JP2002524552A - Aza-bicyclo compounds that modulate inhibition of cell adhesion - Google Patents

Abstract

  (57) [Summary] The present invention relates to physiologically active compounds of the following general formula (I): Embedded image Where R¹Is R^Three-Z^Three-, R^Three-L^Two-R^Four-Z^Three-, R^Three-L^Three-Ar¹-L^Four-Z^Three-Or R^Three-L^Three-Ar¹-L^Two-R^Four-Z^Three-Represents R^TwoRepresents hydrogen, halogen, lower alkyl or lower alkoxy, A¹Is optionally alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, imino, oxo, thioxo, or -ZR⁶, -NY¹Y^Two, -COOR⁶, Or -C (= O) -NY¹Y ^TwoMay be substituted with one or more groups selected from alkyl substituted with _1-3Represents an alkylene bond, L¹Is a direct bond; each optionally (a) an acidic functional group, cyano, oxo, -S (O)_mR⁹, R^Three, -C (= O) -R^Three, -C (= O) -OR^Three, -N (R⁸) -C (= O) -R⁹, -N (R⁸) -C (= O) -OR ⁹, -N (R⁸) -SO_Two-R⁹, -NY¹Y^TwoOr-[C (= O) -N (R^Ten) -C (R^Five) (R¹¹)]_p-C (= O) -NY¹Y^TwoOr (b) an acidic functional group, or -S (O)_mR⁹, -C (= O) -NY¹Y^TwoOr -NY¹Y^TwoAlkenylene, alkylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene, or arylene bond substituted with an alkyl group substituted with-[C (= O) -N (R^Ten) -C (R^Five) (R¹¹)]_p-Bond; -Z^Two-R¹²-Bond; -C (= O) -CH_Two-C (= O) -bond; -R¹²-Z^Two-R¹²-Bond; -C (R^Four) (R¹³)-[C (= O) -N (R^Ten) -C (R^Five) (R¹¹)]_p-Bond; or -L^Five-L⁶-L⁷-Represents a bond, Z¹Is C (R⁷) (R^7a), C (= O) or CH (OH), and Y is a carboxy or acidic bioisostere. The compounds of the present invention include the corresponding N-oxide and prodrugs thereof, and pharmaceutically acceptable salts and solvates of the compound, its N-oxide and prodrugs. Such compounds have valuable pharmacological properties, in particular the ability to modulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (α4β1).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

【Technical field】

The present invention relates to azabicyclo compounds, their preparation, pharmacological compositions containing these compounds, and their pharmacological use in the treatment of disease states, which can be modulated by inhibiting cell adhesion.

[0002]

[Background Art]

Cell adhesion is a process by which cells bind to each other, move toward a specific target, and localize within the extracellular matrix. Many cell-cell and cell-extracellular matrix interactions involve protein binding (e.g., fibronectin, VCAM-1
And vitronectin) and its integrin receptors (e.g., α5β1 (VLA-5)
, Α4β1 (VLA-4) and αVβ3). Recent studies have shown that these interactions can affect many physiological (e.g., embryonic development and wound healing) and pathological conditions (
For example, it has been shown to play an important role in tumor-cell invasion and metastasis, inflammation, atherosclerosis and autoimmune diseases). A wide range of proteins function as ligands for integrin receptors. Generally, these proteins, which are recognized by integrins, are divided into three groups:
That is, it belongs to one of extracellular matrix proteins, plasma proteins and cell surface proteins. Extracellular matrix proteins such as collagen fibronectin, fibrinogen, laminin, thrombospondin and vitronectin are
Binds to many integrins. Many of the adhesive proteins also circulate in plasma,
And binds to activated red blood cells. Ancillary components in plasma that are ligands for integrins include fibrinogen and factor X. Cell-bound complement C
3bi and several transmembrane proteins, such as Ig-like cell adhesion molecules (ICAM-1, 2, 3) and vascular cell adhesion molecules (VCAM-1), which are members of the Ig supergroup. Functions as a cell surface ligand for integrins.

[0003] Integrins are heterodimeric cell surface receptors consisting of two subunits called α and β. At least 15 different α-subunits (α1 to α
There are 9, α-L, α-M, α-X, α-IIb, α-V and α-E) and at least 7 different β subunits (β1-β7). This group of integrins can be further subdivided based on the β subunit and bind to one or more α-subunits. The most widely distributed integrins belong to the β1 group and are also known as late stage antigens (VLA). The second group of integrins are leukocyte-specific receptors and bind to the β2 protein.
It consists of one of the species α-subunits (α-L, α-M or α-X). These cytoadhesins α-IIbβ3 and α-Vβ3 constitute a third group of integrins.

[0004]

DISCLOSURE OF THE INVENTION

The present invention mainly relates to the ligand VCAM-1 and its integrin receptor α4β1 (VLA-
4) In connection with drugs that modulate the interaction with, the receptor is expressed on a large number of hematopoietic cells and established cell lines, which cells are hematopoietic precursors, peripheral and cytotoxic
Includes T lymphocytes, B lymphocytes, monocytes, thymocytes and eosinophils. The integrin α4β1 mediates both cell-cell and cell-matrix interactions. Cells expressing α4β1 bind the carboxy-terminal cell binding domain (CS-1) of the extracellular matrix protein fibronectin, the cytokine-inducible endothelial cell surface protein VCAM-1, and homologous aggregation To promote. Expression of the VCAM-1 by endothelial cells is dependent on pro-inflammatory cytokines such as INF-γ, TNF-α
, Regulated by IL-1β and IL-4.

[0005] Modulation of α4β1-mediated cell adhesion involves T-cell proliferation, B-cell localization to the germ center, activated T-cells and eosinophil adhesion to endothelial cells, It is important in many physiological processes. Various disease processes, such as melanoma cell division in metastasis, rheumatoid arthritis, autoimmune diabetes, T-cell infiltration of synovial membrane in colitis and experimental autoimmune encephalomyelitis, atherosclerosis, peripheral blood vessels VLA-4 / VCAM-1 in leukocyte permeation of blood-brain barrier in diseases, cardiovascular diseases and multiple sclerosis
Evidence for involvement in the interaction is that peptide CS-1 (the variable region of fibronectin, to which α4β1 binds via the sequence Leu-Asp-Val, in in vivo and in vitro experimental models of various inflammations ) And the role of antibodies specific for VLA-4 or VCAM-1 are being accumulated. For example, in a streptococcal cell wall-induced experimental model of rat arthritis, intravenous administration of CS-1 during early arthritis suppresses both acute and chronic inflammation (SM Wahl et al.,
J. Clin. Invest. 1994, 94: 655-662). Inflammatory oxazalone (oxa) in mice
zalone)-In the sensitization model, intravenous administration of anti-α4 specific monoclonal antibody,
Significantly inhibited efferent responses (50-60% reduction in ear swelling response) (PL Chisho
lm et al., J. Immunol. 1993, 23: 682-688). In a sheep model of allergic bronchoconstriction, intravenously or aerosolically administered HP1 / 2, an anti-α4 monoclonal antibody, blocked the late response and blocked the onset of airway hyperresponsiveness (WM Abraham et al., J. Clin. Invest. 1994, 93: 776-787). We have now found a new group of aza-bicyclo compounds, which have valuable pharmacological properties, especially VCAM-1 and fibronectin and the integrin VLA-4 (α4
It has the ability to regulate the interaction with β1). That is, in one aspect, the present invention relates to an aza-bicyclo compound represented by the following general formula (I):

[0006]

Embedded image

Here, R ¹ is (i) R ³ -Z ^3- ; (ii) R ³ -L ² -R ⁴ -Z ^3- ; (iii) R ³ -L ³ -Ar ¹ -L ⁴ -Z ^3- ; or (iv) represents R ³ -L ³ -Ar ¹ -L ² -R ⁴ -Z ^3- , wherein R ² represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group,
R ³ is alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, hetero R ⁴ represents an alkylene chain, alkenylene chain, or alkynylene chain; R ⁵ represents a hydrogen atom or a lower alkyl group; R ⁶ represents a hydrogen atom; an arylalkenyl, a heteroarylalkynyl, a heterocycloalkyl or a heterocycloalkylalkyl group; Represents an atom, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl or heteroarylalkyl group; R ⁷ and R ^7a independently represents a hydrogen atom or a lower alkyl group; R ⁸ represents a hydrogen atom, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl Represents a group,

R ⁹ is an alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl group, or an aryl, acidic functional group, cycloalkyl, heteroaryl, heterocycloalkyl, —S (O) _m R ³ , —C ( = O) -NY ⁴ Y ⁵ or -NY represent ⁴ Y ⁵ alkyl group substituted by a group, R ¹⁰ is a hydrogen atom, R ³ or alkoxy, cycloalkyl, hydroxy, mercapto, alkylthio or -NY ⁴ Y ⁵ group R ¹¹ and R ¹³ each independently represent a hydrogen atom or an amino acid side chain, an acidic functional group, R ³ , -C (= O
) -R ³ or ^{-C (= O) -NY 4 Y} 5 consists group or an acidic functional group or ^{R 3,,, -NY 4 Y} 5, -NH-C (
= O) -R ³ , -C (= O) -R ⁴ -NH ₂ , -C (= O) -Ar ¹ -NH ₂ , -C (= O) -R ⁴ -COOH, or -C (= O) is selected from an alkyl group substituted by -NY ⁴ Y ⁵ group, or R ¹⁰ and R ¹¹ or R ¹⁰ and R ¹² together with the atoms to which they are attached, 3-or 6-membered heterocyclo Forming an alkyl ring; R ¹² represents a C _1-6 alkylene group optionally substituted with R ³ ; R ¹⁴ is alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Represents a heterocycloalkyl or a heterocycloalkylalkyl group,

A ¹ is optionally one or more of alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, imino, oxo, thiooxo, or —ZR ⁶ , —NY ¹ Y ² , —CO
OR ⁶ or -C (= O) -NY ¹ represents a linear C _1-3 alkylene bond which may be substituted by a group selected from an alkyl group substituted with Y ² , wherein Ar ¹ is arylene, or Represents a heteroaryldiyl group, L ¹ represents (i) a direct bond; (ii) an alkenylene, alkylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene or arylene bond, each of these groups According to (a) acidic functional group, cyano,
^{_{Oxo, -S (O) m R 9}} , R 3, -C (= O) -R 3, -C (= O) -OR 3, -N (R 8) -C (= O) -R 9, -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ or-[C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p- C (= O) -NY ⁴ Y ⁵ substituted or (b) acidic functional group or S (O) _m R ⁹ , -C (= O) -NY ⁴ Y ⁵ or -NY ⁴ Y ⁵
(Iii)-[C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -bond; (iv) -Z ² -R ¹² - binding; (v) -C (= O ) -CH 2 -C (= O) - bond; (vi) -R ¹² -
Z ² -R ¹² - ^{bond; (vii) -C (R 4} ) (R 13) - [C (= O) -N (R 10) -C (R 5) (R 11)] p - linkage; ( viii)-
L ⁵ -L ⁶ -L ⁷ -bond; where L ² is -NR ⁵ -C (= Z) -NR ^5- , -C (= Z) -NR ^5- , -C (= O)-,- C (= Z) -O-,-
^{NR 5 -C (= Z) -} , - Z -, - S (O) m -, - NR 5 -, - SO 2 -NR 5 -, - NR 5 -SO 2 -, - NR 5 -C (= O) -O-, -OC (= O)-
, Or -OC (= O) -NR ⁵ -bond,

L ³ is heteroaryldiyl, -NR ⁵ -C (= Z) -NR ^5- , -C (= Z) -NR ^5- , -C (= Z) -O-, -NR ⁵ -C (= Z
) -, - Z -, - S (O) m -, - NR 5 -, - SO 2 -NR 5 -, - NR 5 -SO 2 -, - NR 5 -C (= O) -O -, - OC (= O)-or-
OC (= O) -NR ⁵ - represents a bond, L ⁴ is a direct bond, represents an alkylene, alkenylene or alkynylene chain, L ⁵ and L ⁷ represents a direct bond or an alkylene chain each independently, L ⁶ is cycloalkylene Y ¹ and Y ² each independently represent a hydrogen atom, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group —NY ¹ Y ² represents Y ⁴ and Y ⁵ are each independently a hydrogen atom, alkenyl, alkyl, alkynyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl, or alkoxy, aryl, cyano , Cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, -NY ¹ Y ² , an alkyl substituted with one or more —COOR ⁸ or —C (= O) —NY ¹ Y ² groups; or the group —NY ⁴ Y ⁵ is a 5- or 7-membered cyclic amine. Wherein the cyclic amine is selected from (i) optionally alkoxy, carboxamide, carboxy, hydroxy, oxo (or a 5-, 6- or 7-membered cyclic acetal derivative thereof), R ¹⁰ It may be substituted at the species or more substituents, (ii) or even O, S, may contain heteroatoms selected from SO _2, or NY ^6, also (iii) incidental aryl, heteroaryl Fused with an aryl, heterocycloalkyl or cycloalkyl ring to form a bicyclic or tricyclic ring system;

Y ⁶ represents a hydrogen atom, alkyl, aryl, arylalkyl, —C (= O) —R ¹⁴ , —C (= O) —OR ¹⁴ or —SO ₂ R ¹⁴ , and Z represents an oxygen atom or sulfur Z ¹ is C (R ⁷ ) (R ^7a ), C (、 O) or CH (OH), and Z ² is O, S (O) _n , NR ⁵ , SONR ⁵ , C (= O) is -NR ⁵ or C (= O), Z ³ is a direct bond, C (= O), OC (= O), NR 5 C (= O), or a SO _2, m is an integer 1 Or 2; n is zero or an integer 1 or 2; p is zero or an integer 1-4
And Y is carboxy (or an acidic bioisostere), and its corresponding N-oxide, and its prodrugs, and pharmaceutically acceptable such compounds and its N-oxides and its prodrugs Salts and solvates (eg, hydrates) except those compounds in which an oxygen, nitrogen or sulfur atom is directly bonded to a carbon-carbon multiple bond of an alkenylene, alkynylene or cycloalkenylene residue.

As used herein, the term “compound of the present invention” and equivalents thereof include the compounds represented by the general formula (I) as described above, and such expressions include prodrugs, Protected derivatives of compounds of general formula (I), containing one or more acidic functional groups and / or amino acid side chains, content acceptable pharmaceutically acceptable salts and solvates, e.g. water Including Japanese. Similarly, intermediates, whether claimed or not, include salts and solvates of the compounds that are contextually acceptable. For the sake of clarity, specific examples that are contextually acceptable are often provided in this text, but these examples are merely illustrative and do not exclude other examples that are contextually acceptable. The following terms, used above and throughout the description of the present invention, should be understood to have the following meanings, unless otherwise indicated. "Patient" includes humans and other mammals. By "acid bioisosteres" is meant a group of chemical and physical similarities that result in biological properties that are broadly similar to carboxy (Lipinski, Anpin).
nual Reports in Medicinal Chemistry, 1986, 21: 283: "Bioisosterism In Dru
g Design "; Yun, Hwahak Sekye, 1993, 33: 576-579:" Application Of Bioisost
erism To New Drug Design "; Zhao, Huaxue Tongbao, 1995, pp.34-38:" Bioiso
steric Replacement And Development Of Lead Compounds In Drug Design "; Gr
aham, Theochem, 1995, 343: 105-109: "Theoretical Studies Applied To Drug
Design: ab initio Electronic Distributions In Bioisosteres ")
. Examples of suitable acidic isosteres, -C (= O) -NHOH, -C (= O) -CH 2 OH, -C (= O) -CH 2 SH, -C (= O) -NHC
N, sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2
, 4-oxadiazolidinyl or heterocyclic phenols, such as 3-hydroxyisoxazolyl and 3-hydroxy-1-methylpyrazolyl.

An “acidic functional group” is a group that contains an acidic hydrogen atom within the group. The "protected derivative" is one in which the acidic hydrogen atom has been replaced with a suitable protecting group. For such suitable protecting groups, see TW Greene & PGM Wuts: "Protective Groups in Organic
Chemistry ", John Wiley & Sons, 1991. Examples of acidic functional groups include carboxyl (and acidic isotopes), hydroxy, mercapto, and imidazole groups. Examples of protected derivatives include carboxy groups (Ie, -COOR ¹⁴ ), an ether of a hydroxy group (ie, -OR ¹⁴ ), a thioether of a mercapto group (ie, -SR ¹⁴ ), and N-benzyl derivatives of imidazole. , H-CO- or alkyl-CO-, wherein the alkyl group is as described herein. “Acylamino” is an acyl-NH— group, where acyl is as defined herein. "Alkenyl" is an aliphatic hydrocarbon group containing a carbon-carbon double bond, which may be a straight or branched group containing about 2 to 15 carbon atoms in the chain. Preferred alkenyl groups are those containing 2 to about 12 carbon atoms in the chain, and more preferably those containing about 2 to about 4 carbon atoms in the chain. As used herein and throughout this specification, a "branched chain" means that a lower alkyl group such as methyl, ethyl or propyl is attached to a straight chain, which here refers to a linear alkenyl chain. means. "Lower alkenyl" means about 2 to about 4 carbon atoms in the chain, which may be straight or branched. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbutenyl-2, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.

“Alkenylene” means a divalent aliphatic group derived from a straight-chain or branched-chain alkenyl group, wherein the alkenyl group is as defined above. Examples of alkenylene groups include vinylene and / or propylene. "Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-
Includes butoxy and heptoxy. "Alkoxycarbonyl" means an alkyl-O-CO- group in which the alkyl group is as previously described. Examples of the alkoxycarbonyl groups include methoxy- and ethoxycarbonyl. `` Alkyl, '' unless otherwise specified, means an aliphatic hydrocarbon group, which may be a straight or branched chain group containing about 1 to about 15 carbon atoms in the chain, It may be optionally substituted by an alkoxy group or one or more halogen atoms. Particularly preferred alkyl groups are those having 1 to about 6 carbon atoms. A `` lower alkyl, '' as a group or part of a lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group, unless otherwise specified, is a straight chain containing from about 1 to about 4 carbon atoms in the chain. It means an aliphatic hydrocarbon group which may be either a chain or a branched chain. Examples of these alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, s
-Butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl.

“Alkylene” means a divalent aliphatic group derived from a straight or branched chain C _1-6 alkyl group, wherein the alkyl group is as defined above. Examples of alkylene groups are
Including methylene, ethylene and trimethylene. “Alkylenedioxy” means the group —O-alkyl-O—, wherein the alkyl group is as defined above. Examples of alkylenedioxy groups include methylenedioxy or ethylenedioxy. "Alkylsulfinyl" means an alkyl-SO- group in which the alkyl group is as previously described. Preferred alkylsulfinyl groups are those in which the alkyl group is C _1-4 alkyl. The term "alkylsulfonyl" means an alkyl -SO ₂ -, group in which the alkyl group are those mentioned above. Preferred alkylsulfonyl groups are those in which the alkyl group is C _1-4 alkyl. “Alkylsulfonylcarbamoyl” means an alkyl-SO ₂ —NH—C (= O) — group in which the alkyl group is as described above. Preferred alkylsulfonylcarbamoyl groups are such that the alkyl group is C _1-4 alkyl.

“Alkylthio” means an alkyl-S— group in which the alkyl group is as previously described. Examples of the alkylthio group include methylthio, ethylthio, isopropylthio and heptylthio. "Alkynyl" is an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups are those containing about 2 to about 12, more preferably about 2 to about 4 carbon atoms in the chain. Examples of alkynyl groups are ethynyl, propynyl, n-butynyl, i
-Butynyl, 3-methyl-2-butynyl, and n-pentynyl. “Alkynylene” is a divalent aliphatic group derived from a C _2-6 alkynyl group.
Examples of alkynylene groups are ethynylene and propynylene groups. "Amino acid side chain" means a substituent found on a carbon atom between an amino group and a carboxy group in an α-amino acid. For examples of "protected derivatives" of amino acid side chains, see TW Greene & PGM Wuts: "Protective Groups in Organic Chemis
try ", John Wiley & Sons, 1991.

“Aroyl” means an aryl-CO— group in which the aryl group is as defined herein. Examples of aroyl groups include benzoyl and 1- and 2-naphthoyl. "Aroylamino" is an aroyl-NH- group wherein the aroyl group is as previously defined. `` Aryl '' as a group or part of a group refers to (i) an optionally substituted monocyclic or polycyclic aromatic carbocyclic moiety having from about 6 to about 14 carbon atoms, such as a phenyl or naphthyl group Or (ii) an aryl and cycloalkyl or cycloalkenyl group fused together to form a cyclic structure, for example a tetrahydronaphthyl, indenyl or indanyl ring, optionally substituted, partially saturated polycyclic Represents an aromatic carbocyclic moiety. An aryl group may be substituted with one or more aryl group substituents, which may be the same or different, wherein “aryl group substituent” includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, Alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy, cyano, halo, heteroaroyl, hetero Aryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, Y ¹ Y ² N-,
^{Y 1 Y 2 NCO-, Y 1} Y 2 NSO 2 -, Y 1 Y 2 NC 2-6 alkylene -Z ⁴ - (where Z ⁴ is O, NR ⁶ or S (O) _n),
Encompasses Y ¹ N-or optionally aryl, heteroaryl, hydroxy, or Y ¹ Y ² N-substituted alkyl group - alkyl ^{C (= O) -Y 1 N-} , alkyl SO _2.

“Arylalkenyl” refers to an aryl-alkenyl-group in which the aryl and alkenyl groups are as previously described. Preferred arylalkenyl groups contain a lower alkenyl moiety. Examples of the arylalkenyl groups include styryl and phenylallyl groups. "Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl groups are as described above. Preferred arylalkyl groups contain a C _1-4 alkyl moiety. Examples of the arylalkyl groups include benzyl, 2-phenethyl and naphthylenemethyl groups. “Arylalkyloxy” represents an arylalkyl-O— group in which the arylalkyl group is as previously described. Examples of arylalkyloxy groups include
Contains benzyloxy and 1- or 2-naphthalenemethoxy groups. "Arylalkyloxycarbonyl" represents an arylalkyl-O-CO- group,
Here, the arylalkyl group is as described above. An example of an arylalkyloxycarbonyl group is benzyloxycarbonyl. "Arylalkylthio" refers to an arylalkyl-S- group wherein the arylalkyl group is as previously described. An example of an arylalkylthio group is benzylthio.

“Arylalkynyl” refers to an aryl-alkynyl-group in which the aryl and alkynyl are as previously described. Examples of the arylalkynyl group include phenylethynyl and 3-phenyl-2-butynyl. "Arylene" means an optionally substituted divalent group derived from an aryl group. Examples of arylene groups represent optionally substituted phenylene, naphthylene and indanylene. If Ar ¹ is arylene, this can particularly represent an optionally substituted phenylene. Suitable substituents include one or more "aryl group substituents" as defined above, especially halogen atoms, methyl or methoxy. "Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Examples of aryloxy groups include phenoxy and naphthoxy optionally substituted. "Aryloxycarbonyl" means an aryl-OC (= O)-group in which the aryl group is as previously described. Examples of the aryloxycarbonyl group include phenoxycarbonyl and naphthoxycarbonyl.

“Arylsulfinyl” means an aryl-SO— group in which the aryl group is as previously described. The term "arylsulfonyl", aryl -SO ₂ - group in which the aryl groups are those previously described. "Aryl sulfonyl carbamoyl" aryl _{-SO 2 -NH-C (= O} ) - group in which the aryl groups are those previously described. "Arylthio" means an aryl-S- group in which the aryl group is as previously described. Examples of the arylthio group include phenylthio and naphthylthio. "Azaheteroaryl" means an aromatic carbocyclic moiety comprising about 5 to about 10 ring members, wherein one of the ring members is a nitrogen atom and the other ring members are The members are selected from carbon, oxygen, sulfur or nitrogen atoms. Examples of azaheteroaryl groups are pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl,
Includes imidazolyl and benzimidazolyl groups. "Azaheteroaryldiyl" means an optionally substituted divalent group derived from a heteroaryl group.

“Cyclic amine” means a 3- to 8-membered monocyclic cycloalkyl ring system wherein one of the ring carbon atoms is replaced by a nitrogen atom and (i) optionally O 2 , S or NY ^3, wherein Y ³ is a hydrogen atom, an alkyl, an arylalkyl, and an aryl group, and (ii) an optional aryl or heteroatom. It can be fused with an aryl to form a bicyclic ring system. Examples of cyclic amines include pyrrolidine, piperidine, morpholine, piperazine, indoline and pyrindoline. "Cycloalkenyl" means a non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Examples of monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. "Cycloalkenylalkyl" means a cycloalkenyl-alkyl- group in which the cycloalkenyl and the alkyl moiety are as previously described. Examples of the cycloalkenylalkyl group include cyclopentenylmethyl, cyclohexenylmethyl or cycloheptenylmethyl.

“Cycloalkenylene” refers to the removal of a hydrogen atom from an unsaturated monocyclic hydrocarbon having about 3 to about 10 carbon atoms from each of two different carbon atoms in the ring.
Derived divalent groups are meant. Examples of the cycloalkenylene group include cyclopentechylene or cyclohexenylene. "Cycloalkyl" means about 3 to about 10 carbon atoms, optionally substituted with oxo.
Means a saturated monocyclic or bicyclic ring system. Examples of monocyclic cycloalkyl rings include C _3-8 cycloalkyl rings, such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl. “Cycloalkylalkenyl” means a cycloalkyl-alkenyl-group in which the cycloalkyl and alkenyl moieties are as described above. Examples of the monocyclic cycloalkylalkenyl group include cyclopentylvinylene and cyclohexylvinylene. “Cycloalkylalkyl” means a cycloalkyl-alkyl-group in which the cycloalkyl and alkyl moieties are as described above. Examples of the monocyclic cycloalkylalkyl group include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.

“Cycloalkylalkynyl” means a cycloalkyl-alkynyl-group in which the cycloalkyl and alkynyl moieties are as described above. Examples of monocyclic cycloalkylalkynyl groups include cyclopropylethynyl, cyclopentylethynyl and cyclohexylethynyl. "Cycloalkylene" refers to a divalent group derived from a saturated monocyclic hydrocarbon having about 3 to about 10 carbon atoms by removing a hydrogen atom from each of two different carbon atoms in the ring. Means Examples of the cycloalkylene group include cyclopentylene and cyclohexylene. "Halo" or "halogen" means fluoro, chloro, bromo or iodo. Preferred is fluoro or chloro. “Heteroaroyl” means a heteroaryl-C (= O) — group in which the heteroaryl group is as described herein. An example of this group is pyridylcarbonyl. "Heteroaroylamino" means a heteroaroyl-NH- group wherein the heteroaroyl moiety is as previously described.

“Heteroaryl” as a group or as part of a group refers to (i) from about 5 to about
An optionally substituted aromatic monocyclic or polycyclic organic moiety comprising 10 ring members, wherein one or more of the ring members has an element other than carbon, such as nitrogen, oxygen or Is sulfur (examples of such groups are benzimidazolyl, benzthiazolyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, optionally substituted with one or more aryl group substituents as defined above. , Oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3
2,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups); (ii) optionally substituted and partially saturated polycyclic heterocarbocyclic moieties wherein heteroaryl and cycloalkyl or cycloalkenyl groups are Represents such as fused together to form a cyclic structure (examples of such groups include pyrindanyl groups). Optional substituents include one or more “aryl group substituents” as defined above. Where R ¹ or L ¹ comprises an optionally substituted heteroaryl group, this may particularly represent an optionally substituted “azaheteroaryl” group. "Heteroarylalkenyl" means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl moieties are as previously described. Preferred heteroarylalkenyl groups contain a lower alkenyl moiety. Examples of the heteroarylalkenyl group include pyridylethenyl and pyridylallyl.

“Heteroarylalkyl” means a heteroaryl-alkyl-group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a C _1-4 allyl moiety. Examples of the heteroarylalkyl group include pyridylmethyl. "Heteroarylalkyloxy" means a heteroarylalkyl-O- group in which the heteroarylalkyl group is as previously described. Examples of heteroaryloxy groups include optionally substituted pyridylmethoxy. "Heteroarylalkynyl" means a heteroaryl-alkynyl-group in which the heteroaryl and alkynyl moieties are as previously described. Examples of the heteroarylalkynyl group include pyridylethynyl and 3-pyridyl-2-butynyl. "Heteroaryldiyl" means a divalent group derived from an aromatic mono- or polycyclic organic moiety having about 5 to about 10 ring members, wherein one or more The ring member is an element other than carbon, for example, nitrogen, oxygen or sulfur, and optionally
It is substituted with one or more of the above “aryl group substituents”. When Ar ¹ is an optionally substituted heteroaryldiyl group, this may in particular represent an optionally substituted “azaheteroaryldiyl” group.

“Heteroaryloxy” means a heteroaryl-O— group in which the heteroaryl group is as previously described. Examples of heteroaryloxy groups include optionally substituted pyridyloxy. "Heteroaryl sulfonyl carbamoyl" heteroaryl -SO ₂ -NH-C (=
O)-group, wherein said heteroaryl group is as defined above. "Heterocycloalkyl", (i) 1 or more O, S or contain a heteroatom selected from NY ^3, and may be substituted by oxo, optionally, about 3 to 7 ring members A cycloalkyl group comprising: (ii) an optionally substituted, partially saturated, polycyclic heterocarbocyclic moiety comprising an aryl (or heteroaryl ring)
And a heterocycloalkyl group are meant to be fused together to form a cyclic structure (examples of such groups include chromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl groups). "Heterocycloalkylalkyl" means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moiety is as previously described.

“Heterocycloalkylene” refers to about 5 to about 7 atoms containing one or more heteroatoms selected from O, S or NY ³ and optionally substituted by oxo. By removing a hydrogen atom from each of the two different carbon atoms of the ring from a saturated monocyclic hydrocarbon comprising, or if NY ³ represents NH, a hydrogen atom from one carbon atom of the ring. removed, and removing the hydrogen atom from the NH, or contain heteroatoms said ring into two NY ^3, and when NY ³ represents NH, by removal of a hydrogen from these two nitrogen atoms , Derived divalent groups. When L ¹ is a heterocycloalkylene group, this is especially a divalent group derived from pyrrolidine, especially
3,4-pyrrolidindiyl can be represented. A "prodrug" is defined by metabolic means in vivo (e.g., by hydrolysis).
, A compound of formula (I) and a compound that can be converted to its N-oxide. For example, an ester of a compound of formula (I) that contains a hydroxy group can be converted to its parent molecule by hydrolysis in vivo. Alternatively, an ester of a compound of formula (I) containing a carboxy group can be converted to its parent molecule by hydrolysis in vivo.

Suitable esters of compounds of the formula (I) containing a hydroxy group are, for example, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-β-hydroxynaphtho Ethates, gentisates, isethionates, di-p-toluoyl tartrate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate, cyclohexylsulphamate and quinates. Suitable esters of compounds of formula (I) containing a carboxy group are, for example, FJ Leinweber
, Drug Metab. Res. 1987, 18: 379. Suitable esters of the compounds of formula (I) containing both carboxy and hydroxy groups in the -L ¹ -Y moiety include lactones formed by loss of water between the carboxy and hydroxy groups. Examples of lactones include caprolactone and butyrolactone.

A particularly useful group of esters of the compounds of formula (I) containing a hydroxy group is Bu
ndgaard et al., J. Med. Chem. 1989, 32: 2503-2507, which can be prepared from an acid moiety selected from those described above, including substituted (aminomethyl) -benzoates, such as dialkylamino-methyl benzoates, where The two alkyl groups may be linked together and / or may be separated by an oxygen atom or by the interposition of an optionally substituted nitrogen atom, for example an alkylated nitrogen atom, more particularly (
Morpholino-methyl) -benzoate, for example 3- or 4- (morpholino-methyl)-
Includes benzoate and (4-alkylpiperazin-1-yl) -benzoates, such as 3- or 4- (4-alkylpiperazin-1-yl) -benzoate. When the compounds of the present invention contain a carboxy group or a sufficiently acidic bioisostere, base addition salts can be formed, which are a simpler more convenient form of use, and in fact,
Use in the salt form is essentially equivalent to its use in the free acid form. The base available for the preparation of a base addition salt is preferably a pharmaceutically acceptable salt when combined with the free acid, i.e., the pharmacological administration of the salt, the cation of which is harmless to the patient, resulting in the The beneficial inhibitory effects inherent to the free base include those which form salts which are not harmed by the side effects attributable to the cation. Pharmaceutically acceptable salts, including salts derived from alkali and alkaline earth metal salts, within the scope of the present invention include those derived from the following bases: sodium hydride, sodium hydroxide, water Potassium oxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methylglucamine, lysine,
Arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tri (hydroxymethyl) aminomethane, tetramethylammonium hydroxide and the like.

Some of the compounds of the present invention are basic, and such compounds are useful as the free base or a pharmaceutically acceptable acid addition salt thereof. Acid addition salts are a more advantageous form for use, and in fact use in the salt form is essentially equivalent to use as the free base form. The acid that can be used to prepare the acid addition salt is preferably a pharmaceutically acceptable salt, that is, when combined with the free base, its anion is harmless to the patient at the pharmacological dose of the salt, and And those that form salts that produce salts such that the beneficial inhibitory action inherent to the free base is not harmed by the side effects attributable to the anion. Pharmaceutically acceptable salts of the basic compounds are preferred, but the particular salt itself is used, for example, when the salt is prepared for purification and identification purposes only, or by ion exchange procedures to prepare a pharmaceutically acceptable salt. When using this as an intermediate in, all acid addition salts are useful as a source of the free base form, even if only it is desired as an intermediate. Pharmaceutically acceptable salts within the scope of the present invention include those derived from inorganic and organic acids and include hydrohalides such as hydrochlorides and bromates, sulfates, phosphates, nitrates, sulfamates, Acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-b-hydroxynaphthoate, gentisate, isethionate, di
-Includes p-toluoyl tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.

In addition to being useful as active compounds per se, salts of the compounds of the present invention may be prepared by techniques well known to those skilled in the art, for example, by taking advantage of the solubility difference between the salt and the parent compound. Useful for purifying the compound from by-products and / or starting materials. With reference to the above formula (I), those described below are particularly preferred groups. R ¹ can especially represent the group R ³ —Z ³ —, where Z ³ is as defined above, especially C (
A = O), also R ³ are as defined above, especially (i) optionally substituted aryl groups, for example substituents of the phenyl group [preferably optionally substituted by case, aryloxy, cyano, halo (E.g., chloro or fluoro), lower alkoxy (e.g.,
Methoxy), lower alkyl (eg, methyl), nitro and perfluorolower alkyl (eg, trifluoromethyl)], (ii) optionally substituted heteroaryl,
For example, isoquinolinyl, isoxazolyl, pyrazolopyrimidinyl, pyridyl, pyrimidinyl, quinolinyl, thiazolyl, and triazolyl, each of which optionally has one or more arylki substituents as described above [preferred optional substituents are alkyl-
C (= O)-, aryl, cyano, halo (e.g., chloro or fluoro), lower alkoxy (
(E.g., methoxy), lower alkyl (e.g., methyl), lower alkylsulfonyl, lower alkylthio, nitro and perfluoro-lower alkyl (e.g., trifluoromethyl)], or (iii) the aryl group is Sometimes
An optionally substituted arylalkyl substituted with one or preferably two arylki substituents (preferred optional substituents include halo, hydroxy and methoxy). R ¹ may particularly represent R ³ -C (= O)-, wherein R ³ is a substituted aryl group, wherein said aryl group is 2-chlorophenyl, 5-chloro-2-cyanophenyl , 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl , 2-nitrophenyl, 3-nitrophenyl, 2-phenoxyphenyl, or an optionally substituted heteroaryl, wherein the heteroaryl is quinolin-4-yl, isoquinolin-2-yl, 2,4- Pyridin-3-yl, 2,6-dimethyl-4
-Trifluoromethylpyridin-3-yl, 4-trifluoromethylpyridin-3-yl, 2
-Phenyl-4-methyl-1,2,3-triazol-5-yl, 3,5-dimethylisoxazole-
4-yl, 2,7-dimethylpyrazolo- [1,5-a] -pyrimidin-6-yl, 2-isopropyl-4-
Methylthiazol-5-yl, 4-trifluoromethylpyrimidin-5-yl, 4-hydroxybenzyl, 3-chloro-4-hydroxybenzyl, 3-fluoro-4-hydroxybenzyl, and 4-hydroxy-3-methoxybenzyl Is selected from

R ¹ also especially represents the group R ³ -L ³ -Ar ¹ -L ⁴ -Z ^3- , wherein Z ³ is as described above, especially C (= O), L ⁴ represents a linear or branched C _1-6 alkylene chain, more specifically a linear C _1-4 alkylene chain, such as methylene or ethylene, preferably methylene, and Ar ¹ is an optionally substituted phenylene For example, optionally substituted m- or p-phenylene, preferably optionally substituted p-phenylene, more preferably
Represents 3-substituted p-phenylene, wherein the substituent is in the o-position to the group: R ³ -L ^3- (
Preferably optional substituents include halo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl and C _1-4 alkylsulfonyl, especially chloro, methyl, methoxy , methylthio, including Finiru and methylsulfonyl methyl), or Ar ¹ is heteroaryl-diyl, optionally substituted, substituted azaheteroaryl diyl (e.g. optionally example, pyridinediyl which is optionally substituted, preferably p -Pyridinediyl), wherein the optional substituent is C _1-4
Alkyl and C _1-4 alkoxy, especially methyl and methoxy, more preferably pyridine-2,5-diyl, wherein R ³ -L ³ -is adjacent to the pyridyl nitrogen atom and its 4- or Substituted at the 6-position with methyl or methoxy, and L ³ is -NH-C
Represents a () O) -NH- bond, wherein R ³ is as defined above, especially an optionally substituted aryl group (e.g., optionally substituted phenyl) or an optionally substituted heteroaryl group (e.g., Optionally substituted pyridyl), and preferably 2-
Or 3-methyl (or methoxy) -phenyl, more preferably 2-methylphenyl or 3-methyl-2-pyridyl.

R ¹ also especially represents the group R ³ -L ³ -Ar ¹ -L ⁴ -Z ^3- , wherein Z ³ is as described above, especially C (= O), L ⁴ represents a linear or branched C _1-6 alkylene chain, more specifically a linear C _1-4 alkylene chain, for example methylene or ethylene, preferably methylene, wherein Ar ¹ is optionally substituted Represents an 8- to 10-membered bicyclic system of:

[0034]

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Where (i) the following rings:

[0036]

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Is an optionally substituted 5- to 6-membered heterocyclic ring, preferably a 5-membered heteroaryl ring, and (ii) the following rings:

[0038]

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Is an optionally substituted 5-6 membered heterocyclic ring or an optionally substituted benzene ring, preferably a benzene ring; (iii) each ring is optionally
Substituted with one or more `` aryl group substituents '' as defined above, and (iv) the two rings are joined together by a carbon-carbon or carbon-nitrogen bond to form the bicyclic system :

[0040]

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Is preferably optionally substituted benzoxazolyl or optionally substituted benzimidazolyl, wherein each of the rings (especially the following formula:

[0042]

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The ring represented by is optionally substituted with one or more “aryl group substituents” as defined above [eg, lower alkyl (eg, methyl), lower alkoxy (eg, methoxy), amino, halogen, hydroxy, lower alkylthio] , Lower alkylsulfinyl, lower alkylsulfonyl, nitro or trifluoromethyl], L ³ is NR ⁵ , especially NH, and R ³ is as defined above, especially optionally substituted aryl, such as is 2-substituted phenyl, [examples of particular aryl group substituents include lower alkyl (such as methyl), lower alkoxy (methoxy, etc.), halo (e.g., fluoro or chloro) and Y ¹ Y ² N- (e.g., Dimethylamino)], preferably 2-methylphenyl.

R ¹ also especially represents the group R ³ -L ³ -Ar ¹ -L ⁴ -Z ^3- , wherein Z ³ is as described above, especially C (= O), L ⁴ represents a linear or branched C _1-6 alkylene chain, more specifically a linear C _1-4 alkylene chain, such as methylene or ethylene, preferably methylene, and Ar ¹ is an optionally substituted phenylene E.g. optionally substituted m- or p-phenylene, preferably optionally substituted p-phenylene, more preferably
3-substituted p-phenylene wherein the substituent is in the o-position to the group: R ³ -L ^3- (
Preferably optional substituents include chloro, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl and C _1-4 alkylsulfonyl, especially chloro, methyl, methoxy , Methylthio, methylsulfinyl and methylsulfonyl), or Ar ¹ is an optionally substituted heteroaryldiyl, such as an optionally substituted azaheteroaryldiyl (e.g., optionally substituted pyridinediyl, preferably p- pyridine-diyl), wherein該随meaning of the substituents is C _1-4 alkyl, and C _1-4 alkoxy, in particular includes methyl and methoxy, more preferably pyridine-2,5-diyl, wherein R ³ -L ³ -is adjacent to the pyridyl nitrogen atom,
And substituted at the 4- or 6-position with methyl or methoxy, and L ³ is -C (
= O) represents an -NH- bond, R ³ is heterocycloalkyl, more particularly a bicyclic amine containing 9-10 atoms, especially represents indolinyl.

R ² can especially represent a hydrogen atom. R ² can also particularly represent a lower alkyl group (eg methyl). R ² can particularly represent a lower alkoxy group (eg, methoxy). A ¹ can especially represent an unsubstituted linear C _1-3 alkylene bond, ie methylene, ethylene and trimethylene, especially methylene or ethylene. Z ¹ can particularly represent C (R ⁷ ) (R ^7a ), wherein both R ⁷ and R ^7a are hydrogen atoms. L ¹ may represent an optionally substituted alkylene bond, especially an optionally substituted ethylene or propylene, preferably an optionally substituted ethylene. Substituents preferred optional lower alkyl, aryl, heteroaryl, -N (R ⁸⁾ -
C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ and-(C (= O ) -N (R ¹⁰ ) -C (R ⁵ )
(R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ or carboxy (or acidic isotope), -ZH, -ZR ³ , -C (= O
) Including -NY ⁴ Y ⁵ or -NY ⁴ Y ⁵ . In one preferred embodiment, L ¹ is:

[0046]

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Wherein R ⁵ is a hydrogen atom or a lower alkyl group (eg, methyl), and R ¹⁵ is a hydrogen atom or a lower alkyl group, or R ⁵ is a hydrogen atom, and R ¹⁵ is an aryl, ^{heteroaryl, -N (R 8) -C (} = O) -R 9, -N (R 8) -C (= O) -OR 9, -N (R 8) -SO 2 -R 9, -NY ⁴ Y ⁵ or-[C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ or carboxy (or acidic bioisostere) ^{, -ZH, -ZR 3, -C (} = O) -NY is ⁴ Y ⁵ or alkyl substituted by -NY ⁴ Y ^5, and more preferably, L ¹ is the following groups:

[0048]

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In particular, a group represented by the following formula:

[0050]

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Here, R ¹⁵ is a hydrogen atom, a lower alkyl group, an aryl, a heteroaryl, —N (R ⁸ ) —C (= O) —
R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ , or carboxy, -OH, -OR ³ or -C (= O) -NY ⁴ Y ⁵ is an alkyl group substituted with. In another preferred embodiment, L ¹ is:

[0052]

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Wherein R ⁵ is a hydrogen atom or a lower alkyl group (eg, methyl), and R ^15a is a lower alkyl group, or R ⁵ is a hydrogen atom, and R ^15a is an aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ ,-[C (= O) -N
(R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ , or carboxy (or acidic bioisostere),
-ZH, -ZR ^3, a ^{-C (= O) -NY 4 Y} 5 or alkyl substituted by -NY ⁴ Y ^5, L ¹ is more preferably the following groups:

[0054]

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In particular, a group represented by the formula:

[0056]

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Here, R ^15a is —N (R ⁸ ) —C (= O) —R ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ . L ¹ may also particularly represent an unsubstituted alkylene bond, especially vinylene. L ¹ is also especially a -Z ² -R ¹² bond, such as -O-CH _2- , -S (O) _n -CH _2- , -S (O) _n -CH ₂ -CH _2- , or especially- NH-CH ₂ -can be represented. L ¹ may also particularly represent a -L ⁵ -L ⁶ -L ⁷ -bond, wherein (i) both L ⁵ and L ⁷ are direct bonds, and L ⁶ is optionally substituted A heterocycloalkylene, such as pyrrolidinediyl, especially 3,4-pyrrolidindiyl, or a cycloalkylene, such as cyclopentyl; (ii) L ⁵ is an alkylene, such as methylene, L ⁶ is a cycloalkylene, such as cyclopentyl, and L ⁷ is a direct bond, or (
iii) L ⁵ is a direct bond, L ⁶ is cycloalkylene, for example cyclopentyl,
And L ⁷ is alkylene, such as methylene. Y can especially represent carboxy. It is to be understood that this invention includes all suitable combinations of the specific and preferred groups described herein. A particular group of compounds according to the invention are compounds of the following general formula (Ix):

[0058]

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[0059] Here, R ^{1 is, (i) R 3 -;} (ii) R 3 -L 2 -R 4 -; (iii) R 3 -L 3 -Ar 1 -L 4 -; or (iv) ^{R 3 -L 3 -Ar 1 - L} 2 -R 4 - represents, wherein R ³ is alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl , cycloalkylalkynyl, cycloalkenyl, represents cycloalkenyl alkyl, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, heteroarylalkynyl, heterocycloalkyl or heterocycloalkylalkyl group, L ² is -NR ⁵ -C (= Z ) -NR ^5- , -C (= Z) -NR ^5- , -C (= O)-, -C (= Z) -O-, -NR ⁵ -C (= Z)-, -Z-, -SO-,-
SO _2- , -NR ^5- , -SO ₂ -NR ^5- , -NR ⁵ -SO _2- , -NR ⁵ -C (= O) -O-, -OC (= O)-, or -OC ( = O) -N
R ⁵ represents a bond, L ³ is heteroaryldiyl, heterocycloalkylene, -NR ⁵ -C (= Z) -NR ^5- , -C (= Z) -N
R ^5- , -C (= O)-, -C (= Z) -O-, -NR ⁵ -C (= Z)-, -Z-, -SO-, -SO _2- , -NR ^{5- _{, -SO 2 -NR 5 -, -}} NR 5 -SO 2 -, - NR 5 - C (= O) -O -, - OC (= O) -, or -OC (= O) -NR ⁵ - bond L ⁴ represents a direct bond, an alkylene, alkenylene or alkynylene chain or -L ⁵ -NR ^5- , L ⁵ represents a direct bond or an alkylene chain, R ⁴ represents an alkylene chain, an alkenylene chain, or an alkynylene chain R ⁵ represents a hydrogen atom or a lower alkyl group,

Ar ¹ represents phenylene or heteroaryldiyl, and Z represents an oxygen or sulfur atom, provided that the oxygen, nitrogen or sulfur atom is a carbon atom of an alkenylene or alkynylene residue.
R ² represents hydrogen, halogen, lower alkyl or lower alkoxy, except for compounds directly attached to a carbon multiple bond, and A ¹ is optionally one or more alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, imino, oxo, thioxo, or ^{-ZR 6,, -NY 1 Y 2} , -CO
OR ⁶ or -C (= O) -NY ¹ Y ² (where R ⁶ is hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl or heteroarylalkyl, and Y ¹ and Y ² are each independently a hydrogen atom, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl, or the group: —NY ¹ Y ² can form a heterocycloalkyl group) Represents a linear C _1-3 alkylene chain, which may be substituted by a group selected from an alkyl group substituted with: Z ¹ is C (R ⁷ ) (R ^7a ) or C (= O) (Where R ⁷ and R ^7a each independently represent a hydrogen atom or a lower alkyl group),

L ¹ is (i) a direct bond; (ii) an alkenylene, alkylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene or arylene bond, each of these groups optionally being (a) Group (or corresponding protected derivative), R ³ , -C (= O) -R ³ , -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -S
O ₂ -R ⁹ ,-[C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -substituted by -NY ⁴ Y ⁵ or -NY ⁴ Y ⁵ it is, or (b) an acidic functional group (or corresponding protected derivative), or -C (= O) by alkyl substituted by -NY ⁴ Y ⁵ or -NY ⁴ Y ⁵ may be substituted; ( iii)-[C
(= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -bond; (iv) -Z ² -R ¹² -bond; (v) -C (= O) -CH _2- C (= O)-
A bond; (vi) -R ¹² -Z ² -R ¹² -bond; (vii) -C (R ⁴ ) (R ¹³ )-[C (= O) -N (R ¹⁰ )-C (R ⁵ ) ( R ¹¹ )] represents a _p -bond, wherein R ⁸ represents a hydrogen atom, an alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl group R ⁹ is an alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl group, or an aryl, acidic functional group (or corresponding protected derivative), cycloalkyl, heteroaryl, heterocycloalkyl, -ZH, -ZR ³ , -C (= O) -NY ⁴ Y ⁵
Or represents an alkyl group substituted by a -NY ⁴ Y ⁵ group,

R ¹⁰ is a hydrogen atom, R ³ , or alkoxy, cycloalkyl, hydroxy, mercapto,
Represents an alkyl group substituted by alkylthio or -NY ⁴ Y ⁵ group, R ¹¹ and R ¹³ are each independently a hydrogen atom or an amino acid side chains and corresponding protected derivatives, protected acidic functional group (or corresponding A group consisting of R ³ , -C (= O) -R ³ , or -C (= O) -NY ⁴ Y ⁵ , or an acidic functional group (or a corresponding protected derivative).
) Or R ³ , -NY ⁴ Y ⁵ , -NH-C (= O) -R ³ , -C (= O) -R ⁴ -NH ₂ , -C (= O) -Ar ¹ -NH ₂ ,- C (= O) -R ⁴ -CO
OH or -C (= O) is selected from -NY ⁴ Y ⁵ alkyl group substituted by a group, or R ¹⁰ and R ¹¹ or R ¹⁰ and R ¹² together with the atoms to which they are bonded, 3- Form a 6-membered heterocycloalkyl ring, R ¹² represents a C _1-6 alkylene group optionally substituted with R ³ , Y ⁴ and Y ⁵ each independently represent a hydrogen atom, an alkenyl, an alkyl, Alkynyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl, or alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, -NY ¹ Y ² , or one or more -COOR Alkyl substituted with a ⁷ or -C (= O) -NY ¹ Y ² group; or the group -NY ⁴ Y ⁵ can form a 5- or 7-membered cyclic amine, wherein the cyclic amine is (i) In some cases, alkoxy, carboxa De, carboxy, hydroxy, oxo (or a 5-, 6- or 7-membered, the cyclic acetal derivative thereof), may be substituted with one or more substituents selected from R ^10, also (ii) Further, O, S, SO ₂ or NY ⁶ [where Y ⁶ is a hydrogen atom, alkyl, aryl, arylalkyl, -C (= O) -R ¹⁴ , -C () O) -OR ¹⁴ or -SO ₂ Represents R ¹⁴ , wherein R ¹⁴ is alkyl, aryl,
Arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl], and (iii) ancillary aryl, heteroaryl, heterocycloalkyl Or fused with a cycloalkyl ring to form a bicyclic or tricyclic ring system,

Z ² is O, S (O) _n , NR ⁵ , SONR ⁵ , C (= O) -NR ⁵ or C (= O), and Z ³ is a direct bond, C (= O), OC (= O), a NR ⁵ C (= O), or SO _2, p is zero or an integer from 1 to 4, and Y is carboxy (or an acid bioisosteric). The present invention also relates to these corresponding N
-Oxides, and prodrugs thereof, and also pharmaceutically acceptable salts and solvates (eg, hydrates) of such compounds and N-oxides thereof and prodrugs thereof. Another particular group of compounds according to the invention are those represented by the following general formula (Ia):

[0064]

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Wherein R ² , R ³ , A ¹ , Ar ¹ , L ¹ , L ⁴ , Y and Z ¹ are as defined above, and this group of compounds comprises the corresponding N-oxide and its prodrug And said compound and its N-
Also included are pharmaceutically acceptable salts and solvates (eg, hydrates) of the oxides and prodrugs. Preference is given to compounds of the general formula (Ia) in which R ³ is an optionally substituted aryl group, in particular an optionally substituted phenyl group, for example a 2-substituted phenyl group, especially a 2-methylphenyl group. R ³ is an optionally substituted heteroaryl group, especially an optionally substituted pyridyl group, for example an optionally substituted 2-pyridyl group, especially a 3-methyl-2-pyridyl group, of the general formula (Ia) Compounds are also preferred. Ar ¹ is optionally substituted phenylene, especially optionally substituted m- or p
-Phenylene, more particularly optionally substituted p-phenylene, of the general formula (
Compounds of Ia) are preferred. Ar ¹ is 3-substituted p-phenylene, wherein the substituent is R ^3-
Compounds of general formula (Ia) which are in the o-position to NH—C (= O) —NH— are particularly preferred. Preferred optional substituents are halo, C _1-4 -alkyl, C _1-4 -alkoxy, C _1-4 -alkylthio, C _1-4 -alkylsulfinyl and C _1-4 -alkylsulfonyl, especially chloro, methyl ,
Includes methoxy, methylthio, methylsulfinyl and methylsulfonyl.

Ar ¹ is an optionally substituted heteroaryldiyl, such as an optionally substituted pyridinediyl, especially p-pyridinediyl, more particularly pyridine-2,5-diyl, wherein the R ³ —NH A -C (= O) -NH- group is adjacent to the nitrogen atom of the pyridyl, and
Compounds of the general formula (Ia) which are substituted in the 4- and 6-position are also preferred. Preferred optional substituents are C _1-4 -alkyl and C _1-4 -alkoxy, especially methyl and methoxy. L ⁴ is preferably a linear or branched C _1-6 alkylene chain, more specifically a linear C _1-4 -alkylene chain, such as methylene or ethylene, particularly a compound of the general formula (Ia) representing methylene. . Compounds of the general formula (Ia) in which A ¹ represents methylene are preferred. Compounds of the general formula (Ia) in which A ¹ represents ethylene are also preferred. Compounds of the general formula (Ia) in which Z ¹ represents CH ₂ are preferred. Compounds of the general formula (Ia) in which R ² represents a hydrogen atom are preferred.

L ¹ is an optionally substituted alkylene linkage, especially optionally substituted ethylene or optionally substituted propylene, especially optionally lower alkyl, aryl, heteroaryl, —N (R ⁸ ) —C ( = O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ ,
-NY ⁴ Y ⁵ or-[C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ , or carboxy (
Or acidic ^{bioisosteric), - ZH, -ZR 3,} -C (= O) -NY 4 Y 5 or -NY ⁴ Y ⁵ represents ethylene substituted by an alkyl group substituted by the general formula (Ia )) Are preferred. In one preferred embodiment, L ¹ is:

[0068]

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Where R ⁵ is a hydrogen atom or a lower alkyl group (eg, methyl), and R ¹⁵ is a hydrogen atom or a lower alkyl group, or R ⁵ is a hydrogen atom, and R ¹⁵ is an aryl, ^{heteroaryl, -N (R 8) -C (} = O) -R 9, -N (R 8) -C (= O) -OR 9, -N (R 8) -SO 2 -R 9, -NY ⁴ Y ⁵ or-[C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ , or carboxy (or acidic biological isotope) ^{), - ZH, -ZR 3,} -C (= O) -NY is ⁴ Y ⁵ or alkyl substituted by -NY ⁴ Y ^5, and more preferably, L ¹ is the following groups:

[0070]

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In particular, a group represented by the following formula:

[0072]

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Here, R ¹⁵ is a hydrogen atom, a lower alkyl group, an aryl, a heteroaryl, —N (R ⁸ ) —C (= O) —
R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ , or carboxy, -OH, -OR ³ or -C (= O) -NY ⁴ Y ⁵ is an alkyl group substituted with. In another preferred embodiment, L ¹ is:

[0074]

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Where R ⁵ is a hydrogen atom or a lower alkyl group (eg, methyl), and R ^15a is a lower alkyl group, or R ⁵ is a hydrogen atom, and R ^15a is an aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ ,-[C (= O) -N
(R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ , or carboxy (or acidic bioisostere),
Or -ZH, -ZR ^3, a ^{-C (= O) -NY 4 Y} 5 or alkyl substituted by -NY ⁴ Y ^5, and more preferably, L ¹ is the following groups:

[0076]

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In particular, a group represented by the following formula:

[0078]

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Here, R ^15a is —N (R ⁸ ) —C (= O) —R ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ . Compounds of the general formula (Ia) in which Y represents a carboxy group are preferred. A preferred group of compounds according to the invention are compounds of general formula (Ia), wherein R ² is a hydrogen atom and R ³ is a phenyl group substituted in the 2-position [especially 2-methyl (or methoxy) Phenyl], A ¹ is methylene or ethylene, and Ar ¹ is an optionally substituted m-
Or p-phenylene (especially 3-chloro-p-phenylene, 3-methyl-p-phenylene, 3-methoxy-p-phenylene, 3-methylthio-p-phenylene, 3-methylsulfinyl-p-phenylene and 3- Methylsulfonyl-p-phenylene) or optionally substituted p-pyridinediyl (especially 4- or 6-methyl (or methoxy) -p-pyridine-2,5-
Diyl] and L ¹ is the following group:

[0080]

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In particular, groups of the general formula:

[0082]

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(Where R ¹⁵ is a hydrogen atom, a lower alkyl group, an aryl, a heteroaryl, —N (R ⁸ ) —C (= O)
-R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ , or carboxy (or an acidic biological isotope), -OH, -OR ³ or -C (= O) -NY ⁴ Y ⁵ is an alkyl group),
L ⁴ represents a straight or branched C _1-6 alkylene chain, in particular methylene, Y represents carboxy and Z ¹ represents CH ₂ . This group also includes the corresponding N-oxides and their prodrugs; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds and their N-oxides and prodrugs. I do. Another preferred group of compounds according to the invention are compounds of general formula (Ia),
Here, R ² is a hydrogen atom, R ³ is a phenyl group substituted at the 2-position [especially, 2-methyl (or methoxy) phenyl], A ¹ is methylene or ethylene, and Ar ¹ is M- or p-phenylene substituted by (particularly 3-chloro-p-phenylene, 3-methyl
-p-phenylene, 3-methoxy-p-phenylene, 3-methylthio-p-phenylene, 3-methylsulfinyl-p-phenylene and 3-methylsulfonyl-p-phenylene) or optionally substituted p-pyridinediyl [ In particular, 4- or 6-methyl (or methoxy) -p-pyridine-2,5-diyl], wherein L ¹ is the following group:

[0084]

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In particular, groups of the general formula:

[0086]

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(Where R ^15a is —N (R ⁸ ) —C (= O) —R ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ ), and L ⁴ is a linear or branched C _1-6 alkylene chain, especially a methylene, Y represents a carboxy, Z ¹ represents CH _2. Compounds of this group represented by general formula (Ia) include the corresponding N-oxides and prodrugs thereof; and pharmaceutically acceptable salts and solvates of the compound and its N-oxides and prodrugs (e.g., Hydrate). Another particular group of compounds according to the invention is that of the following general formula (Ib):

[0088]

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Where R ² , R ³ , A ¹ , L ² , Y and Z ¹ are as defined above, X is NR ⁵ or O, Z ⁴ is a direct bond, NR ⁵ , O or S ( O) _n (where R ⁵ and n are as defined above), and R is a hydrogen atom or an aryl substituent. Compounds of this group also include the corresponding N-oxides and prodrugs thereof; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds and N-oxides and prodrugs thereof. Include. Preference is given to compounds of the general formula (Ib) in which R ³ is optionally substituted aryl, in particular 2-substituted phenyl. Preferred optional substituents are lower alkyl (e.g., methyl), lower alkoxy (e.g., methoxy), halo (e.g., fluoro or chloro).
) And Y ¹ Y ² N- (eg, dimethylamino). R ³ especially represents o-tolyl. Compounds of the general formula (Ib) wherein Z ⁴ is NH are preferred. R is hydrogen, halo (e.g., chloro), lower alkyl group (e.g., methyl or ethyl)
Alternatively, a compound represented by the general formula (Ib) representing a lower alkoxy group (for example, methoxy) is preferable. Compounds of the general formula (Ib) in which L ⁴ represents a straight-chain or branched C _1-6 alkylene chain, in particular a straight-chain or branched C _1-4 alkylene chain, more particularly methylene, are preferred. A compound represented by the general formula (Ib) in which A ¹ represents methylene is preferable. A compound represented by the general formula (Ib) in which A ¹ represents ethylene is also preferable. The compound represented by the general formula (Ib) wherein Z ¹ represents CH ₂ is preferable. Compounds represented by the general formula (Ib) in which R ² represents a hydrogen atom are preferred.

L ¹ is an optionally substituted alkylene linkage, especially optionally substituted ethylene or optionally substituted propylene, especially optionally lower alkyl, aryl, heteroaryl, —N (R ⁸ ) —C ( = O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ or-[C (= O)- N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ , or carboxy (or acidic bioisostere), -ZH, -ZR ³ , -C ( = O) -NY represents ethylene substituted by an alkyl group substituted with ⁴ Y ⁵ or -NY ⁴ Y ^5, compound represented by the general formula (Ib) are preferred.
In one preferred embodiment, L ¹ is:

[0091]

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Where R ⁵ is a hydrogen atom or a lower alkyl group (eg, methyl) and R ¹⁵ is a hydrogen atom or a lower alkyl group, or R ⁵ is a hydrogen atom, and R ¹⁵ is an aryl, ^{heteroaryl, -N (R 8) -C (} = O) -R 9, -N (R 8) -C (= O) -OR 9, -N (R 8) -SO 2 -R 9, -NY ⁴ Y ⁵ or-[C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ , or carboxy (or acidic biological isotope) ), - ZH, -ZR ^3, a ^{-C (= O) -NY 4 Y} 5 or alkyl substituted by -NY ⁴ Y ^5. More preferably, L ¹ is the following group:

[0093]

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In particular, a group represented by the following formula:

[0095]

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Here, R ¹⁵ is a hydrogen atom, a lower alkyl group, an aryl, a heteroaryl, —N (R ⁸ ) —C (= O) —
R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ , or carboxy, -OH, -OR ³ or -C (= O) -NY ⁴ Y ⁵ is an alkyl group substituted with. In another preferred embodiment, L ¹ is:

[0097]

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Wherein R ⁵ is a hydrogen atom or a lower alkyl group (eg, methyl), and R ^15a is a lower alkyl group, or R ⁵ is a hydrogen atom, and R ^15a is an aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ Or-[C (
= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ , or carboxy (or acidic bioisostere), -ZH, -ZR ³ , -C (= O) -NY ⁴ Y ⁵ or an alkyl group substituted with -NY ⁴ Y ⁵ . More preferably, L ¹ is the following group:

[0099]

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In particular, a group represented by the following formula:

[0101]

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Here, R ^15a is —N (R ⁸ ) —C (= O) —R ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ . Compounds of general formula (Ib) wherein Y is carboxy are preferred. The group represented by the following formula:

[0103]

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Preferably, when the 6-position or X of the ring is NR ⁵ and R ⁵ is lower alkyl, the bond is preferably at the 5- or 6-position of the ring. A preferred group of compounds according to the invention are those of the general formula (Ib), wherein
R is a hydrogen atom, chloro, methyl, ethyl or methoxy; R ² is a hydrogen atom;
R ³ is optionally substituted aryl (especially o-tolyl), A ¹ is methylene or ethylene, and L ¹ is the following group:

[0105]

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In particular, groups of the following formula:

[0107]

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(Where R ¹⁵ is a hydrogen atom, a lower alkyl group, an aryl, a heteroaryl, —N (R ⁸ )
-C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ , or carboxy (
Or acidic ^{bioisosteric), - OH, -ZR 3,} -C (= O) -NY is ⁴ Y ⁵ or -NY ⁴ Y ^{5-substituted} alkyl group), L ⁴ is a straight or branched chain C _1-4 represents an alkylene chain, especially methylene, X
Is O, Y represents carboxy, Z ¹ represents CH ₂ , Z ⁴ is NH, and 6 of the ring
-Place the following groups:

[0109]

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Are bound. Compounds of this group also include the corresponding N-oxides and prodrugs thereof; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds and N-oxides and prodrugs thereof. Include. Another preferred group of compounds according to the invention are those of the general formula (Ib), wherein R is hydrogen, chloro, methyl, ethyl or methoxy, R ² is hydrogen, R ³ is an optionally substituted aryl (especially o-tolyl), A ¹ is methylene or ethylene, and L ¹ is the following group:

[0111]

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In particular, groups of the following formula:

[0113]

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Wherein R ^15a is —N (R ⁸ ) —C (= O) —R ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ and L ⁴ is linear or branched The chain C _1-4 represents an alkylene chain, especially methylene, X is O, Y represents carboxy, Z ¹ represents CH ₂ , Z ⁴ is NH, and at the 6-position of the ring: The group is attached:

[0115]

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Compounds of this group further include the corresponding N-oxides and prodrugs thereof; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds and N-oxides and prodrugs thereof. ). Another preferred group of compounds according to the present invention are those represented by the general formula (Ib), wherein R ² is a hydrogen atom, optionally substituted aryl R ³ (especially, o- tolyl) Wherein A ¹ is methylene or ethylene, and L ¹ is

[0117]

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In particular, groups of the formula:

[0119]

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Wherein R ¹⁵ is a hydrogen atom, a lower alkyl group, an aryl, a heteroaryl, —N (R ⁸ )
-C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ , or carboxy (
Or acidic bioisosteric), - OH, -OR ^3, a ^{-C (= O) -NY 4 Y} 5 or alkyl substituted by -NY ⁴ Y ^5), L ⁴ is a straight or branched chain C _1-4 represents an alkylene chain (particularly, methylene),
X is NR ⁵ (especially NH), Y represents carboxy, Z ¹ represents CH ₂ , Z ⁴ is NH, and the following group is bonded to the 5- or 6-position of the ring. ing:

[0121]

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Compounds of this group further include the corresponding N-oxides and prodrugs thereof; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds and N-oxides and prodrugs thereof. ). Another preferred group of compounds according to the present invention are those represented by the general formula (Ib), wherein R ² is a hydrogen atom, optionally substituted aryl R ³ (especially, o- tolyl) Wherein A ¹ is methylene or ethylene, and L ¹ is a group represented by the following formula:

[0123]

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In particular, groups of the formula:

[0125]

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Wherein R ^15a is —N (R ⁸ ) —C (= O) —R ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ , and L ⁴ is linear or branched The chain C _1-4 represents an alkylene chain (especially methylene), X is NR ⁵ (especially NH), Y
Represents carboxy, Z ¹ represents CH ₂ , Z ⁴ is NH, and the following groups are attached at the 5- or 6-position of the ring:

[0127]

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This group of compounds further includes the corresponding N-oxides and prodrugs thereof; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds and its N-oxides and prodrugs ). Another particular group of compounds according to the invention are compounds of the formula (Ic) below:

[0129]

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Wherein Ar ¹ , L ⁴ , A ¹ , R ² , L ¹ , Y and Z ¹ are as defined in any of the above related claims. Also, compounds in this group include the corresponding N-oxides and prodrugs thereof; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds and N-oxides and prodrugs thereof. Is also included. Preferred compounds of the formula (Ic) are those in which the phenylene is optionally substituted with Ar ¹ , especially the optionally substituted m- or p-phenylene, more particularly the optionally substituted Represents p-phenylene. Preferred compounds of the formula (Ic) are those in which Ar ¹ represents 3-substituted p-phenylene, wherein the substituent is a group of the following formula:

[0131]

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Is at the o-position with respect to Substituents preferred optional are halo, C _1-4 alkyl, C _{1 -4} - alkoxy, C _1-4 - alkylthio, C _1-4 - alkylsulphinyl and C _1-4 - alkyl sulfonyl, especially chloro, methyl, Includes methoxy, methylthio, methylsulfinyl and methylsulfonyl. Preferred compounds of the formula (Ic) are also compounds of the formula (Ic) in which Ar ¹ is optionally substituted heteroaryldiyl, for example optionally substituted pyridinediyl,
Particularly p-pyridinediyl, more particularly pyridine-2,5-diyl, a group of the formula:

[0133]

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Is adjacent to the nitrogen atom of the pyridyl group, and is substituted at the 4- or 6-position. Preferred optional substituents include C _1-4 alkyl and C _1-4 -alkoxy, especially methyl and methoxy. In formula (Ic), L ⁴ is a linear or branched C _1-6 -alkylene chain, in particular a linear or branched C _1-4 -alkylene chain, more particularly represented by formula (Ic), which is methylene Are preferred. Compounds of formula (Ic) wherein A ¹ is methylene are preferred. Compounds of formula (Ic) wherein A ¹ is ethylene are also preferred. Compounds of formula (Ic) wherein Z ¹ is CH ₂ are preferred. Compounds of formula (Ic) wherein R ² is a hydrogen atom are preferred. In formula (Ic), L ¹ is an optionally substituted alkylene bond, especially optionally substituted ethylene or optionally substituted propylene, especially optionally lower alkyl, aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ or-(C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p- C (= O) -NY ⁴ Y ⁵ , or carboxy (or acidic bioisostere), -ZH, -ZR ³ , -C (= O) -NY compound represents ethylene substituted by an alkyl group substituted with a ⁴ Y ⁵ or -NY ⁴ Y ⁵ are preferred. In one preferred embodiment, L ¹ is a group of the formula:

[0135]

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Here, R ⁵ is a hydrogen atom or a lower alkyl group (eg, methyl), and R ¹⁵ is a hydrogen atom or a lower alkyl group, or R ⁵ is a hydrogen atom, and R ¹⁵ is an aryl, ^{heteroaryl, -N (R 8) -C (} = O) -R 9, -N (R 8) -C (= O) -OR 9, -N (R 8) -SO 2 -R 9, -NY ⁴ Y ⁵ or - [C (= O) -N (R 10) - C (R 5) (R 11)] p -C (= O) -NY 4 Y 5 or carboxy (or an acid bioisosteric, ), - ZH, -ZR ^3, a ^{-C (= O) -NY 4 Y} 5 or alkyl substituted by -NY ⁴ Y ^5. More preferably, L ¹ is the following group:

[0137]

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In particular, groups of the formula:

[0139]

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Wherein R ¹⁵ is a hydrogen atom, a lower alkyl group, an aryl, a heteroaryl, —N (R ⁸ )
-C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ , or carboxy,
-OH, it is -OR ³ or -C (= O) alkyl group substituted by -NY ⁴ Y ^5. In another preferred embodiment, L ¹ is a group represented by the following formula:

[0141]

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Here, R ⁵ is a hydrogen atom or a lower alkyl group (eg, methyl), and R ^15a is a lower alkyl group (eg, methyl), or R ⁵ is a hydrogen atom, and R ^15a is aryl, ^{heteroaryl, -N (R 8) -C (} = O) -R 9, -N (R 8) -C (= O) -OR 9, -N (R 8) -SO 2 -R 9, -
NY ⁴ Y ⁵ or-[C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ , or carboxy (or acidic organisms) ^{body), - ZH, -ZR 3,} -C (= O) -NY 4 Y 5 or -NY an alkyl group substituted by ⁴ Y ^5, and more preferably L ¹ the following groups:

[0143]

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In particular, a group represented by the following formula:

[0145]

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Here, R ^15a is —N (R ⁸ ) —C (= O) —R ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ . In the formula (Ic), compounds wherein Y represents carboxy are preferred. A preferred group of compounds according to the invention are compounds of formula (Ic), wherein R ² is a hydrogen atom, A ¹ is methylene or ethylene, and Ar ¹ is an optionally substituted m- or p-phenylene (especially 3-chloro-p-phenylene, 3-methyl-p-phenylene, 3-methoxy-p-phenylene, 3-methylthio-p-phenylene, 3-methylsulfinyl-p-phenylene and 3-methyl Sulfonyl-p-phenylene) or optionally substituted p-pyridinediyl [especially 4- (or 6-) methyl (or methoxy) -p-pyridine-2,5-diyl], wherein L ¹ is Base:

[0147]

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In particular, groups of the formula:

[0149]

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(Where R ¹⁵ is a hydrogen atom, methyl, aryl, heteroaryl, —N (R ⁸ ) —C (= O) —R ⁹ , —N (R ⁸ ) —C (= O) — OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ , or an alkyl group substituted with carboxy, -OH, -OR ³ or -C (= O) -NY ⁴ Y ⁵ A), L ⁴ is a linear or branched C _1-4 alkylene chain (especially methylene), Y represents carboxy, and Z ¹ represents CH ₂ . Also, compounds in this group include the corresponding N-oxides and prodrugs thereof; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds and N-oxides and prodrugs thereof. Including. A further preferred group of compounds according to the invention are compounds of the formula (Ic), wherein R ² is a hydrogen atom, A ¹ is methylene or ethylene and Ar ¹ is an optionally substituted m- Or p-phenylene (especially 3-chloro-p-phenylene, 3-methyl-p-phenylene, 3-methoxy-p-phenylene, 3-methylthio-p-phenylene, 3-methylsulfinyl-p-phenylene and 3- Methylsulfonyl-p-phenylene) or optionally substituted p-pyridinediyl (especially 4- (or 6-) methyl (or methoxy) -p
-Pyridine-2,5-diyl] and L ¹ is the following group:

[0151]

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In particular, groups of the formula:

[0153]

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Wherein R ^15a is -N (R ⁸ ) -C (= O) -R ⁹ or -N (R ⁸ ) -SO ₂ -R ⁹ and L ⁴ is linear or branched Chain C _1-4 alkylene chain (especially methylene), Y represents carboxy and Z ¹ represents CH ₂ . Compounds of this group also include the corresponding N-oxides and prodrugs thereof; and pharmaceutically acceptable salts and solvates (hydrates) of the compounds and their N-oxides and prodrugs. Another specific group of compounds according to the present invention are those represented by the following general formula (Id):

[0155]

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Here, R ³ , A ¹ , R ² , L ¹ , Y and Z ¹ are as defined above, and this group corresponds to the corresponding N-
And pharmaceutically acceptable salts and solvates (hydrates) of the compounds and their N-oxides and prodrugs. In the formula (Id), preference is given to compounds of the formula (Id) in which R ³ represents an optionally substituted aryl, in particular an optionally substituted phenyl group. Preferred optional substituents are aryloxy, cyano, halo (e.g., chloro or fluoro), lower alkoxy (e.g., methoxy), lower alkyl (e.g., methyl), nitro and perfluoro lower alkyl (e.g., trifluoromethyl) including. R ³ is especially 2-chlorophenyl,
5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, Represents 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl and 2-phenoxyphenyl. In preferred compounds of the general formula (Id), R ³ represents optionally substituted heteroaryl, in particular isoquinolinyl, isoxazolyl, pyrazolopyrimidinyl, pyridyl, pyrimidinyl, quinolinyl, thiazolyl and triazolyl, each of which is optionally one or more. It is substituted with an arylki substituent. Preferred optional substituents are
Alkyl-C (= O)-, aryl, cyano, halo (e.g., chloro or fluoro), lower alkoxy (e.g., methoxy), lower alkyl (e.g., methyl), lower alkylsulfinyl, lower alkylthio, nitro and perfluoro lower Includes alkyl (eg, trifluoromethyl). R ³ is especially quinolin-4-yl, isoquinolin-2-yl, 2,4-
Pyridin-3-yl, 2,6-dimethyl-4-trifluoromethylpyridin-3-yl, 4-trifluoromethylpyridin-3-yl, 2-phenyl-4-methyl-1,2,3-triazol- Five-
Yl, 3,5-dimethylisoxazol-4-yl, 2,7-dimethylpyrazolo- [1,5-a] pyrimidin-6-yl, 2-isopropyl-4-methylthiazol-5-yl and 4 -Trifluoromethylpyrimidin-5-yl.

In a similarly preferred compound of general formula (Id), R ³ represents arylalkyl, wherein said aryl group optionally has one or more aryl group substituents, particularly where the optional substituents are halo, hydroxy and Methoxy). R ³ especially represents an optionally substituted benzyl group, especially 4-hydroxybenzyl, 3-chloro-4-hydroxybenzyl, 3-fluoro-4-hydroxybenzyl and 4-hydroxy-3-methoxybenzyl. In the general formula (Id), a compound in which A ¹ represents methylene is preferable. In the general formula (Id), a compound in which A ¹ represents ethylene is preferable. In the general formula (Id), a compound in which Z ¹ represents CH ₂ is preferable. In the general formula (Id), L ¹ is an optionally substituted alkylene bond, especially an optionally substituted ethylene or an optionally substituted propylene, especially an optionally substituted lower alkyl (e.g. methyl), aryl, hetero, Aryl, -N (R ⁸ )-
C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ or-(C (= O ) -N (R ¹⁰ ) -C (R ⁵ )
(R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ , or carboxy (or acidic bioisostere), -ZH, -ZR ³ , -C (=
O) -NY compound represents ethylene substituted by an alkyl group substituted with a ⁴ Y ⁵ or -NY ⁴ Y ⁵ are preferred. In one preferred embodiment, L ¹ is the following group:

[0158]

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Wherein R ⁵ is a hydrogen atom or a lower alkyl group (for example, methyl), and R ¹⁵ is a hydrogen atom or a lower alkyl group, or R ⁵ is a hydrogen atom and R ^{1 5} is aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ^9, -NY ⁴ Y ⁵ or - [C (= O) - N (R 10) -C (R 5) (R 11)] p -C (= O) -NY 4 Y 5 or carboxy,
(Or acidic bioisosteric), - ZH, -ZR ^3, a ^{-C (= O) -NY 4 Y} 5 or alkyl substituted by -NY ⁴ Y ^5. More preferably, L ¹ is the following group:

[0160]

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In particular, groups of the general formula:

[0162]

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Here, R ¹⁵ is a hydrogen atom, a lower alkyl group, an aryl, a heteroaryl, —N (R ⁸ ) —C (= O) —
R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ , or carboxy, -OH, -OR ³ or -C (= O) -NY ⁴ Y ⁵ is an alkyl group substituted with. In another preferred embodiment, L ¹ is a group represented by the following formula:

[0164]

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Here, R ⁵ is a hydrogen atom or a lower alkyl group (eg, methyl), and R ^15a is a lower alkyl group, or R ⁵ is a hydrogen atom, and R ^15a is an aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ Or-[C (
= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ , or carboxy (or acidic bioisostere), -ZH, -ZR ³ , -C (= O) -NY ⁴ Y ⁵ or an alkyl group substituted with -NY ⁴ Y ⁵ . Also, more preferably, L ¹ is the following group:

[0166]

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In particular, groups of the formula:

[0168]

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Here, R ^15a is —N (R ⁸ ) —C (= O) —R ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ . In the formula (Id), a compound in which Y represents carboxy is preferable. A preferred group of compounds according to the present invention are compounds of formula (Id), wherein R ² is hydrogen and R ³ is optionally substituted phenyl (especially 2-chlorophenyl, 5-chloro-2- Cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-
Difluorophenyl, 4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl and 2-
Phenoxyphenyl), optionally substituted heteroaryl (especially quinolin-4-yl, isoquinolin-2-yl, 2,4-pyridin-3-yl, 2,6-dimethyl-4-trifluoromethylpyridine-3- Yl, 4-trifluoromethylpyridin-3-yl, 2-phenyl-4-methyl-1,2,3-triazol-5-yl, 3,5-dimethylisoxazol-4-yl, 2,7- Dimethylpyrazolo- [1,5-a] pyrimidin-6-yl, 2-isopropyl-4-methylthiazol-5-yl and 4-trifluoromethylpyrimidin-5-yl) or optionally substituted benzyl (especially 4-hydroxybenzyl, 3-chloro-4-hydroxybenzyl,
Represents 3-fluoro-4-hydroxybenzyl and 4-hydroxy-3-methoxybenzyl), A ¹ is methylene or ethylene, and L ¹ is a group shown below:

[0170]

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In particular, groups of the formula:

[0172]

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Here, R ¹⁵ is a hydrogen atom, methyl, aryl, heteroaryl, —N (R ⁸ ) —C (= O) —R ⁹ , —N (R ⁸ ) —C (= O) —OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ , or carboxy, -OH, -OR ³ or-
C (= O) -NY ⁴ Y ⁵ is an alkyl group substituted with Y representing carboxy and Z ¹ representing CH ₂ . This group of compounds further includes the corresponding N-oxides and prodrugs thereof;
And pharmaceutically acceptable salts and solvates (eg, hydrates) of the compound and its N-oxides and prodrugs. A preferred group of compounds according to the present invention are compounds of formula (Id), wherein R ² is hydrogen and R ³ is optionally substituted phenyl (especially 2-chlorophenyl, 5-chloro-2- Cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-
Difluorophenyl, 4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl and 2-
Phenoxyphenyl), optionally substituted heteroaryl (especially quinolin-4-yl, isoquinolin-2-yl, 2,4-pyridin-3-yl, 2,6-dimethyl-4-trifluoromethylpyridine-3- Yl, 4-trifluoromethylpyridin-3-yl, 2-phenyl-4-methyl-1,2,3-triazol-5-yl, 3,5-dimethylisoxazol-4-yl, 2,7- Dimethylpyrazolo- [1,5-a] pyrimidin-6-yl, 2-isopropyl-4-methylthiazol-5-yl and 4-trifluoromethylpyrimidin-5-yl) or optionally substituted benzyl (especially 4-hydroxybenzyl, 3-chloro-4-hydroxybenzyl,
Represents 3-fluoro-4-hydroxybenzyl and 4-hydroxy-3-methoxybenzyl), A ¹ is methylene or ethylene, and L ¹ is a group shown below:

[0174]

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In particular, groups of the formula:

[0176]

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Where R ^15a is —N (R ⁸ ) —C (= O) —R ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ , Y represents carboxy, and Z ¹ is CH Represents ₂ . This group further includes the corresponding N-oxides and their prodrugs; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds and their N-oxides and prodrugs. Preference is given to compounds of the general formulas (Ia), (Ib), (Ic) and (Id), wherein R ¹⁵ represents hydrogen. R ¹⁵ represents lower alkyl (e.g., methyl, ethyl, propyl, butyl);
Compounds of a), (Ib), (Ic) and (Id) are also preferred. Formulas (Ia), (I), wherein R ¹⁵ represents aryl (e.g., optionally substituted phenyl).
Compounds b), (Ic) and (Id) are also preferred. R ¹⁵ is -N (R ⁸ ) -C (= O) -R ⁹ group, especially R ⁸ is hydrogen or lower alkyl (for example, methyl)
And R ⁹ is lower alkyl (e.g., methyl), aryl (e.g., optionally substituted phenyl), heteroaryl (e.g., pyridyl, isoxazolyl, triazolyl, pyrimidinyl, thiazolyl, or pyrazolopyrimidinyl, each of which may be substituted with one or more aryl group substituents optionally), alkoxy (e.g., -CH ₂ -O-CH ₂ - alkyl substituted by CH ₂ -O-CH _3), carboxy (e.g. Represents the above group, which is an alkyl substituted with -CH ₂ -CH ₂ -COOH and -CH ₂ -CH ₂ -CH ₂ -COOH) or an alkyl substituted with -NY ⁴ Y ⁵ , a general formula (Ia) , (Ib), (Ic) and (Id) are also preferred.

When R ¹⁵ is a —N (R ⁸ ) —C (= O) —OR ⁹ group, particularly where R ⁸ is hydrogen or lower alkyl (eg, methyl)
And R ⁹ is lower alkyl (e.g., ethyl) or aryl (e.g., benzyl)
Also preferred are compounds of the general formulas (Ia), (Ib), (Ic) and (Id), which represent the above groups substituted by R ¹⁵ is -N (R ⁸ ) -SO ₂ -R ⁹ , especially where R ⁸ is hydrogen or lower alkyl (e.g., methyl), and R ⁹ is lower alkyl (e.g., methyl), aryl (e.g., Substituted phenyl or optionally substituted naphthyl (especially dimethylaminonaphth-1
-Yl)), heteroaryl (e.g., optionally substituted pyridyl or optionally substituted imidazolyl), representing general formulas (Ia), (Ib), (Ic) and (I
Compounds of d) are also preferred. Wherein R ¹⁵ represents -NY ⁴ Y ⁵ , in particular Y ⁴ and Y ⁵ represent said group, wherein hydrogen is hydrogen, general formulas (Ia), (Ib),
And the compounds of (Id) are also preferred. R ¹⁵ is -NY ⁴ Y ⁵ , especially Y ⁴ is hydrogen, and Y ⁵ is lower alkyl (e.g., propyl) or alkyl substituted with aryl (e.g., -CH ₂ -Ph or -CH ₂ -CH Preference is also given to compounds of the general formulas (Ia), (Ib), (Ic) and (Id), representing this group being _2- Ph). R ¹⁵ is -NY ⁴ Y ⁵ , especially an alkyl in which Y ⁴ and Y ⁵ are substituted by aryl (for example, -C
H ₂ -Ph or -CH (CH ₃ ) -Ph), which represents the group represented by the general formulas (Ia), (Ib), (Ic) and (Id)
Are preferred.

Formula (Ia), wherein R ¹⁵ represents alkyl substituted with carboxy (or acidic bioisostere), especially lower alkyl substituted with carboxy (eg, carboxymethyl).
, (Ib), (Ic) and (Id) are also preferred. Also preferred are compounds of general formulas (Ia), (Ib), (Ic) and (Id), wherein R ¹⁵ represents alkyl substituted with -OH, especially lower alkyl substituted with -OH (e.g. hydroxymethyl). . Alkyl R ¹⁵ is substituted by -OR ^3, especially -OR ³ (e.g., methoxymethyl) represents lower alkyl substituted by the general formula (Ia), compounds of (Ib), (Ic) and (Id) Is also preferred. Lower alkyl wherein R ¹⁵ is substituted by -C (= O) -NY ⁴ Y ⁵ , especially -C (= O) -NY ⁴ Y ⁵ , for example the following groups:

[0180]

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Preference is also given to compounds of the general formulas (Ia), (Ib), (Ic) and (Id) Particularly preferred compounds of the general formulas (Ia), (Ib), (Ic) and (Id) are those in which R ¹⁵ is

[0182]

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[0183]

Embedded image

[0184]

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(Where R is hydrogen or an aryl group substituent), —CH ₃ , —CH ₂ CH ₃ , —CH ₂ CH ₂ CH ₂ CH ₃ , —
_{CH 2 CH 2 CH 2 CH 3} , -CH 2 -OH, -CH 2 -COOH or -CH ₂ -OMe. R ^15a is -N (R ⁸ ) -C (= O) -R ⁹ group, especially R ⁸ is hydrogen or lower alkyl (for example, methyl)
And R ⁹ is lower alkyl (e.g., methyl), aryl (e.g., optionally substituted phenyl), heteroaryl (e.g., pyridyl, isoxazolyl, triazolyl, pyrimidinyl, thiazolyl, or pyrazolopyrimidinyl, each of which may be substituted with one or more aryl group substituents optionally) substituted with an alkoxy alkyl _{(e.g., -CH 2 -O-CH 2 -CH} 2 -O- CH 3), substituted by carboxy alkyl (e.g., -CH ₂ -CH ₂ -COOH and _{-CH 2 -CH 2 -CH 2 - COOH} ) or -NY ⁴ Y alkyl substituted with ⁵ (e.g., aminomethyl and morpholin-1-ylmethyl ), The compounds of the general formulas (Ia), (Ib), (Ic) and (Id) are preferred. R ^15a is a -N (R ⁸ ) -C (= O) -R ⁹ group, wherein R ⁹ is 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2 , 6-Dichlorophenyl, 2,6-difluorophenyl, 4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-
Compounds of general formulas (Ia), (Ib), (Ic) and (Id), which are substituted phenyl groups selected from methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl or 2-phenoxyphenyl Is particularly preferred.

R ^15a is a —N (R ⁸ ) —C (= O) —R ⁹ group, wherein R ⁹ is quinolin-4-yl, isoquinolin-2
-Yl, 2,4-pyridin-3-yl, 2,6-dimethyl-4-trifluoromethylpyridin-3-yl, 4-trifluoromethylpyridin-3-yl, 2-phenyl-4-methyl-1 , 2,3-Triazol-5-yl, 3,5-dimethylisoxazol-4-yl, 2,7-dimethylpyrazolo- [1,
5-a] pyrimidin-6-yl, 2-isopropyl-4-methylthiazol-5-yl and 4-trifluoromethylpyrimidin-5-yl, optionally substituted heteroaryl, general formula Compounds of (Ia), (Ib), (Ic) and (Id) are also particularly preferred. Particular compounds of the present invention may be obtained by replacing one acyl carbon atom (C *) of a fragment (A1-A34) shown in Table 1 with one nitrogen atom of an aza-bicyclo fragment (B1-B6) shown in Table 2. (N *) and the carbon atom (C *) of the phenyl ring of one of the aza-bicyclo fragments (B1-B6) shown in Table 2 was replaced with the acidic fragment (C1-C59) shown in Table 3.
A compound formed by bonding to a carbon atom (C *), and the corresponding
N-oxides and prodrugs thereof; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds and N-oxides and prodrugs thereof.

[0187]

[Table 1]

[0188]

[0189]

[Table 2]

[0190]

[Table 3]

[0191]

[Table 4]

[0192]

[Table 5]

[0193]

[Table 6]

[0194]

[Table 7]

[0195]

[Table 8]

[0196]

[Table 9]

[0197]

[Table 10]

[0198]

[Table 11]

[0199]

[Table 12]

[0200]

[Table 13]

[0201]

[Table 14]

[0202]

[Table 15]

[0203]

[Table 16]

[0204]

[Table 17]

[0205]

[Table 18]

[0206]

[Table 19]

[0207]

[Table 20]

[0208]

[Table 21]

[0209]

[Table 22]

[0210]

[Table 23]

[0211]

[Table 24]

[0212]

[Table 25]

[0213]

[Table 26]

[0214]

[Table 27]

[0215]

[Table 28]

[0216]

[Table 29]

[0219]

[Table 30]

[0218]

[Table 31]

[0219]

[Table 32]

[0220]

[Table 33]

[0221]

[Table 34]

[0222]

[Table 35]

[0223]

[Table 36]

[0224]

[Table 37]

[0225]

[Table 38]

[0226]

[Table 39]

[0227]

[Table 40]

[0228]

[Table 41]

[0229]

[Table 42]

[0230]

[Table 43]

[0231]

[Table 44]

[0232]

[Table 45]

[0233]

[Table 46]

[0234]

[Table 47]

[0235]

[Table 48]

[0236]

[Table 49]

[0237]

[Table 50]

[0238]

[Table 51]

[0239]

[Table 52]

[0240]

[Table 53]

[0241]

[Table 54]

[0242]

[Table 55]

[0243]

[Table 56]

[0244]

[Table 57]

[0245]

[Table 58]

[0246]

[Table 59]

[0247]

[Table 60]

[0248]

[Table 61]

[0249]

[Table 62]

[0250]

[Table 63]

[0251]

[Table 64]

[0252]

[Table 65]

[0253]

[Table 66]

[0254]

[Table 67]

[0255]

[Table 68]

[0256]

[Table 69]

[0257]

[Table 70]

[0258]

[Table 71]

[0259]

[Table 72]

[0260]

[Table 73]

[0261]

[Table 74]

[0262]

[Table 75]

[0263]

[Table 76]

[0264]

[Table 77]

[0265]

[Table 78]

[Table 79]

[0266]

[Table 80]

[0267]

[Table 81]

[0268]

[Table 82]

Thus, for example, in the above list, the compound designated as A1-B1-C1 is
A product consisting of a combination of Group A1 and Group B1 of Table 2 and Group C1 of Table 3, that is, a compound represented by the following formula:

[0270]

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Preferred compounds of the present invention are those listed below: 3- (1-[[3-methoxy-4- (3
-[2-Methylphenyl] -ureido) -phenyl] -acetyl] -1,2,3,4-tetrahydro-
Quinolin-6-yl) -propionic acid; 3- (1-[[3-methoxy-4- (3-o-tolyl-ureido)
-Phenyl] -acetyl] -2,3-dihydro-1H-indol-5-yl) -butyric acid; 3- (1-[[3-
Methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl] -1,2,3,4-tetrahydro-quinolin-6-yl) -butyric acid; 3- (1-[[3-methoxy- 4- (3-o-tolyl-ureido) -phenyl] -acetyl] -2,3-dihydro-1H-indol-5-yl) -pentanedioic acid; 3- (
1-[[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl] -1,2,3,4-tetrahydro-quinolin-6-yl) -pentanedioic acid; 4- [ 2-carboxy-1- (1-[[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl] -1,2,3,4-tetrahydro-
Quinolin-6-yl) -ethylcarbamoyl] -butyric acid; N- [2-carboxy-1- (1-[[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl] -1 , 2,3,4-tetrahydro-quinolin-6-yl) -ethyl] -succinamic acid; 3- (1-[[3-methoxy-4- (3-o-tolyl)
-Ureido) -phenyl] -acetyl] -1,2,3,4-tetrahydro-quinolin-6-yl) -3- [
(5-methylisoxazole-3-carbonyl) -amino] -propionic acid; 2- (2-chloro-
6-methyl-benzoylamino) -3- [1- (2,6-dichloro-benzoyl) -1,2,3,4-tetrahydro-quinolin-6-yl] -propionic acid; 2- (2,6- Dichloro-benzoylamino)-
3- [1- (2,6-dichloro-benzoyl) -1,2,3,4-tetrahydro-quinolin-6-yl] -propionic acid; 3- (1-[[3-methoxy-4- (3 -o-Tolyl-ureido) -phenyl] -acetyl
] -2,3-dihydro-1H-indol-5-yl) -3-phenyl-propionic acid; 3- (1-[[3-
Methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl] -2,3-dihydro-1H-indol-5-yl) -pentanoic acid; and the corresponding N-oxide, and prodrugs thereof; And pharmaceutically acceptable salts and solvates (eg, hydrates) of the compound and its N-oxides and prodrugs.

The compounds of the present invention have useful pharmacological activity and are therefore incorporated into pharmacological compositions and utilized for treating patients suffering from certain medical disorders. Thus, according to a further aspect, the invention provides a compound of the invention and a composition comprising the compound of the invention for use in therapy. Compounds within the scope of the present invention have shown the interaction of the ligand VCAM-1 with its integrin receptor VLA-4 (α4β1) according to tests described in the literature and hereinafter in in vitro and in vivo procedures. And its test results are believed to correlate with pharmacological activity in humans and other mammals. Accordingly, in a further embodiment, the present invention provides a method for treating a patient suffering from or suffering from a condition, which may be ameliorated by administering a compound of the present invention and an inhibitor of α4β1-mediated cell adhesion. A composition comprising a compound of the invention is provided. For example, the compounds of the present invention may be useful in treating inflammatory diseases, such as joint inflammation, including arthritis, rheumatoid arthritis and other arthritic conditions, such as rheumatoid spondylitis, urate arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis. And in the treatment of osteoarthritis. Further, the compound of the present invention may be used for synovitis, autoimmune diabetes, autoimmune encephalomyelitis, colitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, multiple sclerosis, asthma, psoriasis. It may also be useful in the treatment of melanoma cell division in restenosis, myocarditis, inflammatory bowel disease and metastases.

[0273] A particular aspect of the treatment methods of the invention is the treatment of asthma. Another particular embodiment of the treatment according to the invention is the treatment of joint inflammation. A further particular aspect of the treatment according to the invention is the treatment of inflammatory bowel disease. According to a further feature of the invention, the ligand VCAM-1 has its integrin receptor V
A method is provided for treating a human or animal patient having a condition ameliorated by administering an inhibitor of an interaction with LA-4 (α4β1), for example, a human or animal suffering from or suffering from a condition as described above, The method comprises the step of administering to the patient an effective amount of a compound of the invention or a composition comprising a compound of the invention. "An effective amount" refers to the ligand V
It refers to the amount of a compound of the present invention that is effective in inhibiting the interaction of CAM-1 with its integrin receptor VLA-4 (α4β1), and thus required to achieve a given therapeutic effect.

[0274] Treatment as used herein should be understood to include prophylactic treatment as well as treatment of established conditions. The present invention also includes within its scope pharmaceutical compositions comprising at least one compound of the present invention in combination with a pharmaceutically acceptable carrier or excipient. The compounds of the present invention can be administered by any suitable means. In fact, the compounds of the invention can generally be administered parenterally, topically, rectally, orally or by inhalation, in particular by the oral route.

The compositions of the present invention can be prepared in a conventional manner, using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvant contains, inter alia, diluents, sterile aqueous media and various non-toxic organic solvents. The composition of the present invention comprises a tablet, a pill,
It can have the form of granules, powders, aqueous solutions or suspensions, solutions for injection, elixirs or syrups, and one or more selected from the group consisting of sweeteners, flavors, colorants or stabilizers Drugs can be included to prepare pharmaceutically acceptable formulations. The choice of the vehicle and the amount of active substance in the vehicle is generally determined according to the solubility and chemical nature of the active substance, the particular mode of administration, and the rules found in pharmaceutical practice. For example, to make a tablet, some combination with excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and lubricants such as starch, alginic acid and magnesium stearate, sodium lauryl sulfate and talc. Composite silicate can be used. To prepare capsules, it is advantageous to use lactose and high molecular weight polyethylene glycols. If an aqueous suspension is used, the suspension may contain emulsifiers or agents to facilitate suspension. Also, sucrose,
It is also possible to use ethanol, polyethylene glycol, glycerin and chloroform or mixtures thereof.

For parenteral administration, edible oils such as sesame oil, groundnut oil or olive oil, or aqueous organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, and pharmaceutically acceptable salts. An emulsion, suspension or solution of the product of the invention dissolved or dispersed in a sterile aqueous solution of the salt is used. Solutions of the salts of the products according to the invention are of particular importance for administration by intramuscular or subcutaneous injection. The aqueous solutions, including also the solutions of the salts dissolved in pure distilled water, are available for intravascular administration, but the pH needs to be appropriately adjusted, i.e., they are sufficient Buffered and isotonic with glucose or sodium chloride, and these need to be sterilized by heating, irradiation or microfiltration. For topical administration, gels (water or alcohol based), creams, or ointments containing the compounds of the invention may be used. The compounds of the present invention can also be formulated in gel or matrix bases for application as patches, which allow for controlled release of the compound through a transdermal barrier. For administration by inhalation, the compounds of the present invention may be dissolved or dispersed in a suitable carrier for use in a nebulizer or suspension or solution aerosol, or may be suitable for use in a dry powder inhaler. The compound of the present invention can be absorbed or adsorbed on a suitable solid carrier.

Solid compositions for rectal administration are formulated according to known methods and include suppositories containing at least one compound of the present invention. The percentage of active ingredient in the compositions of the present invention can be varied and needs to be such as to provide a suitable dose. Obviously, several unit dosage forms can be administered at about the same time. The dosage employed will be determined by the practitioner, and will depend upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient to be treated.
In adults, the dose generally ranges from about 0.001 per day by inhalation.
About 50, preferably about 0.001 to about 5 mg / kg body weight, or about
0.01 to about 100, preferably about 0.1 to about 70, more preferably about 0.5 to about 10 mg / kg body weight, and for intravascular administration about 0.001 to about 10, preferably about 0.01 to about 1 m / day.
g / kg body weight. In each particular case, the dose depends on factors specific to the subject to be treated,
For example, it will be determined according to age, weight, general health condition and other characteristics that may affect the efficacy of the medicament.

The compounds of the present invention can be administered as often as necessary to achieve the desired therapeutic effect. Some patients respond quickly to higher or lower doses, and lower maintenance doses may be found to be sufficient. For other patients, depending on the physiological requirements of each particular patient, one to four doses per day may require prolonged treatment. Generally, the active product can be administered orally 1 to 4 times per day. Of course, for some patients, it may also be necessary to prescribe no more than one or two doses per day. The compounds of the invention can be prepared by known methods, i.e.
It can be prepared by the method described in .C. Larock, Comprehensive Organic Transformations, VCH Publishing, 1989. In the reactions described below, it is necessary to protect reactive functional groups, such as hydroxy, amino, imino, thio or carboxy groups, to avoid their undesired participation in the reaction, where these groups Are required in the final product. Known protecting groups can be used according to standard practices. About this, for example, T.
W. Greene & PGM Wuts, "Protective Groups in Organic Chemistry", John
See Wiley & Sons, 1991.

Formula (I) wherein R ¹ , R ² , A ¹ , L ¹ and Z ¹ are as defined above and Y is carboxy
A compound of the formula wherein R ¹ , R ² , A ¹ , L ¹ and Z ¹ are as defined above, and Y is a —COOR ¹⁶ group, wherein R ¹⁶ is alkyl, alkenyl or arylalkyl. The ester of (I) can be prepared by hydrolysis. This hydrolysis is carried out with a base,
Using an alkali metal hydroxide such as sodium hydroxide or lithium hydroxide or an alkali metal carbonate such as potassium carbonate, in the presence of an aqueous / organic solvent mixture, using an organic solvent such as dioxane, tetrahydrofuran or methanol. It can be advantageously carried out by alkaline hydrolysis at a temperature in the range from about ambient temperature to about reflux temperature. The ester is hydrolyzed using an inorganic acid, such as hydrochloric acid, in the presence of an aqueous / inert organic solvent mixture, using an organic solvent such as dioxane or tetrahydrofuran at a temperature of about 50 to about 80 ° C. It is also possible to carry out by acid hydrolysis. Formula (I), wherein R ¹ , R ² , A ¹ , L ¹ and Z ¹ are as defined above and Y is carboxy.
Another example of a compound of is where R ¹ , R ² , A ¹ , L ¹ and Z ¹ are as defined above, and Y is -C
From a t-butyl ester of formula (I), which is an OOR ¹⁶ group (where R ¹⁶ is t-butyl), reaction with trifluoroacetic acid, etc., under standard reaction conditions, for example, at about room temperature, It can be prepared by removing the t-butyl group with an acid catalyst.

Another example, a compound of formula (I) wherein R ¹ , R ² , A ¹ , L ¹ and Z ¹ are as defined above, and Y is carboxy, is represented by R ¹ , R ² , a formula (I) wherein A ¹ , L ¹ and Z ¹ are as defined above and Y is a —COOR ¹⁶ group, wherein R ¹⁶ is arylmethyl, for example benzyl.
)) Can be prepared by hydrogenation of the compound. The reaction is carried out in the presence of ammonium formate and a suitable metal catalyst, for example palladium on an inert support such as carbon, preferably in a solvent such as methanol or ethanol, at about reflux temperature. Can be. Alternatively, the reaction can be carried out in the presence of a suitable metal catalyst such as platinum or palladium optionally supported on an inert support such as carbon, preferably in a solvent such as methanol or ethanol. is there. This reaction is most suitable for compounds of formula (I) wherein L ¹ does not contain a carbon-carbon multiple bond. In this step A, a compound of formula (I) containing an amide bond is obtained by coupling an acid (or acid halide) with an amine using standard peptide coupling procedures as described below. , By forming an amide bond.

As an example of Step A, R ² , A ¹ , L ¹ , Y and Z ¹ are as defined above, and R ¹ is R ³ -Z ^3- , R ³ -L ² -R ⁴ -Z ^3- , R ³ -L ³ -Ar ¹ -L ⁴ -Z ³ -or R ³ -L ³ -Ar ¹ -L ² -R ⁴ -Z ^3- (where R ³ , R ⁴ , L ² ,
L ³ , L ⁴ and Ar ¹ are as defined above, and Z ³ is C (OO)), a compound of formula (I) can be prepared by the following procedure: i) a bromo-one resin (4-bromomethylphenoxylated styrene / divinylbenzene copolymer) wherein A ¹ , Z ¹ , R ² , and L ¹ are as defined above, and R ¹⁷ is a suitable imino protecting group; An acid of formula (II), for example 9H-fluoren-9-ylmethoxycarbonyl, in the presence of a tertiary amine such as diisopropylethylamine and cesium iodide in an inert solvent such as dimethylformamide. Treatment at room temperature gives the following resin A:

[0282]

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Here, the following symbols represent a polymer core comprising polystyrene cross-linked with 1% to 2% divinylbenzene:

[0284]

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(Ii) Treatment of resin A with piperidine at about room temperature in an inert solvent such as dimethylformamide to give the following resin B:

[0286]

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Where A ¹ , Z ¹ , R ² , L ¹ and the following symbols are as defined above:

[0288]

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[0289 (iii) The resin B, R ¹⁸ is ^{R 3 -, R 3 -L 2} -R 4 -, R 3 -L 3 -Ar 1 -L 4 - or R ³ -L ³ -Ar ¹ -L ² -R ⁴ - is (wherein ^{R 3, R 4, L 2} , L 3, Ar 1 and L ⁴ is as defined above), and X ¹ is hydroxy or halogen, preferably a chlorine atom formula Reaction with the compound of (III) gives a resin C with R ² , R ¹⁸ , A ¹ , Z ¹ , L ¹ and the following symbols as defined above:

[0290]

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[Where X ¹ is hydroxy, the reaction is performed using standard peptide coupling procedures, such as O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetra It can be carried out using coupling at room temperature in tetrahydrofuran (or dimethylformamide) in the presence of methyluronium hexafluorophosphate and triethylamine (or diisopropylethylamine). When X ¹ is a halogen atom, the acylation reaction can be carried out with the aid of a base such as pyridine, preferably in a solvent such as tetrahydrofuran at a temperature near room temperature]:

[0292]

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(Iv) Resin C is treated with trifluoroacetic acid in an inert solvent such as dichloromethane at about room temperature. As another example of Step A, R ¹ , R ² , A ¹ , Y and Z ¹ are as defined above, and L ¹ is -N (R ⁸ ) -C (= O) -R ⁹ group ( Wherein R ⁸ and R ⁹ are as defined above), wherein R ¹ , R ² , A ¹ , Y and Z ¹ are as defined above, and L ¹ is- A corresponding compound of formula (I) containing an N (R ⁸ ) group, where R ⁸ is as defined above, and a compound of the formula: R ⁹ -C (= O) -X ^1, wherein R ⁹ and X ¹ is as defined above), and can be prepared by a reaction using an acid (or acid chloride) represented by the following standard coupling conditions, for example, the conditions described above. R ¹ , R ² , A ¹ and Z ¹ are as defined above, Y is a —COOR ¹⁶ group (where R ¹⁶ is as defined above), and L ¹ is —N (R ⁸ ) — Esters of formula (I), including C (= O) -R ⁹ groups, where R ⁸ and R ⁹ are as defined above, also have L ¹ as a -NHR ⁸ group, where R ⁸ is From the corresponding esters of formula (I), as defined above, a compound of the formula: R ⁹ —C (= O) —X ¹ (where R ⁹ and X ¹ are as defined above) Can be prepared by the reaction with

R ² , A ¹ , L ¹ and Z ¹ are as defined above, and R ¹ is R ³ -Z ^3- , R ³ -L ² -R ⁴ -Z ^3- , R ³ -L ^3- Ar ¹ -L ⁴ -Z ³ -or R ³ -L ³ -Ar ¹ -L ² -R ⁴ -Z ^3- (where R ³ , R ⁴ , L ² , L ³ , L ⁴ and Ar ¹ are as defined above As defined, and Z ³ is a group selected from C (= O)), wherein Y is a -COOR ¹⁶ group, where R ¹⁶ is as defined above. ester, R ¹⁸ is ^{R 3 -, R 3 -L 2} -R 4 -, R 3 -
L ³ -Ar ¹ -L ⁴ - or ^{R 3 -L 3 -Ar 1 -L 2} -R 4 - ( wherein ^{R 3, R 4, L 2} , L 3, Ar 1 and L ⁴ is as defined above And X ¹ is a hydroxy or halogen, preferably a chlorine atom, and can be prepared by reacting a compound of formula (IV) with an amine of formula (IV):

[0295]

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Here, R ² , A ¹ , L ¹ , Z ¹ and R ¹⁶ are as defined above. The reaction is performed under standard coupling conditions, for example, as described above. R ² , A ¹ , L ¹ and Z ¹ are as defined above, and R ¹ is R ³ -Z ^3- , R ³ -L ² -R ⁴ -Z ^3- , R ³ -L ³ -Ar ^1- L ⁴ -Z ³ -or R ³ -L ³ -Ar ¹ -L ² -R ⁴ -Z ^3- (where R ³ , R ⁴ , L ² , L ³ , L ⁴ and Ar ¹ are as defined above And Z ³ is SO ₂ ), and the ester of formula (I) wherein Y is a —COOR ¹⁶ group (where R ¹⁶ is as defined above) is R ² , It can be prepared by sulfonylation of a compound of formula (IV) wherein A ¹ , L ¹ , Z ¹ and R ¹⁶ are as defined above using a sulfonyl chloride of formula (V): R ¹⁸ -SO ₂ -Cl (V) Here, R ¹⁸ is as defined above. The reaction is preferably carried out with the aid of a base, for example a tertiary amine such as triethylamine, preferably in a solvent such as tetrahydrofuran, at a temperature from about 0 ° C. to about room temperature.

R ¹ , R ² , A ¹ and Z ¹ are as defined above, Y is a —COOR ¹⁶ group (where R ¹⁶ is as defined above), and L ¹ is —N (R ⁸ ) esters of formula (I) containing a -SO ₂ -R ⁹ group (wherein R ⁸ and R ⁹ is as defined above) is likewise L ¹ is -NHR ⁸ group (wherein R ⁸ is as defined above Can be prepared by reaction with a sulfonyl chloride of the formula: R ⁹ —SO ₂ —Cl, wherein R ⁹ is as defined above, from the corresponding ester of formula (I), wherein R ⁹ is as defined above. R ² , A ¹ , L ¹ and Z ¹ are as defined above, and R ¹ is R ³ -L ³ -Ar ¹ -L ⁴ -Z ^3- (where R ³ , L ³ ,
L ⁴ and Ar ¹ are as defined above, Z ³ is NHC (= O) a), Y is -COOR ¹⁶ group (where R ¹⁶ is defined as above) the formula (I) Can be prepared by reacting a compound of formula (IV), wherein R ² , A ¹ , L ¹ , Z ¹ and R ¹⁶ are as defined above, with an isocyanate of formula (VI): R ³ − L ³ -Ar ¹ -L ⁴ -NCO (VI) wherein R ³ , L ³ , L ⁴ and Ar ¹ are as defined above. The reaction is preferably carried out with the aid of a base, for example a tertiary amine such as triethylamine, preferably in a solvent such as dichloromethane, at a temperature of about room temperature.

R ² , A ¹ , L ¹ and Z ¹ are as defined above, R ¹ is R ³ -Z ^3- (where R ³ is as defined above and Z ³ is NHC (= O) The ester of formula (I) is also R ² , A ¹ , L ¹ , Z ¹ and
It can be prepared by reacting a compound of formula (IV), wherein R ¹⁶ is as defined above, with an isocyanate of formula R ³ —NCO, wherein R ³ is as defined above. R ² , A ¹ , L ¹ and Z ¹ are as defined above, and R ¹ is R ³ -Z ^3- (where R ³ is as defined above
A [except aryl and heteroaryl], Z ³ is a direct ^{bond), R 3 -L 2 -R 4} -
Z ^3- , R ³ -L ³ -Ar ¹ -L ⁴ -Z ³ -or R ³ -L ³ -Ar ¹ -L ² -R ⁴ -Z ^3- (where R ³ , L ² , L ³ , L ⁴ and Ar ¹ are as defined above, and Z ³ is a direct bond), wherein Y is -C
An ester of formula (I) wherein the OOR ¹⁶ group (where R ¹⁶ is as defined above) is a compound of formula (IV) wherein R ² , A ¹ , L ¹ , Z ¹ and R ¹⁶ are as defined above. It can be prepared by alkylation of a compound with a compound of formula (VII): R ³ -X ² (VII) where R ³ is as previously defined and X ² is a halogen atom, preferably a bromine atom It is. For example, the alkylation can be performed in dimethylformamide or dimethylsulfoxide in the presence of a base, for example, an alkali metal hydride such as sodium hydride, at a temperature ranging from about 0 ° C to about 100 ° C. it can.

R ¹ , R ² , A ¹ and Z ¹ are as defined above, Y is a —COOR ¹⁶ group (where R ¹⁶ is as defined above), and L ¹ is a —NHR ⁸ group (Where R ⁸ is alkyl, arylalkyl,
Cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl) out esters of formula (I), likewise the corresponding derivative of formula (I) L ¹ contains a -NH ₂ group, suitable alkyl (or Arylalkyl, cycloalkylalkyl,
Heteroarylalkyl or heterocycloalkylalkyl) halides. R ² , A ¹ , L ¹ and Z ¹ are as defined above, and R ¹ is R ³ -Z ^3- (where R ³ is as defined above and Z ³ is OC (= O)) An ester of the formula (I) selected from the group consisting of a compound of the formula (IV) wherein R ² , A ¹ , L ¹ , Z ¹ and R ¹⁶ are as defined above, and a compound of the following formula (VIII) It can be prepared by reaction. R ³ —OC (= O) —X ³ (VIII) where R ³ is as defined above, and X ³ is a halogen atom, preferably a chlorine atom. The reaction is carried out in the presence of a suitable base, for example triethylamine or pyridine,
It is performed at a temperature of about 0 ° C. to about room temperature.

R ¹ , R ² , A ¹ and Z ¹ are as defined above, Y is a —COOR ¹⁶ group (where R ¹⁶ is as defined above), and L ¹ is —N (R ⁸ ) -C (= O) -OR ⁹ groups, wherein R ⁸ and R ⁹ are as defined above, also include those wherein L ¹ is a --NHR ⁸ group (where R ⁸ is as defined above, from a corresponding derivative of formula (I) including the formula: R ⁹ —OC (= O) —X ³ (where R ⁹ and X ³ are as defined above) By reaction with the compound to be prepared. R ¹ , R ² , A ¹ and Z ¹ are as defined above, Y is a —COOR ¹⁶ group (where R ¹⁶ is as defined above), and L ¹ is a group represented by the following formula: :

[0301]

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An ester of formula (I) wherein L ¹ is a group of the formula:

[0303]

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Can be prepared by hydrogenation of the corresponding derivative of formula (I) This reaction can be carried out at a temperature of about 60 ° C. in the presence of formic acid and a suitable metal catalyst, for example palladium supported on an inert element such as carbon. The reaction can be advantageously carried out in the presence of a suitable metal catalyst, for example platinum or palladium optionally on an inert support such as carbon, preferably in a solvent such as methanol or ethanol. R ¹ , R ² , A ¹ and Z ¹ are as defined above, Y is a —COOR ¹⁶ group (where R ¹⁶ is as defined above), and L ¹ is a bond represented by the following formula: :

[0305]

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The esters of formula (I) are also suitable for use according to standard recrystallization of suitable salts (eg, recrystallization of tartrate) or by standard enzymatic resolution procedures (eg, Soloshonok, VA, etc. Te
trahedron: Asymmetry, 6 (1995) 7, 1601-1610) can be obtained from the racemic mixture. R ¹ , R ² , A ¹ and Z ¹ are as defined above, Y is a —COOR ¹⁶ group (where R ¹⁶ is as defined above), and L ¹ is a bond represented by the following formula: :

[0307]

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An ester of formula (I) wherein R ¹ , R ² , A ¹ and Z ¹ are as defined above and Y is —COOR ¹⁶
A group of formula (I) wherein R ¹⁶ is as defined above, and L ¹ is a -CH = CH- bond, and an alkali metal hydride such as sodium hydride. In an inert solvent at about room temperature and then treated with dibenzylamine or (S) -N-benzyl-α-methylbenzylamine with butyllithium and an anion derived from about- It can be prepared by reacting at 78 ° C. R ¹ , R ² , A ¹ and Z ¹ are as defined above, Y is a —COOR ¹⁶ group (where R ¹⁶ is as defined above), and L ¹ is alkylene, alkynylene or cycloalkenylene Wherein the aliphatic carbon-carbon multiple bond is directly attached to the phenyl moiety in formula (I), wherein the ester of formula (I) is a compound of formula (IX):

[0309]

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(Wherein R ¹ , R ² , A ¹ and Z ¹ are as defined above, and X ⁴ is a halogen, preferably a bromine or iodine atom) and a compound represented by the following formula (X) R ¹⁹ -COOR ¹⁶ (X) wherein R ¹⁶ is as defined above and R ¹⁹ is alkenyl, alkynyl or cycloalkenyl. When X ⁴ is a bromine or iodine atom, the reaction is carried out at temperatures up to about 110 ° C. in the presence of palladium acetate, triarylphosphines such as tri-o-tolylphosphine and tertiary amines such as tributylamine. Can be performed advantageously. This reaction is particularly suitable for preparing esters of formula (I) wherein L ¹ is vinylene. When X ⁴ is a chlorine atom, the reaction is carried out with sodium iodide, nickel bromide, palladium (0) bis (dibenzylideneacetone), triarylphosphines such as tri-o-tolylphosphine and tertiary amines such as tributylamine. It can be advantageously carried out in the presence of an amine at temperatures up to about 110 ° C.

According to a further feature of the invention, the compounds of the present invention can be prepared by the interconversion of other compounds according to the present invention. For example, R ¹ , R ² , A ¹ , L ¹ and Z ¹ are as defined above and Y is a group: —C (= O) —NHOH
A compound of formula (I) wherein R ¹ , R ² , A ¹ , L ¹ and Z ¹ are as defined above, and Y is carboxy, and hydroxylamine It can be prepared using standard peptide coupling procedures, such as treatment with a carbodiimide such as dicyclohexylcarbodiimide, by reacting in the presence of triethylamine in an inert solvent such as dichloromethane or tetrahydrofuran at about room temperature. . This coupling can also be performed using 1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide in dichloromethane at room temperature. This preparation also uses an O-protected hydroxylamine, such as O- (trimethylsilyl) -hydroxylamine, O- (t-butyldimethylsilyl) -hydroxylamine, or O- (tetrahydropyranyl) -hydroxylamine, Then, it can be carried out by treating with an acid.

As another example of this interconversion method, compounds of formula (I) containing a sulfoxide bond can be prepared by oxidation of the corresponding compound containing an -S- bond. For example, the oxidation may be by reaction with a peroxy acid such as 3-chloroperbenzoic acid, preferably in an inert solvent such as dichloromethane, preferably at or near room temperature, or buffered to a pH of about 5. It can be advantageously carried out with potassium hydrogen peroxomonosulfuric acid in a medium such as aqueous methanol at a temperature in the range of about 0 ° C. to room temperature. This latter method is preferred for compounds containing acid-active groups. As another example of this interconversion method, compounds of formula (I) containing a sulfone linkage can be prepared by oxidation of the corresponding compound containing a -S- or sulfoxide linkage. For example, the oxidation can be advantageously performed by reaction with a peroxy acid such as 3-chloroperbenzoic acid, preferably in an inert solvent such as dichloromethane, preferably at or near room temperature.

Another example of this interconversion method is a compound of formula (I) wherein R ¹ , R ² , A ¹ , Z ¹ and Y are as defined above and L ¹ is optionally substituted alkylene. Can be prepared by hydrogenation of the corresponding compound of formula (I), wherein L ¹ is the corresponding optionally substituted alkylene. This hydrogenation is carried out in the presence of a suitable metal catalyst, for example platinum or palladium optionally supported on an inert element such as carbon, preferably in a solvent such as methanol or ethanol, at a temperature near room temperature. It can be performed using hydrogen (optionally pressurized). As another example of this interconversion method, R ¹ , R ² , A ¹ , L ¹ and Z ¹ are as defined above, and L ¹ is an alkylene bond substituted with -CONY ⁴ Y ⁵ ; And compounds of formula (I) wherein Y is carboxy, wherein R ¹ , R ² , A ¹ , L ¹ and Z ¹ are as defined above, and L ¹ is -C
A compound of the formula (I), which is an alkylene bond substituted with OOH and Y is carboxy, is reacted with an anhydride such as trifluoroacetic anhydride in an inert solvent such as tetrahydrofuran. It can be prepared by treatment with ⁴ Y ^5.

As another example of this interconversion method, a compound of formula (I) wherein R ¹ , R ² , A ¹ , L ¹ and Y are as defined above and Z ¹ is C (= O) Compounds can be prepared by oxidation of a compound of formula (I) wherein R ¹ , R ² , A ¹ , L ¹ and Y are as defined above and Z ¹ is CH ₂ . For example, this oxidation can be advantageously performed by reaction with potassium permanganate. As another example of this interconversion method, a compound of formula (I) wherein R ¹ , R ² , A ¹ , L ¹ and Y are as defined above and Z ¹ is CH (OH) is ^It can be prepared by reduction of a compound of formula (I) wherein ¹ , R ² , A ¹ , L ¹ and Y are as defined above and Z ¹ is C (= O). For example,
This reduction can be advantageously carried out by reaction with sodium borohydride in aqueous ethanol at a temperature near room temperature. As another example of this interconversion method, compounds of the present invention that contain a heterocyclic group, wherein the heteroatom is a nitrogen atom, can be oxidized to its corresponding N-oxide. The oxidation can be advantageously carried out by reaction of hydrogen peroxide with a mixture of an organic acid, such as acetic acid, preferably at or above room temperature, for example at a temperature of about 60-90 ° C.
Alternatively, this oxidation can be carried out by reaction with a peracid such as peracetic acid or m-chloroperoxybenzoic acid in an inert solvent such as chloroform or dichloromethane at about room temperature to reflux, preferably at elevated temperature. . The oxidation can be further performed by reaction with hydrogen peroxide in the presence of sodium tungstate at a temperature ranging from room temperature to about 60 ° C.

It will be appreciated that the compounds of the present invention may contain asymmetric centers. These asymmetric centers may each independently be in the R or S configuration. One skilled in the art will appreciate that some compounds of the present invention may exhibit geometric isomerism. It is to be understood that the present invention includes the individual geometric and stereoisomers of the compounds of formula (I) above and mixtures thereof (including racemic mixtures). Such isomers are
The mixture can be separated by applying or employing known methods, for example, chromatography and recrystallization techniques, or they can be prepared separately from the appropriate isomers of the intermediate. According to a further feature of the invention, the acid addition salts of the compounds of this invention may be prepared by reaction of the free base with a suitable acid by the application or adoption of known methods. For example, the acid addition salt of a compound of the invention may be isolated by dissolving the free base in water or aqueous alcoholic solution or other suitable solvent containing the appropriate acid and evaporating the solution, or It can be prepared by reacting the free base with an acid in an organic solvent. In the latter case, the salt can be separated directly or obtained by concentration of the solution. The acid addition salt of the compound of the present invention, by applying or employing a known method,
It can be regenerated from its salt. For example, a parent compound of the invention can be regenerated from its acid addition salt by treating it with an alkali, for example, aqueous sodium bicarbonate solution or aqueous ammonia solution. The compound of the present invention can be regenerated from its base addition salt by applying or employing a known method. For example, the parent compound of the present invention can be regenerated from its base addition salt by treating it with an acid such as hydrochloric acid.

The compounds of the invention can be advantageously prepared or formed during the process of the invention as solvates (eg, hydrates). Hydrates of the compounds of the present invention can be advantageously prepared by recrystallization from an aqueous / organic solvent mixture using an organic solvent such as dioxane, tetrahydrofuran or methanol. According to a further feature of the invention, base addition salts of the compounds of this invention can be prepared by reacting the advantageous base with a suitable acid, employing or employing known methods. For example, a base addition salt of a compound of this invention can be obtained by dissolving the free acid in water or an aqueous alcohol solution containing a suitable base or other suitable solvent, isolating the salt by evaporation of the solution, or It can be prepared by reacting the advantageous acid with a base in an organic solvent, in the latter case the salt can be separated directly or obtained by concentration of the solution. The starting materials and intermediates can be prepared by applying or employing known methods, for example, the methods described in Reference Examples or obvious chemical equivalents thereof. Formula (III) wherein R ¹⁸ is an R ³ -L ³ -Ar ¹ -L ⁴ -group wherein R ³ , R ⁴ , L ² , L ³ , L ⁴ and Ar ¹ are as defined above. ) Can be prepared by applying or employing the method described in International Patent Application Publication No. WO 96/22966. R ¹⁸ is an R ³ -L ³ -Ar ¹ -L ⁴ -group (where R ³ and L ⁴ are as defined above, L ³ is NH, and Ar ¹ is a group represented by the following formula:

[0317]

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An acid of formula (III) wherein R is as defined above and X ¹ is a hydroxy group is a compound of formula (1):

[0319]

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(Where R and L ⁴ are as defined above, R ¹⁶ is lower alkyl and X is O) and the formula: R ³ -N = C = O, where R ³ is Is reacted in ethanol at room temperature, followed by reaction with a carbodiimide such as dicyclohexylcarbodiimide or diisopropylcarbodiimide in ethanol at a temperature ranging from about room temperature to about reflux temperature. And then by hydrolysis using standard conditions, such as those described above. R ¹⁸ is an R ³ -L ³ -Ar ¹ -L ⁴ -group (where R ³ and L ⁴ are as defined above, and Ar ¹ is a group represented by the following formula:

[0321]

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(Where R is as defined above), L ³ is NH, and X ¹ is a hydroxy group, and the acids of formula (III) are also R, L ⁴ and R ¹⁶ Is as defined above, and X is NH. R ¹⁸ is as defined above, and X ¹ is a chlorine atom, the acid of formula (III) is from the corresponding acid of formula (II), wherein R ¹⁸ is as defined above and X ¹ is a hydroxy group. Can be prepared by standard procedures for converting acids to acid chlorides, for example by reaction with oxalyl chloride. R ² and R ¹⁶ are as defined above, Z ¹ is CH ₂ , L ¹ is as defined above (
However, the compound of formula (IV) wherein L ¹ contains a non-aromatic carbon-carbon multiple bond), and A ¹ is an ethylene bond is a compound of the corresponding quinoline analog of the following formula (2) Can be prepared by hydrogenation in the presence of a suitable metal catalyst:

[0323]

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Here, R ² and R ¹⁶ are as defined above, and L ¹ is as defined immediately above. This reduction can be advantageously carried out in hydrochloric acid in a hydrogen pressure of 5 MPa (50 bar) in the presence of 5% rhodium in carbon powder as a catalyst at a temperature near room temperature. A compound of formula (2) wherein R ² and R ¹⁶ are as defined above and L ¹ is alkylene,
A compound of the following formula (3):

[0325]

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Wherein R ² is as defined above and X ⁵ is an iodine or bromine atom, and an alkenoic ester of formula (X) wherein R ¹⁶ is as defined above and R ²⁰ is alkenyl Between
It can be prepared by an electrochemical coupling reaction. The reaction is carried out in the presence of a nickel salt catalyst, such as nickel bromide trihydrate, tetrabutylammonium bromide, tetrabutylammonium iodide and 1,2-dibromoethane, in an inert solvent or a mixture thereof, such as dimethylformamide and pyridine. In this case, it can be advantageously carried out at a temperature of about 60 ° C. This reaction is particularly suitable for preparing compounds of formula (I) wherein L ¹ is ethylene. Compounds of formula (2) wherein R ² and R ¹⁶ are as defined above and L ¹ is an alkylene bond substituted with -CH ₂ OR ³ (e.g., -CH ₂ OCH ₃ ) are represented by R ² and R ¹⁶ Is as defined above, from a compound of formula (2) wherein L ¹ is an alkylene bond (where the carbon-carbon double bond is replaced with a methyl group), utilizing standard procedures such as: Can be prepared by: (i) N-
Ariruburomo reduction by-bromosuccinimide, (ii) formula: R ³ O ^- M ⁺ alkali metal salts (e.g., sodium methoxide) represented by via a reaction with substitution of OR ³ of the Ariruburomo, (iii) hydrogenated .

A compound of the formula wherein R ² and R ¹⁶ are as defined above, and L ¹ is alkylene, alkynylene or cycloalkenylene, wherein the carbon-carbon multiple bond is directly attached to the phenyl moiety in formula (I) The compound of (2) is a compound of formula (3) wherein R ² is as defined above and X ⁵ is iodine or preferably a bromine atom, and a compound of formula (X) wherein R ¹⁶ and R ¹⁹ are as defined above. Using standard Heck coupling reaction conditions,
For example, it can be prepared by reacting at a temperature up to about 120 ° C. in the presence of palladium acetate, triphenylphosphine and tributylamine. A compound of formula (2) wherein R ² and R ¹⁶ are as defined above and L ¹ is an optionally substituted arylene or an optionally substituted heteroaryldiyl bond, wherein R ² is as defined above, It can be prepared by reacting a compound of formula (3) wherein X ⁵ is an iodine or bromine atom with a compound of formula (4): Br-L ¹ -COOR ¹⁶ (4) where R ¹⁶ is As defined, L ¹ is an optionally substituted arylene or an optionally substituted heteroaryldiyl linkage. This reaction is carried out in the presence of a complexing metal catalyst, such as tetrakis (triphenylphosphine) palladium (0), under standard reaction conditions, such as Trecourt et al., Tetrahedron, 51 (1995), 43, pp. 11743-11750.
The reaction is performed under the conditions described in R ² and R ¹⁶ are as defined above, and L ¹ is a group represented by the following formula:

[0328]

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Compounds of formula (IV) or (2), which are for example Organic Syntheses On Name Reaction
s and Unnamed Reactions, A. Hassner & C. Stumer, Pergamon, pp. 275, 374
Can be prepared by standard methods for producing α-amino acids, as described in R ² and R ¹⁶ are as defined above, and L ¹ is a group represented by the following formula:

[0330]

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The compound of formula (2) is a compound of the following formula (5):

[0332]

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[0333]

(Where R ² is as defined above and X ⁶ is a bromine or chlorine atom) and (2R)-(−)-2
The anion derived from the reaction of 2,5-dihydro-3,6-dimethyl-2-isopropylpyrazine with butyllithium was converted to an anion derived from DL Boger & D. Yohannes, J. Org. Chem. [JOCE
AH], 1990, 55 (p. 6010 for the preparation of compound 31). R ² , R ¹⁶ , A ¹ and Z ¹ are as defined above, and L ¹ is a group represented by the following formula:

[0335]

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A compound of formula (IV) can also be prepared from a compound of formula (6):

[0337]

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Here, R ² , A ¹ , X ⁶ and Z ¹ are as defined above.

Compounds of formula (6) wherein R ² , A ¹ , X ⁶ are as defined above and Z ¹ is CH ₂ can be obtained by applying or employing the method described in US Pat. No. 4,156,734 For example, the patent discloses that the N-protected dihydroindole, 1-benzoyl-5-chloromethyl-2,3-dihydro-1H-indole, is prepared from 1-benzoyl-2,3-dihydro-1H-indole The method is described as Example 23A. R ² , R ¹⁶ and L ¹ are as defined above, Z ¹ is CH ₂ , A ¹ is a linear C _1-3 alkylene bond, and L ¹ is an alkenylene, alkynylene or cycloalkenylene group
Wherein the aliphatic carbon-carbon multiple bond is directly attached to the phenyl moiety in formula (IV), wherein the compound of formula (IV) is a compound of formula (7):

[0340]

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(Where R ² is as defined above, A ¹ is a linear C _1-3 alkylene bond, X ⁷ is a halogen, preferably a bromine or iodine atom, and Z ¹ is CH ₂ A) can be prepared by coupling a compound of formula (X) wherein R ¹⁶ is as defined above and R ¹⁹ is alkenyl, alkynyl or cycloalkenyl. This coupling reaction can be advantageously performed in the presence of palladium acetate and tris (o-tolyl) phosphine by utilizing standard coupling conditions, such as those described above. In this reaction, a suitable protecting group for the NH group is, for example, t
-Butyloxycarbonyl group. R ² , R ¹⁶ and L ¹ are as defined above, Z ¹ is CH ₂ , A ¹ is a linear C _1-3 alkylene bond, and L ¹ is a formula containing an alkylene or cycloalkylene group ( Compounds of formula (IV) wherein L ¹ comprises an alkenylene, alkynylene or cycloalkenylene group
The corresponding compounds of V) can be prepared by hydrogenation, for example using standard hydrogenation procedures as described above. A compound of formula (7) wherein R ² is hydrogen, A ¹ is ethylene, Z ¹ is CH ₂ and X ⁶ is an iodine atom bonded to the 6-position of the tetrahydroquinoline ring, It can be prepared by iodination of 1,2,3,4-tetrahydroquinoline with iodine monochloride at a temperature near room temperature. 2,2 of the formula (7) wherein R ² is hydrogen, A ¹ is ethylene, Z ¹ is C (ハ ロ ゲ ン O), and X ⁶ is a halogen atom bonded to the 6-position of the tetrahydroquinoline ring. 3-dihydro-4 (1H)-
Quinolones are described in S. Kano et al., J. Chem. Soc. Perkin Trans. 1 1098, 10, pp. 2105-21
It can be prepared by applying or employing Fries-type acid-catalyzed rearrangement of 1-arylazetidin-2-ones described in 11. R ² , R ¹⁶ , L ¹ and A ¹ are as defined above, Z ¹ is CH ₂ , and L ¹ is a bond represented by the following formula:

[0342]

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A compound of formula (IV) wherein R ¹ , R ² and A ¹ are as defined above, Y is —COOR ¹⁶ (where R ¹⁶ is as defined above), and Z ¹ is CH Formula (I) wherein R is ₂ and L ¹ is a -CH = CH- bond.
And dimethyl malonate in the presence of an alkali metal alkoxide such as sodium methoxide in methanol at a temperature near the reflux temperature. R ² , R ¹⁶ and A ¹ are as defined above, Z ¹ is CH ₂ and the moiety -L ² -Y has the formula:

[0344]

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A compound of formula (IV) wherein R ² and A ¹ are as defined above and X ⁶ is a halogen atom, preferably bromine or iodine, -Dihydropyran-2-
Prepared by coupling in a sealed container in an inert solvent such as dimethylformamide at a temperature of about 95 ° C. in the presence of tetrakis (triphenylphosphine) palladium (0) and triethylamine. it can. R ² , R ¹⁶ , L ¹ and A ¹ are as defined above, Z ¹ is CH ₂ , and L ¹ is -N (R ⁸ ) -C (=
O) -R ⁹ group (wherein the compound of formula (IV) R ⁸ and R ⁹ containing defined above) is, L ¹ is -NHR ⁸
From the corresponding compound of formula (IV) containing a group (where R ⁸ is as defined above), R ⁹ and X ¹ are as defined above using, for example, standard peptide coupling procedures as described above. an ^{expression: R 9 -C (= O)} - can be prepared by reaction of a compound of X ^1. R ¹ , R ² , A ¹ and Z ¹ are as defined above, Y is —COOR ¹⁶ (where R ¹⁶ is as defined above) and L ¹ is a group of the formula:

[0346]

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A compound of formula (IV) wherein L ¹ is a group of the formula:

[0348]

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Can be prepared by hydrogenation of the corresponding derivative of formula (IV) The reaction can be carried out in the presence of formic acid and a suitable metal catalyst, for example palladium on an inert support such as carbon, at a temperature of about 60 ° C. The reaction can be advantageously carried out in the presence of a suitable metal catalyst, for example platinum or palladium, optionally on an inert support such as carbon, preferably in a solvent such as methanol or ethanol. R ¹ , R ² , A ¹ and Z ¹ are as defined above, Y is —COOR ¹⁶ (where R ¹⁶ is as defined above) and L ¹ is a bond of the formula:

[0350]

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Compounds of formula (IV) are also suitable for standard recrystallization of suitable salts (eg, recrystallization of tartrate) or standard enzymatic resolution procedures (eg, Soloshonok, VA et al., Tetrahedro
n: Asymmetry, 6 (1995) 7, 1601-1610) can be applied to obtain from a racemic mixture. R ¹ , R ² , A ¹ and Z ¹ are as defined above, Y is —COOR ¹⁶ (where R ¹⁶ is as defined above) and L ¹ is a bond of the formula:

[0352]

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A compound of formula (IV) wherein R ¹ , R ² , A ¹ and Z ¹ are as defined above and Y is —COOR ¹⁶ (
Wherein R ¹⁶ is as defined above), and L ¹ is a compound of formula (IV) in which -CH = CH- bond, and an alkali metal hydride such as sodium hydride in an inert solvent such as tetrahydrofuran. At about room temperature, then dibenzylamine or (S)-
It can be prepared by reacting an anion derived by treating N-benzyl-α-methylbenzylamine with butyllithium at a temperature of about −78 ° C. Compounds of formula (IX) wherein R ¹ , R ² and X ⁴ are as defined above, A ¹ is methylene and Z ¹ is C (= O) are described in Bourlot, AS, etc., Synthesis, 1994, 4: 411-416 can be prepared by applying or employing the method described therein. Compounds of formula (IX) wherein R ¹ , R ² and X ⁴ are as defined above, A ¹ is ethylene and Z ¹ is C (= O) are described in U.S. Patent Application No.US4421918. It can be prepared by applying or employing the method described above. The intermediates of formulas (IV), (IX) and (2) are novel compounds, and thus the intermediates themselves and their individually described processes further feature the invention. In the nuclear magnetic resonance spectrum (NMR), the chemical shift is expressed in ppm relative to tetramethylsilane. Abbreviations have the following meanings: s = singlet; d = doublet; t = triplet; m = multiplet.

The mass spectrum (MS) for Example 4 (b) and Reference Example (unless otherwise specified) was
Recorded on a Micromass Platform II mass spectrometer equipped with an Electrospray source and HP1100 liquid chromatograph, using an acetonitrile / water mixture (1: 1 v / v) as the mobile phase Flow rate 0.3 ml / min, injection volume 20 μl, operation time 2.0 min, scanning range 150-850 dalton positive / negative,
A scan time of 2.0 seconds, an ESI potential of 3.5 KV, and an ESI pressure of 20 n / m2 nitrogen were used. The mass spectra [MS (ES ⁺ )] for Examples 1-12 were obtained using a Z-Flow Atmospheric pre-ionizer operating in positive ion electrospray mode (ES ⁺ ).
Micro Latt Mass Spectrometer (Orthogonal Acceleration Time of Flight Mass Spectrometer) equipped with an HP1100 Liquid Chromatograph and equipped with a ssure ionization source.
celeration Time of Flight Mass Spectrometer)). The conditions used were as follows: as the mobile phase gradient, gradient elution conditions using an acetonitrile-water mixture: 95% water: 5% acetonitrile (0.00 min); 95% water: 5% acetonitrile (0.50 Min); 5% water: 95% acetonitrile (4.50 min); 5% water: 95% acetonitrile
(5.00 min); 3% Luna C18 HP, running on 95% water: 5% acetonitrile (5.50 min)
LC column (30 mm x 4.6 mm); flow rate 2 ml / min, dispensed about 200 ml / min to mass spectrometer; injection volume 10-40 ml; in-line diode array detection (220-450 nm), in-line evaporation (
Evaporative) Light scattering (ELS) detection ELS-Temperature 50 ° C, Gain 8-1.8 ml / min; Source temperature 150 ° C.

Example 1 3- (1-[[3-methoxy-4- (3- [2-methylphenyl] -ureido) -phenyl ] -acetyl] -1,2,3,4-tetrahydro-quinoline 6-yl) - (in 4 ml), ethyl 3- (1 - [[3-methoxy-4 - [(2-preparative Luigi Bruno carbonyl) amino] phenyl] acetyl] absolute ethanol propionic acid 20 ° C. -1 A solution of 2,2,3,4-tetrahydro-quinolin-6-yl) -propionate (0.24 g, Reference Example 1) is added dropwise, distilled water (1 ml)
Was treated with a solution of lithium hydroxide monohydrate (33 mg). After stirring at 20 ° C. for 3 hours, the reaction mixture was evaporated at 40 ° C. under reduced pressure (2.7 kPa). The resulting residue was treated with distilled water (35 ml), the resulting solution was washed twice with diethyl ether (20 ml), then acidified to pH 3 by the addition of hydrochloric acid (0.8 ml, 1N) and then ethyl acetate (25ml) 2
Extracted times. The combined organic extracts were washed twice with water (5 ml), then dried over magnesium sulfate and evaporated at 40 ° C. under reduced pressure (2.7 kPa). The foamy white solid obtained
(191 mg) was chromatographed on a silica gel plate (4 plates, 20 × 20 cm,
Thickness = 0.5 mm) and eluted with a dichloromethane-methanol mixture (9: 1, v / v) to give the title compound (148 mg) as a foamy white solid. ¹ H NMR (300 MHz, (CD ₃ ) ₂ SO): δ
1.81 (m, 2H); 2.27 (s, 3H); 2.45-2.70 (m, 4H); 2.82 (t, J = 7.5Hz, 2H); 3
.72 (t, J = 6.5Hz, 2H); 3.82 (s, 2H); 3.87 (s, 3H); 6.60-7.50 (m, 8H); 7.8
2 (d, J = 8Hz, 1H); 8.05 (d, J = 8Hz, 1H); 8.50 (s, 1H); 8.60 (s, 1H); MS (7
Electron Impact recorded on a Finnigan SSQ 7000 spectrometer at 0 eV: 501 (M ⁺ ).

Example 2 (a) (R / S) 3- (1-[[3-Methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl]-
Ethyl (R / S) 3- (1-[[3-methoxy-4- (3-o-tolyl) dissolved in 2,3-dihydro-1H-indol-5-yl) -methanol butyrate (about 150 ml) -Ureido) -phenyl] -acetyl] -2,3-dihydro-1H-indol-5-yl) -butyrate (2.8 g, Reference Example 4 (a)) in aqueous sodium hydroxide solution (15 ml, 1 M ). The mixture is warmed at about 50 ° C. for hours, then aqueous sodium hydroxide solution (7.5
ml) with an additional aliquot. Further, after 2-3 hours at 50 ° C., TLC analysis indicated that the reaction was complete. Most of the methanol was removed by evaporation, and the resulting residue was diluted with hydrochloric acid (about 200 ml, 1M). The resulting mixture was stirred for about 30 minutes, then the solid was collected by filtration, washed with water and dried to give the title compound (2.3g) as a very pale orange powder. LC-MS: _RT = 3.84 min (100% of total area according to ELS); MS (ES ^<+> ) 502 (MH ^<+> ), 524 (MNa ^<+> ). (b) Ethyl (R / S) 3- [1-[(2-o-tolylamino-3H-benzimidazol-5-yl) -acetyl] -1,2,3,4-tetrahydroquinolin-6-yl] Using butyrate (Reference Example 4 (k)) and proceeding in the same manner as in Example 2 (a), the hydrolysis was carried out at room temperature, and (R / S) 3- [1-[(2
-o-Tolylamino-3H-benzimidazol-5-yl) -acetyl] -1,2,3,4-tetrahi
Droquinolin-6-yl] -butyric acid was prepared as a white solid. [Elemental analysis: C, 71.11; H
, 6.55; N, 8.66%: Calculated for C ₃₀ H ₃₁ N ₃ O ₄・ 0.5H ₂ O: C, 71.15; H, 6.32; N, 8
.30%], MS (ES ⁺ ) 498 (MH ⁺ ).

(C) Ethyl (R / S) 3- (1-[[3-methoxy-4- (3-o-) in industrial methylated spirits
Tolyl-ureido) -phenyl] -acetyl] -2,3-dihydro-1H-indol-5-yl)-
Using heptanoate (Reference Example 4 (p)) and proceeding as in Example 2 (a), the reaction was
At 45 ° C for 45 minutes to give (R / S) 3- (1-[[3-methoxy-4- (3-o-tolyl-urea) as a white solid.
Id) -Phenyl] -acetyl] -2,3-dihydro-1H-indol-5-yl) -heptanoic acid was prepared. LC-MS (replacement of the acetonitrile for the gradient elution with a formic acid (0.1 v / v) / acetonitrile mixture): R _T = 4.31 min (100% of total area according to ELS); MS (ES ⁺ ) 544 (MH ^<+> ), 566 (MNa ^<+> ). (d) Ethyl (R / S) 3-[-([4-[(2,3-dihydro-indole-1-carbonyl) -amino] -3-methoxy-phenyl]-in industrial methylated spirits Example 2 (a) using (acetyl) -2,3-dihydro-1H-indol-5-yl] -heptanoate (Reference Example 4 (q)).
The reaction was carried out at 80 ° C. for 45 minutes, and (R / S) 3-[-([4-[(2
, 3-Dihydro-indole-1-carbonyl) -amino] -3-methoxy-phenyl] -acetyl
L) -2,3-Dihydro-1H-indol-5-yl] -heptanoic acid was prepared. LC-MS (the acetonitrile for the gradient elution was replaced by a formic acid (0.1 v / v) / acetonitrile mixture): R _T =
4.47 min (100% of total area according to ELS); MS (ES ⁺ ) 556 (MH ⁺ ), 578 (MNa ⁺ ). (e) Ethyl (R / S) 3- (1-[[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl] -2,3-dihydro-1H-indole-5- Yl) -pentanoate (Reference Example 4 (r)) and proceeding as in Example 2 (a), the reaction was carried out at reflux temperature for 1 hour to give (R / S) 3- (1-[[3-Methoxy-4- (3-o-tolyl-ureido) -phenyl
[Acetyl] -2,3-dihydro-1H-indol-5-yl) -pentanoic acid . LC-MS
: R _T = 3.01 min; MS (ES ⁺ ) 538 (MNa ⁺ ).

(F) Ethyl (R / S) 3-[-([4-[(2,3-dihydro-indole-1-carbonyl) -amino] -3-methoxy- in industrial methylated spirits. Example 2 (a) using phenyl] -acetyl) -2,3-dihydro-1H-indol-5-yl] -pentanoate (Reference Example 4 (s)).
The reaction was carried out at 80 ° C. for 45 minutes, and (R / S) 3-[-([4-[(2
, 3-Dihydro-indole-1-carbonyl) -amino] -3-methoxy-phenyl] -acetyl
L) -2,3-Dihydro-1H-indol-5-yl] -pentanoic acid was prepared. LC-MS (the acetonitrile for the gradient elution was replaced by a formic acid (0.1 v / v) / acetonitrile mixture): R _T =
4.17 min (100% of total area according to ELS); MS (ES ⁺ ) 528 (MH ⁺ ), 550 (MNa ⁺ ). (g) Ethyl (R / S) 3- (1-[[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl] -2,3-dihydro-1H-indole-5- Yl) -3-phenyl-propionate (Reference Example 4 (s)) and proceeding as in Example 2 (a), the reaction was carried out at reflux temperature for 1 hour, as a gray solid, (R / S) 3- (1-[[3-methoxy-4- (3-o-tolyl-ureido) -f
[Enyl] -acetyl] -2,3-dihydro-1H-indol-5-yl) -3-phenyl-propio
Acid was obtained. LC-MS: _RT = 3.17 min; MS (ES ^<+> ) 564 (MH ^<+> ), 586 (MNa ^<+> ). (h) Ethyl (R / S) 3-[-([4-[(2,3-dihydro-indole-1-carbonyl) -amino] -3-methoxy-phenyl]-in industrial methylated spirits Acetyl) -2,3-dihydro-1H-indol-5-yl] -3-phenyl-propionate (Reference Example 4 (u)) and proceeding as in Example 2 (a), At 90 ° C. for 90 minutes to obtain a gray powder (
R / S) 3-[-([4-[(2,3-dihydro-indole-1-carbonyl) -amino] -3-methoxy-
[Phenyl] -acetyl) -2,3-dihydro-1H-indol-5-yl] -3-phenyl-propyl
Ononic acid was prepared. LC-MS (the acetonitrile for the gradient elution was replaced by a formic acid (0.1 v / v) / acetonitrile mixture): R _T = 4.27 min (100% of the total area according to ELS); MS (ES ⁺ ) 5
76 (MH ⁺ ), 598 (MNa ⁺ ).

Example 3 (a) (R / S) 3- (1-[[4- (3-o-tolyl-ureido) -phenyl] -acetyl] -2,3-dihydride
B-1H-Indol-5-yl) butyrate ethyl (R / S) 3- (1-[[4- (3-o-tolyl-ureido) -phenyl] -acetyl] -2,3-dihydro-1H- A mixture of indole-5-yl) -butyrate [0.55 g, Reference Example 4 (b)], aqueous sodium hydroxide solution (5.5 ml, 1 M), methanol (5.5 ml) and tetrahydrofuran (11 ml) was added at room temperature overnight. Stir and then evaporated to low volume. The residue obtained was diluted with water and the mixture was acidified by the addition of hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and dried to give the title compound (0.41 g) as a white powder. LC-
MS: R _T = 3.77 min (100% of total area according to ELS); MS (ES ⁺ ) 472 (MH ⁺ ), 494 (MNa ⁺ ). (b) Ethyl (R / S) 3- (1-[[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl] -1,2,3,4-tetrahydro-quinoline- Using (6-yl) -butyrate (Reference Example 4 (e)) and proceeding in the same manner as in Example 3 (a), (R / S) 3- (1-[[3-methoxy-4- ( 3-o-tolyl-U
(Reid) -phenyl] -acetyl] -1,2,3,4-tetrahydro-quinolin-6-yl) -butyric acid was prepared as a white powder. LC-MS: _RT = 3.89 min (100% of total area according to ELS); MS (ES ^<+> ) 516 (MH ^<+> ), 538 (MNa ^<+> ). (c) Ethyl (R / S) 3- (1-[[4- (3-o-tolyl-ureido) -phenyl] -acetyl] -1,2,
Using 3,4-tetrahydro-quinolin-6-yl) -butyrate (Reference Example 4 (f)), proceeding in the same manner as in Example 3 (a), (R / S) 3- (1- [ [4- (3-o-tolyl-ureido) -phenyl] -ace
[Tyl] -1,2,3,4-tetrahydro-quinolin-6-yl) -butyric acid was prepared as a white solid. LC-MS: _RT = 2.92 min (100% of total area according to ELS); MS (ES ^<+> ) 508 (MNa ^<+> ).

(D) Ethyl (R / S) 3- [1-[(2-o-tolylamino-benzoxazol-6-yl) -acetyl] -1,2,3,4-tetrahydro-quinoline-6 (R / S) 3- [1-[(2-o-tolylamino-benzoxazosol ) using (-yl) -butyrate (Reference Example 4 (g)) and proceeding as in Example 3 (a).
Ru-6-yl) -acetyl] -1,2,3,4-tetrahydro-quinolin-6-yl] -butyric acid was prepared as a colorless foam. LC-MS: R _T = 3.01 min (100% of total area according to ELS); MS (ES ⁺ )
484 (MH ^<+> ), 506 (MNa ^<+> ). Example 4 (a) 3- (1-[[3-Methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl] -2,3-
Dihydro-1H-indol-5-yl) -pentanedioic acid Dispersed in ethanol (10 ml), dimethyl 3- (1-[[3-methoxy-4- (3-o-tolyl
-Ureido) -phenyl] -acetyl] -2,3-dihydro-1H-indol-5-yl) -pentanedioate (270 mg, Reference Example 4 (c)) in water (2 ml). ) Was treated with a solution of sodium hydroxide (190 mg), and the mixture was stirred at reflux for 3 hours. After cooling to room temperature, the mixture was treated with water (10 ml) and then carefully acidified to pH 1 by the addition of hydrochloric acid (3M) with ice cooling. The resulting precipitate was collected by filtration, then dried and recrystallized from ethyl acetate to afford the title compound (6
0 mg). LC-MS: R _T = 2.44 min (100% of total area according to ELS); MS (ES ⁺ ) 568 (MNa ⁺ )
. (b) Dimethyl 3- (1-[[4- (3-o-tolyl-ureido) -phenyl] -acetyl] -2,3-dihydro-1H-indol-5-yl) -pentanedioate (Reference Example) Using 4 (d)) and proceeding in the same manner as in Example 4 (a), 3- (1-[[4- (3-o-tolyl-ureido) -phenyl] -acetyl ] -2,3 -Dihydro-1H-indol-5-yl) -pentanedionic acid was prepared as a white solid. ^{MS (ES -) 514 (M} -).

(C) Dimethyl 3- (1-[[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl] -1,2,3,4-tetrahydro-quinoline-6- Yl) -pentane dioate (Reference Example 4 (h)) and proceeding as in Example 4 (a), the product obtained is flash chromatographed on silica, methanol and dichloromethane Mixture with (1: 9, v / v)
And eluted with 3- (1-[[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl]
-1,2,3,4-Tetrahydro-quinolin-6-yl) -pentanedionic acid was obtained as a white foam. LC-MS: _RT = 2.40 min (100% of total area according to ELS); MS (ES ^<+> ) 582 (MNa ^<+> ).
(d) (R) 4- [2-methoxycarbonyl-1- (1-[[3-methoxy-4- (3-o-tolyl-ureido)
) -Phenyl] -acetyl] -1,2,3,4-tetrahydro-quinolin-6-yl) -ethylcarbamoyl] -butyrate (Reference Example 4 (i)) Proceeding similarly, the product obtained was subjected to flash chromatography on silica, eluting with a mixture of methanol and dichloromethane (1: 9, v / v) to give (R) 4- [2-carboxy- 1- (1-[[3-me
Toxi-4- (3-o-tolyl-ureido) -phenyl] -acetyl] -1,2,3,4-tetrahydro- quinolin-6-yl) -ethylcarbamoyl] -butyric acid was obtained as a white powder. LC-MS: _RT = 2.43 min (100% total area by ELS); MS (ES ^<+> ) 653 (MNa ^<+> ). (e) Methyl (R) N- [2-methoxycarbonyl-1- (1-[[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl] -1,2,3, 4-tetrahydro-quinolin-6-yl) -ethyl
] -Succinamate (Reference Example 4 (j)) and proceeded as in Example 4 (a), the product obtained was subjected to flash chromatography on silica to give a mixture of methanol and dichloromethane ( 1: 9, v / v) and eluted with (R) N- [2-carboxy-1- (1-[[3-meth
Xy-4- (3-o-tolyl-ureido) -phenyl] -acetyl] -1,2,3,4-tetrahydro-ki
Norin-6-yl) -ethyl] -succinamic acid was obtained as a colorless gum. LC-MS:
R _T = 2.44 min (100% of total area according to ELS); MS (ES ⁺ ) 639 (MNa ⁺ ).

Example 5: (R / S) 1- (4- [2-oxo-2- [6- (2-oxo-tetrahydro-pyran-4-yl)
-3,4-dihydro-2H-quinolin-1-yl] -ethyl] -phenyl) -3-o-tolyl-urea [4- (3-o-tolyl-ureido) -phenyl] -acetic acid (310 mg) and A solution of diisopropylethylamine (310 mg) and dimethylformamide (5 ml) was continuously treated with O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate ( 450 mg) and then treated with (R / S) 4- (1,2,3,4-tetrahydro-quinolin-6-yl) -tetrahydropyran-2-one (250 mg, Reference Example 5 (c)). After standing at room temperature for 2 hours, the mixture was partitioned between ethyl acetate (100ml) and dilute hydrochloric acid solution (100ml). The phases were separated and the organic phase was washed with water, dried and evaporated. The resulting residue was flash chromatographed on silica eluting with ethyl acetate to give a yellow gum which was dissolved in a minimum volume of ethanol, then the solution was treated with ether to give a yellow gum. to give a solid, which was collected by filtration and dried, the title as a yellow solid
The compound (80 mg) was obtained. LC-MS: R _T = 3.74 min (100% of total area according to ELS); MS (ES ⁺ ) 520
(MNa ⁺ ).

Example 6: (R) 3- (1-[[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl]
Methyl ] -1,2,3,4-tetrahydro-quinolin -6-yl) -3-[(5-methyl-isoxazole-3- carbonyl) -amino] -propionate (R) 3- (1-boc -1,2,3,4-tetrahydro-quinolin-6-yl) -3-[(5-methyl-
Isoxazole-3-carbonyl) -amino] -propionate (310 mg, Reference Example 17) was dissolved in a mixture of trifluoroacetic acid and dichloromethane (1: 3, v / v) and the resulting clear solution was allowed to stand at room temperature. Left for 2 hours. The residue obtained by the evaporation of this solution was treated with [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetic acid (280 mg), O- (7-azabenzotriazol-1-yl)- N, N, N ', N'-tetramethyluronium hexafluorophosphate (340mg) and diisopropylethylamine (1ml) and dimethylformamide
(30 ml). The resulting mixture was stirred at room temperature for 3 hours and then left overnight. The mixture was evaporated to low volume and the resulting residue was partitioned between ethyl acetate and dilute hydrochloric acid solution. The phases were separated and the organic phase was washed with sodium carbonate solution, dried and evaporated to give 580mg of an orange oil. Purification by flash chromatography, eluting with 1: 1 ethyl acetate-dichloromethane,
This gave an orange foam. This product was dissolved in methanol (20 ml) and the solution was
Treated with sodium hydroxide solution. After refluxing for 2 hours, the mixture was evaporated to low volume and the resulting residue was diluted with water. Acidification with dilute hydrochloric acid gave a gummy product, which was extracted with ethyl acetate solution. The solution was dried and evaporated to give the title compound (110mg) as a pale yellow foam. LC-MS: R _T = 2.94 min (100% of total area according to ELS); MS (ES ⁺ ) 648 (MNa ⁺ ).

[0364]Example 7 (a)(S) 2- (2-chloro-6-methyl-benzoylamino) -3- [1- (2,6-dichloro-ben
Zoyl) -1,2,3,4-tetrahydro-quinolin-6-yl] -propionic acid Methyl (S) 2-amino-3- [1- (2,6-dichloro-benzoy) in dimethylformamide
Ru) -1,2,3,4-tetrahydro-quinolin-6-yl] -propionate (200 mg, Reference Example 18)
, O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium
From xafluorophosphate (200mg) and 2-chloro-6-methylbenzoic acid (90mg)
The resulting mixture was treated with diisopropylethylamine (150 mg) and the resulting clear solution
The solution was left overnight at room temperature. The reaction mixture was mixed with ethyl acetate (50 ml) and dilute hydrochloric acid solution (
50 ml). The organic phase obtained is washed with sodium bicarbonate solution and
And dried and evaporated. The obtained residue is subjected to thin layer chromatography on silica.
Investigated using a mixture of ethyl acetate and dichloromethane (1: 9, v / v)
. The results showed two spots of very close intensity and very close. This generation
The product was flash chromatographed on silica, ethyl acetate and dichloro
When eluted with a mixture with methane (1: 9, v / v), most of the fractions showed mixed spots.
However, another fraction containing each pure component was obtained. Solution over about 1 hour
When maintained in pure form, each pure component returned to an equivalent mixture of the two components, but this
This suggests that these two spots are stable rotamers. Obedience
Thus, all fractions containing either or both of these spots were combined and evaporated.
This gave a colorless oil (160 mg). Dissolve this material in methanol (10 ml) and add
Treated with a solution of titanium (4 ml, 1M). After standing at room temperature for 30 minutes, the mixture is
And the resulting residue was dissolved in water (10 ml). Acidification with dilute hydrochloric acid produces white
A color precipitate is obtained, which is collected by filtration, washed with water and then dried to give a white solid Title compound (105 mg) was obtained. LC-MS: (Must be a mixture of two stable rotamers
): Rotamer 1, R_T= 2.79 min (57% of total area according to ELS); MS (ES⁺) 567, 56
9 (MNa⁺); Rotamer 2, R_T= 3.96 min (43% of total area according to ELS); MS (ES⁺) 567, 56
9 (MNa⁺).

(B) Using tetrahydro-pyran-4-carboxylic acid and operating as in Example 7 (a), (S) 3- [1- (2,6-dichloro-benzoyl)- 1,2,3,4-Tetrahydro-quinolin -6- yl] -2-[(tetrahydro-pyran-4-carbonyl) -amino] -propionic acid was obtained as a white powder. LC-MS: (indicating a mixture of two stable rotamers):
Rotamer 1, R _T = 2.47 min (52% of total area according to ELS); MS (ES ⁺ ) 527 and 529 (MN
a ⁺ ); rotamer 2, _RT = 2.66 min (48% of total area according to ELS); MS (ES ⁺ ) 527 and 529 (MNa ⁺ ). Example 8: (S) 2- (2,6-dichloro-benzoylamino) -3- [1- (2,6-dichloro-benzo)
Yl) -1,2,3,4-tetrahydro-quinolin-6-yl] -propionate methyl (S) 2-amino-3- [1- (2,6-dichloro-benzoyl) -1,2,3 , 4-tetrahydro-
A solution of [quinolin-6-yl] -propionate (180 mg, Reference Example 18) in dichloromethane (10 ml) was treated with diisopropylethylamine (150 mg) and then with 2,6-dichlorobenzoyl chloride (130 mg). After standing at room temperature overnight, the mixture was added to ethyl acetate (50 ml
) And dilute hydrochloric acid solution (50 ml). The organic phase was washed with a sodium bicarbonate solution, then dried and evaporated. The resulting residue was subjected to flash chromatography on silica, eluting with a mixture of ethyl acetate and dichloromethane (1: 9, v / v) to give a colorless oil (160 mg). This material was treated with methanol (10ml) followed by lithium hydroxide solution (4ml, IM). After standing at room temperature for 1 hour, the mixture was evaporated to low volume and the residue obtained was dissolved in water (10 ml). The solution was made acidic by the addition of dilute hydrochloric acid. The resulting white precipitate was filtered, washed with water, and dried to give the title compound (120 mg) as a white solid. LC-MS: (indicating a stable rotamer mixture): rotamer 1, R _T = 2.79 min (48% of total area according to ELS); MS (ES ⁺ ) 587 and 599 (MNa ⁺ ); Rotamer 2, R _T = 3.74 min (10 of total area according to ELS); MS (ES ⁺ ) 58
7 and 589 (MNa ⁺ ); rotamer 3, R _T = 3.96 min (46% of total area by ELS); MS (ES ⁺ ) 587 and 599 (MNa ⁺ ).

Example 9: (R / S) 3- [1-([4-[(2,3-dihydro-indole-1-carbonyl) -amino]-
3-methoxy-phenyl] -acetyl) -1,2,3,4-tetrahydro-quinolin-6-yl] -butyric
Acid step 1 : bromo-won resin (1 g, nominal input 1 mM / g, Novabiochem) is suspended in dimethylformamide (15 ml) and continuously suspended in 6- (2-carboxy-1-methyl-ethyl) -3, 4-Dihydro-2H-quinoline-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (880 mg, Reference Example 28) in dimethylformamide (5 ml) solution, diisopropylethylamine (0.35 ml
) And cesium iodide (270 mg). The mixture was left overnight at room temperature with occasional shaking. The resin was drained and then (i) 5 times with dimethylformamide, (i
Washed 3 times with i) water, 3 times with (iii) dimethylformamide, 3 times with (iv) methanol, 4 times with (v) dichloromethane and 2 times with (vi) ether and then dried. Step 2 : Next, the resin from step 1 is mixed with piperidine and dimethylformamide (
20 ml, 1: 4, v / v) and the mixture was kept at room temperature for about 2 hours with occasional shaking. The resin was drained and then washed (i) five times with dimethylformamide, (ii) three times with methanol, (iii) four times with dimethylformamide, and (vi) twice with ether, and then dried.

Step 3 : The resin from step 2 is then suspended in dimethylformamide (15 ml) and successively
O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (570 mg), [4-[(2,3-dihydro-indole-1- Carbonyl)
Treated with -amino] -3-methoxy-phenyl] -acetic acid (490 mg) and diisopropylethylamine (0.52 ml) and left overnight at room temperature with occasional shaking. The resin was drained and then washed (i) five times with dimethylformamide, (ii) three times with methanol, (iii) four times with dimethylformamide, and (vi) twice with ether, and then dried. Step 4 : The resin from Step 3 is mixed with a mixture of trifluoroacetic acid and dichloromethane (about 10
ml, 1: 1, v / v) and the mixture was kept at room temperature for about 1 hour with occasional shaking.
The resin is drained and a mixture of trifluoroacetic acid and dichloromethane (about 1 ml, 1: 1, v / v
Washed in v). The combined filtrates were evaporated and the remaining brown oil was washed with ether, then with dichloromethane and then acidified by adding hydrochloric acid. The precipitated product was extracted four times with dichloromethane. The combined extracts were dried and then evaporated. The obtained residue was crushed with ether to obtain the title compound (120 mg) as a creamy solid. LC-MS: _RT = 3.16 min (100% of total area according to ELS); MS (ES ^<+> ) 550 (MNa ^<+> ). Example 10: (S) 2-acetylamino-3- (1-[[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl] -1,2,3,4-tetrahydro -Quinolin-6-yl) -methyl propionate (S) 2-acetylamino-3- (1-[[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl] -1, 2,3,4-tetrahydro-quinolin-6-yl) -propionate (2
20 mg, Reference Example 4 (l)) in dioxane (3 ml) was treated with lithium hydroxide hydrate (50 mg) in water (1
ml) solution. The mixture was stirred at room temperature for 3 hours, then treated with water (5 ml) and further acidified (with ice cooling) to pH 1-2 by addition of dilute hydrochloric acid. The resulting precipitate was extracted three times with ethyl acetate, and the combined extracts were washed with water and brine, dried and evaporated. The residue was recrystallized from ethyl acetate to give the title compound (21 mg) as a white powder. LC-MS: _RT = 2.77 min (100% of total area according to ELS); MS (ES ^<+> ) 581 (MNa ^<+> ).

Example 11: (R / S) 3- (1-[[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -ace
Tyl] -2,3-dihydro-1H-indol-5-yl) -butyric acid, Na salt (R / S) 3- (1-[[3-methoxy-4- (3-o-tolyl-ureido)- Phenyl] -acetyl] -2,
3-Dihydro-1H-indol-5-yl) -butyric acid (2.1 g) in methanol (about 150 ml)
Treated with exactly one equivalent of 0.1 M sodium hydroxide solution. Evaporating the methanol,
The residue obtained was diluted with water (about 120 ml) and lyophilized. The lyophilizate was crushed with ether, and the insoluble matter was washed with ether, then with pentane, and further dried.
The title compound (1.9 g) was obtained as a gray free flowing powder. MS (ES ⁺ ) 552 (MH ⁺ ). [Elemental analysis: C, 60.01; H, 6.13 ; N, 7.28; H 2 O, 8.25%: C 29 H 30 N 3 NaO 5 · 0.3H 2 O Calculation: C, 60.25; H, 6.20 ; N, 7.27 _{; H 2 O, 9.3%]} . Example 12 (a) (S) 2- (2,6-dichloro-benzoylamino) -3- [1-[(2-o-tolylamino-benzo)
Xazol-6-yl) -acetyl] -1,2,3,4-tetrahydro-quinolin-6-yl] -pro
Methyl acid (S) 2- (N-boc- amino) -3- [1 - [(2 -o- tolylamino - benzoxazole-6-
Yl) -acetyl] -1,2,3,4-tetrahydro-quinolin-6-yl] -propionate (200
mg, Reference Example 4 (m)) was treated with trifluoroacetic acid (3 ml), and the resulting solution was treated at room temperature for 15 minutes.
Let stand for minutes and then evaporate. The obtained residue was dissolved in dichloromethane (20 ml),
Diisopropylethylamine (260 mg), followed by 2,6-dichlorobenzoyl chloride (1
40 mg). After standing at room temperature overnight, the mixture was evaporated to low volume and the resulting residue was partitioned between ethyl acetate (50ml) and dilute hydrochloric acid. The organic phase obtained was washed with sodium bicarbonate solution, then dried and evaporated. The obtained residue is
Flash chromatography on silica, eluting with a mixture of ethyl acetate and dichloromethane (15:85, v / v). The obtained colorless gum, methanol (10 ml),
Then treated with lithium hydroxide solution (2 ml, 1M). After standing at room temperature for 2 hours, the mixture was evaporated to low volume, the residue obtained was treated with water (10 ml) and the mixture was acidified by addition of dilute hydrochloric acid. The resulting white precipitate was filtered off, washed with water and dried to give the title compound (90 mg) as a white powder. LC-MS: R _T = 2.97 min (100% of total area according to ELS); MS (ES ⁺ ) 657 and 659 (MH ⁺ ), 679 and 681 (MNa ⁺ ).

(B) Methyl (S) 3- [1- (2-chloro-benzoyl) -1,2,3,4-tetrahydro-quinoline-6
-Yl] -2- (N-boc-amino-propionate (Reference Example 4 (n)) and 2-chloro-6-methylbenzoyl chloride, operating in the same manner as in Example 12 (a), (S) 3- [1- (2-black
(R-benzoyl) -1,2,3,4-tetrahydro-quinolin-6-yl] -2- (2-chloro-6-methyl
Ru-benzoylamino) -propionic acid was prepared as a white powder. LC-MS: R _T = 2.7
6 min (100% of total area according to ELS); MS (ES ⁺ ) 533 and 535 (MNa ⁺ ). (c) methyl (S) 3- [1-[(4-acetoxy-3-chloro-phenyl) -acetyl] -1,2,3,4-
Tetrahydro-quinolin-6-yl] -2- (N-boc-amino) -propionate (Reference Example 4 (o)
) And 2-chloro-6-methylbenzoyl chloride, operating as in Example 12 (a), yielding (S) 3- [1-[(3-chloro-4-hydroxy-phenyl)- Acetyl] -1,2,3,4-te
Trahydro-quinolin-6-yl] -2- (2-chloro-6-methyl-benzoylamino ) -pro
Pionic acid was prepared. LC-MS: R _T = 2.67 min (100% of total area according to ELS); MS (ES ⁺ ) 56
3 and 565 (MNa ⁺ ). Reference Example 1: Ethyl 3- [1- (2- [3-methoxy-4-[(2-toluidinocarbonyl) -amino ]-
[Phenyl] -acetyl) -1,2,3,4-tetrahydro-6-quinolinyl] -propionate 3-methoxy-4- [3- (2-methylphenyl) stirred at 20 ° C. under an argon atmosphere.
Ureido] phenylacetic acid (0.232 g, prepared as described in Example 52B of International Patent Application Publication No. -(1,2,3,4-tetrahydro-6-quinolinyl) propionate (
0.115 g, Reference Example 2), triethylamine (0.275 ml), O- (7-azabenzotriazole-1-
Yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (0.223 g)
And 4-dimethylaminopyridine (6 ml). After stirring at 20 ° C. for 1 hour, the reaction mixture was filtered through a pad of celite. This filtrate is under reduced pressure (2.7 kPa)
At 40 ° C. and the resulting residue was treated with ethyl acetate (25 ml). The resulting solution was washed twice with a saturated aqueous ammonium chloride solution (5 ml), then with water (5 ml), dried over magnesium sulfate and evaporated at 40 ° C. under reduced pressure (2.7 kPa) . The resulting white foamy solid (0.457 g) was subjected to flash chromatography on silica (0.040-0.063 mm) to give a mixture of cyclohexane and ethyl acetate (250 ml of 9: 1, then 7: 3 Eluting with 500 ml of the product and 1000 ml of the 4: 6 product (v / v)) to give the title compound as a white foamy solid.
To obtain a thing (0.244g).

Reference Example 2 Ethyl 3- (1,2,3,4-tetrahydro-6-quinolinyl) propionate Ethyl 3- (6-quinolinyl) propionate (0.3 g, Reference Example) in hydrochloric acid (3 ml, 0.1 N) A stirred mixture containing 3) and 5% rhodium in carbon powder (33 mg) was hydrogenated in a 22 cm ³ volume stainless steel pressure reactor at a hydrogen pressure of 5 MPa (50 bar). twenty five
After stirring at 4 ° C. for 4 hours, an additional 30 mg of 5% rhodium (33 mg) in carbon powder was added,
The hydrogenation was continued at 25 ° C. for 1 hour at a pressure of 5 MPa (50 bar). This reaction mixture is
Filtration through a pad of celite, the filter pad was washed with hydrochloric acid (3 ml, 0.1 N) followed by ethyl acetate (25 ml). The combined filtrate and washings were combined and the aqueous phase was decanted from the organic phase. The aqueous phase was extracted twice with ethyl acetate (25ml) and these were combined with the organic phase described above. The combined solution was dried over magnesium sulfate and then evaporated under reduced pressure (2.kPa) at 40 ° C. to afford the title compound as a brown oil (
0.121 g). Reference Example 3: Ethyl 3- (6-quinolinyl) propionate Dimethylformamide (45 ml) and pyridine (5
ml), tetrabutylammonium bromide (250 mg), tetrabutylammonium iodide (18.8 mg) and 1,2-dibromoethane (0.15 ml). In this solution,
Oxygen was removed from the solution by bubbling argon for 10 minutes. After performing a preliminary electrolysis at a constant current of 125 mA for 30 minutes, the stirred mixture was mixed with nickel bromide trihydrate (341 mg), 6-bromoquinoline (2.6 g), and ethyl acrylate (3.12 g).
Processed. Stirring was continued until complete dissolution. The reaction medium was heated to 60 ° C. and then electrolysis was performed using a constant current of 250 mA and maintaining the temperature at 60 ° C. After 3 hours and reaching a current of 2810 coulombs (ie 2.33 farads per mole of 6-bromoquinoline), the electrolysis was stopped. The electrolyzed solution plus a dimethylformamide wash of the electrochemical device and electrodes (20 ml) was treated with water (20 ml), then treated with heptane (70 ml), ethyl acetate (50 ml) and diethyl ether (50 ml). Extracted times. The combined extracts were evaporated at 40 ° C. under reduced pressure (2.7 kPa). Residual yellow oil (2.78
g) was subjected to pressure column chromatography on silica (40 mm diameter column, 100
g of silica 60 Merck (0.040-0.063 mm)) and apply slight argon pressure (about 30 k
Pa), cyclohexane, ethyl acetate and 2-propanol (90: 8: 2 then 85/12 /
3; v / v / v) to give the title compound (1.92 g) as a yellowish oil.

The electrochemical device was provided concentrically around a cylindrical body (50 ml capacity) containing the reaction medium and into which a 10 mm diameter soft iron bar (consumable anode) was inserted, and the anode. , Cylindrical nickel foam grid (diameter 30mm, height 42.5mm, surface connection about 40ml)
A glass lid with five screw-in outputs; a central output for electrical contact of the anode; a cathode, a thermometer, a tubing for supplying argon and four peripheral outputs for a coolant containing water. It consists of a part. The two parts of the electrolyzer are joined by the interposition of a flat grinding with an inner diameter of 60 mm, ensuring a tight seal. The reaction medium is maintained under an inert atmosphere by continuously blowing argon through the solution during the electrolysis. The electrodes are connected to a stabilized power supply or intentiostat. Further, in the anode circuit, a current integrator is connected in series. The reaction medium is stirred by a magnetic bar coated with Teflon (Teflon ^R). The body of the electrochemical device can be immersed in an oil bath at the temperature required for the reaction. Reference Example 4 (a) Ethyl (R / S) 3- (1-[(3-methoxy-4- (3-o-tolyl-ureido) -phenyl) -a
[Cetyl] -2,3-dihydro-1H-indol -5-yl) -butyrate dimethylformamide (about 40 ml) in [3-methoxy-4- (3-o-tolyl-ureido)
-Phenyl] -acetic acid (2.9 g) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N'
A solution of -tetramethyluronium hexafluorophosphate (3.7 g) was treated with diisopropylethylamine (10 ml), and after about 30 seconds, dimethylformamide (about 10 m
l), (R / S) ethyl 3- (2,3-dihydro-1H-indol-5-yl) -butyrate (about 2.5
g, the solution of Reference Example 5 (a)). The resulting clear dark brown solution was maintained at room temperature for 1 hour and then evaporated to low volume. The residue obtained was partitioned between water and ethyl acetate, and the organic phase was washed with dilute hydrochloric acid, then with aqueous sodium bicarbonate solution, then with brine, then dried and evaporated. The residual brown gum is flash chromatographed on silica and a mixture of ethyl acetate and gasoline (3: 2 to 3: 1, v / v)
To give the title compound (2.8 g) as a pale yellow amorphous foam. MS (ES ⁺ ) 552 (MNa ⁺ ).

(B) [4- (3-o-Tolyl-ureido) -phenyl] -acetic acid and (R / S) ethyl 3- (2,3-dihydro-1H-indol-5-yl) -butyrate Reference Example 4 (a) except that
In the same manner as described above, ethyl (R / S) 3- (1-[( 4- (3-o-tolyl-ureido) -phenyl) -a
[Cetyl] -2,3-dihydro-1H-indol -5-yl) -butyrate was prepared as a gray solid. ^{MS (ES +) 500 (MH} +); 522 (MNa +); MS (ES -) 498 (M -). (c) [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetic acid and dimethyl 2- (2
2,3-dihydro-1H-indol-5-ylmethyl) -pentanedioate (Reference Example 9), except that coupling was carried out in the same manner as in Reference Example 4 (a) to obtain dimethyl 3- (1-[( 3-Metoki
C-4- (3-o-tolyl-ureido) -phenyl) -acetyl] -2,3- dihydro-1H-indole
Ru-5-yl) -pentanedioate was obtained as a gray foam. MS (ES ⁺ ) 574 (MH ⁺ ); 596 (MNa ⁺ ). (d) [4- (3-o-tolyl-ureido) -phenyl] -acetic acid and dimethyl 2- (2,3-dihydro-
Except for coupling with 1H-indol-5-ylmethyl) -pentanedioate (Reference Example 9), the same operation as in Reference Example 4 (a) was carried out to give dimethyl 3- (1- [(Four
-(3-o-Tolyl-ureido) -phenyl) -acetyl] -2,3-dihydro-1H-indol-5- yl) -pentanedioate . ^{MS (ES +) 566 (MNa} +); MS (ES -) 542 (M -).
(e) [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetic acid and ethyl (R / S) 3
-(1,2,3,4-tetrahydro-quinolin-6-yl) -butyrate (Reference Example 5 (b)), except that coupling was carried out in the same manner as in Reference Example 4 (a) to obtain a yellow As a gum, ethyl (R / S
) 3- (1-[(3-Methoxy-4- (3-o- tolyl-ureido) -phenyl) -acetyl] -1,2,3,4- tetrahydro-quinolin-6-yl) -butyrate Was. MS (ES ⁺ ) 544 (MH ⁺ ); 566 (M
^{Na +); MS (ES -} ) 542 (M -). (f) [4- (3-o-tolyl-ureido) -phenyl] -acetic acid and ethyl (R / S) 3- (1,2,3,4-tetrahydro-quinolin-6-yl) -butyrate ( Except for coupling with Reference Example 5 (b)), the same operation as in Reference Example 4 (a) was carried out to obtain ethyl (R / S) 3- (1-[(4- (3-o-tolyl-ureido). )
-Phenyl) -acetyl] -1,2,3,4-tetrahydro-quinolin-6-yl) -butyrate was obtained.

(G) (2-o-tolylamino-benzoxazol-6-yl) -acetic acid and ethyl (R / S) 3- (1,2
, 3,4-tetrahydro-quinolin-6-yl) -butyrate (Reference Example 5 (b)) except that coupling was carried out in the same manner as in Reference Example 4 (a) to obtain ethyl (R / S) 3 -[1-[(2-o-tolylami
No-benzoxazol-6-yl) -acetyl]-1,2,3,4-tetrahydro-quinoline-6-
Yl] -butyrate was obtained. (h) [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetic acid and dimethyl 3- (1
, 2,3,4-tetrahydro-quinolin-6-yl) -pentanedioate (Reference Example 9 (b)) and the product was flash chromatographed on silica, ethyl acetate The same procedure as in Reference Example 4 (a) was carried out except that the mixture was eluted with a mixture with gasoline (3: 1, v / v) to give dimethyl 3- (1-[(3-methoxy-4- (3-o- Tolyl-ureido) -phenyl ) -acetyl] -1,2,3,4-tetrahydro -quinolin-6-yl) -pentanedioate ,
Obtained as a gray foam. ^{MS (ES +) 588 (MH} +); 610 (MNa +); MS (ES -) 586 (M -).
(i) [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetic acid and methyl (R) 4- [1-
(1,2,3,4-tetrahydro-quinolin-6-yl) -2-methoxycarbonyl-ethylcarbamoyl] -butyrate (Reference Example 13 (a)) and the product was purified on silica. The same procedure as in Reference Example 4 (a) was carried out, except that the mixture was subjected to flash chromatography and eluted with a mixture of methanol and dichloromethane (1:19, v / v), to give methyl (R) 4- [2-methyl
Toxicarbonyl-1- (1-[[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -a
Cetyl] -1,2,3,4-tetrahydro-quinolin-6-yl) -ethylcarbamoyl] -butyl
The product was obtained as a pale orange foam. ^{MS (ES +) 659 (MH} +); 681 (MNa +); MS (ES -) 658 (M -). (j) [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetic acid and (R) N- [2-methoxycarbonyl-1- (1,2,3,4-tetrahydro- Quinolin-6-yl) -ethyl] -succinamate (Reference Example 13 (b)) and the product was subjected to flash chromatography on silica to give a mixture of methanol and dichloromethane (1:19, v / v)
And the same operation as in Reference Example 4 (a), except that the methyl (R) N- [2-methoxycarbo
Nyl-1- (1-[[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl] -1,2,3
, 4-Tetrahydro-quinolin-6-yl ) -ethyl] -succinamate was obtained as a pale orange foam. MS (ES ⁺ ) 667 (MNa ⁺ ).

(K) Ethyl (R / S) 3- (1,2,3,4-tetrahydro-quinolin-6-yl) -butyrate (Reference Example 5 (b)) and (1-boc-2- o-tolylamino-1H-benzimidazol-5-yl) -acetic acid (
Reference Example 22) was coupled and flash chromatographed on silica, eluting with a mixture of ethyl acetate and cyclohexane (3: 7, v / v), except that Reference Example 4 (a ), And treated in the same manner as for ethyl (R / S) 3- [1-[(2-o-tolylamino-3H-
Nzimidazol-5-yl) -acetyl] -1,2,3,4-tetrahydro-quinolin-6- yl]
-I got butyric acid . (l) [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetic acid and (S) methyl 2-
Acetylamino-3- (1,2,3,4-tetrahydro-quinolin-6-yl) -propionate (
Reference Example 19 (b)) and the product was subjected to flash chromatography on silica, eluting with a mixture of methanol and dichloromethane (1:19, v / v), except that Reference Example 4 Operating in the same manner as in (a), methyl (S) 2-acetylamino-3- (1-[[3
-Methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl]-1,2,3,4-tetrahi
Dro-quinolin-6-yl) -propionate was obtained as a gray foam. MS (ES ⁺ ) 53
^{7 (MH +); MS (} ES -) 572 (M -). (m) (2-o-tolylamino-benzoxazol-6-yl) -acetic acid and (S) methyl 2- (N-boc
-Amino) -3- (1,2,3,4-tetrahydro-quinolin-6-yl) -propionate (Reference Example 1
9), and the product was subjected to flash chromatography on silica, eluting with a mixture of ethyl acetate and dichloromethane (1: 9, v / v), except for Reference Example 4 (a). Proceeding similarly, (S) methyl 2- (N-boc-amino) -3- [1-[(2-o-tolyl
Mino-benzoxazol-6-yl) -acetyl] -1,2,3,4-tetrahydro-quinolin-6- yl] -propionate was obtained as a colorless gum.

(N) 2-chlorobenzoic acid and methyl (S) 2- (N-boc-amino) -3- (1,2,3,4-tetrahydro-quinolin-6-yl) -propionate (reference Example 19), except that the product was subjected to flash chromatography on silica, eluting with a mixture of ethyl acetate and dichloromethane (15:85, v / v). using the same method as the eyes
Tyl (S) 3- [1- (2-chloro-benzoyl ) -1,2,3,4-tetrahydro-quinolin-6-yl]-
2- (N-boc-amino) -propionate was obtained as a colorless oil. (o) (4-acetoxy-3-chloro-phenyl) -acetic acid and methyl (S) 2- (N-boc-amino) -3
-(1,2,3,4-tetrahydro-quinolin-6-yl) -propionate (Reference Example 19) and the product was subjected to flash chromatography on silica, ethyl acetate and dichloromethane. Reference Example 4 (a) except that the mixture was eluted with a mixture of (15:85, v / v)
(S) methyl 3- [1-[(4-acetoxy-3-chloro-phenyl) -acetyl
Ru] -1,2,3,4-tetrahydro-quinolin -6-yl] -2- (N-boc-amino) -propione
Was obtained as a colorless oil. (p) 3-methoxy-4- (3-o-tolyl-ureido) -phenylacetic acid and ethyl (R / S) 3- (2,3
-Dihydro-1H-indol-5-yl) -heptanoate (Reference Example 24 (a)) and the product was subjected to flash chromatography on silica to give a mixture of ethyl acetate and pentane (11 : 9, v / v), and the same operation as in Reference Example 4 (a) was carried out, except that ethyl (R / S) 3- (1-[[3-methoxy-4- (3-o-tolyl -Ureido) -phenyl] -ace
[Tyl] -2,3-dihydro-1H-indol-5-yl) -heptanoate was obtained as a foam.

(Q) 4-[(2,3-dihydro-indole-1-carbonyl) -amino] -3-methoxy-phenylacetic acid and ethyl (R / S) 3- (2,3-dihydro-1H -Indole-5-yl) -heptanoate
(Reference Example 24 (a)), except that coupling was carried out in the same manner as in Reference Example 4 (a) to obtain ethyl (R / S) 3-[-([4-[(2,3-dihydro- Indole-1-carbonyl) -amino] -3-methoxy- phenyl] -acetyl) -2,3-dihydro-1H-indol-5-yl] -heptanoate
Obtained as a white solid. MS (ES ⁺ ) 606 (MNa ⁺ ). (r) 3-methoxy-4- (3-o-tolyl-ureido) -phenylacetic acid and ethyl (R / S) 3- (2,
3-Dihydro-1H-indol-5-yl) -pentanoate (Reference Example 24 (b)) was coupled and the product was subjected to flash chromatography on silica to give a mixture of dichloromethane and methanol (99 : 1, v / v), except that the compound was eluted with the same procedure as in Reference Example 4 (a), except that ethyl (R / S) 3- (1-[[3-methoxy-4- (3-o-tolyl -Ureido) -phenyl ] -acetyl] -2,3-dihydro-1H-indol-5-yl) -pentanoate was obtained as a glass. (s) 4-[(2,3-dihydro-indole-1-carbonyl) -amino] -3-methoxy-phenylacetic acid and ethyl (R / S) 3- (2,3-dihydro-1H-indole- Except for coupling with 5-yl) -pentanoate (Reference Example 24 (b)), the same operation as in Reference Example 4 (a) was carried out to give an ethyl compound.
(R / S) 3-[-([4-[(2,3-dihydro- indole-1-carbonyl) -amino] -3-methoxy
[Ci-phenyl] -acetyl) -2,3-dihydro-1H-indol-5-yl] -pentanoate was obtained as a white solid. MS (ES ^<+> ) 578 (MNa ^<+> ).

(T) 3-methoxy-4- (3-o-tolyl-ureido) -phenylacetic acid and ethyl (R / S) 3- (2,3
-Dihydro-1H-indol-5-yl) -3-phenyl-propionate (Reference Example 24 (c)) and the product was subjected to flash chromatography on silica, giving pentane and ethyl acetate. Of ethyl (R / S) 3- (1-[[3-methoxy-4- (3 -o-tolyl-ureido) -fe
Nyl ] -acetyl] -2,3-dihydro-1H-indol-5-yl) -3-phenyl -propione
The product was obtained as a foam. (u) 4-[(2,3-dihydro-indole-1-carbonyl) -amino] -3-methoxy-phenylacetic acid and ethyl (R / S) 3- (2,3-dihydro-1H-indole- 5-yl) -3-phenyl-
Except for coupling with propionate (Reference Example 24 (c)), the same operation as in Reference Example 4 (a) was carried out to obtain ethyl (R / S) 3-[-([4-[(2,3-dihydro -Indole-1-carbonyl) -amid
[No] -3-methoxy-phenyl] -acetyl) -2,3-dihydro-1H-indol-5-yl] -3- phenylpropionate was obtained as a gray solid. MS (ES ⁺ ) 626 (MNa ⁺ ). Reference Example 5 (a) Ethyl (R / S) 3- (2,3-dihydro-1H-indol-5-yl) -butyrate (R / S) ethyl 3 cooled in an ice bath -(1-boc-2,3-dihydro-1H-indol-5-yl
A solution of) -butyrate (3.1 g, Reference Example 6) in dichloromethane (30 ml) was treated with trifluoroacetic acid (30 ml). After about 30 minutes, the mixture was evaporated and traces of trifluoroacetic acid were removed (twice) by chasing with toluene to give the title compound as a dark viscous gum, which was further purified. Used immediately without.

(B) Reference Example except that ethyl (R / S) 3- (1-boc-1,2,3,4-tetrahydro-quinolin-6-yl) -butyrate (Reference Example 11) was used Operating in the same manner as 4 (a), ethyl (R / S) 3- (1,
2,3,4-Tetrahydro-quinolin-6-yl) -butyrate was obtained. (c) using (R / S) 4- (1-boc-1,2,3,4-tetrahydro-quinolin-6-yl) -tetrahydropyran-2-one (Reference Example 16), and Reference Example 4 except that
( R / S) 4- (1,2,3,4-tetrahydro-quinolin-6-yl) -tetra
Lahydropyran-2-one was prepared as a brown solid. Reference Example 6: (R / S) ethyl 3- (1-boc-2,3-dihydro-1H-indol-5- yl) -butylene
Containing ethyl 3- (1-boc-2,3-dihydro-1H-indol-5-yl) -crotonate (11.4 g, Reference Example 7) and ammonium formate (about 30 g) in triethanol (about 200 ml) The mixture was warmed to 60 ° C. in an oil bath. Palladium activated carbon (10%, about 1 g) was added all at once under a nitrogen atmosphere and foaming started immediately. About 60 ° C.
Stir for 1 hour, then cool to room temperature and filter through celite. The filtrate obtained was evaporated and the residue obtained was partitioned between water and ethyl acetate. The resulting organic phase was washed with water, dried, followed by evaporation of the title as a colorless mobile oil
Compound (11.1 g) was obtained.

Reference Example 7 (a) Ethyl 3- (1-boc-2,3-dihydro-1H-indol-5-yl) -crotonate 1-boc-5-bromoindoline (60 ml) in dimethylformamide (60 ml) 15.0 g, Reference Example 8)
A mixture containing ethyl crotonate (8.6 g), palladium acetate (480 mg), tris (o-tolyl) phosphine and triethylamine (10 ml) at about 100 ° C. for about 4 hours.
The mixture was stirred in a sealed container under an argon atmosphere. After cooling to room temperature, the dark whole was poured into hydrochloric acid (about 1 L, 1 M) and the product was extracted with ethyl acetate. The combined extracts were washed with aqueous sodium bicarbonate solution, then with brine, then dried and evaporated. The remaining pale yellow oil was subjected to flash chromatography on silica, eluting first with a mixture of ethyl acetate and gasoline (5:95, v / v) to remove highly eluting impurities and then Elution with a mixture of ethyl acetate and gasoline (1: 9, v / v) gave the title compound (11.4 g) as a colorless mobile oil. (b) The same operation as in Reference Example 7 (a) was carried out except that methyl acrylate was used, and the reaction was carried out at 80 ° C., to give methyl 3- (1-boc-2, 3-dihydro-1H
-Indol-5-yl) -acrylate was prepared. MS (ES ⁺ ) 629 (MNa ⁺ ). (c) Except for using 1-boc-6-indo-1,2,3,4-tetrahydroquinoline (Reference Example 12), operating in the same manner as in Reference Example 7 (a), as a pale yellow solid, Ethyl 3- (1-boc-1,2,3,
4-Tetrahydro-quinolin-6-yl) -crotonate was prepared. (d) 1-boc-6-indo-1,2,3,4-tetrahydroquinoline (Reference Example 12) Except that methyl acrylate was used and the reaction was carried out at 80 ° C, Reference Example 7 (a ), Methyl 3- (1-boc-1,2,3,4-tetrahydro-quinoline-6-
Yl) -acrylate was prepared.

Reference Example 8 1-boc-5-bromoindoline 5-bromoindoline (10 g) was added in one portion to molten Boc-anhydride (11.6 g) at 30-40 ° C. A solid cake formed with immediate bubbling, which was crushed with pentane to give the title compound (15 g) as a white powder. Reference Example 9 (a) Dimethyl 2- (2,3-dihydro-1H-indol-5-ylmethyl) -pentanedioe
Over preparative dimethyl 3- (1-boc-2,3- dihydro -1H- indol-5-yl) -2-methoxycarbonyl - pentanedioate and (530 mg, Reference Example 10 (a)), concentrated hydrochloric acid (20ml) Was left overnight at reflux temperature and then evaporated. The remaining clear foam (370 mg) was treated with methanol (20 ml) followed by concentrated sulfuric acid (10 drops). The resulting solution was stirred at reflux for 2 hours and then evaporated. The resulting residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic and extract phases were washed with brine, dried and evaporated. The resulting residue was subjected to flash chromatography on silica, eluting with a mixture of ethyl acetate and gasoline (1: 1, v / v) to give the title compound (150 mg) as a clear oil.
MS (ES ^<+> ) 278 (MH ^<+> ). (b) Except for using ethyl 3- (1-boc-1,2,3,4-tetrahydro-quinolin-6-yl) -2-ethoxycarbonyl-pentanedioate (Reference Example 10 (b)), By operating in the same manner as in Example 9 (a), dimethyl 3- (1,2,3,4-tetrahydro-quinolin-6- yl was obtained as a colorless oil.
) -Pentanedioate was prepared. MS (ES ⁺ ) 292 (MH ⁺ ), 314 (MNa ⁺ ).

Reference Example 10 (a) Dimethyl 3- (1-boc-2,3-dihydro-1H-indol-5-yl) -2-methoxycarbo
Nyl-pentanedioate A stirred solution of sodium (156 mg) in methanol (15 ml) was treated with dimethyl malonate (0.8 ml) and after stirring for 15 minutes, the mixture was treated with methyl 3- (1-boc- It was treated with a solution of 2,3-dihydro-1H-indol-5-yl) -acrylate (1.0 g, Reference Example 7 (b)) in tetrahydrofuran (15 ml). The mixture was stirred at reflux for 3 hours, then cooled to room temperature, treated with water (2ml) and then evaporated. The resulting residue was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with fresh ethyl acetate. The combined organic and extract phases were washed with brine, dried and evaporated. The resulting residue was subjected to flash chromatography on silica, eluting with a mixture of ethyl acetate and gasoline (15:85, v / v) to give the title compound (530 mg) as a clear oil.
I got ^{MS (ES +) 458 (MNa} +), MS (ES -) 434 (M -). (b) methyl 3- (1-boc-1,2,3,4-tetrahydro-quinolin-6-yl) -acrylate (
Except for using Reference Example 7 (d)), the same operation as in Reference Example 10 (a) was carried out to obtain ethyl 3- (1-boc-1,2
, 3,4-tetrahydro-quinolin-6-yl) -2-ethoxycarbonyl-pentanedioie
Was prepared. ^{MS (ES +) 514 (MNa} +), MS (ES -) 490 (M -).

Reference Example 11 (a) Ethyl (R / S) 3- (1-boc-1,2,3,4- tetrahydro-quinolin-6-yl) -butylene
Ethyl 3- (1-boc-1,2,3,4-tetrahydro-quinoline-6- in triethanol (250 ml)
A mixture containing (yl) -crotonate (9 g, Reference Example 7 (c)) and 5% palladium on activated carbon (2.5 g) was hydrogenated at room temperature and pressure overnight. The spent catalyst was removed by filtration through celite and the filtrate was evaporated to give the title compound as a colorless oil.
(9.1 g) was obtained. (b) E and Z using ethyl 3- (1-acetyl-2,3-dihydro-1H-indol-5-yl) -hept-2-enoate (Reference Example 26 (a)) and 0.2 MPa ( 2 bar) hydrogen pressure, 4
The operation was performed in the same manner as in Reference Example 11 (a), except that hydrogenation was performed for 0.5 hour, and ethyl (R / S) 3
-(1-Acetyl-2,3-dihydro-1H-indol-5-yl) -heptanoate was prepared as a white solid. (c) E and Z using ethyl 3- (1-acetyl-2,3-dihydro-1H-indol-5-yl) -pent-2-enoate (Reference Example 26 (b)) and 0.2 MPa ( Under a hydrogen pressure of 2 bar), operating in the same manner as in Reference Example 11 (a), except that hydrogenation was performed for 100 minutes, ethyl (R / S)
3- (1-Acetyl-2,3-dihydro-1H-indol-5-yl) -pentanoate was prepared as a white solid. (d) E and Z Ethyl 3- (1-acetyl-2,3-dihydro-1H-indol-5-yl) -cinnamate (Reference Example 26 (c)) is used, and the pressure becomes 0.2 MPa (2 bar). Operating under the same conditions as in Reference Example 11 (a) except that hydrogenation was performed for 120 minutes under hydrogen pressure, ethyl (R / S) 3- (1- acetyl-2,3-dihydro-1H-indole -5-yl) -3-phenylpropionate ,
Prepared as a white solid.

Reference Example 12: A solution of iodine monochloride (16.2 g) dissolved in 1-boc-6-indo-1,2,3,4-tetrahydroquinolineacetic acid (30 ml) was dissolved in acetic acid (125 ml). To a stirred solution of 1,2,3,4-tetrahydroquinoline (12.6 ml) was added at room temperature under a nitrogen atmosphere. After stirring for another hour at room temperature, the resulting dark mixture was
The mixture was made basic by pouring into water (about 500 ml) and careful addition of solid potassium carbonate. The resulting aqueous phase was extracted with t-butyl methyl ether, the extract was washed successively with aqueous sodium thiosulfate solution, brine, dried and evaporated. The remaining brown gum (22 g) was treated with boc anhydride (44 g) in tetrahydrofuran (250 ml). The mixture was stirred at reflux temperature overnight, then evaporated and the resulting residue was partitioned between ethyl acetate and dilute hydrochloric acid. The organic phase obtained was washed with brine, then dried and evaporated. The residue was recrystallized from heptane to obtain the title compound (15 g) as a pale yellow powder.

Reference Example 13 (a) Methyl (R) 4- [1- (1,2,3,4-tetrahydro-quinolin-6-yl) -2-methoxycarb
Bonyl-ethylcarbamoyl] -butyrate methyl (R) 3-amino-3- (1-boc-1,2,3,4-tetrahydro-quinolin-6-yl) -propionate (1.7 g, Reference Example 14) was added to tetrahydrofuran (50 ml) and the stirred solution was treated with glutaric anhydride. After stirring for 4 hours, the mixture was evaporated to dryness and the residue obtained was dissolved in methanol (40 ml) and treated with concentrated sulfuric acid (20 drops). The solution was stirred at reflux for 3 hours and then left at room temperature overnight. Solid sodium bicarbonate (10
After addition of g), the mixture was evaporated to dryness and the residue obtained was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The resulting aqueous phase was extracted with fresh ethyl acetate. The combined organic and extract phases were washed with brine, dried and evaporated. The resulting residue was subjected to flash chromatography on silica, eluting with ethyl acetate to give the title compound (1.6g) as a yellow oil. MS (ES ⁺ ) 363 (MH ⁺ ), 38
^{5 (MNa +); MS (} ES -) 361 (M -). (b) The same treatment as in Reference Example 13 (a) was carried out except that succinic anhydride was used, to give (R) N- [2-meth
Xycarbonyl-1- (1,2,3,4-tetrahydro-quinolin-6-yl) -ethyl] -succina
The mate was obtained as a colorless oil. MS (ES ⁺ ) 371 (MNa ⁺ ).

Reference Example 14: (R) methyl 3-amino-3- (1-boc-1,2,3,4-tetrahydro- quinolin-6-i
3- propionate methyl 3- (R)-[benzyl-((S) -1-phenyl-ethyl) -amino] -3- (1-boc-1,2,3,4
-Tetrahydro-quinolin-6-yl) -propionate (6.5 g, Reference Example 15), a solution of ethanol (100 ml) dissolved in 20% palladium hydroxide-activated carbon (1.0 g), acetic acid (3.6 ml)
And water (10 ml) and the resulting mixture was hydrogenated at room temperature overnight. The spent catalyst was removed by filtration through Celite and the resulting filtrate was evaporated to low volume. The residue was taken up in ether, the solution was washed with aqueous sodium bicarbonate solution and the resulting phases were separated. The aqueous phase was extracted twice with fresh ether, and the combined ether extracts were washed with brine, dried, and evaporated. The resulting residue was subjected to flash chromatography on silica, eluting with a mixture of methanol and dichloromethane (1: 9, v / v) to give the title compound as a clear oil (1.7 g). Slowly crystallized on standing. MS (ES ⁺ ) 335 (MH ⁺ ), 357 (MNa ⁺ ), 669 (2MH ⁺ ).

Reference Example 15: Methyl 3- (R)-[benzyl-((S) -1-phenyl-ethyl) -amino] -3- (1-boc
-1,2,3,4-tetrahydro-quinolin-6-yl) -propionate (S) -N-benzyl-α-methylbenzylamine (2.6 ml) in anhydrous tetrahydrofuran (
50 ml), cooled to −70 ° C., and placed under a nitrogen atmosphere for about 5 minutes.
Treatment by dropwise addition of a solution of butyllithium in hexane (5 ml, 2.5 M) gave a red solution. After stirring for a further 40 minutes at -70 ° C, the mixture is allowed to stand for about 10 minutes.
Methyl 3- (1-boc-1,2,3,4-tetrahydro-quinolin-6-yl) -acrylate (2.0 g,
The solution was treated by dropwise addition of a solution of Reference Example 7 (d)) in tetrahydrofuran (20 ml). Stirring was continued at low temperature for another 20 minutes, then the reaction mixture was warmed to room temperature. The mixture was partitioned between ether and water, the phases formed were separated, the organic phase obtained was washed with water, then with brine, dried and then evaporated. The residue obtained is subjected to flash chromatography on silica and a mixture of ethyl acetate and gasoline (first 1: 9 then 15:
Elution at 85, v / v) gave the title compound (1.5 g) as a viscous, colorless oil.

Reference Example 16: (R / S) 4- (1-boc-1,2,3,4-tetrahydro-quinolin-6-yl) -tetrahydride
Lo-pyran-2-one 1-boc-6-indo-1,2,3,4-tetrahydroquinoline (2.0 g, Reference Example 12), 5,6-dihydro-pyran-2-one (1.1 g), A mixture of tetrakis (triphenylphosphine) palladium (0) and triethylamine (2.2 g) dispersed in dimethylformamide (5 ml) was stirred overnight at about 95 ° C. in a sealed container under a nitrogen atmosphere. The reaction mixture was partitioned between ethyl acetate and dilute hydrochloric acid, the resulting phases were separated, the organic phase was washed with sodium bicarbonate solution, then dried and evaporated. The residue is subjected to flash chromatography on silica to give a mixture of ethyl acetate and cyclohexane (
2: 3, v / v) to give the title compound (1.2 g) as a brown oil. Reference Example 17: Methyl (R) 3- (1-boc-1,2,3,4-tetrahydro-quinolin-6-yl ) -3-[(5- methyl-isoxazole-3-carbonyl) -amino]- Propionate 5-methyl-isoxazole-3-carboxylic acid (65 mg) in dimethylformamide (30 ml)
The solution was sequentially O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (190 mg), diisopropylethylamine (1 ml
) And methyl (R) 3-amino-3- (1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)-
Treated with propionate (200 mg, Reference Example 14). After standing at room temperature overnight, the mixture was evaporated to low volume and the residue was partitioned between ethyl acetate and dilute hydrochloric acid. The phases obtained were separated and the organic phase was washed with sodium bicarbonate solution, dried and evaporated. The residue was purified by flash chromatography to give the title compound as an orange gum (310m
g) was obtained.

Reference Example 18: Methyl (S) 2-amino-3- [1- (2,6-dichloro-benzoyl) -1,2,3,4-tetra
Lahydro-quinolin-6-yl] -propionate methyl (S) 2- (N-boc-amino) -3- (1,2,3,4-tetrahydro-quinolin-6-yl) -propionate (500 mg, Reference Example A solution of 19 (a)) in tetrahydrofuran (20 ml) was treated sequentially with triethylamine (360 mg) and 2,6-dichlorobenzoyl chloride (380 mg). The mixture was stirred at 40 ° C. for 2 hours, then ethyl acetate (100 ml) and dilute hydrochloric acid (100 ml)
And was distributed between The organic phase obtained was washed with sodium bicarbonate solution, then dried and evaporated. The residue obtained was dissolved in trifluoroacetic acid (2 ml) and the resulting clear solution was left at room temperature for 30 minutes and then evaporated. The residue obtained was partitioned between ethyl acetate and dilute hydrochloric acid. The organic layer was washed with sodium bicarbonate solution, then dried and evaporated to give the title compound (200mg) as a colorless oil. Reference Example 19 (a) (S) methyl 2- (N-boc-amino ) -3- (1,2,3,4-tetrahydro-quinolin -6-yl)
-Propionate maintained at 60 ° C., a solution of methyl (S) 2- (N-boc-amino) -3-quinolin-6-yl-propionate (3.8 g, Reference Example 20 (a)) in ethanol (100 ml), Treated with ammonium formate (10 g) and 10% palladium on activated carbon (500 mg). After stirring at 60 ° C., further ammonium formate (about 5 g) and palladium on activated carbon (about 250 mg) were added, and this was repeated for another 2 hours at 30 minute intervals, at which point TLC analysis showed that the reaction was Has been completed. After cooling to room temperature, the mixture was filtered through celite to remove the spent catalyst and the resulting filtrate was evaporated. The obtained residue was treated with ethyl acetate (
(200 ml) and sodium bicarbonate solution (200 ml). Drying the organic layer,
Evaporation gave the title compound (3.8 g) as a colorless oil, which gradually crystallized on standing.

(B) Methyl (S) 2- (acetylamino) -3-quinolin-6-ylpropionate (Reference Example 2
0 (b)), and operating in the same manner as in Reference Example 19 (a), except that the reaction was carried out at reflux temperature for 2 hours, to obtain methyl (S) 2-acetylamino-3- ( 1,2,3,4-tetrahydro-quinoli
-6-yl) -propionate was obtained as a colorless oil. MS (ES ⁺ ) 277 (MH ⁺ ), 299 (
MNa ⁺ ). Reference Example 20 (a) Methyl (S) 2- (N-boc-amino) -3-quinolin-6-yl-propionate in tetrahydrofuran (30 ml), methyl (S) 2-amino-3-quinoline-6- A mixture containing il-propionate (3.0 g, Reference Example 21) and boc-anhydride (3.2 g) was stirred at reflux temperature for 30 minutes. The reaction mixture was evaporated and the resulting residue was crushed with pentane to give the title compound (3.8g) as a white powder. (b) Except for using acetic anhydride, operating in the same manner as in Reference Example 20 (a), methyl (S)
-(Acetyl-amino) -3-quinolin-6-yl-propionate was obtained as a colorless oil, which gradually crystallized on standing. ^{MS (ES +) 273 (MH} +), MS (ES -) 271 (M -)
.

Reference Example 21: A solution of methyl (S) 2-amino-3-quinolin-6-yl-propionate butyllithium in hexane (13.4 ml, 2.5 M) was stirred with (R) 2,5-dihydro-
3,6-Dimethoxy-2-isopropylpyrazine (5.2 g) in anhydrous tetrahydrofuran (80 ml
) The solution was added dropwise at -78 ° C under a nitrogen atmosphere. After stirring at −78 ° C. for 10 minutes, the solution was added to 6- (chloromethyl) -quinoline (5.0 g, Mahiou et al., J. Org. Chem. 1990, 55 (1
4): Prepared according to the procedure described in 4466-9) in tetrahydrofuran (20 ml). The resulting dark orange mixture was stirred at -78 ° C for 2 hours. The cooled reaction mixture was poured into a mixture of ethyl acetate (200ml) and brine (200ml). The organic phase obtained was dried and then evaporated. The residue was subjected to flash chromatography on silica, eluting with a mixture of ethyl acetate and dichloromethane (1: 1, v / v) to give a colorless oil (6 g). This material was treated with hydrochloric acid (250ml, 0.25M) and the resulting solution was left at room temperature for 1 hour and then evaporated. The residue was treated with water (30ml) and the resulting solution was made basic by the addition of concentrated ammonia (50ml). The mixture was extracted three times with dichloromethane (100ml). The combined extracts were dried and then evaporated. The resulting residue is subjected to flash chromatography on silica, eluting with a mixture of ethyl acetate to remove highly eluting impurities, and then a mixture of methanol and ethyl acetate (1: 1, v / v) To give the title compound (3.0 g) as a colorless gum.

[0391]Reference Example 22: (1-boc-2-o-tolylamino-1H-benzimidazol-5-yl)- Acetic acid Ethyl (R / S) (2-o-tolylamino-1H-benzimidazol-5-yl) -acetate (
1.6 g, Reference Example 23) was suspended in ethanol (30 ml), and sodium hydroxide solution (5 ml, 1 M) was used.
Processed. After stirring at 40 ° C. for 2 hours, the mixture was evaporated. The obtained residue is
Partitioned between dilute acetic acid (50ml) and dichloromethane (50ml) and the resulting white precipitate (65
0 mg) was dissolved in acetonitrile (30 ml) and the solution was then boc-anhydride (580 mg) and
And dimethylaminopyridine (10 mg). After standing overnight at room temperature,
The mixture was evaporated and the resulting residue was partitioned between ethyl acetate and dilute acetic acid. Obtained
The organic phase was dried and then evaporated. This residue was dissolved in methanol (2 ml),
The solution was treated with ether. The resulting precipitate was collected by filtration, and as a white powder,
Title compound(500 mg).Reference Example 23: Ethyl (R / S) (2-o-tolylamino-1H-benzimidazol-5-yl) -a
Acetate Ethyl (3,4-diaminophenyl) -acetate (4.1 g) in ethanol (50 ml)
Treated with o-tolyl isothiocyanate (3.1 g). After standing overnight at room temperature,
The clear solution was evaporated to give a yellow gum, which was treated with ethanol (70ml). Get
The resulting solution was treated with diisopropylcarbodiimide (5.3 g) and the mixture was brought to 55 ° C.
After stirring for 4 hours, the mixture was evaporated. The resulting residue is flash chromatographed on silica.
Chromatography, eluting first with ether and then mixing with methanol and ether.
Eluting with the compound (1: 9, v / v), as a pale yellow gum,Title compound(4.1 g) was obtained.

[0392]Reference Example 24 (a)Ethyl (R / S) 3- (2,3-dihydro-1H-indol-5-yl) -heptanoate (R / S) 3- (2,3-dihydro-1H-indol-5-yl) -heptane hydrochloride (4.13 g, reference
A solution of Example 25 (a)) in anhydrous ethanol (100 ml) containing concentrated sulfuric acid (1.4 ml) was stirred for 6 hours.
And left overnight at room temperature. The mixture is concentrated to a low volume and the resulting residue is
Partitioned between ethyl acid (200ml) and saturated aqueous sodium bicarbonate solution (200ml).
The resulting organic phase was washed with a saturated aqueous sodium bicarbonate solution (50 ml). The aqueous phase
, And further extracted with ethyl acetate, and the combined organic phases were dried over magnesium sulfate.
And evaporated. The residue obtained is subjected to flash chromatography on silica.
Eluting with a mixture of pentane and ethyl acetate (2: 1, v / v) as a pale yellow oil, Title compound (2.88 g) was obtained. (b) (R / S) 3- (2,3-dihydro-1H-indol-5-yl) -pentanoic acid hydrochloride (Reference Example
Except that 25 (b)) was used, the same treatment as in Reference Example 24 (a) was carried out to give a pale yellow oil. Ethyl (R / S) 3- (2,3-dihydro-1H- Indole-5-yl) -pentanoate Prepared
Was. (c) (R / S) 3- (2,3-dihydro-1H-indol-5-yl) -3-phenylpropionic acid
Except for using the hydrochloride (Reference Example 25 (c)), the same treatment as in Reference Example 24 (a) was carried out to give a pale orange
As oil,Ethyl (R / S) 3- (2,3-dihydro-1H-indol-5-yl) -3-phenyl
LepropionateWas prepared.

Reference Example 25 (a) Ethyl (R / S) 3- ( 2,3-dihydro-1H-indol-5-yl) -heptane hydrochloride (R / S) 3- (1-acetyl-2 , 3-Dihydro-1H-indol-5-yl) -heptanoate (3.95 g, Reference Example 11 (b)) was dispersed in an aqueous hydrochloric acid solution to give a suspension (120 ml, 6M).
Heated at ° C. for 7 hours. After cooling to room temperature, the mixture was evaporated. The resulting residue was treated with toluene and the solvent was evaporated under reduced pressure (these operations were repeated two more times). Final drying in a desiccator to afford the title compound (4
.13g). LC-MS: _RT = 3.36 min; MS (ES ^<+> ) 248 (MH ^<+> ). (b) Reference Example 25 except that ethyl (R / S) 3- (1-acetyl-2,3-dihydro-1H-indol-5-yl) -pentanoate (Reference Example 11 (c)) was used. The same treatment as in (a) was performed to prepare (R / S) 3- (2,3-dihydro-1H- indol-5-yl) -pentanoic acid hydrochloride as a brown oil. (c) Except that ethyl (R / S) 3- (1-acetyl-2,3-dihydro-1H-indol-5-yl) -3-phenylpropionate (Reference Example 11 (d)) was used. And treated in the same manner as in Reference Example 25 (a) to give (R / S) 3- (2,3-dihydro -1H-indol-5-yl) -3-fe
Nylpropionate hydrochloride was prepared.

Reference Example 26 (a) E and Z ethyl 3- (1-acetyl-2,3-dihydro-1H-indol-5-yl) -hep
To-2-enoate sodium hydride (1.09 g, 60% inorganic oil dispersion), tetrahydrofuran (150 ml
). The mixture was cooled in an ice bath under a nitrogen atmosphere and triethylphosphonoacetate (4.75 ml) was added over 3 minutes. 45 minutes later, tetrahydrofuran of 1-acetyl-5-pentanoyl-2,3-dihydro-1H-indole (5.33 g, Reference Example 27 (a))
(50 ml) solution was added dropwise over 50 minutes. After stirring for 15 minutes, the reaction mixture was warmed to room temperature and then heated in a steam bath under a nitrogen atmosphere for 20 minutes. In a separate flask, sodium hydride (1.09 g, 60% inorganic oil dispersion) was suspended in tetrahydrofuran (150 ml). The mixture was cooled in an ice bath under a nitrogen atmosphere, triethylphosphonoacetate (4.75 ml) was added over 3 minutes and the mixture was stirred for 70 minutes. This mixture was cannulated into the main reaction mixture while cooling in an ice bath. The reaction mixture was then refluxed for 43 hours, then cooled, concentrated to half volume, and then partitioned between ethyl acetate and a 0.33 M aqueous hydrochloric acid solution. The organic phase was separated and the aqueous phase was extracted again with ethyl acetate. The combined organic phases are dried over magnesium sulfate,
Evaporation then gave an orange-brown oil, which was flash chromatographed on silica, eluting with a mixture of ethyl acetate and pentane (1: 1, v / v) to give the title
Compound (4.3 g) was obtained.

(B) 1-acetyl-5-propanoyl-2,3-dihydro-1H-indole (Reference Example 27 (b))
And treated as in Reference Example 26 (a), except that E was used, and E and Z ethyl 3- (1-acetyl-2,3-dihydro-1H-indol-5-yl) -pento as a creamy solid -2-enoe
A plate was prepared. (c) Except that 1-acetyl-5-benzoyl-2,3-dihydro-1H-indole (Reference Example 27 (c)) was used, the same treatment as in Reference Example 26 (a) was carried out to give a yellow solid. E and Z ethyl 3
-(1-Acetyl-2,3-dihydro-1H-indol-5-yl) -cinnamate was prepared.
Reference Example 27 (a) 1-acetyl-5-pentanoyl-2,3-dihydro-1H-indolepentanoyl chloride (10.8 g) in 1,2-dichloroethane (100 ml), anhydrous aluminum chloride (28.2 g) And 1-acetyl-2,3-dihydro-1H-indole (10 g) was added dropwise with mechanical stirring. The mixture was stirred at reflux for 16 hours, then cooled and poured into ice water. This mixture was extracted with dichloroethane. The extract was washed with 1 M aqueous sodium hydroxide solution, then dried over magnesium sulfate and evaporated to give the title compound (10.3 g) as a dark gum.

(B) Except that using propionyl chloride and subjecting the resulting product to flash chromatography on silica, eluting with a mixture of ethyl acetate and pentane (3: 2, v / v) Treated in the same manner as in Reference Example 27 (a), and obtained as a cream-orange solid, 1-
Acetyl-5-propanoyl-2,3-dihydro-1H-indole was prepared. (c) Reference Example 27 except using benzoyl chloride and subjecting the resulting product to flash chromatography on silica, eluting with a mixture of ethyl acetate and pentane (3: 2, v / v). Treated in the same manner as in (a), and as a creamy solid, 1-acetyl-5
-Benzoyl-2,3-dihydro-1H-indole was prepared. Reference Example 28: (R / S) 6- (2-carboxy -1-ylmethyl-ethyl) -3,4-dihydro-2H-quino
Phosphorus-1-carboxylic acid 9H-fluoren-9-ylmethyl ester In acetone (40 ml) and water (40 ml), (R / S) 3- (1,2,3,4-tetrahydroquinoline-
6-yl) -butyric acid (2.6 g) and a suspension of sodium bicarbonate (2.2 g) were dispersed in 2,5-dioxopyrrolidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (4.0 g). )
And the resulting mixture was stirred overnight at room temperature. The mixture was filtered and the filtrate was evaporated to low volume. The resulting residue was treated with dilute hydrochloric acid, and the resulting gummy precipitate was extracted with a mixture of tetrahydrofuran, ethyl acetate and dichloromethane. The solution was washed with brine, then dried and evaporated to mark as a light brown oil
The title compound (5.8 g) was obtained, which solidified on standing. ^{MS (ES +) 464 (MNa} +), MS (ES -) 440 (M -).

In Vivo and In Vitro Test Procedures 1. Compounds on VLA4-Dependent Cell Adhesion to Fibronectin and VCAM
1.1 Inhibition of RAMOS labeling by metabolism of RAMOS cells Culture in medium (UK, Gibco).
Prior to the assay, the cells were suspended at a concentration of 0.5 × 10 ⁶ cells / ml RPMI and labeled with 400 μCi / 100 ml of [ ³ H] -methionine (UK, Amersham) at 37 ° C. for 18 hours. I do. 1.2 Preparation of 96-well plates for adhesion assays Cytostar plates (UK, Amersham) were used at 50 μl / well, 3 μl
ml human soluble VCAM-1 (UK, R & D Systems) or 28.8 μg / ml human tissue fibronectin (UK, Sigma). 50 μl of phosphate buffered saline was added to non-specific binding wells for controls. The plates were dried in an incubator at 25 ° C. overnight. The following day, the plates were blocked with 200 μl / well of Packs buffer (UK, Gibco) supplemented with 1% BSA (UK, Sigma). The plates were kept in the dark at room temperature for 2 hours. The blocking buffer was then discarded, the plate was inverted, and the plate was dried by tapping on tissue paper. 50 μl / well in pack buffer supplemented with 5 mM manganese chloride (for integrin receptor activation, Sigma, UK)
3.6% dimethyl sulfoxide was added to the appropriate control binding and non-specific binding assay wells in the plate. 50 μl / well of the test compound, diluted in 3.6% dimethyl sulfoxide in pack buffer supplemented with 5 mM manganese chloride and 0.2% BSA, was added to the test well at the appropriate concentration.

The metabolically labeled cells were suspended at 4 × 10 ⁶ cells / ml in pack buffer supplemented with manganese chloride and BSA as described above. In pack buffers and supplements
50 μl / well of cells in 3.6% dimethyl sulfoxide were added to all plate wells. Plates coated with either VCAM-1 or fibronectin were treated in a similar manner and data on compound inhibition of cell binding to both substrates was measured. 1.3 Perform Assay and Data Analysis Plates containing cells in control and compound test wells were incubated for 1 hour at room temperature in the dark. These plates were then counted on a Wallac Microbeta scintillation counter (UK, Wallac) and the resulting data was processed with Microsoft Excel (US, Microsoft). These data are expressed as IC50, the concentration at which 50% of the control binding is inhibited. The% binding was determined from the following formula: {[(C _TB -C _NS )-(C _I -C _NS )] / (C _TB -C _NS )} × 100 =% binding where C _TB is inhibited without the presence of agents, a fibronectin (or VCAM-1) cell binding numbers for coated wells, C _NS are cell bound counts in the wells in the absence of substrate, also C _I comprises a cell adhesion inhibitor The number of cell bonds in the well. The data for the compounds of the present invention is expressed as an IC ₅₀ for cell adhesion inhibition for both fibronectin and VCAM-1. Certain compounds of the invention have a concentration of 100 μM
Inhibits cell adhesion to fibronectin and VCAM-1 with an IC ₅₀ of 〜0.1 nM. Preferred compounds of the invention inhibit cell adhesion to fibronectin and VCAM-1 with an IC ₅₀ in the range of 10 nM to 0.1 nM.

2. Inhibition of antigen-induced airway inflammation in mice and rats 2.1 Sensitization of the animals Rats (UK, Harland Olac, Brown Norway
Norway)) with aluminum hydroxide adjuvant (100 ml) in saline (1 ml, intraperitoneal [ip]).
Sensitization was performed on days 0, 12, and 21 with ovalbumin (100 μg, ip, UK, Sigma) administered with mg, ip, UK, Sigma. In addition, mice (C57) were treated with aluminum hydroxide adjuvant in saline (0.2 ml, ip).
Ovalbumin (10 μg, ip) administered with (20 mg, ip) was sensitized on days 0 and 12. 2.2 Stimulation with Antigen Rats were stimulated any day during days 28-38, while mice were stimulated any day during days 20-30. The animals were exposed to an ovalbumin (10 g / l) aerosol generated by an ultrasonic nebulizer (US, de Vilbiss Ultraneb) and passed through an exposure chamber for 30 minutes (rat
) Or 1 hour (mouse) exposure. 2.3 Treatment protocol Animals were treated before or after stimulation with antigen as needed. The aqueous-soluble compounds of the present invention can be prepared as aqueous dispersions (oral, po administration) or saline dispersions (intratracheal, it administration). Non-soluble compounds are 0.5% methylcellulose / 0.2% polysorbate
In an aqueous solution (po administration) or an aqueous salt solution (it administration) of 80 (both manufactured by Merck UK),
The solid is prepared as a suspension by grinding or ultrasonic irradiation. The dose volume is 1 ml / kg (po) or 0.5 mg / kg (it) for rats and 10 ml / kg (po) or 1 ml / kg (it) for mice.

2.4 Assessment of Airway Inflammation The accumulation of the cells in the lungs is assessed 24 hours after stimulation (rat) or 48-72 hours after stimulation (mouse). These animals were treated with sodium pentobarbitone (200 mg / kg, ip,
The animals were euthanized in Pasteur Merieux, France and the trachea was immediately cannulated. Cells are collected from the airway lumen by bronchoalveolar lavage (BAL) and cells are collected from lung tissue by the following enzyme (collagenase, UK, Sigma) separation. BAL contains RPMI1640 medium (UK, Gibco) containing 10% fetal bovine serum (FCS, UK, Serotec).
Performed by flushing the airways with two aliquots (10 mg / kg each). Pool the collected BAL aliquots and count cells as described above. Immediately after BAL, the vascular system of the lung is flushed with RPMI 1640 / FCS to remove the blood pool of cells. The lung lobe is removed and cut into 0.5 mm pieces. A sample of homogenized lung tissue (rat: 400 mg; mouse: 150 mg) was collected with collagenase (20 U / ml, 2 hours;
Incubate with RPMI1640 / FCS with 60 U / ml, 1 hour, 37 ° C.) to separate cells from the tissue. The collected cells are washed with RPMI1640 / FCS. Counting of total white blood cells recovered from the airway lumen and lung tissue is performed with an automated cell counter (US, Cobas Argos). Differential counting of eosinophils, neutrophils and monocytes is performed by light microscopy of cytocentrifuge formulations stained with Wright-Giemza staining (Sigma, UK). . T cells are C
D2 (a pan-T cell marker used to quantify total T cells), CD4, CD8 and CD25 (
Counting is performed by flow cytometry (EPICS XL, US, Coulter Electronics) using a fluorophore-labeled antibody against activated T-cell marker). All antibodies are UK
Obtained from Serotec. 2.5 Data analysis Cellular data were expressed as mean cell numbers in unstimulated, stimulated and vehicle treated groups, and stimulated and compound treated groups, including the standard error of the mean. Statistical analysis of differences within treatment groups is via the Mann-Whitney test,
The variability was assessed using a one-way analysis. If p <0.05, there was no statistical significance.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 29/00 A61P 29/00 C07D 215/08 C07D 215/08 403/12 403/12 405/04 405 / 04 413/06 413/06 413/12 413/12 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC , NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA , BB, BG, BR BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP , KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Bourza Jean Dominique France F-94403 Bepe 14 Vitly-sur-Seine Cedex Cai-Jour Guessed 13 Centre-de-Rucherche-de-Vittorie-le-Fortville Rhone-Poulin-Laur-Roucherde Developmentman (72) Inventor Comalcon Alle France F-94403 Bepe14 Vittori-sur-Seine Cedex Cai Jules Guessed 13 Center de Recherche-de-Vittorie-le-Fortville Rhone-Pouleurne-Laur-le-Cherche Developmentman (72) Inventor Firoche Bruno Jack Christophe France F-94403 Bepe14 Vittori-sur-Seine Cedex Cai Jules Guessed 13 Center de Recherche de Vittriy-le-Fortville Rhone-Poulin-Laura-Rucherche Within the development man (72) Inventor Harris Neil Victor United Kingdom Essex R.E.M. 10 7 XS Dagnum Raynam Road South (No address) Inside the Rhone Poulenc Roller Limited (72) Inventor McCarthy Clive England Essex 7M XS Dagnum Raynam Road South (No address) F-term in Rh ヌ ne Poulin Roller Limited 4C063 BB01 CC14 CC51 CC52 CC78 DD06 DD14 EE01 4C086 AA01 AA03 BA14 BC13 BC28 BC67 BC69 GA09 MA01 MA04 NA14 NA15 Z204 CB03 DB01 EB02 FB21 GB17

Claims (99)

[Claims] 1. A compound represented by the following general formula (I): Where R ¹ is (i) R ³ -Z ^3- ; (ii) R ³ -L ² -R ⁴ -Z ^3- ; (iii) R ³ -L ³ -Ar ¹ -L ⁴ -Z ³ -; Or (iv) represents R ³ -L ³ -Ar ¹ -L ² -R ⁴ -Z ^3- , wherein R ² represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group,
R ³ is alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, hetero R ⁴ represents an alkylene chain, alkenylene chain, or alkynylene chain; R ⁵ represents a hydrogen atom or a lower alkyl group; R ⁶ represents a hydrogen atom; an arylalkenyl, a heteroarylalkynyl, a heterocycloalkyl or a heterocycloalkylalkyl group; Represents an atom, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl or heteroarylalkyl group; R ⁷ and R ^7a independently represents a hydrogen atom or a lower alkyl group; R ⁸ represents a hydrogen atom, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl R ⁹ represents an alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl group, or an aryl, acidic functional group, cycloalkyl, heteroaryl, heterocycloalkyl, -S (O) _m R ³ , -C (= O) -NY ⁴ Y ⁵ or an alkyl group substituted by a -NY ⁴ Y ⁵ group, wherein R ¹⁰ is a hydrogen atom, R ³ or alkoxy, cycloalkyl, hydroxy, mercapto, alkylthio or -NY ⁴ Y ⁵ represents an alkyl group substituted with a group, R ¹¹ and R ¹³ are each independently a hydrogen atom or an amino Side chains, an acidic functional group, R ^3, -C (= O
) -R ³ or ^{-C (= O) -NY 4 Y} 5 consists group or an acidic functional group or ^{R 3,,, -NY 4 Y} 5, -NH-C (
= O) -R ³ , -C (= O) -R ⁴ -NH ₂ , -C (= O) -Ar ¹ -NH ₂ , -C (= O) -R ⁴ -COOH, or -C (= O) -NY ⁴ Y ⁵ selected from an alkyl group substituted by a group, wherein R ¹⁰ and R ¹¹ or R ¹⁰ and R ¹² together with the atoms to which they are attached, together with a 3- to 6-membered heterocycloalkyl Forming a ring, R ¹² represents a C _1-6 alkylene group optionally substituted with R ³ , R ¹⁴ is alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hetero Represents a cycloalkyl or heterocycloalkylalkyl group, wherein A ¹ is optionally one or more of alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, imino, oxo, thiooxo, or -ZR ⁶ , -NY ¹ Y ² , -CO
OR ⁶ or -C (= O) -NY ¹ represents a linear C _1-3 alkylene chain which may be substituted by a group selected from an alkyl group substituted with Y ² , wherein Ar ¹ is arylene, or Represents a heteroaryldiyl group, L ¹ is (i) a direct bond; (ii) alkenylene, alkylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene or arylene bond, each of these groups is optionally ( a) acidic functional groups, cyano, oxo,
-S (O) _m R ⁹ , R ³ , -C (= O) -R ³ , -C (= O) -OR ³ , -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ )
-SO ₂ -R ⁹ , -NY ⁴ Y ⁵ or-[C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ Substituted or (b) alkyl substituted with an acidic functional group or S (O) _m R ⁹ , —C (= O) —NY ⁴ Y ⁵ or —NY ⁴ Y ⁵ ; (iii)-[C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -bond; (iv) -Z ² -R ¹² -bond; (v) -C (= _{O) -CH 2 -C (= O} ) - ^{bond; (vi) -R 12 -Z 2} -R 12 - ^{bond; (vii) -C (R 4} ) (R 13) - [C (= O) - N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -bond; (viii) -L ⁵ -L ^6-
L ⁷ -bond; where L ² is -NR ⁵ -C (= Z) -NR ^5- , -C (= Z) -NR ^5- , -C (= O)-, -C (= Z)- O-, -NR ⁵ -C (
= Z) -, - Z - , - S (O) m -, - NR 5 -, - SO 2 - NR 5 -, - NR 5 -SO 2 -, - NR 5 -C (= O) -O- , -OC (= O) -, or -OC (= O) -NR ⁵ - represents a bond, L ³ is ^{heteroaryldiyl, -NR 5 -C (= Z)} -NR 5 -, - C (= Z ) -NR ^5- , -C (= O)-, -C (= Z) -O-,-
^{NR 5 -C (= Z) -} , - Z -, - S (O) m -, - NR 5 -, - SO 2 - NR 5 -, - NR 5 -SO 2 -, - NR 5 -C (= O) -O-, -OC (= O)
-, or -OC (= O) -NR ⁵ - represents a bond, L ⁴ is a direct bond, represents an alkylene, alkenylene or alkynylene chain, L ⁵ and L ⁷ represents a direct bond or an alkylene chain each independently, L ⁶ represents a cycloalkylene or a heterocycloalkylene bond; Y ¹ and Y ² each independently represent a hydrogen atom, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; ¹ Y ² can form a cyclic amine; Y ⁴ and Y ⁵ are each independently a hydrogen atom, alkenyl, alkyl, alkynyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl, or alkoxy , Aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, Kiso, -NY ¹ Y ^2, 1 or more -COOR ⁸ or -C (= O) alkyl substituted by -NY ¹ Y ² groups; or base -NY ⁴ Y ⁵ are 5- or 7-membered From (i) optionally alkoxy, carboxamide, carboxy, hydroxy, oxo (or a 5-, 6- or 7-membered cyclic acetal derivative thereof), R ¹⁰ may be substituted with one or more substituents selected, (ii) or even O, S, may contain SO _2, or NY ^6, also (iii) incidental aryl, heteroaryl, fused with heterocycloalkyl or cycloalkyl rings, may form a bicyclic or tricyclic ring system, Y ⁶ is a hydrogen atom, an alkyl, aryl, arylalkyl, -C (= O) -R ¹⁴ , -C (= O) -OR ¹⁴ or -SO ₂ R ¹⁴ , Z is an oxygen atom or a sulfur atom, Z ¹ is C (R ⁷ ) (R ^7a ), C (= O) Or CH (OH), Z ² is O, S (O) _n , NR ⁵ , SONR ⁵ , C (= O) -NR ⁵ or C (= O), Z ³ is a direct bond, C ( = O), OC (= O ), NR 5 C (= O), or a SO _2, m is an integer 1 or 2, n is zero or an integer 1 or 2, p is zero or an integer 1 ~Four
And Y is carboxy (or an acidic bioisostere), and its corresponding N-oxide, and its prodrugs, and pharmaceutically acceptable such compounds and its N-oxides and its prodrugs Salts and solvates, except those compounds in which an oxygen, nitrogen or sulfur atom is directly bonded to a carbon-carbon multiple bond of an alkenylene, alkynylene or cycloalkenylene residue. 2. R ¹ represents the group R ³ —Z ³ —, wherein Z ³ is C (= O) and R ³ is optionally substituted aryl, optionally substituted heteroaryl Or the compound of claim 1, which is an optionally substituted arylalkyl group. 3. The process according to claim 2, wherein R ³ is phenyl or phenyl substituted by one or two aryloxy, cyano, halo, lower alkoxy, nitro or CF _3.
A compound as described. 4. R ³ is isoquinolinyl, isoxazolyl, pyrazolopyrimidinyl, pyridyl, pyrimidinyl, quinolinyl, thiazolyl and triazolyl, each of which optionally has one or two alkylcarbonyl, aryl, cyano, halo,
_3. The compound according to claim 2, which may be substituted by lower alkoxy, lower alkyl, lower alkylsulfonyl, lower alkylthio, nitro or CF3. 5. The compound of claim 2, wherein R ³ is a benzyl group optionally substituted on the phenyl ring with one or two halo, hydroxy or methoxy. 6. R ³ is 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-fluoro-2-triphenyl 3. The compound according to claim 2, which is a fluoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl or 2-phenoxyphenyl group. 7. R ¹ represents the group R ³ -L ³ -Ar ¹ -L ⁴ -Z ^3- , wherein Z ³ is C (= O) and L ⁴ is a linear or branched C _{A 1-6} alkylene chain, Ar ¹ is an optionally substituted phenylene or an optionally substituted heteroaryldiyl group, and L ³ is -NH-C (=
O) is -NH- bond, and R ³ is a heteroaryl group which is optionally substituted aryl or optionally substituted compound of claim 1. 8. The compound of claim 7, wherein L ⁴ is methylene, Ar ¹ is an optionally substituted p-phenylene group, and R ³ is an optionally substituted phenyl group. 9. Ar ¹ is halo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl or C _1-4 alkylsulfonyl at the p-phenylene group or at the 3-position. in a substituted p- phenylene group, and R ³ is a phenyl group substituted with a C _1-4 alkyl in the 2-position, according to claim 8 a compound according. 10. R ¹ represents a group: R ³ -L ³ -Ar ¹ -L ⁴ -Z ^3- , wherein Z ³ is C (= O),
L ⁴ is a linear or branched C _1-6 alkylene chain, and Ar ¹ is an optionally substituted 8 to ¹
0-membered bicyclic system: Where the following rings: Is a 5- to 6-membered heterocyclic ring, the following rings: Is a heterocyclic ring or benzene ring 5-6 membered, these two rings, carbon - carbon bond or a carbon - are coupled together by nitrogen bond, L ³ represents NH, and R ³ is 2. The compound according to claim 1, which is an optionally substituted aryl group. 11. The compound according to claim 10, wherein L ⁴ is a methylene group and Ar ¹ is an optionally substituted benzoxazolyl or an optionally substituted benzimidazolyl group. 12. A benzoxazolyl, wherein Ar ¹ is each optionally substituted with one or more lower alkyl, lower alkoxy, amino, halogen atom, hydroxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, nitro or trifluoromethyl group. 12. The compound according to claim 11, wherein the compound is a benzimidazolyl group and R ³ is a phenyl group substituted at the 2-position with a lower alkyl, lower alkoxy, halo or diC _1-4 alkylamino group. 13. R ¹ represents the group: R ³ -L ³ -Ar ¹ -L ⁴ -Z ^3- , wherein Z ³ is C (= O) and L ⁴ is a linear or branched C _{A 1-6} alkylene chain, Ar ¹ is an optionally substituted phenylene or an optionally substituted heteroaryldiyl group, and L ³ is -C (= O
The compound according to claim 1, wherein the compound is a) -NH- bond, and R ³ is a heterocycloalkyl group. 14. The compound according to claim 13, wherein L ⁴ is methylene and Ar ¹ is an optionally substituted p-phenylene group. 15. Ar ¹ is a p-phenylene group or a halo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl or C _1-4 alkylsulfonyl at the 3-position. 15. The compound according to claim 14, wherein the compound is a p-phenylene group substituted with, and R ³ is an indolinyl group. 16. The compound according to claim 1, wherein R ² is a hydrogen atom. 17. The compound according to any one of the preceding claims, wherein A ¹ is an unsubstituted linear C _1-3 alkylene bond. 18. The compound according to claim 17, wherein A ¹ is methylene. 19. The compound according to claim 17, wherein A ¹ is ethylene. 20. The compound according to any one of the preceding claims, wherein Z ¹ is CH ₂ , CHOH or C (= O). 21. The compound of claim 20, wherein Z ¹ is CH ₂ . 22. The compound according to any one of the preceding claims, wherein L ¹ is an optionally substituted alkylene bond. 23. L ¹ is ethylene or propylene, each of which is optionally lower alkyl, aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O)
-OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ and-[C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ or carboxy or acidic bioisosteric,, -ZH, -ZR ^3, the ^{-C (= O) -NY 4 Y} 5 or alkyl substituted by -NY ⁴ Y ⁵ Optionally substituted (where R ³ , R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , Y ⁴ , Y ⁵ , Z and P are as defined in claim 1), 22. The compound according to 22. 24. L ¹ is the following group: Here, R ⁵ is a hydrogen atom or a lower alkyl group, and R ¹⁵ is a hydrogen atom or a lower alkyl group, or R ⁵ is a hydrogen atom, and R ¹⁵ is an aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ ,-(C ( ^{= O) -N (R 10)} - C (R 5) (R 11)] p -C (= O) -NY 4 Y 5 or carboxy or acidic bioisosteric, or
^{-ZH, -ZR 3, -C (=} O) -NY 4 Y 5 or -NY ⁴ Y ⁵ is an alkyl group substituted with (wherein ^{R 3, R 5, R 8} , R 9, R 10, R ¹¹ , Y ⁴ , Y ⁵ , Z and P are as defined in claim 1), the compound of claim 22. 25. L ¹ is a group represented by the following formula: Wherein R ¹⁵ is a hydrogen atom, a lower alkyl group, an aryl, a heteroaryl, -N (R ⁸ )
-C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ , or carboxy,
-OH, -OR ³ or ^{-C (= O) -NY 4 Y} 5 is an alkyl group substituted by (wherein ^{R 3, R 8, R 9} , Y 4 and Y ⁵ as defined in claim 1 25. The compound of claim 24, wherein 26. L ¹ is a group represented by the following formula: Here, R ¹⁵ is a hydrogen atom, a lower alkyl group, an aryl, a heteroaryl, -N (R ⁸ ) -C (= O)-
R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ , or carboxy, -OH, -OR ³ or -C (= O) -NY ⁴ Y ⁵ is an alkyl group substituted with (where R ³ , R ⁸ , R ⁹ , Y ⁴ and Y ⁵ are as defined in claim 1), claim 24. Compound. 27. L ¹ is a group represented by the following formula: Wherein R ⁵ is a hydrogen atom or a lower alkyl group, and R ^15a is a lower alkyl group, or R ⁵ is a hydrogen atom, and R ^15a is an aryl, heteroaryl,
-N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ ,-[C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ , or carboxy or acidic bioisosteres, or -ZH ^{, -ZR 3, -C (= O} ) -NY 4 Y 5 or -NY ⁴ Y ⁵ is an alkyl group substituted by (wherein ^{R 3, R 5, R 8} , R 9, R 10, R 11 , Y ⁴ , Y ⁵ , Z and P are as defined in claim 1), the compound of claim 22. 28. L ¹ is a group represented by the following formula: Wherein R ^15a is -N (R ⁸ ) -C (= O) -R ⁹ or -N (R ⁸ ) -SO ₂ -R ⁹ (where R ⁸ and R ⁹ are claim 1 28. The compound of claim 27, wherein the compound is as defined in 29. L ¹ is a group represented by the following formula: Wherein R ^15a is -N (R ⁸ ) -C (= O) -R ⁹ or -N (R ⁸ ) -SO ₂ -R ⁹ (where R ⁸ and R ⁹ are defined in claim 1) 28. The compound of claim 27, wherein 30. The compound according to claim 1, wherein Y represents a carboxy group. 31. The compound according to claim 1, which is represented by the following formula (Ia): Wherein R ² , R ³ , A ¹ , Ar ¹ , L ¹ , L ⁴ , Y and Z ¹ are as defined in any of the above related claims, and the corresponding N-oxide, and Prodrugs; and pharmaceutically acceptable salts and solvates of the compound and its N-oxide and prodrug. 32. The compound according to claim 1, which is represented by the following formula (Ib): Wherein R ² , R ³ , A ¹ , L ² , Y and Z ¹ are as defined in any of the above related claims, X is NR ⁵ or O, Z ⁴ is a direct bond, NR ⁵ , O or S (O) _n (where R ⁵ and n are as defined in any of the related claims above), R is a hydrogen atom or an aryl substituent, and the corresponding N And pharmaceutically acceptable salts and solvates of the compound and its N-oxide and prodrug. 33. The compound according to claim 1, which is represented by the following formula (Ic): Wherein Ar ¹ , L ⁴ , A ¹ , R ² , L ¹ , Y and Z ¹ are as defined in any of the above related claims, and the corresponding N-oxides and prodrugs thereof; And pharmaceutically acceptable salts and solvates of the compound and its N-oxide and prodrug. 34. The compound according to claim 1, which is represented by the following formula (Id): Wherein R ³ , A ¹ , R ² , L ¹ , Y and Z ¹ are as defined in any of the above related claims, and the corresponding N-oxides and prodrugs thereof; and said compound And pharmaceutically acceptable salts and solvates of the N-oxide and prodrug thereof. 35. The compound of claim 31, wherein R ³ is a phenyl group substituted at the 2-position with a C _1-4 alkyl. 36. Ar ¹ is p-phenylene or halo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl or C _1-4 alkylsulfonyl at the 3-position. 36. The compound according to any one of claims 31, 33 and 35, which is a substituted p-phenylene. 37. The compound of claim 32, wherein R ³ is a phenyl group substituted at the 2-position by lower alkyl, lower alkoxy, halo or di-C _1-4 alkylamino. 38. The compound according to claim 32, wherein Z ⁴ represents NH. 39. The compound according to any one of claims 32, 37 and 38, wherein R represents a hydrogen atom, a halo, a lower alkyl or a lower alkoxy group. 40. The method of claim 31, wherein L ⁴ is a straight or branched C _1-4 alkylene chain.
32. The compound according to any one of 32, 33 and 35-39. 41. The compound of claim 40, wherein L ⁴ is methylene. 42. The compound of claim 34, wherein R ³ is a phenyl group or a phenyl group substituted with one or two aryloxy, cyano, halo, lower alkoxy, lower alkyl, nitro or CF ₃ . 43. The compound of claim 34, wherein R ³ is a benzyl group in the phenyl ring substituted with one or two halo, hydroxy or methoxy. 44. R ³ is 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-fluoro-2-triphenyl 35. The compound according to claim 34, which is fluoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl or 2-phenoxyphenyl. 45. The method of claim 31, wherein A ¹ is an unsubstituted linear C _1-3 alkylene bond.
The compound according to any one of the above. 46. The compound of claim 45, wherein A ¹ is methylene. 47. The compound of claim 45, wherein A ¹ is ethylene. 48. The compound according to any one of claims 31 to 47, wherein Z ¹ is CH ₂ . 49. The compound according to any one of claims 31 to 48, wherein R ² is a hydrogen atom. 50. The method according to claim 3, wherein L ¹ is an optionally substituted alkylene bond.
50. The compound according to any one of 1 to 49. 51. L ¹ is ethylene or propylene, each of which is optionally lower alkyl, aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O)
-OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ and-[C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ or carboxy or acidic bioisosteric,, -ZH, -ZR ^3, the ^{-C (= O) -NY 4 Y} 5 or alkyl substituted by -NY ⁴ Y ⁵ Optionally substituted (where R ³ , R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , Y ⁴ , Y ⁵ , Z and P are as defined in claim 1), 50. The compound according to 50, 52. L ¹ is the following group: Here, R ⁵ is a hydrogen atom or a lower alkyl group, and R ¹⁵ is a hydrogen atom or a lower alkyl group, or R ⁵ is a hydrogen atom, and R ¹⁵ is an aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ ,-(C ( ^{= O) -N (R 10)} - C (R 5) (R 11)] p -C (= O) -NY 4 Y 5 or carboxy or acidic bioisosteric, or
^{-ZH, -ZR 3, -C (=} O) -NY 4 Y 5 or -NY ⁴ Y ⁵ is an alkyl group substituted with (wherein ^{R 3, R 5, R 8} , R 9, R 10, R ¹¹ , Y ⁴ , Y ⁵ , Z and P are as defined in claim 1), the compound of claim 50. 53. L ¹ is the following group: Here, R ¹⁵ is a hydrogen atom, a lower alkyl group, an aryl, a heteroaryl, -N (R ⁸ ) -C (= O)-
R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ , or carboxy, -OH, -OR ³ or -C (= O) -NY ⁴ Y ⁵ is an alkyl group substituted with (where R ³ , R ⁸ , R ⁹ , Y ⁴ and Y ⁵ are as defined in claim 1), claim 52. Compound. 54. L ¹ is a group represented by the following formula: Here, R ¹⁵ is a hydrogen atom, a lower alkyl group, an aryl, a heteroaryl, -N (R ⁸ ) -C (= O)-
R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ , or carboxy, -OH, -OR ³ or -C (= O) -NY ⁴ Y ⁵ is an alkyl group substituted with (where R ³ , R ⁸ , R ⁹ , Y ⁴ and Y ⁵ are as defined in claim 1), claim 52. Compound. 55. L ¹ is the following group: Here, R ⁵ is a hydrogen atom or a lower alkyl group, and R ^15a is a lower alkyl group, or R ⁵ is a hydrogen atom, and R ^15a is aryl, heteroaryl, -N (R ⁸ )
-C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ ,-(C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p- C (= O) -NY ⁴ Y ⁵ , or a carboxy or acidic biological isotope, or -ZH, -ZR ³ ,- C (=
O) -NY ⁴ Y ⁵ or -NY ⁴ Y ⁵ is an alkyl group substituted by (wherein ^{R 3, R 5, R 8} , R 9, R 10, R 11, Y 4, Y 5, Z and P is as defined in claim 1), wherein the compound of claim 50. 56. L ¹ is the following group: Wherein R ^15a is -N (R ⁸ ) -C (= O) -R ⁹ or -N (R ⁸ ) -SO ₂ -R ⁹ (where R ⁸ and R ⁹ are defined in claim 1) 55. The compound of claim 55, wherein 57. L ¹ is a group represented by the following formula: Wherein R ^15a is -N (R ⁸ ) -C (= O) -R ⁹ or -N (R ⁸ ) -SO ₂ -R ⁹ (where R ⁸ and R ⁹ are defined in claim 1) 55. The compound of claim 55, wherein 58. The compound according to any one of claims 31 to 57, wherein Y represents a carboxy group. 59. R ² is a hydrogen atom, R ³ is a phenyl group substituted at the 2-position, A ¹ is methylene or ethylene, and Ar ¹ is an optionally substituted m- or p
-Phenylene or optionally substituted p-pyridinediyl, wherein L ¹ is the following group: (Where R ¹⁵ is a hydrogen atom, a lower alkyl group, an aryl, a heteroaryl, -N (R ⁸ ) -C (= O)
-R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ , or carboxy (or an acidic biological isotope), -OH, -OR ³ or -C (= O) -NY ⁴ Y ⁵ is an alkyl group),
The compound of formula (Ia) and the corresponding N-oxide according to claim 31, wherein L ⁴ represents a straight or branched C _1-6 alkylene chain, Y represents carboxy, and Z ¹ represents CH ₂ , and the corresponding N-oxides. Prodrugs; and pharmaceutically acceptable salts and solvates of the compound and its N-oxide and prodrug. 60. R ² is a hydrogen atom, R ³ is a phenyl group substituted at the 2-position, A ¹ is methylene or ethylene, and Ar ¹ is an optionally substituted m- or p
-Phenylene or optionally substituted p-pyridinediyl, wherein L ¹ is the following group: (Where R ^15a is -N (R ⁸ ) -C (= O) -R ⁹ or -N (R ⁸ ) -SO ₂ -R ⁹ ), wherein L ⁴ is a linear or branched C _1-6 represents an alkylene chain, Y represents a carboxy compounds and the corresponding N- oxide of formula of claim 31, wherein Z ¹ represents CH ₂ (Ia), and their prodrugs; and the compounds and their N- oxides and Pharmaceutically acceptable salts and solvates of the prodrug. 61. R is hydrogen, chloro, methyl, ethyl or methoxy; R ² is hydrogen; R ³ is optionally substituted aryl; A ¹ is methylene or ethylene; ¹ is the following group: (Where R ¹⁵ is a hydrogen atom, a lower alkyl group, an aryl, a heteroaryl, -N (R ⁸ ) -C (= O)
-R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ , or carboxy (or an acidic biological isotope), ^{-OH, -ZR 3, -C (=} O) -NY is ⁴ Y ⁵ or -NY ⁴ Y ^{5-substituted} alkyl group), L ⁴ represents a straight or branched chain C _1-4 alkylene chain , X is O, Y represents carboxy, Z ¹ represents CH ₂ , Z ⁴ is NH, and the following group is attached to the 6-position of the ring: 33. A compound of formula (Ib) according to claim 32 and corresponding N-oxides and prodrugs thereof; and pharmaceutically acceptable salts and solvates of said compound and its N-oxides and prodrugs. 62. R is hydrogen, chloro, methyl, ethyl or methoxy; R ² is hydrogen; R ³ is optionally substituted aryl; A ¹ is methylene or ethylene; ¹ is the following group: (Where R ^15a is -N (R ⁸ ) -C (= O) -R ⁹ or -N (R ⁸ ) -SO ₂ -R ⁹ ), wherein L ⁴ is a linear or branched C _1-4 Represents an alkylene chain, X is O, Y represents carboxy, Z ¹ represents CH ₂ ,
Z ⁴ is NH and the following group is attached to the 6-position of the ring: 33. A compound of formula (Ib) according to claim 32 and corresponding N-oxides and prodrugs thereof; and pharmaceutically acceptable salts and solvates of said compound and its N-oxides and prodrugs. 63. R ² is a hydrogen atom, R ³ is an optionally substituted aryl, A ¹ is methylene or ethylene, and L ¹ is: (Where R ¹⁵ is a hydrogen atom, a lower alkyl group, an aryl, a heteroaryl, -N (R ⁸ ) -C (= O)
-R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ , or carboxy (or an acidic biological isotope), ^{-OH, -OR 3, -C (=} O) -NY is ⁴ Y ⁵ or -NY ⁴ Y ^{5-substituted} alkyl group), L ⁴ represents a straight or branched chain C _1-4 alkylene chain , X is NR ⁵ , Y represents carboxy, Z ¹ represents CH ₂ , Z ⁴ is NH, and the following groups are attached at the 5- or 6-position of the ring: Embedded image 33. A compound of formula (Ib) according to claim 32 and corresponding N-oxides and prodrugs thereof; and pharmaceutically acceptable salts and solvates of said compound and its N-oxides and prodrugs. 64. R ² is a hydrogen atom, R ³ is an optionally substituted aryl, A ¹ is methylene or ethylene, and L ¹ is: (Where R ^15a is -N (R ⁸ ) -C (= O) -R ⁹ or -N (R ⁸ ) -SO ₂ -R ⁹ ), wherein L ⁴ is a linear or branched C _1-4 represents an alkylene chain, X is NR ^5, Y represents carboxy, Z ¹ represents CH _2, Z ⁴ is NH, and the following groups are attached to the 5- or 6-position of the ring Is: 33. A compound of formula (Ib) according to claim 32 and corresponding N-oxides and prodrugs thereof; and pharmaceutically acceptable salts and solvates of said compound and its N-oxides and prodrugs. 65. R ² is a hydrogen atom, A ¹ is methylene or ethylene;
Ar ¹ is optionally substituted m- or p-phenylene or optionally substituted p
-Pyridinediyl, wherein L ¹ is the following group: (Where R ¹⁵ is a hydrogen atom, methyl, aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ , or carboxy, -OH, -OR ³ or
-C (= O) -NY ⁴ is an alkyl group substituted with Y ⁵ ), L ⁴ represents a linear or branched C _1-4 alkylene chain, Y represents carboxy, and Z ¹ represents CH ₂ 34. A compound of formula (Ic) according to claim 33 and the corresponding N-oxide, and a prodrug thereof; and pharmaceutically acceptable salts and solvates of said compound and its N-oxide and prodrug. 66. R ² is a hydrogen atom, A ¹ is methylene or ethylene,
Ar ¹ is optionally substituted m- or p-phenylene or optionally substituted p
-Pyridinediyl, wherein L ¹ is the following group: (Where R ^15a is -N (R ⁸ ) -C (= O) -R ⁹ or -N (R ⁸ ) -SO ₂ -R ⁹ ), wherein L ⁴ is a linear or branched C _1-4 represents an alkylene chain, Y represents a carboxy, Z ¹ represents CH _2, the compounds and the corresponding N- oxide of formula of claim 33 (Ic), and prodrugs thereof; and the compounds and their N- oxides And prodrugs, pharmaceutically acceptable salts and solvates. 67. R ² is a hydrogen atom and R ³ is an optionally substituted phenyl;
Optionally substituted heteroaryl or optionally substituted benzyl, A ¹ is methylene or ethylene and L ¹ is the following group: (Where R ¹⁵ is a hydrogen atom, methyl, aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ , or carboxy, -OH, -OR ³ or
-C (= O) -NY ⁴ Y ⁵ is an alkyl group), Y represents carboxy, and Z ¹ represents
Represents a CH _2, the compounds and the corresponding N- oxide of Formula of claim 34, wherein (Id), and prodrugs thereof; in and the compounds and their N- oxides and prodrugs,
Pharmaceutically acceptable salts and solvates (eg, hydrates). 68. R ² is a hydrogen atom, and R ³ is an optionally substituted phenyl;
Optionally substituted heteroaryl or optionally substituted benzyl, A ¹ is methylene or ethylene, and L ¹ is the following group: (Where R ^15a is -N (R ⁸ ) -C (= O) -R ⁹ or -N (R ⁸ ) -SO ₂ -R ⁹ ), Y represents carboxy, and Z ¹ is CH ₂ 35. The compound of formula (Id) according to claim 34 and the corresponding N-oxide and prodrug thereof, and pharmaceutically acceptable salts and solvates of said compound and N-oxide and prodrug thereof. 69. The method of claim 60, 64, 66, and wherein L ¹ is a group represented by the following formula:
68. The compound according to any one of the above 68: 70. The method of claim 61,63,65, and wherein L ¹ is a group represented by the following formula:
67. The compound according to any one of 67: 71. The compound according to claim 70, wherein R ¹⁵ is a hydrogen atom. 72. The compound of para 70, wherein R ¹⁵ is lower alkyl. 73. The compound of para 70, wherein R ¹⁵ is optionally substituted phenyl. 74. R ¹⁵ represents —N (R ⁸ ) —C (= O) —R ⁹ , R ⁸ is a hydrogen atom or lower alkyl, and R ⁹ is lower alkyl, aryl, heteroaryl, alkoxy in substituted alkyl, alkyl substituted with alkyl or -NY ⁴ Y ⁵ substituted by carboxy, claim 70 a compound according. 75. R ¹⁵ represents —N (R ⁸ ) —C (= O) —OR ⁹ , R ⁸ is a hydrogen atom or lower alkyl, and R ⁹ is alkyl substituted with lower alkyl or aryl. 71. The compound of claim 70, which is 76. The method according to claim 76, wherein R ¹⁵ represents —N (R ⁸ ) —SO ₂ —R ⁹ , R ⁸ is a hydrogen atom or lower alkyl, and R ⁹ is lower alkyl, aryl or heteroaryl. 70. The compound according to 70, wherein 77. R ¹⁵ represents -NY ⁴ Y ⁵ , wherein Y ⁴ and Y ⁵ represent a hydrogen atom,
71. The compound of claim 70. 78. The compound of para 70, wherein R ¹⁵ represents -NY ⁴ Y ⁵ , wherein Y ⁴ represents a hydrogen atom, and Y ⁵ represents alkyl substituted with lower alkyl or aryl. 79. The compound of para 70, wherein R ¹⁵ represents -NY ⁴ Y ⁵ , wherein Y ⁴ and Y ⁵ represent alkyl substituted with aryl. 80. The compound of para 70, wherein R ¹⁵ represents lower alkyl substituted by carboxy. 81. The method according to claim 70, wherein R ¹⁵ represents lower alkyl substituted by —OH.
A compound as described. 82. The method according to claim 70, wherein R ¹⁵ represents lower alkyl substituted by —OR ^3.
A compound as described. 83. R ¹⁵ represents lower alkyl substituted by -C (= O) -NY ⁴ Y ⁵ ;
71. The compound of claim 70. 84. R ¹⁵ is -H, -NH ₂ , -NHCH ₂ CH ₂ CH ₃ , Embedded image Embedded image (Where R is hydrogen or aryl _{substituents), - CH 3, -CH 2} CH 3, -CH 2 CH 2 CH 3, -
_{CH 2 CH 2 CH 2 CH 3} , represents a -CH ₂ OH, -CH ₂ COOH or -CH ₂ OMe, claim 70 A compound according. 85. R ^15a represents —N (R ⁸ ) —C (= O) —R ⁹ , R ⁸ is a hydrogen atom or lower alkyl, and R ⁹ is lower alkyl, aryl, heteroaryl, alkoxy in substituted alkyl, alkyl substituted with alkyl or -NY ⁴ Y ⁵ substituted by carboxy, claim 69 a compound according. 86. R ^15a represents —N (R ⁸ ) —C (= O) —R ⁹ , R ⁸ is a hydrogen atom or lower alkyl, and R ⁹ is 2-chlorophenyl, 5-chloro-2 -Cyanophenyl, 2-chloro
-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-fluoro
70.A group selected from 2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl and 2-phenoxyphenyl. A compound as described. 87. R ^15a represents —N (R ⁸ ) —C (= O) —R ⁹ , R ⁸ is a hydrogen atom or lower alkyl, and R ⁹ is quinolin-4-yl, isoquinolin-2 -Yl, 2,4-pyridine-3-
Yl, 2,6-dimethyl-4-trifluoromethylpyridin-3-yl, 4-trifluoromethylpyridin-3-yl, 2-phenyl-4-methyl-1,2,3-triazol-5-yl, 3,5-dimethylisoxazol-4-yl, 2,7-dimethylpyrazolo- [1,5-a] pyrimidin-6-yl,
70. The compound of claim 69, wherein the compound is selected from 2-isopropyl-4-methylthiazol-5-yl, and 4-trifluoromethylpyrimidin-5-yl. 88. 3- (1-[[3-methoxy-4- (3- [2-methylphenyl] -ureido)-
Phenyl] -acetyl] -1,2,3,4-tetrahydro-quinolin-6-yl) -propionic acid;
3- (1-[[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl] -2,3-dihydro-1H-indol-5-yl) -butyric acid; 3- (1 -[[3-Methoxy-4- (3-o-tolyl-ureido)
-Phenyl] -acetyl] -1,2,3,4-tetrahydro-quinolin-6-yl) -butyric acid; 3- (1- [
[3-Methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl] -2,3-dihydro-1H-
Indole-5-yl) -pentanedioic acid; 3- (1-[[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl] -1,2,3,4-tetrahydro- Quinolin-6-yl) -pentanedioic acid; 4- [2-carboxy-1- (1-[[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl] -1,2 , 3,4-tetrahydro-quinolin-6-yl) -ethylcarbamoyl] -butyric acid; N- [2-carboxy-1- (1-[[3-methoxy-4- (3-o-tolyl-ureido)-] Phenyl] -acetyl] -1,2,3,4-tetrahydro-quinolin-6-yl) -ethyl] -succinamic acid; 3- (1-[[3-methoxy-4- (3-o-tolyl- Ureido) -phenyl] -acetyl] -1,
2,3,4-tetrahydro-quinolin-6-yl) -3-[(5-methylisoxazole-3-carbonyl) -amino] -propionic acid; 2- (2-chloro-6-methyl-benzoylamino ) -3- [1-
(2,6-dichloro-benzoyl) -1,2,3,4-tetrahydro-quinolin-6-yl] -propionic acid; 2- (2,6-dichloro-benzoylamino) -3- [1- (2 , 6-Dichloro-benzoyl) -1
, 2,3,4-tetrahydro-quinolin-6-yl] -propionic acid; 3- (1-[[3-methoxy-4- (
3-o-tolyl-ureido) -phenyl] -acetyl] -2,3-dihydro-1H-indol-5-yl) -3-phenyl-propionic acid; 3- (1-[[3-methoxy-4- (3-o-tolyl-ureido)-
Phenyl] -acetyl] -2,3-dihydro-1H-indol-5-yl) -pentanoic acid; and the corresponding N-oxide, and its prodrugs; and the compound and its N-oxide
2. The compound of claim 1, wherein the compound is selected from pharmaceutically acceptable salts and solvates (eg, hydrates) of oxides and prodrugs. 89. An intermediate compound represented by formulas (IV), (IX) and (2). 90. A compound of claim 1 or a corresponding N-oxide, or a prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient; or a compound of the compound or an N-oxide or prodrug thereof. A pharmaceutical composition comprising an effective amount of a pharmaceutically acceptable salt or solvate. 91. A compound according to claim 1 or the corresponding N-oxide, or a prodrug thereof, for use in therapy; or said compound or an N-oxide thereof.
Pharmaceutically acceptable salts or solvates of the oxides or prodrugs. 92. The compound of claim 1, or a corresponding N, for use in treating a patient suffering from or suffering from a condition that can be ameliorated by administering an inhibitor of α4β1-mediated cell adhesion. -An oxide or a prodrug thereof;
Or a pharmaceutically acceptable salt or solvate of the compound or an N-oxide or prodrug thereof. 93. The compound of claim 90, for use in treating a patient suffering from or suffering from a condition that can be ameliorated by administering an inhibitor of α4β1-mediated cell adhesion. 94. A compound or composition according to claim 1 or 90, respectively, for use in the treatment of an inflammatory disease. 95. Each of claims 1 or 90 for use in treating asthma.
3. The compound or composition according to item 1. 96. The compound of claim 1 or a corresponding N in the manufacture of a medicament for treating a patient afflicted with or suffering from a condition that can be ameliorated by administering an inhibitor of α4β1-mediated cell adhesion. The use of an oxide or a prodrug thereof; or a pharmaceutically acceptable salt or solvate of the compound or an N-oxide or prodrug thereof. 97. The compound of claim 1 or the corresponding N-oxide, or a prodrug thereof, in the manufacture of a medicament for the treatment of asthma;
The use of pharmaceutically acceptable salts or solvates of the oxides or prodrugs. 98. A method of treating a non-human patient suffering from or suffering from a condition that can be ameliorated by administering an inhibitor of α4β1-mediated cell adhesion, comprising administering to said patient an effective amount. Administering a compound according to claim 1 or the corresponding N-oxide or a prodrug thereof; or a pharmaceutically acceptable salt or solvate of said compound or an N-oxide or a prodrug thereof. The above method. 99. A compound substantially as described in connection with the examples.