RU2278115C2 - DERIVATIVES OF INDOLE ORDER AS p38 KINASE INHIBITORS - Google Patents

Abstract

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indole of the formula (1):

and their pharmaceutically acceptable salts wherein

represents a double bond; Z¹ represents nitrogen atom (N), -CR⁵ wherein R⁵ represents hydrogen atom (H), (C₁-C₆)-alkyl, hydroxy-group (OH),(C₁-C₆)-alkoxy-group or halogen atom; Z² at position 2 represents CR¹ and at position it represents CA wherein each R¹ means independently (C₁-C₆)-alkyl; A represents -W_i-COX_jY wherein Y means -COR² wherein R² means -OR, -NR_2, -NRNR₂ or -NROR wherein each R represents independently hydrogen atom (H), (C₁-C₆)-alkyl, or (C_5-C₆)-heteroaryl comprising one or two heteroatoms in ring chosen from atoms N, O and S wherein each of them is substituted with one or some groups chosen from -NR'₂, -OR', -COOR', (C₁-C₆)-alkyl, -CN, =O, and -SR' wherein each R' represents hydrogen atom (H) or (C₁-C₆)-alkyl and wherein two R or R' jointed to the same nitrogen atom (N) can form 3-8-membered ring chosen from the group comprising piperazine ring, morpholine ring, thiazolidine ring, oxazolidine ring, pyrrolidine ring, piperidine ring, azacyclopropane ring, azacyclobutane ring and azacyclooctane ring and wherein indicated ring can be substituted additionally with (C₁-C₆)-alkyl or -COO-(C₁-C₆)-alkyl; X represents unsubstituted (C₁-C₆)-alkylene, or Y means imidazole substituted with methyl group; i = 0; j = 0 or 1; R⁷ means hydrogen atom (H) or (C₁-C₆)-alkyl, -SOR, -SO₂R, -RCO, -COOR, (C₁-C₆)-alkyl-COR, -CONR₂, -SO₂NR₂,-CN, -OR, (C₁-C₆)-alkyl-SR, (C₁-C₆)-alkyl-OCOR, (C₁-C₆)-alkyl-COOR, (C₁-C₆)-alkyl-CN, or (C₁-C₆)-alkyl-CONR₂ wherein each R represent independently hydrogen atom (H), (C₁-C₆)-alkyl or aryl that is substituted optionally with halogen atom, (C₁-C₄)-alkyl or (C₁-C₄)-alkoxy-group; or R⁷ represents methoxymethyl, methoxyethyl, ethoxymethyl, benzyloxymethyl or 2-methoxyethyloxymethyl; each R³ represent independently halogen atom, (C₁-C₆)-alkyl, -OR, -SR or -NR₂ wherein R represents hydrogen atom (H) or (C₁-C₆)-alkyl; n = 0-3; L¹ means -CO; L² means (C₁-C₄)-alkylene optionally substituted with one or two groups of (C₁-C₄)-alkyl; each R⁴ is chosen independently from the group comprising (C₁-C₆)-alkyl, halogen atom, -OR, -NR₂, -SR, -SOR, -SO₂R, -RCO, -COOR, -CONR₂, -SO₂NR₂ wherein each R represents independently hydrogen atom (H) or (C₁-C₆)-alkyl; or R⁴ represents =O; m = 0-4; Ar means aryl group substituted with from 0 to 5 substitutes chosen from the group comprising (C₁-C₆)-alkyl, halogen atom, -OR, -NR₂, -SR, -SOR, -SO₂R, -RCO, -COOR, -CONR₂ and -SO₂NR₂ wherein each R represents independently hydrogen atom (H) or (C₁-C₆)-alkyl. Compounds of the formula (I) possess the inhibitory activity with respect to p38-α kinase that allows their using as components of the pharmaceutical composition.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

63 cl, 3 tbl, 9 sch, 16 ex

Description

This application claims priority in accordance with Section 35 of the Code of US Laws, § 119 (e) according to US Application Serial No. 60/154594 (Registry No. 21900-30290.20), filed May 9, 2000, and US Application Serial No. 60 / 154594, filed September 17, 1999. Priority is claimed in accordance with section 35 of the Code of US Law § 120 according to US application serial number 09/316761 of May 21, 1999. The contents of these applications are fully incorporated into this description by reference.

Technical field

This invention relates to the treatment of various diseases associated with increased p36-α kinase activity. More specifically, it relates to compounds that belong to derivatives of the indole series associated with groups of the piperazine or piperidine type, as suitable in the claimed methods of treatment.

State of the art

It was found that a significant number of chronic and acute conditions are associated with the occurrence of an inflammatory reaction. A huge number of cytokines are involved in this reaction, including IL-1, IL-6, IL-8, and TNF. It turned out that the activity of such cytokines in regulating inflammation is at least partially due to the activation of the enzyme in the signal transduction pathway of a cell, a member of the MAP kinase family, better known as p38 and, alternatively, known as CSBP and RK. This kinase is activated by double phosphorylation after stimulation with physiochemical stress, treatment with lipopolysaccharides or pro-inflammatory cytokines such as IL-1 and TNF. Therefore, inhibitors of p38 kinase activity are useful anti-inflammatory agents.

Ophthalmic diseases associated with a fibro-proliferative condition include retinal replantation accompanied by proliferative vitreoretinopathy, cataract removal with implantation of an intraocular lens and post-glaucoma drainage.

PCT applications WO 98/06715, WO 98/07425 and WO 96/40143, which are incorporated herein by reference, describe the relationship of p38 kinase inhibitors with various disease states. As noted in these applications, p38 kinase inhibitors are useful in the treatment of various diseases associated with chronic inflammation. These applications list rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, Gram-negative microorganisms sepsis, toxic shock syndrome, asthma, adult respiratory distress syndrome, stroke damage, reperfusion CNS damage, such as neural trauma and ischemia, psoriasis, restenosis, cerebral malaria, chronic pneumonia, silicosis, multiple tumors in the lung tissue, bone resorption th, such as osteoporosis, a homologous disease (graft versus host disease), Crohn's disease, ulcerative colitis, including digestive tract inflammation (IBD) and pyresis.

In the above PCT applications, compounds are described that are inhibitors of p38 kinase and may be useful in the treatment of the above disease conditions. Such compounds are either imidazoles or indoles substituted at the 3 or 4 positions by a piperazine ring attached via a carboxamide bond. Additional compounds, which are conjugates of piperazics with indoles, are described as insecticides in WO 97/26252, also incorporated herein by reference.

Certain aroyl / phenyl-substituted piperazines and piperidines which inhibit p38 kinase _-α, described in PCT application WO 00/12074, opublikozannoy 9 March 2000. In addition, piperidines and indolilzameschennye piperazines which inhibit this enzyme are described in PCT Application Publication WO 99/61426, published 2 December 1999. Karbolenovye piperidine and piperazine derivatives useful as inhibitors of p38 kinase _-α, described in PCT / US00 / 07934, filed March 24 2000.

None of the above patents disclose indole derivatives described herein that specifically inhibit p38 _-α .

Description of the invention

This invention relates to methods and compounds useful in treating conditions that are characterized by increased p38 _-α activity. Such conditions include inflammation, proliferative diseases, and certain cardiovascular disorders, as well as Alzheimer's disease, described below.

The compounds of this invention have been found to inhibit p38 kinase, in particular its _α- isoform, and thus may be useful in the treatment of diseases mediated by the activity of said kinase. The compounds of this invention are compounds of the formula

and their pharmaceutically acceptable salts or their pharmaceutical compositions in which

представляет одинарную или двойную связь;

represents a single or double bond;

one Z ² is CA or CR ⁸ A and the other is CR ¹ , CR ¹ ₂ , NR ⁶ or N, where each R ¹ , R ^6, and R ⁸ are independently hydrogen or an non-influence substituent;

и каждый i и j независимо равен 0 или 1;A is —W _i —COX _j Y, where Y is COR ² or an isoster thereof and R ² is hydrogen or an unaffecting substituent, each of W and X is a 2-6 dividing unit

and each i and j are independently 0 or 1;

Z ³ is NR ⁷ or O;

each R ^{3 is} independently an non-affecting substituent;

n is 0-3;

each of L ¹ and L ² is a link;

each R ^{4 is} independently an non-affecting substituent;

m is 0-4;

Z ¹ is CR ⁵ or N, where R ⁵ is hydrogen or an non-affecting substituent;

each of l and k is an integer from 0 to 2, where the sum of l and k is from 0 to 3;

Ar is an aryl group substituted with from 0 to 5 non-influencing substituents, where two non-influencing substituents can form a fused ring; and

.the distance between the Ar atom attached to L ² and the center of the α ring is 4.5-24

.

This invention relates to methods for treating inflammatory or proliferative conditions using these compounds. The present invention also relates to the treatment of conditions associated with heart failure and Alzheimer's disease using the compounds of the present invention.

MODES FOR CARRYING OUT THE INVENTION

The compounds of formula (I) are useful in the treatment of conditions that are characterized by increased p38 kinase activity, in particular its _α- isoform. The states “characterized by increased p38 _-α activity” include those in which the enzyme is present in an increased amount, or in which the enzyme is modified to increase its normal activity, or both. Thus, "increased activity" refers to any condition in which the effectiveness of these proteins is undesirably high, regardless of the cause.

The compounds of this invention are useful in conditions in which p38 _-α kinase exhibits increased activity. Such conditions include those in which organ fibrosis and sclerosis are caused, or are accompanied, by inflammation, oxidative damage, hypoxia, altered temperature or extracellular osmolarity, conditions causing cell stress, apoptosis or necrosis. Such conditions include ischemic-reperfusion injury, congestive heart failure, progressive pulmonary and bronchial fibrosis, hepatitis, arthritis, digestive tract inflammation, glomerular sclerosis, interstitial renal fibrosis, chronic scarring of the eyes, bladder and genital tract, bone marrow dysplasia, chronic infections or autoimmune conditions and traumatic or surgical wounds. These conditions, of course, can be treated with compounds that inhibit p38 _-α . Methods of treatment with the compounds of this invention are described below.

The compounds of this invention

Compounds suitable in this invention are derivatives of indole compounds containing the obligatory substituent A at the position corresponding to the position 2 or 3 of the indole. In general, indole cores are preferred, although alternatives within the scope of this invention are also illustrated below.

In the description below, certain positions of the molecule are described as possible “non-affecting substituents”. This term is used because substituents in these positions generally do not affect the basic activity of the molecule taken as a whole. Numerous substituents can be used in these provisions, and one skilled in the art can easily determine whether any particular arbitrary substituent is “influencing” or “not influencing”.

In the context of this description, the term “non-affecting substituent” refers to a substituent that leaves the ability of a compound of formula (I) to inhibit p38 _-α activity qualitatively unchanged. Thus, a substituent can alter the degree of inhibition of p38 _-α . However, since the compound of formula (I) retains the ability to inhibit p38 _-α activity, a substituent can be defined as “not affecting”. The results of many experiments conducted to determine the ability of a compound to inhibit p38 _-α activity are available in the art. The studies of whole blood undertaken for this purpose are presented below: the gene for p38 _-α was cloned, the protein was prepared by recombinant method and its activity was evaluated, including the ability of an arbitrarily selected compound to influence its activity. The basic characteristics of the molecule were clearly defined. The positions that are occupied by “non-influencing substituents” may be substituted by ordinary organic groups, as is customary in the art. For the present invention, it is not relevant to determine the external limits of such substitution. Clear definitions of the main characteristics of the compounds are given below. In addition, L ₁ and L _{2 are} described in this invention as linking units. The nature of such linking units is less important than the distance that they establish between the parts of the molecule. Typical linkers include alkylene, i.e., (CH ₂ ) _n —R; alkenylene, i.e., an alkylene group that contains a double bond, including a double bond at one end. Other suitable linkers include, for example, substituted alkylene or alkenylene, carbonyl groups and the like.

In the context of this description, the term "hydrocarbyl residue" refers to a residue that contains only carbon and hydrogen atoms. The residue may be aliphatic or aromatic, have a straight chain, be cyclic, branched, saturated or unsaturated. The hydrocarbyl residue, as defined, however, may contain heteroatoms in addition to the carbon and hydrogen members of the substituent residue. Thus, if it is determined that it contains such heteroatoms, the hydrocarbyl residue may also contain carbonyl groups, amino groups, hydroxyl groups and the like, or contain heteroatoms in the “backbone” of the hydrocarbyl residue.

In the context of this description, the term "inorganic residue" refers to a residue that does not contain carbon. Examples include, but are not limited to, halogen, hydroxy, NO _2, or NH ₂ .

In the context of this description, the terms “alkyl”, “alkenyl” and “alkynyl” include straight, branched and cyclic monovalent substituents. Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl, 2-propenyl, 3-butynyl and the like. Typically, alkyl, alkenyl and alkynyl substituents contain 1-10C (alkyl) or 2-10C (alkenyl or alkynyl). Preferably, they contain 1-6C (alkyl) or 2-6C (alkenyl or alkynyl). Heteroalkyl, heteroalkenyl and heteroalkynyl are also defined, but may contain 1-2 O, S or N heteroatoms or combinations thereof in the backbone of the residue.

In the context of this description, the term "acyl" covers the definitions of alkyl, alkenyl, alkynyl and their heteroform, which are attached to the additional residue through a carbonyl group.

An “aromatic” group refers to a monocyclic or bicyclic group, such as phenyl or naphthyl; “Heteroaromatic” also refers to a monocyclic or fused bicyclic ring system containing one or more heteroatoms selected from O, S and N. The introduction of a heteroatom makes it possible to include 5-membered rings, as well as 6-membered rings. Thus, conventional aromatic systems include pyridyl, pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl and the like. Any monocyclic or fused bicyclic ring systems that are aromatic with respect to the electron distribution in the ring system are included in this definition. Typically, the ring system contains 5-12 atoms in the ring.

Similarly, “arylalkyl” and “heteroalkyl” refer to aromatic and heteroaromatic systems that are attached to another residue through a carbon chain, including substituted or unsubstituted, saturated or unsaturated carbon chains, usually containing 1-6C. Such carbon chains may also include a carbonyl group, which makes them capable of giving substituents such as an acyl group.

If the compound of formula 1 contains one or more chiral centers, this invention includes optically pure forms, as well as mixtures of stereoisomers or enantiomers.

, предпочтительно, 6-20

, более предпочтительно, 7,5-10

. Расстояние измеряют от центра кольца α до атома Ar, к которому присоединено связующее звено L². Обычно, но не ограничиваясь ими, L¹ и L² представляют собой СО и их изостеры, или необязательно замещенные изостеры, или формы с более длинной цепью L², в частности, может быть алкиленом или алкениленом, необязательно замещенным не оказывающими влияния заместителями, или L¹ или L² могут быть, или могут включать гетероатом, такой как N, S или О. Такие заместители включают, но не ограничены ими, группу, выбранную из группы, включающей алкил, алкенил, алкинил, арил, арилалкил, ацил, ароил, гетероарил, гетероалкил, гетероалкенил, гетероалкинил, гетероалкиларил, NH-ароил, галоген, OR, NR₂, SR, SOR, SO₂R, OCOR, NRCOR, NRCONR₂, NRCOOR, OCONR₂, RCO, COOR, алкил-OOR, SO₃R, CONR₂, SO₂NR₂, NRSO₂NR₂, CN, CF₃, R₃Si и NO₂, где каждый R независимо является Н, алкилом, алкенилом или арилом или их гетероформами, и где два заместителя на L² могут быть объединены с образованием неароматического насыщенного или ненасыщенного кольца, которое включает 0-3 гетероатома, таких как О, S и/или N, и которое содержит от 3 до 8 членов, или указанные два заместителя могут быть объединены с образованием карбонильной группы или оксима, простого эфира оксима, сложного эфира оксима или кеталя указанной карбонильной группы.As for the part of the compound between the Ar atom attached to L ² and the ring α, L ¹ and L ² are the connecting units that separate the substituent Ar from the ring α by a distance of 4.5-24

preferably 6-20

more preferably 7.5-10

. The distance is measured from the center of the ring α to the Ar atom to which the connecting link L ² is attached. Typically, but not limited to, L ¹ and L ² are CO and their isosteres, or optionally substituted isosteres, or forms with a longer chain of L ² , in particular, can be alkylene or alkenylene, optionally substituted with no effecting substituents, or L ¹ or L ² may or may include a heteroatom such as N, S or O. Such substituents include, but are not limited to, a group selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl , heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroal kylaryl, NH-aroyl, halogen, OR, NR ₂ , SR, SOR, SO ₂ R, OCOR, NRCOR, NRCONR ₂ , NRCOOR, OCONR ₂ , RCO, COOR, alkyl-OOR, SO ₃ R, CONR ₂ , SO ₂ NR ₂ , NRSO ₂ NR ₂ , CN, CF ₃ , R ₃ Si and NO ₂ , where each R is independently H, alkyl, alkenyl or aryl or their heteroforms, and where two substituents on L ² can be combined to form a non-aromatic saturated or an unsaturated ring that includes 0-3 heteroatoms, such as O, S and / or N, and which contains from 3 to 8 members, or the two substituents can be combined to form a carbonyl group or an oxime, an oxime ether, a complex fira oxime or ketal of said carbonyl group.

Isosteres of CO and CH ₂ include SO, SO ₂ or CHOH. CO and CH _{2 are} preferred. Thus, L ^{2 is} substituted with 0-2 substituents. Where appropriate, two optional L ² substituents may be combined to form a non-aromatic saturated or unsaturated hydrocarbyl ring that includes 0-3 heteroatoms such as O, S and / or N, and which contains from 3 to 8 members . Two optional substituents can be combined to form a carbonyl group, which can be successively converted to oxime, oxime ether, oxime ester or ketal.

Ar is aryl, heteroaryl, including 6-5 fused heteroaryl, cycloaliphatic or cycloheteroaliphatic, which may optionally be substituted. Preferably Ar is optionally substituted phenyl. Each substituent on Ar is independently a hydrocarbyl residue (1-20C) containing 0-5 heteroatoms selected from O, S and N, or an inorganic residue. Preferred substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkyl, NH-aroyl, halogen, OR, NR ₂ , SR, SOR, SO ₂ R , OCOR, NRCOR, NRCONR ₂ , NRCOOR, OCONR ₂ , RCO, COOR, alkyl-OOR, SO ₃ R, CONR ₂ , SO ₂ NR ₂ , NRSO ₂ NR ₂ , CN, CF ₃ , R ₃ Si and NO ₂ , where each R is independently H, alkyl, alkenyl or aryl or their heteroforms, and where the two indicated substituents can be combined to form a fused optionally substituted aromatic or non-aromatic eskogo, saturated or unsaturated ring which contains from 3 to 8 members. More preferred substituents include halogen, alkyl (1-4C), and more preferably fluoro, chloro and methyl. These substituents can occupy all available positions of the aryl ring Ar, preferably 1-2 positions, most preferably one position. These substituents may optionally be substituted with substituents the same as those listed above. Of course, some substituents, such as halogen, cannot be further substituted, as is known to those skilled in the art.

Two substituents on Ar can be combined to form a fused, optionally substituted, aromatic or non-aromatic, saturated or unsaturated ring, which contains 3-8 members.

Between L ¹ and L ² is a piperidine group of the following formula:

Z ¹ is CR ⁵ or N, where R ⁵ is H or an non-affecting substituent. Each of l and k is an integer from 0 to 2, where the sum of l and k is from 0 to 3. Non-affecting R ⁵ substituents include, but are not limited to, halogen, alkyl, alkoxy, aryl, arylalkyl, aryloxy, heteroaryl, acyl, carboxy or hydroxy. Preferably, R ⁵ is H, alkyl, OR, NR ₂ , SR or halogen, where R is H or alkyl. In addition, R ⁵ may be combined with an R ⁴ substituent to form an optionally substituted non-aromatic, saturated or unsaturated hydrocarbyl ring that contains 3-8 members and 0-3 heteroatoms such as O, N and / or S. Preferred options include compounds in which Z ¹ is CH or N, and those in which both l and k are 1.

R ⁴ is a non-affecting substituent, such as a hydrocarbyl residue (1-20C) containing 0-5 heteroatoms selected from O, S and N. Preferably R ⁴ is alkyl, alkoxy, aryl, arylalkyl, aryloxy, heteroalkyl, heteroaryl, heteroarylalkyl, RCO, = O, acyl, halogen, CN, OR, NRCOR, NR, where R is H, alkyl (preferably 1-4C), aryl or their heteroforms. Each of the suitable substituents is itself unsubstituted or substituted with 1-3 substituents. The substituents are preferably selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl, halogen, OR, NR ₂ , SR, SOR, SO ₂ R, OCOR, NRCOR, NRCONR ₂ , NRCOOR, OCONR ₂ , RCO, COOR, alkyl-OOR, SO ₃ R, CONR ₂ , SO ₂ NR ₂ , NRSO ₂ NR ₂ , CN, CF ₃ , R ₃ Si and NO ₂ where each R is independently H, alkyl, alkenyl or aryl or their heteroforms, and where two substituents on R ⁴ at adjacent positions can be combined to form a fused, optionally substituted aromatic or non-ar an aromatic saturated or unsaturated ring that contains from 3 to 8 members, or R ⁴ is = O or its oxime, oxime ether, oxime ester or ketal. R ⁴ may be contained in the ring m times; m is an integer from 0 to 4. Preferred R ⁴ variants include alkyl (1-4C), especially two alkyl substituents and carbonyl. Most preferably, R ⁴ contains two methyl groups at positions 2 and 5 or 3 and 6 of the piperidinyl or piperazinyl ring, or ═O preferably at position 5 of the ring. Substituted forms may be chiral and may preferably be a single enantiomer.

R ^{3 is} also an unaffecting substituent. Said substituents include hydrocarbyl residues (1-6C) containing 0-2 heteroatoms selected from O, S and / or N, and inorganic residues; n is an integer from 0 to 3, preferably 0 or 1. Preferably, the substituent represented by R ³ is independently halogen, alkyl, heteroalkyl, OCOR, OR, NRCOR, SR or NR ₂ , where R is alkyl, aryl or their heteroforms . Most preferably, R ³ substituents are selected from alkyl, alkoxy or halogen, and most preferably from methoxy, methyl and chlorine. Most preferably, n is 0 and the ring α is not substituted, with the exception of L ¹ , or n is 1 and R ³ is halogen or methoxy.

In the ring designated as β, Z ³ may be NR ⁷ or O, i.e. the compounds may be indole or benzofuran. If Z ³ is NR ⁷ , preferred R ⁷ variants include H or optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, or is SOR, SO ₂ R, RCO, COOR, alkyl-OOR, SO ₃ R, CONR ₂ , SO ₂ NR ₂ , CN, CF ₃ , NR ₂ , OR, alkyl-SR, alkyl-SOR, alkyl-SO ₂ R, alkyl-OCOR, alkyl-COOR, alkyl-CN, alkyl-CONR ₂ or R ₃ Si, where each R is independently H, alkyl, alkenyl or aryl or their heteroforms. More preferably, R ⁷ is hydrogen or alkyl (1-4C), preferably methyl, or acyl (1-4C), or COOR, where R is H, alkyl, alkenyl or aryl or their heteroforms. R ^{7 is} also preferably substituted alkyl, where preferred substituents either form bonds or contain sulfinic or sulfonic acid groups. Other preferred substituents include sulfhydryl substituted alkyl substituents. Other preferred substituents include CONR ₂ where R is as defined above.

Preferably, if the indicated dashed line is a double bond; however, compounds that contain a saturated β ring are also included within the scope of this invention.

Preferably, the obligatory substituent CA or CR ⁸ A is at position 3; regardless of the position taken by said substituent, the other position is substituted with CR ¹ , CR ¹ ₂ , NR ⁶ or N. Preferably CR ¹ . Preferred R ¹ variants include alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl, halogen, OR, NR ₂ , SR, SOR, SO ₂ R, OCOR, NRCOR, NRCONR ₂ , NRCOOR, OCONR ₂ , RCO, COOR, alkyl OOR, SO ₃ R, CONR ₂ , SO ₂ NR ₂ , NRSO ₂ NR ₂ , CN, CF ₃ , R ₃ Si and NO ₂ , where each R independently is H, alkyl, alkenyl or aryl or their heteroforms, and wherein two R ¹ substituents may be combined to form a fused, optionally substituted aromatic or non-aromatic saturated or unsaturated ring, otoroe contains from 3 to 8 members. Most preferably, R ¹ is alkyl, such as methyl, most preferably, ring α contains a double bond and CR ¹ is CH or C-alkyl. Other preferred forms of R ¹ include H, alkyl, acyl, aryl, arylalkyl, heteroalkyl, heteroaryl, halogen, OR, NR ₂ , SR, NRCOR, alkyl-OOR, RCO, COOR and CN, where each R is independently H, alkyl or aryl or their heteroforms.

Although in a preferred embodiment, the position not occupied by CA includes CR ¹ , this position may also be N or NR ⁶ . Although NR ^{6 is the} least preferred (since in this case the ring designated β will be saturated), if NR ^{6 is} present, the preferred options for R ⁶ are H or alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, or SOR, SO ₂ R, RCO, COOR, alkyl COR, SO ₃ R, CONR ₂ , SO ₂ NR ₂ , CN, CF ₃ or R ₃ Si, where each R is independently H, alkyl , alkenyl or aryl or their heteroforms.

Preferably, CR ⁸ A or CA is in position 3, and preferably Z ² in this position is CA. However, if the β ring is saturated and R ^{8 is} present, preferred R ⁸ options are H, halogen, alkyl, alkenyl, and the like. Preferably R ⁸ is a relatively small substituent corresponding, for example, to H or lower alkyl 1-4C.

A is —W _i —COX _j Y, where Y is COR ² or an isoster thereof and R ² is an unaffecting substituent. Each of W and X is a dividing unit and may be, for example, optionally substituted by alkyl, alkenyl or alkynyl, each of i and j is 0 or 1. Preferably, W and X are not substituted. Preferably, j is 0, so that the two carbonyl groups are adjacent. Preferably, also, i is 0, so that the nearest CO is near the ring. However, compounds in which the nearest CO is separated from the ring can easily be obtained by selective reduction of the initially glyoxal-substituted β ring. In the most preferred embodiments of the invention, the α / β ring system is an indole containing CA at position 3, where A is COCR ₂ .

A non-affecting R ² substituent, if R ² is other than H, is a hydrocarbyl residue (1-20C) containing from 0 to 5 heteroatoms selected from O, S and / or N, or an inorganic residue. Variants are preferred in which R ² is H or straight or branched alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl or heteroarylalkyl, each of which is optionally substituted with halogen, alkyl, heteroalkyl, SR, OR, NR ₂ , OCOR, NRCOR , NRCONR ₂ , NRSO ₂ R, NRSO ₂ NR ₂ , OCONR ₂ , CN, COOR, CONR ₂ , COR or R ₃ Si, where each R is independently H, alkyl, alkenyl or aryl or heteroatom containing them, or where R ² is oR, NR _2, SR, NRCONR _2, OCONR _2, or NRSO ₂ NR _2, wherein each R is independently H, alkyl, alkenyl or aryl, or with heteroatom-containing forms, and where two R attached to the same atom can form a 3-8 membered ring, and where said ring can be further substituted by alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl or heteroarylalkyl, each of which is optionally substituted with halogen, SR, OR, NR ₂ , OCOR, NRCOR, NRCONR ₂ , NRSO ₂ R, NRSO ₂ NR ₂ , OCONR ₂ , or R ₃ Si, where each R is independently H, alkyl, alkenyl or aryl or their heteroatom containing forms, where two R, attached to the same atom, can form 3-6 membered ring substituted by the above substituents.

Other preferred R ² variants include H, heteroarylalkyl, —NR ₂ , heteroaryl, —COOR, —NHRNR ₂ , heteroaryl — COOR, heteroaryloxy, —OR, heteroaryl — NR ₂ , —NROR, and alkyl. Most preferably R ² is izopropilpiperazinilom, methylpiperazinyl, dimethylamine, piperazinyl, izobutilkarboksilatom, oksikarboniletilom, morpholinyl, aminoetildimetilaminom, izobutilkarboksilatpiperazinilom, oksipiperazinilom, etilkarboksilatpiperazinilom, methoxy, ethoxy, hydroxy, methyl, amino, amknoetilom, pyrrolidinyl, aminopropanediol, piperidinyl, pyrrolidinyl-piperidinyl, or metilpiperidinilom .

The COR ² isosteres represented by Y are defined as follows.

Isosteres have variable lipophilicity and can contribute to improved metabolic stability. Thus, Y, as shown, can be replaced by isosteres shown in table 1.

Table 1
Acid isotherms Name of groups Chemical structures Substitute Groups (MH) tetrazole

n / a 1,2,3-triazole

H; SCH ₃ ; COCH ₃ ; Br, SOCH ₃ ; SO ₂ CH ₃ ; NO ₂ ; CF ₃ : CN; Coome 1,2,4-triazole

H; SCH ₃ ; COCH ₃ ; Br; SOCH ₃ ; SO ₂ CH ₃ ; NO ₂ imidazole

H; SCH ₃ ; COCH ₃ ; Br; SOCH ₃ ; SO ₂ CH ₃ ; NO ₂

Thus, isosteres include tetrazole, 1,2,3-triazole, 1,2,4-triazole and imidazole.

The compounds of formula (I) may be in the form of their pharmaceutically acceptable acid addition salts, including salts of inorganic acids such as hydrochloric, sulfuric, hydrobromic or phosphoric acids, or salts of organic acids such as acetic, tartaric, succinic, benzoic, salicylic and like that. If a carboxyl group is present in the compound of formula (I), the compound may also be in the form of a salt with a pharmaceutically acceptable cation.

The synthesis of compounds in accordance with this invention

The following reaction schemes illustrate the conversion of 4-benzylpiperidinylindole-5-carboxamide to the glyoxalic acid compounds of the present invention and their derivatives.

Of course, the illustrative 4-benzylpiperidinylcarbonyl at position 5 can be summarized as

and the glyoxal type substituent at position 3 can be generalized to W _i COX _j Y.

Also in these schemes can be used options in which the group of the indole series is

Methods for synthesizing the compounds of this invention are generally known in the art.

Such methods can be illustrated by the following general schemes.

Substituted aminobenzoic acid esters such as I can be treated with reagents such as thiomethylacetaldehyde dimethylacetal and N-chlorosuccinamide in methylene chloride at low temperature, followed by treatment with a base such as triethylamine at reflux temperature in methylene chloride, dichloroethane or chloroform to give indoles II, Scheme 1. Treatment with reagents such as Raney nickel in a suitable solvent such as ethanol, methanol or isopropanol gives the corresponding ester to arboxylic acid, which upon hydrolysis under basic conditions gives the desired derivative of indolecarboxylic acid.

Alternatively, substituted aminobenzoic acid esters I can be converted to ketals IV, Scheme 2, by treatment with a suitable aldehyde under reductive alkylation conditions with reagents such as sodium triacetoxyborohydride in acetic acid in the presence of sodium sulfate. The amines can then be treated with Lewis acids, such as aluminum chloride, titanium chloride, a BF ₃ ether in dichloromethane or dichloroethane, at reflux temperature to give the corresponding substituted indole methyl esters with the corresponding substituents.

Another method may include treating the substituted esters of aminobenzoic acid I with iodine and sodium periodate in a suitable solvent, such as dimethylformamide, to give the corresponding iodanilines V, Scheme 3. They can be reacted with acetylene, such as trimethylsilylacetylene or ethyl ethinyl ether in the presence of a suitable a catalyst, such as palladium and copper, and a base, such as triethylamine, to obtain silyl-bound products, such as VI. Subsequent cyclization in a solvent such as dimethylformamide and in the presence of a catalyst such as copper iodide gives suitably substituted indoles VII.

The synthesis of the desired piperidines can be carried out by treating a suitable piperidone, such as VIII, Scheme 4, with substituted benzyl phosphonate esters in the presence of a base such as sodium hydride, to obtain alkenes that can be reduced to the corresponding substituted 4-benzyl piperidines, such as IX. Hydrogenation is usually carried out in the presence of catalytic metals, in solvents such as methanol, ethanol and ethyl acetate.

An alternative method may include the use of isonipecotoyl chlorides, such as X, to acylate suitably substituted benzenes (ArH) in the presence of a Lewis acid such as aluminum chloride to give ketones XI, Scheme 5. Further modifications of the carbonyl group in XI using methods and methods, well known in the art, give the desired compounds XII.

Substituted piperazines can be reacted with various suitable ArL ² X in the presence or absence of a base or other catalytic reagent to produce substituted piperazines XV, Scheme 6. They can then be separated to chiral components using a chiral resolving agent such as tartaric acid, obtaining any enantiomer of substituted piperazines XV.

Compounds III can be treated with halides, acid chlorides or other electrophiles (BX), Scheme 7, containing many different substituents, in the presence of a base such as sodium hydride, in many different solvents, to give compounds XVI. They can be converted to the corresponding acids XVII by treatment with suitable reagents, such as an aqueous base. The acids can then be reacted with substituted amines IX, XII or XV using a condensing agent such as EDAC.HCl in various solvents, including methylene chloride, dimethylformamide, to give compounds XVIII.

Compounds XVIII can be first treated with acid chlorides, such as oxalyl chloride, in methylene chloride under anhydrous conditions, followed by treatment with various WH nucleophiles to give compound XIX, Scheme 8.

Compounds XXIV can be synthesized starting from appropriately substituted benzofurans XX by reacting them with amines IX, XII or XV in the presence of appropriate condensing agents to give compounds XXI, Scheme 9. Further acylation to XXII can be carried out using an acylating agent such as acetic anhydride in the presence of a catalyst such as Fe (III). Oxidation of the acetyl group XXII to the glyoxalic acid group XXIII can be carried out using an oxidizing agent such as selenium dioxide (ref: F Da Settimo et al., Eur. J. Med. Chem (1996), 31, 951-956; M. C. Cook et al., (1975) UK patent 1399089; E. Campaigne et al., J. Med. Chem (1965), 136-137). Finally, a combination of an acid with a corresponding nucleophile in WH can be carried out using any of a variety of known condensing agents, in various solvents, to give compounds XXIV.

P38α kinase inhibition studies

For each of the research methods described below, TNF-α production is correlated with p38-α kinase activity.

A. Study of the inhibition of p38-α kinase using whole human blood.

Venous blood from healthy male volunteers is collected in a heparinized syringe and used within 2 hours after blood sampling. Test compounds are dissolved in 100% DMSO and 1 μl aliquots of the drug at concentrations from 0 to 1 mM are placed in four repetitions in cells of a 24-well microtiter plate (Nunclon Delta SI, Applied Scientific, So. San. Francisco, CA). Whole blood was added in a volume of 1 ml / well and the mixture was incubated for 15 minutes with constant shaking (Titer Plate Shaker, Lab-Line Instruments, Inc., Melrose Park, IL) in a humidified atmosphere of 5% CO ₂ at 37 ° C. Whole blood is cultured either undiluted or with a final dilution of 1:10 with RPMI 1640 (Gibco 31800 + NaHCO ₃ , Life Technologies, Rockville, MD and Scios, Inc., Sunnyvale, CA). At the end of the incubation period, 10 μl of LPS was added to each well [E. coli 0111: B4, Sigma Chemical Co., St. Louis, MO) to a final concentration of 1 or 0.1 μg / ml for undiluted or 1:10 diluted whole blood, respectively. Incubation is continued for another 2 hours. The reaction is stopped by placing microtiter plates in an ice bath, and plasma or cell-free supernatants are collected by centrifugation at 3000 rpm for 10 minutes at 4 ° C. Plasma samples are stored at -80 ° C until testing of TNF-α levels is performed by ELISA following the instructions attached to the Quantikine Human TNF-α assay kit (R&D Systems, Minneapolis, MN).

IC ₅₀ values are calculated using inhibitor concentrations that give a 50% reduction compared to the control.

B. Investigation of inhibition of p38 kinase in enriched mononuclear cells

In a study using enriched mononuclear cells, the protocol of which is presented below, cryopreserved mononuclear cells of human peripheral blood (CLCC) (Clonetics Corp.), which are washed and resuspended in a warm mixture of cell growth medium, are used as initial ones. The resuspended cells are then counted and plated at 1 × 10 ⁶ cells / well in a 24-well microtiter plate. Then the tablets are placed in an incubator for one hour to precipitate the cells in each cell. After cell deposition, the medium is aspirated and a new medium containing 100 ng / ml cytokine stimulating lipopolysaccharide factor (LPS) and a test chemical compound is added to each cell of the microtiter plate. Thus, each cell contains OKPKCH, LPS and the test chemical compound. Cells are then incubated for 2 hours and the amount of cytokine Alpha Necrosis Factor Factor Tumors (TNF-α) is measured using an enzyme-linked immunosorbent assay (ELISA). One such TNF-α level ELISA is commercially available from R&D Systems. The amount of TNF-α produced by CBCC in each well is then compared with a control well to determine if the chemical compound acts as an inhibitor of cytokine production.

LPS-Induced Cytokine Synthesis in CBCC

Cryopreserved OKKCH (Cat. No. CC-2702 Clonetics Corp.)

LGM-3 Medium (Cat. No. CC-3212 Clonetics Corp.)

LPS stock solution 10 g / ml (Cat. No. 2630 serotype 0111: Sigma B4)

ELISA for human TNF (R&D Systems)

DNase I (10 mg / ml stock solution)

Cell production

LGM-3 medium is heated to 37 ° C

5 μl of the stock solution of DNase I is added to 10 ml of medium.

Cells thaw quickly and disperse into the above medium.

Centrifuge 200xg × 10 min @ CT

The precipitate after centrifugation is diluted to 10 ml with sterile saline solution with phosphate buffer.

Centrifuge 200xg × 10 min @ CT

The centrifuge pellet was resuspended in 10 ml LGM-3, then diluted to 50 ml with LGM-3 medium.

Cell count

Bring to 1 × 10 ⁶ cells / cell.

Sow 1 ml / well in a 24-well plate

Place the plate in an incubator for precipitation for 1 hour

Obtaining incubation medium

LGM-3 containing 100 ng / ml LPS (e.g. 50 ml medium plus 0.5 ml LPS stock solution)

Divide without residue into 2 ml aliquots and add 1000X diluted inhibitor

Incubation

After cell deposition, the medium is aspirated and coated with 1 ml of the appropriate incubation medium. The tablet is returned to the incubator for 2 hours or 24 hours. After incubation, the supernatant is transferred to a labeled tube and either an ELISA TNF (or other) is performed immediately or frozen for later examination.

IC ₅₀ values are calculated using an inhibitor concentration that gives a 50% decrease compared to the control.

Introduction and Application

The compounds of this invention are suitable, among other indications, for the treatment of conditions associated with inflammation. Thus, the compounds of formula (I) or their pharmaceutically acceptable salts are used for the manufacture of drugs for the prevention or therapeutic treatment of mammals, including humans, in the event of conditions characterized by excessive production of cytokines and / or unacceptable or unregulated cytokine 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, which are important pro-inflammatory components in many different disease states and syndromes. Thus, inhibition of these cytokines is important for the control and mitigation of many diseases. The compounds of this invention, as shown herein, inhibit the MAP kinase family, also called p38 MAPK (or p38), CSBP, or SAPK-2. Activation of this protein has been shown to accompany exacerbation of diseases in response to the stress caused, for example, by the action of lipopolysaccharides or cytokines such as TNF and IL-1. Inhibition of p38 activity, therefore, determines the ability of drugs to have a beneficial effect in the treatment of diseases such as Alzheimer's disease, coronary heart disease, congestive heart failure, cardiomyopathy, myocarditis, vasculitis, restenosis, such as may occur after plastic surgery on coronary vessels, atherosclerosis, IBD, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, multiple sclerosis, acute respiratory depression distress syndrome (ARDS), asthma, chronic obstruction of the lungs (COP), silicosis, pathological proliferation of lung tissue, sepsis, septic shock, endotoxic shock, sepsis caused by gram-negative microorganisms, toxic shock syndrome, heart and brain failure (stroke), which are characterized by ischemia and reperfusion injuries, surgical interventions such as transplantation and transplant rejection, cardiopulmonary bypass, coronary artery bypass grafting, central nervous system injuries, including open and behind indoor head injuries, inflammatory eye diseases such as conjunctivitis and uveitis, acute renal failure, glomerulonephritis, inflammatory diseases of the digestive tract such as Crohn's disease or ulcerative colitis, homologous disease, bone resorption, such as osteoporosis, type II diabetes, pyresis, psoriasis , cachexia, viral diseases such as those caused by HIV, cytomegalovirus (CMV) and herpes, and cerebral malaria.

Over the past seven years, p38 has been shown to contain a group of MAP kinases designated p38-α, p38-β, p38-γ and p38-δ. In Jiang, Y et al, J. Biol Chem (1996) 271: 17920-17926, p38-β is characterized as a protein containing 372-aminocytes closely related to p38-α. When comparing p38-α activity with p38-β activity, the authors found that although both are activated by proinflammatory cytokines and external stress, p38-β is mainly activated by a MAP kinase such as kinase-6 (MKK6) and is mainly activated by factor transcription 2, therefore, it can be assumed that different mechanisms of action may be associated with these forms.

Kumar, S., et al., Biochem Blophys Res Comm (1997) 235: 533-538 and Stein, B et al., J. Biol Chem (1997) 272: 19509-19517 describe the second isoform p38-β, p38 -β2 containing 364 amino acids with 73% identity to p38-α. From all these references, it is obvious that p38-β is activated by pro-inflammatory cytokines and external stress, although the second indicated isoform of p38-β, p38-β2, is presumably mainly expressed in the central nervous system, heart and skeletal muscle, in contrast to that found almost everywhere in p38-α expression tissue. Moreover, observations have shown that activated transcription factor-2 (ATF-2) is a better substrate for p38-β2 than for p38-α, therefore, it is believed that various mechanisms of action may be associated with these forms. The physiological role of p38-β1 has been called into question in the last two studies, since it was not found in human tissues and does not show significant kinase activity with p38-α substrates.

Identification of p38-γ is presented in Li, Z. et al., Biochem Blophys Res Comm (1996) 228: 334-340 and p38-δ in Wang, X. et al., J Biol Chem (1997) 272: 23668-23674 and Kumar, S. et al., Biochem Biophys Res Comm (1997) 235: 533-538. The data suggest that the two p38 isoforms (γ and δ) represent a unique subpopulation of the MAPK family, based on their forms of tissue expression, substrate use, response to direct and indirect stimulation, and sensitivity to kinase inhibitors.

Various results related to the response to drugs directed to the p38 family regarding p38-α and either the putative p38-β1 or p38-β2, or both, are presented by Jiang, Kumar and Stein mentioned above, as well as by Eyers, PA et al., Chem and Biol (1995) 5: 321-328. Another work by Wang, Y. et al., J Biol Chem (1998) 273: 2161-2168 suggests the significance of such a differential action. As noted by Wang, many stimuli, such as myocardial infarction, hypertension, heart valve defects, viral myocarditis, and expanded cardiomyopathy lead to increased heart function and increased mechanical pressure on cardiomyocytes. It is indicated that this leads to an adaptive hypertrophic response, which, if not controlled, will have undoubtedly negative consequences. Wang refers to earlier studies showing that with ischemic reperfusion of the heart, p38 MAPK activity increases due to hypertrophy and programmed cell death. In the link cited, Wang shows that activation of the action of p-38β leads to hypertrophy, while activation of the action of p38-α leads to apoptosis of myocytes. Thus, selective inhibition of p38-α activity compared to p38-β activity will be advantageous in the treatment of conditions caused by heart failure. Such conditions include congestive heart failure, cardiomyopathy, myocarditis, vasculitis, vascular restenosis, heart valve defects, conditions associated with cardiopulmonary bypass, coronary artery bypass grafting, grafts and vascular grafts. Further, given that the α-isoform is toxic in other types of muscle cells, α-selective inhibitors can be used in conditions associated with cachexia inherent to TNF or other conditions, such as cancer, infection, or autoimmune disease.

Thus, the present invention encompasses the use of compounds that selectively inhibit the activity of p38-α isoform, for the treatment of conditions associated with activation of p38-α, in particular those associated with cardiac hypertrophy, ischemia and other external stresses, such as oxidative damage, hyperosmolarity or other agents or factors that activate p38-α kinase or heart failure, for example, congestive heart failure, cardiomyopathy and myocarditis.

The route of administration and formulations of the compounds useful in this invention and their related compounds depend on the nature of the condition, the severity of the condition, the particular subject being treated, and the assessment of the practitioner; the formulation depends on the route of administration. Since the compounds of this invention are small molecules, they are conveniently administered orally when mixed with suitable pharmaceutical excipients to prepare tablets, capsules, syrups and the like. Suitable compositions for oral administration may also include adjuvants, such as buffers, flavors, and the like. Typically, the amount of active ingredient in a composition is from 5% to 95% of the total weight of the composition, but wider ranges may be used depending on the carrier. Suitable carriers include sucrose, pectin, magnesium stearate, lactose, peanut butter, olive oil, water and the like.

Compounds useful in this invention may also be administered by suppositories or other transmucosal carriers. Typically, such compositions include excipients that facilitate the passage of the compound through the mucous membrane, such as pharmaceutically acceptable detergents.

The compounds may also be administered topically, for topical conditions such as psoriasis, or in a formulation intended to pass through the skin. Such formulations include lotions, creams, ointments and the like, which can be obtained by known methods.

The compounds may also be administered by injection, including intravenous, intramuscular, subcutaneous or intraperitoneal injections. Typical compositions for this route of administration include liquid formulations in isotonic diluents, such as Hank's solution or Ringer's solution.

Alternative formulations include intranasal sprays, liposome formulations, sustained release formulations, and the like, such as are known in the art.

Any suitable formulation may be used. A summary of formulations known in the art can be found in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Company, Easton, PA. Reference to this manual is common in the art.

The dosage of the compounds of this invention depends on many factors, which vary from patient to patient. However, it is believed that in general, the daily oral dose should be 0.001-100 mg / kg body weight, preferably from 0.01 to 50 mg / kg, and more preferably from about 0.01 mg / kg to 10 mg / kg. The dosage regimen may vary depending on the condition being treated and the assessment of the practitioner.

It should be noted that the compounds of formula (I) can be administered either as independent active ingredients, or as a mixture of several such compounds of formula I. In addition, p38 kinase inhibitors can be used as independent therapeutic agents or in combination with other therapeutic agents. Medicines that can be advantageously combined with such compounds include natural and synthetic corticosteroids, especially prednisone and its derivatives, monoclonal antibodies directed to cells of the immune system, antibodies or soluble receptors or a fusion protein receptor directed to immune or non-immune cytokines, and inhibitors of cell division, protein synthesis, or transcription or translation of small molecule mRNAs, or inhibitors of differentiation or activation of immune cells.

As mentioned above, although the compounds of this invention can be used for humans, they can also be used in veterinary medicine to treat animals.

The following examples are intended to illustrate, but not limit the invention, and illustrate the use of the above reaction schemes.

Example 1

6-Methoxy- (4-benzylpiperidinyl) indole-5-carboxamide-3-glyoxalic acid

0.348 mg (1 mmol) of 6-methoxy- (4-benzylpiperidinyl) indole-5-carboxamide is dissolved in 15 ml of dry dichloromethane and cooled to 0 ° C in an ice bath. Using a syringe, 0.6 ml of a 2 molar solution of oxalyl chloride in dichloromethane (Aldrich) in an inert atmosphere was added dropwise and the mixture was stirred at 0 ° C. for one hour. The ice bath was removed and the mixture was stirred for another hour at room temperature. The solvent was evaporated and the residue was dried in vacuo for 30 minutes. The resulting solid was dissolved in a THF / water mixture and made basic with 20% aq. NaOH. The solvents were removed and the residue was dissolved in water and acidified with conc. HCl. The precipitated solid was collected by filtration, dried and recrystallized from ethanol / water to give 350 mg of the title compound.

ESMS 421, M ⁺

Example 2

4-methylpiperazinamide 6-methoxy- (4-benzylpiperidinyl) -5-carboxamidoindole-3-glyoxalic acid

This compound is prepared using the procedure described above for the corresponding acid, but replacing aqueous NaOH with 4-methylpiperazine and carrying out the reaction in dry dichloromethane instead of THF / water.

ESMS 503, M ⁺

Example 3

6- Methoxy- (4-benzylpiperidinyl) -5-carboxamidoindole-3-glyoxalic acid 1- (2-aminoethylpyrrolidine) amide

This compound is prepared using the procedure described above, but replacing 4-methylpiperazine with 1- (2-aminoethyl) pyrrolidine.

MS M ⁺ , 517

Example 4

4-benzylpiperidinyl-5-carboxamidoindole-3-glyoxalic acid amide

0.318 mg, 1 mmol, 4-benzylpiperidinylindole-5-carboxamide was dissolved in dry dichloromethane and reacted with 0.6 ml of a 2 molar solution of oxalyl chloride at 0 ° C. for 1 hour under nitrogen. The cooling bath was removed and the mixture was stirred for another hour at room temperature. The solvent was evaporated and the residue was dried in vacuo for 30 minutes. The product was redissolved in THF and excess conc. ammonium hydroxide. After stirring for 1 hour, the solvent was removed and the residue was recrystallized from ethyl acetate-hexane.

Yield: 220 mg, MS. M ⁺ , 389; 345, M ⁺ -CONH ₂

Example 5

4-methylpiperazinamide 6-chloro- (4'-fluoro-4-benzylpiperidinyl) -5-carboxamidoindole-3-glyoxalic acid

Receive according to the method described above.

MS M ⁺ , 524

Example 6

Preparation of 6-methoxy- (4-benzylpiperidinyl) indole-5-carboxamide-3-glyoxalic acid methyl ester

This compound is prepared according to the procedure described for the starting glyoxalic acid, but replacing sodium hydroxide with methanol in THF / water.

ESMS M ⁺ , 435

Example 7

Preparation of 1-methyl-6-methoxy- [4'-fluoro- (4-benzylpiperidinyl)] indole-5-carboxamide-3-glyoxalic acid methyl ester

0.435 g of 6-methoxy- [4'-fluoro- (4-benzylpiperidinyl)] indole-5-carboxamide-3-glyoxalic acid methyl ester was dissolved in 10 ml of dry DMF and cooled to 0 ° C in an ice bath. 80 mg of NaH (60% dispersion) was added and the mixture was stirred for 15 minutes at 0 ° C and for 30 minutes at room temperature in an inert atmosphere. The reaction mixture was cooled to 0 ° C. and 200 μl of iodomethane was added. After 30 minutes at 0 ° C., the mixture was warmed to room temperature and stirring was continued for another 4 hours. The reaction mixture was poured into water and extracted with dichloromethane (3 × 50 ml). The extract was dried, evaporated and purified by silica gel column chromatography and ethyl acetate-hexane (50-90% ethyl acetate, gradient).

Yield: 70%.

MS M ⁺ , 466

Example 8

Preparation of 1-methyl-6-methoxy- [4'fluoro- (4-benzylpiperidinyl)] indole-5-carboxamide-3-glyoxalic acid

0.24 g (0.51 mmol) of 1-methyl-6-methoxy- [4'-fluoro- (4-benzylpiperidnyl)] indole-5-carboxamide-3-glyoxalic acid methyl ester was dissolved in THF (10 ml), add 1 ml of 20% aq. sodium hydroxide and stirred for 4 hours. The mixture was diluted with water (5 ml) and stirring was continued for 1 hour. THF is removed under reduced pressure and the remaining solution is diluted with water and acidified with conc. HCl and the product was collected by filtration. It is dried in vacuo and recrystallized from ethyl acetate.

Yield: 180 mg

ESMS M ⁺ , 453

Example 9

3- (methoxybenzoyl) - (4-benzylpiperidinyl) indole-5-carboxamide

Acylation at position 3 of the indole ring is carried out according to the method of C.X. Yang et al. (Synth. Commun, 27 (12), 2125 (1997). To a solution of 0.318 g (1.0 mmol) of 5- (4-benzylpiperidinyl) indolecarboxamide in dichloromethane was added 2.2 ml (2.2 mmol) of a 1M ZnCl solution ₂ in ether, followed by dropwise addition of EtMgBr (1.0 mmol). The mixture was stirred for 1 hour and p-anisoyl chloride (180 mg, 1.1 mmol) was added. The suspension was stirred for 1 hour and AlCl _{3 was} added (0, 05 mmol). The resulting mixture was stirred for 2 hours and quenched with saturated solution of NB ₄ Cl. The organic layer was washed with aq. NaHCO ₃ and brine, dried over MgSO ₄ and filtered. The product is purified by silica gel column chromatography.

MS M ⁺ , 452

Example 10

3-benzoyl-5- (4-benzylpiperidinyl) indolecarboxamide

Obtained using the procedure described above, but replacing p-anisoyl chloride with benzoyl chloride.

MS M ⁺ , 422

Example 11

3-Acetyl-5- (4-benzylpiperidinyl) indole-5-carboxamide

Obtained using the procedure described above, but replacing p-anisoyl chloride with acetyl chloride.

MS M ⁺ , 360

Example 12

Preparation of 3- (2-hydroxyacetyl) -5- (4-benzylpiperidinyl) indolecarboxamide

3- (2-Chloroacetyl) -5- (4-benzylpiperidinyl) indolecarboxamide was prepared using the procedure described above, but replacing p-anisoyl chloride with chloroacetyl chloride.

Hydrolysis of the chloroacetyl group to hydroxyacetyl is carried out using a published technique (J. Org. Chem., 1988, 53, 5446). To a solution of 50 mg (0.13 mmol) of 3- (2-chloroacetyl) -5- (4-benzylpiperidine) indolecarboxamide in dioxane (3 ml) was added 5 ml of formamide-water (10: 1). The reaction mixture was heated to 110 ° C for 5 hours and cooled to room temperature. The reaction was quenched with sat. NH ₄ Cl solution, extracted with dichloromethane, dried (MgSO ₄ ) and concentrated. The residue was purified by preparative TLC with dichloromethane-methanol (20: 1) to give 20 mg (42%) of the title compound.

MS M ⁺ , 376

Example 13

5- (4-Benzylpiperidinyl) carboxamidoindole-3- (3'-oxo) ethyl propionate

Acylation at position 3 of the indole ring is carried out according to the published procedure [Synth. Commun, 1977, 27 (12), 2125]. To a solution of 3.6 ml of ZnCl ₂ (3.6 mmol, 1M solution in diethyl ether) in THF was added dropwise n-BuLi (2.2 ml, 3.6 mmol) at a temperature of 0 ° C. A white suspension forms during the addition. The reaction mixture was warmed to room temperature, stirred for 1 hour, and a solution of 5- (4-benzylpiperidinyl) indolecarboxamide in dichloromethane (10 ml) was added. The resulting mixture was stirred for 1 hour and ethyl 3-chloro-3-oxopropionate (585 mg, 3.9 mmol) was added. After 1 hour, the reaction mixture was quenched with saturated NH ₄ Cl, extracted with dichloromethane, dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel column chromatography to give 200 mg of the desired product.

MC> M ⁺ , 431

Compounds 1-55 of Table 2 were prepared by the same procedure.

Example 14

Synthesis of (2S, 5R) N-4-Fluorobenzyl-trans-2,5-dimethylpiperazine

(+/-) N-Benzyl-trans-2,5-dimethylpiperazine is synthesized as follows

50 g of trans-2,5-dimethylpiperazine are dissolved in 300 ml of ethanol and treated with 26.36 ml (1/2 equivalent) of benzyl bromide. The mixture was stirred at room temperature for 12 hours and concentrated. The residue was taken up in ethyl acetate and washed with 10% aqueous sodium bicarbonate and saturated sodium chloride; dried over anhydrous magnesium sulfate and concentrated to give crude 1-benzyl-trans-2,5-dimethylpiperazine as an oil.

The resulting material was chromatographed using DCM / MeOH 95/5 to remove the dialkylated product, and then DCM / MeOH / TEA 90/10 / 0.1 to elute benzyl trans-2,5-dimethylpiperazine. 19.6 g of product are obtained in the form of an oil.

To a solution of (+/-) N-benzyl-trans-2,5-dimethylpiperazine (59 g, 0.29 mol) in methanol (150 ml) was added dropwise a solution of (+) tartaric acid (87 g, 0.58 mol ) in methanol (250 ml) for 5 minutes. Crystallization is carried out while maintaining the mixture at a temperature of 0 ° C for 48-72 hours. Mashing the solution after 12-16 hours contributes to the crystallization process. The mixture was filtered and washed with cold methanol and dried to give the divinic acid salt (75.9 g) as white crystals. A single recrystallization from methanol, cooling to room temperature gives the salt in the form of white crystals. (58 g) [α] _D = + 47, (c = 1.00, methanol).

31 g, 15.27 mmol, dimethylbenzylpiperazine are treated with 43 g, 19.85 mmol, di-tert-butyl dicarbonate in 250 ml of THF for 4 hours. The reaction was monitored by TLC and it was almost complete by the addition of (BOC) ₂ O. The solvent was removed and the residue was taken up in ethyl acetate and washed with 10% aqueous sodium carbonate and saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to obtain 39.3 g of compound with Vos-protecting group. The resulting compound is used in the next step without further purification.

39.3 mg, 131 mmol, benzylpiperazine with a Boc-protecting group was treated with 3.93 g of Pearlman's catalyst, 150 ml of methanol with 3 mL acetic acid for 4 hours at a hydrogen pressure of 2,812 kg / cm ² (40 lb / d ²⁾ Parr mixer. The reaction mixture was filtered through celite and concentrated to give a residue, which was dried under high vacuum and then dissolved in 250 ml of dry ethanol and treated with 1.2 equivalents, 158 mmol, 4-fluorobenzyl bromide and 2 equivalents, 262 mmol, triethylamine for 5 hours. The reaction mixture was monitored by TLC, which showed completion of the reaction by this time. The solvent was removed and the residue was taken up in ethyl acetate and washed with 10% aqueous sodium carbonate and saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to obtain 47 g of a crude product. The crude product was subjected to silica gel column chromatography using hexane / ethyl acetate 95/5 to elute the product. After chromatography, 29 g of 4-fluorobenzyl-trans-2,5-dimethyl-piperazine are obtained. 20 g of 1- (4-Fluoro) benzyl-trans-2,5-dimethyl-piperazine, 62 mmol, is treated with a mixture of 200 ml of 4N HCl / dioxane / 2M HCl / ether (1: 3) for 1 hour. Electron impact mass spectroscopy confirms product formation and disappearance of starting materials. The reaction mixture was concentrated to give a solid. This material is re-washed with hexane and ether to remove residual dioxane and then dried for a long time in vacuum before use. Obtain 17.6 g of the final product as a white fluffy solid.

Example 15

Synthesis of chiral compounds

6-chloroindole-5-carboxylic acid (1.56 g, 7.44 mmol) was dissolved in dry methylene chloride, 60 ml, EDAC.HCl (1.57 g, 8.18 mmol) and DMAP (10%) were added to the resulting solution. mole). After stirring under nitrogen for 10 minutes, an amine (2.19 g, 7.5 mmol) was added followed by triethylamine (3 ml, 21.52 mmol). After standing overnight at room temperature, the reaction mixture was concentrated and the residue was taken up in ethyl acetate and washed with 10% aq. sodium carbonate saturated with sodium chloride, dried over anhydrous sodium sulfate and filtered. Concentration gives a crude product that is chromatographed on a silica gel column using a gradient of EtOAc / Hexane 2 / 8-6 / 4. TLC R _f 0.435 (EtOAc: hexane, 1: 1), EUMS M + 413.

The product from the previous step with 1.02 g is dissolved in 30 ml of dry DCM. The reaction mixture was purged with nitrogen and placed in an ice bath. To the resulting mixture was added 4 ml of 2M oxalyl chloride in DCM. The reaction mixture was stirred at room temperature for 1 hour and then at room temperature for 2 hours. The reaction mixture was concentrated on a rotary evaporator. After drying in vacuo for 15 minutes, the residue (yellow solid) was dissolved in DCM, 30 ml, to which 4 ml of a 2M solution of dimethylamine in THF was added. After 30 minutes, the reaction mixture was concentrated and the residue was taken up in ethyl acetate and washed with 10% aq. sodium carbonate saturated with sodium chloride, dried over anhydrous sodium sulfate and filtered. Concentration gives a crude product which is subjected to silica gel column chromatography using a EtOAc 100% - EtOAc / MeOH 9: 1 gradient. TLC R _f 0/5 (EtOAc: MeOH, 9: 1), EUMS M + 513.

The white solid from the previous step is dissolved in 10 ml of dry DCM. To the resulting solution was added 2M HCl in ether until a precipitate formed. The mixture was then concentrated to dryness on a rotary evaporator and then dried overnight under high vacuum to give the final product (1.08 g).

Additional examples

Synthesis of Compound 2: Methyl 4-amino-2-chlorobenzoate (1) (18.5 g) was dissolved in dichloromethane (350 ml) and methylthioacetaldehyde dimethylacetal (13.6 g) was added. The mixture was cooled to -45 ° C (dry ice / acetonitrile bath). N-chlorosuccinimide (16.0 g) in 350 ml of dichloromethane was added dropwise over 1 hour 30 minutes, keeping the bath temperature at -45 ° C. The reaction mixture was stirred for another 1 hour, then triethylamine (16 ml, 100 mmol) in 30 ml of dichloromethane was added dropwise over 5 minutes, the reaction mixture was warmed to room temperature, then refluxed for 16 hours. The solvent is removed and the residue is taken up in 500 ml of carbon tetrachloride, the triethylamine hydrochloride acid is removed by filtration, the filtrate is heated at the boiling temperature under reflux for 2 hours. The solvent is removed on a rotary evaporator.

The residue was dissolved in 250 ml of tetrahydrofurac and 250 ml of 10% hydrochloric acid was added. The mixture was stirred overnight at room temperature until the starting material completely disappeared. The solvent was removed in vacuo, the acidic aqueous solution was extracted with ethyl acetate (3 × 125 ml). The combined ethyl acetate extracts were washed with 10% hydrochloric acid, water and dried over anhydrous sodium sulfate. The solvent is removed in vacuo. The crude product mixture was purified on a silica gel column, eluting with ethyl acetate: hexane (15:85) to give 6.4 g of the desired product 2.

Synthesis of compound 3: Methyl 6-chloro-3-thiomethyl-5-indolecarboxylate (5.2 g) was dissolved in 150 ml of ethanol: tetrahydrofuran (9: 3) and treated with Raney nickel. The reaction is monitored by mass spectral analysis at 30-minute intervals, followed by the addition of Raney nickel until the reaction is complete. After completion of the reaction, the reaction mixture was carefully filtered through celite, the celite was washed with methanol several times, and the filtrate was evaporated. The residue was taken up in ethyl acetate, washed with water, dried over anhydrous sodium sulfate. The solvent was removed to give compound 3 (3.2 g).

Synthesis of compound 4: Methyl ether, 1.5 g, was dissolved in 30 ml of 50:50 methanol / water. The reaction mixture is heated to a temperature of 50 ° C. for 2 hours with 4 molar equivalents of sodium hydroxide. The reaction mixture is cooled in an ice bath, acidified to pH 3 with 5M hydrochloric acid. Ethanol was removed on a rotary evaporator and the residue was extracted with ethyl acetate. The extract was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Evaporation of the solvent gave the desired acid 4 (1/48 g).

Synthesis of compound 5:

STEP A: Phosphonate A (38.4 g) and piperidone B (35.4 g) are dissolved in anhydrous dimethylformamide (400 ml). Sodium hydride (60% suspension in oil) was added in portions to the resulting solution, while maintaining the temperature of the reaction mixture at 0 ° C. After completion of the addition of sodium hydride, the reaction mixture was stirred for 30 minutes and then the ice bath was removed, the reaction mixture was stirred for 6 hours and slowly heated to ambient temperature. The reaction mixture was again cooled in an ice bath and quenched with methanol. Water was added to the reaction mixture, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed to give a crude alkene, which was purified by column chromatography eluting with ethyl acetate / hexane (1: 9) to give 21/8 g of the desired product C.

STAGE B: 10.1 g of compound C are dissolved in 50 ml of methanol. After purging the solution with nitrogen, a 5% palladium carbon catalyst (1 g) was added, followed by 1 ml of acetic acid. The reaction mixture was hydrogenated in a Parr apparatus for 4 hours at 2.812-3.515 kg / cm ² (40-50 f / d ² ). The reaction mixture was filtered through celite and concentrated. The residue is treated with 2 M hydrochloric acid in ether to obtain a salt with hydrochloric acid. The resulting white solid was dried continuously under vacuum to give 7.8 g of compound 5 as the hydrochloride.

Synthesis of compound 6: A mixture of 6-chloroindole-5-carboxylic acid (1.95 g), 4-fluorobenzylpiperidine hydrochloride (2.76 g) was placed in 50 ml of dry dichloromethane and treated with triethylamine (1.7 ml). The mixture is stirred until a clear solution is obtained. 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide (2.3 g) and dimethylaminopyridine (0.25 g) were added and the mixture was stirred for 20 hours at ambient temperature. The mixture was poured into water and the organic layer was separated. The aqueous solution is then extracted twice with dichloromethane. The combined extract is washed with 10% hydrochloric acid. The organic layer was dried over magnesium sulfate and evaporated. The product was purified by silica gel column chromatography, eluting with ethyl acetate: hexane (3: 7), to give compound 6 (2.78 g).

Synthesis of compound 7: 8.61 g of 6-chloro- (4-F-benzylpiperidinyl) indole-5-carboxamide (6) was dissolved in about 100 ml of dry DMF and the solution was cooled in an ice bath. To a cold solution, 30 ml of a 1M solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran in an inert atmosphere was added. The reaction mixture was stirred at 0 ° C. for 15 minutes and at ambient temperature for another 30 minutes. The reaction mixture was again cooled in an ice bath and 2.5 ml of iodomethane was added. After stirring for 30 minutes at 0 ° C., the mixture was warmed to ambient temperature and stirring was continued for 18 hours at ambient temperature. The mixture was diluted with water (or brine) and the product was extracted with ethyl acetate (4 × 75 ml). The combined extract is washed with water and dried over bezv. MgSO ₄ . The solvent was removed and the product was purified by silica gel column chromatography eluting with ethyl acetate: hexane (1: 4) to obtain 8.0 g of the desired product 7.

Synthesis of compound 8: 8 g of compound 7 are dissolved in approximately 100 ml of anhydrous dichloromethane and cooled in an ice bath. A 2M solution of oxalyl chloride (20.8 ml) in dichloromethane was slowly added via syringe to the resulting solution, and the mixture was stirred at 0 ° C for 1 hour. The ice bath was removed and stirring was continued for another 2 hours at ambient temperature. The solvent was removed under reduced pressure and the residue was evacuated for 15 minutes to remove excess oxalyl chloride. The product is immediately redissolved in anhydrous. dichloromethane (150 ml), cooled in an ice bath, quickly add 30 ml of a 2M solution of dimethylamine in tetrahydrofuran via a syringe. After 15 minutes of stirring, stirring was continued for another 15 minutes at ambient temperature. The solution was washed with water to remove salt and dried. After evaporation, the residue was purified on a silica gel column, eluting with chloroform: methanol (99: 1) to obtain 9.3 g of compound 8.

Synthesis of compound 10:

STEP A: To a solution of dimethylpiperazine 9 (25 g) in 300 ml of absolute ethanol is added 400 ml of 2N hydrogen chloride in diethyl ether. The solution is heated to a temperature of 70 ° C in an oil bath for 20 minutes. Then the solution was cooled to room temperature and stood overnight at a temperature of 6 ° C. A solid is obtained which is collected by filtration. Yield 39.8 g (trans-2,5-dimethylpiperazine dihydrochloride) after drying overnight in high vacuum.

STEP B: An ethanolic solution of 42.9 g of dimethylpiperazine dihydrochloride with STAGE A and 26.1 g of trans-2,5-dimethylpiperazine are vigorously stirred in an oil bath at a temperature of 80 ° C until all starting compounds are dissolved. The temperature of the oil bath was lowered to 65 ° C. and 33.1 g of 4-fluorobenzyl chloride was added. After stirring at this temperature for 30 minutes, the solution was placed overnight in a refrigerator with a temperature of 6 ° C. The solid was removed from the solution by filtration, and 2N hydrogen chloride in diethyl ether was added to the filtrate. The filtrate was stored at 6 ° C. overnight and the solid was collected. The solid is suspended in a 5% aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate and dried to give a yellow oil.

STEP C: A solution of 50.7 g of (L) -varic acid in 130 ml of boiling methanol is added to 70 ml of a hot methanol solution of 37.5 g of the product from STAGE B. The solution is allowed to stand at 6 ° C for 96 hours, then white crystals collected by filtration. The resulting compound was recrystallized from boiling methanol. The product was collected by filtration after standing at 6 ° C. overnight. Yield 30.5 g of salt of divinic acid ([α] = + 43.2 °, s = 1).

Synthesis of compound 11: Indole 3 ester (0.526 g) was dissolved in 10 ml of acetone (dry) and placed in an ice bath. Ground potassium hydroxide (0.7 g, 12.5 mmol) is added to the resulting solution, and after stirring for 5 minutes at 0 ° C, methyl iodide (400 μl, 6.272 mmol) is added to the reaction mixture. The reaction mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 30 minutes. After removing the solvent, the residue was taken up in ethyl acetate and washed with saturated sodium chloride. After drying over anhydrous sodium sulfate, filtration and rotary evaporation, a solid is obtained, 0.7 g. Chromatography on a silica gel column with ethyl acetate: hexane (2: 8) gives the methyl ester of compound 11 as a white solid. 0.52 g of the resulting product was dissolved in 50 ml of methanol and treated with 5 ml of 10N sodium hydroxide, the reaction mixture was heated to a temperature of 50 ° C for 2 hours. The reaction mixture was cooled to room temperature and concentrated to a solid on a rotary evaporator. The residue was taken up in 50 ml of water, washed with ether and placed in an ice bath. The basic solution was acidified with 10% hydrochloric acid to pH 2. The precipitate was extracted with ethyl acetate and the ethyl acetate layer was washed with a saturated sodium chloride solution. Drying over anhydrous sodium sulfate, filtration, and concentration on a rotary evaporator afforded compound 11 (0.48 g) as a white solid.

Synthesis of compound 12: 1.56 g of acid (11) was dissolved in dry methylene chloride, 10 ml, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (1.57 g) and dimethylaminopyridine (catalytic) were added to the resulting solution. After stirring under nitrogen for 10 minutes, 2.19 g of amine (10) was added, followed by triethylamine (3 ml). After stirring overnight at room temperature, the reaction mixture was concentrated and the residue was taken up in ethyl acetate and washed with 10% aq. sodium carbonate, aq. saturated sodium chloride, dried over anhydrous sodium sulfate and filtered. Concentration gives a crude product, which is subjected to silica gel column chromatography using ethyl acetate: hexane (4: 6) as an eluent to obtain 1.02 g of the desired product.

Synthesis of compound 13: 1.02 g of compound 12 from the previous step is dissolved in 30 ml of dry dichloromethane. The reaction mixture was purged with nitrogen and placed in an ice bath. To the resulting mixture was added 4 ml of 2M oxalyl chloride in dichloromethane. The reaction mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 2 hours. The reaction mixture was concentrated on a rotary evaporator. After drying in vacuo for 15 minutes, the residue (yellow solid) was dissolved in dry dichloromethane (30 ml), to which 4 ml of a 2M solution of dimethylamine in tetrahydrofuran was added. After 30 minutes, the reaction mixture was concentrated and the residue was taken up in ethyl acetate and washed with 10% aq. sodium carbonate saturated with sodium chloride, dried over anhydrous sodium sulfate and filtered. Concentration gives a crude product, which is subjected to silica gel column chromatography with ethyl acetate: methanol (9: 1). The resulting white substance was dissolved in 10 ml of dry dichloromethane. A sufficient amount of 2M hydrochloric acid is added to the resulting solution until a precipitate forms. The mixture was then concentrated to dryness on a rotary evaporator and then dried overnight under high vacuum to give compound 13 (1.08 g).

Synthesis of compound 15: Anhydrous sodium sulfate (71.0 g) was added to a solution of aniline 1 (9.25 g, 0.05 mol) and pyruvic aldehyde dimethyl acetal 14 (11.8 g, 0.1 mol) in 200 ml of glacial acetic acid , 0.5 mol) and the mixture is stirred for 30 minutes. Then, sodium triacetoxyborohydride powder (31.8 g, 0.15 mol) is added in portions over 5 minutes. The reaction mixture was stirred for another 2 hours. Acetic acid was removed under reduced pressure and the residue was alkalinized by adding a sufficient amount of saturated sodium bicarbonate solution. The product is then extracted with ethyl acetate, dried with sodium sulfate and evaporated to give an oil. The resulting oil was subjected to silica gel column chromatography using ethyl acetate: hexane (3: 7) to obtain compound 15 (14 g) as a colorless oil.

Synthesis of compounds 16 and 17: To a suspension of fresh aluminum chloride (18.5 g) in 200 ml of dry chloroform at a temperature of 0 ° C, a solution of ketal 15 (13.3 g) in 100 ml of chloroform is slowly added, and the mixture is warmed to room temperature and stirred in overnight. The aluminum chloride is carefully quenched by addition of ice water and the organic layer is separated and washed with sodium bicarbonate solution, dried and evaporated to give a white solid. Isomers were separated using silica gel column chromatography using ethyl acetate: hexane (1: 9). First, 6-chloroindole 17 (2.0 g) was eluted, then the 4-chloro isomer 16 (3.8 g).

Synthesis of compound 18: To a solution of 1.3 g of indole 17 in 15 ml of methanol, a solution of 0.9 g of sodium hydroxide in 20 ml of water is added. The reaction mixture is heated at a temperature of 50 ° C for 4 hours until a clear solution is obtained. The mixture was cooled and the methanol was evaporated, the residue was diluted with water and acidified with 10% hydrochloric acid. The product is extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to give indole acid 18 (1.2 g) as a white solid.

2-Methyl-6-methoxyindole-5-carboxylic acid is synthesized according to the procedure described above.

Synthesis of compound 21: To a solution of methyl 4-amino-6-methoxy 5-benzoate 19 (6.0 g, 0.033 mol) and dimethyl acetal 20 (7.0 g, 0.066 mol) in 150 ml of glacial acetic acid anhydrous sodium sulfate ( 47.0 g, 0.33 mol) and the mixture is stirred for 30 minutes. Sodium triacetoxyborohydride powder (20.1 g, 0.099 mol) was added in portions over 5 minutes. The reaction mixture was stirred for another 2 hours. Acetic acid was removed under reduced pressure and the residue was alkalinized by adding a sufficient amount of saturated sodium bicarbonate solution. The product is then extracted with ethyl acetate, washed with saturated sodium chloride, dried over sodium sulfate and evaporated to give an oil. The resulting oil was subjected to silica gel column chromatography using ethyl acetate: hexane (3: 7) as the eluent, and the desired product 21 (5.2 g) was obtained as an oil.

Synthesis of compound 22: To a solution of compound 21 (3.6 g) and iodomethane (5.7 g) in 50 ml of anhydrous dimethylformamide was added tert-butoxide potassium (1.0 M in tetrahydrofuran, 20 ml) at ambient temperature. The reaction mixture was stirred at ambient temperature for 0.5 hours and poured into 250 ml of ethyl acetate, washed with water (4 × 100 ml), brine (50 ml) and dried over magnesium sulfate. Evaporation of the solvent gives 3/26 g of compound 22. The product is used in the next step without purification.

Synthesis of compound 23: To a suspension of anhydrous aluminum chloride (0.71 g) in 20 ml of anhydrous 1,2-dichloroethane is added dropwise a solution of compound 22 (1 g) in 10 ml of 1,2-dichloroethane with stirring. The reaction mixture is heated to a temperature of 80 ° C for 0.5 hours. After the indicated time, the reaction mixture was quenched with methanol, the solvents were evaporated, then ethyl acetate (100 ml) was added. The organic phase is washed with water, aq. sodium bicarbonate solution and brine and concentrated. The crude product was purified by silica gel column chromatography using ethyl acetate: hexane (3: 7) to give compound 23 (0.22 g).

Synthesis of compound 24: To a suspension of 1.2 g of indole acid 18 and 1.6 g of compound 5 in 30 ml of dichloromethane, 0.7 g of triethylamine was added, followed by 1.4 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. The resulting clear solution was stirred for 4 hours. The solvent was evaporated and the residue was taken up in ethyl acetate and washed with water, dec. hydrochloric acid and brine. The organic layer was dried with sodium sulfate and evaporated. The product was isolated (1.3 g) as a white solid after chromatography on a silica gel column using ethyl acetate: hexane (1: 4).

Synthesis of compound 25: A solution of 1.3 g of compound 24 in 20 ml of dichloromethane was cooled to 0 ° C and a 2 M solution of oxalyl chloride in dichloromethane (3.4 ml, 6.8 mmol) was added, the reaction mixture was stirred at 0 ° C in within 1 hour. The temperature was raised to room temperature and stirring was continued for another 1 hour. The solvent was evaporated and the residue was dried in vacuo. The acid chloride is dissolved in dichloromethane (25 ml) and immediately the whole solution of 6.8 ml (13.6 mmol) of 2 M N, N-dimethylamine in tetrahydrofuran is added. The solvent was removed and the product was purified by silica gel column chromatography using methanol: chloroform (2:98). The product was obtained as a white solid (1.4 g).

Synthesis of compound 27: A solution of compound 26 (130 mg) in anhydrous dimethylformamide (5 ml) was stirred at 0 ° C. under nitrogen. Sodium hydride (25 mg, 60% dispersion in oil) was added and stirred for 5 minutes, then at room temperature for 30 minutes. The mixture was cooled to 0 ° C. and chloromethyl methyl sulfide (70 μl) was added. The reaction mixture was stirred for 20 hours at room temperature and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated in vacuo. The residue was purified on a chromatotron using methanol: chloroform (2:98) to give 100 mg of compound 27.

Synthesis of compound 28: A solution of oxone (120 mg) in water (1 ml) was added to a suspension of compound 27 (100 mg) in glacial acetic acid (4 ml). The reaction mixture was stirred at room temperature for 18 hours, washed with water and concentrated in vacuo. The residue was purified on a chromatotron using methanol: chloroform (2:98) to give 60 mg of compound 28.

Synthesis of compound 30: To a solution of compound 29 (200 mg) in tetrahydrofuran (20 ml) was added dropwise sodium bis (trimethylsilyl) amide (0.51 ml, 0.51 mmol) at a temperature of 0 ° C. The mixture, which turned into a light yellow solution, is slowly heated to ambient temperature and stirred for 30 minutes. Methoxymethyl chloride is then added and the reaction mixture is stirred overnight. The reaction mixture was quenched with ammonium chloride and extracted with dichloromethane. The combined organic layer was washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography, eluting with methanol: dichloromethane (5:95), to give 190 mg of compound 30.

Synthesis of compound 31: to a solution of compound 29 (200 mg) in tetrahydrofura (10 ml) was added dropwise sodium bis (trimethylsilyl) amide (0.56 ml, 0.56 mmol) at a temperature of 0 ° C. The mixture was slowly warmed to ambient temperature, stirred for 30 minutes, and then added to a solution of tosyl cyanide (115 mg) in tetrahydrofuran (10 ml). The resulting mixture was stirred for 2 hours at room temperature, quenched with ammonium chloride and extracted with dichloromethane. The combined organic layer was washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with methanol: dichloromethane (5:95) to obtain 90 mg of compound 31.

Synthesis of compound 34: Piperidone 33 is slowly added to a solution of 4-fluorobenzyl magnesium chloride (32) (33 ml, 8.3 mmol, 0.25 M in ethyl ether) at a temperature of 0 ° C. The reaction mixture was warmed to ambient temperature and then at reflux for 6 hours. The resulting cloudy solution was treated with ammonium chloride (saturated) and extracted with ether. The combined organic layer was washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography, eluting with hexane: ethyl acetate (4: 1), to give 990 mg of compound 34.

Synthesis of compound 35: Alcohol 34 (670 mg) in dichloromethac (10 ml) was added to a solution of diethylamino sulfur trifluoride (0.5 ml, 4/34 mmol) in dichloromethane (20 ml) at a temperature of -78 ° C. The reaction mixture was slowly warmed to ambient temperature and stirred for 2 hours, and then treated with sodium carbonate (saturated) and extracted with dichloromethane. The combined organic layer was washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography, eluting with hexane: ethyl acetate (8: 1), to give 300 mg of compound 35.

Synthesis of compound 36: A mixture of compound 35 (456 mg) and 4 M hydrochloric acid in dioxane (10 ml) was stirred for 4 hours. The reaction mixture was neutralized with sodium carbonate, extracted with ethyl acetate. The combined organic layer was washed with brine, dried and concentrated. The crude product is used in the next reaction without further purification.

Synthesis of compound 38: To a suspension of indolecarboxylic acid 37 (475 mg) in anhydrous dichloromethane (20 ml), piperidine 36 (350 mg, 1.66 mmol) was added. The mixture was stirred for 10 minutes and then 1- [3- (dimethylaminopropyl) 1-3-ethylcarbodiimide hydrochloride (475 mg) and dimethylaminopyridine (202 mg) were added. The reaction mixture becomes clear and is continuously stirred overnight. Then the reaction mixture is treated with 10% hydrochloric acid and extracted with dichloromethane. The combined organic extracts were washed with sodium bicarbonate, brine, dried and concentrated. The residue was purified by silica gel column chromatography, eluting with dichloromethane: ethyl acetate (9: 1), to give 300 mg of compound 38 as a white foam.

Synthesis of compound 39: Oxalyl chloride (0.52 ml, 1.04 mmol, 2M in dichloromethane) was added dropwise to a suspension of compound 38 (200 mg) at a temperature of 0 ° C. The reaction mixture was stirred at 0 ° C. for 30 minutes, then warmed to room temperature and stirred for 5 hours. A yellow suspension forms. The solvent and excess oxalyl chloride are removed under reduced pressure. The resulting yellow solid was dried in vacuo and dissolved in dichloromethane, then cooled in an ice bath. Dimethylamine (1.04 ml, 2.08 mmol, 2 M in tetrahydrofuran) was added. After 30 minutes, the reaction mixture was treated with water and extracted with dichloromethane. The organic extracts were washed with water, brine, dried and concentrated. The residue was purified by silica gel column chromatography, eluting with 3% MeOH in dichloromethane, to give 190 mg of compound 39 as a white solid.

Synthesis of compound 40: To a solution of compound 39 (75 mg) in tetrahydrofuran (10 ml) was added dropwise KHMDS (0.46 ml, 0.23 mmol, 0.5 M in toluene) at a temperature of 0 ° C. The mixture was slowly warmed to room temperature and stirred for 30 minutes. Methyl iodide (33 mg, 0.23 mmol) was slowly added to the reaction mixture, followed by stirring for 2 hours. The reaction mixture was quenched with ammonium chloride and extracted with dichloromethane. The combined organic extracts were washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with methanol: dichloromethane (2:98) to obtain 50 mg of compound 40.

Synthesis of compound 41: To a solution of compound 40 (75 mg) in tetrahydrofuran (10 ml) was added dropwise KHMDS (0.46 ml, 0.23 mmol, 0.5 M in toluene) at a temperature of 0 ° C. The mixture was slowly warmed to room temperature and stirred for 30 minutes. Methoxymethyl chloride (18 mg, 0.23 mmol) was slowly added to the reaction mixture, then stirred overnight. The reaction mixture was quenched with ammonium chloride and extracted with dichloromethane. The combined organic extracts were washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography, eluting with methanol: dichloromethane (2:98), to give 65 mg of compound 41.

Synthesis of compound 43: To a suspension of 6-methoxy-5-indolecarboxylic acid (37) (200 mg) in dichloromethac (5 ml), 1- [3- (dimethylaminopropyl)] - 3-ethylcarbodiimide hydrochloride (258 mg, 1, 35 mmol). The reaction mixture is stirred until all solids are dissolved. 4-Benzyl-4-hydroxypiperidine (42) (258 mg), obtained by removing the protecting group from compound 34 by the method of synthesis of compound 36, was added, and the resulting mixture was stirred at ambient temperature. The reaction mixture becomes cloudy. A catalytic amount of dimethylaminopyridine (10 mg) was added and stirred at ambient temperature overnight. The reaction mixture was treated with water and extracted with dichloromethane. The combined organic layer was washed with 10% hydrochloric acid, sodium bicarbonate (saturated) and brine, then dried and concentrated to give 300 mg (82%) of compound 43 as a yellow foam.

Synthesis of compound 44: Oxalyl chloride (0.41 ml, 1.65 mmol, 2 M in dichloromethane) was added dropwise to a solution of 6-methoxy- (4-benzyl-4-hydroxypiperidinyl) indole-5-carboxamide (300 mg) in dichloromethane (20 ml) at a temperature of 0 ° C. The reaction mixture was stirred at 0 ° C. for 30 minutes and then slowly heated to ambient temperature. After 2 hours, a yellow precipitate forms. The reaction mixture was concentrated under reduced pressure and dried for 1 hour under reduced pressure. The resulting yellow solid was suspended in dichloromethane (20 ml). At room temperature, methylpiperazine (0.2 ml) and diisopropylethylamine (0.2 ml) are added. The mixture was stirred for 1 hour, treated with water and extracted with dichloromethane. The residue was purified by silica gel column chromatography eluting with dichloromethane: methanol (10: 1) to obtain 180 mg of a white solid. 20 mg of the obtained solid was dissolved in methanol (1 ml). A saturated solution of hydrochloric acid was added dropwise to the resulting solution until a pH of about 3 was reached. Then, the solvents were removed and the product was dried to give compound 44.

Synthesis of compound 45: To a solution of compound 44 (65 mg) in anhydrous tetrahydrofuran (10 ml) was added dropwise sodium bis (trimethylsilyl) amide (0.25 ml, 0.25 mmol, 1.0 M solution in tetrahydrofuran) at ambient temperature Wednesday. The mixture was stirred at ambient temperature for 30 minutes, and then ethyl chloroformate (0.024 ml, 0.25 mmol) was added to the reaction mixture. After 1 hour, the reaction mixture was quenched with ammonium chloride (saturated) and extracted with ethyl acetate. The combined organic layer was washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane: methanol (10: 1), to give 15 mg of the title compound 45 as a white solid. The resulting solid was dissolved in methanol (1 ml), and a saturated solution of hydrochloric acid in methanol was added dropwise to the resulting solution until the pH was about 3. Then, the solvent was removed and the product was dried to give compound 45 hydrochloride.

Synthesis of compound 47:

STEP A: Piperazinone 46 (5.0 g) is dissolved in 15 ml of tetrahydrofuran, a solution of di-tert-butyl dicarbonate (12.04 g in 50 ml of tetrahydrofuran) is added to the resulting solution. After stirring at room temperature for 4 hours, the reaction mixture was concentrated to dryness on a rotary evaporator and the resulting solid was used in the next reaction without further purification.

STEP B: 10 g of the product from step A are dissolved in anhydrous acetone and the reaction mixture is cooled in an ice tank. Ground potassium hydroxide (14.02 g) was added to the resulting solution. After stirring at 0 ° C. for 10 minutes, 4-fluorobenzyl bromide (23.5 g) was added and the reaction mixture was stirred at 0 ° C. for 20 minutes and at room temperature for 1 hour. After removing the solvent on a rotary evaporator, the residue was taken up in ethyl acetate and washed with 10% aqueous sodium carbonate, brine and dried over anhydrous sodium sulfate. Filtration and concentration gave a crude product, which was purified by silica gel column chromatography using ethyl acetate: hexane, to give 14 g of compound 47.

Synthesis of compound 48: 14 g of compound 47 are dissolved in 100 ml of methylene chloride and treated with 100 ml of 2 M hydrochloric acid in ether for 2 hours. The solvent was removed and the resulting solid was washed with ether and hexane and dried under high vacuum to give compound 48 (11/3 g) as the hydrochloride salt.

Synthesis of compound 49: 1 g of compound 48 was dissolved in 20 ml of methylene chloride and treated with 6-methoxy-5-indolecarboxylic acid (37) (0.87 g), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (0.95 g), triethylamine (700 μl) and dimethyl-aminopyridine (catalytic) and the reaction mixture was stirred overnight. The reaction mixture was concentrated and the residue was taken up in ethyl acetate, washed with 10% aqueous sodium carbonate, brine and dried over anhydrous sodium sulfate. Filtration and concentration gave a crude material which was purified by silica gel column chromatography using ethyl acetate / hexane to give compound 49 (1.6 g).

Synthesis of compound 50: 1.6 g of compound 49 are dissolved in 25 ml of dry dichloromethane. The reaction mixture was purged with nitrogen and placed in an ice bath. To the resulting solution was added 5 ml of 2M oxalyl chloride in dichloromethane. The reaction mixture was stirred at room temperature for 1 hour and then at room temperature for 2 hours. The reaction mixture was concentrated on a rotary evaporator and then dried in vacuum for 15 minutes, the residue (yellow solid) was dissolved in dry dichloromethane. To the resulting residue was added a 2M solution of dimethylamine in THF (5 ml) and the reaction mixture was stirred for 0.5 hour. Then the reaction mixture was concentrated, and the residue was taken up in ethyl acetate and washed with 10% aq. sodium carbonate saturated with sodium chloride, dried over anhydrous sodium sulfate and filtered. Concentration gives a crude product, which is subjected to silica gel column chromatography using ethyl acetate / hexane, to give compound 50 (1.45 g).

Synthesis of compound 52: 2R, 5S-transdimethylpiperazine 51 (5.0 g) was dissolved in 15 ml of ethanol, 2-bromoethylbenzene (4.4 g) was added to the resulting solution. The resulting mixture was stirred at a temperature of 40 ° C for 30 minutes, cooled to room temperature and concentrated to dryness on a rotary evaporator. The residue was taken up in ethyl acetate and washed with 10% aqueous sodium carbonate, brine and dried over anhydrous sodium sulfate. Filtration and concentration gave the crude material, which was purified by silica gel column chromatography using ethyl acetate / hexane, to give compound 52 (5.4 g).

Synthesis of compound 53: 5 g of compound 52 was dissolved in 60 ml of methylene chloride and treated with 60 ml of 2 M hydrochloric acid in ether for 3 hours. The solvent was removed and the resulting solid was washed with ether and hexane and dried under high vacuum to give compound 53 as a hydrochloride salt (3.6 g).

Synthesis of compound 54: compound 53 (1.32 g) was dissolved in 20 ml of methylene chloride and treated with 6-methoxy-5-indolecarboxylic acid (37) (0.9 g) in the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (1.04 g), 800 μl of triethylamine and catalytic DMAP, overnight. The reaction mixture was concentrated and the residue was taken up in ethyl acetate, washed with 10% aqueous sodium carbonate, brine and dried over anhydrous sodium sulfate. Filtration and concentration gave the crude material, which was purified by silica gel column chromatography using ethyl acetate / hexane to give compound 54 (0.95 g).

Synthesis of compound 55: 0.6 g of compound 54 was dissolved in 20 ml of methylene chloride. The reaction mixture was purged with nitrogen and placed in an ice bath. To the resulting solution was added 2 ml of 2M oxalyl chloride in methylene chloride. The reaction mixture was stirred at room temperature for 1 hour and then at room temperature for 2 hours. The reaction mixture was concentrated on a rotary evaporator and then dried in vacuo for 15 minutes. The residue (yellow solid) is dissolved in 15 ml of dry methylene chloride, 2 ml of a 2M solution of dimethylamine in tetrahydrofuran are added to the resulting solution. After 30 minutes, the reaction mixture was concentrated and the residue was taken up in ethyl acetate and washed with 10% aq. sodium carbonate saturated with sodium chloride, dried over anhydrous sodium sulfate and filtered. Concentration gave a crude product, which was purified by silica gel column chromatography using ethyl acetate / hexane to give compound 55 (0.78 g).

Synthesis of compound 57: 7.65 g (19.97 mmol) of indole 56 was dissolved in 80 ml of anhydrous dimethylformamide and cooled in an ice bath. In an inert atmosphere, 40 ml (2M solution in dichloromethane) of oxalyl chloride are added dropwise over 20 minutes. After stirring for 15 minutes at 0 ° C., the reaction mixture was warmed to ambient temperature and stirring was continued for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate (3 × 100 ml). The combined extract was washed with water, dried over sodium sulfate and evaporated. The product was then purified by silica gel column chromatography, eluting with ethyl acetate: hexane (30:70), to give 8 g (97.5%) of aldehyde 57.

Synthesis of compound 58: To a solution of 1-methylimidazole (149 mg) in tetrahydrofuran (10 ml) was added dropwise n-butyllithium (1/14 ml, 1.82 mmol, 1.6 M in hexane) at a temperature of -78 ° C. The reaction mixture was stirred at −40 ° C. for 30 minutes. Compound 57 (500 mg) in tetrahydrofuran (10 ml) was added. The reaction mixture was warmed to ambient temperature and stirred overnight. The reaction mixture was quenched with ammonium chloride (saturated), extracted with ethyl acetate. The combined organic layer was washed with brine, dried and concentrated. The crude mixture was refluxed with phenylhydrazine (0.6 ml) in ethanol (10 ml) to remove compound 57, which was not consumed during the reaction. After removing the solvent, the residue was purified by silica gel column chromatography, eluting with ethyl acetate: hexane (4: 1), to give 120 mg of compound 58.

Using the methods described above, the compounds of Tables 2 and 3 are prepared, which are tested to determine the ability to inhibit p38-α kinase. It was found that the compounds in tables 2 and 3 have IC ₅₀ values for inhibition of p38-α in the range from 0.1 to 1.5 μmol.

table 2 Connection No. Structure MM (calculated) MM (found.) one

466 466 2

452 453 3

535 534 four

573 573 5

480 480

Connection No. Structure MM (calculated) MM (found.) 6

418 418 7

551 551 8

524 523 9

590 590

Connection No. Structure MM (calculated) MM (found.) 10

521 520 eleven

620 620 12

592 592 13

579 580

Connection No. Structure MM (calculated) MM (found.) fourteen

523 522 fifteen

509 509 16

484 484 17

567 567

Connection No. Structure MM (calculated) MM (found.) eighteen

593 592 19

537 537 twenty

526 525 21

678 678

Connection No. Structure MM (calculated) MM (found.) 22

579 578 23

522 522 24

650 650 25

480 480

Connection No. Structure MM (calculated) MM (found.) 26

648 648 27

549 548 28

620 620 29th

597 596

Connection No. Structure MM (calculated) MM (found.) thirty

539 538 31

519 519 32

553 553 33

513 513

Connection No. Structure MM (calculated) MM (found.) 34

609 609 35

592 591 36

596 595 37

542 541

Connection No. Structure MM (calculated) MM (found.) 38

571 571 39

541 541 40

494 494 41

548 548

Connection No. Structure MM (calculated) MM (found.) 42

570 570 43

514 513 44

490 490 45

595 595

Connection No. Structure MM (calculated) MM (found.) 46

566 566 47

537 537 48

573 573 49

536 536

Connection No. Structure MM (calculated) MM (found.) fifty

543 543 51

509 509 52

507 507 53

572 572

Connection No. Structure MM (calculated) MM (found.) 54

565 565 55

599 599 56

537 537 57

513 513 58

456 456

Connection No. Structure MM (calculated) MM (found.) 59

485 485 60

551 551 61

511 511 62

499 500

Connection No. Structure MM (calculated) MM (found.) 63

543 543 64

584 584 65

493 493 66

494 494

Connection No. Structure MM (calculated) MM (found.) 67

477 477 68

542 542 69

584 584 70

530 529 71

512 511

Connection No. Structure MM (calculated) MM (found.) 72

523 522 73

539 539 74

495 495 75

512 511 76

528 528

Connection No. Structure MM (calculated) MM (found.) 77

499 499 78

552 551 79

512 511 80

498 497 81

496 495

Connection No. Structure MM (calculated) MM (found.) 82

525 525 84

510 509 85

540 539 86

485 486 87

495 495

Connection No. Structure MM (calculated) MM (found.) 88

552 551 89

508 508 90

562 562 91

558 558 92

539 539

Connection No. Structure MM (calculated) MM (found.) 93

542 542 94

590 590 95

528 528 96

555 555

Connection No. Structure MM (calculated) MM (found.) 97

510 509 98

497 497 99

527 527 one hundred

550 550 101

569 569

Connection No. Structure MM (calculated) MM (found.) 102

527 527 103

526 525 104

528 528 105

526 525 106

540 539

Connection No. Structure MM (calculated) MM (found.) 107

538 537 108

498 498 109

524 523 110

542 541 111

530 529

Connection No. Structure MM (calculated) MM (found.) 112

499 500 113

508 508 114

542 541 115

504 504 116

492 504

Table 3

Connection No. Structure MM (calculated) MM (found.) 117

472.5858 472.5858 118

404.4636 404.4636 119

390.4368 390.4368 120

502.6116 502.6116

Connection No. Structure MM (calculated) MM (found.) 121

558.6752 558.6752 122

458.559 458.559 123

389.4527 389.4527 124

420.4626 420.4626 125

516.6384 516.6384

Connection No. Structure MM (calculated) MM (found.) 126

504.6027 504.6027 127

422.4537 422.4537 128

525.021 525.021 129

434.4894 434.4894 130

422.4537 422.4537

Connection No. Structure MM (calculated) MM (found.) 131

438.4527 438.4527 132

452.4795 452.4795 133

408.4269 408.4269 134

420.4626 420.4626 135

391.4249 391.4249 136

528.5582 528.5582

Connection No. Structure MM (calculated) MM (found.) 137

435.4775 435.4775 138

419.4785 419.4785 139

486.6126 486.6126 140

511.547 511.547 141

507.559 507.559

Connection No. Structure MM (calculated) MM (found.) 142

505.5868 505.5868 143

574.6931 574.6931 144

465.5222 465.5222 145

437.4686 437.4686

Connection No. Structure MM (calculated) MM (found.) 146

480.9931 480.9931 147

518.6106 518.6106 148

535.0845 535.0845 149

460.5748 460.5748

Connection No. Structure MM (calculated) MM (found.) 150

548.6553 548.6553 151

520.6017 520.6017 152

446.548 446.548 153

450.4677 450.4677

Connection No. Structure MM (calculated) MM (found.) 154

494.5639 494.5639 155

511.0189 511.0189 156

606.6911 606.6911 157

521.5858 521.5858

Connection No. Structure MM (calculated) MM (found.) 158

490.6006 490.6006 159

506.5749 506.5749 160

490.6006 490.6006 161

536.6007 536.6007 162

498.9832 498.9832

Connection No. Structure MM (calculated) MM (found.) 163

469.9415 469.9415 164

541.02 541.02 165

511.9783 511.9783 166

497.9951 497.9951 167

497.9951 497.9951 168

483.9683 483.9683

Connection No. Structure MM (calculated) MM (found.) 169

539.0478 539.0478 170

549.6434 549.6434 171

476.5738 476.5738 172

476.5738 476.5738

Connection No. Structure MM (calculated) MM (found.) 173

476.5738 476.5738 174

469.9415 469.9415 175

479.549 479.549 176

513.01 513.01 177

494.5639 494.5639

Connection No. Structure MM (calculated) MM (found.) 178

534.6285 534.6285 179

508.5907 508.5907 180

522.6175 522.6175 181

483.5123 483.5123

Claims (66)

1. Derivatives of indole formulas

and their pharmaceutically acceptable salts, Where

represents a double bond; Z ¹ represents N or CR ⁵ where R ⁵ represents H, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy or halogen; Z ² at position 2 represents CR ¹ and Z ² at position 3 represents CA, where each R ¹ independently is hydrogen or C ₁ -C ₆ alkyl; A is —W _i —COX _j Y, where Y is COR ² , where R ² is OR, NR ₂ , NRNR _2, or NROR, where each R independently represents H, C ₁ -C ₆ alkyl, or C ₅ -C ₆ heteroaryl containing in the ring one or two heteroatoms selected from N, O and S, each of which is optionally substituted with one or more groups selected from NR ′ ₂ , OR ′, COOR ′, C ₁ -C ₆ alkyl, CN, = O and SR ', where each R' is H or C ₁ -C ₆ alkyl, and where two R or R 'attached to the same N atom can form a 3-8 membered ring selected from the group consisting of piperazine ring, morpholine ring, ty zolidinovoe ring, oxazolidine ring, a pyrrolidine ring, a piperidine ring, azatsiklopropanovoe ring azatsiklobutanovoe ring and azatsiklooktanovoe ring; and wherein said ring may be further substituted with C ₁ -C ₆ alkyl or COO-C ₁ -C ₆ alkyl, and X is unsubstituted alkylene (1-6C), or Y is imidazole substituted with methyl, i is 0, j is 0 or 1; R ⁷ is H or C ₁ -C ₆ alkyl, SOR, SO ₂ R, RCO, COOR, C ₁ -C ₆ alkyl-COR, CONR ₂ , SO ₂ NR ₂ , CN, OR, C ₁ -C ₆ alkyl- SR, C ₁ -C ₆ alkyl-OCOR, C ₁ -C ₆ alkyl-COOR, C ₁ -C ₆ alkyl-CN or C ₁ -C ₆ alkyl-CONR ₂ , where each R independently represents H, C ₁ -C ₆ alkyl or aryl, which is optionally substituted with halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy, or R ⁷ is methoxymethyl, methoxyethyl, ethoxymethyl, benzyloxymethyl or 2-methoxyethyloxymethyl; each R ³ independently is halogen, C ₁ -C ₆ alkyl, OR, SR or NR ₂ , where R is H or C ₁ -C ₆ alkyl; n is 0-3; L ¹ is CO; L ² is alkylene (1-4C) optionally substituted with one or two C ₁ -C ₄ alkyl groups; each R ^{4 is} independently selected from the group consisting of C ₁ -C ₆ alkyl, halogen, OR, NR ₂ , SR, SOR, SO ₂ R, RCO, COOR, CONR ₂ , SO ₂ NR ₂ , where each R independently represents H or C ₁ -C ₆ alkyl, or R ⁴ represents = O; m is 0-4; Ar is an aryl group substituted with from 0 to 5 substituents selected from the group consisting of C ₁ -C ₆ alkyl, halogen, OR, NR ₂ , SR, SOR, SO ₂ R, RCO, COOR, CONR ₂ and SO ₂ NR ₂ where each R independently represents H or C ₁ -C ₆ alkyl. 2. The compound according to claim 1, where Z ¹ represents N. 3. The compound according to claim 1, where j is 0. 4. The compound according to claim 1, where R ⁷ is H, C ₁ -C ₆ alkyl or C ₁ -C ₆ acyl. 5. The compound according to claim 1, where Z ¹ represents CH. 6. The compound according to claim 1, where L ² is unsubstituted C ₁ -C ₄ alkylene. 7. The compound according to claim 1, where L ² is unsubstituted methylene or methylene substituted by C ₁ -C ₄ alkyl. 8. The compound according to claim 1, where Ar is optionally substituted phenyl. 9. The compound of claim 8, wherein said optional substituent is halogen, OR or C ₁ -C ₆ alkyl, where each R is independently H or C ₁ -C ₆ alkyl. 10. The compound of claim 8, wherein said phenyl is unsubstituted or substituted with one substituent. 11. The compound according to claim 1, where each R ⁴ is halogen, C ₁ -C ₆ alkoxy or C ₁ -C ₆ alkyl. 12. The compound according to claim 11, where m is 0, 1 or 2. 13. The compound of claim 12, wherein m is 2 and both R ⁴ are C ₁ -C ₆ alkyl. 14. The compound according to claim 1, where R ³ is halogen or C ₁ -C ₆ alkoxy. 15. The compound of claim 14, wherein n is 0, 1, or 2. 16. The compound according to claim 1, where L ¹ is associated with the ring α in the 4-, 5- or 6-position. 17. The compound according to clause 16, where L ¹ is associated with the ring α in the 5-position. 18. The compound according to claim 1, where R ¹ represents N. 19. The compound according to 17, where Z ¹ represents N. 20. The compound according to 17, where Z ¹ represents CH. 21. The compound according to claim 1 or its pharmaceutically acceptable salts as an active ingredient for the manufacture of a medicament for the treatment of a pathological condition characterized by increased p38-α activity. 22. The compound according to item 21, where the pathological condition is rheumatoid arthritis. 23. The compound according to claim 19, where a represents COCOR ² and R ² has the meanings indicated in claim 1. 24. The compound according to item 23, where Z ² in position 2 is CH. 25. The compound according to claim 20, where A is COCOR ² , where R ² has the meanings indicated in claim 1. 26. The compound of claim 25, wherein Z ² at position 2 is CH. 27. The compound according to paragraph 24, where n is 0 or 1. 28. The compound of claim 27, wherein Ar is substituted phenyl. 29. The compound of claim 27, wherein L ² is unsubstituted C ₁ -C ₄ alkylene. 30. The compound according to clause 29, where n is 1 and R ³ is halogen or methoxy. 31. The compound of claim 30, wherein R ⁷ is H or C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-COR, C ₁ -C ₆ alkyl-SR, C ₁ -C ₆ alkyl-OCOR, C ₁ -C ₆ alkyl-COOR, C ₁ -C ₆ alkyl-CN or C ₁ -C ₆ alkyl-CONR ₂ , where R is as defined in claim 1. 32. The compound according to p, where R ⁷ represents methyl or methoxymethyl, methoxyethyl, ethoxymethyl, benzyloxymethyl or 2-methoxyethylmethyl. 33. The compound of claim 32, wherein Ar is para-fluorophenyl. 34. The compound of claim 33, wherein R ² is OR or NR ₂ , where each R is independently H or C ₁ -C ₆ alkyl, and where two R attached to the same N atom can form a 6-membered a ring selected from a morpholine ring, a piperidine ring and a piperazine ring. 35. The compound according to clause 34, where R ² is NR ₂ , where each R is independently H or C ₁ -C ₆ alkyl, and where two R attached to the same N atom can form a 6-membered ring, selected from a morpholine ring, a piperidine ring and a piperazine ring. 36. The compound according to claim 1, selected from the group including Connection No. Connection Name one {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1-methyl-1H-indol-3-yl} oxoacetic acid methyl ester; 2 {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1-methyl-1H-indol-3-yl} oxoacetic acid; 3 1- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1-methyl-1H-indol-3-yl} -2- (4-methylpiperazin-1-yl) ethane- 1,2-dione; four 5- (4-Benzylpiperidin-1-carbonyl) -1- (4-chlorobenzoyl) -6-methoxy-1H-indol-3-yl] oxoacetic acid methyl ester; 5 {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1-methyl-1H-indol-3-yl} oxoacetic acid ethyl ester; 6 [5- (4-Benzylpiperidin-1-carbonyl) -1-methyl-1H-indol-3-yl] -oxoacetic acid methyl ester; 7 1- {5- [4- (4-Chlorobenzyl) piperidin-1-carbonyl] -6-methoxy-1-methyl-1H-indol-3-yl} -2- (4-methylpiperazin-1-yl) ethane- 1,2-dione; 8 5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-3-
methoxyoxalindole-1-carboxylic acid ethyl ester; 9 5- (4-Benzyl-4-hydroxypiperidin-1-carbonyl) -6-methoxy-3- [2- (4-methylpiperazin-1-yl) -2-oxoacetyl] indole-1-carboxylic acid ethyl ester; 10 1- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1-methyl-1H-indol-3-yl} -2-piperazin-1-ylethan-1,2-dione ; eleven 4- (2- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1-methyl-1H-indol-3-yl} -2-oxoacetyl) piperazine-1-carboxylic acid tert-butyl ether; 12 4- (2- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1-methyl-1H-indol-3-yl} -2-oxoacetyl) piperazine-1-carboxylic acid ethyl ether; 13 5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-3- (2-morpholin-4-yl-2-oxoacetyl) indole-1-carboxylic acid ethyl ester; fourteen N- (2-Dimethylaminoethyl) -2- {5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1-methyl-1H-indol-3-yl} -2-oxoacetamide; fifteen 1-methyl-6-methoxy- [4'-fluoro- (4-benzyl-2,5-dimethyl-piperazinyl)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 16 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl) -N, N-dimethyl-2-oxoacetamide; 17 1-Ethoxycarbonyl-6-methoxy- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazinyl)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; eighteen 5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-3- [2- (4-methylpiperazin-1-yl) -2-oxoacetyl] indole-1-carboxylic acid ethyl ester; 19 3-Dimethylamino-oxalyl-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -6-methoxyindole-1-carboxylic acid ethyl ester; twenty 1- {6-Chloro-5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -2-morpholin-4-ylethan-1,2-dione ; 21 3- [2- (4-tert-butoxycarbonylpiperazin-1-yl) -2-oxoacetyl] -5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxyindole-1-carboxylic acid ethyl ester ; 22 5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-3- (2-oxo-2-piperazin-1-ylacetyl) -indole-1-carboxylic acid ethyl ester; 23 1- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1-methyl-1H-indol-3-yl} -2-morpholin-4-ylethan-1,2-dione ; 24 3- [2- (4-Ethoxycarbonylpiperazin-1-yl) -2-oxoacetyl] -5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxyindole-1-carboxylic acid ethyl ester; 25 2- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1-methyl-1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 26 4- (2- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1-methyl-1H-indol-3-yl} -2-oxoacetyl) -2,5-trans dimethylpiperazine-1-carboxylic acid tert-butyl ether; 27 1- (2,5-trans-dimethylpiperazin-1-yl) -2- {5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1-methyl-1H-indole-3- silt} ethane-1,2-dione; 28 4- (2- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1-methyl-1H-indol-3-yl} -2-oxoacetyl) -2,5-trans dimethylpiperazine-1-carboxylic acid ethyl ester; 29th 6-Chloro-5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -3- [2- (4-methylpiperazin-1-yl) -2-oxoacetyl] indole-1-carboxylic acid ethyl ester; thirty 1- {6-Chloro-5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -2- (4-methylpiperazin-1-yl) ethane- 1,2-dione; 31 1- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -1,2-dimethyl-1H-indol-3-yl} -2- (4-methylpiperazin-1-yl) ethan-1, 2-dione; 32 1- {6-Chloro-5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -1,2-dimethyl-1H-indol-3-yl} -2- (4-methylpiperazin-1-yl) ethane-1,2-dione; 33 1-methyl-6-chloro- [4'-fluoro- (4-benzyl-2,5-dimethylpiperazinyl)] -indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 34 6-Methoxy-5- [4- (4-Fluorobenzyl) -2,5-dimethylpiperazin-1-carbonyl] -3- [2- (morpholin-4-yl) -2-oxoacetyl] indole-1-carboxylic acid ethyl ether; 35 5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-3- [2- (4-methylpiperazin-1-yl) -2-oxoacetyl] indole-1-carboxylic acid dimethylamide; 36 6-Chloro-5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -3- [2- (4-methylpiperazin-1-yl) -2-oxoacetyl] indole-1-carboxylic acid dimethylamide; 37 2- {6-Chloro-1-ethoxycarbonyl-5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 38 1-Ethoxycarbonyl-6-chloro- [4'-fluoro- (4-benzyl-2R, 5S-dimethyl-piperazinyl)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 39 2- {6-Chloro-1-dimethylaminocarbonyl-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 40 2- {6-Chloro-1-cyano-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 41 2- {6-Chloro-5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -1-methanesulfonyl-1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 42 6-Chloro-3-dimethylamino-oxalyl-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] indole-1-carboxylic acid tert-butyl ether; 43 2- {6-Chloro-5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -1-methoxymethyl-1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 44 2- {1-Cyano-5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 45 1-tert-Butoxycarbonyl-6-methoxy- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazinyl)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 46 2- {6-Methoxy-1-dimethylaminocarbonyl-5- [4- (4-Fluorobenzyl) -2R, 5S-dimethylpiperazin-1-carbonyl] -1H-indol-3-yl} -N, N-dimethyl-2- oxoacetamide; 47 1-Acetyl-6-methoxy- [4'-fluoro- (4-benzyl-2,5-dimethylpiperazinyl)] -indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 48 1-Methanesulfonyl-6-methoxy- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazinyl)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 49 3-Dimethylamino-oxalyl-5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxyindole-1-carboxylic acid dimethylamide; fifty 2- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -1-methanesulfonyl-6-methoxy-1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 51 2- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1-methoxymethyl-1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 52 2- {1-Acetyl-5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 53 2- {1-Dimethylsulfamoyl-5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1H-indol-3-yl] -N, N-dimethyl-2-oxoacetamide; 54 3-Dimethylamino-oxalyl-5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxyindole-1-carboxylic acid tert-butyl ether; 55 1- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -1-methanesulfonyl-6-methoxy-1H-indol-3-yl} -2- (4-methylpiperazin-1-yl) ethane- 1,2-dione; 56 1-Acetyl-6-methoxy- [4'-fluoro- (4-benzyl-2R, 5S-dimethyl-piperazinyl)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 57 1-Methyl-6-chloro- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazinyl)] -indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 58 2- {6-Chloro-5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -2-oxoacetamide; 59 1-Methyl-6-chloro- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazinyl)] - indole-5-carboxamide-3-amide of glyoxylic acid; 60 1-Acetyl-2-methyl-6-methoxy- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazinyl)] -indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 61 2- {6-Chloro-5- [4- (4-fluorobenzylidene) piperidin-1-carbonyl] -1-methoxymethyl-1H-indol-3-yl) -N, N-dimethyl-2-oxoacetamide; 62 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methoxymethyl-1H-indol-3-yl} -N-methyl-2-oxoacetamide; 63 1-Methoxymethyl-6-chloro- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazinyl)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 64 2- {1-tert-Butoxycarbonylmethyl-6-chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 65 2- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1-methyl-1H-indol-3-yl} -N-ethyl-N-methyl-2-oxoacetamide; 66 2- {6-Ethoxy-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 67 2- {5- [4- (4-Fluorobenzylidene) -6-methoxypiperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 68 {6-Chloro-3-dimethylamino-oxalyl-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] indol-1-yl} acetic acid methyl ester; 69 6-Chloro-3-dimethylamino-oxalyl-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] indol-1-ylmethyl ester of 2,2-dimethylpropionic acid; 70 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methylthiomethyl-1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 71 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -N, N-diethyl-2-oxoacetamide; 72 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -N- (2-cyanoethyl) -N-methyl-2 -oxoacetamide; 73 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -2-oxo-1H-thiazol-2-yl-acetamide; 74 1-Azetidin-1-yl-2- {6-chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-N-indol-3-yl} ethan-1,2- dion; 75 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-isopropyl-1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 76 2- [6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1- (2-methoxyethyl) -1H-indol-3-yl] -N, N-dimethyl-2-oxoacetamide ; 77 1-Methyl-6-chloro- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazinyl)] indole-5-carboxamide-3-glyoxylic acid N-methylamide; 78 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -N-cyclopropylmethyl-N-propyl-2-oxoacetamide; 79 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -N-isopropyl-N-methyl-2-oxoacetamide; 80 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -N-ethyl-N-methyl-2-oxoacetamide; 81 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -N-cyclopropyl-2-oxoacetamide; 82 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -2-oxo-N-pyrrolidin-1-yl-acetamide; 84 1- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -2-pyrrolidin-1-ylethan-1,2-dione ; 85 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -N, N-diisopropyl-2-oxoacetamide; 86 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -N-methoxy-2-oxoacetamide; 87 1- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -2- (2-methylaziridin-1-yl) ethane- 1,2-dione; 88 1-Azocan-1-yl-2- {6-chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} ethan-1,2- dion; 89 1-Methyl-6-methoxy- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazinyl)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 90 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methanesulfonylmethyl-1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 91 2- [6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1- (2-methoxyethoxymethyl) -1H-indol-3-yl] -N, N-dimethyl-2-oxoacetamide ; 92 1-Methoxymethyl-6-methoxy- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazinyl)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 93 2- {1-Acetoxymethyl-6-chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 94 2- {1-Benzyloxymethyl-6-chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 95 2- {6-Chloro-1-ethoxymethyl-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 96 1-methyl-6-chloro- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazinyl)] indole-5-carboxamide-3-glyoxylic acid morpholinamide; 97 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -N-cyclopropyl-N-methyl-2-oxoacetamide; 98 2- {5- [4-Fluoro-4- (4-fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1-methyl-1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide ; 99 2- {5- [4-Fluoro-4- (4-fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1-methoxymethyl-1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide ; one hundred 1-methyl-6-methoxy- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazinyl)] indole-5-carboxamide-3-glyoxylic acid morpholinamide; 101 2- {6-Chloro-1- (2-diethylaminoethyl) -5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1H-indol-3-yl} -N, N-dimethyl-2- oxoacetamide; 102 1-Methyl-6-chloro- [4- (1-4'-fluorophenylethyl) piperazinyl] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 103 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -N-ethyl-2-oxo-N-propylacetamide; 104 1- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -2-thiazolidin-3-yl-ethan-1,2-dione ; 105 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -N-ethyl-N-isopropyl-2-oxoacetamide; 106 1- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -2- (4,4-dimethyloxazolidin-3-yl) ethane-1,2-dione; 107 1- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -2- (2,5-dimethylpyrrolidin-1-yl) ethane-1,2-dione; 108 {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} oxoacetic acid N ', N'-dimethylhydrazide; 109 1- {6-Chloro-5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -2-piperidin-1-ylethan-1,2-dione ; 110 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -N-ethyl-N- (2-methoxyethyl) -2 -oxoacetamide; 111 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -N- (2-methylsulfanylethyl) -2-oxoacetamide; 112 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -N-methoxy-N-methyl-2-oxoacetamide; 113 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl} -N-cyanomethyl-N-methyl-2-oxoacetamide; 114 [(2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1-methyl-1H-indol-3-yl) -2-oxoacetyl) methylamino] acetic acid methyl ester; 115 2- {1-Cyanomethyl-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1H-indol-3-yl} N, N-dimethyl-2-oxoacetamide; 116 [6-Chloro-1-methyl-3- (1-methyl-1H-imidazole-2-carbonyl) -1H-indol-5-yl] - [4- (4-fluorobenzyl) piperidin-1-yl] methanone ; 117 1- [5- (4-Benzylpiperidin-1-carbonyl) -1H-indol-3-yl] -2- (4-methylpiperazin-1-yl) ethan-1,2-dione; 118 [5- (4-Benzylpiperidin-1-carbonyl) -1H-indol-3-yl] -oxoacetic acid methyl ester; 119 [5- (4-Benzylpiperidin-1-carbonyl) -1H-indol-3-yl] oxoacetic acid; 120 1- [5- (4-Benzylpiperidin-1-carbonyl) -6-methoxy-1H-indol-3-yl] -2- (4-methylpiperazin-1-yl) ethane-1,2-dione; 121 4- {2- [5- (4-Benzylpiperidin-1-carbonyl) -1H-indol-3-yl] -2-oxoacetyl} piperazine-1-carboxylic acid tert-butyl ether; 122 1- [5- (4-Benzylpiperidin-1-carbonyl) -1H-indol-3-yl] -2-piperazin-1-yl-ethan-1,2-dione; 123 2- [5- (4-Benzylpiperidin-1-carbonyl) -1H-indol-3-yl] -2-oxoacetamide; 124 [5- (4-Benzylpiperidin-1-carbonyl) -6-methoxy-1H-indol-3-yl] oxoacetic acid; 125 2- [5- (4-Benzylpiperidin-1-carbonyl) -6-methoxy-1H-indol-3-yl] -2-oxo-N- (2-pyrrolidin-1-yl-ethyl) acetamide; 126 1- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -2-methyl-1H-indol-3-yl} -2- (4-methylpiperazin-1-yl) ethan-1,2- dion; 127 {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -2-methyl-1H-indol-3-yl} oxoacetic acid; 128 1- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1H-indol-3-yl} -2- (4-methylpiperazin-1-yl) ethan-1,2- dion; 129 [5- (4-Benzylpiperidin-1-carbonyl) -6-methoxy-1H-indol-3-yl] oxoacetic acid methyl ester; 130 {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -1H-indol-3-yl} oxoacetic acid methyl ester; 131 {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1H-indol-3-yl} oxoacetic acid; 132 {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1H-indol-3-yl} oxoacetic acid methyl ester; 133 {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -1H-indol-3-yl) oxoacetic acid; 134 [5- (4-Benzylpiperidin-1-carbonyl) -4-methoxy-1H-indol-3-yl] oxoacetic acid; 135 {5- [4- (4-Fluorobenzyl) piperazin-1-carbonyl] -1H-indol-3-yl} oxoacetic acid; 136 [5- (4-Benzylpiperidin-1-carbonyl) -4-methoxy-1H-indol-3-yl] oxoacetic acid 2-methyl-4-oxo-4H-pyran-3-yl ether; 137 6-Methoxy- (4-benzylpiperazinyl) indole-5-carboxamide-3-glyoxylic acid methyl ester; 138 [4- (1-Phenylethyl) piperazinyl] indole-5-carboxamide-3-glyoxylic acid methyl ester; 139 1- {5- [4- (4-Fluorobenzyl) piperazin-1-carbonyl] -6-methoxy-1H-indol-3-yl} -2- (4-methylpiperidin-1-yl) ethan-1,2- dion; 140 N- (2,3-Dihydroxypropyl) -2- {5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1H-indol-3-yl} -2-oxoacetamide; 141 1- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1H-indol-3-yl} -2-morpholin-4-ylethane-1,2-dione; 142 1- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1H-indol-3-yl} -2-piperidin-1-yl-ethan-1,2-dione; 143 1- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1H-indol-3-yl} -2- (4-pyrrolidin-1-ylpiperidin-1-yl) ethane- 1,2-dione; 144 2- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 145 2- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1H-indol-3-yl) -2-oxoacetamide; 146 [3'-Chloro- (4-benzyl-2,5-dimethylpiperazinyl)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 147 1- [5- (4-Benzyl-4-hydroxypiperidin-1-carbonyl) -6-methoxy-1H-indol-3-yl] -2- (4-methylpiperazin-1-yl) ethane-1,2-dione ; 148 1- {5- [4- (3'-Chloro-4-benzyl-2,5-dimethylpiperazine) -1-carbonyl] -1H-indol-3-yl} -2- (4-methylpiperidin-1-yl) ethane-1,2-dione; 149 [4- (3'-Chloro-1-phenylethyl) -2,5-dimethylpiperazinyl] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 150 1- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1H-indol-3-yl} -2- (4-isopropylpiperazin-1-yl) ethan-1,2- dion; 151 1- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1H-indol-3-yl} -2- (4-methylpiperazin-1-yl) ethane-1,2 dione; 152 (4-Benzyl-2R, 5S-piperazinyl) indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 153 (4-Benzyl-oxopiperazinyl) indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 154 6-Methoxy- [4'-fluoro- (4-benzyl-2,5-dimethylpiperazinyl)] -indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 155 6-Methoxy- [3'-chloro- (4-benzyl-2R, 5S-dimethylpiperazinyl)] -indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 156 4- (2- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1H-indol-3-yl} -2-oxoacetyl) piperazine-1-carboxylic acid tert .- butyl ether; 157 1- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1H-indol-3-yl} -2- (4-hydroxypiperidin-1-yl) ethan-1,2- dion; 158 4-Methoxy- [4- (1-phenylethyl) piperazinyl] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 159 1- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1H-indol-3-yl} -2-piperazin-1-ylethane-1,2-dione; 160 6-Methoxy- [4- (1-phenylethyl) piperazinyl] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 161 6-Methoxy- [4'-fluoro- (4-benzyl-2,5-dimethylpiperazinyl)] -indole-5-carboxamide-3-glyxylic acid morpholinamide; 162 6-Chloro- [4'-fluoro- (4-benzyl-2,5-dimethylpiperazinyl)] -indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 163 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 164 6-Chloro- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazinyl)] -indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 165 1- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1H-indol-3-yl} -2-morpholin-4-ylethane-1,2-dione; 166 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1H-indol-3-yl} -N, N-diethyl-2-oxoacetamide; 167 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1H-indol-3-yl} -N-isopropyl-N-methyl-2-oxoacetamide; 168 2- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -2-methyl-1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 169 1- {6-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -2-methyl-1H-indol-3-yl} -2- (4-methylpiperazin-1-yl) ethane- 1,2-dione; 170 6-Methoxy- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazinyl)] -indole-5-carboxamide-3-glyoxylic acid 4-methylpiperazinamide; 171 6-Methoxy- (4-benzyl-2,5-dimethylpiperazinyl) indole-5-carboxamide-3-glyoxylic acid N-dimethylamide; 172 6-Methoxy- (4-benzyl-2S, 5R-dimethylpiperazinyl) indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 173 6-Methoxy- (4-benzyl-2R, 5S-dimethylpiperazinyl) indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 174 2- {4-Chloro-5- [4- (4-fluorobenzyl) piperidin-1-carbonyl] -1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 175 2- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-2-methyl-1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide; 176 6-Chloro- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazinyl)] - 2-methylindole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 177 6-Methoxy- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazinyl)] -indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 178 1- {5- [4- (4-Fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-2-methyl-1H-indol-3-yl} -2- (4-methylpiperazin-1-yl) ethane- 1,2-dione; 179 6-Methoxy- [4- (4'-fluorobenzyl) -2R, 5S-dimethylpiperazinyl] -2-methylindole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 180 6-Methoxy- {4- [1- (4'-fluorophenyl) ethyl] -2R, 5S-dimethylpiperazinyl} -2-methylindole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide; 181 2- {5- [4-Fluoro-4- (4-fluorobenzyl) piperidin-1-carbonyl] -6-methoxy-1H-indol-3-yl} -N, N-dimethyl-2-oxoacetamide and their pharmaceutically acceptable salts. 37. The compound according to claim 1, selected from the group including 6-methoxy- [4'-fluoro- (4-benzylpiperidinyl)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide (compound 144); 1-methyl-6-chloro- [4'-fluoro- (4-benzylpiperidinyl)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide (compound 58); 1-methyl-6-methoxy- [4'-fluoro- (4-benzylpiperidinyl)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide (compound 25); 1-methyl-6-chloro- [4'-fluoro- (4-benzylpiperidinyl)] indole-5-carboxamide-3-glyoxylic acid morpholinamide (compound 20); 1-methyl-6-methoxy- [4'-fluoro- (4-benzylpiperidinyl)] indole-5-carboxamide-3-glyoxylic acid morpholinamide (compound 23); 6-methoxy- [4'-fluoro- (4-benzylpiperidinyl)] indole-5-carboxamide-3-glyoxylic acid morpholinamide (compound 141); 6-chloro- [4'-fluoro- (4-benzylpiperidinyl)] indole-5-carboxamide-3-glyoxylic acid morpholinamide (compound 165); 6-methoxy- [4'-fluoro- (4-benzylpiperidinyl)] indole-5-carboxamide-3-amide of glyoxylic acid (compound 145); 6-chloro- [4'-fluoro- (4-benzylpiperidinyl)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide (compound 163), and their pharmaceutically acceptable salts. 38. The compound according to claim 1, selected from the group including 1-methyl-6-methoxy- [4'-fluoro- (4-benzyl-2,5-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide (compound 15); 1-methyl-6-chloro- [4'-fluoro- (4-benzyl-2,5-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide (compound 33); 1-methyl-6-chloro- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide (compound 57); 1-methyl-6-chloro- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid amide (compound 59); 1-methyl-6-chloro- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid N-methylamide (compound 77); 1-methyl-6-methoxy- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide (compound 89); 1-methyl-6-chloro- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid morpholinamide (compound 96); 1-methyl-6-methoxy- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazine)] indole- 5-carboxamide-3-glyoxylic acid morpholinamide (compound 100), and their pharmaceutically acceptable salts. 39. The compound of claim 38, wherein said compound is 1-methyl-6-methoxy- [4'-fluoro- (4-benzyl-2,5-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide (compound 15) or a pharmaceutically acceptable salt thereof. 40. The compound of claim 38, wherein said compound is 1-methyl-6-chloro [4'-fluoro- (4-benzyl-2,5-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide (compound 33) or a pharmaceutically acceptable salt thereof. 41. The compound of claim 38, wherein said compound is 1-methyl-6-chloro- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide (compound 57) or a pharmaceutically acceptable salt thereof. 42. The compound of claim 38, wherein said compound is 1-methyl-6-chloro- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazine)] indole-5-carboxamide-3-amide glyoxylic acid ( compound 59) or a pharmaceutically acceptable salt thereof. 43. The compound of claim 38, wherein said compound is 1-methyl-6-chloro- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid N- methylamide (compound 77) or a pharmaceutically acceptable salt thereof. 44. The compound of claim 38, wherein said compound is 1-methyl-6-methoxy- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide (compound 89) or a pharmaceutically acceptable salt thereof. 45. The compound of claim 38, wherein said compound is 1-methyl-6-chloro- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid morpholinamide ( compound 96) or a pharmaceutically acceptable salt thereof. 46. The compound according to claim 1, where the specified compound is 6-chloro- [4'-fluoro- (4-benzyl-2,5-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide ( compound 144) or a pharmaceutically acceptable salt thereof. 47. The compound of claim 38, wherein said compound is 1-methyl-6-methoxy- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid morpholinamide ( compound 100) or a pharmaceutically acceptable salt thereof. 48. The compound according to claim 1, where the specified compound is 1-ethoxycarbonyl-6-methoxy- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide (compound 34) or a pharmaceutically acceptable salt thereof. 49. The compound according to claim 1, where the specified compound is 1-ethoxycarbonyl-6-chloro- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide (compound 38) or a pharmaceutically acceptable salt thereof. 50. The compound according to claim 1, where the specified compound is 1-tert-butoxycarbonyl-6-methoxy- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide (compound 45) or a pharmaceutically acceptable salt thereof. 51. The compound according to claim 1, wherein said compound is 1-acetyl-6-methoxy- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide (compound 56) or a pharmaceutically acceptable salt thereof. 52. The compound according to claim 1, wherein said compound is 1-acetyl-2-methyl-6-methoxy- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazine)] indole-5-carboxamide-3- glyoxylic acid N, N-dimethylamide (compound 60) or a pharmaceutically acceptable salt thereof. 53. The compound according to claim 1, where the specified compound is 1-methoxymethyl-6-chloro- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide (compound 63) or a pharmaceutically acceptable salt thereof. 54. The compound of claim 1, wherein said compound is 1-methoxymethyl-6-methoxy- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazine)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide (compound 92) or a pharmaceutically acceptable salt thereof. 55. The compound of claim 1, wherein said compound is 1-methyl-6-chloro- [4- (1- (4'-fluorophenyl) ethyl) -2R, 5S-dimethylpiperazine)] indole-5-carboxamide-3- glyoxylic acid N, N-dimethylamide (compound 102) or a pharmaceutically acceptable salt thereof. 56. The compound of claim 1, wherein said compound is 6-methoxy- (4-benzylpiperazinyl) indole-5-carboxamide-3-glyoxylic acid methyl ester (compound 137) or a pharmaceutically acceptable salt thereof. 57. The compound of claim 1, wherein said compound is [4- (1-phenylethyl) piperazinyl] indole-5-carboxamide-3-glyoxylic acid methyl ester (compound 138) or a pharmaceutically acceptable salt thereof. 58. The compound of claim 1, wherein said compound is (4-benzyl-2R, 5S-piperazine) indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide (compound 152) or a pharmaceutically acceptable salt thereof. 59. The compound of claim 1, wherein said compound is 6-methoxy- [4'-fluoro- (4-benzyl-2,5-dimethylpiperazinyl)] indole-5-carboxamide-3-glyoxylic acid morpholinamide (compound 161) or its pharmaceutically acceptable salt. 60. The compound according to claim 1, where the specified compound is 6-methoxy- [4'-fluoro- (4-benzyl-2R, 5S-dimethylpiperazinyl)] indole-5-carboxamide-3-glyoxylic acid N, N-dimethylamide ( compound 177) or a pharmaceutically acceptable salt thereof. 61. The compound according to claim 1, wherein said compound is (6-methoxy-2-methyl- [4- (1- (4'-fluorophenyl) ethyl) -2R, 5S-dimethylpiperazinyl) indole-5-carboxamide-3- glyoxylic acid N, N-dimethylamide (compound 180) or a pharmaceutically acceptable salt thereof. 62. Indole derivatives of the formula

and their pharmaceutically acceptable salts, Where

represents a double bond; Z ¹ represents N, CH, SON or CF; Z ² at position 2 is CR, where R is H or alkyl (C _1-6 ); Z ² at position 3 is CC (= O) —C (= O) —OR or CC (= O) —C (= O) —NR ₂ , where each R is independently H or alkyl (C _1-6 ), or where NR ₂ represents a morpholine, piperidine or piperazine ring, each of which can be substituted with up to 3 groups selected from R 'and -OR', where R 'is alkyl (C _1-6 ); R ⁷ is H or is C ₁ -C ₆ alkyl, SO ₂ R, RCO, COOR, C ₁ -C ₆ alkyl-COR, CONR ₂ , SO ₂ NR ₂ , CN, CF ₃ , NR ₂ , OR, C ₁ -C ₆ alkyl-SR, C ₁ -C ₆ alkyl-OR, C ₁ -C ₆ alkyl-COOR or C ₁ -C ₆ alkyl-CN, where each R is independently H or C ₁ -C ₆ alkyl, or R ⁷ is methoxymethyl, methoxyethyl, ethoxymethyl; each R ³ independently is halogen, C ₁ -C ₆ alkyl, OR, SR or N (R) ₂ , where R is H or C ₁ -C ₆ alkyl; n is 0-3; m is 0-4; L ¹ is CO; L ² is alkylene (1-4C) optionally substituted with one or two C ₁ -C ₄ alkyl groups; each R ^{4 is} independently selected from the group consisting of C ₁ -C ₆ alkyl, halogen, OR, SR, SOR, SO ₂ R, RCO, COOR, CONR ₂ and SO ₂ NR ₂ , where each R is independently H or C ₁ -C ₆ alkyl; Ar is an aryl group substituted with 0-5 substituents selected from the group consisting of C ₁ -C ₆ alkyl, halogen, OR, SR, SOR, SO ₂ R, RCO, COOR, CONR ₂ and SO ₂ NR ₂ , where each R independently is H or C ₁ -C ₆ alkyl. 63. A pharmaceutical composition having p38-α kinase inhibitory activity, comprising at least one pharmaceutically acceptable excipient and indole derivative of formula (I)

and its pharmaceutically acceptable salts, Where

represents a double bond; Z ¹ represents N or CR ⁵ where R ⁵ represents H, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy or halogen; Z ² at position 2 represents CR ¹ and Z ² at position 3 represents CA; where each R ¹ independently is hydrogen or C ₁ -C ₆ alkyl; A is -W _i -COX _j Y, where Y is COR ² , where R ² is OR, NR ₂ , NRNR ₂ or NROR, where each R independently represents H, C ₁ -C ₆ alkyl, or C ₅ -C ₆ heteroaryl containing in the ring one or two heteroatoms selected from N, O and S, each of which is optionally substituted by one or more groups selected from NR _'2, oR', COOR ', C ₁ -C ₆ alkyl, CN, = O and SR', wherein each R 'is H or C ₁ -C _{6 is} alkyl, and where two R or R 'attached to the same N atom can form a 3-8 membered ring selected from the group consisting of piperazine ring, morpholine ring, thiazolidine ring, oxazolidine ring, pyrrolidine ring, piperidine ring, azacyclopropane ring, azacyclobutane ring and azacyclooctane ring; and where said ring may be further substituted with C ₁ -C ₆ alkyl or COO-C ₁ -C ₆ alkyl, and X is unsubstituted alkylene (1-6C), or Y is imidazole substituted with methyl, i is 0, j is 0 or 1; R ⁷ is H or C ₁ -C ₆ alkyl, SOR, SO ₂ R, RCO, COOR, C ₁ -C ₆ alkyl-COR, CONR ₂ , SO ₂ NR ₂ , CN, OR, C ₁ -C ₆ alkyl- SR, C ₁ -C ₆ alkyl-OCOR, C ₁ -C ₆ alkyl-COOR, C ₁ -C ₆ alkyl-CN or C ₁ -C ₆ alkyl-CONR ₂ , where each R independently represents H, C ₁ -C ₆ alkyl or aryl, which is optionally substituted with halogen, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkoxy, or R ⁷ is methoxymethyl, methoxyethyl, ethoxymethyl, benzyloxymethyl or 2-methoxyethyloxymethyl; each R ³ independently is halogen, C ₁ -C ₆ alkyl, OR, SR or NR ₂ , where R is H or C ₁ -C ₆ alkyl; n is 0-3; L ¹ is CO; L ² is alkylene (1-4C) optionally substituted with one or two C ₁ -C ₄ alkyl groups; each R ^{4 is} independently selected from the group consisting of C ₁ -C ₆ alkyl, halogen, OR, NR ₂ , SR, SOR, SO ₂ R, RCO, COOR, CONR ₂ , SO ₂ NR ₂ , where each R independently represents H or C ₁ -C ₆ alkyl, or R ⁴ represents = O; m is 0-4; Ar is an aryl group substituted with from 0 to 5 substituents selected from the group consisting of C ₁ -C ₆ alkyl, halogen, OR, NR ₂ , SR, SOR, SO ₂ R, RCO, COOR, CONR ₂ and SO ₂ NR ₂ where each R independently represents H or C ₁ -C ₆ alkyl. Priority on points and signs: 05/21/1999 according to claims 1, 2-6, 8-35, 62, 65, for compounds of formula I or their pharmaceutically acceptable salts, where Z ¹ represents N or CH, L ² is unsubstituted alkylene (1-4C), Ar is an aryl group substituted by 0 to 5 substituents selected from the group consisting of C ₁ -C ₆ alkyl, halogen, OR, NR ₂ , SR, RCO, COOR, CONR ₂ , and where Z ² , R, R ¹ , A , R ² , R ', R ³ , R ⁴ , R ⁷ , L ¹ , W, X, Y, I, j, n and m are as defined in claim 1; 09/17/1999 according to claims 1, 7, 37-61, 62, 63 for compounds of the formula I or their pharmaceutically acceptable salts, where Z ¹ represents CR ⁵ , where R ⁵ represents C ₁ -C ₆ alkyl, hydroxy, C ₁ - C ₆ alkoxy or halogen; L ² is alkylene (1-4C) substituted with one or two C ₁ -C ₄ alkyl groups; Ar is an aryl group substituted with from 0 to 5 substituents selected from the group consisting of SOR, SO ₂ R, SO ₂ NR ₂ ; and where Z ² , R, R ¹ , A, R ² , R ', R ³ , R ⁴ , R ⁷ , L ¹ , W, X, Y, I, j, n and m have the meanings specified in paragraph one; 05/09/2000 according to clause 38.