JP2002541257A - Substituted bicyclic heteroaryl compounds as integrin antagonists - Google Patents

Abstract

(57) [Summary] The present invention provides a compound represented by the general formula (I): R ¹ Z ¹ ─Het─L ¹ ─Ar ¹ ─L ² ─Y (I) wherein Het is selected from O, S or N An optionally substituted saturated, partially saturated or fully unsaturated 8-10 membered bicyclic ring containing at least one heteroatom; R ¹ is an optionally substituted aryl, hetero Z ¹ represents a direct bond, an alkylene chain, NR ⁴ , O or S (O) _n ; L ¹ is —R ⁵ —R ^6. Aryl, alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl; A bond (where R ⁵ is alkylene, alkenylene or alkynylene, and R ⁶ is a direct bond, cycloalkylene, heterocycloalkylene, arylene, heteroaryldiyl, —C (＝ Z ³ ) —NR ⁴ —, —NR ⁴ -C ( ^{Z 3) -, - Z 3} -, - C (= O) -, - C (= NOR 4) -, - NR 4 -, - NR 4 -C (= Z 3) -NR 4 -, - SO 2 ^{-NR 4 -, - NR 4 -SO} 2 -, - O-C (= O) -, - C (= O) -O -, - NR 4 -C (= O) -O- or -O-C (= O) -NR ⁴ - it is a a); L ² is a direct bond; alkylene optionally substituted, alkenylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene or arylene linkage; - [C (= O) -N ( R 9) -C (R 4) (R l0)] p - bond; -Z ⁴ -R ¹¹ - _{bond; -C (= O) -CH 2} -C (= O ) - bond; -R ¹¹ -Z ⁴ -R ¹¹ - linkage; or -L ³ -L ⁴ -L ⁵ - represents a bond; and Y is a representative of the biological isostere carboxy or acid) Expressed physiologically active Compounds, the corresponding N-oxides and their prodrugs; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds, their N-oxides and prodrugs. The compounds have useful pharmaceutical properties, especially the ability to modulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (α4β1).

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to substituted bicyclic compounds, their preparation, pharmaceutical compositions containing said compounds and their pharmaceutical use in the treatment of disease states that can be modulated by inhibiting cell adhesion.

[0002] Cell adhesion is the process by which cells associate with each other, migrate to specific targets, or concentrate locally within the extracellular matrix. Many of the cell-cell and cell-extracellular matrix interactions are based on protein ligands (eg, fibronectin, VCAM-1 and vitronectin) and their integrin receptors [eg, α5βl (VLA-5), α4βl (VLA-4) And αVβ3]. Recent studies have shown that these interactions are associated with many physiological conditions (eg, embryonic development and wound healing) and pathological conditions (eg, tumor cell invasion and metastasis,
(Inflammation, atherosclerosis and autoimmune diseases).

[0003] A variety of proteins serve as ligands for integrin receptors. In general,
Proteins recognized by integrins fall into one of three classes: extracellular matrix proteins, plasma proteins and cell surface proteins. Extracellular matrix proteins such as collagen, fibronectin, fibrinogen, laminin, thrombospondin and vitronectin bind to many integrins. Many of the adhesive proteins also circulate in the plasma and bind to activated blood cells. Still other components in plasma that are ligands for integrins are fibrinogen and factor X. Cell binding component 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 Igspar family, also serve as cell surface ligands for some integrins.

[0004] Integrins are heterodimeric cell surface receptors consisting of two subunits called α and β. At least 15 different α subunits (α
There are 1-α9, α-L, α-M, α-X, α-IIb, α-V and α-E) and at least seven different β (β1-β7) subunits. The integrin family is subdivided into classes based on β subunits, which are able to associate with one or more α-subunits. The most widely distributed integrins are β1, also known as very slow antigen (VLA)
Belongs to class. The second class of integrins are leukocyte-specific receptors,
Three types of α-subunits (α-L, α-M or α-
X). The cell adhesives α-IIbβ3 and α-Vβ3 constitute a third class of integrins.

The present invention is primarily directed to the ligand VCAM-1 and its integrin receptor α4βl
(VLA-4). The interaction is expressed on numerous hematopoietic cells and established cell lines such as hematopoietic progenitors, peripheral and cytotoxic T lymphocytes, B lymphocytes, monocytes, thymocytes and eosinophils.

The integrin receptor α4βl mediates both cell-cell and cell-matrix interactions. Cells expressing α4βl are derived from the carboxy-terminal cell binding domain (CS) of the extracellular matrix protein fibronectin.
-1) binds to the cytokine-induced endothelial cell surface protein VCAM-1 and to each other to promote homotypic aggregation. VCAM-1 expression by endothelial cells is completely regulated by pro-inflammatory cytokines such as INF-γ, TNF-α, IL-1β and IL-4.

[0007] The regulation of α4βl-mediated cell adhesion is dependent on many physiological processes such as T-cell proliferation,
It is important in the localization of B-cells to germinal centers and in the adhesion of activated T-cells and eosinophils to endothelial cells. Various disease processes such as melanoma cell division in metastasis, rheumatoid arthritis, autoimmune diabetes, T-cell infiltration of the synovium in colitis, and experimental autoimmune encephalomyelitis, atherosclerosis, V in blood-brain barrier leukocyte invasion in peripheral vascular disease, cardiovascular disease and multiple sclerosis
Demonstration of the involvement of LA-4 / VCAM-1 indicates that peptide CS-1 (α4βl has the sequence L
variable region of fibronectin that binds via eu-Asp-Val) and has been gathered by investigating the role of antibodies specific for VLA-4 or VCAM-1 in various in vitro and in vivo inflammation experimental models. . For example, in an experimental model of arthritis induced by streptococcal cell wall in rats, C
Intravenous administration of S-1 suppresses both acute and chronic inflammation (SM. Wahl et al.
l., J. Clin. Invest, 1994, 94, pages 655-662). In a model of oxazolone-sensitized inflammation (contact hypersensitivity reaction) in mice, intravenous administration of an anti-α4-specific monoclonal antibody significantly blocked the export response (50-60% of the ear swelling response).
Decrease) (see PL. Chisholm et al. J. ImmunoI., 1993, 23, pages 682-688)
. In a model of allergic bronchoconstriction in sheep, the intravenous or aerosolized anti-α4 monoclonal antibody HP1 / 2 blocked the late response and progression of airway hyperresponsiveness (WM Abraham et al. J. Clin . Invest, 1994,93, pages
776-787).

[0008] Now, according to the present inventors, a new group of substituted bicyclics having useful pharmaceutical properties, especially the ability to modulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (α4βl). Formula compounds have been found.

That is, in one aspect, the present invention provides a compound of the general formula (I): R¹Z¹─Het─L¹─Ar¹─L^Two─Y (I) wherein Het contains at least one heteroatom selected from O, S or N
And optionally substituted with one or more aryl group substituents,
Represents an 8-10 membered bicyclic ring system which is fully saturated or completely unsaturated;¹Is aryl, heteroaryl, optionally substituted alkyl, alk
Nil or alkynyl (where each is R^Two, -Z^TwoR^Three, -Z^ThreeH, -C (=
O) -R^Three, -NR^FourC (= Z^Three)-R^Three, -NR^Four-C (= O) -OR^Three, -NR^Four-S
O_Two-R^Three, -SO_Two-NY¹Y^Two, -NY¹Y^TwoOr -C (= Z^Three) -NY¹Y^TwoIn case
Substituted), or optionally substituted cycloalkyl or
Rocycloalkyl (where each is R^Three, -Z^TwoR^Three, -Z^ThreeH, -C (= O) -R ^Three , -NR^Four−C (= Z^Three) -R^Three, -NR^Four-C (= O) -OR^Three, -NR^Four-SO_Two-R ^Three , -SO_Two-NY¹Y^Two, -NY¹Y^TwoOr -C (= Z^Three) -NY¹Y^TwoIn some cases
R)^TwoIs aryl, cycloalkyl, cycloalkenyl, heteroaryl or
Represents heterocycloalkyl; R^ThreeIs alkyl, alkenyl, alkynyl, aryl, arylalkyl,
Arylalkenyl, arylalkynyl, cycloalkyl, cycloalkyl
Alkyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, hete
Loarylalkyl, heteroarylalkenyl, heteroarylalkynyl,
R represents heterocycloalkyl or heterocycloalkylalkyl;^FourRepresents hydrogen or lower alkyl;

[0010] R^FiveIs a direct bond or an alkylene chain, alkenylene chain or
A quinylene chain; R⁶Is a direct bond, cycloalkylene, heterocycloalkylene, arylene
, Heteroaryldiyl, -C (= Z^Three) -NR^Four-, -NR^Four−C (= Z^Three)-, -Z ^Three -, -C (= O)-, -C (= NOR^Four)-, -NR^Four-, -NR^Four−C (= Z^Three) −
NR^Four-, -SO_Two-NR^Four-, -NR^Four-SO_Two-, -OC (= O)-, -C (= O
) -O-, -NR^Four-C (= O) -O- or -OC (= O) -NR^Four-Is R⁷Is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl,
Chloroalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl
R is a heteroalkyl or a heterocycloalkylalkyl;⁸Is alkyl, aryl, cycloalkyl, heteroaryl or
Rocycloalkyl or aryl, acidic functional groups (or corresponding
Protected derivatives), cycloalkyl, heteroaryl, heterocycloalkyl,
-Z^ThreeH, -Z^TwoR^Three, -C (= O) -NY^ThreeY^FourOr -NY^ThreeY^FourReplaced with
Kill; R⁹Is hydrogen, R^ThreeOr alkoxy, cycloalkyl, hydroxy
, Mercapto, alkylthio or -NY^ThreeY^FourR is an alkyl substituted with^TenAnd R¹¹Are each independently hydrogen, an amino acid side chain and the corresponding
A group consisting of a protected derivative, an acidic functional group or a corresponding protected derivative, R ^Three , -Z^TwoR^Three, -C (= O) -R^ThreeOr -C (= O) -NY^ThreeY^FourOr acidic sensuality
Group or a corresponding protected derivative, or R^Three<-Z^TwoR^Three<-NY^ThreeY ^Four , -NH-C (= O) -R^Three<-C (= O) -R^Five-NH_Two, -C (= O) -Ar^Two-N
H_Two, -C (= O) -R^Five-CO_TwoH or -C (= O) -NY^ThreeY^FourReplaced by
Or R is selected from⁹And R^TenIs, together with the atom to which they are attached, a 3- to 6-member
Forming a heterocycloalkyl ring of¹¹Is R^ThreeC optionally substituted with_1-6R is alkylene;¹²Is alkyl, aryl, arylalkyl, cycloalkyl, cycloa
Alkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl
R is a cycloalkyl or a heterocycloalkylalkyl;^l3Is hydrogen, or aryl, an acidic functional group or a corresponding protected group.
Derivatives, cycloalkyl, heteroaryl, heterocycloalkyl, -Z^Three
H, -Z^TwoR^Three, -C (= O) -NY^ThreeY^FourOr -NY^ThreeY^FourOptionally replaced by
Alkyl;

Ar¹Is heteroaryldiyl; Ar^TwoIs arylene or heteroaryldiyl; L¹Is -R^Five-R⁶-Represents a bond; L^TwoAre (i) a direct bond; (ii) alkylene, alkenylene, alkynylene, cycloalkenylene, cycloalkyl
Loalkylene, heteroaryldiyl, heterocycloalkylene or aryle
[Each is (a) an acidic functional group (or corresponding protected derivative), R ^Three , -Z^ThreeH, -Z^TwoR⁸, -C (= O) -R^Three, -N (R⁷) -C (= O) -R⁸, -N (R ⁷ ) -C (= O) -OR⁸, -NC (R⁷) -C (= O) -NR^FourR⁸, -N (R⁷) -SO_Two−
R⁸, -NY^ThreeY^Four, Or-[C (= O) -N (R⁹) -C (R^Four) (R^Ten)]_p-C (= O)-
NY^ThreeY^FourOr (b) until the acidic functional group (or the corresponding protected derivative)
Or -Z^ThreeH, -Z^TwoR^Three, -C (= O) -NY^ThreeY^FourOr -NY^ThreeY^FourIs replaced by
(Iii)-[C (= O) -N (R⁹) -C (R^Four) (R^l0)]_p-Bond; (iv) -Z^Four-R¹¹-Bond; (v) -C (= O) -CH_Two-C (= O) -bond; (vi) -R¹¹-Z^Four-R¹¹-Bond; or (vii)-L^Three-L^Four-L^FiveL represents a bond; L^ThreeRepresents a direct bond, and L^FiveRepresents an alkylene chain; or L^ThreeRepresents an alkylene chain, and L^FiveRepresents a direct bond or an alkylene chain;^FourRepresents a cycloalkylene or heterocycloalkylene bond;

Y represents a carboxy or acid bioisostere; Y ¹ and Y ² are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl Or the group -NY ¹ Y ² may form a cyclic amine; Y ³ and Y ⁴ are independently hydrogen, alkenyl, alkyl, alkynyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, or heterocycloalkyl, or alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, -NY ¹ Y ² or one or more -CO ₂ R ⁷ or -C, (= O ) -NY ¹ Y is ² alkyl substituted with group; or a group -NY ³ Y ⁴ is a 5- to 7-membered A Jo amine, it (i)
Alkoxy, carboxamido, carboxy, hydroxy, oxo (or its 5-, cyclic acetal derivative of 6- or 7-membered), optionally substituted with 1 or more substituents selected from R ⁸ Well; (ii) O, S
, SO ₂ or NY ^5, and (iii) further fused to another aryl, heteroaryl, heterocycloalkyl or cycloalkyl ring Y ⁵ may be hydrogen, alkyl, aryl, arylalkyl, —C (＝ O) —R ¹² , or may form a bicyclic or tricyclic ring system.
-C (= O) be -OR ¹² or -SO ₂ R ^12;

Z ¹ represents a direct bond, an alkylene chain or NR ⁴ , O or S (O) _n ; Z ² is O or S (O) _n ; Z ³ is O or S; Z ⁴ is, O, be a ^{_{S (O) n, NR 13}} , SO 2 NR 13, NR 13 C (= O), C (= O) NR 1 3 or C (= O); and n is 0 Or p is an integer of 1 or 2; and p is 0 or an integer of 1 to 4 wherein the oxygen, nitrogen or sulfur atom is an alkenyl or alkynyl residue. Except when directly attached to a carbon-carbon multiple bond], the corresponding N-oxides and their prodrugs; and the compounds, their N-oxides.
It relates to pharmaceutically acceptable salts and solvates (eg hydrates) of oxides and prodrugs.

In a particularly preferred embodiment of the present invention, in formula (I), L ² is (i), (ii), (iii)
), (Iv), (v) or (vi).

In the present specification, the term “the compound of the present invention” and similar expressions are represented by the aforementioned general formula (I)
) Is meant to include the prodrugs, pharmaceutically acceptable salts and solvates thereof, as the context so reads. Similarly, with respect to intermediates, whether or not they are themselves claimed, is meant to include their salts and solvates, as long as the context reads so. For the sake of clarity, specific examples are often mentioned in the specification where the context so reads, but these examples are purely illustrative and the context This does not exclude other examples.

As used above and in the description of the present invention, the following terms, unless otherwise indicated,
It should have the following meaning: "Patient" includes both humans and other mammals. "Acid bioisostere" means a group that has chemical and physical similarities that result in broadly similar biological properties to the carboxy group (Lipinski, Annual Reports in Medicinal). Chemistry, 1986, 21, p283 “Bioiso
sterism In Drug Design ”; Yun, Hwahak Sekye, 1993, 33, p576-579“ Applicati
on Of Bioisosterism To New Drug Design ”; Zhao, Huaxue Tongbao, 1995, p34
-38 “Bioisosteric Replacement And Development Of Lead Compounds In Drug
Design ”; Graham, Theochem, 1995, 343, pl05-109“ Theoretical Studies App
lied To Drug Design: ab initio Electronic Distributions In Bioisostere
s "). Examples of suitable acid bioisosteres include -C (= O) -NHO
H, -C (= O) -CH 2 OH, -C (= O) -CH 2 SH, -C (= O) -NH-CN
, 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.

“Acyl” refers to an H—CO— or alkyl-CO— group, where the alkyl group is as described herein. "Acylamino" is an acyl-NH- group wherein acyl has the definition described herein. "Alkenyl" is an aliphatic hydrocarbon group containing about 2 to about 15 carbon atoms in the chain and which may be straight or branched and containing a carbon-carbon double bond. Means Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain, more preferably 2 to about 6 carbon atoms in the chain (e.g., 2 to 4 carbon atoms). As used herein and herein, "branched" means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear chain, here a linear alkenyl chain. Means that. "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-
Mention may be made of butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.

“Alkenylene” means an aliphatic divalent group derived from a straight-chain or branched alkenyl group, wherein the alkenyl group is as described herein. Examples of alkenylene groups include vinylene and propylene. "Alkoxy" means an alkyl-O- group in which the alkyl group is as described herein. Examples of alkoxy groups are methoxy, ethoxy,
Mention may be made of n-propoxy, i-propoxy, n-butoxy and heptoxy. "Alkoxycarbonyl" means an alkyl-O-CO- group in which the alkyl group is as described herein. Examples of alkoxycarbonyl groups include methoxy- and ethoxycarbonyl. “Alkyl” means a straight chain having from about 1 to about 15 carbon atoms in the chain, which may be optionally substituted by alkoxy or one or more halogen atoms, unless otherwise specified. Or an aliphatic hydrocarbon group which may be branched. Particularly preferred alkyl groups have 1 to about 6 carbon atoms. A "lower alkyl group" as a group or as part of a lower alkoxy, lower alkylthio, lower alkylsulfinyl, or lower alkylsulfonyl group, unless otherwise specified, has from 1 to about 4 carbon atoms in the chain. Means an aliphatic hydrocarbon group which may be linear or branched. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl, and dodecyl. be able to.

“Alkylene” means an aliphatic divalent group derived from a straight or branched chain alkyl group, wherein the alkyl group is as described herein. Examples of alkylene groups include methylene, ethylene and trimethylene. "Alkylenedioxy" means an -O-alkylene-O- group wherein alkylene has the previously defined meaning. Examples of the alkylenedioxy group include methylenedioxy and ethylenedioxy. "Alkynylsulfinyl" 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. "Alkylsulfonyl" represents an alkyl -SO ₂ - group (wherein the alkyl group is as defined above) means. Preferred alkylsulfonyl groups are those in which the alkyl group is C _1-4 alkyl. “Alkylsulfonylcarbamoyl” is alkyl-SO ₂ —NH—C (＝ O)
-Group (where the alkyl group is as described above). Preferred alkylsulfonylcarbamoyl groups are those in which 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 alkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio.

“Alkynyl” is an aliphatic hydrocarbon which may contain a carbon-carbon triple bond and may have about 2 to about 15 carbon atoms in the chain, which may be straight or branched. Means a group. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain, and more preferably 2 to about 6 carbon atoms (eg, 2 to 4 carbon atoms) in the chain. Examples of alkynyl groups include ethynyl, propynyl, n-butynyl, i-
Butynyl, 3-methylbut-2-ynyl and n-pentynyl can be mentioned. "Alkynylene" means an aliphatic divalent group derived from a straight-chain or branched alkynyl group, wherein alkynyl group is as described herein. Examples of alkynylene groups include ethynylene and propynylene. "Aroyl" means an aryl-CO- group in which the aryl group is as described herein. Examples of aroyl groups include benzoyl and 1- and 2-naphthoyl. "Aroylamino" means an aroyl-NH- group in which aroyl has the aforementioned definition.

“Aryl” as a group or part of a group includes (i) about 6 to about 1
An optionally substituted monocyclic or polycyclic aromatic carbocyclic moiety consisting of 4 carbon atoms, for example phenyl or naphthyl; or (ii) optionally substituted partially saturated polycyclic A formula aromatic carbocyclic moiety wherein the aryl and cycloalkyl or cycloalkenyl groups are fused together to form a cyclic structure,
For example, it forms a tetrahydronaphthyl, indenyl or indanyl ring. An aryl group can be substituted with one or more identical or different aryl group substituents. Here, the “aryl group substitution” 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, heteroaryl, heteroarylalkyloxy, heteroaroylamino amino, heteroaryloxy, hydroxy, nitro, ^{trifluoromethyl, Y 1 Y 2 N-, Y} 1 Y 2 NCO-, Y 1 Y 2 NSO 2 -, Y ¹ Y ² N—C _2-6 alkylene-Z ¹ —, alkyl C (＝ O) —Y ¹ N—, alkyl SO ₂ —Y ¹ N—, or aryl, heteroaryl, hydroxy or Y ¹ Y ² N And-optionally substituted alkyl. When R ¹ is an optionally substituted aryl group, this especially represents an optionally substituted phenyl.

“Arylalkenyl” means an aryl-alkenyl-group in which the aryl and alkenyl are as previously described. Preferred arylalkenyls contain one lower alkenyl moiety. Examples of alkenylaryl groups include styryl and phenylallyl. "Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C _1-4 alkyl moiety. Examples of arylalkyl groups are benzyl,
Mention may be made of 2-phenethyl and naphthalenemethyl. "Arylalkyloxy" means an arylalkyl-O- group in which the arylalkyl group is as previously described. Examples of arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. "Arylalkyloxycarbonyl" means an arylalkyl-O-CO- group in which the arylalkyl group is as previously described. An example of an arylalkyloxycarbonyl group is benzyloxycarbonyl. "Arylalkylthio" means an arylalkyl-S- group in which the arylalkyl group is as previously described. An example of an arylalkylthio group is benzylthio. "Arylalkynyl" means an aryl-alkynyl-group in which the aryl and alkynyl are as previously described. Examples of arylalkynyl groups include phenylethynyl and 3-phenylbut-2-ynyl.

“Arylene” means an optionally substituted divalent radical derived from an aryl group. Examples of arylene groups include optionally substituted phenylene, naphthylene and indanylene. Suitable substituents include "aryl substituents" having one or more of the above definitions, especially halogen, methyl or methoxy. "Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Examples of aryloxy groups include optionally substituted phenoxy and naphthoxy. “Aryloxycarbonyl” means an aryl-OC (＝ O) group, where 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. "Arylsulfonyl" means an aryl -SO ₂ - group (where the aryl group is as defined above) means. “Arylsulfonylcarbamoyl is aryl-SO ₂ —NH—C (＝ O) —
Group (where the aryl group is as described above). "Arylthio" means an aryl-S- group in which the aryl group is as previously described. Examples of arylthio groups include phenylthio and naphthylthio.

“Azaheteroaryldiyl” refers to 5 to about 10 ring members, wherein one of the ring members is nitrogen and the other ring member is selected from carbon, oxygen, sulfur or nitrogen. A divalent group derived from an aromatic carbocyclic moiety consisting of Examples of azaheteroaryldiyl groups include pyridinediyl, pyrimidinediyl, quinolinediyl, isoquinolindiyl, quinazolinediyl, imidazolediyl, isoxazolediyl, isothiazolediyl, oxazolediyl, thiazolediyl and benzimidazolediyl.

“Cyclic amine” is one in which one of the ring carbon atoms has been replaced with nitrogen,
Means a 3- to 8-membered monocyclic cycloalkyl ring system, which comprises (i) O, S or NY ^Three (Where Y^ThreeIs hydrogen, alkyl, arylalkyl and aryl)
Optionally further heteroatoms selected, and (ii)
Further fused to another aryl or heteroaryl ring to form a bicyclic ring system,
Is also good. Examples of cyclic amines are pyrrolidine, piperidine, morpholine, pipera
Gin, indoline and pyrindrin can be mentioned.

“Cycloalkenyl” means a non-aromatic mono- or polycyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. I do. Examples of monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. "Cycloalkenylalkyl" means a cycloalkenyl-alkyl- group in which the cycloalkenyl and alkyl portions are as previously described. Examples of cycloalkenylalkyl groups include cyclopentenylmethyl, cyclohexenylmethyl or cycloheptenylmethyl. "Cycloalkenylene" is derived from an unsaturated monocyclic hydrocarbon of about 3 to about 10 carbon atoms by removing one hydrogen atom from each of two different carbon atoms in the ring. Means a divalent group. Examples of cycloalkenylene groups include cyclopentenylene and cyclohexenylene.

“Cycloalkyl” means a saturated mono- or bicyclic ring system of about 3 to about 10 carbon atoms, optionally substituted with oxo. Examples of monocyclic cycloalkyl rings include C _3-8 cycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl. "Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl portions are as previously described. Examples of monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. "Cycloalkylene" is derived from a saturated monocyclic hydrocarbon of about 3 to about 10 carbon atoms by removing one hydrogen atom from each of two different carbon atoms in the ring. It means a divalent group. Examples of cycloalkylene groups include cyclopentylene and cyclohexylene.

“Halo” or “halogen” refers to 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 heteroaryl moiety is as previously described.

“Heteroaryl” as a group or part of a group means that (i) one or more of the ring members is an element other than carbon, such as nitrogen, oxygen or sulfur, Optionally substituted aromatic mono- or polycyclic organic moieties consisting of 5 to about 10 ring members (examples of such groups are benzimidazolyl, benzoxazolyl, benzothiazolyl, furyl , Imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups These may be one or more, as the case may be. (Optionally substituted with an aryl group substituent as defined above); (ii) optionally substituted partially saturated polycyclic heterocarbocyclic moieties wherein heteroaryl and cycloalkyl or cycloalkyl Alkenyl groups are fused together to form a cyclic structure) (examples of such groups include pyridanyl groups). Optional substituents have one or more of the foregoing definitions.
Aryl group substitution ".

“Heteroarylalkenyl” means a heteroaryl-alkenyl-group in which the heteroaryl and alkenyl portions are as previously described. Preferably, the heteroarylalkenyl group has a lower alkenyl moiety. Examples of heteroarylalkenyl groups include pyridylethenyl and pyridylallyl. "Heteroarylalkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl portions are as previously described. Preferably, the heteroarylalkyl group contains a C _1-4 alkyl moiety. An example of a heteroarylalkyl group is pyridylmethyl. "Heteroarylalkyloxy" means a heteroarylalkyl-O- group in which the heteroarylalkyl group is as previously described. An example of a heteroarylalkyloxy group is an optionally substituted pyridylmethoxy.

“Heteroarylalkynyl” means a heteroaryl-alkynyl-group in which the heteroaryl and alkynyl portions are as previously described. Examples of heteroarylalkynyl groups include pyridylethynyl and 3-pyridylbut-2-ynyl. "Heteroaryldiyl" consists of about 5 to about 10 ring members, wherein one or more of the ring members is an element other than carbon, for example, nitrogen, oxygen or sulfur,
A divalent radical is derived from an aromatic monocyclic or polycyclic organic moiety optionally substituted with one or more "aryl group substituents" as defined above. "Heteroaryloxy" means a heteroaryl-O- group in which the heteroaryl group is as previously described. Examples of heteroaryloxy groups include optionally substituted pyridyloxy. “Heteroarylsulfonylcarbamoyl” is heteroaryl-SO ₂ —N
It means an H—C (＝ O) — group (where the heteroaryl group is as described above).

“Heterocycle” is an optionally substituted one or more of the ring members being an element other than carbon, eg, nitrogen, oxygen or sulfur, consisting of 5 or 6 ring members. Saturated, partially saturated or fully unsaturated monocyclic organic moiety. 5 or 6
Examples of membered heterocycles are furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, oxazinyl, piperidinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, 1,3,4-thiadiazolyl, thiazolyl, Thienyl and triazolyl groups may be mentioned. Optional substituents include one or more "aryl group substituents" as defined above.

“Heterocycloalkyl” is (i) a cycloalkyl group consisting of about 3 to 7 ring members containing one or more heteroatoms selected from O, S or NY ³ ; ii) optionally substituted partially saturated polycyclic heterocarbocyclic moieties wherein the aryl (or heteroaryl ring) and heterocycloalkyl groups are fused together to form a cyclic structure (such groups Examples include the groups chromanyl, dihydrobenzofuranyl, indolinyl, and pyrindolinyl). “Heterocycloalkylalkyl” refers to heterocycloalkyl-alkyl-
Groups (where the heterocycloalkyl and alkyl moieties are as described above)
Means

“Heterocycloalkylene” contains one or more heteroatoms selected from O, S or NY ^6, wherein Y ⁶ is hydrogen, alkyl, arylalkyl and aryl; By removing one hydrogen atom from each of two different carbon atoms of the ring from a saturated monocyclic hydrocarbon of about 5 to about 7 atoms, optionally substituted with oxo. Or when NY ⁶ is NH, one hydrogen atom from one carbon atom of the ring and one
By removing hydrogen atoms, or when the ring is contains two NY ⁶ heteroatoms and NY ⁶ is NH is induced by both the nitrogen atoms of the removal of one hydrogen atom Means a divalent group.

“Prodrugs” are represented in vivo by metabolic means (eg, by hydrolysis) of the formula (
It means a compound convertible to the compound of I) (including its N-oxide). For example, an ester of a compound of formula (I) containing a hydroxy group can be converted to the original molecule by in vivo hydrolysis. Alternatively, an ester of a compound of formula (I) containing a carboxy group may be converted to the original molecule by in vivo hydrolysis.

Suitable esters of hydroxy-containing compounds of formula (I) are, for example, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-
Bis-P-hydroxynaphthoate, gentisate, isethionate, di-p-
Toluoyl tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfonate, sulfamate and quinate. Suitable esters of compounds of formula (I) containing a carboxy group are, for example, FJ Lein
weber, Drug Metab. Res., 1987, 18, page 379.

Formula (I) containing both a carboxy group and a hydroxy group within the moiety of -L ² -Y
Suitable esters of the compounds of formula I include lactones formed by the loss of water between the carboxy and hydroxy groups. Examples of lactones include caprolactone, valerolactone and butyrolactone.

A particularly useful class of hydroxy-containing esters of formula (I) is Bundgaard eL
aL, J. Med. Chem., 1989, 32, page 2503-2507, which may be formed from substituted (aminomethyl)-
Benzoates, such as dialkylamino-methylbenzoates, wherein the two alkyl groups may be linked together and / or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, for example an alkylated nitrogen atom And more preferably (morpholino-methyl) benzoate such as 3- or 4- (morpholinomethyl) -benzoate, and (4-alkylpiperazin-1-yl) benzoate such as 3- or 4- (4- (Alkylpiperazin-1-yl) benzoate.

If the compounds of the present invention contain a carboxy group or a sufficiently acidic bioisostere, base addition salts can be formed, which are in a form which is entirely convenient to use. is there. In fact, the use of this salt form is essentially equivalent to the use of its free acid form. The bases that can be used to prepare these base addition salts, when combined with the free acid, are pharmaceutically acceptable salts, i.e., the beneficial inhibitory effects inherent to the free base are not compromised by the side effects of the cation. As such, it is preferred that the cation be a base that produces a non-toxic salt to the patient at pharmaceutical dosages of the salt. Pharmaceutically acceptable salts within the scope of the present invention, such as salts derived from alkali and alkaline earth, include the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide,
Aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, And salts derived from N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane, tetramethylammonium hydroxide and the like.

Certain compounds of the present invention are basic and such compounds are useful in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof. Acid addition salts are a more convenient form to use; in fact, use of this salt form is essentially equivalent to use of the free base form. The acids that can be used to prepare these acid addition salts, when combined with a free base, are pharmaceutically acceptable salts, i.e., the beneficial inhibitory effects inherent to the free base are not impaired by the side effects of the anion. Thus, an acid whose anion produces a non-toxic salt to the patient at pharmaceutical dosages of the salt. Although pharmaceutically acceptable salts of the basic compounds are more preferred, all acid addition salts are preferred, even if the particular salt is itself, e.g., for purification and identification purposes. Only when it is formed or when it is used as an intermediate in preparing a pharmaceutically acceptable salt by ion exchange operations, if desired only as an intermediate product, the free base form Useful as a source. Pharmaceutically acceptable salts within the scope of the present invention include those derived from inorganic and organic acids, such as hydrohalides such as hydrochlorides and hydrobromides, sulfates , Phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate , Methylene-bis-b-
Hydroxynaphthoate, gentisate, isethionate, di-p-toluoyl tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinic acid Salts may be mentioned.

While useful as active compounds by themselves, salts of the compounds of the present invention are useful for preparing salts which differ in solubility between the salts and the starting compounds, by-products and / or starting materials by techniques well known to those skilled in the art. Is useful for purification of the compound.

With respect to the above formula (I), particularly preferred groups are as follows. R ¹ may especially represent an optionally substituted aryl, more preferably an optionally substituted phenyl. Z ¹ particularly preferably represents NH.

Het in particular

Embedded image (Here ring

Embedded image Is a 5- or 6-membered heterocycle, and

Embedded image Is a 5- or 6-membered fully unsaturated heterocyclic or benzene ring, each ring optionally substituted with one or more "aryl group substituents" as defined above; Rings may be linked together by a carbon-carbon or carbon-nitrogen bond).

Ring

Embedded image In particular represents a 5-membered heteroaryl ring optionally substituted with one or more "aryl group substituents" as defined above.

Ring

Embedded image In particular represents a benzene ring optionally substituted with one or more "aryl group substituents" as defined above.

[0046]

Embedded image Are especially 9-membered bicyclic systems (where the ring

Embedded image Has the above definition, and these two rings are joined together by a carbon atom bond).

Embedded image Is benzoxazolyl or benzimidazolyl (where the ring

Embedded image Is one or more "aryl group substituents" as defined above [particularly preferred aryl group substituents include C _1-4 alkyl (eg, methyl or ethyl), C _1-4 alkoxy (eg, Methoxy), amino, halogen, hydroxy,
C _1-4 alkylthio, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl,
Nitro or trifluoromethyl).

L ¹ is a —R ⁵ —R ⁶ — bond (where R 5 is a straight-chain or branched C _1-6 alkylene chain, particularly a straight-chain or branched C _1-4 alkylene chain) And R ⁶ is -C (
ＺZ ³ ) —NR ⁴ , preferably —C (＝ O) —NR ⁴ —, where R ⁴ is hydrogen or lower alkyl (eg methyl).

Ar ¹ is in particular azaheteroaryldiyl, especially optionally substituted pyridinediyl, preferably p-pyridinediyl, more preferably pyridine-2,5-
It is good to represent diyl. Examples of preferred optional substituents may represent _C1-4 alkyl, especially methyl, and _C1-4 alkoxy, especially methoxy.

L ² is, in particular, (a) a direct bond, (b) an optionally substituted alkylene bond,
Especially ethylene optionally substituted, (c) alkenylene bond, especially vinylene which is not substituted or ^{(d) -Z 4 -R 11,} - bonds, for example, -O-CH ₂ -, - S
_{(O) n -CH 2 -,} - S (O) n -CH 2 -CH 2 -, - NH-CH 2 - better represent. The optional preferred substituents in (b) above lower alkyl (e.g. methyl), aryl, ^{heteroaryl, -Z 2 R 8, -N (} R 7) -C (= O) -R 8 <-N ( R ⁷ ) −
^{C (= O) -OR 8,} -N (R 7) -SO 2 -R 8, -NY 3 Y 4, - [C (= O) -N (R 9)
—C (R ⁴ ) (R ¹⁰ )] _p —C (＝ O) —NY ³ Y ⁴ , and further hydroxy, —OR ³ ,
-C (= O) is an alkyl substituted with -OR ³ or -NY ³ Y ⁴ is. L ² is a lower alkyl (e.g. methyl), aryl, ^{heteroaryl, -Z 2 R 8, -N (} R 7)
^{-C (= O) -R 8,} -N (R 7) -C (= O) -OR 8, -N (R 7) -SO 2 -R 8, -N
^{Y 3 Y 4, - [C} (= O) -N (R 9) -C (R 4) (R 10)] p -C (= O) -NY 3 in Y ⁴ or hydroxy, -OR ^3,, A C _1-4 alkylene bond optionally substituted with alkyl substituted by —C (＝ O) —OR ³ or —NY ³ Y ⁴ (eg, ethylene)
Is more preferable. L ² is a group

Embedded image[Where R^FifteenIs hydrogen or lower alkyl (eg, methyl) and R¹⁴Is low
Represents a primary alkyl (eg methyl), or^FifteenIs hydrogen and R¹⁴Is
Aryl, heteroaryl, -Z^TwoR⁸, -N (R⁷) -C (= O) -R⁸, -N (R⁷)
-C (= O) -OR⁸, -N (R⁷) -SO_Two-R⁸, -NY^ThreeY^Four,-[C (= O) -N (R ⁹ ) -C (R^Four) (R^Ten)]_p-C (= O) -NY^ThreeY^FourOr hydroxy, -O
R^Three, -C (= O) -OR^ThreeOr -NY^ThreeY^FourIs an alkyl substituted with
Is preferred. L^TwoIs the base

Embedded image In particular

Embedded image [Where R ¹⁴ is lower alkyl (eg methyl), -Z ² R ⁸ , -N (R ⁷ ) -C (= O
^{) -R 8, -N (R 7} ) -C (= O) -OR 8, -N (R 7) -SO 2 -R 8, -NY 3 Y 4 or represents, or hydroxy, -OR ^3, -C (= O) alkyl substituted by -OR ³ or -NY ³ Y ^4] and more preferably. Y particularly preferably represents carboxy.

It is to be understood that the present invention includes all suitable combinations of the individual or more preferred groups described herein. A particularly preferred group of the compounds of the invention are compounds of the formula (Ia):

Embedded image Wherein R ¹ , Ar ¹ , R ⁴ , R ⁵ , L ² , Y and Z ¹ have the previously defined definitions, R ¹⁶ is hydrogen or a substituted aryl group, and X Is O or NR ^17, wherein R ¹⁷ is H or lower alkyl.] And their prodrugs and the pharmaceutically acceptable compounds of formula (Ia) and their prodrugs Salts and solvates (eg hydrates).

Compounds of formula (Ia) in which R 1 represents optionally substituted aryl, in particular optionally substituted phenyl, are preferred. Optional preferred substituents can include lower alkyl (eg, methyl), lower alkoxy (eg, methoxy), halo (eg, fluoro), and Y ¹ Y ² N- (eg, dimethylamino).
R ¹ particularly preferably represents o-tolyl.

In formula (Ia), especially when attached to the 4-position of the ring, R ¹⁶ is hydrogen, C _1-4 alkyl (eg methyl or ethyl) or C _1-4 alkoxy (eg methoxy)
Are preferred. Compounds in which Z ¹ represents NH in formula (Ia) are more preferred. In the formula (Ia), a compound in which R ⁵ represents a straight-chain or branched C _1-6 alkylene chain, particularly a straight-chain or branched C _1-4 alkylene chain, more preferably methylene, is more preferred.

Compounds in which R ⁴ represents hydrogen in formula (la) are more preferred. Compounds in which R ⁴ in formula (la) represents lower alkyl (eg methyl) are also preferred. Also preferred are those compounds of formula (la) wherein Ar ¹ is optionally substituted pyridinediyl, especially optionally substituted p-pyridinediyl, more preferably pyridine-2,5-diyl. Examples of preferred substituents include C _1-4 alkyl and C _1-4 alkoxy, especially compounds that are methyl and methoxy.

Preference is given to compounds of the formula (la) in which L ² represents an optionally substituted alkylene bond, in particular ethylene or substituted ethylene. Optional preferred substituents include lower alkyl (eg, methyl), aryl, heteroaryl, —Z ² R ⁸ , —N
^{(R 7) -C (= O} ) -R 8, -N (R 7) -C (= O) -OR 8, -N (R 7) -SO 2 -R 8
, There is -NY ³ Y ^4, or hydroxy, -OR ^3, there is -C (= O) alkyl substituted with -OR ³ or -NY ³ Y ^4.

In the formula (la), L ² is

Embedded imageBond (where R^FifteenIs hydrogen or lower alkyl (eg, methyl); ¹⁴ Is hydrogen or lower alkyl (eg methyl), or R^FifteenIs hydrogen
And then R¹⁴Is aryl, heteroaryl, -Z^TwoR⁸, -N (R⁷) -C (= O)
-R⁸, -N (R⁷) -C (= O) -OR⁸, -N (R⁷) -SO_Two-R⁸, -NY^ThreeY^Four,
-[C (= O) -N (R⁹) -C (R^Four) (R^Ten)]_p-C (= O) -NY^ThreeY^FourIs also
Is hydroxy, -OR^Three, -C (= O) -OR^ThreeOr -NY^ThreeY^FourReplaced by
Is particularly preferred. In the formula (la), L^TwoBut

Embedded image Binding, especially

Embedded image (Where R ¹⁴ is lower alkyl (eg, methyl), aryl, heteroaryl,-
^{Z 2 R 8, -N (R} 7) -C (= O) -R 8, -N (R 7) -C (= O) -OR 8, -N (R 7)
—SO ₂ —R ⁸ , —NY ³ Y ⁴ , or hydroxy, —OR ³ , —C (＝ O)
-OR ³ or -NY ³ Y ⁴ has been alkyl substituted with) those compounds are particularly preferred. Compounds of formula (la) wherein Y is carboxy are preferred.

The group

Embedded image Is at the 6-position of the ring when X is O or NH, or X is NR ¹⁷ ;
When R ¹⁷ is lower alkyl, it is preferably bonded to the 5- or 6-position of the ring.

A more preferred group of the compounds of the invention are phenyl (particularly o-tolyl), wherein R ¹ in formula (la) is optionally substituted, Z ¹ is NH, X is O,
R ¹⁶ is hydrogen, especially C _1-4 alkyl (eg, methyl or ethyl) or C _1-4 alkoxy (eg, methoxy) bonded to the 4-position of the ring, and R ⁵ is a linear or branched C _{1 -4} is an alkylene chain (especially methylene); R ⁴ is hydrogen or lower alkyl (e.g. methyl), a pyridinediyl which Ar ¹ is optionally substituted (in particular pyridine-2,5-diyl), L ² But

Embedded image Group, preferably

Embedded image Group, especially

Embedded image (Where R ¹⁴ is hydrogen, lower alkyl (eg, methyl), aryl, heteroaryl, —Z ² R ⁸ , —N (R ⁷ ) —C (＝ O) —R ⁸ , —N (R ⁷ ) —C (= O) -OR ^8, -N
(R ⁷ ) —SO ₂ —R ⁸ , —NY ³ Y ⁴ , or hydroxy, —OR ³ , —C (
ＯO) —OR ³ or alkyl substituted with —NY ³ Y ⁴ ), Y is carboxy and

Embedded image Is attached to the 6-position of the ring, the corresponding N-oxides and their prodrugs and pharmaceutically acceptable salts and solvates of the compounds, their N-oxides and prodrugs (e.g. hydration Thing).

Another more preferred group of compounds of the present invention is phenyl (particularly o-tolyl) wherein R ¹ in formula (la) is optionally substituted, Z ¹ is NH and X is NR ¹⁷
(Especially NH), wherein R ¹⁶ is hydrogen, especially a C _1-4 alkyl (
Such as methyl or ethyl) or C _1-4 alkoxy (e.g. methoxy), R ⁵ is straight or branched C _1-4 alkylene chain (especially methylene); R ⁴
Is hydrogen or lower alkyl (eg, methyl); Ar ¹ is optionally substituted pyridinediyl (especially pyridine-2,5-diyl); and L ² is

Embedded image Group, preferably

Embedded image Group, especially

Embedded image (Where R ¹⁴ is hydrogen, lower alkyl (eg, methyl), aryl, heteroaryl, —Z ² R ⁸ , —N (R ⁷ ) —C (＝ O) —R ⁸ , —N (R ⁷ ) —C (= O) -OR ^8, -N
(R ⁷ ) —SO ₂ —R ⁸ , —NY ³ Y ⁴ , or hydroxy, —OR ³ , —C (
ＯO) —OR ³ or alkyl substituted with —NY ³ Y ⁴ ), Y is carboxy and

Embedded image Is attached at the 5- or 6-position of the ring, the corresponding N-oxides and their prodrugs and pharmaceutically acceptable salts and solvates of the compounds, their N-oxides and prodrugs (e.g., Hydrate).

Particular compounds of the present invention are selected from: 3- {5- [2- (2-phenylamino-benzoxazol-6-yl) acetylamino] -pyridin-2-yl}. -Butyric acid; 3- {5- [2- (2-o-tolylamino-benzoxazol-6-yl)]
Acetylamino] -pyridin-2-yl} -butyric acid; 3- (5- {2- [2- (2-methoxy-phenylamino) -benzoxazol-6-yl] acetylamino} -pyridin-2-yl) 3- (5- {2- [2- (2-isopropyl-phenylamino) -benzoxazol-6-yl] acetylamino} -pyridin-2-yl) -butyric acid; 3- (5- {2 -[2- (2,6-dimethyl-phenylamino) -benzoxazol-6-yl] acetylamino} -pyridin-2-yl) -butyric acid; 3- (5- {2- [2- (3-methoxy) -(Phenylamino) -benzoxazol-6-yl] acetylamino} -pyridin-2-yl) -butyric acid; 3- (5- {2- [2- (2,3-dimethyl-phenylamino) -benzoxazole- 6- Yl] acetylamino {-pyridin-2-yl) -butyric acid; 3- (5- {2- [2- (2,6-diethyl-phenylamino) -benzoxazol-6-yl] acetylamino} -pyridine- 2- (2-yl) -butyric acid; 3- (5- {2- [2- (2-methoxy-5-methyl-phenylamino) -benzoxazol-6-yl] acetylamino} -pyridin-2-yl) -butyric acid 3- (5- {2- [2- (pyridin-3-ylamino) -benzoxazol-6-yl] acetylamino} -pyridin-2-yl) -butyric acid; 3- (5- {2- [2- [2] -(2-cyano-phenylamino) -benzoxazol-6-yl] acetylamino} -pyridin-2-yl) -butyric acid; 3- (5- {2- [2- (pyridin-2-ylamino) -benzo) Oxazole-6 Yl] acetylamino {-pyridin-2-yl) -butyric acid; 3- (5- {2- [2- (2-chloro-phenylamino) -benzoxazol-6-yl] acetylamino} -pyridin-2- Yl) -butyric acid;

3- (5- {methyl-[(2-phenylamino-benzoxazol-6-yl) acetyl] -amino} -pyridin-2-yl) -butyric acid; 3- (5- {methyl-[(2 -O-tolylamino-benzoxazole-6
Yl) acetyl] -amino} -pyridin-2-yl) -butyric acid; 3- [5-({[2- (2-methoxy-phenylamino) -benzoxazol-6-yl] acetyl} -methyl-amino) -Pyridin-2-yl] -butyric acid; 3- [5-({[2- (2-isopropyl-phenylamino) -benzoxazol-6-yl] acetyl} -methyl-amino) -pyridin-2-yl] -Butyric acid; 3- [5-({[2- (2,6-dimethyl-phenylamino) -benzoxazol-6-yl] acetyl} -methyl-amino) -pyridin-2-yl] -butyric acid; [5-({[2- (3-methoxy-phenylamino) -benzoxazol-6-yl] acetyl} -methyl-amino) -pyridin-2-yl] -butyric acid; 3- [5-({[2 -(2,3-diethyl Phenylamino) -benzoxazol-6-yl] acetyl} -methyl-amino) -pyridin-2-yl] -butyric acid; 3- [5-({[2- (2,6-diethyl-phenylamino) -benzo] Oxazol-6-yl] acetyl} -methyl-amino) -pyridin-2-yl] -butyric acid; 3- [5-({[2- (2-methoxy-5-methyl-phenylamino) -benzoxazole-6] -Yl] -acetyl} -methyl-amino) -pyridine-2-
3- [5- (methyl-{[2- (pyridin-3-ylamino) -benzoxazol-6-yl] acetyl} -amino) -pyridin-2-yl] -butyric acid; 3- [ 5-({[2- (2-cyano-phenylamino) -benzoxazole-
6-yl] -acetyl} -methyl-amino) -pyridin-2-yl] -butyric acid; 3- [5- (methyl-{[2- (pyridin-2-ylamino) -benzoxazol-6-yl]- Acetyl {-amino) -pyridin-2-yl] -butyric acid;

3- [5-({[2- (2-chloro-phenylamino) -benzoxazole-
6-yl] -acetyl} -methyl-amino) -pyridin-2-yl] -butyric acid; 3- {6- [2- (2-phenylamino-benzoxazol-6-yl)-
Acetylamino] -pyridin-3-yl} -butyric acid; 3- {6- [2- (2-o-tolylamino-benzoxazol-6-yl)]
-Acetylamino] -pyridin-3-yl} -butyric acid; 3- (6- {2- [2- (2-methoxy-phenylamino) -benzoxazol-6-yl] -acetylamino} -pyridin-3- 3- (6- {2- [2- (2-isopropyl-phenylamino) -benzoxazol-6-yl] -acetylamino} -pyridin-3-yl) -butyric acid; 3- (6 -{2- [2- (2,6-dimethyl-phenylamino) -benzoxazol-6-yl] -acetylamino} -pyridin-3-yl) -butyric acid; 3- (6- {2- [2- (3-methoxy-phenylamino) -benzoxazol-6-yl] -acetylamino} -pyridin-3-yl) -butyric acid; 3- (6- {2- [2- (2,3-dimethyl-phenylamino) ) -Benzoxazo 2- (6-yl) -acetylamino} -pyridin-3-yl) -butyric acid; 3- (6- {2- [2- (2,6-diethyl-phenylamino) -benzoxazol-6-yl] -Acetylamino {-pyridin-3-yl) -butyric acid; 3- (6- {2- [2- (2-methoxy-5-methyl-phenylamino) -benzoxazol-6-yl] -acetylamino}- 3- (6- {2- [2- (pyridin-3-ylamino) -benzoxazol-6-yl] -acetylamino} -pyridin-3-yl) -butyric acid; 3 -(6- {2- [2- (2-cyano-phenylamino) -benzoxazol-6-yl] -acetylamino} -pyridin-3-yl) -butyric acid; 3- (6- {2- [2 -(Pyridin-2-ylamino) -be Zookisazoru-6-yl] - acetylamino} - pyridin-3-yl) - butyric acid;

3- (6- {2- [2- (2-chloro-phenylamino) -benzoxazol-6-yl] -acetylamino} -pyridin-3-yl) -butyric acid; Methyl-[(2-methylamino-benzoxazol-6-yl) -acetyl] -amino} -pyridin-3-yl) -butyric acid; 3- (6- {methyl-[(2-o-tolylamino-benzoxazole) -6
Yl) -acetyl] -amino} -pyridin-3-yl) -butyric acid; 3- [6-({[2- (2-methoxy-phenylamino) -benzoxazol-6-yl] -acetyl} -methyl- Amino) -pyridin-3-yl] -butyric acid; 3- [6-({[2- (2-isopropyl-phenylamino) -benzoxazol-6-yl] -acetyl} -methyl-amino) -pyridin-3 -Il]-
Butyric acid; 3- [6-({[2- (2,6-dimethyl-phenylamino) -benzoxazol-6-yl] -acetyl} -methyl-amino) -pyridin-3-yl]-
3- [6-({[2- (3-methoxy-phenylamino) -benzoxazol-6-yl] -acetyl} -methyl-amino) -pyridin-3-yl] -butyric acid; 3- [6 -({[2- (2,3-dimethyl-phenylamino) -benzoxazol-6-yl] -acetyl} -methyl-amino) -pyridin-3-yl]-
Butyric acid; 3- [6-({[2- (2,6-diethyl-phenylamino) -benzoxazol-6-yl] -acetyl} -methyl-amino) -pyridin-3-yl]-
Butyric acid; 3- [6-({[2- (2-methoxy-5-methyl-phenylamino) -benzoxazol-6-yl] -acetyl} -methyl-amino) -pyridine-3-
Yl] -butyric acid; 3- [6- (methyl-{[2- (pyridin-3-ylamino) -benzoxazol-6-yl] -acetyl} -amino) -pyridin-3-yl] -butyric acid;

3- [6-({[2- (2-cyano-phenylamino) -benzoxazole-
6-yl] -acetyl} -methyl-amino) -pyridin-3-yl] -butyric acid; 3- [6- (methyl-{[2- (pyridin-2-ylamino) -benzoxazol-6-yl]- Acetyl {-amino) -pyridin-3-yl] -butyric acid; 3- [6-({[2- (2-chloro-phenylamino) -benzoxazole-
6-yl] -acetyl} -methyl-amino) -pyridin-3-yl] -butyric acid; 3- [6- (methyl-{[2- (3-methyl-pyridin-4-ylamino)-]
Benzoxazol-6-yl] -acetyl} -amino) -pyridin-3-yl] -butyric acid; 3- {6- [methyl-({2- [methyl- (3-methyl-pyridin-4-yl)-]- Amino] -benzoxazol-6-yl} -acetyl) -amino] -pyridin-3-yl} -butyric acid; 3- {6- [ethyl-({2- [methyl- (3-methyl-pyridin-4-) Yl) -amino] -benzoxazol-6-yl} -acetyl) -amino] -pyridin-3-yl} -butyric acid; 3- (6- {2- [4-methoxy-2- (3-methyl-pyridine) -4-ylamino) -benzoxazol-6-yl] -acetylamino} -pyridine-3-
Yl) -butyric acid; 3- (6- {2- [7-methoxy-2- (3-methyl-pyridin-4-ylamino) -benzoxazol-6-yl] -acetylamino} -pyridine-3-
Yl) -butyric acid; 3- [6- (2- {2- [methyl- (3-methyl-pyridin-4-yl) -amino] -benzoxazol-6-yl} -acetylamino) -pyridine-3-
Yl] -butyric acid; 3- [5- (methyl-{[2- (4-methyl-pyridin-3-ylamino)-
Benzoxazol-6-yl] -acetyl {-amino) -pyridin-2-yl] -butyric acid;

3- {5- [methyl-({2- [methyl- (4-methyl-pyridin-3-yl) -amino] -benzoxazol-6-yl} -acetyl] -amino] -pyridine-2 -Yl} -butyric acid; 3- {5- [ethyl-({2- [methyl- (4-methyl-pyridin-3-yl) -amino] -benzoxazol-6-yl} -acetyl) -amino]- Pyridin-2-yl} -butyric acid; 3- (5- {2- [4-methoxy-2- (4-methyl-pyridin-3-ylamino) -benzoxazol-6-yl] -acetylamino} -pyridine- 2-
Yl) -butyric acid; 3- (5- {2- [7-methoxy-2- (4-methyl-pyridin-3-ylamino) -benzoxazol-6-yl] -acetylamino} -pyridin-2-
Yl) -butyric acid; 3- [5- (2- {2- [methyl- (4-methyl-pyridin-3-yl) -amino] -benzoxazol-6-yl} -acetylamino) -pyridine-2-
Yl] -butyric acid; N-methyl-N- [4- (2-oxo-oxepan-4-yl) -phenyl]
-2- (2-o-tolylamino-benzoxazol-6-yl) -acetamide; N-methyl-2- [2- (methyl-o-tolyl-amino) -benzoxazol-6-yl] -N- [ 4- (2-oxo-oxepan-4-yl) -phenyl] -acetamide; N-ethyl-2- [2- (methyl-o-tolyl-amino) -benzoxazol-6-yl] -N- [4 -(2-oxo-oxepan-4-yl) -phenyl] -acetamide; 2- (4-methoxy-2-o-tolylamino-benzoxazol-6-yl) -N- [4- (2-oxo-oxepane -4-yl) -phenyl] -acetamide;

2- [7-methoxy-2-o-tolylamino-benzoxazol-6-yl) -N- [4- (2-oxo-oxepan-4-yl) -phenyl] -acetamide; 2- [2 -(Methyl-o-tolyl-amino-benzoxazol-6-yl)
-N- [4- (2-oxo-oxepan-4-yl) -phenyl] -acetamide; 3- {5- [2- (2-phenylamino-3H-benzimidazol-5-yl) -acetylamino] -Pyridin-2-yl} -butyric acid; 3- {5- [2- (2-o-tolylamino-3H-benzimidazole-5-
Yl) -acetylamino] -pyridin-2-yl} -butyric acid; 3- [6- (2- {2- [methyl- (3-methyl-pyridin-4-yl) -amino] -1H-benzimidazole- 5- (yl) -acetylamino) -pyridin-3-yl] -butyric acid; 3- (6- {2- [3-methyl-2- (3-methyl-pyridin-4-ylamino) -3H-benzimidazole- 5-yl] -acetylamino} -pyridine-
3- (6- {2- [1-methyl-2- (3-methyl-pyridin-4-ylamino) -1H-benzimidazol-5-yl] -acetylamino} -pyridine-
3- (6-yl) -butyric acid; 3- (6- (methyl-{[2- (3-methyl-pyridin-4-ylamino)-
[1H-benzimidazol-5-yl] -acetyl} -amino) -pyridine-3
-Yl] -butyric acid; 3- [6- (ethyl-{[2- (3-methyl-pyridin-4-ylamino)-]
[1H-benzimidazol-5-yl] -acetyl} -amino) -pyridine-3
-Yl] -butyric acid; 3- (6- {2- [7-methoxy-2- (3-methyl-pyridin-4-ylamino) -1H-benzimidazol-5-yl] -acetylamino} -pyridine-3 -(Yl) -butyric acid; 3- (6- {2- [4-methoxy-2- (3-methyl-pyridin-4-ylamino) -1H-benzimidazol-5-yl] -acetylamino} -pyridine-3 -Yl) -butyric acid;

3- [5- (2- {2- [methyl- (4-methyl-pyridin-3-yl) -amino] -3H-benzimidazol-5-yl} -acetylamino) -pyridine-2- Yl] -butyric acid; 3- (5- {2- [3-methyl-2- (4-methyl-pyridin-3-ylamino) -3H-benzimidazol-5-yl] -acetylamino} -pyridine-
3- (5- {2- [1-methyl-2- (4-methyl-pyridin-3-ylamino) -1H-benzimidazol-5-yl] -acetylamino} -pyridine-
2- [yl] -butyric acid; 3- [5- (methyl-{[2- (4-methyl-pyridin-3-ylamino)-]
[1H-benzimidazol-5-yl] -acetyl} -amino) -pyridine-2
-Yl] -butyric acid; 3- [5- (ethyl-{[2- (4-methyl-pyridin-3-ylamino)-
[1H-benzimidazol-5-yl] -acetyl} -amino) -pyridine-2
-Yl] -butyric acid; 3- (5- {2- [7-methoxy-2- (4-methyl-pyridin-3-ylamino) -1H-benzimidazol-5-yl] -acetylamino} -pyridine-2 -(Yl) -butyric acid; 3- (5- {2- [4-methoxy-2- (4-methyl-pyridin-3-ylamino) -1H-benzimidazol-5-yl] -acetylamino} -pyridine-2 -Yl) -butyric acid; 2- [2- (methyl-o-tolyl-amino) -3H-benzimidazole-5
-Yl] -N- [4- (2-oxo-oxepan-4-yl) -phenyl] -acetamide; 2- (3-methyl-2-o-tolylamino-3H-benzimidazole-5-
Yl) -N- [4- (2-oxo-oxepan-4-yl) -phenyl] -acetamide;

2- (1-methyl-2-o-tolylamino-1H-benzimidazole-5
Yl) -N- [4- (2-oxo-oxepan-4-yl) -phenyl] -acetamide; N-methyl-N- [4- (2-oxo-oxepan-4-yl) -phenyl]
-2- (2-o-tolylamino-3H-benzimidazol-5-yl) -acetamide; N-ethyl-N- [4- (2-oxo-oxepan-4-yl) -phenyl]
2- (2-o-tolylamino-3H-benzimidazol-5-yl) -acetamide; 2- (7-methoxy-2-o-tolylamino-3H-benzimidazole-5
-Yl) -N- [4- (2-oxo-oxepan-4-yl) -phenyl] -acetamide; 2- (4-methoxy-2-o-tolylamino-3H-benzimidazole-5
-Yl) -N- [4- (2-oxo-oxepan-4-yl) -phenyl] -acetamide; 3- {5- [2- (4-methyl-2-o-tolylaminobenzoxazole-
6-yl) acetylamino] pyrid-2-yl} -butyric acid; and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates (eg, hydrates) of such compounds. , And its N-
Oxides and prodrugs.

The set of specific compounds of the present invention comprises one fragment (A1-A3) shown in Table 1.
The acyl carbon atom (C ^* ) of 2) is one fragment (B1 to B1) shown in Table 2.
B10) is bonded to the nitrogen atom (N ^* ), and the carbon atom (C ^* ) of the phenyl ring in one fragment (B1 to B4) shown in Table 2 is one acidic fragment described in Table 3. It is selected from compounds formed by bonding to carbon atoms of (C1 to C40).

[0069]

[Table 1]

[0070]

[Table 2]

[0071]

[Table 3]

[0072]

[Table 4]

[0073]

[Table 5]

[0074]

[Table 6]

Examples of particularly preferred fragments “A”, “B” and “C” are illustrated below.

[0076]

[Table 7]

[0077]

[Table 8]

[0078]

[Table 9]

[0079]

[Table 10]

[0080]

[Table 11]

[0081]

[Table 12]

[0082]

[Table 13]

[0083]

[Table 14]

[0084]

[Table 15]

[0085]

[Table 16]

[0086]

[Table 17]

[0087]

[Table 18]

[0088]

[Table 19]

[0089]

[Table 20]

[0090]

[Table 21]

[0091]

[Table 22]

[0092]

[Table 23]

[0093]

[Table 24]

[0094]

[Table 25]

[0095]

[Table 26]

[0096]

[Table 27]

[0097]

[Table 28]

[0098]

[Table 29]

[0099]

[Table 30]

[0100]

[Table 31]

[0101]

[Table 32]

[0102]

[Table 33]

[0103]

[Table 34]

[0104]

[Table 35]

[0105]

[Table 36]

[0106]

[Table 37]

[0107]

[Table 38]

[0108]

[Table 39]

[0109]

[Table 40]

[0110]

[Table 41]

[0111]

[Table 42]

[0112]

[Table 43]

[0113]

[Table 44]

[0114]

[Table 45]

[0115]

[Table 46]

[0116]

[Table 47]

[0117]

[Table 48]

[0118]

[Table 49]

[0119]

[Table 50]

[0120]

[Table 51]

[0121]

[Table 52]

[0122]

[Table 53]

[0123]

[Table 54]

[0124]

[Table 55]

[0125]

[Table 56]

[0126]

[Table 57]

[0127]

[Table 58]

[0128]

[Table 59]

[0129]

[Table 60]

[0130]

[Table 61]

[0131]

[Table 62]

[0132]

[Table 63]

[0133]

[Table 64]

[0134]

[Table 65]

[0135]

[Table 66]

[0136]

[Table 67]

Thus, for example, in the above list, the compound designated as A 1 -B 1 -C 1 is the product of the combination of the group A 1 in Table 1, the group B 1 in Table 2 and the group C 1 in Table 3, ie

Embedded image It is.

The compounds of the present invention exhibit useful pharmacological activity and are therefore formulated into pharmaceutical compositions and used for treating patients suffering from certain medical disorders. Thus, the present invention, according to a further aspect, provides a compound of the present invention and a composition comprising a compound of the present invention for use in therapy.

Compounds within the scope of the present invention have been described in the literature and are described in vitro below.
According to the tests described in ro and in vivo procedures, the interaction between the ligand VCAM-1 and its integrin receptor VLA-4 (α4β1) was blocked, and the results of this test indicate the pharmacology of humans and other mammals. It is thought to be related to activity. Accordingly, in a further embodiment, the present invention is for use in the treatment of a patient suffering from or susceptible to a condition that can be ameliorated by administering an inhibitor of α4β1 that mediates cell adhesion. Provided are compounds and compositions comprising the compounds of the present invention. For example, the compounds of the present invention may be useful in treating inflammatory diseases such as arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and osteoarthritis. It is useful for treating joint inflammation including. In addition, the compound is useful for the treatment of acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, colitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, multiple sclerosis, asthma, psoriatic disease. Useful in the treatment of melanoma cell division in stenosis, myocarditis, inflammatory bowel disease and metastases.

A particular embodiment of the treatment method of the present invention is for treating asthma. Another specific embodiment of the treatment method of the present invention is to treat joint inflammation. Another specific embodiment of the treatment method of the present invention is for treating inflammatory bowel disease.

According to a further feature of the invention, the ligand VCAM-1 and its integrin receptor VLA-4α4β1 comprise administering to a patient an effective amount of a compound of the invention or a composition comprising a compound of the invention. There is provided a method of treating a human or animal patient suffering from or susceptible to a condition that can be ameliorated by administering an inhibitor of the interaction of, for example, a condition described herein below. An “effective amount” is defined as the ligand VCAM-1 and its integrin receptor VLA-4 (
refers to the amount of a compound of the present invention effective to inhibit its interaction with α4β1) and thereby achieve the desired therapeutic effect. It should be understood that the criteria for treatment herein include prophylactic treatment as well as treatment of established conditions.

The invention also includes within its scope pharmaceutical compositions comprising at least one of the compounds of the invention together with a pharmaceutically acceptable carrier or excipient. The compounds of the present invention can be administered by any suitable means. In practice, the compounds of the invention can generally be administered parenterally, topically, rectally, orally or by inhalation, in particular by the oral route.

The compositions according to the invention can be manufactured according to the customary methods using one or more pharmaceutically acceptable auxiliaries or excipients. Auxiliaries include, inter alia, diluents, sterile aqueous media and various non-toxic organic solvents. The compositions can be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injection solutions, elixirs or syrups, and sweeteners to obtain pharmaceutically acceptable formulations. And one or more agents selected from the group consisting of flavorings, colorants or stabilizers. The choice of excipients and the content of active substance in the excipients generally depends on the solubility of the active compounds. And chemistry, the particular mode of administration and the regulations to be followed in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate,
Certain complex silicates, together with disintegrants such as starch, alginic acid, and lubricants such as magnesium stearate, sodium lauryl sulfate and talc, can be used to make tablets. It is advantageous to use lactose and high molecular weight polyethylene glycols for producing capsules. When using aqueous suspensions, they may contain emulsifying agents or substances which facilitate suspension. Also, diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof can be used.

For parenteral administration, emulsions of the products according to the invention in vegetable oils, for example sesame oil, peanut oil or olive oil, or in water and aqueous organic solutions such as propylene glycol, injectable organic esters such as ethyl oleate Liquids, suspensions or solutions as well as sterile aqueous solutions of pharmaceutically acceptable salts are used. The solutions of the salts and products according to the invention are particularly useful for administration by intramuscular or subcutaneous injection. An aqueous solution consisting of a pure distilled water salt solution can also be used for intravenous administration, provided that the pH of the aqueous solution is appropriately adjusted, the aqueous solution has an appropriate buffering action, and It has been rendered isotonic with glucose or sodium chloride and sterilized by heating, irradiation or microfiltration.

For topical administration, gels (water or alcohol based), creams or ointments containing the compounds of the present invention may be used. Also, the compounds of the present invention can be formulated in gels or matrix bases for use in patches, which control the release of the compound through transdermal barriers.

For administration by inhalation, the compounds of the present invention can be dissolved or suspended in nebulizers or carriers suitable for use in suspensions or aerosols of solutions,
It can also be absorbed or adsorbed on a solid carrier suitable for use in a dry powder inhaler. As a solid composition for rectal administration, formulated according to known methods,
Also included are suppositories that contain 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 constitute a ratio so that a suitable dosage will be obtained. Obviously, several unit dosage forms can be administered simultaneously. The dose used is determined by the doctor,
It depends on the desired therapeutic effect, on the route of administration and on the duration of the treatment and on the condition of the patient. In adults, the dosage generally ranges from about 0.001 to 1 kg / kg body weight per day for inhalation.
About 50 mg / kg, preferably 0.001 to about 5 mg / kg, in the case of oral administration, 1 body weight per day
about 0.01 to about 100 mg / kg, preferably 0.1 to 70 mg / kg, especially 0.5 to 10 m / kg
g / kg, and for intravenous administration, from about 0.001 to about 10 mg / kg of body weight per day.
kg, preferably 0.01-1 mg / kg. In each particular case, the dose will be determined by factors specific to the patient, such as age, weight, general health and other characteristics that may affect the efficacy of the pharmaceutical product.

The compounds according to the invention can be administered as often as necessary to achieve the desired therapeutic effect. Some patients can respond quickly to higher or lower doses and find that very little maintenance is sufficient. For other patients, it may be necessary to provide long-term treatment at a rate of 1 to 4 doses per day, each according to the physiological requirements of the particular patient. Generally, the active product is
It can be administered orally one to four times a day. Of course, for some patients it will be necessary to prescribe no more than one or two doses per day.

The compounds of the present invention can be manufactured by applying or adapting known methods, including those used hitherto, ie, those described in the literature It is, for example, RCLarock in Comprehensive Or
ganic Transformations, VCH publishers, 1989.

In the reactions described below, reactive functional groups such as hydroxy, amino, imino, thio or carboxy groups, if desired in the final product, need to be protected to avoid their undesired participation during the reaction. There can be. Conventional protecting groups can be used according to standard practices, for example, TW Greene and PGM W
uts in “Protective Groups in Organic Chemistry” John Wiley and Sons, 19
See 91.

Compounds of formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ , L ² and Z ¹ are as defined above, and Y is carboxy, are compounds of formula (I) Wherein Het, R ¹ , Ar ¹ , L ¹ , L ² and Z ¹ are as defined above, and Y is a —CO ₂ R ¹⁸ group (wherein R ¹⁸ is alkyl,
Alkenyl or arylalkyl)). The hydrolysis is carried out at a temperature near ambient to near reflux using an organic solvent such as dioxane, tetrahydrofuran or methanol in the presence of an aqueous / organic solvent mixture in the presence of an alkali metal hydroxide (eg sodium hydroxide or water). It is convenient to carry out by alkali hydrolysis using a base such as lithium oxide) or an alkali metal carbonate (eg potassium carbonate). The hydrolysis of the ester also used 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 ° C. to about 80 ° C. It can also be carried out by acid hydrolysis.

As another example, compounds of formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ , L ² and Z ¹ are as defined above and Y is carboxy are Formula (I) [Het, R ¹ , Ar ¹ , L ¹
, L ² and Z ¹ are as defined above, and Y is a —CO ₂ R ¹⁸ group, wherein R ¹⁸ is tert-
The tert-butyl group of the tert-butyl ester is removed by an acid catalyst using standard reaction conditions, for example, a reaction with trifluoroacetic acid at about room temperature. it can.

As another example, a compound of formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ , L ² and Z ¹ are as defined above and Y is carboxy is Formula (I) [Het, R ¹ , Ar ¹ , L ¹
, L ² and Z ¹ are as defined above, and Y is a —CO ₂ R ¹⁸ group, wherein R ¹⁸ is benzyl. The reaction can be 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 a temperature near the reflux temperature. . Alternatively, the reaction can be 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. .

Formula (I) wherein Het, R ¹ , Ar ¹ , L ² and Z ¹ are as defined above, wherein L ¹ is -R ^5-
An R ⁶ -bond where R ⁵ is as defined above, R ⁶ is —C (= O) —NR ⁴ —, and Y is a —CO ₂ R ¹⁸ group, wherein , R ¹⁸ is as defined above)] is an ester of formula (II): R ¹ Z ¹ -Het-R ⁵ -C (= O) -X ¹ (II) wherein Het, R ¹ , R ⁵ and Z ¹ are as described above and X ¹ is a hydroxy group or a halogen, preferably a chlorine atom) of formula (III): R ⁴ —NH—Ar ¹ —L ² —CO ² ₂ R ¹⁸ (III) wherein R ⁴ , Ar ¹ , R ¹⁸ and L ² are as defined above with an amine. When X ¹ is a hydroxy group, the reaction is carried out by standard peptide coupling methods, such as O- (7-azabenzotriazol-1-yl) -1,1,3, in dimethylformamide (or tetrahydrofuran) at room temperature. It can be carried out using coupling in the presence of 3-tetramethyluronium hexafluorophosphate and diisopropylethylamine (or triethylamine). When X ¹ is a halogen atom, the acylation reaction can be carried out using a base such as pyridine, preferably in a solvent such as tetrahydrofuran at a temperature around room temperature.

Formula (I) wherein Het, R ¹ , Ar ¹ , L ² and Z ¹ are as defined above, and L ¹ is a —R ⁵ —R ⁶ — bond [wherein R ⁵ is as defined above, and R ⁶ is -NR ⁴ -C (= O)-(
Wherein R ⁴ is as defined above), and Y is a —CO ₂ R ¹⁸ group, wherein R ¹⁸ is as defined above. Formula (IV): R ¹ Z ¹ -Het-R ⁵ -NHR ⁴ (IV), wherein Het, R ¹ , R ⁴ are prepared using the procedure described above for coupling an acid or acid halide to an amine. , R ⁵ and Z ¹ are as defined above, with a compound of formula (V): X ² —C (= O) —Ar—L ² —CO ₂ R ¹⁸ (V), wherein Ar ¹ , R ¹⁸ and L ² are as defined above, and X ² can be prepared by reacting with a compound of the formula hydroxy or halogen, preferably chlorine.

Formula (I) wherein Het, R ¹ , Ar ¹ , L ² and Z ¹ are as defined above, and L ¹ is a —R ⁵ —R ⁶ — bond, wherein R ⁵ Is as defined above, R ⁶ is —O—, and Y is a —CO ² R ¹⁸ group, wherein R ¹⁸ is as defined above. And a compound of formula (VI): R ¹ Z ¹ -Het-R ⁵ -OH (VI) wherein Het, R ¹ , R ⁵ and Z ¹ are as defined above, and HZ ³ -Ar ^1- L ² -CO ² R ¹⁸ (VII) wherein Ar ¹ , R ¹⁸ and L ² are as defined above, and Z ³ is O, with a dialkylazodicarboxylate For example, in the presence of diethyl azodicarboxylate and triphenylphosphine, preferably in a dry ethereal solvent such as diethyl ether or tetrahydrofuran, preferably at or near room temperature. Can be manufactured.

Alternatively, a compound of formula (I) wherein Het, R ¹ , Ar ¹ , L ² and Z ¹ are as defined above and L ¹ is a —R ⁵ —R ⁶ — bond (formula Wherein R ⁵ is as defined above, and R ⁶ is -O
- can be) and Y is -CO ₂ R ¹⁸ group (wherein, R ¹⁸ is an ester of the a) a] As defined above, the formula (VII) (wherein, using standard alkylation conditions Medium, Ar ¹ ,
R ¹⁸ and L ² are as defined above, and Z ³ is O).
): Of R ¹ Z ¹ -Het-R ⁵ -X ³ (VIII) wherein Het, R ¹ , R ⁵ and Z ¹ are as defined above and X ³ is a halogen, preferably a bromine atom. It can be prepared by alkylating with an appropriate alkyl bromide. The alkylation is carried out, for example, in dimethylformamide or dimethylsulfoxide in the presence of a base such as an alkali metal carbonate, for example potassium carbonate or an alkali metal hydride, for example sodium hydride at about 0 °
It can be carried out at temperatures from about 100 ° C.

Formula (I) wherein Het, R ¹ , Ar ¹ , L ² and Z ¹ are as defined above, and an L ¹ -R ⁵ -R ⁶ -bond wherein R ⁵ is Wherein R ⁶ is as defined above, R ⁶ is —S—, and Y is a —CO ² R ¹⁸ group, wherein R ¹⁸ is as defined above. , Of the formula (VII), wherein Ar ¹ , R ¹⁸ and L ² are as defined above, and Z ³ is S.

Formula (I) wherein Het, R¹, Ar¹, L^TwoAnd Z¹Is as defined above, and L¹ Is -R^Five-R⁶-Bond (where R^FiveIs as defined above, and R⁶Is -NR^Four-(Where R^Four Is as defined above)) and Y is -CO_TwoR¹⁸Group (wherein
R¹⁸Is as defined above)) is an ester of the formula (III) ¹ , R^Four, R¹⁸And L^TwoIs as defined above).
Can be similarly manufactured.

[0160] Formula (I) ^{{wherein, Het, R 1, Ar,} L 2 and Z ¹ are as defined above, L ¹
-R ⁵ -R ⁶ are - bond wherein, R ⁵ is alkylene, R ⁶ is -C (= O) - in which] is and Y in the -CO ₂ R ¹⁸ group (wherein, R ¹⁸ is as defined above) can be prepared by applying or adapting the methodology described by RDRieke et al., Synth. Commun., 1995, 23, pp. 3923-3930. ) Wherein Het, R ¹ and Z ¹ are as defined above, X ¹ is chloro and R ⁵ is alkylene, with the formula (IX): Br-Ar ^1- L ² -CO ₂ R ¹⁸ (IX) where R ¹⁸ , Ar ¹ and L ² are as defined above.

Formula (I) wherein Het, R ¹ , Ar ¹ , L ² and Z ¹ are as defined above, and L ¹ is a —R ⁵ —R ⁶ — bond [wherein R ⁵ Is as defined above, and R ⁶ is -NR ⁴ -C (= O) -NH-
Wherein R ⁴ is as defined above] and Y is a —CO ₂ R ¹⁸ group wherein R ¹⁸ is as defined above. Is the formula (IV)
Wherein Het, R ¹ , R ⁴ , R ⁵ and Z ¹ are as defined above, with a compound of formula (X): O = C = N-Ar ¹ -L ² -CO ₂ R ¹⁸ (X) wherein Ar ¹ , R ¹⁸ and L ² are as defined above with an isocyanate. The reaction is preferably carried out using a base such as a tertiary amine, for example triethylamine, preferably in a solvent such as dichloromethane, at a temperature near room temperature.

Formula (I) wherein Het, R ¹ , Ar ¹ , L ² and Z ¹ are as defined above, and L ¹ is a —R ⁵ —R ⁶ — bond [wherein R ⁵ are as is that defined above, R ⁶ is -NH-C (= O) -NR 4 -
(R ⁴ is as defined above), and Y is a -CO ₂ R ¹⁸ group, wherein R ¹⁸ is as defined above. An amine of (III) wherein Ar ¹ , R ⁴ , R ¹⁸ and L ² are as defined above is converted to a compound of formula (XI): R ¹ Z1-Het-R ⁵ -N = C = O ( XI) by reacting with a compound of the formula where Het, R ¹ , R ⁵ and Z ¹ are as defined above.

Formula (I) wherein Het, R ¹ , Ar ¹ , L ² and Z ¹ are as defined above, and L ¹ is a —R ⁵ —R ⁶ — bond [wherein R ⁵ Is as defined above, R ⁶ is —SO ₂ —NR ⁴ —, wherein R ⁴ is as defined above, and Y is a —CO ₂ R ¹⁸ group ( Wherein the ester of｝, wherein R ¹⁸ is as defined above, is represented by the formula (XII): R ¹ Z ¹ -Het-R ⁵ -SO ₂ Cl (XII) wherein Het, R ¹ , R ⁵ and Z ¹ are as defined above) with a compound of formula (
III) wherein Ar ¹ , R ⁴ , R ¹⁸ and L ² are as defined above. The reaction is preferably carried out using a base such as a tertiary amine, for example triethylamine, preferably in a solvent such as tetrahydrofuran at a temperature near room temperature.

Formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ , L ² and Z ¹ are as defined above, and L ¹ is a —R ⁵ —R ⁶ — bond [wherein , R ⁵ is as defined above, and R ⁶ is -NR ⁴ -SO _2- (
Wherein R ⁴ is as defined above) and Y is a —CO ₂ R ¹⁸ group wherein R ¹⁸ is as defined above. , Formula (IV) (
Wherein Het, R ¹ , R ⁵ , R ⁴ and Z ¹ are as defined above) with a compound of formula (XIII): Cl—SO ₂ —Ar ¹ —L ² —CO ₂ R ¹⁸ (XIII Wherein R ¹ is as defined above, wherein Ar ¹ , R ¹⁸ and L ² are as defined above.

Formula (I) wherein Het, R ¹ , Ar ¹ , L ² and Z ¹ are as defined above, and L ¹ is a —R ⁵ —R ⁶ — bond [wherein R ⁵ Is as defined above, R ⁶ is —OC (= O) —], and Y is a —CO ₂ R ¹⁸ group, wherein R ¹⁸ is as defined above. Certain エ ス テ ル esters can be used to convert a compound of formula (VI), wherein Het, R ¹ , R ⁵ and Z ¹ are as defined above, to a compound of formula (V) wherein Ar ¹ , R ¹⁸ And L ² are as defined above, and X ² is a chlorine atom), and can be prepared by o-acylation. The reaction is performed using standard o-acylation conditions,
For example, the reaction can be carried out in the presence of a base such as triethylamine or pyridine at a temperature of about 0 ° C. to about room temperature.

Formula (I) wherein Het, R ¹ , Ar ¹ , L ² and Z ¹ are as defined above, and L ¹ is a —R ⁵ —R ⁶ — bond [wherein R ⁵ Is as defined above, R ⁶ is —C (= O) —O—], and Y is a —CO ₂ R ¹⁸ group, wherein R ¹⁸ is as defined above ) Is a compound of formula (VII), wherein Ar ¹ , R ¹⁸ and L ² are as defined above, and Z ³ is O. Wherein Het, R ¹ , R ⁵ and Z ¹ are as defined above, and X ¹ is a chlorine atom), which can be similarly prepared by O-acylation.

Formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ , L ² and Z ¹ are as defined above, and L ¹ is a —R ⁵ —R ⁶ — bond (wherein , R ⁵ is as defined above, and R ⁶ is -OC (= O) -NH
- a a a), and Y is -CO ₂ R ¹⁸ group (wherein, esters of R ¹⁸ is at a) as hereinbefore defined above, the formula (VI) (wherein Het, R ¹ , R ⁵ and Z ¹ are as defined above, with an isocyanate of formula (X), wherein Ar ¹ , R ¹⁸ and L are as defined above, Can be manufactured. The reaction is preferably carried out in a solvent such as dichloromethane at a temperature near room temperature using a base such as a tertiary amine, for example triethylamine.

Formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ , L ² and Z ¹ are as defined above, and L ¹ is a —R ⁵ —R ⁶ — bond (wherein , R ⁵ is as defined above, and R ⁶ is -NH-C (= O) -O
- a a a), and Y is -CO ₂ R ¹⁸ group (wherein, esters of R ¹⁸ is at a) as hereinbefore defined above, the formula (XI) (wherein Het, R ¹ , R ⁵ and Z ¹ are as defined above, an isocyanate of formula (VII), wherein Ar ¹ R ¹⁸ and L ² are as defined above, and Z ³ is O ) Can be produced similarly.

Formula (I) wherein Het, R ¹ , Ar ¹ , L ² and Z ¹ are as defined above, and L ¹ is a —R ⁵ —R ⁶ — bond (wherein R ⁶ Is a direct bond, R ⁵ is a straight or branched C _2-6 alkenylene chain with the carbon-carbon double bond directly attached to the phenyl ring containing the -L ² -Y group), and Y Is an —CO ₂ R ¹⁸ group, where R ¹⁸ is as defined above), using standard Wittig (or Horner-Wadsworth-Emmons) coupling methods (eg, Tetrahedron Organic Chemistry). Series Volume 11, Organic Syn
thesis Based On Name Reactions and Unnamed Reactions, Editors, JE Bal
Using win and PD Magnus, pages 181 and 421), formula (XIV): HC (= O) -Ar ¹ -L ² -CO ₂ R ¹⁸ (XIV) A compound of formula (XV) wherein Ar ¹ , R ¹⁸ and L ² are as defined above
): R ¹ Z ¹ -Het-R ⁵ -X ⁴ (XV) wherein Het, R ¹ and Z ¹ are as defined above, and R ⁵ is a linear or branched C _{1- 5} is an alkylene chain and X ⁴ is = PPh ₃ ⁺ Br ^- (or -P (= O) (OEt) ₂₎ appropriate phosphorane (or phosphonate ester) of an a! and be prepared by reacting Can be.

An ester of formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ and Z ¹ are as defined above, and Y is a —CO ₂ R ¹⁸ group, wherein R ¹⁸ is And L ¹ is NY ³ Y ⁴ wherein one of Y ³ and Y ⁴ is hydrogen and the other is alkyl, or alkoxy, aryl, cyano, cycloalkyl , Heteroaryl, heterocycloalkyl, hydroxy, oxo, -NY ¹ Y ² , or one or more CO ₂ R ⁷
Or -C (= O) -NY is an alkyl substituted by ¹ Y ² group) is an alkylene linkage substituted by] in the presence of sodium cyanoborohydride,
Formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ and Z ¹ are as defined above, and Y is-
A CO ₂ R ¹⁸ group, wherein R ¹⁸ is as defined above, and L ² is —NH ₂
An ester of the formula (XVI): R ¹⁹ -CHO (XVI) wherein R ¹⁹ is hydrogen or alkyl, or alkoxy, aryl, cyano,
Cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, -NY ¹ Y ² , or alkyl substituted by one or more -CO ₂ R ⁷ or -C (= O) -NY ¹ Y ² groups )). The reaction can be conveniently carried out in methanol, optionally in the presence of sodium acetate and 4% molecular sieve, at a temperature near room temperature.

Formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ and Z ¹ are as defined above;
A is -CO ₂ R ¹⁸ group (wherein, R ¹⁸ is as hereinbefore defined above), and L ² is -N
Esters of (R ⁷ ) -C (= O) -R ⁸ groups) include compounds of formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ and Z ¹ are as defined above. , Y is a —CO ₂ R ¹⁸ group, wherein R ¹⁸ is as defined above, and L ² comprises an —NH (R ⁷ ) group], with an amine of formula (XVII
): R ⁸ —C (= O) —X ⁵ (XVII) wherein R ⁸ is as defined above, X ⁵ is hydroxy or halogen,
(Preferably a chlorine atom). When X ⁵ is a hydroxy group, as described above, the reaction can be carried out using standard peptide coupling methods. When X ⁵ is a halogen atom, the reaction, using a base such as pyridine, preferably in a solvent such as tetrahydrofuran, it can be carried out at temperatures near room temperature.

Formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ and Z ¹ are as defined above;
A is -CO ² R ¹⁸ group (wherein, R ¹⁸ is as hereinbefore defined above), and L ² is -N
Esters of (R ⁷ ) —C (= O) —OR ⁸ groups) can be prepared according to standard reaction conditions according to formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ and Z ¹ are as defined above As defined, Y is a —CO ² R ¹⁸ group (
Wherein R ¹⁸ is as defined above), and L ² comprises a —NH (R ⁷ ) group] with an appropriate chloroformate such as ethyl (or benzyl) chloroformate. It can be produced by reacting with a compound.

Formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ and Z ¹ are as defined above;
A is -CO ₂ R ¹⁸ group (wherein, R ¹⁸ is as hereinbefore defined above), and L ² is -N
Esters (including R ⁷ -SO ₂ -R ⁸ groups) are prepared according to standard reaction conditions according to formula (I) wherein H
et, R ¹ , Ar ¹ , L ¹ and Z ¹ are as defined above, Y is a —CO ₂ R ¹⁸ group wherein R ¹⁸ is as defined above, and L ² contains a -NH (R ⁷ ) group] with an appropriate sulfonyl chloride, for example an aryl (or heteroaryl) sulfonyl chloride such as phenyl (or pyridyl) sulfonyl chloride. .

Formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ and L ¹ are as defined above,
Is a -CO ₂ R ¹⁸ group, wherein R ¹⁸ is as defined above, and L ² is

Embedded image An ester of formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ and Z ¹ are as defined above, and Y is a —CO ₂ R ¹⁸ group ( Wherein R ¹⁸ is as defined above) and L ² is

Embedded image Which is a bond). The 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 on an inert support such as carbon. The reaction can be conveniently 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.

Formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ and Z ¹ are as defined above,
Is a -CO ₂ R ¹⁸ group, wherein R ¹⁸ is as defined above, and L ² is

Embedded image An ester of the formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ and Z ¹ are as defined above, and Y is a —CO ₂ R ¹⁸ group, wherein R ¹⁸ is as defined above) and L ² is

Embedded image Can be similarly prepared by hydrogenation of an ester which is a bond.

In addition, Formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ and Z ¹ are as defined above, and Y is a —CO ₂ R ¹⁸ group (wherein R ¹⁸ Is as defined above), and L ² is

Embedded image The ester of a bond can be obtained according to standard recrystallization of a salt of a racemic mixture, for example, recrystallization of tartrate.

Further, a compound represented by the formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ and Z ¹ are as defined above, and Y is a —CO ₂ R ¹⁸ group (where R ¹⁸ is And L ² is as defined above)

Embedded image Ester) can be prepared by standard enzymatic degradation methods, such as Soloshonok, VA,
Et al., Tetrahedron: Asymmetry 6 (1995) 7, 1601-1610.

Formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ and Z ¹ are as defined above;
Is -CO ₂ R ¹⁸ , wherein R ¹⁸ is as defined above, and L ² is

Embedded image The ester of formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ and Z ¹ are as defined above in an inert solvent such as tetrahydrofuran at a temperature near room temperature. There, Y is -CO ₂ R ¹⁸ group (wherein, R ¹⁸ is as is defined above), and and L ² is an ester of -CH = CH- is bonded], as sodium hydride Reaction with an alkali metal hydride followed by dibenzylamine or (S) at a temperature of about -78 ° C.
It can be prepared by treating -N-benzyl-methylbenzylamino with butyllithium and reacting with an anion derived therefrom.

Formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ and Z ¹ are as defined above, and -L ^2-
Y part

Embedded image The lactone of formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ and Z ¹ are as defined above, and the -L ² -Y moiety is

Embedded image (Wherein R ²⁰ is lower alkyl)] selectively (eg, using a borane derivative or lithium borohydride), followed by spontaneous cyclization of the intermediate hydroxy compound. Can be manufactured. Reduction is C.
J. Francis and J. Bryan Jones. J. Chem. Soc, Chem. Commun., 1984, (9), 579.
-58, J. Hiratake et al., J. Chem. Soc, Perkin Trans, 1987, 1 (5), 1053-8 or LKPLam et al., J. Org. Chem. (1986), 51 (11), 2047-50 Can be implemented by applying or adapting the method described in.

Formula (I) wherein Het, R¹, Ar¹, L¹And Z¹Is as defined above, and -L ^Two -Y part is

Embedded image The lactone of formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ and Z ¹ are as defined above, and the -L ² -Y moiety is

Embedded image (Wherein R ²⁰ is lower alkyl)].

Formula (I) wherein Het, R¹, Ar¹, L¹And Z¹Is as defined above, and -L ^Two -Y part is

Embedded image The lactone of formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ and Z ¹ are as defined above, and the -L ² -Y moiety is

Embedded image (Wherein R ²⁰ is lower alkyl)].

Formula (I) represented by Formula (XVIII), wherein Het, R ¹ , Ar ¹ , R ⁵ , L ² and Z ¹
Is as defined above and Y is carboxy) can be prepared using resin technology as shown in Scheme 1.

[0183]

Embedded image

For example, Wang resin, 4-hydroxymethylphenoxylated styrene / divinylbenzene copolymer, where ●-represents the polymer core (comprising polystyrene cross-linked with 1% to 2% divinylbenzene) ] Is a compound represented by the formula (XIX): O ₂ N-Ar ¹ -L ² O ₂ H (XIX) in step 1 in the presence of dimethylaminopyridine at room temperature, wherein Ar ¹ and L ² are defined above. Acid), diisopropylcarbodiimide in dimethylformamide. The resulting ester (Resin 1) (where Ar ¹ , L ² and ● — are as defined above) is then treated in step 2 with tin chloride in dimethylformamide at room temperature Resin 2 is obtained, where Ar ¹ , L ² and ●-are as defined above. The resin 2 was then used in step 3 in the presence of O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide At room temperature, the general formula (II)
Wherein Het, R ¹ , R ⁵ and Z ¹ are as described above, and X ¹ is hydroxy.
Acid. The resulting resin 3 (where Het, R ¹ , Ar ¹ , R ⁵ , L ² , Z ¹ and ● — are as defined above) is then used in step 4 such as dichloromethane. Treatment with trifluoroacetic acid in an inert solvent at room temperature to give a compound of the general formula (XVIII) wherein Het, R ¹ , Ar ¹ , R ⁵ , L ² and Z ¹ are as defined above ) Can be released.

Compounds of formula (Ia) represented by formula (XX), wherein R ¹ , R ⁵ , R ¹⁶ , Ar ¹ and
L ² is as defined above, R ⁴ is hydrogen, X is O, Z ¹ is NH, and Y is carboxy) using resin technology as shown in Scheme 2. Can be manufactured.

[0186]

Embedded image

For example, resin 2 (where Ar ¹ , L ² and ● — are as defined above) was prepared in step 1 by adding O- (7-azabenzotriazol-1- in dimethylformamide
Yl) in the presence of -1,1,3,3-tetramethyluronium hexafluorophosphate and diisopropylethylamine at room temperature at the general formula (XXI):

Embedded image (Wherein R ⁵ is as defined above and X is O) and the resin 4 (wherein R ⁵ , R ¹⁶ , Ar ¹ , L ² and As it was done). Resin 4 is then treated with tin chloride in dimethylformamide at room temperature, followed by the formula (XXII) in dimethylformamide at room temperature: R ¹ -N = C = S (XXII) ¹ is as defined above) and then at 75 ° C. with diisopropylcarbodiimide in dimethylformamide. The resulting resin 5 (wherein R ¹ , R ¹⁶ , Ar ¹ , R ⁵ , L ² and ● — are as defined above) is then treated in step 3 with an inert solvent such as dichloromethane. Treatment at room temperature with trifluoroacetic acid in the general formula (
XX) wherein R ¹ , R ¹⁶ , Ar ¹ , R ⁵ and L ² are as defined above.

Formula (Ia) wherein R ¹ , R ⁴ , R ⁵ , Ar ¹ and L ² are as defined above;
Is O, Z ¹ is NH, and Y is a —CO ₂ R ¹⁸ group, wherein R ¹⁸ is as defined above.] At room temperature has the formula (XXIII) :

Embedded image Wherein R ⁴ , R ⁵ , R ¹⁶ , R ¹⁸ , Ar ¹ and L ² are as defined above, with a compound of formula (XXII) in dimethylformamide, wherein R ¹ is (As defined), followed by treatment with diisopropylcarbodiimide in dimethylformamide at 75 ° C.

According to a further feature of the present invention, the compounds of the present invention can be prepared by interconversion of other compounds of the present invention.

For example, Formula (I) (where Het, R¹, Ar¹, L¹, L^TwoAnd Z¹Is as defined above
And Y is -C (= O) -NHOH) is a compound of
In an inert solvent such as lofran, in the presence of triethylamine, at a temperature near room temperature
When treated with carbodiimide, for example, dicyclohexylcarbodiimide,
Using standard peptide coupling methods such as these, the formula (I) (where Het, R ¹ , Ar¹, L¹, L^TwoAnd Z¹Is as defined above, and Y is carboxy
) Can be prepared by reacting a compound of formula
Wear. Also, the coupling is performed at room temperature with 1-hydroxybenzotolone in dichloromethane.
Liazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide
It can also be carried out using. In addition, production is based on O- (trimethylsilyl) hydroxy
Silamine, O- (t-butyldimethylsilyl) -hydroxylamine or O- (
O-protected hydroxy such as trahydropyranyl) hydroxylamine
It can be carried out using a silamine followed by treatment with an acid.

As another example of an interconversion method, the formula (I) wherein Het, R ¹ , Ar ¹ , L ¹ , Z ¹ and Y are as defined above and L ² is optionally substituted Compounds of formula (I), wherein R ² is a corresponding optionally substituted alkenylene bond, can be prepared by hydrogenation of the corresponding compound of formula (I), wherein L ² is a corresponding optionally substituted alkenylene bond. Hydrogenation is 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, at a temperature near room temperature, at a temperature close to room temperature. Under pressure).

As another example of the interconversion method, a compound of the formula (I) wherein Het, R ¹ Ar ¹ , L ² , Z ¹ and Y are as described above, and L ¹ is —R ⁵ —R ⁶ - bond (wherein, R ⁵ is C _2-6 alkylene chain straight or branched chain, R ⁶ is a direct bond a is) a compound of a] is the formula (I) wherein, L ¹ Is a -R ⁵ R ⁶ -bond, wherein R ⁵ is a straight or branched C _2-6 alkenylene chain and R ⁶ is a direct bond. It can be manufactured similarly.

As another example of an interconversion method, compounds of the present invention that contain a heterocyclic group wherein the heteroatom is a nitrogen atom can be oxidized to their corresponding N-oxides. Oxidation is
The reaction can be conveniently carried out by reaction with a mixture of hydrogen peroxide and an organic acid such as acetic acid, preferably at room temperature or above, for example at a temperature of 60 to 90 ° C. Alternatively, the oxidation employs a peracid such as peracetic acid or m-chloroperoxybenzoic acid in an inert solvent such as chloroform or dichloromethane at a temperature from about room temperature to reflux, preferably at elevated temperature. The reaction can be carried out according to the reaction. Alternatively, the oxidation is carried out by reaction with hydrogen peroxide at a temperature between room temperature and about 60 ° C. in the presence of sodium tungstate.

It has been recognized that compounds of the present invention can contain asymmetric centers. These asymmetric centers can independently exist in either the R or S configuration. It is also apparent to those skilled in the art that certain compounds of the present invention can exhibit geometric isomerism. It is to be understood that the present invention includes each geometric and stereoisomer of the compounds of formula (I) above and mixtures thereof, including racemic mixtures. Such isomers can be separated from their mixtures by applying or adapting known methods, such as chromatography and recrystallization techniques, or can be separated from the appropriate isomers of their intermediates It is manufactured in.

According to a further feature of the invention, acid addition salts of the compounds of this invention may be prepared by reacting the free base with a suitable acid by applying or adapting known methods. For example, the acid addition salts of the compounds of this invention can be prepared by dissolving the free base in water or aqueous alcoholic solution or other suitable solvent containing the appropriate acid and evaporating the solution to isolate the salt, or Reacting a free base with an acid in a solvent (
In that case, the salts can either be obtained directly or obtained by concentration of the solution).

The acid addition salts of the compounds of this invention can be regenerated from the salts by applying or adapting known methods. For example, a parent compound of the present invention can be regenerated from its acid addition salt by treatment with an alkali, for example, aqueous sodium bicarbonate or aqueous ammonia.

The compounds of the present invention can be regenerated from their base addition salts by applying or adapting known methods. For example, a parent compound of the invention can be regenerated from its base addition salt by treatment with an acid, such as hydrochloric acid.

The compounds of the present invention can be conveniently prepared or formed during the process of the present invention as solvates (eg, hydrates). Hydrates of the compounds of the present invention can be conveniently 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 may be prepared by reacting the free acid with a suitable base by applying or adapting 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 aqueous alcoholic solution or other suitable solvent containing the appropriate base, and evaporating the solution to isolate the salt. Or by reacting the free acid with a base in an organic solvent, in which 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 adapting known methods, for example those described in the Reference Examples or their chemically obvious equivalents.

Formula (II) wherein R ¹ and R ⁵ are as defined above, and Het is

Embedded image Wherein R ¹⁶ is as defined above, Z ¹ is NH, and X ¹ is hydroxy. The acid in ethanol at room temperature has the formula (XXIV):

Embedded image Wherein R ⁵ and R ¹⁶ are as defined above, R ¹⁸ is lower alkyl, and X is O, and the compound of formula (XXII) wherein R ¹ is as defined above As described above), followed by reaction with a carbodiimide such as dicyclohexylcarbodiimide or diisopropylcarbodiimide in ethanol at a temperature from about room temperature to reflux temperature, followed by standard conditions, e.g., It can be produced by hydrolysis using the above.

Formula (II) wherein R ¹ and R ⁵ are as defined above, and Het is

Embedded image Wherein R ¹⁶ is as defined above, Z ¹ is NH, and X ¹
Is an hydroxy] acid from a compound of formula (XXIV), wherein R ⁵ and R ¹⁶ are as defined above, R ¹⁸ is lower alkyl, and X is NH. It can be manufactured similarly.

The acid chloride of the formula (II) wherein Het, R ¹ , R ⁵ and Z ¹ are as defined above and X ¹ is a chlorine atom converts the acid to the acid chloride. By applying standard techniques for preparing, for example, by reaction with oxalyl chloride, formula (II) wherein Het, R ¹ , R ⁵ and Z ¹ are as defined above, X ¹ Is hydroxy).

An acid chloride of the formula (V) wherein Ar ¹ , R ¹⁸ and L ² are as defined above and X ² is a chlorine atom is represented by the formula (V) Ar ¹ , R ¹⁸ and L ² are as defined above, and X ² is hydroxy) can be similarly prepared from the corresponding acid.

Compounds of formula (III) wherein Ar ¹ , R ¹⁸ and L ² are as defined above, and R ⁴ is methyl, are compounds of formula (III) wherein Ar ¹ , R ¹⁸ and L ² are as defined above and R ⁴ is hydrogen), treating the corresponding compound with formic acetic anhydride followed by LC Humber et al., J Med. Chem., 1971, 14, It can be prepared by reduction with lithium aluminum hydride according to the procedure described by page 982.

Compounds of formula (IV), wherein Het, R ¹ , R ⁵ and Z ¹ are as defined above, and R ⁴ is methyl, are prepared according to formula (IV), wherein Het , R ¹ , R ⁵ and Z ¹ are as defined above, and R ⁴ is hydrogen).

Compounds of formula (III), wherein Ar ¹ , R ¹⁸ and L ² are as defined above, and R ⁴ is hydrogen, have the formula (XXV): O ₂ N—Ar ¹ -L ² -CO ₂ R ¹⁸ (XXV) wherein R ¹⁸ , Ar ¹ and L ² are as defined above, can be prepared by reduction of the corresponding nitro compound. Reduction can be accomplished using standard techniques, for example, (i) by treatment with ammonium formate and palladium on charcoal at a temperature of about 50 ° C. in ethanol or (ii) in aqueous ethanol at a temperature near reflux It can be carried out by treatment with iron powder and ammonium chloride.

Compounds of formula (XXIII), wherein R ⁴ , R ⁵ , R ¹⁶ , R ¹⁸ , Ar ¹ and L ² are as defined above, have the formula (XXVI):

Embedded image Similarly, they can be prepared by reduction of a compound of the formula wherein R ⁴ , R ⁵ , R ¹⁶ , R ¹⁸ , Ar ¹ and L ² are as defined above.

Formula (XXIV) wherein R ⁵ , R ¹⁶ , R ¹⁸ are as defined above, and X is O
Is a compound of formula (XXVII):

Embedded image (R ⁵ , R ¹⁶ , and R ¹⁸ are as defined above).

Compounds of formula (XXIV) wherein R ⁵ , R ¹⁶ and R ¹⁸ are as defined above and X is NH are represented by the formula (XXVIII):

Embedded image(Where R^Five, R¹⁶, R¹⁸Is as defined above, and R^{twenty one}Is NH^TwoOr NO ^Two Can be similarly prepared by reduction of the compound of formula (I).

Formula (III) wherein Ar ¹ and R ¹⁸ are as defined above, R ⁴ is hydrogen, and L ² is alkylene (eg, —CH (CH ₃ ) —CH ₂ —) Is a compound of formula (XXV) using standard conditions such as those described above, wherein R ¹⁸ and Ar ¹ are as defined above, and L ² is a corresponding alkenylene chain (eg, -C (CH ₃ ) = CH-)].

Compounds of formula (IV), wherein Het, R ¹ , R ⁵ and Z ¹ are as defined above, and R ⁴ is hydrogen, can be prepared by reacting a compound of formula (VIII) wherein Het , R ¹ , R ⁵ and Z ¹ are as defined above and X ³ is bromo) with phthalimide potassium salt in dimethylformamide, followed by reaction with hydrazine hydrate in ethanol (For example, using the conditions described in O. Diouf et al., Heterocycles, 1995, 41, pp. 1219-1233).

Of formula (VI) wherein Het, R ¹ and Z ¹ are as defined above and R ⁵ is methylene (ie a C _2-6 straight or branched alkylene chain) The compound has the formula (
XXIX): R ¹ Z ¹ -Het-R ²² -CO ₂ R ¹⁸ (XXIX) wherein Het, R ¹ and Z ¹ are as defined above, R ¹⁸ is alkyl and R ²² Is a direct bond (or a C _1-5 linear or branched alkylene chain)]. The reduction can be conveniently carried out using diisobutylaluminum hydride in an inert solvent such as tetrahydrofuran at a temperature from about -78 ° C to about room temperature. The reduction can also be carried out using lithium aluminum hydride in an inert solvent such as ether, for example, diethyl ether at a temperature near room temperature to near reflux.

Compounds of formula (VII) wherein R ¹⁸ , Ar ¹ and L ² are as defined above and Z ³ is O can be prepared by standard esterification methods, such as acid catalysis such as those of the formula by reaction with a lower alkyl alcohol in the presence of hydrogen chloride or sulfuric acid (such as ^{methanol) (XXX): HZ 3 -Ar} 1 -L 2 -CO 2 H (XXX) ( wherein, Ar ¹ and L ² is as defined above, and Z ³ is O).

Compounds of formula (VIII) wherein Het, R ¹ and Z ¹ are as defined above, R ⁵ is an alkylene chain and X ³ is bromo inert solvent such as, at a temperature around room temperature, the formula (VI) (wherein, Het, R ¹ and Z ¹ are as defined above, R ⁵ is an alkylene chain) three compounds It can be produced by reacting with phosphorus bromide.

Compounds of formula (X) wherein R ¹⁸ , Ar ¹ and L ² are as defined above are prepared using phosgene according to standard reaction conditions for converting amines to isocyanates. Can be prepared from a compound of formula (III), wherein R ¹⁸ , Ar ¹ and L ² are as defined above, and R ⁴ is hydrogen.

Formula (XI) (where Het, R¹, R^FiveAnd Z¹Is as defined above)
The compound is represented by the formula (IV) (where Het, R¹, R^FiveAnd Z¹Is as defined above, and R ^Four Is hydrogen).

Compounds of formula (XII), wherein Het, R ¹ , R ⁵ and Z ¹ are as defined above, are prepared according to PNCulshaw and JC Walton, J. Chem. Soc., Perkin Trans II, 1991.
8, Reaction with sodium sulfite followed by phosphorus trichloride according to the method described on pages 1201-1208, wherein Het, R ¹ , R ⁵ and Z ¹ are as defined above. And X ³ is bromo).

Formula (XIII) (wherein, R¹⁸, Ar¹And L^TwoIs as defined above)
Converts aminopyrazole to the corresponding pyrazolylsulfonyl chloride
J.A. Diaz and S. Vega J. Heterocycl.Chem., 1994, 31, pp. 93-96.
By applying or adapting the method described, formula (III) (wherein R¹⁸, Ar¹And L ^Two Is as defined above, and R^FourIs hydrogen)
Can be.

Formula (XV) wherein Het, R ¹ and Z ¹ are as defined above, R ⁵ is a linear or branched C _1-5 alkylene chain, and X ⁴ is = PPh ₃ ⁺ Br ⁻ ) in an inert solvent at a temperature from around room temperature to the reflux temperature of the solvent, where Het, R ¹ and Z ¹ are as defined above. in and, R ⁵ is C _1-5 alkylene chain linear or branched, and X ₃ can be prepared by reacting a compound of a bromine atom) with triphenylphosphine.

A compound of formula (XIX), wherein Ar ¹ and L ² are as defined above,
It can be prepared by hydrolyzing the corresponding ester of formula (XXV) using the standard conditions described above.

Formula (XIX) wherein Ar ¹ is as defined above, and L ² is

Embedded image Is a standard methodology for producing α-amino acids, such as Or
ganic Syntheses Based On Name Reactions and Unnamed Reactions, A. Hassner
and C. Stumer, Pergamon, pp. 275 and 374.

Also, formula (XIX), wherein Ar ¹ is as defined above, and L ² is

Embedded image ) Are described in DL Boger and D. Yohannes, J. Org. Chem. [JOCEAH],
Derived from the reaction of (2R)-(-)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine with butyllithium according to the process for preparing compound 31 on page 6010 described in 1990, 55. Formula (XXXI) using a modified anion: O ₂ N—Ar ¹ —CH ₂ X ⁶ (XXXI) wherein Ar ¹ is as defined above and X ⁶ is a bromine or chlorine atom
Can be produced by reacting a compound of the formula

Formula (XXV) wherein Ar ¹ is as defined above, and L ² is alkenylene, alkynylene or cycloalkenylene (where the aliphatic carbon-carbon multiple bond is represented by the formula
A compound of formula (XXXII): O ₂ N-Ar ¹ -X ⁷ (XXXII) wherein Ar ¹ is as defined above. , X ⁷ is a halogen, preferably a bromine or iodine atom, and a compound of formula (XXXIII): R ²³ -CO ₂ R ¹⁸ (XXXIII), wherein R ¹⁸ is as defined above, and R ²³ is alkenyl, alkynyl or cycloalkenyl). When X ⁶ is a bromine or iodine atom, the reaction may be carried out in an inert solvent such as dimethylformamide at a temperature of about 100 ° C. or less at a temperature of about 100 ° C. ) And a tertiary amine such as triethylamine. This reaction is particularly formula (XXV) (L ² is vinylene or -C (CH ₃₎ = CH- and is) suitable for the preparation of compounds of. When X ⁶ is a chlorine atom, the reaction is carried out using sodium iodide, nickel bromide, palladium (0) bis (
Dibenzylideneacetone), a triarylphosphine such as tri-o tolylphosphine and a tertiary amine such as tributylamine at a temperature of about 110 ° C. or less.

Formula (XXV) wherein Ar ¹ is pyridinediyl, R ¹⁸ is alkyl, and L ² is —C (R ²⁴ ) = C (R ²⁵ ) — (wherein R ²⁴ and R ²⁵ is independently hydrogen or alkyl)) in the presence of a base such as an alkali metal alkoxide (eg, potassium t-butoxide) or an alkali metal hydride (eg, sodium hydride). (XXXIV): a compound of the formula O ₂ N—Ar ¹ —C (= O) —R ²⁴ (XXXIV), wherein Ar ¹ is as defined above and R ²⁴ is hydrogen or alkyl. , formula ^{(XXXV): (26 O R} ) 2 P (= O) -CH (R 25) -CO 2 R 18 (XXXV) ( wherein, R ¹⁸ is as defined above, R ²⁵ is hydrogen Or alkyl,
And R ²⁶ is a C _1-4 alkyl group). The reaction is preferably performed in a solvent such as dimethylformamide or tetrahydrofuran.

Compounds of formula (XXVI) wherein R ⁴ , R ⁵ , R ¹⁶ , R ¹⁸ , Ar ¹ and L ² are as defined above are prepared using the standard peptide coupling conditions described above. Using the formula (I
II) an amine of formula (XXI) wherein R ⁴ , R ¹⁸ , Ar ¹ and L ² are as defined above, wherein R ⁵ and R ¹⁶ are as defined above , X is O)). This reaction involves the hydroxyl group
It is preferably carried out with the appropriate protection of HX-.

Formula (XXVII) wherein R ⁵ , R ¹⁶ , R ¹⁸ and Ar ¹ are as defined above.
At a temperature near room temperature has the formula (XXXVI):

Embedded image Wherein R ⁵ , R ¹⁶ and R ¹⁸ are as defined above, and R ²⁷ is alkyl-
Or a suitable protecting group such as arylcarbonyl)) with a base such as lithium hydroxide. This method is particularly suited for the preparation of compounds of formula (XXVII), wherein R ⁵ is methylene, R ¹⁶ is lower alkyl, and R ¹⁸ is tertiary butyl.

The acids of formula (XXX), wherein Ar ¹ and L ² are as defined above and Z ³ is O, are described by AGMeyers and JLGleason, J. Org. Chem., 1996. 61 , Pp. 813-815. This methodology is particularly suitable for compounds where Ar ¹ is pyridinediyl.

In addition, Formula (XXX) (wherein, Ar ¹ and L ² are as defined above, and Z ³ is O
Can be prepared by applying or adapting the method described in SR Schow et al., J. Org. Chem., 1994, 59, pp. 6850-6852. This methodology is particularly suitable for compounds where Ar ¹ is pyridinediyl.

Formula (XXXVI) wherein R ⁵ and R ¹⁸ are as defined above, R ¹⁶ is a lower alkyl group attached to a ring position adjacent to the nitro group, and R ²⁷ is an alkyl -Or a suitable protecting group such as arylcarbonyl) can be prepared by reacting a compound of formula (XXXVII) in an inert solvent such as tetrahydrofuran at a temperature of about -15 ° C.

Embedded image Wherein R ⁵ and R ¹⁸ are as defined above, and R ²⁷ is a suitable protecting group such as alkyl- or arylcarbonyl. Can be produced by reacting

The intermediates of formulas (XXIII) and (XXVI) are novel compounds and, therefore, those novel compounds described herein and their methods of manufacture constitute a further feature of the present invention.

The invention is further described below by way of example and in accordance with examples and reference examples, but is not limited thereto.

The conditions of high pressure liquid chromatography (HPLC) for measuring the retention time (R _T ) are as follows: Hypersil Elite C-18 column (15 cm), Els detector; solvent acetonitrile / water gradient (Both are buffered with 0.5% trifluoroacetic acid): 3 minutes, 20% acetonitrile; ramp to 80% over the next 12 minutes; maintain 80% acetonitrile for 3 minutes; Back to 20% acetonitrile with a ramp (total run time 20 minutes).

High Pressure Liquid Chromatography / Mass Spectrometry (LC) to Measure Retention Time (R _T )
M) Conditions are as follows: 3 micron Luna C18 (2) HPLC column (30 mm × 4
.6 mm) under gradient elution conditions using a mixture of (A) water containing 0.1% formic acid and (B) acetonitrile containing 0.1% formic acid as mobile phase gradient: 0.00 min (95% A: 5% B); 0.5
0 minutes (95% A: 5% B); 4.50 minutes (5% A: 95% B); 5.00 minutes (5% A: 95% B); 5.50 minutes (95% A: 5% B); mass spectrometry. Flow rate of 2 ml / min with a splitter at about 200 μl / min; injection volume 10-40 μl; Diode Array (220-450 nm) in line, vapor light scattering in line
(Evaporative light scattering; ELS) detection, ELS-temperature 50 ℃, gain 8 ~ 1.8 ml /
Min; operated at a starting temperature of 150 ° C.

The mass spectrum (MS) shows a mixture of acetonitrile and water (1
1, v / v), flow rate of 0.3 ml / min, injection volume of 20 μl, run time of 2.0 min, +/− scan range of 150-850 daltons, scan time of 2.0 sec, ESI voltage of 3.5 kv, Recording was performed on a Micromass Platform LC mass spectrometer equipped with an electrospray source and HP1100 liquid chromatography using an ESI pressure of 20 n / m2 nitrogen. The ions handled are
It is a positive ion. Thin layer chromatography (TLC) was performed on Merck silica (silica gel 60F245) plates.

Example 1 (3RS) -3- [5- [2-o-tolylaminobenzoxazol-6-yl) -acetylamino]-
Pyrid-2-yl] -butyric acid (3RS) -3- [5- [2- (2-o-tolylamino-benzoxazole-) in methanol (4 mL)
A solution of 6-yl) -acetylamino] -pyrid-2-yl] butyric acid ethyl ester (0.3 g, Reference Example 1) was treated with an aqueous solution of sodium hydroxide (1.5 mL, 1 M), and treated at 40 ° C. in a water bath at 3 ° C. Left for hours. The mixture was partially evaporated, diluted with more water and partially evaporated again. Dilute the residue with water (10 mL) and add diethyl ether (10 mL).
). The pH of the aqueous phase was adjusted to 7 by adding dilute hydrochloric acid. The resulting white solid was filtered, dried, and then triturated with boiling acetonitrile to give the title compound (0.06 g) as a white powder. 195-196 ° C (with decomposition) MS: 445 (MH ⁺ )

Example 2 (3RS) -3- [5- [2-o-Tolylamino-3H-benzimidazol-5-yl) -acetylamino] -pyridin-2-yl｝ -butyric acid trifluoroacetate in dimethylformamide (3RS) -3- (5-aminopyrid-2-yl) butyrate (200 mg, Reference Example 5) and ｛1-[(2-trimethylsilylethoxy) methyl
] -2-o-Tolylamino-5-benzimidazoyl diacetic acid (390 mg, Reference Example 7) was treated with O- (7-azabenzotriazol-1-yl) -1,1,3,3- Tetramethyluronium hexafluorophosphate (380 mg) followed by diisopropylethylamine (2
60 mg). After standing at room temperature for 2 hours, the mixture was diluted with ethyl acetate (100 m
L) and water (50 mL). The layers were separated, then the organic layer was dried and evaporated. The residue was subjected to flash chromatography on silica, eluting with ethyl acetate. The main component (350 mg) was dissolved in methanol (10 mL) and the solution was treated with aqueous sodium hydroxide (3 mL, 1 M). After standing at room temperature for 4 hours, the mixture was evaporated to low volume, diluted with water (20 mL) and then treated with acetic acid until a white precipitate formed. The white precipitate was extracted into ethyl acetate. The solution was dried and evaporated to give a white gum (40mg), which was dissolved in trifluoroacetic acid (5mL). After standing at room temperature for 2 hours, the solution was evaporated to give the title compound (21 mg) as a light yellow foam. HPLC: R _T = 4.63 min (100%) MS (ES ⁺ ): 444 (MH ⁺ )

Example 3 Dimethyl (3RS) -3- [5- [2- (4-methyl-2-o-tolylaminobenzoxazol-6-yl) -acetylamino] -pyrid-2-yl] -butyrate A stirred solution of 2- (4-methyl-2-o-tolylaminobenzoxazol-6-yl) acetic acid (0.13 g, Reference Example 9) in formamide (5 mL) was treated with O- (7-azabenzotriazole- 1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (0.166 g), diisopropylethylamine (0.153 mL), and then ethyl (3RS) -3- (4-) in dimethylformamide (5 mL) Aminopyrid-2-yl) butyrate (0.
091 g, using the solution of Reference Example 5). After stirring for 1 hour and standing at room temperature overnight, the reaction mixture was diluted with water and then extracted with t-butyl methyl ether. The extract was dried over magnesium sulfate and then evaporated to a gum (3RS
) -3- [5- [2- (4-Methyl-2-o-tolylaminobenzoxazol-6-yl) -acetylamino] pyrid-2-yl] butyric acid ethyl ester was obtained. A solution of this gum in ethanol was treated with aqueous lithium hydroxide (1M) and after stirring at room temperature for 1 hour, the mixture was partially evaporated. The residue was acidified to pH 6.7 by adding concentrated hydrochloric acid. This mixture was extracted with ethyl acetate. The extract is dried over magnesium sulfate,
Evaporation then gave the title compound (0.012 g) as a creamy solid. ^{MS (ES -): 457 (} MH -)

Example 4 (a) (RS) -3- [5- [2- (2-phenylamino-benzoxazol-6-yl) -acetylamino) -pyridin-2-yl] -butyric acid ethanol (1 mL ) In (RS) methyl 3- [5- [2- (4-amino-3-hydroxyphenyl)
A solution of -acetylamino] -pyridin-2-yl] -butyrate (41.2 mg, Reference Example 24) was treated with a solution of phenylisothiocyanate (16.23 mg) in ethanol (2 mL). The mixture was left at room temperature for 48 hours, heated at 70 ° C. for 16 hours and then evaporated. The residue, (RS) methyl 3- [5- [2- (3-hydroxy-4- (3-phenylthioureido) -phenyl) -acetylamino] -pyridin-2-yl] -butyrate was converted to dry dimethylformamide ( 1 mL) and the solution was treated with a solution of dicyclohexylcarbodiimide (74.2 mg) in dry dimethylformamide (2 mL). 70 of this mixture
Heated at ° C. for 12 hours then evaporated. Dissolve the residue in methanol (2 mL),
The solution was treated with an aqueous sodium hydroxide solution (600 μL, 1 M). After shaking for 24 hours, the mixture was filtered and the filtrate was acidified with aqueous acetic acid (1 mL, 1M). The precipitate was filtered and dissolved in dimethylformamide. Evaporate this solution,
The residue was purified on a Hypersil Elite C18 column (0.05% TFA in acetonitrile water).
(00 mm x 21 mm) on reverse phase HPLC to give the title compound. LCM-MS: _RT = 2.36 min;
MS (ES ⁺ ): 431 (MH ⁺ )

(B) Except for using 2-chlorophenylisothiocyanate, (RS) 3- (5- [2- [2- (2-chlorophenylamino) -Benzoxazol-6-yl] -acetylamino] -pyridin-2-yl) -butyric acid was prepared. LC-MS: R _T = 2.52 min; MS (ES +): 465,467 (MH ⁺ ). RS) 3- [5- [2- (2-o-Tolylamino-benzoxazol-6-yl) -acetylamino] -pyridin-2-yl] -butyric acid was produced. LC-MS: R _T = 2.37 min; MS (ES ⁺ ): 445 (MH ⁺ )

(D) Performed in a similar manner to Example 4 (a) except that 2-methoxyphenylisothiocyanate was used, to give (RS) 3- (5- [2- [2- (2-methoxy- Phenylamino) -benzoxazol-6-yl] -acetylamino｝ -pyridin-2-yl) -butyric acid was produced. L
C-MS: R _T = 2.45 min; MS (ES ⁺ ): 461 (MH ⁺ ) (e) (RS) Methyl 3- [6- [2- (4-amino-3-hydroxy-phenyl) -acetylamino ]
Example 4 (a) except that -pyridin-3-yl} -butyrate (Reference Example 1) was used.
) To produce (RS) 3- [6- [2- (2-phenylamino-benzoxazole-6-) acetylamino] pyridin-3-yl} -butyric acid. LC-MS: R _T = 2
.37 min; MS (ES ⁺ ): 431 (MH ⁺ )

(F) (RS) Methyl 3- [6- [2- (4-amino-3-hydroxyphenyl) -acetylamino]
(RS) 3- (6- [2- [2 [2- [2
-(2-chloro-phenylamino) -benzoxazol-6-yl {-acetylamino}
-Pyridin-3-yl) -butyric acid was prepared. LC-MS: _RT = 2.52 min; MS (ES ⁺ ): 465
, 467 (MH ⁺ ) (g) (RS) Methyl 3- [6- [2- (4-amino-3-hydroxyphenyl) -acetylamino]-
(RS) 3- [6- [pyridin-3-yl} -butyrate (Reference Example 14) 2- (2-o-
Tolylamino-benzoxazol-6-yl) -acetylamino] -pyridin-3-yl) -butyric acid was prepared. LC-MS: R _T = 2.37 min; MS (ES ⁺ ): 445 (MH ⁺ )

(H) (RS) Methyl 3- (6- (2- (4-amino-3-hydroxyphenyl) -acetylamino]
(RS) 3-pyridin-3-yl) -butyrate (Reference Example 14) and 2-methoxyphenylisothiocyanate, except that (RS) 3-
(6- [2- [2- (2-Methoxy-phenylamino) -benzoxazol-6-yl} -acetylamino} -pyridin-3-yl) -butyric acid was produced. LC-MS: R _T = 2.46 min; MS
(ES ⁺ ): 461 (MH ⁺ ) (i) (RS) methyl 3- [6- [2- (4-amino-3-hydroxyphenyl) -acetylamino]-
(RS) 3- (6- [6- [pyridin-3-yl} -butyrate (Reference Example 14) and 3-methoxyphenylisothiocyanate were used in the same manner as in Example 4 (a) except that 3-methoxyphenylisothiocyanate was used.
2- [2- (3-Methoxy-phenylamino) -benzoxazol-6-yl-acetylamino} -pyridin-3-yl) butyric acid was produced. LC-MS: R _T = 2.42 min; MS (ES ⁺ ):
461 (MH ⁺ )

Reference Example 1 (3RS) -3- [5- [2- (2-o-tolylaminobenzoxazol-6-yl) -acetylamino] -pyrid-2-yl} -butyric acid ethyl ester dimethylformamide 2-O-tolylamino-benzoxazole-6- in (15 mL)
A stirred solution of acetic acid (0.42 g, Reference Example 2) was mixed with O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (0.57 g),
Then diisopropylethylamine (0.4 g) and then dimethylformamide (
Treated with a solution of ethyl (3RS) -3- (5-aminopyrid-2-yl) butyrate (0.3 g, Reference Example 5) in 5 mL). The mixture was stirred at room temperature for 5 hours, then left overnight and then evaporated to low volume. The residue was partitioned between water and ethyl acetate. The organic phase was washed with dilute acetic acid, then with water, aqueous bicarbonate solution (5%), water, brine, dried and evaporated. The residue was subjected to flash chromatography on silica, eluting with ethyl acetate to give the title compound (0.5 g) as a colorless glass. TLC: R _F = 0.36 (eluted with ethyl acetate) MS: 473
(MH ⁺ )

Reference Example 2 2-o-tolylamino-benzoxazole 6-acetic acid Ethyl 4-amino-3-hydroxyphenylacetate (150 mL) in ethanol (150 mL)
A mixture of 3.3 g, Reference Example 3) and o-tolyl isothiocyanate (2.5 mL) was stirred at room temperature for about 2 hours. After standing at room temperature overnight, the mixture was evaporated and the residue was subjected to flash chromatography on silica, eluting with a mixture of pentane and ethyl acetate (7: 3, v / v) to give a yellow foam. A solution of this material in ethanol (150 mL) was treated with dicyclohexylcarbodiimide (3.0 g) and the mixture was heated at reflux for 2 hours. The mixture is evaporated and the residue is washed with 5-10
Dicyclohexyl urea was removed by short column chromatography on silica, eluting with a mixture of tert-butyl methyl ether at 10%. Dissolve the resulting bright yellow oil in ethanol (100 mL) and add the solution to a sodium hydroxide solution (15 mL).
, 1M) and then heated at reflux for 2 hours. The reaction mixture is evaporated,
And the residue was dissolved in water. The solution was washed with ethyl acetate and the aqueous layer was acidified to pH 1 by adding concentrated hydrochloric acid. The resulting white precipitate was collected by filtration, washed thoroughly with water, and then dried to give the title compound (1.8 g) as a white solid.

Reference Example 3 Ethyl 4-amino-3-hydroxyphenyl acetate A solution of ethyl 3-hydroxy-4-nitrophenyl acetate (5.0 g, Reference Example 4) dissolved in ethanol (about 200 mL) was treated with ammonium formate (about 20g). The mixture was warmed to 50 ° C. and then treated carefully with palladium on charcoal (炭 1 g, 5%). Foaming was observed. After 30 minutes, the mixture was filtered hot through a pad of celite and the filtrate was concentrated to give the title compound (3.3 g) as a black solid.

Reference Example 4 Ethyl 3-hydroxy-4-nitrophenylacetate A solution of 3-hydroxy-4-nitrophenylacetic acid (4.0 g) in ethanol (about 100 mL)
, Meyer et al., J. Med. Chem., 1997, 40, pp. 1049-1062) were treated with concentrated hydrochloric acid (5-8 drops) and refluxed for 3 hours. Heated and evaporated. The residue was dissolved in tert-butyl methyl ether and the solution was washed with saturated aqueous sodium bicarbonate, then with water, dried and evaporated to give the title compound (5.0 g) as a light yellow solid.

Reference Example 5 Ethyl (3RS) -3- (5-aminopyrid-2-yl) butyrate Ethyl (E, Z)-(5-nitropyrid-2-yl) but-2-enoate (11.0 g, reference A mixture of Example 6), ethanol (450 ml) and 5% palladium on charcoal (2.0 g) was stirred at ambient temperature under a hydrogen atmosphere for 7 hours and then allowed to stand overnight. The reaction mixture was filtered through a short pad of diatomaceous earth. The filtrate was evaporated to give the title compound (9.7g) as a colorless oil. TLC: R _F = 0.28 (elution with ethyl acetate)

Reference Example 6 Ethyl (E, Z)-(5-nitropyrid-2-yl) but-2-enoate Sodium hydride (4 mL) in anhydrous tetrahydrofuran (250 mL) under an inert atmosphere
(4 g, 60% dispersion in mineral oil) was treated dropwise with a solution of triethylphosphonoacetate (28.0 g) in anhydrous tetrahydrofuran (150 mL) and until hydrogen evolution ceased (~ 1 hour) The mixture was stirred. The mixture was then treated with 2-acetyl-5-nitropyridine (12.2 g, J. Chem. Soc.) In anhydrous tetrahydrofuran (150 mL).
(Prepared according to the method described in 1971, 772).
After 1 hour, the reaction mixture was treated with ethyl acetate and saturated ammonium chloride solution. The organic phase was dried over magnesium sulfate and evaporated. The residue was flash chromatographed on silica gel eluting with dichloromethane to give the title compound (16.7g) as a white solid. TLC: R _F = 0.66 for Z and E isomers
And 0.72 (eluting with ethyl acetate)

Reference Example 7 {1-[(2-Trimethylsilylethoxy) methyl] -2-tolylamino-5-benzimidazolyl} acetic acid Ethyl (2-o-tolylamino-3H-benzimidazole-5 in tetrahydrofuran (200 mL) A solution of -yl) acetate (5 g, Reference Example 8) was treated with sodium hydride (0.71 g, 60% dispersion in mineral oil) with stirring at room temperature under nitrogen. When the addition was complete, the mixture was stirred for a further 30 minutes at room temperature and then treated with (2-trimethylsilylethoxy) methyl chloride (2.95 g). Another hour,
After stirring at room temperature, the mixture was evaporated to a low volume and the residue was taken up in ethyl acetate (
(500 mL) and water (500 mL). The organic phase was separated, dried and evaporated. The residue was subjected to flash chromatography on silica, eluting with a mixture of pentane and ether (3: 2, v / v). The material from the chromatography (5.2 g) was dissolved in methanol (100 mL) and the solution was treated with aqueous sodium hydroxide (30 mL, 1 M). After standing at room temperature for 4 hours, the mixture was evaporated to a low volume and then diluted with water (50 mL). The mixture was acidified by the addition of acetic acid and decanted from the aqueous mother liquor to give a white gum. The gum was washed once by decantation with a small amount of water and then triturated with a minimum of ethanol to give the title compound (910 mg) as a white solid. Evaporation of the ethanol solution gave an additional amount of the title compound (3.0 g) as an orange foam.

Reference Example 8 Ethyl (2-o-tolylamino-3H-benzimidazol-5-yl) acetate Ethyl 3,4-diaminophenylacetate (5.8 g, Med) in ethanol (100 mL)
erski et al., Bioorg Med Chem Lett, 1998, 8, pp. 17-22) and o-tolyl isothiocyanate (4.9 g) were kept at room temperature overnight and then with diisopropylcarbodiimide (7.6 g). Processed. The mixture was stirred at reflux for 5 hours and evaporated. The residue was mixed with 10% methanol and ether (
Flash chromatography on silica eluting with 1: 9, v / v) gave the title compound (5.2 g) as a yellow gum.

Reference Example 9 2- (4-Methyl-2-o-tolylaminobenzoxazol-6-yl) acetic acid t-butyl 4-amino-3-hydroxy-5-methylphenyl acetate in ethanol (10 mL) (0.38 g, Reference Example 10) and o-tolyl isothiocyanate (0.24 g)
The mixture was stirred for 7 hours, then left overnight and evaporated. The residue was dissolved in ethanol (10 mL) and the solution was diluted with dicyclohexylcarbodiimide (0.36
g). The mixture was heated at reflux for 2 hours and then evaporated. The remaining gum was dissolved in dichloromethane (15 mL) and the solution was treated with trifluoroacetic acid (4.75 mL). After standing at room temperature for 3 hours, the mixture was evaporated and the residue was dissolved in diethyl ether. The solution was extracted twice with saturated sodium bicarbonate solution, and the pH of the combined aqueous extracts was adjusted to 1-2 by addition of dilute hydrochloric acid.
The solution was then extracted with ethyl acetate and the extract was washed with brine, dried and evaporated to give the title compound (0.33g) as a pale yellow solid.

Reference Example 10 t-butyl 4-amino-3-hydroxy-5-methylphenyl acetate t-butyl 3-hydroxy-5-methyl-4-nitrophenyl acetate (0.47 g, reference run in ethanol (25 mL)) Example 11) solution of palladium on charcoal (about 0.08 g, 10%
) And stirred under a hydrogen atmosphere. After 4 hours, the mixture was filtered through a pad of celite and the filtrate was evaporated to give the title compound (0.38 g) as a green oil.

Reference Example 11 t-butyl 3-hydroxy-5-methyl-4-nitrophenyl acetate t-butyl 3-acetoxy-5-methyl-4-nitrophenyl acetate (0.5 g, reference) in methanol (6 mL) The solution of Example 12) was mixed with lithium hydroxide (0.2 mL) in water (1.5 mL).
g). After stirring for 2 hours, the mixture was carefully acidified to pH 5 and then treated with ethyl acetate and sodium chloride. The organic layer was evaporated and the residue was dissolved in dichloromethane. The solution was dried and evaporated to give the title compound (0.45g) as a yellow-green oil.

Reference Example 12 t-butyl-3-acetoxy-5-methyl-4-nitrophenylacetate t-butyl-3-acetoxy-4-nitrophenylacetate in tetrahydrofuran (350 mL) at -15 ° C under argon (8.0 g, Reference Example 13) was treated dropwise with a solution of methylmagnesium chloride in diethyl ether (7 mL, 3 M),
Two hours later, a methylmagnesium chloride solution in diethyl ether (7 m
(L, 3M). After stirring for an additional hour, the reaction mixture was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (10.4 g), stirred at room temperature overnight, then partially evaporated and treated with dichloromethane. Processed.
The mixture was washed with water, dried and evaporated. The residue was flash chromatographed on silica eluting with dichloromethane to give the title compound (1.66g) as a yellow oil.

Reference Example 13 t-Butyl-3-acetoxy-4-nitrophenylacetate A stirred suspension of 3-acetoxy-4-nitrobenzoic acid (10.5 g) in dichloromethane (100 mL) was treated with oxalyl chloride (33 mL). ) Then treated with dimethylformamide (2 drops). After stirring at room temperature overnight, the mixture was evaporated. The residue was dissolved in acetonitrile (100 mL) and the solution was triturated with trimethylsilyldiazomethane (25 mL, 2M in hexane) and triethylamine (5.05 mL) in acetonitrile (50 mL) at 0 ° C. under nitrogen.
g) was added dropwise to the stirred mixture and stirring at 0 ° C. was continued overnight. The mixture was evaporated and partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was dried and then evaporated. The residue was dissolved in refluxing t-butanol and then treated dropwise with a solution of silver benzoate (2.8 g) in triethylamine (15 mL) over 30 minutes. After standing for 30 minutes, the cooled reaction mixture was evaporated and then partitioned between ethyl acetate and hydrochloric acid (1M). The organic phase was washed with saturated sodium bicarbonate solution, then dried and evaporated to give the title compound as a viscous brown oil (10.6 g
) Got.

Reference Example 14 (RS) Methyl 3- [6- [2- (4-amino-3-hydroxy-phenyl) -acetylamino] -pyridin-3-yl} -butyrate ammonium formate (1.7 g) and 10% palladium on charcoal in ethanol (15mL)
(RS) methyl-3- {6- [2- (3-hydroxy-4-nitrophenyl) -acetyl) amino] -pyridin-3-yl) -butanoate (180 mg, Reference Example 15) Was added. The mixture was stirred at 60 ° C. for 1 hour, cooled to room temperature, and then filtered through a pad of diatomaceous earth. The filter pad was washed with ethanol. The combined filtrate and washings were evaporated and the residue was dissolved in ethyl acetate. The solution was washed with water, dried over magnesium sulfate and then evaporated to give the title compound (134mg) as a light brown oil, which was used without further purification.

Reference Example 15 (RS) Methyl 3- [6- [2- (3-hydroxy-4-nitrophenyl) -acetylamino] -pyridin-3-yl} -butanoate (RS) in dichloromethane (50 mL) ) Methyl 3- [6- [2- (3-acetoxy-4-nitrophenyl) -acetylamino] -pyridin-3-yl} -butanoate (1.5 g, Reference Example 1)
The solution of 6) was treated with piperidine (5.0 mL). After stirring at room temperature for 1.5 hours, the reaction mixture was washed with aqueous acetic acid (1M), dried over magnesium sulfate and evaporated. The light brown oil that remained was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1: 1 v / v) to give the title compound (1.26 g) as a pale yellow solid.

Reference Example 16 (RS) Methyl 3- [6- [2- (3-acetoxy-4-nitrophenyl) -acetylamino] -pyridin-3-yl} -butanoate (RS) in dichloromethane (20 mL) ) A solution of methyl 3- (6-aminopyrid-3-yl) -butanoate (3.26 g, Reference Example 19) was added at 10 ° C. to (3-acetoxy-4-nitrophenyl) -acetyl chloride in dichloromethane (30 mL). (4.32g, Reference Example 1
Using the solution of 7), the mixture was dropped over 5 minutes. The mixture was stirred for a further 5 minutes at 10 ° C. and then treated dropwise with triethylamine (2.47 mL) over 5 minutes. The resulting black solution was stirred at room temperature for 1 hour, then allowed to stand overnight, then flash chromatographed on silica eluting with a mixture of ethyl acetate and pentane (3: 2 v / v) to give a viscous gum. The title compound (5.9 g) was obtained.

Reference Example 17 (3-acetoxy-4-nitrophenyl) acetyl chloride (3-acetoxy-4-nitrophenyl) acetic acid (2.0 g) in dichloromethane (20 mL)
The solution of Reference Example 18) was treated with a solution of oxalyl chloride in dichloromethane (4.4 ml, 2M), followed by dry dimethylformamide (1 drop). After vigorous bubbling, the mixture was stirred at room temperature for 4 hours, then evaporated to give the title compound as a viscous oil, which was used immediately without further purification.

Reference Example 18 (3-Acetoxy-4-nitro-phenyl) acetic acid (3-hydroxy-4-nitro-phenyl) acetic acid (12.0 g), aqueous sodium hydroxide solution (152.3 mL, 1M) and diethyl ether ( The stirred mixture, cooled to 0 ° C. in a 150 mL ice salt water bath, was treated dropwise with acetic anhydride (8.1 g) at a rate to maintain the temperature at 0 ° C. After the addition was complete, the mixture was stirred at 0 ° C. for a further 2 hours and acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The extract was dried over magnesium sulfate and then evaporated to give the title compound (12.6g) as an oil.

Reference Example 19 (RS) Methyl 3- (6-aminopyrid-3-yl) -butanoate (RS) 3- (6-aminopyrid-3-yl) -butane hydrochloride in methanol (300 mL) 12.0 g, a solution of Reference Example 20) was treated with concentrated sulfuric acid (3.0 mL), and then for 8 hours.
Heated at reflux temperature. The reaction mixture was concentrated, then basified with 5% aqueous sodium bicarbonate and then extracted with ethyl acetate. The extract was washed with water, then with brine, dried over magnesium sulfate and evaporated to give the title compound as a yellow oil (7.6g).

Reference Example 20 (RS) 3- (6-Aminopyrid-3-yl) -butanic acid hydrochloride (RS) ethyl 3- (6-acetylamino-pyrido-3 in aqueous hydrochloric acid (500 ml, 6M) -Yl) -butanoate (25.56 g, Reference Example 21) was heated to 100 ° C. for 3.5 hours,
It was then cooled and evaporated to give the title compound as a crystalline solid.

Reference Example 21 (RS) Ethyl 3- (6-acetylamino-pyrid-3-yl) -butanoate (E / Z) ethyl 3- (6-acetylamino-pyrido-3) in ethanol (500 mL) -Yl) -but-2-enoate (27.3 g, Reference Example 22) was catalyzed by 10
Hydrogenation at 50 ° C. with 3% palladium (1.0 g) (3 bar hydrogen pressure). After 48 hours, the mixture was degassed, filtered through a pad of diatomaceous earth, and the pad was rinsed well with ethanol. The filtrate was evaporated to give the title compound as an oil.

Reference Example 22 N- (5-bromopyrid-2-yl) in (E / Z) ethyl 3- (6-acetylamino-pyrid-3-yl) -but-2-enoate dimethylformamide (250 mL) ) A mixture of acetamide (31.4 g, Reference Example 23), ethyl crotonate (37.0 mL), triethylamine (33 mL), tetrakis (tri-otolylphosphine) palladium (o) and tetrabutylammonium bromide (9.36 g) was treated with argon. Atmosphere, 100 ℃
For 48 hours. The reaction mixture was cooled then evaporated. The residue was partitioned between ethyl acetate and water, and the organic phase was washed with brine, then dried over magnesium sulfate and evaporated. The resulting light brown solid was subjected to flash chromatography on silica, eluting with a mixture of pentane and ethyl acetate (7: 3 v / v) to give the title compound (27.3 g) as a pale yellow solid.

Reference Example 23 N- (5-Bromopyrid-2-yl) acetamide Acetic anhydride (27.4 mL) was added to 2-amino-5-bromopyridine (10.0 g) in acetic acid (40 mL).
) Was added to the stirred suspension. The mixture was heated at reflux for 4 hours, cooled to room temperature, and then poured into water (200 mL). The resulting solid was collected, washed three times with water (300 mL), and then dried under vacuum at 70 ° C. to give the title compound (10.9 g) as a white solid.

Reference Example 24 (RS) Methyl 3- [5- (2- (4-amino-3-hydroxyphenyl) -acetylamino] pyridin-2-yl} -butanoate (RS) in ethanol (80 mL) A solution of methyl 3- [5- [2- (3-hydroxy-4-nitrophenyl) -acetylamino] -pyridin-2-yl} butanoate (2.0 g, Reference Example 25) was treated at 60 ° C. with ammonium formate. (4.0 g) and 10% palladium on charcoal (0.
After treatment with 5 g) and stirring at 60 ° C. for 1 hour, the reaction mixture was cooled and then filtered. The filtrate was evaporated and the residue was dissolved in ethyl acetate. The solution was washed twice with water, then dried over magnesium sulfate and evaporated to give the title compound as an oil (1.37g).

Reference Example 25 (RS) Methyl 3- [5- [2- (3-hydroxy-4-nitrophenyl) -acetylamino] -pyridin-2-yl} -butanoate (RS) in methanol (80 mL) ) 3- [5- [2- (3-Hydroxy-4-nitrophenyl) -acetylamino] -pyridin-2-yl} -butanoic acid (2.1 g, Reference Example 26) was treated with concentrated sulfuric acid (0 g).
.5 mL). The mixture was heated at reflux for 24 hours, then cooled, then concentrated to low volume and diluted with ethyl acetate. The solution was washed with 5% aqueous sodium bicarbonate, then with water, dried over magnesium sulfate and evaporated to give the title compound as an oil (2.0 g).

Reference Example 26 (RS) 3- [5- [2- (3-hydroxy-4-nitrophenyl) -acetylamino] -pyridine-2
-Ill-butanoic acid (RS) ethyl 3- [5- [2- (3-acetoxy-4-nitrophenyl) -acetylaminopyridin-2-yl} butanoate in methanol (100 mL) (6.18 g, reference run) Example 27)
Was treated with a solution of sodium hydroxide (3.5 g) in water (20 mL). The mixture was heated at 50 ° C. for 5 hours and then evaporated. The residue was dissolved in water, the resulting solution was washed with ethyl acetate, then acidified to pH 5 by adding glacial acetic acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated.
The remaining black oil was subjected to flash chromatography on silica, eluting with ethyl acetate to give the title compound (2.1 g) as a brown solid.

Reference Example 27 (RS) Ethyl 3- [5- [2- (3-acetoxy-4-nitrophenyl) -acetylamino] -pyridin-2-yl) -butanoate in dry dimethylformamide (20 mL) A solution of O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (10.95 g) was treated with (RS) in dimethylformamide (90 mL) under a nitrogen atmosphere. ) Ethyl 3- (5-aminopyrid-2-yl) butanoate (3.0 g, Reference Example 5), diisopropylethylamine (10 mL) and (3-acetoxy-4-nitro-phenyl) acetic acid (6.89 g, Reference Example 17) ). After stirring at 30 ° C. for 24 hours, the reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate.
The organic phase was washed with water, then brine, dried over magnesium sulfate, treated with decolorizing charcoal, followed by filtration and evaporation of the filtrate to give the title compound as a black oil.

In vitro and in vivo assays 1. Inhibitory effects of compounds on VLA4-dependent cell adhesion to fibronectin and VCAM 1.1 Labeling of RAMOS cell metabolism RAMOS cells (pre-B cell line from ECACC, Porton Down, UK) Was cultured in RPMI medium (Gibco, UK) supplemented with 5% fetal calf serum (FCS, Gibco, UK). Prior to the assay, cells were suspended at a concentration of 0.5 × 10 6 cells / ml RPMI and 400 μCi / 100 m
Labeled with 1 [3H] -methionine (Amersham, UK) at 37 ° C. for 18 hours.

1.2 Preparation of 96-Well Plate for Adhesion Assay Cytostar plates (Amersham, UK) were loaded with 3 μg / ml human soluble VCAM-1 (R & D Syst
ems Ltd, UK) or 28.8 μg / ml human tissue fibronectin (Sigma, UK). 50 μl of phosphate buffered saline was added to the control non-specific binding wells. The plate was then dried in an incubator at 25 ° C. overnight. The next day, Puck supplemented with 1% BSA (Sigma, UK)
Plates were blocked with 200 ul / well s buffer (Gibco, UK). The plate was left in the dark at room temperature for 2 hours. Then, process the blocking buffer,
The plate was dried by inverting the plate and gently tapping it on the paper tissue. 3.6% dimethyl sulfoxide in Packs buffer supplemented with 5 mM manganese chloride and 0.2% BSA (Sigma, UK) (to activate integrin receptors, Sigma,
UK) 50 μl / well was added to the appropriate control and non-specific binding assay wells in the plate. 50 μl / well of test compound diluted at appropriate concentration in 3.6% dimethyl sulfoxide in Pucks buffer supplemented with 5 mM manganese chloride and 0.2% BSA was added to the test wells.

The metabolically labeled cells were suspended at 4 × 10 6 cells / ml in Packs buffer supplemented with manganese chloride and BSA as described above. 50 ul / well of cells in 3.6% dimethyl sulfoxide in Pucks buffer and supplement was added to all plate wells. A similar procedure was performed on plates coated with either VCAM-1 or fibronectin, and data was measured for inhibition of the compound on cell binding to both substrates.

1.3 Perform Assay and Data Analysis Plates containing cells in control wells or compound test wells were incubated for 1 hour at room temperature in the dark. Plates were then counted on a Wallac Microbeta scintillation counter (Wallac, UK) and the resulting data was processed with Microsoft Excel (Microsoft, US). Data were expressed as IC ₅₀ (ie, the concentration of inhibitor at which 50% of control binding occurred). The percentage of binding is determined from the following formula: [[(CTB-CNS)-(CI-CNS)] / (CTB-CNS)] x 100 =% binding where CTB is expressed without fibronectin (or The total number bound to the wells coated with VCAM-1), the CNS is the total number present in the wells without substrate, and the CI is the total number present in the wells containing the cell adhesion inhibitor.

The data for compounds of the present invention were expressed as IC ₅₀ for inhibition of cell adhesion to both fibronectin and VCAM-1. Certain compounds of the invention inhibit cell adhesion to fibronectin and VCAM-1 with IC ₅₀ in the range of 100 micromolar to 10 nanomolar. Preferred compounds of the invention have an IC _{50 in} the range of 100 nanomolar to 10 nanomolar.
Inhibits cell adhesion to fibronectin.

[0276] 2. Inhibition of antigen-induced airway inflammation in mice and rats 2.1 Animal sensitization Rats (Brown Norway, Harland Olac, UK) were challenged with ovalbumin (100 μg, intraperitoneal [ip], Sigma, UK) on days 0, 12 and 21. Sensitize with saline (1 ml,
Aluminum hydroxide adjuvant in ip) (100 mg, ip, Sigma. UK) was administered. In addition, mice (C57) were sensitized on days 0 and 12 with ovalbumin (10 ug, ip) and treated with aluminum hydroxide adjuvant (2 ml) in saline (0.2 ml, ip).
0 mg, ip).

2.2 Antigen challenge Rats were challenged any day between days 28-38, whereas mice were challenged daily.
Challenged any day between 20-30. The animal is an ultrasonic nebulizer (deVilbi
ss Ultraneb, US) produced ovalbumin (10 g / l) aerosol
Challenges were made by exposing for minutes (rats) or 1 hour (mouse) and passing through an exposure chamber.

2.3 Treatment Protocol Animals were treated as needed before or after antigen challenge. The water-soluble compounds of the present invention can be prepared in water (for oral (po) administration) or saline (for endotracheal (it) administration). Insoluble compounds include water (for po administration) or saline (i.
t. Dosing) 0.5% methylcellulose / 0.2% polysorbate 80 (both Me
rck UK Ltd., UK) and prepared as a suspension by grinding and sonicating the solid. The dose volume is 1 ml / kg (po) or 0.5 mg / k for rats
g (it); 10 ml / kg (po) or 1 ml / kg (it) for mice.

2.4 Assessment of Airway Inflammation Cell accumulation in the lung was assessed 24 hours post-challenge (rat) or 48-72 hours post-challenge (mouse). Sodium pentobarbitone (200mg / kg, ip, Pasteur M
The animals were euthanized using erleux, France) and the trachea was immediately cannulated. Cells were harvested from airway lumen by bronchoalveolar lavage (BAL) and from lung tissue by enzyme (collagenase, Sigma, UK) degradation as follows. BAL
Was prepared from an RPMI 1640 culture medium (Gibco,
Airways were flushed using two aliquots (10 ml / kg each) of UK). The collected BAL aliquots were pooled and counted for cells as described below. Immediately after BAL, pulmonary vessels were flushed using RPMI 1640 / FCS to remove the blood pool of cells. The lung lobe was removed and cut into 0.5 mm pieces. A sample of homogeneous lung tissue (rat: 400 mg; mouse: 150 mg) was incubated with collagenase in RPMI 1640 / FCS (2 hours at 20 U / ml and 1 hour at 60 U / ml, 37 ° C.) Was disassembled. The collected cells were washed in RPMI 1640 / FCS. Counting of total leukocytes recovered from airway lumen and lung tissue was performed on an automated cell counter (Cobas Argos, US). Differential counting of eosinophils, neutrophils and mononuclear cells was performed using Wright-Giemza stain (Si
gma. UK) were performed by light microscopy on cytocentrifuged specimens stained. T cells were CD2 (all-T cell labeling used to quantify total T cells)
Offer (fluophore) for CD4, CD4, CD8 and CD25 (labeling of activated T cells)
) -Labeled antibody for flow cytometry (EPICS XL, Coulter Electronics, US
). All antibodies were supplied by Serotec Ltd., UK.

2.5 Data Analysis Cellular data was expressed as the mean number of cells in the unchallenged, challenged and vehicle-treated, and challenged and compound-treated groups, including the standard error of the mean. Statistical analysis of differences among treatment groups was evaluated using a one-way analysis of variance with the Mann-Whitney test. When p <0.05, there was no statistical difference.

[Procedural Amendment] Submission of translation of Article 34 Amendment

[Submission date] April 9, 2001 (2001.4.9)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Contents of correction]

[Claims]

Embedded image (Here ring

Embedded image Is a 5- or 6-membered heterocycle, and

Embedded image Is a 5- or 6-membered fully unsaturated heterocyclic or benzene ring, each ring is optionally substituted, and the two rings are linked together by a carbon-carbon or carbon-nitrogen bond The compound according to claim 1 or 2, which represents

Embedded image (Here ring

Embedded image Is a 5-membered fully unsaturated heterocyclic ring,

Embedded image Is an optionally substituted benzene, and the two rings are joined together by a carbon atom bond).

Embedded image Is C _1-4 alkyl, C _1-4 alkoxy, amino, halogen, hydroxy, C _1-4
Alkylthio, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, nitro or compounds optionally according to any one of claims 1 to 5 is a benzene ring substituted by one of the trifluoromethyl .

Embedded image Wherein R ¹⁵ is hydrogen or C _1-4 alkyl and R ¹⁴ represents C _1-4 alkyl, or R ¹⁵ is hydrogen and R ¹⁴ is aryl, heteroaryl, —Z ^{2
R 8, -N (R 7)} -C (= O) -R 8, -N (R 7) -C (= O) -OR 8, -N (R 7) -S
_{^{O 2 -R 8, -NY 3 Y}} 4, - [C (= O) -N (R 9) -C (R 4) (R 10)] p -C (= O) -
NY ³ Y ⁴ or hydroxy, —OR ³ , —C (＝ O) —OR ³ or —N
Represents an alkyl substituted with Y ³ Y ⁴ ].

Embedded image[Where R¹⁴Is C_1-4Alkyl, -Z^TwoR⁸, -N (R⁷) -C (= O) -R⁸, -N (R ⁷ ) -C (= O) -OR⁸, -N (R⁷) -SO_Two-R⁸, -NY^ThreeY^FourOr
Droxy, -OR^Three, -C (= O) -OR^ThreeOr -NY^ThreeY^FourAlkyl substituted with
The compound according to claim 15, wherein

Embedded image [Wherein R ¹ , Ar ¹ , R ⁴ , R ⁵ , L ² , Y and Z ¹ have the definition according to any of claims 1 to 17, and R ¹⁶ is hydrogen, acyl, acylamino, alkoxy , Alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy , cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino amino, 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 ¹ —, alkyl C (＝ O) —
Y ¹ —, alkyl SO ₂ —Y ¹ N—, or aryl, heteroaryl,
Hydroxy or alkyl optionally substituted with Y ¹ Y ² N—, and X
Is O or NR ^17, wherein R ¹⁷ is H or lower alkyl. Salts and solvates (eg hydrates)
.

Embedded imageIs at the 6-position of the ring when X is O or NH, or X is NR¹⁷And R ¹⁷ 20. The method according to claim 18, wherein when is a lower alkyl, it is bonded to the 5- or 6-position of the ring.
Or a compound according to 19.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 29/00 A61P 29/00 35/00 35/00 37/06 37/06 C07D 413/12 C07D 413 / 12 (81) Designated countries 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, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, C A, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, 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, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Paul Robert East Wood R.M.E.S.E. 10.7 XS. Dagenham. Raynham Road South. Aventis Pharma Limited (72) Inventor Neil Victor Harris Earl M.E.S. Dagenham. Raynham Road South. Aventis Pharma Limited (72) Inventor Clive McCarthy RMS 107 Essex, United Kingdom. Dagenham. Raynham Road South. Aventis Pharma Limited (72) Inventor Andrew David Morley Earl Ms 107 Essex, England Dagenham. Raynham Road South. Aventis Pharma Limited (72) Inventor Stephen Dennis Pickett Earl Ms 107 Essex, Essex, England Dagenham. Raynham Road South. Aventis Pharma Limited F-term (reference) 4C063 AA01 BB09 CC26 CC52 DD12 EE01 4C086 AA01 AA02 AA03 BC17 BC39 BC70 GA07 GA08 GA09 NA14 NA15 ZA45 ZA59 ZA89 ZA96 ZB11 ZB13 ZB15 ZB26

Claims (31)

[Claims] 1. Formula (I): R¹Z¹─Het─L¹─Ar¹─L^Two─Y (I) wherein Het contains at least one heteroatom selected from O, S or N
And optionally substituted with one or more aryl group substituents,
Represents an 8-10 membered bicyclic ring system which is fully saturated or completely unsaturated;¹Is aryl, heteroaryl, optionally substituted alkyl, alk
Nil or alkynyl (where each is R^Two, -Z^TwoR^Three, -Z^ThreeH, -C (=
O) -R^Three, -NR^FourC (= Z^Three) -R^Three, -NR^Four-C (= O) -OR^Three, -NR^Four-SO _Two -R^Three, -SO_Two-NY¹Y^Two, -NY¹Y^TwoOr -C (= Z^Three) -NY¹Y^TwoIn case
Substituted), or optionally substituted cycloalkyl or hetero
Cycloalkyl (where each is R^Three, -Z^TwoR^Three, -Z^ThreeH, -C (= O) -R^Three
, -NR^Four−C (= Z^Three) -R^Three, -NR^Four-C (= O) -OR^Three, -NR^Four-SO_Two-R^Three , -SO_Two-NY^lY^Two, -NY¹Y^TwoOr -C (= Z^Three) -NY¹Y^TwoIn some cases
R)^TwoIs aryl, cycloalkyl, cycloalkenyl, heteroaryl or
Represents heterocycloalkyl; R^ThreeIs alkyl, alkenyl, alkynyl, aryl, arylalkyl,
Arylalkenyl, arylalkynyl, cycloalkyl, cycloalkyl
Alkyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, hete
Loarylalkyl, heteroarylalkenyl, heteroarylalkynyl,
R represents heterocycloalkyl or heterocycloalkylalkyl;^FourRepresents hydrogen or lower alkyl; R^FiveIs a direct bond or an alkylene chain, alkenylene chain or
A quinylene chain; R⁶Is a direct bond, cycloalkylene, heterocycloalkylene, arylene
, Heteroaryldiyl, -C (= Z^Three) -NR^Four-, -NR^Four−C (= Z^Three)-, -Z ^Three -, -C (= O)-, -C (= NOR^Four)-, -NR^Four-, -NR^Four−C (= Z^Three) -N
R^Four-, -SO_Two-NR^Four-, -NR^Four-SO_Two-, -OC (= O)-, -C (= O)
-O-, -NR^Four-C (= O) -O- or -OC (= O) -NR^Four-Is R⁷Is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl,
Chloroalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl
R is a heteroalkyl or a heterocycloalkylalkyl;⁸Is alkyl, aryl, cycloalkyl, heteroaryl or
Rocycloalkyl or aryl, acidic functional groups (or corresponding
Protected derivatives), cycloalkyl, heteroaryl, heterocycloalkyl,
-Z^ThreeH, -Z^TwoR^Three, -C (= O) -NY^ThreeY^FourOr -NY^ThreeY^FourReplaced with
Kill; R⁹Is hydrogen, R^ThreeOr alkoxy, cycloalkyl, hydroxy
, Mercapto, alkylthio or -NY^ThreeY^FourR is an alkyl substituted with^TenAnd R¹¹Are each independently hydrogen, an amino acid side chain and the corresponding
A group consisting of a protected derivative, an acidic functional group or a corresponding protected derivative, R ^Three , -Z^TwoR^Three, -C (= O) -R^ThreeOr -C (= O) -NY^ThreeY^FourOr acidic sensuality
Group or a corresponding protected derivative, or R^Three, -Z^TwoR^Three, -NY^ThreeY ^Four , -NH-C (= O) -R^Three, -C (= O) -R^Five-NH_Two, -C (= O) -Ar^Two-N
H_Two, -C (= O) -R^Five-CO_TwoH or -C (= O) -NY^ThreeY^FourReplaced by
Or R is selected from⁹And R^TenIs, together with the atom to which they are attached, a 3- to 6-member
Forming a heterocycloalkyl ring of¹¹Is R^ThreeC optionally substituted with_1-6R is alkylene;¹²Is alkyl, aryl, arylalkyl, cycloalkyl, cycloa
Alkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl
R is a cycloalkyl or a heterocycloalkylalkyl;^l3Is hydrogen, or aryl, an acidic functional group or a corresponding protected group.
Derivatives, cycloalkyl, heteroaryl, heterocycloalkyl, -Z^Three
H, -Z^TwoR^Three, -C (= O) -NY^ThreeY^FourOr -NY^ThreeY^FourOptionally replaced by
Aryl; Ar¹Is heteroaryldiyl; Ar^TwoIs arylene or heteroaryldiyl; L¹Is -R^Five-R⁶-Represents a bond; L^TwoAre (i) a direct bond; (ii) alkylene, alkenylene, alkynylene, cycloalkenylene, cycloalkyl
Loalkylene, heteroaryldiyl, heterocycloalkylene or aryle
[Each optionally, (a) an acidic functional group (or the corresponding protected
Derivatives), R^Three, -Z^ThreeH, -Z^TwoR⁸, -C (= O) -R^Three, -N (R⁷) -C (= O)-
R⁸, -N (R⁷) -C (= O) -OR⁸, -NC (R⁷) -C (= O) -NR^FourR⁸, -N (
R⁷) -SO_Two-R⁸, -NY^ThreeY^FourOr-[C (= O) -N (R⁹) -C (R^Four) (R^Ten)]_p
-C (= O) -NY^ThreeY^FourOr (b) an acidic functional group (or corresponding protected
Derivative) or -Z^ThreeH, -Z^TwoR^Three, -C (= O) -NY^ThreeY^FourOr -NY^ThreeY^Four
Iii)-[C (= O) -N (R⁹) -C (R^Four) (R^l0)]_p-Bond; (iv) -Z^Four-R¹¹-Bond; (v) -C (= O) -CH_Two-C (= O) -bond; (vi) -R¹¹-Z^Four-R¹¹-Bond; or (vii)-L^Three-L^Four-L^FiveL represents a bond; L^ThreeRepresents a direct bond, and L^FiveRepresents an alkylene chain; or L^ThreeRepresents an alkylene chain, and L^FiveRepresents a direct bond or an alkylene chain;^FourRepresents a cycloalkylene or heterocycloalkylene bond; Y represents a carboxy or acid bioisostere; Y¹And Y^TwoIs independently hydrogen, alkenyl, alkyl, aryl, aryl
Alkyl, cycloalkyl, heteroaryl or heteroarylalkyl
Or group -NY¹Y^TwoMay form a cyclic amine; Y^ThreeAnd Y^FourIs independently hydrogen, alkenyl, alkyl, alkynyl, aryl
, Cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl
Or an alkoxy, aryl, cyano, cycloalkyl, heteroaryl
Reel, heterocycloalkyl, hydroxy, oxo, -NY¹Y^TwoOr one or more
-CO on_TwoR⁷Or -C (= O) -NY¹Y^TwoOr an alkyl substituted with a group; or a group —NY^ThreeY^FourIs a 5- to 7-membered cyclic amine, which comprises (i)
Coxy, carboxamide, carboxy, hydroxy, oxo (or 5-
, A 6- or 7-membered cyclic acetal derivative), R⁸One or
May be optionally substituted with further substituents; (ii) also O, S, S
O_TwoOr NY^FiveAnd may contain one further heteroatom selected from:
And (iii) yet another aryl, heteroaryl, heterocycloalkyl or
Or may be fused to a cycloalkyl ring to form a bicyclic or tricyclic ring system.
; Y^FiveIs hydrogen, alkyl, aryl, arylalkyl, -C (= O) -R¹²,
-C (= O) -OR¹²Or -SO_TwoR¹²And Z¹Is a direct bond, an alkylene chain or NR^Four, O or S (O)_nZ;^TwoIs O or S (O)_nAnd Z^ThreeIs O or S; Z^FourIs O, S (O)_n, NR¹³, SO_TwoNR¹³, NR¹³C (= O), C (= O) NR^{1 Three} Or C (= O); and n is 0 or an integer of 1 or 2; and p is 0 or an integer of 1 to 4]. N-oxides and their prodrugs, and
Pharmaceutically acceptable salts and the like of the compounds, their N-oxides and prodrugs
And solvates wherein the oxygen, nitrogen or sulfur atom is alkenyl or alkynyl
Excluding those compounds directly bonded to the carbon-carbon multiple bond of the residue.] 2. L ² is: (i) a direct bond; (ii) an alkylene, alkenylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene or arylene bond [each optionally (a) functional group (or corresponding protected ^{derivative), R 3, -Z 3 H} , -Z 2 R 8, -C (= O) -R 3, -N (R 7) -C (= O) -
^{R 8, -N (R 7)} -C (= O) -OR 8, -N (R 7) -C (= O) -NR 4 R 8, -N (R 7) -SO 2 -R 8, -NY ³ Y ⁴ or - [C (= O) -N (R 9) -C (R 4) (R 10)] p -C
(= O) -NY ³ in Y ^4, or (b) an acidic functional group (or corresponding protected derivative) or ^{-Z 3 H, -Z 2 R 3} , -C (= O) -NY 3 Y 4 Or (iii)-[C (= O) -N (R ⁹ ) -C (R ⁴ ) (R ¹⁰ )] _p ^-bond ; (iii) substituted with alkyl substituted by -NY ³ Y ⁴ ]; iv) -Z ⁴ -R ¹¹ - binding; (v) -C (= O ) -CH 2 -C (= O) - bond; or ^{(vi) -R 11 -Z 4 -R} 11 - linkage; represents a A compound according to claim 1. 3. Het is: (Where the ring is Is a 5- or 6-membered heterocyclic ring, and the ring Is a 5- or 6-membered fully unsaturated heterocyclic or benzene ring, each ring is optionally substituted, and the two rings are linked together by a carbon-carbon or carbon-nitrogen bond The compound according to claim 1 or 2, which represents 4. Het is an optionally substituted 9-membered bicyclic system. (Where the ring is Is a 5-membered fully unsaturated heterocycle, wherein the ring is Is an optionally substituted benzene, and the two rings are joined together by a carbon atom bond). 5. A compound according to claim 1 or 2, wherein Het represents optionally substituted benzoxazolyl or optionally substituted benzimidazolyl, wherein the benzene ring contains any substituents. 6. Ring 6 Is C _1-4 alkyl, C _1-4 alkoxy, amino, halogen, hydroxy, C _1-4
Alkylthio, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, nitro or compounds optionally according to any one of claims 1 to 5 is a benzene ring substituted by one of the trifluoromethyl . 7. A method according to claim 1, wherein R ¹ represents optionally substituted phenyl.
The compound according to any one of the above. 8. The compound according to claim 1, wherein Z ¹ represents NH. 9. L ¹ is a —R ⁵ —R ⁶ — bond, wherein R ⁵ is a straight or branched C _1-4 alkylene chain, and R ⁶ is —C (ＯO) -NR ⁴ - represents, wherein R ⁴ is a compound according to any one of claims 1 to 8 represent hydrogen or C _1-4 alkyl). 10. The method of claim 1, wherein Ar ¹ represents azaheteroaryldiyl.
The compound according to any one of the above. 11. The compound according to claim 10, wherein Ar ¹ represents optionally substituted pyridine-2,5-diyl. 12. The compound according to claim 10, wherein Ar ¹ represents unsubstituted pyridine-2,5-diyl. 13. L^TwoBut C_1-4Alkyl, aryl, heteroaryl, -Z ^Two R⁸, -N (R⁷) -C (= O) -R⁸, -N (R⁷) -C (= O) -OR⁸, -N (R⁷) −
SO_Two-R⁸, -NY^ThreeY^Four,-[C (= O) -N (R⁹) -C (R^Four) (R^Ten)]_p-C (= O)
-NY^ThreeY^FourOr hydroxy, -OR^Three, -C (= O) -OR^ThreeOr -NY^Three
Y^FourC optionally substituted with alkyl substituted by_1-4Table showing alkylene bonds
A compound according to any one of claims 1 to 12. 14. L^TwoBut C_1-4Alkyl, aryl, heteroaryl, -Z ^Two R⁸, -N (R⁷) -C (= O) -R⁸, -N (R⁷) -C (= O) -OR⁸, -N (R⁷) −
SO_Two-R⁸, -NY^ThreeY^Four,-[C (= O) -N (R⁹) -C (R^Four) (R^Ten)]_p-C (= O)
-NY^ThreeY^FourOr hydroxy, -OR^Three, -C (= O) -OR^ThreeOr -NY^Three
Y^Four2. An ethylene optionally substituted with an alkyl substituted by
3. The compound according to 3. 15. L ² is a group represented by the formula: Wherein R ¹⁵ is hydrogen or C _1-4 alkyl and R ¹⁴ represents C _1-4 alkyl, or R ¹⁵ is hydrogen and R ¹⁴ is aryl, heteroaryl, —Z ^{2
R 8, -N (R 7)} -C (= O) -R 8, -N (R 7) -C (= O) -OR 8, -N (R 7) -S
_{^{O 2 -R 8, -NY 3 Y}} 4, - [C (= O) -N (R 9) -C (R 4) (R 10)] p -C (= O) -
NY ³ Y ⁴ or hydroxy, —OR ³ , —C (＝ O) —OR ³ or —N
Represents an alkyl substituted with Y ³ Y ⁴ ]. 16. L^TwoIs the group[Where R¹⁴Is C_1-4Alkyl, -Z^TwoR⁸, -N (R⁷) -C (= O) -R⁸, -N (R ⁷ ) -C (= O) -OR⁸, -N (R⁷) -SO_Two-R⁸, -NY^ThreeY^FourOr
Droxy, -OR^Three, -C (= O) -OR^ThreeOr -NY^ThreeY^FourAlkyl substituted with
The compound according to claim 15, wherein 17. The compound according to any one of claims 1 to 16, wherein Y is carboxy. 18. A compound of formula (Ia): [Wherein R ¹ , Ar ¹ , R ⁴ , R ⁵ , L ² , Y and Z ¹ have the definition according to any of claims 1 to 17, and R ¹⁶ is hydrogen, acyl, acylamino, alkoxy , Alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy , cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino amino, 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 ¹ —, alkyl C (＝ O) —
Y ¹ —, alkyl SO ₂ —Y ¹ N—, or aryl, heteroaryl,
Hydroxy or alkyl optionally substituted with Y ¹ Y ² N—, and X
Is O or NR ^17, wherein R ¹⁷ is H or lower alkyl. Salts and solvates (eg hydrates)
. 19. The compound according to claim 18, wherein R ¹⁶ represents hydrogen, C _1-4 alkyl or C _1-4 alkoxy. 20. The groupIs at the 6-position of the ring when X is O or NH, or X is NR¹⁷And R ¹⁷ 20. The method according to claim 18, wherein when is a lower alkyl, it is bonded to the 5- or 6-position of the ring.
Or a compound according to 19. 21. A pharmaceutical composition comprising the compound of claim 1, the corresponding N-oxide or prodrug, or a pharmaceutically acceptable salt or solvate of said compound, N-oxide or prodrug thereof. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient. 22. The compound according to claim 1, for use in therapy, the corresponding N-
An oxide or prodrug, or a pharmaceutically acceptable salt or solvate of the compound, its N-oxide or prodrug. 23. The method of claim 1 for use in treating a patient suffering from or susceptible to a condition that can be ameliorated by administration of an inhibitor of α4β1-mediated cell adhesion.
Or a corresponding N-oxide or prodrug, or a compound thereof,
A pharmaceutically acceptable salt or solvate of the N-oxide or prodrug. 24. Use according to claim 2 for the treatment of a patient suffering from or susceptible to a condition which can be ameliorated by administration of an inhibitor of α4β1-mediated cell adhesion.
The composition of claim 1. 25. A compound or composition according to claim 1 or 21 for use in the treatment of an inflammatory disease. 26. A compound or composition according to claim 1 or 21 for use in treating asthma. 27. The compound according to claim 1, or a corresponding N-oxide or a corresponding N-oxide or in the manufacture of a medicament for the treatment of a patient suffering from or susceptible to a condition which can be ameliorated by administration of an inhibitor of α4β1-mediated cell adhesion. Use of a prodrug, or a pharmaceutically acceptable salt or solvate of the compound, its N-oxide or prodrug. 28. The compound according to claim 1, in the manufacture of a medicament for treating asthma.
Use of the corresponding N-oxide or prodrug, or a pharmaceutically acceptable salt or solvate of the compound, its N-oxide or prodrug. 29. A method of treating a human or non-human animal patient suffering from or susceptible to a condition that can be ameliorated by administration of an inhibitor of α4β1-mediated cell adhesion. A method of treatment comprising administering to the patient an effective amount of an oxide or prodrug, or a pharmaceutically acceptable salt or solvate of the compound, N-oxide or prodrug thereof. 30. Intermediates represented by formulas (XXIII) and (XXVI). 31. A compound substantially as described in the examples.