WO2008125215A1 - Bicyclic and heterobicyclic derivatives, processes for preparing them and their uses - Google Patents

Abstract

The present invention concerns bicyclic and heterobicyclic derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals. Formula (I).

Description

BICYCLIC AND HETEROBICYCLIC DERIVATIVES, PROCESSES FOR PREPARING THEM AND THEIR USES

The present invention concerns bicyclic and heterocyclic derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals.

The integrin α4 is predominantly expressed on eosinophils, T and B lymphocytes, monocytes and basophils. It binds primarily to the vascular cell surface adhesion molecule VCAM-1 that is expressed on endothelium in response to inflammatory cytokines (TNF-α, IL-1 and selectively IL-4 and IL-13), extracellular matrix protein fibronectin and a cell surface adhesion molecule MAdCAM-1 that is expressed preferentially in the gastrointestinal track.

Because α.4 is not expressed on circulating neutrophils, which are the first defence against infection, it is a target for the pharmacological control of inflammatory diseases. Several in vitro and in vivo studies have indicated an important role of α4 in cell adhesion mediated inflammatory pathologies and that blocking its function is beneficial. Diseases include asthma, multiple sclerosis (MS), rheumatoid arthritis (RA) or inflammatory bowel diseases. α.4 is also expressed on leukemic cells that show increased survival through binding to fibronectin expressed on bone marrow stormal cells. Blocking this interaction in the presence of chemotherapy is beneficial in preventing relapse of acute myelogenous leukemia. α4 and VCAM-1 have also been identified in smooth muscle cells from intimal atherosclerotic thickening of adult aorta. Blocking this interaction is beneficial in preventing smooth muscle differentiation and atherosclerosis.

The interaction of α4 on inflammatory cells with fibronectin has also been shown to increase chronic allograft failure. Blocking this interaction is beneficial in supporting transplant survival. α4-has also been related to cancers (including cancers, whether solid or haematopoietic) but not limited to, lung e.g. non-small cell lung, pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer.

International patent application WO 03/093237 discloses 2,6-quinolinyl and 2,6- naphthyl derivatives as pharmaceuticals for the treatment of VLA-4 dependent inflammatory diseases. International patent application WO 2006/131200 discloses2,6-quinolinyl derivatives as pharmaceuticals for the treatment of VLA-4 dependent inflammatory diseases.

We have now found some bicyclic and heterobicyclic compounds that are potent inhibitors of α4 integrins and having a basic pKa.

In one aspect, the invention therefore provides a compound having formula I, its enantiomers, diastereoisomers or a pharmaceutically acceptable salt thereof,

formula I wherein:

X is CH or N; W is CH or N;

R ic, ohlnrin^ nr mpthnγ\/"

R-* is chlorine or methoxy; Y is CH or N;

R² Js RS Or G₁R⁴; n is 1 or 2; m is 1 , 2, 3 or 4;

() means CH2; R3 is hydrogen; or is C3.10 cycloalkyl optionally substituted by groups selected from halogen, Cf .ρ alkyl;

G₁ is -C(O)-, -S(O)₂- or -C(O)N(R⁵)-;

R⁴ is C-_|_5 alkyl optionally substituted by groups selected from halogen, C3.-10 cycloalkyl, amino, C-\.Q alkylamino groups, C-j.β dialkylamino groups, C5.-10 aryl, cyano, nitro; or is Cz_<\ 0 cycloalkyl optionally substituted by groups selected from halogen, C₁.5 alkyl; or is C5.-10 aryl optionally substituted by groups selected from halogen, C_{1 -6} alkylamino groups, C_{1 -6} dialkylamino groups, C_{1 -6} alkyloxy, C_{1 -6} alkylsulfides, C_{1 -6} alkylsulfones, C_{1 -6} alkylsulfoxides, C_3-10 cycloalkyl, C-|_6 alkyl, cyano, carboxylic acid, hydroxyl, C3.10 non aromatic heterocyle, amino,CONH(C_{1 -6} alkyl), CONH(C3_io cycloalkyl ), CON(C-I -6 alkylX C_{1 -6} alkyl), CON(C₁ _₆ alkyl )( C₃.-] ₀ cycloalkyl), CONH(C₆.₁₀ aryl ), CON(C-] _₆ alkyl) C₆-Io ^ary' )• ^CONH(^C6-10 heteroaryl ), CON(C_{1 -6} alkyl) (C₆.-] ₀ heteroaryl) , CONH (C3.-10 non aromatic heterocycle), CON(C-] _₆ alkyl) (C3.10 non aromatic heterocycle) , CONH2, CO(C-] _-6 alkyl), CO(C_3-10 cycloalkyl) , CO (C_3-10 non aromatic heterocycle ), CO (C₆.-] 0 aryl) , CO (C₆.-] ₀ heteroaryl) , NHSO2(C-|_₆ alkyl), NHSO2 (C3.10 cycloalkyl) , NHSO2 (C₆.-|o aryl), NHSO2 (C_6-10 heteroaryl), N(C_{1 -6} alkyl)S02 (C₁ _₆ alkyl), N(C₁.₆ alkyl)SO₂ (C₃_₁₀ cycloalkyl) , N(C₁.₆ alkyl)SO₂ (C_6-10 aryl) , N(C_{1 -6} alkyl)SO₂ (C₆.-, ₀ heteroaryl) , NHCO(C₁.₆ alkyl), NHCO (C₃.₁₀ cycloalkyl) , NHCO (C₆.-, ₀ aryl ), NHCO (C₆.-] 0 heteroaryl), NHCO (C3.-10 non aromatic heterocycle) , N(C_{1 -6} alkyl)CO(Ci_₆ alkyl), N(C<| _β alkyl)CO (C₃.^ cycloalkyl), N(C-|.₆ alkyl)CO (C_6-10 aryl) , N(C-].₆ alkyl)CO (C₆.-]o heteroaryl), N(C_{1 -6} alkyl)CO (C_3-10 non aromatic heterocycle) ; or is C₆.-] 0 heteroaryl optionally substituted by groups selected from C_{1 -6} alkyl, C2-₆ alkenyl, halogen, C_{1 -6} alkylamino, C₁ _₆ dialkylamino, C_{1 -6} alkyloxy, C₁ _₆ alkylsulfides, C₁-₍S alkylsulfones, C-|_₆ alkylsulfoxides, C₃.-] ₀ cycloalkyl, C₆_₁₀ arylsulfones, C_6-10 arylsulfoxides, C₆.-] ₀ arylsulfides, cyano, carboxylic acid, hydroxyl, C_3-10 non aromatic heterocyle, amino, CONH(C_{1 -6} alkyl), CONH(C3_-|o cycloalkyl ), C0N(C-|_₆ alkyl)( C_{1 -6} alkyl), CON(C_{1 -6} alkyl )( C_3-10 cycloalkyl), CONH(C_6-10 aryl ), CON(C_{1 -6} alkyl)(C_6-10 aryi ), CONH(C_6-10 heterυaryi ), CON(C_{1 -6} aikyi) (C_6-10 heteroaryl) , CONH (C_3-10 non aromatic heterocycle), CON(C_{1 -6} alkyl) (C₃.₁₀ non aromatic heterocycle) , CONH2, CO(C-].₆ alkyl), CO(C₃.-_{] 0} cycloalkyl) , CO (C₃.₁₀ non aromatic heterocycle ), CO (C_6-I ₀ aryl) , CO (C_6-I Q heteroaryl) , NHSO2(C_{1 -6} alkyl), NHSO2 (C_3-10 cycloalkyl) , NHSO2 (C_6-10 aryl), NHSO2 (C_6-10 heteroaryl), N(C_{1 -6} alkyl)SO2 (C_{1 -6} alkyl), N(C_{1 -6} alkyl)S02 (C_3-10 cycloalkyl) , N(C_{1 -6} alkyl)SO₂ (C₆.₁₀ aryl) , N(C_{1 -6} alkyl)SO₂ (C_6-10 heteroaryl) , NHCO(C_{1 -6} alkyl), NHCO (C_3-10 cycloalkyl) , NHCO (C_6-10 aryl ), NHCO (C_6-10 heteroaryl), NHCO (C_3-10 non aromatic heterocycle) , N(Ci_-6 alkyl)CO(C_{1 -6} alkyl), N(C_{1 - 6} alkyOCO (C_3-10 cycloalkyl), N(C_{1 -6} alkyl)CO (C_6-10 aryl) , N(C_{1 -6} alkyl)CO (C_6-10 heteroaryl), N(C_{1 -6} alkyl)CO (C_3-10 non aromatic heterocycle) ; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C_{1 -6} alkyl, halogen, C_{1 -6} alkylamino, C_{1 -6} dialkylamino, C_{3-1 0} cycloalkyl;

R5 is hydrogen; or is Ci_5 alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, C-|.β alkylamino groups, C<|_ Q dialkylamino groups, Cβ.-|o aryl. cyano, nitro.

In another aspect the invention therefore provides a compound having formula Ia and the configuration at the asymmetric carbon atom is in the "S" configuration, or a pharmaceutically acceptable salt thereof

formula Ia wherein X, W, R, R¹ , Y, n, m, and R^ are defined as above. The term "C-j.β alkyl", as used herein, represents saturated, monovalent hydrocarbon radicals having linear or branched moieties or combinations thereof and containing 1-6 carbon atoms. One methylene (-CH2-) group, of the alkyl moiety, can be reⁿ!aced b" ox^wnβn or sulfur. A!k^λ/! ⁿrQuⁿs can be oⁿtiona!!^w substituted b^w one or more substituents. Alkyl groups can be optionally substituted by groups selected from halogen, C3.-10 cycloalkyl, amino, C^.β alkylamino groups, C-|_6 dialkylamino groups, C6-10 ^ary'_> cyano, nitro. Usually alkyl group, in the present case, is methyl.

The term "C3-10 cycloalkyl", as used herein, refers to a monovalent or divalent group of 3 to 10 carbon atoms, derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be mono- or polycyclic. Cycloalkyl groups can be optionally substituted by one or more substituents. Cycloalkyl groups can be optionally substituted by groups selected from halogen or C-\ .Q alkyl groups as defined above.

The term "C2-6 alkenyl", as used herein, represents a 2-6 carbon atom chain as defined above having an unsaturated bond.

The term "cyano", as used herein, refers to a group of formula -CN. The term "nitro", as used herein, refers to a group of formula -NO2.

The term "halogen", as used herein, refers to an atom of chlorine, bromine, fluorine, iodine. Usually halogen is chlorine. The term "methoxy", as used herein, refers to a group of formula -OCH3.

The term "carboxylic acid", as used herein, refers to a group of formula - COOH. The term "amino", as used herein, refers to a group of formula - NH2.

The term "C_6-10 ^ary' " ^{as use}^ herein, refers to an organic moiety derived from an aromatic hydrocarbon consisting of a ring or multiple rings, containing 6 to 10 carbon atoms by removal of one hydrogen atom. Aryl groups can be optionally substituted by one or more substituents. Aryl groups can be optionally substituted by groups selected from halogen, C_{1 -6} alkylamino groups, C_{1 -6} dialkylamino groups, C-) .5 alkyloxy, C-_{) -6} alkylsulfides, C_{1 -6} alkylsulfones, C_{1 -6} alkylsulfoxides, C_3-10 cycloalkyl, C_{1 -6} alkyl, cyano, carboxylic acid, hydroxyl, C3.-10 non aromatic heterocyle, amino,

CONH(C₁.₆ alkyl), CONH(C₃.₁₀ cycloalkyl ), CON(C_{1 -6} alkyl)( C₁.₆ alkyl), CON(C_{1 -6} alkyl )( C_3-10 cycloalkyl), CONH(C₆.₁₀ aryl ), CON(C_{1 -6} alkyl)(C₆.₁₀ aryl) , CONH(C₆.! ₀ heteroaryl ), CON(C₁ _₆ alkyl) (C_6-1Q heteroaryl) ,

CONH (C3.-10 non aromatic heterocycle), CON(C_{1 -6} alkyl) (C3.-10 non aromatic heterocycle) , CONH2, CO(C_{1 -6} alkyl), CO(C3_-|o cycloalkyl) , CO (Cs_-1Q non aromatic heterocycle ), CO (C_6-10 aryl) , CO (C₆.-] ₀ heteroaryl) , NHSO2(C_{1 -6} alkyl), NHSO2 (C_3- -IO cycloalkyl) , NHSO2 (C_6-1O aryl), NHSO2 (C_6-1Q heteroaryl), N(C_{1 -6} alkyl)SO2 (C_{1 -6} alkyl), N(C_{1 -6} alkyl)SO₂ (C_3-10 cycloalkyl) , N(C_{1 -6} alkyl)SO₂ (C_6-10 aryl) , N(C_{1 -6} alkyl)SO₂ (C_6-10 heteroaryl) , NHCO(C_{1 -6} alkyl), NHCO (C_3-10 cycloalkyl) , NHCO (C_{6- 10} aryl ), NHCO (C_6-10 heteroaryl), NHCO (C_3-10 non aromatic heterocycle) , N(C_{1 -6} alkyl)CO(C-_{| -6} alkyl), N(C_{1 -6} alkyl)CO (C_3-10 cycloalkyl), N(C_{1 -6} alkyl)CO (C_6-10 aryl) , N(C_{1 -6} aikyi)CO (C_6-10 neteroaryi), N(C_{1 -6} aikyi)CO (C3_-10 non aromatic heterocycie) . The term "C_6-10 heteroaryl", as used herein refers to a 6 -10 member ring, containing at least one nitrogen atom interrupting the carbocyclic ring structure. Heteroaryl groups can be optionally substituted by one or more substituents. Heteroaryl groups can be optionally substituted by groups selected from C_{1 -6} alkyl, C2-₆ alkenyl, halogen, C_{1 -6} alkylamino, C_{1 -6} dialkylamino, C_{1 -6} alkyloxy, C_{1 -6} alkylsulfides, C_{1 -6} alkylsulfones, C_{1 -6} alkylsulfoxides, C3_-10 cycloalkyl, C_6-10 arylsulfones, C_6-10 arylsulfoxides, C_6-10 arylsulfides, cyano, carboxylic acid, hydroxyl, 03.-1₀ non aromatic heterocyle, amino, CONH(C_{1 -6} alkyl), CONH(C_3-10 cycloalkyl ), CON(C_{1 -6} alkyl)( C_{1 -6} alkyl),CON(C_{1 -6} alkyl )( C_3-10 cycloalkyl), CONH(C_6-10 aryl ), CON(Ci_-6 alkyl)(C_6-10 aryl ), CONH(C_6-10 heteroaryl ), CON(C_{1 -6} alkyl) (C_6-10 heteroaryl) , CONH (C_3-10 non aromatic heterocycle), CON(C_{1 -6} alkyl) (C_3-10 non aromatic heterocycle) , CONH2, CO(C_{1 -6} alkyl), CO(C₃.! Q cycloalkyl) , CO (C_3-10 non aromatic heterocycle ), CO (C_6-10 aryl) , CO (C_6-10 heteroaryl) , NHSO2(C_{1 -6} alkyl), NHSO2 (C₃.-_{) 0} cycloalkyl) , NHSO2 (C_6-10 aryl), NHSO₂ (C₆.-|o heteroaryl), N(C_{1 -6} alkyl)SO₂ (C_{1 -6} alkyl), N(C_{1 -6} alkyl)SO₂ (C_3-10 cycloalkyl) , N(C_{1 -6} alkyl)SO₂ (C_6-1Q aryl) , N(C_{1 -6} alkyl)SO₂ (C_6-1Q heteroaryl) , NHCO(C_{1 -6} alkyl), NHCO (C_{3-1 0} cycloalkyl) , NHCO (C_6-10 aryl ), NHCO (C_6-10 heteroaryl), NHCO (C_3-10 non aromatic heterocycle) , N(C_{1 -6} alkyl)CO(C_{1 -6} alkyl), N(C_{1 - 6} alkyl)CO (C_3-10 cycloalkyl),

N(C_{1 -6} alkyl)CO (C_6-10 aryl) , N(C_{1 -6} alkyl)CO (C_6-10 heteroaryl), N(C_{1 -6} alkyl)CO (C_3-10 non aromatic heterocycle) .

The term "3-10 ring member non-aromatic heterocycle", as used herein refers to a 3 to 10 ring member, containing one N or O heteroatom interrupting the carbocyclic ring structure. Heterocyclic groups can be optionally substituted by one or more substituents. Heterocyclic groups can be optionally substituted by groups selected from C_{1 -6} alkyl, halogen, C_{1 -6} alkylamino, C_{1 -6} dialkylamino, C_3-10 cycloalkyl.

The term " C_{1 -6} alkyloxy", as used herein refers, to a refers to a group of formula - 0R^a, wherein R^a is a C_{1 -6} alkyl group as defined above. The term " C_{1 -6} alkylsulfides", as used herein refers, to a refers to a group of formula -SRb, wherein FtP is a C_{1 -6} alkyl group as defined above.

The term " C_{1 -6} alkylsulfones", as used herein refers, to a refers to a group of formula -S(=O)₂R^C, wherein R^c is a C_{1 -6} alkyl group as defined above.

The term " C_{1 -6} alkylsulfoxides", as used herein refers, to a refers to a group of formula -S(=O)R^C', wherein R^ is a C_{1 -6} alkyl group as defined above.

The term " C_6-10 arylsulfones", as used herein refers, to a refers to a group of formula -S(=O)₂R^e, wherein R^e is a C_6-10 aryl group as defined above.

The term " C_6-10 arylsulfoxides", as used herein refers, to a refers to a group of formula -S(=O)Rf, wherein R^ is a C_6-10 aryl group as defined above. The term " C_6-10 arylsulfides", as used herein refers, to a group of formula -SR9, wherein R9 is a C_6-10 aryl group as defined above.

Usually X is CH or N. Preferred X is CH. Usually W is CH or N. Preferred W is N. Usually R is chlorine or methoxy. Preferred R is chlorine. Usually R1 is chlorine or methoxy. Preferred R-I is chlorine.

Usually Y is CH or N. Preferred Y is CH. Usually n is 1 or 2. Preferred n is 1. Usually m is 1 , 2 or 3. Preferred m is 3. Usually R² is R³ or G₁ R⁴. Preferred R² is R³. Usually R³ is hydrogen; or is C_3-10 cycloalkyl optionally substituted by groups selected from halogen, C_{1 -6} alkyl. Preferred R^ is C_3-10 cycloalkyl.

Usually G₁ is -C(O)-, -S(0)2- or C(O)N(RS)-.

Usually R⁴ is C_{1 -6} alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, C_{1 -6} alkylamino groups, C_{1 -6} dialkylamino groups, C_6-10 ^arY'. cyano, nitro; or is C3.-10 cycloalkyl optionally substituted by groups selected from halogen, C-|_6 alkyl; or is C_6-10 ^aryl optionally substituted by groups selected from halogen, C_{1 -6} alkylamino groups, C_{1 -6} dialkylamino groups, C-|_6 alkyloxy, C_{1 -6} alkylsulfides, C_{1 -6} alkylsulfones, C_1-6 alkylsulfoxides, C_3-10 cycloalkyl, C_1-6 alkyl, cyano, carboxylic acid, hydroxyl, C_3-10 non aromatic heterocyle, amino,

CONH(C₁ _e alkyl), CONH(C3_-|n cycloalkyl ), CON(C_{1 -6} alkyl)( C_{1 -6} alkyl), CON(C₁.₆ alkyl )( C₃.₁₀ cycloalkyl), CONH(C₆.! ₀ aryl ), CON(C₁.₆ alkyl)(C₆.₁₀ aryl ), CONH(C6--|0 heteroaryl ), CON(C_{1 -6} alkyl) (C_6-10 heteroaryl) , CONH (C3.-10 non aromatic heterocycle), CON(C_{1 -6} alkyl) (C3.-10 non aromatic heterocycle) , CONH2, CO(C₁.₆ alkyl), CO(C_3-1Q cycloalkyl) , CO (C3.10 non aromatic heterocycle ), CO (C_6-1Q aryl) , CO (C₆.-] ₀ heteroaryl) , NHSO₂(C_{1 -6} alkyl), NHSO₂ (C₃.₁₀ cycloalkyl) , NHSO₂ (C_6-10 aryl), NHSO₂ (C_6-1Q heteroaryl), N(C^₆ alkyl)SO₂ (C-|_₆ alkyl), N(C_{1 -6} alkyl)SO₂ (Cs_-1Q cycloalkyl) ,

N(C_{1 -6} alkyl)SO₂ (C_6-10 aryl) , N(C_{1 -6} alkyl)SO₂ (C_6-1Q heteroaryl) , NHCO(C_{1 -6} alkyl), NHCO (Cs_-10 cycloalkyl) , NHCO (C_6-1Q aryl ), NHCO (C_6-1Q heteroaryi), NHCO (C3-IO ^{non aromat}'^c heterocycle) ,

N(C_{1 -6} alkyl)C0(C-|_6 alkyl), N(C_{1 -6} alkyl)CO (C_3-1 Q cycloalkyl), N(C_{1 -6} alkyl)CO (C₆.-] 0 aryl) , N(C₁.₆ alkyl)CO (C₆.-] 0 heteroaryl), N(C₁.₆ alkyl)CO (C_3-1Q non aromatic heterocycle); or is C_6-1O heteroaryl optionally substituted by groups selected from C_{1 -6} alkyl,

C_2-6 alkenyl, halogen, C_{1 -6} alkylamino, C_{1 -6} dialkylamino, C_{1 -6} alkyloxy, C_{1 -6} alkylsulfides, C_{1 -6} alkylsulfones, C_{1 -6} alkylsulfoxides, C_{3-1 Q} cycloalkyl, C_{6-1 Q} arylsulfones, C_6-1Q arylsulfoxides, C_6-1Q arylsulfides, cyano, carboxylic acid, hydroxyl, C_3-1Q non aromatic heterocyle, amino, CONH(Ci_-6 alkyl), CONH(C_3-1Q cycloalkyl ), CON(C_{1 -6} alkylX C_{1 -6} alkyl),CON(C_{1 -6} alkyl )( C_3-10 cycloalkyl), CONH(C_6-10 aryl ), CON(C_{1 -6} alkyl)(C_6-10 aryl), CONH(C_6-10 heteroaryl ), CON(C_{1 -6} alkyl) (C_{6-1 Q} heteroaryl) , CONH (C3-10 ^non aromatic heterocycle), CON(C₁ _₆ alkyl) (C3.10 non aromatic heterocycle) , CONH2, CO(C-] _-6 alkyl), CO(C3_-|o cycloalkyl) , CO (C3.-10 non aromatic heterocycle ), CO (C_6-10 aryl) , CO (C_6-10 heteroaryl) , NHSO2(C_{1 -6} alkyl), NHSO2 (C3. 10 cycloalkyl) , NHSO2 (C6-10 ^ary0. NHSO2 (C_6-10 heteroaryl), N(C-|_6 alkyl)S02 (C-] .₆ alkyl), N(C_{1 -6} alkyl)SO₂ (C₃.₁₀ cycloalkyl) , N(C_{1 -6} alkyl)SO₂ (C₆_₁₀ aryl) , N(C_{1 -6} alkyl)SO₂ (C_6-10 heteroaryl) , NHCO(C₁.₆ alkyl), NHCO (C_3-10 cycloalkyl) , NHCO (C₆. "IO aryl ), NHCO (C₆_₁₀ heteroaryl), NHCO (C3.-10 non aromatic heterocycle) , N(C_{1 -6} alkyl)CO(C-|_₆ alkyl), N(C_{1 -6} alkyl)CO (C_3-10 cycloalkyl), N(C_{1 -6} alkyl)CO (C_6-10 aryl) , N(C_{1 -6} alkyl)CO (C_6-10 heteroaryl), N(C_{1 -6} alkyl)CO (C3.-10 non aromatic heterocycle) ; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C_{1 -6} alkyl, halogen, C_{1 -6} alkylamino, C_{1 -6} dialkylamino, C_3-10 cycloalkyl.

Usually R^ is hydrogen; or is C_{1 -6} alkyl optionally substituted by groups selected from halogen, C_3-10 cycloalkyl, amino, C_{1 -6} alkylamino groups, C_{1 -6} dialkylamino groups, C_6-10 aryl, cyano, nitro.

In a preferred embodiment of the invention X is CH or N; and W is CH or N; and R is chlorine or methoxy; and R^ is chlorine or methoxy; and R^ js R^; and R^ is C3_₁₀ cycloalkyl optionally substituted by groups selected from halogen, C_{1 -6} alkyl; and n is 1 or

2; and Y is CH or N; and m is 1 , 2 or 3. Preferred compound of the invention is (2S)-2-{[(1-cyclohexylpiperidin-3- yl)carbonyl]amino}-3-[2-(2,6-dichlorophenyl)quinolin-6-yl]propanoic acid.

Compounds of formula I and some of their intermediates have at least one stereogenic centre in their structure. This stereogenic centre may be present in "/?' or "S" configuration, said "R" and "S" notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30.

In all the above-mentioned scopes, the asymmetric carbon atom, is preferably in the "S" configuration.

The "pharmaceutically acceptable salts" according to the invention include therapeutically active, non-toxic base and acid salt forms which the compounds of formula I are able to form.

The acid addition salt form of a compound of formula I that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, a hydrohalic such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and the like; or an organic acid, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p- aminosalicylic, pamoic, formic and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta - Zurich, 2002, 329- 345). The compounds of formula I containing acidic protons may be converted into their therapeutically active, non-toxic base addition salt forms, e.g. metal or amine salts, by treatment with appropriate organic and inorganic bases. Appropriate base salt forms include, for example, ammonium salts, alkali and earth alkaline metal salts, e.g. lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. N-methyl-D-glucamine salts, and salts with amino acids such as, for example, arginine, lysine and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta - Zurich, 2002, 329-345). Conversely said salt forms can be converted into the free forms by treatment with an appropriate base or acid. Compounds of formula I and their salts, can be in the form of a solvate, which is included within the scope of the present invention. Such solvates include for example hydrates, alcoholates and the like.

The invention also relates to all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds of formula I or mixtures thereof (including all possible mixtures of stereoisomers).

Some of the compounds of formula I may also exist in tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.

With respect to the present invention reference to a compound or compounds, is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof unless the particular isomeric form is referred to specifically.

Compounds according to the present invention may exist in different polymorphic forms. Although not explicitly indicated in the above formula, such forms are intended to be included within the scope of the present invention. The present invention concerns also processes for preparing the compounds of formula I.

When compounds of formula I present one stereogenic centre, and that non- stereoselective methods of synthesis are used, resolution of the mixture of stereoisomers can best be effected in one or several steps, involving generally sequential separation of mixtures of diastereomers into their constituting racemates, using preferably chromatographic separations on achiral or chiral phase in reversed or preferably in direct mode, followed by at least one ultimate step of resolution of each racemate into its enantiomers, using most preferably chromatographic separation on chiral phase in reversed or preferably in direct mode. Alternatively, when partly stereoselective methods of synthesis are used, the ultimate step may be a separation of diastereomers using preferably chromatographic separations on achiral or chiral phase in reversed or preferably in direct mode.

It has now been found that compounds of formula I and their pharmaceutically acceptable salts are useful in a variety of pharmaceutical indications. For example, the compounds according to the invention are useful for the treatment of asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, multiple sclerosis and other autoimmune disorders, acute myelogenous leukaemia, transplantation and atherosclerosis, transplant rejection, α4-related cancers such as lung e.g. non-small cell lung, pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer.

Thus, the present invention, in a further aspect, concerns the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of disorders such as mentioned above.

In particular, the present invention concerns the use of a compound of formula I or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of α4 dependent inflammatory or medical conditions such as for example asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, multiple sclerosis and other autoimmune disorders, acute myelogenous leukaemia, transplantation and atherosclerosis, transplant rejection, α4-related cancers such as lung e.g. non-small cell lung, pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer.

The compounds of the invention are useful for treating conditions mediated by adhesion mechanisms. These conditions include asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, multiple sclerosis and other autoimmune disorders, acute myelogenous leukaemia, transplantation and atherosclerosis, transplant rejection, α4-related cancers such as lung e.g. non-small cell lung, pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer.

Subjects in need of treatment for a α4 dependent inflammatory or medical condition, asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, multiple sclerosis and other autoimmune disorders, acute myelogenous leukaemia, transplantation and atherosclerosis, transplant rejection, α4-related cancers such as lung e.g. non-small cell lung, pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer, can be treated by administering to the patient an effective amount of one or more of the above-identified compounds or a pharmaceutically acceptable derivative or salt thereof in a pharmaceutically acceptable carrier or diluent to reduce formation of oxygen radicals. The active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermal^, subcutaneously, intramuscularly or topically, in liquid, cream, gel or solid form, via a buccal or nasal spray, or aerosol, a patch or suppositories. The invention further concerns the use of the compounds of formula I for the manufacture of a medicament for therapeutic application. In particular, the invention concerns the use of the compounds of formula I for the manufacture of a medicament useful for treating conditions in which there is likely to be a α4 dependent component. The invention concerns the use of the compound of formula I for the manufacture of a medicament useful for treating asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, multiple sclerosis and other autoimmune disorders, acute myelogenous leukaemia, transplantation and atherosclerosis, transplant rejection, α4-related cancers such as lung e.g. non-small cell lung, pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer. The invention further concerns the compounds of formula I for use as medicaments. The invention concerns the compounds of formula I for use as a medicament for treating asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, multiple sclerosis and other autoimmune disorders, acute myelogenous leukaemia, transplantation and atherosclerosis, transplant rejection, α4-related cancers such as lung e.g. non-small cell lung, pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer.

The activity and properties of the active compounds, oral availability and stability in vitro or in vivo can vary significantly among the optical isomers of the disclosed compounds.

In a preferred embodiment, the active compound is administered in an enantiomerically enriched form, i.e., substantially in the form of one isomer.

The present invention also concerns a method for treating α4 dependent inflammatory or medical condition (preferably asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, multiple sclerosis and other autoimmune disorders, acute myelogenous leukaemia, transplantation and atherosclerosis, transplant rejection, α4-related cancers such as lung e.g. non-small cell lung, pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer) in a mammal in need of such treatment, comprising administering a therapeutic dose of at least one compound of formula I or a pharmaceutically acceptable salt thereof to a patient.

The methods of the invention comprise administration to a mammal (preferably human) suffering from above mentioned conditions or disorders, of a compound according to the invention in an amount sufficient to alleviate or prevent the disorder or condition. The compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing 0.01 to 2000 mg, preferably 0.05 to 500 mg of active ingredient per unit dosage form.

The term "treatment" as used herein includes curative treatment and prophylactic treatment. The term "substantially" as used herein refers to a composition of equal or higher than 85% of one isomer, usually 90% and preferably 95%.

By "curative" is meant efficacy in treating a current symptomatic episode of a disorder or condition. By "prophylactic" is meant prevention of the occurrence or recurrence of a disorder or condition.

The compounds are of use in modulating cell adhesion and in particular are of use in the prophylaxis and treatment of diseases or disorders in which the extravasation of leukocytes plays a role and the invention extends to such a use and to the use of the compounds for the manufacture of a medicament for treating such diseases or disorders.

Diseases or disorders of this type include inflammatory arthritis such as rheumatoid arthritis, vasculitis or polydermatomyositis, multiple sclerosis, transplantation, diabetes, inflammatory dermatoses such as psoriasis or dermatitis, asthma and inflammatory bowel disease. One aspect of the invention includes methods for treating α4-related cancers

(including cancers, whether solid or haematopoietic). Examples of such cancers include, but are not limited to, lung e.g. non-small cell lung, pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer. Results obtained with compounds of formula I are indicative of a strong pharmacological effect.

For treating diseases, compounds of formula I or their pharmaceutically acceptable salts, may be employed at an effective daily dosage and administered in the form of a pharmaceutical composition. Therefore, another embodiment of the present invention concerns a pharmaceutical composition comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier.

To prepare a pharmaceutical composition according to the invention, one or more of the compounds of formula I or a pharmaceutically acceptable salt thereof, is intimately admixed with a pharmaceutical diluent or carrier according to conventional pharmaceutical compounding techniques known to the skilled practitioner.

Suitable diluents and carriers may take a wide variety of forms depending on the desired route of administration, e.g., oral, rectal, or parenteral. Pharmaceutical compositions comprising compounds according to the invention can, for example, be administered orally or parenterally, i.e., intravenously, intramuscularly, subcutaneously or intrathecally.

Pharmaceutical compositions suitable for oral administration can be solids or liquids and can, for example, be in the form of tablets, pills, dragees, gelatine capsules, solutions, syrups, and the like.

To this end the active ingredient may be mixed with an inert diluent or a non-toxic pharmaceutically acceptable carrier such as starch or lactose. Optionally, these pharmaceutical compositions can also contain a binder such as microcrystalline cellulose, gum tragacanth or gelatine, a disintegrant such as alginic acid, a lubricant such as magnesium stearate, a glidant such as colloidal silicon dioxide, a sweetener such as sucrose or saccharin, or colouring agents or a flavouring agent such as peppermint or methyl salicylate.

The invention also contemplates compositions which can release the active substance in a controlled manner. Pharmaceutical compositions which can be used for parenteral administration are in conventional form such as aqueous or oily solutions or suspensions generally contained in ampoules, disposable syringes, glass or plastics vials or infusion containers.

In addition to the active ingredient, these solutions or suspensions can optionally also contain a sterile diluent such as water for injection, a physiological saline solution, oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulphite, chelating agents such as ethylene diamine-tetra-acetic acid, butters such as acetates, citrates or phosphates and agents for adjusting the osmolarity, such as sodium chloride or dextrose. These pharmaceutical forms are prepared using methods which are routinely used by pharmacists.

The amount of active ingredient in the pharmaceutical compositions can fall within a wide range of concentrations and depends on a variety of factors such as the patient's sex, age, weight and medical condition, as well as on the method of administration. Thus the quantity of compound of formula I in compositions for oral administration is at least 0.5 % by weight and can be up to 80 % by weight with respect to the total weight of the composition.

For the preferred oral compositions, the daily dosage is in the range 0.01 to 2000 milligrams (mg) of compounds of formula I. In compositions for parenteral administration, the quantity of compound of formula I present is at least 0.5 % by weight and can be up to 33 % by weight with respect to the total weight of the composition. For the preferred parenteral compositions, the dosage unit is in the range 0.01 mg to 2000 mg of compounds of formula I. The daily dose can fall within a wide range of dosage units of compound of formula

I and is generally in the range 0.01 to 2000 mg. However, it should be understood that the specific doses could be adapted to particular cases depending on the individual requirements, at the physician's discretion.

The compounds of the invention may be co-administered with another therapeutic agent most likely from a different therapeutic area.

Co-administration in this context means the dosing either of components, which are formulated together as a single dosage form; or the administration of separately formulated agents at substantially the same time, or sequential dosing of a compound of the invention followed by a therapeutic agent of a different therapeutic area. In this context suitable examples of therapeutic agents may include, but are not limited to, histamine H1 antagonists such as cetirizine, histamine H2 antagonists, histamine H3 antagonists, leukotriene antagonists, PDE4 inhibitors such as 3-cyclo- propylmethoxy-4-difluoromethoxy-Λ/-[3,5-di-chloropyrid-4-yl]-benzamide, muscarinic M3 antagonists, β₂ agonists, theophylline, sodium cromoglycate, anti-TNF antibodies such as certolizumab pegol or adalimumab, anti-IL6 antibodies, anti-IL17 antibodies, adhesion molecule inhibitors, inhibitors of cytokine synthesis such as P38 MAP kinase inhibitors and inhibitors of PI3 kinase, methotrexate.

The present invention concerns also processes for preparing the compounds of formula I . The compounds of formula I according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry.

The following processes description sets forth certain synthesis routes in an illustrative manner. Other alternative and/or analogous methods will be readily apparent to those skilled in this art.

Most compounds of formula I may be prepared according to the following scheme: Scheme 1

Compounds of formula Ia can be prepared according to scheme 1 , starting with Methyl-(2S)-2-[(tert-butoxycarbonyl)amino]-3-[2-(2,6-dichlorophenyl)-6- quinoiinyi]ρroρanoate (RN 623144-30-9) or with 6-quinoϋneprcpanoic acid 1-(2,6- dimethoxyphenyl)-α-[[(1 ,1-dimethylethoxy)carbonyl]amino]-, methylester (αS) (RN-623147- 28-4).

The f-butyl group is removed using Trifluoroacetic acid in dichloromethane to yield the free amine. The amino group is coupled with 1-(tert-butoxycarbonyl)piperidine-3- carboxylic acid (RN 71381-75-4 ). The BOC protecting group is removed using Trifluoroacetic acid in dichloromethane, followed by the addition of cyclohexanone and triacetoxyborohydride. Saponification of the ester to the acid using 2N NaOH yields the desired product.

Most compounds of formula I may be prepared according to scheme 1 , starting with the 6-quinolinepropanoic acid 1-(2,6-dichlorophenyl)-α-[[(1 ,1- dimethylethoxy)carbonyl]amino]-, methylester (RN-623144-13-8) or with 6- quinolinepropanoic acid 1-(2,6-dimethoxyphenyl)-α-[[(1 ,1-dimethylethoxy)carbonyl]amino]-, methylester (RN-623146-89-4). The present invention also relates to synthetic intermediates geometrical isomers, enantiomers, diastereoisomers, pharmaceutically acceptable salts and all possible mixtures thereof.

The following examples are provided for illustrative purposes only and are not intended, nor should they be construed, as limiting the invention in any manner. Those skilled in the art will appreciate that routine variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention.

Unless specified otherwise in the examples, characterization of the compounds is performed according to (LCMS) liquid chromatography mass spectra, preparative liquid chromatography LC, NMR, and silica gel chromatography methods.

NMR spectra are recorded on Bruker AV300 and DRX 400 spectrometers at 300 and 400 MHz respectively.

Chromatographic separations are performed on Davis 5 μM silica gel. The Waters mass spectrometers used are of model ZMD or ZQ both Waters. Various reactions took place in an Emrys Optimiser microwave reactor. The following abbreviations are used in the examples: NaOH - sodium hydroxide DCM - Dichloromethane;

TBS - Tris buffered saline RT - Retention time;

FACS - Fluorescent Activated Cell Sorting EtOAc - Ethyl acetate; DIPEA - Λ/,Λ/-Diisopropylethylamine; DMSO - Dimethyl sulphoxide; de-DMSO - Dimethyl-d₆ sulphoxide; TFA - Trifluoroacetic acid;

EDCI - 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride MgSO₄ - Magnesium Sulfate NaHCO₃ - Sodium Hydrogen Carbonate

HCI - hydrochloric acid TFA - Trifluoroacetic acid; THF - Tetrahydrofuran MnCl2 - manganese chloride

HOBt - tertbutanol

LCMS_Prep LC conditions and abbreviations

The following LCMS conditions are used to obtain the retention times (RT) as described herein: LCMS conditions (Method A):

HP1100 (Diode Array) linked to a Finnigan LC-Q Mass Spectrometer, ESI mode with Pos/Neg ionisation

Column: Luna C18(2) 100x4.6mm, 5μm particle size Analytical column

Column Temp: 35°C Mobile Phase: A: Water + 0.08' Vo formic acid

B: Acetonitrile + 0.08% formic acid

Flow rate: 3ml/min

Gradient: Time (mins): % Composition B:

0 5

4 .4 95

5 .30 95

5 .32 5

6 .5 5 Run time: 6.5 mins

Typical Injection VoI: 10μl

Detector Wavelength: DAD 200-400nm

Preparative LC conditions (Method B): Gilson 215 liquid handler setup. Column: Luna C18(2) 250x21.2mm, 5μM particle size prep column

Column Temp: Ambient

Gradient: Variable - depends on retention time of sample in LC-MS analysis.

Run Time: 20 mins

Flow rate: 25ml/min Typical Injection VoI: 0.5 - 4.0ml at 25mg/ml

Detector Wavelength:210 and 254nm

Mobile Phase: A: Water + 0.08% formic acid

B: Acetonitrile + 0.08% formic acid

The IUPAC names of the compounds mentioned in the examples are generated with ACD version 6.00.

Unless specified otherwise in the examples, characterization of the compounds is performed according to the following methods:

NMR spectra are recorded on a Bruker AV-300 or DRX-400 Spectrometers operating at 300.13 MHz or 400.13 MHz for protons, and running the Bruker XWINNMR software package. Spectra are acquired at room temperature unless otherwise stated. Chemical shifts are given in ppm referenced either to internal TMS or to the residual solvent signal. Synthetic example:

Example 1 : Synthesis of (2S)-2-{r(1-cvclohexylpiperidin-3-yl)carbonvnamino)-3-r2-

(2.6-dichlorophenyl)quinolin-6-vπpropanoic acid (Compound 1)

To a stirred solution of Ethyl-(2S)-2-[(tert-butoxycarbonyl)amino]-3-[2-(2,6- dichlorophenyl)-6-quinolinyl]propanoate (prepared in the same manner as RN 623144-30- 9) (1Og) in DCM (70ml) at 0°C is added TFA (1.2ml) in portions over 5-10 mins. The ice- bath is removed and the reaction stirred at room temperature for 18 hours. The reaction mixture is concentrated in vacuo. EtOAc (100ml) is added and the mixture treated with saturated aqueous NaHCO₃ (100ml), followed by solid NaHCO₃ in small portions until the effervescence ceases. A further 100ml EtOAc is added and the layers separated. The aqueous phase is extracted with EtOAc (2 x 50ml) and the combined organic extracts are washed with brine (100ml), dried (MgSO₄) and concentrated in vacuo to afford a yellow oil. A aliquot (140mg) is taken up in DCM (3ml), with EDCI (73mg), HOBt (3mg, DIPEA (0.135ml) and 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (RN 71381-75-4 ) (83mg) and stirred at room temperature overnight, before the solvent is removed in vacuo and purified using flash chromatography (eluent Heptane to EtOAc). Removal of the solvent yielded a clear oil (80mg). The oil was taken up in DCM (4ml) and TFA (1ml) is added and the reaction is stirred for 20minutes before the solvent is removed in vacuo. The resulting slurry is taken up in THF and cyclohexanone (0.015ml) added, followed by sodium tiacetoxyborohydride (42mg) and the reaction is stirred for 5 days. EtOH (4ml) is added followed by HCI (5N, 4ml) and the reaction is heated to reflux for 30 minutes. On cooling the solvent is removed in vacuo and dissolved in DMSO. Purification using Method C yields the title compound (27mg) as a white solid. LCMS (Method A) M+1 (554, 556), Retention Time 2.30min, ¹H NMR, 300Mz, DMSO δ 0.91-1.21 (5H, m), 1.31-1.76 (5H, m), 2.25-2.81 (6H, m), 3.10-3.65 (6H, m), 4.60 (1H, dt), 7.50-7.56 (2H, m), 7.60-7.72 (3H, m), 7.85 (1 H, d), 7.96 (1 H, d), 8.44 (1 H, d). Biological examples: Example 2

The following cellular assay is used to demonstrate the potency of the compounds according to the invention. In each of these assays an IC50 value is determined for each test compound and represents the concentration of compound necessary to achieve 50% inhibition of cell adhesion where 100% = adhesion assessed in the absence of the test compound and 0% = absorbance in wells that did not receive cells. Whole blood VCAM-bindinq assay for α4 inteqrins; The following reagents are added to FACS tubes: 3μl 10OmM MnCl2 (100X required cone), 1 μl 1mg/ml streptavidin-FITC (supplier Pierce 100X required cone), 2μl 500 μg/ml biotinylated hVCAM-1-mFc (5OX required cone), and 2μl serially-diluted test compound at 5OX desired final concentrations. 100μl heparinised blood from healthy human donors is then added to each FACS tube which are then sealed and rocked for 30 minutes at RT. 2ml "FACS Lysing Solution" (BD Biosciences) solution is added to tubes for 5 minutes at room temperature, and tubes are spun at 1200 rpm and washed 2X in 3ml TBS, before final suspension in 100μl TBS. Flow cytometry is then performed on a Becton Dickinson FACScan to assess the % of cells in the lymphocyte gate capable of binding VCAM.

The compounds of the invention are tested in this assay and show IC50 values of 1.5 μM and below.

(2S)-2-{[(1-cyclohexylpiperidin-3-yl)carbonyl]amino}-3-[2-(2,6- dichlorophenyl)quinolin-6-yl]propanoic acid_has an activity of 0.2 - 0.8 μM in the above assay.

Claims

1. A compound having formula I or pharmaceutically acceptable salts thereof or stereoisomeric forms thereof, and the geometrical isomers, enantiomers, diastereoisomers, and pharmaceutically acceptable salts thereof

formula I wherein: X is CH or N; W is CH or N; R is chlorine or methoxy;

Y is CH or N; R² Js R³ Or G₁R⁴; n is 1 or 2; m is 1 , 2, 3 or 4; () means CH2 ;

R3 is hydrogen; or is C3.10 cycloalkyl optionally substituted by groups selected from halogen, C₁ _β alkyl;

G₁ is -C(O)-, -S(O)₂- or -C(O)N(R⁵)-;

R⁴ is C₁.6 alkyl optionally substituted by groups selected from halogen, C3.-10 cycloalkyl, amino, C₁.5 alkylamino groups, C₁^ dialkylamino groups, CQ.^ Q aryl, cyano, nitro; or is C3.-10 cycloalkyl optionally substituted by groups selected from halogen, C₁.5 alkyl; or is C6_-| o aryl optionally substituted by groups selected from halogen, C₁^ alkylamino groups, C-|_6 dialkylamino groups, C-|._β alkyloxy, C-\ .Q alkylsulfides, C-j.g alkylsulfones, C-|_6 alkylsulfoxides, C_3-1Q cycloalkyl, C_{1 -6} alkyl, cyano, carboxylic acid, hydroxyl, C3.10 non aromatic heterocyle, amino, CONH(Ci_6 alkyl), CONH(C3_-|o cycloalkyl ), CON(C_{1 -6} alkylX C-|.₆ alkyl), CON(C_{1 -6} alkyl )( C₃.-] ₀ cycloalkyl), CONH(C₆.₁₀ aryl ), CON(C₁ _₆ alkyl) (C₆_I Q aryl ). CONH(C_{6-1 0} heteroaryl ), CON(C_{1 -6} alkyl) (C_6-10 heteroaryl) , CONH (C_3-10 ^non aromatic heterocycle), CON(Ci _g alkyl) (C3.-10 non aromatic heterocycle) , CONH2, CO(C_{1 -6} alkyl), CO(C_3-1O cycloalkyl) , CO (C3.10 non aromatic heterocycle ), CO (Ce-10 ^ary!) . ^co (^c6-10 heteroaryl) , NHSO₂(C_{1 -6} alkyl), NHSO2 (C3.10 cycloalkyl) , NHSO₂ (C₆.₁₀ aryl), NHSO₂ (C₆._{1 0} heteroaryl), N(C-|_₆ alkyl)SO₂ (C-|.₆ alkyl), N(C_{1 -6} alkyl)SO₂ (C₃.₁₀ cycloalkyl) , N(C_{1 -6} alkyl)SO₂ (C₆.₁₀ aryl) , N(C-|_₆ alkyl)SO₂ (C₆.₁₀ heteroaryl) , NHCO(C-] .5 alkyl), NHCO (C3.1 Q cycloalkyl) , NHCO (C_6-10 aryl ), NHCO (C_6-10 heteroaryl), NHCO (C3.-10 non aromatic heterocycle) , N(C_{1 -6} alkyl)C0(C-|.6 alkyl), N(C₁ _₆ alkyl)CO (C₃.-] ₀ cycloalkyl), N(C₁.₆ alkyl)CO (C₆-10 aryl) , N(C₁.₆ alkyl)CO (C₆_-|o heteroaryl), N(C_{1 -6} alkyl)CO (C₃_-|o non aromatic heterocycle) ; or is C_{6-1 Q} heteroaryl optionally substituted by groups selected from C_{1 -6} alkyl, C₂.₆ alkenyl, halogen, C_{1 -6} alkylamino, C-|_₆ dialkylamino, C-].₆ alkyloxy, C_{1 -6} alkylsulfides, C₁ _₆ alkylsulfones, C₁ _₆ alkylsulfoxides, C₃.-] Q cycloalkyl, C₆.-] Q arylsulfones, C₆.-] Q aryl s u If oxides, C₆.-|o arylsulfides, cyano, carboxylic acid, hydroxyl, C_3-1Q non aromatic heterocyle, amino, CONH(C_{1 -6} alkyl), CONH(C₃.-] ₀ cycloalkyl ), CON(C_{1 -6} alkyl)( C_{1 -6} alkyl), CON(C_{1 -6} alkyl )( C_3-10 cycloalkyl), CONH(C₆.₁₀ aryl ), CON(C_{1 -6} alkyl)(C₆._{1 υ} aryl ), CONH(C_6-1O heteroaryl ), CON(C_{1 -6} alkyl) (C_6-1O heteroaryl) ,

CONH (C_3-1O non aromatic heterocycle), CON(C_{1 -6} alkyl) (C₃^ Q non aromatic heterocycie) , CONH₂, CO(C_{1 -6} aikyi), CO(C_3-1O cycioaikyi) , CO (C_3-1Q non aromatic heterocycle ), CO (C₆_₁₀ aryl) , CO (C₆_₁₀ heteroaryl) , NHSO₂(C₁ _₆ alkyl), NHSO₂ (C_3- -IO cycloalkyl) , NHSO₂ (C_6-I Q aryl), NHSO₂ (C_6-1Q heteroaryl), N(C_{1 -6} alkyl)SO₂ (C_{1 -6} alkyl), N(C_{1 -6} alkyl)SO₂ (C_3-10 cycloalkyl) , N(C₁ _₆ alkyl)SO₂ (C_6-10 aryl) , N(C_{1 -6} alkyl)SO₂ (C_6-10 heteroaryl) , NHCO(C_{1 -6} alkyl), NHCO (C₃.₁₀ cycloalkyl) , NHCO (C₆. ₁₀ aryl ), NHCO (C₆.₁₀ heteroaryl), NHCO (C_3-1Q non aromatic heterocycle) , N(C_{1 -6} alkyl)CO(C_{1 -6} alkyl), N(C_{1 -6} alkyl)CO (C_3-10 cycloalkyl), N(C-|_₆ alkyl)CO (C_6-10 aryl) , N(C_{1 -6} alkyl)CO (C₆.₁₀ heteroaryl), N(C_{1 -6} alkyl)CO (C_3-10 non aromatic heterocycle) ; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C_{1 -6} alkyl, halogen, C_{1 -6} alkylamino, C_{1 -6} dialkylamino, C_{3-1 0} cycloalkyl;

R⁵ is hydrogen; or is C_{1 -6} alkyl optionally substituted by groups selected from halogen, C_3-1O cycloalkyl, amino, C_{1 -6} alkylamino groups, C_{1 -6} dialkylamino groups, C_6-1Q aryl, cyano, nitro.

2. A compound according to claim 1 , wherein the compound has formula Ia and the configuration at the asymmetric carbon atom, is in the "S" configuration

formula Ia.

■5

3 . A compound according to claim 1 or 2 wherein: X is CH or N; and W is CH or N; and R is chlorine or methoxy; and R¹ is chlorine or methoxy; and R² is R^; and R^ is C3. 10 cycloalkyl optionally substituted by groups selected from halogen, C-) .5 alkyl; and n is 10 or 2; and Y is CH or N; and m is 1 , 2 or 3.

4. (2S)-2-{[(1-cyclohexylpiperidin-3-yl)carbonyl]amino}-3-[2-(2,6-

or»JH 5

5. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable adjuvant, diluent or carrier.

6. A pharmaceutical composition comprising as active ingredient a therapeutically0 effective amount of a compound according to any one of claims 1 to 4 for use as a medicine.

7. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 4 in the manufacture5 of a medicament.

8. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of α4 dependent inflammatory or medical conditions.

9. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment of asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, multiple sclerosis and other autoimmune disorders, acute myelogenous leukaemia, transplantation and atherosclerosis, transplant rejection, α4-related cancers such as lung e.g. non-small cell lung, pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer.

10. Compound according to any one of claims 1 to 4 for use as a medicament.

11. Compound according to any one of calims 1 to 4 for curing asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, multiple sclerosis and other autoimmune disorders, acute myelogenous leukaemia, transplantation and atherosclerosis, transplant rejection, α4-related cancers such as lung e.g. non-small cell lung, pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer.