MXPA00011505A

MXPA00011505A - Heterocyclic compounds and methods to treat cardiac failure and other disorders

Info

Publication number: MXPA00011505A
Application number: MXPA/A/2000/011505A
Authority: MX
Inventors: Babu J Mavunkel; David Y Liu; George F Schreiner; John A Lewicki; John J Perumattam
Original assignee: Scios Inc
Priority date: 1998-05-22
Filing date: 2000-11-22
Publication date: 2002-07-25

Abstract

Compounds of formulae&agr;or&bgr;, and the pharmaceutically acceptable salts thereof, wherein each of Z1 and Z2 is independently CR4 or N;where each R4 is independently H or is alkyl (1-6C) or aryl, each of said alkyl or aryl optionally including one or more heteroatoms selected from O, S and N and optionally substituted by one or more of halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, or NROCR where R is H or alkyl (1-6C), or by one or more CN or=O, or by one or more aliphatic or aromatic 5- or 6-membered rings optionally containing 1-2 heteroatoms;R1 is formula (I);wherein X1 is CO or an isostere thereof;m is 0 or 1;Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl or two Y taken together may form an alkylene (2-3C) bridge;n is 0 or 2;Z3 is CH or N;X2 is CH, CH2 or an isostere thereof;and Ar consists of one or two phenyl moieties directly coupled to X2 optionally substituted by halo, nitro, alkyl(1-6C), alkenyl(1-6C), alkynyl(1-6C), CN or CF3, or by RCO, COOR, CONR2, NR2, OR, SR, OOCR or NROCR wherein R is H or alkyl(1-6C) or by phenyl, itself optionally substituted by the foregoing substituents;R2 is H, or is alkyl(1-6C) or aryl, each or said alkyl or aryl optionally including one heteroatome which is O, S or N, and optionally substituted by one or more of halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, or NROCR where R is H or alkyl(1-6C), alkynyl(1-6C), or by one or more CN or=O, or by one or more aliphatic or aromatic 5- or 6-membered rings optionally containing 1-2 heteroatoms;R3 is H, halo, NO2, alkyl(1-6C), alkenyl(1-6C), alkynyl(1-6C), CN, OR, SR, NR2, RCO, COOR, CONR2, OOCR, or NROCR where R is H or alkyl(1-6C) are disclosed. These compounds are selective inhibitors of p38&agr;kinase.

Description

HETEROCICLIC COMPOUNDS AND METHODS TO TREAT CARDIAC INSUFFICIENCY AND OTHER DISORDERS FIELD OF THE INVENTION The invention relates to compounds which are useful in the treatment of inflammation and which contain piperazine or piperidine portions coupled to the 5 or 6 position of indole, benzimidazole or benzotriazole. More particularly, the invention relates to novel Orthosubstituted and N-Substituted Intents as well as to methods for treating cardiac and renal conditions using these compounds and their derivatives.

BACKGROUND OF THE INVENTION A large number of chronic and acute conditions have been identified as being associated with disturbance of the inflammatory response. A large number of cytokines participate in this response, including IL-1, IL-6, IL-8 and TNF. It seems that the activity of these cytokines in the regulation of inflammation depends at least in part on the activation of an enzyme in the cellular signal pathway, a member of the MAP kinase family generally known as p38 and alternatively known as CSBP and RK. This kinase is activated by dual phosphorylation after simulation by physiochemical stress, treatment with lipopolysaccharides or with proinflammatory cytokines such as IL-1 and TNF. Accordingly, inhibitors of p38 kinase activity are useful anti-inflammatory agents. PCT applications WO98 / 282 2, WO98 / 06715, WO98 / 07425, and WO96 / 40143, which are incorporated herein by reference, describe the relationship of p38 kinase inhibitors to various disease states. As mentioned in these applications, p38 kinase inhibitors are useful in the treatment of a wide variety of diseases associated with chronic inflammation. These requests include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, asthma, adult respiratory distress syndrome, stroke, reperfusion injury, CNS lesions such as neural trauma and ischemia, psoriasis, restenosis, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcosis, bone resorption diseases such as osteoporosis, graft vs. host reaction, Crohn's disease, ulcerative colitis including inflammatory bowel disease (IBD) ) and piresis. The PCT applications referred to show compounds which are p38 kinase inhibitors which are thought to be useful in the treatment of these pathological conditions. These compounds are imidazoles or Índoles substituted in the 3 or 4 position with a piperazine or piperidine ring attached through a carboxamide bond. Other compounds that are "^ Litheii piperazine conjugates with indoles are described as insecticides in WO97 / 26252, also included herein by way of reference.

BRIEF DESCRIPTION OF THE INVENTION The invention relates to compounds useful in the treatment of inflammation in general, including specific conditions such as those described in the above background section. It has been observed that certain novel compounds inhibit p38 kinase, in particular p38 kinase, and therefore are useful in the treatment of diseases mediated by this enzyme. The compounds of the invention have the formula: preferably those of the formulas: twenty ^^^^^ ^^^^^^ f »* aa¿a» ate and its pharmaceutically acceptable salts, characterized in that each Z1 and Z is independently CR4 or N; wherein each R4 is independently H or is (1-6C) alkyl or aryl, each alkyl or aryl optionally including one or more heteroatoms selected from O, S and N and optionally substituted by one or more halogen, OR, SR, NR2 , RCO, COOR, CONR2, OOCR, or NROCR where R is H or alkyl (from 1-6C) or by one or more CN or = O, or by one or more 5- or 6-membered, aliphatic or aromatic rings containing optionally 1-2 heteroatoms; R1 is where X1 is CO or an isostere thereof; m is 0 or 1; And it is optionally substituted alkyl, optionally substituted aryl, or optionally arylalkyl substituted or two and together can form an alkylene bridge (of 2-3C); n is 0, 1 or 2; Z3 is CH or N; X2 is CH, CH2 or an isostere thereof; and Ar consists of one or two phenyl portions directly coupled to X2 optionally substituted by halogen, nitro, (1-6C) alkyl, (1-6C) alkenyl, (1-6C) alkynyl, CN or CF3, or by RCO, COOR, CONR2, NR2, OR, SR, OOCR or NROCR wherein R is H or (1-6C) alkyl or phenyl, optionally substituted with the following substituents; R2 is H, or is (1-6C) alkyl or aryl, each alkyl or aryl optionally including one or more heteroatoms of O, S or N, and optionally substituted by one or more halogen, OR, SR, NR2, RCO, COOR, CONR2, OOCR, or NROCR where R is H or alkyl (of 1-6C), or by one or more CN or = O, or by one or more rings of 5 or 6 aliphatic or aromatic members which optionally contain 1-2 heteroatoms; R3 is H, halogen, NO2, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, OR, SR, NR2, RCO, COOR, CONR2, OOCR, or NROCR wherein R is H or alkyl (1-6C). Thus, in one aspect, the invention relates to compounds of the formulas set forth above. In other aspects, the invention relates to methods for producing these compounds, to pharmaceutical compositions containing them, and to methods of treating inflammation using these compounds. The invention also relates to the treatment of conditions associated with heart failure using the compounds of the invention and other compounds described herein.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the formulas 1-4 are useful in a wide variety of physiological contexts, as described below. Among the preferred embodiments are those wherein both Z 1 and Z 2 are CH or where Z 1 is CR 4 and Z 2 is CH; thus, among the preferred compounds of the invention are the indole derivatives. Substituents in the 3-position especially preferable are those which are coupled via carboxamide bonds. Thus, some of the preferred embodiments of R4 have the formula RNHCO- wherein R is alkyl or substituted alkyl. In general, substituents in the nitrogen-containing portion of the idol, benzimidazole, or benzotriazole nuclei are designed to improve solubility. In this manner, typically, substituents R2 and R4 are polar or contain polar groups. In other preferred embodiments, the substituents shown for the compounds of the invention are as set forth below. With respect to R1: X is CO or a sterostero thereof. In this way, in addition to CO, X1 there can be CH2, SO, SO2 or CHOH. CO is preferred. Z3 is CH or N; Z3 = CH is preferred. m is typically 1; however, in some compounds of the invention, m may be 0; in this way, this substituent is a 5-membered ring. X2 is CH2 if Ar consists of a single portion of phenyl or CH if Ar consists of two portions of phenyl or may be a part thereof. Thus, for suitable modes of Ar, X2 can be any of the alternatives discussed above for X1. The phenyl portions represented by AR can be optionally substituted by substituents among which are (1-6C) alkyl, halogen, RCO, COOR, CONR2, OR, SR, NR2, OOCR, NROCR, NO2, CN, or CF3 ) wherein R is H or alkyl (from 1 -6 C). The phenyl portions can also be substituted with an additional phenyl residue, preferably in the 4-position. The additional phenyl residue itself can be substituted with the above-mentioned substituents. The additional phenyl can be substituted in all 5 positions, but preferably in less, preferably in 1-2 positions or in none. Preferred substituents include alkyl (1-6C), OR, NR2 and halogen, especially halogen and OCH3. The substituents may occupy the 5 positions of the phenyl substituent, preferably of 1-2 positions or the phenyl may not be substituted. n can be 0, 1 or 2, and is preferably 0. However, when n is 1, Y is present and can be alkyl, arylalkyl or aryl, all of which can be optionally substituted by the substituents set forth above with reference to Ar. When n is 2, the two Y groups together can constitute an alkylene bridge. A preferred bridge is an ethylene bridge. Preferred embodiments of Y when n is 1 include unsubstituted alkyl and unsubstituted arylalkyl. With reference to R2: R2 is preferably H, but it can also be a suitable substituent. Said substituents are typically and preferably alkyl or substituted alkyl. The alkyl or substituted alkyl may optionally include one or more heteroatoms which may be O, N or S, preferably N and O. The permitted substitutions in the alkyl group are discussed above; the Preferred substituents include OR, wherein R is H or alkyl (from 1-6C) y = 0. Also included within the preferred substituents in the alkyl group are typical portions, such as piperazine, pyridine, piperidine, phenyl, and the like. Preferably, the alkyl embodiments of R2 contain 0.1 or 2 substituents. Preferred embodiments of R2 include those of the formula - (CO) OY 'where Y' is, for example, - (CH2) nNR2, where n is an integer of 0-6 and R is as defined above; or Y 'is, for example, an aliphatic or aromatic ring system, as Other illustrative embodiments of R2 include nicotinoyl and its isomers, loyl, and substituents of the general formula Y1 (CH2) nNH (CH2) nCHOH (CH2) n- wherein Y1 is a generic substituent such as for example alkyl, piperazinyl, optionally substituted piperidinyl, cyclohexyl, phenyl or methoxy, and the like wherein each n is independently an integer of 1-3. Y1 is quite variable and can generally include any portion that does not interfere. Other embodiments include those of the general formula Y1NH (CH2) n-CO, wherein Y1 and n are as described above; also included are those of the general formula Y1 (CH2) nNH (CH2) nCO wherein Y1 and n are as described above; and Y1 of the formula (CH2) nCO and Y1 (CH2) NNHCO, wherein Y1 and n are as previously described are R2N (CH2) n-; and those of the formula R2N (CH2) n- wherein R is alkyl (from 1-6C) and n is an integer of 1-3. With respect to R3: Although R3 can be H, other modalities are included and may be preferred. Among these are halogen, OR, NR2, and alkyl (1-6C), as particularly desired. Characterized in that Z1 or Z2 forms, preferably Z1 is CR4, wherein R4 is other than H, preferred embodiments of R4 include those of the formula R2N (CH2) n- wherein each R is independently alkyl (1-6C) or H and n is an integer of 1-6; or of the formula Y1 (-CH2) n- wherein Y1 is as defined above and n is an integer of 1-6; or those of the formula Y1 NHCO; or those of the formula R2NCO, wherein the R2 substituents taken together form a ring that can be substituted, preferably by alkyl, arylalkyl, and the like. When R4 is Y1 (CH2) n-, for example, Y1 can be or R4 can be ^^^ ^^^ ™ ^ ^ g ^ aij Other illustrative embodiments of R4 include 2-, 3- and 4-pyridyl, 2-, 3- and 4-piperidyl. The compounds of the formulas (1) - (4) can be substituted in the form of their pharmaceutically acceptable acid addition salts including salts of inorganic acids such as hydrochloric, sulfuric, hydrobromic, or phosphoric acid or salts of organic acids such as acetic, tartaric , succinic, benzoic, salicylic, and the like. If a carboxyl portion is present, these compounds can also be supplied as a salt with a pharmaceutically acceptable base, including inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide and the like or a salt with a base organic like caffeine. Particularly preferred compounds of the invention have the formulas (5) and (6): In these compounds, R1 has the formula shown, wherein each X3 is independently halogen, alkyl (1-6C), OR or NR2, wherein R is H or alkyl (from 1-6C), and p is an integer of 0 --3. R2, R3 and R4 are as described above. Similar compounds are also preferred wherein the positions of R3 and the illustrated embodiment of R1 are reversed; that is, R3 is in position 5 and R1 is in position 6.

Synthesis of the compounds of the invention The compounds of the invention can be synthesized by a variety of methods, most of which are known per se in the art. The portion of idol, benzimidazole or benzotriazole can be delivered per se and the R1 substituent coupled thereto. R1 may be supplied as such, or its synthesis can be completed when the residue piperazyl or piperidyl already coupled to the portion of Ndol, benzimidazole or benzotriazole. Alternatively, especially in the embodiments wherein R3 represents a non-hydrogen substituent, the appropriately substituted p-aminoenzoic acid derivative can be cyclized and replaced with piperazine or piperidine. Thus, for example, as shown in reaction scheme 1, a piperazine protected with tert-butyloxycarbonyl (BOC) is coupled to 5-carboxybenzimidazole (or 5-carboxy-indole, or 5-carboxy-benzothrazole) in a reaction mixture containing a coupling agent such as EDAC in an inert, aprotic solvent to obtain the coupled carboxamide which is then deprotected and treated with substituted or unsubstituted benzyl or benzoyl halides.

SCHEME 1 Ra = for example, 2,6-difluorophenyl; 3,4-difluorophenyl; 2,3- difluorophenyl; 3,5-difluorophenyl, 3-chlorophenyl; 4-chlorophenyl; 4- 20 carboxymethylphenyl; 4-methoxyphenyl; 4-trifluoromethyloxyphenyl; 4-methylphenyl; 6- chloropiperonyl; t-butylcarboxyphenyl; 3-trifluorophenyl; 2,4-dichlorophenyl; 3,4-dichlorophenyl; phenyl; methoxyphenyl; or p-toluyl. ** á * m ?? ulßttmU! ak * JM L Alternatively, as shown in reaction scheme 2, the 5-carboxylated benzimidazole (or indole or benzotriazole) is reacted with a piperazine or piperidine moiety already substituted by X2-Ar. In this reaction, the piperazyl or piperidyl derivative is reacted directly with the carboxylated bicycloheteroatom containing core in the presence of a coupling agent such as EDAC, in the presence of an inert solvent as set forth above.

SCHEME 2 In order to form the substituted piperazine required for scheme 2, the piperazine is first converted to the BOC derivative and then reacted with ArCHO in the presence of a borohydride under acidic conditions to give the substituted piperazine as shown in the reaction scheme 3.

SCHEME 3 Ar = for example, An alternative for coupling piperazine or piperidine derivatized to indole, benzimidazole or benzotriazole is shown in reaction scheme 4. In this reaction the piperidine ring is derivatized to an appropriate leaving group as shown and then treated with a base such as NaH in a inert solvent to obtain the desired conjugate. ^^^^^ ¿^ ^ * ^ g «g ^ ¡* £ SCHEME 4 Another alternative is shown in the reaction scheme 5. In this perspective, a protected piperidone is reacted in the presence of a base such as NaH, with the appropriate phosphonate ester to obtain a protected benzyl piperidine. The product is then deprotected and reacted with the indole, benzimidazole or benzotriazole carboxylate using an appropriate dehydrating agent. The product is then reduced to the desired arylalkylated piperidine derivative.

SCHEME 5 The reaction of scheme 6 illustrates a method for preparing compounds of the invention in which the indole is substituted in its 6-membered ring. In reaction scheme 6, the aniline is reacted suitably substituted with 1-methylmercaptyl-2,2, -dialkoxyethane in the presence of tertiary butyryl chloride and a base to provide the desired indole. Depending on the nature of the substitution of the aniline starting material, more than one isomer may result as shown. The methyl mercaptyl group that remains in the 5-membered ring is reduced with Raney nickel and, a mandatory methyl group included in the original aniline portion is hydrolyzed to the corresponding carboxylic acid. The resulting acid is then reacted with the desired piperidine or piperazine derivative in the presence of a coupling agent such as EDC. s Jáá? ^ ííá. , SCHEME 6 X = CI, 0CH3, CH3 The alkylation of the nitrogens in the indole, benzimidazole or benzotriazole nucleus in the compounds per se is carried out by conventional means by reacting the halide of the substituent to be added in the presence of a base and acetone, as shown in the descriptions of scheme 7.

SCHEME 71 where X = H, OMe, Cl; each R is H or alkyl; n is an integer; or . > »^ ^^^^^^^^^^^^^^^ where X = H, OHC3, Cl, CH3) etc .; each R is H, alkyl, aryl or both R together / \. NR / Substituents at position 3 of indole can be modified using the general procedures shown in Scheme 8: SCHEME 8 where X = OMe, Cl, CH3; each R is H, alkyl, aryl or the R groups together are piperazinyl, 4-benzylpiperazinyl, etc. For the synthesis of the compounds wherein n is 1, ie, wherein the piperidine ring contains other substituents in addition to those bound in the compounds of the invention, the substituted piperidine 4 is first protected using BOC2O in THF or another aprotic solvent and then it is reacted with, for example, alkyl iodide in the presence of S-butylithium / TMEDA using, for example, ether as solvent to produce the alkylated piperidine. The alkylated piperidine is then converted to the compound of the invention by deprotection followed by formation of the carboxamide bond to the indoyl residue. This is exemplified below. For the compounds of the invention which are substituted in the 3-position, the reaction scheme shown at the beginning of Example 23 can be conveniently used. Typically, the carboxamide starting material is treated with trifluoroacetic anhydride to obtain the immediate trifluoroacetyl, which is also a compound of the invention. After treatment with the base, the 3-carboxylic acid is formed and can then be reacted with a suitable amine to obtain other compounds of the invention.

Administration and uses The compounds of the invention are useful in the treatment of conditions associated with inflammation. Thus, the compounds of the formulas (1) - (4) or their pharmaceutically acceptable salts are used in the manufacture of a medicament for the prophylactic or therapeutic treatment of mammals, including humans, with respect to conditions characterized by excessive production of cytokines and / or inappropriate or unregulated cytosine activity in cells such as cardiomyocytes, cardiofibroblasts and macrophages. The compounds of the invention inhibit the production of cytokines such as TNF, IL-1, IL-6 and IL-8, cytokines that are important > . i > t. proinflammatory components in several states and different pathological syndromes. In this way, the inhibition of these cytokines benefits the control and mitigation of many diseases. The compounds of the invention are shown herein to inhibit a member of the MAP kinase family called variously as p38 MAPK (or p38), CSBP, or SAPK-2. The activation of this protein has been shown to regulate the production of prostanoids, such as PGE2, and matrix metalloproteinases, such as collagenase-3, and to accompany the exacerbation of diseases in response to stress caused, for example, by treatment with lipopolysaccharides or cytokines as TNF and IL-1. The inhibition of p38 activity, therefore, is predictive of the ability of a drug to provide a beneficial effect in the treatment of diseases such as coronary artery disease, congestive heart failure, cardiomyopathy, myocarditis, vasculitis, restenosis, as occurs after coronary angioplasty, atherosclerosis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, multiple sclerosis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), silicosis, pulmonary sarcosis, sepsis, septic shock, endotoxic shock, toxic shock syndrome, cerebral and cardiac insufficiency (cerebrovascular accident) characterized by ischemia and reperfusion injury, surgical procedures, such as transplant and graft rejection procedures, cardiopulmonary pacemaker, coronary artery pacemaker graft , injuries of the SNC, in including open and closed head trauma, inflammatory ophthalmic conditions such as conjunctivitis and uveitis, acute renal failure, glomerulonephritis, inflammatory bowel diseases, such as Crohn's disease or ulcerative colitis, graft-versus-host disease, bone resorption diseases such as osteoporosis, type II diabetes, pyresis, psoriasis, cachexia, viral diseases such as those caused by HIV, CMV, herpes, and cerebral malaria, tumor metastasis and acute pain, such as that associated with dental surgery, dysmenorrhea and post-orthopedic surgery. In recent years, p38 has been shown to comprise a group of MAP kinases designated p38a, p38ß, p38? and p38d. Jiang, Y. et al., J Biol Chem (1996) 271: 17920-17926 was the first report of recognition of p38β as a 372-amino acid protein closely related to p38a. Kumar, S. et al., Biochem Biophys Res Comm (1997) 235: 533-538 and Stein, B. et al., J Biol Chem (1997) 272: 19509-19517 reported a second isoform of p38ß, p38ß2, which contains 364 amino acids with 73% identity with p38a. All these reports show evidence that p38ß is activated by proinflammatory cytokines and environmental stress, although the second reported pattern of p38ß, p38ß2, seems to be expressed preferably in the CNS, compared to more ubiquitous tissue expression. of the p38a. In addition, it was observed that the activated transcription factor -2 (ATF-2) is a better substrate for p38ß2 than for p38a, thus suggesting that separate mechanisms of action may be associated with these forms. The physiological role of p38ß1 has been questioned by the latter ^^^^^^^^^^^^^^ * two reports since it can not be found in human tissue and does not show a significant kinase activity with the substrates of p38a. The identification of p38? reported in Li, Z, et al., Biochem Biophys Res Comm (1996) 228: 334-340 and p38d in VVang, X, et al., J. Biol Chem (1997) 272: 23668-23674 and in Kumar, S, et al., Biochem Biophys Res Comm (1997) 235: 533-538. The data suggest that these two isoforms of p38 (? And d) represent a unique subset of the MAPK family based on their tissue expression patterns, substrate utilization, response to direct and indirect stimuli, and susceptibility to kinase inhibitors. Several results were reported regarding the response to drugs targeting the p38 family between p38a and either putative p38β1 or p38β2 or both by Jiang, Kumar, and Stein cited above, as well as Eyers, PA and others, Chem and Biol (1995) 5: 321-328. Another document, Wang, Y. and others, J Biol Chem (1998) 273: 2161-2168 comments on the importance of such differential effects. As Wang pointed out, a number of stimuli, such as myocardial infarction, hypertension, vascular diseases, viral myocarditis, and dilated cardiomyopathy, cause an increase in cardiac workload and elevated mechanical stress in cardiomyocytes. These presumably lead to an adaptive hypertrophic response that, if unchecked, has decidedly negative consequences. Wang cites previous studies that have shown that in hearts treated by reperfusion of ischemia, the activities of p38 MAPK increase in association with hypertrophy and programmed cell death. . 1 r. »? ? Ryi Wang shows in the cited paper that activation activity p38SS gives as result hypertrophy, whereas activation of p38a activity leads to myocyte apotheosis. Thus, the selective inhibition of p38a activity compared to the activity of p38ß will have benefits in the treatment of conditions associated with heart failure. These conditions include congestive heart failure, cardiomyopathy, myocarditis, vasculitis, vascular restenosis, vascular disease, conditions associated with cardiopulmonary pacemakers, coronary artery pacemakers, grafts and vascular grafts. Furthermore as the isoform is toxic in other muscle cell types, the a-selective inhibitors would be useful for conditions associated with cachexia attributed to TNF or other conditions such as cancer, infection, or autoimmune disease. The compounds described herein that selectively inhibit the activity of the p38a isoform are useful for the treatment of conditions associated with the activation of p38a, in particular those associated with cardiac hypertrophy, ischemia or other environmental stresses such as oxidation injury, hyperosmolarity or other agents or factors that activate the p38a kinase, or cardiac insufficiencies, for example congestive heart failure, cardiomyopathy and myocarditis. The compounds that show this activity have the formula wherein R > 1, D R2, D R3, Z -7I, and Z are as described in accordance with claim 1. The manner of administration and formulation of the compounds described herein depend on the nature of the condition, the severity of the condition, the particular subject to be treated, and the judgment of the doctor; the formulation will depend on the form of administration. Since these compounds are small molecules, they are conveniently administered by oral administration by compressing them with suitable pharmaceutical excipients in order to provide tablets, capsules, serums and the like. Among the formulations suitable for oral administration are also included minor components such as compensators, flavoring agents and the like. Typically, the amount of active ingredient in the formulations will be on the scale of 5% -95% of the total formulation, but wide variation is allowed depending on the carrier. Suitable carriers include sucrose, peptin, magnesium stearate, lactose, peanut oil, olive oil, water and the like. The compounds useful in the invention may also be administered through suppositories or other transmucosal vehicles.

Typically such formulations will include excipients that facilitate passage of the compound through the mucosa such as pharmaceutically acceptable detergents. The compounds can also be administered topically, for topical conditions such as psoriasis, or in a formulation designed to penetrate the skin. These include lotions, creams, ointments and the like which can be formulated by known methods. The compounds can also be administered by injection, including intravenous, intramuscular, subcutaneous, or intraperitoneal. Typical formulations for this use are liquid formulations in isotonic vehicles such as Hank's solution or Ringer's solution. Alternative formulations include nasal sprays, liposomal formulations, slow release formulations and the like as are known in the art. Any suitable formulation can be used. A compendium of formulations known in the art is found in Remington Pharmaceutical Sciences, latest edition, Editorial Mack Publishing Company, Easton, PA. The consultation of this manual is common in the art.

The doses of the compounds of the invention will depend on a variety of factors that may be different for each patient. However, it is believed that generally, the daily oral dose uses 0.001-100 mg / kg total body weight, preferably 0.01-50 mg / kg and more preferably about 0.01 mg / kg-10 mg / kg. In dosage regimen it will vary, however, depending on the conditions being treated and the doctor's judgment. As explained above, although the compounds of the invention can be used in humans, they are also available for veterinary use in the treatment of animal subjects. The following examples are intended to illustrate but not to limit the invention. The examples in 1-3 illustrate reaction scheme 1: EXAMPLE 1 Preparation of 4-BOC piperazinyl-benzimidazole-5-carboxamide -Benzimidazole carboxylic acid (3.25 g, 20 mmol) was reacted with 2.52 g (20 mmol) of diisopropylcarbodiimide in dry DMF at room temperature for 15 minutes. To this reaction mixture was added 3.75 g (20 mmol) of f-butyl-1-piperazine caroxylate, and the mixture was stirred for 18 h. The mixture was poured into water and extracted with methylene chloride (3x100 ml). The combined extracts were washed again with water, saline and dried over MgSO. After removing the solvent in vacuo, the residue was chromatographed on a column of silica gel eluting with CHCb Methanol (gradient, 0 to 5% methanol) to yield 5.69 g (86%) of the product. 1 H-NMR (DMSO d 6): s8.3 (1 H); m 7.7-7.6 (2H), m 7.2-7.3 (1 H), m 3.6-3.3 (8H) s 1.4 (9H); MS (ESI) m / e 330 (m +). EXAMPLE 2 Preparation of piperazinyl-benzimidazole-5-carboxamide The N-BOC piperazinyl-benzimidazole-5-carboxamide (5.6 g) was stirred in 20 mL of 4 molar HCl-dioxane for 1 hour. The dioxane was removed under reduced pressure to obtain a hydrochloride salt in quantitative yield. This was used for alkylations without any additional purification. ^^^ g¡Í¿¡ ^ j ?? g * Éi ^ EXAMPLE 3 Preparation of 4- (2,6-difluorobenzyl) -piperazinyl-benzimidazole-5-carboxamide A. Piperazinyl-benzimidazole-5-carboxamide (0.186 g, 0.5 mmol) was taken up in 5 mL of DMF and 0.101 g (1 mmol) of triethylamine and stirred for 15 minutes at room temperature. To this reaction mixture was added 0.104 g of 2,6-difluorobenzyl bromide and the mixture was stirred for 20 hours. This was poured into water and extracted with methylene chloride (3x50 mL). The combined extract was washed, in addition, with saline, water and dried over MgSO. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with chloroform-methanol (0 to 5% methanol gradient). Evaporation of the desired fraction gave 48.9 mg of the desired product; MS (ESI) m / e 356 (M +). B. Using the procedure set forth in paragraph A, the following compounds were prepared: , ..

Example 4 illustrates the reaction scheme 2: EXAMPLE 4 Preparation of 4- (314-dichlorophenyl) -piperazinyl-benzimidazole-5-carboxamide A. Benzimidazole-5-carboxylic acid (1 mmol, 162 mg) was dissolved in 5 mL of dry DMF and reacted with 1-ethyl-3- (3-dimethylaminepropyl) -carbodimide hydrochloride for 15 minutes. 1- (3,4-Dichlorophenyl) -piperazine (1 mmol, 231 mg) was added, followed by 10 mg of DMAP. The mixture was stirred for 20 hours at room temperature. The reaction mixture was poured into water and extracted with methylene chloride (3x50 mL). The extracts were combined, washed with saline, water and dried over MgSO4. After evaporation of the solvent, the residue was chromatographed on silica gel with chloroform-methanol (0-5% methanol, gradient). Evaporation of the desired fractions gave 150 mg (40% of the title compound: MS (ESI) m / e 375 (M +) B. Using the procedure of paragraph A, the following compounds were prepared: Example 5 illustrates the reaction scheme 3: EXAMPLE 5 A. Preparation of 4- (4-methylthiobenzyl) -piperazinyl-benzimidazole-5-carboxamide A mixture of 4- (methylthio) -benzaldehyde (305 mg, 2 mmol) and N-BOC piperazine (372 mg, 2 mmol) was mixed with dry methanol for 30 minutes. To this mixture was added 1.6 g of borohydride supported on polymer (2.5 mmoles / g, in Amberlite, IRA-400, Aldrich) and the mixture was stirred for 24 hours. The polymer was removed by filtration and evaporation of the solvent resulted in 4-BOC-1- (4-methylthio) -benzylpiperazine in quantitative yield. MS (ESI) m / e 322, (M +). The 4-BOC-1- (4-methylthio) -benzylpiperazine was taken up in 10 mL 1: 1 TFA / methylene chloride and stirred for 1 hour at room temperature. The solvents were removed in vacuo and the residue was used without purification to couple with benzimidazole-5-carboxylic acid. The benzimidazole-5-carboxylic acid (2 mmole, 324 mg) was taken up in 15 mL of dry DMF and reacted with 2 mmole (382 mg) of EDAC at room temperature for 15 minutes. The 1- (4-methylthio) -benzylpiperazine described above was added as a solution of DMF, followed by 505 mg (5 mmol) of TEA. The mixture was stirred for 20 hours. The mixture was poured into water and extracted with methylene chloride (3x50 mL). The combined extracts were washed with saline, water and dried over MgSO. The solvent was removed in vacuo and the residue was chromatographed. Evaporation of the desired fractions gave the title compound; MS (ESI) m / e 366 (M +). Using this procedure, the following compounds were prepared: B. Preparation of 4-benzyl-piperidyl-n-benzimidazole-5-carboxamide The benzimidazole-5-carboxylic acid (1.62 g, 10 mmol) was reacted with EDAC (1.92 g, 10 mmol) in 40 mL of dry DMF at room temperature for 15 minutes. To the reaction mixture was added 4-benzylpiperidine (1.75 g, 10 mmol) and DMAP (-20 mg, catalyst) and the mixture was stirred at room temperature for 20 hours. It was vacuum in water and extracted with methylene chloride (3x100 mL). The combined extract was washed with water, saline and again with water. The extract was dried over MgSO4 and evaporated. The residue was chromatographed on a column of silica gel with chloroform-methanol (0 to 5% methanol). Evaporation of the desired fractions gave 1.5 g (47%) of the product after recrystallization from ethyl acetate-hexane. 1 H NMR (CDCl 3): d = 7.8 (s, 1 H); 7.1-7.3 (rn, 8H); 4.8-4.7 (broad m, 1 H), 3.7-3.9 (broad m, 1 H); 3.1-2.7 (broad m, 2H); 2.55 (d, 2H); 2.0-1.1 (m, 5H). MS (ESI) m / e 319 (M +), 318 (M + -H).

EXAMPLE 6 Preparation of additional benzimidazolpiperidinyl modalities The reaction scheme in this example is usually as follows: a) Nitric acid / sulfuric acid, 100 ° C, 1 hour. b) Methanol, 10% PdC, formic acid, 1-3 hours. c) 90% aqueous formic acid, reflux, 1.5 hours. d) Benzylpiperidine, EADC-HCI, DMAP, DMF. 2-Methoxy-3,4-dinitrobenzoic acid: 4-nitro-2-methoxybenzoic acid, 3.09 g, was added to 20 mL of nitric acid: sulfuric acid 1: 1 at 0 ° C. After the addition was complete, the reaction mixture was heated at 100 ° C for 30 minutes. It was cooled to room temperature and emptied into 200 mL of ice water. The aqueous layer was extracted with ethyl acetate and washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to obtain a yellow solid. This material was purified by chromatography on silica using ethyl acetate / hexane / methanol / acetic acid 5/5/1 / 0.1. The yellow solid was used for the next step. EIMS M + 242 (Exp. 242). NMR, d6 DMSO: s (1H) 8.5, s (1 H) 7.5, s (3H) 4.05 2-Methoxy-3,4-diaminobenzoic acid 2-methoxy-3,4-dinitrobenzoic acid (1.0 g) was dissolved in methanol (50 mL) and treated with 100 mg of 100% palladium in carbon. The reaction mixture was purified with nitrogen and placed in a cooling bath. Under treatment with 5 mL of formic acid, an energetic effervescence was noted, which was quenched with additional cooling. The reaction mixture was filtered through Celite and concentrated to obtain a tan solid. (A color change occurs quickly when maintained) EIMS M + 182, Exp. 182. 6-methoxy-5-benzimidazolecarboxylic acid 2-methoxy-3,4-d-aminobenzoic acid (0.5 g) was dissolved in 10 mL of 90% aqueous formic acid. The mixture was brought to reflux and kept there for 90 minutes. It was cooled to room temperature and the solvent was removed under pressure to obtain a dark solid. EIMS M + 192, Eixp. 192 6-methoxy- (4-benzylpiperidinyl) benzimidazole-5-carboxamide: 6-Methoxy-5-benzimidazolecarboxylic acid (1 equivalent) was treated with 1.1 equivalents of EDAC-HCI and 1 equivalent of 4-benzylpiperidine in the presence of a catalytic amount of DMAP in DMF / DCM 1: 1 for 3-6 hours . The reaction mixture was then concentrated and taken up in ethyl acetate. After washing with 5% aqueous sodium carbonate and a -to-*""". u-M. ^^^ &g ^^^^ saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude material. This crude material was purified by chromatography on silica. M + 349, Exp. 349. 6-Chloro- (4-benzylpiperidinyl) benzimidazole-5-carboxamide: It was prepared in a similar way. MH + 353, Exp. 353.

EXAMPLE 7 N-Propylation of 4-benzyl-piperidinyl-benzimidazole-5-carboxamide B8 «i ¡i y. & amp; amp; amp; < 4 > 4- (4-Benzyl) -piperidinyl-benzimidazole-5-carboxamide (318 mg, 1 mmol) in 20 mL of acetone was collected. KOH (solid, 280 mg, 5 mmol) was added followed by 2-iodopropane (1 g ~ 6 mmol) and the mixture was refluxed for 20 hours. The acetone was removed in vacuo and the residue was extracted from the water with methylene chloride (3x50 mL). The extract was dried, evaporated and the residue chromatographed on silica gel with CHCl3-methanol (0 to 3% methanol). MS (ESI) m / e 360 (M +). HPLC: (C18 Vydac column, 5 to 40% acetonitrile / water containing 0.1% TFA) two peaks show both isomers.

EXAMPLE 8 Preparation of 4-benzylpiperidinyl-indole-5-carboxamide The indole-5-carboxylic acid (1.61 g, 10 mmol) was reacted with EDAC (1.92 g, 10 mmol) in 40 mL of dry DMF for 15 minutes. 4-benzylpiperidine (1.75 g, 10 mmol) was added followed by DMAP (20 mg, catalyst) and the reaction mixture was stirred for 20 hours. The mixture was poured into water and extracted with methylene chloride (3x100 mL). The combined extract was washed with dilute hydrochloric acid, saturated sodium bicarbonate and water and dried over MgSO4. After evaporation of the solvent, the residue was chromatographed with methylene chloride-methanol (0 to 2% methanol, gradient) to obtain 1.60 g (50%) of the product after recrystallization from ether-hexane. MS (ESI) m / e 318 (M +), (317 + -H). 1 H NMR (CDCl 3) d = 8.5 (s, 1 H); 7.7 (s, 1 H); 7.4-7.15 (m, 8H); 6.8 (s, 1 H); 4.8-4.6 (br, m, 1 H); 4.1-3.9 (br, m, 1 H); 3.1-2.7 (br, m, 2H); 2.6 (d, 2H); 1.9-1.7 (br, m, 3H); 1.4-1.2 (br, m, 2H).

EXAMPLE 9 Preparation of 4-benzylpiperidinyl-1- (2-propyl) -indole-5-carboxamide A mixture of 4-benzylpiperidinyl-benzimidazole-5-carboxamide (318 mg, 1 mmol), solid KOH (280 mg, 5 mmol) and 2-iodopropane (1 g, 6 mmol) was refluxed in 20 mL of acetone for 20 hours. After removal of acetone in vacuo, the residue was extracted from the water with methylene chloride (3x50 mL). The combined extract was dried, evaporated and chromatographed to obtain 180 mg (50%) of the desired product. 1 H NMR (CDCl 3): d = 7.7 (s, 1 H); 7.4-7.1 (m, 7H); 4.8-4.6 (m, 1 H); 3.0-2.7 (br, m, 4H); 2.6 (d, 2H); 1.8-1.45 (m, 3H); 1.5 (d, 6H); 1.3-1.1 (m, 2H). MS (ESI) m / e 360 (M).

EXAMPLE 10 Preparation of 4- (4-chlorobenzyl) -piperazinyl-1- (2-propyl) -indole-5-carboxamide 4- (4-Chlorobenzyl) piperazinyl-indole-5-carboxamide (420 mg, 1.32 mmol) was taken in acetone. Solid KOH (280 mg, 5 mmol) was added followed by the addition of 2-iodopropane (1 g, 6 mmol) and the mixture was refluxed and stirred for 20 hours. The acetone was removed in vacuo and the residue was extracted from the water using methylene chloride. The extract was dried and evaporated and the residue was chromatographed on a column of silica gel using ethyl acetate-hexane (ethyl acetate, 0 to 25%, gradient) and recrystallized from ether-hexane to obtain 300 mg of the product. 1 H NMR (CDCl 3): d = 7.6 (s, 1 H); 7.3-7.1 (m, 6H); 6.5 (s, 1 H); 4.65-4.55 (m, 1 H); 3.8-3.5 (m, 4H); 3.4 (s, 2H); 2.4-2.5 (s, 4H); 1.5 (d, 6H). MS (ESI) m / e 395 (M +).

EXAMPLE 11 Preparation of additional analogues Using the procedure of Example 8, the following compounds were prepared: Using the procedure of Example 10, these compounds were alkylated; for example, ^^^^ $ & EXAMPLE 12 Preparation of 3-chlorobenzylpiperazyl-N-benzyl-benzamidozol-5- and 6-carboxamides A. This paragraph describes the process of formation of the N-benzyl derivatives of the compounds of the invention; the following paragraphs describe the alkylation with other portions. 3-Chlorobenzylpiperazinyl-benzimidazole-5-carboxamide (0.12 g, 0.33 mmol) and benzyl bromide (0.058 g, 0.33 mmol) in 15 mL of DMF 10 were combined with K 2 C 3 (0.09 g, 0.66 mmol). The mixture was stirred at room temperature overnight, then heated at 45 ° C for 3 hours. EtOAc was added and washed with water. The organic layer was evaporated and the isomers were separated by silica gel column chromatography using 5% MeOH in EtOAc. Isomer a (70 mg, 15 48%), EM (ESI) m / e 444 (M +) and isomer b (40 mg, 27%), MS (ESI) m / e 444 (M +) were obtained. A similar treatment of 6-carboxamide gives the corresponding compound, wherein R2 is benzyl. B. 3-Chlorobenzylpiperazinyl-N- (2-propyl) -benzimidazole-5- and 6-carboxamides 3-Chlorobenzylpiperazinyl-benzamidazole-5-carboxamide was substituted by substituting benzyl bromide for 2. -iodopropane in paragraph A. The isomers were separated using the same chromatographic conditions. Isomer a, MS (ESI) m / e 396 (M +); isomer b, MS (ESI) m / e 396 (M +). A similar treatment of 6-carboxamide gives the corresponding compound, wherein R2 is 2-propyl.

C. 3-Chlorobenzylpiperazinyl-N-methyl-benzimidazole-5 and 6-carboxamide 3-Chlorobenzylpiperazinyl) -benzimidazole-5-carboxamide was substituted by substituting benzyl bromide for iodomethane in the procedure of paragraph A. The isomers were separated using column of silica gel, using 50% acetone in acetonitrile as the eluting solvent.

Isomer a, MS (ESI) m / e 368 (M +), isomer b, MS (ESI) m / e 368 (M +). A similar treatment of 6-carboxamide gives the corresponding compound, wherein R2 is methyl. Similarly, 4-benzylpiperidinyl- (1-meth1) -indole-5-carboxamide (MS (ESI) m / e 332 (M +)) was prepared from 4-benzylpiperidinyl-indole-5-carboxamide. A similar treatment of 6-carboxamide gives the corresponding compound, wherein R2 is methyl. - ^. 3-Chlorobenzylpiperazinyl-N-ethyl-1-benzimidazole-5 and 6-carboxamide 3-chlorobenzylpiperazinyl-benzimidazole-5-carboxamide was alkylated by substituting benzyl bromide for iodomethane in the paragraph A. Isomer a, MS (ESI) m / e 382 (M +), isomer b, MS (ESI) m / e 382 (M +). A similar treatment of 6-carboxamide gives the corresponding compound, wherein R2 is ethyl. Similarly, 4-benzylpiperidinyl- (1-ethyl) -indole-5-carboxamide (MS (ESI) m / e 346 (M +)) was prepared from 4-benzylpyridinyl-5-benzyl -ca rboxa mid a. A similar treatment of 6-carboxamide gives the corresponding compound, wherein R2 is ethyl.

EXAMPLE 13 Preparation of 4- (4-chlorobenzyl) -piperidinyl-indole-5-carboxamide 1 - . 1 - • ^ i ^ -S ^^ .- i This example illustrates the reaction scheme 5.

A. Preparation of N-BOC-4- (4-chlorobenzylene) -piperidine N-BOC-4-piperidone (2.0 g, 10 moles) was taken up in diethyl-4-chlorobenzylphosphonate (2.6 g, 10 mmole in dry THF) Sodium hydride (400 mg, 60% dispersion in mineral oil; mmoles) and the mixture was refluxed for 3 hours THF was removed in vacuo and the residue was extracted from the water with methylene chloride.The extract was dried over MgSO4 and the residue was chromatographed on silica gel to give 0.615 g 1 H NMR (CDCl 3): d = 7.3 (d, 2H); 7.1 (d, 2H); 6.3 (s, 1 H); 3.55-.350 (m, 2H); 3.45-3.35 (m, 2H), 2.45-2.35 (m, 2H), 2.30-2.25 (m, 2H), 1.25 (s, 9H), EIMS: 307 (M +), 251 (M + -C3H8).

B. Coupling of 4-chlorobenzylene-piperidine with indole-5-carboxylic acid The N-BOC-4- (4-chlorobenzylene-piperidine), described above, was deprotected by stirring in 20 mL of dichloromethane-trifluoroacetic acid 1: 1 for 1 hour. hour. It was evaporated and dried under vacuum for 1 hour to remove all traces of trifluoroacetic acid. It was dissolved in 15 mL of dichloromethane and the TFA salt was neutralized by the addition of a slight excess of triethylamine. Solution A. Indole-5-carboxylic acid (0.32 grams, 2 mmol) was reacted with 0.383 grams of EDAC in 30 mL of dry dichloromethane for 15 minutes. To this solution was added the methylene chloride solution of 4-chlorobenzylene-piperidine (solution A), followed by the addition of 10 mg of DMAP. The mixture was stirred for 20 hours. The mixture was washed with water, 2N HCl, 5% sodium carbonate and then with water. The organic solution was dried, evaporated and the residue was chromatographed on silica gel eluting with ethyl acetate-hexane (1: 4). Yield: 260 mg (37%). EIMS: 350 (M +), 315 (M + -CI) 1 H NMR (CDCl 3): d = 8.4 (s, 1H); 7.7 (s, 1H); 7.3-7.0 (m, 7H); 6.5 (s, 1H); 6.25 (s, 1 H); 3.8-3.0 (m, br, 4H); 2.6-2..20 (m, br, 4H).

C. Hydrogenation of 4- (4-chlorobenzylene) -pyridin-indole-5-carboxamide 4- (4-chlorobenzylene) -peridin-indole-5-carboxamide (240 mg, 0.68 mmol) was dissolved in 40 mL of THF . Pd / C (25 mg) was added and the mixture was hydrogenated (1 atm) for 20 hours with rapid stirring. The catalyst was removed by filtration through Celite and the organic solution was evaporated and the residue was recrystallized from methylene chloride / hexane. EIMS quantitative yield: 352 (M +), 351 (M + -H).

EXAMPLE 14 Using the general procedure set forth in example 13, the following compounds were prepared: EXAMPLE 15 Synthesis of cis-methyl-4-benzylpiperidin-1-yl-indole-5-carboxamide A. A mixture of 4-benzylpiperidine (3.52 mL, 20.0 mmol) and di-tert-butyl-dicarbonate (5.45 g, 25.0 mmol) in 100 mL of THF was refluxed for 20 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (2 x 100 mL). The combined organic extract was washed with water and saline. The extract was dried over Na SO4 and evaporated. The residue was chromatographed in , Jtlna¡ & .- * & - « y-yjy "'•• --TtHlH''1- * - *» "- *" - a column of silica gel with 10% ethyl acetate-Híxano The evaporation of the desired fractions yielded 5.02 g (91%). %) of the product as an oil, MS (ESI) m / e 275 (M +) B. A mixture of 1-BOC-4-benzylpiperidine (0.825 g, 3.0 mmol) and N, N, N ', N', - tetramethylethylenediamine (TMEDA) (0.59 mL, 3.9 mmol) in 6 mL of Et2O was cooled to -78 ° C under argon, a 1.3 M solution of s-BuLi in cyclohexane (3.0 mL, 3.9 mmol) was added dropwise.After the addition was complete, the reaction mixture was stirred at -20 ° C for 30 minutes and cooled again to -78 ° C. Methyl iodide (0.28 mL was added. , 4.5 mmol) and the reaction mixture was stirred at -78 ° C for 5 minutes, the cooling bath was removed and heating continued for 3 more minutes The reaction mixture was poured into water and extracted with ethyl acetate (2 x 25 mL) The combined organic extract was washed with water and saline. The reaction was dried over Na2SO4 and evaporated to give 0.58 grams (67%) of an oil which was a spot by TLC (silica gel)., 10% ethyl acetate-hexane). This material was used directly in the next step. MS (ESI) m / e 289 (M +). C. To a solution of 1-BOC-2-methyl-4-benzylpiperidine (0.29 g, 1.0 mmol) in 5 mL of dichloromethane was added trifluoroacetic acid (TFA) (0.5 mL). After stirring at room temperature for 10 hours, the reaction mixture was evaporated in vacuo and azeotroped twice with dichloromethane and twice with hexane. The residue was dissolved in 5 mL of dichloromethane and diisopropylethylamine (1.6 mL, 10 mmol) was added. In a separate flask, a mixture of 5-indolecarboxylic acid (0.19 g, 1.2 mmol) and EDAC (0.23 grams, 1.2 mmol) in 15 mL of dichloromethane was dissolved and stirred at room temperature for 5 minutes. The first solution was added to this reaction mixture and the resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into water and extracted with ethyl acetate (2 x 50 mL). The combined organic extract was washed with water and saline. The extract was dried over Na2SO and evaporated. The residue was chromatographed on a silica gel column of 1% MeOH-dichloromethane. Evaporation of the desired fractions gave 0.18 g (54%) of the product as an oil. When tested as described below, the title compound has a 1C5o = 280 nM.

EXAMPLE 16 Preparation of 4-chloro- (4-benzylpiperidinyl) indole-5-carboxamide and 6-chloro- (4-benzylpiperidinyl) indole-5-carboxamide A. The synthesis of idol was carried out by the method of Gassman, P.G. J Am Chem Soc (1974) 96: 5495-5507. To a solution of 2.0 grams (10.8 mmol) of 4-amino-2-chloro methylbenzoate in 30 mL of CH2CI2 at -60 ° C 1.2 g (10.8 mmol) of t-butyl hypochlorite in 20 mL of CH2CI2 they were added. After 10 minutes, 10.8 mmol of methylthioacetaldehyde dimethylacetal in 10 mL of CH2Cl2 were added and stirring was continued at 60 ° C for 1 hour. Subsequently, 10.8 mmoles of Et3N in 10 mL of CH2Cl2 were added and the solution was allowed to warm to room temperature. The solvent was evaporated and the residue was dissolved in 30 mL of CCI4, 5 mL of ET3N was added and the mixture was refluxed for 4 hours. The solvent was removed and the residue was dissolved in 50 mL of ether. The cyclization from acetal to indole was carried out by stirring this solution for 3 hours with 20 mL of 2N HCl. The ether layer was washed with saturated NaHCO3, dried, filtered and evaporated. The isomeric characters were separated by column chromatography on silica gel. The structure of the isomers was identified by NMR spectroscopy. Isomer: 5-carboximet¡l-4-chloro-3-tiometil¡ndol, H NMR (CDCl3) d 2.35 (s, 3H), 3.95 (s, 3H), 7.32 (s, 1H), 7.42 ( s, 1H), 8.33 (s, 1H), 8.61 (s, 1H) Isomer b: 5-carboxymethyl-6-chloro-3-tiometilindol, 1H NMR (CDCl3) d 2.42 (s, 3H) , 3.97 (s, 3H), 7.20 (s, 1 H), 7.25 (d, 1 H), 7.71 (d, 1 H), 8.58 (s, 1 H). A solution of 100 mg of 5-carboxymethyl-4-chloro-3-thiomethylindole (isomer a) in 10 mL of ethanol was treated with Raney W-2 nickel until the dethomethylation was complete. Ester isolated indole was treated with NaOH in metanokagua (1: 1), and thus 60 mg of 4-chloroindole-5-carboxylic acid were isolated as a white solid, 1H NMR (DMSO-d6), dd 6.61 (s, 1 H), 7.41 (d, 1 H), 7.52 (s, 1 H), 7.62 (d, 1 H) 11.62 (s, 1 H). To a solution of 50 mg (0.25 mmol) of the aforementioned indole acid in 10 mL of DMF were added 50 mg (0.28 mmol) of 4-benzylpiperidine and 60 mg (0.28 mmol) of EDAC. The reaction mixture was stirred overnight, diluted with ethyl acetate and washed with water. The organic layer was dried, filtered and evaporated to obtain a white solid. This was purified by silica gel chromatography followed by crystallization to obtain 50 mg of 4-chloro-5- (4-benzylpperidinyl) -indole carboxamide as a white solid, MS (M + 352). Isomer b was converted to 6-chloroindole-acid 5-carboxylic acid using the same reaction sequence as described above and 4-benzylpiperidine for coupled to 6-chloro-5- (4-benzylpiperidinyl) -indole carboxamide as a solid white, MS (M + 352). B. Using the method of paragraph A, 4-chloro- (4- (4-fluorobenzyl) piperidinyl) indole-5-carboxamide and 6-chloro- (4- (4-fluorobenzyl) -piperidinyl) indole-5 were prepared carboxamida.

^^? ^ ^ J ^ j wH EXAMPLE 17 The corresponding derivatives of 6-piperidinylindole Compounds similar to those of paragraphs A and B of Example 16, but in which the piperidinyl substituent is in the 6-position are synthesized as follows: a) Methanol, thionyl chloride, reflux b) ^^ * i) N-chlorosuccinimide, DCM, metiltioacetaldehído dimethylformamide, triethylamine, reflux ii) CHCI3, reflux iii) HCl c) Raney Ni, EtOH d) Methanol, sodium hydroxide, reflux e) benzylpiperidine, EDAC "HCI, DMAP , DMF / DCM. f) Acetone, potassium hydroxide, nicotinoyl chloride. Specifically, the following compounds were prepared according to this method: 4-benzylpiperidinyl-5-chloroindole-6-carboxamide: MH + 351, exp 352; 4-benzylpiperidinyl-7"chloroindole-6-carboxamide: MH + 351, exp 352; 1-N-Cyano-4-benzyl-pyridinyl-7-chloroindole-6-carboxamide: MH + 457, exp 457; 1-nicotinoyl-3- (2-dimethylamino) ethylaminocarbonyl-4-benzylpiperidinyl-7-chloroindole-6-carboxamide: MH + 571, exp 571. (See examples 19 to 21 for the addition of substituents at positions 1 and 3.) EXAMPLE 18 Preparation of 4-methoxy- (4-benzylpperienyl) indole-5-carboxamide and 6-methoxy- (4-benzylpiperidinyl) -dol-5-carboxamide A. Preparation of 4-methoxyindole- and 6-methoxyindole-5-carboxylic acid The corresponding methyl esters of these indole acids were prepared by a modified method of scheme 6 in accordance with Inoue, S. Heterocycles, (1992 34: 1017-1029, in which the two isomeric indole acids were obtained in a ratio of 3: 2, 5-carboxymethyl-4-methoxyindole, 1 H NMR (CDCl 3), d 2.42 (s). , 3H), 3.92 (s, 3H), 4.13 (s, 3H), 7.14 < gf ^^ j ^ (d, 1 H), 7.18 (d, 1 H), 7.55 (d, 1H), 9.41 (s, 1 H). 5-carboxymethyl 6-methoxyindole. 1 H NMR (CDCl 3), d 2.38 (s, 3 H), 3.81 (s, 3 H), 3.95 (s, 3 H), 6.83 (s, 1 H), 7.21 (s, 1 H), 8.22 (s, 1 H) ), 8.50 (s, 1 H).

B. Conversion to the title compound 4-Methoxy or 6-methoxy-indole-5-carboxylic acid was coupled with 4-benzylpiperidine to obtain the title compounds, MS (M + 349). In addition, 4-methoxy-indole-5-carboxylic acid was coupled with 4- (4-fluorobenzyl) piperidine to obtain 4-methoxy-4- (4-fluorobenzyl) p-peridinyl) -dol-5-carboxamide, MS (M + 367) and 6-methoxy-indole-5-carboxylic acid was coupled with 4- (4-fluorobenzyl) piperidine to obtain 6-methoxy- (4-fluorobenzyl) piperidinyl) indole-5-carboxamide. MS (M + 367).

EXAMPLE 19 Preparation of N- (3-cyclohexylmethylamino-2-hydroxypropyl) -4-benzylpiperidinyl-indole-5-carboxamide A. The title compound was prepared according to scheme 7. To an ice-cooled solution of 1.0 g (3.0 mmol) of 4-benzylpiperidinyl indole-5-carboxamide in acetone, 15 mmol of powdered KOH was added followed by 3.0 mmoles of epibromidrine, and the mixture was stirred for 30 minutes. The mixture was filtered and the solution evaporated. The residue was dissolved in ethyl acetate, washed with water, dried and evaporated. After purification by silica gel column chromatography, 435 mg of epoxide was obtained. MS (M + 373). To a solution of 200 mg (0.54 mmoles) of the above indole epoxide in 5 ml of MeOH, 121 mg (1.1 mmoles) of ciciohexylmethylamine was added and the mixture was refluxed for one hour. The crude product was purified on a silica gel column. The amino compound was converted to its HCL salt by treating it with ethanolic HCL. MS (M + 487). B. Following the procedure of paragraph A, but substituting piperazine for cyclohexylmethylamine, N- (3-methylpiperazin-2-hydroxypropyl) -4-benzylpiperidinyl indole-5-carboxamide: He prepared. MS (M + 473); substituting benzylamine for cyclohexylmethylamine N- (3-benzylamino-2-hydroxypropyl) -4-benzylpiperidinyl indol-5-carboxamide: EM (M + 481) was prepared; substituting p-methoxybenzylamine for cyclohexylmethylamine, N- [3-. { (4-methoxybenzyl) -amino} -2-hydroxypropyl] 5- (4-benzylpiperidinyl indole-5-carboxamide: MS (M + 511) was prepared; Y substituting propylamine for cyclohexylmethylamine, N-. { 3-n-propylamino-2-hydroxypril} -4-benzylpiperidinyl indole-5-carboxamide: MS (M +) 433 was prepared. - to- -. a ^ - * EXAMPLE 20 Preparation of additional 1-substituted derivatives A. Preparation of additional N- (4-pyrido-P-4-benzylpiperidinyl indol-5-carboxamide 0. 318 mg (1 mmol) of 4-benzylpiperidinyl indole-5-carboxamide were dissolved in 15 ml of dry DMF. 80 mg (60% suspension in oil) of sodium hydride was added, and the mixture was stirred for 30 minutes under nitrogen. The mixture was cooled to 0 ° C, and 200 mg (1.1 mmol) of isonicotinyl chloride hydrochloride was added, and the mixture was stirred for 20 hours at room temperature. The reaction was quenched by the addition of saturated ammonium chloride solution, diluted with water, and the product extracted with dichloromethane. The extract was dried, evaporated and the residue was chromatographed on silica gel (ethyl acetate-hexane, gradient, 50-75% ethyl acetate) to yield 150 mg of the pure product. ESI MS (M + 423, M + -H, 422). Using the procedure of the preceding paragraph, but substituting 4-picolyl chloride hydrochloride for isonicotinyl chloride hydrochloride, N- (4-pyridylmethyl) -4-benzylpiperidinyl indol-5-caboxamide: MS (M + 409) was prepared.

B. Preparation of 1-nicotinnoyl- (4-benzylpperidinyl) -indole-6-carboxamide: This compound was prepared in a similar manner. M + 423 C. Preparation of 1-nicotinoyl-6-methoxy-4-benzylpiperidinyl indole-5-carboxamide: This compound was prepared in a similar manner. M + 490.

D. preparation of N-methylacetyl-4-benzylpiperidinyl indole-5-carboxamide and its free acid: 1. 95 g (6.13 mmoles) of 4-benzylpiperidinyl indole-5-carboxamide were dissolved in 30 ml of DMF and treated with 320 mg (8 mmol, 60% suspension in oil) of sodium hydride for 30 minutes. The reaction mixture was cooled to 0 ° C and 1,225 g (8 mmol) of 5-bromomethylacetate were added and stirring was continued for 1 hour at 0 ° C. The ice bath was removed and stirring was continued for another 6 hours at room temperature. The reaction was quenched by adding saturated ammonium chloride solution, diluted with water and extracted with dichloromethane. The extract was dried, evaporated and the residue was purified by silica gel column chromatography, eluting with ethyl acetate-hexane (25-35% ethyl acetate) to yield 2.2 g (92%) of the desired product. MS: M +, 390; M + -1, 389. 1H NMR (CDCl 3): d 7.7 (s, 1 H); 7.35-7.1 (m, 8H); 6.6 (s, 1 H); 5.1 (s, 2H); 3.75 (s, 3H); 3.0-2.7 (br, m, 4H); 2.6 (d, 2H); 1.9-1.2 9m, 5H). 2.15 g (5.5 mmol) of 4-benzylpiperidinyl indole-5-carboxamide-1-methylacetate from the previous paragraph were taken up in 20 ml of ethanol. A solution of 2.0 g of K2CO3 in 20 ml of water was added, and the mixture was refluxed for 2 hours. The ethanol was extracted under reduced pressure, the remaining solution was diluted with water and acidified with concentrated HCL. The precipitated product was collected by filtration, washed with water and dried to produce 1.9 g of the product. MS: M +, 376; M + -H, 375. and ^^ at ^ a ^ g ^ t ^ wíB ^ at Preparation of 1-acrylic- (4-benzylpiperidinyl) -indole-5-carboxamide 0.318 g (1 mmol) of (4-benzylpiperidinyl) - indol-5-carboxamide were taken up in 15 ml of dry acetone, and reacted with 0.2 g (5 mmol) of powdered KOH for 15 minutes. The mixture was cooled in ice and 0.225 mg (2.5 mmol) of acryloyl chloride were added in one batch. Stirring was continued at 0 ° C for 20 minutes, after which the reaction was continued stirring at room temperature for 1 hour, the solvent was removed in vacuo and the residue was extracted with ethyl acetate from water. The extract was dried and evaporated. TLC (ethyl acetate-hexane) and the mass spectrum (M + at 372) confirmed the desired product. This product was used without further purification for the next step. 1-f3- (2-propylamino) -proponyl-1- (4-benzylpiperidinyl) -5-indole caboxamide: The product obtained above was dissolved in 20 ml of dichloromethane, and reacted with 0.1 ml of isopropylamine at room temperature for 18 hours. The solvent was removed and the product was purified by column chromatography on silica gel eluting with chloroform-methanol (95: 5). Product: 180 mg, M +, 431.

G. 1- (3-piperazinylproponyl) - (4-benzyl) -piperidinyl-indole-5-carboxamide The 1-acryloyl- (4-benzyl) -piperidinyl-indole-5-carboxamide was reacted with tert-butyl-1-piperazine carboxylate as described above. The product was deprotected using methanolic HCl. M + 458 • rMá? M. ,,. L..M-V.a i. l, i H. 1- (3-benzylaminopropionyl-4-benzylpiperidinyl) -indole-5-carboxamide: was prepared by reacting 1-acryloyl- (4-benzylpperidinyl) -indole-5-carboxamide with benzylamine. M + 479. 1- (3-morpholinylpropionyl) -4- (4-benzylpyridinyl) -indole-5-carboxamide was prepared by reacting 1-acryloyl- (4-benzylpiperidinyl) -indole-5-carboxamide with morpholine, M + 459.

J. Preparation of 4-benzylpiperidinyl indole-5-carboxamide-1-acetic acid n-propylamide: The 4-Benzylpiperidinyl indole-5-carboxamide-1-acetic acid (200 mg, 0.53 mmol) of Example 21 was reacted with 120 mg (0.61 mmol) of EDC in 10 mL of dry dichloromethane for 30 minutes. N-propylamine (100 μl, excess) was added and the mixture was stirred for 20 hours. The solution was diluted with dichloromethane, washed with water and 5% sodium carbonate solution. The organic solution was dried and evaporated, and the residue was purified by silica gel chromatography with ethyl acetate-hexane (3: 2) to yield 100 mg of the product. MS (M + 417).

K. Preparation of 4-benzylpiperidinyl-indole-5-carboxamide-1-acetic acid, (4-methoxybenzyl) amide: Following the procedure in the previous paragraph, but substituting p-methoxybenzylamine for n-propylamine, 4-benzylpipperidinyl-indole-5-carboxamia-1-acetic acid, (4-methoxybenzyl) amide was prepared. MS, ESI: M + H, 496.

Preparation of 1- (Diethylaminoethyl) -6-methoxy- (4-benzylpyridinyl) -indole-5-carboxamide: 0. 3 g (0.862 mmol) of 6-methoxy- (4-benzylpperidinyl) -indole-5-carboxamide were dissolved in 20 ml of dry DMF. This was cooled in an ice bath and reacted with 0.12 g of NaH (3 mmol, 60% suspension). 0.172 mg (1 mmol) of 2- (diethylamino) -ethylchloride hydrochloride were added and the mixture was stirred for 18 hours. The reaction mixture was poured into water and extracted with dichloromethane (3 x 75 ml). The combined extract was washed again with water, dried over anhydrous MgSO 4, evaporated and purified by silica gel chromatography on a chromatroton, using CH 2 Cl 2 -Metanol (95: 5), to yield 0.22 g of the desired product. This was converted to the HCl salt and lyophilized, M + 448.

M. Following the procedure of the previous paragraph, but substituting 1- (diethylamino) -n-propylchloride hydrochloride for 1- (diethylamino) -ethylchloride hydrochloride, 1- (diethylamino) -n-propyl- (4-benzylpiperidinyl) -indole -5- 15 carboxamide: He prepared. M + 468 Similarly, 1- (diethylamino) -ethyl- (4-benzylpiperidinyl) -indole-5-carboxamide, He prepared. M + 454. Similarly, 1- (diethylamino) -n-propyl-6-chloro- (4-benzylpiperidinyl) -indole-5-carboxamide, was prepared, M + 502. Similarly, 1- (diethylamino) -ethyl- (4'-fluoro-4-benzylpperidinyl) -indole-5-carboxamide, was prepared, M + 472. In addition, 1- (diethylamino) -n-propyl-6-methoxy- (4-benzylpiperidinyl) -indole-5-carboxamide, prepared, M +, 498.

EXAMPLE 21 Preparation of 3-Substituted Intents The general procedure for the synthesis of 3-substituted indoles is schematized in the following way: a) trifluoroacetic anhydride, THF, 0 ° C, 3 hours. b) Aqueous NaOH, reflux, 3-6 hours. c) R2NH, EDACHCI, DMAP, DCM / DMF, 3-6 hours.

A. 3-Trifluoroacetyl-4-benzylpiperidinyl-indol-5-carboxamide: 4-benzyl piperidinyl-indole-5-carboxamide (1 equivalent) was dissolved in anhydrous THF. The reaction vessel was purged with nitrogen and placed in an ice bath. Trifluoroacetic anhydride (1.2-1.3 equivalents) was added by syringe. The reaction was allowed to continue at 0 ° C, until no more initial material was discovered by thin layer chromatography. In some cases, the addition of additional trifluoroacetic anhydride was required to facilitate conclusion of the reaction. After completion of the reaction, the reaction mixture was concentrated and redissolved in the minimum amount of ethyl acetate for chromatography using silica. The crude material was chromatographed using ethyl acetate and hexanes (1: 1). The identity of the product 3-trifluoroacetyl-4-benzyl piperidinyl indole-5-carboxamide was determined by electronic impact mass spectroscopy. (MH + 413 (exp.414), base peak 240.) Similarly, using as the starting material, 4-benzyl piperidinyl indole-6-carboxamide or 6-methoxy- (4-benzyl piperidinyl) indole-5 -carboxamide, the corresponding 3-trifluoroacetyl derivatives were prepared.

B. 4-Benzylpiperidinyl indole-5-carboxamide-3-carboxylic acid: the trifluoroacetyl indole derivative of paragraph A, was suspended in aqueous sodium hydroxide (10 N, 5-6 equivalent) and brought to reflux. At the beginning of the reflux, a minimum amount of methanol was added to facilitate solubility. The reaction mixture was refluxed for 3-6 hours. Upon completion of the reaction, the mixture was cooled to room temperature and diluted with water, and washed with ether. The aqueous layer was acidified to pH4 with concentrated HCl, while placed in an ice bath. The acid was extracted into ethyl acetate and washed with saturated sodium chloride solution., dried over anhydrous sodium sulfate and concentrated to give a solid. This solid was purified by chromatography on silica using ethyl acetate: hexanes: methanol: acetic acid, 5: 5: 1: 0.1. The identity of the product was determined by electronic impact mass spectroscopy. (MH + 361 (exp.361), 317, base peak 144). Similarly, the additional 3-fluoroacetyl derivatives prepared in paragraph A were converted to the corresponding 3-carboxylic acids.

C. 3- (2-Dimethylamino) ethylaminocarboxamidyl- (4-benzylpperidine!) Indole-5-carboxamide: the carboxylic acid of paragraph B (1 equivalent) was treated with 1.1 equivalents of EDAC »HCl and 1 equivalent of dimethylaminoethylenediamine in the presence of a catalytic amount of DMAP in DMF / DCM 1: 1 for 3-6 hours. The reaction mixture was concentrated and taken up in ethyl acetate. After washing with 5% aqueous sodium carbonate and a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate and concentrated to give crude material. This crude material was purified by chromatography on silica. The identity of the product, shown below, was determined by electronic impact mass spectroscopy. (MH + 432 (exp 432)). ."4. Finally, by making the appropriate substitutions for the carboxamide and for the reactive amine, the following compounds of the invention were prepared according to the reaction scheme set out at the beginning of this example; all are of the formula set forth above, but with alternative substituents on the carbonyl portion at the 3-position of the indole portion, as noted. i. 3- (2-methoxyethylaminocarboxamidyl) - (4-benzylpylinidinyl) indole-5-carboxamide (the 3-carbonyl substituent is 2-methoxy-ethylamine, MH + 418, exp 418); I. 3- (2-methylaminoethylaminocarboxamidyl) - (4-benzylpiperidinyl) indole-5-carboxamide (the 3-carbonyl substituent is 2-methylamino ethylamine, MH + 418, exp 418); iii. 3- (N-methyl-2-aminoethylaminocarboxamidyl) - (4-benzylpiperidinyl) indole-5-carboxamide (the 3-carbonyl substituent is 2-aminoethyl (methyl) amine, MH + 418, exp 418); V. 3- (4-benzylpiperidinylcarboxamidyl) - (4-benzylpperodinyl) -dol-5-carboxamide (the 3-carbonyl substituent is 4-benzylpiperidinyl, MH + 519, exp 519); v. 3- (4-benzylpiperidinylcarboxamidyl) - (4-benzylpiperidinyl) -dol-6-carboxamide (the 3-carbonyl substituent is 4-benzyl piperidinyl, MH + 519, exp 519); saw. 3- (4-fluorobenzylaminocarboxamidl) - (4-benzylpiperidinyl) indole-5-carboxamide (the 3-carbonyl substituent is 4-fluorobenzylamine, MH + 469, exp 469); vii.3-2- (3,4-dimethoxyphenyl) ethylamidocarboxamidyl- (4-5-benzylpiperidinyl) indole-5-carboxamide (the 3-carbonyl substituent is 2- (3,4-dimethoxyphenyl) ethylamine, MH + 525 exp 525); viii. 3-trifluoroacetyl- (4-benzylpiperidinyl) indole-5-carboxamide (the 3-carbonyl substituent is trifluoromethyl, MH + 413, exp 414); ix. 3-trifluoroacetyl- (4-benzylpiperidinyl) indole-6-carboxamide (the 3-carbonyl substituent is trifluoromethyl, MH + 413, exp 414); x. 6-methoxy-3- (2-dimethylaminoethylamino) carboxamidyl- (4-benzylpiperidinyl) indole-5-carboxamide (the 3-carbonyl substituent is 2-dimethylaminoethyl, also including a substituent of 6-methoxy at the 6-position, MH + 462, exp 462). The formulas of the compounds i-x indicated above are shown below. - * - > -. - * ¡- & * * * #, Alternatively, the compounds of the invention which are indole derivatives with 3-position substitutions, can be prepared using the reaction scheme 8 set forth above.

Y) . i I LßáU &tees E. Preparation of 3-morpholinomethyl- (4-benzylpiperidinyl) -indole-5-ca rboxa mid a: Using scheme 8, 0.318 g (1 mmol) of 4-benzylpiperidinyl-indole-5-carboxamide, 0.1 g of paraformaldehyde (3.3 moles) and 0.1 ml of morpholine were collected in 25 ml absolute of ethanol and acidified by the addition of 1 ml of ethanolic HCl. The mixture was refluxed for 18 hours. The solvent was removed and the residue was extracted from the 5% sodium carbonate solution with dichloromethane. The extract was dried, evaporated and the residue was purified by column chromatography using ethyl acetate-methanol (95: 5), to yield 0.15 g of the desired product. This was converted to the HCl salt and lyophilized. M + 454 ^^ ¡^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ F. Preparation of Diethylaminomethyl- (4-benzylpperidinyl) -indole-5-carboxamide: Using scheme 8, this compound was prepared in the following manner. To a suspension of 0.41 g (1.28 mmol) of 4-benzylpiperidinyl) -indole-5-carboxamide in 5 ml of glacial acetic acid, an ice-cooled mixture of 1.2 ml of aqueous formaldehyde (37%) and 0.16 ml of ice was added. ethylamine (1.5 mmol). The reaction mixture was stirred for 30 minutes at 0 ° C and then stirring was continued at room temperature for 18 hours. This was poured into water, made basic by the addition of 20% sodium hydroxide solution, and extracted with ethyl acetate. The extract was dried and evaporated. The residue was purified by chromatography on silica gel eluting with chloroform-methanol-triethylamine (95: 5: 0.5) to yield 0.22 g of the title compound. MS: 403 M \ 331, M + -Net2. ^^^ ^^^^^ & EXAMPLE 22 Test for inhibition of p38 kinase The compounds to be tested were solubilized in DMSO and diluted in water to the desired concentrations. The p38 kinase was diluted to 10 μg / ml in a retarder containing 20 mM MOPS, pH 7.0, 25mM of beta-glycerol phosphate, 2mg / ml of gelatin, 0.5mM of EGTA, and 4mM of DTT. The reaction was carried out by mixing 20 μl of the test compound with 10 μl of a substrate mixture containing 500 μg / ml of peptide substrate and 0.2 mM of ATP (+200 μCi / ml gamma-32P-ATP) in a retarder 4x test The reaction was initiated by the addition of 10 μl of p38 kinase. The final test conditions were 25 mM MOPS, pH 7.0, 26.25 mM beta-glycerol phosphate, 80 mM KCl, 22 mM mgCI2, 3 mM MgSO4, 1 mg / ml gelatin, 0.625 mM EGTA, 1 mM of DTT, 125 μg / ml of peptide substrate, 50 μM of ATP and 2.5 μg / ml of enzyme. After an incubation of 40 minutes at room temperature, the reaction was stopped by addition of 10 μl by reaction of 0.25M phosphoric acid. A portion of the reaction was spotted onto a P81 phosphocellulose paper disk, the filters were dried for 2 minutes and then washed 4 times in 75 mM HsPO. The filters were briefly rinsed in 95% ethanol, dried, then placed in scintillation flasks with liquid scintillation mixture.

Alternatively, the substrate is biotinylated previously and the resulting reactions are applied in points on SAM2 ™ streptavidin filter frames (Promega). The filters are washed 4 times in 2M NaCl, 4 times in 2M NaCl with 1% phosphoric acid, twice in water, and briefly in 95% ethanol. The filter frames are dried and placed in scintillation flasks with liquid scintillation mixture. The incorporated accounts are determined in a scintillation counter. The relative enzymatic activity is calculated by subtracting the backup accounts (counts measured in the absence of enzyme) from each result, and comparing the resulting counts with those obtained in the absence of the inhibitor. The IC50 values were determined with curve fitting graphs available with common programs. Approximate values of Cl50 were calculated using the formula IC50 (approx.) = (A x i) / (1 - A) where A = fractional activity, i = total concentration of the inhibitor.

EXAMPLE 23 Activity of the compounds of the invention The activity of the compounds of the invention was tested as described below. The compounds tested were 4-benzylpiperidinyl or 4-benzylpiperidinyl indol-5 or 6-carboxamides. In general, the piperidinyl derivative was superior to the corresponding piperazinyl derivative. The Cl 0 for inhibition of p38a, are shown in table 1.

It is also observed that positioning the piperidinyl or piperazinyl substituent in positions 3,4,5 and 6, leads to a higher activity than positioning the substituents in positions 2 or 7. The specificity for p38a was tested for the same compounds, compared to p38ß. The results are shown in table 2.

Activity was also tested with respect to p38β for compounds of the invention, to determine the influence of the position of the piperidinyl or piperazinyl substituent. The influence of the substitution on the benzyl portion attached to the 4-position of the piperazine or piperidine was also tested. The results are shown in Table 3 in terms of percentage inhibition of p38-β activity at 50 μM concentration of the compound.

By substituting the indole portion for benzimidazole in the compounds of the invention, it also resulted in significant inhibition of p38β, when the compounds were tested at 50 μM. 4-Benzylpiperidinylbenzimidazole-5-carboximide showed 85% inhibition; 4- (3-chlorobenzyl) piperizinylbenzimidazole-5-carboxamide showed 66% inhibition. The compounds of the invention are generally specific for p38a compared to p38-β. It is observed that the specificity for a, in comparison with ß, is generally of the order of ten times. The specificity of the compounds of the invention was also tested with respect to other kinases, including p38- ?, ERK-2, PKA, PKC, cdc-2, EGF-R, and DNA-PK, as shown in Table 4 The compounds tested were 4-benzylpiper-dinylindole-5- and 6-carboxamides with the number indicating the position of the carboxamide in the ring.

The results are given in terms of approximate values of Cl50 (μM), when the compounds were tested at 50 μM, and calculated using the formula of Example 22. The exception is for p38a values, where the IC50 values were determined from the curve-dependent curve-dependent analysis analysis. concentration. As shown, all tested compounds are highly specific for p38a, compared to these additional kinases. Table 5 shows the inhibition of p38a by compounds of the invention which are 4- (benzyl-piperidinyl) indole-5-carboxamides or 4 - [(4-fluorobenzyl) piperidinyl] indole-5-carboxamides, ie compounds of formula (1) 0 (2): where R1 is of formula (11) or (12): (11) (12) The given values are IC50 in μM.

Several other compounds of the invention were also tested.

A compound of formula (3) - that is, wherein the carboximide is in the 6-position, R1 is of the formula (11), R3 is H, R2 is H, Z1 is CCOCF3 and Z2 is CH, showed 41% inhibition and 1 μM. Similarly, a compound in the 1 that R is of formula (11) and substituted in position 6 of indole, R is and both Z1 and Z2 are CH, showed an IC50 of 0.505 μM. Two compounds were also tested where R1 is of the formula: (7) in one, of formula (2) wherein R3 is MeO, R2 is H and both Z1 and Z2 are CH, gave 63% inhibition at 0.2 μM; in the other case, which is of formula (3) wherein R3 is H, R2 is H, Z1 is N and Z2 is CH, IC50 was 2.15 μM. Finally, a compound was tested in which R1 was of the formula: (8) and wherein the compound of the invention is of formula (3), wherein R3 is H, R2 is H, and both Z1 and Z2 are CH, gave 51% inhibition at 1 μM.

. . LaíA ffefel k j-JÉ

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula:

10 and its pharmaceutically acceptable salts, characterized in that each Z1 and Z2 is independently CR4 or N; wherein each R4 is independently H or is (1-6C) alkyl or aryl, each alkyl or aryl optionally including one or more heteroatoms selected from O, S and N and optionally substituted by one or more halogen, OR, SR, NR2 , RCO, COOR, CONR2,

15 OOCR, or NROCR wherein R is H or alkyl (of 1-6C) or by one or more CN or = O, or by one or more 5- or 6-membered, aliphatic or aromatic rings optionally containing 1- 2 heteroatoms; R1 is

where X1 is CO or an isostere thereof; m is 0 or 1; And it is optionally substituted alkyl, optionally substituted aryl, or optionally arylalkyl

substituted or two and together can form an alkylene bridge (of 2-3C); n is 0, 1 or 2; Z3 is CH or N; X2 is CH, CH2 or an isostere thereof; and Ar consists of one or two portions of phenyl directly coupled to X2 optionally substituted by halogen, nitro, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN or CF3, or by RCO, COOR, CONR2, NR2, OR, SR, OOCR or NROCR wherein R is H or (1-6C) alkyl or by phenyl, optionally substituted with the following substituents; R2 is H, or is (1-6C) alkyl or aryl, each alkyl or aryl optionally including one or more heteroatoms of O, S or N, and optionally substituted by one or more halogen, OR, SR, NR2, RCO, COOR, CONR2, OOCR, or NROCR wherein R is H or alkyl (of 1-6C), or by one or more CN or = O, or by one or more rings of 5 or 6 aliphatic or aromatic members optionally containing 1-2 heteroatoms; R3 is H, halogen, NO2, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, OR, SR, NR2, RCO, COOR, CONR2, OOCR, or NROCR wherein R is H or alkyl (1-6C).

2. The compound according to claim 1, further characterized by having the formula

- & i) The compound according to claim 1, further characterized in that m is 1 and each n is 0.

4. The compound according to claim 1, further characterized in that X1 is CO.

5. The compound according to claim 1, further characterized in that X2 is CH2.

6. The compound according to claim 2, further characterized in that n is 0, m is 1, X1 is CO and X2 is CH2.

7. The compound according to claim 1, further characterized in that Z1 and Z2 are CR4.

8. The compound according to claim 6, further characterized in that Z1 and Z2 are CR4.

9. The compound according to claim 1, further characterized in that Z1 is N and Z2 is CH.

10. The compound according to claim 6, further characterized in that Z1 is N and Z2 is CH.

11. The compound according to claim 2, further characterized in that it has the formula (2).

12. The compound according to claim 6, further characterized in that it has the formula (2).

13. The compound according to claim 2, further characterized in that R3 is halogen or OR where R is alkyl (1-6C).

14. - The compound according to claim 6, further characterized in that R3 is halogen or OR where R is alkyl (1-6C).

15. The compound according to claim 1, further characterized in that Z3 is CH.

16. The compound according to claim 6, further characterized in that Z3 is CH.

17. The compound according to claim 1, further characterized in that Ar is where each X is independently alkyl (from 1-6C), halogen, OR, or NR2 and p is 0, 1, 2 or 3.

18.- The compound according to claim 6, further characterized in that Ar is wherein each X3 is independently alkyl (of 1-6C), halogen OR, or NR2, and p is 0, 1, 2 or 3.

19. The compound of according to claim 6, further characterized in that it has the formula:

or having the structure of formula (5) or (6) characterized in that the positions of the indole or benzimidazole nuclei occupied by R3 and the substituent illustrated as R1 are reversed, further characterized in that R2, R3 and R4 are as described in Claim 1, and each X3 is independently halogen, alkyl (1-6C), OR, or NR2, wherein R is H or alkyl (from 1-6C) and p is 0, 1, 2 or 3.

20.- The compound according to claim 19, further characterized in that p is O op is IO 2 and each X 3 is halogen or OR where R is alkyl (from 1-3C).

21. The compound according to claim 19, further characterized in that R4 is H or has the formula CONY1 wherein Y1 is alkyl, aryl or arylalkyl optionally containing one or more heteroatoms.

?

22. The compound according to claim 19, further characterized in that R2 is H.

23. The compound according to claim 19, further characterized in that R3 is H, halogen or OR, wherein R is alkyl (of 1 -6C).

24. The compound according to claim 23, further characterized in that R3 is chloro or methoxy.

25. The compound according to claim 19, further characterized in that the R1 substituent shown at position 5 of the indole or benzimidazole nucleus is in the 6 position and R3 is in the position 5.

26.- The compound in accordance with Claim 19, further characterized in that the substituents in formulas (5) and (6) are in these positions as shown.

27. The compound according to claim 19, further characterized by having the formula

. F t i i teta-afr "wherein R2, R4 and X3 and p are defined according to claim 19.

28.- The compound according to claim 27, further characterized in that at least one of R2 and R4 is a polar group.

29. The compound according to claim 27, further characterized in that R4 is H or has the formula R2N (CH2) nNHCO wherein n is an integer of 1-3 and each R is independently H or alkyl (from 1-6C) ) or where Rs taken together form a cycle optionally containing a heteroatom which is S, O or N. The compound according to claim 19, further characterized by having the formula

wherein R3, X3 and p are described according to claim 19.

31. The compound according to claim 30, further characterized in that R2 is a polar group.

32. - The compound according to claim 29, characterized in that wherein R4 is H or has the formula R2N (CH2) nNHCO wherein n is an integer of 1-3 and each R is independently H or alkyl (from

1-6C) or wherein the Rs taken together form a cycle optionally containing a heteroatom which is S, O or N. 33.- The compound according to claim 1 which is 4-benzylpiperidinyl indole-5-carboxamide; 4-chloro-4-benzylpiperidinyl indole-5-carboxamide; 6-chloro-4-benzylpiperidinyl indole-5-carboxamide; 4-chloro- (4- (4-fluorobenzyl) piperidinyl) -indole-5-carboxamide; 6-chloro- (4 - (- fluorobenzyl) piperidinyl) -indole carboxamide; 4-methoxy- (4-benzylpiperidinyl) -indole-5-carboxamide; 6-methoxy- (4-benzylpiperidinyl) -indole-5-carboxamide; 4-methoxy- (4- (4-fluorobenzyl) piperidinyl) -indole-5-carboxamide; 6-methoxy- (4- (4-fluorobenzyl) piperidinyl) -indole-5-carboxamide; N- (3-cyclohexylmethylamino-2-hydroxypropyl) - (4-benzylpiperidinyl) -indole-5-carboxamide; N- (3-N-methylpiperazinyl-2-hydroxypropyl) - (4-benzylpiperidinyl) -indole-5-carboxamide; N- (3-benzylamino-2-hydroxypropyl) - (4-benzylpiperidinyl) -indole-5-carboxamide; N- [3-. { (4-methoxybenzyl) -amino} -2-hydroxypropyl-] - (4-benzylpiperidinyl) -indole-5-carboxamide; N-. { 3-n-propylamine-2-hydroxypropyl} - (4-benzylpiperidinyl) -indole-5-carboxamide; N- (4-pyridol) - (4-benzylpiperidinyl) indole-5-carboxamide; N- (4-pyridylmethyl) - (4-benzylpiperidinyl) -indole-5-carboxamide; N-methylacetyl- (4-benzylpiperidinyl) -indole-5-carboxamide; N-acetyl-4-benzylpiperidinyl indol-5-carboxamide; N- (n-propylamide) acetyl 4-benzylpiperidinyl indole-5-carboxamide; 4-benzylpiperidinyl-indole-5-carboxamide-1-acetic acid-n-butylamide; 4-benzylpiperidinyl-idol-5-carboxamide-1-acetic acid 4-methoxybenzyl amide; 3- (2-methoxyethylaminocarboxamidyl) - (4-benzylpiperidinyl) -dol-5-carboxamide; 3- (2-methylaminoethylaminocarboxamidyl) - (4-benzylpperidinyl) -dol-5-carboxamide; 3- (2-aminoethylaminocarboxamidyl) - (4-benzylpiperidinyl) indole-5-carboxamide; 3- (4-benzylpiperidylcarboxamidyl) - (4-benzylpiperidinyl) indole-5-carboxamide; 3- (4-Fluorobenzylcarboxamidyl) - (4-benzylpiperidinyl) indol-5-carboxamide; 3- [2- (3,5-dimethoxyphenyl) ethylcarboxamidyl] - (4-benzylpperidinyl) indole-5-carboxamide; 6-methoxy- (4-benzylpiperidinyl) indole-5-carboxamide; 3-trifluoroacetyl- (4-benzylpiperidinyl) indole-5-carboxamide; 6-methoxy-3- (2-d-methylaminoethanolyl) -carboxamidyl- (4-benzylpiperidinyl) indole-5-carboxamide; 3-trifluoroacetyl-4-benzylpiperidinylindole-5-carboxamide; 4-benzylpiperidinyl indole-5-carboxamide-3-carboxylic acid; 3- (2-dimethylamino) ethylaminocarboxamidyl- (4-benzylpiperidinyl) indole-5-carboxamide; or is a compound as explained in table 5. 34.- The compound according to claim 32 which is 4-benzylpiperidinyl-idol-5-carboxamide; 3- [2-dimethylaminoethylaminocarbonyl] -4-benzylpiperidinyl-6-methoxy indole-5-carboxamide; or 4-benzylpiperidinyl-6-methoxy benzimidazole-5-carboxamide. The use of a compound according to claim 1 or a pharmaceutical composition thereof for the manufacture of a medicament for treating a condition characterized by a proinflammation response in a subject.

36. - The use of a compound as claimed in claim 35, wherein the condition characterized by inflammation is acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, uveitis, IBD, acute renal failure, cephalic trauma, injury by reperfusion / ischemic, multiple sclerosis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, other arthritic conditions, sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, respiratory disease syndrome in adults, cerebrovascular disease , reperfusion injury, central nervous system damage, psoriasis, restenosis, cerebral malaria, chronic pulmonary inflammatory disease, pulmonary sarcosis silicosis, bone resorption disease, graft-versus-host reaction. Crohn's disease, ulcerative colitis or pyresis. 37.- The use of a compound of the formula

wherein R1, R2, R3, Z1, and Z2 are as defined in claim 1, or a pharmaceutical composition thereof for the manufacture of a medicament for treating a cardiac condition associated with heart failure in the subject. 38.- The use of a compound as claimed in claim 37, wherein the chronic heart condition is congestive heart failure, cardiomyopathy or myocarditis.

SUMMARY OF THE INVENTION

Compounds of the formulas a or ß,

and their pharmaceutically acceptable salts, wherein each Z1 and Z2 is independently CR4 or N; wherein each R4 is independently H or is (1-6C) alkyl or aryl, each alkyl or aryl optionally including one or more heteroatoms selected from O, S and N and optionally substituted by one or more halogen, OR, SR, NR2 , RCO, COOR, CONR2, OOCR, or NROCR where R is H or alkyl (of 1-6C), or by one or more CN or = O, or by one or more rings of 5 or 6 aliphatic or aromatic members which optionally contain 1-2 heteroatoms; R1 is formula (I);

wherein X1 is CO or an isostere thereof; m is 0 or 1; Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl or two Y's taken together can form an alkylene bridge (of 2-3C); n is 0 or 2; Z3 is CH or N; X2 is CH, CH2 or an isostere thereof; and Ar

. « .fe.A 1 .i «a? aawa ^ t».

consists of 1 or 2 portions of phenyl directly coupled to X2 optionally substituted by halogen, nitro, alkyl (from 1 -6C), alkynyl (from 1-6C), CN or CF3 or by RCO, COOR, CONR2, NR2, OR, SR, OOCR, or NROCR where R is H or (1-6C) alkyl or phenyl, optionally substituted by the following substituents; R2 is H, or is (1-6C) alkyl or aryl, each alkyl or aryl optionally an O, S or N heteroatom, and optionally substituted by one or more halogen, OFL SR, NR2, RCO, COOR, CONR2 , OOCR, or NROCR where R is H or alkyl (from 1-6C), alkynyl (from 1-6C), or from one or more CN or = O, or by one or more rings of 5 or 6 aliphatic or aromatic members which optionally contain 1-2 heteroatoms; R3 is H, halogen, NO2, alkyl (1-6C); these compounds are selected inhibitors of p38a kinase.

EV / MR / MV / igp * sff * ald * osu * rcp * jtr * mvh * jtc * kra * aom P00 / 1624F