutions of 0.01 percent to 10 percent, at a pH of about 5 to 7, with the appropriate salts.

. Compositions for Other Administration Channels. Other routes of administration, such as transdermal patches, including iontophoretic and electrophoretic devices, and rectal administration are also contemplated herein. Transdermal patches, including iontophoretic and electrophoretic devices, are well known to those skilled in the art. For example, these patches are disclosed in the Patents of the United States of North America Numbers 6,267,983; 6,261,595; 6,256,533; 6,167,301; 6,024,975; 6,010,715; 5,985,317; 5,983,134; 5,948,433; and 5,860,957. For example, the pharmaceutical dosage forms for rectal administration are suppositories, capsules, and rectal tablets for a systemic effect. Rectal suppositories used herein mean solid bodies for insertion into the rectum, which melt or soften at body temperature, releasing one or more pharmacologically or therapeutically active ingredients. The pharmaceutically acceptable substances in rectal suppositories are bases or vehicles and agents for raising the melting point. Examples of the bases include cocoa butter (theobroma oil), glycerin-gelatin, carbocera (polyoxyethylene glycol), and appropriate mixtures of mono-, di-, and tri-glycerides of fatty acids. You can use combinations of different bases. Agents for raising the melting point of suppositories include spermaceti and wax. Rectal suppositories can be prepared either by the compression method, or by molding. The weight of a rectal suppository, in one embodiment, is approximately 2 to 3 grams. The tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for the formulations for oral administration. 6. Directed Formulations. The compounds provided herein, or the pharmaceutically acceptable derivatives thereof, may also be formulated to target a particular tissue, receptor, or other body area of the subject to be treated. Many of these management methods are well known to those skilled in the art. All of these steering methods are contemplated herein for use in the present compositions. For non-limiting examples of the steering methods, see, for example, United States Patents Nos. 6,316,652 6,274,552 6,271,359 6,253,872 6,139,865 6,131, 570 6,120,751 6,071, 495 6,060,082 6,048,736 6,039,975 6,004,534 5,985,307 5,972,366 5,900,252 5,840,674 5,759,542; and 5,709,874.

In one embodiment, liposomal suspensions, including tissue-directed liposomes, such as liposomes targeted to the tumor, may also be suitable as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome formulations can be prepared as described in U.S. Patent Number 4,522,811. Briefly stated, liposomes can be formed, such as multilamellar vesicles (MLV), by drying the egg phosphatidylcholine and the brain phosphatidylserine (molar ratio of 7: 3) inside a flask. A solution of a compound provided herein is added in phosphate-buffered serum lacking divalent cations (PBS), and the flask is shaken until the lipid film is dispersed. The resulting vesicles are washed to remove the unencapsulated compound, granulated by centrifugation, and then resuspended in phosphate-buffered serum. 7. Articles of Manufacture. The pharmaceutically acceptable compounds or derivatives can be packaged as articles of manufacture containing packaging material, a compound or a pharmaceutically acceptable derivative thereof provided herein, which is effective to modulate the activity of the p38 kinase, or for the treatment, prevention, or the reduction of one or more symptoms of the diseases or disorders mediated by the p38 kinase, or of the diseases or disorders in which p38 kinase activity is involved, within the packaging material, and a label indicating that the compound or composition, or the pharmaceutically acceptable derivative thereof, is used to modulate the activity of the p38 kinase, or for the treatment, prevention, or reduction of one or more symptoms of the diseases or disorders mediated by the kinase p38, or of the diseases or disorders in which the p38 kinase is involved. The articles of manufacture provided herein contain packaging materials. Packaging materials to be used for the purpose of packaging pharmaceutical products are well known to those skilled in the art. See, for example, Patents of the United States of North America Nos. 5,323,907; 5,052,558; and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, bubble packs, bottles, tubes, inhalers, pumps, bags, flasks, containers, syringes, bottles, and any suitable packaging material for a selected formulation and for the intended mode of administration and treatment. A broad set of formulations of the compounds and compositions provided herein are contemplated, as well as a variety of treatments for any disease or disorder in which the p38 kinase is involved as a mediator or contributor to the symptoms or cause.

E. Evaluation of the Activity of the Compounds. Conventional physiological, pharmacological and biochemical methods are available to test the compounds in order to identify those possessing biological activities that modulate the activity of the cytokines., including the activity of the p38 kinase. The inhibitory activity of the compound was measured in a radioactive enzymatic assay. The regulatory composition was adopted by Lisnock et al. (Biochemistry, 1998, volume 37, pages 16573-16581). The peptide substrate was selected from Chen et al. (Biochemistry, 2000, volume 39, pages 2079-2087). The concentration of p38a, [α-33P-ATP], and peptide, was equal to 1 nM, 85 μM, and 250 μM, respectively. Incorporation of 33P into the peptide was measured using absorption on filter mats, with subsequent washing with 100 mM phosphoric acid, followed by ethanol. Other conditions for the enzymatic assay of p38a are also described in the literature. They are different from the assay described either in the regulatory composition (Biochemistry, 2000, volume 39, pages 2079-2087), or the substrate (Biochemistry, 1998, volume 37, pages 16573-16581), or both (Protein Sci., 1998 , volume 7, pages 2249-2255).

F. Methods of Use of the Compounds and Compositions In certain embodiments, the compounds provided herein are selective inhibitors of the activity of the p38 kinase, and in one embodiment, the compounds are inhibitors of the isoforms of the p38 kinase, including , but not limited to, p38a and p38ß kinases. In accordance with the foregoing, the compounds of Formula (I) have utility in the treatment of conditions associated with the activity of p38 kinase. These conditions include diseases wherein 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.

In view of their activity as inhibitors of the p38a / β kinase, the compounds of Formula (I) are useful in the treatment of conditions associated with p38, including, but not limited to, inflammatory diseases, autoimmune diseases, destructive bone disorders. , proliferative disorders, angiogenic disorders, infectious diseases, neurodegenerative diseases, and viral diseases. Inflammatory diseases related to the condition associated with p38 include, but are not limited to, acute pancreatitis, chronic pancreatitis, asthma, allergies, and adult respiratory distress syndrome. Autoimmune diseases related to the condition associated with p38 include, but are not limited to, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, insulin-dependent diabetes mellitus (Type I), anemia autoimmune hemolytic, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, or graft-versus-host disease. Destructive bone disorders related to the condition associated with p38 include, but are not limited to, osteoporosis, osteoarthritis, and bone disorder related to multiple myeloma. Proliferative diseases that are related to the condition associated with p38 include, but are not limited to, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, and multiple myeloma. Infectious diseases related to the condition associated with p38 include, but are not limited to, sepsis, septic shock, and Shigellosis. Viral diseases related to the condition associated with p38 include, but are not limited to, acute hepatitis infection (including hepatitis A, hepatitis B, and hepatitis C), HIV infection, and CMV retinitis. Degenerative diseases related to the condition associated with p38 include, but are not limited to, Alzheimer's disease, Parkinson's disease, cerebral ischemia, and other neurodegenerative diseases. "Conditions associated with p38" also include ischemia / reperfusion in embolism, heart attacks, myocardial ischemia, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, and platelet accumulation induced by thrombin. In addition, the p38 inhibitors provided herein are also capable of inhibiting the expression of inducible pro-inflammatory proteins, such as prostaglandin-2 endoperoxide synthase (PGHS-2), also referred to as cyclo-oxygenase-2 ( COX -2). Accordingly, other "conditions mediated by p38" are edema, analgesia, fever and pain, such as neuromuscular, headache, cancer pain, dental pain, and arthritis pain. Diseases that can be treated or prevented by the p38 inhibitors provided herein can also be conveniently grouped by the cytokine (IL-1, TNF, IL-6, IL-8), which is believed to be responsible for the disease. Therefore, a disease or condition mediated by IL-1 includes rheumatoid arthritis, osteoarthritis, embolism, endotoxemia, and / or toxic shock syndrome, inflammatory reaction induced by endotoxin, inflammatory bowel disease, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis , Reiter syndrome, gout, traumatic arthritis, rubela arthritis, acute synovitis, diabetes, pancreatic beta-cell disease, and Alzheimer's disease. The disease or condition mediated by TNF includes rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria , chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft-versus-host reaction, allograft rejections, fever and myalgias due to infection, cachexia secondary to infection, AIDS, ARC or malignancy , keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis. TNF-mediated diseases also include viral infections, such as HIV, CMV, influenza, and herpes; and veterinary viral infections, such as lentivirus infections, including, but not limited to, equine infectious anemia virus, goat arthritis virus, visna virus or aedi virus; or retroviral infections, including feline immunodeficiency virus, bovine immunodeficiency virus, or canine immunodeficiency virus. The disease or condition mediated by IL-8 includes diseases characterized by massive infiltration of neutrophils, such as psoriasis, inflammatory bowel disease, asthma, cardiac and renal reperfusion injury, adult respiratory distress syndrome, thrombosis, and glomerulonephritis.

In addition, the compounds provided herein may be used topically to treat or prevent conditions caused or exacerbated by IL-1 or TNF. These conditions include inflamed joints, eczema, psoriasis, inflammatory conditions of the skin such as sunburn, inflammatory conditions of the eyes, such as conjunctivitis, pyresis, pain, and other conditions associated with inflammation. In one embodiment, specific conditions or diseases that can be treated with the compounds provided herein include, but are not limited to, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease. , glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory disease of the bowel, ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory reaction, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter syndrome, gout, traumatic arthritis, rubela arthritis, acute synovitis , cell disease pancreatic s-ß; diseases characterized by massive infiltration of neutrophils; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, allograft rejections, fever and myalgias due to infection, cachexia secondary to infection, myeloid formation, of scar tissue, ulcerative colitis, pyresis, influenza, osteoporosis, osteoarthritis and bone disorder related to multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson's disease, cerebral ischemia or neurodegenerative disease caused by traumatic injury; angiogenic disorders, including solid tumors, ocular neovascularization, and infantile hemangiomas; viral diseases, including acute hepatitis infection (including hepatitis A, hepatitis B, and hepatitis C), HIV infection, and CMV retinitis, AIDS, SARS, ARC, or malignancy, and herpes; embolism, myocardial ischemia, ischemia in heart attacks due to embolism, organ hypoxia, vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, platelet accumulation induced by thrombin, endotoxemia and / or toxic shock syndrome, and conditions associated with prostaglandin-2 endoperoxidase synthase. In addition, the p38 inhibitors provided herein inhibit the expression of inducible pro-inflammatory proteins, such as prostaglandin-2 endoperoxide synthase (PGHS-2), also referred to as cyclo-oxygenase-2 (COX-2). . In accordance with the above, conditions associated with additional p38 include edema, analgesia, fever and pain, such as neuromuscular pain, headache, pain caused by cancer, dental pain, and arthritis pain. The compounds provided herein may also be used to treat veterinary viral infections, such as lentivirus infections, including, but not limited to, equine infectious anemia virus; or retroviral infections, including feline immunodeficiency virus, bovine immunodeficiency virus, and canine immunodeficiency virus.

G. Combination therapy. Also provided herein are methods for the treatment of conditions associated with p38 kinase, by administration to a subject in need thereof, of an effective amount of the compounds of Formula (I) alone or in combination with each other and / or with other suitable therapeutic agents useful in the treatment of these conditions. Examples of these other therapeutic agents include corticosteroids, rolipram, calfostin, CSAIDs, imidazo- (1, 2-A) -quinoxalines 4-substituted, as disclosed in United States Patent Number 4,200,750, and S. Ceccarelli et al, "lmidazo ( 1,2-a) quinoxaline-4-amines: A novel Class of Nonxanthine A i Adenosine Receptor Antagonists ", European Journal of Medicinal Chemistry Volume 33, (1998), on pages 943-955; Interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; inhibitors of nuclear translocation, such as deoxy-espergualine (DSG); nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, celecoxib, and rofecoxib; steroids, such as prednisone or dexamethasone; antiviral agents, such as abacavir; anti-proliferative agents, such as methotrexate, leflunomide, FK506 (tacrolimus, Prograft); cytotoxic drugs, such as azathioprine and cyclophosphamide; TNF-α inhibitors, such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof. The other therapeutic agents above, when employed in combination with the compounds provided herein, may be used, for example, in the amounts indicated in the Physicians' Desk Reference (PDR), or as otherwise determined by an ordinary expert in this field. In the methods provided herein, these other therapeutic agents may be administered prior to, concurrent with, or following the administration of the compounds provided herein. The following Examples are provided for illustrative purposes only, and are not intended to limit the scope of the invention. The abbreviations employed in the Examples are defined herein. The compounds of the Examples are identified by the example and the step in which they are prepared (for example, "1A" denotes the title compound of step A of Example 1), or by example only when the compound is the compound of title of the example (for example, "2" denotes the title compound of Example 2).

General Methods. The mass spectral data were obtained in a Thermo Finnigan LCQ Duo Ion Trap mass spectrometer. The HPLC data were obtained on a Betasol C18 column (2.1 x 50 millimeters) using an elution gradient of 10 to 90 percent (solvent A, acetonitrile + trifluoroacetic acid 0.025 percent by volume, solvent B, water + trifluoroacetic acid 0.025 percent by volume) for 4 minutes (flow rate of 0.50 milliliters / minute). Purification by HPLC preparation on a Thermo Hypersi-Keystone Betasil C18 column of 250 x 21.2 millimeters, particle size of 5 microns, mobile phase: A, water + 0.025 percent trifluoroacetic acid; B, acetonitrile + 0.025 percent trifluoroacetic acid; gradient from 40 to 70 percent of B; flow rate of 15 milliliters / minute.

Example 1 Preparation of N-cyclopropyl-4-methyl-3- (4-phenyl-pyrazolo-f3,4-dl-pyridin-1-yl) -benzamide.

A. 3-amino-N-cyclopropyl-4-methyl-benzamide. To a mixture of 3-amino-4-methyl-benzoic acid (10.2 grams, 67.5 mmol) and cyclo-propyl-amine (9.33 milliliters, 135.0 mmol, 2 equivalents) in dimethylformamide (150 milliliters) was added EDCI (15.5 mg). grams, 81 millimoles, 1.2 equivalents) followed by DMAP (catalyst) at room temperature. The reaction was stirred overnight at room temperature, and then concentrated. The residue was redissolved in water and extracted with EtOAc. The organic layer was washed with an aqueous solution of NaCl, dried over Na2SO4, and concentrated. The crude product was purified by flash chromatography on silica gel (elution gradient: 1: 1 EtOAc / hexanes, then 100 percent EtOAc) to give 1A as a solid (9.5 grams, 72 percent). B. N-cyclo-propyl-3-hydrazino-4-methyl-benzamide. To a stirred solution of 3-amino-N-cyclopropyl-4-methyl-benzamide (52 milligrams, 0.27 mmol) in water (3 milliliters) at 0 ° C was added concentrated HCl (3 milliliters) followed by the addition of sodium nitrite (20 milligrams, 0. 30 millimoles). The reaction mixture was stirred at 0 ° C for 40 minutes, then a solution of tin (II) chloride (114 milligrams, 0.61 millimole) in concentrated HCl (1 milliliter) was added and the mixture was stirred for 1 hour, then it was left to stand at -20 ° C for 20 hours before heating it to room temperature. It was neutralized with Na 2 CO 3 solution and extracted with CH 2 Cl 2 six times. The combined extracts were dried over Na2SO, concentrated, and the resulting solid was used without further purification. HPLC t R 1.60 minutes; MS m / z 205.9 [M + H] +. C. 3- (5-amino-4-benzoyl-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide. To a stirred solution of hydrazine 1B in EtOH (10 milliliters) was added 2-benzoyl-3-phenyl-amino-acrylonitrile (676 milligrams, 0.27 millimoles, preparation: Grothaus, J.

Am. Chem. Soc. 58, 1334 (1936)) and the mixture was heated (bath T = 65-70 ° C) for 16 hours. The mixture was cooled to room temperature, concentrated and purified by flash chromatography, eluting with 1: 1 EtOAc / hexanes to remove impurities, then 8: 2 EtOAc / hexanes to give the title compound as a grayish solid. (18 milligrams, 0.05 millimoles, 19 percent). HPLC tR 2.11 minutes; MS m / z 361.1 [M + H] +; 1 H NMR (CD 3 OD, 300 MHz) d 7.92 (d, J = 7.6, 1 H), 7.81 (m 4 H), 7.54 (m, 4 H), 2.85 (m, 1 H), 2.22 (s, 3 H), 0.80 (d , J = 5.7, 2H), 0.63 (s, 2H), ppm; 13C NMR (CD3OD, 75MHz) d 191.2, 170.1, 153.8, 143.3 142.0, 141.1, 136.9, 134.8, 132.9, 132.7, 130.1, 129.7, 129.2, 128.1, 104.8, 24.1, 17.7, 6.6 ppm. D. N-cyclopropyl-4-methyl-3- (4-phenyl-pyrazolo-f3,4-d1-pyrimidin-1-yl) -benzamide. The mixture of 3- (5-amino-4-benzoyl-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide (72 milligrams, 0.20 mmol), formamide (1.0 milliliter, excess), and acetic acid ( 0.2 milliliter) was heated in a microwave oven at 160 ° C for 20 minutes. After cooling, the mixture was diluted with CH2Cl2 and water, and the layers of CH2Cl2 were separated, dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC to provide the title compound (46 milligrams, 62 percent) as a white solid. HPLC tR = 2.3 minutes; MS m / z 370.3 [M + H] +. The following compounds are prepared analogously from the appropriately substituted starting materials: Table 1 Example 2 Preparation of N-cyclopropyl-4-methyl-3- (6-phenyl-purin-9-yl) -benzamide.

A ^ 3- (5-amino-4-cyano-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide. A mixture of 3-am ino-N-cyclopropyl-4-methyl-benzamide (380 milligrams, 2.0 mmol, see Example 1A) in 2.0 milliliters of orfo-triethyl formate was stirred at 120 ° C in a microwave oven for 20 minutes. minutes The solvent was removed under reduced pressure. The residue was redissolved in 5 milliliters of acetic acid, and then amino-malononitrile p-toluene sulphonate (506 milligrams, 2.0 millimoles) and sodium acetate (164 milligrams, 2.0 millimoles) were added. at room temperature overnight The mixture was diluted with 20 milliliters of water and the pH was adjusted to 8.0 with aqueous NaOH The resulting mixture was extracted with EtOAc (50 milliliters, 3 times) The combined organic layers were washed with water (10 milliliters) and brine (10 milliliters), dried over MgSO 4, filtered and concentrated in vacuo, The residue was purified by silica gel column chromatography (10/1, methylene chloride / methanol) to give 2A. as a colorless solid (170 milligrams, 30 percent), HPLC tR = 1.39 minutes, MS m / z 282 [M + H] +.

B. 3- (5-amino-4-benzoyl-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide. To a solution of 3- (5-amino-4-cyano-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide (56.4 milligrams, 0.2 mmol) in tetrahydrofuran (10 milliliters) under nitrogen a 1M solution of phenylmagnesium bromide in tetrahydrofuran (1 milliliter, excess) was added at room temperature. After 1 hour, a 3N HCl solution (10 milliliters) was added and the mixture was stirred overnight. The solution was neutralized with dilute aqueous NaOH. The mixture was extracted with ethyl acetate (100 milliliters, twice), washed with water and dried over Na 2 SO, and concentrated. The crude product was purified by HPLC to give 3B as a white solid (56 milligrams, 78 percent). HPLC t R = 2.07 minutes; MS m / z 361.17 [M + H] +.

C. N-cyclopropyl-4-methyl-3- (6-phenyl-purin-9-yl) -benzamide. The mixture of 3- (5-amino-4-benzoyl-im-idazol-1-yl) -N-cyclopropyl-4-methyl-benzamide (33 milligrams, 0.09 mmol), formamide (0.5 milliliters, excess), and acetic acid (0.1 milliliter) was heated in the microwave oven at 200 ° C for 20 minutes. After cooling, the mixture was diluted with CH2Cl2 and water, and the CH2Cl2 layer was separated, dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC to give the title compound (20 milligrams, 59 percent) as a white solid: HPLC tR = 2.20 minutes; MS m / z 370.3 [M + H] +.

The following compounds were prepared in an analogous manner from the appropriately substituted starting materials: Example 3 Preparation of N-cyclopropyl-4-methyl-3-r6- (4-mercapto-phenyl) -purin-9-iM-benzamide.

TO_. 3- (5-amino-4-cyano-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide. A mixture of 3-amino-N-cyclopropyl-4-methyl-benzamide (380 milligrams, 2.0 millimoles) in 2.0 milliliters of triethyl orio-format was stirred at 120 ° C in a microwave oven for 20 minutes. The solvent was removed under reduced pressure. The residue was dissolved in 5 milliliters of acetic acid and then amino-malononitrile p-toluene sulphonate (506 milligrams, 2.0 millimoles), and sodium acetate (164 milligrams, 2.0 millimoles) were added. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with 20 milliliters of water, and the resulting precipitate was filtered to give 3- (5-am ino-4-cyano-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide 3A as a colorless solid (170 milligrams, 30 percent). HPLC t R = 1.39 minutes; MS m / z 282 [M + H] +. B. 3- (5-amino-4-benzoyl-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide. To a solution of 3- (5-amino-4-cyano-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide (100 milligrams, 0.36 mmol) in dry tetrahydrofuran (15 milliliters) under nitrogen was added a 0.5 M solution of 4-mercapto-phenylmagnesium bromide in tetrahydrofuran (5 milliliters), excess) at room temperature. After 1 hour, a 3 N solution of HCl (10 milliliters) was added and the mixture was stirred overnight. The solution was neutralized with dilute aqueous NaOH. The mixture was extracted with ethyl acetate (100 milliliters, 2 times), washed with water, dried over Na 2 SO, and concentrated. The crude product was purified by HPLC to give 3B as a white solid. C_. N-cyclopropyl-4-methyl-3-f6- (4-mercapto-phenyl) -purin-9-ill-benzamide. The mixture of 3- [5-amino-4- (4-mercapto-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide (33 milligrams, 0.09 mmol), formamide (0.5 milliliters, excess ), and p-toluenesulfonic acid (10 milligrams) was heated in the microwave oven at 180 ° C for 30 minutes. After cooling, the mixture was diluted with EtOAc and water, and the EtOAc layer was separated, dried over Na 2 SO, filtered and concentrated. The crude product was purified by preparative HPLC to give the title compound (20 milligrams, 59 percent) as white solid: HPLC tR = 2.47 minutes; MS m / z 416.27 [M + H] +.

The following compounds were prepared in an analogous manner from the appropriately substituted starting materials: Table 3 Example 4 Preparation of N-cyclopropyl-3-f 6- (3-methansulfonyl-amino-phenyl) -purin-9-ii1-4-methy-benzamide.

A. 3- (5-amino-6-chloro-pyrimidin-4-ylamino) -N-cyclopropyl-4-methyl-benzamide. A mixture of 4,6-dichloro-pyrimidin-5-ylamine (328 milligrams, 2.0 mmol) and 3-amino-N-cyclopropyl-4-methyl-benzamide (760 milligrams, 4.0 mmol) in NMP (1.5 milliliters) was added N, N-di-isopropyl-ethyl-amine (348 microliters, 2.0 mmol). The reaction mixture was heated in a microwave at 220 ° C for 30 minutes. It was then cooled to room temperature and purified by flash chromatography, eluting with 3: 1 EtOAc / hexanes to give compound 4A as a grayish solid (267 milligrams, 0.84 mmol, 42 percent). HPLC t R = 1.59 minutes; MS m / z 318 [M + H] +; H NMR (300 MHz, CD3OD) d 0.64-0.68 (m, 2H), 0.80-0.84 (m, 2H), 2.23 (s, 3H), 2.83-2.87 (m, 1H), 7.40 (d, J = 7.9 , 1H), 7.66 (d, J = 7.9, 1H), 7.80 (m, 2H) ppm. B. 3- (6-chloro-purin-9-yl) -N-cyclopropyl-4-methyl-benzamide. The mixture of 3- (5-amino-6-chloro-pyrimidin-4-ylamino) -N-cyclopropyl-4-methyl-benzamide (420 milligrams, 1.32 mmol) in triethyl orfo-formate (1 milliliter) and acid acetic acid (3 drops) was heated with a microwave oven at 120 ° C for 15 minutes. It was cooled to room temperature and purified by column chromatography eluting with 1: 1 of EtOAc / hexanes to give compound 4B as a white solid (350 milligrams, 1.07 millimoles, 81 percent). HPLC t R = 2.07 minutes; MS m / z 328 [M + H] +; 1 H NMR (300 MHz, CD.OD) d 0.58 - 0.59 (m, 2H), 0.72 - 0.77 (m, 2H), 2.13 (s, 3H), 2.77-2.82 (m, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.82 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 8.65 (s, 1H), 8.69 (s, 1H) ppm.

C. N-cyclopropyl-3-r6- (3-methanesulfonyl-amino-phenyl) -purin-9-ill-4-methyl-benzamide. To a mixture of a compound 4B (16 milligrams, 0. 046 millimole), 3-methanesulfonyl oni l-amino-boronic acid and Pd (Ph3P) 4 (5.5 milligrams, 0.0048 millimoles) was added 1,4-dioxane (0.2 milliliters) and saturated K2C03 (0.1 milliliters).

Then, the resulting suspension was heated with a microwave oven at 120 ° C for 10 minutes. It was then cooled to room temperature and purified by HPLC to give the title compound as a white solid (7.6 milligrams, 0.016 millimoles, 33 percent). HPLC t R = 1.96 minutes; MS m / z 463 [M + H] +; 1 H NMR (300 MHz, CD 3 OD) d 0. 64 (m, 2H), 0.79 - 0.82 (m, 2H), 2.21 (s, 3H), 2.84 - 2.88 (m, 1H), 3.08 (s, 3H), 7.47-7.62 (m, 3H), 7.89-7.98 (m, 2H), 8.57 - 8.68 (m, 3H), 8.95 (s, 1H) ppm. The following compounds were prepared in an analogous manner from appropriately substituted boric acid: Table 4 Example 5 Preparation of N-cyclopropyl-4-methyl-3- (6-pyridin-2-yl-purin-9-yl) -benzamide.

A mixture of 3- (6-chloro-purin-9-yl) -N-cyclopropyl-4-methyl-benzamide (16 milligrams, 0.049 mmol), Pd (PPh3) 4 (5.7 milligrams, 0.0049 mmol) and 2- tributylstannanyl pyridine (36 milligrams, 0.098 millimoles) was suspended in dimethyl formamide (0.25 milliliters). The mixture was heated with a microwave oven at 160 ° C for 10 minutes. The mixture was purified by HPLC to give the desired product as a white solid (16 milligrams, 0.043 millimoies, 88 percent). HPLC t R = 1.59 minutes; MS m / z 371 [M + H] +. The following compounds were prepared in an analogous manner from the appropriately substituted organostannane: Example 5-2, N-cyclopropyl-4-methyl-3- (6-pyrimidin-2-yl-purin-9-yl) -benzamide, HPLC tR = 1.40 minutes; MS m / z 371.4 [M + Hj +. Example 5-3, N-cyclopropyl-4-m ethi-3- (6-pyrimidin-2-yl-purin-9-yl) -benzamide, HPLC t R = 1.40 minutes; MS m / z 372 [M + H] +. Example 5-4, N-cyclopropyl-4-methyl-3- (6-thiazol-2-yl-purin-9-yl) -benzamide, HPLC t R = 1.85 minutes; MS m / z 377 [M + H] +.

Example 6 Preparation of N-cyclopropyl-3- (2-hydroxy-6-phenyl-purin-9-yl) -4-methyl-benzamide.

To a solution of 3- (5-amino-4-benzoyl-l-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide (9.2 milligrams, 0.026 mmol) in 0.3 milliliters of acetic acid was added urea ( 20 milligrams) and the mixture was heated at 180 ° C for 20 minutes in the microwave oven. The crude product was purified by HPLC to give a colorless solid (2.4 milligrams, 24 percent). HPLC t R = 1.63 minutes; MS m / z 386 [M + H] +.

Example 7 Preparation of N-cyclopropyl-4-methyl-3- (6-phenyl-amine-purin-9-yl) -benzamide.

The mixture of 3- (6-chloro-purin-9-yl) -N-cyclopropyl-4-methyl-benzam ida (10 milligrams, 0.029 mmol) and aniline (14 milligrams, 0.15 mmol) in 0.2 milliliters of dioxane was heated with a microwave oven at 140 ° C for 20 minutes. It was then cooled to room temperature and purified by HPLC to give the title compound as a grayish solid (5.2 milligrams, 46 percent). HPLC t R = 2.09 minutes; MS m / z 385 [M + H] +. The following compounds were prepared in an analogous manner from the appropriately substituted amine: Table 5 Example 8 Preparation of N-cyclopropyl-4-methyl-3- (6-phenyl-purin-9-ylmethyl-benzam ida.

A. 3 - [(5-amino-6-chloro-pyrimidin-4-ylamino) -metip-N-cyclopro-pyl-4-methyl-benzamide. To a mixture of benzyl amine (41 milligrams, 0.2 mmol) and 4,6-dichloro-pyrimidin-5-ylamine (99 milligrams, 0.6 mmol) in 0.5 milliliters of 1-butanol was added triethylamine (28 microliters, 0.2 millimoles). The reaction mixture was stirred at 80 ° C for 6 hours. Then it was cooled to room temperature. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography, eluting with 3: 1 EtOAc / hexanes to give the chloride as a grayish solid (32 milligrams, 48 percent). HPLC t R = 1.97 minutes; MS m / z 332 [M + H] +. B. N-cyclopropyl-4-methyl-3- (6-phenyl-purin-9-ylmethyl) -benzamide. The title compound was prepared using the method described in Example 4C. HPLC t R = 1.86 minutes; MS m / z 342 [M + H] +.

Example 9 Preparation of 3- (6-cyclopentyl-purin-9-yl) -N-cyclopropyl-4-m e t i I - b e n zami d a.

To a stirred solution of 3- (5-amino-4-cyano-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide (140 milligrams) in tetrahydrofuran (25 milliliters, dry) under nitrogen at room temperature, cyclopentyl magnesium bromide (2.5 milliliters, 2M in diethyl ether) was added. The mixture was stirred at room temperature for 3 hours before removing the solvent. The residue was redissolved in EtOAc, washed with water, brine, dried over Na 2 SO 4, and concentrated. The residue was redissolved in MeOH (2.0 milliliters), HC (OMe) 3 (2.0 milliliters), and TsOH (catalytic amount) was added. The mixture was irritated at 120 ° C using a microwave for 20 minutes. The solvent was removed and the crude product was purified by column chromatography on silica gel eluting with EtOAc, followed by further purification by HPLC preparation to give the title compound as a white solid (41.2 milligrams, 23 percent). HPLC t R = 2.07 minutes; MS m / z 362.31 [M + H] +. The following compounds were prepared in an analogous manner from the appropriately substituted Grignard reagent: Example 9-2, N-cyclopropyl-3- (6-cyclopropyl-purin-9-yl) -4-methyl-benzamide, HPLC tR = 1.78 minutes; MS m / z 334.28 [M + H] +. Example 9-3, N-cyclopropyl-4-methyl-3- [6- (tetrahydro-pyran-4-yl) -purin-9-yl] -benzamide, HPLC t R = 1.78 minutes; MS m / z 378.23 [M + H] +.

Example 10 Preparation of N-cyclopropyl-4-methyl-3- (6-phenoxy-purin-9-yl) -b in z-amide.

To a solution of 3- (6-chloro-purin-9-yl) -N-cyclopropyl-4-methy-benzamide (Example 4B) (21 milligrams, 0.064 mmol) in dimethyl formamide (0.2 milliliters) was added cyclopentanol (59 microliters, 0.64 millimoles). The mixture was heated with a microwave oven at 150 ° C for 30 minutes. It was cooled to room temperature and then purified by PTLC or HPLC to give the desired compound as a white solid (10 milligrams, 0.027 millimoles, 41 percent). HPLC t R = 2.09 minutes; MS m / z 386 [M + H] +.

Example 11 Preparation of N-cyclopropyl-4-methyl-3-r6- (4-morpholin-4-ylmethyl-phenyl) -purin-9-p-benzamide.

A. Preparation of 3 - [, 6- (4-bromo-methyl-phenyl) -purin-9-yl '| -N-cyclopropyl-4-methyl-benzamide. To a mixture of N-cyclopropyl-3- [6- (4-hydroxy-methyl-phenyl) -purin-9-yl] -4-methyl-benzamide (58 milligrams, 0.145 mmol, see example 4C-31) in dichlor -methane (0.5 milliliters) was added carbon tetrabromide (58 milligrams, 0.175 millimoles), then triphenyl-phosphine (47 milligrams, 0.179 millimoles). The mixture was stirred at room temperature for one hour, then purified by column, eluting with EtOAc / Hexanes (1: 1) to give the desired product as a crude (88 milligrams, 0.19 milliols, 63 percent). B. Preparation of N-cyclopropyl-4-methyl-3- [6- (4-morpholin-4-ylmethyl-phenyl) -purin-9-ill-benzamide. To a mixture of a compound 11A (10 milligrams, 0.022) in dichloromethane (0.2 milliliters) was added morpholine (19 microliters, 0.21 millimoles). The mixture was stirred at room temperature for 10 minutes, and then purified by TLC preparation with 10 percent MeOH / CH 2 Cl 2 to give the desired compound as a white solid (4.8 milligrams, 0.01 millimole, 47 percent). HPLC t R = 1.65 minutes; MS m / z 469 [M + H] +.

The following compounds were prepared analogously from the appropriately substituted amine: Example 11B-2, N-cyclopropyl-4-methyl-3- [6- (4-morpholin-4-ylmethyl-phenyl) -purin-9- il] -benzamide, HPLC t R = 1.65 minutes; MS m / z 469 [M + H] +. Example 11B-3, N-cyclopropyl-3- [6- (4-dimethyl-amino-methyl-phenyl) -purin-9-yl] -4-methyl-benzamide, HPLC t R = 1.66 minutes; MS m / z 427 [M + H] +.

Example 12 Preparation of N-cyclopropyl-4-methyl-3-f6- (4-methyl-carbamoyl) pheny-purin-9-ill-benzamide.

A. 4-R9- (5-Cyclo-propyl-carbamoyl-2-methyl-phenyl) -9H-purin-6-ip-benzoic acid. To a solution of 4-9- (5-cyclopropyl-carbamoyl-2-methyl-phenyl) -9H-purin-6-yl] -benzoic acid methyl ester (65 milligrams, 0.87 mmol) in 2 milliliters of tetrahydrofuran, 2 milliliters of methanol, and 1 milliliter of water was added sodium hydroxide (2M, 0.15 milliliters, 0.3 millimoles) at 20 ° C. The reaction mixture was stirred at this temperature for 5 hours, and then the clear solution was neutralized by further dropping 2N aqueous hydrochloric acid to give a solid. The product was collected by filtration to give a colorless solid (50 milligrams, 80 percent). HPLC t R = 2.01 minutes; MS m / z 414 [M + H] +. B. N-Cyclopropii-4-methyl-3-r6- (4-methyl-carbamoyl-phenyl) -purin-9-ill-benzamide. To a solution of 4- [9- (5-cyclopropyl-carbamoyl-2-methyl-phenyl) -9H-purin-6-yl] -benzoic acid (10 milligrams, 0.024 mmol) and the methyl amine (3.0 milligrams, 0.097 millimoles) in 0.5 milliliters of dry dimethylformamide was added 1-hydroxy-benzotriazole (7.4 milligrams, 0.048 millimoles), and 1- (3-dimethylaminopropyl) -3-ethyl-carbodi-imide hydrochloride (9.2 milligrams) , 0.048 millimoles) at 20 ° C. The reaction mixture was stirred at 20 ° C for 4 hours. And then 2 milliliters of water were added. The product was collected by filtration to give a colorless solid (8.2 milligrams, 80 percent). HPLC t R = 1.99 minutes; MS m / z 427 [M + H] +. The following compound was prepared in an analogous manner from the appropriately substituted orfo-forma: Example 12B-2, N-cyclopropyl-3- [6- (4-cyclopropyl-carbamoyl-phenyl) -purin-9-yl] - 4-methyl-benzamide, HPLC t R = 2.12 minutes, MS m / z 453 [M + H] +.

Example 13 Preparation of N-cyclopropyl-4-methyl-3-r6- (4-M.3,4T oxadiazol-2-yl-phenyl) -purin-9-ill-benzamide.

A. N-cyclopropyl-3-yl- (4-hydrazino-carbonyl-phenyl) -purin-9-ill-4-methyl-benzam ida. To a solution of 4- [9- (5-cyclopropyl-carbamoyl-2-methyl-phenyl) -9H-purin-6-yl] -benzoic acid methyl ester (65 milligrams, 0.15 mmol) in 1 milliliter of methanol 1 milliliter of hydrazine monohydrate was added. The reaction mixture was stirred at room temperature for 4 hours. The methanol was removed and then 2 milliliters of water was added. The product was collected by filtration to give a colorless solid (47 milligrams, 72 percent). HPLC tR = 1.62 minutes; MS m / z 428 [M + H] +. B. N-cyclopropyl-4-methyl-3-r6- (4-ri, 3,4, -oxadiazol-2-yl-phenyl) -purin-9-in-benzamide. To a solution of N-cyclopropyl-3- [6- (4-hydrazino-carbonyl-phenyl) -purin-9-yl] -4-methyl-benzamide (8.0 milligrams, 0.019 mmol) in 0.5 milliliters of orfo-forma trimethyl, three drops of acetic acid were added. The reaction mixture was stirred at 120 ° C in a microwave oven for 10 minutes. Then, 0.5 milliliters of methylene chloride, and 3 milliliters of hexanes were added. The product was collected by filtration to give a colorless solid (6.0 milligrams, 73 percent). HPLC t R = 2.12 minutes; MS m / z 438 [M + H] +. The following compounds were prepared analogously from the appropriately substituted orfo-format: Example 13B-2, N-cyclopropyl-4-methyl-3-. { 6- [4- (5-methyl- [1,3,4] -oxadiazol-2-yl) -phenyl] -purin-9-yl} -benzamide, HPLC t R = 2.14 minutes; MS m / z 452 [M + H] +.

Example 13B-3, N-cyclopropi l-3-. { 6- [4- (5-ethyl- [1, 3,4] -oxadiazol-2-yl) -phenyl] -purin-9-yl} -benzamide, HPLC t R = 2.24 minutes, MS m / z 466 [M + H] +. The following compounds were prepared analogously from appropriately substituted 12A and orfo-format: Example 13B-4, N-cyclopropyl-4-methyl-3- [6- (3- [1, 3,4] -oxadiazoi -2-yl-phenyl) -purin-9-yl] -benzamide, HPLC t R = 2.12 minutes; MS m / z 438 [M + H] +. Example 13B-5, N-ci cl opropi l-4-m eti-3. { 6- [3- (5-methyl- [1,3,4] -oxadiazol-2-yl-pheny] -purin-9-yl}. -benzamide, HPLC t R = 2.14 minutes; MS m / z 452 [M + H] + Example 13B-6, N-cyclopropi l -3. {6- [3- (5-ethyl- [1,3,4] -oxadiazol-2-yl) -phenyl] -purin-9-yl.} -4-methyl-benzamide, HPLC tR = 2.26 minutes; MS m / z 466 [M + H] +.

Example 14 Preparation of 3- (6-cyclohexyl-2-hydroxy-purin-9-yl) -N-cyclopropyl-4-methyl-benzamide.

To a solution of 3- (5-amino-4-cyano-imidazol-1-yl) -N-cyclopropylo-4-methyl-benzamide (28 milligrams, 0.1 mmol, see Example 2A) in dry tetrahydrofuran ( 5 milliliters) under nitrogen was added a 1M solution of cyclohexyl magnesium bromide in tetrahydrofuran (2M, 0.25 milliliters, 0.5 mmol) at room temperature. Then, the reaction of the mixture was stirred at this temperature for 4 hours, and 5 milliliters of water were added. The mixture was extracted with ethyl acetate (20 milliliters, 3 times), washed with water, and dried over MgSO4, and concentrated. The crude product was dissolved in 2 milliliters of methylene chloride. And then 1, 1 -carbonyl-di-amidazole (32 milligrams, 0.2 mmol) was added. After being stirred at room temperature for 1 hour, the mixture was diluted with 50 milliliters of ethyl acetate and water, and the ethyl acetate layer was separated, washed with water and brine, and then dried over MgSO4. After filtration and concentration, the crude product was purified by preparative HPLC to give a solid (22 milligrams, 57 percent). HPLC t R = 1.94 minutes; MS m / z 392 [M + H] +.

Example 15. The ability of the compounds provided herein to inhibit the synthesis or activity of cytokines can be demonstrated using the following in vitro assays.

Generation of kinases p38. The p38a and human ß cDNAs were cloned by polymerase chain reaction. The cDNAs of a and β were subcloned into the plasmid DEST2 (Gateway, InVitrogen). The His6-p38 fusion protein was expressed in £. coli, and purified from bacterial lysates by affinity chromatography using Ni + 2-NTA-agarose. The His6-p38 protein was activated by incubation with constitutively active MKK6. Active p38 was separated from MKK6 by affinity chromatography. The constitutively active MKK6 was generated in a manner similar to that mentioned in Raingeaud et al [Mol. Cell. Biol., 1247-1255 (1996)]. Production of TNF-a through PBMCs Stimulated by LPS Heparinized human whole blood was obtained from healthy volunteers. Peripheral blood mononuclear cells (PBMCs) were purified from human whole blood by Accu-paque density gradient centrifugation, and resuspended at a concentration of 5 × 10 6 / milliiitre in the assay medium (RPMI medium containing fetal bovine serum). 10 percent). 175 microliters of the cell suspension were incubated with 10 microliters of the test compound (in 4 percent dimethyl sulfoxide) in 96-well tissue culture plates for 30 minutes at room temperature. Then 15 microliters of LPS (13.33 micrograms / milliliter supply) was added to the cell suspension, and the plate was incubated for 18 hours at 37 ° C in a humidified atmosphere containing 5 percent C02. Following the incubation, the culture medium was collected and stored at -20 ° C. THP-1 cells (TIB-202, ATCC) were washed and resuspended at a concentration of 1 x 10 s / ml in the test medium (RPMI medium containing 3 percent fetal bovine serum) . 175 microliters of the cell suspension were incubated with 10 microliters of the test compound (in 4 percent dimethyl sulfoxide) in 96-well tissue culture plates for 30 minutes at room temperature. Then 15 microliters of LPS (13.33 micrograms / milliliter supply) was added to the cell suspension, and the plate was incubated for 18 hours at 37 ° C in a humidified atmosphere containing 5 percent C02. Following the incubation, the culture medium was collected and stored at -20 ° C. The concentration of TNF-a in the medium was quantified using a standard ELISA diagnostic kit (BioSource International, Camarillo, CA). The concentrations of TNF-a and the IC 50 values for the test compounds (concentration of the compound that inhibited the production of TNF-α stimulated by the LPS by 50%) were calculated, by means of the logistic curve of four parameters (SigmaPlot, SPSS, Inc.).

P38a assay. The p38a assay employed is based on the measurement of ATP released in the reaction of interest through the oxidation of NADH obtained by coupling reactions with pyruvate kinase and lactate dehydrogenase. The tests were carried out in 384-well ultraviolet plates. The final volume was 25 microliters, prepared from the addition of 2.5 microliters of the compound dissolved in dimethyl sulfoxide at 10 percent, 17.5 microliters of assay regulator, and 5 microliters of ATP. The test regulator contains the following reagents, to give a final concentration in the assay of: 25 mM HEPES, 20 mM 2-g lyopho-phosphate, pH of 7.6, 10 mM MgCl 2, 0.1 mM sodium orfo-vanadate, 0.5 phosphoenol pyruvate. mM, 0.12 mM NADH, 3.1 milligrams / milliliter of LDH, 6.67 milligrams / milliliter of pyruvate kinase, 0.25 mM peptide substrate, 2 mM DTT, 0.005 percent Tween 80, and 20 nM Upstate p38a kinase. The test compounds were previously incubated with the p38a kinase for 60 minutes, and the reaction was initiated by the addition of ATP to a final concentration of 0.15 mM. The reaction rates were measured at 340 nanometers, using the SpextraMax plate reading spectrophotometer for 10 minutes at 37 ° C. The inhibition data were analyzed by nonlinear least squares regression, using SigmaPlot. Production of TNF-a by Mice Stimulated by LPS. Mice (female Balb / c, 6 to 8 weeks old, Taconic Labs; n = 8 / treatment group) were injected intraperitoneally with lipopol i taking (LPS) (50 micrograms / kilogram of E. coli strain 0111: B4 , Sigma) suspended in sterile serum. Ninety minutes later, the mice were sedated by inhalation of C02: 02, and a blood sample was obtained. The serum was separated and analyzed for TNF-a concentrations by a commercial ELISA assay according to the manufacturer's instructions (BioSource International). The test compounds were administered orally at different times before the LPS injection. The compounds were dosed either as suspensions or as solutions in the different vehicles or solubilizing agents. Because the modifications will be apparent to those skilled in the art, it is intended that the invention be limited only by the scope of the appended claims.

Claims (104)

1. CLAIMS 1. A compound having the formula I: I or pharmaceutically acceptable derivatives thereof, wherein: R is halogen, alkyl, cycloalkyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, pseudo-halogen, -NR4R5, or -OR4; R2, in each presentation, is independently selected from alkyl, substituted alkyl, lower cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, -OR4, -CN, -NR4R5, -S (= 0) alkyl, -S ( = 0) -aryl, -NHS02-arylene-R4, -NH S02-alkyl, -C02R4, -CONH3, -SO.H, -S (0) -alkyl, -S (0) -aryl, -S02NHR4, and -NHC (= 0) NH R4; n is 0, 1, or 2; R3 is selected from hydrogen, alkyl, -OR4, substituted alkyl, cycloalkyl, -CR4-cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; Y is -C (= 0) NH-, -NH (C = 0) -, -NH (C = 0) NH-, -S02NH-, -NHS02-, or -C (= 0) -; X1 is an individual bond, alkylene, -O-, -S-, -S (O) -, -SO2-, -C (O) -, -CO (O) - or -C (0) NH-; A is a bicyclic heterocyclic ring system with at least one heteroatom in each ring, wherein the heteroatoms are each independently selected from N, O, and S, and is optionally substituted with up to two R13; X2 is an individual bond, alkylene, -O-, -S-, -NH-, -N (alkyl of 1 to 4 carbon atoms) -, -NH-alkylene of 1 to 4 carbon atoms-, -N ( alkyl of 1 to 4 carbon atoms) -alkylene of 1 to 4 carbon atoms, -S (O) -, -SO2-, -C (O) -, -CO (O) -, or -C (0) NH-; D is a monocyclic or bicyclic aromatic or non-aromatic ring system optionally containing up to four heteroatoms selected from N, O, and S, and wherein a CH2 adjacent to any of the N, O, or S heteroatoms is optionally substituted with oxo (= 0), or D is alkyl of 1 to 6 carbon atoms, wherein D is optionally substituted by one to four groups (CR9R10) WE; w is an integer from 0 to 4; R10 is selected from H, alkyl of 1 to 4 carbon atoms-hydroxyl, alkyl of 1 to 4 carbon atoms-aryl, and alkyl of 1 to 4 carbon atoms-heteroaryl, wherein this aryl or heteroaryl group is unsubstituted or substituted with 1 to 3 groups independently selected from halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 atoms carbon, haloalkyl, haloalkoxy, OH, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms - carbonyl, CN, NH2, NR6R7, SR6, S (0) R6, S02R6, S03R6, S02NR6, C02H , C02R6, and CONR6R7; E is selected from H, halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl, haloalkoxy, OH, OR6, CN, CHO, C02R6, CONR6R7, OCOR6, OC (= 0) OR6, OC (= 0) NR6R7, OCH2C02R6, C (= 0) R6, NH2, NHR6, NR6R7, NR7C (= 0) R6, NR7C (= 0) OR6, N R7C (= 0) C (= 0) OR R6, NR7C (= 0) C (= 0) NR6R7, N R7C (= O) C (= 0) (alq ui I or from 1 to 6 carbon atoms), NR7C (= NCN) OR6, NR7C (= 0) NR6R7, NR7C (= NCN) NR6R7, N R7C (= NR6) N R7R8, NR6S02NR6R7, NR7S02R6, SR6, S (= 0) R6, S02R6, S03R7, S02NR6R7, NHOH, NHOR6, NR6NR7NR8, N (COR6) OH, N (C02R6) OH, CONR7 (CR9R10) rR6, CO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R0) rR6 , CO (CR9R10) pO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10) rOR6, CO (CR9R10) pO (CR9R0) qR6, CO (CR6R10) rNR6R7, OC (O) O (CR9R10) mNR6R7, O ( CO) p (CR9R10) R6, O (CR9R10) mNR6R7, N R7C (O) (C R9R 1 °) rO R6, NR7C (= NC) (CR9R10) rR6, NR7CO (CR9R10) rNR6R7, NR7 (CR9R10) mOR6, NR7 (CR9R10) rCO2R6, NR 7 (CR9 R1 °) m N R6 R7, NR7, NR3 (CR9R10) nSO2 (CR9R10) rCO2R6, N R7 (C R9R1 °) mN R6R7, NR7 (CR9R10) nSO2 (CR9R10) qR6, CONR7 (CR9R10) nSO2 (CR9R10 ) qR6, SO2NR7 (CR9R10) qR6, SO2NR6 (CR9R10) mOR6, aryl, heterocyclic optionally substituted with 1 or 2 alkyl groups, heteroaryl optionally substituted with 1 or 2 alkyl groups, and alkyl aryl, wherein the aryl groups are unsubstituted or substituted with 1 or 2 substituents, each independently selected from R12, or two E groups, which substitute the adjacent atoms on D, and which together form alkylenedioxyl, thioalkyleneoxy or alkylenedithioxyl; m is an integer that has a value of 2 to 6; p is an integer that has a value of 1 to 3; q is an integer that has a value from 0 to 3; r is an integer that has a value from 0 to 6; R, in each presentation, is independently selected from halogen, No2, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms carbon, haloalkyl, haloalkoxy, OH, oxo, alkoxy of 1 to 4 carbon atoms, OR6, O (CR9R10) CO2R6, O (CR9R10) mNR6R7, O (CR9R10) pCN, O (C R9R1 °) rC (= 0) N R6R7, C 1 -C 4 alkyl, CN, NH 2, NHR 6, NR 6 R 7, N R 7 (CR 9 R 10) CO2 R 6, NR 7 OR 6, N R 7 (CR 9 R 1) m O R 6, N R 7 CH ((CR 9 R 10) POR 6) 2, N R 7 C ((C R9R1 °) pO R6) 3, NR7C (= 0) R6, NR7 (CR9R10) mNR6R7, N R7 (C R9R 1 °) q R6, SR7, S (0) R7, S02R7, S02NR6, S03R7, C02H , C02R6, and CONR6R7; R 4 is hydrogen, lower alkyl, and lower cycloalkyl; R5 is hydrogen, lower alkyl, and lower cycloalkyl; R6, R7, and R8 are independently selected as follows: i) R6, R7, and R8 are independently selected from H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-carbonyl, cycloalkyl of 3 to 7 carbon atoms- (alkyou of 0 to 5 carbon atoms) -carbonyl, alkoxy 1 to 6 carbon atoms -carbonyl, aryl- (alkyl of 0 to 5 carbon atoms) -carbonyl, aryl- (alkoxy of 1 to 5 carbon atoms) -carbonyl, heterocyclic- (alkyl of 0 to 5 carbon atoms) ) -carbonyl, heterocyclic- (alkoxy of 1 to 5 carbon atoms) -carbonyl, alkyl of 1 to 6 carbon atoms-sulfonyl, aryl-sulfonyl, heteroaryl-sulfyl, alkyl of 0 to 4 carbon atoms-aryl, alkyl of 0 to 4 carbon atoms-heterocyclic, wherein the cycloalkyl, aryl, or heterocyclic groups are unsubstituted or substituted with 1 or 2 substituents entities, each independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, hydroxyl, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, haloalkyl, N02, and CN; or ii) R6 and R7, or R6 and R8, or R7 and R8, when both substituents are on the same nitrogen atom (as in (-NR6R7) or (NR7R8)), can be taken together with the nitrogen atom with which are joined, to form a heterocycle selected from 1-aziridi nyl, 1-azetidinyl, 1-piperidinyl, 1-morphinoyl, 1-pi rrolidinyl, thiamorpholinyl, thiazole idyl, 1-piperazinyl, 1 - imidazolyl, 3-azabicyclo- (3,2,2) -nonan-3-yl, and 1-tetrazolyl, this heterocycle being optionally substituted with 1 to 3 groups, each independently selected from oxo, alkyl from 0 to 4 carbon-OH atoms, alkyl of 0 to 4 carbon atoms-O-alkyl of 1 to 4 carbon atoms, alkyl of 0 to 4 carbon atoms-CONH2, alkyl of 0 to 4 carbon atoms-C02-alkyl from 0 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkyl of 0 to 6 carbon atoms-carbonyl, C 3 -C 7 -cycloalkyl-carbonyl, C 1 -C 6 -alkoxycarbonyl, C 3 -C 7 -cycloalkoxycarbonyl, -NHCO-alkyl, aryl, heteroaryl, aryl-alkoxycarbonyl, heteroaryl- alkoxycarbonyl, alkyl of 1 to 6 carbon atoms-sulfonyl, aryl-sulfonyl, and heteroaryl-sulfonyl; R9 is hydrogen or alkyl of 1 to 4 carbon atoms; and R13 is hydrogen, alkyl, haloalkyl, aminocarbonyl, hydroxyl, hydroxycarbonyl, alkoxycarbonyl, cycloalkyl-aminocarbonyl, substituted alkyl, aryl, substituted aryl, heteroaryl, heterocyclyl, thioalkyl, alkyl-amino-carbonyl, or lower cycloalkyl; wherein the substituents on the alkyl group are selected from 1 to 4 substituents selected from halogen, hydroxyl, alkoxy, oxo (= 0), alkanoyl, aryloxy, alkanoyloxy, amino, alkyl-amino, arylamino, aralkyl -amino, disubstituted amines, wherein the two amino substituents are selected from alkyl, aryl, or aralkyl; alkanoyl-amino, aroyl-amino, aralkanoyl-amino, substituted alkanoyl-amino, substituted aryl-amino, substituted aralkanoyl-amino, thiol, thioalkyl, thioaryl, thioaralkyl, thionoalkyl, thionoaryl, thionoaralkyl, alkyl-sulfonyl, aryl-sulfonyl , aralkyl sulfonyl, sulfonamido, for example S02NH2, substituted sulfonamido, nitro, cyano, carboxyl, carbamyl, for example C0NH2, substituted carbamyl, for example CONH-alkyl, CONH-aryl, CON H -ralkyl, or the cases in which there are two substituents on the nitrogen selected from alkyl, aryl, or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino, and substituted or unsubstituted heterocycles, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, and the like, and the substituents on the aryl group are selected from from 1 to 4 substituents selected from alkyl, substituted aryl, haloalkyl, halogen, trifluoromethoxyl, trifluoromethyl, hydroxyl, hydroxy-alkyl, amino-alkyl, alkoxy, alkanoyl, alkanoyloxy, amino, arylamino, aralkylamino, dialkyl amino, alkanoylamino, thiol, thioalkyl, ureido, nitro, cyano, cyano-alkyl, heterocyclyl, carboxyl, carboxy-alkyl, carbamyl, alkoxy-carbonyl, amino-carbonyl, thionoalkyl, thionoaryl, aryl-sulfonyl-amine, sulfonic acid, alkylsulfonyl, sulfonamido, aryloxy, and CONRaRb, wherein Ra and Rb are selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxycarbonyl-amine-alkyl, and alkylamino; or Ra and Rb, together with the nitrogen with which they are substituted, form a heterocyclic or heteroaryl ring of 3 to 6 members. The substituent may be further substituted by hydroxyl, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl, or aralkyl.
2. 2. The compound of claim 1, wherein R1 is lower alkyl, lower cycloalkyl, alkenyl, or alkynyl.
3. 3. The compound of claim 1, or claim 2, wherein R1 is methyl, halogen, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, -NH2 or -NR4R5 .
4. 4. The compound of claims 1 to 3, wherein R1 is methyl, halogen, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, -NH2, -NR4R5, or - OR4.
5. 5. The compound of claims 1 to 4, wherein R1 is methyl, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, -NH2, -NR4R5, or -OR4.
6. 6. The compound of claims 1 to 5, wherein R1 is lower alkyl.
7. 7. The compound of claims 1 to 6, wherein R1 is methyl.
8. 8. The compound of claims 1 to 7, wherein R2 is alkyl or cycloalkyl.
9. 9. The compound of claims 1 to 8, wherein R2 is alkyl.
10. 10. The compound of claims 1 to 9, wherein R2 is hydrogen.
11. 11. The compound of claims 1 to 10, wherein R3 is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, heterocyclyl, and heteroaryl.
12. 12. The compound of claims 1 to 10, wherein R3 is selected from alkyl, -OR4, substituted alkyl, cycloalkyl, -CR4-cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle.
13. 13. The compound of claims 1 to 12, wherein R3 is cycloalkyl, cycloalkyl-alkyl, alkoxyalkyl, or heteroaryl. The compound of claims 1 to 13, wherein R3 is methyl, isopropyl, ethyl, cyclopropyl, cyclopropyl-methyl, methoxy-methyl, oxazolyl, or thiazolyl. 15. The compound of claims 1 to 14, wherein R3 is cyclopropyl. 16. The compound of claims 1 to 15, wherein Y is -C (= 0) NH- or -S02NH-. 17. The compound of claims 1 to 16, wherein Y is -C (= 0) NH-. 18. The compound of claims 1 to 17, wherein X1 is an individual bond or alkylene. 19. The compound of claims 1 to 18, wherein X1 is an individual bond or -CH2-. 20. The compound of claims 1 to 19, wherein X1 is an individual bond. The compound of claims 1 to 20, wherein A is a bicyclic heterocyclic ring system, wherein each ring contains at least one N atom, and is optionally substituted with up to two R 3. claims 1 to 21, wherein A is a bicyclic heteroaryl ring system, wherein each ring contains at least one N atom, and is optionally substituted with up to two R13. 23. The compound of claims 1 to 22, wherein A is a bicyclic heteroaryl ring system, wherein each ring contains two N atoms, and is optionally substituted with up to two R13. 24. The compound of claims 1 to 23, wherein A is an imidazolo-pyrimidine, pyrazolo-pyrimide, imidazolo-pyrimidinone, or pyrazolo-pyrimidinone group. 25. The compound of claims 1 to 24, wherein A is an imidazolo-pyrimidine group, or pyrazolo-pyrimidine. 26. The compound of claims 1 to 25, wherein X2 is an individual bond, alkylene, or -NH-. 27. The compound of claims 1 to 26, wherein X2 is an individual bond, -CH2-, or -NH-. 28. The compound of claims 1 to 27, wherein X2 is an individual bond. 29. The compound of claims 1 to 28, wherein D is heterocyclyl, cycloalkyl, heteroaryl, or aryl, and is optionally substituted by one to four, in a one or two (CR9R10) WE mode. 30. The compound of claims 1 to 29, wherein D is cyclohexyl, cyclopentyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or phenyl, and is optionally substituted by one to four, in one or two groups (CR9R10). WE. 31. The compound of claims 1 to 30, wherein D is phenyl, and is optionally substituted by one to four, in one or two groups (CR9R10) WE mode. 32. The compound of claims 1 to 31, wherein R13 is alkyl, OH, or NH2. 33. The compound of claims 1 to 32, wherein R13 is methyl, OH, or NH2. 34. The compound of claims 1 to 33, wherein (CR9R10) E is alkyl, alkoxy, halogen, -CH2-heterocyclyl, -CONH-chloroalkyl, alkylsulfonyl, thioalkyl, alkylsulfonyl-amino , haloalkyl, aminocarbonyl, pseudo halogen, or heterocyclyl, or two groups (CR9R10) WE, which substitute the adjacent atoms on D together form alkylene dioxyl. 35. The compound of claims 1 to 34, wherein (CR9R10) E is methoxy, methyl, 1,4-thiazolyl, methyl-sulfonyl, ethoxy, 4-methyl-1-piperazinyl-methyl, fluorine, chlorine, cyclohexyl-aminocarbonyl, methanesulfonyl-amino, thiomethyl, 4-morpholinyl, trifluoromethyl, aminocarbonyl, iodine, cyano, or cyclo-propyl-aminocarbonyl, or two groups (CR9R10) WE, which replace the adjacent atoms on D form together methylenedioxyl or ethylenedioxyl. 36. The compound of claims 1 to 35, wherein the compound has the formula II: wherein k is an integer from 0 to 4. 37. The compound of any of claims 1 to 35, wherein the compound has the formula III: wherein k is an integer from 0 to 4. 38. The compound of claims 1 to 35, wherein the compound has the formula IV: wherein k is an integer from 0 to 4. 39. The compound of claims 1 to 35, wherein the compound has the formula V: wherein k is an integer from 0 to 4. 40. The compound of claims 1 to 35 wherein the compound has the formula VI: wherein k is an integer from 0 to 4. 41. The compound of claims 1 to 35, wherein the compound has the formula VI wherein f is an integer from 0 to 3. 42. The compound of claims 1 to 35, wherein the compound has the formula VIII: wherein f is an integer from 0 to 3. 43. The compound of claims 1 to 35, wherein the compound has the formula IX: wherein k is an integer from 0 to 4. 44. The compound of claims 1 to 35, wherein the compound has the formula X: wherein k is an integer from 0 to 4. 45. The compound of claims 1 to 35, wherein the compound has the formula XI: wherein k is an integer from 0 to 4. 46. The compound of claims 1 to 35, wherein the compound has the formula XII: wherein k is an integer from 0 to 4. 47. The compound of claims 1 to 35 wherein k is an integer from 0 to 4. 48. The compound of claims 1 to 35 wherein the compound has the formula XIV: wherein f is an integer from 0 to 3. 49. The compound of claims 1 to 35, wherein the compound has the formula XV: wherein f is an integer from 0 to 3. 50. The compound of claims 1 to 49, wherein the compound is selected from those shown in the EXAMPLES. 51. A pharmaceutical composition, which comprises a compound of any of claims 1 to 50, and 95 to 103, and a pharmaceutically acceptable carrier. 52. The pharmaceutical composition of claim 51, which is formulated for administration of a single dose. 53. A compound of claims 1 to 50, and 95 to 103, when used in the treatment of a disease mediated by p38 kinase. 54. The use of a compound of claims 1 to 50, and 95 to 103, in the preparation of a medically for the treatment of a disease mediated by p38 kinase. 55. A method for the treatment, prevention, or abatement of one or more symptoms of a disease or disorder that is modulated or otherwise affected by the activity of the cytokine or in which the activity of the cytokine is involved, which it comprises administering to a patient in need thereof an effective amount of the compound of formula I: or pharmaceutically acceptable derivatives thereof, wherein: R1 is hydrogen, halogen, alkyl, cycloalkyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, pseudo-halogen, -NR4R5, or -OR4; R2, in each presentation, is independently selected from alkyl, substituted alkyl, lower cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, -OR4, -CN, -NR4R5, -S (= 0) alkyl, -S ( = 0) -aryl or, -NHS02-arylene-R4, -NH S02-alkyl, -C02R4, -CONH3, -S03H, -S (0) -alkyl, -S (0) -aryl, -S02NHR4, and -NHC (= 0) NH R4; n is 0, 1, or 2; R3 is selected from hydrogen, alkyl, -OR4, substituted alkyl, cycloalkyl, -CR4-cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; Y is an individual bond, -C (= 0) NH-, -NH (C = 0) -, -NH (C = 0) NH-, -S02NH-, -NHS02-, or -C (= 0) -; X1 is an individual bond, alkylene, -O-, -S-, -S (O) -, -S02-, -C (O) -, -CO (O) - or -C (0) NH-; A is a bicyclic heterocyclic ring system with at least one heteroatom in each ring, wherein the heteroatoms are each independently selected from N, O, and S, and is optionally substituted with up to two R13; X2 is an individual bond, alkylene, -O-, -S-, -NH-, -N (alkyl of 1 to 4 carbon atoms) -, -NH-alkylene of 1 to 4 carbon atoms-, -N ( alkyl of 1 to 4 carbon atoms) -alkylene of 1 to 4 carbon atoms, -S (O) -, -S02-, -C (O) -, -CO (O) -, or -C (0) NH-; D is a monocyclic or bicyclic aromatic or non-aromatic ring system optionally containing up to four heteroatoms selected from N, O, and S, and wherein a CH2 adjacent to any of the N, O, or S heteroatoms is optionally substituted with oxo (= 0), or D is alkyl of 1 to 6 carbon atoms, wherein D is optionally substituted by one to four groups (CR9R10) WE; w is an integer from 0 to 4; R10 is selected from H, alkyl of 1 to 4 carbon atoms-hydroxyl, alkyl of 1 to 4 carbon atoms-aryl, and alkyl of 1 to 4 carbon atoms-heteroaryl, wherein this aryl or heteroaryl group is unsubstituted or substituted with 1 to 3 groups independently selected from halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 atoms carbon, haloalkyl, haloalkoxy, OH, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms - carbonyl, CN, NH2, NR6R7, SR6, S (0) R6, S02R6, S03R6, S02NR6, C02H , C02R6, and CONR6R7; E is selected from H, halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl, haloalkoxy, OH, OR6, CN, CHO, C02R6, CONR6R7, OCOR6, OC (= 0) OR6, OC (= 0) NR6R7, OCH2C02R6, C (= 0) R6, NH2, NHR6, NR6R7, NR7C (= 0) R6, NR7C (= 0) OR6, N R7C (= 0) C (= 0) OR R6, NR7C (= 0) C (= 0) NR6R7, N R7C (= O) C (= O) (alq u il or from 1 to 6 carbon atoms), NR7C (= NCN) OR6, N R7C (= 0) N R6R7, NR7C (= NCN) NR6R7, N R7C (= NR6) N R7R8, NR6S02NR6R7, NR7S02R6, SR6, S (= 0) R6, S02R6, S03R7, S02NR6R7, NHOH, NHOR6, NR6NR7NR8, N (COR6) OH, N (C02R6) OH, CONR7 (CR9R10) rR6, CO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10) rR6, CO (CR9R10) pO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10) rOR6, CO (CR9R10) pO (CR9R10) qR6, CO (CR6R10) rNR6R7, OC (O) O (CR9R10) mNR6R7, O ( CO) n (CR9R10) R6, O (CR9R10) mNR6R7, N R7C (O) (CR9R °) rO R6, NR7C (= NC) (CR9R10) rR6, NR7CO (CR9R10) rNR6R7, NR7 (CR9R10) mOR6, NR7 ( CR9R10) rCO2R6, N R7 (C R9 R1 °) m N R6R7, NR7, NR3 (CR9R10) nSO2 (CR9R10) rCO2R6, N R7 (C R9R 1) mN R6R7, NR7 (CR9R10) nSO2 (CR9R10) qR6, CONR7 (CR9R10) nSO2 (CR9R10) qR6 , SO2NR7 (CR9R10) qR6, SO2NR6 (CR9R0) mOR6, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms-methyl, aryl, heterocyclic optionally substituted with 1 or 2 alkyl, heteroaryl groups optionally substituted with 1 or 2 alkyl groups, and alkylaryl, wherein the aryl groups are unsubstituted or substituted with 1 or 2 substituents, each independently selected from R12, or two E groups, which replace the adjacent atoms on D, and which together form alkylenedioxyl, thioalkyleneoxy or alkylenedithioxyl; m is an integer that has a value of 2 to 6; p is an integer that has a value of 1 to 3; q is an integer that has a value from 0 to 3; r is an integer that has a value from 0 to 6; R12, in each presentation, is independently selected from halogen, No2, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms carbon, haloalkyl, haloalkoxy, OH, oxo, alkoxy of 1 to 4 carbon atoms, OR6, O (CR9R10) CO2R6, O (CR9R10) mNR6R7, O (CR9R10) pCN, O (C R9 R1 °) rC (= 0 ) N R6R7, C 1 -C 4 alkyl, CN, NH 2, NHR 6, NR 6 R 7, NR 7 (CR 9 R 10) CO2 R 6, NR 7 OR 6, N R 7 (C R 9 R 1) m O R 6, N R 7 CH ((CR 9 R 10) POR 6) 2, N R7C ((CR9R1 °) pOR6) 3, NR7C (= 0) R6, NR7 (CR9R10) mNR6R7, N R7 (CR9R 1 °) R6, SR7, S (0) R7, S02R7, S02NR6, S03R7, C02H, C02R6, and CONR6R7; R 4 is hydrogen, lower alkyl, and lower cycloalkyl; R5 is hydrogen, lower alkyl, and lower cycloalkyl; R6, R7, and R8 are independently selected as follows: i) R6, R7, and R8 are independently selected from H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms - carbonyl, cycloalkyl of 3 to 7 carbon atoms - (alkyl of 0 to 5 carbon atoms) - carbonyl, C 1 -C 6 -alkoxycarbonyl, aryl- (C 0 -C 5 -alkyl) -carbonyl, aryl- (C 1-5 alkoxy) -carbonyl, heterocyclic- (C 0 -C alkyl) 5 carbon atoms) -carbonyl, heterocyclic- (alkoxy of 1 to 5 carbon atoms) -carbonyl, alkyl of 1 to 6 carbon atoms-sulfonyl, aryl-sulfonyl, heteroaryl-sulfonyl, alkyl of 0 to 4 carbon atoms -aryl, C 1-4 -alkyl heterocyclic alkyl, wherein the cycloalkyl, aryl, or heterocyclic groups are unsubstituted or substituted with 1 or 2 substituents, each independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, hydroxyl, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, haloalkyl, N02, and CN; or ii) R6 and R7, or R6 and R8, or R7 and R8, when both substituents are on the same nitrogen atom (as in (-NR6R7) or (NR7R8)), can be taken together with the nitrogen atom with which are joined, to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, 1-piperazinyl, 1-imidazolyl, 3-azabicyclo- (3,2,2) -nonan-3-yl, and 1-tetrazolyl, this heterocycle being optionally substituted with 1 to 3 groups, each independently selected from oxo, alkyl of 0 to 4 carbon atoms-OH, alkyl of 0 to 4 carbon atoms-O-alkyl of 1 to 4 carbon atoms, alkyl of 0 to 4 carbon atoms-CON H2, alkyl of 0 to 4 carbon atoms-C02-alkyio of 0 to 4 atoms of carbon, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkyl of 0 to 6 carbon atoms-carbonyl, cycloalkyl alkyl of 3 to 7 carbon atoms-carbonyl, alkoxy of 1 to 6 carbon atoms-carbonyl, cycloalkoxy of 3 to 7 carbon atoms-carbonyl, -NHCO-alkyl, aryl, heteroaryl, aryl-alkoxy-carbonyl, heteroaryl- alkoxycarbonium, alkyl of 1 to 6 carbon atoms-sulfonyl, aryl-sulfonyl, and heteroaryl-sulfonyl; R9 is hydrogen or alkyl of 1 4 carbon atoms; and 13 is hydrogen, alkyl, haloalkyl, aminocarbonyl, hydroxyl, hydroxycarbonyl, alkoxycarbonyl, cycloalkyl-aminocarbonyl, substituted alkyl, aryl, substituted aryl, heteroaryl, heterocyclyl, thioalkyl, alkyl-amino-carbonyl , or lower cycloalkyl; wherein the substituents on the alkyl group are selected from 1 to 4 substituents selected from halogen, hydroxyl, alkoxy, oxo (= 0), alkanoyl, aryloxy, alkanoyloxy, amino, alkyl-amino, arylamino, aralkyl -amino, disubstituted amines, wherein the two amino substituents are selected from alkyl, aryl, or aralkyl; alkanoyl-amino, aroyl-amino, aralkanoyl-amino, substituted alkanoyl-amino, substituted aryl-amino, substituted aralkanoyl-amino, thiol, thioalkyl, thioaryl, thioaralkyl, thionoalkyl, thionoaryl, thionoaralkyl, alkyl-sulfonyl, aryl-sulfonyl, aralkyl -sulfonyl, sulfonamido, for example S02NH2, substituted sulfonamido, nitro, cyano, carboxyl, carbamyl, for example CONH2, substituted carbamyl, for example CONH-alkyl, CONH-aryl, WITH H-aralkyl, or the cases wherein there are two substituents on the nitrogen selected from alkyl, aryl, or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino, and substituted or unsubstituted heterocycles, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, and the like, and the substituents on the aryl group are selected from from 1 to 4 substituents selected from alkyl, substituted aryl, haloalkyl, halogen, trifluoromethoxyl, trifluoromethyl, hydroxy, hydroxy-alkyl, amino-alkyl, alkoxy, alkanoyl, alkanoyloxy, amino, arylamino, aralkylamino, dialkyl amino, alkanoylamino, thiol, thioalkyl, ureido, nitro, cyano, cyanoalkyl, heterocyclyl, carboxy, carboxy-alkyl, carbamyl, alkoxy-carbonyl, amino-carbonyl, thionoalkyl, thionoaryl, aryl-sulfon i I- amine, sulfonic acid, alkylsulfonyl, sulfonamido, aryloxy, and CONRaRb, wherein Ra and R are selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxycarbonyl-amino-alkyl, and alkylamino; or Ra and Rb, together with the nitrogen with which they are substituted, form a heterocyclic or heteroaryl ring of 3 to 6 members. The substituent may be further substituted by hydroxyl, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl, or aralkyl. 56. The method of claim 55, wherein the activity of the cytokine is modulated by the p38 kinase. 57. The method of claim 55 or 56, wherein the p38 kinase is p38a, p38β, p38 ?, or p38d. 58. The method of any of claims 55 to 57, wherein the disease or disorder is selected from inflammatory disease, autoimmune disease, destructive bone disorder, proliferative disorder, angiogenic disorder, infectious disease, neurodegenerative disease and viral disease. 59. The method of claim 58, wherein the inflammatory disease is selected from acute pancreatitis, chronic pancreatitis, asthma, allergies, and adult respiratory distress syndrome. 60. The method of claim 58, wherein the autoimmune disease is selected from glomeralonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves disease, autoimmune gastritis, insulin dependent diabetes mellitus (Type I). , autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, and graft-versus-host disease. 61. The method of claim 58, wherein the destructive bone disorder is selected from osteoporosis, osteoarthritis, and bone disorder related to multiple myeloma. 62. The method of claim 58, wherein the proliferative disease is selected from myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, and multiple myeloma. 63. The method of claim 58, wherein the infectious disease is selected from sepsis, septic shock, and Shigellosis. 64. The method of claim 58, wherein the viral disease is selected from acute hepatitis infection (including hepatitis A, hepatitis B, and hepatitis C), HIV infection, and CMV retinitis. 65. The method of claim 58, wherein the degenerative disease is selected from acute Alzheimer's disease, Parkinson's disease, cerebral ischemia, and other neurodegenerative diseases. 66. The method of claim 55, wherein the disease or disorder is modulated or otherwise affected by the activity of the cytokine IL-1, TNF, I L-6, or IL-8. 67. The method of claim 66, wherein the disease or disorder is modulated or otherwise affected by the activity of the cytokine IL-1. 68. The method of claim 65 or 66, wherein the disease or disorder modulated by cytokine IL-1 is selected from rheumatoid arthritis, osteoarthritis, embolism, endotoxemia and / or toxic shock syndrome, inflammatory reaction induced by endotoxin, Inflammatory bowel disease, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter syndrome, gout, traumatic arthritis, rubela arthritis, acute synovitis, diabetes, pancreatic beta-cell disease, and Alzheimer's disease. 69. The method of claim 66 or 67, wherein the disease or disorder modulated by the cytokine TNFa is selected from rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, and other arthritic conditions, sepsis, septic shock, endotoxic shock. , sepsis g ram-negative, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, reperfusion injury, graft-versus-host disease, rejection of allograft, fever and myalgias due to infection, cachexia after infection, AIDS, malignancy, keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis or pyresis. 70. The method of claim 66 or 67, wherein the disease or disorder modulated by the cytokine TNFa is associated with a viral infection. 71. The method of claim 70, wherein the viral infection is selected from HIV, CMV, influenza and herpes. 72. The method of claim 70, wherein the viral infection is a veterinary viral infection caused by equine infectious anemia virus, caprine arthritis virus, visna virus, maede virus, retrovirus infections. 73. The method of claim 66 or 67, wherein the disease or disorder modulated by the cytokine IL-8 is selected from psoriasis, inflammatory bowel disease, asthma, cardiac reperfusion injury, renal reperfusion injury, respiratory failure of adults, thrombosis, and gomerulonephritis. 74. A method for reducing the expression of inducible pro-inflammatory proteins, which comprises administering to a patient in need, an effective amount of a compound of the formula I: I or pharmaceutically acceptable derivatives thereof, wherein: R1 is hydrogen, halogen, alkyl, cycloalkyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, pseudo-halogen, -NR4R5, or -OR4; in each presentation, it is independently selected from alkyl, substituted alkyl, lower cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, -OR4, -CN, -NR4R5, -S (= 0) alkyl, -S (= O ) -ari lo, -NHS02-arylene-R4, -N HS 02-alkyl, -C02R4, -CONH3, -S03H, -S (0) -alkyl, -S (0) -aryl, -S02NHR4, and - NHC (= 0) NH R4; n is 0, 1, or 2; R3 is selected from hydrogen, alkyl, -OR4, substituted alkyl, cycloalkyl, -CR4-cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; Y is an individual bond, -C (= 0) NH-, -NH (C = 0) -, -NH (C = 0) NH-, -S02NH-, -NHS02-, or -C (= 0) -; X1 is an individual bond, alkylene, -O-, -S-, -S (O) -, -S02-, -C (O) -, -CO (O) - or -C (0) NH-; A is a bicyclic heterocyclic ring system with at least one heteroatom in each ring, wherein the heteroatoms are each independently selected from N, O, and S, and is optionally substituted with up to two R13; X2 is an individual bond, alkylene, -O-, -S-, -NH-, -N (alkyl of 1 to 4 carbon atoms) -, -NH-alkylene of 1 to 4 carbon atoms-, -N ( alkyl of 1 to 4 carbon atoms) -alkylene of 1 to 4 carbon atoms, -S (O) -, -S02-, -C (O) -, -CO (O) -, or -C (0) NH-; D is a monocyclic or bicyclic aromatic or non-aromatic ring system optionally containing up to four heteroatoms selected from N, O, and S, and wherein a CH2 adjacent to any of the N, O, or S heteroatoms is optionally substituted with oxo (= 0), or D is alkyl of 1 to 6 carbon atoms, wherein D is optionally substituted by one to four groups (CR9R10) WE; w is an integer from 0 to 4; R10 is selected from H, alkyl of 1 to 4 carbon atoms-hydroxyl, alkyl of 1 to 4 carbon atoms-aryl, and alkyl of 1 to 4 carbon atoms-heteroaryl, wherein this aryl or heteroaryl group is unsubstituted or substituted with 1 to 3 groups independently selected from halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 atoms carbon, haloalkyl, haloalkoxy, OH, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms-carbonyl, CN, NH2, NR6R7, SR6, S (0) R6, S02R6, S03R6, S02NR6, C02H , C02R6, and CONR6R7; E is selected from H, halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl, haloalkoxy, OH, OR6, CN, CHO, C02R6, CONR6R7, OCOR6, OC (= 0) OR6, OC (= 0) NR6R7, OCH2C02R6, C (= 0) R6, NH2, NHR6, NR6R7, NR7C (= 0) R6, NR7C (= 0) OR6, N R7C (= 0) C (= 0) OR R6, NR7C (= 0) C (= 0) NR6R7, N R7C (= 0) C (= 0) (a Iq ui I or from 1 to 6 carbon atoms), N R7C (= NCN) OR6, NR7C (= 0) NR6R7, NR7C (= NCN) NR6R7, N R7C (= NR6) N R7R 8, NR6S02NR6R7, NR7S02R6, SR6, S (= 0) R6, S02R6, S03R7, S02NR6R7, NHOH, NHOR6, NR6NR7NR8, N (COR6) OH, N (C02R6) OH, CONR7 (CR9R10) rR6, CO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10 ) rR6, CO (CR9R10) pO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10) rOR6, CO (CR9R10) pO (CR9R10) qR6, CO (CR6R10) rNR6R7, OC (O) O (CR9R10) mNR6R7, O (CO) p (CR9R10) R6, O (CR9R10) mNR6R7, N R7C (O) (C R9R1 °) rO R6, NR7C (= NC) (CR9R10) rR6, NR7CO (CR9R10) rNR6R7, NR7 (CR9R10) mOR6, NR7 (CR9R10) rCO2R6 , N R7 (CR9R1 °) mN R6 R7, NR7, NR3 (CR9R10) nSO2 (CR9R10) rCO2R6, N R7 (C R9R 1) mN R6R7, NR7 (CR9R10) nSO2 (CR9R10) qR6, CONR7 (CR9R10) nSO2 ( CR9R10) qR6, SO2NR7 (CR9R10) qR6, SO2NR6 (CR9R10) mOR6, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms-methyl, aryl, heterocyclic optionally substituted with 1 or 2 alkyl groups, heteroaryl optionally substituted with 1 or 2 alkyl groups, and alkylaryl, wherein the aryl groups are unsubstituted or substituted with 1 or 2 substituents, each independently selected from R 12, or two E groups, which they replace the adjacent atoms on D, and together they form alkylenedioxyl, thioalkyleneoxy or alkylenedithioxyl; m is an integer that has a value of 2 to 6; p is an integer that has a value of 1 to 3; q is an integer that has a value from 0 to 3; r is an integer that has a value from 0 to 6; R12, in each 'presentation, is independently selected from halogen, No2, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 atoms carbon, haloalkyl, haloalkoxy, OH, oxo, alkoxy of 1 to 4 carbon atoms, OR6, 0 (CR9R1 °) C02R6, O (CR9R10) mNR6R7, O (CR9R10) pCN, O (C R9R 1 °) rC ( = 0) N R 6 R 7, C 1 -C 4 alkyl, CN, NH 2, NHR 6, NR 6 R 7, N R 7 (CR 9 R 10) CO2 R 6, N R 7 OR 6, N R 7 (C R 9 R 1) m O R 6, N R 7 CH ((CR 9 R 10) POR 6) 2, N R7C ((C R9 R 1 °) pO R6) 3, NR7C (= 0) R6, NR7 (CR9R10) mNR6R7, N R7 (C R9R1 °) qR6, SR7, S (0) R7, S02R7, S02NR6 , S03R7, C02H, C02R6, and CONR6R7; R 4 is hydrogen, lower alkyl, and lower cycloalkyl; R5 is hydrogen, lower alkyl, and lower cycloalkyl; R6, R7, and R8 are independently selected as follows: i) R6, R7, and R8 are independently selected from H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-carbonyl, cycloalkyl of 3 to 7 carbon atoms- (alkyl of 0 to 5 carbon atoms) -carbonyl, alkoxy of 1 to 6 carbon atoms-carbonyl, aryl- (alkyl of 0 to 5 carbon atoms) - carbonyl, aryl- (alkoxy of 1 to 5 carbon atoms) - carbonyl, heterocyclic- (alkyl of 0 to 5 carbon atoms) carbonyl, heterocyclic- (alkoxy of 1 to 5 carbon atoms) -carbonyl, alkyl of 1 to 6 carbon atoms-sulfonyl, aryl-sulfonyl, heteroaryl-sulfonyl, alkyl of 0 to 4 carbon atoms-aryl, alkyl of 0 to 4 carbon atoms-heterocyclic, wherein the cycloalkyl, aryl, or heterocyclic groups are unsubstituted or substituted with 1 or 2 substituents each one independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, hydroxyl, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, haloalkyl, N02, and CN; or ii) R6 and R7, or R6 and R8, or R7 and R8, when both substituents are on the same nitrogen atom (as in (-NR6R7) or (NR7R8)), can be taken together with the nitrogen atom with which are bound to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, 1-piperazinyl, 1-imidazolyl, 3-azabicyclo- ( 3,2,2) -nonan-3-yl, and 1-tetrazolyl, this heterocycle being optionally substituted with 1 to 3 groups, each independently selected from oxo, alkyl of 0 to 4 carbon atoms-OH, alkyl from 0 to 4 carbon atoms-O-alkyl of 1 to 4 carbon atoms, alkyl of 0 to 4 carbon atoms-CON H2, alkyl of 0 to 4 carbon atoms-C02-alkyl of 0 to 4 carbon atoms , alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkyl of 0 to 6 carbon atoms, carbonyl, cycloalkyl 3 to 7 carbon atoms-carbonyl, C 1 -C 6 -alkoxycarbonyl, cycloalkoxyl of 3 to 7 carbon atoms, -NHCO-alkyl, aryl, heteroaryl, aryl-alkoxycarbonyl, heteroaryl- alkoxycarbonyl, alkyl of 1 to 6 carbon atoms-sulfonyl, aryl-sulfonyl, and heteroaryl-sulfonyl; R9 is hydrogen or alkyl of 1 to 4 carbon atoms; and R13 is hydrogen, alkyl, haloalkyl, aminocarbonyl, hydroxyl, hydroxycarbonyl, alkoxycarbonyl, cycloalkyl-aminocarbonyl, substituted alkyl, aryl, substituted aryl, heteroaryl, heterocyclyl, thioalkyl, alkyl-amino-carbonyl , or lower cycloalkyl; wherein the substituents on the alkyl group are selected from 1 to 4 substituents selected from halogen, hydroxyl, alkoxy, oxo (= 0), alkanoyl, aryloxy, alkanoyloxy, amino, alkyl-amino, arylamino, aralkyl -amino, disubstituted amines, wherein the two amino substituents are selected from alkyl, aryl, or aralkyl; alkanoyl-amino, aroyl-amino, aralkanoyl-amino, substituted alkanoyl-amino, substituted aryl-amino, substituted aralkanoyl-amino, thiol, thioalkyl, thioaryl, thioaralkyl, thionoalkyl, thionoaryl, thionoaralkyl, alkylsulfonyl, aryl sulphonyl, aralkyl sulfonyl, sulfonamido, for example S02NH2, substituted sulfonamido, nitro, cyano, carboxyl, carbamyl, for example CONH2, substituted carbamyl, for example CONH-alkyl, CONH-aryl, CON H-aralkyl, or the where there are two substituents on the nitrogen selected from alkyl, aryl, or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino, and substituted or unsubstituted heterocycles, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, and the like, and the substituents on the aryl group are selected from from 1 to 4 substituents selected from alkyl, substituted aryl, haloalkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxyl, hydroxy-alkyl, amino-alkyl, alkoxy, alkanoyl, alkanoi-loxyl, amino, arylamino, aralkylamino, dialkylamino, alkanoylamino, thiol, thioalkyl, ureido, nitro, cyano, cyano-alkyl, heterocyclyl, carboxyl, carboxy-alkyl, carbamyl, alkoxy-carbonyl, amino-carbonyl, thionoalkyl, thionoaryl, aryl- sulfonyl-amine, sulfonic acid, alkylsulfonyl, sulfonamide, aryloxy, and CONRaRb, wherein Ra and R are selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxycarbonyl-amino-alkyl, and alkylamino; or Ra and Rb, together with the nitrogen with which they are substituted, form a heterocyclic or heteroaryl ring of 3 to 6 members. The substituent may be further substituted by hydroxyl, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl, or aralkyl. 75. The method of claim 74, wherein the pro-inflammatory protein is prostaglandin-2 endoperoxide synthase (PGHS-2). 76. A method for treating, preventing, or decreasing one or more symptoms of the diseases or disorders associated with inducible pro-inflammatory proteins, which comprises administering to a subject in need thereof, a compound of formula I: or pharmaceutically acceptable derivatives thereof, wherein: R1 is hydrogen, halogen, alkyl, cycloalkyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, pseudo-halogen, -NR4R5, or -OR4; R2, in each presentation, is independently selected from alkyl, substituted alkyl, lower cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, -OR4, -CN, -NR4R5, -S (= 0) alkyl, -S ( = 0) -aryl, -NHS02-arylene-R4, -NH S02-alkyl, -C02R4, -CONH3, -S03H, -S (0) -alkyl, -S (0) -aryl, -S02NHR4, and - NHC (= 0) NH R4; n is 0, 1, or 2; R3 is selected from hydrogen, alkyl, -OR4, substituted alkyl, cycloalkyl, -CR4-cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; Y is an individual bond, -C (= 0) NH-, -NH (C = 0) -, -NH (C = 0) NH-, -S02NH-, -NHS02-, or -C (= 0) -; X1 is an individual bond, alkylene, -O-, -S-, -S (O) -, -S02-, -C (O) -, -CO (O) - or -C (0) NH-; A is a bicyclic heterocyclic ring system with at least one heteroatom in each ring, wherein the heteroatoms are each independently selected from N, O, and S, and is optionally substituted with up to two R13; X2 is an individual bond, alkylene, -O-, -S-, -NH-, -N (alkyl of 1 to 4 carbon atoms) -, -NH-alkylene of 1 to 4 carbon atoms-, -N ( alkyl of 1 to 4 carbon atoms) -alkylene of 1 to 4 carbon atoms, -S (O) -, -S02-, -C (O) -, -CO (O) -, or -C (0 ) NH-; D is a monocyclic or bicyclic aromatic or non-aromatic ring system optionally containing up to four heteroatoms selected from N, O, and S, and wherein a CH2 adjacent to any of the N, O, or S heteroatoms is optionally substituted with oxo (= 0), or D is alkyl of 1 to 6 carbon atoms, wherein D is optionally substituted by one to four groups (CR9R10) WE; w is an integer from 0 to 4; R10 is selected from H, alkyl of 1 to 4 carbon atoms-hydroxyl, alkyl of 1 to 4 carbon atoms-aryl, and alkyl of 1 to 4 carbon atoms-heteroaryl, wherein this aryl or heteroaryl group is unsubstituted or substituted with 1 to 3 groups independently selected from halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 atoms carbon, haloalkyl, haloalkoxy, OH, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms-carbonyl, CN, NH2, NR6R7, SR6, S (0) R6, S02R6, S03R6, S02NR6, C02H , C02R6, and CONR6R7; E is selected from H, halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl, haloalkoxy, OH, OR6, CN, CHO, C02R6, CONR6R7, OCOR6, OC (= 0) OR6, OC (= 0) NR6R7, OCH2C02R6, C (= 0) R6, NH2, NHR6, NR6R7, NR7C (= 0) R6, NR7C (= 0) OR6, N R7C (= 0) C (= 0) OR R6, NR7C (= 0) C (= 0) NR6R7, N R7C (= O) C (= 0) (a Iq u 1 to 6 carbon atoms), NR7C (= NCN) OR6, N R7C (= 0) N R6R7, NR7C (= NCN) NR6R7, N R7C (= NR6) N R7R8, NR6S02NR6R7, NR7S02R6, SR6, S (= 0) R6, S02R6, S03R7, S02NR6R7, NHOH, NHOR6; NR6NR7NR8, N (COR6) OH, N (C02R6) OH, CONR7 (CR9R10) rR6, CO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10) rR6, CO (CR9R10) pO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10) rOR6, CO (CR9R10) pO (CR9R10) qR6, CO (CR6R10) rNR6R7, OC (O) O (CR9R10) mNR6R7, O (CO) n (CR9R10) R6, O (CR9R10) mNR6R7, N R7C (O) (C R9R 1) rO R6, NR7C (= NC) (CR9R10) rR6, NR7CO (CR9R10) rNR6R7, NR7 (CR9R10) mOR6, NR7 (CR9R10) rCO2R6, N R7 (C R9R 1) m N R6R7, NR7, NR3 (CR9R10) nSO2 (CR9R10) rCO2R6, N R7 (C R9R 1) m N R6R7, NR7 (CR9R10) nSO2 (CR9R10) qR6, CONR7 (CR9R10) nSO2 (CR9R1 °) qR6, SO2NR7 (CR9R10 ) qR6, SO2NR6 (CR9R10) mOR6, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms-methyl, aryl, heterocyclic optionally substituted with 1 or 2 alkyl groups, heteroaryl optionally substituted with 1 or 2 alkyl groups, and alkylaryl, wherein the aryl groups are unsubstituted or substituted with 1 or 2 substituents, each independently selected from R 12, or two E groups, which substitute the adjacent atoms on D, and together they form alkylenedioxyl, thioalkyleneoxy or alkylenedithioxyl; m is an integer that has a value of 2 to 6; p is an integer that has a value of 1 to 3; q is an integer that has a value from 0 to 3; r is an integer that has a value from 0 to 6; R12, in each presentation, is independently selected from halogen, No2, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms carbon, haloalkyl, haloalkoxy, OH, oxo, alkoxy of 1 to 4 carbon atoms, OR6, O (CR9R10) CO2R6, O (CR9R10) mNR6R7, O (CR9R10) pCN, O (C R9 R1 °) rC (= 0 ) N R6 R7, C 1 -C 4 alkyl, CN, NH 2, NHR 6, NR 6 R 7, NR 7 (CR 9 R 10) CO2 R 6, NR 7 OR 6, N R 7 (CR 9 R 1) m O R 6, N R 7 CH ((CR 9 R 10) p OR 6) 2 , N R7C ((C R9R1 °) pO R6) 3, NR7C (= 0) R6, NR7 (CR9R10) mNR6R7, N R7 (C R9R1 °) q R6, SR7, S (0) R7, S02R7, S02NR6, S03R7 , C02H, C02R6, and CONR6R7; R 4 is hydrogen, lower alkyl, and lower cycloalkyl; R5 is hydrogen, lower alkyl, and lower cycloalkyl; R6, R7, and R8 are independently selected as follows: i) R6, R7, and R8 are independently selected from H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-carbonyl, cycloalkyl of 3 to 7 carbon atoms- (alkyl of 0 to 5 carbon atoms) -carbonyl, alkoxy of 1 to 6 carbon atoms-carbonyl, aryl- (alkyl of 0 to 5 carbon atoms) - carbonyl, aryl- (alkoxy of 1 to 5 carbon atoms) - carbonyl, heterocyclic- (alkyl of 0 to 5 carbon atoms) -carbonyl, heterocyclic- (alkoxy of 1 to 5 carbon atoms) -carbonyl, alkyl of 1 to 6 carbon atoms-sulfonyl, aryl-sulfonyl, heteroaryl-sulfonyl, alkyl of 0 to 4 carbon atoms-aryl, alkyl of 0 to 4 carbon atoms-heterocyclic, wherein the cycloalkyl, aryl, or heterocyclic groups are unsubstituted or substituted with 1 or 2 substituted and each independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, hydroxyl, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, haloalkyl, N02, and CN; or ii) R6 and R7, or R6 and R8, or R7 and R8, when both substituents are on the same nitrogen atom (as in (-NR6R7) or (NR7R8)), can be taken together with the nitrogen atom with which are bound, to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-pi peridinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, 1-piperazinyl, 1-imidazolyl, 3-azabicyclo- (3,2,2) -nonan-3-yl, and 1-tetrazolyl, this heterocycle being optionally substituted with 1 to 3 groups, each independently selected from oxo, alkyl of 0 to 4 carbon atoms-OH, alkyl of 0 to 4 carbon atoms-O-alkyl of 1 to 4 carbon atoms, alkyl of 0 to 4 carbon atoms-CONH2, alkyl of 0 to 4 carbon atoms-C02-alkyio of 0 to 4 carbon atoms , alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkyl of 0 to 6 carbon atoms-carbonyl, cyclo alkyl of 3 to 7 carbon atoms-carbonyl, alkoxy of 1 to 6 carbon atoms-carbonyl, cycloalkoxy of 3 to 7 carbon atoms, -NHCO-alkyl, aryl, heteroaryl, aryl-alkoxy-carbonyl, heteroaryl -alkoxycarbonyl, alkyl of 1 to 6 carbon atoms-sulfonyl, aryl-sulfonyl, and heteroaryl-sulfonyl; R9 is hydrogen or alkyl of 1 to 4 carbon atoms; and R13 is hydrogen, alkyl, haloalkyl, aminocarbonyl, hydroxyl, hydroxycarbonyl, alkoxycarbonyl, cycloalkyl-aminocarbonyl, substituted alkyl, aryl, substituted aryl, heteroaryl, heterocyclyl, thioalkyl, alkyl-amino-carbonyl, or lower cycloalkyl; wherein the substituents on the alkyl group are selected from 1 to 4 substituents selected from halogen, hydroxyl, alkoxy, oxo (= 0), alkanoyl, aryloxy, alkanoyloxy, amino, alkyl-amino, arylamino, aralkylamino, disubstituted amines, wherein the two amino substituents are selected from alkyl, aryl, or aralkyl; alkanoyl-amino, aroyl-amino, aralkanoyl-amino, substituted alkanoyl-amino, substituted aryl-amino, substituted aralkanoyl-amino, thiol, thioalkyl, thioaryl, thioaralkyl, thionoalkyl, thionoaryl, thionoaralkyl, alkyl-sulfonyl, aryl-sulfonyl, aralkyl sulfonyl, sulfonamido, for example S02NH2, substituted sulfonamido, nitro, cyano, carboxyl, carbamyl, for example CONH2, substituted carbamyl, for example CONH-alkyl, CONH-aryl, CON H-aralkyl, or the cases where there are two substituents on nitrogen selected from alkyl, aryl, or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino, and substituted or unsubstituted heterocycles, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, and the like, and substituents on the aryl group are selected from from 1 to 4 substituents selected from alkyl, substituted aryl, haloalkyl, halogen, trifluoromethoxyl, trifluoromethyl, hydroxy, hydroxy-alkyl, amino-alkyl, alkoxy, alkanoyl, alkanoyloxy, amino, arylamino, aralkyl- amino, dialkylamino, alkanoylamino, thiol, thioalkyl, ureido, nitro, cyano, cyanoalkyl, heterocyclyl, carboxyl, carboxy-alkyl, carbamyl, alkoxy-carbonyl, amino-carbonyl, thionoalkyl, thionoaryl, aryl- sulfonyl-amine, sulphonic acid, alkylsulfonyl, sulfonamido, aryloxy, and CONRaRb, wherein Ra and Rb are selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy-carbonyl-amine, and alkylamino; , and alkylamino; or Ra and Rb, together with the nitrogen with which they are substituted, form a heterocyclic or heteroaryl ring of 3 to 6 members. The substituent may be further substituted by hydroxyl, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl, or aralkyl. 77. The method of claim 76, wherein the disease or disorder is selected from edema, analgesia, fever, pain, neuromuscular pain, headache, pain caused by cancer, dental pain, and arthritic pain. 78. The method for inhibiting the activity of p38 kinase, which comprises administering to a patient in need, an effective amount of a compound of formula I: I or pharmaceutically acceptable derivatives thereof, wherein: R is hydrogen, halogen, alkyl, cycloalkyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, pseudo-halogen, -NR4R5, or -OR4; R2, in each presentation, is independently selected from alkyl, substituted alkyl, lower cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, -OR4, -CN, -NR4R5, -S (= 0) alkyl, -S ( = O) -ari lo, -NHS02-aryieno-R4, -NH S02-alkyl, -C02R4, -CONH3, -S03H, -S (0) -alkyl, -S (0) -aryl, -S02NHR4, and - N HC (= 0) NH R4; n is 0, 1, or 2; R3 is selected from hydrogen, alkyl, -OR4, substituted alkyl, cycloalkyl, -CR4-cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; Y is an individual bond, -C (= 0) NH-, -NH (C = 0) -, -NH (C = 0) NH-, -S02NH-, -NHS02-, or -C (= 0) -; X1 is an individual bond, alkylene, -O-, -S-, -S (O) -, -S02-, -C (O) -, -CO (O) - or -C (0) NH-; A is a bicyclic heterocyclic ring system with at least one heteroatom in each ring, wherein the heteroatoms are each independently selected from N, O, and S, and is optionally substituted with up to two R13; X2 is an individual bond, alkylene, -O-, -S-, -NH-, -N (alkyl of 1 to 4 carbon atoms) -, -N H-alkylene of 1 to 4 carbon atoms-, -N (alkyl of 1 to 4 carbon atoms) -alkylene of 1 to 4 carbon atoms, -S (O) -, -S02-, -C (O) -, -CO (O) -, or -C (0 ) NH-; D is a monocyclic or bicyclic aromatic or non-aromatic ring system optionally containing up to four heteroatoms selected from N, O, and S, and wherein a CH2 adjacent to any of the N, O, or S heteroatoms is optionally substituted with oxo (= 0), or D is alkyl of 1 to 6 carbon atoms, wherein D is optionally substituted by one to four groups (CR9R0) WE; w is an integer from 0 to 4; R10 is selected from H, alkyl of 1 to 4 carbon atoms-hydroxyl, alkyl of 1 to 4 carbon atoms-aryl, and alkyl of 1 to 4 carbon atoms-heteroaryl, wherein this aryl or heteroaryl group is unsubstituted or substituted with 1 to 3 groups independently selected from halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 atoms carbon, haloalkyl, haloalkoxy, OH, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms-carbonyl, CN, NH2, NR6R7, SR6, S (0) R6, S02R6, S03R6, S02NR6, C02H , C02R6, and CONR6R7; E is selected from H, halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl, haloalkoxy, OH, OR6, CN, CHO, C02R6, CONR6R7, OCOR6, OC (= 0) OR6, OC (= 0) NR6R7, OCH2C02R6, C (= 0) R6, NH2, NHR6, NR6R7, NR7C (= 0) R6, NR7C (= 0) OR6, N R7C (= O) C (= 0) OR R6, NR7C (= 0) C (= 0) NR6R7, N R7C (= O) C (= O) (alq u I or from 1 to 6 carbon atoms), NR7C (= NCN) OR6, N R7C (= 0) N R6R7, NR7C (= NCN) NR6R7, N R7C (= NR6) N R7R8, NR6S02NR6R7, NR7S02R6, SR6, S (= 0) R6, S02R6, S03R7, S02NR6R7, NHOH, NHOR6, NR6NR7NR8, N (COR6) OH, N (C02R6) OH, CONR7 (CR9R10) rR6, CO (CR9R0) pO (CHR9) qCO2R6, CO ( CR9R10) rR6, CO (CR9R10) pO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10) rOR6, CO (CR9R10) pO (CR9R10) qR6, CO (CR6R10) rNR6R7, OC (O) O (CR9R10) mNR6R7, O (CO) n (CR9R10) R6, O (CR9R10) mNR6R7, N R7C (O) (C R9R 1 °) rO R6, NR7C (= NC) (CR9R10) rR6, NR7CO (CR9R10) rNR6R7, NR7 (CR9R10) mOR6, NR7 (CR9R10) rCO2R6, N R7 (CR9R 1) m N R6R7, NR7, NR3 (CR9R10) nSO2 (CR9R10) rCO2R6, N R7 (C R9R 1) m N R6R7, NR7 (CR9R10) nSO2 (CR9R10) qR6, CONR7 (CR9R10) nSO2 (CR9R10) qR6, SO2NR7 (CR9R10) qR6, SO2NR6 (CR9R10) mOR6, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms-methyl, aryl, heterocyclic optionally substituted with 1 or 2 alkyl groups, heteroaryl optionally substituted with 1 or 2 alkyl groups, and alkylaryl, wherein the aryl groups are unsubstituted or substituted with 1 or 2 substituents, each independently selected from R12, or two groups E, which substitute the adjacent atoms on D, and which together form alkylenedioxyl, thioalkyleneoxy or alkylenedithioxyl; m is an integer that has a value of 2 to 6; p is an integer that has a value of 1 to 3; q is an integer that has a value from 0 to 3; r is an integer that has a value from 0 to 6; R, in each presentation, is independently selected from halogen, No2, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms carbon, haloalkyl, haloalkoxy, OH, oxo, alkoxy of 1 to 4 carbon atoms, OR6, O (CR9R10) CO2R6, O (CR9R10) mNR6R7, O (CR9R10) pCN, O (C R9 R1 °) rC (= 0 ) N R6 R7, C 1 -C 4 alkyl, CN, NH 2, NHR 6, NR 6 R 7, NR 7 (CR 9 R 10) CO2 R 6, NR 7 OR 6, N R 7 (CR 9 R 1) m O R 6, N R 7 CH ((CR 9 R 10) POR 6) 2, N R7C ((C R9R 1 °) pO R6) 3, NR7C (= 0) R6, NR7 (CR9R10) mNR6R7, N R7 (C R9R1 °) qR6, SR7, S (0) R7, S02R7, S02NR6, S03R7, C02H, C02R6, and CONR6R7; R 4 is hydrogen, lower alkyl, and lower cycloalkyl; R5 is hydrogen, lower alkyl, and lower cycloalkyl; R6, R7, and R8 are independently selected as follows: R1 R7, are independently selected from H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-carbonyl, cycloalkyl of 3 to 7 carbon atoms- (alkyl of 0 to 5 carbon atoms) -carbonyl, alkoxy of 1 to 6 carbon atoms-carbonyl, aryl- (alkyl of 0 to 5) carbon atoms) -carbonyl, aryl- (alkoxy of 1 to 5 carbon atoms) -carbonyl, heterocyclic- (alkyl of 0 to 5 carbon atoms) -carbonyl, heterocyclic- (alkoxy of 1 to 5 carbon atoms) - carbonyl, alkyl of 1 to 6 carbon atoms-sulfonyl, aryl-sulfonyl, heteroaryl-sulfonyl, alkyl of 0 to 4 carbon atoms-aryl, alkyl of 0 to 4 carbon atoms-heterocyclic, wherein the cycloalkyl, aryl groups , or heterocyclic are unsubstituted or substituted with 1 or 2 substituents, each independently selected from the group that it consists of alkyl of 1 to 4 carbon atoms, hydroxyl, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, haloalkyl, N02, and CN; or i) R6 and R7, or R6 and R8, or R7 and R8, when both substituents are on the same nitrogen atom (as in (-NR6R7) or (NR7R8)), can be taken together with the nitrogen atom with which they are attached, to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, 1-piperazinyl, 1-imidazolyl, 3-azabicyclo- (3,2,2) -nonan-3-yl, and 1-tetrazolyl, this heterocycle being optionally substituted with 1 to 3 groups, each independently selected from oxo, alkyl of 0 to 4 carbon atoms-OH, alkyl of 0 to 4 carbon atoms-O-alkyl of 1 to 4 carbon atoms, alkyl of 0 to 4 carbon atoms-CO N H2, alkyl of 0 to 4 carbon atoms-CO 2 -alkyl 0 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkyl of 0 to 6 carbon atoms-carbonyl, C3-C7-C3-C3-C3alkyl, C1-C6alkoxycarbonyl, C3-C7-cycloalkoxycarbonyl, -NHCO-alkyl, aryl, heteroaryl, aryl-alkoxycarbonyl, heteroaryl -alkoxycarbonyl, alkyl of 1 to 6 carbon atoms-sulfonyl, aryl-sulfonyl, and heteroaryl-sulfonyl; R9 is hydrogen or alkyl of 1 to 4 carbon atoms; and 13 is hydrogen, alkyl, haloalkyl, aminocarbonyl, hydroxyl, hydroxycarbonyl, alkoxycarbonyl, cycloalkyl-alkylaminocarbonyl, substituted alkyl, aryl, substituted aryl, heteroaryl, heterocyclyl, thioalkyl, alkyl-amino-carbonyl , or lower cycloalkyl; wherein the substituents on the alkyl group are selected from 1 to 4 substituents selected from halogen, hydroxyl, alkoxy, oxo (= 0), alkanoyl, aryloxy, alkanoyloxy, amino, alkyl-amino, arylamino, aralkyl -amino, disubstituted amines, wherein the two amino substituents are selected from alkyl, aryl, or aralkyl; alkanoyl-amino, aroyl-amino, aralkanoyl-amino, substituted alkanoyl-amino, substituted aryl-amino, substituted aralkanoyl-amino, thiol, thioalkyl, thioaryl, thioaralkyl, thionoalkyl, thionoaryl, thionoaralkyl, alkyl-su Ifonyl, aryl- sulfonyl, aralkyl sulfonyl, sulfonamido, for example S02NH2, substituted sulfonamido, nitro, cyano, carboxyl, carbamyl, for example CONH2, substituted carbamyl, for example CONH-alkyl, CONH-aryl, CON H-aralkyl, or the cases in which there are two substituents on the nitrogen selected from alkyl, aryl, or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino, and substituted or unsubstituted heterocycles, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, and the like, and substituents on the aryl group are selected from from 1 to 4 substituents selected from alkyl, substituted aryl, haloalkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, hydroxy-alkyl, amino-alkylamino, alkoxy, alkanoyl, alkanoyloxy, amino, arylamino, aralkylamino, dialkylamino, alkanoylamino, thiol, thioalkyl, ureido, nitro, cyano, cyano-alkyl, heterocyclyl, carboxyl, carboxy-alkyl, carbamyl, alkoxy-carbonyl, amino-carbonyl, thionoalkyl, thionoaryl, aryl-sulfonyl-amine, sulfonic acid, alkylsulfonyl, sulfonamido, aryloxy , and CONRaRb, wherein Ra and Rb are selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy-carbonyl-amino-alkyl, and alkylamino; or Ra and Rb, together with the nitrogen with which they are substituted, form a heterocyclic or heteroaryl ring of 3 to 6 members. The substituent may be further substituted by hydroxyl, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl, or aralkyl. 79. The method of claim 78, wherein the p38 kinase is selected from p38a kinase, p38β kinase, p38? Kinase and p38d kinase. 80. The method of claim 78 or 79, wherein the p38 kinase is selected from p38a kinase and p38β kinase. 81. The method of claim 55, wherein the disease or disorder is selected from pancreatitis, asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, thyroiditis chronic, Graves 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, and graft against the host, inflammatory reaction induced by endotoxin, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter syndrome, gout, traumatic arthritis, rubela arthritis, acute synovitis, pancreatic β-cell disease; diseases characterized by massive infiltration of neutrophils; rheumatoid spondylitis, gouty arthritis, and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, graft rejection, fever and myalgias due to infection, cachexia secondary to infection, myeloid formation, formation of scar tissue, ulcerative colitis, pyresis, influenza, osteoporosis, osteoarthritis and bone disorder related to multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson's disease, cerebral ischemia, or neurodegenerative disease caused by traumatic injury; angiogenic disorders, solid tumors, ocular neovasculization, infantile hemangiomas; viral diseases, acute hepatitis infection, hepatitis A, hepatitis B, hepatitis C, HIV infection, CMV retinitis, AIDS, SARS, ARC, malignancy, herpes, embolism, myocardial ischemia, ischemia in heart attacks due to embolism, hypoxia organs, vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, platelet accumulation induced by thrombin, endotoxemia and / or toxic shock syndrome, and conditions associated with prostaglandin-2 endoperoxide synthase. 82. A method for inhibiting the activity of a protein kinase, which comprises contacting the protein with a compound of the formula I: I or pharmaceutically acceptable derivatives thereof, wherein: R1 is hydrogen, halogen, alkyl, cycloalkyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, pseudo-halogen, -NR4R5, or -OR4; R2, in each presentation, is independently selected from alkyl, substituted alkyl, lower cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, -OR4, -CN, -NR R5, -S (= 0) alkyl, -S (= 0) -aryl, -NHS02-arylene-R4, -NH S02-alkyl, -C02R4, -CONH3, -S03H, -S (0) -alkyl, -S (0) -aryl, -S02NHR4, and -NHC (= 0) NH R4; n is 0, 1, or 2; R3 is selected from hydrogen, alkyl, -OR4, substituted alkyl, cycloalkyl, -CR4-cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; Y is an individual bond, -C (= 0) NH-, -NH (C = 0) -, -NH (C = 0) NH-, -S02NH-, -NHS02-, or -C (= 0) -; X1 is an individual bond, alkylene, -O-, -S-, -S (O) -, -S02-, -C (O) -, -CO (O) - or -C (0) NH-; A is a bicyclic heterocyclic ring system with at least one heteroatom in each ring, wherein the hetero-atoms are each independently selected from N, O, and S, and is optionally substituted with up to two R13; X2 is an individual bond: alkylene, -O-, -S-, -NH-, -N (alkyl of 1 to 4 carbon atoms) -, -NH-alkylene of 1 to 4 carbon atoms-, -N ( alkyl of 1 to 4 carbon atoms) -alkylene of 1 to 4 carbon atoms, -S (O) -, -S02-, -C (O) -, -CO (O) -, or -C (0) NH-; D is a monocyclic or bicyclic aromatic or non-aromatic ring system optionally containing up to four heteroatoms selected from N, O, and S, and wherein a CH2 adjacent to any of the N, O, or S heteroatoms is optionally substituted with oxo (= 0), or D is alkyl of 1 to 6 carbon atoms, wherein D is optionally substituted by one to four groups (CR9R10) WE; w is an integer from 0 to 4; R10 is selected from H, alkyl of 1 to 4 carbon atoms-hydroxyl, alkyl of 1 to 4 carbon atoms-aryl, and alkyl of 1 to 4 carbon atoms-heteroaryl, wherein this aryl or heteroaryl group is unsubstituted or substituted with 1 to 3 groups independently selected from halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 atoms carbon, haloalkyl, haloalkoxy, OH, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms-carbonyl, CN, NH2, NR6R7, SR6, S (0) R6, S02R6, S03R6, S02NR6, C02H , C02R6, and CONR6R7; E is selected from H, halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl, haloalkoxy, OH, OR6, CN, CHO, C02R6, CONR6R7, OCOR6, OC (= 0) OR6, OC (= 0) NR6R7, OCH2C02R6, C (= 0) R6, NH2, NHR6, NR6R7, NR7C (= 0) R6, NR7C (= 0) OR6, N R7C (= 0) C (= 0) OR R6, NR7C (= 0) C (= 0) NR6R7, N R7C (= O) C (= O) (alq u il or from 1 to 6 carbon atoms), NR7C (= NCN) OR6, N R7C (= 0) N R6R7, NR7C (= NCN) NR6R7, N R7C (= NR6) N R7R8, NR6S02NR6R7, NR7S02R6, SR6, S (= 0) R6, S02R6, S03R7, S02NR6R7, NHOH, NHOR6, NR6NR7NR8, N (COR6) OH, N (C02R6) OH, CONR7 (CR9R10) rR6, CO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10) rR6, CO (CR9R10) pO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10) rOR6, CO (CR9R10) pO (CR9R0) qR6, CO (CR6R10) rNR6R7, OC (O) O (CR9R10) mNR6R7, O (CO) n (CR9R10) R6, O (CR9R10) mNR6R7, N R7C (O) (C R9R1 °) rO R6, NR7C (= NC) (CR9R10) rR6, NR7CO (CR9R10) rNR6R7, NR7 (CR9R10) mOR6, NR7 (CR9R 0) rCO2R6 , N R7 (CR9 R1) mN R6R7, NR7, NR3 (CR9R10) nSO2 (CR9R10) rCO2R6, N R7 (C R9 R1) mN R6R7, NR7 (CR9R10) nSO2 (CR9R10) qR6, CONR7 (CR9R10) nSO2 (CR9R10) qR6, SO2NR7 (CR9R10) qR6, SO2NR6 (CR9R10) mOR6, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms-methyl, aryl, heterocyclic optionally substituted with 1 or 2 alkyl groups, heteroaryl optionally substituted with 1 or 2 alkyl groups, and alkylaryl, wherein the aryl groups are unsubstituted or substituted with 1 or 2 substituents, each independently selected from R 12, or two E groups, which replace the adjacent atoms on D, and which together form alkylenedioxyl, thioalkyleneoxy or alkylenedithioxyl; m is an integer that has a value of 2 to 6; p is an integer that has a value of 1 to 3; q is an integer that has a value from 0 to 3; r is an integer that has a value from 0 to 6; R12, in each presentation, is independently selected from halogen, No2, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 atoms carbon, haloalkyl, haloalkoxy, OH, oxo, alkoxy of 1 to 4 carbon atoms, OR6, O (CR9R10) CO2R6, O (CR9R10) mNR6R7, O (CR9R10) pCN, O (C R9 R 1 °) rC ( = 0) N R 6 R 7, C 1 -C 4 alkyl, CN, NH 2, NHR 6, NR 6 R 7, N R 7 (CR 9 R 10) CO2 R 6, N R 7 OR 6, N R 7 (C R 9 R 1) m O R 6, N R 7 CH ((CR 9 R 10) p OR 6) 2, N R7C ((C R9R1 °) pO R6) 3, NR7C (= 0) R6, NR7 (CR9R10) mNR6R7, N R7 (C R9 R1 °) R6, SR7, S (0) R7, S02R7, S02NR6 , S03R7, C02H, C02R6, and CONR6R7; R 4 is hydrogen, lower alkyl, and lower cycloalkyl; R5 is hydrogen, lower alkyl, and lower cycloalkyl; R6, R7, and R8 are independently selected as follows: i) R6, R7, and R8 are independently selected from H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-carbonyl, cycloalkyl of 3 to 7 carbon atoms- (alkyl of 0 to 5 carbon atoms) -carbonyl, alkoxy 1 to 6 carbon atoms -carbonyl, aryl- (alkyl of 0 to 5 carbon atoms) -carbonyl, aryl- (alkoxy of 1 to 5 carbon atoms) -carbonyl, heterocyclic- (alkyl of 0 to 5 carbon atoms) ) -carbonyl, heterocyclic- (alkoxy of 1 to 5 carbon atoms) -carbonyl, alkyl of 1 to 6 carbon atoms-sulfonyl, aryl-sulfonyl, heteroaryl-sulfonyl, alkyl of 0 to 4 carbon atoms-aryl, alkyl from 0 to 4 carbon atoms-heterocyclic, wherein the cycloalkyl, aryl, or heterocyclic groups are unsubstituted or substituted with 1 or 2 substituted and each independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, hydroxyl, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, haloalkyl, N02, and CN; or i) R6 and R7, or R6 and R8, or R7 and R8, when both substituents are on the same nitrogen atom (as in (-NR6R7) or (NR7R8)), can be taken together with the nitrogen atom with which they are attached, to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, f-aiazolidinyl, 1-piperazinyl, 1-imidazolyl, 3-azabicyclo - (3,2,2) -nonan-3-yl, and 1-tetrazolyl ilo, this heterocycle being optionally substituted with 1 to 3 groups, each independently selected from oxo, alkyl of 0 to 4 carbon atoms- OH, alkyl of 0 to 4 carbon atoms-O-alkyl of 1 to 4 carbon atoms, alkyl of 0 to 4 carbon atoms-CON H2, alkyl of 0 to 4 carbon atoms-C02-alkyio of 0 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkyl of 0 to 6 carbon atoms-carbonyl, loalkyl of 3 to 7 carbon atoms-carbonyl, alkoxy of 1 to 6 carbon atoms-carbonyl, cycloalkoxy of 3 to 7 carbon atoms-carbonyl, -NHCO-alkyl, aryl, heteroaryl, aryl-alkoxy-carbonyl, heteroaryl- alkoxycarbonyl, alkyl of 1 to 6 carbon atoms-sulfonyl, aryl-sulfonyl, and heteroaryl-sulfonyl; R9 is hydrogen or alkyl of 1 to 4 carbon atoms; and R13 is hydrogen, alkyl, haloalkyl, aminocarbonyl, hydroxyl, hydroxycarbonyl, alkoxycarbonyl, cycloalkyl-aminocarbonyl, substituted alkyl, aryl, substituted aryl, heteroaryl, heterocyclyl, thioalkyl, alkyl-amino-carbonyl, or lower cycloalkyl; wherein the substituents on the alkyl group are selected from 1 to 4 substituents selected from halogen, hydroxyl, alkoxy, oxo (= 0), alkanoyl, aryloxy, alkanoyloxy, amino, alkyl-amine, arylamino , aralkylamino, disubstituted amines, wherein the two amino substituents are selected from alkyl, aryl, or aralkyl; alkanoyl-amino, aroyl-amino, aralkanoyl-amino, substituted alkanoyl-amino, substituted aryl-amino, substituted aralkanoyl-amino, thiol, thioalkyl, thioaryl, thioaralkyl, thionoalkyl, thionoaryl, thionoaralkyl, alkyl-sulfonyl, aryl-sulfonyl, aralkyl sulfonyl, sulfonamido, for example S02NH2, substituted sulfonamido, nitro, cyano, carboxyl, carbamyl, for example CONH2, substituted carbamyl, for example CONH-alkyl, CONH-aryl, CON H-aralkyl, or the cases where there are two substituents on the nitrogen selected from alkyl, aryl, or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino, and substituted or unsubstituted heterocycles, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, and the like, and substituents on the aryl group are selected from from 1 to 4 substituents selected from alkyl, substituted aryl, haloalkyl, halogen, trifluoromethoxyl, trifluoromethyl, hydroxyl, hydroxy-alkyl, amino-alkyl, alkoxy, alkanoyl, alkanoyloxy, amino, arylamino, aralkylamino, dialkyl amino, alkanoylamino, thiol, thioalkyl, ureido, nitro, cyano, cyanoalkyl, heterocyclyl, carboxyl, carboxy-alkyl, carbamyl, alkoxycarbonyl, aminocarbonyl, thionoalkyl, thionoaryl, arylsulfonyl-amine , sulfonic acid, alkylsulfonyl, sulfonamido, aryloxyl, and CONRaR, wherein Ra and Rb are selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxycarbonyl-ammonium, and alkylamino; or Ra and Rb, together with the nitrogen with which they are substituted, form a heterocyclic or heteroaryl ring of 3 to 6 members. The substituent may be further substituted by hydroxyl, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl, or aralkyl. 83. A method for treating, preventing, or decreasing one or more symptoms of a disease characterized by dysregulation of the activity of a protein kinase, which comprises administering a compound of the formula I: or pharmaceutically acceptable derivatives thereof, wherein: R is hydrogen, halogen, alkyl, cycloalkyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, pseudo-halogen, -NR R5, or -OR4; R2, in each presentation, is independently selected from alkyl, substituted alkyl, lower cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, -OR4, -CN, -NR4R6, -S (= 0) alkyl, -S ( = 0) -ari lo, -NHS02-arylene-R4, -NH S02-alkyl, -C02R4, -CONH3, -S03H, -S (0) -aikyl, -S (0) -aryl, -S02NHR4, and -NHC (= 0) NH R4; n is 0, 1, or 2; R3 is selected from hydrogen, alkyl, -OR4, substituted alkyl, cycloalkyl, -CR4-cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and heterocycle; Y is an individual bond, -C (= 0) NH-, -NH (C = 0) -, -NH (C = 0) NH-, -S02NH-, -NHS02-, or -C (= 0) -; X1 is an individual bond, alkylene, -O-, -S-, -S (O) -, -S02-, -C (O) -, -CO (O) - or -C (0) NH-; A is a bicyclic heterocyclic ring system with at least one heteroatom in each ring, wherein the heteroatoms are each independently selected from N, O, and S, and is optionally substituted with up to two R13; X2 is an individual bond, alkylene, -O-, -S-, -NH-, -N (alkyl of 1 to 4 carbon atoms) -, -NH-alkylene of 1 to 4 carbon atoms-, -N (alkyl of 1 to 4 carbon atoms) -alkylene of 1 to 4 carbon atoms, -S (O) -, -S02-, -C (O) -, -CO (O) -, or -C (0 ) NH-; D is a monocyclic or bicyclic aromatic or non-aromatic ring system optionally containing up to four heteroatoms selected from N, O, and S, and wherein a CH2 adjacent to any of the N, O, or S heteroatoms is optionally substituted with oxo (= 0), or D is alkyl of 1 to 6 carbon atoms, wherein D is optionally substituted by one to four groups (CR9R10) WE; w is an integer from 0 to 4; R10 is selected from H, alkyl of 1 to 4 carbon atoms-hydroxyl, alkyl of 1 to 4 carbon atoms-aryl, and alkyl of 1 to 4 carbon atoms-heteroaryl, wherein this aryl or heteroaryl group is unsubstituted or substituted with 1 to 3 groups independently selected from halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 atoms carbon, haloalkyl, haloalkoxy, OH, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms-carbonyl, CN, NH2, NR6R7, SR6, S (0) R6, S02R6, S03R6, S02NR6, C02H , C02R6, and CONR6R7; E is selected from H, halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl, haloalkoxy, OH, OR6, CN, CHO, C02R6, CONR6R7, OCOR6, OC (= 0) OR6, OC (= 0) NR6R7, OCH2C02R6, C (= 0) R6, NH2, NHR6, NR6R7, NR7C (= 0) R6, NR7C (= 0) 0R6, N R7C (= 0) C (= 0) OR R6, NR7C (= 0) C (= 0) NR6R7, N R7C (= O) C (= 0) (at which ilo from 1 to 6 carbon atoms), NR7C (= NCN) OR6, NR7C (= 0) N R6R7, NR7C (= NCN) NR6R7, N R7C (= NR6) N R7R8, NR6S02NR6R7, NR7S02R6, SR6, S (= 0) R6, S02R6, S03R7, S02NR6R7, NHOH, NHOR6, NR6NR7NR8, N (COR6) OH, N (C02R6) OH, CONR7 (CR9R10) rR6, CO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10) rR6, CO (CR9R10) pO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10) rOR6, CO (CR9R10) pO (CR9R10) qR6, CO (CR6R10) rNR6R7, OC (O) O (CR9R10) mNR6R7, O (CO) n (CR9R10) R6, O (CR9R10) mNR6R7, N R7C (O) (C R9R1 °) rO R6, NR7C (= NC) (CR9R10) rR6, NR7CO (CR9R10) rNR6R7, NR7 (CR9R10) mOR6, NR7 (CR9R10 ) rCO2R6, N R7 (C R9 R °) mN R6 R7, NR7, NR3 (CR9R10) nSO2 (CR9R10) rCO2R6, N R7 (C R9 R1) mN R6R7, NR7 (CR9R10) nSO2 (CR9R10) qR6, CONR7 (CR9R10) nSO2 (CR9R10) qR6, SO2NR7 (CR9R10) qR6, SO2NR6 (CR9R10) mOR6, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms-methyl, aryl, heterocyclic optionally substituted with 1 or 2 alkyl, heteroaryl groups optionally substituted with 1 or 2 alkyl groups, and alkylaryl, wherein the aryl groups are unsubstituted or substituted with 1 or 2 substituents, each independently selected from R12, or two E groups, which replace the adjacent atoms on D, and that together form alkylenedioxyl, thioalkyleneoxy or alkylenedithioxyl; m is an integer that has a value of 2 to 6; p is an integer that has a value of 1 to 3; q is an integer that has a value from 0 to 3; r is an integer that has a value from 0 to 6; R12, in each presentation, is independently selected from halogen, No2, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms carbon, haloalkyl, haloalkoxy, OH, oxo, alkoxy of 1 to 4 carbon atoms, OR6, O (CR9R10) CO2R6, O (CR9R10) mNR6R7, O (CR9R10) pCN, O (C R9 R1 °) rC (= 0 ) N R6R7, C 1 -C 4 alkyl, CN, NH 2, NHR 6, NR 6 R 7, NR 7 (CR 9 R 10) CO2 R 6, NR 7 OR 6, N R 7 (CR 9 R 1) m O R 6, N R 7 CH ((CR 9 R 10) POR 6) 2, N R7C ((CR9R1 °) pO R6) 3, NR7C (= 0) R6, NR7 (CR9R10) mNR6R7, N R7 (C R9 R1 °) R6, SR7, S (0) R7, S02R7, S02NR6, S03R7, C02H , C02R6, and CONR6R7; R 4 is hydrogen, lower alkyl, and lower cycloalkyl; R5 is hydrogen, lower alkyl, and lower cycloalkyl; R7, and R8 are independently selected as follows: i) R6, R7, and R8 are independently selected from H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 atoms of carbon, alkynyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-carbonyl, cycloalkyl of 3 to 7 carbon atoms- (alkyl of 0 to 5 carbon atoms) -carbonyl, alkoxy of 1 to 6 carbon-carbonyl atoms, aryl I - (a C uyl of 0 to 5 carbon atoms) -carbonyl, aryl- (C 1-5 alkoxy) - carbonyl, heterocyclic- (alkyl of 0 to 5 carbon atoms) carbon) - carbonyl, heterocyclic- (alkoxy of 1 to 5 carbon atoms) - carbonyl, alkyl of 1 to 6 carbon atoms - sulfonyl, aryl-sulfonyl, heteroaryl-sulfonyl, alkyl of 0 to 4 carbon atoms - aryl, alkyl of 0 to 4 carbon atoms-heterocyclic, wherein the cycloalkyl, aryl, or heterocyclic groups are unsubstituted or substituted with 1 or 2 s substituents, each independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, hydroxyl, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, haloalkyl, N02, and CN; or ii) R6 and R7, or R6 and R8, or R7 and R8, when both substituents are on the same nitrogen atom (as in (-NR6R7) or (NR7R8)), can be taken together with the nitrogen atom with which are attached, to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, 1-piperazinyl, 1-imidazolyl, 3-azabicyclo- ( 3,2,2) -nonan-3-yl, and 1-tetrazolyl ilo, this heterocycle being optionally substituted with 1 to 3 groups, each independently selected from oxo, alkyl of 0 to 4 carbon atoms-OH, alkyl of 0 to 4 carbon atoms-O-alkyl of 1 to 4 carbon atoms, alkyl of 0 to 4 carbon atoms-CONH2, alkyl of 0 to 4 carbon atoms-C02-alkyio of 0 to 4 carbon atoms , alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkyl of 0 to 6 carbon atoms, carbonyl alkyl of 3 to 7 carbon atoms-carbonyl, alkoxy of 1 to 6 carbon atoms-carbonyl, cycloalkoxy of 3 to 7 carbon atoms-carbonyl, -NHCO-alkyl, aryl, heteroaryl, aryl-alkoxycarbonyl, heteroaryl- alkoxycarbonyl, alkyl of 1 to 6 carbon atoms-sulfonyl, aryl-sulfonyl, and heteroaryl-sulfonyl; R9 is hydrogen or alkyl of 1 to 4 carbon atoms; and R13 is hydrogen, alkyl, haloalkyl, aminocarbonyl, hydroxyl, hydroxycarbonyl, alkoxycarbonyl, cycloalkyl-alkyl-aminocarbonyl, substituted alkyl, aryl, substituted aryl, heteroaryl, heterocyclyl, thioalkyl, alkyl-amino-carbonyl, or lower cycloalkyl; wherein the substituents on the alkyl group are selected from 1 to 4 substituents selected from halogen, hydroxyl, alkoxy, oxo (= 0), alkanoyl, aryloxy, alkanoyloxy, amino, alkyl-amino, arylamino, aralkyl -amino, disubstituted amines, wherein the two amino substituents are selected from alkyl, aryl, or aralkyl; alkanoyl-amino, aroyl-amino, aralkanoyl-amino, substituted alkanoyl-amino, substituted aryl-amino, substituted aralkanoyl-amino, thiol, thioalkyl, thioaryl, thioaralkyl, thionoalkyl, thionoaryl, thionoaralkyl, alkyl-sulfonyl, aryl-sulfonyl, aralkyl sulfonyl, sulfonamido, for example S02NH2, substituted sulfonamido, nitro, cyano, carboxyl, carbamyl, for example CONH2, substituted carbamyl, for example CONH-alkyl, CONH-aryl, CON H-aralkyl, or cases where there are two substituents on nitrogen selected from alkyl, aryl, or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino, and substituted or unsubstituted heterocycles, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, and the like, and the substituents on the aryl group are selected from 1 to 4 substituents selected from alkyl, substituted aryl, haloalkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, hydroxy-alkyl, amino-alkyl, alkoxy, alkanoyl, alkanoyloxy, amino, arylamino, aralkyl- amino, dialkylamino, alkanoylamino, thiol, thioalkyl, nitro, cyano, cyano-alkyl, heterocyclyl, carboxyl, carboxy-alkyl, carbamyl, alkoxy-carbonyl, amino-carbonyl, thionoalkyl, thionoaryl, aryl- sulfonyl-amine, sulfonic acid, alkylsulfonyl, sulfonamido, aryloxy, and CONRaRb, wherein Ra and Rb are selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy-carbonyl-amine-alkyl, and alkylamino; or Ra and Rb, together with the nitrogen with which they are substituted, form a heterocyclic or heteroaryl ring of 3 to 6 members. The substituent may be further substituted by hydroxyl, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl, or aralkyl. 84. The method of claim 82, wherein the protein kinase is a tyrosine protein kinase. 85. The method of claim 82, wherein the protein kinase is FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, flt-1, IGF-1R, KDR, PDGFR, tie-2, or VEGFR. 86. A method for treating, preventing or reducing one or more symptoms of disorders of blood vessel proliferation, fibrotic disorders, disorders of mesangial cell proliferation, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration or cancer, which comprises administering a compound of formula I: or pharmaceutically acceptable derivatives thereof, wherein: R 1 is hydrogen, halogen, alkyl, cycloalkyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, pseudo-halogen, -NR R 5, or -OR 4; in each presentation, it is independently selected from alkyl, substituted alkyl, lower cycloalkyl, halogen, trifluoro-meiyl, trifluoro-methoxy, -OR4, -CN, -NR4R5, -S (= 0) alkyl, -S (= 0 ) -aryl, -NHS02-aryieno-R4, -NHS02-alkyl, -C02R4, -CONH3, -S03H, -S (0) -alkyl, -S (0) -aryl, -S02NHR4, and -NHC (= 0 ) NH R4; n is 0, 1, or 2; R3 is selected from hydrogen, alkyl, -OR4, substituted alkyl, cycloalkyl, -CR4-cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; Y is an individual bond, -C (= 0) NH-, -NH (C = 0) -, -NH (C = 0) NH-, -S02NH-, -NHS02-, or -C (= 0) -; X1 is an individual bond, alkylene, -O-, -S-, -S (O) -, -S02-, -C (O) -, -CO (O) - or -C (0) NH-; A is a bicyclic heterocyclic ring system with at least one heteroatom in each ring, wherein the heteroatoms are each independently selected from N, O, and S, and is optionally substituted with up to two R13; X2 is an individual bond, alkylene, -O-, -S-, -NH-, -N (alkyl of 1 to 4 carbon atoms) -, -NH-alkylene of 1 to 4 carbon atoms-, -N ( alkyl of 1 to 4 carbon atoms) -alkylene of 1 to 4 carbon atoms, -S (O) -, -S02-, -C (O) -, -CO (O) -, or -C (0) NH-; D is a monocyclic or bicyclic aromatic or non-aromatic ring system optionally containing up to four heteroatoms selected from N, O, and S, and wherein a CH2 adjacent to any of the N, O, or S heteroatoms is optionally substituted with oxo (= 0), or D is alkyl of 1 to 6 carbon atoms, wherein D is optionally substituted by one to four groups (CR9R10) WE; w is an integer from 0 to 4; R10 is selected from H, alkyl of 1 to 4 carbon atoms-hydroxyl, alkyl of 1 to 4 carbon atoms-aryl, and alkyl of 1 to 4 carbon atoms-heteroaryl, wherein this aryl or heteroaryl group is unsubstituted or substituted with 1 to 3 groups independently selected from halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 atoms carbon, haloalkyl, haloalkoxy, OH, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms-carbonyl, CN, NH2, NR6R7, SR6, S (0) R6, S02R6, S03R6, S02NR6, C02H , C02R6, and CONR6R7; E is selected from H, halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl, haloalkoxy, OH, OR6, CN, CHO, C02R6, CONR6R7, OCOR6, OC (= 0) OR6, OC (= 0) NR6R7, OCH2C02R6, C (= 0) R6, NH2, NHR6, NR6R7, NR7C (= 0) R6, NR7C (= 0) OR6, N R7C (= O) C (= 0) OR R6, NR7C (= 0) C (= 0) NR6R7, N R7C (= O) C (= O) (at which ilo from 1 to 6 carbon atoms), N R7C (= NCN) OR6, N R7C (= 0) N R6R7, NR7C (= NCN) NR6R7, N R7C (= NR6) N R7R8, NR6S02NR6R7, NR7S02R6, SR6, S (= 0) R6, S02R6, S03R7, S02NR6R7, NHOH, NHOR6, NR6NR7NR8, N (COR6) OH, N (C02R6) OH, CONR7 (CR9R10) rR6, CO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10) rR6, CO (CR9R10) pO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10) rOR6, CO (CR9R10) pO (CR9R10) qR6, CO (CR6R10) rNR6R7, OC (O) O (CR9R10) mNR6R7, O ( CO) n (CR9R10) R6, O (CR9R10) mNR6R7, N R7C (O) (C R9R 1 °) rO R6, NR7C (= NC) (CR9R10) rR6, NR7CO (CR9R10) rNR6R7, NR7 (CR9R10) mOR6, NR7 (CR9R10) rCO 2R6, N R7 (CR9 R1) m N R6R7, NR7, NR3 (CR9R10) nSO2 (CR9R10) rCO2R6, N R7 (C R9 R1) mN R6R7, NR7 (CR9R10) nSO2 (CR9R10) qR6, CONR7 (CR9R10) nSO2 (CR9R10) qR6, SO2NR7 (CR9R10) qR6, SO2NR6 (CR9R0) mOR6, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms-methyl, aryl, heterocyclic optionally substituted with 1 or 2 alkyl groups, heteroaryl optionally substituted with 1 or 2 alkyl groups, and alkylaryl, wherein the aryl groups are unsubstituted or substituted with 1 or 2 substituents, each independently selected from R12, or two groups E, which substitute the adjacent atoms on D, and which together form alkylenedioxyl, thioalkyleneoxy or alkylenedithioxyl; m is an integer that has a value of 2 to 6; p is an integer that has a value of 1 to 3; q is an integer that has a value from 0 to 3; r is an integer that has a value from 0 to 6; 12 in each presentation, is independently selected from halogen, No2, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms , haloalkyl, haloalkoxy, OH, oxo, alkoxy of 1 to 4 carbon atoms, OR6, O (CR9R10) CO2R6, O (CR9R10) mNR6R7, O (CR9R10) pCN, O (C R9R1 °) rC (= 0) N R6R7, alkyl of 1 to 4 carbon atoms-carbonyl, CN, NH2, NHR6, NR6R7, NR7 (CR9R10) CO2R6, NR7OR6, NR7 (C R9 R1 °) mO R6, NR7CH ((CR9R10) POR6) 2, N R7C ((C R9R °) pO R6) 3, NR7C (= 0) R6, NR7 (CR9R10) mNR6R7, N R7 (C R9 R1 °) R6, SR7, S (0) R7, S02R7, S02NR6, S03R7, C02H, C02R6, and CONR6R7; R 4 is hydrogen, lower alkyl, and lower cycloalkyl; R5 is hydrogen, lower alkyl, and lower cycloalkyl; R6, R7, and R8 are independently selected as follows: i) R 'R7, and R' are independently selected from H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-carbonyl, cycloalkyl of 3 to 7 carbon atoms- (alkyl of 0 to 5 carbon atoms) -carbonyl, alkoxy 1 to 6 carbon atoms -carbonyl, aryl- (alkyl of 0 to 5 carbon atoms) -carbonyl, aryl- (alkoxy of 1 to 5 carbon atoms) -carbonyl, heterocyclic- (alkyl of 0 to 5 carbon atoms) ) - carbonyl, heterocyclic- (C 1 -C 5 alkoxy) -carbonyl, C 1-6 -alkyl sulfonyl, aryl-sulfonyl, heteroaryl-sulfonyl, C 0 -C 4 -alkyl, alkyl from 0 to 4 carbon atoms -heterocyclic, wherein the cycloalkyl, aryl, or heterocyclic groups are unsubstituted or substituted with 1 or 2 their Synonyms, each independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, hydroxyl, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, haloalkyl, N02, and CN; or ii) R6 and R7, or R6 and R8, or R7 and R8, when both substituents are on the same nitrogen atom (as in (-NR6R7) or (NR7R8)), can be taken together with the nitrogen atom with which are attached, to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, 1-piperazinyl, 1-imidazolyl, 3-azabicyclo- ( 3,2,2) -nonan-3-yl, and 1-tetrazolyl, this heterocycle optionally being substituted with 1 to 3 groups, each independently selected from oxo, 0 to 4 alkyl, OH-alkyl, alkyl 0 to 4 carbon-O-alkyl atoms from 1 to 4 carbon atoms, alkyl from 0 to 4 carbon atoms-CON H2, alkyl from 0 to 4 carbon atoms-C02-alkyl from 0 to 4 carbon atoms , alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkyl of 0 to 6 carbon-carbon atoms ilo, cycloalkyl of 3 to 7 carbon-carbonyl atoms, alkoxyl of 1 to 6 carbon-carbonyl atoms, cycloalkoxy of 3 to 7 carbon-carbonyl atoms, -NHCO-alkyl, aryl, heeroaryl, aryl-alkoxy-carbonyl, heeroaryl-alkoxycarbonyl, alkyl of 1 to 6 carbon-sulfonyl, aryl-sulfonyl, and heeroaryl-sulfonyl; R9 is hydrogen or alkyl of 1 to 4 carbon atoms; and R13 is hydrogen, alkyl, haloalkyl, aminocarbonyl, hydroxyl, hydroxycarbonyl, alkoxycarbonyl, cycloalkyl-amino-carbonyl, unsaturated alkyl, aryl, aryl, heteroaryl, heteroaryl, alkyl, alkyl-amino-carbonyl, or lower cycloalkyl; wherein the susíiuyeníes on the alkyl group are selected from 1 to 4 susíiuuyenf is selected from halogen, hydroxyl, alkoxyl, oxo (= 0), alkanoyl, aryloxy, alkanoyloxy, amino, alkyl-amino, arylamino, aralkyl-amino, disulfide amines, wherein the two amino-amino-amines are selected from alkyl, aryl, or aralkyl; alkanoyl-amino, aroyl-amino, aralkanoyl-amino, alkanoyl-amino-substituted, aryl-amino-substituted, aralkanoyl-amino-substituted, thiol, thioalkyl, thioaryl, thioaralkyl, isoalkyl, ionaryloyl, ionaloaralkyl, alkyl-sulfonyl, arylsulfonyl, aralkyl sulphonyl, sulfonamido, for example S02NH2, sulfonamido susíiuuido, niíro, cyano, carboxilo, carbamilo, for example CONH2, carbamilo susíiuuido, for example CONH-alkyl, CONH-aril, CON H-aralq uilo, or cases where there are two susíiúuyeníes on the niírógeno selected to paríir of alkyl, aril, or aralquilo; alkoxycarbonyl, aryl, substituted aryl, guanidino, and the substituted heterocycles, such as indolyl, imidazolyl, furyl, pentyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, and the like, and the substituents on the aryl group are selected to be from 1 to 4 members selected from alkyl, aryl, haloalkyl, halogen, trifluoro-mefoxyl, trifluoromethyl, hydroxy, hydroxy-alkyl, amino-alkyl, alkoxy, alkanoyl, alkanoyloxy, amino, arylamino, aralkylamino, dialkyl amino, alkanoylamino, thiol, thioalkyl, ureido, nitro, cyano, cyano-alkyl, heterocyclyl, carboxyl, carboxy-alkyl, carbamyl, alkoxy-carbonyl, amino-carbonyl, thionoalkyl, thionoaryl, aryl-sulfonyl-amine, sulfonic acid, alkyl sulfonyl, sulfonamido, aryloxy, and CONRaRb, wherein Ra and R are selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxycarbonyl-amino-alkyl, and alkylamino; or Ra and Rb, June with the nihologen with which they are subsituted, form a heterocyclic or heteroaryl ring of 3 to 6 members. The substituent may also be suspended by hydroxyl, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl, or aralkyl. 87. A method to eradicate, prevent or diminish one or more symptoms of a disease associated with undigested angiogenesis, which comprises administering a compound of formula I: i or pharmaceutically acceptable derivatives thereof, wherein: R1 is hydrogen, halogen, alkyl, cycloalkyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, pseudo-halogen, -NR4R5, or -OR4; R2, in each occurrence, is selected independently from alkyl, substituted alkyl, lower cycloalkyl, halogen, trifluoromethyl, trifluoro-methoxy, -OR4, -CN, -NR4R5, -S (= 0) alkyl, -S ( = 0) -ari lo, -NHS02-arylene-R4, -NHS02-alkyl, -C02R4, -CONH3, -S03H, -S (0) -alkyl, -S (0) -aryl, -S02NHR4, and -N HC (= 0) N HR4; n is O, 1, or 2; R3 is selected from hydrogen, alkyl, -OR4, substituted alkyl, cycloalkyl, -CR4-cycloalkyl, heleroaryl, heteroaryl heteroaryl, heteroaryl, and solid heterocycle; Y is an individual bond, -C (= 0) NH-, -NH (C = 0) -, -NH (C = 0) NH-, -S02NH-, -NHS02-, or -C (= 0) -; X1 is an individual bond, alkylene, -O-, -S-, -S (O) -, -S02-, -C (O) -, -CO (O) - or -C (0) NH-; A is a bicyclic heyerocyclic ring system with at least one heyerous in each ring, where the heleralloids are each selected independently from N, O, and S, and optionally subsumed with two R13; X2 is a n-individual bond, alkylene, -O-, -S-, -NH-, -N (alkyl of 1 to 4 carbon atoms) -, -NH-alkylene of 1 to 4 carbon atoms-, -N (alkyl of 1 to 4 carbon atoms) -alkylene of 1 to 4 carbon atoms, -S (O) -, -S02-, -C (O) -, -CO (O) -, or -C (0 ) NH-; D is a monocyclic or bicyclic aromatic or non-aromatic ring system that optionally contains four selected heterogeneous compounds from N, O, and S, and where one CH2 is adjacent to any of the N, O, or S optionally susíerous substances. with oxo (= 0), or D is alkyl of 1 to 6 carbon atoms, wherein D is optionally susiiuuido by one to four groups (CR9R10) WE; w is an integer from 0 to 4; R10 is selected from H, alkyl of 1 to 4 carbon atoms-hydroxyl, alkyl of 1 to 4 carbon atoms-aryl, and alkyl of 1 to 4 carbon atoms-heteroaryl, wherein this aryl or heteroaryl group is insustiluido or susíiluido with 1 to 3 independent groups selected from halogen, N02, alkyl of 1 to 4 atoms of carbon, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 atoms carbon, haloalkyl, haloalkoxy, OH, alkoxy from 1 to 4 carbon atoms, alkyl from 1 to 4 carbon-carbonyl atoms, CN, NH2, NR6R7, SR6, S (0) R6, S02R6, S03R6, S02NR6, C02H , C02R6, and CONR6R7; E is selected from H, halogen, N02, alkyl from 1 to 4 carbon atoms, cycloalkyl from 3 to 10 carbon atoms, alkenyl from 2 to 6 carbon atoms, alkynyl from 2 to 6 carbon atoms, haloalkyl, haloalkoxy, OH, OR6, CN, CHO, C02R6, CONR6R7, OCOR6, OC (= 0) OR6, OC (= 0) NR6R7, OCH2C02R6, C (= 0) R6, NH2, NHR6, NR6R7, NR7C (= 0) R6, NR7C (= 0) OR6, N R7C (= 0) C (= 0) OR R6, NR7C (= 0) C (= 0) NR6R7, N R7C (= O) C (= 0) (alq u il or from 1 to 6 carbon atoms), NR7C (= NCN) OR6, N R7C (= 0) N R6R7, NR7C (= NCN) NR6R7, N R7C (= NR6) N R7 R8, NR6S02NR6R7, NR7S02R6, SR6, S (= 0) R6, S02R6, S03R7, S02NR6R7, NHOH, NHOR6, NR6NR7NR8, N (COR6) OH, N (C02R6) OH, CONR7 (CR9R10) rR6, CO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10 ) rR6, CO (CR9R10) pO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10) rOR6, CO (CR9R10) pO (CR9R10) qR6, CO (CR6R10) rNR6R7, OC (O) O (CR9R10) mNR6R7, O (CO) n (CR9R10) R6, O (CR9R10) mNR6R7, N R7C (O) (C R9R1 °) rO R6, NR7C (= NC) (CR9R10) rR6, NR7CO (CR9R10) rNR6R7, NR7 (CR9R10) mOR6, NR7 (CR9R10) rCO2 R6, N R7 (C R9 R1) m N R6R7, NR7, NR3 (CR9R10) nSO2 (CR9R10) rCO2R6, N R7 (C R9 R1) mN R6R7, NR7 (CR9R10) nSO2 (CR9R10) qR6, CONR7 ( CR9R10) nSO2 (CR9R10) qR6, SO2NR7 (CR9R10) qR6, SO2NR6 (CR9R10) mOR6, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon-membered atoms, aryl, optionally heteroaryl with 1 or 2 alkyl groups, optionally heteroaryl with 1 or 2 alkyl groups, and alkylaryl, wherein the aryl groups are unsuspected or susiiuid with 1 or 2 subsides, each independently selected by R12. , or two groups E, which support the adjacent atoms on D, and which together form alkylenedioxyl, fioalkyleneoxy or alkylenedioxy; m is an integer that has a value of 2 to 6; p is an enlero that has a value of 1 to 3; q is a value that has a value from 0 to 3; r is a value that has a value from 0 to 6; R12, in each occurrence, is selected independently from halogen, No2, alkyl from 1 to 4 carbon atoms, cycloalkyl from 3 to 10 carbon atoms, alkenyl from 2 to 6 carbon atoms, alkynyl from 2 to 6 atoms from carbon, haloalkyl, haloalkoxy, OH, oxo, alkoxy from 1 to 4 carbon atoms, OR6, O (CR9R10) CO2R6, O (CR9R10) mNR6R7, O (CR9R10) pCN, O (C R9 R1 °) rC (= 0 ) N R6 R7, alkyl of 1 to 4 carbon-carbonyl atoms, CN, NH2, NHR6, NR6R7, NR7 (CR9R10) CO2R6, NR7OR6, NR7 (CR9R1 °) mO R6, NR7CH ((CR9R10) POR6) 2 , N R7C ((C R9R 1 °) pO R6) 3, NR7C (= 0) R6, NR7 (CR9R 0) mNR6R7, N R7 (C R9R1 °) q R6, SR7, S (0) R7, S02R7, S02NR6 , S03R7, C02H, C02R6, and CONR6R7; R 4 is hydrogen, lower alkyl, and lower cycloalkyl; R5 is hydrogen, lower alkyl, and lower cycloalkyl; R6, R7, and R8 are independently selected as follows: i) R6, R7, and R8 are independently selected from H, alkyl from 1 to 6 carbon atoms, cycloalkyl from 3 to 10 carbon atoms, alkenyl from 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon-carbonyl atoms, cycloalkyl of 3 to 7 carbon atoms- (alkyl of 0 to 5 carbon atoms) -carbonyl, alkoxy of 1 to 6 carbon atoms to 6 carbon-carbonyl atoms, aryl- (alkyl of 0 to 5 carbon atoms) - carbonyl, aryl- (alkoxy of 1 to 5 carbon atoms) -carbonyl, cyclic ether- (0 to 5 alkyl of carbon atoms) -carbonyl, heterocyclic- (alkoxy of 1 to 5 carbon atoms) -carbonyl, alkyl of 1 to 6 carbon atoms-sulfonyl, aryl-sulfonyl, heteroaryl-sulfonyl, alkyl of 0 to 4 carbon atoms-aryl, alkyl of 0 to 4 carbon atoms-heyerocyclic, wherein the cycloalkyl, aryl, or heterocyclic groups are unsuspected or susíiuuid with 1 or 2 substituents, each independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, hydroxyl, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, haloalkyl, N02, and CN; or ii) R6 and R7, or R6 and R8, or R7 and R8, when both subscripts are on the same nigorgen (as in (-NR6R7) or (NR7R8)), June may be added with the nihinogen atom with which they are bound, to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, 1-piperazinyl, 1-imidazolyl, 3-azabicyclo- (3,2,2) -nonan-3-yl, and 1-yaryloyl, which is optionally heteroally cycled with 1 to 3 groups, each independently selected from oxo, alkyl from 0 to 4 carbon atoms-OH , alkyl of 0 to 4 carbon atoms-O-alkyl of 1 to 4 carbon atoms, alkyl of 0 to 4 carbon atoms-CON H2, alkyl of 0 to 4 carbon atoms-C02-alkyl of 0 to 4 atoms of carbon, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkyl of 0 to 6 carbon atoms non-carbonyl, cycloalkyl of 3 to 7 carbon atoms-carbonyl, alkoxy of 1 to 6 carbon atoms-carbonyl, cycloalkoxy of 3 to 7 carbon atoms-carbonyl, -NHCO-alkyl, aryl, heteroaryl, aryl-alkoxy- carbonyl, heteroaryl-alkoxycarbonyl, alkyl of 1 to 6 carbon-sulfonyl, aryl-sulfonyl, and hepheroarylsulfonyl; R9 is hydrogen or alkyl of 1 to 4 carbon atoms; and R13 is hydrogen, alkyl, haloalkyl, aminocarbonyl, hydroxyl, hydroxycarbonyl, alkoxycarbonyl, cycloalkyl-alkyl-amino-carbonyl, alkylsilyl, aryl, aryl, heteroaryl, heteroaryl, alkyl-alkyl, amino-carbonyl, or lower cycloalkyl; wherein the substituents on the alkyl group are selected from 1 to 4 selected by halogen, hydroxyl, alkoxy, oxo (= 0), alkanoyl, aryloxy, alkanoyloxy, amino, alkyl-amino, arylamino, aralkyl. -amino, disusified amines, wherein the two amino-amino groups are selected from alkyl, aryl, or aralkyl; alkanoyl-amino, aroyl-amino, aralkanoyl-amino, substituted alkanoyl-amino, substituted aryl-amino, substituted aralkanoyl-amino, thiol, thioalkyl, thioaryl, thioaralkyl, ioionalkyl, ioionaryl, thionoaralkyl, alkyl-sulfonyl, aryl-sulfonyl, aralkyl sulfonyl, sulfonamido, for example S02NH2, substituted sulfonamido, nitro, cyano, carboxyl, carbamyl, for example CONH2, substituted carbamyl, for example CONH-alkyl, CONH-aryl, CON H -ralkyl, or the cases where there are two substituents on the nylogen selected from alkyl, aryl, or aralkyl; alkoxycarbonyl, aryl, suslylfluid aryl, guanidino, and unsubstituted or unsusilifiable helerocycles such as indolyl, imidazolyl, furyl, pennyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, and the like, and substitutes on the aryl group are selected from give from 1 to 4 substituents selected from alkyl, aryl, haloalkyl, halogen, trifluoromethyl, trifluoromethyl, hydroxyl, hydroxy-alkyl, amino-alkyl, alkoxy, alkanoyl, alkanoyloxy, amino, arylamino, aralkyl -amino, dialkylamino, alkanoylamino, thiol, thioalkyl, ureido, nitro, cyano, cyano-alkyl, heterocyclyl, carboxyl, carboxy-alkyl, carbamyl, alkoxy-carbonyl, amino-carbonyl, thionoalkyl, thionoaryl, aryl-sulfonyl -amine, sulphonic acid, alkyl-sulfonyl, sulfonamido, aryloxy, and CONRaRb, wherein Ra and Rb are selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy-carbonyl-amino-alkyl, and alkylamino; or Ra and Rb, together with the nitrogen with which they are suspended, form a helerocyclic or heeroaryl ring of 3 to 6 members. The susíifuyenfe can also be substituted by hydroxyl, alkyl, alkoxyl, aryl, substituted aryl, substituted alkyl, or aralkyl. 88. A method for tracing, preventing or diminishing one or more symptoms of an oncological disease, which comprises administering a compound of formula I: I or pharmaceutically acceptable derivatives thereof, wherein: R 1 is hydrogen, halogen, alkyl, cycloalkyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, pseudohalogene, -NR 4 R 5, or -OR 4; R2, in each presentation, is independently selected from alkyl, substituted alkyl, lower cycloalkyl, halogen, trifluoromethyl, trifluoro-meioxyl, -OR4, -CN, -NR4R5, -S (= O) alkyl, -S (= 0) -aryl, -NHS02-arylene-R4, -NH S02 -alkyl, -C02R4, -CONH3, -S03H, -S (0) -alkyl, -S (0) -aryl, -S02NHR4, and -N HC (= 0) NH R4; n is 0, 1, or 2; R3 is selected from hydrogen, alkyl, -OR4, unsaturated alkyl, cycloalkyl, -CR4-cycloalkyl, heteroaryl, substituted heteroaryl, heteroaryl, and solidified cyclohexyl; Y is an individual bond, -C (= 0) NH-, -NH (C = 0) -, -NH (C = 0) NH-, -S02NH-, -NHS02-, or -C (= 0) -; X1 is an individual bond, alkylene, -O-, -S-, -S (O) -, -S02-, -C (O) -, -CO (O) - or -C (0) NH-; A is a bicyclic erocyclic ring system with at least one ring in each ring, wherein the ring cells are each independently selected from N, O, and S, and optionally substituted with up to two R13; X2 is an individual bond, alkylene, -O-, -S-, -NH-, -N (alkyl of 1 to 4 carbon atoms) -, -NH-alkylene of 1 to 4 carbon atoms-, -N ( alkyl of 1 to 4 carbon atoms) -alkylene of 1 to 4 carbon atoms, -S (O) -, -S02-, -C (O) -, -CO (O) -, or -C (0) NH-; D is a monocyclic or bicyclic aromatic or nonaromatic ring system optionally containing up to four heteroatoms selected from N, O, and S, and terminating a CH2 adjacent to any of the heteroatoms N, O, or S is optionally substituted with oxo (= 0), or D is alkyl of 1 to 6 carbon atoms, wherein D is optionally substituted by one to four groups (CR9R0) WE; w is an enero from 0 to 4; R 10 is selected from H, alkyl of 1 to 4 carbon atoms-hydroxyl, alkyl of 1 to 4 carbon atoms-aryl, and alkyl of 1 to 4 carbon atoms -heteroaryl, wherein said aryl or heleroaryl group is unsusceptible or susíiuuido with 1 to 3 groups independently selected from halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 atoms carbon, haloalkyl, haloalkoxy, OH, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms-carbonyl, CN, NH2, NR6R7, SR6, S (0) R6, S02R6, S03R6, S02NR6, C02H , C02R6, and CONR6R7; E is selected from H, halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl, haloalkoxy, OH, OR6, CN, CHO, C02R6, CONR6R7, OCOR6, OC (= 0) OR6, OC (= 0) NR6R7, OCH2C02R6, C (= 0) R6, NH2, NHR6, NR6R7, NR7C (= 0) R6, NR7C (= 0) OR6, N R7C (= 0) C (= 0) OR R6, NR7C (= 0) C (= 0) NR6R7, N R7C (= O) C (= O) (to whom I or from 1 to 6 carbon atoms), NR7C (= NCN) OR6, N R7C (= 0) NR6R7, NR7C (= NCN) NR6R7, N R7C (= NR6) N R7R8, NR6S02NR6R7, NR7S02R6, SR6, S ( = 0) R6, S02R6, S03R7, S02NR6R7, NHOH, NHOR6, NR6NR7NR8, N (COR6) OH, N (C02R6) OH, CONR7 (CR9R10) rR6, CO (CR9R0) pO (CHR9) qCO2R6, CO (CR9R10) rR6, CO (CR9R10) pO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10) rOR6, CO (CR9R10) pO (CR9R10) qR6, CO (CR6R10) rNR6R7, OC (O) O (CR9R10) mNR6R7, O ( CO) n (CR9R10) R6, O (CR9R10) mNR6R7, N R7C (O) (C R9R1 °) rO R6, NR7C (= NC) (CR9R10) rR6, NR7CO (CR9R10) rNR6R7, NR7 (CR9R10) mOR6, NR7 (CR9R10) rCO2R6, N R7 (CR9 R1) mN R6R7, NR7, NR3 (CR9R10) nSO2 (CR9R10) rCO2R6, N R7 (C R9R 1) mN R6R7, NR7 (CR9R10) nSO2 (CR9R10) qR6, CONR7 (CR9R0) nSO2 (CR9R10) qR6, SO2NR7 (CR9R10) qR6, SO2NR6 (CR9R10) mOR6, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon-mephyl atoms, aryl, optional cyclic ether -substituted substituent with 1 or 2 alkyl groups, optionally substituted with 1 or 2 alkyl groups, and alkylaryl, wherein the aryl groups are unsubstituted or substituted by 1 or 2 sushyloyenyes, each independently selected from R 12, or two groups E, which support the adjoining atoms on D, and which together form alkylenedioxyl, thioalkyleneoxy or alkylene diisoxy; m is an integer that has a value of 2 to 6; p is an integer that has a value of 1 to 3; q is an integer that has a value from 0 to 3; r is an integer that has a value from 0 to 6; R12, in each presentation, is independently selected from halogen, No2, alkyl from 1 to 4 carbon atoms, cycloalkyl from 3 to 10 carbon atoms, alkenyl from 2 to 6 carbon atoms, alkynyl from 2 to 6 atoms from carbon, haloalkyl, haloalkoxy, OH, oxo, alkoxy from 1 to 4 carbon atoms, OR6, 0 (CR9R1 °) C02R6, O (CR9R10) mNR6R7, O (CR9R10) pCN, O (C R9 R1 °) rC (= 0) N R6 R7, alkyl of 1 to 4 carbon-carbonyl atoms, CN, NH2, NHR6, NR6R7, NR7 (CR9R10) CO2R6, NR7OR6, NR7 (CR9 R1 °) mO R6, NR7CH ((CR9R10) POR6) 2, N R7C ((C R9 R 1 °) pO R6) 3, NR7C (= 0) R6, NR7 (CR9R10) mNR6R7, N R7 (C R9 R1 °) qR6, SR7, S (0) R7, S02R7, SO.NR6, S03R7, C02H, C02R6, and C0NR6R7; R 4 is hydrogen, lower alkyl, and lower cycloalkyl; R5 is hydrogen, lower alkyl, and lower cycloalkyl; R6, R7, and R8 are independently selected as follows: i) R6, R7, and R8 are independently selected from H, alkyl from 1 to 6 carbon atoms, cycloalkyl from 3 to 10 carbon atoms, alkenyl from 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon-carbonyl atoms, cycloalkyl of 3 to 7 carbon atoms- (0 to 5 alkyl of carbon atoms) -carbonyl, alkoxy of 1 to 6 carbon atoms-carbonyl, aryl- (alkyl of 0 to 5 carbon atoms) -carbonyl, aryl- (alkoxy of 1 to 5 carbon atoms) -carbonyl, heterocyclic- (alkyl of 0 to 5 carbon atoms) carbonyl, heterocyclic- (alkoxy of 1 to 5 carbon atoms) -carbonyl, alkyl of 1 to 6 carbon atoms-sulfonyl, aryl-sulfonyl, heteroaryl-sulfonyl, alkyl of 0 to 4 carbon atoms-aryl, alkyl of 0 to 4 carbon atoms-heterocyclic, wherein the cycloalkyl, aryl, or heterocyclic groups are unsubstituted or substituted with 1 or 2 their tituyeníes, each independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, hydroxyl, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, haloalkyl, N02, and CN; or ii) R6 and R7, or R6 and R8, or R7 and R8, when both substituents are on the same nitrogen atom (as in (-NR6R7) or (NR7R8)), they can be taken together with the nitrogen atom with which are joined, to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorphoylinyl, thiazolidinyl, 1-piperazinyl, 1-imidazolyl, 3-azabicyclo- ( 3,2,2) -nonan-3-yl, and 1-tetrazolyl, this heterocycle being optionally substituted with 1 to 3 groups, each independently selected from oxo, alkyl of 0 to 4 carbon atoms-OH, alkyl from 0 to 4 carbon atoms-O-alkyl of 1 to 4 carbon atoms, alkyl of 0 to 4 carbon atoms-CON H2, alkyl of 0 to 4 carbon atoms-C02-alkyl of 0 to 4 carbon atoms , alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkyl of 0 to 6 carbon atoms, carbonyl alkyl of 3 to 7 carbon atoms-carbonyl, alkoxy of 1 to 6 carbon atoms-carbonyl, cycloalkoxy of 3 to 7 carbon atoms-carbonyl, -NHCO-alkyl, aryl, heteroaryl, aryl-alkoxy-carbonyl, heteroaryl- alkoxycarbonyl, alkyl of 1 to 6 carbon-sulfonyl, aryl-sulfonyl, and heleroaryl-sulfonyl; R9 is hydrogen or alkyl of 1 to 4 carbon atoms; and R13 is hydrogen, alkyl, haloalkyl, aminocarbonyl, hydroxyl, hydroxycarbonyl, alkoxycarbonyl, cycloalkyl-amino-carbonyl, substituted alkyl, aryl, aryl s, heteroaryl, heteroaryl, thioalkyl, alkylamino-carbonyl, or lower cycloalkyl; wherein the substitutes on the alkyl group are selected from 1 to 4 substituents selected from halogen, hydroxyl, alkoxy, oxo (= 0), alkanoyl, aryloxy, alkanoyloxy, amino, alkyl-amino, arylamino, aralkyl -amino, dis amines, wherein the two amino-amines are selected from alkyl, aryl, or aralkyl; alkanoyl-amino, aroyl-amino, aralkanoyl-amino, unsaturated alkanoyl-amino, aryl-amino susiiluido, aralcanoyl-amino substituted, thiol, thioalkyl, thioaryl, thioaralkyl, thionoalkyl, thionoaryl, thionoaralkyl, alkyl-sulfonyl, aryl-sulfonyl, aralkylsulfonyl, sulfonamido, for example S02NH2, substituted sulfonamido, nitro, cyano, carboxyl, carbamyl, for example CONH2, substituted carbamyl, for example CONH-alkyl, CONH-aryl, CON H-aralkyl, or the cases wherein there are two sustif uyeníes on nitrogen selected from alkyl, aryl, or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino, and the unsubstituted or unsusiluted heterocycles, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, and the like, and the substituents on the aryl group are selected to be from 1 to 4 susíiúufes selected from alkyl, substituted aryl, haloalkyl, halogen, trifluoro-methoxy, trifluoromethyl, hydroxyl, hydroxy-alkyl, amino-alkyl, alkoxy, alkanoyl, alkanoyloxy, amino, arylamino, aralkylamino, dialkyl amino, alkanoylamino, thiol, thioalkyl, ureido, nitro, cyano, cyano-alkyl, heterocyclyl, carboxyl, carboxy-alkyl, carbamyl, alkoxy-carbonyl, amino-carbonyl, thionoalkyl, thionoaryl, aryl-sulfonyl-amine, sulfonic acid, alkyl sulfonyl, sulfonamido, aryloxy, and CONRaRb, wherein Ra and Rb are selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxycarbonyl-amino-alkyl, and alkylamino; or Ra and Rb, together with the nitrogen with which they are substituted, form a heterocyclic or heteroaryl ring of 3 to 6 members. The substitute may also be suspended by hydroxyl, alkyl, alkoxy, aryl, substituted aryl, susiifluid alkyl, or aralkyl. 89. A method to eradicate, prevent or diminish one or more symptoms of cancer, which comprises administering a compound of formula I: I or pharmaceutically acceptable derivatives thereof, wherein: R1 is hydrogen, halogen, alkyl, cycloalkyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, pseudo-halogen, -NR4R5, or -OR4; R2, in each presentation, is independently selected from alkyl, substituted alkyl, lower cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, -OR4, -CN, -NR4R5, -S (= 0) alkyl, -S ( = 0) -aryl, -NHS02-arylene-R4, -NH S02-alkyl, -C02R4, -CONH3, -S03H, -S (0) -alkyl, -S (0) -aryl, -S02NHR4, and -NHC (= 0) NH R4; n is 0, 1, or 2; R 3 is selected from hydrogen, alkyl, -OR 4, unsaturated alkyl, cycloalkyl, -CR-cycloalkyl, heteroaryl, heteroaryl heteroaryl, heteroaryl, and substituted heterocycle; Y is an individual bond, -C (= 0) NH-, -NH (C = 0) -, -NH (C = 0) NH-, -S02NH-, -NHS02-, or -C (= 0) -; X1 is an individual bond, alkylene, -O-, -S-, -S (O) -, -S02-, -C (O) -, -CO (O) - or -C (0) NH-; A is a bicyclic heterocyclic ring system with at least one hetero chain in each ring, where the hephenoiomes are each independently selected from N, O, and S, and optionally substituted with up to two R13; X2 is an individual bond, alkylene, -O-, -S-, -NH-, -N (alkyl of 1 to 4 carbon atoms) -, -N H-alkylene of 1 to 4 carbon atoms-, -N (alkyl of 1 to 4 carbon atoms) -alkylene of 1 to 4 carbon atoms, -S (O) -, -S02-, -C (O) -, -CO (O) -, or -C (0 ) NH-; D is a monocyclic or bicyclic aromatic or non-aromatic ring system optionally containing up to four heteroatoms selected from N, O, and S, and wherein a CH2 adjacent to any of the heteroatoms N, O, or S is optionally susfiuid. with oxo (= 0), or D is alkyl of 1 to 6 carbon atoms, wherein D is optionally unsubstituted by one to four groups (CR9R10) WE; w is an enero from 0 to 4; R 10 is selected from H, alkyl from 1 to 4 carbon-hydroxyl groups, alkyl from 1 to 4 carbon atoms-aryl, and alkyl from 1 to 4 carbon atoms-heeroaryl, wherein said aryl or heeroaryl group is unsubstituted or susíiluido with 1 to 3 groups independently selected from halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 atoms carbon, haloalkyl, haloalkoxy, OH, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms-carbonyl, CN, NH2, NR6R7, SR6, S (0) R6, S02R6, S03R6, S02NR6, C02H , C02R6, and CONR6R7; E is selected from H, halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl, haloalkoxy, OH, OR6, CN, CHO, C02R6, CONR6R7, OCOR6, OC (= 0) OR6, OC (= 0) NR6R7, OCH2C02R6, C (= 0) R6, NH2, NHR6, NR6R7, NR7C (= 0) R6, NR7C (= 0) OR6, N R7C (= 0) C (= 0) OR R6, NR7C (= 0) C (= 0) NR6R7, N R7C (= O) C (= O) (alq u il or from 1 to 6 carbon atoms), NR7C (= NCN) OR6, N R7C (= 0) N R6R7, NR7C (= NCN) NR6R7, N R7C (= NR6) N R7 R8, NR6S02NR6R7, NR7S02R6, SR6, S (= 0) R6, S02R6, S03R7, S02NR6R7, NHOH, NHOR6, NR6NR7NR8, N (COR6) OH, N (C02R6) OH, CONR7 (CR9R10) rR6, CO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10 ) rR6, CO (CR9R0) pO (CR9R10) pO (CHR9) qCO2R6, CO (CR9R10) rOR6, CO (CR9R10) pO (CR9R10) qR6, CO (CR6R10) rNR6R7, OC (O) O (CR9R10) mNR6R7, O (CO) n (CR9R10) R6, O (CR9R10) mNR6R7, N R7C (O) (C R9R 1 °) rO R6, NR7C (= NC) (CR9R10) rR6, NR7CO (CR9R10) rNR6R7, NR7 (CR9R10) mOR6, NR7 (CR9R 0) rCO2R6 , N R7 (C R9 R1) m N R6R7, NR7, NR3 (CR9R10) nSO2 (CR9R10) rCO2R6, N R7 (C R9R 1) m N R6R7, NR7 (CR9R10) nSO2 (CR9R10) qR6, CONR7 (CR9R10 ) nSO2 (CR9R10) qR6, SO2NR7 (CR9R10) qR6, SO2NR6 (CR9R10) mOR6, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms-methyl, aryl, heterocyclic optionally substituted with 1 or 2 alkyl groups, heteroaryl optionally substituted with 1 or 2 alkyl groups, and alkylaryl, wherein the aryl groups are unsubstituted or substituted with 1 or 2 substituents, each independently selected from R12, or two groups E, which substitute the adjacent atoms on D, and which together form alkylenedioxyl, thioalkyleneoxy or alkylenedithioxyl; m is an integer that has a value of 2 to 6; p is an integer that has a value of 1 to 3; q is an integer that has a value from 0 to 3; r is an integer that has a value from 0 to 6; R12, in each presentation, is independently selected from halogen, No2, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms carbon, haloalkyl, haloalkoxy, OH, oxo, alkoxy of 1 to 4 carbon atoms, OR6, O (CR9R10) CO2R6, O (CR9R10) mNR6R7, O (CR9R0) pCN, O (C R9 R1 °) rC (= 0) N R6R7, alkyl of 1 to 4 carbon-carbonyl atoms, CN, NH2, NHR6, NR6R7, NR7 (CR9R10) CO2R6, NR7OR6, NR7 (CR9R1 °) mO R6, NR7CH ((CR9R10) POR6) 2, N R7C ((CR 9R 1 °) pOR6) 3, NR7C (= 0) R6, NR7 (CR9R10) mNR6R7, N R7 (C R9 R 1 °) R6, SR7, S (0) R7, S02R7, S02NR6, S03R7, C02H, C02R6, and CONR6R7; R 4 is hydrogen, lower alkyl, and lower cycloalkyl; R5 is hydrogen, lower alkyl, and lower cycloalkyl; R6, R7, and R8 are independently selected as follows: i) R6, R7, and R8 are independently selected from H, alkyl from 1 to 6 carbon atoms, cycloalkyl from 3 to 10 carbon atoms, alkenyl from 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon-carbonyl atoms, cycloalkyl of 3 to 7 carbon atoms- (alkyl of 0 to 5 carbon atoms) -carbonyl, alkoxy of 1 to 6 carbon atoms-carbonyl, aryl- (alkyl of 0 to 5 carbon atoms) -carbonyl, aryl- (alkoxy of 1 to 5 carbon atoms) -carbonyl, heterocyclic- (alkyl of 0 to 5 carbon atoms) -carbonyl, heyerocyclic- (alkoxy of 1 to 5 carbon atoms) -carbonyl, alkyl of 1 to 6 carbon atoms-sulfonyl, aryl-sulfonyl, heteroaryl-sulfonyl, alkyl of 0 to 4 carbon atoms-aryl, alkyl from 0 to 4 carbon atoms-heterocyclic, wherein the cycloalkyl, aryl, or heterocyclic groups are unsubstituted or substituted with 1 or 2 substituents, each independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, hydroxyl, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, haloalkyl, NO 2, and CN; or ii) R6 and R7, or R6 and R8, or R7 and R8, when both substituents are on the same nitrogen atom (as in (-NR6R7) or (NR7R8)), can be taken together with the nitrogen atom with which are attached, to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, 1-piperazinyl, 1-imidazolyl, 3-azabicyclo- ( 3.2, 2) -nonan-3-i lo, and 1-tetrazolyl, this heterocycle optionally being substituted with 1 to 3 groups, each independently selected from oxo, alkyl from 0 to 4 carbon atoms-OH , alkyl of 0 to 4 carbon atoms- O-alkyl of 1 to 4 carbon atoms, alkyl of 0 to 4 carbon atoms-CON H2, alkyl of 0 to 4 carbon atoms-C02-alkyio of 0 to 4 atoms of carbon, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkyl of 0 to 6 carbon atoms - carbonyl , cycloalkyl of 3 to 7 carbon atoms-carbonyl, alkoxy of 1 to 6 carbon atoms-carbonyl, cycloalkoxy of 3 to 7 carbon-carbon atoms, -NHCO-alkyl, aryl, heteroaryl, aryl-alkoxycarbonyl, heteroaryl -alkoxycarbonyl, alkyl of 1 to 6 carbon atoms-sulfonyl, aryl-sulfonyl, and heteroaryl-sulfonyl; R9 is hydrogen or alkyl of 1 to 4 carbon atoms; and R13 is hydrogen, alkyl, haloalkyl, aminocarbonyl, hydroxyl, hydroxycarbonyl, alkoxycarbonyl, cycloalkyl-aminocarbonyl, substituted alkyl, aryl, substituted aryl, heleroaryl, heterocyclyl, thioalkyl, alkyl-amino-carbonyl, or lower cycloalkyl; wherein the substitutes on the alkyl group are selected from 1 to 4 susyituyenyes selected from halogen, hydroxyl, alkoxy, oxo (= 0), alkanoyl, aryloxy, alkanoyloxy, amino, alkyl-amino, arylamino, aralkyl -amino, disusified amines, wherein the two amino-substituted amines are selected from alkyl, aryl, or aralkyl; alkanoyl-amino, aroyl-amino, aralkanoyl-amino, alkanoyl-amino-substituted amino, aryl-amino-unsaturated, aralkenyl-amino-substituted, thiol, thioalkyl, thioaryl, thioaralkyl, thionoalkyl, thionoaryl, thionoaralkyl, alkyl-sulfonyl, aryl-sulfonyl, aralkyl sulphonyl, sulphonamido, for example S02NH2, substituted sulfonamido, niino, cyano, carboxyl, carbamyl, for example CONH2, substituted carbamyl, for example CONH-alkyio, CONH-aryl, CON H-aralkyl, or the cases where there are two substituents on nitrogen selected from alkyl, aryl, or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino, and substituted or unsubstituted heterocycles, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, and the like, and the substituents on the aryl group are selected from from 1 to 4 substituents selected from alkyl, substituted aryl, haloalkyl, halogen, trifluoro-methoxy, trifluoro-meityl, hydroxy, hydroxy-alkyl, amino-alkyl, alkoxy, alkanoyl, alkanoyloxy, amino, arylamino, aralkyl- amino, dialkylamino, alkanoylamino, thiol, thioalkyl, ureido, nitro, cyano, cyano-alkyl, heterocyclyl, carboxyl, carboxy-alkyl, carbamyl, alkoxy-carbonyl, amino-carbonyl, thionoalkyl, thionoaryl, aryl-sulfonyl- amine, sulfonic acid, alkylsulfonyl, sulfonamido, aryloxy, and CONRaRb, wherein Ra and Rb are selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxycarbonyl-amino-alkyl, and alkylamino; or Ra and Rb, together with the nitrogen with which they are substituted, form a heyerocyclic or heleroaryl ring of 3 to 6 members. The substituent may be further substituted by hydroxyl, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl, or aralkyl. 90. The method of claim 89, wherein the disease is a solid fumor. 91. The method of claim 89 or 90, wherein the cancer is resistant to cytotoxic agents. 92. The method of claim 89 or 90, wherein the cancer is breast cancer, stomach cancer, ovarian cancer, colon cancer, lung cancer, brain cancer, laryngeal cancer, cancer of the lymphatic system, cancer of genito-urinary traumas including bladder and prostate, bone cancer, and pancreatic cancer. 93. A method of cancer chemotherapy, which comprises administering a compound of formula 1: or pharmaceutically acceptable derivatives thereof, wherein: R1 is hydrogen, halogen, alkyl, cycloalkyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, pseudo-halogen, -NR R5, or -OR4; in each presentation, it is independently selected from alkyl, lower alkyl, lower cycloalkyl, halogen, trifluoro-m-yl, trifluoro-methoxy, -OR4, -CN, -NR4R5, -S (= 0) alky, -S (= 0) -ari lo, -NHS02-arylene-R4, -N HS02-alkyl, -C02R4, -CONH3, -S03H, -S (0) -alkyl, -S (0) -aryl, -S02NHR4, and - N HC (= 0) NH R4; n is 0, 1, or 2; R3 is selected from hydrogen, alkyl, -OR4, substituted alkyl, cycloalkyl, -CR4-cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; Y is an individual bond, -C (= 0) NH-, -NH (C = 0) -, -NH (C = 0) NH-, -S02NH-, -NHS02-, or -C (= 0) -; X1 is an individual bond, alkylene, -O-, -S-, -S (O) -, -S02-, -C (O) -, -CO (O) - or -C (0) NH-; A is a bicyclic heterocyclic ring system with at least one hetero-atom in each ring, wherein the heteroerobes are each independently selected from N, O, and S, and optionally subsumed with two R13; X2 is an individual bond, alkylene, -O-, -S-, -NH-, -N (alkyl of 1 to 4 carbon atoms) -, -NH-alkylene of 1 to 4 carbon atoms-, -N ( alkyl of 1 to 4 carbon atoms) -alkylene of 1 to 4 carbon atoms, -S (O) -, -S02-, -C (O) -, -CO (O) -, or -C (0) NH-; D is a monocyclic or bicyclic aromatic or non-aromatic ring system that optionally contains only selected compounds selected from N, O, and S, and wherein a CH2 adjacent to any of the N, O, or S heteroaryols is optionally unsuitable. with oxo (= 0), or D is alkyl of 1 to 6 carbon atoms, wherein D is optionally substituted by one to four groups (CR9R10) WE; w is an integer from 0 to 4; R10 is selected from H, alkyl of 1 to 4 carbon atoms-hydroxyl, alkyl of 1 to 4 carbon atoms-aryl, and alkyl of 1 to 4 carbon atoms-heteroaryl, wherein this aryl or heteroaryl group is unsubstituted or substituted with 1 to 3 groups independently selected from halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 atoms carbon, haloalkyl, haloalkoxy, OH, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms-carbonyl, CN, NH2, NR6R7, SR6, S (0) R6, S02R6, S03R6, S02NR6, C02H , C02R6, and CONR6R7; E is selected from H, halogen, N02, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl, haloalkoxy, OH, OR6, CN, CHO, C02R6, C0NR6R7, OCOR6, OC (= 0) OR6, OC (= 0) NR6R7, OCH2C02R6, C (= 0) R6, NH2, NHR6, NR6R7, NR7C (= 0) R6, NR7C (= 0) OR6, N R7C (= O) C (= 0) OR R6, NR7C (= 0) C (= 0) NR6R7, N R7 C (= O) C (= 0) (a Iq ui I of 1 to 6 carbon atoms), NRC (= NCN) OR6, N R7C (= 0) N R6R7, NR7C (= NCN) NR6R7, N R7C (= N R6) N R7R8, NR6S02NR6R7, NR7S02R6, SR6 , S (= 0) R6, S02R6, S03R7, S02NR6R7, NHOH, NHOR6, NR6NR7NR8, N (COR6) OH, N (C02R6) OH, CONR7 (CR9R10) rR6, CO (CR9R10) pO (CHR9) qCO2R6, CO ( CRaR1u) rR CO (CRaR1u) pO (CRaR1u) pO (CHR8) qC02R, CO (CR9R10) rOR6, CO (CR9R10) pO (CR9R10) qR6, CO (CR6R10) rNR6R7, OC (O) O (CR9R10) mNR6R7, O (CO) n (CR9R10) R6, O (CR9R10) mNR6R7, N R7C (O) (C R9R 1) r0 R6, NR7C (= NC) (CR9R10) rR6, N R7CO (CR9 R 1) rN R6R7 , NR7 (CR9R10) mOR6, NR7 (CR9R1 0) rCO2R6, N R7 (C R9 R 1 °) m N R6R7, NR7, NR3 (CR9R0) nSO2 (CR9R10) rCO2R6, NR7 (CR9R1 °) mN R6R7, NR7 (CR9R0) nSO2 (CR9R10) qR6, CONR7 (CR9R10) nSO2 (CR9R10) qR6, SO2NR7 (CR9R10) qR6, SO2NR6 (CR9R10) mOR6, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms-methyl, aryl, heterocyclic optionally substituted with 1 or 2 alkyl groups, optionally substituted heteroaryl with 1 or 2 alkyl groups, and alkyl aryl, wherein the aryl groups are unsubstituted or substituted with 1 or 2 substituents, each independently selected from R12, or two E groups, which substitute the adjacent atoms on D, and that together they form alkylenedioxyl, thioalkyleneoxy or alkylenedithioxyl; m is an integer that has a value of 2 to 6; p is an integer that has a value of 1 to 3; q is an integer that has a value from 0 to 3; r is an integer that has a value from 0 to 6; R12, in each presentation, is independently selecfrom halogen, No2, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms carbon, haloalkyl, haloalkoxy, OH, oxo, alkoxy of 1 to 4 carbon atoms, OR6, O (CR9R10) CO2R6, O (CR9R10) mNR6R7, O (CR9R10) pCN, O (C R9R1 °) rC (= 0) N R6 R7, alkyl of 1 to 4 carbon atoms-carbonyl, CN, NH2, NHR6, NR6R7, NR7 (CR9R10) CO2R6, NR7OR6, NR7 (CR9R10) mOR6, NR7CH ((CR9R10) pOR6) 2, N R7C ( (C R9R1 °) pO R6) 3, NR7C (= 0) R6, NR7 (CR9R10) mNR6R7, N R7 (C R9 R1 °) q R6, SR7, S (0) R7, S02R7, S02NR6, S03R7, C02H, C02R6, and CONR6R7; R 4 is hydrogen, lower alkyl, and lower cycloalkyl; R5 is hydrogen, lower alkyl, and lower cycloalkyl; R6, R7, and R8 are independently selecas follows: i) R6, R7, and R8 are independently selecfrom H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-carbonyl, cycloalkyl of 3 to 7 carbon atoms- (alkyl of 0 to 5 carbon atoms) -carbonyl, alkoxy of 1 to 6 carbon atoms -carbonyl, aryl- (alkyl of 0 to 5 carbon atoms) -carbonyl, aryl- (alkoxy of 1 to 5 carbon atoms) -carbonyl, heterocyclic- (alkyl of 0 to 5 carbon atoms) carbonyl, heterocyclic (C 1-5 alkoxy) -carbonyl, alkyl of 1 to 6 carbon atoms-sulfonyl, aryl-sulfonyl, heteroaryl-sulfonyl, alkyl of 0 to 4 carbon atoms-aryl, alkyl from 0 to 4 carbon-helerocyclic atoms, wherein the cycloalkyl, aryl, or heterocyclic groups are substituor unsubstituwith 1 or 2 their substituents, each independently selecfrom the group consisting of alkyl of 1 to 4 carbon atoms, hydroxyl, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, haloalkyl, N02, and CN; or ii) R6 and R7, or R6 and R8, or R7 and R8, when both substituents are on the same nihologen atom (as in (-NR6R7) or (NR7R8)), June can be added with the nihologen which are joined, to form a heterocycle selecfrom 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, lyazolidinyl, 1-piperazinyl, 1-imidazolyl, 3- azabicyclo- (3,2,2) -nonan-3-yl, and 1-epinephthyl, which is optionally substituwith 1 to 3 groups, each independently selecfrom oxo, alkyl of 0 to 4 carbon atoms. carbon-OH, alkyl of 0 to 4 carbon atoms-O-alkyl of 1 to 4 carbon atoms, alkyl of 0 to 4 carbon atoms-CONH2, alkyl of 0 to 4 carbon atoms-C02-alkyl of 0 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkyl of 0 to 6 carbon atoms carbonyl, cycloalkyl of 3 to 7 carbon atoms-carbonyl, alkoxy of 1 to 6 carbon atoms-carbonyl, cycloalkoxy of 3 to 7 carbon atoms-carbonyl, -NHCO-alkyl, aryl, heteroaryl, aryl-alkoxy-carbonyl, heteroaryl-alkoxycarbonyl, alkyl of 1 to 6 carbon-sulfonyl, aryl-sulfonyl, and heteroaryl-sulfonyl; R9 is hydrogen or alkyl of 1 to 4 carbon atoms; and R13 is hydrogen, alkyl, haloalkyl, aminocarbonyl, hydroxyl, hydroxycarbonyl, alkoxycarbonyl, cycloalkyl-aminocarbonyl, substitualkyl, aryl, substituaryl, heteroaryl, heterocyclyl, thioalkyl, alkyl-amino-carbonyl, or lower cycloalkyl; wherein the substitutes on the alkyl group are selecfrom 1 to 4 selecsubstitutents from halogen, hydroxyl, alkoxy, oxo (= 0), alkanoyl, aryloxy, alkanoyloxy, amino, alkyl-amino, arylamino, aralkylamino, disubstituamines, wherein the two amino substituents are selecfrom alkyl, aryl, or aralkyl; alkanoyl-amino, aroyl-amino, aralkanoyl-amino, substituted alkanoyl-amino, aryl-amino-substituted amino, aralkanoyl-amino-substituted amino, thiol, thioalkyl, thioaryl, thioaralkyl, thionoalkyl, thionoaryl, thionoaralkyl, alkyl-sulfonyl, aryl-sulfonyl, aralkyl sulfonyl, sulfonamido, for example S02NH2, substituted sulfonamido, nitro, cyano, carboxyl, carbamyl, for example CONH2, substituted carbamyl, for example CONH-alkyl, CONH-aryl, CON H -ralkyl, or the cases wherein there are two Substituted on the nihogen selected to be alkyl, aryl, or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino, and the unsubstituted or heterocyclic heterocycles, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, and the like, and the substitutes on the aryl group are selected from 1 to 4 substituents selected from alkyl, substituted aryl, haloalkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, hydroxy-alkyl, amino-alkyl, alkoxy, alkanoyl, alkanoyloxy, amino, arylamino, aralkyl- amino, dialkyl-amino, alkanoylamino, thiol, thioalkyl, ureido, niino, cyano, cyanoalkyl, heterocyclyl, carboxyl, carboxy-alkyl, carbamyl, alkoxycarbonyl, aminocarbonyl, ionionalkyl, ionionaryl, aryl- sulfonyl-amine, sulphonic acid, alkylsulfonyl, sulfonamido, aryloxy, and CONRaRb, wherein Ra and R are selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy-carbonyl-amino-alkyl, and alkylamino; or Ra and Rb, June with the nihologen with which they are substituted, form a heyerocyclic or heeroaryl ring of 3 to 6 members. The solvent may also be substituted by hydroxyl, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl, or aralkyl. 94. The method of any of claims 55 to 93, wherein R1 is methyl, halogen, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoro-methyl, methoxy, trifluoromethoxy, cyano, -NH2, -NR4R5 or -OR4; and Y is -C (= 0) NH-, -NH (C = 0) -, -NH (C = 0) NH-, -S02NH-, -NHS02-, or -C (= 0) -. 95. The compound of any of claims 1 to 50, wherein, when D is alkyl of 1 to 6 carbon atoms, then X2 is not an individual bond or alkylene. 96. The compound of any of claims 1 to 50, wherein D is a monocyclic or bicyclic aromatic or non-aromatic ring system, optionally confining up to four heteroaloms selected from N, O, and S, and wherein CH2 adjacent to any of these heteroatoms N, O, or S is optionally substituted with oxo (= 0), and wherein D is optionally substituted by one to four groups (CR9R10) WE. 97. The compound of any of claims 1 to 50, wherein D is alkyl of 1 to 6 carbon atoms, when X2 is -NH-, -N (alkyl of 1 to 4 carbon atoms) -, -NH- alkylene of 1 to 4 carbon atoms, -N (alkyl of 1 to 4 carbon atoms) -alkylene of 1 to 4 carbon atoms; 98. The compound of claims 1 to 50 and 95 to 97, wherein X 2 is an individual bond, alkylene, -N (alkyl of 1 to 4 carbon atoms) -, or -NH-. 99. The compound of claims 1 to 50 and 95 to 98, wherein X2 is an individual bond, -CH2-, -NH-, -N (Me) -, -N (Ei) -, -N (n- Pr) -, -N (i-Pr) -, -NNCH2-, or -N (n- Pr) CH2-. 100. The compound of claims 1 to 50 and 95 to 99, wherein D is azacinyl, diazepinyl, azepinyl, thiazolyl, cycloheptyl, bicyclo- [2.2.1] -heptyl, cyclopropyl, cyclobutyl, morpholinyl, piperazinyl, neopentyl, -methyl-isopentyl, 3-pentyl, 1,4-oxazepinyl, methyl, propyl normal, ethyl, 2-butyl, terbuyl, iohydro-furanyl, iorahydro-pyranyl, 7-azabicyclo- [2.2.1] - h ept i I or, cyclohexyl, cyclopentyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or phenyl, and is optionally substituted by one to one, in one or two groups (CR9R10) WE mode. 101. The compound of claims 1 to 50 and 95 to 100, wherein D is azacinyl, diazepinyl, azepinyl, thiazolyl, cycloheptyl, bicyclo- [2.2.1] - eptyl, cyclopropyl, cyclobutyl, morpholinyl, piperazinyl, 1,4-oxazepinyl, tetra-hydro-furanyl, teirahydro-pyranyl, 7-azabicyclo- [2.2.1] -heptyl, cyclohexyl, cyclopenfyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or phenyl, and is optionally substituted by one to four, in a modality one or two groups (CR9R10) WE. 102. The compound of claims 1 to 50 and 95 to 101, wherein (CR9R10) WE is alkyl, alkoxy, halogen, -CH2-helerocyclyl, -CONH-cycloalkyl, alkyl-sulfonyl, thioalkyl, alkyl-sulfonyl-amino, haloalkyl, aminocarbonyl, alkylcarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, alkoxycarbonyl, hydroxy-alkyl, alkoxy-alkyl, hetero-cyclyl-alkyl, alkyl-carbonyl-N (alkyl) -, cycloalkylamino -carbonyl, alkyl-amino-carbonyl, heleroaryl, dialkyl-amine-alkyl, pseudo-halogen, or helerocyclyl, or two groups (CR9R10) E, which substitute adjacent atoms on D together form alkylene dioxyl. 103. The compound of claims 1 to 50 and 95 to 102, wherein (CR9R1 °) WE is methoxy, methyl, 1,2,4-triazolyl-methylsulphonyl, ethoxy I or, 4-methyl-1-piperazinyl -methyl, fluorine, chlorine, cyclohexyl-aminocarbonyl, methanesulfonyl-amino, thiomethyl, 4-morpholinyl, trifluoro-methyl, aminocarbonyl, methoxy-carbonyl, hydroxy-methyl, ethoxy-carbonyl, ethyl, methoxy-methyl, methyl-carbonyl -amino, dimethyl-amino-carbonyl, methyl-carbonyl, dimethyl-amino-methyl, methyl-carbonyl-N- (Me) -, diethyl-amino-methyl, morpholin-ylmethyl, methyl-amino-carbonyl, 1, 3, 4-oxadiazolyl, cyclopropyl-ami-non-carbonyl, 5-methyl-1, 3,4-oxadiazolyl, 5-ethyl-1, 3,4-oxadiazolyl, iodine, cyano, or cyclopropyl-amino-carbonyl, two groups (CR9R10) E, which replace the adjacent atoms on D together form meylenedioxyl, or ethylenedioxyl. 104. The method of any of claims 55 to 94, wherein the compound is selected from the compounds of any of claims 1 to 50 and 95 to 103.