JP2005526831A - Pharmaceutical compounds - Google Patents

Abstract

The present invention provides a compound for use in the prevention or treatment of conditions or symptoms mediated by p38 MAP kinase, such as rheumatoid arthritis and osteoarthritis; the compound is of the general formula (I): T, V and W are each a nitrogen atom or a group CR ^{4 provided} that 3 or less of U, T, V and W are nitrogen atoms; R ⁰ is hydrogen, C _1-4 hydrocarbyl, halogen or group- It is ^{a-R 3; R 1} is _hydrogen, is a _{C 1-4} hydrocarbyl or a group ^{-A-R 3;} however, only one of ^{R 0} and ^{R 1} is a group ^{-A-R 3; R 2} Is hydrogen, C _1-4 hydrocarbyl or halogen; A is a carbon- or heteroatom-containing linker group having a linking chain length of 1 or 2 atoms; R ³ is a monocycle containing 5 to 12 ring members Formula or Each group R ⁴ is hydrogen, hydroxy, halogen, nitro, cyano, a monocyclic heterocyclic group having up to 7 ring members, a group N (R ⁵ ) ₂ , a group C ( _{^{O) N (R 6) 2}} , group _{^{SO 2 N (R 6) 2}} , are independently selected from the group ^R a -R ^b and group Y; provided that no more than one group Y is present; ^{R a} is A bond, O, S, SO, SO ₂ , NH or N—C _1-4 hydrocarbyl; R ^b is optionally mediated by O, S, SO, SO ₂ , NH or N—C _1-4 hydrocarbyl And optionally substituted C with one or more substituents selected from hydroxy, amino, mono- or di-C _1-4 hydrocarbylamino, C _1-4 hydrocarbyloxy, oxo, C _1-4 hydrocarbylthio and halogen _1-8 hydrocarbyl der ; ^{R 5} each group, _{hydrogen, C 1-4 alkyl, C 1-4} acyl and _{C 1-4} is independently selected from alkylsulfonyl; each group ^{R 6} is independently from hydrogen and _{C 1-4} hydrocarbyl Y is a group —N (R ⁷ ) —C (O) —R ⁸ or —N (R ⁷ ) —SO ₂ —R ⁸ ; R ⁷ is hydrogen, C _1-4 hydrocarbyl or The group C (O) —R ⁸ or SO ₂ —R ⁸ ; R ⁸ is C _1-10 hydrocarbyl, C _1-10 hydrocarbylamino, C _1-10 hydrocarbylthio, C _1-10 hydrocarbyloxy, aryl, aryl amino, arylthio and aryloxy groups; these aryl moiety is a carbocyclic or heterocyclic, 5 to 12 having ring members; each substituent R ⁸ is one or more groups other than Y R Or, R ⁷ and R ^8, which together with the nitrogen and carbon or sulfur atoms attached are connected to form a ring structure of 4 to 7 ring members; optionally being substituted in; In combination, when U, T, V and W are all CH and R ¹ and R ² are both hydrogen, R ⁰ is other than a 2- (2,4-diamino-6-triazinyl) ethyl group; Provided that the group -A-R ³ contains an acidic substituent selected from carboxylic, phosphones, sulfonic acids and tetrazoles, or contains a -C (O) NSO ₂ -group, or -A- is When -C (O) N- and the nitrogen atom of the group A is directly linked to the furan or thiophene ring, R ¹ is -AR ³ and both R ⁰ and R ² are hydrogen, or ^{R 0} is at the ^{-A-R 3, 1} is a hydrogen.
[Chemical 1]

Description

  The present invention relates to compounds that inhibit or modulate the activity of p38 MAP kinase, the use of the compounds in the treatment or prevention of disease states or conditions mediated by p38 MAP kinase, and novel compounds having p38 MAP kinase inhibitory or modulating activity. Also provided are pharmaceutical compositions containing the compounds and novel chemical intermediates.

Background of the Invention

  Protein kinases constitute a large family of structurally related enzymes involved in the control of various signal transduction processes in the cell (Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book I and II, Academic Press, San Diego, CA). Kinases are classified into families according to the substrates they phosphorylate (eg, protein-tyrosine, protein-serine / threonine, lipids, etc.). Sequence motifs generally applicable to each of these kinase families have been identified (eg Hanks, SK, Hunter, T., FASEB J., 9: 576-596 (1995); Knighton, et al., Science, 253: 407-414 (1991); Hiles, et al., Cell, 70: 419-429 (1992); Kunz, et al., Cell, 73: 585-596 (1993); Garcia-Bustos, et al. , EMBO J., 13: 2352-2361 (1994)).

  Protein kinases are characterized by their regulatory mechanisms. These mechanisms include, for example, autophosphorylation, phosphate transfer by other kinases, protein-protein interactions, protein-lipid interactions and protein-polynucleotide interactions. Individual protein kinases may be regulated by more than one mechanism.

  Kinases regulate many different cellular processes by adding phosphate groups to target proteins, including but not limited to proliferation, differentiation, apoptosis, motility, transcription, translation and other signaling processes. These phosphorylation events act as molecular on / off switches that can modulate or regulate the target protein biological function. Target protein phosphorylation occurs in response to various extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle phenomena, environmental or nutritional stress, and the like. Suitable protein kinases function in the signaling pathway to activate or inactivate (directly or indirectly), for example, metabolic enzymes, regulatory proteins, receptors, cytoskeletal proteins, ion channels or pumps, or transcription factors. Uncontrolled signaling due to a defective regulation of protein phosphorylation is associated with several diseases, including, for example, inflammation, cancer, allergies / asthma, immune system diseases and conditions, central nervous system diseases and conditions, and angiogenesis Was involved in.

The mitogen-activated protein (MAP) kinase family is a series of structurally related, activated by growth factors (eg EGF) and phorbol esters (ERK), or IL-1, TNF or stress (p38, JNK) Proline-directed serine / threonine kinase. These kinases mediate the effects of many extracellular stimuli in various biological processes such as cell growth, differentiation and death. Three groups of mammalian MAP kinases: extracellular signal-regulated kinase (ERK), c-Jun NH _2- terminal kinase (JNK) and p38 MAP kinase have been studied in detail.

  There are five known human isoforms of p38 MAP kinase, p38α, p38β, p38β2, p38γ and p38δ. p38 kinase, also known as cytokine-suppressing anti-inflammatory drug binding protein (CSBP), stress-activated protein kinase (SAPK) and RK, is a transcription factor (eg, ATF-2, MAX, CHOP and C / ERPb) Involved in phosphorylation (Stein et al., Ann. Rep. Med. Chem., 31, 289-298 (1996)) and activation of and other kinases such as MAPKAP-K2 / 3 or MK2 / 3, And itself are activated by chemical and chemical stresses (eg UV, osmotic stress), pro-inflammatory cytokines and bacterial lipopolysaccharide (LPS) (Herlaar, E & Brown, Z., Molecular Medicine Today, 5: 439- 447 (1999)). Products of p38 phosphorylation have been shown to mediate the production of inflammatory cytokines including TNF and IL-1 and cyclooxygenase-2 (COX-2). Each of these cytokines has been implicated in many medical conditions and symptoms. IL-1 and TNF are also known to stimulate the production of other proinflammatory cytokines such as IL-6 and IL-8.

  Interleukin (IL-1) and tumor necrosis factor (TNF) are biological materials produced by various cells such as monocytes or macrophages. IL-1 has been shown to mediate a variety of biological activities that appear to be important for immune regulation and other physiological conditions such as inflammation (eg, Dinarello, et al., Rev. Infect. Disease) 6:51 (1984)). The myriad biological activities known for IL-1 include T helper cell activation, fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, induction of acute phase proteins and suppression of plasma iron levels There is.

  There are many medical conditions in which excessive or unregulated IL-1 production is involved in disease exacerbation and / or induction. These include rheumatoid arthritis (Arend et al., Arthritis & Rheumatism 38 (2): 151-160), osteoarthritis, endotoxemia and / or toxic shock syndrome, other acute or chronic inflammatory conditions such as internal Inflammatory responses induced by toxins or inflammatory bowel disease; tuberculosis, atherosclerosis, Hodgkin's disease (Benharroch et al., Euro. Cytokine Network 7 (1): 51-57), muscle degeneration, cachexia, If you have psoriatic arthritis, Reiter syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis and Alzheimer's disease. Evidence has also linked IL-1 activity to diabetes and pancreatic B cells (Dinarello, J. Clinical Immunology, 5: 287-297 (1985)). Since inhibition of p38 leads to inhibition of IL-1 production, it is believed that p38 inhibitors will be useful in the treatment of the above diseases.

  Excessive or unregulated TNF production is associated with rheumatoid arthritis (Maini et al., APMIS, 105 (4): 257-263), rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic Shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, reperfusion injury, graft-versus-host reaction, allograft Single rejection, infections such as influenza, type 1 herpes simplex virus (HSV-1), HSV-2, cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), human herpesvirus- 6 (HHV-6), HHV-7, HHV-8 fever and muscle pain, pseudorabies, nose derived from infection or malignancy Includes ductitis and cachexia, cachexia derived from acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related syndrome), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis or heartburn Was involved in mediating or exacerbating several diseases. Since inhibition of p38 leads to inhibition of TNF production, it is believed that p38 inhibitors will be useful in the treatment of the above diseases.

  Interleukin-8 (IL-8) is a chemotactic factor produced by several cell types, including mononuclear cells, fibroblasts, endothelial cells and keratinocytes. Its production from endothelial cells is induced by IL-1, TNF or lipopolysaccharide (LPS). IL-8 stimulates several functions in vitro. It has been shown to have chemoattractant properties of neutrophils, T lymphocytes and basophils. In addition, it induces histamine release from basophils of both normal and atopic individuals, as well as lysosomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11 bl CD18) in neutrophils without de novo protein synthesis; this may contribute to increased neutrophil adhesion to vascular endothelial cells . Many diseases are characterized by massive neutrophil infiltration. Symptoms associated with increased IL-8 production (involved in chemotaxis of neutrophils into the inflammatory site) will benefit from treatment with compounds that inhibit IL-8 production. Recently, chronic obstructive pulmonary disease (COPD) has been associated with elevated IL-8 levels (Barnes et al., Curr. Opin. Pharmacol., 1: 242-7 (2001)). Other symptoms associated with IL-8 include acute respiratory distress syndrome (ARDS), asthma, pulmonary fibrosis and bacterial pneumonia.

  IL-1 and TNF affect a variety of cells and tissues, and these and other leukocyte-derived cytokines are important inflammatory mediators in a variety of disease states and conditions. Inhibition of these cytokines is beneficial in suppressing, reducing and alleviating many of these conditions.

  In addition to the above IL-1, TNF and IL-8, also required for the synthesis and / or action of several other proinflammatory proteins (ie IL-6, GM-CSF, COX-2, collagenase and stromelysin) Inhibition of signaling by p38 is expected to be a highly effective mechanism in regulating excessive and detrimental activation of the immune system. This expectation is supported by the strong diverse anti-inflammatory activity described for p38 kinase inhibitors (Badger, et al., J. Pharm. Exp. Thera, 279: 1453-1461 (1996); Griswold, et al., Pharmacol. Comm., 7: 323-229 (1996)).

  WO 01/47922 (Aventis Pharma) discloses a class of substituted azindoles and their use to treat conditions that can be mediated by inhibition of protein kinases, particularly Syk kinase, ie 72 kDa cytoplasmic protein tyrosine kinase.

  WO 02/10137 (Signal Pharmaceuticals Inc.) discloses a class of indazole compounds as inhibitors of JNK kinase. The compounds are disclosed as having various therapeutic uses, such as the treatment of arthritis.

    WO 01/02369 (Agouron Pharmaceuticals) also relates to indazole compounds that modulate and / or inhibit the activity of certain protein kinases, particularly tyrosine kinases. The compound has a substituted or unsubstituted aryl or heteroaryl group at the 3-position of the indazole ring.

  WO 00/71535 (Scios Inc.) discloses indole type compounds as inhibitors of p38 kinase. The 6-membered ring in the indole-like nucleus of the compound is linked to a piperidine or piperazine group with a short linker group.

WO 00/46198 (Astra Zeneca) discloses a class of indole derivatives with anti-inflammatory activity in which the compound has an aryl or heteroaryl ring linked to the 1-position of the indole nucleus with a CH ₂ or SO ₂ linking group doing. The compound is disclosed to be an antagonist of the pro-inflammatory cytokine MCP-1.

  WO 93/1408 (Smith-Kline Beecham) discloses 1,3,4-triarylimidazoles as inhibitors of p38 MAP kinase.

  WO 99/15164 (Zeneca) discloses various bis-benzamidophenyl derivative compounds that exhibit inhibition of p38 activity.

  WO 99/32111 (Bayer) discloses a series of diarylurea compounds that act as p38 MAP kinase inhibitors.

  WO 99/00357 (Vertex) discloses another class of diaryl urea compounds as p38 MAP kinase inhibitors.

  WO 99/43651 and WO 99/43654 (both from the Genetics Institute) disclose substituted indoles as phospholipase inhibitors useful in treating or preventing inflammatory conditions.

Summary of the Invention

  The present invention provides a class of partially known and partially novel compounds that have p38 MAP kinase inhibitory or modulating activity and are considered useful in preventing or treating conditions or symptoms mediated by p38 MAP kinase.

上記においてＵ、Ｔ、ＶおよびＷは各々窒素原子または基ＣＲ^４であるが、但しＵ、Ｔ、ＶおよびＷのうち３以下は窒素原子である；
Ｒ^０は水素、Ｃ_１‐４ヒドロカルビル、ハロゲンまたは基‐Ａ‐Ｒ^３である；
Ｒ^１は水素、Ｃ_１‐４ヒドロカルビルまたは基‐Ａ‐Ｒ^３である；但し、Ｒ^０およびＲ^１のうち一方のみが基‐Ａ‐Ｒ^３である；
Ｒ^２は水素、Ｃ_１‐４ヒドロカルビルまたはハロゲンである；
Ａは、１または２原子の連結鎖長を有する炭素‐またはヘテロ原子含有リンカー基である；
Ｒ^３は５〜１２環員を含有する単環式または二環式ヘテロアリール基である；
各基Ｒ^４は、水素、ヒドロキシ、ハロゲン、ニトロ、シアノ、７環員以内を有する単環へテロ環式基、基Ｎ（Ｒ^５）_２、基Ｃ（Ｏ）Ｎ（Ｒ^６）_２、基ＳＯ_２Ｎ（Ｒ^６）_２、基Ｒ^ａ‐Ｒ^ｂおよび基Ｙから独立して選択される；但し、１以下の基Ｙが存在する；
Ｒ^ａは結合、Ｏ、Ｓ、ＳＯ、ＳＯ_２、ＮＨまたはＮ‐Ｃ_１‐４ヒドロカルビルである；
Ｒ^ｂは、Ｏ、Ｓ、ＳＯ、ＳＯ_２、ＮＨまたはＮ‐Ｃ_１‐４ヒドロカルビルで場合により介在され、かつヒドロキシ、アミノ、一または二‐Ｃ_１‐４ヒドロカルビルアミノ、Ｃ_１‐４ヒドロカルビルオキシ、オキソ、Ｃ_１‐４ヒドロカルビルチオおよびハロゲンから選択される１以上の置換基で場合により置換されたＣ_１‐８ヒドロカルビルである；
各基Ｒ^５は、水素、Ｃ_１‐４アルキル、Ｃ_１‐４アシルおよびＣ_１‐４アルキルスルホニルから独立して選択される；
各基Ｒ^６は、水素およびＣ_１‐４ヒドロカルビルから独立して選択される；
Ｙは基‐Ｎ（Ｒ^７）‐Ｃ（Ｏ）‐Ｒ^８または‐Ｎ（Ｒ^７）‐ＳＯ_２‐Ｒ^８である；
Ｒ^７は水素、Ｃ_１‐４ヒドロカルビルまたは基Ｃ（Ｏ）‐Ｒ^８またはＳＯ_２‐Ｒ^８である；
Ｒ^８は、Ｃ_１‐１０ヒドロカルビル、Ｃ_１‐１０ヒドロカルビルアミノ、Ｃ_１‐１０ヒドロカルビルチオ、Ｃ_１‐１０ヒドロカルビルオキシ、アリール、アリールアミノ、アリールチオおよびアリールオキシ基から選択される；それらのアリール部分は炭素環式またはヘテロ環式であり、５〜１２環員を有する；各置換基Ｒ^８はＹ以外の１以上の基Ｒ^４で場合により置換されている；または、Ｒ^７およびＲ^８は、それらが結合する窒素および炭素またはイオウ原子と一緒になって、４〜７環員の環構造を形成するように連結される；
組合せとして、Ｕ、Ｔ、ＶおよびＷがすべてＣＨで、Ｒ^１およびＲ^２が双方とも水素であるとき、Ｒ^０は２‐（２，４‐ジアミノ‐６‐トリアジニル）エチル基以外である；
但し、基‐Ａ‐Ｒ^３がカルボン、ホスホン、スルホン酸類およびテトラゾール類から選択される酸性置換基を含有するか、または‐Ｃ（Ｏ）ＮＳＯ_２‐基を含有するとき、あるいは‐Ａ‐が‐Ｃ（Ｏ）Ｎ‐で、基Ａの窒素原子がフランまたはチオフェン環へ直接連結されているとき、Ｒ^１は‐Ａ‐Ｒ^３で、Ｒ^０およびＲ^２が双方とも水素であるか、またはＲ^０は‐Ａ‐Ｒ^３で、Ｒ^１は水素である。 Accordingly, in a first aspect, the present invention provides a compound for use in the prevention or treatment of a disease state or condition mediated by p38 MAP kinase; the compound is of the general formula (I):

In the above, U, T, V and W are each a nitrogen atom or group CR ^{4 provided} that 3 or less of U, T, V and W are nitrogen atoms;
R ⁰ is hydrogen, C _1-4 hydrocarbyl, halogen or the group —AR ³ ;
R ¹ is hydrogen, C _1-4 hydrocarbyl or a group —A—R ³ ; provided that only ^one of R ⁰ and R ¹ is a group —A—R ³ ;
R ² is hydrogen, C _1-4 hydrocarbyl or halogen;
A is a carbon- or heteroatom-containing linker group having a linking chain length of 1 or 2 atoms;
R ³ is a monocyclic or bicyclic heteroaryl group containing 5-12 ring members;
Each group R ⁴ is hydrogen, hydroxy, halogen, nitro, cyano, a monocyclic heterocyclic group having up to 7 ring members, a group N (R ⁵ ) ₂ , a group C (O) N (R ⁶ ) ₂ , Independently selected from the group SO ₂ N (R ⁶ ) ₂ , the groups R ^a -R ^b and the group Y; provided that no more than one group Y is present;
R ^a is a bond, O, S, SO, SO ₂ , NH or N—C _1-4 hydrocarbyl;
R ^b is optionally mediated by O, S, SO, SO ₂ , NH or N—C _1-4 hydrocarbyl, and is hydroxy, amino, mono- or di-C _1-4 hydrocarbylamino, C _1-4 hydrocarbyloxy C _1-8 hydrocarbyl optionally substituted with one or more substituents selected from, oxo, C _1-4 hydrocarbylthio and halogen;
Each group R ⁵ is independently selected from hydrogen, C _1-4 alkyl, C _1-4 acyl and C _1-4 alkylsulfonyl;
Each group R ⁶ is independently selected from hydrogen and C _1-4 hydrocarbyl;
Y is a group —N (R ⁷ ) —C (O) —R ⁸ or —N (R ⁷ ) —SO ₂ —R ⁸ ;
R ⁷ is hydrogen, C _1-4 hydrocarbyl or the group C (O) —R ⁸ or SO ₂ —R ⁸ ;
R ⁸ is selected from C _1-10 hydrocarbyl, C _1-10 hydrocarbylamino, C _1-10 hydrocarbylthio, C _1-10 hydrocarbyloxy, aryl, arylamino, arylthio and aryloxy groups; their aryl moieties Is carbocyclic or heterocyclic and has 5 to 12 ring members; each substituent R ⁸ is optionally substituted with one or more groups R ⁴ other than Y; or R ⁷ and R ⁸ are Linked together with the nitrogen and carbon or sulfur atoms to which they are attached to form a 4-7 ring member ring structure;
In combination, when U, T, V and W are all CH and R ¹ and R ² are both hydrogen, R ⁰ is other than a 2- (2,4-diamino-6-triazinyl) ethyl group;
Provided that the group -A-R ³ contains an acidic substituent selected from carboxylic, phosphones, sulfonic acids and tetrazoles, or contains a -C (O) NSO ₂ -group, or -A- is When -C (O) N- and the nitrogen atom of the group A is directly linked to the furan or thiophene ring, R ¹ is -AR ³ and both R ⁰ and R ² are hydrogen, Or R ⁰ is —A—R ³ and R ¹ is hydrogen.

  The compounds of formula (I) as described above have activity to modulate or inhibit p38 MAP kinase activity. It is expected that compounds having such activity will be useful therapeutic agents in the prevention or treatment of diseases where the activity of p38 MAP kinase is a disease or condition that initiates or promotes disease progression. Examples of symptoms that are alleviated by inhibition of p38 MAP kinase are described above and include rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and other arthritic conditions; Alzheimer's disease; inflammatory reaction induced by toxic shock syndrome, endotoxin or inflammatory bowel disease; tuberculosis, atherosclerosis, muscle degeneration, Reiter's syndrome, gout, acute synovitis, sepsis, septic shock, endotoxin Septic shock, Gram-negative sepsis, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, reperfusion injury, graft-versus-host reaction, allograft rejection, infection, eg due to influenza Fever and muscle pain, cachexia, especially cachexia derived from infection or malignancy, acquired immune deficiency symptoms (AIDS), cachexia, AIDS, ARC (AIDS related syndrome), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, heartburn, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome ( ARDS), asthma, pulmonary fibrosis and bacterial pneumonia, but are not limited to them.

  Of particular interest are compounds for use in the treatment or prevention of inflammatory diseases and conditions, rheumatoid arthritis and osteoarthritis.

  In another aspect, the invention provides the use of a compound of formula (I) as defined herein for the manufacture of a medicament for the prevention or treatment of a disease state or condition mediated by p38 MAP kinase.

  In another aspect, the invention relates to the prevention or treatment of a disease state or condition mediated by p38 MAP kinase, comprising administering to a subject in need thereof a compound of formula (I) as defined herein. Provide a way.

  The present invention also provides a method of inhibiting p38 MAP kinase, comprising contacting p38 MAP kinase with a kinase inhibitor compound of formula (I) as defined herein.

  The present invention further provides a method of modulating cellular processes by inhibiting the activity of p38 MAP kinase using a compound of formula (I) as defined herein.

  In the definition of compounds of formula (I) above as used below, the term “hydrocarbyl” is a generic term encompassing aliphatic, alicyclic and aromatic groups having a total carbon backbone. . Examples of such groups are alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, carbocyclic aralkyl, alkenyl and alkynyl groups. Such groups may be unsubstituted or substituted with one or more substituents as defined herein. The examples and preferences presented below are hydrocarbyl substituents or hydrocarbyl containing substituents mentioned in various definitions of substituents for compounds of formula (I), unless stated otherwise. It applies to each of.

Reference to a hydrocarbyl group “optionally mediated” by one or more atoms or groups (eg O, S, SO, SO ₂ , NH or N—C _1-4 hydrocarbyl in the case of the group R ^b ) It means that one or more of the above atoms or groups are inserted between adjacent carbon atoms in the carbon main chain of the hydrocarbyl group. For example, according to this definition, a —CH ₂ —CH ₂ —O—CH ₂ —CH ₂ — group can be regarded as a butylene group mediated by an oxygen atom.

  Except where stated otherwise, preferred aliphatic hydrocarbyl groups are those having 1 to 8 carbon atoms, more typically 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. . Preferred alicyclic hydrocarbyl groups are those containing up to 10 ring members, more generally up to 6 ring members. Preferred aromatic carbocyclic groups are those having 10 ring members or less, more preferably 6 ring members or less.

  The term “alkyl” includes both straight and branched chain alkyl groups. Unless stated otherwise, the term “alkyl” relates to groups having 1 to 8 carbon atoms, typically 1 to 6 carbon atoms, for example 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl and the like There are isomers.

  Examples of cycloalkyl groups are those having 3 to 10 ring atoms, specific examples being those derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, bicycloheptane and decalin.

  Examples of alkenyl groups include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, butenyl, buta-1,4-dienyl, pentenyl and hexenyl.

  Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl. Examples of alkynyl groups are those having 2-8 carbon atoms, more typically 2-6 carbon atoms, for example 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl (propargyl) groups.

  Examples of carbocyclic aryl groups are phenyl, naphthyl, indenyl and tetrahydronaphthyl.

  Examples of cycloalkylalkyl, cycloalkenylalkyl, carbocyclic aralkyl, alkenyl and alkynyl groups include phenethyl, benzyl, naphthylmethyl, styryl, phenylethynyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopropylmethyl And cyclopentenylmethyl groups.

  Of the substituents directly attached to the fused 5- and 6-membered rings, small alkyl groups are usually preferred, and currently preferred groups include methyl and ethyl, with methyl being particularly preferred.

The term “aryl” as used herein (for example, with the terms “arylamino” and “arylthio”), unless stated otherwise, is an aromatic carbocyclic or Relates to a heterocyclic group. An aryl group is a monocyclic or bicyclic group and may be unsubstituted or substituted with one or more substituents. The term “aryl” includes polycyclic (eg, bicyclic) ring systems in which one or more rings are non-aromatic, but at least one ring is aromatic. Examples of non-heterocyclic aryl groups include phenyl, indenyl, tetrahydronaphthyl and naphthyl, which groups can be unsubstituted or substituted with one or more substituents. Examples of heterocyclic groups are those described herein with respect to the group R ³ .

As used herein, the term “monocyclic heterocyclic group” refers to both aromatic and non-aromatic heterocyclic groups, unless stated otherwise. Examples of aromatic heterocyclic groups are the monocyclic groups listed for the substituent R ³ . Examples of non-aromatic heterocyclic groups include, but are not limited to, rings containing up to 3 heteroatoms selected from nitrogen, sulfur and oxygen. There is typically at least one nitrogen atom. Specific examples of such groups include piperidine, piperazine, N-methylpiperazine, morpholine, pyrrolidine, imidazoline, imidazolidine, diazoline, diazolidine, oxazoline, oxazolidine and tetrahydrofuran. Preferred non-aromatic heterocyclic groups include morpholine and piperidine, especially morpholine.

  The term “halogen” as used herein includes fluorine, chlorine, bromine and iodine, although fluorine and chlorine are usually preferred as substituents.

  The compounds of formula (I) are indoles or azaindoles containing 1, 2 or 3 nitrogen atoms in a 6-membered ring. Typically, a 6-membered ring contains no more than 2, preferably no more than 1, nitrogen atoms. Indoles are particularly preferred.

In one embodiment, T and V are each a group CR ⁴ , preferably at least one (eg U), more preferably both U and W are each a group CR ⁴ .

In another embodiment, one of U and W is a group CR ⁴ , preferably T and V are both groups CR ⁴ . For example, U is a group CR ⁴ and W is a nitrogen atom, or U and W are both CR ⁴ .

The group R ⁴ can be hydrogen or the group Y, as described above, or a relatively small substituent such as hydroxy, halogen, nitro, cyano, a monocyclic heterocyclic group having up to 7 ring members, the group N (R ⁵ ) ₂ , the group C (O) N (R ⁶ ) ₂ , the group SO ₂ N (R ⁶ ) ₂ or the group R ^a -R ^b . Only one group Y is typically present.

  Therefore, the 6-membered ring of the indole / azaindole nucleus may be unsubstituted or substituted. In one embodiment (eg when the compound is indole) the 6-membered ring is unsubstituted or within 2 (eg 1) small substitutions selected from methyl, chlorine, amino, fluorine, nitro and acetamide Substituted with a group.

For example, in one subgroup of compounds, V is CH and / or W is CH or C—CH ₃ and / or U is CH, C—CH ₃ and fluorine as defined above. Selected and / or T is a carbon atom substituted with methyl, chloro, nitro or a group (R ⁵ ) ₂ N.

In another aspect, both U and W are groups CR ⁴ . Typically V is CH.

When R ⁴ is a group R ^a -R ^b , the moiety R ^a is a chemical bond or it is O, S, SO, SO ₂ , NH or N—C _1-4 hydrocarbyl, and the group R ^b is , O, S, SO, SO ₂ , NH or C _1-8 hydrocarbyl optionally intervened with N—C _1-4 hydrocarbyl and optionally substituted with one or more substituents. Examples of hydrocarbyl groups and preferred hydrocarbyl groups are as described above. In the context of the groups R ^a and R ^b , small alkyl groups such as methyl groups are particularly preferred. Optional substituents for R ^b are selected from hydroxy, amino, mono- or di-C _1-4 hydrocarbylamino, C _1-4 hydrocarbyloxy, oxo, C _1-4 hydrocarbylthio and halogen. Small substituents such as C ₁ groups and small halogens such as chlorine and fluorine are preferred.

Each group R ⁵ in the optional group N (R ⁵ ) ₂ is independently selected from hydrogen, C _1-4 alkyl, C _1-4 acyl and C _1-4 alkylsulfonyl. Hydrogen and _{C 1} groups are preferred.

Each group R ⁶ , when present, is independently selected from hydrogen and C _1-4 hydrocarbyl, with hydrogen and methyl being preferred.

One specific set of compounds of formula (I) has a substituent Y which is a group —N (R ⁷ ) —C (O) —R ⁸ or —N (R ⁷ ) —SO ₂ —R ^8. A set of compounds.

The group R ⁷ includes hydrogen, C _1-4 hydrocarbyl or the group C (O) —R ⁸ or SO ₂ —R ⁸ . When it is C _1-4 hydrocarbyl, it is typically methyl.

R ⁸ is selected from the group C _1-10 hydrocarbyl, C _1-10 hydrocarbylamino, C _1-10 hydrocarbylthio, C _1-10 hydrocarbyloxy, aryl, arylamino, arylthio and aryloxy, the term hydrocarbyl and aryl Is generally as described above.

In the context of group Y, the aryl moiety is carbocyclic or heterocyclic and has 5 to 12 ring members. Carbocyclic aryl groups such as phenyl or monocyclic heterocyclic groups containing 1 or 2 nitrogen atoms are presently preferred. Each substituent R ⁸ may be unsubstituted or substituted with one or more groups R ⁴ (other than Y) as described above.

  Therefore, Y can take the form of an amide, carbamate, urea or thiourea compound.

On the other hand, R ⁷ and R ⁸ can be linked together with the nitrogen and carbon or sulfur atoms to which they are attached to form a 4-7 ring member ring structure. When R ⁸ is an aryl, arylamino, arylthio or aryloxy group, it may be linked to R ⁷ to form a fused bicyclic heterocyclic structure.

In one preferred subgroup of compounds, R ⁸ is selected from optionally substituted aryl, arylamino, arylthio and aryloxy, and R ⁸ is typically carbocyclic or heterocyclic aryl, arylamino, arylthio Or an aryloxy group, wherein the aryl moiety has 5 or 6 ring members. It is currently preferred that R ⁸ is selected from unsubstituted aryl and arylamino groups, and substituted aryl and arylamino groups, wherein the aryl group is phenyl or a 5 or 6 membered heterocycle having 1 or 2 nitrogen ring members Formula groups, such as groups selected from pyridyl, pyrazolyl and isoxazolyl groups. Particularly preferred aryl groups are phenyl, pyridyl (eg 4-pyridyl) and pyrazolyl (eg 2-pyrazolyl).

For example, an aryl (eg, phenyl, pyridyl or pyrazolyl) ring is substituted with one or more substituents selected from halogen, monocyclic heterocyclic groups having up to 7 ring members, and groups R ^a -R ^b sell. Preferred substituents are fluorine, chlorine, methoxy, trifluoromethoxy, trifluoromethyl, methyl, ethyl, isopropyl, isobutyl, t-butyl, phenyl and 5- and 6-membered monocyclic heterocyclic groups. When the aryl group is a pyrimidinyl group, especially a 2-pyrimidinyl group, it is preferred that the aryl group is not substituted with phenyl. More preferably, the aryl group is other than 5-phenylpyrimidin-2-yl.

  In one preferred form, the aryl group is a phenyl ring containing 1 or 2 meta substituents, for example, the 1 meta position on the phenyl ring is unsubstituted or fluorine, chlorine, methoxy, trifluoromethoxy. Substituted with a group selected from trifluoromethyl, ethyl, methyl and isopropyl; the other meta positions are fluorine, chlorine, methoxy, trifluoromethoxy, trifluoromethyl, ethyl, methyl, isopropyl, isobutyl, t- Substituted with a group selected from butyl, phenyl, substituted phenyl, and 5- and 6-membered monocyclic heterocyclic groups.

  In a particular subgroup of compounds, the phenyl ring contains a single substituent selected from m-trifluoromethyl and m-trifluoromethoxy. On the other hand, the phenyl ring can have a fluoro substituent at one meta position and a morpholino group at another meta position.

  In another preferred subgroup of compounds, the aryl ring is a pyridyl ring substituted with a 5- or 6-membered monocyclic heterocyclic group such as morpholino, such as a 4-pyridyl ring.

In another preferred subgroup of compounds, the aryl ring is a pyrazolyl or isoxazolyl (preferably substituted with a phenyl group and / or a C _1-4 hydrocarbyl group, in particular a C _1-4 alkyl group, most preferably a tertiary butyl group. Pyrazolyl) group. The 2-phenyl-5-t-butylpyrazol-3-yl group has been found to be particularly advantageous.

The 5-membered ring of the compound of formula (I) is connected to the heteroaryl group R ³ via the linker group A. The linker group has a linking chain length of 1 or 2 atoms: in other words, the number of atoms in the main chain of the linker group is 1 or 2. Thus, for example, the group —CH ₂ — has a linking chain length of 1 and the group —CH ₂ —CH ₂ — has a linking chain length of 2.

_Examples of the linker group _{A, CH 2, C = O,} O, S, SO, SO 2, NR ', CHR, CR 2, CR 2 CR 2, CR = CR, OCH 2, CH 2 O, CH 2 _{S, SCH 2, SOCH 2,} CH 2 SO, SO 2 CH 2, CH 2 SO 2, NR'CH 2, CH 2 NR ', CONR', R'NCO, SO 2 NR ', NR'SO 2, COCH _{There are 2} and CH ₂ CO, where R is independently selected from hydrogen, methyl and fluoro when present, and R ′ is independently selected from hydrogen and methyl when present. Currently preferred linker groups A include CH ₂ or CH ₂ CH ₂ , with ethylene groups being particularly preferred.

The heteroaryl group R ³ is a monocyclic or bicyclic group containing 5-12 ring members, more generally 5-10 ring members. Heteroaryl groups are, for example, 5- and 6-membered monocyclic or bicyclic structures formed from fused 5- and 6-membered rings or two fused 6-membered rings. Each ring may contain about 4 or less, more typically 3 or less, typically 1, 2 or 3 heteroatoms. Heteroatoms are typically selected from nitrogen, sulfur and oxygen. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atom of the heteroaryl ring may be basic, as in pyridine or pyrimidine, or essentially non-basic, as in indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in a heteroaryl group is less than 5, including any amino substituents on the ring.

Examples of heteroaryl groups R ³ include pyridyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, isoquinolinyl, tetrazolyl, benzfuranyl , Chromanyl, thiochromanyl, benzimidazolyl, benzoxazolyl, benzisoxazole, benzthiazolyl and benzisothiazole, isobenzofuranyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (eg, adenine, guanine), indazolyl, benzodi Oxolyl, chromenyl, isochromenyl, chroman, isochromanyl, benzodioxanyl, quinolizini And benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl.

The group R ³ is presently preferably a monocyclic heteroaryl group containing at least one nitrogen atom, one specific example of such a group being a pyridyl, for example a 4-pyridyl group.

The group R ³ may be unsubstituted or halogen, nitro, cyano, a monocyclic heterocyclic group having up to 7 ring members, a group N (R ⁵ ) ₂ , a group C (O) N (R ⁶ ) ₂ , a group One or more groups selected from SO ₂ N (R ⁶ ) ₂ and the group R ^a -R ^b may be substituted; wherein R ⁵ , R ⁶ , R ^a and R ^b are as described above.

In one subgroup of compounds, R ³ is unsubstituted.

In another subgroup of compounds, R ³ is substituted.

When a substituent is present on the heteroaryl ring, examples of substituents include C _1-6 alkyl, C _1-6 alkoxy, amino, C _1-6 alkylamino, di-C _1-6 alkylamino, halogen, Hydroxy, trifluoromethyl, cyano, nitro, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkylthio, amino C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-4 alkoxyalkyl, phenyl -C _1-6 alkyl, hydroxyalkylamino, aminoalkylamino and aminoalkoxy, C _3-7 cycloalkyl and monocyclic C _5-6 carbocyclic or heterocyclic groups containing up to 3 heteroatoms , But not limited to them. Specific examples of the substituent include chlorine, fluorine, methyl, unsubstituted amino, 2-hydroxyethylamino, 2-hydroxyprop-2-ylamino, 2-hydroxy-2-methylprop-2-ylamino, 1-phenylethyl, There are morpholino and piperazino groups.

When two or more substituents (“major substituents”) each having a chain length of 4 or more atoms are present in the heteroaryl group R ³ , they are preferably located “on the same side” of the ring. In other words, for example when three such large substituents are present in a 6-membered ring, they are preferably located in the adjacent ortho, meta and para positions relative to the point of attachment of the group A. When two such large substituents are present, they are preferably located in the adjacent ortho and meta positions, or in the adjacent meta and para positions, or in the adjacent (separated by one ring position) ortho and para positions. The term “chain length” in this context relates to the number of atoms extending in a continuous chain outward from the heteroaryl ring. Thus, for example, a chlorine substituent has a chain length of 1, a methyl group has a chain length of 2, and an ethyl group has a chain length of 3. “Small substituents”, ie substituents having a chain length of 3 or less, may be present on one or both “sides” of the ring, with or without “large” substituents.

The group —A—R ³ preferably does not contain any carboxylic, phosphonic, sulfonic acid groups, nor any tetrazole or —C (O) NSO ₂ — groups.

  It is also preferred that when -A- is -C (O) N-, the nitrogen atom of the group A is not directly linked to the furan or thiophene ring.

In combination, when U, T, V and W are all CH, R ¹ and R ² are both hydrogen and R ⁰ is a group —CH ₂ —CH ₂ —R ³ , R ³ is pyrazin-3-yl or It is preferably other than a pyridi-3-yl group.

The group -A-R ³ may be bonded to the 1- or 3-position, preferably the 3-position, of the 5-membered ring.

When —A—R ³ is bonded to the 3 position (ie R ⁰ is —A—R ³ ), R ¹ is preferably hydrogen or methyl, especially hydrogen.

When -A-R ³ is bonded in position 1 (ie R ¹ is -A-R ³ ), R ⁰ is preferably hydrogen or methyl, especially hydrogen.

When -AR ³ is bonded to the 3 position (ie R ⁰ is -AR ³ ) and the group Y is present, the group Y is preferably the 5 position of a bicyclic (eg indole) group Exists.

When -AR ³ is bonded to the 1-position (ie R ¹ is -AR ³ ) and the group Y is present, the group Y is preferably the 6-position of the bicyclic (eg indole) group Exists.

The group R ² is typically a small substituent and is preferably selected from hydrogen and methyl. Most typically, R ² is hydrogen.

Novel compounds Many of the compounds of formula (I) are novel. Accordingly, in another aspect, the present invention provides the novel compound of formula (I) itself. One group of novel compounds within the scope of the present invention is the group of compounds of formula (I) as described above, provided that one group R ⁴ is a group Y and in combination R ¹ and R ² Except for known compounds wherein is hydrogen, U, V and W are all CH and T is a carbon atom having an unsubstituted benzamide group.

In the novel compounds of the present invention, it is most preferred that the group -A-R ³ does not contain a carboxylic, phosphonic, sulfonic acid group nor any tetrazole or -C (O) NSO ₂ -group. It is also preferred that when -A- is -C (O) N-, the nitrogen atom of the group A is not directly linked to the furan or thiophene ring.

In the novel compounds of formula (I), R ¹ is more preferably H or methyl.

One subgroup of novel compounds is that T or V (preferably T) is a group CY and Y is a group -N (R ⁷ ) -C (O) -R ⁸ or -N (R ⁷ ) —SO ₂ —R ⁸ is a group of compounds of formula (I).

Within this subgroup of compounds, R ⁸ is selected from carbocyclic or heterocyclic aryl, arylamino, arylthio and aryloxy groups, wherein the aryl moiety has 5 or 6 ring members (provided that Of the known unsubstituted benzamide compounds), a group of compounds themselves, where R ⁷ is hydrogen or C _1-4 hydrocarbyl (preferably hydrogen or methyl).

One group of preferred novel compounds themselves are those in which the aryl moiety is carbocyclic, for example R ⁸ is selected from unsubstituted phenyl and phenylamino groups, and substituted phenyl and phenylamino groups.

  In another preferred group of novel compounds, the aryl moiety is a 5- or 6-membered heterocyclic group having 1 or 2 nitrogen ring members, such as a pyridyl or pyrazolyl group.

Specific novel compounds of the invention include one or more selected from ^a phenyl, pyridyl or pyrazolyl ring selected from halogen, monocyclic heterocyclic groups having up to 7 ring members and groups R ^a -R ^b as described above It is a compound substituted with a substituent. Specific examples of substituents are selected from fluorine, chlorine, methoxy, trifluoromethoxy, trifluoromethyl, methyl, ethyl, isopropyl, isobutyl, t-butyl, phenyl, and 5- and 6-membered monocyclic heterocyclic groups The

  One subgroup of the compound itself is that the phenyl ring contains one or two meta substituents, eg one meta position on the phenyl ring is unsubstituted or fluorine, chlorine, methoxy, trifluoromethoxy , Substituted with a group selected from trifluoromethyl, ethyl, methyl and isopropyl, and other meta positions are fluorine, chlorine, methoxy, trifluoromethoxy, trifluoromethyl, ethyl, methyl, isopropyl, isobutyl, t-butyl, A group of compounds substituted with a group selected from phenyl, substituted phenyl, and 5- and 6-membered monocyclic heterocyclic groups.

  Examples of particularly preferred novel compounds of the invention are those in which the phenyl ring contains a single substituent selected from m-trifluoromethyl and m-trifluoromethoxy groups.

  Another example of a particularly preferred novel compound is one in which the aryl ring is a pyrazolyl ring substituted with a phenyl group and a tert-butyl group.

In another group of novel compounds, the compound is a pyrimidinyl group in which R ⁰ is —A—R ³ , A is ethylene, and R ³ is substituted at the 2-position with a hydroxyalkylamino group or a phenylethyl group. It is indole.

Specific examples of novel compounds within the scope of the present invention include the following:
3- (2- (4-pyridyl) ethyl) -5- (3-trifluoromethoxybenzamido) indole;
3- (2- (4-pyridyl) ethyl) -5- (3-trifluoromethylbenzamido) indole;
3- (2- (4-pyridyl) ethyl) -5- (3-fluoro-5- (1-N-morpholino) benzamido) indole;
1- (2- (4-pyridyl) ethyl) -5- (3-fluoro-5- (1-N-morpholino) benzamido) indole;
5- (phenylcarbamoylamino) -3- (2- (4-pyridyl) ethyl) indole;
5- (3-tert-butyl-1-phenylpyrazol-5-ylcarbamoylamino) -3- (2- (4-pyridyl) ethyl) indole;
3- (2- (2- (2-hydroxyethylamino) -4-pyrimidinyl) ethyl) indole;
3- (2- (2- (3-hydroxy-2-methylprop-2-ylamino) -4-pyrimidinyl) ethyl) indole;
3- (2- (2-((S)-(−)-α-methylbenzylamino) -4-pyrimidinyl) ethyl) indole;
3- (2- (2-((S)-(+)-α-methylbenzylamino) -4-pyrimidinyl) ethyl) indole;
6- (3-Fluoro-5- (4-morpholino) benzamido) -3- (2- (4-pyridyl) ethyl) indole; and 6- (3-fluoro-5- (4-morpholino) benzamido) -1 -(2- (4-Pyridyl) ethyl) indole

  In another aspect, the present invention provides a novel compound of formula (I) as described above for use in medicaments and pharmaceutical compositions comprising the novel compound of formula (I) together with a pharmaceutically acceptable carrier. A compound is provided.

  Many compounds of formula (I) may exist in the form of salts, for example acid addition salts, or in some cases salts of organic and inorganic bases such as carboxylic acids, sulfonic acids and phosphates. All such salts are within the scope of this invention and references to compounds of formula (I) include the salt forms of the compounds.

  Acid addition salts can be formed from a variety of acids, both inorganic and organic. Examples of acid addition salts include hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, There are salts formed with methanesulfonic acid, ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, acetic acid, propanoic acid, butanoic acid, malonic acid, glucuronic acid and lactobionic acid.

  The compounds of the formula may exist in several different geometric isomers and tautomers, and all such forms are included when referring to the compounds of formula (I). For the avoidance of doubt, a compound can exist in one of several geometric isomers or tautomers, and only one is specifically described or shown, but all others are in formula (I) include.

  Compound polymorphs, solvates of compounds (eg, hydrates), complexes (eg, inclusion complexes or inclusion complexes with compounds such as cyclodextrins, or complexes with metals), and Prodrugs of the compounds are also included in formula (I). “Prodrug” means any compound that is converted, for example, in vivo to a bioactive compound of formula (I).

  When a compound of formula (I) contains a chiral center, all individual optical forms such as enantiomers, epimers and diastereomers, and racemic mixtures of the compounds belong within the scope of formula (I).

（上記式中、Ｕ、Ｔ、Ｖ、ＷおよびＲ^２は式（Ｉ）に関して定義されたとおりであり、Ｒ^１は水素またはＣ_１‐４アルキル基である）を、完全基Ａ‐Ｒ^３またはその前駆体（例えば、保護基）を導入しうる求電子基と反応させることで製造しうる。Ａがエチレン基である場合、式（II）の化合物は、例えば酢酸のような酸の存在下で、ビニル化合物Ｈ_２Ｃ＝ＣＨ‐Ｒ^３と反応させられる。反応は、典型的には、高温、例えば７５℃以上、更に一般的には１００℃以上、例えば約１３０℃の温度で行われる。得られた生成物はクロマトグラフィーにより常法で精製しうる。 Process for the preparation of compounds of formula (I) The compounds of formula (I) may be prepared according to methods known per se or as described herein. For example, compounds of formula (I) in which the group AR ³ is bonded to the 3-position of a 5-membered ring are described in US Pat. US Pat. No. 3,300,506 and US 3,409,626 may be made according to similar or similar methods, the disclosures of each of which are incorporated herein by reference. Therefore, the compounds of formula (I) in the 3-position of 5-membered ring having a group A-R ^3, the compound of by the following formula (II):

(Wherein U, T, V, W and R ² are as defined for formula (I), R ¹ is hydrogen or a C _1-4 alkyl group) and the complete group AR ³ Or it can manufacture by making it react with the electrophilic group which can introduce | transduce the precursor (for example, protective group). When A is an ethylene group, the compound of formula (II) is reacted with the vinyl compound H ₂ C═CH—R ^{3 in} the presence of an acid such as acetic acid. The reaction is typically carried out at an elevated temperature, for example, 75 ° C or higher, more generally at a temperature of 100 ° C or higher, for example about 130 ° C. The product obtained can be purified by chromatography in a conventional manner.

The compound of formula (I) in which the linker group is CH, CR, C (O), S (O), S (O ₂ ) or C (O) CH ₂ and bonded to the 3-position of the 5-membered ring, The compounds of formula (II) as described above can be prepared by electrophilic substitution, for example in the Friedel Crafts type reaction. Reagents for performing electrophilic substitution are those where X is a suitable leaving group such as halogen (eg, chlorine) and A ′ is CH, CR, C (O), S (O), S (O ₂ ) And C (O) CH ₂ can take the R ³ -A′-X form.

Alkylation at the 3-position is under conditions similar or similar to those described in WO 99/43654, in the presence of silver (I) oxide in a polar solvent such as dioxane, A 'is methylene or ethylene, Can also be reacted with a suitably substituted 3-unsubstituted indole compound of the formula R ³ -A'-X, wherein is a leaving group such as bromine.

A compound of formula (I) in which the linker group is —CO— has the corresponding 3-under-situation under conditions similar or similar to those described in Indian J. Chem., 24B (10), 1012-14, 1985. It can be prepared by formation of a 3-indole organometallic reagent (eg, Grignard) from a halogen (eg, iodine) substituted indole, followed by treatment with a suitable R ³ heterocyclic acid chloride. Indole-3-halogen may be obtained from commercial sources or prepared by known methods.

Compounds of formula (I) in which the linker group is —CH ₂ CO— are suitable under conditions similar or similar to those described in Khim. Geterotsikl. Soedin., (1), 55-58, 1980. Prepared by reacting the appropriate N-1 protected derivative of indole or azaindole acetate with a strong base in the presence of a substituted heterocyclic ester (eg methyl 4-pyridylcarboxylate) followed by hydrolysis and decarboxylation Yes. Indole carboxylic acids (eg, indole-3-acetic acid) may be obtained from commercial sources or prepared by known methods. Indole or azaindole carboxylic acids or their reactive derivatives can also be used to prepare compounds in which the linker group is CONH by reaction with a suitable amino-substituted heterocyclic group R ³ .

Compounds in which the linker is the group OCH ₂ or SCH ₂ are compounds R ³ —CH ₂ under conditions similar or similar to those described in J. Med. Chem., 32 (6), 1360-6; 1989. It can be prepared from the appropriate substituted N-protected indoles having a hydroxyl or SH group at the 3 position by reaction with -Br. Such a reaction can be carried out in a polar solvent such as dimethylformamide (DMF) in the presence of a base such as sodium hydride. In some cases, it may be desirable for 3-hydroxyindoles to be substituted at the 2-position with an ester group (eg, methoxycarbonyl) to aid O- or S-alkylation. Thereafter, the ester group is reduced to a methyl group to obtain a compound of formula (I) wherein R ² is methyl, or a carboxylic acid is obtained to obtain a compound of formula (I) wherein R ² is hydrogen. It is hydrolyzed to an acid and then removed by decarboxylation.

Compounds in which the linker is the group CH ₂ O, CH ₂ S, CH ₂ NH or CH ₂ NMe can be prepared from a suitable N-protected indole having the group CH ₂ NMe ₂ in the 3 position. Methylation of the dimethylamino group yields a quaternary ammonium compound, followed by reaction with an oxygen, sulfur or amino nucleophile suitable for introducing the group OR ³ , SR ³ , NHR ³ or NMeR ³ Trimethylamine is eliminated from the compound to give the desired product. The methylation reaction can be carried out as a standard by reaction with methyl iodide in a solvent such as benzene under the conditions described in, for example, Tetrahedron Letters, 36 (33), 5929-32: 1995. Indoles having a CH ₂ NMe ₂ group at the 3 position can be prepared from the corresponding 3-formyl compound by standard reductive alkylation using, for example, dimethylamine and sodium cyanoborohydride. On the other hand, the appropriate substituted indole 3-carboxylic acid methyl or ethyl ester may be subjected to hydride reduction to give the 3-hydroxymethyl derivative and then converted to the dimethylamino group by known techniques.

A compound in which the linker group A is CH═CH can be obtained by a Heck-type reaction between compounds of the formula R ³ —CH═CH ₂ in the presence of palladium (II) under standard conditions or similar conditions, or by a tributyltin analog R ^It can be prepared by a Stille type reaction with ³ -CH = CH-SnBu ₃ and a suitable substituted 3-haloindole (eg 3-bromoindole).

On the other hand, a compound in which the linker group is CH = CH is a metal hydride reducing agent such as lithium aluminum hydride according to conditions similar or similar to those described in Tetrahedron, 31 (17), 2063-73: 1975. Can be prepared by reduction of an indole having the substituent R ³ —CH (Cl) —CO— at the 3-position.

In another method of preparing compounds where the linker group is CH═CH, an N-protected indole or azaindole having a 3-CHO group is a triphenyl (arylmethyl) phosphonium compound suitable for introducing the group R ³ and It can be reacted under Wittig type conditions. N protecting groups include, for example, phenylsulfonyl groups. Such reactions are typically performed at low temperatures under anhydrous conditions in polar aprotic solvents such as tetrahydrofuran.

Compounds in which the linker group A is SO ₂ CH ₂ or SOCH ₂ can be prepared by reaction of a suitable substituted indole with a sulfonylating agent such as R ³ CH ₂ SO ₂ Cl.

Compounds in which the linker group A is SO ₂ NR can be obtained under conditions similar or similar to those described, for example, in Buyanov et al, Khim. Geterotsikl. Soedin (1996), (1), 40-42 or WO 00/73264. Can be prepared by reacting ^3- indolylsulfolinyl chloride with an amine of formula R ³ NH ₂ or R ³ NH ₂ Me, optionally in the presence of other bases.

Compounds in which the linker group A is NHSO ₂ can be obtained under conditions similar or similar to those described in J. Chem. Soc., Perkin Transactions 1, (8), 1688-92, 1980, for example dimethyl sulfoxide (DMSO) Can be prepared by reacting the azide compound of formula R ³ SO ₂ N ₃ with the appropriate 1-protected 3-unsubstituted indole. On the other hand, a compound in which the linker group A is NHSO ₂ is obtained by converting _3- aminoindole to R ³ under conditions similar or similar to those described in, for example, Khim.Geterotsikl.Soedin., (4), 481-5,1977. It can be produced by reacting with SO ₂ Cl.

Compounds in which the linker group A is NRCH ₂ can be prepared by suitable substituted 1-acyl-3-under conditions similar or similar to those described for example in Khim. Geterotsikl. Soedin., (7), 939-43, 1978. It can be prepared by reacting oxindole with the compound R ³ CH ₂ NH ₂ or R ³ CH ₂ NHMe. On the other hand, compounds in which the linker A is the group NRCH ₂ can be prepared by reduction of a compound in which A is NHCO with a metal hydride reducing agent such as LiAlH ₄ .

Compounds in which the linker group A is NHCO can form the corresponding oxime from the appropriate substituted 3-acylindole having the substituent R ³ C (O) in position 3 by reaction with hydroxylamine and then for example J. Chem. ., Res. Synop., (1), 4-5, 1983 can be prepared by obtaining an amide by Beckmann rearrangement under similar or similar conditions. 3-Acylindoles can be prepared from Friedel-Crafts acylation of 3-unsubstituted indoles by reaction with the appropriate acid halide. On the other hand, a compound in which the linker group A is NHCO can be obtained by using 3-amino-2-ethoxy under conditions similar or similar to those described in, for example, J. Heterocycl. Chem., 24 (2), 437-9, 1987. From the carbonylindole, it can then be prepared by reduction of the ester group to give the 2-methyl compound or by hydrolysis and decarboxylation to give the 2-unsubstituted compound.

A compound in which the linker group A is S is obtained from the reaction of an aryl-substituted hydrazine of the formula ArNHNH ₂ with Ar being a substituted or unsubstituted phenyl group and a compound of the formula R ² —C (O) —CH ₂ —SR ^3. It can be prepared by forming a hydrazone and then cyclizing the hydrazone in the presence of an acid such as acetic acid to give the desired compound. The reaction can be performed under conditions similar or similar to those described in Synthesis, (3), 270-2, 1994.

Compounds of formula (I) in which R ⁴ had a group CR ⁴ is a substituted amino group may be prepared from the corresponding aminoindole or amino azaindole compound. For example, if the amino group is substituted with an acyl group such as a benzoyl or substituted benzoyl group, the compound can be prepared by acylation of the corresponding amino compound. Such acylation reactions can be performed in polar solvents (eg, dimethylformamide or dimethyl sulfoxide), typically in non-extreme temperatures such as room temperature, in the presence of an acylation catalyst such as hydroxybenzotriazole. Acylation of the amino group on the 6-membered ring of the fused ring system can be done before or after the introduction of the group R ³ .

Where the amino group R ⁴ is substituted with a carbamoyl group, for example an optionally substituted phenylcarbamoyl group, the carbamoyl group is introduced by reacting the corresponding amino analog with an isocyanate such as an optionally substituted phenyl isocyanate. Yes. The reaction with the isocyanate can be carried out in a solvent, for example a chlorinated solvent such as chloroform or dichloromethane, at medium to high temperatures, for example 60-100 ° C.

Compounds in which the group R ⁴ is an amino group can be prepared by reduction of the corresponding nitro-substituted compound. The reducing agent is usually selected such that it results in the reduction of the nitro group, but does not reduce any heterocyclic group R ³ present. An example of a suitable reducing agent is a Fe / Fe (II) mixture that can be used in a suitable polar solvent such as dioxane at medium to high temperatures (eg, about 90 ° C.) at 60-100 ° C.

Compounds of formula (I) in which the group AR ³ is bonded to the 1-position of the 5-membered ring are both unsubstituted or substituted with the group R ² at the 2- and 3-positions of the 5-membered ring, R ¹ May be prepared from a compound of formula (II) as described above wherein is hydrogen, optionally in the presence of a base, by reaction with a suitable alkylation or acylating agent. For example, a compound in which the linker group A is an ethylene group can be obtained by converting a 1-N-unsubstituted indole or an azaindole into a vinyl heterocycle (R ³ CH═CH in the presence of a metal such as sodium and copper reagents such as copper sulfate. It can be produced by reacting with ₂ ). A compound having a substituent AR ³ in the 1-position can be obtained by converting a 1-N-unsubstituted compound to L Can also be produced by reacting with a compound LA—R ^{3 in} which is a leaving group (eg, a halide).

  Compounds of formula (I) can also be prepared from other compounds of formula (I) by functional group interconversion or reaction with suitable reagents in a known manner.

In many of the synthetic schemes used to prepare compounds of formula (I), the indole 1 position is protected so that it does not participate in the reaction. The protecting group used can be a simple alkyl group such as methyl, which can directly reach the compound of formula (I) wherein R ¹ is alkyl. On the other hand, however, the protecting group may be a removable protecting group such as an acyl group, a phenylsulfonyl group or a trialkylsilyl group such as triisopropylsilyl. Such protecting groups can be removed at appropriate points in the reaction path by methods known per se, for example in the case of silyl protecting groups using fluorine ions. Examples of protecting groups are described in the above literature and also described, for example, in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

上記においてＵ、Ｔ、Ｖ、ＷおよびＲ^２は式（Ｉ）の新規化合物に関して定義されたとおりである；Ｒ^９は水素、Ｃ_１‐４ヒドロカルビルまたはハロゲンであり、Ｒ^１０は水素またはＣ_１‐４ヒドロカルビルであるが、但しＲ^９およびＲ^１０のうち少くとも一方は水素である。 Novel chemical intermediates Some of the important intermediates useful for preparing compounds of formula (I) are novel compounds. Thus, in another aspect, the present invention provides a novel compound of formula (III):

In the above, U, T, V, W and R ² are as defined for the novel compounds of formula (I); R ⁹ is hydrogen, C _1-4 hydrocarbyl or halogen and R ¹⁰ is hydrogen or C _{1 -4} hydrocarbyl with the proviso that at least one of R ⁹ and R ¹⁰ is hydrogen.

A specific group of novel intermediates corresponds to the preferred novel compounds themselves as described above, but lacking the -AR ³ group.

Specific intermediate compounds that are considered new include the following:
5- (3-trifluoromethoxybenzamide) indole;
5- (3-trifluoromethylbenzamide) indole;
5- (3-fluoro-5- (1-N-morpholino) benzamido) indole;
5- (3-fluoro-5- (1-N-morpholino) benzamido) indole;
5- (phenylcarbamoylamino) indole; and 5- (2- (4-morpholino) isonicotinamide) indole

Pharmaceutical Formulation The present invention also provides a compound of formula (I) as described above in the form of a pharmaceutical composition.

  The pharmaceutical composition may be in any form suitable for oral, parenteral, topical, intranasal, intraarticular, ocular, otic, rectal, vaginal or transdermal administration, or inhalation administration. If the compositions are for parenteral administration, they may be formulated for intravenous, intramuscular or subcutaneous administration.

  Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs, suspensions, sublingual tablets, wafers or patches and buccal patches.

  Pharmaceutical compositions containing a compound of formula (I) may be formulated according to known techniques (see, eg, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA).

  As such, the tablet composition is an inert diluent or carrier such as a sugar or sugar alcohol such as lactose, sucrose, sorbitol or mannitol; and / or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, cellulose or It may contain unit dosage forms of the active compounds together with derivatives thereof such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and starch such as corn starch. Tablets may contain binding and granulating agents such as polyvinylpyrrolidone, disintegrants (eg, swellable cross-linked polymers such as cross-linked carboxymethylcellulose), lubricants (eg, stearates), preservatives (eg, parabens), Standard ingredients such as antioxidants (eg, BHT), buffers (eg, phosphate or citrate buffers), and blowing agents, eg, citrate / bicarbonate mixtures may also be included. Such excipients are well known and need not be described in detail here.

  Capsule formulations may be of either hard or soft gelatin type and may contain the active ingredient in solid, semi-solid or liquid form. Gelatin capsules may be formed from animal gelatin or its synthetic or plant equivalents.

Solid dosage forms (eg, tablets, capsules, etc.) may be coated or uncoated, but typically have a coating, such as a protective coating (eg, wax or varnish) or a controlled release coating. The coating (eg, Eudragit ^™ type polymer) can be designed to release the active ingredient at a desired location within the gastrointestinal tract. Thus, the coating may be chosen to selectively release the compound in the stomach, ileum or duodenum by degrading under certain pH conditions in the gastrointestinal tract.

  Instead of or in addition to a coating, the drug in a solid matrix comprising a controlled release agent, for example a release retardant that can be adapted to selectively release the compound under various acidic or alkaline conditions of the gastrointestinal tract Is provided. On the other hand, the matrix material or release-retarding coating can take the form of an erodible polymer (eg, maleic anhydride polymer) that erodes substantially continuously as the dosage form passes through the gastrointestinal tract.

  Topical compositions include ointments, creams, sprays, patches, gels, liquid drops and inserts (eg intraocular inserts). Such compositions can be formulated according to known methods.

  Compositions for parenteral and intra-articular administration are typically provided as sterile aqueous or oily solutions or fine suspensions, or as finely sterile powder forms for immediate preparation with sterile water for injection. May be.

  Examples of formulations for rectal or vaginal administration are pessaries or suppositories which can be formed, for example, from moldable or waxy substances containing the active compound.

  Compositions for inhalation administration take the form of inhalable powder compositions or liquid or powder sprays and may be administered in standard form using powder inhalers or aerosol dispensers. Such instruments are well known. For administration by inhalation, powder formulations typically contain the active compound together with an inert solid powder diluent such as lactose.

  The compounds of the present invention are usually provided in unit dosage form, which typically contains sufficient compounds to exhibit the desired level of biological activity. For example, formulations for oral administration contain from 0.1 mg to 2 g, more usually from 10 mg to 1 g, such as from 50 to 500 mg of active ingredient. The active compound is administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to obtain the desired therapeutic effect.

Therapeutic Compounds of Formula (I) are believed to be useful for the prevention or treatment of a range of medical conditions or symptoms mediated by p38 MAP kinase. Examples of such medical conditions and symptoms are described above.

  The compound of formula (I) is usually administered to a subject in need of such administration, for example a human or animal patient, preferably a human. The compound is typically administered in a generally non-toxic amount that is therapeutically or prophylactically useful. However, in certain situations (eg in the case of life threatening diseases) the benefits of administering a compound of formula (I) may outweigh the disadvantages of toxic effects or side effects, in which case an amount with some toxicity It may be desirable to administer the compound.

  A typical daily dose of the compound ranges from 100 pg to 10 mg / kg body weight, more typically from 10 ng to 1 mg / kg body weight, although higher or lower doses may be administered as needed. Ultimately, the amount of compound administered will depend on the extent of the condition or physiological condition being treated and is at the discretion of the physician.

  The compounds of formula (I) may be administered as the sole therapeutic agent or they may be administered in combination therapy with one or more other compounds for the treatment of certain medical conditions such as rheumatoid arthritis or osteoarthritis Good. Examples of other therapeutic agents that can be administered with a compound of formula (I) (simultaneously or at different time intervals) include methotrexate, prednisolone, sulfasalazine, leflunomide and NSAIDs such as COX-2 inhibitors such as celecoxib and rofecoxib is there.

Example

  The invention is also illustrated by the specific embodiments described in the examples below, but is not limited thereto.

酢酸（１ｍｌ）中４‐ビニルピリジン（１．０mmol）およびインドール（１．０mmol）の混合液を１３０℃で１６時間攪拌した。室温まで冷却後、溶媒を減圧下で除去し、残渣をシリカゲルのフラッシュクロマトグラフィーによる精製に付した。酢酸エチルまたは酢酸エチル中１０％メタノールによる溶離で、標題化合物を得た。 Example 1
3- (2- (4-Pyridyl) ethyl) indole

A mixture of 4-vinylpyridine (1.0 mmol) and indole (1.0 mmol) in acetic acid (1 ml) was stirred at 130 ° C. for 16 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was subjected to purification by flash chromatography on silica gel. Elution with ethyl acetate or 10% methanol in ethyl acetate gave the title compound.

  The following compounds were prepared using the method of Example 1 using the appropriate vinyl substituted monoheterocycle in place of vinylpyridine and the appropriate indole or azaindole.

４‐ビニルピリジンおよび１‐メチルインドールから；SPECS（製品コードＡＥ４７３／３０３６４０１４）から Example 2
1-Methyl-3- (2- (4-pyridyl) ethyl) indole

From 4-vinylpyridine and 1-methylindole; from SPECS (product code AE473 / 30364014)

２‐ビニルピリジンおよびインドールから；Salor（製品コードＳ６４，１７６‐６）から Example 3
3- (2- (2-Pyridyl) ethyl) indole

From 2-vinylpyridine and indole; from Salor (product code S64, 176-6)

４‐ビニルピリジンおよび５‐メチルインドールから；δ_Ｈ（４００ＭＨｚ，ＣＤＣｌ_３）８．４８（２Ｈ，ｄ，Ｊ６），７．９７（１Ｈ，ｂｒ ｓ），７．３７（１Ｈ，ｓ），７．２６（１Ｈ，ｄ，Ｊ８），７．１７（２Ｈ，ｄ，Ｊ６），７．０４（１Ｈ，ｄ，Ｊ８），６．８２（１Ｈ，ｄ，Ｊ２），３．０６（４Ｈ，ｍ），２．４７（３Ｈ，ｓ）． Example 4
5-Methyl-3- (2- (4-pyridyl) ethyl) indole

From 4-vinylpyridine and 5-methylindole; δ _H (400 MHz, CDCl ₃ ) 8.48 (2H, d, J6), 7.97 (1H, br s), 7.37 (1H, s), 7 .26 (1H, d, J8), 7.17 (2H, d, J6), 7.04 (1H, d, J8), 6.82 (1H, d, J2), 3.06 (4H, m ), 2.47 (3H, s).

４‐ビニルピリジンおよび５‐クロロインドールから；δ_Ｈ（４００ＭＨｚ，ＣＤＣｌ_３）８．４８（２Ｈ，ｄ，Ｊ５．５），８．１０（１Ｈ，ｂｒ ｓ），７．５６（１Ｈ，ｄ，Ｊ２），７．２８（１Ｈ，ｄ，Ｊ８．５），７．１５（１Ｈ，ｄｄ，Ｊ８．５，２），７．１２（２Ｈ，ｄ，Ｊ５．５），６．８８（１Ｈ，ｄ，Ｊ２），３．０３（４Ｈ，ｍ）． Example 5
5-Chloro-3- (2- (4-pyridyl) ethyl) indole

From 4-vinylpyridine and 5-chloroindole; δ _H (400 MHz, CDCl ₃ ) 8.48 (2H, d, J5.5), 8.10 (1H, br s), 7.56 (1H, d, J2), 7.28 (1H, d, J8.5), 7.15 (1H, dd, J8.5, 2), 7.12 (2H, d, J5.5), 6.88 (1H, d, J2), 3.03 (4H, m).

４‐ビニルピリジンおよび５‐ニトロインドールから；δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１１．５８（１Ｈ，ｂｒ ｓ），８．５４（１Ｈ，ｄ，Ｊ２），８．４４（２Ｈ，ｄ，Ｊ６），７．９８（１Ｈ，ｄｄ，Ｊ９，２），７．５０（１Ｈ，ｄ，Ｊ９），７．３９（１Ｈ，ｓ），７．３０（２Ｈ，ｄ，Ｊ６），３．１２（２Ｈ，ｔ，Ｊ８），３．００（２Ｈ，ｔ，Ｊ８）． Example 6
5-Nitro-3- (2- (4-pyridyl) ethyl) indole

From 4-vinylpyridine and 5-nitroindole; δ _H (400 MHz, d ₆ -DMSO) 11.58 (1H, br s), 8.54 (1 H, d, J2), 8.44 (2H, d, J6), 7.98 (1H, dd, J9, 2), 7.50 (1H, d, J9), 7.39 (1H, s), 7.30 (2H, d, J6), 3.12 (2H, t, J8), 3.00 (2H, t, J8).

４‐ビニルピリジンおよび５‐アミノインドールから；δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１０．６８（１Ｈ，ｂｒ ｓ），９．７３（１Ｈ，ｂｒ ｓ），８．４４（２Ｈ，ｄ，Ｊ６），７．８５（１Ｈ，ｓ），７．２６（２Ｈ，ｄ，Ｊ６），７．２１（１Ｈ，ｄ，Ｊ８．５），７．１８（１Ｈ，ｄｄ，Ｊ８．５，２），７．０５（１Ｈ，ｄ，Ｊ２），２．９６（４Ｈ，ｓ），２．０２（３Ｈ，ｓ）． Example 7
5-acetamido-3- (2- (4-pyridyl) ethyl) indole

From 4-vinylpyridine and 5-aminoindole; δ _H (400 MHz, d ₆ -DMSO) 10.68 (1 H, br s), 9.73 (1 H, br s), 8.44 (2 H, d, J 6 ), 7.85 (1H, s), 7.26 (2H, d, J6), 7.21 (1H, d, J8.5), 7.18 (1H, dd, J8.5, 2), 7.05 (1H, d, J2), 2.96 (4H, s), 2.02 (3H, s).

４‐ビニルピリジンおよび２‐メチルインドールから；δ_Ｈ（４００ＭＨｚ，ＣＤＣｌ_３）８．４８（２Ｈ，ｄ，Ｊ６），７．８５（１Ｈ，ｂｒ ｓ），７．４８（１Ｈ，ｄ，Ｊ７．５），７．２９（１Ｈ，ｄ，Ｊ７），７．１１（４Ｈ，ｍ），３．００（４Ｈ，ｍ），２．０７（３Ｈ，ｓ）． Example 8
2-Methyl-3- (2- (4-pyridyl) ethyl) indole

From 4-vinylpyridine and 2-methylindole; δ _H (400 MHz, CDCl ₃ ) 8.48 (2H, d, J6), 7.85 (1H, br s), 7.48 (1H, d, J7. 5), 7.29 (1H, d, J7), 7.11 (4H, m), 3.00 (4H, m), 2.07 (3H, s).

４‐ビニルピリジンおよび４‐メチルインドールから；δ_Ｈ（４００ＭＨｚ，ＣＤＣｌ_３）８．５０（２Ｈ，ｄ，Ｊ６），８．０３（１Ｈ，ｂｒ ｓ），７．２１（１Ｈ，ｄ，Ｊ８），７．１４（２Ｈ，ｄ，Ｊ６），７．０８（１Ｈ，ｔ，Ｊ７．５），６．８７（１Ｈ，ｄ，Ｊ７．５），６．８４（１Ｈ，ｄ，Ｊ２），３．２６（２Ｈ，ｔ，Ｊ８．５），３．０１（２Ｈ，ｔ，Ｊ８．５），２．７５（３Ｈ，ｓ）． Example 9
4-Methyl-3- (2- (4-pyridyl) ethyl) indole

From 4-vinylpyridine and 4-methylindole; δ _H (400 MHz, CDCl ₃ ) 8.50 (2H, d, J6), 8.03 (1H, br s), 7.21 (1H, d, J8) 7.14 (2H, d, J6), 7.08 (1H, t, J7.5), 6.87 (1H, d, J7.5), 6.84 (1H, d, J2), 3 .26 (2H, t, J8.5), 3.01 (2H, t, J8.5), 2.75 (3H, s).

４‐ビニルピリジンおよび７‐メチルインドールから；δ_Ｈ（４００ＭＨｚ，ＣＤＣｌ_３）８．５２（２Ｈ，ｄ，Ｊ６），７．９５（１Ｈ，ｂｒ ｓ），７．４７（１Ｈ，ｄ，Ｊ８），７．１２（２Ｈ，ｄ，Ｊ６），７．０７（１Ｈ，ｄｄ，Ｊ８．７），７．０２（１Ｈ，ｄ，Ｊ７），６．８９（１Ｈ，ｄ，Ｊ２．５），３．０６（４Ｈ，ｍ），２．４９（３Ｈ，ｓ）． Example 10
7-Methyl-3- (2- (4-pyridyl) ethyl) indole

From 4-vinylpyridine and 7-methylindole; δ _H (400 MHz, CDCl ₃ ) 8.52 (2H, d, J6), 7.95 (1H, br s), 7.47 (1H, d, J8) , 7.12 (2H, d, J6), 7.07 (1H, dd, J8.7), 7.02 (1H, d, J7), 6.89 (1H, d, J2.5), 3 .06 (4H, m), 2.49 (3H, s).

４‐ビニルピリジンおよび４‐フルオロインドールから；δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１１．０７（１Ｈ，ｂｒ ｓ），８．４４（２Ｈ，ｄ，Ｊ６），７．２３（２Ｈ，ｄ，Ｊ６），７．１６（１Ｈ，ｄ，Ｊ８），７．０９（１Ｈ，ｄ，Ｊ２），７．０１（１Ｈ，ｔｄ，Ｊ８，５．５），６．７２（１Ｈ，ｄｄ，Ｊ１１．５，８），３．０７（２Ｈ，ｔ，Ｊ７），２．９６（２Ｈ，ｔ，Ｊ７）． Example 11
4-Fluoro-3- (2- (4-pyridyl) ethyl) indole

From 4-vinylpyridine and 4-fluoroindole; δ _H (400 MHz, d ₆ -DMSO) 11.07 (1H, br s), 8.44 (2H, d, J6), 7.23 (2H, d, J6), 7.16 (1H, d, J8), 7.09 (1H, d, J2), 7.01 (1H, td, J8, 5.5), 6.72 (1H, dd, J11. 5, 8), 3.07 (2H, t, J7), 2.96 (2H, t, J7).

４‐ビニルピリジンおよび７‐アザインドールから；δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）８．４０（２Ｈ，ｄ，Ｊ６），８．２４（１Ｈ，ｄ，Ｊ４．５），７．９４（１Ｈ，ｄ，Ｊ８），７．４７（１Ｈ，ｄ，Ｊ３），７．１６（２Ｈ，ｄ，Ｊ６），７．０７（１Ｈ，ｄｄ，Ｊ８，４．５），６．４２（１Ｈ，ｄ，Ｊ３），４．５５（２Ｈ，ｔ，Ｊ７），３．１７（２Ｈ，ｔ，Ｊ７）． Example 12
3- (2- (4-Pyridyl) ethyl) -7-azaindole

From 4-vinylpyridine and 7-azaindole; δ _H (400 MHz, d ₆ -DMSO) 8.40 (2H, d, J6), 8.24 (1H, d, J4.5), 7.94 (1H , D, J8), 7.47 (1H, d, J3), 7.16 (2H, d, J6), 7.07 (1H, dd, J8, 4.5), 6.42 (1H, d , J3), 4.55 (2H, t, J7), 3.17 (2H, t, J7).

ＤＭＦ（５ｍｌ）中５‐アミノインドール（１．０mmol）、安息香酸（１．０mmol）、１‐ヒドロキシベンゾトリアゾール（１．１mmol）および塩酸ＥＤＣ（１．１mmol）の混合液を、混合液のＴＬＣ分析が反応の終了を示すまで、室温で攪拌した。溶媒を減圧下で除去し、残渣を水と酢酸エチルに分配した。有機層を（Ｎａ_２ＳＯ_４）乾燥し、濾過し、蒸発させて、残渣をシリカのカラムクロマトグラフィーにより精製した。石油エーテルおよび酢酸エチルの混合液による溶離で、標題化合物を得た。
δ_Ｈ（４００ＭＨｚ，ＣＤ_３ＯＤ）８．４８（２Ｈ，ｄ，Ｊ８），８．３９（１Ｈ，ｓ），８．０８（３Ｈ，ｍ），７．９１（１Ｈ，ｄ，Ｊ８．５），７．８５（１Ｈ，ｄ，Ｊ８．５），７．１８（１Ｈ，ｄ，Ｊ３），６．９８（１Ｈ，ｄ，Ｊ３）． Example 13
13A. 5-Benzamide indole

A mixture of 5-aminoindole (1.0 mmol), benzoic acid (1.0 mmol), 1-hydroxybenzotriazole (1.1 mmol) and EDC hydrochloride (1.1 mmol) in DMF (5 ml) was added to the TLC of the mixture. Stir at room temperature until analysis indicates the reaction is complete. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was dried (Na ₂ SO ₄ ), filtered and evaporated, and the residue was purified by column chromatography on silica. Elution with a mixture of petroleum ether and ethyl acetate gave the title compound.
δ _H (400 MHz, CD ₃ OD) 8.48 (2H, d, J8), 8.39 (1H, s), 8.08 (3H, m), 7.91 (1H, d, J8.5) , 7.85 (1H, d, J8.5), 7.18 (1H, d, J3), 6.98 (1H, d, J3).

例１で記載された条件下で４‐ビニルピリジンおよび５‐ベンズアミドインドールを反応させて、標題化合物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１０．７６（１Ｈ，ｂｒ ｓ），１０．１０（１Ｈ，ｂｒ ｓ），８．４４（２Ｈ，ｄ，Ｊ６），８．００（２Ｈ，ｄ，Ｊ９），７．９８（１Ｈ，ｓ），７．５４（３Ｈ，ｍ），７．４２（１Ｈ，ｄｄ，Ｊ８．５，１．５），７．３４（１Ｈ，ｄ，Ｊ９），７．２７（２Ｈ，ｄ，Ｊ６），７．０８（１Ｈ，ｄ，Ｊ２），３．００（４Ｈ，ｓ）． 13B. 5-Benzamido-3- (2- (pyrid-4-yl) ethyl) indole

Reaction of 4-vinylpyridine and 5-benzamidoindole under the conditions described in Example 1 gave the title compound.
_{δ H (400MHz, d 6 -DMSO} ) 10.76 (1H, br s), 10.10 (1H, br s), 8.44 (2H, d, J6), 8.00 (2H, d, J9 ), 7.98 (1H, s), 7.54 (3H, m), 7.42 (1H, dd, J8.5, 1.5), 7.34 (1H, d, J9), 7. 27 (2H, d, J6), 7.08 (1H, d, J2), 3.00 (4H, s).

例１３Ａで記載された方法に従い、但し５‐アミノインドールおよび安息香酸の代わりに５‐アミノインドールおよび３‐フルオロ‐５‐（４‐モルホリノ）安息香酸を用いて、標題化合物を製造した。
δ_Ｈ（４００ＭＨｚ，ＣＤＣｌ_３）８．２５（１Ｈ，ｂｒ ｓ），７．９４（１Ｈ，ｓ），７．８１（１Ｈ，ｂｒ ｓ），７．３８（１Ｈ，ｄ，Ｊ８．５），７．３４（１Ｈ，ｄ，Ｊ８．５），７．２４（２Ｈ，ｍ），６．９８（１Ｈ，ｄ，Ｊ８．５），６．７２（１Ｈ，ｄｔ，Ｊ１１．５，２），６．５６（１Ｈ，ｔ，Ｊ２），３．８６（４Ｈ，ｍ），３．２３（４Ｈ，ｍ）． Example 14
14A. 5- (3-Fluoro-5- (4-morpholino) benzamido) indole

The title compound was prepared according to the method described in Example 13A, but using 5-aminoindole and 3-fluoro-5- (4-morpholino) benzoic acid instead of 5-aminoindole and benzoic acid.
δ _H (400 MHz, CDCl ₃ ) 8.25 (1H, brs), 7.94 (1H, s), 7.81 (1H, br s), 7.38 (1H, d, J8.5), 7.34 (1H, d, J8.5), 7.24 (2H, m), 6.98 (1H, d, J8.5), 6.72 (1H, dt, J11.5, 2), 6.56 (1H, t, J2), 3.86 (4H, m), 3.23 (4H, m).

例１で記載された条件下で４‐ビニルピリジンおよび５‐（３‐フルオロ‐５‐（４‐モルホリノ）ベンズアミド）インドールを反応させて、標題化合物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１０．７７（１Ｈ，ｂｒ ｓ），１０．０７（１Ｈ，ｂｒ ｓ），８．４４（２Ｈ，Ｊ６），７．９６（１Ｈ，ｄ，Ｊ２），７．３９（１Ｈ，ｄｄ，Ｊ９．２），７．３６（１Ｈ，ｔ，Ｊ２），７．３０（１Ｈ，ｄ，Ｊ８．５），７．２７（２Ｈ，ｄ，Ｊ６），７．１７（１Ｈ，ｄｍ，Ｊ９），７．０９（１Ｈ，ｄ，Ｊ２），６．９８（１Ｈ，ｄｔ，Ｊ１２，２），３．７６（４Ｈ，ｍ），３．２４（４Ｈ，ｍ），２．９９（４Ｈ，ｓ）． 14B. 5- (3-Fluoro-5- (4-morpholino) benzamido) -3- (2- (4-pyridyl) ethyl) indole

Reaction of 4-vinylpyridine and 5- (3-fluoro-5- (4-morpholino) benzamido) indole under the conditions described in Example 1 gave the title compound.
δ _H (400 MHz, d ₆ -DMSO) 10.77 (1H, br s), 10.07 (1H, br s), 8.44 (2H, J6), 7.96 (1H, d, J2), 7.39 (1H, dd, J9.2), 7.36 (1H, t, J2), 7.30 (1H, d, J8.5), 7.27 (2H, d, J6), 7. 17 (1H, dm, J9), 7.09 (1H, d, J2), 6.98 (1H, dt, J12, 2), 3.76 (4H, m), 3.24 (4H, m) , 2.99 (4H, s).

例１３Ａで記載された方法に従い、但し５‐アミノインドールおよび安息香酸の代わりに６‐アミノインドールおよび３‐フルオロ‐５‐（４‐モルホリノ）安息香酸を用いて、中間標題化合物を製造した。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１１．０７（１Ｈ，ｂｒ ｓ），１０．１１（１Ｈ，ｂｒ ｓ），８．０２（１Ｈ，ｓ），７．４８（１Ｈ，ｄ，Ｊ８．５），７．３２（１Ｈ，ｓ），７．３０（１Ｈ，ｍ），７．２５（１Ｈ，ｄｄ，Ｊ８．５，２），７．１５（１Ｈ，ｄ，Ｊ８．５），６．９８（１Ｈ，ｄｍ，Ｊ１２．５），６．３８（１Ｈ，ｓ），３．７６（４Ｈ，ｍ），３．２４（４Ｈ，ｍ）． Example 15
15A. 6- (3-Fluoro-5- (4-morpholino) benzamido) indole

The intermediate title compound was prepared according to the method described in Example 13A, but using 6-aminoindole and 3-fluoro-5- (4-morpholino) benzoic acid instead of 5-aminoindole and benzoic acid.
δ _H (400 MHz, d ₆ -DMSO) 11.07 (1H, br s), 10.11 (1 H, br s), 8.02 (1 H, s), 7.48 (1 H, d, J 8.5) ), 7.32 (1H, s), 7.30 (1H, m), 7.25 (1H, dd, J8.5, 2), 7.15 (1H, d, J8.5), 6. 98 (1H, dm, J12.5), 6.38 (1H, s), 3.76 (4H, m), 3.24 (4H, m).

例１で記載された条件下で４‐ビニルピリジンおよび６‐（３‐フルオロ‐５‐（４‐モルホリノ）ベンズアミド）インドールを反応させて、標題化合物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１０．７８（１Ｈ，ｂｒ ｓ），１０．１０（１Ｈ，ｂｒ ｓ），８．４４（２Ｈ，ｄ，Ｊ６），７．９６（１Ｈ，ｄ，Ｊ１．５），７．５０（１Ｈ，ｄ，Ｊ８．５），７．３２（１Ｈ，ｓ），７．２８（２Ｈ，ｄ，Ｊ６），７．２４（１Ｈ，ｄｄ，Ｊ８．５，１．５），７．１５（１Ｈ，ｄ，Ｊ８．５），７．０６（１Ｈ，ｄ，Ｊ２），６．９８（１Ｈ，ｄｍ，Ｊ１２．５），３．７６（４Ｈ，ｍ），３．２４（４Ｈ，ｍ），２．９８（４Ｈ，ｓ）． 15B. 6- (3-Fluoro-5- (4-morpholino) benzamido) -3- (2- (4-pyridyl) ethyl) indole

4-vinylpyridine and 6- (3-fluoro-5- (4-morpholino) benzamido) indole were reacted under the conditions described in Example 1 to give the title compound.
δ _H (400 MHz, d ₆ -DMSO) 10.78 (1 H, br s), 10.10 (1 H, br s), 8.44 (2 H, d, J 6), 7.96 (1 H, d, J 1 .5), 7.50 (1H, d, J8.5), 7.32 (1H, s), 7.28 (2H, d, J6), 7.24 (1H, dd, J8.5, 1 .5), 7.15 (1H, d, J8.5), 7.06 (1H, d, J2), 6.98 (1H, dm, J12.5), 3.76 (4H, m), 3.24 (4H, m), 2.98 (4H, s).

例１３Ａで記載された方法に従い、但し５‐アミノインドールおよび安息香酸の代わりに５‐アミノインドールおよび３‐（トリフルオロメトキシ）安息香酸を用いて、標題化合物を製造した。
δ_Ｈ（４００ＭＨｚ，ＣＤＣｌ_３）８．２４（１Ｈ，ｂｒ ｓ），７．９５（１Ｈ，ｓ），７．８５（１Ｈ，ｓ），７．８１（１Ｈ，ｄ，Ｊ８），７．７７（１Ｈ，ｓ），７．５３（１Ｈ，ｔ，Ｊ８），７．３７（３Ｈ，ｍ），７．２４（１Ｈ，ｔ，Ｊ２．５），６．５５（１Ｈ，ｓ）． Example 16
16A. 5- (3-Trifluoromethoxybenzamide) indole

The title compound was prepared according to the method described in Example 13A, except that 5-aminoindole and 3- (trifluoromethoxy) benzoic acid were used in place of 5-aminoindole and benzoic acid.
δ _H (400 MHz, CDCl ₃ ) 8.24 (1H, brs), 7.95 (1H, s), 7.85 (1H, s), 7.81 (1H, d, J8), 7.77 (1H, s), 7.53 (1H, t, J8), 7.37 (3H, m), 7.24 (1H, t, J2.5), 6.55 (1H, s).

例１で記載された条件下で４‐ビニルピリジンおよび５‐（３‐トリフルオロメトキシベンズアミド）インドールを反応させて、標題化合物を得た。
δ_Ｈ（４００ＭＨｚ，ＣＤＣｌ_３）８．４６（２Ｈ，ｄ，Ｊ６），８．１１（１Ｈ，ｂｒ ｓ），７．９８（２Ｈ，ｓ），７．８３（１Ｈ，ｄ，Ｊ８），７．８０（１Ｈ，ｓ），７．５４（１Ｈ，ｔ，Ｊ８），７．４０（１Ｈ，ｄ，Ｊ８），７．３２（１Ｈ，ｔ，Ｊ８．５），７．０９（２Ｈ，ｄ，Ｊ６），６．８９（１Ｈ，ｄ，Ｊ２），３．０４（４Ｈ，ｍ）． 16B. 5- (3-Trifluoromethoxybenzamide) -3- (2- (4-pyridyl) ethyl) indole

Reaction of 4-vinylpyridine and 5- (3-trifluoromethoxybenzamido) indole under the conditions described in Example 1 gave the title compound.
δ _H (400 MHz, CDCl ₃ ) 8.46 (2H, d, J6), 8.11 (1H, brs), 7.98 (2H, s), 7.83 (1H, d, J8), 7 .80 (1H, s), 7.54 (1H, t, J8), 7.40 (1H, d, J8), 7.32 (1H, t, J8.5), 7.09 (2H, d , J6), 6.89 (1H, d, J2), 3.04 (4H, m).

例１３Ａで記載された方法に従い、但し５‐アミノインドールおよび安息香酸の代わりに５‐アミノインドールおよび３‐（トリフルオロメチル）安息香酸を用いて、標題化合物を製造した。
δ_Ｈ（４００ＭＨｚ，ＣＤＣｌ_３）８．２６（１Ｈ，ｂｒ ｓ），８．１６（１Ｈ，ｓ），８．１０（１Ｈ，ｄ，Ｊ７．５），７．９６（１Ｈ，ｓ），７．９２（１Ｈ，ｓ），７．８０（１Ｈ，ｄ，Ｊ７．５），７．６３（１Ｈ，ｔ，Ｊ７．５），７．３８（２Ｈ，ｍ），７．２４（１Ｈ，ｍ），６．５５（１Ｈ，ｔ，Ｊ２）． Example 17
17A. 5- (3-Trifluoromethylbenzamide) indole

The title compound was prepared according to the method described in Example 13A, but using 5-aminoindole and 3- (trifluoromethyl) benzoic acid instead of 5-aminoindole and benzoic acid.
_{δ H (400MHz, CDCl 3)} 8.26 (1H, br s), 8.16 (1H, s), 8.10 (1H, d, J7.5), 7.96 (1H, s), 7 .92 (1H, s), 7.80 (1H, d, J7.5), 7.63 (1H, t, J7.5), 7.38 (2H, m), 7.24 (1H, m ), 6.55 (1H, t, J2).

例１で記載された条件下で４‐ビニルピリジンおよび５‐（３‐トリフルオロメチルベンズアミド）インドールを反応させて、標題化合物を得た。
δ_Ｈ（４００ＭＨｚ，ＣＤＣｌ_３）８．４６（２Ｈ，ｄ，Ｊ６），８．１８（１Ｈ，ｓ），８．１１（１Ｈ，ｄ，Ｊ８），８．０６（１Ｈ，ｓ），８．０１（１Ｈ，ｓ），７．９８（１Ｈ，ｓ），７．８１（１Ｈ，ｄ，Ｊ８），７．６４（１Ｈ，ｔ，Ｊ８），７．３４（２Ｈ，ｍ），７．１０（２Ｈ，ｄ，Ｊ６），６．９０（１Ｈ，ｄ，Ｊ２），３．０６（４Ｈ，ｍ）． 17B. 5- (3-Trifluoromethylbenzamide) -3- (2- (4-pyridyl) ethyl) indole

Reaction of 4-vinylpyridine and 5- (3-trifluoromethylbenzamido) indole under the conditions described in Example 1 gave the title compound.
δ _H (400 MHz, CDCl ₃ ) 8.46 (2H, d, J6), 8.18 (1H, s), 8.11 (1H, d, J8), 8.06 (1H, s), 8. 01 (1H, s), 7.98 (1H, s), 7.81 (1H, d, J8), 7.64 (1H, t, J8), 7.34 (2H, m), 7.10 (2H, d, J6), 6.90 (1H, d, J2), 3.06 (4H, m).

無水エタノール（３ｍｌ）中４‐ビニルピリジン（１０．０mmol）、５‐アミノインドール（５．０mmol）、ナトリウム（３０ｍｇ）および無水硫酸銅（３０ｍｇ）の混合液を、密封チューブ中１３０℃で１６時間攪拌した。室温まで冷却後、溶媒を減圧下で除去し、残渣をシリカゲルのフラッシュクロマトグラフィーによる精製に付した。酢酸エチル中５％メタノールによる溶離で、標題化合物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）８．４１（２Ｈ，ｄ，Ｊ６），７．１８（３Ｈ，ｍ），７．０４（１Ｈ，ｄ，Ｊ３），６．６５（１Ｈ，ｄ，Ｊ２），６．５１（１Ｈ，ｄｄ，Ｊ８．５，２），６．０６（１Ｈ，ｄ，Ｊ３），４．４６（２Ｈ，ｂｒ ｓ），４．３１（２Ｈ，ｔ，Ｊ７），３．０４（２Ｈ，ｔ，Ｊ７）． Example 18
18A. 5-Amino-1- (2- (4-pyridyl) ethyl) indole

A mixture of 4-vinylpyridine (10.0 mmol), 5-aminoindole (5.0 mmol), sodium (30 mg) and anhydrous copper sulfate (30 mg) in absolute ethanol (3 ml) was placed in a sealed tube at 130 ° C. for 16 hours. Stir. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was subjected to purification by flash chromatography on silica gel. Elution with 5% methanol in ethyl acetate gave the title compound.
δ _H (400 MHz, d ₆ -DMSO) 8.41 (2H, d, J6), 7.18 (3H, m), 7.04 (1H, d, J3), 6.65 (1H, d, J2) ), 6.51 (1H, dd, J8.5, 2), 6.06 (1H, d, J3), 4.46 (2H, br s), 4.31 (2H, t, J7), 3 .04 (2H, t, J7).

例１３Ａで記載された操作に従い５‐アミノ‐１‐（２‐（４‐ピリジル）エチル）インドール（例１８Ａ）および３‐フルオロ‐５‐（４‐モルホリノ）安息香酸を反応させて、上記の生成物を得た。
δ_Ｈ（４００ＭＨｚ，ＣＤ_３ＯＤ）８．３４（２Ｈ，ｄ，Ｊ６），７．８７（１Ｈ，ｓ），７．３６（３Ｈ，ｓ），７．１４（２Ｈ，ｄ，Ｊ６），７．０９（１Ｈ，ｄ，Ｊ３），６．９２（１Ｈ，ｄｔ，Ｊ１２，２），６．４１（１Ｈ，ｄ，Ｊ３），４．５２（２Ｈ，ｔ，Ｊ７），３．８８（４Ｈ，ｍ），３．２６（４Ｈ，ｍ），３．２１（２Ｈ，ｔ，Ｊ７）． 18B. 5- (3-Fluoro-5- (4-morpholino) benzamido) -1- (2- (4-pyridyl) ethyl) indole

The 5-amino-1- (2- (4-pyridyl) ethyl) indole (Example 18A) and 3-fluoro-5- (4-morpholino) benzoic acid are reacted according to the procedure described in Example 13A above. The product was obtained.
δ _H (400 MHz, CD ₃ OD) 8.34 (2H, d, J6), 7.87 (1H, s), 7.36 (3H, s), 7.14 (2H, d, J6), 7 .09 (1H, d, J3), 6.92 (1H, dt, J12, 2), 6.41 (1H, d, J3), 4.52 (2H, t, J7), 3.88 (4H) , M), 3.26 (4H, m), 3.21 (2H, t, J7).

例１８Ａで記載された操作に従い、但し５‐アミノインドールの代わりにインドールを用いて、上記の生成物を製造した。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）８．４１（２Ｈ，ｄ，Ｊ６），７．５１（２Ｈ，ｔ，Ｊ７．５），７．２７（１Ｈ，ｄ，Ｊ３），７．２０（２Ｈ，ｄ，Ｊ６），７．１１（１Ｈ，ｔｍ，Ｊ７．５），６．９９（１Ｈ，ｔｍ，Ｊ７．５），６．３７（１Ｈ，ｄ，Ｊ３），４．４６（２Ｈ，ｔ，Ｊ７．５），３．０９（２Ｈ，ｔ，Ｊ７．５）． Example 19
1- (2- (4-Pyridyl) ethyl) indole

The above product was prepared according to the procedure described in Example 18A, but using indole instead of 5-aminoindole.
δ _H (400 MHz, d ₆ -DMSO) 8.41 (2H, d, J6), 7.51 (2H, t, J7.5), 7.27 (1H, d, J3), 7.20 (2H , D, J6), 7.11 (1H, tm, J7.5), 6.99 (1H, tm, J7.5), 6.37 (1H, d, J3), 4.46 (2H, t , J7.5), 3.09 (2H, t, J7.5).

１，４‐ジオキサン（６ｍｌ）および水（１．５ｍｌ）中５‐ニトロ‐３‐（２‐（４‐ピリジル）エチル）インドール（例６参照）（０．５mmol）、鉄粉（５．０mmol）、硫酸鉄(II)七水和物（０．３mmol）の混合液を９０℃で２〜３時間攪拌した。室温まで冷却後、混合液を濾過し、溶媒を減圧下で除去し、残渣をシリカゲルのフラッシュクロマトグラフィーによる精製に付した。酢酸エチルまたは酢酸エチル中１０％メタノールによる溶離で、示された生成物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１０．２５（１Ｈ，ｂｒ ｓ），８．４４（２Ｈ，ｄ，Ｊ６），７．２６（２Ｈ，ｄ，Ｊ６），７．０２（１Ｈ，ｄ，Ｊ８．５），６．８８（１Ｈ，ｄ，Ｊ２），６．７０（１Ｈ，ｄ，Ｊ２），６．４８（１Ｈ，ｄｄ，Ｊ８．５，２），４．４２（２Ｈ，ｂｒ ｓ），２．９１（４Ｈ，ｍ）． Example 20
20A. 5-Amino-3- (2- (4-pyridyl) ethyl) indole

5-Nitro-3- (2- (4-pyridyl) ethyl) indole (see Example 6) (0.5 mmol), iron powder (5.0 mmol) in 1,4-dioxane (6 ml) and water (1.5 ml) ) And iron (II) sulfate heptahydrate (0.3 mmol) were stirred at 90 ° C. for 2 to 3 hours. After cooling to room temperature, the mixture was filtered, the solvent was removed under reduced pressure, and the residue was subjected to purification by flash chromatography on silica gel. Elution with ethyl acetate or 10% methanol in ethyl acetate gave the indicated product.
δ _H (400 MHz, d ₆ -DMSO) 10.25 (1H, br s), 8.44 (2H, d, J6), 7.26 (2H, d, J6), 7.02 (1H, d, J8.5), 6.88 (1H, d, J2), 6.70 (1H, d, J2), 6.48 (1H, dd, J8.5, 2), 4.42 (2H, br s) ), 2.91 (4H, m).

クロロホルム（１ｍｌ）中例２０Ａの５‐アミノ‐３‐（２‐（４‐ピリジル）エチル）インドール化合物（０．１mmol）の溶液を８０℃で攪拌し、フェニルイソシアネート（０．１mmol）で処理し、３０分間攪拌し、室温まで冷却した。減圧下で沈殿物の濾過により、５‐（フェニルカルバモイルアミノ）‐３‐（２‐（４‐ピリジル）エチル）インドールを得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１０．６５（１Ｈ，ｂｒ ｓ），８．５６（１Ｈ，ｂｒ ｓ），８．４４（２Ｈ，ｄ，Ｊ６），８．４０（１Ｈ，ｂｒ ｓ），７．７１（１Ｈ，ｄ，Ｊ２），７．４６（２Ｈ，ｄ，Ｊ７．５），７．２６（５Ｈ，ｍ），７．０４（２Ｈ，ｍ），６．９４（１Ｈ，ｔｔ，Ｊ７．５，１），２．９８（４Ｈ，ｍ）． 20B. 5- (Phenylcarbamoylamino) -3- (2- (4-pyridyl) ethyl) indole

A solution of the 5-amino-3- (2- (4-pyridyl) ethyl) indole compound (0.1 mmol) of Example 20A in chloroform (1 ml) was stirred at 80 ° C. and treated with phenyl isocyanate (0.1 mmol). , Stirred for 30 minutes and cooled to room temperature. Filtration of the precipitate under reduced pressure gave 5- (phenylcarbamoylamino) -3- (2- (4-pyridyl) ethyl) indole.
δ _H (400 MHz, d ₆ -DMSO) 10.65 (1H, br s), 8.56 (1H, br s), 8.44 (2H, d, J6), 8.40 (1H, br s) 7.71 (1H, d, J2), 7.46 (2H, d, J7.5), 7.26 (5H, m), 7.04 (2H, m), 6.94 (1H, tt J7.5, 1), 2.98 (4H, m).

クロロホルム（１ｍｌ）中５‐アミノインドール（０．１mmol）の溶液を８０℃で攪拌し、フェニルイソシアネート（０．１mmol）で処理し、３０分間攪拌し、室温まで冷却した。減圧下で沈殿物の濾過により、上記の中間生成物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１０．９５（１Ｈ，ｂｒ ｓ），８．５７（１Ｈ，ｂｒ ｓ），８．４０（１Ｈ，ｂｒ ｓ），７．６７（１Ｈ，ｄ，Ｊ２），７．４６（２Ｈ，ｄ，Ｊ７．５），７．２８（４Ｈ，ｍ），７．０６（１Ｈ，ｄｄ，Ｊ８．５，２），６．９４（１Ｈ，ｔｔ，Ｊ７．５，１），６．３５（１Ｈ，ｍ）． Example 21
5- (Phenylcarbamoylamino) indole

A solution of 5-aminoindole (0.1 mmol) in chloroform (1 ml) was stirred at 80 ° C., treated with phenyl isocyanate (0.1 mmol), stirred for 30 minutes and cooled to room temperature. The intermediate product was obtained by filtration of the precipitate under reduced pressure.
δ _H (400 MHz, d ₆ -DMSO) 10.95 (1 H, br s), 8.57 (1 H, br s), 8.40 (1 H, br s), 7.67 (1 H, d, J 2) 7.46 (2H, d, J7.5), 7.28 (4H, m), 7.06 (1H, dd, J8.5, 2), 6.94 (1H, tt, J7.5, 1), 6.35 (1H, m).

  The compound of this example can be converted to 5- (phenylcarbamoylamino) -3- (2- (4-pyridyl) ethyl) indole by reaction with 4-vinylpyridine following the procedure of Example 1.

例１で記載された条件下で２‐クロロ‐４‐ビニルピリミジンおよびインドールを反応させて、標題化合物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１０．７９（１Ｈ，ｂｒ ｓ），８．６１（１Ｈ，ｄ，Ｊ５），７．５３（１Ｈ，ｄ，Ｊ８），７．４７（１Ｈ，ｄ，Ｊ５），７．３２（１Ｈ，ｄ，Ｊ８），７．１１（１Ｈ，ｄ，Ｊ２），７．０６（１Ｈ，ｔ，Ｊ８），６．９７（１Ｈ，ｔ，Ｊ８），３．１２（４Ｈ，ｍ）． Example 22
3- (2- (2-Chloro-4-pyrimidinyl) ethyl) indole

2-Chloro-4-vinylpyrimidine and indole were reacted under the conditions described in Example 1 to give the title compound.
_{δ H (400MHz, d 6 -DMSO} ) 10.79 (1H, br s), 8.61 (1H, d, J5), 7.53 (1H, d, J8), 7.47 (1H, d, J5), 7.32 (1H, d, J8), 7.11 (1H, d, J2), 7.06 (1H, t, J8), 6.97 (1H, t, J8), 3.12. (4H, m).

５‐アミノインドールおよび２‐（４‐モルホリノ）イソニコチン酸を例１３Ａで記載された条件下で一緒に反応させて、標題化合物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１１．０７（１Ｈ，ｂｒ ｓ），１０．１７（１Ｈ，ｂｒ ｓ），８．２８（１Ｈ，ｄ，Ｊ５），７．９６（１Ｈ，ｓ），７．３６（２Ｈ，ｓ），７．３４（１Ｈ，ｔ，Ｊ３），７．２８（１Ｈ，ｓ），７．１５（１Ｈ，ｄｄ，Ｊ５，２），６．４２（１Ｈ，ｄｄ，Ｊ３，２），３．７３（４Ｈ，ｔ，Ｊ５），３．５３（４Ｈ，ｔ，Ｊ５）． Example 23
23A. 5- (2- (4-morpholino) isonicotinamide) indole

5-aminoindole and 2- (4-morpholino) isonicotinic acid were reacted together under the conditions described in Example 13A to give the title compound.
δ _H (400 MHz, d ₆ -DMSO) 11.07 (1H, br s), 10.17 (1 H, br s), 8.28 (1 H, d, J5), 7.96 (1H, s), 7.36 (2H, s), 7.34 (1H, t, J3), 7.28 (1H, s), 7.15 (1H, dd, J5, 2), 6.42 (1H, dd, J3, 2), 3.73 (4H, t, J5), 3.53 (4H, t, J5).

４‐ビニルピリジンおよび５‐（２‐（４‐モルホリノ）イソニコチンアミド）インドールを例１で記載された条件下で一緒に反応させて、標題化合物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１０．７８（１Ｈ，ｂｒ ｓ），１０．１９（１Ｈ，ｂｒ ｓ），８．４４（２Ｈ，ｄ，Ｊ６），８．２８（１Ｈ，ｄ，Ｊ５），７．９７（１Ｈ，ｂｒ ｓ），７．３９（１Ｈ，ｄｄ，Ｊ８．５，２），７．２９（４Ｈ，ｍ），７．１６（１Ｈ，ｄｄ，Ｊ５，１），７．１０（１Ｈ，ｓ），３．７３（４Ｈ，ｔ，Ｊ５），３．５３（４Ｈ，ｔ，Ｊ５），３．００（４Ｈ，ｓ）． 23B. 5- (2- (4-morpholino) isonicotinamide) -3- (2- (4-pyridyl) ethyl) indole

4-Vinylpyridine and 5- (2- (4-morpholino) isonicotinamide) indole were reacted together under the conditions described in Example 1 to give the title compound.
δ _H (400 MHz, d ₆ -DMSO) 10.78 (1 H, br s), 10.19 (1 H, br s), 8.44 (2 H, d, J 6), 8.28 (1 H, d, J 5 ), 7.97 (1H, brs), 7.39 (1H, dd, J8.5, 2), 7.29 (4H, m), 7.16 (1H, dd, J5, 1), 7 .10 (1H, s), 3.73 (4H, t, J5), 3.53 (4H, t, J5), 3.00 (4H, s).

トルエン（５ｍｌ）中５‐アミノインドール（３．０mmol）および無水フタル酸（３．０mmol）の混合液を攪拌しながら、還流温度で２〜３時間保持した。室温まで冷却後、溶媒を減圧下で除去し、残渣をシリカのカラムクロマトグラフィーにより精製した。ジエチルエーテルによる溶離で、標題化合物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１１．３２（１Ｈ，ｂｒ ｓ），７．９６（２Ｈ，ｍ），７．９０（２Ｈ，ｍ），７．５７（１Ｈ，ｄ，Ｊ２），７．５０（１Ｈ，ｄ，Ｊ８．５），７．４６（１Ｈ，ｔ，Ｊ２），７．０９（１Ｈ，ｄｄ，Ｊ８．５，２），６．５１（１Ｈ，ｍ）． Example 24
24A. 5- (1-phthalimido) indole

A mixture of 5-aminoindole (3.0 mmol) and phthalic anhydride (3.0 mmol) in toluene (5 ml) was held at reflux temperature for 2-3 hours with stirring. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was purified by silica column chromatography. Elution with diethyl ether gave the title compound.
δ _H (400 MHz, d ₆ -DMSO) 11.32 (1H, br s), 7.96 (2H, m), 7.90 (2H, m), 7.57 (1H, d, J2), 7 .50 (1H, d, J8.5), 7.46 (1H, t, J2), 7.09 (1H, dd, J8.5, 2), 6.51 (1H, m).

４‐ビニルピリジンおよび５‐（１‐フタルイミド）インドールを例１で記載された条件下で一緒に反応させて、標題化合物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１１．０３（１Ｈ，ｂｒ ｓ），８．４３（２Ｈ，ｄ，Ｊ６），７．９７（２Ｈ，ｍ），７．９１（２Ｈ，ｍ），７．６４（１Ｈ，ｄ，Ｊ２），７．４４（１Ｈ，ｄ，Ｊ８．５），７．２８（２Ｈ，ｄ，Ｊ６），７．２３（１Ｈ，ｄ，Ｊ２），７．０８（１Ｈ，ｄｄ，Ｊ８．５，２），３．００（４Ｈ，ｍ）． 24B. 5- (1-phthalimido) -3- (2- (4-pyridyl) ethyl) indole

4-Vinylpyridine and 5- (1-phthalimido) indole were reacted together under the conditions described in Example 1 to give the title compound.
δ _H (400 MHz, d ₆ -DMSO) 11.03 (1H, br s), 8.43 (2H, d, J6), 7.97 (2H, m), 7.91 (2H, m), 7 .64 (1H, d, J2), 7.44 (1H, d, J8.5), 7.28 (2H, d, J6), 7.23 (1H, d, J2), 7.08 (1H) , Dd, J8.5, 2), 3.00 (4H, m).

４‐ビニルピリジンおよび６‐アミノインドールを例１８Ａの方法に従い一緒に反応させて、標題化合物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）８．４４（２Ｈ，ｄ，Ｊ６），７．２１（２Ｈ，ｄ，Ｊ６），７．１７（１Ｈ，ｄ，Ｊ８），６．８８（１Ｈ，ｄ，Ｊ３），６．６０（１Ｈ，ｄ，Ｊ２），６．４１（１Ｈ，ｄｄ，Ｊ８，２），６．１３（１Ｈ，ｄ，Ｊ３），４．７７（２Ｈ，ｂｒ ｓ），４．２４（２Ｈ，ｔ，Ｊ７．５），３．０４（２Ｈ，ｔ，Ｊ７．５）． Example 25
25A. 6-Amino-1- (2- (4-pyridyl) ethyl) indole

4-Vinylpyridine and 6-aminoindole were reacted together according to the method of Example 18A to give the title compound.
δ _H (400 MHz, d ₆ -DMSO) 8.44 (2H, d, J6), 7.21 (2H, d, J6), 7.17 (1H, d, J8), 6.88 (1H, d , J3), 6.60 (1H, d, J2), 6.41 (1H, dd, J8, 2), 6.13 (1H, d, J3), 4.77 (2H, brs), 4 .24 (2H, t, J7.5), 3.04 (2H, t, J7.5).

例１３Ａで記載された方法を用い、６‐アミノ‐１‐（２‐（４‐ピリジル）エチル）インドールおよび３‐フルオロ‐５‐（４‐モルホリノ）安息香酸を一緒に反応させて、標題化合物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１０．２４（１Ｈ，ｂｒ ｓ），８．５０（２Ｈ，ｄ，Ｊ６），８．１１（１Ｈ，ｂｒ ｓ），７．５５（１Ｈ，ｄ，Ｊ８．５），７．４２（１Ｈ，ｂｒ ｓ），７．３７（１Ｈ，ｄｄ，Ｊ８．５，１．５），７．２６（４Ｈ，ｍ），７．０６（１Ｈ，ｄｔ，Ｊ１２．５，２），６．４０（１Ｈ，ｄ，Ｊ３），４．４８（２Ｈ，ｔ，Ｊ７），３．８３（４Ｈ，ｔ，Ｊ５），３．３１（４Ｈ，ｔ，Ｊ５），３．１８（２Ｈ，ｔ，Ｊ７）． 25B. 6- (3-Fluoro-5- (4-morpholino) benzamido) -1- (2- (4-pyridyl) ethyl) indole

Using the method described in Example 13A, reacting 6-amino-1- (2- (4-pyridyl) ethyl) indole and 3-fluoro-5- (4-morpholino) benzoic acid together to give the title compound Got.
_{δ H (400MHz, d 6 -DMSO} ) 10.24 (1H, br s), 8.50 (2H, d, J6), 8.11 (1H, br s), 7.55 (1H, d, J8 .5), 7.42 (1H, brs), 7.37 (1H, dd, J8.5, 1.5), 7.26 (4H, m), 7.06 (1H, dt, J12. 5, 2), 6.40 (1H, d, J3), 4.48 (2H, t, J7), 3.83 (4H, t, J5), 3.31 (4H, t, J5), 3 .18 (2H, t, J7).

５アミノ‐３‐（２‐（４‐ピリジル）エチル）インドールおよび４‐（２‐オキソピロリジン‐１‐イル）安息香酸を例１３Ａで記載された条件下で一緒に反応させて、標題化合物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１０．７４（１Ｈ，ｂｒ ｓ），１０．０３（１Ｈ，ｂｒ ｓ），８．４４（２Ｈ，ｄ，Ｊ６），８．０２（２Ｈ，ｄ，Ｊ９），８．００（１Ｈ，ｓ），７．８２（２Ｈ，ｄ，Ｊ９），７．４２（１Ｈ，ｄ，Ｊ８．５），７．３０（１Ｈ，ｄ，Ｊ８．５），７．２８（２Ｈ，ｄ，Ｊ６），７．０９（１Ｈ，ｓ），３．９０（２Ｈ，ｔ，Ｊ７．５），３．００（４Ｈ，ｓ），２．５５（２Ｈ，ｔ，Ｊ７．５），２．０９（２Ｈ，quin，Ｊ７．５）． Example 26
5- (4- (2-Oxopyrrolidin-1-yl) benzamido) -3- (2- (4-pyridyl) ethyl) indole

5-amino-3- (2- (4-pyridyl) ethyl) indole and 4- (2-oxopyrrolidin-1-yl) benzoic acid are reacted together under the conditions described in Example 13A to give the title compound. Obtained.
δ _H (400 MHz, d ₆ -DMSO) 10.74 (1H, br s), 10.03 (1 H, br s), 8.44 (2H, d, J6), 8.02 (2H, d, J9) ), 8.00 (1H, s), 7.82 (2H, d, J9), 7.42 (1H, d, J8.5), 7.30 (1H, d, J8.5), 7. 28 (2H, d, J6), 7.09 (1H, s), 3.90 (2H, t, J7.5), 3.00 (4H, s), 2.55 (2H, t, J7. 5), 2.09 (2H, quin, J7.5).

３‐（２‐（２‐クロロ‐４‐ピリミジニル）エチル）インドール（０．５mmol）およびエタノールアミン（０．５ｍｌ）の混合液を攪拌し、２５０℃で５分間マイクロ波照射した。室温まで冷却後、水を加え、有機層を酢酸エチル中に抽出して、（Ｎａ_２ＳＯ_４）乾燥し、濾過し、蒸発させ、得られた残渣をシリカのカラムクロマトグラフィーに付した。ジエチルエーテルまたは酢酸エチルによる溶離で、標題生成物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１０．７６（１Ｈ，ｂｒ ｓ），８．１２（１Ｈ，ｄ，Ｊ５），７．５２（１Ｈ，ｄ，Ｊ８），７．３２（１Ｈ，ｄ，Ｊ８），７．１１（１Ｈ，ｓ），７．０６（１Ｈ，ｔ，Ｊ８），６．９７（１Ｈ，ｔ，Ｊ８），６．９０（１Ｈ，ｂｒ ｓ），６．５０（１Ｈ，ｄ，Ｊ５），４．６８（１Ｈ，ｂｒ ｓ），３．５１（２Ｈ，ｔ，Ｊ６），３．３４（２Ｈ，ｔ，Ｊ６），３．０４（２Ｈ，ｔ，Ｊ８），２．８７（２Ｈ，ｔ，Ｊ８）． Example 27
3- (2- (2- (2-hydroxyethylamino) -4-pyrimidinyl) ethyl) indole

A mixture of 3- (2- (2-chloro-4-pyrimidinyl) ethyl) indole (0.5 mmol) and ethanolamine (0.5 ml) was stirred and irradiated with microwaves at 250 ° C. for 5 minutes. After cooling to room temperature, water was added and the organic layer was extracted into ethyl acetate, dried (Na ₂ SO ₄ ), filtered and evaporated, and the resulting residue was subjected to column chromatography on silica. Elution with diethyl ether or ethyl acetate gave the title product.
δ _H (400 MHz, d ₆ -DMSO) 10.76 (1 H, br s), 8.12 (1 H, d, J 5), 7.52 (1 H, d, J 8), 7.32 (1 H, d, J8), 7.11 (1H, s), 7.06 (1H, t, J8), 6.97 (1H, t, J8), 6.90 (1H, br s), 6.50 (1H, d, J5), 4.68 (1H, br s), 3.51 (2H, t, J6), 3.34 (2H, t, J6), 3.04 (2H, t, J8), 2. 87 (2H, t, J8).

３‐（２‐（２‐クロロ‐４‐ピリミジニル）エチル）インドール（０．５mmol）および２‐アミノ‐２‐メチルプロパン‐１‐オール（０．５ｍｌ）の混合液を攪拌し、２００℃で５分間マイクロ波照射した。反応混合液を冷却させ、例２７で記載されたように後処理して、標題生成物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１０．７６（１Ｈ，ｂｒ ｓ），８．１１（１Ｈ，ｄ，Ｊ５），７．５１（１Ｈ，ｄ，Ｊ８），７．３２（１Ｈ，ｄ，Ｊ８），７．１０（１Ｈ，ｓ），７．０６（１Ｈ，ｔ，Ｊ８），６．９６（１Ｈ，ｔ，Ｊ８），６．５０（１Ｈ，ｄ，Ｊ５），６．３１（１Ｈ，ｂｒ ｓ），５．１１（１Ｈ，ｔ，Ｊ５．５），３．４９（２Ｈ，ｄ，Ｊ５．５），３．０５（２Ｈ，ｔ，Ｊ７．５），２．８６（２Ｈ，ｔ，Ｊ７．５），１．３２（６Ｈ，ｓ）． Example 28
3- (2- (2- (3-Hydroxy-2-methylprop-2-ylamino) -4-pyrimidinyl) ethyl) indole

Stir a mixture of 3- (2- (2-chloro-4-pyrimidinyl) ethyl) indole (0.5 mmol) and 2-amino-2-methylpropan-1-ol (0.5 ml) at 200 ° C. Microwave irradiation for 5 minutes. The reaction mixture was allowed to cool and worked up as described in Example 27 to give the title product.
_{δ H (400MHz, d 6 -DMSO} ) 10.76 (1H, br s), 8.11 (1H, d, J5), 7.51 (1H, d, J8), 7.32 (1H, d, J8), 7.10 (1H, s), 7.06 (1H, t, J8), 6.96 (1H, t, J8), 6.50 (1H, d, J5), 6.31 (1H) , Br s), 5.11 (1H, t, J5.5), 3.49 (2H, d, J5.5), 3.05 (2H, t, J7.5), 2.86 (2H, t, J7.5), 1.32 (6H, s).

３‐（２‐（２‐クロロ‐４‐ピリミジニル）エチル）インドール（０．５mmol）および（Ｓ）‐（−）‐α‐メチルベンジルアミン（０．５ｍｌ）の混合液を攪拌し、２００℃で５分間マイクロ波照射した。混合液を例２７の方法に従い後処理し、標題生成物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１０．７３（１Ｈ，ｂｒ ｓ），８．０７（１Ｈ，ｄ，Ｊ５），７．５８（１Ｈ，ｄ，Ｊ７．５），７．４９（１Ｈ，ｄ，Ｊ７．５），７．４０（２Ｈ，ｄ，Ｊ７．５），７．３０（３Ｈ，ｍ），７．１７（１Ｈ，ｔ，Ｊ７．５），７．０５（２Ｈ，ｔ，Ｊ７．５），６．９６（１Ｈ，ｔ，Ｊ７．５），６．４４（１Ｈ，ｂｒ ｓ），５．１１（１Ｈ，ｍ，Ｊ７），３．００（２Ｈ，ｂｒ ｓ），２．８３（２Ｈ，ｔ，Ｊ７．５），１．４３（３Ｈ，ｄ，Ｊ７）． Example 29
3- (2- (2-((S)-(-)-α-methylbenzylamino) -4-pyrimidinyl) ethyl) indole

A mixture of 3- (2- (2-chloro-4-pyrimidinyl) ethyl) indole (0.5 mmol) and (S)-(−)-α-methylbenzylamine (0.5 ml) was stirred and stirred at 200 ° C. For 5 minutes. The mixture was worked up according to the method of Example 27 to give the title product.
_{δ H (400MHz, d 6 -DMSO} ) 10.73 (1H, br s), 8.07 (1H, d, J5), 7.58 (1H, d, J7.5), 7.49 (1H, d, J7.5), 7.40 (2H, d, J7.5), 7.30 (3H, m), 7.17 (1H, t, J7.5), 7.05 (2H, t, J7.5), 6.96 (1H, t, J7.5), 6.44 (1H, br s), 5.11 (1H, m, J7), 3.00 (2H, br s), 2 .83 (2H, t, J7.5), 1.43 (3H, d, J7).

３‐（２‐（２‐クロロ‐４‐ピリミジニル）エチル）インドールおよび（Ｒ）‐（＋）‐α‐メチルベンジルアミンを例２９の方法に従い一緒に反応させて、標題生成物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１０．７３（１Ｈ，ｂｒ ｓ），８．０７（１Ｈ，ｄ，Ｊ５），７．５８（１Ｈ，ｄ，Ｊ７．５），７．４９（１Ｈ，ｄ，Ｊ７．５），７．４０（２Ｈ，ｄ，Ｊ７．５），７．３０（３Ｈ，ｍ），７．１７（１Ｈ，ｔ，Ｊ７．５），７．０５（２Ｈ，ｔ，Ｊ７．５），６．９６（１Ｈ，ｔ，Ｊ７．５），６．４４（１Ｈ，ｂｒ ｓ），５．１１（１Ｈ，ｍ，Ｊ７），３．００（２Ｈ，ｂｒ ｓ），２．８３（２Ｈ，ｔ，Ｊ７．５），１．４３（３Ｈ，ｄ，Ｊ７）． Example 30
3- (2- (2-((R)-(+)-α-methylbenzylamino) -4-pyrimidinyl) ethyl) indole

3- (2- (2-Chloro-4-pyrimidinyl) ethyl) indole and (R)-(+)-α-methylbenzylamine were reacted together according to the method of Example 29 to give the title product.
_{δ H (400MHz, d 6 -DMSO} ) 10.73 (1H, br s), 8.07 (1H, d, J5), 7.58 (1H, d, J7.5), 7.49 (1H, d, J7.5), 7.40 (2H, d, J7.5), 7.30 (3H, m), 7.17 (1H, t, J7.5), 7.05 (2H, t, J7.5), 6.96 (1H, t, J7.5), 6.44 (1H, br s), 5.11 (1H, m, J7), 3.00 (2H, br s), 2 .83 (2H, t, J7.5), 1.43 (3H, d, J7).

エタノール（２ｍｌ）中３‐（２‐（２‐クロロ‐４‐ピリミジニル）エチル）インドール（０．３５mmol）、１０％パラジウム炭素（２０ｍｇ）およびトリエチルアミン（０．７mmol）の混合液を水素雰囲気下室温で１６時間攪拌した。混合液を濾過し、蒸発させ、得られた残渣をシリカのカラムクロマトグラフィーに付した。ジエチルエーテルによる溶離で、標題化合物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１０．７７（１Ｈ，ｂｒ ｓ），９．１０（１Ｈ，ｄ，Ｊ１），８．６３（１Ｈ，ｄ，Ｊ５．５），７．５２（１Ｈ，ｄ，Ｊ８），７．４２（１Ｈ，ｄｄ，Ｊ５，１），７．３２（１Ｈ，ｄ，Ｊ８），７．０９（１Ｈ，ｓ），７．０６（１Ｈ，ｔ，Ｊ８），６．９７（１Ｈ，ｔ，Ｊ８），３．１１（４Ｈ，ｓ）． Example 31
3- (2- (4-Pyrimidinyl) ethyl) indole

A mixture of 3- (2- (2-chloro-4-pyrimidinyl) ethyl) indole (0.35 mmol), 10% palladium on carbon (20 mg) and triethylamine (0.7 mmol) in ethanol (2 ml) at room temperature under a hydrogen atmosphere. For 16 hours. The mixture was filtered and evaporated, and the resulting residue was subjected to column chromatography on silica. Elution with diethyl ether gave the title compound.
_{δ H (400MHz, d 6 -DMSO} ) 10.77 (1H, br s), 9.10 (1H, d, J1), 8.63 (1H, d, J5.5), 7.52 (1H, d, J8), 7.42 (1H, dd, J5, 1), 7.32 (1H, d, J8), 7.09 (1H, s), 7.06 (1H, t, J8), 6 97 (1H, t, J8), 3.11 (4H, s).

ジクロロメタン（２ｍｌ）中５‐アミノ‐３‐tert‐ブチル‐１‐フェニルピラゾール（０．５mmol）およびカルボニルジイミダゾール（０．５５mmol）の混合液を室温で６〜８時間攪拌した。５‐アミノ‐３‐（２‐（４‐ピリジル）エチル）インドール（０．５mmol）を加え、混合液を攪拌しながら、還流下で一夜保持した。次いで混合液を室温まで冷却し、溶媒を蒸発させ、得られた残渣をシリカのカラムクロマトグラフィーに付した。酢酸エチルによる溶離で、標題化合物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１０．６６（１Ｈ，ｂｒ ｓ），８．７８（１Ｈ，ｂｒ ｓ），８．４３（２Ｈ，ｄ，Ｊ６），８．２９（１Ｈ，ｂｒ ｓ），７．６８（１Ｈ，ｄ，Ｊ２），７．５４（４Ｈ，ｄ，Ｊ４），７．４２（１Ｈ，ｍ），７．２６（２Ｈ，ｄ，Ｊ６），７．２２（１Ｈ，ｄ，Ｊ８．５），７．０４（１Ｈ，ｄ，Ｊ２），６．９８（１Ｈ，ｄｄ，Ｊ８．５，２），６．３８（１Ｈ，ｓ），２．９６（４Ｈ，ｓ），１．２８（９Ｈ，ｓ）． Example 32
5- (3-tert-butyl-1-phenylpyrazol-5-ylcarbamoylamino) -3- (2- (4-pyridyl) ethyl) indole

A mixture of 5-amino-3-tert-butyl-1-phenylpyrazole (0.5 mmol) and carbonyldiimidazole (0.55 mmol) in dichloromethane (2 ml) was stirred at room temperature for 6-8 hours. 5-Amino-3- (2- (4-pyridyl) ethyl) indole (0.5 mmol) was added and the mixture was kept under reflux overnight with stirring. The mixture was then cooled to room temperature, the solvent was evaporated, and the resulting residue was subjected to silica column chromatography. Elution with ethyl acetate gave the title compound.
δ _H (400 MHz, d ₆ -DMSO) 10.66 (1H, br s), 8.78 (1H, br s), 8.43 (2H, d, J6), 8.29 (1H, br s) 7.68 (1H, d, J2), 7.54 (4H, d, J4), 7.42 (1H, m), 7.26 (2H, d, J6), 7.22 (1H, d , J8.5), 7.04 (1H, d, J2), 6.98 (1H, dd, J8.5, 2), 6.38 (1H, s), 2.96 (4H, s), 1.28 (9H, s).

窒素雰囲気下無水テトラヒドロフラン（３０ｍｌ）中塩酸トリフェニル（３‐ピリジルメチル）ホスホニウムクロリド（３．０mmol）の攪拌溶液を−７８℃に冷却し、ｎ‐ブチルリチウム（ヘキサン中１．６Ｍ、４．０ｍｌ、６．４mmol）で１０分間かけて滴下処理した。得られた溶液を−７８℃で更に３０分間攪拌し、１‐〔（４‐メチルフェニル）スルホニル〕インドール‐３‐カルバルデヒド（３．０mmol）を加え、混合液を室温で一夜攪拌した。水を加え、混合液をジエチルエーテルで抽出し、有機層を（Ｎａ_２ＳＯ_４）乾燥し、濾過し、蒸発させ、得られた残渣をシリカのカラムクロマトグラフィーに付した。石油エーテルおよび酢酸エチルの混合液による溶離で、標題化合物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）８．４３（２Ｈ，ｍ），７．９１（１Ｈ，ｄ，Ｊ８），７．７８（２Ｈ，ｄ，Ｊ８），７．５４（２Ｈ，ｍ），７．３９（２Ｈ，ｄ，Ｊ８），７．３４（１Ｈ，ｄ，Ｊ８），７．２６（２Ｈ，ｍ），７．１７（１Ｈ，ｔ，Ｊ８），６．８２（２Ｈ，ｓ），２．３３（３Ｈ，ｓ）． Example 33
E-1-[(4-Methylphenyl) sulfonyl] -3- (2- (3-pyridyl) ethenyl) indole

A stirred solution of triphenyl (3-pyridylmethyl) phosphonium chloride (3.0 mmol) in anhydrous tetrahydrofuran (30 ml) under a nitrogen atmosphere was cooled to −78 ° C. and n-butyllithium (1.6 M in hexane, 4.0 ml). 6.4 mmol) for 10 minutes. The resulting solution was stirred at −78 ° C. for an additional 30 minutes, 1-[(4-methylphenyl) sulfonyl] indole-3-carbaldehyde (3.0 mmol) was added, and the mixture was stirred at room temperature overnight. Water was added, the mixture was extracted with diethyl ether, the organic layer was dried (Na ₂ SO ₄ ), filtered and evaporated, and the resulting residue was subjected to column chromatography on silica. Elution with a mixture of petroleum ether and ethyl acetate gave the title compound.
δ _H (400 MHz, d ₆ -DMSO) 8.43 (2H, m), 7.91 (1H, d, J8), 7.78 (2H, d, J8), 7.54 (2H, m), 7.39 (2H, d, J8), 7.34 (1H, d, J8), 7.26 (2H, m), 7.17 (1H, t, J8), 6.82 (2H, s) 2.33 (3H, s).

エタノール（２ｍｌ）中Ｅ‐１‐〔（４‐メチルフェニル）スルホニル〕‐３‐（２‐（３‐ピリジル）エテニル）インドール（０．５mmol）および１０％パラジウム炭素（２０ｍｇ）の混合液を水素雰囲気下室温で１６時間攪拌した。混合液を濾過し、蒸発させ、得られた残渣をシリカのカラムクロマトグラフィーに付した。石油エーテルおよび酢酸エチルの混合液による溶離で、標題化合物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）８．４３（１Ｈ，ｄ，Ｊ１．５），８．４０（１Ｈ，ｄｄ，Ｊ４．５，１．５），７．８７（１Ｈ，ｄ，Ｊ８．５），７．７２（２Ｈ，ｄ，Ｊ８．５），７．６２（２Ｈ，ｍ），７．５１（１Ｈ，ｓ），７．３３（３Ｈ，ｍ），７．２６（２Ｈ，ｍ），２．９８（４Ｈ，ｓ），２．３１（３Ｈ，ｓ）． Example 34
1-[(4-Methylphenyl) sulfonyl] -3- (2- (3-pyridyl) ethyl) indole

A mixture of E-1-[(4-methylphenyl) sulfonyl] -3- (2- (3-pyridyl) ethenyl) indole (0.5 mmol) and 10% palladium on carbon (20 mg) in ethanol (2 ml) was hydrogenated. The mixture was stirred at room temperature for 16 hours. The mixture was filtered and evaporated, and the resulting residue was subjected to column chromatography on silica. Elution with a mixture of petroleum ether and ethyl acetate gave the title compound.
_{δ H (400MHz, d 6 -DMSO} ) 8.43 (1H, d, J1.5), 8.40 (1H, dd, J4.5,1.5), 7.87 (1H, d, J8. 5), 7.72 (2H, d, J8.5), 7.62 (2H, m), 7.51 (1H, s), 7.33 (3H, m), 7.26 (2H, m) ), 2.98 (4H, s), 2.31 (3H, s).

メタノール（２ｍｌ）中１‐〔（４‐メチルフェニル）スルホニル〕‐３‐（２‐（３‐ピリジル）エチル）インドール（０．５mmol）および２Ｍ水酸化カリウム（０．５ｍｌ）の混合液を攪拌しながら、還流下で４０時間保持し、次いで混合液を室温まで冷却し、蒸発させた。水を加え、混合液を酢酸エチルで抽出し、有機層を（Ｎａ_２ＳＯ_４）乾燥し、濾過し、蒸発させ、得られた残渣をシリカのカラムクロマトグラフィーに付した。ジエチルエーテルによる溶離で、標題化合物を得た。
δ_Ｈ（４００ＭＨｚ，ｄ_６‐ＤＭＳＯ）１０．７７（１Ｈ，ｂｒ ｓ），８．４３（１Ｈ，ｄ，Ｊ１．５），８．３８（１Ｈ，ｄｄ，Ｊ５，１．５），７．６６（１Ｈ，ｄｔ，Ｊ８，１．５），７．５４（１Ｈ，ｄ，Ｊ８），７．３２（１Ｈ，ｄ，Ｊ８），７．２８（１Ｈ，ｄ，Ｊ８，５），７．０８（１Ｈ，ｓ），７．０６（１Ｈ，ｔ，Ｊ８），６．９７（１Ｈ，ｔ，Ｊ８），２．９８（４Ｈ，ｓ）． Example 35
3- (2- (3-pyridyl) ethyl) indole

Stir a mixture of 1-[(4-methylphenyl) sulfonyl] -3- (2- (3-pyridyl) ethyl) indole (0.5 mmol) and 2M potassium hydroxide (0.5 ml) in methanol (2 ml) While maintaining under reflux for 40 hours, the mixture was then cooled to room temperature and evaporated. Water was added, the mixture was extracted with ethyl acetate, the organic layer was dried (Na ₂ SO ₄ ), filtered and evaporated, and the resulting residue was subjected to column chromatography on silica. Elution with diethyl ether gave the title compound.
δ _H (400 MHz, d ₆ -DMSO) 10.77 (1H, br s), 8.43 (1H, d, J1.5), 8.38 (1H, dd, J5, 1.5), 7. 66 (1H, dt, J8, 1.5), 7.54 (1H, d, J8), 7.32 (1H, d, J8), 7.28 (1H, d, J8, 5), 7. 08 (1H, s), 7.06 (1H, t, J8), 6.97 (1H, t, J8), 2.98 (4H, s).

Biological activity
Example 36
p38 MAP Kinase Inhibitory Activity The compounds of the present invention were tested for p38 MAP kinase inhibitory activity using the following protocol.

In 1 ml of fresh assay buffer (20 mM HEPES pH 7.4, 25 mM β-glycerophosphate, 5 mM EDTA, 15 mM MgCl ₂ , 100 μM ATP, 1 mM sodium orthovanadate, 1 mM DTT) 35 μg of inactive purified α p38 and active MKK6 ( 1688 U / mg-Upstate Biotechnology) was mixed and incubated overnight at room temperature to activate p38. Activated p38 is then diluted 6-fold with assay buffer and 10 μL of MBP mix (150 μL 10 × strength assay buffer (250 mM HEPES pH 7.4, 250 mM β-glycerophosphate, 50 mM EDTA, 150 mM MgCl ₂ ), Test compound in DMSO mixed with 10 μL of 5 μM 10 mM DTT and 1 mM sodium orthovanadate, 7.5 μM 10 mM ATT, 723 μM water, 35 μCiγ ³³ P-ATP, 100 μL myelin basic protein (MBP) (5 mg / ml)) Were added to 96-well plates along with 5 μL of various dilutions (within 10%). The reaction was allowed to proceed for 5 minutes before being stopped with excess orthophosphoric acid (30 μL at 2%). Γ ³³ P-ATP that was not incorporated into myelin basic protein was separated from phosphorylated MBP on a Millipore (RTM) MAPH filter plate. The wells of the MAPH plate were wetted with 0.5% orthophosphoric acid, and the final reaction was then filtered from the wells with a Millipore vacuum filtration unit. After filtration, the residue was washed twice with 200 μL of 0.5% orthophosphoric acid. When the filter was dry, 25μ of Microscint 20 ^™ scintillant was added and then counted for 30 seconds on a Packard Topcount ^™ counter. The percentage inhibition of p38 activity was calculated and plotted to determine the concentration of test compound required to inhibit 50% of p38 activity (IC ₅₀ ). The results are shown in Table 1 below.
Table 1
p38 activity data-IC ₅₀ value
Compound of Example No (μM unless otherwise specified)
1 33
2 240
3 820
4 250
5 122
6 300
7 650
13B 40
8 270
14B 500nM
9 111
10 35
16B 2
17B 4
18B 3
19 200
20A 23% @ 1 mM
20B 28
11 45
12 177
15B 36% @ 3μM
22 120
23B 1.3
24B 25% @ 300 μM
25A 475
25B 300nM
26 28% @ 1 μM
27 38
28 1.5
29 3
30 15
31 715
32 145nM
33 1 mM
34> 1 mM
35 1 mM

Example 37
Inhibition of LPS-induced TNF-α production in THP-1 cells, in vitro assay The ability of the compounds of the invention to inhibit TNF-α release was demonstrated by Rawlins P., et al., “Inhibition of endotoxin-induced TNF-α production. In macrophages by 5Z-7-oxo-zeaenol and other fungal resorcyclic acid lactones ", International J. of Immunopharmacology, 21, 799 (1999).

THP-1 cells (human monocyte leukemia cell line ECACC) were cultured in static culture at about 37 ° C. in a constant humidity of 5% CO ₂ [RPMI 1640 (Invitrogen) supplemented with 10% fetal bovine serum (Invitrogen) and 2 mM] L-glutamine]. THP-1 cells were suspended in a medium containing 50 ng / ml PMA (SIGMA) and seeded at 1 × 10 ⁵ cells / well (100 μL / well) in a 96-well tissue culture plate (IWAKI). Incubated as follows. The medium was then aspirated and the wells were washed twice with phosphate buffer and 1 μg / ml LPS (SIGMA) in the medium was added (200 μL / well).

  Test compounds were reconstituted with DMSO (SIGMA) and then diluted with medium to a final DMSO concentration of 0.1%. 20 μL of test solution or medium containing DMSO only (solvent control) was added to triple wells immediately after addition of LPS and incubated for 6 hours as described above. Culture supernatants were collected and the amount of human TNF-α present was determined by ELISA (R & D Systems) according to the manufacturer's instructions.

IC ₅₀ was defined as the concentration of test compound corresponding to half-maximal inhibition of control activity by non-linear regression analysis of the inhibition curve. The IC ₅₀ of compound 14B (5- (3-fluoro-5- (4-morpholino) benzamide) -3- (2- (4-pyridyl) ethyl) indole) was found to be 530 nM.

Pharmaceutical prescription
Example 38
( I) A tablet composition containing the compound of the formula (I) has a composition of 197 mg of lactose (BP) as a diluent and 3 mg of magnesium stearate as a lubricant and 50 mg of a compound to form tablets by a known technique. Are mixed and compressed.

(Ii) Capsule Formulation A capsule formulation is prepared by mixing 100 mg of the compound of formula (I) with 100 mg lactose and filling the resulting mixture into a standard opaque hard gelatin capsule.

Equivalents The foregoing examples are presented for purposes of illustrating the invention and should not be construed as imposing any limitation on the scope of the invention. It will be readily apparent that various modifications and changes can be made to the specific embodiments of the invention described above and in the examples without departing from the principles underlying the invention. All such modifications and changes are intended to be included in this application.

Claims (67)

A compound for use in the prevention or treatment of a disease state or condition mediated by p38 MAP kinase; the compound is of the following general formula (I):

In the above, U, T, V and W are each a nitrogen atom or group CR ^{4 provided} that 3 or less of U, T, V and W are nitrogen atoms;
R ⁰ is hydrogen, C _1-4 hydrocarbyl, halogen or the group —AR ³ ;
R ¹ is hydrogen, C _1-4 hydrocarbyl or a group —A—R ³ ; provided that only ^one of R ⁰ and R ¹ is a group —A—R ³ ;
R ² is hydrogen, C _1-4 hydrocarbyl or halogen;
A is a carbon- or heteroatom-containing linker group having a linking chain length of 1 or 2 atoms;
R ³ is a monocyclic or bicyclic heteroaryl group containing 5-12 ring members;
Each group R ⁴ is hydrogen, hydroxy, halogen, nitro, cyano, a monocyclic heterocyclic group having up to 7 ring members, a group N (R ⁵ ) ₂ , a group C (O) N (R ⁶ ) ₂ , Independently selected from the group SO ₂ N (R ⁶ ) ₂ , the groups R ^a -R ^b and the group Y; provided that no more than one group Y is present;
R ^a is a bond, O, S, SO, SO ₂ , NH or N—C _1-4 hydrocarbyl;
R ^b is optionally mediated by O, S, SO, SO ₂ , NH or N—C _1-4 hydrocarbyl, and is hydroxy, amino, mono- or di-C _1-4 hydrocarbylamino, C _1-4 hydrocarbyloxy C _1-8 hydrocarbyl optionally substituted with one or more substituents selected from, oxo, C _1-4 hydrocarbylthio and halogen;
Each group R ⁵ is independently selected from hydrogen, C _1-4 alkyl, C _1-4 acyl and C _1-4 alkylsulfonyl;
Each group R ⁶ is independently selected from hydrogen and C _1-4 hydrocarbyl;
Y is a group —N (R ⁷ ) —C (O) —R ⁸ or —N (R ⁷ ) —SO ₂ —R ⁸ ;
R ⁷ is hydrogen, C _1-4 hydrocarbyl or the group C (O) —R ⁸ or SO ₂ —R ⁸ ;
R ⁸ is selected from C _1-10 hydrocarbyl, C _1-10 hydrocarbylamino, C _1-10 hydrocarbylthio, C _1-10 hydrocarbyloxy, aryl, arylamino, arylthio and aryloxy groups; their aryl moieties Is carbocyclic or heterocyclic and has 5 to 12 ring members; each substituent R ⁸ is optionally substituted with one or more groups R ⁴ other than Y; or R ⁷ and R ⁸ are Linked together with the nitrogen and carbon or sulfur atoms to which they are attached to form a 4-7 ring member ring structure;
In combination, when U, T, V and W are all CH and R ¹ and R ² are both hydrogen, R ⁰ is other than a 2- (2,4-diamino-6-triazinyl) ethyl group;
Provided that the group -A-R ³ contains an acidic substituent selected from carboxylic, phosphones, sulfonic acids and tetrazoles, or contains a -C (O) NSO ₂ -group, or -A- is When -C (O) N- and the nitrogen atom of the group A is directly linked to the furan or thiophene ring, R ¹ is -AR ³ and both R ⁰ and R ² are hydrogen, Or R ⁰ is —A—R ³ and R ¹ is hydrogen. Linker group A _{is, CH 2, C = O,} O, S, SO, SO 2, NR ', CHR, CR 2, CR 2 CR 2, CR = CR, OCH 2, CH 2 O, CH 2 S, SCH _{2, SOCH 2, CH 2 SO} , SO 2 CH 2, CH 2 SO 2, NR'CH 2, CH 2 NR ', CONR', R'NCO, SO 2 NR ', NR'SO 2, COCH 2 and CH is selected from ₂ CO, where R is hydrogen when present, are independently selected from methyl and fluoro, R 'is selected independently from hydrogen and methyl, when present, for use according to claim 1 Compound. Linker group A is CH ₂ or _CH 2 CH _2, the compound for use according to claim 2. Linker group A is _CH 2 CH _2, the compound for use according to claim 3. R ³ is pyridyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, isoquinolinyl, tetrazolyl, benzfuranyl, chromanyl, thiochromanyl, Imidazolyl, benzoxazolyl, benzisoxazole, benzthiazolyl and benzisothiazole, isobenzofuranyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (eg, adenine, guanine), indazolyl, benzodioxolyl, chromenyl, isochromenyl , Chroman, isochromanyl, benzodioxanyl, quinolidinyl, benzoxazinyl A compound for use according to any one of claims 1-4, selected from: benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl. R ³ is a monocyclic heteroaryl group, compounds for use according to any one of claims 1 to 5. R ³ is a monocyclic group having 6 ring members, compound for use according to claim 6. R ³ is pyridyl group or pyrimidinyl group, the compound for use according to claim 7. R ³ is a 4-pyridyl group or 4-pyrimidinyl group, the compound for use according to claim 8. R ⁰ is a group ^{-A-R 3,} compound for use according to any one of claims 1 to 9. 11. A compound according to claim 10, wherein R < ¹ > is hydrogen or methyl. 12. A compound according to claim 11, wherein R < ¹ > is hydrogen. R ¹ is a group ^{-A-R 3,} A compound according to any one of claims 1 to 9. R ² is selected from hydrogen and methyl, the compound for use according to any one of claims 1 to 13. R ² is hydrogen, compound for use according to claim 14. T and V is a group CR ^4, respectively, the compounds for use according to any one of claims 1 to 15. One at least of the U and W is a group CR ^4, compound for use according to any one of claims 1 to 16.   The compound according to claim 17, wherein W is a nitrogen atom. Both U and W is a group CR ^4, compound for use according to claim 17.   20. A compound for use according to any one of claims 1 to 19, wherein V is CH. W is CH or C-CH _3, compounds for use according to any one of claims 1 to 20. U is is selected from CH, C-CH ₃ and fluorine, the compound for use according to any one of claims 1 to 21. T is methyl, chloro, nitro, group (R ⁵⁾ is selected from 2 _N, and group Y, the compound for use according to any one of claims 1 to 22. U, T, at least one of V and W is 1 Tsugamoto CR ^4, wherein ^{R 4} is a group Y, the compound for use according to any one of claims 1 to 23. U, T, each of V and W is a group CR ^4, 1 radicals ^{R 4} is a group Y, the compound according to claim 24. R ⁰ is ^{-A-R 3,} T is a group ^{C-R 4,} wherein ^{R 4} is Y, the compounds for use according to claim 24 or 25. Y is a group ^{-N (R 7) -C (O} ) -R 8, a compound for use according to any one of claims 24 to 26. R ⁷ is hydrogen or _{C 1-4} hydrocarbyl, compound for use according to claim 27. R ⁷ is hydrogen, compound for use according to claim 28. Aryl R ⁸ is optionally substituted, aryl amino, arylthio and aryloxy, compound for use according to any one of claims 27 to 29. R ⁸ is a carbocyclic or heterocyclic aryl, arylamino, selected from arylthio and aryloxy groups in which the aryl moiety has 5 or 6 ring members, of use for according to claim 30 Compound.   32. A compound for use according to claim 31 wherein the aryl moiety is carbocyclic. R ⁸ is selected from unsubstituted phenyl and phenyl amino group, the compound for use according to claim 32. R ⁸ is selected from substituted phenyl and phenylamino group, the compound for use according to claim 32. 35. The use according to claim 34, wherein the phenyl ring is substituted with one or more substituents selected from halogen, monocyclic heterocyclic groups having up to 7 ring members and groups R ^a -R ^b Compound.   One or more substituents are selected from fluorine, chlorine, methoxy, trifluoromethoxy, trifluoromethyl, methyl, ethyl, isopropyl, isobutyl, t-butyl, phenyl, and 5- and 6-membered monocyclic heterocyclic groups 36. A compound for use according to claim 35.   37. A compound for use according to any one of claims 34 to 36, wherein the phenyl ring contains 1 or 2 meta substituents.   One meta position on the phenyl ring is unsubstituted or substituted with a group selected from fluorine, chlorine, methoxy, trifluoromethoxy, trifluoromethyl, ethyl, methyl and isopropyl, the other meta position is fluorine, Substituted with a group selected from chlorine, methoxy, trifluoromethoxy, trifluoromethyl, ethyl, methyl, isopropyl, isobutyl, t-butyl, phenyl, substituted phenyl, and 5- and 6-membered monocyclic heterocyclic groups 38. A compound for use according to claim 37.   39. A compound for use according to claim 38, wherein the phenyl ring contains a single substituent selected from m-trifluoromethyl and m-trifluoromethoxy.   39. A compound for use according to claim 38, wherein the phenyl ring contains a fluoro substituent at one meta position and a morpholino group at the other meta position.   32. A compound for use according to claim 31 wherein the aryl moiety is a group selected from 5 or 6 membered heterocyclic groups having 1 or 2 nitrogen ring members, such as pyridyl, pyrazolyl and isoxazolyl groups.   42. A compound for use according to claim 41, wherein the heterocyclic group is selected from pyridyl (e.g. 4-pyridyl) and pyrazolyl (e.g. 2-pyrazolyl).   Heterocyclic groups are fluorine, chlorine, methoxy, trifluoromethoxy, trifluoromethyl, methyl, ethyl, isopropyl, isobutyl, t-butyl, phenyl, and 5- and 6-membered monocyclic heterocyclic groups (eg, 43. A compound for use according to claim 42 having at least one substituent selected from morpholino). T is a group CR ^4, wherein R ⁴ is a group Y, according to claim 10 and a compound for use according to any one of the dependent claims. V is a group CR ^4, wherein R ⁴ is a group Y, according to claim 13 and a compound for use according to any one of the dependent claims. When the group -A-R ³ does not contain any carboxylic, phosphonic and sulfonic acid groups, nor any tetrazole or -C (O) NSO ₂ -group, where -A- is -C (O) N- 46. A compound for use according to any one of claims 1-45, wherein the nitrogen atom of group A is not directly linked to a furan or thiophene ring.   47. A compound for use according to any one of claims 1-46, wherein when -A- is -C (O) N-, the nitrogen atom of group A is not directly linked to a furan or thiophene ring. Group R ³ is containing 4 or less basic nitrogen atom, the compounds for use according to any one of claims 1-47. Group R ³ is unsubstituted or halogen, nitro, cyano, monocyclic heterocyclic group having up to 7 ring members, group N (R ⁵ ) ₂ , group C (O) N (R ⁶ ) ₂ Substituted with one or more groups selected from the group SO ₂ N (R ⁶ ) ₂ and the groups R ^a -R ^b , wherein R ⁵ , R ⁶ , R ^a and R ^b are defined in claim 1. 49. A compound for use according to any one of claims 1 to 48, wherein: R ³ is unsubstituted compound for use according to claim 49. Group R ³ is substituted, the compounds for use according to claim 49. R ³ is a chlorine, fluorine, methyl, unsubstituted amino, 2-hydroxyethylamino, 2-hydroxyprop-2-ylamino, 2-hydroxy-2-methylprop-2-ylamino, 1-phenylethyl, morpholino and piperazino group 52. A compound for use according to claim 51, which is substituted with one or more substituents selected from: In combination, when the linker group A is CO, CH (OH), CH ₂ or CH—S, one of R ¹ and R ² is C _1-4 alkyl and the other is hydrogen, R ³ is oxazole 53. A compound for use according to any one of claims 1 to 52 which is other than an imidazole, imidazole, triazole or benzotriazole group. In combination, when U, T, V and W are all CH, R ¹ and R ² are both hydrogen, and A is a group —CH ₂ CH ₂ — attached to the 3-position of the 5-membered ring, R ³ 54. A compound for use according to any one of claims 1 to 53, wherein is other than a pyrazin-3-yl or pyridi-3-yl group or a 2,4-diamino-6-triazinyl group. R ³ is pyrazin-3-yl or pyrid-3-yl group, or is other than 2,4-diamino-6-triazinyl group, the compound for use according to any one of claims 1-54.   56. Use of a compound of formula (I) according to any one of claims 1 to 55 for the manufacture of a medicament for the prevention or treatment of a disease state or condition mediated by p38 MAP kinase.   56. A method for the prevention or treatment of a disease state or condition mediated by p38 MAP kinase, comprising administering a compound of formula (I) according to any one of claims 1 to 55 to a subject in need.   58. A compound, use or method for use according to any one of claims 1 to 57, wherein the disease state or condition mediated by p38 MAP kinase is other than diabetes, insulin resistance and hyperglycemia.   The condition or symptom is rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and other arthritic conditions; Alzheimer's disease; toxic shock syndrome, endotoxin or inflammatory Inflammatory reaction induced by bowel disease; tuberculosis, atherosclerosis, muscle degeneration, Reiter syndrome, gout, acute synovitis, sepsis, septic shock, endotoxic shock, gram-negative sepsis, adult respiratory distress syndrome, Derived from cerebral malaria, chronic lung inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, reperfusion injury, graft-versus-host reaction, allograft rejection, fever and muscle pain due to infection, cachexia, infection or malignancy Cachexia, cachexia derived from acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related syndrome), keloid Adult, scar tissue formation, Crohn's disease, ulcerative colitis, heartburn, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), asthma, pulmonary fibrosis, bacterial pneumonia, proliferative diseases such as cancer ( 59. A compound, use or method for use according to any one of claims 1 to 58, selected from special colon and breast cancer) and alopecia. A compound for use in the prevention or treatment of a medical condition or symptom; the compound is of the following general formula (I):

In the above, U, T, V and W are each a nitrogen atom or group CR ^{4 provided} that 3 or less of U, T, V and W are nitrogen atoms;
R ⁰ is hydrogen, C _1-4 hydrocarbyl, halogen or the group —AR ³ ;
R ¹ is hydrogen, C _1-4 hydrocarbyl or a group —A—R ³ ; provided that only ^one of R ⁰ and R ¹ is a group —A—R ³ ;
R ² is hydrogen, C _1-4 hydrocarbyl or halogen;
A is a carbon- or heteroatom-containing linker group having a linking chain length of 1 or 2 atoms;
R ³ is a monocyclic or bicyclic heteroaryl group containing 5-12 ring members;
Each group R ⁴ is hydrogen, hydroxy, halogen, nitro, cyano, a monocyclic heterocyclic group having up to 7 ring members, a group N (R ⁵ ) ₂ , a group C (O) N (R ⁶ ) ₂ , Independently selected from the group SO ₂ N (R ⁶ ) ₂ , the groups R ^a -R ^b and the group Y; provided that no more than one group Y is present;
R ^a is a bond, O, S, SO, SO ₂ , NH or N—C _1-4 hydrocarbyl;
R ^b is optionally mediated by O, S, SO, SO ₂ , NH or N—C _1-4 hydrocarbyl, and is hydroxy, amino, mono- or di-C _1-4 hydrocarbylamino, C _1-4 hydrocarbyloxy C _1-8 hydrocarbyl optionally substituted with one or more substituents selected from, oxo, C _1-4 hydrocarbylthio and halogen;
Each group R ⁵ is independently selected from hydrogen, C _1-4 alkyl, C _1-4 acyl and C _1-4 alkylsulfonyl;
Each group R ⁶ is independently selected from hydrogen and C _1-4 hydrocarbyl;
Y is a group —N (R ⁷ ) —C (O) —R ⁸ or —N (R ⁷ ) —SO ₂ —R ⁸ ;
R ⁷ is hydrogen, C _1-4 hydrocarbyl or the group C (O) —R ⁸ or SO ₂ —R ⁸ ;
R ⁸ is selected from C _1-10 hydrocarbyl, C _1-10 hydrocarbylamino, C _1-10 hydrocarbylthio, C _1-10 hydrocarbyloxy, aryl, arylamino, arylthio and aryloxy groups; their aryl moieties Is carbocyclic or heterocyclic and has 5 to 12 ring members; each substituent R ⁸ is optionally substituted with one or more groups R ⁴ other than Y; or R ⁷ and R ⁸ are Linked together with the nitrogen and carbon or sulfur atoms to which they are attached to form a 4-7 ring member ring structure;
In combination, when U, T, V and W are all CH and R ¹ and R ² are both hydrogen, R ⁰ is other than a 2- (2,4-diamino-6-triazinyl) ethyl group;
Provided that the group -A-R ³ contains an acidic substituent selected from carboxylic, phosphones, sulfonic acids and tetrazoles, or contains a -C (O) NSO ₂ -group, or -A- is When -C (O) N- and the nitrogen atom of the group A is directly linked to the furan or thiophene ring, R ¹ is -AR ³ and both R ⁰ and R ² are hydrogen, Or R ⁰ is —A—R ³ and R ¹ is hydrogen;
The condition or symptom is rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and other arthritic conditions; Alzheimer's disease; toxic shock syndrome, endotoxin or inflammation Inflammatory reaction induced by inflammatory bowel disease; tuberculosis, atherosclerosis, muscle degeneration, Reiter syndrome, gout, acute synovitis, sepsis, septic shock, endotoxic shock, gram-negative sepsis, adult respiratory distress syndrome From cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, reperfusion injury, graft-versus-host reaction, allograft rejection, fever and muscle pain due to infection, cachexia, infection or malignancy Derived cachexia, cachexia derived from acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related syndrome), Keloy Formation, scar tissue formation, Crohn's disease, ulcerative colitis, heartburn, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), asthma, pulmonary fibrosis, bacterial pneumonia, proliferative diseases such as cancer ( Selected from special colon and breast cancer) and alopecia.   61. A compound, use or method for use according to any one of claims 1-60, wherein the condition or symptom is selected from inflammatory diseases and conditions, rheumatoid arthritis and osteoarthritis.   62. A compound, use or method for use according to any one of claims 1 to 61, wherein the compound of formula (I) is in the form of a salt.   63. A compound, use or method for use according to any one of claims 1 to 62, wherein the compound of formula (I) is in the form of a solvate. The compound is as described in any one of claims 1 to 55, 60, 62 and 63, provided that one group R ⁴ is a group Y and in combination, R ¹ and R ² are hydrogen, The compound of formula (I) itself, except for compounds in which U, V and W are all CH and T is a carbon atom having an unsubstituted benzamide group.   65. A pharmaceutical composition comprising the compound of claim 64 and a pharmaceutically acceptable carrier.   65. A compound according to claim 64 for use in medicine. The compound of formula (III) itself:

Wherein U, T, V, W and R ² are as described in any one of claims 1 to 55 and 60;
One group R ⁴ is a group Y;
R ⁹ is selected from hydrogen, C _1-4 hydrocarbyl and halogen;
R ¹⁰ is selected from hydrogen and C _1-4 hydrocarbyl; provided that at least one of R ⁹ and R ¹⁰ is hydrogen;
However, in combination, R ⁹ , R ¹⁰ and R ¹² are hydrogen, U, V and W are all CH, and T is a carbon atom having an unsubstituted benzamide group.