Indian Patents. 270793:NOVEL BRONCHODILATING ALPHA, BETA-UNSATURATED AMIDES

Title of Invention	NOVEL BRONCHODILATING ALPHA, BETA-UNSATURATED AMIDES
Abstract	The invention relates to novel compounds having the general formula (I), and which compounds are useful to manufacture a medicament to treat a disorder or disease characterized by bronchoconstriction, e.g. COPD and asthma, and vasoconstriction, e.g. hypertension.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & The Patent Rules, 2003 COMPLETE SPECIFICATION 1. TITLE OF THE INVENTION: NOVEL BRONCHODILATING ALPHA, BETA-UNSATURATED AMIDES 2. APPLICANT: Name: Respiratorius AB Nationality: Sweden Address : Magistratsvagen 10, 226 43 LUND, Sweden. 3. PREAMBLE TO THE DESCRIPTION: The following specification particularly describes the invention and the manner in which it is to be performed: Field of (lie invention The present invention relates to novel bronchorclaxing compounds, pharmaceutical compositions comprising such compounds, and a method of treating or alleviating conditions accompanied by broncho con strict ion and/or inflammation of the respiratory tract, and/or vasoconstriction, by use of such compounds. Background Asthma and chronic obstructive pulmonary disease (COPD) arc diseases affecting the respiratory system, which millions of people suffer from. These diseases are today regarded as inflammatory diseases and the symptoms comprise constriction of the airways. Common treatment of the associated bronchoconstriction involves use of beta-agonists, such as tcrbutalin and formotcrol, and anticholinergics, such as ipratropium bromide and thiotropium bromide. Hypertension, i.e. high blood pressure, increases the risk of stroke, heart attacks, heart failure and kidney disease. Medications presently used for the treatment of hypertension include the administration of bcta-b lockers, calcium channcl blockers, diuretics, angiotensin-converting enzyme inhibitors and angiotensin II rcccptor antagonists. Vasoconstriction results in an increase in the blood pressure. The treatments for prevention or reduction of bronchoconstri cion, inflammation, such as inflammation of the respiratory tract, and vasoconstriction are in many ways insufficient and there is a need for alternative treatments. Summary Accordingly, various embodiments of the present invention seek to mitigate, alleviate, circumvent or eliminate one or more of the above-identified deficiencies identified herein. According to one aspect of the present invention, there is provided a compound of the general formula (I), G R4 (I) G2 G= CR10)P G1 (R7) wherein R1 is selected from I i and methyl; R2 is selected from II and methyl; R3 is selected from H, fluoro, ehloro, bromo, CI-3 alkyL and CH2 phenyl; R4 is selected from H, fluoro, chloro. bromo, CI-3 alkyl and CH2 phenyl; G is sclcctcd from Gl and G2; in Gl the stereochemistry of the double-bond of Gl, onto which the substituents R5 and R6 arc attached, is such that R5 and R6 arc oriented in a cis- fashion, or in a trans-fash ion, relative to each other; R5 is selected from H, Cl-5 alkyl, CH2 phenyl and CI-5 fluoroalkyl; R6 is selected from H, Cl-5 alkyl, CH2 phenyl and Cl-5 fluoroalkyl; XI, X2, X3, X4 and X5 are. independently of each other, selected from N and C; 0 (zero), I or 2 of XI, X2, X3, X4 and X5 is N; Q is optionally substituted with a maximum of "n" independently selected substituent(s) R7 at any substitutablc ring carbon atom, wherein "n" represents an integer number; the integer number "n1 is 0 to 2; R7 is selected from Cl-5 alkyl, CI-5 fluoroalkyl, halo, hydroxy, CO-3 alkyleneOCO-5 alkyl, CO-3 alkylencOC1-5 fluoroalkyl, CO-3 alkyleneNH2, CO-3 alkyleneNHCl-3 alkyl, CO-3 alkyIcncNfC 1-5 alkyl)2, in which the Cl-5 alkyl may be the same or different, N(C4-5 alkylcnc), Cl-5 alkylthio, S(0)C 1-5 alkyl, S02C1 -5 alkyl, Cl-5 fluoroalkylthio, NH(CO)Cl-5 alkyl, NH(CO)CI-5 alkoxy, NHS02C1-5 alkyl (CO)Cl-5 alkyl, COOH, (CO)Cl-5 alkoxy, (CO)NH2, (CO)NHCI-5 alkyl. (CO)N(Cl-5 alkyl)2, in which the Cl-5 alkyl may be the same or different, cyano, S02NHCQ-5 alkyl, nitro, aryl, heteroaryl, azido (N3), and morpholinyl; inG2 the stereochemistry of the double-bond of G2, onto which the substituents RS and R9 are attached, is such that RN arid R9 are oriented in a cis-fashion, or in a trans-fash ion, relative to each other; R8 is selected from H, Cl-5 alkyl, CH2 phenyl and Cl-5 fluoroalkyl; R9 is selected from H, Cl-5 alkyl, CH2 phenyl and Cl-5 fluoroalkyl; the condensed rings W1 and W2 together represent a bicyclic aromatic system, in which. X6, X7 and X8, independently of each other, arc selected from N and C; none or one of X6, X7 and X8 is N , said bicyclic aromatic system is optionally substituted with a maximum of "p" independently selected substituent(s) R10, at any substitutable ring carbon atom of any of the rings W1 and W2, wherein lip" represents an integer number; the integer number "p'1 is 0 to 2; RIO is selected from Cl-5 alkyl, Cl-5 fluoroalkyl, halo, hydroxy, CO-3 alkylencOC1-5 alkyl, CO-3 alkylencOCO-5 fluoroalkyl, CO-3 alkyleneNH2, CO-3 alkyleneNHCl-3 alkyl, CO-3 alkylcneN(Cl-5 alkyl)2, in which the Cl-5 alkyl may be the same or different, N(C4-5 alkylcnc), CI 5 alkylthio, S(0)C1~5 alkyl, S02C1-5 alkyl. C1-5 fluoroalkylthio, NH(CO)Cl-5 alkyl, NH(CO)Cl-5 alkoxy, NHS02C1-5 alkyl (CO)Cl-5 alkyl, COOH, (CO)Cl-5 alkoxy, (CO)NH2, (CO)NHCl- 5 alkyl, (CO)N(Cl-5 alkyl)2, in which the Cl-5 alkyl may be the same or different, cyano. SO2NHC0-5 alkyl, nitro, aryl, heteroaryl, azido (N3), and morpholinyl; as a free base, an acid in its non-charged proton ate d form or a pharmaceutical^ acceptable salt, solvate or solvate of a salt thereof and as a pure stereoisomer, a raccmic-, diastereomeric- or scalemic mixture; with the provisio that not both of R1 and R2 is methyl. Aecording to another aspect such a compound or a composition comprising such a compound may be used in medicine. Such compounds or compositions may also be used to manufacture a mcdicament. Aecording to another aspect a medicament comprising a compound according to formula 1 may be used to treat or prevent a disease or disorder of the respiratory apparatus characterized by bronchoconstriction. Furthermore, a medicament comprising a compound according to formula I may be used to treat or prevent a disease or disorder characterized by inflammation or vaso con strict ion. Diseases and disorders, whieh compounds according to formula 1 may be used to treat comprise asthma, chronic obstructive pulmonary disease, which comprises chronic bronchitis and emphysema, bronchiectasis, cystic fibrosis, bronchiolitis or bronchopulmonary dysplasia. According to another aspect a compound according to formula I or a medicamcnt comprising such a compound, may also be used in a method to treat or prevent pulmonary disease characterized by bronchoconstrict ion. Such a method comprises the administration to a person in need of a broncho constrict ion relaxing dose of a compound according to formula I. Further features of the invention are defined in the dependent claims and embodiments disclosed herein. Detailed description of the invention Definitions: In the context of the present application and invention, the following definitions apply: The term "addition salt'1 is intended to mean salts formed by the addition of a pharmaceutical acccptablc acid, such as organic or inorganic acids, or a pharmaceutical acceptable base. The organic acid may be, but is not limited to, acetic, propanoic, mcthanesulfonic, bcnzcncsulfonic, lactic, malic, citric, tartaric, succinic or malcic acid. The inorganic acid may be, but is not limited to, hydrochloric, hydrobromic, sulfuric, nitric acid or phosphoric acid. The base may be. but is not limited to, ammonia and hydroxides of alkali or alkaline earth metals. The term "addition salt" also comprises the hydrates and solvent addition forms, such as hydrates and alcoholates. As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo. As used herein, "alkyl11 used alone or as a suffix or prefix, is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having from 1 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number is intended. For example "Cl-6 alkyl" denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms. When the specific number denoting the alkyl-group is the integer 0 (zero), a hydrogen-atom is intended as the substitucnt at the position of the alkyl-group. For example. "N(C0 alkyl)2" is equivalent to "NH2" (amino). Examples of alkyl include, but arc not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. As used herein, "alkylenyl" or "alkylene" used alone or as a suffix or prefix, is intended to mean straight chain saturated aliphatic hydrocarbon groups having from 1 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number is intended. For example "CI-(5 alkylene" or "Cl-6 alkylenyl" denotes "alkylene" or "alkylenyl" having 1, 2, 3,4, 5 or 6 carbon atoms. When the specific number denoting the alkylenyl or alkylcne-group is the integer 0 (zero), a bond is intended to link the groups onto which the alkylenyl or alkylene-group is substituted, For example, "NH(C0 alkylene)NH2" is equivalent to 'NHNFK" (hydrazino). As used herein, the groups linked by an alkylene or alkylenyl-group arc intended to be attached to the first and to the last carbon of the alkylene or alkylenyl-group. In the case of methylene, the first and the last carbon is the same. For example, "H2N(C2 alkylene)NH2", "H2N{C3 alkylene)NH2", "N(C4 alkylene)", "N(C5 alkylene)" and "N(C2 alkylene)2NH" is equivalent to 1,2-diamino ethane, 1,3-diamino propane, pyrrolidinyl, piperidinyl and pipcrazinyI, respectively. Examples of alkylene or alkylenyl include, but arc not limited to, methylene, ethylene, propylene, and butylene. As used herein, "alkoxy" or "alkyloxy" is intended to mean an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, mcthoxy, cthoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, isopentoxy, eyclopropyl mcthoxy, allyloxy and propargyloxy, Similarly, "alky It bio" or '"thioalkoxy" represent an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge. As used herein, "fluoroalkyl", "fluoroalkylcne" and "fluoroalkoxy", used alone or as a suffix or prefix, refers to groups in which one, two, or three of the hydrogen(s) attached to any of the carbons of the corresponding alkyl, alkylene and alkoxy-groups arc replaced by fluoro. Examples of fluoroalkyl include, but arc not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, 2.2,2-tri fluoro ethyl, 2-fluoroethyl and 3- tluoropropyl. Examples of fluoroalkylene include, but are not limited to, di fluoro methylene, fluoromethylenc, 2,2-difluorobutylcnc and 2,2,3-trifluorobutylene. Examples of fluoroalkoxy include, but arc not limited to, tri fluoro mcthoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy and 2.2-dtfluoropropoxy. As used herein, the term "substi tut able" refers to an atom to which a hydrogen is covalently attached, and to which another substituent may be attached instead of the hydrogen, directly or indirectly through synthesis. A non-limiting example of substitutable atoms include the carbon-atoms of pyridine. The nitrogen-atom of pyridine is not substitutable according to this definition. As used herein, the Lerm "aryl" refers Lo a ring structure, comprising at least one aromatic ring, made up of from 5 to 14 carbon atoms. Ring structures containing 5, 6, 7 and 8 carbon atoms would be single-ring aromatic groups, for example phenyl. Ring structures containing 8, 9, 10, 11, 12, 13, or 14 would be polycyclic, for example naphthyl. The aromatic ring may be substituted at one or more ring positions. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, for example, the other cyclic rings can be cycloalkyls, cycloalkenylst cycloalkynyls,. aryls and/or heterocyclyls. The terms ortho, met a and para apply to 1,2-, 1,3- and 1,4-disubstitutcd benzenes, respectively. For example, the names 1,2-di methyl benzene and ortho-dimcthylbcnzcne arc synonymous. As used herein, "heteroaryl" refers to a hctcroaromatic hctcrocyclc, having at least one ring with aromatic character, (e.g. (S delocalized electrons) or at least two conjugated rings with aromatic character, (e.g. 4n + 2 delocalized electrons where "ti" is an integer), and comprising up to about 14 carbon atoms, and having at least one hctcroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic and bicyclic (e.g., having 2 fused rings) systems. Examples of heteroaryl groups includc without limitation, pyridyl (i.e., pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl (i.e. furanyl), quinolyl, tctrahydroquinolyl, isoquinolyl, tctrahydroisoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl. pyrryl, oxazolyl. benzofuryl, benzothicnyl, bcnzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl. benzothienyl,benzimidazolyl, indolitiyl, and the like. As used herein, the term "substitutable" refers to an atom to which a hydrogen atom may be covalently attached, and to which another substituent may be present instead of the hydrogen atom. A non-limiting example oi substitutable atoms include the carbon-atoms of pyridine, The nitrogen-atom of pyridine is not substitutable according to this definition. Further, according to the same definition, the iminc nitrogen at position 3 in imidazole is not substitutable, while the amine nitrogen at position 1 is. According to one embodiment of the present invention there is disclosed a compound according to formula (I) i G R4 (I) Gl G2 (R10)P G= wherein R1 and R2 arc, independently of each other, selected from [ I and methyl and at least ore of them is H; R3 and R4 are, independently of each other, selected from H, fluoro, chloro, bromo, C1-3 alkyl and CH2 phenyl; G is selected from Gl to G2; the stereochemistry of the double-bond of Gl, onto which the substituents R5 and R6 arc attached, is such that R5 and R6 are oriented in a cis-fashion, or in a trans- fashion, relative to each other; R5 and R6 arc, independently of each other, selected from H. Cl-5 alkyl, CH2 phenyl and Cl-5 fluoroalkyl, Q is selected from phenyl, i.e. all of X 1, X2, X3, X4 and X5 arc C, and nitrogen containing heteroaryl, such as pyridyl and pyrimidinyl, i.e. XI, X2, X3, X4 and X5 are, independently of each other, selected from N and C and no more than two of X1, X2, X3, X4 and X5 are N. the residue being C, Q is optionally substituted wiih a maximum of "n" independently selected substituent(s) R7 at any substitutable ring carbon atom; "n" represent an integer number oTO, 1 or 2, i.e. if "n" is 0, then Q is unsubstituted; R7 is selected from Cl-5 alkyl, Cl-5 fluoroalkyl, halo, hydroxy, CO-3 alkyleneOCO-5 alkyl, CO-3 alkyleneOCl-5 fluoroalkyl, CO-3 alkylcneNH2, CO-3 alkylcneNHC 1-3 alkyl, CO-3 alkylencN(Cl-5 alkyl)2, N(C4-5 alkylene). Cl-5 alkylthio, S(0)Cl-5 alkyl, S02C1-5 alkyl, Cl-5 fluoroalkylthio. NH(CO)C 1 -5 alkyl,NH(CO)Cl-5 alkoxy. NHSO2C1-5 alkyl, (CO)Cl-5 alkyl, COOH. (CO)C1-5 alkoxy, (CO)NH2, (CO)NHCl-5 alkyl. (CO)N(Cl-5 alky 1)2, eyano, SO2NHC0-5 alkyl, nitro, aryl, heteroaryl, azido (N3), and morpholinyl; the stereochemistry of the double-bond of G2, onto which the substituents RK and R9 are attached, is such that R8 and R9 are oriented in a cis-fashion, or in a trans-fash ion, relative to each other; R8 and R9 are, independently of each other, selected from H, Cl- 5 alkyl, CH2 phenyl and Cl-5 fluoroalkyl; the condensed rings W1 and W2 together represent a bicyclic aromatic system, wherein X6, X7 and X8 are. independently of each other, selected from N and C and no more than one of X6, X7 and X8 arc N, the residue being C; said bicyclic aromatic system is optionally substituted with a maximum of "p" independently selected substituent(s) R10, at any substitutable ring carbon atom of any of the rings Wl and W2; "p' represents an integer number of 0, l or 2. i.e. if l4p" is 0, then Wl and W2 is unsubstituted; R10 is selected from Cl-5 alkyl, Cl-5 fluoroalkyl, halo, hydroxy, CO-3 alkylencOCO-5 alkyl, CO-3 alkylencOCI -5 fluoroalkyl, CO-3 alkylcncNH2, CO-3 alkyleneNHCl-3 alkyl, CO-3 alkyleneN(Cl-5 alky 1)2, N(C4-5 alkylene), Cl-5 alkylthio, S(O)Cl-5 alkyl, S02C1-5 alkyl, Cl-5 fluoroalkylthio, NH{CO)Cl-5 alkyl, NH(CO)C1-5 alkoxy, NHS02C1-5 alkyl, (CO)C1-5 alkyl, COOH, (CO)Cl-5 alkoxy, (CO)NH2, (CO)NHCl-5 alkyl (CO)N(Cl-5 alky 1)2, cyano, S02NHC0 5 alkyl, nitro, aryl, heteroaryl, azido (N3), and morpholinyl, such as N- morphnlinyl; A compound according to formula (1) as disclosed above may be present as a free base, an acid in its non-charged protonated form or a pharmaceutical ly acceptable addition salt, solvate or solvate of a salt thereof Further a compound according to formula (I) as disclosed herein may be present as pure stereoisomer, a racemic-, diastercomeric- or scalcmic mixture. As disclosed below, various embodiments of the present invent arc drawn to compounds according to the general formula (I), as disclosed above, wherein the various generic groups (R1 to R10, XI to X8, Q. Wl and W2) as well as the integers "nv1 and "p" arc elaborately disclosed. As disclosed above, at least one of R l and R2 should be hydrogen in formula (I). Compounds, in which at least one of R1 and R2 is hydrogen was shown to be more potent, in at least one of the herein described in-vitro methods, than the corresponding di-methoxy derivatives. In one embodiment both Rl and R2 are hydrogen. In one embodiment R3 and R4 arc, independently of each other, selected from H, fluoro, chloro, bromo. and methyl In another embodiment they arc independently of each other, selected from H, chloro and bromo, more preferred from chloro and bio mo and particularly preferred from chloro. In one embodiment R3 and R4 may also both be In another embodiment both R3 and R4 arc the same and arc selected from H, fluoro, chloro, bromo, and methyl In another embodiment they are selected from H, chloro and bromo,, more preferred from chloro and bromo. One advantage of a compound wherein R3 is identical lo R4 is, among others, thai the purification of synthetic intermediates to produce such a compound is easier. In another embodiment G is G1 and the stereochemistry of the double-bond of Gl, onto which the substituents R5 and R6 are attached, is such that R5 and R6 are oriented in a trans-fashion relative to each other. In an embodiment wherein G is G1, R5 and R6 may be, independently of each other, selected from H, Cl-5 alkyl, such as methyl, CH2 phenyl and Cl-5 fluoroalkyl, such as CF3. R5 and R6 may also be, independently of each other, selected from H and methyl. Further, R5 may be H or Me, such as being H. Also R6 may be H or Me, such as being H. In another embodiment G is Gl and Q is phenyl, i.e. X1 to X5 arc C. In another embodiment G is G1 and at least one of X1 to X5 is "N, Further two of X1 to X5, such as X1 and X3 or X1 and X5, may be N and the residue being C. In another embodiment G is G1 and Q is pyridyl, i.e. one of X1 to X5 arc N and the residue being C, In an embodiment wherein Q is pyridyl, it is preferred if X1 or X2 isN. In another embodiment G is Gl, "n11 is 1 or 2 and R7 is, independently of each other if "n" is 2, selected from C1-C3 alkyl, such as methyl, tri fluoro methyl, halo, such as fluoro and chloro, hydroxy, N(C4-5 alkylene), methoxy, S02Mc, cyano, thienyl, nitro, phenyl, morpholinyl, such as N-morpholinyl, and N(Cl-3 alkyl)2, in which the CI-3 alkyl may be the same or different, such as N(Me)2, In another embodiment G is Gl, "n" is I or 2 and R7 may be, independently of each other if "n" is 2, selected from methyl, trifluoromethyl. hydroxy I. fluoro, chloro and N(C5 alkylene). In another embodiment wherein G is Gl, "n" may be I or 2 and R7 may be, independently of each other if un?: is 2, selected from trifluoromethyl, fluoro, chloro, NMe2 and methyl. In one embodiment at least one R7 is a heteroaryl, such as 5- or 6-membered heteroaryl. In another embodiment at least one R7 is a 5-membercd heteroaryl, such as a thienyl. In an embodiment wherein G is Gl and "n" is 1 or 2, one substituent R7 may be positioned at X3. In an embodiment wherein G is GI and "n" is 2, one substituent R7 may posit ioncd at X3 and the other at X1 or X5. In another embodiment G is Gl and "n" is 0 (zero), i.e. Q is unsubstitufed. In another embodiment G is G2 and the stereochemistry of the double-bond of Gl, onto which the substituents RS and R9 are attached, is such that RK and R9 are oriented in a trans-fashion relative to cach other. In an embodiment wherein C is G2, R8 and R9 may be, independently of cach other, selected from H and methyl. In another embodiment G is G2 and at least one of X6, X7 and X8 is N, the residue being C. In an embodiment wherein G is G2, one of X6, X7 and X8 may be N. If at least one of X6, X7 and X8 is N, then it is preferred if XK is N. Similarly, it is preferred if X8 is N if one ofX6, X7 andX8 is N. In another embodiment G is G2, "n" is 1 or 2 and R10 is. independently of cach other if "n" is 2, selected from C1-C3 alkyl, such as methyl, trifluoromcthyl, halo, such as fluoro and chloro, hydroxy, N(C4-5 alkylcnc), mcthoxy, S02Me, cyano, thienyl, nitro, phenyl, morpholinyl, such as N-morpholinyl and N(CI-3 alkyl)2, in which the C1 -3 alkyl may be the same or different, such as N(Me)2. In another embodiment G is G2, "n1" is 1 or 2 and R10 may be, independently of each other if "n" is 2, selected from methyl, irilluoromethyl, hydroxyl, fluoro, chloro and N(C5 alkylene). In another embodiment G is G2, "n" is 1 or 2 and R10 is, independently of cach other if "n11 is 2, selected from methyl, trifluoromcthyl, NMc2, fluoro and chloro. In another embodiment G is G2 and "n1' is 0 (zero), i.e. W1 and W2 are unsubstituted. In another embodiment, a compound according to the invention is selected from the group consisting of: In another embodiment, a compound according to the invention is selected from the group consisting of: A compound according to formula (I) may be used in therapy. It may be used to treat revoke, mitigate, alleviate or prevent a disease or condition characterized by bronchoconstrietion of the respiratory apparatus of a mammal, such as a human being. Further it might be used to treat, revoke, mitigate, alleviate or prevent a disease or condition characterized by inflammation or vasoconstriction of the respiratory apparatus, or other organs or parts of the body, of a mammal, such as a human being. A method to treat, revoke, mitigate, alleviate or prevent bronchoconstrietion in a mammal, such as a human being, in need thereof is also disclosed. Furthermore a method to treat, revoke, mitigate, alleviate or prevent inflammation or vasoconstriction of the respiratory apparatus, or other organs or parts of the body, of a mammal, sueh as a human being, in need thereof is also disclosed. Such method includes the administration of therapeutically effective amount of a compound according to formula (1). Furthermore a compound according to formula (I) may be used for the prevention and/or treatment of a disease or condition selected from the group consisting of asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis, bronchiolitis and bronchopulmonary dysplasia Additionally, a compound according to formula (1) may be used to manufacture a medicament, such as pharmaceutical composition. Such a medicament may be useful to treat, revoke, mitigate, alleviate or prevent a disease or condition characterized by bronchoconstrietion of the respiratory apparatus of a mammal, such as a human being. It may also be useful to treat, revoke, mitigate, alleviate or prevent a disease or condition characterized by inflammation or vasoconstriction of the respiratory' apparatus or other organs or parts of the body of a mammal, such as a human being. A molecule according to formula (I) may further be used to manufacture a mcdicamcnt for the prevention and/or treatment of asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis, bronchiolitis and bronchopulmonary dysplasia. When used in herein, "prevent/preventing" should not be construed to mean that a condition and/or a disease never might occur again after use of a compound or medicament according to embodiments disclosed herein to achieve prevention. Further, the term should neither be construed to mean that a condition not might occur, at least to some extent, after such use to prevent said condition. Rather, "prevent/preventing'" is intended to mean that the condition to be prevented, if occurring despite such use, will be less severe than without such use. The usefulness of the compounds, as defined in the preceding embodiments, in treating, prctrcating, revoking, mitigating, alleviating and'or preventing a condition of the respiratory apparatus characterized by broncho constrict ion, were evaluated in a complex and relevant in vitro model, The in vitro model was in accordance with the in vitro model disclosed in US 2006-0040254 AI and by Skogvall, S., Berglund, M., Da 1 ence-Guzman, M. F,, Svensson, Kr, Jonsson, P., Persson. C. G. A and Sterner, 0„ in Pulmonary Pharmacology and Therapeutics, vol 20:3, 2007, p, 273-280. All refercnccs disclosed herein are hereby incorporated in their entirety by reference. In short, lung tissue was obtained from patients undergoing lobectomia or pulmectomia due to lung carcinoma. From the bronchus of this tissue were rectangular oblong preparations obtained. The contraction induced by inflammatory mediators, such as Lcukotricnc D4, histamine, prostaglandin D2 or acetylcholine, in the presence and absence of the compound to be evaluated, were compared. Capsazepine, one of the first reported TRPV1 -antagonists, has been shown to have an cffcct of human airways (Skogvall, S., BcrgJund, M., Da I en cc-Guzman, M. F., Svensson, K., Jonsson, P., Persson, C. G. A and Sterner, O., Pulmonary Pharmacology and Therapeutics, vol 20:3, 2007, p. 273-280), but is also known to posses a range of other biological effects. Consequently capsazepine is not selective towards one target and accordingly its usefulness as a molccular tool has been questioned (Gunthorpc, M. J., Neurpharmacology, 2004, 46, 133). Aecording to one embodiment, preferred compounds according to any of the embodiments disclosed herein arc those being at least comparably active to Capsazepine, in the in vitro model referred to herein. Aecording to another embodiment, preferred compounds according to any of the embodiments disclosed herein arc those being at least comparably active to Rcs-4- 95, disclosed in Pulmonary Pharmacology & Therapeutics, 2007, 21(1), 125-133 as a potent analogue to Capsazepine, in the in vitro model referred to herein. Inflammation is closely associated with COPD. New drugs that rcduce pulmonary inflammation by modulation of inflammatory pathways involving inflammatory mediators, such as lcukotricnc B4 (LTB4) and monocyte chemotactic protein-1 (MCP-1), is believed to provide effective and disease-modifying therapies and is therefore much desired (Friedman et a!, Clinical Cornerstone, 2003, 5, 45-51). MCP-1 attracts monocytes that can differentiate into macrophages. Macrophages are generally believed to be responsible for the continued protolytic activity in the lungs of COPD-paticnts, as well as driving the inflammatory process in the same by recruitment of neutrophils. The fact that increased levels of various inflammatory mediators, or associated receptors, correlates with the diagnosis of COPD, is indicative of their rclevancc in disease severity and progression. Comparative studies between COPD-paticnts and non-COPD subjects have, for example, shown that the former group has increased levels of MCP-I in the sputum (Traves, L.S. eta!, Thorax, 2002. 57, 590-595). increased mRN A expression of MCP-1 in lung tissue (Tomaki, M. et aL Pulmonary Pharmacology & Therapeutics, 2007, 20, 596-605), and increased lipopolysaccharide (TPS) stimulated release of MCP-1 from isolated blood monocytes (Aldonyte, R. et al, Respiratory Research, 2003, http://respiratory- research.com/content/4/1/11). LTB4 is an araeidonic acid metabolite involved in leukocyte recruitment. LTD4 is a potent chcmoattractant and activator for neutrophils. The LTB4-receptors BLT1 and PPAR are upregulatcd in peripheral lung of COPD patients (Marian, E. et al 2006. 129, 1523-1530). Higher sputum- (Profita, M. et al Allergy, 2005, 60. 13611369) and scrum- (Scgger, J.S. etaU Chest, 1991, 99, 289-291) concentrations of LTB4 is found in COPD-paticnts as compared to healthy controls. Reduction of serum inflammatory mediator levels, including LTB4-levels, by a dietary supplement containing omega-3 polyunsaturated fatty acids, correlated significantly to a clinical improvement in COPD-paticnts (Matsuyama, W. et al, Chest, 2005, 128, 3817-3827). Accordingly, the anti-inflammatory effect, i.e. the usefulness in treating, prctrcating. revoking, mitigating, alleviating and/or preventing an inflammation, such as an inflammation of the airways, of the compounds, as defined in the embodiments herein, may be assessed in an in vitro human peripheral blood mononuclear cell (PBMC) model. Further, the anti-inflammatory effect may be compared to the effect of dcxamcthasone, a known potent anti-inflammatory glucocorticoid. According to one embodiment, preferred compounds according to any of the preceding embodiments arc those being at least comparably active to dexamethaonsc in such an anti-inflammatory in-vitro model. A mcdicamcnt, e.g. a pharmaceutical composition, as has been dcscribcd herein above may further comprise pharmaceutical^ acceptable carriers, diluents, stabilisers and/or exeipients, "Pharmaceutically acceptablc" means a carrier, stabiliser, diluent, cxcipicntor other constituents that, at the dosage and concentrations employed, does not cause any unwanted effects in the patients to whom it is administered. Such pharmaceuiically acceptable carriers, stabilisers, dilutents or exeipients arc well-known in the art, and examples of such are for example disclosed in Remington's Pharmaceutical Sciences, 18th edition, A.R Gennaro, Ed,, Mack Publishing Company (1990) and handbook of Pharmaceutical Excipients, 3rd edition, A. Kibbc, Ed., Pharmaceutical Press (2000). A medicament according to embodiments herein maybe administered to a patient in a pharmaccutically effective dose. By "pharmaceutically effective dose" is meant a dose that is sufficient to produce the desired effects in relation to the condition for which it is administered. The exact dose may depend on the activity of the compound, manner of administration, nature and severity of the disorder and/or disease and the general conditions, such as age and body weight olThe patient, Aecording to one embodiment, a medicament aecording embodiments herein may be administered id one or in combination with other therapeutic agents, such as anti-asthmatics. These agents may be incorporated as part of the same medicament or may be administered separately. It is well known in the art that a combination of mechanistically unrelated therapeutic agents in the same mcdicamcnt may have beneficial effects in the treatment of conditions or diseases characterized by bronchocon strict ion, as described in, tor example, M.F. Fitzgerald and J.C. Fox, Drug Disco very Today, 2007, 12 (11/12), p. 472-478. In one embodiment of the invention such other therapeutic agents to be administered in combination with a mcdicamcnt according to embodiments of the invention arc selected from therapeutic agents known to the one skilled in the art to prevent bronchoconstriction or revoke, fully or partly, any present bronchoconstriction. Examples of such agents are, but not limited to, p2-agonists, anticholinergics calcium antagonists, and other agents suitable for the treatment of asthma and/or COPD and related diseases and/or disorders. Preferred agents in this aspect arc p2-agonists and anticholinergics. Furthermore such other therapeutic agents to be administered in combination with the medicament of the invention may also comprise therapeutic agents known to the one skilled in the art to be useful to treat, revoke, mitigate, alleviate or prevent inflammation associated with diseases and disorders of rcspiratoiy tract. Examples of such agents arc corticosteroids. When a compound according to embodiments disclosed herein is combined with at least another therapeutic agent, such as an anti-asthmatic, in a mcdicamcnt, such as a pharmaceutical composition, a therapeutically effective dose of said medicament may comprise I to 10 times less than the respective established therapeutically effective dose of the components, i.e. a compound according to embodiments disclosed herein and the therapeutic agent, when administered alone for prevention or treatment of the same disease or condition of each. Accordingly, by combining a compound according to the present invention with another therapeutic agent, such as an anti-asthmatic, it may be possible to achieve synergistic effects compared to if only a compound according to the present invention, or the other therapeutic agent, were administrated alone. Furthermore, it may be possible to improve both the underlying cause, e.g. the inflammation, and the clinical signs, e.g. airflow obstruction and exacerbations. A method to treat, revoke, mitigate, alleviate or prevent bronchoconstriction and/or an inflammatory condition in a mammal, such as a human being, in need thereof, by the administration of a compound or medicament, such as a pharmaceutical composition, according to embodiments disclosed herein may also include the simultaneous or consecutive administration a therapeutic agent, such as an antiasthmatic. In such a method the therapeutically effective dose of said compound, medicament or pharmaceutical composition and said therapeutic agent may comprise 1 to 10 times less than the respective established therapeutically effective dose when administered alone for prevention or treatment of the same disease or condition. The advantageous of such co-ad ministration arc discussed above. A medicament according to embodiments disclosed herein may be administered through different routes such as, but not limited to, intravenously, intraperitoncaly, intramuscularly, intranasaleously, subcutancously, sublingually, rcctally, orally or through inhalation or insufflation. Particular suitable formulations of the medicament of the invention are formulations suitable to be taken orally or to be administrated through inhalation or insufflation. Administration by inhalation or insufflation will allow a high proportion of the delivered dose to reach the site of action, that is, the bronchi and the lung in general. Furthermore the systemic effects may be lower if the mcdicamcnt is administrated through inhalation or insufflation compared toother administration routes. Inhalation may be by the oral or the nasal route. Conventional pulmonary applicators may be employed, such as pressurized spray containers comprising suitable propel I ants for aerosols and powder spray dcviccs for preparations in form of fine powders. Pharmaceutical compositions suitable for administration by the inhalation or insufflation route are known in the art. The compound may be dissolved in a suitable vehicle or employed as a fine powder, such as a micronized powder of a particle size from about 2 pm to about 20 pm. An indicated daily dose for administration by inhalation may be 10 times and more lower than the corresponding oral dose. Satisfactory doses, preferably metered by using a device capable of metering, or by single doses of predetermined size, may easily be determined by experimentation. Compounds according to embodiments of the present invention may also be useful in treatment or prevention of hypertension. In the treatment of conditions or diseases characterized by hypertension, by employment of the compounds of the present invention, oral administration is the preferred route of administration. In addition to their use in therapeutic medicine, compounds according to formula I may also be useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of other compounds with similar activity. Furthermore, compounds of formula I may be used as molecular probes to identify and/or locate the target of their action, such as a target within the airways, as well as employed as a diagnostic tool for diagnosis of a disease or condition in vivo, ex vivo or in vitro, or as synthetic precursors to such probes. Molecular probes of formula I may include reactive, labeled, i.e. compounds of formula I wherein one or several of the composing atoms have been enriched with a radioactive or by other means detectable isotope, and fluorescent compounds as well known to the one skilled in the art. Methods of preparation Other embodiments of the present invention relates to processes for preparing a compound according to formula I as a free base, acid, or salts thereof. Further, additionally embodiments relate to synthetic intermediates, which are useful in the synthesis of a compound of formula 1 as a free base, acid, or salts thereof. Specific and generic examples of such intermediates are given below. Further, such intermediates may include compounds according to formula I, which may be used to produce another compound according to formula I. Throughout the following description of such processes it is to be understood that, where appropriate, suitable protecting groups will be attached to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups, as well as examples of suitable protecting groups, are well known within the art. Further such procedures and groups are described in the literature, such as in "Protective Groups in Organic Synthesis", 3rd ed., T.W. Green, P.G.M. Wuts, Wiley-lnterscience, New York (1999). It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conductcd on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carricd by the molecule at that stage to the condilions or reagenis employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to the one skilled in the art of organic synthesis. Examples of transformations arc given below, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions on other suitable transformations are for example given in "Comprehensive Organic Transformations A Guide to Functional Group Preparations'1. 2nd ed., R. C. Larock, Wiley-VCH, New York (1999). References and descriptions of'other suitable reactions are described in textbooks of organic chcmistry well known to the one skilled in the art, such as "March's Advanced Organic Chemistry1', 5th ed., M. B. Smith, J. March, John Wiley & Sons (2001) or, "Organic Synthesis", 2nd ed., M. B. Smith, McGraw-Hill, (2002). Techniques for purification of intermediates and final products include for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily understood by the one skilled in the art. The terms ""room temperature" and 1Lambient temperature" shall mean, unless otherwise specified, a temperature between 16 and 25 The term "reflux" shall mean, unless otherwise stated, in reference to an employed solvent using a temperature at or slightly above the boiling point of the named solvent. It is understood that microwaves can be used for the heating of reaction mixtures. The terms "flash chromatography" or "flash column chromatography" shall mean preparative chromatography on silica using an organic solvent, or mixtures thereof, as mobile phase. Abbreviations aq. aqueous: CDI 1,1'-carbonyl diimidazole; CH2C12 dichloromcthane; DABCO 1.4- diazab ic yclo [2.2.21 oc tanc; DMAP 4-d i methylam i nopy rid ine; DMF N,N-dim ethyl form amide; DMSO dimethyl sulfoxide; EDCHCI N (3 -d i methylam i nop ropy I )-N '-ethyl carbodiimide; Et,N triethylamine; EtOAc ethyl acetate; EtOH ethanol; Et2G diethyl ether; h hour(s); HRr hydrogen bromide; HCI hydrogen chloride; HOBt 1 -hydroxybenzotriazole hydrate; K2CO3 potassium carbonate; ma major; McOH methanol; MgS04 magnesium sulphate; mi minor: NaHCO* sodium bicarbonate; NaOH sodium hydroxide; Pet. Ether petroleum ether; r.t. or rt room temperature; rot. mix. rotameric mixture sat. saturated; THF tctrahydrofurane; TLC thin layer chromatography; TMS tetramethylsilanc, Methods of preparation of final compounds of formula I by coupling of intermediates II and HI (Scheme I) R1 R3 Scheme 1 Formation of compounds of formula I, may be accomplished by coupling of II and 111 (wherein depleted "(het)Ar" is represented by aryl or heteroaryl, R corresponds to R5 and RK of formula I, R* corresponds to R6 and R9 of formula I) under standard amide coupling conditions, such as in the presence of N-(3-dimcthylami nop ropy l)-N ethyl-carbodiimidc hydrochloride, 1-hydro xybenzotri azoic hydrate, 4- d imethylaminopyridine and caesium carbonate (see for example Toftered et a I., SYNLETT, 2004, 2517-2520), or, for example, via initial conversion of the acid 111 into the corresponding acid chloride, followed by coupling with II according to standard protocols. The N-acylation of 11 may be accompanied by competing O-acylation when one or both of the substituents R1 and R2 arc hydrogens. Thus, it is preferred to protcct the corresponding phenolic moieties with suitable protective groups, such as methyl, before N-acylation of II, Methyl protective groups may be introduced by treatment with a methyl halide in the presence of a base according to standard procedures, and removed after the N-acylation by treatment with, for example, hydrogen bromide or boron tribromide (Hall et ah, Bioorg. Med. Chem, 2005, 13, 1409-1413). Other aromatic methyl ethers, optionally present in the molecule, are then simultaneously cleaved off. Methods of preparation of intermediates of formula II (Scheme 2) II Scheme 2 Examples of two nan-limiting methods for the preparation of intermediates of formula II, by assembly of the tetrahydroisoquinoline ring, include pathway A and pathway B. The synthesis according to pathway A involves a Pictct-Spcngler reaction in which readily available phenylcthylaminc IV is reacted with formaldehyde to yield V, followed by cyclisatiori under acidic conditions (Yokoyama et al., J Org Chem, 1999, 64, 611-617; for a modified procedure allowing eyelisation onto electron poor aromatics see for example Stokker et al., Tetrahedron Lett, 1996, 37, 5453-5456). The synthesis corresponding to pathway B involves a Pomcrantz-Fritsch reaction under reductive conditions in which readily available benzaldchydcs VI arc reacted with aminoacetales VII (depicted "alkyl" is preferably short alky Is such as ethyl) to yield VII I, followed by cyclisation under acidic and reductive conditions to yield II (see for example: Bobbit et al., J Org Chem. 1965, 30. 2247-2250; Bobbit et al., J Org Chem, 1968, 33, 856-858). Additional methods for the preparation of intermediates II include, for example, the direct introduction of the substituents R3 and R4 by electrophilic aromatic substitution, such as chlorination by treatment with sulphury I chloride in acetic acid, or bromination as described in Okano et al., Tetrahedron, 2006. 128, 7136-7137. Methods of preparation of intermediates of formula 11 1 (Scheme 3) alkyl Heck + X—(het)Ar O R' (het)Ar R XI 0 hydrolysis H A.. IX XII + Knoevenagel Scheme 3 0 (het)Ar (MI R=R-=H) XIII Intermediates of formula 111 may be prepared from readily available esters IX (depicted "alkyl" is preferably short alkyls such as methyl) by, for example, standard palladium catalyzed Heck-coupling with aryl- and hcteroaryl-halidcs X (depicted X is lodo, bromo or chloro), followed by hydrolysis with, for example, sodium hydroxide in a mixture of THF and ethanok The suitable reaction conditions, and the type of palladium catalyst employed in the Heck-co up ling, is much dependant on the nature of the substituent R' of IX and to the type of halide in X as well known to the one skilled in the art. For example, for electron-rich aryl- and hcteroaryl-halidcs X, iodo or bromo is preferred over chloro as the halide unless a palladium-catalyst w ilh relatively high activity is employed. Additional methods for the preparation of intermediates of formula III include standard Knoevenagel condensation between malonic acid XII. and aryl- or heteroaryl aldehydes XIII, followed by decarboxylation (lower part of scheme 3). Furthermore, when aiming for intermediates of formula XI (and then III after hydrolysis, as described above) in which R' ^ H, the Heck reaction may be low yielding bccause of steric hindrance at the terminal position of the double bond of structures such as IX, Instead one may employ the Homer Wads worth Emmons (HWE) reaction, in which a phosphinc oxide of general formula XIV reacts with a heteroaryl ketone of general formula XV (Scheme 4). ¥ R' HWE hydrolysis -alkyl + 0* CT (het)Ar XV alky V i alkyl R XIV Scheme 4 Compound examples General Methods All materials were obtained from commercial sources, unless not stated otherwise, and were used without further purification unless otherwise noted. DMF was dried over molecular sieves (4A). THF was distilled from sodium and benzophenone. HRMS (ESI) spectra were recorded with a micro mass Q-TOF Micro spectrometer. NMR spectra (in CDCI3, CD30D or DMS0-d6) were recorded on a Bruker DRX 400 or on a Bruker U It rash i eld 400 spectrometer at400MHz.All chemical shifts are in ppm on the delta-scalc (5) relative to TMS using the residual CHCI3 peak in CDC13, or the residual CD2HOD peak in CD30D, or the residual CD3SOCD2H peak in (CD3)2SO as internal standard (7.26, 3.31 or 2.50 ppm respectively relative to TMS) and the fine splitting of the signals as appearing in the recordings (s: singlet, d: doublet, t: triplet, q: quartet, m: multiples br: broad signal). Flash chromatography was performed using 60A 35-70 um Davisil silica gel. TLC analyses were made on Silica Gel 60 F254 (Merck) plates and visualised under a 254/365 nm UV-lamp, Preparation of intermediates Below follows non-limiting examples on the synthesis of intermediates useful for the preparation of compounds of fonnula I. 5,8-Dichloro-6,7-dimethoxv-l,2,3,4-tetrahydroisoquinoline hydrochloride Dimethoxy-L2,3,4-tctrahydroisoquinoline hydrochloride (200 mg, 0.870 mmol) was suspended in glacial acctic acid (5 mL) and sulphuiyl chloride (154 pL, 1.92 mmol) was added slowly. The resulting mixture was stirred at room temperature for 3 hours and then evaporated to give the title compound (quant) as a yellowish mass. 'H NMR (400 MHz, CD.^OD) 5 4.35 (br s, 2H), 3.90 (br d, 6H), 3.50 (br, 2H). 3.05 (br, 2H). 5.8- D ic h I or o-6,7- dihy d rosy-1,2,3,4-tetr ah y d roi soq u in o M ne liy d r o h r omide CI 5,8-Dichloro-6,7-dimcthoxy-l,2,3,4-tctrahydroisoquino[inc hydrochloride (1.0 g, 3,35 mmol) was suspended in aqueous HBr (48%, 10 mL) and refluxed for 5 hours before evaporation. The remaining residue was evaporated twice from toluene to give 1.05 g (quant) of the title compound as a pale solid. 'H NMR (400 MHz, CD,OD) 6 6.60 (s, 1H) 6.57 (s, 1H) 4.26 (s, 2H) 3.50 (t 2H, ,J=6 Hz) 3.01 (t, 2H, ,/=6 Hz). 5,8-Bi s (chioromethy1)- 6,7-dimet hoxy-1,2,3,4- tetrahydroisoq uinoline acetamide CI 6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline hydrochloride (2.0 g, 8.71 mmol) was dissolved in water (20 ml) and NaOH (10 ml, 2M aq). The aqueous phase was extracted with dichloromethane (420 ml) and the combined organics were dried (MgSCK)) and filtered. The filtered liquid was cooled to 0 °C before slow addition of acetyl chloride (620 JJ.1, ft.71 mmol) followed by slow addition of EuN (1.22 ml, 8.71 mmol). The resulting mixture was stirred at rt for 30 minutes, washed with HC1 (280 ml, 1M aq.) and NaHCO.* (80 ml, sat aq.), dried (MgS04). filtered and evaporated into a pale mass. This mass was dissolved in nitromethane (40 ml) and cooled to 0 °C. Tin(IV)chloride (8.15 ml, 70.0 mmol) was added slowly followed by slow addition of methoxyacetyl chloride (3.18 ml, 34.8 mmol) and the resulting mixture was stirred at rt for 24 h. The reaction was then diluted with HCI (30 ml, conentrated. aq.) and extracted with dichloromethane (340 ml). Combined organics were washed with water (20 ml), dried (MgSO^), filtered and evaporated into a pale solid foam. The product was purified by flash chromatography using Pet. Ethcr/EtOAc (1/2) as eluent to give 420 mg (14 %} of 5.8-bis(chloromcthyl)-6,7-dimcthoxy-L23,4-tctrahydroisoquinoline acet amide as a pale, sticky mass, 'HNMR (CDC1?) rot. mix. 5 4.77-4.55 (br, 2H) 4.20-4,05 (br, 2H) 3,82 (s, 6H) 4.81-4.70 (br, 2H) 3.96-3.85 (br, 2H) 3.85-3.75 (br, IH) 3.75-3.63 (br, 2H) 2.94-2.83 (br, 2H) 2.80-2.62 (br, 2H) 1.46 (s, 9H). TLC (Pet. Ethcr/EtOAc 1/1) Rf 0.23. 6,7-Dimetlioxy-5,8-dimethyl-l,23^4-tetrahydroisoquino]ine acel amide 5,8-Bis(chloromethy l)-6,7 -di mctho x y-1,2,3,4-dihydroisoquinoline acctam id c (420 mg, 1.26 mmol), was dissolved in DMF (6 ml) at rt. Sodium cyanoborohydride (199 mg, 3.16 mmol) was added and the reaction was stirred at 100 °C for 20 h. The reaction was cooled, diluted with HC1 (60 ml, IM aq.) and extracted with EtOAc (320 ml). Combined organ ics were washed with NaHCCh (30 ml, sat. aq.) followed by brine (30 ml), dried (MgSO4). filtered and evaporated to give 396 mg of crudc 6,7- dimethoxy-5,8-dimethyl-l,2,3,4-tetrahydroisoquinoline acetamide as a pale oil. This material was used in subsequent reactions without further purification, 'H NMR (CDCIV) rot. mix. 5 4.55 (ma)(sf 2H) 4.43 (mi)(s, 2H) 3.79 (mi)(br t, 2H) 3.78 (s, 6H) 3.65 (ma)(br t, 2H) 2.73 (ma)(br t, 2H) 2.66 (mi)(br t, 2H) 2.18 (br d, 3H) 2.13 (br d, 3H)2.02 (s, 3H). 6,7- Dimethoxy-5,8-dim ethyl-1,2 3,4-tetra hydroisoquinoline 6,7-Dimethoxy-5,8-dimethyI-1,2,3,4-tetrahydroisoquinoline acetamide (396 mg) was dissolved in 1,4-dioxanc (10 ml). NaOH (10 ml, 2M aq.) was added and the mixture was rcfluxcd for 21 h. Organic solvents were evaporated and the aq. residue was extracted with dichloromethane (420 ml). Combined organics were dried (MgSOj), filtered and evaporated. The product was purified by flash chromatography using EtOAc/MeOH/EtjN (20/2/1 16/4/1) as clucnt to give 116 mg (42 %) of 6,7- dimethoxy-5,8-dimethyl-1,2,3,4-tetrahydroisoquincline as a clear, oily residue, 'HNMR (CDCl3) 5 3.87 (s, 2H) 3.80 (s, 6H) 3.13 (t, J= 6 Hz, 2H) 2,60 (t,7 6 Hz, 211) 2.14 (s, 311)2.09 (s, 3H). TLC (EtOAc/MeOH/Et,N 16/4/1) Rf0.35. 3-l0d0-2-(piperidin-1 -yl)-6- (tri flu o r o meth y l)py r idin e A solution of 2-chloro-3-iodo-6-(trifliioromcthyI)pyridme (Tet. Lett., 1998, 39(13), I749-1752)(350 mg, 1.14 mmol), piperidinc (135 pi, 1.37 mmol) and Et,N (640 pi, 4,56 mmol) in /-PrOH (2 ml ) was heated for 1 h at 140 °C in a microwave reactor. The reaction mixture was concentrated to dryness and the crudc was purified through flash chromatography (Si02, heptane) to afford 237 mg (58%) of the title compound. 1H NMR (CDCh) 8 8 J 7 (dd, J= 7.6 Hz, J= 0.8 Hz. 1H) 6.91 (d, J= 7.6 Hz, 1H) 3.29 (m, 4H) 1.75 (m. 4H) 1.63 (m, 2H). General procedure for the llcck reaction to yield compounds X (Scheme 3) Aryl bromide X (1.0 equiv,), Pd(OAc)2 (2 mol%), DABCO (4 mol%) and KJC03(1.0 equiv.) were suspended in DMF (5.2 mL/mmol aryl bromide X) together with the unsaturated ester IX (1.5 equiv.). The mixture was flushed with argon before the tube was scaled and heated at 125 °C for 12 hours. Then, the mixture was filtered through Celite, rinsed with CH2O2 and evaporated, The remaining residue was then purified by column chromatography to yield compounds XI. The following compounds were prepared according to the general procedure described above. (E)-Met h y 1 3-(q u i nol i n -3-y l)acry lat e O The title compound was obtained as a white solid in 85% yield (Sit>2, petroleum ether/ethyl acetate 85/15 —► 50/50). 'H NMR (400 MHz, CDCb) 6 9.10 (d, 1H, J=2.0 Hz) 8.25 (d, 1H. 7=2.0 Hz) 8.12 (d, 1H, ,7=8.4 Hz) 7.86 (d, 1H, .7=16.0 Hz) 7.87-7.85 (m, 1H) 7.78-7.74 (m, 1H) 7.62-7.58 (m, 1H) 6.68 (d, 1H.,/= 16.0 Hz) 3.86 (s, 3H). (ZT/Z)-Methyl 3-(quinolin-3-yl)but-2-enoatc The title compound was obtained as a diastereomeric mixture (E- and Z- isomers), as a white solid, in 52% yield. Rf0.21 (SiO2, petroleum ether/ethyl acetate 80/20). 'HNMR (400 MHz, CDCh) 5 9.05 (d, IH, J=2.4 Hz) 8.22 (d, 1H, ,7=2.4 Hz) 8.13-8.11 (m, 111)7.87-7.85 (m, 1H) 7.77-7.73 (m. 111) 7.61-7.57 (m, 111)6.34-6.33 (m, 1H) 3.81 (5, 3H) 2.71 (s, 3H). (E)-ethyl 3 - (6-{t rifluoromethyl)pyridin -3-yl)ac rylate F F F O k o This material was used directly in the next step without any further purification. Yield: 97%. 'H NMR (CDCl3)δ8.85 (d, J=1.6 Hz. 1H)8,00 (dd, >2.0, 8.0 Hz, 1H)7.72 (d, J=8.4 Hz, IH) 7.71 (d, J=16.0 Hz, 1H) 6.60 (d, >16.0 Hz, 1H)4.31 (%J=12 Hz, 2H) 1.36 (t, .7=7.2 Hz, 3H), (E)-methyl 3-(2-(pipeiidin-l-yl)-6-(trifluoi0iiiethyl)pyridin-3-yl)flCrylate 70 µl (1.0 mmol) methyl aery late was added to a mixture of 237 mg (0.66 mmol) 3-iodo-2-(pipcridin-l-yl)-6-(trifluoromcthyl)pyridmc, 3 mg(0.01 mmol) Pd(OAcK 2.2 mg (0.02 mmol) DABCO and 91 mg (0.66 mmol) KXO; in 3 ml DMF under a nitrogen atmosphere. The reaction mixture was stirred in a sealed tube at 80 °C for 24 h. The mixture was cooled to RT, filtered through celite with EtOAc eluation. The organic phase was washed with w ater, dried and concentrated. Flash chromatography (Si02, Pet. Ether/ EtOAc 8/1) afforded 196 mg (94%) of the title compound. 'H NMR (CDCh) 5 7.74 (d, 1H), 7.69 (d, 1H), 7.15 (d. 1H), 6.42 (d, 1H), 3.82 (s, 3H), 3.28 (m, 4H), 1.72 (m, 4H), 1.65 (m. 2H). To a solution of 2-trifluoromethyl-5-hromopyridine (5.0 g. 22 mmol) in EtiO (50 mL) was added.veoBuLi (0.91 M in cyclohexane, 24 niL, 22 mmol) at -78 °C. 1 - (6-( T r i flu or o methy l)py ri din-3 -y I) eth a n on e F After 10 minutes of stirring, N,N-dimethylaminoacetamidc (2.3 mL, 24 mmol) dissolved in Et2O (10 mL) was added drop wise. Stirring was continued at -78 DC for 1 h and then at rt over night. The reaction mixture wras poured into water (100 mL) and the water phase was extracted with Et?0 (3 >=100 mL), Combined organics were washed with water and brine and dried (MgS04). After careful evaporation of the solvent, the crudc was purified by column chromotography (SiO^ pcntanc/ether 9/1) to give the title compound (2.3 g, 12 mmol, 54%) as a light yellow solid. 'H NMR (CDCL) S 9.26 (br s, 1H) 8.43 (br d, .7=5.6 Hz, 1H) 7.83 (br d, J=7.2 Hz, 1H) 2.71 (s, 3H). E thy] 3-(6-(t r i fl uo r om et hv I) py r id in -3-vl)b u t- 2-en oate O F Tricthyl phosphonoacctatc (6.2 mL. 31 mmol) was added drop wise to a suspension of NaH (95%, 760 mg, 30 mmol) in dry THF (10 mL) at 0 °C. After 30 minutes of stirring at 0 °C\ 1 -(6-(trifluoro methy l)pyridin-3-yI)ethanone (2.3 g. 12 mmol) in THF (8 mL) was added drop wise. The resulting mixture was heated at reflux for 12 h and was then allowed to cool to rt. The reaction mixture was poured into sat. NH^CI (aq.) (15 mL) and extracted with Et20 (315 mL). Combined organics were washed with water and brine and dried (MgS(V) After evaporation the crudc was purified by column chromatography (SiO;, Pet. Ether/EtOAc 95/5) to give the title compound (2,9 g, 11 mmol, 94%) as a light yellow oil, as a mixture of E- and Z- isomcrs. 'H NMR (CDC 1.0 d 8.81 (br s, 1H) 7.92 (br d. >8.4 Hz, 1H) 7.71 (br d, >8.0 Hz, 1H) 6.19 (br s, 1H) 4.26 (q,>7.2 Hz, 2H) 2.60 (br s, 3H) 1.34 (t, >7.2 Hz, 3H). I - (5- Flu o ropy ri di n-2 - v I) etli a n o n c .ftfc-BuLi (1.9 mL, 1.4 M in hcxane) was added drop wise to a solution of 2- bromo-5-fluoropyridine (500 mg, 2.8 mmol) in dry Et2O (6 mL) at -78 C'C. Stirring was continued at this temperature for 10 minutes, after which a solution of N,N-dimethylacetamide (290 pL, 3.1 mmol) in dry Et70 (1 mL) was added drop wise. Stirring was continued at -78 °C For 1 h, where after the reaction mixture was allowed to slowly reach rt. The reaction mixture was again cooled to -78 °C and was qucnchcd by adding 1M HCl aq. .solution (6 mL) before it was left to warm to rt over night. The water and organic phases were separated and the water phase extracted with Et?0 (2 : 1EI NMR (CD3OD) δ 8.51 (d,,/=2.8 Hz, 111)8.11 (ddd,J=0.4, 4.8, 8.8 llz, HI) 7.52 (ddt, 0.8, 2,8, 8,8 Hz, IH) 2.71 (s, 3H). General procedure for ester hydrolysis (scheme 3) A solution of NaOH (s) (500 mg) in water (1.1 mL) was added to a mcthanolic solution of the ester X1 (2.5 mmol). Stirring was continued at rt for 2h. After that, the reaction mixture was neutralized by adding 1M HCl (aq,). A white precipitate formed which was isolated by filtration and washed with water and methanol. The white chty/stalline product was dried in a vacuum oven at 45 °C. The following compounds were prepared according to the general procedure described above. (iT)-3-(quinoLin-3-y I )a c r y lie acid The title compound was obtained as a white solid in 71 % yield and was used directly in the next step without further purification. O (E)-3-(quinolin-3-vl)but-2-enoic acid o The title compound was obtained as a white solid in 94% yield and was used directly in the next step without further purification. The following compounds of formula III were also prepared as indicated (£)-3 - (6-(trifl u o r o in ethyl )p vr id in-3-yl)aeryl ic a ci d o To a solution of (£)-ethy 1-3-(6-(trifluoromethyl)pyridin-3-yl)acrylate (2.65 g, 10.8 mmol) inTHF/EtOH (1/1, 20 mL) was added 2.28 M NaOH (aq.) (14.2 mL) at it. The reaction mixture was stirred at rt for 4 h and was then neutralized by adding IM HCl (aq.). The water-phase was extracted with CH^Cb/MeOH 9/1 (5 - 20 mL), the combined organics dried (MgSO4), filtered and evaporated to give the title compound (2.15 g, 9.90 mmol, 91%) as an off white solid. This material was used directly in the next step without further puriUcation. 'H NMR (CD3OD) 6 8.91 (d, >1.6 Hz, 1H) 8.29 (dd, >2.0, 8.4 Hz. 1H) 7.85 (d,>8.4 Hz, 1H) 7.75 (d,>16.0 Hz, 1H)6.75 8d,>16.0 Hz, 1H). 3-(6-(Trl fluoro methyl)pyrldln-3-yl)but-2-enolc acid o To a solution of ethyl 3-(6-(trifluoromethyl)pyridin-3-yl)but-2-enoate (2.9 g, 11 mmol) in EtOH/THF 1/1 (34 mL) was added 1M NaOH (aq.) (34 mL). The resulting mixture was heated at 60 °C for I h after which the reaction mixture was allowed to cool to rt. The volatilcs were evaporated and the remaining water phase neutralized with 1 M HCl (aq.). The title compound (2,4 g, 10 mmol, 91%), which precipitated as a white solid, was filtered off and dried under vacuum at 55 °C over night. This material was used directly in the next step, without further purification. (F)-3 - (2- m ethy )-6-{t ri fl uo r o m ethyl) pyr idi n -3-y l)acr vl ic ac i d O OH rT " F To a solution of (E)-methyl 3-(2-mcthyl-6-(trifluoromcthyl)pyridin-3- y1)acrylate (Gray, M.; Andrews, I. P.; Hook, D. F.; Kitteringham, J.; Voyle, M. Tet, Lett. 2001, 41, 6237-6240.) (150 mg, 0.61 mmol) in MeOH (2.0 mL) was added 1M NaOH (aq.) (1.8 mL). The reaction mixture was stirred for 2 h at 40 °C. The vulatiles were then evaporated and the remaining water phase neutralized with 1M HCl (aq). The Litle compound (141 mg, 0.61 mmol, quant.), which precipitated as a white solid, was filtered off and dried under vacuum at 45 "C. This material was used directly in the next step without further purification. {E,Z)-3-(5-fluoropyridin-2-yl)but-2-en ok acid Triethyl phosphonoacctate (740 pL, 3.7 mmol) was added drop wise to a suspension of NaH (95%, 86 mg, 3.6 mmol) in dry7 THF (1.0 mL) at 0 °C. Stirring was continued at this temperature for 30 minutes, after which a solution of l-(5- fluoropyridin-2-yl)ethanone (200 mg, 1.4 mmol) in dry THF (1 mL) was added drop wise to the reaction mixture. The resulting mixture was heated at reflux for 6 h and was then left to cool to rt over night. The reaction was quenched by careful addition of NH^Cl sat. aq, solution (1,5 mL) and was then extracted with Et^O (210 mL), Combined organics wore washed with water and brine and dried (MgSO^ i. After filtration and evaporation crudc (E,Z)-ethyl 3-(5-fluoropyridin-2-yl)but-2-cnoate was obtained pure enough to be used directly in the next step. 1M NaOH aq. solution (4.2 mL) was added to a solution of (£.Z)-ethyl 3-(5- fluoropyridin-2-yl)but-2-cnoate (293 mg, 1.4 mmol) in EtOH/THF (4 mL, 1/1). The resulting mixture was heated at 40 X1 for 12 h and was then left to cool to rt. The volatiles were evaporated and the remaining water phase acidified to pH 6-7 using 1 M HCl aq. solution. The water phase was extracted w ith CH2Cl2 (5X10 mL) and combined organics were washed with brine and dried (MgSC>4). After filtration and evaporation the title compound (190 mg, 1.0 mmol, 75%) was obtained as a mixture of E- and Z- isomers which was considered to be pure enough to be used directly in the next step. The isomers were not separated at this stage. 'H NMR (CD?OD) 6 8.48 (d, >3.2 Hz, 1H) 7.78-7.73 (m, 1H) 7.66-7.60 (m, 1H) 6.63 (d, .7=1,2 Hz, 1H) 2.56 (d, ./=1.6 Hz, 3H). General procedure for amide coupling to yield methyl ethers of formula I (R l=R2=methvl. Scheme 1) 5P8-dichloro-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol ine hydrochloride (1.0 mmol), a carboxylic acid of general formula III (1.1 mmol), EDC HC1 (1.5 mmol), HOBt (1.0 mmol), DMAP (2.0 mmol) and cesium carbonate (2.0 mmol) were suspended in DMF (30 mL) and stirred at rt for 48 h. The reaction mixture was then diluted with water (30 mL) and extracted with EtOAc (3x30 mL). The combined organics were washed with NaHCO3 (2x30 mL, sat aq), water (3x30 mL) and brine and dried (MgS04). After evaporation the resulting methyl ethers of formula 1 were purified by column chromatography. The following compounds were prepared according to the general procedure described above. (E)-1 - (5,8-d ich In ru-6,7- dimetho xy-3,4-d i hyd roisoq u i n o 1 i n-2 (1 //)-yl)-3- (pyridin-3-yl)prop-2-en-l-oue The title compound was obtained as a yellowish oil in 52% yield, R\| 0,26 (SiO?, petroleum ether/ethyl acetatc 3/7). 'HNMR (400 MHZ,CDCI3) rot. mix. ri 8.79 (d. 1H, .7=2.0 Hz) 8.59 (dd, 1H, ,7=1.6, 4.8 Hz) 7.85 (td, 1H,.7=1,8,8,0 Hz) 7.71 (d, 1H, >15,6 HZ) 7.35-7.32 (m, 1H) 7.04 (d, 1H, >15.6 Hz) 4.82-4.75 (ma+mi, m, 2H) 3.99-3.84 (m, 2H) 3.91 (br s, 6H) 2.99-2.88 (M, 2H). (E)-1 - (5,8-d ichl o ro-6,7- dim e t h o xv-3,4- d i hyd r oisoq u in o li n-2 - (l//)-vl)-3 -(5 fluoropyridin-2-yl)prop-2-en-l-one The title compound was obtained as a colourless oil in 47% yield, Rj 0.28 (SiCb, petroleum ether/ethyl acetate 1/1). JH NMR (400 MHz, McOD) rot. mix. 6 8.53 (d, 1H,>2.8 Hz) 7.74-7.62 (m. 4H) 4.82 (br s, 2H) 4.01-3.98 (m, 2H)3.89 (brs, 6H) 2.99-2.90 (ma+mi,m, 2H). (E)-1 - (5,8-d ich I o r o-6,7- d i m et h o xy-3,4- d I li y d r oisoq u 1 n o 1 i n-2 (I H)-y l)-3- (q u i n o li n-3 -y l)pr op- 2-en-1 - on e The title compound was obtained as a white solid in 39% yield (SiOz, petroleum ether/ethyl acetate). 'H NMR (400 MHz, CDCh) rot. mix. 5 9.15 (d, 1H,>2.4 Hz) 8.26 (d. 1H >2.0 Hz) 8.13 (d, 1H, >8.4 Hz) 7.90 (d, 1H,> 15.6 Hz) 7.88 (br d, 1H,>7.2 Hz) 7.78-7.74 (m, 1H) 7.62-7.58 (m, 1H) 7-21 (d, 1H, > 15.2 Hz) 4.87-4.82 (ma+mi)(m. 211) 3.99-3.91 (m, 211) 3.93 (s, 311) 3.92 (s, 311) 3.00-2.94 (ma i mi, m,2H). (E)-1 - (5,8-d ich I o r o-6,7- d i m et h o xy -3,4- d i liv d r oisoq u i n o 1 i n-2 (l//)-y l)-3- (quin o li n-3 -y l)bu t- 2-en- 1-one The title compound was obtained as a colour less oil in 40% yield (SiOj, petroleum ether/ethyl acctatc 6/4). 'HNMR (400 MHz. CDCh) rot. mix. ri 9.10 (d. 1H.>2.0 Hz) 8.20 (brs. 1H) 8.13 (br d, 1H, >8.4 Hz) 7.87 (br d, 1H, >8.0 Hz) 7.75 (br t, 1H, >7.8 Hz) 7.60 (br t, 1H, >7.4 Hz) 6.57 (br 5, 1H) 4.84 (ma, br s, 2H) 4.71 (mi, br s, 2H) 3.98-3.81 (ma+mi m, 2H) 3.93 (s, 6H) 2.97-2.89 (m, 2H) 2.45 (ma, br s. 2H) 2.41 (mi, br s, 2H). (E)- I - (5,8-dichl 0 r0-6,7- d i m e t h 0 xy-3,4-di h y d roiso q u i n 01 i n-2 (I H)- yl)-3-(4- m etho xy p heny l)p r 0 p-2 - e n -1 -0 n e The title compound was obtained as a white solid in 43% yield (SiO^, petroleum ether/ethyl acetate 75/25). 'H NMR (400 MHz, DMSO-A) rot. mix. 6 7.76-7.64 (m, 2H) 7.50 (br d, 1H, >15.2 Hz) 7.23 (br d, 1H, >15.2 Hz) 6.99-6.96 (m, 211) 4.78 (mi, br s, 2H) 4.70 (ma, brs, 2H) 4.02-3.91 (m, 2H) 3.84 (s, 3H) 3.83 (s, 3H) 3.80 (s, 3H) 2.87-2.72 (m, 2H). (Z)-1 - (5,8-dich lo ro-6,7- d imet ho xy-3,4-dihyd roisoqu in olm-2 (lif)-y l)-3-(2- methoxyphenyl)prop-2-en-l-one The title compound was obtained as a colourless oil in 46% yield, (SiO;, petroleum ether/ethyl acetate 8/2). 'H NMR (400 MHz, McOD) rot. mix. 5 7.06-7.00 (m, 2H) 7.00 (d, 1 H,>I2.4 Hz) 6.95-6.91 (m, 1H) 6,63-6.61 (m, 1H) 6.56-6.52 (m, lH)6.08(d, 1H,>l2.4Hz) 4.66 (mi, br s, 2H) 4.39 (ma, br s, 2H) 3.86 (s, 3H) 3.83 (s, 3H) 3.79 (ma, t, 2H, .7=6.0 Hz) 3.76 (s, 3H) 3.61 (mi, t, 2H,>6.0 Hz) 2.66 (ma, t, 2H,>6.0 Hz) 2.35 (mi, t,2H, >6.0 Hz). (E) 1 - (5,8-d ichl o ro-6,7-dim e t h o xv-3,4-d i h yd roisoq u in o li n-2 (1 H)-y l)-3-(5 fl uo r opyr i d i n - 2-yl)hut-2-en-1 - o 11 e The title compound was obtained as a yellow solid in 32% yield (Si02, Pet. ether/EtOAc 75/25). The Z-isomer was not isolated. 'h NMR (CDCb) rot. mix. S 8.47 (d, ,/=2.8 Hz, 1H) 7.54-7.50 (m, 1H)7.45- 7.39 (m, 1H) 7.05 (ma)(s; 1H) 7.00 (mi)(s, 1H) 4.82 (ma)(s, 2H) 4.66 (mi)(s; 2H) 3.91 (st 6H) 3,86-3.76 (mf 2H) 2.94-2.86 (m, 2H) 2.33 (br s, 3H). The following methyl ether of formula 1 (Schcmc 1, R I - R4=methyl) was also prepared as indicated, (E)-6,7-d ira cthoxy-5,8-d i m ethyl-1,2,3,4-tetrahyd roisoq uinolmc 3-(6- (trifluoromethyl)pyridln-3-yl)acrylamide 6,7-diniethoxy-5,8-dimetliyl-l,2,3,4-tetraliydroisoquinoline (116 mg, 0.52 mmol), (£)-3-(6-(tTifluoromcthyl)pyridi:i-3-yl)acrylic acid (114 mg, 0.52 mg), PyBroP (269 mg, 0.58 mmol) and DMAP (128 mg, 1.05 mmol) were suspended in THF (12 ml) and stirred at rt for 2.5 h before evaporation. The product was purified by flash chromatography using Pet. Ether/EtOAc (2/1 1/1) as clucnt to give 190 mg (87 %) of (E)6,7 -d imethoxy- 5,8 - d i methy 1-1,2,3,4 -t ctrahy d roiso q u i no line 3 - (6- (trifluoromcthyl)pyridin-3-yl)acrylamide as a pale solid. 'HNMR (CDCU) rot. mix. 5 8.87 (s, lH)8.00(brd, IH) 7.72 (br d, 1H) 7.70 (d, J= 8 Hz, IH) 7.14 (d, J= 16 Hz)4.71 (ma)(br s, 2H) 4.64 (mi)(br s. 2H) 3.93 (mi)(br, 211) 3.88 (maXbr, 211) 3.81 (s, 611) 2.82 (ma)(br, 211) 2.76 (mi)(br, 211.) 2.18 (s 3H) 2.16 (s, 3H). TLC (Pet. Ether/EtOAc 1/1) Rt 0.66. Preparation of final compounds The following non-limiting examples of compounds of formula I did all show less than 80% remaining contraction, at a concentration of 10pM, of human bronchiols after LTD4 induced contraction according to the method described herein. Example 1 (E)-1 -(5,8-dichloro-6,7-dihydroxy-3,4-dihy droisoquinolin-2( l //)-vl)-3- p h e nvl p r op-2-en -1 -o n e ci o CI franj-Cinnamoyl chloride (79 mg, 0.476 mmol) was suspended in DMT (7 mL) together with 5,8-dichloro-6,7-dihydroxy-l,2.3,4-tetrahydroisoquinoline hydrobromide (150 mg, 0.476 mmol) followed by triethylaminc (133 ,uL, 0.952 mmol). The resulting mixture was stirred at room temperature for 16 hours and then diluted with ethyl acetate (50 mL). The resulting mixture was washed twice with saturated .sodium bicarbonate (2x40 mL), dried (MgSO4) and evaporated into a yellowish mass. Purification with column chromatography (petroleum ether/ethyl acetate 1/1 —* 1/2) yielded 69 mg (40%) of the title compound as a yellowish solid. 'H NMR (400 MHz, CD,OD) rot. mix. 6 7.70-7.56 (m, 3H) 7.44-7.33 (m, 3H) 7.21 (br d, 1H)4.78 (mi, s, 2H) 4.71 (ma, s, 2H) 4.00-3.93 (ma, br t, 2H) 3.92-3.86 (mi, br t, 211) 2.92-2.86 (ma, brt, 211)2.85-2.69 (mi, br t, 211). TLC (petroleum ether/ethyl acetate 1/1) R( 0.33. HRMS (ESI) ealc for C18H16NO3Cl2 [M+H] 364.0507, found 364.0539. General procedure for the demethvlation of methyl ethers of formula I A methyl ether of formula 1 (RI ,R2=Mc) (1.0 equiv.) was dissolved in CH2Cb (20 mL) and cooled to 0 C, Boron tribromide (1M in CH2Cl2, 3,0 equiv.) was then added slowly and the resulting mixture was stirred at 0JC for 5 minutes, then at rt for 12 h. The reactions were quenched with methanol (5 mL) and evaporated to dryness. The obtained residue was dissolved in methanol (20 mL), sodium bicarbonate (6.16 mmol) was added and the resulting suspension was stirred at rt for 30 minutes before evaporation. The resulting crude products were then purified by column chro matography. Example 2 (F)-1 - (5,S-d ichl oro-6,7-dihyd ro xy-3,4-dihydroi so quin oli n-2 (1 /7>vl)-3 (pyridin-3-vl)prop-2-en-1 -one CI o CI The title compound was obtained from (E)-l-(5,8-diehloro-6.7-dimethoxy-3,4- dihydroisoqui noli n-2 (l//)-yl)-3-(pyridi n-3-yl)prop-2-en-l-one as an orange solid in 19% yield, Rt 0.08 (Si02t ethyl acetate). 'H NMR (400 MHz, DMSQ-4) rot. mix. 6 9.59 (br s, 1H (OH)) 8.91 (br s, 1H) 8.56 (dd, 1H,>1.6,4.8 Hz) 8.23 (brd, lH,>8.0Hz) 7.59-7.43 (m, 311) 4.74 (mi, brs, 2H) 4.63 (ma, br s, 2H) 3.97-3.94 (ma, m, 2H) 3.83-3.76 (mi, m, 2H) 2.83-2.73 (ma, m, 2H) 2.73-2.65 (mi,m, 2H). HRMS (ESI) calc for C17H15Cl2N2O3 [M+H] 365.0460, found 365.0425. Example 3 (E)-1 - (5,8-dichIoro-6,7- dihydroxy-3,4-dihydroisoquinolin-2-( 1 H)-y l)-3-( 5- fluoropyridin- 2-yl)prop-2-en-1-one CI 0 CI The title compound was obtained from (E)-l-(5,8-dichloro-6,7-dimethoxy-3,4- dihydroisoquinolin-2-(l//)-yl)-3-(5-fluoropyridin-2-yl)prop-2-en-l-one as a yellow solid in 86% yield, Rj 0.13 (Si02, chloroform/methanoI 9/1}. JH NMR (400 MHz, DMSO-rf6) rot. mix. 6 9.60 (s, 1H) 9.57 (s, 1H(0H)) 8.63 (s, 1H) 7.94-7.90 (m, 1H) 7.83-7.80 (m, 1H) 7.56 (s, 2H) 4.70 (mi, br s. 2H) 4.63 (ma, brs, 2H) 3.90-3.80 (ma+mi, m, 2H) 2.78-2.67 (ma+mi, m, 2H). HRMS (ESI) calc for CnHnChFNzOj [M+H] 383.0366, found 383.0354. Example 4 (E) 1 - (5.8-d ich I o ro-6,7- dihyd roxy-3,4-dihy d roisoq uinolln-2( 1 H)-x l)-3- (quinolin-3-yl)prop-2-en-l-one CI o CI The crude title compound was obtained from (E)-! -(5,8-dichloro-6,7- di mcthoxy-3,4-di hydro isoquinolin-2( 1H)- y 1) -3 -(qu i no I i n-3-y I )p rop- 2-en-1 -one, and was purified via the following procedure: The crudc was dissolved in methanol. After addition of a small amount of SiO: the mixture was filtered through Celite and the solvent evaporated. The oily residue was dissolved in a small amount of methanol and the product precipitated via addition of petroleum ether. The solvent was decantated. The title compound was obtained as a greenish solid in 61% yield. 'H NMR (400 MHz, MeOD) rot. mix. 6 9.60 (br d, 1H, 7=9.2 Hz) 9.40 (br st 1H) 8.35 (br d, 1H, 7=8.4 Hz) 8.23 (br d, 111,7=8.4 Hz) 8.17 (br t 1 fl:7=7.6 Hz) 7.99 (br t, 1H, 7=7.6 Hz) 7.90-7.71 (m, 2H) 4.79 (br s, 2H) 4.09-4.03 (ma, m, 2H) 3.98-3.92 (mi, m, 2H) 3.00-2.92 (ma, m, 2H> 2.89-2.81 (mi, m, 2H). HRMS (ESI) calc for C21H17CI2N2O5 [M+H] 415.0616. found 415.0598. Example 5 {£)-1 - (5,8-dichlo ro-6,7- dihy dro xv-3,4-di hvdroisoq uinoli n-2 (l//)-y])-3 - (quinolin-3-yl )hu t-2-en-1 -on e CI The title compound was obtained from (E)-l-(5,8-dichloro-6.7-dimethoxy-3,4- dihydroisoquinolin-2(lH)-yl)-3-(quinolin-3-yl)but-2-en-l-one as a yellow solid in 14% yield (SiO2, ethyl acctatc/mcthanol 95/5). 'H NMR (400 MHz, ) rot. mix. 6 9.62-9.57 (m, 1H) 9.23-9.18 (m, 1H) 8.548.49 (m, 1H) 8.06-8.01 (m. 2H) 7.80-7.76 (m, 1H) 7.66-7.63 (m. 1H) 6.91 (s, 1H) 4.63 (br s, 2H) 3.82-3.79 (m, 2H) 2.79-2.73 (ma+mi, m, 2H) 2.33 (ma, br s, 3H) 2.23 (mi, br s, 3H). HRMS (ESI) calc for C32H19Cl2N3O1 [M+H] 429.0773, found 429.0836. Example 6 (E)-1 -y l)-3-(4- hvdroxvph envl)prop-2-en-1 -one CI o CI The title compound was obtained from (E)-1-(5,8-dichloro-6,7-dimethoxy-3,4- dihydroisoquinolin-2(1 H)-y 1)-3-(4-methoxyphenyl)prop-2-en-1 -one as an orange solid in 97% yield, Rr 0.34 (Si02, petroleum ether/ethyl acetate 1/1 + 15% EtOH). 'HNMR (400 MHz, MeOD) rot. mix. 6 7.60-7.51 (in, 3H) 7.07-6.95 (m, 1H) 6.82-6.80 (m, 2H) 4.80-4.69 (mi+ma){m, 2H) 4.00-3.84 (ma+mi, m, 2H) 2.94-2.77 (man mi, m, 211). HRMS (ESI) calc for C1KH]^C12N04 [M+H] 380.0456, found 380.0393. Example 7 (Z)-1-(5,8-dichloro-6,7-dihyroxy-3,4-dihydroisoquinolin-2(1//)-yl)-3-(2- h ydr oxyph enyl)prop-2-en- 1-one ff^ ci o ci The title compound was obtained fro m (Z)-l- (5,8-die h lo ro - 6,7- d i methoxy-3,4 - dihydroisoquinolin-2( l//)-yl)-3-(2-metho xypheny l)p rop-2-en-1-one as a yellow solid in 29% yield, Rt 0.38 (Si02, petroleum ether/ethyl acetate l/l + 5% EtOH). 'H NMR (400 MHz, MeOD) rot. mix. 6 7.96-7.83 (m, 1H) 7.61-7.47 (m, 1H) 7.38-7.27 (m, 1H) 7.22-7.17 (m, 111) 6.88-6.84 (m, 211)4.78-4.75 (mi+ma)(m, 211) 4.00-3.87 (m, 2H) 2.97-2.79 (ma+mi, m, 2H). HRMS (ESI) calc lor CiSHJ6C12N04 [M+H] 380.0456, found 380.0422. Example 8 (E)-1 - (5,8-d ich lo ro-6,7- dihyd ro xv-3,4-dihy dr oi so q uinoll n-2{ lH)-y l)-3 - (5- fl uo r opy r i d i ii - 2-y I )b u t- 2- e n -1 - o n e The title compound was obtained from (E)- l-(5,8-dichloro-6,7-dimethoxy-.3,4- dihydroisoquinolm-2(lH)-yl)-3-(5-fluoropyridm-2-yl)but-2-en-1 -one as an off-white solid in 40% yield (Si02, Pet. Ether/EtOAc 4/6 — 4/6+10% EtOH). 'H NMR (CDCh) rot. mix. 3.2 Hz, 1H) 7.56-7.49 (m, 1H) 7.477.38 (m, 1H) 7.05 (ma)(s, 1H)7.01 (mi)(s, 1H) 4.79 (ma)(s, 2H) 4.64 (mi)(s, 2H) 3.95 (mf)(t, 7=6.0 Hz, 2H) 3.80 (ma)(t, 7=6.0 Hz, 2H) 2.91-2.82 (m, 2H) 2.33 (ma)(s, 3H) 2.28 (mi)(s, 3H). Example 9 (ZT)-6,7-d ih yd ro xy-5,8-d i m ethyl-1,2,3,4-tetrahy d ro isoq ui nol inc 3-(6- (t r i □ u o r o methy I) py r id i n -3-y l)a c rv I am ide O * HO, (E)-6,7-D imethoxy- 5,8-d imet hy I-1,2,3,4-tctrahyd ro isoqu incline 3-(6- (trifhioromcthyl)pyridin-3-yl)acrylamidc (190 mg, 0.45 mmol) was dissolved in dichloromethane (13 mL) and cooled to 0 °C. Boron tribromide (1.49 ml, 1.49 mmol, 1M in dichloro methane) was added slowly. The resulting suspension was stirred at 0 °C for 15 minutes, then at rt for 3.5 h and finally rcfluxcd for 1.5 h. The reaction was cooled, quenched with MeOH (5 mL) and evaporated. The residue was dissolved in MeOH (15 mL), neutralized with NaHCOi (57mg,0.68 mmol) and evaporated. The product was purified by flash chromatography using Pet. Ether/EtOAc/MeOH (4/6/1) as eluent to give 165 mg (93 %) of (E)6,7-dihydroxy-5,8-dimethyl-l,2,3,4- tetrahydroisoquinoline 3-(6-(trifluoromethyl)pyridin-3-yl)acrylamide as a reddish mass, 'HNMR(CD?OD) rot. mix. 5 8.93 (s, 1H)8.31 (d,7=8Hz, 1H) 7.82 (d,7= 8 Hz, 1H) 7.63 (in, 1H) 7.51 (d,7= 16 Hz) 4.70 (mi)(s, 2H) 4.63 (ma)(s, 2H) 3.93 (ma)(br t, 2H) 3.85 (mi)(br t, 2H) 2.77 (ma)(br t, 2H) 2.69 (mi)(br t, 2H) 2.12 (s, 3H) 2.08 (s, 3H). TLC (Pet, Ether/EtOAc/MeOH 5/5/1) Rf 0.58. Example 10 (E)-1 -{5,8-dlchlor o-6,7-dlhy dr o xy-3,4-di hyd roisoq ulno I i n-2( l//)-yl>-3-(2 (pipe r i d in -1-vl)-6-(tr i fl uor om ethyl)py rid in -3-yl) pr o p-2 - en -1 -on e NaOH (1.0 M aq., 2.9 ml, 2.9 mmol) was added to a solution of (E)-methyl 3- (2-(piperidin-l-yl)-6-(trffluoroinethyl)pyridin-3-yl)acrylate (181 mg, 0.58 mmol) in T( ir/EtOU 1/1 (6 mL). The mixture was stirred for 24 h at rt. The solution was diluted with water and acidified with 1M HCl. The precipitate was collected through filtration, dried under vacuum and used directly in the next step. (E) -3 -(2 -(p i per i d i ti-1 - y I)- 6-( trifluo ro methy 1 )pyri d i n-3 - y 1 )acry 1 ic ac i d (15 0.0 mg, 0.50 mmol) was suspended in dry THF (7.0 mL). DMAP (111.4 mg, 0.91 mmol) and caesium carbonate (296.0 mg, 0,91 mmol) were added and the mixture was stirred atrt for 15 minutes. 5,8-Dichloro-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromidc (143.0 mg, 0.45 mmol), EDC-HC1 (130.6 mg, 0.68 mmol), HOBt (69.8 mg, 0,45 mmol) were then added. The mixture was stirred at rt overnight. Water (100 mL) was added and the product extracted w ith EtOAc, Combined organic extracts were dried (MgSO^), filtered and concentrated. Purification was done first using flash column chromatography (CH^Ch/MeOH 98/2 —» 95/5) and then by size exclusion (Sephadex LH20; CHCU'McOH 1/1) to yield 55.0 mg (24%) of the title product. 'H NMR (CD^OD) rot. mix. 6 8,11 (ma)(d,> 7.2 Hz, 1H) 8.05 (mi)(d, J= 7.2 Hz, 1H) 7.66 (m, 1H) 7.30 (bs, 1H), 7.26 (d, J=7.6 Hz, 1H) 4.79 (mi)(s, 2H) 4.74 (ma)(s, 2H) 3.97 (ma)(br t, 2H) 3.90 (mi)(br t, 2H) 3.26 (m, 4H) 2.88 (ma)(br t, 2H) 2.81 (mi)(br t, 2H) 1.68 (m, 6H), HRMS (ESI) calc for C23H23N3Cl2, [M+H] 516.1069, found 516.1116. Example 11 (F)-1 - (5,8-d ichl 0 r n-6,7- d ihy d r o xy-3,4-d ihydroisoquinnlin-2(l H)-yl)-3 - (2- m ethy l-6-(t r i fl u 0 ro m e thy I) py r idi n -3-y l)p ro p-2 - e n -1 - 011 e ci o 5,8-Dichloro-1 ,2,3,4-tetrahydroisoquinolinc-6.7-diol hydro bromide (183 mg. 0.58 mmol), (E)-3-(2-methy 1-6-(trifluoromethyI)pyridin-3-y Ijacrv1ic acid (140mg, 0.64 mmol), EDC HCl (I67mg, 0.87 mmol), llOBt (89 mg, 0.58 mmol), DMAP (147 mg, 1.2 mmol) arid Cs^CO.i (391 mg, 1.2 mmol) were suspended in DMF (15 mL) and stirred at rt for 12 h. The reaction mixture was then diluted with water (30 mL) and extracted with EtOAc (330 mL). Combined organics were washed with NaHCOi (230 mL, sat. aq.), water (330 mL) and brine and dried (MgSO4). After filtration and evaporation the residue was purified by column chromatography (SiO:, CH2Ch:McOH 95:5) and was then further purified by size exclusion chromatography (sephadex, CHCU:MeOH 1:1) to give the title compound (28 mg, 63 pmol, 11 %) as a yellow solid. 'HNMR (CD,OD) rot. mix. 6 8.33 (ma)(d,,7=8.0 Hz, 1H) 8.28 (mi)(d,,7=8.0 Hz, 1H) 7.88 (ma)(d, 7=15,6 Hz, 1H) 7.84 (mi)(d, ,7=15,6 Hz, 1H) 7.67 (d, ,7=8.0 Hz, HI) 7.35 (ma)(d,7=15.6 llz, 111)7.29 (mi)(d,7=15.6 11 z, 1(1)4.81 (mi)(s, 211) 4.76 (ma)(s, 2H) 3.98 (ma)(t, 7=6.0 Hz, 2H) 3.92 (mi)(t, 7=6.0 Hz, 2H) 2.91 (ma)(t, 7=5.6 Hz, 2H) 2.84 (mi >(1,7-5.6 Hz, 2H) 2.70 (s, 3H). HRMS (ESI) calc for C19H16Cl2F3N2O3 [M+H] 447.0490, found 447.0550. Example 12 (E)-l - (5,8-tl ich I o r o-6,7- d ihy d r o xv-3,4-d i liy d roi so q u in o I i n -2 (1H )-yl)-3 - (6- (trifl uor o m ethv I) pvr id i n-3-vl) p r o p-2 - c n-1 -on c CI " o To a solution of CD I (83 mg, 0.51 mmol) in EtOAc (2 mL) was added (E)-3- (6-(trifluoromethyl)pyridin-3-yl)acrylie acid (100 mg, 0.46 mmol). The resulting mixture was heated at reflux for 1 h after which HOBt (35 mg, 0,23 mmol) and 5,8- dichloro-1,2,3,4-tetrahydro isoqui no line-6,7 -d io 1 hydro bromide (145 mg, 0.46 mmol) were added. Heating at reflux was continued for 3 h before the reaction mixture was allowed to cool to rt. It was then poured into water (15 mL) and the water-phase was extracted with EtOAc (315 mL). Combined organics were washed with water (10 mL) and brine (10 mL) and dried (MgSO4). After filtration and evaporation, the crudc was purified by column chromatography (Si02, EtOAc;pctroleum ether 50:50) to give a bright yellow solid which was purified further by precipitating the product in EtOAc via addition of petroleum ether. After decantation of the solvent and drying, the title compound (NO mg, 0,25 mmol, 55%) was obtained as a light reddish solid. 'H NMR (CD3OD) rot. mix. 3 8.98 (ma)(s, 1H) 8.94 (mi)(s, 1H) 8.36-8.33 (m, 1H) 7.87-7.83 (m, 1H) 7.71-7.63 (m, 1H) 7.57-7.52 (m, 1H) 4.82 (mi)(s, 2H) 4.76 (ma)(s, 211) 3.99 (ma)(t, >6.0 I Iz, 2H) 3.91 (mi)(t, >6.0 1 lz, 211) 2.92 (ma)(t, >6.0 Hz, 2H) 2.83 (mi)(t, >6.0 Hz, 2H). HRMS (ESI) calc for C18H14Cl2N2O3 [M+H] 433.0334, found 433.0338. Example 13 (E)-1 - (5,8-d ichl o ro-6,7- dihy d ro x v-3,4-d i hvd r oi so q u in oJ i n -2 (lH)-y J)-3 - (6- tr iflu o ro m etii v l)pyridin-3 -v 1) b ut-2 - e u-1 -o n e r^o CI F To a solution of 3-(6-(trifluoromethyl)pyridin-3-yl)but-2-enoic acid (2.4 g, 10 mmol) in. EtOAc (24 mL) was added CD1 (1.7 g, 11 mmol). After heating at reflux for 1 h, TLC (CH2Cl2;Me0H 9:1) confirmed 3-(6-(trifluoromethyl)pyridin-3-yl)but-2-enoic acid to be consumed. Then 5,8-Dichloro-1,2,354-tetrahydroisoquinoline-6,7-diol hydro bromide (3.1 g, 9.7 mmol) was added and the mixture was heated at reflux over night. After cooling to rt the mixture was diluted with EtOAc (24 mL) and the remaining solids were dissolved with small amounts of 1M HCl (aq,). The water and organic phases were separated and the water phase neutralized by addition of IM NaOH (aq.). The product, which precipitated as a sticky solid, was extracted with EtOAc (5*24 mL, difficult extraction). Combined organics were washed with sat. NaHCO3 (aq.), water and brine and dried (MgSO4). Crude title compound (3.6 g) was purified twice by column chromatography (SiO2, CHiCbrMcOH 98:2) (amount title compound after second cromatography: 1.95g). Then the product was washed with MeOH repeatedly to yield pure title compound (I 0g, 2,3 mmol, 23% (pure £-isomer, the Z-isomer could not be isolated)) as a light yellow solid. 'H NMR (CD.;OD) rot. mix. S 8.92 (ma)(d, >2.0 Hz. 1H) 8.88 (mi)(d,>1.6 Hz, 1H) 8.21 (ma)(dd,>2.0, 8.4 Hz, 1H) 8.17 (mi)(dd,>2.0, 8.4 Hz, 1H) 7,84 (d, ,7=8.4 Hz, 1H) 6.72 (ma)(brs, 1H) 6.70 (mi)(br s. 1H)4.72 (ma)(s, 2H) 4.66 (mi)(s, 2H) 3.91 (mi)(t, >6.0 Hz, 2H) 3.82 (ma)(t,>6.0 Hz, 2H) 2.87-2.82 (m, 2H) 2.29 (ma)(d, > 1.2 Hz, 3H) 2.19 (mi)(d, > 1.0 Hz, 3H). HRMS (ESI) calc lor C19H16Cl2F3N2O3 [M+H] 447.0490, found 447.0374. a 0 CH, ^OrW'J , 11 9 O f 12 6 a o en, 13 7 Biological example 2 The remaining contraction, after pre-treatment with various compound examples at a concentration of 10 pM, of human bronchiols or rat hronhi after the induction of contraction by treatment with the contractile agents acetylcholine (100uM), carbachol (10uM), histamine (100uM), mcthacholine (100uM) or a mixture of acetylcholine (100uM), leukotriene D4 (LTD4) (0.01uM) and histamine (100uM), according to the in vitro method described herein above, arc tabulated below: CONTRACTILE COMPOUND REMAINING AGENT [concentration SPECIES (EXAMPLE CONTRACTION (uM)] NUMBER) (%) Acetylcholine (100uM) human 12 4 13 7 rat 12 40 13 52 Carbachol (10uM) human 12 10 rat 12 27 Histamine (lOOuM) human 12 1 13 3 Methacholine (100uM) human 12 7 rat 12 49 Mixture of Acetylcholine (100uM), LTD4 (0.01 uM} and histamine (100uM) human 3 43 11 25 12 12 13 18 Biological example 3; Human peripheral blood mononuclear cell (PBMC) in vitro model Cryoprcscrvcd PBMC's (SeraCare, # 72001) were thawed, washed with eulture media (RPM1-1640 from Invitrogen, # 61870-036 + 10% heat inactivated fetal bovine serum from fnvitrogen. # 10082-147 + 100 U/ml penicillin + lOO^ml streptomycin) and tested for viability using Trypan blue (PBMC viability = 96%). Cells were then resuspended to 1 x 106 cells/ml in culture media and 0.5 ml was plated into 24 well culture plates (5 x 105 cells/well) before incubation for 30 minutes at 37°C with 5% C02 prior to addition of a compound of the present invention (10 pM) or dcxamcthasone (1 pM). One hour thereafter, LPS (0.1 pg/rnl, Salmonella abortus eqiti, Sigma, # LI 887) was added and the cells were incubated for another 24h before collection of the cell culture supematants, which were assayed for the prescncc of MCP- 1 and LTB4. MCP-1 levels were quantified employing a Luminex-based assay according the manufacturer's instructions. Data was collected using a Luminex 100 (Luminex Corporation, Austin, TX). Standard curves were generated using a 5-parameter logistic curve fitting equation weighted by 1/y (StarStation V 2.0; Applied Cytometry Systems, Sacramento, CA). F.ach sample reading was interpolated from the appropriate standard curve. Calculated concentrations were mu hip lied by the appropriate dilution factor when ncccssary. LTB4 levels were quantified by EL ISA follow ing the manufacturer's instructions. Absorb ance readings were detected using a ThermoMax mi crop I ate reader (Molecular Devices). Standard curvcs were generated using a4-paramctcr logistic curve fitting equation (SoftMax Pro 4.7.1; Molecular Devices). Each sample reading was interpolated from the appropriate standard curve. Duplicate interpolated sample values were averaged and standard deviations were calculated. Calculated concentrations were multiplied by the appropriate dilution factor. The inhibitory effect of compounds of the present invention, dexamethasone, and vehicle on production of MCP-1 and LTB4 in the PBMC model as described herein above, with (+LPS) or without (-LPS) LPS-induccd mediator production, is tabulated below. Compound Mean MCP- 1 (petml) Standard deviation Mean LTB-4 fpc/mD Standard deviation (MCP-1) CLTB-4) Vchiccl (-LPS) 133.5 19.2 19 05 Vchiccl (+LPS) 858,2 25.5 30.4 L5 Example 12 (-LPS) "TV/^YX f C F 229.7 60.9 19 02 Example 12 (+LPS) c, 0 303,1 94.3 9,9 13 IXo^o^ CI F Example 13 (-LPS) Gl 0 V^nr 217,1 45.7 4A 02 HO , • •• CI F Example 13 (+LPS) c o Yr-1 -'V) HO M CI F 250.7 11.5 M M Dexamethasone (-LPS) 0 0 17 OJ Dcx am cthason c (+L PS) 1425.6 193.8 12.6 03 We claim: 1. A compound according to formula I wherein R1 is selected from H and methyl: R2 is selected from H and methyl: R3 is selected from H. fluoro. chloro. bromo. C 1-3 alky! and CH2 phenyl; R4 is selected from H. fluoro. chloro. bromo. C 1-3 alkyl and CH2 phenyl; G is selected from G1 and G2: in G1 the stereochemistry of the double-bond of Gl. onto which the substituents R5 and R6 are attached, is such that R5 and R6 are oriented in a cis- fashion, or in a trans- fashion. relative to each other: R5 is selected from H. C 1-5 alkyl. CH2 phenyl and C 1-5 fluoroalkyl: R6 is selected fiom H, C 1-5 alkyl. CH2 phenyl and C 1-5 fluoroalkyl: X1 X2. X3, X4 and X5 are. independently of each other, selected fromN and C; 0 (zero). 1 or 2 of X1. X2, X3, X4 and X5 is X: Q is optionally substituted with a maximum of "n" independently selected substituent(s) R7 at any substitutable ring carbon atom, wherein "n" represents an integer number: the integer number "n" is 0 to 2: R7 is selected from C 1-5 alkyl. Cl-5 fluoroalkyl. halo, hydroxy, CO-3 alkyleneOCO-5 alkyl. CO-3 alkyleneOCl-5 fluoroalkyl, CO-3 alkyleneNH2, CO-3 alkyleneNHCl-3 alkyl CO-3 alkyleneN(Cl-5 a Iky 1)2. in which the C 1-5 alkyl may be the same or different. N(C4-5 alkylene). Cl-5 alkylthio. S(O)C 1 -5 alkyl. SO2C 1 -5 alkyl. C 1-5 fluoroalkylthio. XH(CO)C 1-5 alkyl. NH(CO)C 1-5 alkoxy. XHSO2C1-5 alkyl. (CO)C 15 alkyl. COOH, (CO)C 1-5 alkoxy. (CO)NH2, (CO)XHC 1-5 alkyl. (CO)N(C 1-5 alky 1)2. in which the Cl-5 alkyl may be the same or different, cyano. SQ2NHC0-5 alkyl. nitro. aryl. heteroaryl. azido (N3). and morpholinyl; in G2 the stereochemistry of the double-bond of G2. onto which tlie substituents RS and R9 are attached, is such that R8 and R9 are oriented in a cis- fashion, or in a trans- fashion. relative to each other; RS is selected fiomH, C 1-5 alkyl. CH2 phenyl and C 1-5 fluoroalkyl: R9 is selected fiomH, C 1-5 alkyl. C'H2 phenyl and C 1-5 fluoroalkyl: the condensed rings Wl and W2 together represent a bicyclic aromatic system, in which X6. X7 and XS. independently of each other, are selected fromN and C: none or one of X6. X7 and X8 is N: said bicyclic aromatic system is optionally substituted, with a maximum of "p"' independently selected substituent(s) RIO. at any substitutable ring carbon atom of any of the rings Wl and W2. wherein "p" represents an integer number; The integer number "p" is 0 to 2: RlO is selected from Cl-5 alkyl, Cl-5 fluoroalkyl. kilo, hydroxy. CO-3 alkyleneOCO-5 alkyl. CO-3 alkyleneOCl-5 fluoroalkyl. CO-3 alkyleneNH2, CO-3 alkyleneNHC 1 -3 alkyl. CO-3 alkyleneN(C 1 -5 alkyl)2. in which the Cl-5 alkyl may be the same or different, N(C4-5 alkylene). C 1-5 alkylthio, S(O)C 1-5 alkyl. SO2C1-5 alkyl. C 1-5 fluoroalkylthio. NH(CO)C 1-5 alkyl. NH(CO)C 1-5 alkoxy. XHSO2C1-5 alkyl, (CO)C 15 alkyl. COOH, (CO)C 1-5 alkoxy. (C0)NH2. (CO)NHC 1-5 alkyl. (CO)N(C 1-5 alkyl)2. in which the Cl-5 alkyl may be the same or different, cyano, S02NHCQ-5 alkyl. nitro, aryl. heteroaryl. azido (N3). and morpholinyl; as a free base, an acid in its no n-charged protonated form or a pharmaceutic ally acceptable salt, solvate or solvate of a salt thereof and as a pure stereoisomer, a racemic- . dia stereo me lie- or scalemic mixture; with the proviso that not both of Rl and R2 is methyl. 2. The compound according to claim 1. wherein Rl and R2 is H. 3. The compound according to claim 1 or 2. wherein R3 and R4. independent of each other, are selected from H, fluoro, chloro, bromo. and methyl. 4. The compound according to claim 3. wherein R3 and R4 are chloro. 5. The compound according to any of the claims 1 to 4. wherein G is Gl and the stereochemistry of the double-bond of Gl. onto which the substituents R5 and R6 are attached, is such that R5 and R6 are oriented in a trans-fashion relative to each other. 6. The compound according to any of the claims 1 to 5. wherein G is Gl and at least one of X1 to X5 is N. 7. The compound according to claim 6, wherein G is Gl. X1 or X2 is X' and only one of X1 to X5 is X. S. The compound according to any of the claims 1 to 7. wherein G is Gl. "n" is 1 or 2. and R7 is selected from C1-C3 alkyl. trifluoromethyl. halo, hydroxy. N(C4-5 alkylene). metlioxy, SO2Me. cyano. thienyl, nitro. phenyl, morpholinyl and NMe2. 9, The compound according to claim 8. wherein R7 is selected from methyl, trifluoromethyl. fluoro. chloro andNMe2. 10, The compound according to any of the claims 1 to 9. wherein G is Gl and R5 is H. 11, The compound according to any of the claims 1 to 10. wherein G is Gl and R6 is H or methyl. 12, The compound according to any of the claims 1 to 4. wherein G is G2 and the stereochemistry of the double-bond of G2. onto which the substituents R8 and R9 are attached, is such that R8 and R9 are oriented in a trans-fashion relative to each other. 13, The compound according to any of the claims 1 to 4 or 12. wherein G is G2. at least one of X6 to X8 is X. 14, The compound according to any of the claims 1 to 4. or 12 to 13. wherein G is G2 and R8 and R9 are. independently or each other, selected from H and methyl. 15, The compound according to claim 1. wherein said compound is selected from the group consisting of: 16. The compound according to claim 1. wherein said compound is selected from the group consisting of: 17. A pharmaceutical composition comprising a compound according to any of the claims 1 to 16 and at least one pharmaceutic ally acceptable carrier. 18. The pharmaceutical composition according to claim 17. comprising an antiasthmatic. 19. The pharmaceutical composition according to claim 18. wherein the principal mechanism of action of the anti-asthmatic is selected from the group consisting of p2- agonist, anticholinergic and calcium antagonist, or wherein the antiasthmatic is a corticosteroid. 20. The compound according to any of the claims 1 to 16 or a composition according to any of the claims 17 to 19 as and when used in the preparation of a medicament for use in the prevention and/or treatment of a disease or condition relating to broncho con strict ion of the respiratory apparatus, inflammation of the respiratory apparatus, asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis, bronchiolitis and bronchopulmonary dysplasia.

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
1. TITLE OF THE INVENTION:
NOVEL BRONCHODILATING ALPHA, BETA-UNSATURATED AMIDES
2. APPLICANT:
Name: Respiratorius AB Nationality: Sweden
Address : Magistratsvagen 10, 226 43 LUND, Sweden.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed:

Field of (lie invention
The present invention relates to novel bronchorclaxing compounds, pharmaceutical compositions comprising such compounds, and a method of treating or alleviating conditions accompanied by broncho con strict ion and/or inflammation of the respiratory tract, and/or vasoconstriction, by use of such compounds.
Background
Asthma and chronic obstructive pulmonary disease (COPD) arc diseases affecting the respiratory system, which millions of people suffer from. These diseases are today regarded as inflammatory diseases and the symptoms comprise constriction of the airways. Common treatment of the associated bronchoconstriction involves use of beta-agonists, such as tcrbutalin and formotcrol, and anticholinergics, such as ipratropium bromide and thiotropium bromide.
Hypertension, i.e. high blood pressure, increases the risk of stroke, heart attacks, heart failure and kidney disease. Medications presently used for the treatment of hypertension include the administration of bcta-b lockers, calcium channcl blockers, diuretics, angiotensin-converting enzyme inhibitors and angiotensin II rcccptor antagonists. Vasoconstriction results in an increase in the blood pressure.
The treatments for prevention or reduction of bronchoconstri cion, inflammation, such as inflammation of the respiratory tract, and vasoconstriction are in many ways insufficient and there is a need for alternative treatments.
Summary
Accordingly, various embodiments of the present invention seek to mitigate, alleviate, circumvent or eliminate one or more of the above-identified deficiencies identified herein.
According to one aspect of the present invention, there is provided a compound of the general formula (I),

G
R4 (I)

G2
G=
CR10)P
G1
(R7)
wherein R1 is selected from I i and methyl; R2 is selected from II and methyl; R3 is selected from H, fluoro, ehloro, bromo, CI-3 alkyL and CH2 phenyl; R4 is selected from H, fluoro, chloro. bromo, CI-3 alkyl and CH2 phenyl; G is sclcctcd from Gl and G2; in Gl the stereochemistry of the double-bond of Gl, onto which the substituents R5 and R6 arc attached, is such that R5 and R6 arc oriented in a cis- fashion, or in a trans-fash ion, relative to each other; R5 is selected from H, Cl-5 alkyl, CH2 phenyl and CI-5 fluoroalkyl; R6 is selected from H, Cl-5 alkyl, CH2 phenyl and Cl-5 fluoroalkyl; XI, X2, X3, X4 and X5 are. independently of each other, selected from N and C; 0 (zero), I or 2 of XI, X2, X3, X4 and X5 is N; Q is optionally substituted with a maximum of "n" independently selected substituent(s) R7 at any substitutablc ring carbon atom, wherein "n" represents an integer number; the integer number "n1 is 0 to 2; R7 is selected from Cl-5 alkyl, CI-5 fluoroalkyl, halo, hydroxy, CO-3 alkyleneOCO-5 alkyl, CO-3 alkylencOC1-5 fluoroalkyl, CO-3 alkyleneNH2, CO-3 alkyleneNHCl-3 alkyl, CO-3 alkyIcncNfC 1-5 alkyl)2, in which the Cl-5 alkyl may be the same or different, N(C4-5 alkylcnc), Cl-5 alkylthio, S(0)C 1-5 alkyl, S02C1 -5 alkyl, Cl-5 fluoroalkylthio, NH(CO)Cl-5 alkyl, NH(CO)CI-5 alkoxy, NHS02C1-5 alkyl (CO)Cl-5 alkyl, COOH, (CO)Cl-5 alkoxy, (CO)NH2, (CO)NHCI-5 alkyl. (CO)N(Cl-5 alkyl)2, in which the Cl-5 alkyl may be the same or different, cyano, S02NHCQ-5 alkyl, nitro, aryl, heteroaryl, azido (N3), and morpholinyl; inG2 the stereochemistry of the double-bond of G2, onto which the substituents RS and R9 are attached, is such that RN arid R9 are oriented in a cis-fashion, or in a trans-fash ion,
relative to each other; R8 is selected from H, Cl-5 alkyl, CH2 phenyl and Cl-5 fluoroalkyl; R9 is selected from H, Cl-5 alkyl, CH2 phenyl and Cl-5 fluoroalkyl; the condensed rings W1 and W2 together represent a bicyclic aromatic system, in which. X6, X7 and X8, independently of each other, arc selected from N and C; none or one of X6, X7 and X8 is N , said bicyclic aromatic system is optionally substituted with a maximum of "p" independently selected substituent(s) R10, at any substitutable ring carbon atom of any of the rings W1 and W2, wherein lip" represents an integer number; the integer number "p'1 is 0 to 2; RIO is selected from Cl-5 alkyl, Cl-5 fluoroalkyl, halo, hydroxy, CO-3 alkylencOC1-5 alkyl, CO-3 alkylencOCO-5 fluoroalkyl, CO-3 alkyleneNH2, CO-3 alkyleneNHCl-3 alkyl, CO-3 alkylcneN(Cl-5 alkyl)2, in which the Cl-5 alkyl may be the same or different, N(C4-5 alkylcnc), CI 5 alkylthio, S(0)C1~5 alkyl, S02C1-5 alkyl. C1-5 fluoroalkylthio, NH(CO)Cl-5 alkyl, NH(CO)Cl-5 alkoxy, NHS02C1-5 alkyl (CO)Cl-5 alkyl, COOH, (CO)Cl-5 alkoxy, (CO)NH2, (CO)NHCl- 5 alkyl, (CO)N(Cl-5 alkyl)2, in which the Cl-5 alkyl may be the same or different, cyano. SO2NHC0-5 alkyl, nitro, aryl, heteroaryl, azido (N3), and morpholinyl; as a free base, an acid in its non-charged proton ate d form or a pharmaceutical^ acceptable salt, solvate or solvate of a salt thereof and as a pure stereoisomer, a raccmic-, diastereomeric- or scalemic mixture; with the provisio that not both of R1 and R2 is methyl.
Aecording to another aspect such a compound or a composition comprising such a compound may be used in medicine. Such compounds or compositions may also be used to manufacture a mcdicament.
Aecording to another aspect a medicament comprising a compound according to formula 1 may be used to treat or prevent a disease or disorder of the respiratory apparatus characterized by bronchoconstriction. Furthermore, a medicament comprising a compound according to formula I may be used to treat or prevent a disease or disorder characterized by inflammation or vaso con strict ion. Diseases and disorders, whieh compounds according to formula 1 may be used to treat comprise asthma, chronic obstructive pulmonary disease, which comprises chronic bronchitis and emphysema, bronchiectasis, cystic fibrosis, bronchiolitis or bronchopulmonary dysplasia.
According to another aspect a compound according to formula I or a medicamcnt comprising such a compound, may also be used in a method to treat or prevent pulmonary disease characterized by bronchoconstrict ion. Such a method comprises the administration to a person in need of a broncho constrict ion relaxing dose of a compound according to formula I.
Further features of the invention are defined in the dependent claims and embodiments disclosed herein.
Detailed description of the invention
Definitions:
In the context of the present application and invention, the following definitions apply:
The term "addition salt'1 is intended to mean salts formed by the addition of a pharmaceutical acccptablc acid, such as organic or inorganic acids, or a pharmaceutical acceptable base. The organic acid may be, but is not limited to, acetic, propanoic, mcthanesulfonic, bcnzcncsulfonic, lactic, malic, citric, tartaric, succinic or malcic acid. The inorganic acid may be, but is not limited to, hydrochloric, hydrobromic, sulfuric, nitric acid or phosphoric acid. The base may be. but is not limited to, ammonia and hydroxides of alkali or alkaline earth metals. The term "addition salt" also comprises the hydrates and solvent addition forms, such as hydrates and alcoholates.
As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.
As used herein, "alkyl11 used alone or as a suffix or prefix, is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having from 1 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number is intended. For example "Cl-6 alkyl" denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms. When the specific number denoting the alkyl-group is the integer 0 (zero), a hydrogen-atom is intended as the substitucnt at the position of the alkyl-group. For example. "N(C0 alkyl)2" is equivalent to "NH2" (amino). Examples of alkyl include, but arc not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl.
As used herein, "alkylenyl" or "alkylene" used alone or as a suffix or prefix, is intended to mean straight chain saturated aliphatic hydrocarbon groups having from 1 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number is intended. For example "CI-(5 alkylene" or "Cl-6 alkylenyl" denotes "alkylene" or "alkylenyl" having 1, 2, 3,4, 5 or 6 carbon atoms. When the specific number denoting the alkylenyl or alkylcne-group is the integer 0 (zero), a bond is intended to link the groups onto which the alkylenyl or alkylene-group is substituted, For example, "NH(C0 alkylene)NH2" is equivalent to 'NHNFK" (hydrazino). As used herein, the groups linked by an alkylene or alkylenyl-group arc intended to be attached to the first and to the last carbon of the alkylene or alkylenyl-group. In the case of
methylene, the first and the last carbon is the same. For example, "H2N(C2 alkylene)NH2", "H2N{C3 alkylene)NH2", "N(C4 alkylene)", "N(C5 alkylene)" and "N(C2 alkylene)2NH" is equivalent to 1,2-diamino ethane, 1,3-diamino propane, pyrrolidinyl, piperidinyl and pipcrazinyI, respectively.
Examples of alkylene or alkylenyl include, but arc not limited to, methylene, ethylene, propylene, and butylene.
As used herein, "alkoxy" or "alkyloxy" is intended to mean an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, mcthoxy, cthoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, isopentoxy, eyclopropyl mcthoxy, allyloxy and propargyloxy, Similarly, "alky It bio" or '"thioalkoxy" represent an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
As used herein, "fluoroalkyl", "fluoroalkylcne" and "fluoroalkoxy", used alone or as a suffix or prefix, refers to groups in which one, two, or three of the hydrogen(s) attached to any of the carbons of the corresponding alkyl, alkylene and alkoxy-groups arc replaced by fluoro. Examples of fluoroalkyl include, but arc not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, 2.2,2-tri fluoro ethyl, 2-fluoroethyl and 3- tluoropropyl.
Examples of fluoroalkylene include, but are not limited to, di fluoro methylene, fluoromethylenc, 2,2-difluorobutylcnc and 2,2,3-trifluorobutylene.
Examples of fluoroalkoxy include, but arc not limited to, tri fluoro mcthoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy and 2.2-dtfluoropropoxy.
As used herein, the term "substi tut able" refers to an atom to which a hydrogen is covalently attached, and to which another substituent may be attached instead of the hydrogen, directly or indirectly through synthesis. A non-limiting example of substitutable atoms include the carbon-atoms of pyridine. The nitrogen-atom of pyridine is not substitutable according to this definition.
As used herein, the Lerm "aryl" refers Lo a ring structure, comprising at least one aromatic ring, made up of from 5 to 14 carbon atoms. Ring structures containing 5, 6, 7 and 8 carbon atoms would be single-ring aromatic groups, for example phenyl. Ring structures containing 8, 9, 10, 11, 12, 13, or 14 would be polycyclic, for example naphthyl. The aromatic ring may be substituted at one or more ring positions. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings")
wherein at least one of the rings is aromatic, for example, the other cyclic rings can be cycloalkyls, cycloalkenylst cycloalkynyls,. aryls and/or heterocyclyls. The terms ortho, met a and para apply to 1,2-, 1,3- and 1,4-disubstitutcd benzenes, respectively. For example, the names 1,2-di methyl benzene and ortho-dimcthylbcnzcne arc synonymous.
As used herein, "heteroaryl" refers to a hctcroaromatic hctcrocyclc, having at least one ring with aromatic character, (e.g. (S delocalized electrons) or at least two conjugated rings with aromatic character, (e.g. 4n + 2 delocalized electrons where "ti" is an integer), and comprising up to about 14 carbon atoms, and having at least one hctcroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic and bicyclic (e.g., having 2 fused rings) systems. Examples of heteroaryl groups includc without limitation, pyridyl (i.e., pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl (i.e. furanyl), quinolyl, tctrahydroquinolyl, isoquinolyl, tctrahydroisoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl. pyrryl, oxazolyl. benzofuryl, benzothicnyl, bcnzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl. benzothienyl,benzimidazolyl, indolitiyl, and the like.
As used herein, the term "substitutable" refers to an atom to which a hydrogen atom may be covalently attached, and to which another substituent may be present instead of the hydrogen atom. A non-limiting example oi substitutable atoms include the carbon-atoms of pyridine, The nitrogen-atom of pyridine is not substitutable according to this definition. Further, according to the same definition, the iminc nitrogen at position 3 in imidazole is not substitutable, while the amine nitrogen at position 1 is.
According to one embodiment of the present invention there is disclosed a compound according to formula (I)

i

G
R4 (I)

Gl
G2
(R10)P
G=
wherein R1 and R2 arc, independently of each other, selected from [ I and methyl and at least ore of them is H; R3 and R4 are, independently of each other, selected from H, fluoro, chloro, bromo, C1-3 alkyl and CH2 phenyl; G is selected from Gl to G2; the stereochemistry of the double-bond of Gl, onto which the substituents R5 and R6 arc attached, is such that R5 and R6 are oriented in a cis-fashion, or in a trans- fashion, relative to each other; R5 and R6 arc, independently of each other, selected from H. Cl-5 alkyl, CH2 phenyl and Cl-5 fluoroalkyl, Q is selected from phenyl, i.e. all of X 1, X2, X3, X4 and X5 arc C, and nitrogen containing heteroaryl, such as pyridyl and pyrimidinyl, i.e. XI, X2, X3, X4 and X5 are, independently of each other, selected from N and C and no more than two of X1, X2, X3, X4 and X5 are N. the residue being C, Q is optionally substituted wiih a maximum of "n" independently selected substituent(s) R7 at any substitutable ring carbon atom; "n" represent an integer number oTO, 1 or 2, i.e. if "n" is 0, then Q is unsubstituted; R7 is selected from Cl-5 alkyl, Cl-5 fluoroalkyl, halo, hydroxy, CO-3 alkyleneOCO-5 alkyl, CO-3 alkyleneOCl-5 fluoroalkyl, CO-3 alkylcneNH2, CO-3 alkylcneNHC 1-3 alkyl, CO-3 alkylencN(Cl-5 alkyl)2, N(C4-5 alkylene). Cl-5 alkylthio, S(0)Cl-5 alkyl, S02C1-5 alkyl, Cl-5 fluoroalkylthio. NH(CO)C 1 -5 alkyl,NH(CO)Cl-5 alkoxy. NHSO2C1-5 alkyl, (CO)Cl-5 alkyl, COOH. (CO)C1-5 alkoxy, (CO)NH2, (CO)NHCl-5 alkyl. (CO)N(Cl-5 alky 1)2, eyano, SO2NHC0-5 alkyl, nitro, aryl, heteroaryl, azido (N3), and morpholinyl; the stereochemistry of the double-bond of G2, onto which the substituents RK and R9 are attached, is such that R8 and R9 are oriented in a cis-fashion, or in a trans-fash ion,
relative to each other; R8 and R9 are, independently of each other, selected from H, Cl- 5 alkyl, CH2 phenyl and Cl-5 fluoroalkyl; the condensed rings W1 and W2 together represent a bicyclic aromatic system, wherein X6, X7 and X8 are. independently of each other, selected from N and C and no more than one of X6, X7 and X8 arc N, the residue being C; said bicyclic aromatic system is optionally substituted with a maximum of "p" independently selected substituent(s) R10, at any substitutable ring carbon atom of any of the rings Wl and W2; "p' represents an integer number of 0, l or 2. i.e. if l4p" is 0, then Wl and W2 is unsubstituted; R10 is selected from Cl-5 alkyl, Cl-5 fluoroalkyl, halo, hydroxy, CO-3 alkylencOCO-5 alkyl, CO-3 alkylencOCI -5 fluoroalkyl, CO-3 alkylcncNH2, CO-3 alkyleneNHCl-3 alkyl, CO-3 alkyleneN(Cl-5 alky 1)2, N(C4-5 alkylene), Cl-5 alkylthio, S(O)Cl-5 alkyl, S02C1-5 alkyl, Cl-5 fluoroalkylthio, NH{CO)Cl-5 alkyl, NH(CO)C1-5 alkoxy, NHS02C1-5 alkyl, (CO)C1-5 alkyl, COOH, (CO)Cl-5 alkoxy, (CO)NH2, (CO)NHCl-5 alkyl (CO)N(Cl-5 alky 1)2, cyano, S02NHC0 5 alkyl, nitro, aryl, heteroaryl, azido (N3), and morpholinyl, such as N- morphnlinyl;
A compound according to formula (1) as disclosed above may be present as a free base, an acid in its non-charged protonated form or a pharmaceutical ly acceptable addition salt, solvate or solvate of a salt thereof
Further a compound according to formula (I) as disclosed herein may be present as pure stereoisomer, a racemic-, diastercomeric- or scalcmic mixture.
As disclosed below, various embodiments of the present invent arc drawn to compounds according to the general formula (I), as disclosed above, wherein the various generic groups (R1 to R10, XI to X8, Q. Wl and W2) as well as the integers "nv1 and "p" arc elaborately disclosed.
As disclosed above, at least one of R l and R2 should be hydrogen in formula (I). Compounds, in which at least one of R1 and R2 is hydrogen was shown to be more potent, in at least one of the herein described in-vitro methods, than the corresponding di-methoxy derivatives. In one embodiment both Rl and R2 are hydrogen.
In one embodiment R3 and R4 arc, independently of each other, selected from H, fluoro, chloro, bromo. and methyl In another embodiment they arc independently of each other, selected from H, chloro and bromo, more preferred from chloro and bio mo and particularly preferred from chloro. In one embodiment R3 and R4 may also both be
In another embodiment both R3 and R4 arc the same and arc selected from H, fluoro, chloro, bromo, and methyl In another embodiment they are selected from H,
chloro and bromo,, more preferred from chloro and bromo. One advantage of a compound wherein R3 is identical lo R4 is, among others, thai the purification of synthetic intermediates to produce such a compound is easier.
In another embodiment G is G1 and the stereochemistry of the double-bond of Gl, onto which the substituents R5 and R6 are attached, is such that R5 and R6 are oriented in a trans-fashion relative to each other. In an embodiment wherein G is G1, R5 and R6 may be, independently of each other, selected from H, Cl-5 alkyl, such as methyl, CH2 phenyl and Cl-5 fluoroalkyl, such as CF3. R5 and R6 may also be, independently of each other, selected from H and methyl. Further, R5 may be H or Me, such as being H. Also R6 may be H or Me, such as being H.
In another embodiment G is Gl and Q is phenyl, i.e. X1 to X5 arc C.
In another embodiment G is G1 and at least one of X1 to X5 is "N, Further two of X1 to X5, such as X1 and X3 or X1 and X5, may be N and the residue being C.
In another embodiment G is G1 and Q is pyridyl, i.e. one of X1 to X5 arc N and the residue being C, In an embodiment wherein Q is pyridyl, it is preferred if X1 or X2 isN.
In another embodiment G is Gl, "n11 is 1 or 2 and R7 is, independently of each other if "n" is 2, selected from C1-C3 alkyl, such as methyl, tri fluoro methyl, halo, such as fluoro and chloro, hydroxy, N(C4-5 alkylene), methoxy, S02Mc, cyano, thienyl, nitro, phenyl, morpholinyl, such as N-morpholinyl, and N(Cl-3 alkyl)2, in which the CI-3 alkyl may be the same or different, such as N(Me)2, In another embodiment G is Gl, "n" is I or 2 and R7 may be, independently of each other if "n" is 2, selected from methyl, trifluoromethyl. hydroxy I. fluoro, chloro and N(C5 alkylene). In another embodiment wherein G is Gl, "n" may be I or 2 and R7 may be, independently of each other if un?: is 2, selected from trifluoromethyl, fluoro, chloro, NMe2 and methyl.
In one embodiment at least one R7 is a heteroaryl, such as 5- or 6-membered heteroaryl. In another embodiment at least one R7 is a 5-membercd heteroaryl, such as a thienyl.
In an embodiment wherein G is Gl and "n" is 1 or 2, one substituent R7 may be positioned at X3.
In an embodiment wherein G is GI and "n" is 2, one substituent R7 may posit ioncd at X3 and the other at X1 or X5.
In another embodiment G is Gl and "n" is 0 (zero), i.e. Q is unsubstitufed.
In another embodiment G is G2 and the stereochemistry of the double-bond of Gl, onto which the substituents RS and R9 are attached, is such that RK and R9 are
oriented in a trans-fashion relative to cach other. In an embodiment wherein C is G2, R8 and R9 may be, independently of cach other, selected from H and methyl.
In another embodiment G is G2 and at least one of X6, X7 and X8 is N, the residue being C. In an embodiment wherein G is G2, one of X6, X7 and X8 may be N. If at least one of X6, X7 and X8 is N, then it is preferred if XK is N. Similarly, it is preferred if X8 is N if one ofX6, X7 andX8 is N.
In another embodiment G is G2, "n" is 1 or 2 and R10 is. independently of cach other if "n" is 2, selected from C1-C3 alkyl, such as methyl, trifluoromcthyl, halo, such as fluoro and chloro, hydroxy, N(C4-5 alkylcnc), mcthoxy, S02Me, cyano, thienyl, nitro, phenyl, morpholinyl, such as N-morpholinyl and N(CI-3 alkyl)2, in which the C1 -3 alkyl may be the same or different, such as N(Me)2. In another embodiment G is G2, "n1" is 1 or 2 and R10 may be, independently of each other if "n" is 2, selected from methyl, irilluoromethyl, hydroxyl, fluoro, chloro and N(C5 alkylene). In another embodiment G is G2, "n" is 1 or 2 and R10 is, independently of cach other if "n11 is 2, selected from methyl, trifluoromcthyl, NMc2, fluoro and chloro.
In another embodiment G is G2 and "n1' is 0 (zero), i.e. W1 and W2 are unsubstituted.
In another embodiment, a compound according to the invention is selected from the group consisting of:

In another embodiment, a compound according to the invention is selected from the group consisting of:

A compound according to formula (I) may be used in therapy. It may be used to treat revoke, mitigate, alleviate or prevent a disease or condition characterized by bronchoconstrietion of the respiratory apparatus of a mammal, such as a human being. Further it might be used to treat, revoke, mitigate, alleviate or prevent a disease or condition characterized by inflammation or vasoconstriction of the respiratory apparatus, or other organs or parts of the body, of a mammal, such as a human being. A method to treat, revoke, mitigate, alleviate or prevent bronchoconstrietion in a mammal,
such as a human being, in need thereof is also disclosed. Furthermore a method to treat, revoke, mitigate, alleviate or prevent inflammation or vasoconstriction of the respiratory apparatus, or other organs or parts of the body, of a mammal, sueh as a human being, in need thereof is also disclosed. Such method includes the administration of therapeutically effective amount of a compound according to formula (1). Furthermore a compound according to formula (I) may be used for the prevention and/or treatment of a disease or condition selected from the group consisting of asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis, bronchiolitis and bronchopulmonary dysplasia
Additionally, a compound according to formula (1) may be used to manufacture a medicament, such as pharmaceutical composition. Such a medicament may be useful to treat, revoke, mitigate, alleviate or prevent a disease or condition characterized by bronchoconstrietion of the respiratory apparatus of a mammal, such as a human being. It may also be useful to treat, revoke, mitigate, alleviate or prevent a disease or condition characterized by inflammation or vasoconstriction of the respiratory' apparatus or other organs or parts of the body of a mammal, such as a human being. A molecule according to formula (I) may further be used to manufacture a mcdicamcnt for the prevention and/or treatment of asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis, bronchiolitis and bronchopulmonary dysplasia.
When used in herein, "prevent/preventing" should not be construed to mean that a condition and/or a disease never might occur again after use of a compound or medicament according to embodiments disclosed herein to achieve prevention. Further, the term should neither be construed to mean that a condition not might occur, at least to some extent, after such use to prevent said condition. Rather, "prevent/preventing'" is intended to mean that the condition to be prevented, if occurring despite such use, will be less severe than without such use.
The usefulness of the compounds, as defined in the preceding embodiments, in treating, prctrcating, revoking, mitigating, alleviating and'or preventing a condition of the respiratory apparatus characterized by broncho constrict ion, were evaluated in a complex and relevant in vitro model, The in vitro model was in accordance with the in vitro model disclosed in US 2006-0040254 AI and by Skogvall, S., Berglund, M., Da 1 ence-Guzman, M. F,, Svensson, Kr, Jonsson, P., Persson. C. G. A and Sterner, 0„ in Pulmonary Pharmacology and Therapeutics, vol 20:3, 2007, p, 273-280. All refercnccs disclosed herein are hereby incorporated in their entirety by reference.
In short, lung tissue was obtained from patients undergoing lobectomia or pulmectomia due to lung carcinoma. From the bronchus of this tissue were rectangular oblong preparations obtained. The contraction induced by inflammatory mediators, such as Lcukotricnc D4, histamine, prostaglandin D2 or acetylcholine, in the presence and absence of the compound to be evaluated, were compared.
Capsazepine, one of the first reported TRPV1 -antagonists, has been shown to have an cffcct of human airways (Skogvall, S., BcrgJund, M., Da I en cc-Guzman, M. F., Svensson, K., Jonsson, P., Persson, C. G. A and Sterner, O., Pulmonary Pharmacology and Therapeutics, vol 20:3, 2007, p. 273-280), but is also known to posses a range of other biological effects. Consequently capsazepine is not selective towards one target and accordingly its usefulness as a molccular tool has been questioned (Gunthorpc, M. J., Neurpharmacology, 2004, 46, 133).
Aecording to one embodiment, preferred compounds according to any of the embodiments disclosed herein arc those being at least comparably active to Capsazepine, in the in vitro model referred to herein.
Aecording to another embodiment, preferred compounds according to any of the embodiments disclosed herein arc those being at least comparably active to Rcs-4- 95, disclosed in Pulmonary Pharmacology & Therapeutics, 2007, 21(1), 125-133 as a potent analogue to Capsazepine, in the in vitro model referred to herein.
Inflammation is closely associated with COPD. New drugs that rcduce pulmonary inflammation by modulation of inflammatory pathways involving inflammatory mediators, such as lcukotricnc B4 (LTB4) and monocyte chemotactic protein-1 (MCP-1), is believed to provide effective and disease-modifying therapies and is therefore much desired (Friedman et a!, Clinical Cornerstone, 2003, 5, 45-51).
MCP-1 attracts monocytes that can differentiate into macrophages. Macrophages are generally believed to be responsible for the continued protolytic activity in the lungs of COPD-paticnts, as well as driving the inflammatory process in the same by recruitment of neutrophils. The fact that increased levels of various inflammatory mediators, or associated receptors, correlates with the diagnosis of COPD, is indicative of their rclevancc in disease severity and progression. Comparative studies between COPD-paticnts and non-COPD subjects have, for example, shown that the former group has increased levels of MCP-I in the sputum (Traves, L.S. eta!, Thorax, 2002. 57, 590-595). increased mRN A expression of MCP-1 in lung tissue (Tomaki, M. et aL Pulmonary Pharmacology & Therapeutics, 2007, 20, 596-605), and increased lipopolysaccharide (TPS) stimulated release of MCP-1 from isolated blood monocytes
(Aldonyte, R. et al, Respiratory Research, 2003, http://respiratory- research.com/content/4/1/11).
LTB4 is an araeidonic acid metabolite involved in leukocyte recruitment. LTD4 is a potent chcmoattractant and activator for neutrophils. The LTB4-receptors BLT1 and PPAR are upregulatcd in peripheral lung of COPD patients (Marian, E. et al 2006. 129, 1523-1530). Higher sputum- (Profita, M. et al Allergy, 2005, 60. 13611369) and scrum- (Scgger, J.S. etaU Chest, 1991, 99, 289-291) concentrations of LTB4 is found in COPD-paticnts as compared to healthy controls. Reduction of serum inflammatory mediator levels, including LTB4-levels, by a dietary supplement containing omega-3 polyunsaturated fatty acids, correlated significantly to a clinical improvement in COPD-paticnts (Matsuyama, W. et al, Chest, 2005, 128, 3817-3827).
Accordingly, the anti-inflammatory effect, i.e. the usefulness in treating, prctrcating. revoking, mitigating, alleviating and/or preventing an inflammation, such as an inflammation of the airways, of the compounds, as defined in the embodiments herein, may be assessed in an in vitro human peripheral blood mononuclear cell (PBMC) model. Further, the anti-inflammatory effect may be compared to the effect of dcxamcthasone, a known potent anti-inflammatory glucocorticoid.
According to one embodiment, preferred compounds according to any of the preceding embodiments arc those being at least comparably active to dexamethaonsc in such an anti-inflammatory in-vitro model.
A mcdicamcnt, e.g. a pharmaceutical composition, as has been dcscribcd herein above may further comprise pharmaceutical^ acceptable carriers, diluents, stabilisers and/or exeipients,
"Pharmaceutically acceptablc" means a carrier, stabiliser, diluent, cxcipicntor other constituents that, at the dosage and concentrations employed, does not cause any unwanted effects in the patients to whom it is administered. Such pharmaceuiically acceptable carriers, stabilisers, dilutents or exeipients arc well-known in the art, and examples of such are for example disclosed in Remington's Pharmaceutical Sciences, 18th edition, A.R Gennaro, Ed,, Mack Publishing Company (1990) and handbook of Pharmaceutical Excipients, 3rd edition, A. Kibbc, Ed., Pharmaceutical Press (2000).
A medicament according to embodiments herein maybe administered to a patient in a pharmaccutically effective dose. By "pharmaceutically effective dose" is meant a dose that is sufficient to produce the desired effects in relation to the condition for which it is administered. The exact dose may depend on the activity of the
compound, manner of administration, nature and severity of the disorder and/or disease and the general conditions, such as age and body weight olThe patient,
Aecording to one embodiment, a medicament aecording embodiments herein may be administered id one or in combination with other therapeutic agents, such as anti-asthmatics. These agents may be incorporated as part of the same medicament or may be administered separately. It is well known in the art that a combination of mechanistically unrelated therapeutic agents in the same mcdicamcnt may have beneficial effects in the treatment of conditions or diseases characterized by bronchocon strict ion, as described in, tor example, M.F. Fitzgerald and J.C. Fox, Drug Disco very Today, 2007, 12 (11/12), p. 472-478.
In one embodiment of the invention such other therapeutic agents to be administered in combination with a mcdicamcnt according to embodiments of the invention arc selected from therapeutic agents known to the one skilled in the art to prevent bronchoconstriction or revoke, fully or partly, any present bronchoconstriction. Examples of such agents are, but not limited to, p2-agonists, anticholinergics calcium antagonists, and other agents suitable for the treatment of asthma and/or COPD and related diseases and/or disorders. Preferred agents in this aspect arc p2-agonists and anticholinergics. Furthermore such other therapeutic agents to be administered in combination with the medicament of the invention may also comprise therapeutic agents known to the one skilled in the art to be useful to treat, revoke, mitigate, alleviate or prevent inflammation associated with diseases and disorders of rcspiratoiy tract. Examples of such agents arc corticosteroids.
When a compound according to embodiments disclosed herein is combined with at least another therapeutic agent, such as an anti-asthmatic, in a mcdicamcnt, such as a pharmaceutical composition, a therapeutically effective dose of said medicament may comprise I to 10 times less than the respective established therapeutically effective dose of the components, i.e. a compound according to embodiments disclosed herein and the therapeutic agent, when administered alone for prevention or treatment of the same disease or condition of each. Accordingly, by combining a compound according to the present invention with another therapeutic agent, such as an anti-asthmatic, it may be possible to achieve synergistic effects compared to if only a compound according to the present invention, or the other therapeutic agent, were administrated alone. Furthermore, it may be possible to improve both the underlying cause, e.g. the inflammation, and the clinical signs, e.g. airflow obstruction and exacerbations.
A method to treat, revoke, mitigate, alleviate or prevent bronchoconstriction and/or an inflammatory condition in a mammal, such as a human being, in need thereof, by the administration of a compound or medicament, such as a pharmaceutical composition, according to embodiments disclosed herein may also include the simultaneous or consecutive administration a therapeutic agent, such as an antiasthmatic. In such a method the therapeutically effective dose of said compound, medicament or pharmaceutical composition and said therapeutic agent may comprise 1 to 10 times less than the respective established therapeutically effective dose when administered alone for prevention or treatment of the same disease or condition. The advantageous of such co-ad ministration arc discussed above.
A medicament according to embodiments disclosed herein may be administered through different routes such as, but not limited to, intravenously, intraperitoncaly, intramuscularly, intranasaleously, subcutancously, sublingually, rcctally, orally or through inhalation or insufflation.
Particular suitable formulations of the medicament of the invention are formulations suitable to be taken orally or to be administrated through inhalation or insufflation.
Administration by inhalation or insufflation will allow a high proportion of the delivered dose to reach the site of action, that is, the bronchi and the lung in general. Furthermore the systemic effects may be lower if the mcdicamcnt is administrated through inhalation or insufflation compared toother administration routes.
Inhalation may be by the oral or the nasal route. Conventional pulmonary applicators may be employed, such as pressurized spray containers comprising suitable propel I ants for aerosols and powder spray dcviccs for preparations in form of fine powders. Pharmaceutical compositions suitable for administration by the inhalation or insufflation route are known in the art. The compound may be dissolved in a suitable vehicle or employed as a fine powder, such as a micronized powder of a particle size from about 2 pm to about 20 pm. An indicated daily dose for administration by inhalation may be 10 times and more lower than the corresponding oral dose. Satisfactory doses, preferably metered by using a device capable of metering, or by single doses of predetermined size, may easily be determined by experimentation.
Compounds according to embodiments of the present invention may also be useful in treatment or prevention of hypertension. In the treatment of conditions or diseases characterized by hypertension, by employment of the compounds of the present invention, oral administration is the preferred route of administration.
In addition to their use in therapeutic medicine, compounds according to formula I may also be useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of other compounds with similar activity. Furthermore, compounds of formula I may be used as molecular probes to identify and/or locate the target of their action, such as a target within the airways, as well as employed as a diagnostic tool for diagnosis of a disease or condition in vivo, ex vivo or in vitro, or as synthetic precursors to such probes. Molecular probes of formula I may include reactive, labeled, i.e. compounds of formula I wherein one or several of the composing atoms have been enriched with a radioactive or by other means detectable isotope, and fluorescent compounds as well known to the one skilled in the art.
Methods of preparation
Other embodiments of the present invention relates to processes for preparing a compound according to formula I as a free base, acid, or salts thereof. Further, additionally embodiments relate to synthetic intermediates, which are useful in the synthesis of a compound of formula 1 as a free base, acid, or salts thereof. Specific and generic examples of such intermediates are given below. Further, such intermediates may include compounds according to formula I, which may be used to produce another compound according to formula I.
Throughout the following description of such processes it is to be understood that, where appropriate, suitable protecting groups will be attached to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups, as well as examples of suitable protecting groups, are well known within the art. Further such procedures and groups are described in the literature, such as in "Protective Groups in Organic Synthesis", 3rd ed., T.W. Green, P.G.M. Wuts, Wiley-lnterscience, New York (1999).
It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conductcd on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carricd by the molecule at that stage to the condilions or reagenis employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a
suitable order, will be readily understood to the one skilled in the art of organic synthesis.
Examples of transformations arc given below, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified.
References and descriptions on other suitable transformations are for example given in "Comprehensive Organic Transformations A Guide to Functional Group Preparations'1. 2nd ed., R. C. Larock, Wiley-VCH, New York (1999). References and descriptions of'other suitable reactions are described in textbooks of organic chcmistry well known to the one skilled in the art, such as "March's Advanced Organic Chemistry1', 5th ed., M. B. Smith, J. March, John Wiley & Sons (2001) or, "Organic Synthesis", 2nd ed., M. B. Smith, McGraw-Hill, (2002).
Techniques for purification of intermediates and final products include for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily understood by the one skilled in the art.
The terms ""room temperature" and 1Lambient temperature" shall mean, unless otherwise specified, a temperature between 16 and 25 The term "reflux" shall mean, unless otherwise stated, in reference to an employed solvent using a temperature at or slightly above the boiling point of the named solvent. It is understood that microwaves can be used for the heating of reaction mixtures.
The terms "flash chromatography" or "flash column chromatography" shall mean preparative chromatography on silica using an organic solvent, or mixtures thereof, as mobile phase.
Abbreviations
aq. aqueous:
CDI 1,1'-carbonyl diimidazole;
CH2C12 dichloromcthane;
DABCO 1.4- diazab ic yclo [2.2.21 oc tanc;
DMAP 4-d i methylam i nopy rid ine;
DMF N,N-dim ethyl form amide;
DMSO dimethyl sulfoxide;
EDCHCI N (3 -d i methylam i nop ropy I )-N '-ethyl
carbodiimide;

Et,N triethylamine;
EtOAc ethyl acetate;
EtOH ethanol;
Et2G diethyl ether;
h hour(s);
HRr hydrogen bromide;
HCI hydrogen chloride;
HOBt 1 -hydroxybenzotriazole hydrate;
K2CO3 potassium carbonate;
ma major;
McOH methanol;
MgS04 magnesium sulphate;
mi minor:
NaHCO* sodium bicarbonate;
NaOH sodium hydroxide;
Pet. Ether petroleum ether;
r.t. or rt room temperature;
rot. mix. rotameric mixture
sat. saturated;
THF tctrahydrofurane;
TLC thin layer chromatography;
TMS tetramethylsilanc,

Methods of preparation of final compounds of formula I by coupling of intermediates II and HI (Scheme I)
R1 R3

Scheme 1

Formation of compounds of formula I, may be accomplished by coupling of II and 111 (wherein depleted "(het)Ar" is represented by aryl or heteroaryl, R corresponds to R5 and RK of formula I, R* corresponds to R6 and R9 of formula I) under standard amide coupling conditions, such as in the presence of N-(3-dimcthylami nop ropy l)-N ethyl-carbodiimidc hydrochloride, 1-hydro xybenzotri azoic hydrate, 4- d imethylaminopyridine and caesium carbonate (see for example Toftered et a I., SYNLETT, 2004, 2517-2520), or, for example, via initial conversion of the acid 111 into the corresponding acid chloride, followed by coupling with II according to standard protocols. The N-acylation of 11 may be accompanied by competing O-acylation when one or both of the substituents R1 and R2 arc hydrogens. Thus, it is preferred to protcct the corresponding phenolic moieties with suitable protective groups, such as methyl, before N-acylation of II, Methyl protective groups may be introduced by treatment with a methyl halide in the presence of a base according to standard procedures, and removed after the N-acylation by treatment with, for example, hydrogen bromide or boron tribromide (Hall et ah, Bioorg. Med. Chem, 2005, 13, 1409-1413). Other aromatic methyl ethers, optionally present in the molecule, are then simultaneously cleaved off.
Methods of preparation of intermediates of formula II (Scheme 2)

II

Scheme 2

Examples of two nan-limiting methods for the preparation of intermediates of formula II, by assembly of the tetrahydroisoquinoline ring, include pathway A and pathway B.
The synthesis according to pathway A involves a Pictct-Spcngler reaction in which readily available phenylcthylaminc IV is reacted with formaldehyde to yield V, followed by cyclisatiori under acidic conditions (Yokoyama et al., J Org Chem, 1999, 64, 611-617; for a modified procedure allowing eyelisation onto electron poor aromatics see for example Stokker et al., Tetrahedron Lett, 1996, 37, 5453-5456).
The synthesis corresponding to pathway B involves a Pomcrantz-Fritsch reaction under reductive conditions in which readily available benzaldchydcs VI arc reacted with aminoacetales VII (depicted "alkyl" is preferably short alky Is such as ethyl) to yield VII I, followed by cyclisation under acidic and reductive conditions to yield II (see for example: Bobbit et al., J Org Chem. 1965, 30. 2247-2250; Bobbit et al., J Org Chem, 1968, 33, 856-858).
Additional methods for the preparation of intermediates II include, for example, the direct introduction of the substituents R3 and R4 by electrophilic aromatic substitution, such as chlorination by treatment with sulphury I chloride in acetic acid, or bromination as described in Okano et al., Tetrahedron, 2006. 128, 7136-7137.
Methods of preparation of intermediates of formula 11 1 (Scheme 3)
alkyl

Heck
+ X—(het)Ar
O R'

(het)Ar
R XI
0
hydrolysis
H
A..
IX
XII
+
Knoevenagel
Scheme 3
0 (het)Ar (MI R=R-=H) XIII

Intermediates of formula 111 may be prepared from readily available esters IX (depicted "alkyl" is preferably short alkyls such as methyl) by, for example, standard palladium catalyzed Heck-coupling with aryl- and hcteroaryl-halidcs X (depicted X is lodo, bromo or chloro), followed by hydrolysis with, for example, sodium hydroxide in

a mixture of THF and ethanok The suitable reaction conditions, and the type of palladium catalyst employed in the Heck-co up ling, is much dependant on the nature of the substituent R' of IX and to the type of halide in X as well known to the one skilled in the art. For example, for electron-rich aryl- and hcteroaryl-halidcs X, iodo or bromo is preferred over chloro as the halide unless a palladium-catalyst w ilh relatively high activity is employed.
Additional methods for the preparation of intermediates of formula III include standard Knoevenagel condensation between malonic acid XII. and aryl- or heteroaryl aldehydes XIII, followed by decarboxylation (lower part of scheme 3). Furthermore, when aiming for intermediates of formula XI (and then III after hydrolysis, as described above) in which R' ^ H, the Heck reaction may be low yielding bccause of steric hindrance at the terminal position of the double bond of structures such as IX, Instead one may employ the Homer Wads worth Emmons (HWE) reaction, in which a phosphinc oxide of general formula XIV reacts with a heteroaryl ketone of general formula XV (Scheme 4).
¥

R'
HWE hydrolysis
-alkyl +
0*
CT (het)Ar
XV
alky V i
alkyl R XIV
Scheme 4
Compound examples
General Methods
All materials were obtained from commercial sources, unless not stated otherwise, and were used without further purification unless otherwise noted. DMF was dried over molecular sieves (4A). THF was distilled from sodium and benzophenone. HRMS (ESI) spectra were recorded with a micro mass Q-TOF Micro spectrometer. NMR spectra (in CDCI3, CD30D or DMS0-d6) were recorded on a Bruker DRX 400 or on a Bruker U It rash i eld 400 spectrometer at400MHz.All chemical shifts are in ppm on the delta-scalc (5) relative to TMS using the residual CHCI3 peak in CDC13, or the residual CD2HOD peak in CD30D, or the residual CD3SOCD2H peak in (CD3)2SO as

internal standard (7.26, 3.31 or 2.50 ppm respectively relative to TMS) and the fine splitting of the signals as appearing in the recordings (s: singlet, d: doublet, t: triplet, q: quartet, m: multiples br: broad signal). Flash chromatography was performed using 60A 35-70 um Davisil silica gel. TLC analyses were made on Silica Gel 60 F254 (Merck) plates and visualised under a 254/365 nm UV-lamp,
Preparation of intermediates
Below follows non-limiting examples on the synthesis of intermediates useful for the preparation of compounds of fonnula I.
5,8-Dichloro-6,7-dimethoxv-l,2,3,4-tetrahydroisoquinoline hydrochloride

Dimethoxy-L2,3,4-tctrahydroisoquinoline hydrochloride (200 mg, 0.870 mmol) was suspended in glacial acctic acid (5 mL) and sulphuiyl chloride (154 pL, 1.92 mmol) was added slowly. The resulting mixture was stirred at room temperature for 3 hours and then evaporated to give the title compound (quant) as a yellowish mass.
'H NMR (400 MHz, CD.^OD) 5 4.35 (br s, 2H), 3.90 (br d, 6H), 3.50 (br, 2H). 3.05 (br, 2H).
5.8- D ic h I or o-6,7- dihy d rosy-1,2,3,4-tetr ah y d roi soq u in o M ne liy d r o h r omide

CI
5,8-Dichloro-6,7-dimcthoxy-l,2,3,4-tctrahydroisoquino[inc hydrochloride (1.0 g, 3,35 mmol) was suspended in aqueous HBr (48%, 10 mL) and refluxed for 5 hours before evaporation. The remaining residue was evaporated twice from toluene to give 1.05 g (quant) of the title compound as a pale solid.
'H NMR (400 MHz, CD,OD) 6 6.60 (s, 1H) 6.57 (s, 1H) 4.26 (s, 2H) 3.50 (t 2H, ,J=6 Hz) 3.01 (t, 2H, ,/=6 Hz).

5,8-Bi s (chioromethy1)- 6,7-dimet hoxy-1,2,3,4- tetrahydroisoq uinoline acetamide

CI
6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline hydrochloride (2.0 g, 8.71 mmol) was dissolved in water (20 ml) and NaOH (10 ml, 2M aq). The aqueous phase was extracted with dichloromethane (4*20 ml) and the combined organics were dried (MgSCK)) and filtered. The filtered liquid was cooled to 0 °C before slow addition of acetyl chloride (620 JJ.1, ft.71 mmol) followed by slow addition of EuN (1.22 ml, 8.71 mmol). The resulting mixture was stirred at rt for 30 minutes, washed with HC1 (2*80 ml, 1M aq.) and NaHCO.* (80 ml, sat aq.), dried (MgS04). filtered and evaporated into a pale mass.
This mass was dissolved in nitromethane (40 ml) and cooled to 0 °C. Tin(IV)chloride (8.15 ml, 70.0 mmol) was added slowly followed by slow addition of methoxyacetyl chloride (3.18 ml, 34.8 mmol) and the resulting mixture was stirred at rt for 24 h. The reaction was then diluted with HCI (30 ml, conentrated. aq.) and extracted with dichloromethane (3*40 ml). Combined organics were washed with water (20 ml), dried (MgSO^), filtered and evaporated into a pale solid foam. The product was purified by flash chromatography using Pet. Ethcr/EtOAc (1/2) as eluent to give 420 mg (14 %} of 5.8-bis(chloromcthyl)-6,7-dimcthoxy-L23,4-tctrahydroisoquinoline acet amide as a pale, sticky mass,
'HNMR (CDC1?) rot. mix. 5 4.77-4.55 (br, 2H) 4.20-4,05 (br, 2H) 3,82 (s, 6H) 4.81-4.70 (br, 2H) 3.96-3.85 (br, 2H) 3.85-3.75 (br, IH) 3.75-3.63 (br, 2H) 2.94-2.83 (br, 2H) 2.80-2.62 (br, 2H) 1.46 (s, 9H). TLC (Pet. Ethcr/EtOAc 1/1) Rf 0.23.
6,7-Dimetlioxy-5,8-dimethyl-l,23^4-tetrahydroisoquino]ine acel amide

5,8-Bis(chloromethy l)-6,7 -di mctho x y-1,2,3,4-dihydroisoquinoline acctam id c (420 mg, 1.26 mmol), was dissolved in DMF (6 ml) at rt. Sodium cyanoborohydride (199 mg, 3.16 mmol) was added and the reaction was stirred at 100 °C for 20 h. The

reaction was cooled, diluted with HC1 (60 ml, IM aq.) and extracted with EtOAc (3*20 ml). Combined organ ics were washed with NaHCCh (30 ml, sat. aq.) followed by brine (30 ml), dried (MgSO4). filtered and evaporated to give 396 mg of crudc 6,7- dimethoxy-5,8-dimethyl-l,2,3,4-tetrahydroisoquinoline acetamide as a pale oil. This material was used in subsequent reactions without further purification,
'H NMR (CDCIV) rot. mix. 5 4.55 (ma)(sf 2H) 4.43 (mi)(s, 2H) 3.79 (mi)(br t, 2H) 3.78 (s, 6H) 3.65 (ma)(br t, 2H) 2.73 (ma)(br t, 2H) 2.66 (mi)(br t, 2H) 2.18 (br d, 3H) 2.13 (br d, 3H)2.02 (s, 3H).
6,7- Dimethoxy-5,8-dim ethyl-1,2 3,4-tetra hydroisoquinoline

6,7-Dimethoxy-5,8-dimethyI-1,2,3,4-tetrahydroisoquinoline acetamide (396 mg) was dissolved in 1,4-dioxanc (10 ml). NaOH (10 ml, 2M aq.) was added and the mixture was rcfluxcd for 21 h. Organic solvents were evaporated and the aq. residue was extracted with dichloromethane (4*20 ml). Combined organics were dried (MgSOj), filtered and evaporated. The product was purified by flash chromatography using EtOAc/MeOH/EtjN (20/2/1 16/4/1) as clucnt to give 116 mg (42 %) of 6,7- dimethoxy-5,8-dimethyl-1,2,3,4-tetrahydroisoquincline as a clear, oily residue,
'HNMR (CDCl3) 5 3.87 (s, 2H) 3.80 (s, 6H) 3.13 (t, J= 6 Hz, 2H) 2,60 (t,7 6 Hz, 211) 2.14 (s, 311)2.09 (s, 3H).
TLC (EtOAc/MeOH/Et,N 16/4/1) Rf0.35.
3-l0d0-2-(piperidin-1 -yl)-6- (tri flu o r o meth y l)py r idin e

A solution of 2-chloro-3-iodo-6-(trifliioromcthyI)pyridme (Tet. Lett., 1998, 39(13), I749-1752)(350 mg, 1.14 mmol), piperidinc (135 pi, 1.37 mmol) and Et,N (640 pi, 4,56 mmol) in /-PrOH (2 ml ) was heated for 1 h at 140 °C in a microwave reactor. The reaction mixture was concentrated to dryness and the crudc was purified through flash chromatography (Si02, heptane) to afford 237 mg (58%) of the title compound.
1H NMR (CDCh) 8 8 J 7 (dd, J= 7.6 Hz, J= 0.8 Hz. 1H) 6.91 (d, J= 7.6 Hz, 1H) 3.29 (m, 4H) 1.75 (m. 4H) 1.63 (m, 2H).
General procedure for the llcck reaction to yield compounds X (Scheme 3)
Aryl bromide X (1.0 equiv,), Pd(OAc)2 (2 mol%), DABCO (4 mol%) and KJC03(1.0 equiv.) were suspended in DMF (5.2 mL/mmol aryl bromide X) together with the unsaturated ester IX (1.5 equiv.). The mixture was flushed with argon before the tube was scaled and heated at 125 °C for 12 hours. Then, the mixture was filtered through Celite, rinsed with CH2O2 and evaporated, The remaining residue was then purified by column chromatography to yield compounds XI.
The following compounds were prepared according to the general procedure described above.
(E)-Met h y 1 3-(q u i nol i n -3-y l)acry lat e
O

The title compound was obtained as a white solid in 85% yield (Sit>2, petroleum ether/ethyl acetate 85/15 —► 50/50).
'H NMR (400 MHz, CDCb) 6 9.10 (d, 1H, J=2.0 Hz) 8.25 (d, 1H. 7=2.0 Hz) 8.12 (d, 1H, ,7=8.4 Hz) 7.86 (d, 1H, .7=16.0 Hz) 7.87-7.85 (m, 1H) 7.78-7.74 (m, 1H) 7.62-7.58 (m, 1H) 6.68 (d, 1H.,/= 16.0 Hz) 3.86 (s, 3H).
(ZT/Z)-Methyl 3-(quinolin-3-yl)but-2-enoatc

The title compound was obtained as a diastereomeric mixture (E- and Z- isomers), as a white solid, in 52% yield. Rf0.21 (SiO2, petroleum ether/ethyl acetate 80/20).
'HNMR (400 MHz, CDCh) 5 9.05 (d, IH, J=2.4 Hz) 8.22 (d, 1H, ,7=2.4 Hz) 8.13-8.11 (m, 111)7.87-7.85 (m, 1H) 7.77-7.73 (m. 111) 7.61-7.57 (m, 111)6.34-6.33 (m, 1H) 3.81 (5, 3H) 2.71 (s, 3H).
(E)-ethyl 3 - (6-{t rifluoromethyl)pyridin -3-yl)ac rylate
F
F

F
O
k
o
This material was used directly in the next step without any further purification.
Yield: 97%.
'H NMR (CDCl3)δ8.85 (d, J=1.6 Hz. 1H)8,00 (dd, >2.0, 8.0 Hz, 1H)7.72 (d, J=8.4 Hz, IH) 7.71 (d, J=16.0 Hz, 1H) 6.60 (d, >16.0 Hz, 1H)4.31 (%J=12 Hz, 2H) 1.36 (t, .7=7.2 Hz, 3H),
(E)-methyl 3-(2-(pipei*idin-l-yl)-6-(trifluoi*0iiiethyl)pyridin-3-yl)flCrylate

70 µl (1.0 mmol) methyl aery late was added to a mixture of 237 mg (0.66 mmol) 3-iodo-2-(pipcridin-l-yl)-6-(trifluoromcthyl)pyridmc, 3 mg(0.01 mmol) Pd(OAcK 2.2 mg (0.02 mmol) DABCO and 91 mg (0.66 mmol) KXO; in 3 ml DMF under a nitrogen atmosphere. The reaction mixture was stirred in a sealed tube at 80 °C for 24 h. The mixture was cooled to RT, filtered through celite with EtOAc eluation. The organic phase was washed with w ater, dried and concentrated. Flash chromatography (Si02, Pet. Ether/ EtOAc 8/1) afforded 196 mg (94%) of the title compound.
'H NMR (CDCh) 5 7.74 (d, 1H), 7.69 (d, 1H), 7.15 (d. 1H), 6.42 (d, 1H), 3.82 (s, 3H), 3.28 (m, 4H), 1.72 (m, 4H), 1.65 (m. 2H).
To a solution of 2-trifluoromethyl-5-hromopyridine (5.0 g. 22 mmol) in EtiO (50 mL) was added.veoBuLi (0.91 M in cyclohexane, 24 niL, 22 mmol) at -78 °C.
1 - (6-( T r i flu or o methy l)py ri din-3 -y I) eth a n on e

F

After 10 minutes of stirring, N,N-dimethylaminoacetamidc (2.3 mL, 24 mmol) dissolved in Et2O (10 mL) was added drop wise. Stirring was continued at -78 DC for 1 h and then at rt over night. The reaction mixture wras poured into water (100 mL) and the water phase was extracted with Et?0 (3 >=100 mL), Combined organics were washed with water and brine and dried (MgS04). After careful evaporation of the solvent, the crudc was purified by column chromotography (SiO^ pcntanc/ether 9/1) to give the title compound (2.3 g, 12 mmol, 54%) as a light yellow solid.
'H NMR (CDCL) S 9.26 (br s, 1H) 8.43 (br d, .7=5.6 Hz, 1H) 7.83 (br d, J=7.2 Hz, 1H) 2.71 (s, 3H).
E thy] 3-(6-(t r i fl uo r om et hv I) py r id in -3-vl)b u t- 2-en oate
O

F

Tricthyl phosphonoacctatc (6.2 mL. 31 mmol) was added drop wise to a suspension of NaH (95%, 760 mg, 30 mmol) in dry THF (10 mL) at 0 °C. After 30 minutes of stirring at 0 °C\ 1 -(6-(trifluoro methy l)pyridin-3-yI)ethanone (2.3 g. 12 mmol) in THF (8 mL) was added drop wise. The resulting mixture was heated at reflux for 12 h and was then allowed to cool to rt. The reaction mixture was poured into sat. NH^CI (aq.) (15 mL) and extracted with Et20 (3*15 mL). Combined organics were washed with water and brine and dried (MgS(V) After evaporation the crudc was purified by column chromatography (SiO;, Pet. Ether/EtOAc 95/5) to give the title compound (2,9 g, 11 mmol, 94%) as a light yellow oil, as a mixture of E- and Z- isomcrs.
'H NMR (CDC 1.0 d 8.81 (br s, 1H) 7.92 (br d. >8.4 Hz, 1H) 7.71 (br d, >8.0 Hz, 1H) 6.19 (br s, 1H) 4.26 (q,>7.2 Hz, 2H) 2.60 (br s, 3H) 1.34 (t, >7.2 Hz, 3H).
I - (5- Flu o ropy ri di n-2 - v I) etli a n o n c

.ftfc-BuLi (1.9 mL, 1.4 M in hcxane) was added drop wise to a solution of 2- bromo-5-fluoropyridine (500 mg, 2.8 mmol) in dry Et2O (6 mL) at -78 C'C. Stirring was continued at this temperature for 10 minutes, after which a solution of N,N-dimethylacetamide (290 pL, 3.1 mmol) in dry Et70 (1 mL) was added drop wise. Stirring was continued at -78 °C For 1 h, where after the reaction mixture was allowed to slowly reach rt. The reaction mixture was again cooled to -78 °C and was qucnchcd by adding 1M HCl aq. .solution (6 mL) before it was left to warm to rt over night. The water and organic phases were separated and the water phase extracted with Et?0 (2 : 1EI NMR (CD3OD) δ 8.51 (d,,/=2.8 Hz, 111)8.11 (ddd,J=0.4, 4.8, 8.8 llz, HI) 7.52 (ddt, 0.8, 2,8, 8,8 Hz, IH) 2.71 (s, 3H).
General procedure for ester hydrolysis (scheme 3)
A solution of NaOH (s) (500 mg) in water (1.1 mL) was added to a mcthanolic solution of the ester X1 (2.5 mmol). Stirring was continued at rt for 2h. After that, the reaction mixture was neutralized by adding 1M HCl (aq,). A white precipitate formed which was isolated by filtration and washed with water and methanol. The white chty/stalline product was dried in a vacuum oven at 45 °C.
The following compounds were prepared according to the general procedure described above.
(iT)-3-(quinoLin-3-y I )a c r y lie acid
The title compound was obtained as a white solid in 71 % yield and was used directly in the next step without further purification.
O

(E)-3-(quinolin-3-vl)but-2-enoic acid
*o

The title compound was obtained as a white solid in 94% yield and was used directly in the next step without further purification.
The following compounds of formula III were also prepared as indicated
(£)-3 - (6-(trifl u o r o in ethyl )p vr id in-3-yl)aeryl ic a ci d
o

To a solution of (£)-ethy 1-3-(6-(trifluoromethyl)pyridin-3-yl)acrylate (2.65 g, 10.8 mmol) inTHF/EtOH (1/1, 20 mL) was added 2.28 M NaOH (aq.) (14.2 mL) at it. The reaction mixture was stirred at rt for 4 h and was then neutralized by adding IM HCl (aq.). The water-phase was extracted with CH^Cb/MeOH 9/1 (5 - 20 mL), the combined organics dried (MgSO4), filtered and evaporated to give the title compound (2.15 g, 9.90 mmol, 91%) as an off white solid. This material was used directly in the next step without further puriUcation.
'H NMR (CD3OD) 6 8.91 (d, >1.6 Hz, 1H) 8.29 (dd, >2.0, 8.4 Hz. 1H) 7.85 (d,>8.4 Hz, 1H) 7.75 (d,>16.0 Hz, 1H)6.75 8d,>16.0 Hz, 1H).
3-(6-(Trl fluoro methyl)pyrldln-3-yl)but-2-enolc acid
o

To a solution of ethyl 3-(6-(trifluoromethyl)pyridin-3-yl)but-2-enoate (2.9 g, 11 mmol) in EtOH/THF 1/1 (34 mL) was added 1M NaOH (aq.) (34 mL). The resulting mixture was heated at 60 °C for I h after which the reaction mixture was allowed to cool to rt. The volatilcs were evaporated and the remaining water phase neutralized with 1 M HCl (aq.). The title compound (2,4 g, 10 mmol, 91%), which precipitated as a

white solid, was filtered off and dried under vacuum at 55 °C over night. This material was used directly in the next step, without further purification.
(F)-3 - (2- m ethy )-6-{t ri fl uo r o m ethyl) pyr idi n -3-y l)acr vl ic ac i d
O

OH

rT "
F
To a solution of (E)-methyl 3-(2-mcthyl-6-(trifluoromcthyl)pyridin-3- y1)acrylate (Gray, M.; Andrews, I. P.; Hook, D. F.; Kitteringham, J.; Voyle, M. Tet, Lett. 2001, 41, 6237-6240.) (150 mg, 0.61 mmol) in MeOH (2.0 mL) was added 1M NaOH (aq.) (1.8 mL). The reaction mixture was stirred for 2 h at 40 °C. The vulatiles were then evaporated and the remaining water phase neutralized with 1M HCl (aq). The Litle compound (141 mg, 0.61 mmol, quant.), which precipitated as a white solid, was filtered off and dried under vacuum at 45 "C. This material was used directly in the next step without further purification.
{E,Z)-3-(5-fluoropyridin-2-yl)but-2-en ok acid

Triethyl phosphonoacctate (740 pL, 3.7 mmol) was added drop wise to a suspension of NaH (95%, 86 mg, 3.6 mmol) in dry7 THF (1.0 mL) at 0 °C. Stirring was continued at this temperature for 30 minutes, after which a solution of l-(5- fluoropyridin-2-yl)ethanone (200 mg, 1.4 mmol) in dry THF (1 mL) was added drop wise to the reaction mixture. The resulting mixture was heated at reflux for 6 h and was then left to cool to rt over night. The reaction was quenched by careful addition of NH^Cl sat. aq, solution (1,5 mL) and was then extracted with Et^O (2*10 mL), Combined organics wore washed with water and brine and dried (MgSO^ i. After filtration and evaporation crudc (E,Z)-ethyl 3-(5-fluoropyridin-2-yl)but-2-cnoate was obtained pure enough to be used directly in the next step.
1M NaOH aq. solution (4.2 mL) was added to a solution of (£.Z)-ethyl 3-(5- fluoropyridin-2-yl)but-2-cnoate (293 mg, 1.4 mmol) in EtOH/THF (4 mL, 1/1). The resulting mixture was heated at 40 X1 for 12 h and was then left to cool to rt. The volatiles were evaporated and the remaining water phase acidified to pH 6-7 using 1 M
HCl aq. solution. The water phase was extracted w ith CH2Cl2 (5X10 mL) and combined organics were washed with brine and dried (MgSC>4). After filtration and evaporation the title compound (190 mg, 1.0 mmol, 75%) was obtained as a mixture of E- and Z- isomers which was considered to be pure enough to be used directly in the next step. The isomers were not separated at this stage.
'H NMR (CD?OD) 6 8.48 (d, >3.2 Hz, 1H) 7.78-7.73 (m, 1H) 7.66-7.60 (m, 1H) 6.63 (d, .7=1,2 Hz, 1H) 2.56 (d, ./=1.6 Hz, 3H).
General procedure for amide coupling to yield methyl ethers of formula I (R l=R2=methvl. Scheme 1)
5P8-dichloro-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol ine hydrochloride (1.0 mmol), a carboxylic acid of general formula III (1.1 mmol), EDC HC1 (1.5 mmol), HOBt (1.0 mmol), DMAP (2.0 mmol) and cesium carbonate (2.0 mmol) were suspended in DMF (30 mL) and stirred at rt for 48 h. The reaction mixture was then diluted with water (30 mL) and extracted with EtOAc (3x30 mL). The combined organics were washed with NaHCO3 (2x30 mL, sat aq), water (3x30 mL) and brine and dried (MgS04). After evaporation the resulting methyl ethers of formula 1 were purified by column chromatography.
The following compounds were prepared according to the general procedure described above.
(E)-1 - (5,8-d ich In ru-6,7- dimetho xy-3,4-d i hyd roisoq u i n o 1 i n-2 (1 //)-yl)-3- (pyridin-3-yl)prop-2-en-l-oue

The title compound was obtained as a yellowish oil in 52% yield, R| 0,26 (SiO?, petroleum ether/ethyl acetatc 3/7).

'HNMR (400 MHZ,CDCI3) rot. mix. ri 8.79 (d. 1H, .7=2.0 Hz) 8.59 (dd, 1H, ,7=1.6, 4.8 Hz) 7.85 (td, 1H,.7=1,8,8,0 Hz) 7.71 (d, 1H, >15,6 HZ) 7.35-7.32 (m, 1H) 7.04 (d, 1H, >15.6 Hz) 4.82-4.75 (ma+mi, m, 2H) 3.99-3.84 (m, 2H) 3.91 (br s, 6H) 2.99-2.88 (M, 2H).
(E)-1 - (5,8-d ichl o ro-6,7- dim e t h o xv-3,4- d i hyd r oisoq u in o li n-2 - (l//)-vl)-3 -(5 fluoropyridin-2-yl)prop-2-en-l-one

The title compound was obtained as a colourless oil in 47% yield, Rj 0.28 (SiCb, petroleum ether/ethyl acetate 1/1).
JH NMR (400 MHz, McOD) rot. mix. 6 8.53 (d, 1H,>2.8 Hz) 7.74-7.62 (m. 4H) 4.82 (br s, 2H) 4.01-3.98 (m, 2H)3.89 (brs, 6H) 2.99-2.90 (ma+mi,m, 2H).
(E)-1 - (5,8-d ich I o r o-6,7- d i m et h o xy-3,4- d I li y d r oisoq u 1 n o 1 i n-2 (I H)-y l)-3- (q u i n o li n-3 -y l)pr op- 2-en-1 - on e

The title compound was obtained as a white solid in 39% yield (SiOz, petroleum ether/ethyl acetate).
'H NMR (400 MHz, CDCh) rot. mix. 5 9.15 (d, 1H,>2.4 Hz) 8.26 (d. 1H >2.0 Hz) 8.13 (d, 1H, >8.4 Hz) 7.90 (d, 1H,> 15.6 Hz) 7.88 (br d, 1H,>7.2 Hz) 7.78-7.74 (m, 1H) 7.62-7.58 (m, 1H) 7-21 (d, 1H, > 15.2 Hz) 4.87-4.82 (ma+mi)(m. 211) 3.99-3.91 (m, 211) 3.93 (s, 311) 3.92 (s, 311) 3.00-2.94 (ma i mi, m,2H).
(E)-1 - (5,8-d ich I o r o-6,7- d i m et h o xy -3,4- d i liv d r oisoq u i n o 1 i n-2 (l//)-y l)-3- (quin o li n-3 -y l)bu t- 2-en- 1-one

The title compound was obtained as a colour less oil in 40% yield (SiOj, petroleum ether/ethyl acctatc 6/4).
'HNMR (400 MHz. CDCh) rot. mix. ri 9.10 (d. 1H.>2.0 Hz) 8.20 (brs. 1H) 8.13 (br d, 1H, >8.4 Hz) 7.87 (br d, 1H, >8.0 Hz) 7.75 (br t, 1H, >7.8 Hz) 7.60 (br t,
1H, >7.4 Hz) 6.57 (br 5, 1H) 4.84 (ma, br s, 2H) 4.71 (mi, br s, 2H) 3.98-3.81 (ma+mi m, 2H) 3.93 (s, 6H) 2.97-2.89 (m, 2H) 2.45 (ma, br s. 2H) 2.41 (mi, br s, 2H).
(E)- I - (5,8-dichl 0 r0-6,7- d i m e t h 0 xy-3,4-di h y d roiso q u i n 01 i n-2 (I H)- yl)-3-(4- m etho xy p heny l)p r 0 p-2 - e n -1 -0 n e

The title compound was obtained as a white solid in 43% yield (SiO^, petroleum ether/ethyl acetate 75/25).
'H NMR (400 MHz, DMSO-A) rot. mix. 6 7.76-7.64 (m, 2H) 7.50 (br d, 1H, >15.2 Hz) 7.23 (br d, 1H, >15.2 Hz) 6.99-6.96 (m, 211) 4.78 (mi, br s, 2H) 4.70 (ma, brs, 2H) 4.02-3.91 (m, 2H) 3.84 (s, 3H) 3.83 (s, 3H) 3.80 (s, 3H) 2.87-2.72 (m, 2H).
(Z)-1 - (5,8-dich lo ro-6,7- d imet ho xy-3,4-dihyd roisoqu in olm-2 (lif)-y l)-3-(2- methoxyphenyl)prop-2-en-l-one

The title compound was obtained as a colourless oil in 46% yield, (SiO;, petroleum ether/ethyl acetate 8/2).
'H NMR (400 MHz, McOD) rot. mix. 5 7.06-7.00 (m, 2H) 7.00 (d, 1 H,>I2.4 Hz) 6.95-6.91 (m, 1H) 6,63-6.61 (m, 1H) 6.56-6.52 (m, lH)6.08(d, 1H,>l2.4Hz) 4.66 (mi, br s, 2H) 4.39 (ma, br s, 2H) 3.86 (s, 3H) 3.83 (s, 3H) 3.79 (ma, t, 2H, .7=6.0 Hz) 3.76 (s, 3H) 3.61 (mi, t, 2H,>6.0 Hz) 2.66 (ma, t, 2H,>6.0 Hz) 2.35 (mi, t,2H, >6.0 Hz).

(E) 1 - (5,8-d ichl o ro-6,7-dim e t h o xv-3,4-d i h yd roisoq u in o li n-2 (1 H)-y l)-3-(5 fl uo r opyr i d i n - 2-yl)hut-2-en-1 - o 11 e

The title compound was obtained as a yellow solid in 32% yield (Si02, Pet. ether/EtOAc 75/25). The Z-isomer was not isolated.
'h NMR (CDCb) rot. mix. S 8.47 (d, ,/=2.8 Hz, 1H) 7.54-7.50 (m, 1H)7.45- 7.39 (m, 1H) 7.05 (ma)(s; 1H) 7.00 (mi)(s, 1H) 4.82 (ma)(s, 2H) 4.66 (mi)(s; 2H) 3.91 (st 6H) 3,86-3.76 (mf 2H) 2.94-2.86 (m, 2H) 2.33 (br s, 3H).
The following methyl ether of formula 1 (Schcmc 1, R I - R4=methyl) was also prepared as indicated,
(E)-6,7-d ira cthoxy-5,8-d i m ethyl-1,2,3,4-tetrahyd roisoq uinolmc 3-(6- (trifluoromethyl)pyridln-3-yl)acrylamide

6,7-diniethoxy-5,8-dimetliyl-l,2,3,4-tetraliydroisoquinoline (116 mg, 0.52 mmol), (£)-3-(6-(tTifluoromcthyl)pyridi:i-3-yl)acrylic acid (114 mg, 0.52 mg), PyBroP (269 mg, 0.58 mmol) and DMAP (128 mg, 1.05 mmol) were suspended in THF (12 ml) and stirred at rt for 2.5 h before evaporation. The product was purified by flash chromatography using Pet. Ether/EtOAc (2/1 1/1) as clucnt to give 190 mg (87 %) of (E)6,7 -d imethoxy- 5,8 - d i methy 1-1,2,3,4 -t ctrahy d roiso q u i no line 3 - (6- (trifluoromcthyl)pyridin-3-yl)acrylamide as a pale solid.
'HNMR (CDCU) rot. mix. 5 8.87 (s, lH)8.00(brd, IH) 7.72 (br d, 1H) 7.70 (d, J= 8 Hz, IH) 7.14 (d, J= 16 Hz)4.71 (ma)(br s, 2H) 4.64 (mi)(br s. 2H) 3.93 (mi)(br, 211) 3.88 (maXbr, 211) 3.81 (s, 611) 2.82 (ma)(br, 211) 2.76 (mi)(br, 211.) 2.18 (s 3H) 2.16 (s, 3H). TLC (Pet. Ether/EtOAc 1/1) Rt 0.66.

Preparation of final compounds
The following non-limiting examples of compounds of formula I did all show less than 80% remaining contraction, at a concentration of 10pM, of human bronchiols after LTD4 induced contraction according to the method described herein.
Example 1
(E)-1 -(5,8-dichloro-6,7-dihydroxy-3,4-dihy droisoquinolin-2( l //)-vl)-3-
p h e nvl p r op-2-en -1 -o n e
ci o

CI
franj-Cinnamoyl chloride (79 mg, 0.476 mmol) was suspended in DMT (7 mL) together with 5,8-dichloro-6,7-dihydroxy-l,2.3,4-tetrahydroisoquinoline hydrobromide (150 mg, 0.476 mmol) followed by triethylaminc (133 ,uL, 0.952 mmol). The resulting mixture was stirred at room temperature for 16 hours and then diluted with ethyl acetate (50 mL). The resulting mixture was washed twice with saturated .sodium bicarbonate (2x40 mL), dried (MgSO4) and evaporated into a yellowish mass. Purification with column chromatography (petroleum ether/ethyl acetate 1/1 —* 1/2) yielded 69 mg (40%) of the title compound as a yellowish solid.
'H NMR (400 MHz, CD,OD) rot. mix. 6 7.70-7.56 (m, 3H) 7.44-7.33 (m, 3H) 7.21 (br d, 1H)4.78 (mi, s, 2H) 4.71 (ma, s, 2H) 4.00-3.93 (ma, br t, 2H) 3.92-3.86 (mi, br t, 211) 2.92-2.86 (ma, brt, 211)2.85-2.69 (mi, br t, 211). TLC (petroleum ether/ethyl acetate 1/1) R( 0.33. HRMS (ESI) ealc for C18H16NO3Cl2 [M+H] 364.0507, found 364.0539.
General procedure for the demethvlation of methyl ethers of formula I A methyl ether of formula 1 (RI ,R2=Mc) (1.0 equiv.) was dissolved in CH2Cb (20 mL) and cooled to 0 C, Boron tribromide (1M in CH2Cl2, 3,0 equiv.) was then added slowly and the resulting mixture was stirred at 0JC for 5 minutes, then at rt for 12 h. The reactions were quenched with methanol (5 mL) and evaporated to dryness. The obtained residue was dissolved in methanol (20 mL), sodium bicarbonate (6.16 mmol) was added and the resulting suspension was stirred at rt for 30 minutes before evaporation. The resulting crude products were then purified by column chro matography.
Example 2
(F)-1 - (5,S-d ichl oro-6,7-dihyd ro xy-3,4-dihydroi so quin oli n-2 (1 /7>vl)-3
(pyridin-3-vl)prop-2-en-1 -one
CI o

CI
The title compound was obtained from (E)-l-(5,8-diehloro-6.7-dimethoxy-3,4- dihydroisoqui noli n-2 (l//)-yl)-3-(pyridi n-3-yl)prop-2-en-l-one as an orange solid in 19% yield, Rt 0.08 (Si02t ethyl acetate).
'H NMR (400 MHz, DMSQ-4) rot. mix. 6 9.59 (br s, 1H (OH)) 8.91 (br s, 1H) 8.56 (dd, 1H,>1.6,4.8 Hz) 8.23 (brd, lH,>8.0Hz) 7.59-7.43 (m, 311) 4.74 (mi, brs, 2H) 4.63 (ma, br s, 2H) 3.97-3.94 (ma, m, 2H) 3.83-3.76 (mi, m, 2H) 2.83-2.73 (ma, m, 2H) 2.73-2.65 (mi,m, 2H).
HRMS (ESI) calc for C17H15Cl2N2O3 [M+H] 365.0460, found 365.0425.
Example 3
(E)-1 - (5,8-dichIoro-6,7- dihydroxy-3,4-dihydroisoquinolin-2-( 1 H)-y l)-3-( 5-
fluoropyridin- 2-yl)prop-2-en-1-one
CI 0

CI
The title compound was obtained from (E)-l-(5,8-dichloro-6,7-dimethoxy-3,4- dihydroisoquinolin-2-(l//)-yl)-3-(5-fluoropyridin-2-yl)prop-2-en-l-one as a yellow solid in 86% yield, Rj 0.13 (Si02, chloroform/methanoI 9/1}.
JH NMR (400 MHz, DMSO-rf6) rot. mix. 6 9.60 (s, 1H) 9.57 (s, 1H(0H)) 8.63 (s, 1H) 7.94-7.90 (m, 1H) 7.83-7.80 (m, 1H) 7.56 (s, 2H) 4.70 (mi, br s. 2H) 4.63 (ma, brs, 2H) 3.90-3.80 (ma+mi, m, 2H) 2.78-2.67 (ma+mi, m, 2H).
HRMS (ESI) calc for CnHnChFNzOj [M+H] 383.0366, found 383.0354.
Example 4
(E) 1 - (5.8-d ich I o ro-6,7- dihyd roxy-3,4-dihy d roisoq uinolln-2( 1 H)-x l)-3- (quinolin-3-yl)prop-2-en-l-one

CI o

CI
The crude title compound was obtained from (E)-! -(5,8-dichloro-6,7- di mcthoxy-3,4-di hydro isoquinolin-2( 1H)- y 1) -3 -(qu i no I i n-3-y I )p rop- 2-en-1 -one, and was purified via the following procedure: The crudc was dissolved in methanol. After addition of a small amount of SiO: the mixture was filtered through Celite and the solvent evaporated. The oily residue was dissolved in a small amount of methanol and the product precipitated via addition of petroleum ether. The solvent was decantated. The title compound was obtained as a greenish solid in 61% yield.
'H NMR (400 MHz, MeOD) rot. mix. 6 9.60 (br d, 1H, 7=9.2 Hz) 9.40 (br st 1H) 8.35 (br d, 1H, 7=8.4 Hz) 8.23 (br d, 111,7=8.4 Hz) 8.17 (br t 1 fl:7=7.6 Hz) 7.99 (br t, 1H, 7=7.6 Hz) 7.90-7.71 (m, 2H) 4.79 (br s, 2H) 4.09-4.03 (ma, m, 2H) 3.98-3.92 (mi, m, 2H) 3.00-2.92 (ma, m, 2H> 2.89-2.81 (mi, m, 2H). HRMS (ESI) calc for C21H17CI2N2O5 [M+H] 415.0616. found 415.0598.
Example 5
{£)-1 - (5,8-dichlo ro-6,7- dihy dro xv-3,4-di hvdroisoq uinoli n-2 (l//)-y])-3 - (quinolin-3-yl )hu t-2-en-1 -on e

CI
The title compound was obtained from (E)-l-(5,8-dichloro-6.7-dimethoxy-3,4- dihydroisoquinolin-2(lH)-yl)-3-(quinolin-3-yl)but-2-en-l-one as a yellow solid in 14% yield (SiO2, ethyl acctatc/mcthanol 95/5).
'H NMR (400 MHz, ) rot. mix. 6 9.62-9.57 (m, 1H) 9.23-9.18 (m, 1H) 8.548.49 (m, 1H) 8.06-8.01 (m. 2H) 7.80-7.76 (m, 1H) 7.66-7.63 (m. 1H) 6.91 (s, 1H) 4.63 (br s, 2H) 3.82-3.79 (m, 2H) 2.79-2.73 (ma+mi, m, 2H) 2.33 (ma, br s, 3H) 2.23 (mi, br s, 3H).
HRMS (ESI) calc for C32H19Cl2N3O1 [M+H] 429.0773, found 429.0836.

Example 6
(E)-1 -y l)-3-(4-
hvdroxvph envl)prop-2-en-1 -one
CI o

CI
The title compound was obtained from (E)-1-(5,8-dichloro-6,7-dimethoxy-3,4- dihydroisoquinolin-2(1 H)-y 1)-3-(4-methoxyphenyl)prop-2-en-1 -one as an orange solid in 97% yield, Rr 0.34 (Si02, petroleum ether/ethyl acetate 1/1 + 15% EtOH).
'HNMR (400 MHz, MeOD) rot. mix. 6 7.60-7.51 (in, 3H) 7.07-6.95 (m, 1H) 6.82-6.80 (m, 2H) 4.80-4.69 (mi+ma){m, 2H) 4.00-3.84 (ma+mi, m, 2H) 2.94-2.77 (man mi, m, 211).
HRMS (ESI) calc for C1KH]^C12N04 [M+H] 380.0456, found 380.0393.
Example 7
(Z)-1-(5,8-dichloro-6,7-dihyroxy-3,4-dihydroisoquinolin-2(1//)-yl)-3-(2- h ydr oxyph enyl)prop-2-en- 1-one
ff^
ci o

ci
The title compound was obtained fro m (Z)-l- (5,8-die h lo ro - 6,7- d i methoxy-3,4 - dihydroisoquinolin-2( l//)-yl)-3-(2-metho xypheny l)p rop-2-en-1-one as a yellow solid in 29% yield, Rt 0.38 (Si02, petroleum ether/ethyl acetate l/l + 5% EtOH).
'H NMR (400 MHz, MeOD) rot. mix. 6 7.96-7.83 (m, 1H) 7.61-7.47 (m, 1H) 7.38-7.27 (m, 1H) 7.22-7.17 (m, 111) 6.88-6.84 (m, 211)4.78-4.75 (mi+ma)(m, 211) 4.00-3.87 (m, 2H) 2.97-2.79 (ma+mi, m, 2H).
HRMS (ESI) calc lor CiSHJ6C12N04 [M+H] 380.0456, found 380.0422.
Example 8
(E)-1 - (5,8-d ich lo ro-6,7- dihyd ro xv-3,4-dihy dr oi so q uinoll n-2{ lH)-y l)-3 - (5- fl uo r opy r i d i ii - 2-y I )b u t- 2- e n -1 - o n e

The title compound was obtained from (E)- l-(5,8-dichloro-6,7-dimethoxy-.3,4- dihydroisoquinolm-2(lH)-yl)-3-(5-fluoropyridm-2-yl)but-2-en-1 -one as an off-white solid in 40% yield (Si02, Pet. Ether/EtOAc 4/6 — 4/6+10% EtOH).
'H NMR (CDCh) rot. mix. 3.2 Hz, 1H) 7.56-7.49 (m, 1H) 7.477.38 (m, 1H) 7.05 (ma)(s, 1H)7.01 (mi)(s, 1H) 4.79 (ma)(s, 2H) 4.64 (mi)(s, 2H) 3.95 (mf)(t, 7=6.0 Hz, 2H) 3.80 (ma)(t, 7=6.0 Hz, 2H) 2.91-2.82 (m, 2H) 2.33 (ma)(s, 3H) 2.28 (mi)(s, 3H).
Example 9
(ZT)-6,7-d ih yd ro xy-5,8-d i m ethyl-1,2,3,4-tetrahy d ro isoq ui nol inc 3-(6-
(t r i □ u o r o methy I) py r id i n -3-y l)a c rv I am ide
O *
HO,

(E)-6,7-D imethoxy- 5,8-d imet hy I-1,2,3,4-tctrahyd ro isoqu incline 3-(6- (trifhioromcthyl)pyridin-3-yl)acrylamidc (190 mg, 0.45 mmol) was dissolved in dichloromethane (13 mL) and cooled to 0 °C. Boron tribromide (1.49 ml, 1.49 mmol, 1M in dichloro methane) was added slowly. The resulting suspension was stirred at 0 °C for 15 minutes, then at rt for 3.5 h and finally rcfluxcd for 1.5 h. The reaction was cooled, quenched with MeOH (5 mL) and evaporated. The residue was dissolved in MeOH (15 mL), neutralized with NaHCOi (57mg,0.68 mmol) and evaporated. The product was purified by flash chromatography using Pet. Ether/EtOAc/MeOH (4/6/1) as eluent to give 165 mg (93 %) of (E)6,7-dihydroxy-5,8-dimethyl-l,2,3,4- tetrahydroisoquinoline 3-(6-(trifluoromethyl)pyridin-3-yl)acrylamide as a reddish mass, 'HNMR(CD?OD) rot. mix. 5 8.93 (s, 1H)8.31 (d,7=8Hz, 1H) 7.82 (d,7= 8 Hz, 1H) 7.63 (in, 1H) 7.51 (d,7= 16 Hz) 4.70 (mi)(s, 2H) 4.63 (ma)(s, 2H) 3.93 (ma)(br t, 2H) 3.85 (mi)(br t, 2H) 2.77 (ma)(br t, 2H) 2.69 (mi)(br t, 2H) 2.12 (s, 3H) 2.08 (s, 3H). TLC (Pet, Ether/EtOAc/MeOH 5/5/1) Rf 0.58.

Example 10
(E)-1 -{5,8-dlchlor o-6,7-dlhy dr o xy-3,4-di hyd roisoq ulno I i n-2( l//)-yl>-3-(2 (pipe r i d in -1-vl)-6-(tr i fl uor om ethyl)py rid in -3-yl) pr o p-2 - en -1 -on e

NaOH (1.0 M aq., 2.9 ml, 2.9 mmol) was added to a solution of (E)-methyl 3- (2-(piperidin-l-yl)-6-(trffluoroinethyl)pyridin-3-yl)acrylate (181 mg, 0.58 mmol) in T( ir/EtOU 1/1 (6 mL). The mixture was stirred for 24 h at rt. The solution was diluted with water and acidified with 1M HCl. The precipitate was collected through filtration, dried under vacuum and used directly in the next step.
(E) -3 -(2 -(p i per i d i ti-1 - y I)- 6-( trifluo ro methy 1 )pyri d i n-3 - y 1 )acry 1 ic ac i d (15 0.0 mg, 0.50 mmol) was suspended in dry THF (7.0 mL). DMAP (111.4 mg, 0.91 mmol) and caesium carbonate (296.0 mg, 0,91 mmol) were added and the mixture was stirred atrt for 15 minutes. 5,8-Dichloro-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromidc (143.0 mg, 0.45 mmol), EDC-HC1 (130.6 mg, 0.68 mmol), HOBt (69.8 mg, 0,45 mmol) were then added. The mixture was stirred at rt overnight. Water (100 mL) was added and the product extracted w ith EtOAc, Combined organic extracts were dried (MgSO^), filtered and concentrated. Purification was done first using flash column chromatography (CH^Ch/MeOH 98/2 —» 95/5) and then by size exclusion (Sephadex LH20; CHCU'McOH 1/1) to yield 55.0 mg (24%) of the title product.
'H NMR (CD^OD) rot. mix. 6 8,11 (ma)(d,> 7.2 Hz, 1H) 8.05 (mi)(d, J= 7.2 Hz, 1H) 7.66 (m, 1H) 7.30 (bs, 1H), 7.26 (d, J=7.6 Hz, 1H) 4.79 (mi)(s, 2H) 4.74 (ma)(s, 2H) 3.97 (ma)(br t, 2H) 3.90 (mi)(br t, 2H) 3.26 (m, 4H) 2.88 (ma)(br t, 2H) 2.81 (mi)(br t, 2H) 1.68 (m, 6H),
HRMS (ESI) calc for C23H23N3Cl2, [M+H] 516.1069, found 516.1116.
Example 11
(F)-1 - (5,8-d ichl 0 r n-6,7- d ihy d r o xy-3,4-d ihydroisoquinnlin-2(l H)-yl)-3 - (2-
m ethy l-6-(t r i fl u 0 ro m e thy I) py r idi n -3-y l)p ro p-2 - e n -1 - 011 e
ci o

5,8-Dichloro-1 ,2,3,4-tetrahydroisoquinolinc-6.7-diol hydro bromide (183 mg. 0.58 mmol), (E)-3-(2-methy 1-6-(trifluoromethyI)pyridin-3-y Ijacrv1ic acid (140mg, 0.64 mmol), EDC HCl (I67mg, 0.87 mmol), llOBt (89 mg, 0.58 mmol), DMAP (147 mg, 1.2 mmol) arid Cs^CO.i (391 mg, 1.2 mmol) were suspended in DMF (15 mL) and stirred at rt for 12 h. The reaction mixture was then diluted with water (30 mL) and extracted with EtOAc (3*30 mL). Combined organics were washed with NaHCOi (2*30 mL, sat. aq.), water (3*30 mL) and brine and dried (MgSO4). After filtration and evaporation the residue was purified by column chromatography (SiO:, CH2Ch:McOH 95:5) and was then further purified by size exclusion chromatography (sephadex, CHCU:MeOH 1:1) to give the title compound (28 mg, 63 pmol, 11 %) as a yellow solid.
'HNMR (CD,OD) rot. mix. 6 8.33 (ma)(d,,7=8.0 Hz, 1H) 8.28 (mi)(d,,7=8.0 Hz, 1H) 7.88 (ma)(d, 7=15,6 Hz, 1H) 7.84 (mi)(d, ,7=15,6 Hz, 1H) 7.67 (d, ,7=8.0 Hz, HI) 7.35 (ma)(d,7=15.6 llz, 111)7.29 (mi)(d,7=15.6 11 z, 1(1)4.81 (mi)(s, 211) 4.76 (ma)(s, 2H) 3.98 (ma)(t, 7=6.0 Hz, 2H) 3.92 (mi)(t, 7=6.0 Hz, 2H) 2.91 (ma)(t, 7=5.6 Hz, 2H) 2.84 (mi >(1,7-5.6 Hz, 2H) 2.70 (s, 3H).
HRMS (ESI) calc for C19H16Cl2F3N2O3 [M+H] 447.0490, found 447.0550.
Example 12
(E)-l - (5,8-tl ich I o r o-6,7- d ihy d r o xv-3,4-d i liy d roi so q u in o I i n -2 (1H )-yl)-3 - (6-
(trifl uor o m ethv I) pvr id i n-3-vl) p r o p-2 - c n-1 -on c
CI " o

To a solution of CD I (83 mg, 0.51 mmol) in EtOAc (2 mL) was added (E)-3- (6-(trifluoromethyl)pyridin-3-yl)acrylie acid (100 mg, 0.46 mmol). The resulting mixture was heated at reflux for 1 h after which HOBt (35 mg, 0,23 mmol) and 5,8- dichloro-1,2,3,4-tetrahydro isoqui no line-6,7 -d io 1 hydro bromide (145 mg, 0.46 mmol) were added. Heating at reflux was continued for 3 h before the reaction mixture was allowed to cool to rt. It was then poured into water (15 mL) and the water-phase was extracted with EtOAc (3*15 mL). Combined organics were washed with water (10 mL) and brine (10 mL) and dried (MgSO4). After filtration and evaporation, the crudc was purified by column chromatography (Si02, EtOAc;pctroleum ether 50:50) to give a bright yellow solid which was purified further by precipitating the product in EtOAc via addition of petroleum ether. After decantation of the solvent and drying, the title compound (NO mg, 0,25 mmol, 55%) was obtained as a light reddish solid.
'H NMR (CD3OD) rot. mix. 3 8.98 (ma)(s, 1H) 8.94 (mi)(s, 1H) 8.36-8.33 (m, 1H) 7.87-7.83 (m, 1H) 7.71-7.63 (m, 1H) 7.57-7.52 (m, 1H) 4.82 (mi)(s, 2H) 4.76 (ma)(s, 211) 3.99 (ma)(t, >6.0 I Iz, 2H) 3.91 (mi)(t, >6.0 1 lz, 211) 2.92 (ma)(t, >6.0 Hz, 2H) 2.83 (mi)(t, >6.0 Hz, 2H).
HRMS (ESI) calc for C18H14Cl2N2O3 [M+H] 433.0334, found 433.0338.
Example 13
(E)-1 - (5,8-d ichl o ro-6,7- dihy d ro x v-3,4-d i hvd r oi so q u in oJ i n -2 (lH)-y J)-3 - (6- tr iflu o ro m etii v l)pyridin-3 -v 1) b ut-2 - e u-1 -o n e

r^o
CI F
To a solution of 3-(6-(trifluoromethyl)pyridin-3-yl)but-2-enoic acid (2.4 g, 10 mmol) in. EtOAc (24 mL) was added CD1 (1.7 g, 11 mmol). After heating at reflux for 1 h, TLC (CH2Cl2;Me0H 9:1) confirmed 3-(6-(trifluoromethyl)pyridin-3-yl)but-2-enoic acid to be consumed. Then 5,8-Dichloro-1,2,354-tetrahydroisoquinoline-6,7-diol hydro bromide (3.1 g, 9.7 mmol) was added and the mixture was heated at reflux over night. After cooling to rt the mixture was diluted with EtOAc (24 mL) and the remaining solids were dissolved with small amounts of 1M HCl (aq,). The water and organic phases were separated and the water phase neutralized by addition of IM NaOH (aq.). The product, which precipitated as a sticky solid, was extracted with EtOAc (5*24 mL, difficult extraction). Combined organics were washed with sat. NaHCO3 (aq.), water and brine and dried (MgSO4). Crude title compound (3.6 g) was purified twice by column chromatography (SiO2, CHiCbrMcOH 98:2) (amount title compound after second cromatography: 1.95g). Then the product was washed with MeOH repeatedly to yield pure title compound (I 0g, 2,3 mmol, 23% (pure £-isomer, the Z-isomer could not be isolated)) as a light yellow solid.
'H NMR (CD.;OD) rot. mix. S 8.92 (ma)(d, >2.0 Hz. 1H) 8.88 (mi)(d,>1.6 Hz, 1H) 8.21 (ma)(dd,>2.0, 8.4 Hz, 1H) 8.17 (mi)(dd,>2.0, 8.4 Hz, 1H) 7,84 (d, ,7=8.4 Hz, 1H) 6.72 (ma)(brs, 1H) 6.70 (mi)(br s. 1H)4.72 (ma)(s, 2H) 4.66 (mi)(s, 2H) 3.91 (mi)(t, >6.0 Hz, 2H) 3.82 (ma)(t,>6.0 Hz, 2H) 2.87-2.82 (m, 2H) 2.29 (ma)(d, > 1.2 Hz, 3H) 2.19 (mi)(d, > 1.0 Hz, 3H).
HRMS (ESI) calc lor C19H16Cl2F3N2O3 [M+H] 447.0490, found 447.0374.

a 0 CH,
^OrW'J , 11 9
O f 12 6
a o en, 13 7

Biological example 2
The remaining contraction, after pre-treatment with various compound examples at a concentration of 10 pM, of human bronchiols or rat hronhi after the induction of contraction by treatment with the contractile agents acetylcholine (100uM), carbachol (10uM), histamine (100uM), mcthacholine (100uM) or a mixture of acetylcholine (100uM), leukotriene D4 (LTD4) (0.01uM) and histamine (100uM), according to the in vitro method described herein above, arc tabulated below:
CONTRACTILE COMPOUND REMAINING
AGENT [concentration SPECIES (EXAMPLE CONTRACTION
(uM)] NUMBER) (%)
Acetylcholine (100uM) human 12 4
13 7
rat 12 40
13 52
Carbachol (10uM) human 12 10
rat 12 27
Histamine (lOOuM) human 12 1
13 3
Methacholine (100uM) human 12 7
rat 12 49
Mixture of Acetylcholine (100uM), LTD4 (0.01 uM} and histamine (100uM) human 3 43
11 25
12 12
13 18

Biological example 3; Human peripheral blood mononuclear cell (PBMC) in vitro model
Cryoprcscrvcd PBMC's (SeraCare, # 72001) were thawed, washed with eulture media (RPM1-1640 from Invitrogen, # 61870-036 + 10% heat inactivated fetal bovine serum from fnvitrogen. # 10082-147 + 100 U/ml penicillin + lOO^ml streptomycin) and tested for viability using Trypan blue (PBMC viability = 96%). Cells were then resuspended to 1 x 106 cells/ml in culture media and 0.5 ml was plated into 24 well culture plates (5 x 105 cells/well) before incubation for 30 minutes at 37°C with 5% C02 prior to addition of a compound of the present invention (10 pM) or dcxamcthasone (1 pM). One hour thereafter, LPS (0.1 pg/rnl, Salmonella abortus eqiti, Sigma, # LI 887) was added and the cells were incubated for another 24h before collection of the cell culture supematants, which were assayed for the prescncc of MCP- 1 and LTB4.
MCP-1 levels were quantified employing a Luminex-based assay according the manufacturer's instructions. Data was collected using a Luminex 100 (Luminex Corporation, Austin, TX). Standard curves were generated using a 5-parameter logistic curve fitting equation weighted by 1/y (StarStation V 2.0; Applied Cytometry Systems, Sacramento, CA). F.ach sample reading was interpolated from the appropriate standard curve. Calculated concentrations were mu hip lied by the appropriate dilution factor when ncccssary.
LTB4 levels were quantified by EL ISA follow ing the manufacturer's instructions. Absorb ance readings were detected using a ThermoMax mi crop I ate reader (Molecular Devices). Standard curvcs were generated using a4-paramctcr logistic curve fitting equation (SoftMax Pro 4.7.1; Molecular Devices). Each sample reading was interpolated from the appropriate standard curve. Duplicate interpolated sample values were averaged and standard deviations were calculated. Calculated concentrations were multiplied by the appropriate dilution factor.
The inhibitory effect of compounds of the present invention, dexamethasone, and vehicle on production of MCP-1 and LTB4 in the PBMC model as described herein above, with (+LPS) or without (-LPS) LPS-induccd mediator production, is tabulated below.
Compound Mean MCP- 1 (petml) Standard deviation Mean LTB-4 fpc/mD Standard deviation
(MCP-1) CLTB-4)
Vchiccl (-LPS) 133.5 19.2 19 05
Vchiccl (+LPS) 858,2 25.5 30.4 L5
Example 12 (-LPS)
"TV/^YX f
C F 229.7 60.9 19 02
Example 12 (+LPS)
c, 0 303,1 94.3 9,9 13
IXo^o^
CI F
Example 13 (-LPS)
Gl 0
V^nr 217,1 45.7 4A 02
HO , • ••
CI F
Example 13 (+LPS)
c o
Yr-1 -'V)
HO M
CI F 250.7 11.5 M M
Dexamethasone (-LPS) 0 0 17 OJ
Dcx am cthason c (+L PS) 1425.6 193.8 12.6 03

We claim:
1. A compound according to formula I

wherein
R1 is selected from H and methyl:
R2 is selected from H and methyl:
R3 is selected from H. fluoro. chloro. bromo. C 1-3 alky! and CH2 phenyl; R4 is selected from H. fluoro. chloro. bromo. C 1-3 alkyl and CH2 phenyl; G is selected from G1 and G2:
in G1 the stereochemistry of the double-bond of Gl. onto which the substituents R5 and R6 are attached, is such that R5 and R6 are oriented in a cis- fashion, or in a trans- fashion. relative to each other:
R5 is selected from H. C 1-5 alkyl. CH2 phenyl and C 1-5 fluoroalkyl:

R6 is selected fiom H, C 1-5 alkyl. CH2 phenyl and C 1-5 fluoroalkyl:
X1 X2. X3, X4 and X5 are. independently of each other, selected fromN and
C; 0 (zero). 1 or 2 of X1. X2, X3, X4 and X5 is X: Q is optionally substituted with a maximum of "n" independently selected substituent(s) R7 at any substitutable ring carbon atom, wherein "n" represents an integer number:
the integer number "n" is 0 to 2:
R7 is selected from C 1-5 alkyl. Cl-5 fluoroalkyl. halo, hydroxy, CO-3 alkyleneOCO-5 alkyl. CO-3 alkyleneOCl-5 fluoroalkyl, CO-3 alkyleneNH2, CO-3 alkyleneNHCl-3 alkyl CO-3 alkyleneN(Cl-5 a Iky 1)2. in which the C 1-5 alkyl may be the same or different. N(C4-5 alkylene). Cl-5 alkylthio. S(O)C 1 -5 alkyl. SO2C 1 -5 alkyl. C 1-5 fluoroalkylthio. XH(CO)C 1-5 alkyl. NH(CO)C 1-5 alkoxy. XHSO2C1-5 alkyl. (CO)C 15 alkyl. COOH, (CO)C 1-5 alkoxy. (CO)NH2, (CO)XHC 1-5 alkyl. (CO)N(C 1-5 alky 1)2. in which the Cl-5 alkyl may be the same or different, cyano. SQ2NHC0-5 alkyl. nitro. aryl. heteroaryl. azido (N3). and morpholinyl;
in G2 the stereochemistry of the double-bond of G2. onto which tlie substituents RS and R9 are attached, is such that R8 and R9 are oriented in a cis- fashion, or in a trans- fashion. relative to each other;
RS is selected fiomH, C 1-5 alkyl. CH2 phenyl and C 1-5 fluoroalkyl:
R9 is selected fiomH, C 1-5 alkyl. C'H2 phenyl and C 1-5 fluoroalkyl:
the condensed rings Wl and W2 together represent a bicyclic aromatic system, in which X6. X7 and XS. independently of each other, are selected fromN and C: none or one of X6. X7 and X8 is N: said bicyclic aromatic system is optionally substituted, with a maximum of "p"' independently selected substituent(s) RIO. at any substitutable ring carbon atom of any of the rings Wl and W2. wherein "p" represents an integer number;
The integer number "p" is 0 to 2:
RlO is selected from Cl-5 alkyl, Cl-5 fluoroalkyl. kilo, hydroxy. CO-3 alkyleneOCO-5 alkyl. CO-3 alkyleneOCl-5 fluoroalkyl. CO-3 alkyleneNH2, CO-3 alkyleneNHC 1 -3 alkyl. CO-3 alkyleneN(C 1 -5 alkyl)2. in which the Cl-5 alkyl may be the same or different, N(C4-5 alkylene). C 1-5 alkylthio, S(O)C 1-5 alkyl. SO2C1-5 alkyl. C 1-5 fluoroalkylthio. NH(CO)C 1-5 alkyl. NH(CO)C 1-5 alkoxy. XHSO2C1-5 alkyl, (CO)C 15 alkyl. COOH, (CO)C 1-5 alkoxy. (C0)NH2. (CO)NHC 1-5 alkyl. (CO)N(C 1-5 alkyl)2. in which the Cl-5 alkyl may be the same or different, cyano, S02NHCQ-5 alkyl. nitro, aryl. heteroaryl. azido (N3). and morpholinyl;
as a free base, an acid in its no n-charged protonated form or a pharmaceutic ally acceptable salt, solvate or solvate of a salt thereof and as a pure stereoisomer, a racemic- . dia stereo me lie- or scalemic mixture;
with the proviso
that not both of Rl and R2 is methyl.
2. The compound according to claim 1. wherein Rl and R2 is H.
3. The compound according to claim 1 or 2. wherein R3 and R4. independent of each other, are selected from H, fluoro, chloro, bromo. and methyl.
4. The compound according to claim 3. wherein R3 and R4 are chloro.
5. The compound according to any of the claims 1 to 4. wherein G is Gl and the stereochemistry of the double-bond of Gl. onto which the substituents R5 and R6 are attached, is such that R5 and R6 are oriented in a trans-fashion relative to each other.
6. The compound according to any of the claims 1 to 5. wherein G is Gl and at least one of X1 to X5 is N.
7. The compound according to claim 6, wherein G is Gl. X1 or X2 is X' and only one of X1 to X5 is X.
S. The compound according to any of the claims 1 to 7. wherein G is Gl. "n" is 1 or 2. and R7 is selected from C1-C3 alkyl. trifluoromethyl. halo, hydroxy. N(C4-5 alkylene). metlioxy, SO2Me. cyano. thienyl, nitro. phenyl, morpholinyl and NMe2.
9, The compound according to claim 8. wherein R7 is selected from methyl, trifluoromethyl. fluoro. chloro andNMe2.
10, The compound according to any of the claims 1 to 9. wherein G is Gl and R5 is H.
11, The compound according to any of the claims 1 to 10. wherein G is Gl and R6 is H or methyl.
12, The compound according to any of the claims 1 to 4. wherein G is G2 and the stereochemistry of the double-bond of G2. onto which the substituents R8 and R9 are attached, is such that R8 and R9 are oriented in a trans-fashion relative to each other.
13, The compound according to any of the claims 1 to 4 or 12. wherein G is G2. at least one of X6 to X8 is X.
14, The compound according to any of the claims 1 to 4. or 12 to 13. wherein G is G2 and R8 and R9 are. independently or each other, selected from H and methyl.
15, The compound according to claim 1. wherein said compound is selected from the group consisting of:

16. The compound according to claim 1. wherein said compound is selected from the group consisting of:

17. A pharmaceutical composition comprising a compound according to any of the claims 1 to 16 and at least one pharmaceutic ally acceptable carrier.
18. The pharmaceutical composition according to claim 17. comprising an antiasthmatic.
19. The pharmaceutical composition according to claim 18. wherein the principal mechanism of action of the anti-asthmatic is selected from the group consisting of p2- agonist, anticholinergic and calcium antagonist, or wherein the antiasthmatic is a corticosteroid.
20. The compound according to any of the claims 1 to 16 or a composition according to any of the claims 17 to 19 as and when used in the preparation of a medicament for use in the prevention and/or treatment of a disease or condition relating to broncho con strict ion of the respiratory apparatus, inflammation of the respiratory apparatus, asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis, bronchiolitis and bronchopulmonary dysplasia.

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Patent Number

270793

Indian Patent Application Number

101/MUMNP/2010

PG Journal Number

04/2016

Publication Date

22-Jan-2016

Grant Date

20-Jan-2016

Date of Filing

15-Jan-2010

Name of Patentee

Respiratorius AB

Applicant Address

Magistratsvägen 10 226 43 LUND Sweden.

Inventors:

#	Inventor's Name	Inventor's Address
1	DALENCE Maria	Kamnarsvagen 11 N 316 226 46 LUND Sweden.
2	JOHANSSON Martin	Rudbecksgatan 109 216 22 LIMHAMN Sweden.
3	THORNQVIST OLTNER Viveca	Stora Norregatan 259 261 40 LANDSKRONA Sweden.
4	TOFTERED Jörgen	Flygelvägen 35 224 72 LUND Sweden.
5	WENSBO David	Zenithgatan 9 212 14 MALMÖ Sweden.

PCT International Classification Number

C07D 217/06,A61K 31/472,A61K 31/4725

PCT International Application Number

PCT/EP2008/059001

PCT International Filing date

2008-07-10

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0701694-2	2007-07-12	Sweden
2	61/005,742	2007-12-07	Sweden
3	60/959,276	2007-07-12	Sweden